Note: Descriptions are shown in the official language in which they were submitted.
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ALKYLCARBAMOYL NAPHTHALENYLOXY -
OCTENOYLHYDROXYAMIDE DERIVATIVES HAVING
INHIBITORY ACTIVITY AGAINST HISTONE DEACETYLASE AND
PREPARATION THEREOF
FIELD OF THE INVENTION
The present invention relates to a novel alkylcarbamoyl
naphthalenyloxyoctenoyl hydroxyamide derivative, a method for preparing
same and an anticancer 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 group of the
lysine residue. The reversible acetylation is involved in the formation of
chromatin of a higher order structure, the cell division cycle and ultimately
the gene expression, and can be regulated by the dynamic balance established
between the opposing activities of histone acetyl transferases (HATs) and
histone deacetylases (HDACs): means enzymes neutralize or restore the
positive charges of lysine residues (e.g., 4 lysine residues in H4) by
acetylation/deacetylation to regulate the gene transcriptional level.
HDACs play an important role in cell cancerization or differentiation
and their expression is enhanced under conditions such as hypoxia, lowered
glucose, and cell cancerization, to inhibit the expression of cell
proliferation
inhibitors. That is, histone deacetylation by HDAC causes cell proliferation,
while hyperacetylation of histone facilitates the inhibition of cell
proliferation
and cell differentiation. Therefore, when HDACs are inhibited, cell
proliferation and angiogenesis can be controlled.
Abnormal histone deacetylation has been reported to cause acute
promyelocytic leukemica (APL) (Lin R. J. et. al. Oncogene 20: 7204, 2001;
Zelent A. et. al. Oncogene 20: 7186, 2001). Specifically, abnormality in the
regulation of HDAC activity leads to oncoprotein's transcriptional
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suppression and the formation of abnormal chromatin structures, which after
causes normal cells to become cancer. Accordingly, HDAC has been one of
the targets for the study of anticancer drugs as well as gene expression
inhibitor and there have been attempts to develope HDAC inhibitors as
anticancer drugs.
Recent anticancer drug studies through chromatin modeling 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, n-butyrate was reported to be useful for the
treatment of large intestine cancer. But it has to be used in such a high
concentration in the order of milimolar (mM) that it disturbs the functions of
other enzymes in cells, cytoskeleton, cell membrane, etc. Trichostatin A
(TSA) which enhances the differentiation and suppresses the proliferation of
Friend murine erythroleukemia cells has been reported to inhibit HDAC
(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).
Therefore, there has been a need for developing an improved HDAC
inhibitor. The present inventors have unexpectedly found that a novel
alkylcarbamoyl naphthalenyloxyoctenoyl hydroxyamide 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.
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It is still another object of the present invention to provide a
pharmaceutical composition comprising the inventive compound as an active
ingredient for inhibition of the histone deacetylase activity.
In accordance with one aspect of the present invention, there is provided
an alkylcarbamoyl naphthalenyloxyoctenoyl hydroxyamide derivative of
formula (1) or a pharmaceutically acceptable salt thereof:
CONHOH
~.~
~._.
RI--N
RI ~ (1)
wherein:
R, is hydrogen or C1_3 alkyl;
R2 is C1_6 alkyl optionally having one or more substituents selected from
the group consisting of diC1_3 alkylamino, oxopyrrolidinyl, pyrrolidinyl,
piperidinyl, morpholinyl, C1_3 alkylpiperazinyl, cyano, hydroxy, imidazolyl,
methoxy, tetrahydrofuran, C3_8 cycloalkenyl, and thiophenyl; C1_6 alkyl
substituted with hydroxyphenyl, fluorophenyl, diC1_3 alkyl amino phenyl,
methoxyphenyl and trifluoromethoxyphenyl; pyrrolidine substituted with C1_3
alkyl, C3_8 cycloalkyl, C3_8 cycloalkyl C1_3 alkyl, benzyl or C3_8
cycloalkylcarbonyl; piperidine substituted with C3_8 cycloalkyl or C1_6 alkyl;
furan; pyridine substituted with (diC1_3 alkyl amino) C1_3 alkyl amino,
methoxy,
diC1_3 alkyl amino, morpholino C1_3 alkylamino, or C1_3 alkylpiperazinyl; or
C3_
g cycloalkyl; or
R, and R2 may optionally form a morpholinyl, piperidinyl or
piperazinyl ring together with the nitrogen atom to which they are bonded.
In accordance with another aspect of the present invention, there is
provided a method for preparing the compound of formula (1).
In accordance with still another aspect of the present invention, there is
provided an anti-cancer composition and an inhibitor of histone deacetylase
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activity comprising the compound of formula (1) or a pharmaceutically
acceptable salt thereof as an active ingredient.
DETAILED DESCRIPTION OF THE INVENTION
Representative examples of preferred compounds as alkylcarbamoyl
naphthalenyloxyoctenoyl hydroxyamide derivatives of formula (1) include:
(E)-N8-hydroxy-N 1,N 1-dimethyl-2-((naphthalen-l-yloxy)methyl)
octenediamide,
(E)-N 1-(2-(dimethylamino)ethyl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)octenediamide,
(E)-N 1-(2-(dimethylamino)ethyl)-N8 -hydroxy-N 1-methyl-2-
((naphthalene-l-yloxy)methyl)octenediamide,
(E)-N 1-(2-(diethylamino)ethyl)-N8-hydroxy-2-((naphthalen-l-yloxy)
methyl)octenediamide,
(E)-N 1-(2-(diethylamino)ethyl)-N8-hydroxy-N 1-methyl-2-
((naphthalene-l-yloxy)methyl)octenediamide,
(E)-N8-hydroxy-2-((naphthalen-l-yloxy)methyl)-N 1-(2-(pyrrolidin-l-
yl)ethyl)octenediamide,
(E)-N8-hydroxy-2-((naphthalen-l-yloxy)methyl)-N 1-(2-(piperidin-l-
yl)ethyl)octenediamide,
(E)-N8-hydroxy-N 1-(2-morpholinoethyl)-2-((naphthalen-l-yloxy)
methyl)octenediamide,
(E)-N-hydroxy-8-(4-methylpiperazin-l-yl)-7-((naphthalen-l-yloxy)
methyl)-8-oxoocteneamide,
(E)-N8-hydroxy-N 1-(2-(4-methylpiperazin-l-yl)ethyl)-2-((naphthalen
-1-yloxy)methyl)octenediamide,
(E)-N 1-(cyanomethyl)-N8-hydroxy-N 1-methyl-2-((naphthalen-l-
yloxy)methyl)octenediamide,
(E)-N8-hydroxy-N 1-(2-hydroxyethyl)-N 1-methyl-2-((naphthalen-l-
yloxy)methyl)octenediamide,
(E)-N8-hydroxy-N 1-methyl-N 1-(1-methylpyrrolidin-3 -yl)-2-
((naphthalen-l-yloxy)methyl)octenediamide,
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(E)-N 1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)octenediamide,
(E)-N-hydroxy-8-morpholino-7-((naphthalen-l-yloxy)methyl)-8-
oxoocteneamide,
(E)-N8-hydroxy-N 1-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)-2-
((naphthalen-l-yloxy)methyl)octenediamide,
(E)-N 1-(6-(2-morpholinoethylamino)pyridin-3-yl)-N8-hydroxy-2-
((naphthalen-l-yloxy)methyl)octenediamide,
(E)-N 1-(6-(dimethylamino)pyridin-3 -yl)-N8-hydroxy-2-((naphthalen-
1 -yloxy)methyl)octenediamide,
(E)-N 1-(6-(2-(dimethylamino)ethylamino)pyridin-3-yl)-N8-hydroxy-
2-((naphthalen-l-yloxy)methyl)octenediamide,
(E)-N8-hydroxy-N 1-(6-methoxypyridin-3-yl)-2-((naphthalen-l-yloxy)
methyl)octenediamide,
(E)-N 1 -(3 -(1 H-imidazol-l-yl)propyl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)octenediamide,
(E)-N8-hydroxy-N 1-(4-hydroxyphenetyl)-2-((naphthalen-l-yloxy)
methyl)-2-octenediamide,
(E)-N 1 -(3 -(dimethylamino)-2,2-dimethylpropyl)-N8-hydroxy-2-
((naphthalen-l-yloxy)methyl)octenediamide,
(E)-N 1-(2-(diisopropylamino)ethyl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)octenediamide,
(E)-N8-hydroxy-N 1-(1-methoxypropan-2-yl)-2-((naphthalen-l-yloxy)
methyl)-2-octenediamide,
(E)-N8-hydroxy-N 1-(4-methoxybenzyl)-2-((naphthalen-l-yloxy)
methyl)-2-octenediamide,
(E)-N 1-(4-fluorophenetyl)-N8-hydroxy-2-((naphthalen-l-yloxy)
methyl)-2-octenediamide,
(E)-N8-hydroxy-2-((naphthalen-l-yloxy)methyl)-N 1-(tetrahydrofuran
-2-yl)methyl)-2-octenediamide,
(E)-N 1-(2-cyclohexenylethyl)-N8-hydroxy-2-((naphthalen-l-yloxy)
methyl)-2-octenediamide,
(E)-N8-hydroxy-2-((naphthalen-l-yloxy)methyl)-N 1-(3-(2-
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oxopyrrolidin-l-yl)propyl)-2-octenediamide,
(E)-N 1-(furan-2-yl)-N8-hydroxy-2-((naphthalen-l-yloxy)methyl)-2-
octenediamide,
(E)-N 1-(4-(dimethylamino)benzyl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide,
(E)-N8-hydroxy-N 1-(2-methoxyethyl)-2-((naphthalen-l-yloxy)
methyl)-2-octenediamide,
(E)-N 1-cyclohexyl-N8-hydroxy-2-((naphthalen-l-yloxy)methyl)-2-
octenediamide,
(E)-N8-hydroxy-2-((naphthalen-l-yloxy)methyl)-N 1-(thiophen-2-
ylmethyl)-2-octenediamide,
(E)-N8-hydroxy-N 1-(4-methoxyphenetyl)-2-((naphthalen-l-yloxy)
methyl)-2-octenediamide,
(E)-N8-hydroxy-2-((naphthalen-l-yloxy)methyl)-N 1-(4-
1s (trifluoromethoxy)benzyl)-2-octenediamide,
(E)-N 1-(1-(cyclohexylmethyl)pyrrolidin-3-yl)-N8-hydroxy-2-
((naphthalen-l-yloxy)methyl)-2-octenediamide,
(E)-N 1-(1-cyclopentylpiperidin-4-yl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide,
(E)-N 1-(1-benzylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide,
(E)-N8-hydroxy-N 1-(1-isopropylpyrrolidin-3-yl)-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide,
(E)-N 1-(1-(cyclohexanecarbonyl)pyrrolidin-3-yl)-N8-hydroxy-2-
2 5 ((naphthalen-l-yloxy)methyl)-2-octenediamide,
(E)-3-(8-(hydroxyamino)-2-((naphthalen-l-yloxy)methyl)-8-oxo-2-
octeneamido) pyrrolidin-1-carboxylic acid t-butylester,
(E)-N8-hydroxy-2-((naphthalen-l-yloxy)methyl)-N 1-(pyrrolidin-3-
yl)2-octenediamide,
(E)-N1-(1-cyclohexylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-2-
yloxy)methyl)-2-octenediamide,
(E)-N 1-(1-cyclopropylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide,
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(E)-N 1-(1-cyclopropylpiperidin-4-yl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide,
(E)-N 1-(1-ethylpiperidin-4-yl)-N8-hydroxy-2-((naphthalen-l-yloxy)
methyl)-2-octenediamide, and
(E)-N 1-(1-ethylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)
methyl)-2-octenediamide.
The inventive compound of formula (I) may be used in the form of a
pharmaceutically acceptable addition salt formed with an inorganic acid or
organic acid. Examples of the acid include hydrochloric, hydrobromic,
sulfuric, phosphoric, nitric, acetic, glycolic, lactic, pyrubic, malonic,
succinic,
glutaric, fumaric, malic, mandelic, tartaric, citric, ascorbic, palmitic,
maleic,
hydroxy maleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic,
methanesulfonic, benzenesulfonic, and toluenesulfonic acid.
And the inventive alkylcarbamoyl naphthalenyloxyoctenoyl
hydroxyamide derivatives of formula (1) may be prepared by the method
comprising the steps of
1) treating a compound of formula (2) with sulfuric acid, and then with
pyridinium chlorochromate (PCC) to obtain a compound of formula (3);
2) allowing the compound of formula (3) to react with an alkyl acrylate
in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) to obtain a
compound of the formula (4);
3) subjecting the compound of formula (4) to a reaction with
tribromophosphine (PBr3) to obtain a compound of formula (5);
4) bringing the compound of formula (5) to react with 1-naphthol to
obtain a compound of formula (6);
5) hydrolyzing the compound of formula (6) in the presence of an
inorganic or organic acid to obtain a compound of formula (7);
6) acylating the compound of formula (7) with an amine (RIR2NH or
R2NH2) to obtain a compound of formula (8);
7) hydrolyzing the compound of formula (8) in the presence of an
inorganic base to obtain a compound of formula (9);
8) acylating the compound of formula (9) with
tetrahydropyranyloxyamine (NH2OTHP) to obtain a compound of formula
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(10); and
9) removing the tetrahydropyranyl group from the compound of
formula (10) by trifluoroacetic acid (TFA) treatment.
.~-
''~ CQNHOH
cr
RI.."N
R2 ~ (1)
0 (2)
0 (3)
YO~ (4)
Me
(5)
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,~=" f
0
Y020 (6)
r..-
h
Me
HO
0 (7)
A C02Me
R,-~
0
R2 0 (8)
02H
Rz 0 (9)
CONHOT~~
~~- IN
R2
(10)
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Wherein:
Rl and R2 have the same meanings as defined in formula (1) above, and
Y is C1_4 alkyl.
The method described above may be represented by Reaction Scheme 1:
Reaction Scheme 1
/~/C0ZnO CoZn* co2ne
0 I)H2SO4 ~ ~~zt Bu PBr3 Br~
~0 H II)PCC 0 pqBCO Yp2 OH ~= YOZC
2 3 4
/
~I ~ I I COzMe COzMe C02Me
KZCO_p TFq FM5,RlR2NH 0
0 0 _
Acetone - CHZCI2 R~ N
Y0zC ~ 0 R2 0
6 7 6
W2H CONHOTHP ~ ' ~ CONHOH
LIOH EDC,HCI, FOBT TFA ~ /
0 0 ~-~ 0
NH2OTHP -
Rj- N Rl RI-N
Ry 0 R2 0 R 0
2
9 10 1
Wherein:
R, and R2 have the same meanings as defined in formula (1) above, and
Y is C ) -4 alkyl.
In step 1) of Reaction Scheme 1, --caprolactone (formula 2) is
dissolved in methanol and treated with concetrated sulfuric acid to form the
1,
6-hydroxy-hexanoic acid methylester of formula 3, which is then added to a
pyridinium chlorochromate solution and reacted for 2 hrs to obtain 6-oxo-
hexanoic acid methylester (formula 3).
Suitable for use in this step is a solvent such as dichloromethane,
tetrahydrofuran, or dichloroethane.
In step 2), a hydroxy compound (formula 4) is obtained by the Baylis-
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Hillman reaction carried out between a 6-oxo-hexanoic acid methylester
(formula 3) and a C1_4 alkylacrylate in the presence of 1,4-
diazabicyclo[2.2.2]octane (DABCO) at 0-25 C for 5-7 days, above ethyl
acrylate, isobutyl acrylate, or t-butyl acrylate may be used as the alkyl
acrylate.
The reaction step 3) is carried out using a bromination agent in an
organic solvent. Representative examples of the organic solvent include
ethylether, dichloromethane and hydrofuran, and representative examples of the
bromination agent include PBr3, CBr4 and N-bromo succinic acid (NBS).
In step 4), the bromo compound (formula 5) is reacted with 1 -naphthol
to obtain an alcohol compound (formula 6) using acetone or acetonitrile as a
solvent in the presence of potassium carbonate, sodium bicarbonate, or
sodium carbonate.
The ester hydrolysis step 5) is carried out in the presence of an
inorganic or organic acid in a solvent such as dichloromethane,
tetrahydrofuran or N,N' -dimethylformamide. Representative examples of the
inorganic acid include hydrochloric acid, sulfuric acid and phosphoric acid
and representative examples of the organic acid include trifluoroacetic acid
(TFA).
Acylation step 6) is carried out using N-Methanesulfonyloxy-6-
trifluoromethylbenzotriazole (FMS), N-hydroxy-6-trifluorobenzotriazole
(FOBT) or 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDC - HC1) as an acylation agent in an aprotic solvent such as
dimethylformamide, dimethylsulfoxide, tetrahydrofuran or dichloromethane.
The reaction in step 7) is preferably carried out using an aqueous
alcohol or tetrahydrofuran solvent, and lithium hydroxide (LiOH - H2O) or
sodium hydroxide as the inorganic base.
The acylation in step 8) is carried out in an organic solvent in the
presence of N-hydroxy-6-trifluorobenzotriazole (FOBT) and 1-(3-
diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl).
Representative examples of the organic solvent include N,N'-
dimethylformamide, dimethylsulfoxide, tetrahydrofuran and dichloromethane.
Removing the tetrahydropyranyl group from the compound of formula
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(10) in step 9) is carried out in a solvent such as methanol, ethanol,
tetrahydrofuran or dichloromethane.
The starting material (formula 2) for preparing the alkylcarbamoyl
naphthalenyloxyoctenoyl hydroxyamide derivatives of formula (1) is
commercially available.
The inventive alkylcarbamoyl naphthalenyloxyoctenoyl hydroxyamide
derivative of formula (1) efficiently inhibits the activity of histone
deacetylase, resulting in the efficient suppression of the cancer-cell
proliferation.
Accordingly, the present invention also provides an inhibitor of histone
deacetylase activity comprising the compound of formula (1) or a
pharmaceutically acceptable salt thereof as an active ingredient.
Further, the present invention provides an anti-cancer composition
comprising the compound of formula (1) as an active ingredient and a
pharmaceutically acceptable carrier.
The inventive pharmaceutical composition comprises the compound of
formula (1) as an active ingredient in an amount ranging from 0.1 to 75 wt%,
preferably 1 to 50 wt%, based on the total weight of the composition.
The pharmaceutical composition may be formulated for oral or
parenteral administration. The formulation for oral administration may take
various forms such as tablet, pill, powder, sachet, soft and hard capsule,
solution, suspension, emulsion, syrup, granule and the like, which may
contain conventional additives such as a diluent (e.g., lactose, dextrose,
sucrose, mannitol, sorbitol, cellulose and/or glycine), a lubricant (e.g.,
silica,
talc, stearic acid or its zinc, magnesium or calcium salt, and/or polyethylene
glycol). A 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.
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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 (1) 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: 6-hydroxy-hexaenoic acid methyl ester
c-Caprolactone (12.50 g, 109.51 mM) was dissolved in methanol (125
ml), a sulfuric acid solution (1 ml, 0.01 mM) was slowly added thereto, and
the mixture was stirred at room temperature for 2 days. After the
completion of the reaction, methanol was removed under a reduced pressure
and ice water was poured thereinto. The resulting mixture was extracted
with ethyl ether and the isolated organic layer was washed with saturated
sodium bicarbonate and salt water in order. The resulting residue was
subjected to column chromatography (ethyl acetic acid/n-hexane= 1/2) to
obtain 10.18 g of the title compound (yield: 64%).
1H NMR (200 MHz, CDC13) 5 1.23 (m, 2H, CHZ), 1.33-1.42 (m, 4H,
CH2CH2), 1.44-1.74 (t, 4H, CH2CH2), 3.66 (s, 3H, OCH3).
Preparation Example 2: 6-oxo-hexaenoic acid methyl ester (formula 3)
Pyridinium chlorochromate (16.27 g, 75.48 mM) was dissolved in
dichloromethane (140 ml), 6-hydroxy-hexaenoic acid methyl ester (10.03 g,
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68.61 mM) obtained in Preparation Example 1 in dichloromethane (20 ml)
was added dropwise thereto for 30 min, and the mixture was stirred at
25-30 C for 2 hrs. After the completion of the reaction, the reaction
mixture was diluted with ethyl ether, and filtered. The filtrate was distilled
under a reduced pressure, concentrated and subjected to column
chromatography (ethyl acetic acid/n-hexane= 1/4), to obtain 5.77 g of the
title
compound (yield: 59%).
'H NMR (200 MHz, CDC13) 5 1.66 (m, 4H, CH2CH2), 2.33 (m, 2H, CH2),
2.46 (m, 2H, CH2), 3.66 (s, 3H, OCH3), 9.74 (S, 1H, CH).
Preparation Example 3: 3-hydroxy-2-methylene-dinonanoic acid 1-t-
butyl ester 9-methylester (formula 4)
6-Oxo-hexaenoic acid methyl ester(20 g, 168.72 mM) obtained in
Preparation Example 2 was dissolved in the mixture of water and dioxane
(1:1) (100 mL), acrylic t-butyl ester (60.96 ml, 461.17 mM) was added
thereto, and 1,4-diazabicyclo[2.2.2]octane (DABCO) (15.56 g, 138.72 mM)
in the mixture of water and dioxane (1:1) (63 mL) were sequentially added
thereto, and the mixture was stirred for 7 days. After the completion of the
reaction, ice water was poured thereinto and the mixture was extracted with
ethyl ether. The extract was washed with 2 N hydrochloric acid, saturated
sodium bicarbonate and salt water in order, dried, concentrated under a
reduced pressure and subjected to column chromatography (ethyl acetic
acid/n-hexane= 1/9), to obtain 21.7 g of the title compound (yield: 57%).
'H NMR (200 MHz, CDC13) 6 1.46 (m, 2H, CHZ), 1.47 (S, 9H, 3CH3), 1.62
(m, 4H, CH2CH2), 2.96 (m, 4H, CH2CH2), 3.64 (s, 3H, OCH3), 5.67 (s, 1H,
CH), 6.09 (s, 1H, CH).
Preparation Example 4: 2-bromomethyl-2-dioctene acid 1-t-butyl ester 8-
methyl ester (formula 5)
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3-Hydroxy-2-methylene-dinonanoic acid 1-t-butyl ester 9-methyl ester
(10,40 g, 38.20 mM) obtained in Preparation Example 3 was dissolved in
ethyl ether (100 ml) and cooled to 0 C . Then, PBr3 (3.93 ml, 42.02 mM) was
slowly added thereto and stirred at room temperature for 1 hr. After the
completion of the reaction, the reaction mixture was cooled to -10'C by
pouring ice water, then extracted with ethyl ether. The extract was washed
with salt water, dried over MgSO4 and filtered. The solvent was removed
under a reduced pressure and subjected to silica gel column chromatography
(ethyl acetic acid/n-hexane = 1/9), to obtain 6.30 g of the title compound
(yield: 49%).
'H NMR (200 MHz, CDC13) 5 1.50 (s, 9H, CH3), 1.65 (m, 4H, CH2), 2.30 (m,
4H, CH2), 3.66 (s, 3H, OCH3), 4.27 (s, 2H, CHZ), 6.82 (m, 1H, CH).
Preparation Example 5: 2-(naphthalen-1-yloxymethyl)-2-dioctene acid 1-
t-butyl ester 8-methylester (formula 6)
2-Bromomethyl-2-dioctene acid 1-t-butyl ester 8-methylester (11.2 g
33.41 mM) obtained in Preparation Example 4 was dissolved in acetone(50
ml), potassium carbonate (6.93 g 50.11 mM) and 1-naphthol(5.30 g 36.75
mM) were added thereto, and the mixture was boiled for 3 hrs. After the
completion of the reaction, the solvent was then removed under a reduced
pressure at room temperature. The resulting residue was subjected to silica
gel column chromatography (ethyl acetic acid/n-hexane= 1/15) to obtain 11.5
g of the title compound as a white solid (yield: 86%).
'H NMR (200 MHz, CDC13) b 1.45 (s, 9H, CH3), 1.65 (m, 4H, CHZ), 2.30 (m,
4H, CH2), 3.62 (s, 3H, OCH3), 4.80 (s, 2H, CH2), 6.64 (m, 1H, ArH), 6.98 (m,
1 H, CH), 7.40 (m, 4H, ArH), 7.77 (m, 1 H, ArH), 8.19 (m, 1 H, ArH).
Preparation Example 6: 2-(naphthalen-1-yloxymethyl)-2-dioctene aicd 8-
methylester (formula 7)
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2-(Naphthalen-1-yloxymethyl)-2-dioctene acid 1-t-butyl ester 8-
methylester (5.00 g, 12.55 mM) obtained in Preparation Example 5 was
dissolved in dichloromethane (60 ml), trifluoroacetic acid (6.77 ml, 87.83
mM) was slowly added thereto at 0 C, and the mixture was reacted at room
temperature for 7 hrs. After the completion of the reaction, the solvent was
then removed under a reduced pressure at room temperature. The resulting
residue was subjected to silica gel column chromatography (ethyl acetic
acid/n-hexane= 1/4) to obtain 2.08 g of the title compound (yield: 48%).
'H NMR (200 MHz, CDC13) 5 1.46 (m, 2H, CH2), 1.59 (m, 2H, CH2), 2.26 (t,
2H, J = 7.1 Hz, CH2), 2.43 (q, 2H, J = 14.9, 7.5 Hz, CH2), 3.62 (s, 3H, OCH3),
4.94 (s, 2H, CH2), 6.89 (d, 1 H, J= 7.3 Hz, CH), 7.27-7.47 (m, 5H, ArH),
7.80 (dd, 1H, J = 7.3, 1.7 Hz, ArH), 8.20 (t, 1H, J= 7.1, 1.7 Hz, ArH).
The amine compound (R1R2NH or R2NH2) for preparing the
compound of formula 8 is commercially available, or can be readily
synthesized by the conventional method.
Substituted pyrrolidine and piperidine may be synthesized as described
in the Reaction Scheme B.
Reaction Scheme B
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NaOH(aq)
Ph\_N~ t-Boc20 Ph 0~ Pd / C, H2 0~0
NHZ ~N~NH HN~NH
11 12 13
Method A: RCHO or RCOR
AcOH, NaCNBH3 0~\ 0 TFA
7 - R-ND-NHZ
Method B RI or RBr, K2CO3 R-ND-NH
14 15
Ph / NaOH(aq) 0\\ ~ Pd / C, H2 O\\ ~
\--N' )-NHZ t-Boc2O Ph / \ I-O /~ J-0
v '-N, j-NH HN~ rNH
16 17 ~/ 18
Method A: RCHO or RCOR
AcOH, NaCNBH3 OO TFA Q /~
R-NrNHz 10 Method B: RI or RBr, K2C03 R-N, }-NH Method C : RCOCI, TEA ~~//
19 20
Wherein:
R is C1_3 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl C1_3 alkyl, benzyl, or C3_
8 cycloalkyl carbonyl.
And procedures for preparation of the amine compounds are
illustrated below.
Preparation Example I: t-butyl 1-benzylpiperidin-4-ylcarbamate
(formula 12)
1-Benzylpiperidine-4-amine (3g, 15.8mml), the starting material, was
dissolved in 1M aqueous sodium hydroxide solution (35.8 ml) and t-butanol
(32 ml) in the 250 ml reaction vessel, t-butyl dicarbonate ((t-Boc)20; 3.79 g,
17.38 mmol) was added thereto while stirring, and the mixture was reacted
for 12 hrs. After the completion of the reaction, the reaction mixture was
extracted with ethyl ether 2 times. The extract was washed with 0.1N
hydrochloric acid solution and salt water in order. The resulting organic
layer
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was dried over anhydrous sodium sulfate, filtered, concentrated under a
reduced pressure and then subjected to silica gel column chromatography to
obtain 3.80 g of the title compound as a white solid (yield: 82.8%).
IH -NMR (200 MHz, CDC13) b 1.38 (s, 9H), 1.86-2.33 (m, 4H), 2.70 (m, 2H),
3.40 (m, 2H), 3.57 (br, 1H), 4.12 (s, 2H), 7.43 (m, 3H), 7.55 (m, 2H).
LC/MS (M+H): 291.
Preparation Example II: t-butyl piperidin-4-ylcarbamate (formula 13)
t-Butyl-l-benzylpiperidin-4-ylcarbamate (3.80 g, 13.1 mmol) obtained
in Preparation Example I was dissolved in 26 ml of methanol in the 100 ml
reaction vessel, catalytic quantities of 10% active palladium/carbon was
added thereto, and reacted under the hydrogen for 12 hrs. After the
completion of the reaction, the reduction mixture was filtered through a
cellite pad to remove palladium/carbon and the solvent was removed under a
reduced pressure. Then, the mixture was subjected to silica gel column
chromatography to obtain 2.64 g of the title compound (yield: 99%).
'H-NMR (200 MHz, CD3OD) b 1.36 (s, 9H), 1.84-2.36 (m, 4H), 2.74 (m,
2H), 3.42 (m, 2H), 3.60 (br, 1 H).
LC/MS (M+H): 201.
Preparation Example III: t-butyl 1 -R-piperidin-4-ylcarbam ate (formula
14)
(111-1) t-butyl 1-isopropylpiperidin-4-ylcarbamate (14a)
Method A: t-butyl piperidin-4-ylcarbamate (3 g, 15 mmol) obtained in
Preparation Example II was dissolved in methanol (30m1) in the 100 ml
reaction vessel, acetone (7.70 ml, 105 mmol) and acetic acid (0.45 ml, 7.5
mmol) were added thereto while stirring, 4 portions of NaCNBH3 (1.88 mg,
30 mmol) were added dropwise and reacted for 18 hrs. After the completion
of the reaction, ice water was poured thereinto and then the mixture was
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stirred and extracted with ethyl ether. The extract was washed with sodium
bicarbonate and salt water in order. The resulting organic layer was dried
over anhydrous sodium sulfate, filtered, concentrated under a reduced
pressure and then subjected to silica gel column chromatography to obtain
2.644 g of title compound as a white solid (yield: 73.3 %).
'H -NMR (200 MHz, CDC13) S 1.36 (d, J = 7.0 Hz, 6H), 1.44 (s, 9H), 2.00 (m,
2H), 2.17 (m, 2H), 2.94 (m, 2H), 3.3 8(m, 3H), 3.69 (m, 1 H), 4.92 (br, 1 H).
LC/MS (M+H): 243.
(111-2) t-butyl 1-cyclopropylpiperidin-4-ylcarbamate (14b)
The procedure of Preparation Example (III-1) was repeated except for
using bromocyclopropane instead of acetone as the amine substituent to
obtain 0.72 g of the title compound as pale yellow oil (yield: 60%).
'H -NMR (200 MHz, CDC13) S 0.44 (m, 4H), 1.31 (m, 2H), 1.47 (s, 9H), 1.58
(m, 1 H), 1.90 (m, 2H), 2.29 (m, 2H), 2.94 (m, 2H), 3.49 (br, 1 H), 4.42 (br,
1 H).
LC/MS (M+H): 241.
(111-3) t-butyl 1-cyclopentylpiperidin-4-ylcarbamate (14c)
The procedure of Preparation Example (111-1) was repeated except for
using bromocyclophentane instead of acetone as the amine substituent to
obtain 1.16 g of the title compound as pale yellow oil (yield: 86%).
'H-NMR (200 MHz, CDC13) S 1.45 (s, 9H), 1.50-1.80 (m, 8H), 1.81-2.18 (m,
6H), 2.50 (m, 1H), 2.94 (m, 2H), 3.48 (br, 1H), 4.41 (br, 1H).
LC/MS (M+H): 269.
(111-4) t-butyl 1-methylpiperidin-4-ylcarbamate (14d)
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The procedure of Preparation Example (111-1) was repeated except for
using iodomethane instead of acetone as the amine substituent to obtain 1.43
g of the title compound as pale yellow oil (yield: 79.4%).
'H-NMR (200 MHz, CDC13) 8 1.44 (s, 9H), 1.45 (m, 2H), 1.92 (m, 2H), 2.07
(m, 2H), 2.27 (s, 3H), 2.74 (m, 2H), 3.44 (br, 1H), 4.43 (br, 1H).
LC/MS (M+H): 215.
(111-5) t-butyl 1-ethylpiperidin-4-ylcarbamate (14e)
Method B: t-butyl piperidin-4-ylcarbamate (1.5 g, 7.49 mmol)
obtained in Preparation Example II was dissolved in N,N-dimethylformamide
(19 ml) in the 25 ml reaction vessel, K2CO3 (2.07 g, 14.98 mmol, 2 eq.) and
iodoethane (0.60 ml, 7.49 mmol, 1 eq.) were added thereto while stirring,
heated from 0 C to room temperature and kept for 4 hrs. After the
completion of the reaction, the solvent was distilled under a reduced pressure
and the remaining was extracted with ethyl ester. The organic layer was
washed with saturated sodium bicarbonate and salt water in order, dried over
anhydrous magnesium sulfate, concentrated under a reduced pressure and
then subjected to silica gel column chromatography to obtain 1.34 g of the
title compound as pale yellow oil (yield: 78%).
'H-NMR (200 MHz, CDC13) b 1.10 (t, J = 7.4 Hz, 3H), 1.43 (m, 2H), 1.47 (s,
9H), 1.99 (m, 4H), 2.40 (q, J = 7.2 Hz, 2H), 2.85 (m, 2H), 3.47 (br, 1H), 4.43
(br, 1 H).
LC/MS (M+H): 229.
Preparation Example IV: 1-R-piperidin-4-amine (formula 15)
(IV-1) 1- isopropylpiperidin-4-amine (15a)
The compound (14a) obtained in Preparation Example (III-1) (1.5 g,
7.49 mmol) was dissolved in methanol (20 ml) in the 250 ml reaction vessel,
trifluoro acetic acid (4.06 ml, 54.5 mmol, 5 eq.) was added dropwise thereto
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while stirring, and kept for 18 hrs. After the completion of the reaction, the
mixture was concentrated under a reduced pressure, and then subjected to
azeotropic distillation with CHC13 3 times. The reaction mixture was
basified with aqueous KOH solution (20 ml) and extracted with CHC13 3
times. The extract was washed with salt water, dried, filtered and distilled
under a reduced pressure, to obtain 1.23 g of the title compound as yellow oil
(yield: 79.3%).
'H-NMR (200 MHz, CDC13) 8 1.02 (d, J = 6.6 Hz, 6H), 1.38 (m, 2H), 1.56
(br, 2H), 1.80 (d, J = 11.8 Hz, 2H), 2.17 (m, 2H), 2.71 (m, 2H), 2.80 (m, 2H).
LC/MS (M+H): 143.
(IV-2) 1-cyclopropylpiperidin-4-amine (15b)
The procedure of Preparation Example (IV-1) was repeated except for
using the compound obtained in Preparation Example (111-2) as the starting
material, to obtain 286 mg of the title compound as pale yellow oil (yield:
75%).
'H-NMR (200 MHz, CDC13) b 0.44 (m, 4H), 1.33 (m, 2H), 1.52 (m, 1H), 1.76
(m, 2H), 2.20 (m, 2H), 2.66 (m, 1 H), 3.00 (m, 2H).
LC/MS (M+H): 141.
(IV-3) 1-cyclopentylpiperidin-4-amine (15c)
The procedure of Preparation Example (IV-1) was repeated except for
using the compound obtained in Preparation Example (111-3) as the starting
material, to obtain 689 mg of the title compound as pale yellow oil (yield:
95%).
'H-NMR (200 MHz, CDC13) S 1.50-1.80 (m, 8H), 1.81-2.18 (m, 6H), 2.50 (m,
2H), 2.74 (m, 2H).
LC/MS (M+H): 169.
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(IV-4) 1-methylpiperidin-4-amine (15d)
The procedure of Preparation Example (IV-1) was repeated except for
using the compound obtained in Preparation Example (111-4) as the starting
material, to obtain 820 mg of the title compound as pale yellow oil (yield:
86%).
'H-NMR (200 MHz, CDC13) 8 1.37 (m, 2H), 1.78 (m, 2H), 1.99 (m, 2H), 2.27
(s, 3H), 2.70 (m, 1H), 2.81 (m, 2H).
LC/MS (M+H): 115.
(IV-5) 1-ethylpiperidin-4-amine (15e)
The procedure of Preparation Example (IV-1) was repeated except for
using the compound obtained in Preparation Example (111-5) as the starting
material, to obtain 672 mg of the title compound as pale yellow oil (yield:
89%).
'H-NMR (200 MHz, CDC13) 6 1.08 (t, J= 7.2 Hz, 3H), 1.37 (m, 2H), 1.81-
2.08 (m, 4H), 2.37 (q, J = 7.2 Hz, 2H), 2.65 (m, 1H), 2.87 (m, 2H).
LC/MS (M+H): 129.
Preparation Example V: t-butyl 1-benzylpyrrolidin-3-ylcarbamate
(formula 17)
The starting material (10 g, 57 mmol) was dissolved in 3M aqueous
sodium hydroxide solution (21 ml) and t-butanol (114 ml) in the 500 ml
reaction vessel, t-butyl dicarbonate ((t-Boc)20; 13.07 g, 59.9 mmol) was
added thereto while stirring, kept for 12 hrs. After the completion of the
reaction, the reaction mixture was extracted with ethyl acetate 2 times. The
extract was washed with 0.1N hydrochloric acid solution and salt water in
order. The resulting organic layer was dried over anhydrous sodium sulfate,
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filtered, concentrated under a reduced pressure and then subjected to silica
gel
column chromatography to obtain 15.25 g of the title compound as a white
solid (yield: 97%).
'H-NMR (200 MHz, CDC13) 8 1.43 (s, 9H), 2.27 (m, 2H), 2.57 (m, 3H), 2.75
(m, 1H), 3.59 (s, 2H), 4.16 (br, 1H), 4.85 (br, 1H), 7.30 (m, 5H).
LC/MS (M+H): 277.
Preparation Example VI: t-butyl pyrrolidin-3-ylcarbamate (formula 18)
The starting material (15.75 g, 57.0 mmol) was dissolved in methanol
and tetrabutylfuran (4:1) (114 ml) in the 100 ml reaction vessel, catalytic
quantities of 10% active palladium/carbon was added thereto, and reacted
under the hydrogen for 12 hrs. After the completion of the reaction, the
reduction mixture was filtered through a cellite pad to remove
palladium/carbon and the solvent was removed therefrom under a reduced
pressure. Then, the mixture was subjected to silica gel column
chromatography to obtain 9.51 g of the title compound (yield: 99%).
'H-NMR (200 MHz, CDC13) S 1.41 (s, 9H), 2.26 (m, 2H), 2.55 (m, 3H), 2.74
(m, 1H), 4.84 (br, 1 H).
LC/MS (M+H): 187.
Preparation Example VII: t-butyl 1-R-pyrrolidin-3-ylcarbamate
(formula 19)
(VII-1) t-butyl 1-cyclopropylpyrrolidin-3-ylcarbamate (19a)
Method A: t-butyl pyrrolidin-3-ylcarbamate(1.24 g, 6.7 mmol) was
dissolved in methanol (14 ml) in the 250 ml reaction vessel, acetone (3.44 ml,
46.9 mmol) and acetic acid (0.19 ml, 3.35 mmol) were added thereto while
stirring, and 4 portions of NaCNBH3 (842 mg, 13.4 mmol) were added thereto
dropwise and kept for 18 hrs. After the completion of the reaction, ice water
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was poured thereinto and then the mixture was stirred and extracted with
ethyl acetate. The extract was washed with sodium bicarbonate and salt
water in order. The resulting organic layer was dried over anhydrous sodium
sulfate, filtered, concentrated under a reduced pressure and then subjected to
silica gel column chromatography to obtain 897 g of title compound as a
white solid (yield: 58 %).
'H-NMR (200 MHz, CDC13) S 1.40 (d, J = 6.6 Hz, 6Hz), 1.44 (s, 9H), 2.12
(m, 1H), 2.48 (m, 1H), 3.27 (m, 1H), 3.39 (m, 3H), 3.57 (m, 1H), 4.38 (m,
I H), 5.41 (m, 1H).
LC/MS (M+H): 229.
(VII-2) t-butyl 1-cyclopropylpyrrolidin-3-ylcarbamate (19b)
The procedure of Preparation Example (VII-1)was repeated except for
using bromocyclopropane instead of acetone as the amine substituent to
obtain 7.17 g of the title compound as pale yellow oil (yield: 59%).
'H-NMR (200 MHz, CDC13) 8 0.40 (m, 4H), 1.44 (s, 9H), 1.60 (m, 2H), 2.19
(m, 1 H), 2.57 (m, 2H), 2.81 (m, 2H), 4.14 (br, 1 H), 4.80 (br, 1 H).
LC/MS (M+H): 227.
(VII-3) t-butyl 1-cyclohexylpyrrolidin-3-ylcarbamate (19c)
The procedure of Preparation Example (VII-1)was repeated except for
using cyclohexanone instead of acetone as the amine substituent to obtain
1.10 g of the title compound as pale yellow oil (yield: 77%).
'H-NMR (200 MHz, CDC13) 8 1.23 (m, 2H), 1.41 (m, 2H), 1.46 (s, 9H), 1.78
(m, 2H), 1.89 (m, 2H), 2.06 (m, 3H), 2.44 (m, 1 H), 2.76 (m, 1 H), 3.04 (m,
1 H), 3.24 (m, 2H), 3.49 (m, 1 H), 4.34 (m, 1 H), 5.33 (m, 1H).
LC/MS (M+H): 269.
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(VII-4) t-butyl 1-ethylpyrrolidin-3-ylcarbamate (19d)
Method B: The starting material (1.5 g, 8.05 mmol) was dissolved in
N,N-dimethylformamide (20 ml) at 0 C in the 100 ml reaction vessel, K2CO3
(2.23 g, 16.1 mmol, 2 eq.) and iodoethane (0.64 ml, 8.05 mmol, 1 eq.) were
added thereto while stirring, heated from 0 C to room temperature, and kept
for 12 hrs. After the completion of the reaction, the solvent was distilled
under a reduced pressure and the remaining was extracted with ethyl ester.
The extract was washed with saturated sodium bicarbonate and salt water in
order. The resulting organic layer was washed with saturated sodium
bicarbonate and salt water, dried over anhydrous magnesium sulfate,
concentrated under a reduced pressure and then subjected to silica gel column
chromatography to obtain 1.13 g of the title compound as pale yellow oil
(yield: 66%).
'H-NMR (200 MHz, CDC13) S 1.10 (t, J= 7.4 Hz, 3H), 1.44 (s, 9H), 1.69 (m,
1 H), 2.27 (m, 2H), 2.48 (q, J= 7.0 Hz, 2H), 2.57 (m, 1 H), 2.81 (m, 1 H),
4.16 (br, 1H), 4.86 (br, 1H).
LC/MS (M+H): 215.
(VII-5) t-butyl 1-(cyclohexanecarbonyl)pyrrolidin-3-ylcarbamate (19e)
Method C: The starting material (1 g, 5.4 mmol) was dissolved in
dichloromethane (14 ml) at 0 C in the 50 ml reaction vessel, triethyl
amine(0.83 ml, 5.94 mmol, 1.1 eq.) and cyclohexylcarbonyl chloride (0.79 ml,
5.94 mmol, 1.1 were added thereto while stirring, heated from 0 C to room
temperature, and kept for 4 hrs. After the completion of the reaction, the
solvent was distilled under a reduced pressure and the remaining was
extracted with dichloromethane. The extract was washed with sodium
bicarbonate and salt water in order. The resulting organic layer was washed
with saturated sodium bicarbonate and salt water, dried over anhydrous
magnesium sulfate, concentrated under a reduced pressure and then subjected
to silica gel column chromatography to obtain 1.57 g of the title compound as
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pale yellow oil (yield: 98%).
'H-NMR (200 MHz, CDC13) 8 1.26 (m, 4H), 1.46 (s, 9H), 1.79 (m, 6H), 1.98
(m, 1 H), 2.08-2.49 (m, 2H), 3.39 (m, 1 H), 3.59 (m, 2H), 3.73 (m, 1H), 4.22
(m, 1H), 4.63 (m, 1 H).
LC/MS (M+H): 297.
Preparation Example VIII: 1-R- pyrrolidine-3-amine (formula 20)
(VIII-1) 1- isopropyl pyrrolidine-3-amine (20a)
The compound (14a) obtained in Preparation Example (VII-1) (0.90 g,
3.9 mmol) was dissolved in dichloromethane (10 ml) in the 50 ml reaction
vessel, trifluoro acetic acid (1.45 ml, 1.95 mmol, 5 eq.) was slowly added
thereto dropwise while stirring, followed by reacting for 18 hrs. After the
completion of the reaction, the mixture was distilled and concentrated under a
reduced pressure, and then subjected to azeotropic distillation with CHC13 3
times. The reaction mixture was basified with aqueous 2N potassium
hydroxide solution (20 ml) and extracted with CHC13 3 times. The extract
was washed with salt water, dried, filtered and distilled under a reduced
pressure, to obtain 433 mg of the title compound as yellow oil (yield: 86%).
'H-NMR (200 MHz, CDC13) 8 1.38 (d, J = 6.6 Hz, 6Hz), 2.11 (m, 1H), 2.47
(m, 1 H), 3.15 (m, 1 H), 3.29 (m, 4H), 3.5 7(m, 1 H).
LC/MS (M+H): 129.
(VIII-2) 1-cyclopropyl pyrrolidine-3-amine (20b)
The procedure of Preparation Example (VIII-1) was repeated except
for using the compound obtained in Preparation Example (VII-2) as the
starting material, to obtain 477 mg of the title compound as pale yellow oil
(yield: 79%).
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'H-NMR (200 MHz, CDC13) S 0.41 (m, 4H), 1.55 (m, 2H), 2.16 (m, 1H), 2.40
(m, 1 H), 2.68 (m, 1 H), 2.80 (m, 1 H), 2.93 (m, 1 H), 3.47 (m, 1 H).
LC/MS(M+H): 127.
(VIII-3) 1-cyclohexyl pyrrolidine-3-amine (20c)
The procedure of Preparation Example (VIII-1) was repeated except
for using the compound obtained in Preparation Example (VII-3) as the
starting material, to obtain 513 mg of the title compound as pale yellow oil
(yield: 74%).
'H-NMR (200 MHz, CDC13) S 1.19 (m, 4H), 1.39-1.62 (m, 4H), 1.72 (m, 1H),
1.93 (m, 3H), 2.14 (m, 1H), 2.31 (m, 1H), 2.58-2.78 (m, 2H), 2.85 (m, 1H),
3.47 (m, 1 H).
LC/MS (M+H): 169.
(VIII-4) 1-ethyl pyrrolidine-3-amine (20d)
The procedure of Preparation Example (VIII-1) was repeated except
for using the compound obtained in Preparation Example (VII-4) as the
starting material, to obtain 477 mg of the title compound as pale yellow oil
(yield: 79%).
'H-NMR (200 MHz, CDC13) S 1.13 (t, J = 7.2 Hz, 3H), 1.51 (m, 2H), 2.31 (m,
2H), 2.47 (m, 3H), 2.73 (m, 1H), 3.54 (m, 1H).
LC/MS(M+H): 115.
(VIII-5) (3-amino pyrrolidin-1-yl)(cyclohexyl)methanone (20e)
The procedure of Preparation Example (VIII-1) was repeated except
for using the compound obtained in Preparation Example (VII-5) as the
starting material, to obtain 1.51 g of the title compound as pale yellow oil
(yield: 99%).
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'H-NMR (200 MHz, CDC13) S 1.26 (m, 4H), 1.79 (m, 6H), 1.98 (m, 1H),
2.08-2.49 (m, 2H), 3.39 (m, 1H), 3.59 (m, 2H), 3.73 (m, 1H).
LC/MS (M+H): 197.
Example 1: (E)-N8-hydroxy-N1,N1-dimethyl-2-((naphthalen-1-yloxy)
methyl)octenediamide (formula 1)
(1-1):(E)-8-(dimethylamino)-7-((naphthalen-1-yloxy)methyl)-8-oxo-6-
octene acid methylester (formula 8)
2-(Naphthalen-1-yloxymethyl)-2-dioctene acid 8-methylester (423 mg,
1.24 mM) obtained in Preparation Example 6 was dissolved in
dimethylformamide (4 ml) and cooled to 0 C, followed by adding
triethylamine (520 0, 3.72 mM) and N-Methanesulfonyloxy-6-
trifluorobenzotriazole (418 mg, 1.49 mM), and stirring at 0 C for 30 min. A
dimethylaminehydrochloride (111 mg, 1.36 mM) was slowly added thereto,
and stirred at room temperature for 1 hr. After the completion of the
reaction, ice water was poured thereinto and the mixture was extracted with
ethyl acetate. The extract was successively washed with 1 N hydrochloric
acid, sodium bicarbonate and salt water, dried over anhydrous magnesium
sulfate, and filtered. The solvent was removed under a reduced pressure and
resulting residue was subjected to silica gel column chromatography (ethyl
acetic acid/n-hexane= 2/1), to obtain 437 mg of the title compound (yield:
95%).
'H NMR (300 MHz, CDC13) 8 1.46 (m, 2H, CH2), 1.59 (m, 2H, CHZ), 2.43 (q,
4H, J = 14.9, 7.5 Hz, CH2), 3.02 (s, 6H, N(CH3)2), 3.63 (s, 3H, OCH3), 4.95
(s, 2H, CHz), 5.84 (t, 1 H, J = 14.8, 6.5 Hz, CH), 6.85 (d, 1H, J= 7.4 Hz,
ArH),
7.36-7.47 (m, 4H, ArH), 7.79 (t, 1H, J= 9.0, 1.4 Hz, ArH), 8.10 (t, 1H, J
8.8, 7.5 Hz, ArH).
(1-2):(E)-8-(dimethylamino)-7-((naphthalen-1-yloxy)methyl)-8-oxo-6-
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octene acid (formula 9)
(E)-8-(dimethylamino)-7-((naphthalen-1-yloxy)methyl)-8-oxo-6-
octene acid methylester (437 mg, 1.18 mM) obtained in Example (1-1) was
dissolved in 30% aqueous ethanol solution (4 ml), whereto a monohydrated
sodium lithium (248 mg, 5.90 mM) and tetrahydrofuran (4 ml) were added.
The reaction mixture was stirred at room temperature for 10 min and at 50 C
for 3 hrs. After the completion of the reaction, the reaction mixture was
cooled to room temperature by pouring ice water and the solvent was
removed under a reduced pressure. The reaction solution was cooled to 5 C
and 2 N hydrochloric acid was added thereto to adjust its pH to 4. The
resulting mixture was filtered and dried over anhydrous magnesium sulfate,
to obtain 413 mg of the title compound as a white solid (yield: 99%).
(1-3):(E)-N8-hydroxy-N1,N1-dimethyl-2-((naphthalen-1-yloxy)methyl)
octenediamide (formula 1)
(E)-8-(dimethylamino)-7-((naphthalen-l-yloxy)methyl)-8-oxo-6-
octene acid (413 mg, 1.16 mM) obtained in Example (1-2) was dissolved in
dimethylformamide (4 ml) and cooled to 0 C , whereto triethylamine (240 L,
1.74 mM) and N-methanesulfonyloxy-6-trifluorobenzotriazole (391 mg, 1.39
mM) were added, followed by stirring for 20 min. And then, N-t-
butyldimethylsilyloxyamine (256 mg, 1.74 mM) was added thereto and
stirred at room temperature for 1 hr. After the completion of the reaction,
ice water was poured thereinto and the mixture was extracted with ethyl
acetate. The extract was successively washed with sodium bicarbonate, dried
over anhydrous sodium sulfate, and filtered. The solvent was removed and
resulting residue was subjected to silica gel column chromatography, to
obtain 280 mg of the title compound as a white solid (yield: 65%).
'H NMR (300 MHz, MeOH-d4) S 1.46 (m, 2H, CH2)01.59 (m, 2H, CHZ),
2.43 (q, 4H, J = 14.9, 7.4 Hz, CHZ), 3.02 (s, 6H, N(CH3)2), 4.94 (s, 2H, CH2),
5.84 (t, 1H, J = 14.8, 6.5 Hz, CH), 6.85 (d, 1H, J = 7.4 Hz, ArH), 7.36-7.47
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(m, 4H, ArH), 7.79 (d, 1 H, J = 7.4 Hz, ArH), 8.10 (d, 1 H, J= 7.4 Hz, ArH).
Example 2:(E)-N1-(2-(dimethylamino)ethyl)-N8-hydroxy-2-((naphthalen-
1-yloxy)methyl)octenediamide
(2-1):(E)-8-(2-(dimethylamino)ethylamino)-7-((naphthalen-1-yloxy)
methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 2-
(dimethylamino)ethylamine instead of dimethylaminehydrochloride as the
amine to obtain 428 mg of the title compound (yield: 86%).
'H NMR (300 MHz, CDC13) S 1.51 (m, 2H, CHZ), 1.63 (m, 2H, CH2)02.03 (s,
6H, N(CH3)2), 2.23 (m, 4H, CH2CH2), 2.38 (m, 2H, CH2), 2.37 (q, 1H, J =
11.1, 5.7 Hz, CH2), 3.62 (s, 3H, OCH3), 4.92 (s, 2H, CHZ), 6.85 (t, 1H, J =
15.3, 7.6 Hz, CH), 6.91 (d, 1H, J = 7.0 Hz, ArH), 7.44 (m, 4H, ArH), 7.78 (dd,
1H, J = 6.8, 1.8 Hz, ArH), 8.20 (t, 1H, J = 9.3, 7.5 Hz, ArH).
(2-2): (E)-8-(2-(dimethylamino)ethylamino)-7-((naphthalen=l-yloxy)
methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (2-1) as the starting material, to obtain 335
mg of the title compound (yield: 81 %).
'H NMR (300 MHz, MeOH-d4) 6 1.52 (m, 2H, CH2), 1.64 (m, 2H, CH2), 2.20
(m, 2H, CH2), 2.27 (s, 6H, N(CH3)2), 2.38 (m, 2H, CH2), 2.55 (m, 2H, CH2),
3.42 (m, 2H, CH2), 4.97 (s, 2H, CH2), 6.67 (s, 1 H, CH), 6.99 (t, 1 H, J =
7.0,
1.8 Hz, ArH), 7.41 (m, 4H, ArH), 7.77 (d, 1 H, J = 7.0, 1.8 Hz, ArH), 8.14 (d,
1 H, J = 7.2 Hz, ArH).
(2-3):(E)-N1-(2-(dimethylamino)ethyl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)octenediamide
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The procedure of Example (1-3) was repeated except for using the
compound obtained in Example (2-2) as the starting material, to obtain 134
mg of the title compound (yield: 88%).
~H NMR (200 MHz, MeOH-d4) S 1.58 (m, 4H, CH2CH2), 2.40 (m, 2H, CH2),
2.82 (s, 6H, N(CH3)2), 3.30 (m, 4H, CH2CH2), 3.62 (m, 2H, CH2), 5.01 (s, 2H,
CHZ), 6.70 (t, 1 H, J = 15.2, 7.4 Hz, CH), 7.04 (d, 1 H, J = 1.2 Hz, ArH),
7.44
(m, 4H, ArH), 7.81 (m, 1 H, ArH), 8.19 (m, ArH).
Example 3: (E)-N1-(2-(dimethylamino)ethyl)-N8-hydroxy-Nl-methyl-2-
((naphthalen-1-yloxy)methyl)octenediamide
(3-1):(E)-8-((2-(dimethylamino)ethyl)(methyl)amino)-7-((naphthalen-l-
yloxy)methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using (2-
(dimethylamino)ethyl)(methyl)amine instead of dimethylaminehydrochloride
as the amine to obtain 351 mg of the title compound (yield: 77%).
'H NMR (200 MHz, CDC13) S 1.6 (m, 4H, CH2CH2), 2.2 (m, 8H,
CH2CH2CH2CH2), 3.05 (s, 3H, NCH3), 3.55 (m, 2H, CH2), 3.70 (s, 3H,
OCH3), 5.00 (s, 2H, Ph CH2), 5.80 (s, 1 H, CH), 6.89 (d, 1 H, J = 1.4 Hz,
ArH),
7.48 (m, 4H, ArH), 7.80 (dd, 1H, J = 6.0, 2.0 Hz, ArH), 8.20 (m, 1H, ArH).
(3-2): (E)- 8-((2-(dimethylamino)ethyl)(methyl)amino)-7-((naphthalen-l-
yloxy)methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (3-1) as the starting material, to obtain 224
mg of the title compound (yield: 92%).
'H NMR (200 MHz, MeOH-d4) 8 1.6 (m, 4H, CH2CH2), 2.4 (m, 6H,
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CH2CH2CH2), 2.50 (m, 4H, CH2CH2), 2.80 (m, 2H, CH2), 3.01 (s, 3H, NCH3),
3.29 (m, 1 H, CH), 3.65 (m, 1 H, CH), 4.95 (s, 2H, PhCH2), 6.00 (m, 1 H, CH),
7.00 (t, 1 H, J= 16.6, 9.4 Hz, ArH), 7.46 (m, 4H, ArH), 7.82 (m, 1 H, ArH),
8.18 (m, 1 H, ArH).
(3-3): (E)-N1-(2-(dimethylamino)ethyl)-N8-hydroxy-Nl-methyl-2-
((naphthalene-1-yloxy)methyl)octenediamide
The procedure of Example (1-3) was repeated except for using the
compound obtained in Example (3-2) as the starting material, to obtain 155
mg of the title compound (yield: 68%).
1 H NMR (200 MHz, MeOH-d4) S 1.48 (m, 2H, CHZ), 1.58 (m, 2H, CHZ), 2.4
(m, 6H, CH2CH2CH2), 2.49 (m, 4H, CH2CH2), 2.81 (m, 2H, CH2), 3.02 (s, 3H,
NCH3), 3.28 (m, 1H, CH), 3.64 (m, 1H, CH), 4.95 (s, 2H, PhCH2), 6.02 (m,
1 H, CH), 7.00 (d, 1 H, J = 8.2 Hz, ArH), 7.44 (m, 4H, ArH), 7.80 (m, 1 H,
ArH), 8.17 (m, 1 H, ArH).
Example 4: (E)-N1-(2-(diethylamino)ethyl)-N8-hydroxy-2-((naphthalen-
2 0 1-yloxy)methyl)octenediamide
(4-1):(E)-8-(2-(diethylamino)ethylamino)-7-((naphthalen-1-yloxy)methyl)
-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 2-
(diethylamino)ethylamine instead of dimethylaminehydrochloride as the
amine to obtain 164 mg of the title compound (yield: 37%).
'H NMR (200 MHz, CDC13) S 1.24 (m, 6H, CH2CH2CH2), 1.60 (m, 4H,
CH2CH2), 2.14 (t, 2H, J = 14,2, 7.4 Hz, CHZ), 2.40 (m, 2H, CH2), 3.14 (rim,
6H,
CH2CH2CH2CH2), 3.50 (s, 2H, CH2), 3.86 (s, 3H, OCH3), 5.02 (s, 2H, CH2),
6.73 (t, 1 H, J = 14.6, 7.2 Hz, CH), 7.01 (d, 1 H, J = 7.4 Hz, ArH), 7.40 (m,
4H,
ArH), 7.76 (d, 1 H, J = 7.4 Hz, ArH), 8.18 (dd, 1 H, J = 7.4, 2.8 Hz, ArH).
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(4-2):(E)-8-(2-(diethylamino)ethylamino)-7-((naphthalen-1-yloxy)methyl)
-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (4-1) as the starting material, to obtain 130
mg of the title compound (yield: 81 %).
'H NMR (200 MHz, MeOH-d4) S 1.24 (m, 6H, CH2CH2CH2), 1.60 (m, 4H,
CH2CH2), 2.12 (m, 2H, JCHZ), 2.36 (m, 2H, CH2), 3.14 (m, 6H, CH2CH2CH2),
3.50 (s, 2H, CH2), 5.01 (s, 2H, CH2), 6.72 (d, 1H, J = 7.4 Hz, CH), 7.02 (d,
1 H, J = 7.4 Hz, ArH), 7.40 (m, 4H, ArH), 7.80 (dd, 1 H, J = 7.6, 1.8 Hz,
ArH),
8.16 (d, 1 H, J = 7.2 Hz, ArH).
(4-3): (E)-N1-(2-(diethylamino)ethyl)-2-((naphthalen-1-yloxy)methyl)-N8-
(tetrahydro-2H-pyran-2-yloxy)octenediamide
(E)-8-(2-(diethylamino)ethylamino)-7-((naphthalen-l-yloxy)methyl)-
8-oxo-6-octene acid (311 mg, 0.71 mM) obtained in Example (4-2) was
dissolved in dimethylformamide (3 ml), whereto triethylamine (150 0, 1.07
mM) was added, followed by cooling to 0 C . N-hydroxy-6-trifluoro-6-
trifluorobenzotriazole (159 mg, 0.78 mM), 1-(3-diethylaminopropyl)-3-
ethylcarbodiimidhydrochloride (177 mg, 0.92 mM) and tetrahydropyranyl
oxyamine (125 mg, 1.07 mM) were added thereto, and the mixture was
stirred at room temperature for 18 hrs. After the completion of the reaction,
ice water was poured thereinto and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated sodium bicarbonate and
salt water in order, dried over anhydrous magnesium sulfate, and
concentrated under a reduced pressure. The resulting residue was subjected
to silica gel column chromatography, to obtain 320 mg of the title compound
(yield: 87%).
'H NMR (200 MHz, MeOH-d4) S 0.80 (m, 6H, CH2CH2CH2), 1.80 (m, 12H,
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CH2CH2CH2CH2), 2.10 (s, 1H, CH2), 2.35 (m, 6H, CH3CH3), 2.58 (m, 2H,
CH2), 3.40 (m, 2H, CH2), 3.60 (m, 1 H, CH), 3.94 (m, 1 H, CH), 4.96 (s, 2H,
CH2), 6.80 (d, 1H, J = 7.4 Hz, CH), 6.98 (d, 1H, J = 6.8 Hz, ArH), 7.42 (m,
4H, ArH), 7.80 (m, 1 H, ArH), 8.21 (dd, 1 H, J = 12.6, 6.4 Hz, ArH).
(4-4):(E)-N1-(2-(diethylamino)ethyl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)octenediamide
(E)-N 1-(2-(diethylamino)ethyl)-2-((naphthalen-1-yloxy)methyl)-N8-
(tetrahydro-2H-pyran-2-yloxy)octenediamide (320 mg, 0.62 mM) obtained in
Example (4-4) was dissolved in dichloromethane (10 ml), whereto
trifluoroacetic acid (0.46 ml, 6.20 mM) was added slowly at 0 C, followed by
reacting at room temperature for 18 hrs. After the completion of the
reaction, the solvent was then removed under a reduced pressure at room
temperature. The resulting residue was subjected to silica gel column
chromatography (methylalcohol/dichloromethane= 1/9) to obtain 261 mg of
the title compound (yield: 95%).
'H NMR (200 MHz, MeOH-d4) S 1.24 (m, 6H, CH2CH2CH2), 1.60 (m, 4H,
CH2CH2), 2.14 (t, 2H, J = 13,8, 7.0 Hz, CHZ), 2.40 (q, 2H, J = 14.4, 7.0 Hz,
CH2), 3.12 (m, 6H, CHZCH2CH2), 3.51 (s, 2H, CHZ), 5.02 (s, 2H, CHZ), 6.73
(t, 1 H, J = 14.8, 7.4 Hz, CH), 7.02 (d, 1 H, J = 6.4 Hz, ArH), 7.41 (m, 4H,
ArH), 7.80 (dd, 1 H, J = 5.6, 2.0 Hz, ArH), 8.18 (dd, 1 H, J = 7.0, 3.8 Hz,
ArH).
Example 5: (E)-N1-(2-(diethylamino)ethyl)-N8-hydroxy-Nl-methyl-2-
((naphthalen-1-yloxy)methyl)octenediamide
(5-1):(E)-8-((2-(diethylamino)ethyl)(methyl)amino)-7-((naphthalen-l-
yloxy)methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using (2-
(diethylamino)ethyl)(methyl)amine instead of dimethylaminehydrochloride as
the amine to obtain 483 mg of the title compound (yield: 71 %).
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'H NMR (300 MHz, CDC13) S 1.11 (m, 6H, CH2CH2CH2), 1.40 (m, 2H, CH2),
1.65 (m, 2H, CHz), 2.28 (m, 8H, CH2 CH2CH3CH3), 2.90 (s, 2H, CH2), 3.00
(s, 3H, NCH3), 3.57 (s, 2H, CH2), 3.66 (s, 3H, OCH3), 4.93 (s, 2H, CHZ), 6.85
(d, 1 H, J= 7.8 Hz, CH), 6.99 (m, 1 H, ArH), 7.41 (m, 4H, ArH), 7.75 (m, 1 H,
ArH), 8.14 (m, 1 H, NH), 8.17 (m, 1 H, ArH).
(5-2): (E)-8-((2-(diethylamino)ethyl)(methyl)amino)-7-((naphthalen-l-
yloxy)methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (5-1) as the starting material, to obtain 300
mg of the title compound (yield: 65%).
'H NMR (300 MHz, MeOH-d4) S 1.05 (m, 6H, CH2CHZCH2), 1.38 (m, 2H,
CH2), 1.50 (m, 2H, CH2), 2.17 (m, 4H, CH2CH2), 2.99 (m, 6H, CH3CH3),
3.16 (s, 3H, NCH3), 3.60 (m, 2H, CH2), 4.87 (s, 2H, CH2), 5.86 (d, 1H, J =
7.4 Hz, CH), 6.82 (d, 1H, J = 7.4 Hz, ArH), 7.28 (m, 4H, ArH), 7.64 (t, 1 H, J
= 9.4, 6.1 Hz, ArH), 7.92 (d, 1 H, J= 9.7 Hz, ArH).
(5-3): (E)-N1-(2-(diethylamino)ethyl)-2-((naphthalen-1-yloxy)methyl)-
N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (5-2) as the starting material, to obtain 320
mg of the title compound (yield: 87%).
'H NMR (300 MHz, MeOH-d4) 8 1.00 (m, 6H, CH2CH2CH2), 1.54 (m, 4H,
CH2CH2), 1.73 (m, 8H, CH2CH2CH2CH2), 2.14 (d, 2H, J = 7.0 Hz, CH2),
2.36 (d, 2H, J = 7.4 Hz, CH2), 2.58 (d, 2H, J = 6.8 Hz, CH2), 3.07 (m, 6H,
CH3CH3), 3.32 (s, 3H, NCH3), 3.55 (m, 2H, CH2)03.98 (m, 1H, CH), 5.05 (s,
2H, CH2), 5.94 (m, 1 H, CH), 7.01 (d, 1 H, J = 7.4 Hz, ArH), 7.48 (m, 4H,
ArH), 7.82 (t, 1H, J = 9.1, 2.0 Hz, ArH), 8.11 (dd, 1H, J = 7.4, 2.3 Hz, ArH).
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(5-4): (E)-N1-(2-(diethylamino)ethyl)-N8-hydroxy-Nl-methyl-2-
((naphthalen-1-yloxy)methyl)octenediam ide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (5-3) as the starting material, to obtain 285
mg of the title compound (yield: 93%).
1H NMR (300 MHz, MeOH-d4) S 1.10 (m, 6H, CHZCH2CH2), 1.13 (m, 2H,
CH2), 1.58 (m, 2H, CHZ), 2.02 (t, 2H, J = 14.1, 7.0 Hz, CHZ), 2.28 (d, 2H, J =
7.2 Hz, CH2), 3.07 (m, 6H, CH3CH3), 3.21 (s, 3H, NCH3), 3.64 (m, 2H, CHZ),
4.96 (s, 2H, CH2), 5.93 (s, 1 H, CH), 6.90 (d, 1 H, J= 7.2 Hz, ArH), 7.36 (m,
4H, ArH), 7.71 (dd, 1 H, J = 8.0, 3.7 Hz, ArH), 7.98 (d, 1 H, J = 9.4 Hz,
ArH);
MS (LC, 70 eV) m/z 456 (M+1), 382.
Example 6: (E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(2-
(pyrrolidin-1-yl)ethyl)octenediamide
(6-1):(E)-7-((naphthalen-1-yloxy)methyl)-8-oxo-8-(2-(pyrrolidin-l-yl)
thylamino)-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 2-
(pyrrolidin-1-yl)ethylamine instead of dimethylaminehydrochloride as the
amine to obtain 74 mg of the title compound (yield: 29%).
1H NMR (200 MHz, CDC13) 8 1.50 (d, 2H, J = 7.4 Hz, CHZ), 1.62 (d, 2H, J
7.4 Hz, CHZ), 1.89 (m, 4H, CH2), 2.09 (m, 2H, CH2), 2.35 (m, 2H, CH2), 3.13
(m, 5H, CHCH2CH2), 3.32 (s, 1H, CH), 3.58 (t, 2H, J = 12.1, 6.1 Hz, CH2),
3.96 (s, 3H, OCH3), 4.96 (s, 2H, CHZ), 6.80 (d, 1H, J = 7.4 Hz, CH), 6.98 (d,
1 H, J = 7.4 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (m, 1 H, ArH), 8.21 (m, 1 H,
ArH).
(6-2): (E)-7-((naphthalen-1-yloxy)methyl)-8-oxo-8-(2-(pyrrolidin-1-yl)
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thylamino)-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (6-1) as the starting material, to obtain 69 mg
of the title compound (yield: 96%).
'H NMR (200 MHz, MeOH-d4) 8 1.50 (d, 2H, J= 7.2 Hz, CH2), 1.60 (d, 2H,
J = 7.2 Hz, CH2), 1.88 (m, 4H, CH2), 2.08 (m, 2H, CH2), 2.34 (m, 2H, CH2),
3.14 (m, 5H, CHCH2CH2), 3.34 (s, 1H, CH), 3.58 (t, 2H, J = 12.1, 6.1 Hz,
CH2), 4.96 (s, 2H, CH2), 6.80 (d, 1 H, J = 7.0 Hz, CH), 6.98 (d, 1 H, J = 7.2
Hz,
ArH), 7.45 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.21 (m, 1H, ArH).
(6-3):(E)-2-((naphthalen-1-yloxy)methyl)-N1-(2-(pyrrolidin-1-yl)ethyl)-
N8-(tetrahydro-2H-pyran-2-yloxy)octenediamide
The procedure of Example (6-2) was repeated except for using the
compound obtained in Example (4-3) as the starting material, to obtain 87 mg
of the title compound (yield: 85%).
'H NMR (200 MHz, MeOH-d4) 8 1.50 (m, 8H, CH2CH2CH2CH2), 1.80 (m,
4H, CH2CH2), 2.01 (m, 2H, CH2), 2.40 (m, 4H, CH2CH2), 2.59 (m, 5H,
CHCH2CH2), 2.78 (m, 2H, CH2), 3.50 (m, 3H, CHCH2), 3.90 (s, 1H, CH),
4.96 (s, 2H, CHZ), 6.80 (d, 1H, J = 7.2 Hz, CH), 6.98 (d, 1H, J = 7.4 Hz,
ArH),
7.45 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.21 (m, 1 H, ArH).
(6-4): (E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(2-(pyrrolidin-
1-yl)ethyl)octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (6-3) as the starting material, to obtain 72 mg
of the title compound (yield: 84%).
'H NMR (300 MHz, MeOH-d4) S 1.51 (d, 2H, J = 7.0 Hz, CH2), 1.62 (d, 2H,
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J= 7.9 Hz, CH2), 1.89 (m, 4H, CH2CH2), 2.09 (m, 2H, CH2), 2.35 (m, 2H,
CH2), 3.13 (m, 5H, CHCH2CH2), 3.32 (s, 1H, CH), 3.58 (t, 2H, J= 12.1, 6.1
Hz, CH2), 5.01 (s, 2H, CH2), 6.70 (s, 1 H, CH), 7.00 (d, 1 H, J = 7.2 Hz,
ArH),
7.45 (m, 4H, ArH), 7.80 (t, 1H, J = 8.4, 1.8 Hz, ArH), 8.12 (t, 1H, J = 9.4,
7.5
Hz, ArH); MS (LC, 70 eV) m/z 440 (M+1), 425, 328, 313, 242, 210, 192.
Example 7: (E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(2-
(piperidin-1-yl)ethyl)octenediamide
(7-1):(E)-7-((naphthalen-1-yloxy)methyl)-8-oxo-8-(2-(piperidin-l-yl)
thylamino)-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 2-
(piperidin-1-yl)ethylamine instead of dimethylaminehydrochloride as the
amine to obtain 290 mg of the title compound (yield: 94%).
'H NMR (200 MHz, CDC13) 8 1.10 (m, 2H, CH2), 1.21 (m, 2H, CHZ), 1.60
(m, 4H, CHZ), 2.01 (m, 2H, CH2), 2.21 (m, 5H, CHCH2CH2), 2.38 (m, 5H,
CHCH2CH2), 3.41 (t, 2H, J= 11.4, 5.8 Hz, CH), 3.65 (s, 3H, OCH2), 4.95 (s,
2H, CHZ), 6.81 (d, 1 H, J = 7.8 Hz, CH), 6.95 (d, 1 H, J = 7.0 Hz, ArH), 7.10
(brs, 1H, NH), 7.45 (m, 4H, ArH), 7.80 (q, 1H, J = 5.8, 2.4 Hz, ArH), 8.21
(dd, 1H, J= 7.0, 3.4 Hz, ArH).
(7-2): (E)-7-((naphthalen-1-yloxy)methyl)-8-oxo-8-(2-(piperidin-1-yl)
thylamino)-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (7-1) as the starting material, to obtain 256
mg of the title compound (yield: 94%).
'H NMR (300 MHz, MeOH-d4) 8 1.44 (m, 4H, CH2CH2), 1.64 (m, 2H, CH2),
2.12 (m, 2H, CHZ), 2.26 (m, 2H, CH2)03.08 (m, IOH, CH2CH2CH2CH2CH2),
3.51 (d, 2H, J = 6.0 Hz, CH), 4.91 (s, 2H, CH2), 6.61 (s, 1 H, CH), 6.91 (d, 1
H,
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J = 6.2 Hz, ArH), 7.31 (m, 4H, ArH), 7.68 (dd, 1H, J = 6.8, 3.4 Hz, ArH),
8.00 (dd, 1H, J = 7.0, 3.4 Hz, ArH).
(7-3): (E)-2-((naphthalen-1-yloxy)methyl)-Nl-(2-(piperidin-1-yl)ethyl)-
N8-(tetrahydro-2H-pyran-2-yloxy)octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (7-2) as the starting material, to obtain 288
mg of the title compound (yield: 91 %).
'H NMR (300 MHz, MeOH-d4) S 1.42 (m, 2H, CH2), 1.45 (m, 4H, CH2CH2),
1.60 (m, 8H, CH2CH2CH2CH2), 2.09 (s, 2H, CH2), 2.29 (m, lOH,
CH2CH2CH2CH2CH2), 3.21 (m, 2H, CHZ), 3.47 (m, 2H, CHZ), 3.89 (t, 1 H, J=
7.2 Hz, CH), 4.90 (s, 2H, CH2), 6.50 (s, 1 H, CH), 6.90 (d, 1 H, J= 7.2 Hz,
ArH), 7.33 (m, 4H, ArH), 7.70 (t, 1H, J = 9.0, 1.4 Hz, ArH), 8.02 (d, 1H, J
8.2 Hz, ArH).
(7-4):(E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(2-(piperidin-
1-yl)ethyl)octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (7-3) as the starting material, to obtain 213
mg of the title compound (yield: 94%).
'H NMR (300 MHz, MeOH-d4) S 1.41 (m, 4H, CH2CH2), 1.65 (m, 4H,
CH2CH2), 2.10 (t, 2H, J = 14.3, 7.0 Hz, CH2), 2.41 (d, 2H, J = 7.2 Hz, CHz),
2.89 (m, 2H, CH2), 3.22 (t, 2H, J = 11.8, 5.9 Hz, CH), 3.32 (m, 2H, CH2),
3.52 (d, 2H, J = 11.8 Hz, CH2), 3.65 (t, J 11.8, 5.8 Hz, 2H, CHZ), 5.04 (s,
2H, CH2), 6.70 (s, 1H, CH), 7.05 (t, 1H, J 7.3, 1.0 Hz, ArH), 7.45 (m, 4H,
ArH), 7.83 (d, 1 H, J = 7.2 Hz, ArH), 8.13 (d, 1 H, J = 7.2 Hz, ArH).
Example 8: (E)-N8-hydroxy-N1-(2-morpholinoethyl)-2-((naphthalen-l-
yloxy)methyl)octenediamide
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(8-1):(E)-8-(2-morpholinoethylamino)-7-((naphthalen-1-yloxy)methyl)-8-
oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 2-
morpholinoethylamine instead of dimethylaminehydrochloride as the amine
to obtain 266 mg of the title compound (yield: 91 %).
'H NMR (200 MHz, CDC13) S 1.45 (m, 2H, CHZ), 1.64 (m, 2H, CH2), 2.20
(m, 4H, CH2CH2), 2.25 (m, 4H, CH2CH2), 2.40 (m, 2H, CH2), 3.07 (t, 2H, J =
8.6, 4.2 Hz, CH), 3.42 (t, 2H, J = 10.6, 5.4 Hz, CH2), 3.61 (s, 3H, OCH3),
4.89 (s, 2H, CH2), 6.90 (s, 1H, CH), 6.94 (d, 1H, J = 7.8 Hz, ArH), 7.45 (m,
4H, ArH), 7.82 (dd, 1H, J = 7.8, 2.4 Hz, ArH), 8.19 (dd, 1H, J = 7.8, 2.8 Hz,
ArH).
(8-2): (E)-8-(2-morpholinoethylamino)-7-((naphthalen-1-yloxy)methyl)-8-
oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (8-1) as the starting material, to obtain 250
mg of the title compound (yield: 96%).
1 H NMR (300 MHz, MeOH-d4) S 1.50 (m, 2H, CH2), 1.62 (m, 2H, CHZ), 2.24
(m, 4H, CH2CH2), 2.38 (m, 4H, CH2CH2), 2.58 (m, 2H, CH2), 3.32 (q, 2H, J
= 3.1, 1.5 Hz, CH), 3.43 (m, 4H, CH2CH2), 4.96 (s, 2H, CHZ), 6.71 (s, 1H,
CH), 7.01 (d, 1 H, J = 7.3 Hz, ArH), 7.43 (m, 4H, ArH), 7.80 (t, 1 H, J= 7.1,
5.5 Hz, ArH), 8.19 (d, 1H, J = 7.6 Hz, ArH); MS (LC, 70 eV) m/z 416 (M+1),
403, 346, 313, 298, 204, 102.
(8-3): (E)-N8-hydroxy-N1-(2-morpholinoethyl)-2-((naphthalen-1-yloxy)
ethyl)octenediamide
The procedure of Example (1-3) was repeated except for using the
compound obtained in Example (8-2) as the starting material, to obtain 155
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mg of the title compound (yield: 90%).
'H NMR (300 MHz, MeOH-d4) 8 1.48 (m, 2H, CHZ), 1.59 (m, 2H, CH2), 2.25
(m, 4H, CH2CH2), 2.38 (m, 4H, CH2CH2), 2.56 (m, 2H, CHZ), 3.30 (d, 2H, J
= 7.5 Hz, CH), 3.42 (m, 4H, CH2CH2), 5.01 (s, 2H, CH2), 6.78 (s, 1H, CH),
7.00 (d, 1 H, J = 7.4 Hz, ArH), 7.45 (m, 4H, ArH), 7.78 (d, 1 H, J= 7.4 Hz,
ArH), 8.14 (d, 1H, J = 7.6 Hz, ArH); MS (LC, 70 eV) m/z 416 (M+1), 403,
346, 313, 298, 204, 102.
Example 9: (E)-N-hydroxy-8-(4-methylpiperazin-1-yl)-7-((naphthalen-l-
yloxy)methyl)-8-oxoocteneamide
(9-1): (E)-8-(4-methylpiperazin-1-yl)-7-((naphthalen-1-yloxy)methyl)-8-
oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 4-
methylpiperazin-1-ylamine instead of dimethylaminehydrochloride as the
amine to obtain 175 mg of the title compound (yield: 41 %).
'H NMR (300 MHz, CDC13) 6 1.46 (m, 2H, CH2), 1.53 (m, 2H, CH2), 2.17
(m, 4H, CH2CH2), 2.34 (m, 8H, CH2CH2CH2CH2CH2CH2), 3.64 (s, 3H,
NCH3), 3.75 (s, 3H, OCH3), 4.98 (s, 2H, CH2), 5.78 (t, 1H, J = 15.0, 7.5 Hz,
CH), 6.84 (d, 1 H, J = 7.5 Hz, ArH), 7.44 (m, 4H, ArH), 7.79 (t, 1 H, J = 8.7,
1.2 Hz, ArH), 8.13 (d, 1 H, J= 7.8 Hz, ArH).
(9-2): (E)-8-(4-methylpiperazin-1-yl)-7-((naphthalen-1-yloxy)methyl)-8-
oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (9-1) as the starting material, to obtain 168
mg of the title compound (yield: 100%).
'H NMR (300 MHz, MeOH-d4) 6 1.55 (m, 2H, CH2), 1.68 (m, 2H, CHZ), 2.32
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(m, 11H, CHCH2CH2CH2CH2CH2CH2), 3.31 (m, 1H, CH), 3.66 (s, 3H,
NCH3), 5.09 (s, 2H, CH2), 5.92 (s, 1 H, CH), 6.97 (dd, 1 H, J = 6.5, 6.5 Hz,
ArH), 7.46 (m, 4H, ArH), 7.81 (d, 1 H, J = 7.8 Hz, ArH), 8.16 (d, 1 H, J = 7.8
Hz, ArH).
(9-3): (E)-8-(4-methylpiperazin-1-yl)-7-((naphthalen-1-yloxy)methyl)-8-
oxo-N-(tetrahydro-2H-pyran-2-yloxy)-6-octeneamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (9-2) as the starting material, to obtain 317
mg of the title compound (yield: 83%).
'H NMR (300 MHz, MeOH-d4) 8 1.54 (m, 4H, CH2CH2), 1.72 (m, 4H,
CH2CH2), 2.17 (m, 8H, CH2CH2CH2CH2), 2.37 (m, 6H, CH2CH2CH2), 3.32
(q, 2H, J = 3.2, 1.6 Hz, CH2), 3.57 (s, 3H, NCH3), 3,92 (m, 1 H, CH), 5.08 (s,
2H, CH2), 5.86 (s, 1 H, CH), 6.96 (d, 1 H, J = 7.3 Hz, ArH), 7.45 (m, 4H,
ArH),
7.80 (d, 1 H, J = 7.3 Hz, ArH), 8.14 (d, 1 H, J = 7.3 Hz, ArH). .
(9-4):(E)-N-hydroxy-8-(4-methylpiperazin-1-yl)-7-((naphthalen-1-yloxy)
methyl)-8-oxoocteneamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (9-3) as the starting material, to obtain 287
mg of the title compound (yield: 92%).
'H NMR (300 MHz, MeOH-d4) 6 1.52 (m, 2H, CH2), 1.57 (m, 2H, CHZ), 2.13
(t, 2H, J = 14.3, 7.1 Hz, CH2), 2.37 (q, 2H, J = 14.4, 7.1 Hz, CH2), 2.61 (m,
4H, CH2CH2), 3.32 (m, 2H, CH2), 3.76 (m, 2H, CH2), 3.80 (s, 3H, NCH3),
5.10 (s, 2H, CH2), 5.96 (s, 1 H, CH), 6.97 (d, 1 H, J = 7.3 Hz, ArH), 7.47 (m,
4H, ArH), 7.83 (t, 1 H, J = 9.1, 4.0 Hz, ArH), 8.13 (t, 1 H, J= 9.2, 5.1 Hz,
ArH); MS (LC, 70 eV) m/z 426 (M+1), 407, 325, 293, 281, 265, 149, 102.
Example 10: (E)-N8-hydroxy-N1-(2-(4-methylpiperazin-1-yl)ethyl)-2-
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((naphthalen-1-yloxy)methyl)octenediamide
(10-1): (E)-8-(2-(4-methylpiperazin-l-yl)ethylamino)-7-((naphthalen-l-
yloxy)methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 2-(4-
methylpiperazin-1-yl)ethylamine instead of dimethylaminehydrochloride as
the amine to obtain 225 mg of the title compound (yield: 48%).
'H NMR (300 MHz, CDC13) 6 1.53 (m, 2H, CH2), 1.66 (m, 4H, CH2CH2),
1.92 (m, 4H, CH2CH2), 2.31 (m, 8H, CH2CH2CH2CH2), 2.42 (s, 3H, NCH3),
3.40 (q, 2H, J = 10.5, 5.4 Hz, CHZ), 3.63 (s, 3H, OCH3), 4.87 (s, 2H, CH2),
6.95 (dd, 1 H, J = 15.6, 7.8 Hz, CH), 7.05 (s, 1 H, ArH), 7.45 (m, 4H, ArH),
7.80 (dd, 1 H, J= 6.9, 1.8 Hz, ArH), 8.19 (t, 1 H, J = 9.6, 7.8 Hz, ArH).
(10-2):(E)-8-(2-(4-methylpiperazin-1-yl)ethylamino)-7-((naphthalen-l-
yloxy)methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (10-1) as the starting material, to obtain 157
mg of the title compound (yield: 76%).
'H NMR (300 MHz, MeOH-d4) S 1.24 (s, 1H, CH), 1.54 (m, 4H, CHZCH2),
2.20 (m, 4H, CH2CH2), 2.29 (m, 4H, CH2CH2), 2.51 (m, 4H, CH2CH2), 3.05
(m, 1H, CH), 3.24 (s, 3H, NCH3), 3.34 (m, 2H, CH2), 4.94 (s, 2H, CH2), 6.69
(s, 1 H, CH), 7.01 (dd, 1 H, J = 7.2, 1.0 Hz, ArH), 7.42 (m, 4H, ArH), 7.75
(d,
1H, J = 7.2 Hz, ArH), 8.08 (d, 1H, J = 1.7 Hz, ArH).
(10-3):(E)-N1-(2-(4-methylpiperazin-1-yl)ethyl)-2-((naphthalen-1-yloxy)
methyl)-N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (10-2) as the starting material, to obtain 137
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mg of the title compound (yield: 54%).
1H NMR (300 MHz, MeOH-d4) S 1.54 (m, 4H, CH2CH2), 1.64 (m, 6H,
CHCH2CH2), 2.11 (m, 5H, CHCH2CH2), 2.41 (m, 8H, CH2CH2CH2CH2),
3.27 (s, 3H, NCH3), 3.34 (m, 3H, CHCH2), 3.50 (m, 2H, CH2), 3.85 (t, 1H, J
= 7.2, 1.8 Hz, CH), 4.96 (s, 2H, CHz), 6.70 (s, 1 H, CH), 7.01 (d, 1 H, J =
7.2
Hz, ArH), 7.43 (m, 4H, ArH), 7.79 (dd, 1 H, J = 6.6, 1.7 Hz, ArH), 8.10 (t, 1
H,
J= 8.9, 7.2 Hz, ArH).
(10-4):(E)-N8-hydroxy-N1-(2-(4-methylpiperazin-1-yl)ethyl)-2-
((naphthalen-1-yloxy)methyl)octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (10-3) as the starting material, to obtain 118
mg of the title compound (yield: 76%).
'H NMR (300 MHz, MeOH-d4) S 1.53 (d, 2H, J = 7.7 Hz, CHZ), 1.65 (d, 2H,
J = 7.0 Hz, CH2), 2.10 (t, 2H, J = 14.3, 7.0 Hz, CH2), 2.39 (t, 2H, J = 14.2,
7.3
Hz, CHZ), 2.72 (d, 2H, J = 8.2 Hz, CHZ), 2.95 (d, 2H, J = 5.4 Hz, CHZ), 3.12
(m, 6H, CH2CH2CH2), 3.32 (s, 3H, NCH3), 3.56 (t, 2H, J = 11.2, 5.6 Hz,
CH2), 5.02 (s, 2H, CH2), 6.75 (t, 1 H, J = 15.0, 7.2 Hz, CH), 7.05 (d, 1 H, J
=
7.2 Hz, ArH), 7.46 (m, 4H, ArH), 7.82 (d, 1 H, J = 7.5 Hz, ArH), 8.14 (d, 1 H,
J = 8.5 Hz, ArH).
Example 11: (E)-N1-(cyanomethyl)-N8-hydroxy-Nl-methyl-2-
((naphthalen-1-yloxy)methyl)octenediamide
(11-1):(E)-8-((cyanomethyl)(cyanomethyl)amino)-7-((naphthalen-l-
yloxy)methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using
cyanomethylamineas instead of dimethylaminehydrochloride the amine to
obtain 299 mg of the title compound (yield: 76%).
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'H NMR (200 MHz, CDC13) S 1.35 (m, 2H, CH2), 1.60 (m, 2H, CH2), 2.31
(m, 4H, CH2CH2), 3.11 (s, 3H, NCH3), 3.67 (s, 3H, OCH3), 4.38 (s, 2H, CH2),
4.97 (s, 2H, CHZ), 5.98 (s, 1 H, CH), 6.85 (d, 1 H, J = 4.6 Hz, ArH), 7.37 (t,
1H,
J = 10.6, 5.2 Hz, ArH), 7.47 (m, 3H, ArH), 7.79 (dd, 1H, J = 6.2, 1.4 Hz,
ArH), 8.06 (d, 1 H, J = 4.6 Hz, ArH).
(11-2):(E)-8-((cyanomethyl)(cyanomethyl)amino)-7-((naphthalen-l-
yloxy)methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (11-1) as the starting material, to obtain 250
mg of the title compound (yield: 84%).
1H NMR (300 MHz, MeOH-d4) S 1.37 (m, 2H, CH2), 1.61 (m, 2H, CHZ), 2.31
(m, 4H, CH2CH2), 3.31 (s, 3H, NCH3), 4.16 (d, 2H, J = 8.5 Hz, CH2), 5.01 (s,
2H, CH2), 6.21 (m, 1 H, CH), 6.98 (d, 1H, J = 7.0 Hz, ArH), 7.44 (m, 4H,
ArH), 7.81 (t, 1 H, J = 8.8, 2.8 Hz, ArH), 8.13 (d, 1 H, J = 13.6 Hz, ArH).
(11-3):(E)-N1-(cyanomethyl)-N1-methyl-2-((naphthalen-1-yloxy)methyl)-
N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (11-2) as the starting material, to obtain 222
mg of the title compound (yield: 64%).
'H NMR (300 MHz, MeOH-d4) S 1.48 (m, 4H, CH2CH2), 1.71 (m, 4H,
CH2CH2), 1.92 (m, 4H, CH2CH2), 2.32 (m, 4H, CH2CH2), 3.21 (s, 3H, NCH3),
3.73 (t, 1H, J = 7.2 Hz, CH2), 4.39 (s, 2H, CH2), 5.06 (s, 2H, CH2), 6.18 (m,
1 H, CH), 7.20 (d, 1 H, J = 7.0 Hz, ArH), 7.64 (m, 4H, ArH), 8.09 (dd, 1 H, J
14.8, 7.2 Hz, ArH), 8.13 (m, 1H, ArH).
(11-4):(E)-N1-(cyanomethyl)-N8-hydroxy-Nl-methyl-2-((naphthalen-l-
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yloxy)methyl)octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (11-3) as the starting material, to obtain 170
mg of the title compound (yield: 75%).
'H NMR (300 MHz, MeOH-d4) S 1.34 (d, 2H, J = 7.7 Hz, CHZ), 1.50 (d, 2H,
J = 6.7 Hz, CH2), 1.89 (d, 2H, J = 7.2 Hz, CH2), 2.25 (q, 2H, J = 16.2, 7.9
Hz,
CH2), 3.20 (s, 3H, NCH3), 3.91 (d, 2H, J = 7.6 Hz, CH2), 4.98 (s, 2H, CH2),
5.98 (d, 1 H, J = 14.7 Hz, CH), 6.86 (d, 1 H, J= 6.7 Hz, ArH), 7.3 5(m, 4H,
ArH), 7. 5 6(t, 1 H, J = 9.1, 3.4 Hz, ArH), 7.9 8(m, 1 H, ArH).
Example 12: (E)-N8-hydroxy-N1-(2-hydroxyethyl)-Nl-methyl-2-
((naphthalen-1-yloxy)methyl)octenediamide
(12-1):(E)-8-((2-hydroxyethyl)(methyl)amino)-7-((naphthalen-l-
yloxy)methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 2-
2 0 hydroxyethylamine instead of dimethylaminehydrochloride as the amine to
obtain 366 mg of the title compound (yield: 93%).
'H NMR (300 MHz, CDC13) S 1.51 (m, 2H, CH2), 1.68 (m, 2H, CH2), 2.29
(m, 4H, CH2CH2), 3.08 (s, 3H, NCH3), 3.66 (m, 4H, CH2CH2), 3.81 (S, 3H,
OCH3), 4.96 (s, 2H, CH2), 6.86 (d, 1 H, J = 7.0 Hz, CH), 7.26 (s, 1 H, ArH),
7.44 (m, 4H, ArH), 7.77 (d, 1 H, J = 7.2 Hz, ArH), 8.15 (d, 1 H, J = 7.2 Hz,
ArH).
(12-2): (E)-8-((2-hydroxyethyl)(methyl)amino)-7-((naphthalen-1-yloxy)
methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (12-1) as the starting material, to obtain 320
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mg of the title compound (yield: 88%).
'H NMR (300- MHz, MeOH-d4) S 1.30 (m, 4H, CH2CH2), 2.08 (m, 4H,
CH2CH2), 3.07 (s, 3H, NCH3), 3.09 (m, 4H, CH2CH2), 4.74 (s, 2H, CHZ),
6.77 (t, 1H, J = 7.2, 1.2 Hz, CH), 6.95 (s, 1H, ArH), 7.20 (m, 4H, ArH), 7.56
(t, 1 H, J = 7.0, 1.9 Hz, ArH), 7.90 (d, 1 H, J = 7.2 Hz, ArH).
(12-3):(E)-N8-hydroxy-N1-(2-hydroxyethyl)-N1-methyl-2-((naphthalen-
1-yloxy)methyl)octenediamide
The procedure of Example (1-3) was repeated except for using the
compound obtained in Example (12-2) as the starting material, to obtain 262
mg of the title compound (yield: 90%).
ls 'H NMR (300 MHz, MeOH-d4) 8 1.32 (m, 4H, CH2CH2), 2.06 (m, 4H,
CH2CH2), 3.08 (s, 3H, NCH3), 3.13 (m, 4H, CH2CH2), 4.92 (s, 2H, CH2),
6.78 (t, 1H, J= 7.4, 1.8 Hz, CH), 6.92 (s, 1H, ArH), 7.28 (m, 4H, ArH), 7.56
(d, 1H, J = 7.4 Hz, ArH), 7.88 (d, 1H, J = 7.4 Hz, ArH); MS (LC, 70 eV) m/z
448 (M+l), 305, 204.
Example 13: (E)-N8-hydroxy-Nl-methyl-N1-(1-methylpyrrolidin-3-yl)-2-
((naphthalen-1-yloxy)methyl)octenediamide
(13-1):(E)-8-(methyl(1-methylpyrrolidin-3-yl)amino)-7-((naphthalen-l-
yloxy)methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 1-
methylpyrrolidin-3-ylamine instead of dimethylaminehydrochlori.de as the
amine to obtain 355 mg of the title compound (yield: 91%).
'H NMR (200 MHz, CDC13) S 1.42 (m, 4H, CHZCHZ), 1.80 (m, 4H, CHZCH2),
2.20 (m, 4H, CH2CH2), 2.98 (s, 3H, NCH3), 3.61 (s, 3H, NCH3), 3.80 (s, 3H,
OCH3), 4.82 (s, 2H, CH2), 4.96 (s, 2H, CH2), 5.81 (m, 1H, CH), 6.82 (m, 1H,
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ArH), 7.45 (m, 4H, ArH), 7.80 (m, 1H, ArH), 8.15 (m, 1H, ArH).
(13-2):(E)-8-(methyl(1-methylpyrrolidin-3-yl)amino)-7-((naphthalen-l-
yloxy)methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (13-1) as the starting material, to obtain 320
mg of the title compound (yield: 86%).
'H NMR (300 MHz, MeOH-d4) S 1.42 (m, 4H, CH2CH2), 1.76 (m, 4H,
CH2CH2), 2.22 (m, 4H, CH2CH2), 2.88 (s, 3H, NCH3), 3.58 (s, 3H, NCH3),
4.80 (s, 2H, CHZ), 4.99 (s, 2H, CH2), 5.84 (m, 1 H, CH), 6.80 (m, 1 H, ArH),
7.44 (m, 4H, ArH), 7.80 (m, 1 H, ArH), 8.12 (m, 1 H, ArH).
(13-3):(E)-N8-hydroxy-Nl-methyl-N1-(1-methylpyrrolidin-3-yl)-2-
((naphthalen-l-yloxy)methyl)octenediamide
The procedure of Example (1-3) was repeated except for using the
compound obtained in Example (13-2) as the starting material, to obtain 188
mg of the title compound (yield: 41 %).
'H NMR (300 MHz, MeOH-d4) S 1.42 (m, 4H, CHZCH2), 1.80 (m, 4H,
CH2CH2), 2.20 (m, 4H, CH2CH2), 2.98 (s, 3H, NCH3), 3.60 (s, 3H, NCH3),
3.80 (s, 3H, OCH2), 5.00 (s, 2H, CH2), 4.96 (s, 2H, CH2), 5.82 (m, 1 H, CH),
6.84 (m, 1 H, ArH), 7.44 (m, 4H, ArH), 7.78 (m, 1 H, ArH), 8.14 (m, 1H, ArH).
Example 14: (E)-N1-(3-(dimethylamino)propyl)-N8-hydroxy-2-
((naphthalen-1-yloxy)methyl)octenediamide
(14-1):(E)-7-(3-(dimethylamino)propylcarbamoyl)-8-(naphthalen-l-
yloxy)octane acid methylester
The procedure of Example (1-1) was repeated except for using 3-
48
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(dimethylamino)propylamine instead of dimethylaminehydrochloride as the
amine to obtain 467 mg of the title compound (yield: 73%).
'H NMR (200 MHz, CDC13) S 1.45 (m, 2H, CH2), 1.64 (m, 4H, CH2CH2),
2.01 (s, 6H, N(CH3)2), 2.25 (m, 6H, CH2CH2CH2), 3.40 (m, 2H, CH2), 3.60 (s,
3H, OCH3), 4.96 (s, 2H, CH2), 6.81 (t, 1H, J = 15.4, 7.8 Hz, CH), 6.94 (t, 1H,
J = 7.4, 6.2 Hz, ArH), 7.43 (m, 4H, ArH), 7.79 (m, 1 H, ArH), 8.19 (dd, 1 H, J
= 6.8, 3.6 Hz, ArH).
(14-2):(E)-7-(3-(dimethylamino)propylcarbamoyl)-8-(naphthalen-l-
yloxy)octane acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (14-1) as the starting material, to obtain 154
mg of the title compound (yield: 83%).
'H NMR (300 MHz, MeOH-d4) S 1.30 (m, 2H, CHZ), 1.64 (d, 2H, J = 6.9 Hz,
CH2), 1.94 (m, 2H, CH2), 2.27 (t, 2H, J = 14.2, 7.0 Hz, CHZ), 2.39 (d, 2H, J=
7.2 Hz, CH2), 2.74 (s, 6H, N(CH3)2), 3.03 (t, 2H, J = 15.0, 7.2 Hz, CH2), 3.33
(m, 2H, CH2), 5.05 (s, 2H, CH2), 6.66 (s, 1 H, CH), 7.03 (dd, 1 H, J = 7.2,
1.2
Hz, ArH), 7.46 (m, 4H, ArH), 7.80 (d, 1 H, J = 6.9 Hz, ArH), 8.14 (d, 1 H, J
7.0 Hz, ArH).
(14-3):(E)-N1-(3-(dimethylamino)propyl)-2-((naphthalen-1-yloxy)
methyl)-N8-(tetrahydro-2H-pyran-2-yloxy)octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (14-2) as the starting material, to obtain 160
mg of the title compound (yield: 89%).
'H NMR (200 MHz, MeOH-d4) S 1.59 (m, 13H,
CH2CH2CH2CH2CH2CH2CH2), 1.90 (s, 6H, N(CH3)2), 2.23 (m, 6H,
CH2CHZCH2), 3.41 (q, 2H, J = 11.8, 6.2 Hz, CH2), 3.61 (m, 1 H, CH), 3.91 (m,
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1 H, CH), 4.87 (s, 2H, CH2), 6.82 (d, 1 H, J = 7.4 Hz, CH), 6.89 (d, 1 H, J =
6.8
Hz, ArH), 7.44 (m, 4H, ArH), 7.79 (dd, 1 H, J = 5.2, 3.2 Hz, ArH), 8.16 (t, 1
H,
J= 9.4, 6.4 Hz, ArH).
(14-4):(E)-N1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (14-3) as the starting material, to obtain 142
mg of the title compound (yield: 92%).
1 H NMR (300 MHz, MeOH-d4) 6 1.52 (t, 2H, J = 7.5, 4.1 Hz, CH2), 1.64 (d,
2H, J = 7.1 Hz, CHZ), 1.92 (t, 2H, J= 13.8, 7.5 Hz, CH2), 2.10 (t, 1 H, J=
14.2,
7.0 Hz, CH2), 2.37 (d, 2H, J = 7.2 Hz, CH2), 2.72 (s, 6H, N(CH3)2), 3.01 (t,
2H, J = 14.8, 7.3 Hz, CHz), 3.35 (m, 3H, CHCHZ), 5.03 (s, 2H, CH2), 6.62 (t,
1 H, J = 15.0, 7.5 Hz, CH), 7.02 (d, 1 H, J = 7.1 Hz, ArH), 7.46 (m, 4H, ArH),
7.80 (dd, 1 H, J= 6.2, 1.9 Hz, ArH), 8.14 (t, 1 H, J = 8.9, 6.9 Hz, ArH); MS
(LC, 70 eV) m/z 429 (M+1), 413, 301, 256, 224.
Example 15: (E)-N-hydroxy-8-morpholino-7-((naphthalen-l-
yloxy)methyl)-8-oxoocteneamide
(15-1): (E)-8-morpholino-7-((naphthalen-1-yloxy)methyl)-8-oxooctene
acid methylester
The procedure of Example (1-1) was repeated except for using
morpholinoamine instead of dimethylaminehydrochloride as the amine to
obtain 416 mg of the title compound (yield: 67%).
1H NMR (200 MHz, CDC13) S 1.45 (m, 2H, CHZ), 1.63 (m, 2H, CH2), 2.25
(m, 4H, CH2CH2), 3.60 (m, 8H, CH2CH2CH2CH2), 3.71 (s, 3H, OCH3), 5.01
(s, 2H, CH2), 5.82 (t, 1 H, J= 15.0, 7.8 Hz, CH), 6.84 (dd, 1 H, J 7.2, 1.2
Hz,
ArH), 7.46 (m, 4H, ArH), 7.79 (m, 1 H, ArH), 8.13 (dd, 1 H, J= 4.0, 3.2 Hz,
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ArH).
(15-2): (E)-8-morpholino-7-((naphthalen-1-yloxy)methyl)-8-oxooctene
acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (15-1) as the starting material, to obtain 85
mg of the title compound (yield: 89%).
'H NMR (300 MHz, MeOH-d4) S 1.45 (m, 2H, CH2), 1.63 (m, 2H, CH2), 2.24
(m, 4H, CH2CH2), 3.58 (m, 8H, CH2CH2CH2CH2), 5.02 (s, 2H, CHZ), 5.86 (t,
1 H, J = 15.2, 7.6 Hz, CH), 6.82 (dd, 1 H, J = 7.4, 1.2 Hz, ArH), 7.45 (m, 4H,
ArH), 7.80 (d, 1 H, J= 7.4 Hz, ArH), 8.13 (t, 1 H, J = 7.4, 3.4 Hz, ArH).
(15-3):(E)-8-morpholino-7-((naphthalen-1-yloxy)methyl)-8-oxo-N-
(tetrahydro-2H-pyran-2-yloxy)octeneamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (15-2) as the starting material, to obtain 92
mg of the title compound (yield: 88%).
'H NMR (200 MHz, MeOH-d4) 6 1.54 (m, 5H, CH CH2CH2), 1.68 (m, 4H,
CH2CH2), 2.18 (m, 2H, CH2), 2.40 (m, 2H, CH2), 3.25 (m, 5H, CHCH2CH2),
3.59 (m, 6H, CH2CH2CH2), 3.99 (m, 1H, CH), 5.08 (s, 2H, CHZ), 5.90 (t, 1H,
J= 15.0, 7.6 Hz, CH), 6.97 (t, 1 H, J= 7.0, 5.8 Hz, ArH), 7.48 (m, 4H, ArH),
7.91 (dd, 1 H, J = 12.6, 3.0 Hz, ArH), 8.13 (t, 1 H, J = 7.0, 4.0 Hz, ArH).
(15-4): (E)-N-hydroxy-8-morpholino-7-((naphthalen-1-yloxy)methyl)-8-
oxooctenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (15-3) as the starting material, to obtain 64
mg of the title compound (yield: 72%).
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1 H NMR (300 MHz, MeOH-d4) 6 1.53 (s, 2H, CH2), 1.68 (m, 2H, CHZ), 2.13
(t, 2H, J = 14.1, 7.0 Hz, CHZ), 2.35 (q, 2H, J = 14.6, 7.3 Hz, CHZ), 3.33 (m,
2H, CH2), 3.53 (m, 6H, CH2CH2CH2), 5.06 (s, 2H, ArH), 5.86 (t, 1H, J = 14.9,
7.4 Hz, CH), 6.97 (t, 1 H, J = 7.2, 2.4 Hz, ArH), 7.45 (m, 4H, ArH), 7.80 (dd,
1 H, J = 5.6, 2.6 Hz, ArH), 8.13 (dd, 1 H, J = 6.2, 2.6 Hz, ArH); MS (LC, 70
eV) m/z 413 (M+1), 380, 309, 293, 265, 236, 149, 121.
Example 16: (E)-N8-hydroxy-N1-(6-(4-methylpiperazin-1-yl)pyridin-3-
1o yl)-2-((naphthalen-1-yloxy)methyl)octenediamide
(16-1): (E)-8-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)-7-
((naphthalen-1-yloxy)methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 6-(4-
methylpiperazin-1-yl)pyridin-3-ylamine instead of
dimethylaminehydrochloride as the amine to obtain 216 mg of the title
compound (yield: 37%).
'H NMR (300 MHz, MeOH-d4) 8 1.47 (m, 2H), 1.67 (, 2H), 1.88 (m, 2H),
2.37 (t, 2H), 2.93 (s, 3H), 3.34 (m, 4H), 3.61 (s, 3H), 3.79 (br, 4H), 4.34
(t,
1 H), 4.5 8(d, 1 H), 6.91 (d, 1 H), 7.42 (m, 3H), 7.51 (d, 1 H), 7. 8 6(m, 1
H),
7.91 (m, 2H), 8.06 (s, 1 H), 8.11 (m, 1 H), 8.39 (s, 1 H); MS (LC, 70 eV) m/z
517 (M+1).
(16-2):(E)-8-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)-7-
((naphthalen-1-yloxy)methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (16-1) as the starting material, to obtain 249
mg of the title compound (yield: 94%).
1H NMR (300 MHz, MeOH-d4) 6 1.45 (m, 2H), 1,67 (m, 2H), 2.30 (t, 2H),
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2.94 (s, 3H), 3.33 (m, 4H), 3.83 (br, 4H), 4.45 (t, 1H), 4.56 (d) 1H), 7.03
(d,
1 H), 7.41 (m, 4H), 7.76 (m, 2H), 7.92 (d, 1 H), 8.12 (m, 2H), 8.49 (s, 1 H);
MS
(LC, 70 eV) m/z 503 (M+l).
(16-3): (E)-N8-hydroxy-N1-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-2-
((naphthalen-1-yloxy)methyl)octenediamide
The procedure of Example (1-3) was repeated except for using the
compound obtained in Example (16-2) as the starting material, to obtain 132
mg of the title compound (yield: 72%).
'H NMR (300 MHz, MeOH-d4) S 1.45 (m, 2H), 1,67 (m, 2H), 2.11 (t, 2H),
2.94 (s, 3H), 3.33 (m, 4H), 3.83 (br, 4H), 4.45 (t, 1H), 4.56 (d, 1H), 7.03
(d,
1H), 7.41 (m, 4H), 7.76 (m, 2H), 7.92 (d, 1 H), 8.12 (m, 2H), 8.49 (s, 1 H);
MS
(LC, 70 eV) m/z 518 (M+1).
Example 17: (E)-N1-(6-(2-morpholinoethylamino)pyridin-3-yl)-N8-
hydroxy-2-((naphthalen-1-yloxy)methyl)octenediamide
(17-1):(E)-7-(6-(2-morpholinoethylamino)pyridin-3-ylcarbamoyl)-8-
(naphthalen-1-yloxy)-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 6-(2-
morpholinoethylamino)pyridin-3-yl instead of dimethylaminehydrochloride
amine as the amine to obtain 350 mg of the title compound (yield: 64%).
'H NMR (300 MHz, MeOH-d4) 6 1.45 (m, 2H), 1.63 (m, 2H), 1.91 (m, 2H),
2.29 (t, 2H), 2.88 (m, 6H), 3.52 (t, 2H), 3.69 (s, 3H), 3.81 (m, 4H), 4.34 (t,
1 H), 4.78 (d, 1 H), 6.60 (d, 1 H), 7.42 (m, 6H), 7.66 (d, 1 H), 7.74 (m, 1
H),
8.12 (m, 1H), 8.24 (s, 1 H); MS (LC, 70 eV) m/z 547 (M+1).
(17-2):(E)-7-(6-(2-morpholinoethylamino)pyridin-3-ylcarbamoyl)-8-
(naphthalen-1-yloxy)-6-octene acid
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The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (17-1) as the starting material, to obtain 207
mg of the title compound (yield: 87%).
'H NMR (300 MHz, MeOH-d4) S 1.45 (m, 2H), 1.63 (m, 2H), 1.91 (m, 2H),
2.29 (t, 2H), 2.88 (m, 6H), 3.52 (t, 2H), 3.81 (m, 4H), 4.34 (t, 1H), 4.78 (d,
1 H), 6.60 (d, 1 H), 7.42 (m, 6H), 7.66 (d, 1 H), 7.74 (m, 1 H), 8.12 (m, 1
H),
8.24 (s, 1H); MS (LC, 70 eV) m/z 533 (M+1).
(17-3):(E)-N1-(6-(2-morpholinoethylamino)pyridin-3-yl)-N8-hydroxy-2-
((naphthalen-1-yloxy)methyl)octenediamide
The procedure of Example (1-3) was repeated except for using the
compound obtained in Example (17-2) as the starting material, to obtain 171
mg of the title compound (yield: 48%).
'H NMR (300 MHz, DMSO-d6) 8 1.39 (m, 2H), 1.54 (m, 2H), 1.78 (m, 2H),
1.96 (t, 2H), 3.35 (m, 6H), 3.69 (m, 2H), 3.85 (m, 4H), 4.38 (t,1H), 4.52 (d,
1 H), 6.87 (d, 1 H), 7.45 (m, 6H), 7.82 (m, 2H), 8.03 (m, 1 H), 8.3 8(s, 1 H),
10.07 (s, 1H), 10.39 (s, 1H); MS (LC, 70 eV) m/z 548 (M+l ).
Example 18: (E)-N1-(6-(dimethylamino)pyridin-3-yl)-N8-hydroxy-2-
((naphthalen-1-yloxy)methyl)octenediamide
(18-1):(E)-7-(6-(dimethylamino)pyridin-3-ylcarbamoyl)-8-(naphthalen-l-
yloxy)-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using not
dimethylaminehydrochloride but 6-(dimethylamino)pyridin-3-ylamine as the
amine to obtain 256 mg of the title compound (yield: 63%).
'H NMR (300 MHz, CDC13) S 1.64 (m, 4H), 2.36 (m, 4H), 3.07 (s, 6H), 3.68
(s, 3H), 5.06 (s, 2H), 6.52 (d, 1H), 6.98 (m, 2H), 7.44 (t, 1H), 7.53 (m, 3H),
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7.87 (m, 2H), 8.11 (d, 1H), 8.27 (m, 1H); MS (LC, 70 eV) m/z 462 (M+1).
(18-2):(E)-7-(6-(dimethylamino)pyridin-3-ylcarbamoyl)-8-(naphthalen-1-
yloxy)-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (18-1) as the starting material, to obtain 190
mg of the title compound (yield: 76%).
'H NMR (300 MHz, MeOH-d4) 8 1.61 (m, 4H), 2.28 (t, 2H), 2.44 (q, 2H),
3.08 (s, 6H), 5.12 (s, 2H), 6.71 (m, 2H), 7.05 (d, 1H), 7.44 (m, 4H), 7.79 (m,
2H), 8.23 (m, 2H); MS (LC, 70 eV) m/z 448 (M+1).
(18-3):(E)-Nl-(6-(dimethylamino)pyridin-3-yl)-N8-hydroxy-2-
((naphthalen-1-yloxy)methyl)octenediamide
The procedure of Example (1-3) was repeated except for using the
compound obtained in Example (18-2) as the starting material, to obtain 90
mg of the title compound (yield: 46%).
'H NMR (300 MHz, MeOH-d4) S 1.66 (m, 4H), 2.11 (t, 2H), 2.43 (q, 2H),
3.06 (s, 6H), 5.10 (s, 2H), 6.68 (m, 2H), 7.07 (d, 1H), 7.44 (m, 4H), 7.78 (m,
2H), 8.20 (m, 2H); MS (LC, 70 eV) m/z 463 (M+1).
Example 19: (E)-N1-(6-(2-(dimethylamino)ethylamino)pyridin-3-yl)-N8-
hydroxy-2-((naphthalen-1-yloxy)methyl)octenediamide
(19-1):(E)-8-(6-(2-(dimethylamino)ethylamino)pyridin-3-ylamino)-7-
((naphthalen-1-yloxy)methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 6-(2-
(dimethylamino)ethylamino)pyridin-3-ylamine instead of
dimethylaminehydrochloride as the amine to obtain 307 mg of the title
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compound (yield: 31 %).
'H NMR (300 MHz, CDC13) 8 1.65 (m, 4H), 2.08 (m, 2H), 2.31 (s, 6H), 2.38
(m, 2H), 2.59 (t, 2H), 3.35 (q, 2H), 3.67 (s, 3H), 5.06 (s, 2H), 6.44 (d, 1H),
7.03 (m, 2H), 7.45 (t, 1 H), 7.53 (m, 3H), 7.75 (dd, IH), 7.85 (dd, 1H), 8.06
(d,
1H), 8.24 (m, 2H); MS (LC, 70 eV) m/z 505 (M+1).
(19-2):(E)-8-(6-(2-(dimethylamino)ethylamino)pyridin-3-ylamino)-7-
((naphthalen-1-yloxy)methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (19-1) as the starting material, to obtain 226
mg of the title compound (yield: 75%).
'H NMR (300 MHz, MeOH-d4) S 1.64 (m, 4H), 2.27 (t, 2H), 2.47 (m, 2H),
2.91 (s, 6H), 3.28 (q, 2H), 3.65 (t, 2H), 5.11 (s, 2H), 6.66 (d, 1 H), 6.72
(t, 1 H),
7.08 (d, 1 H), 7.44 (m, 4H), 7.67 (dd, 1 H), 7.78 (dd, 1 H), 8.15 (dd, 1 H),
8.29
(m, 1H); MS (LC, 70 eV) m/z 491 (M+1).
(19-3):(E)-N1-(6-(2-(dimethylamino)ethylamino)pyridin-3-yl)-N8-
hydroxy-2-((naphthalen-1-yloxy)methyl)octenediamide
The procedure of Example (1-3) was repeated except for using the
compound obtained in Example (19-2) as the starting material, to obtain 11
mg of the title compound (yield: 5%).
'H NMR (300 MHz, MeOH-d4) 8 1.64 (m, 4H), 2.11 (t, 2H), 2.50 (s, 6H),
2.52 (m, 2H), 2.83 (t, 2H), 4.11 (t, 2H), 5.13 (s, 2H), 6.78 (m, 1H), 7.06 (d,
1 H), 7.45 (m, 4H), 7.5 8(dd, 1 H), 7.78 (dd, 1 H), 8.06 (dd, 1 H), 8.13 (d, 1
H),
8.74 (d, 1 H); MS (LC, 70 eV) m/z 506 (M+1).
Example 20: (E)-N8-hydroxy-N1-(6-methoxypyridin-3-yl)-2-
((naphthalen-1-yloxy)methyl)octenediamide
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(20-1):7-(6-methoxy-pyridin-3-ylcarbamoyl)-8-(naphthalen-1-ylamino)-6-
octene acid methylester
The procedure of Example (1-1) was repeated except for using (6-
methoxypyridin-3-yl)amine instead of dimethylaminehydrochloride as the
amine to obtain 1.67 mg of the title compound (yield: 42%).
1H NMR (300 MHz, CDC13) S 1.54-1.73 (m, 4H), 2.29-2.37 (m, 4H), 3.63 (S,
3H), 3.85 (S, 3H), 6.65 (m, 1H), 6.82-6.98 (m, 2H), 7.39-7.52 (m, 4H),
7.81-7.91 (m, 3H), 8.10 (m, 1H), 9.29 (S, 1H).
(20-2):7-(6-methoxy-pyridin-3-ylcarbamoyl)-8-(naphthalen-1-ylamino)-6-
octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (20-1) as the starting material, to obtain 670
mg of the title compound (yield: 40%).
(20-3):(E)-N8-hydroxy-N1-(6-methoxypyridin-3-yl)-2-((naphthalen-l-
yloxy)methyl)octenediamide
The procedure of Example (1-3) was repeated except for using the
compound obtained in Example (20-2) as the starting material, to obtain 482
mg of the title compound (yield: 69%).
1H NMR (300 MHz, MeOH-d4) S 1.45-1.59 (m, 4H), 1.97 (m, 2H), 2.40 (m,
2H), 3.80 (S, 3H), 4.17 (S, 2H), 6.15 (S, 1H), 6.55 (m, 2H), 6.78 (d, J = 9.0
Hz, 1 H), 7.13 (d, J = 7.7 Hz, 1 H), 7.24-7.41 (m, 3 H), 7.74 (d, J = 8.8 Hz,
1 H),
7.91 (m, 1H), 8.10 (S, 1H), 8.38 (S, 1H), 9.84 (S, 1H), 10.37 (S, 1H).
Example 21: (E)-N1-(3-(1H-imidazol-1-yl)propyl)-N8-hydroxy-2-
((naphthalen-1-yl)methyl)octenediamide
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(21-1):(E)-8-(3-(1H-imidazol-1-yl)propylamino)-7-((naphthalen-l-
yl)methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 3-(1 H-
imidazol-1-yl)propylamine instead of dimethylaminehydrochloride as the
amine to obtain 449 mg of the title compound (yield: 77%).
'H NMR (300 MHz, CDC13) 6 1.53-1.84 (m, 4H), 2.05 (m, 2H), 2.39 (m, 4H),
3.42 (q, J = 6.3Hz, 2H), 3.72 (s, 3H), 3.98 (t, J=7.OHz, 2H), 5.02 (s, 2H),
6.72
(t, J = 6.0 Hz, 1H), 6.88-7.07 (m, 4H), 7.36-7.65(m, 4H), 7.90(d, J = 6.7 Hz,
1 H), 8.22 (d, J = 7.3 Hz, 1 H).
LC/MS (M+H): 450.23.
(21-2):(E)-8-(3-(1H-imidazol-1-yl)propylamino)-7-((naphthalen-l-
yl)methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (21-1) as the starting material, to obtain 350
mg of the title compound (yield: 85%).
(21-3):(E)-N1-(3-(1H-imidazol-l-yl)propyl)-2-((naphthalen-l-yl)methyl)-
N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (21-2) as the starting material, to obtain 220
mg of the title compound (yield: 63%).
'H NMR (200 MHz, CDC13) 6 1.40-1.75 (m, 11H), 1.81 (t, J= 6.4 Hz, 2H),
1.96 (m, 2H), 2.15 (m, 2H), 3.19 (q, J = 6.1 Hz, 2H), 3.38 (d, J = 11.8 Hz,
1 H), 3.76 (t, J = 6.9 Hz, 3H), 4.74 (s, 2H), 6.46 (m, 1 H), 6.67 (m, 2H),
6.83
(m, 2H) 7.32 (m, 5H), 7.65 (d, J = 6.5 Hz, 1H), 7.96 (d, J= 7.7 Hz, 1H),
9.33 (br, 1H).
LC/MS (M+H): 535.28.
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(21-4):(E)-N1-(3-(1H-imidazol-1-yl)propyl)-N8-hydroxy-2-((naphthalen-
1-yloxy)methyl)octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (21-3) as the starting material, to obtain 63
mg of the title compound (yield: 37%).
HPLC purification: 46mg (purity : 97%)
'H NMR (300 MHz, MeOH-d4) S 1.52 (m, 2H), 1.68 (m, 2H), 2.03 (t, J
6.6Hz, 2H), 2.11 (t, J = 6.6 Hz, 2H), 2.3 5(q, J = 7.2Hz, 2H), 5.04 (s, 2H),
6.57 (t, J = 6.3 Hz, 2H), 7.01 (d, J = 7.2 Hz, 1 H), 7.18 (s, 1 H), 7.26 (s, 1
H),
7.43 (m, 4H), 7.78 (d, J = 7.8Hz, 1 H), 8.09 (s, 1 H), 8.13 (d, J =5.1 Hz, 1
H).
LC/MS (M+H): 451.23.
Example 22: (E)-N8-hydroxy-N1-(4-hydroxyphenetyl)-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide
(22-1):(E)-8-(4-hydroxyphenetylamino)-7-((naphthalen-1-yloxy)methyl)-
2 0 8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 4-
hydroxyphenetylamine instead of dimethylaminehydrochloride as the amine
to obtain 461 mg of the title compound (yield: 95%).
'H NMR (300 MHz, CDC13) S 1.50-1.80 (m, 4H), 2.38 (m, 4H), 2.82 (t, J
6.9Hz, 2H), 3.63 (m, 2H), 3.72 (s, 3H), 4.92 (s, 2H), 6.44 (br, 1H), 6.53-6.59
(t, J 5.4 Hz, 1H), 6.66 (d, J 8.4 Hz, 2H), 6.95 (m, 4H), 7.37 (m, 4H), 7.90
(d, J 9.1 Hz, 1 H), 8.12 (d, J 9.7 Hz, 1 H).
LC/MS (M+H): 412.20.
(22-2):(E)-8-(4-hydroxyphenetylamino)-7-((naphthalen-1-yloxy)methyl)-
8-oxo-6-octene acid
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The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (22-1) as the starting material, to obtain 439
mg of the title compound (yield: 92%).
'H NMR (300 MHz, MeOH-d4) 8 1.52 (m, 2H, CH2), 1.64 (m, 2H, CH2), 2.20
(m, 2H, CH2), 2.27 (s, 6H, N(CH3)2), 2.38 (m, 2H, CH2), 2.55 (m, 2H, CH2),
3.42 (m, 2H, CH2), 4.97 (s, 2H, CH2), 6.67 (s, 1 H, CH), 6.99 (t, 1 H, J= 7.0,
1.8 Hz, ArH), 7.41 (m, 4H, ArH), 7.77 (d, 1 H, J= 7.0, 1.8 Hz, ArH), 8.14 (d,
1 H, J = 7.2 Hz, ArH).
(22-3):(E)-N1-(4-hydroxyphenetyl)-2-((naphthalen-1-yloxy)methyl)-N8-
(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (22-2) as the starting material, to obtain 394
mg of the title compound (yield: 75%).
'H NMR (200 MHz, CDC13) S 1.42-1.85 (m, 12H), 2.04 (m, 2H), 2.22 (m,
2H), 2.71 (t, J = 6.4 Hz, 2H), 3.50 (m, 3H), 3.92 (m, 1H), 4.79 (s, 2H), 4.92
(m, 1 H), 6.3 8(t, J = 5.4 Hz, 1 H), 6.67 (m, 3H), 6.86 (m, 3H) 7.18 (br, 1
H),
7.44 (m, 4H), 7.77 (m, 1 H), 8.00 (m, 1 H), 8.93 (br, 1 H).
LC/MS (M+H): 497.26.
(22-4):(E)-N8-hydroxy-N1-(4-hydroxyphenetyl)-2-((naphthalen-1-yloxy)
methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (22-3) as the starting material, to obtain 121
mg of the title compound (yield: 78%).
HPLC purification: 61mg (purity: 95%)
'H NMR (200 MHz, MeOH-d4) S 1.48-1.72 (m, 4H), 2.08 (t, J = 7.2Hz, 2H),
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2.34 (q, J = 6.8 Hz, 2H), 2.73 (t, J = 7.2Hz, 2H), 3.45 (t, 7.0 Hz, 2H), 4.98
(s,
2H), 6.53 (t, J = 7.4 Hz, 1H), 6.63 (d, J = 7.8 Hz, 211), 6.97 (d, J = 8. 2Hz,
3H), 7.43 (m, 4H), 7.78 (d, J = 7.0 Hz, 1H), 8.10 (d, J = 9.2 Hz, 1H).
LC/MS (M+H): 413.20.
Example 23: (E)-N1-(3-(dimethylamino)-2,2-dimethylpropyl)-N8-
hydroxy-2-((naphthalen-1-yloxy)methyl)octenediamide
(23-1):(E)-8-(3-(dimethylamino)-2,2-dimethylpropylamino)-7-
((naphthalen-1-yloxy)methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 3-
(dimethylamino)-2,2-dimethylpropylamine instead of
dimethylaminehydrochloride as the amine to obtain 454 mg of the title
compound (yield: 75%).
'H NMR (200 MHz, CDC13) S 0.87 (s, 6H), 1.45-1.73 (m, 4H), 1.85 (s, 6H),
2.11 (s, 2H), 2.27 (m, 2H), 3.25 (d, J = 4.4 Hz, 2H), 3.60 (s, 3H), 4.87 (s,
2H),
6.92 (m, 2H), 7.42 (m, 4H), 7.72 (d, J = 7.4 Hz, 1 H), 8.19 (d, J = 9.0 Hz, 1
H).
LC/MS (M+H): 405.27.
(23-2):(E)-8-(3-(dimethylamino)-2,2-dimethylpropylamino)-7-
((naphthalen-1-yloxy)methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (23-1) as the starting material, to obtain 339
mg of the title compound (yield: 93%).
'H NMR (200 MHz, MeOH-d4) S 1.6 (m, 4H, CH2CH2), 2.4 (m, 6H,
CH2CH2CH2), 2.50 (m, 414, CH2CH2), 2.80 (m, 2H, CH2), 3.01 (s, 3H, NCH3),
3.29 (m, IH, CH), 3.65 (m, 1 H, CH), 4.95 (s, 2H, PhCH2), 6.00 (m, 1 H, CH),
7.00 (t, 1 H, J= 16.6, 9.4 Hz, ArH), 7.46 (m, 4H, ArH), 7.82 (m, 1 H, ArH),
8.18 (m, 1 H, ArH).
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(23-3):(E)-N1-(3-(dimethylamino)-2,2-dimethylpropyl)-2-((naphthalen-l-
yloxy)methyl)-N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (23-2) as the starting material, to obtain 304
mg of the title compound (yield: 52%).
'H NMR (200 MHz, CDC13) 6 0.88 (s, 6H), 1.49-1.82 (m, 10H), 1.86 (s, 6H),
2.02 (m, 2H), 2.13 (s, 2H), 2.31 (q, J = 7.4 Hz, 2H), 3.27 (d, J = 4.6 Hz,
2H),
3.58 (m, 1H), 3.93 (m, 1H), 4.88 (s, 2H), 4.90 (m, 1H), 6.95 (t, J= 7.4 Hz,
2H), 7.45 (m, 4H), 7.78 (d, J= 6.0 Hz, 1H), 8.21 (d, J = 7.0 Hz, 1H), 8.48
(br,
1 H), 8.62 (br, 1 H).
LC/MS (M+H): 490.32.
(23-4):(E)-N1-(3-(dimethylamino)-2,2-dimethylpropyl)-N8-hydroxy-2-
((naphthalen-1-yloxy)methyl)octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (23-3) as the starting material, to obtain 144
mg of the title compound (yield: 74%).
HPLC purification: 101 mg (purity: 92%)
'H NMR (200 MHz, MeOH-d4) S 0.98(s, 6H), 1.54 (m, 2H), 1.6 6(m, 2H),
2.12 (t, J= 7.4 Hz, 2H), 2.40 (s, 6H), 2.46 (m, 4H), 3.26 (s, 2H), 5.04 (s,
2H),
6.71 (t, J = 8.2 Hz, 1 H), 7.04 (m, 1 H), 7.45 (m, 4H), 7.80 (d, J = 7.8 Hz, 1
H),
8.13 (d, J = 8.6 Hz, 1H.
LC/MS (M+H): 406.26.
Example 24: (E)-Nl-(2-(diisopropylamino)ethyl)-N8-hydroxy-2-
((naphthalen-1-yloxy)methyl)octenediamide
(24-1):(E)-8-(2-(diisopropylamino)ethylamino)-8-oxo-7-((naphthalen-l-
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yloxy)methyl)-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 2-
(diisopropylamino)ethylamine instead of dimethylaminehydrochloride as the
amine to obtain 420 mg of the title compound (yield: 89%).
'H NMR (200 MHz, CDC13) 8 0.87 (d, J = 7.0 Hz, 12H), 1.51 (m, 2H), 1.64
(m, 2H), 2.26 (m, 4H), 2.57 (t, J = 6.0 Hz, 2H), 2.86 (m, 2H), 3.31 (q, J =
5.6
Hz, 2H), 3.61 (s, 3H), 4.90 (s, 1H), 6.90 (m, 3H), 7.44 (m, 4H), 7.77 (d, J
7.2 Hz, 1 H), 8.17 (d, J= 7.0 Hz, 1 H).
LC/MS (M+H): 419.28.
(24-2):(E)-8-(2-(diisopropylamino)ethylamino)-8-oxo-7-((naphthalen-l-
yloxy)methyl)-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (24-1) as the starting material, to obtain 420
mg of the title compound (yield: 78%).
(24-3):(E)-N1-(2-(diisopropylamino)ethyl)-2-((naphthalen-l-
yloxy)methyl)-N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (24-2) as the starting material, to obtain 319
mg of the title compound (yield: 50%).
'H NMR (200 MHz, CDC13) 8 0.95 (br, 9H), 1.50-1.95 (m, lOH), 2.10 (m,
2H), 2.31 (q, J = 6.8 Hz, 2H), 2.67 (m, 2H), 2.96 (s, 2H), 3.46 (m, 2H), 3.57
(m, 2H), 3.97 (m, 1 H), 4.93 (s, 2H), 4.94 (m, 1 H), 6.87 (m, 3H), 7.49 (m,
4H),
7.78 (d, J= 6.8 Hz, 1H), 8.15 (d, J= 8.6 Hz, 1H).
LC/MS (M+H): 504.34.
(24-4):(E)-N1-(2-(diisopropylamino)ethyl)-N8-hydroxy-2-((naphthalen-l-
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yloxy)methyl)octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (24-3) as the starting material, to obtain 145
mg of the title compound (yield: 85%).
HPLC purification: 59 mg (purity: 92%)
'H NMR (200 MHz, MeOH-d4) S 1.32 (t, J = 6.2 Hz, 9H), 1.46-1.78 (m, 4H),
2.10 (t, J 7.0 Hz, 2H), 2.41 (q, J 6.8 Hz, 2H), 3.23 (t, J 6.2 Hz, 2H),
3.63 (t, J 7.0 Hz, 1 H), 3.74 (m, 2H), 5.05 (s, 2H), 6.76 (t, J 6.6 Hz, 1 H),
7.02 (d, J 7.0 Hz, 1 H), 7.45 (m, 4H), 7.80 (d, J = 7.6 Hz, 1 H), 8.12 (d, J
7.8 Hz, 1 H).
LC/MS (M+H): 420.28.
Example 25: (E)-N8-hydroxy-N1-(1-methoxypropan-2-yl)-2-
((naphthalen-1-yloxy)methyl)-2-octenediamide
(25-1):(E)-8-(1-methoxypropan-2-ylamino)-7-((naphthalen-l-
yloxy)methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 1-
methoxypropan-2-ylamine instead of dimethylaminehydrochloride as the
amine to obtain 413 mg of the title compound (yield: 83%).
'H NMR (200 MHz, CDC13) 8 1.15 (d, J = 6.8 Hz, 3H), 1.50 (m, 2H), 1.63 (m,
2H), 2.29 (m, 4H), 3.15 (s, 3H), 3.31 (d, J = 4.0 Hz, 2H), 3.62 (s, 3H), 4.24
(m, 1 H), 4.93 (s, 2H), 6.64 (d, J = 7.8 Hz, 1 H), 6.84 (t, J= 7.8 Hz, 1 H),
6.91
(d, J = 7.2 Hz, 1 H), 7.46 (m, 4H), 7.83 (m, 1H), 8.19 (m, 1 H).
LC/MS (M+H): 414.22.
(25-2):(E)-8-(1-methoxypropan-2-ylamino)-7-((naphthalen-1-yloxy)
methyl)-8-oxo-6-octene acid
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The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (25-1) as the starting material, to obtain 346
mg of the title compound (yield: 81 %).
(25-3):(E)-N1-(1-methoxypropan-2-yl)-2-((naphthalen-1-yloxy)methyl)-
N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (25-2) as the starting material, to obtain 289
mg of the title compound (yield: 75%).
'H NMR (200 MHz, CDC13) S 1.17 (d, J = 6.8 Hz, 3H), 1.41-1.89 (m, lOH),
2.09 (m, 2H), 2.31 (q, J = 7.0 Hz, 2H), 3.17 (s, 3H), 3.57 (m, 1H), 3.93 (m,
1 H), 4.24 (m, 1 H), 4.93 (m, 1 H), 6.69 (d, J = 7.8 Hz, 1 H), 6.84 (t, J =
6.6 Hz,
1 H), 6.91 (d, J = 7.8 Hz, 1 H), 7.41 (m, 4H), 7.8 0(d, J = 7.8 Hz, 1 H), 8.19
(d,
J= 7.8 Hz, 1 H).
LC/MS (M+H): 499.27.
(25-4):(E)-N8-hydroxy-N1-(1-methoxypropan-2-yl)-2-((naphthalen-l-
2 0 yloxy)methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (25-3) as the starting material, to obtain 125
mg of the title compound (yield: 88%).
HPLC purification: 63mg (purity: 97%)
'H NMR (200 MHz, DMSO-d4) 6 1.07 (d, J = 7.0 Hz, 3H), 1.45 (m, 2H), 1.51
(m, 2H), 1.96 (t, J = 7.0 Hz, 2H), 2.29 (m, 2H), 3.24 (s, 3H), 3.36 (s, 2H),
4.09 (m, 1 H), 4.96 (s, 2H), 6.51 (t, J = 7.8 Hz, 1 H), 7.07 (d, J = 6.8 Hz,
1H),
7.47 (m, 4H), 7.86 (m, 2H), 8.06 (d, J = 9.0 Hz, 1H), 8.70 (br, 4H), 10.35
(br,
1 H).
LC/MS (M+H): 415.22.
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Example 26: (E)-N8-hydroxy-N1-(4-methoxybenzyl)-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide
(26-1):(E)-8-(4-methoxybenzylamino)-7-((naphthalen-1-yloxy)methyl)-8-
oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 4-
methoxybenzylamine instead of dimethylaminehydrochloride as the amine to
obtain 461 mg of the title compound (yield: 98%).
'H NMR (200 MHz, CDC13) S 1.49 (m, 2H), 1.59 (m, 2H), 2.29 (m, 4H), 3.62
(s, 3H), 3.77 (s, 3H), 4.44 (d, J = 5.8 Hz, 2H), 4.94 (s, 2H), 6.75 (m, 3H),
6.88
(d, J= 7.4 Hz, 2H), 7.15 (d, J= 8.6 Hz, 2H), 7.44 (m, 4H), 7.78 (d, J= 7.4 Hz,
1 H), 7.99 (d, J = 7.4 Hz, 1 H).
LC/MS (M+H): 462.22.
(26-2):(E)-8-(4-methoxybenzylamino)-7-((naphthalen-1-yloxy)methyl)-8-
oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (26-1) as the starting material, to obtain 454
mg of the title compound (yield: 86%).
(26-3):(E)-N1-(4-methoxybenzyl)-2-((naphthalen-1-yloxy)methyl)-N8-
2 5 (tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (26-2) as the starting material, to obtain 378
mg of the title compound (yield: 85%).
'H NMR (200 MHz, CDC13) S 1.52-1.95 (m, 10H), 2.07 (m, 2H), 2.29 (q, J
7.2 Hz, 2H), 3.75 (s, 3H), 3.91 (m, 1H), 4.43 (d, J = 5.8 Hz, 2H), 4.90 (m,
1H), 4.92 (s, 2H), 6.79 (m, 3H), 6.87 (d, J= 7.6 Hz, 2H), 7.14 (d, J = 8.4 Hz,
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2H), 7.47 (m, 4H), 7.77 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 8.65
(br,
1H).
LC/MS (M+H): 547.27.
(26-4):(E)-N8-hydroxy-N1-(4-methoxybenzyl)-2-((naphthalen-1-yloxy)
methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (26-3) as the starting material, to obtain 142
mg of the title compound (yield: 80%).
HPLC purification: 81mg (purity: 92%)
'H NMR (200 MHz, MeOH-d4) 8 1.52 (m, 2H), 1.58 (m, 2H), 2.08 (t, J = 7.4
Hz, 2H), 2.34 (q, J = 7.6 Hz, 2H), 3.37 (s, 3H), 3.74 (s, 1H), 5.03 (s, 2H),
6.59 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 6.6 Hz, 1H),
7.16 (d, J = 8.4 Hz, 2H), 7.42 (m, 4H), 7.77 (d, J = 7.8 Hz, 1H),8.06(d,J=
7.4 Hz, 1 H).
LC/MS (M+H): 463.22.
Example 27: (E)-N1-(4-fluorophenetyl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide
(27-1):(E)-8-(4-fluorophenetylamino)-7-((naphthalen-1-yloxy)methyl)-8-
oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 4-
fluorophenetylamine instead of dimethylaminehydrochloride as the amine to
obtain 463 mg of the title compound (yield: 93%).
'H NMR (200 MHz, CDC13) S 1.52 (m, 2H), 1.62 (m, 2H), 2.28 (m, 4H), 2.76
(t, J= 6.8 Hz, 2H), 3.54 (q, J = 5.6 Hz, 2H), 3.61 (s, 3H), 4.82 (s, 2H), 6.66
(br, 1H), 6.70 (m, 2H), 6.86 (m, 2H), 6.96 (m, 2H), 7.48 (m, 4H), 7.80 (d, J
7.4 Hz, 1H), 7.99 (d, J = 7.0 Hz, 1 H).
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LC/MS (M+H): 464.21.
(27-2):(E)-8-(4-fluorophenetylamino)-7-((naphthalen-1-yloxy)methyl)-8-
oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (27-1) as the starting material, to obtain 434
mg of the title compound (yield: 86%).
(27-3):(E)-N1-(4-fluorophenetylamino)-2-((naphthalen-1-yloxy)methyl)-
N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (27-2) as the starting material, to obtain 362
mg of the title compound (yield: 651 %).
'H NMR (200 MHz, CDC13) 6 1.48-1.89 (m, 10H), 2.16 (m, 2H), 2.28 (q, J
7.2 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H), 3.53 (q, J= 5.8 Hz, 2H), 3.60 (m, 1H),
3.91 (m, 1 H), 4.81 (s, 2H), 4.90 (m, 1 H), 6.49 (m, 1 H), 6.70 (m, 2H), 6.85
(m,
2H), 6.96 (m, 2H), 7.42 (m, 4H), 7.81 (d, J = 7.4 Hz, 1 H), 7.98 (d, J = 7.6
Hz,
1 H), 8.56 (br, 1 H).
LC/MS (M+H): 549.27.
(27-4):(E)-N1-(4-fluorophenetyl)-N8-hydroxy-2-((naphthalen-1-yloxy)
methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (27-3) as the starting material, to obtain 83
mg of the title compound (yield: 76%).
HPLC purification: 36mg (purity: 92%)
'H NMR (200 MHz, MeOH-d4) S 1.49 (m, 2H), 1.69 (m, 2H), 2.09 (t, J = 6.8
Hz, 2H), 2.34 (q, J = 7.2 Hz, 2H), 2.80 (t, J = 6.8 Hz, 2H), 3.48 (m, 2H),
4.97
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(s, 2H), 6.55 (t, J = 7.8 Hz, 1H), 6.86 (m, 2H), 6.97 (d, J 7.6 Hz, 1H), 7.14
(m, 2H), 7.45 (m, 4H), 7.79 (d, J= 7.8 Hz, 1 H), 8.10 (d, J 8.0 Hz, 1 H).
LC/MS (M+H): 465.21.
Example 28: (E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-
(tetrahydropyran-2-yl)methyl)-2-octenediamide
(28-1):(E)-7-(((naphthalen-1-yloxy)methyl)-8-oxo-8-((tetrahydropyran-2-
yl)methylamino)-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using
tetrahydropyran-2-yl)methylamine instead of dimethylaminehydrochloride as
the amine to obtain 426 mg of the title compound (yield: 87%).
'H NMR (200 MHz, CDC13) S 1.45-1.99 (m, 8H), 2.28 (m, 4H), 3.26 (m, 1H),
3.78 (m, 3H), 3.61 (s, 3H), 3.97 (m, 1H), 4.93 (s, 2H), 6.79 (m, 1H), 6.90 (m,
2H), 7.47 (m, 4H), 7.78 (m, 1H), 8.20 (m, 1H).
LC/MS (M+H): 426.22.
(28-2):(E)-7-(((naphthalen-1-yloxy)methyl)-8-oxo-8-((tetrahydropyran-2-
yl)methylamino)-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (28-1) as the starting material, to obtain 370
mg of the title compound (yield: 90%).
(28-3):(E)-2-((naphthalen-1-yloxy)methyl)-N8-(tetrahydro-2H-pyran-2-
yloxy)-N1-(tetrahydropyran-2-yl)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (28-2) as the starting material, to obtain 323
mg of the title compound (yield: 65%).
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'H NMR (200 MHz, CDC13) 8 1.42-1.95 (m, 14H), 2.08 (m, 2H), 2.25 (q, J
7.6 Hz, 2H), 3.28 (m, 1H), 3.59 (m, 3H), 3.89 (m, 2H), 4.88 (s, 2H), 4.90 (m,
1 H), 6.77 (m, 2H), 6.85 (d, J = 7.2 Hz, 1 H), 7.40 (m, 4H), 7.77 (m, 1 H),
8.14
(m, 1H), 8.68 (br, 1H).
LC/MS (M+H): 511.27.
(28-4):(E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-Nl-
(tetrahydropyran-2-y1)methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (28-3) as the starting material, to obtain 85
mg of the title compound (yield: 85%).
HPLC purification: 32mg (purity: 95%)
'H NMR (200 MHz, MeOH-d4) 8 1.60 (m, 6H), 1.81 (m, 2H), 2.09 (t, J = 7.2
Hz, 2H), 2.37 (q, J = 7.4 Hz, 2H), 3.35 (m, 2H), 3.68 (m, 2H), 4.00 (m, 1H),
5.02 (s, 2H), 6.65 (t, J = 7.8 Hz, 1 H), 7.01 (d, J = 6.8 Hz, 1 H), 7.44 (m,
4H),
7.78 (d, J = 8.6 Hz, 1 H), 8.15 (d, J = 9.4 Hz, 1 H).
LC/MS (M+H): 427.22.
Example 29: (E)-N1-(2-cyclohexenylethyl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide
(29-1):(E)-8-(2-cyclohexenylethylamino)-7-((naphthalen-l-yloxy)methyl)-
8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 2-
cyclohexenylethylamine instead of dimethylaminehydrochloride as the amine
to obtain 449 mg of the title compound (yield: 89%).
1H NMR (200 MHz, CDC13) S 1.25 (m, 2H), 1.30-1.71 (m, 8H), 1.79 (m, 2H),
2.09 (t, J = 7.4 Hz, 2H), 2.28 (m, 4H), 3.39 (q, J = 5.4 Hz, 2H), 3.60 (s,
3H),
4.86 (s, 2H), 5.28 (br, 1 H), 6.41 (br, 1 H), 6.89 (t, J= 7.6 Hz, 2H), 7.46
(m,
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4H), 7.79 (m, 1 H), 8.14 (m, 1 H).
LC/MS (M+H): 450.26.
(29-2):(E)-8-(2-cyclohexenylethylamino)-7-((naphthalen-1-yloxy)methyl)-
8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (29-1) as the starting material, to obtain 401
mg of the title compound (yield: 95%).
(29-3):(E)-N1-(2-cyclohexenylethyl)-2-((naphthalen-1-yloxy)methyl)-N8-
(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-43) was repeated except for using the
compound obtained in Example (29-2) as the starting material, to obtain 370
mg of the title compound (yield: 82%).
'H NMR (200 MHz, CDC13) 8 1.27 (m, 2H), 1.35-2.02 (m, 16H), 2.10 (m,
4H), 2.30 (q, J = 6.8 Hz, 2H), 3.40 (q, J = 5.8 Hz, 2H), 3.63 (m, 1H), 3.96
(m,
1 H), 4.87 (s, 2H), 4.92 (m, 1 H), 5.18 (br, 1 H), 6.44 (br, 1 H), 6.90 (t, J
= 7.6
Hz, 2H), 7.44 (m, 4H), 7.80 (m, 1 H), 8.15 (m, 1 H), 8.80 (br, 1 H).
LC/MS (M+H): 535.31.
(29-4):(E)-N1-(2-cyclohexenylethyl)-N8-hydroxy-2-((naphthalen-1-yloxy)
methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (29-3) as the starting material, to obtain 112
mg of the title compound (yield: 91 %).
HPLC purification: 62 mg (purity: 92%)
'H NMR (200 MHz, MeOH-d4) 6 1.36-1.82 (m, lOH), 1.91 (m, 2H), 2.09 (m,
4H), 2.36 (q, J = 7.4 Hz, 2H), 3.34 (m, 2H), 4.99 (s, 2H), 5.34 (br, 1H), 6.63
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(t, J= 7.8 Hz, 1H), 7.01 (d, J = 6.8 Hz, 1H), 7.45 (m, 4H), 7.79 (d, J = 9.4
Hz,
1 H), 8.13 (d, J = 9.0 Hz, 1 H).
LC/MS (M+H): 451.25.
Example 30: (E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(3-(2-
oxopyrrolidin-1-yl)propyl)-2-octenediamide
(30-1):(E)-7-((naphthalen-1-yloxy)methyl)-8-oxo-8-(3-(2-oxopyrrolidin-l-
yl)propylamino)-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 3-(2-
oxopyrrolidin-1-yl)propylamine instead of dimethylaminehydrochloride as
the amine to obtain 466 mg of the title compound (yield: 79%).
'H NMR (200 MHz, CDC13) S 1.44 (m, 2H), 1.63 (m, 4H), 1.95 (m, 2H), 2.26
(m; 6H), 3.21 (m, 6H), 3.56 (s, 3H), 4.93 (s, 2H), 6.72 (t, J = 7.6 Hz, 1H),
6.88 (d, J = 7.6 Hz, 1H), 7.23 (m, 1H), 7.39 (m, 1H), 7.74 (m,. 1H), 8.12 (m,
1 H).
LC/MS (M+H): 467.25.
(30-2):(E)-7-((naphthalen-1-yloxy)methyl)-8-oxo-8-(3-(2-oxopyrrolidin-l-
yl)propylamino)-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (30-1) as the starting material, to obtain 370
mg of the title compound (yield: 88%).
(30-3):(E)-2-((naphthalen-1-yloxy)methyl)-N1-(3-(2-oxopyrrolidin-1-yl)
propyl)-N8-(tetrahyd ro-2H-pyran-2-yloxy)-2-octenediam ide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (30-2) as the starting material, to obtain 316
mg of the title compound (yield: 80%).
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'H NMR (200 MHz, CDC13) S 1.42-1.90 (m, 12H), 2.04 (m, 4H), 2.39 (m,
4H), 3.27 (m, 6H), 3.59 (m, 1H), 3.95 (m, 1H), 4.94 (m, 1H), 4.99 (s, 2H),
6.73 (t, J 7.6 Hz, 1 H), 6.91 (d, J = 7.4 Hz, 1 H), 7.25 (br, 4H), 7.45 (m,
4H),
7.78 (d, J 7.8 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 9.25 (br, 1H).
LC/MS (M+H): 552.30.
(30-4):(E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(3-(2-
oxopyrrolidin-l-yl)propyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (30-3) as the starting material, to obtain 166
mg of the title compound (yield: 82%).
HPLC purification: 49 mg (purity: 97%)
'H NMR (200 MHz, MeOH-d4) 8 1.53 (m, 2H), 1.74 (m, 4H), 2.06 (m, 4H),
2.36 (m, 4H), 3.33 (m, 6H), 4.86 (s, 2H), 6.61 (t, J = 7.4 Hz, 1H), 7.00 (d, J
6.8 Hz, 1H), 7.43 (m, 4H), 7.78 (d, J = 7.4 Hz, 1 H), 8.14 (d, J = 7.4 Hz, 1
H).
LC/MS (M+H): 468.24.
Example 31: (E)-N1-(furan-2-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)
methyl)-2-octenediamide
(31-1):(E)-8-(furan-2-ylamino)-7-((naphthalen-1-yloxy)methyl)-8-oxo-6-
octene acid methylester
The procedure of Example (1-1) was repeated except for using furan-
2-ylamine instead of dimethylaminehydrochloride as the amine to obtain 421
mg of the title compound (yield: 83%).
'H NMR (200 MHz, CDC13) 8 1.48 (m, 2H), 1.60 (m, 2H), 2.27 (m, 4H), 3.61
(s, 3H), 4.51 (d, J = 5.4 Hz, 2H), 4.93 (s, 2H), 6.20 (dd, J = 10.6 Hz, 3.2
Hz,
2H), 6.90 (m, 3H), 7.45 (m, 4H), 7.78 (d, J = 7.6 Hz, 1H), 8.07 (d, J= 7.6 Hz,
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1 H).
LC/MS (M+H): 408.17.
(31-2):(E)-8-(furan-2-ylamino)-7-((naphthalen-1-yloxy)methyl)-8-oxo-6-
octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (31-1) as the starting material, to obtain 353
mg of the title compound (yield: 90%).
(31-3):(E)-N1-(furan-2-yl)-2-((naphthalen-1-yloxy)methyl)-N8-
(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
ls compound obtained in Example (31-2) as the starting material, to obtain 306
mg of the title compound (yield: 55%).
'H NMR (200 MHz, CDC13) S 1.55-1.98 (m, l OH), 2.17 (m, 2H), 2.41 (q, J
7.4 Hz, 2H), 3.66 (m, 1 H), 3.97 (m, 1 H), 4.61 (d, J = 5.4 Hz, 2H), 4.8 8(m,
1H), 4.90 (s, 2H), 6.31 (d, J = 11.2 Hz, 2H), 6.96 (m, 3H), 7.52 (m, 4H), 7.89
(d, J = 6.8 Hz, 1H), 7.17 (d, J = 6.6 Hz, 1H), 8.45 (br, 1 H).
LC/MS (M+H): 493.23
(31-4):(E)-Nl-(furan-2-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-
2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (31-3) as the starting material, to obtain 156
mg of the title compound (yield: 79%).
HPLC purification: 68 mg (purity: 92%)
1H NMR (200 MHz, MeOH-d4) 6 1.50 (m, 2H), 1.62 (m, 2H), 2.08 (t, J = 6.8
Hz, 2H), 2.37 (q, J = 7.4 Hz, 2H), 4.47 (s, 2H), 5.03 (s, 2H), 6.24 (dd, J
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14.6 Hz, 3.0 Hz, 2H), 6.62 (t, J = 7.4 Hz, 1 H), 6.99 (d, J = 7.2 Hz, 1 H),
7.43
(m, 4H), 7.78 (d, J = 9.0 Hz, 1 H), 8.08 (d, J= 8.2 Hz, 1 H).
LC/MS (M+H): 409.17.
Example 32: (E)-N1-(4-(dimethylamino)benzyl)-N8-hydroxy-2-
((naphthalen-1-yloxy)methyl)-2-octenediamide
(32-1):(E)-8-(4-(dimethylamino)benzylamino)-7-((naphthalen-1-yloxy)
methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 4-
(dimethylamino)benzylamine instead of dimethylaminehydrochloride as the
amine to obtain 547 mg of the title compound (yield: 72%).
'H NMR (200 MHz, CDC13) 6 1.45-1.75 (m, 4H), 2.31 (m, 4H), 2.93 (s, 6H),
3.64 (s, 3H), 4.44 (d, J = 5.4 Hz, 2H), 4.96 (s, 2H), 6.62 (m, 3H), 6.91 (m,
2H), 7.14 (d, J = 8.4 Hz, 2H), 7.40 (m, 4H), 7.84 (d, J = 7.4 Hz, 1 H), 8.05
(d,
J= 7.8 Hz, 1 H).
LC/MS (M+H): 475.
(32-2): (E)-8-(4-(dimethylamino)benzylamino)-7-((naphthalen-1-yloxy)
methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (32-1) as the starting material, to obtain 397
mg of the title compound (yield: 99%).
(32-3): (E)-N1-(4-dimethylamino)benzyl)-2-((naphthalen-1-yloxy)methyl)-
N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (32-2) as the starting material, to obtain 380
mg of the title compound (yield: 96%).
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'H NMR (200 MHz, CDC13) S 1.50-1.92 (m, lOH), 2.05 (m, 2H), 2.30 (q,
J=7.4Hz, 2H), 2.92 (s, 2H), 2.96 (m, 1 H), 3.57 (m, 1 H), 3.92 (m, 1 H), 4.41
(d,
J = 5.2 Hz, 2H), 4.81 (m, 1H), 4.94 (s, 2H), 6.60 (m, 3H), 6.89 (m, 2H), 7.12
(d, J= 8.4 Hz, 2H), 7.41 (m, 4H), 7.78 (d, J= 8.0 Hz, 1 H), 8.02 (d, J = 8.2
Hz,
1H), 8.37 (br, 1H).
LC/MS (M+H): 560.
(32-4):(E)-N1-(4-(dimethylamino)benzyl)-N8-hydroxy-2-((naphthalen-l-
1o yloxy)methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (32-3) as the starting material, to obtain 305
mg of the title compound (yield: 92%).
HPLC purification: 287 mg (purity: 98%)
'H NMR (300 MHz, MeOH-d4) b 1.44 (m, 2H), 1.59 (m, 2H), 2.00 (t, J = 7.2
Hz, 2H), 2.28 (q, J = 7.2 Hz, 2H), 3.04 (s, 6H), 4.38 (s, 2H), 5.01 (s, 2H),
6.54 (t, J = 7.5 Hz, 1H),6.88(d,J=7.2Hz, 1H),7.17(d,J=8.4Hz,2H),
7.33 (m, 6H), 7.70 (d, J = 8.1 Hz, 1 H), 8.01 (d, J= 8.1 Hz, 1 H).
LC/MS (M+H): 476.25.
Example 33: (E)-N8-hydroxy-N1-(2-methoxyethyl)-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide
(33-1):(E)-8-(2-methoxyethylamino)-7-((naphthalen-1-yloxy)methyl)-8-
oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 2-
3 0 methoxyethylamine instead of dimethylaminehydrochloride as the amine to
obtain 399 mg of the title compound (yield: 85%).
'H NMR (200 MHz, CDC13) b 1.44-1.79 (m, 4H), 2.31 (m, 4H), 3.19 (s, 1H),
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3.49 (m, 4H), 3.64 (s, 3H), 4.95 (s, 2H), 6.92 (m, 3H), 7.48 (m, 4H), 7.81 (m,
1 H), 7.81 (m, l H), 8.20 (m, 1 H).
LC/MS (M+H): 400.20.
(33-2):(E)-8-(2-methoxyethylamino)-7-((naphthalen-1-yloxy)methyl)-8-
oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (33-1) as the starting material, to obtain 339
mg of the title compound (yield: 95%).
(33-3):(E)-N1-(2-methoxyethyl)-2-((naphthalen-1-yloxy)methyl)-N8-
(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (33-2) as the starting material, to obtain 313
mg of the title compound (yield: 70%).
'H NMR (200 MHz, CDC13) 6 1.41-1.97 (m, lOH), 2.07 (m, 2H), 2.30 (q, J
7.4 Hz, 2H), 3.17(s, 3H), 3.46 (m, 5H), 3.92 (m, 1 H), 4.90 (m, 1 H), 4.92 (s,
2H), 6.85 (m, 3H), 7.46 (m, 4H), 7.81 (m, 1H), 8.17 (m, 1H), 8.67 (m, 1H).
LC/MS (M+H): 485.26.
(33-4):(E)-N8-hydroxy-N1-(2-methoxyethyl)-2-((naphthalen-1-yloxy)
methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (33-3) as the starting material, to obtain 87
mg of the title compound (yield: 68%).
HPLC purification: 42 mg (purity: 98%)
'H NMR (300 MHz, MeOH-d4) 6 1.44 (m, 2H), 1.57 (m, 2H), 2.02 (t, J = 7.2
Hz, 2H), 2.30 (q, J = 7.2 Hz, 2H), 3.19 (s, 3H), 3.40 (s, 4H), 4.95 (s, 2H),
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6. 5 7(t, J = 7.5 Hz, 1 H), 6.96 (d, J = 6.3 Hz, 1 H), 7.3 8(m, 4H), 7.73 (d,
J
6.9 Hz, 1H), 8.09 (d, J = 7.2 Hz, 1 H).
LC/MS (M+H): 401.20.
Example 34: (E)-N1-cyclohexyl-N8-hydroxy-2-((naphthalen-1-yloxy)
methyl)-2-octenediamide
(34-1):(E)-8-(cyclohexylamino)-7-((naphthalen-1-yloxy)methyl)-8-oxo-6-
octene acid methylester
The procedure of Example (1-1) was repeated except for using
cyclohexylamine instead of dimethylaminehydrochloride as the amine to
obtain 423 mg of the title compound (yield: 94%).
'H NMR (200 MHz, CDC13) b 1.13 (m, 2H), 1.33 (m, 2H), 1.42-1.79 (m, 8H),
1.88 (m, 2H), 2.29 (m, 4H), 3.62 (s, 3H), 3.82 (m, 1H), 4.92 (s, 2H), 6.34 (d,
J
= 7.4 Hz, 1H), 6.84 (t, J = 7.8 Hz, 111), 6.91 (d, J = 7.2 Hz, 1H), 7.47 (m,
4H),
7.81 (m, l H), 8.15 (m, 1 H).
LC/MS (M+H): 424.24.
(34-2):(E)-8-(cyclohexylamino)-7-((naphthalen-1-yloxy)methyl)-8-oxo-6-
octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (34-1) as the starting material, to obtain 397
mg of the title compound (yield: 67%).
(34-3):(E)-N1-cyclohexyl-2-((naphthalen-1-yloxy)methyl)-N8-
(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (34-2) as the starting material, to obtain 257
mg of the title compound (yield: 95%).
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IH NMR (200 MHz, CDC13) 5 1.14 (m, 2H), 1.34 (m, 2H), 1.40-2.00 (m,
16H), 2.08 (m, 2H), 2.30 (q, J = 7.2 Hz, 2H), 3.62 (m, 1H), 3.90 (m, 2H),
4.72 (m, 1 H), 4.93 (s, 2H), 6.40 (d, J = 7.8 Hz, 1 H), 6.83 (t, J = 7.8 Hz,
1H),
6.96 (d, J = 8.6 Hz, 1 H), 7.48 (m, 4H), 7.81 (m, 1 H), 8.16 (m, 1 H), 8.81
(br,
1 H).
LC/MS (M+H): 509.29.
(34-4):(E)-N1-cyclohexyl-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-
1.0 octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (34-3) as the starting material, to obtain 122
mg of the title compound (yield: 83%).
HPLC purification: 78 mg (purity: 93%)
'H NMR (300 MHz, MeOH-d4) 5 1.11-1.39 (m, 5H), 1.40-1.71 (m, 7H), 1.79
(m, 2H), 2.03 (t, J = 6.9 Hz, 2H), 2.29 (m, 2H), 3.69 (m, 1H), 4.96 (s, 1H),
6.47 (t, J = 7.2 Hz, 1 H), 6.93 (d, J = 7.2 Hz, 1 H), 7.37 (m, 4H), 7.75 (d, J
7.5 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H).
LC/MS (M+H): 425.24.
Example 35: (E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-
(thiophen-2-ylmethyl)-2-octenediamide
(35-1):(E)-7-((naphthalen-1-yloxy)methyl)-8-oxo-8-(thiophen-2-
ylmethylamino)-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using
thiophen-2-ylmethylamine instead of dimethylaminehydrochloride as the
amine to obtain 438 mg of the title compound (yield: 100%).
'H NMR (200 MHz, CDC13) b 1.43-1.75 (m, 4H), 2.29 (m, 4H), 3.62 (s, 3H),
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4.68 (d, J = 5.8 Hz, 2H), 4.90 (s, 2H), 6.93 (m, 5H), 7.18 (d, J = 4.8 Hz,
1H),
7.46 (m, 4H), 7.78 (d, J = 8.0 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1 H).
LC/MS (M+H): 438.17.
(35-2):(E)-7-((naphthalen-1-yloxy)methyl)-8-oxo-8-(thiophen-2-
ylmethylamino)-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (35-1) as the starting material, to obtain 438
mg of the title compound (yield: 92%).
(35-3):(E)-2-((naphthalen-1-yloxy)methyl)-N8-(tetrahydro-2H-pyran-2-
yloxy)-N-1-(thiophen-2-ylmethyl)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (35-2) as the starting material, to obtain 390
mg of the title compound (yield: 66%).
'H NMR (200 MHz, CDC13) b 1.46-1.94 (m, lOH), 2.10 (m, 2H), 2.32 (q, J
7.0 Hz, 2H), 3.64 (m, 1 H), 3.93 (m, 1 H), 4.70 (d, J = 5.2 Hz, 2H), 4.90 (m,
5H), 4.95 (s, 1H), 6.91 (m, 5H), 7.19 (d, J = 4.8 Hz, 1H), 7.47 (m, 4H), 7.80
(d, J = 8.8 Hz, 1 H), 8.09 (d, J = 10.0 Hz, 1 H), 8.41 (br, 1 H).
LC/MS (M+H): 523.22.
(35-4): (E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(thiophen-2-
ylmethyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (35-3) as the starting material, to obtain 168
mg of the title compound (yield: 87%).
HPLC purification: 55 mg (purity: 95%)
'H NMR (300 MHz, MeOH-d4) 5 1.34 (m, 2H), 1.58 (m, 2H), 2.10 (m, 2H),
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2.32 (m, 2H), 4.58 (s, 2H), 4.96 (s, 2H), 6.55 (m, 1H), 6.86 (m, 3H), 7.19 (d,
J
= 4.8 Hz, 1 H), 7.3 6 (m, 4H), 7.71 (d, J= 7.8 Hz, 1 H), 8.01 (d, J = 7.8 Hz,
1 H).
LC/MS (M+H): 439.16.
Example 36: (E)-N8-hydroxy-N1-(4-methoxyphenetyl)-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide
(36-1): (E)-8-(4-methoxyphenetylamino)-7-((naphthalen-1-yloxy)methyl)-
8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 4-
methoxyphenetylamine instead of dimethylaminehydrochloride as the amine
to obtain 476 mg of the title compound (yield: 100%).
'H NMR (200 MHz, CDC13) 5 1.45-1.73 (m, 4H), 2.30 (m, 4H), 2.75 (t, J
6.4 Hz, 2H), 3.56 (q, J= 6.6 Hz, 2H), 3.63 (s, 3H), 3.66 (s, 3H), 4.84 (s,
2H),
6.46 (m, 1H), 6.56 (d, J = 8.6 Hz, 2H), 6.88 (m, 2H), 6.95 (d, J = 8.6 Hz,
2H),
7.50 (m, 4H), 7.82 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H).
LC/MS (M+H): 476.24.
(36-2):(E)-8-(4-methoxyphenetylamino)-7-((naphthalen-1-yloxy)methyl)-
8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (36-1) as the starting material, to obtain 476
mg of the title compound (yield: 90%).
(36-3): (E)-N1-(4-methoxyphenetyl)-2-((naphthalen-1-yloxy)methyl)-N8-
(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (36-2) as the starting material, to obtain 121
mg of the title compound (yield: 93%).
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'H NMR (200 MHz, CDC13) b 1.50-1.90 (m, lOH), 2.19 (m, 2H), 2.30 (m,
2H), 2.86 (m, 2H), 3.67 (m, 3H), 3.81 (s, 3H), 3.92 (m, 1H), 4.85 (s, 2H),
4.92 (m, 1H), 6.61 (m, 1H), 6.87 (m, 2H), 7.15 (m, 4H), 7.46 (m, 4H), 7.82 (d,
J = 8.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.39 (br, 1H).
LC/MS (M+H): 561.29.
(36-4):(E)-N8-hydroxy-N1-(4-methoxyphenetyl)-2-((naphthalen-1-yloxy)
methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (36-3) as the starting material, to obtain 155
mg of the title compound (yield: 84%).
HPLC purification: 50 mg (purity: 95%)
'H NMR (300 MHz, MeOH-d4) b 1.44 (m, 2H), 1.57 (m, 2H), 2.03 (t, J = 6.9
Hz, 2H), 2.28 (q, J = 6.9 Hz, 2H), 2.70 (t, J = 6.9 Hz, 2H), 3.4 1(t, J = 7.2
Hz,
2H), 3.61 (s, 3H), 4.91 (s, 2H), 6.50 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 8.1
Hz,
2H), 6.92 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 8.1 Hz, 2H), 7.39 (m, 4H), 7.74
(d,
J = 7.8 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H).
LC/MS (M+H): 478.23.
Example 37: (E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(4-
(trifluoromethoxy)benzyl)-2-octenediamide
(37-1):(E)-7-((naphthalen-1-yloxy)methyl)-8-oxo-8-(4-trifluoromethoxy)
benzylamino)-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 4-
3 0 (trifluoromethoxy)benzylamine instead of dimethylaminehydrochloride as the
amine to obtain 515 mg of the title compound (yield: 57%).
'H NMR (200 MHz, CDC13) 6 1.52-1.71 (m, 6H), 2.32 (m, 4H), 3.62 (s, 3H),
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4.52 (d, J = 5.6 Hz, 2H), 4.96 (s, 2H), 6.82 (br, 1 H), 6.94 (m, 2H), 7.10 (d,
J =
8.2 Hz, 2H), 7.3 8 (m, 2H), 7.48 (m, 2H), 7.82 (d, J = 8.2 Hz, 1 H), 8.02 (d,
J =
8.2 Hz, 1 H).
LC/MS (M+H): 516.19.
(37-2):(E)-7-((naphthalen-1-yloxy)methyl)-8-oxo-8-(4-
trifluoromethoxy)benzylamino)-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (37-1) as the starting material, to obtain 293
mg of the title compound (yield: 95%).
(37-3):(E)-2-((naphthalen-1-yloxy)methyl)-N8-(tetrahydro-2H-pyran-2-
yloxy)-N-1-(4-(trifluoromethoxy)benzyl)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (37-2) as the starting material, to obtain 291
mg of the title compound (yield: 60%).
'H NMR (200 MHz, CDC13) 6 0.86 (m, 2H), 1.28 (m, 2H), 1.44-1.79 (m, 8H),
2.34 (m, 2H), 3.64 (br, 1H), 3.92 (br, 1H), 4.52 (d, J = 5.8 Hz, 2H), 4.90 (m,
1H), 4.98 (s, 2H), 6.92 (m, 3H), 7.10 (m, 2H), 7.32 (m, 2H), 7.42 (m, 2H),
7.82 (d, J = 8.2 Hz, 111), 8.02 (d, J= 8.2 Hz, 1H), 8.29 (br, 1 H).
LC/MS (M+H): 601.24.
(37-4):(E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-Nl-(4-
(trifluoromethoxy)benzyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (37-3) as the starting material, to obtain 74
mg of the title compound (yield: 52%).
HPLC purification: 15 mg (purity: 95%)
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'H NMR (300 MHz, MeOH-d4) 5 1.30 (m, 2H), 1.57 (m, 2H), 1.63 (m, 2H),
2.07 (t, J= 8.2 Hz, 2H), 2.3 8(q, J = 7.4 Hz, 2H), 4.46 (s, 2H), 5.05 (s, 2H),
5.47 (s, 2H), 6.61 (t, J = 7.6 Hz, 1H),6.97(d,J=7.4Hz, 1H),7.06(d,J=8.6
Hz, 1 H), 7.3 8 (m, 6H), 7.77 (d, J = 8.0 Hz, 1 H), 8.07 (d, J = 8.2 Hz, 1 H).
LC/MS (M+H): 517.19.
Example 38: (E)-N1-(1-(cyclohexylmethyl)pyrrolidin-3-yl)-N8-hydroxy-
2-((naphthalen-1-yloxy)methyl)-2-octenediamide
(38-1):(E)-8-(1-(cyclohexylmethyl)pyrrolidin-3-ylamino)-7-((naphthalen-
1-yloxy)methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 1-
(cyclohexylmethyl)pyrrolidin-3-ylamine instead of
dimethylaminehydrochloride as the amine to obtain 506 mg of the title
compound (yield: 26%).
1H NMR (200 MHz, CDC13) S 0.86 (m, 4H), 1.05-1.33 (m, 8H), 1.42-1.87 (m,
4H), 2.09 (m, 2H), 2.17-2.34 (m, 4H), 2.57 (m, 2H), 2.84 (m, 1 H), 3.62 (s,
3H), 4.53 (br, 1H), 4.93 (s, 2H), 5.30 (s, 2H), 6.84 (m, 2H), 7.47 (m, 4H),
7.78 (m, 1 H), 8.15 (m, 1 H).
LC/MS (M+H): 507.31.
(38-2): (E)-8-(1-(cyclohexylm ethyl)pyrrolidin-3-ylam ino)-7-((naphthalen-
1-yloxy)methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (38-1) as the starting material, to obtain 135
mg of the title compound (yield: 89%).
(38-3):(E)-N1-(1-(cyclohexylmethyl)pyrrolidin-3-yl)-2-((naphthalen-l-
yloxy)methyl)-N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
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The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (38-2) as the starting material, to obtain 117
mg of the title compound (yield: 53%).
'H NMR (200 MHz, CDC13) 5 0.83 (m, 4H), 1.07 (m, 2H), 1.28 (m, 4H),
1.42 (m, 1 H), 1.57-1.78 (m, 12H), 2.17 (m, 2H), 2.31 (m, 6H), 2.61-2.89 (m,
311), 3.60 (m, 1 H), 3.92 (m, 1 H), 4.5 7(m, 1 H), 4.93 (s, 2H), 6.82 (t, J =
7.4
Hz, 1 H), 6.91 (d, J = 7.2 Hz, 1 H), 7.46 (m, 4H), 7.78 (d, J = 7.2 Hz, 1 H),
8.16
(d, J = 7.4 Hz, 1 H), 8.43 (br, 1 H).
LC/MS (M+H): 592.37.
(38-4):(E)-N1-(1-(cyclohexylmethyl)pyrrolidin-3-yl)-N8-hydroxy-2-
((naphthalen-1-yloxy)methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (38-3) as the starting material, to obtain 58
mg of the title compound (yield: 77%).
PHLC purification: 24 mg (purity: 95%)
'H NMR (300 MHz, MeOH-d4) b 0.92 (m, 2H), 1.15 (m, 4H), 1.46 (m, 2H),
1.50-1.70 (m, 8H), 2.04 (m, 3H), 2.36 (q, J = 7.2 Hz, 2H), 2.50 (m, 1 H), 2.96
(m, 3H), 3.56 (m, 1H), 3.79 (m, 1H), 4.34 (br, 1H), 4.97 (s, 214), 6.53 (t, J
=
7.0 Hz, 1 H), 6.94 (d, J = 7.2 Hz, 1 H), 7.3 8(m, 4H), 7.73 (d, J = 7.6 Hz, 1
H),
8.06 (d, J = 7.6 Hz, 1H).
LC/MS (M+H): 508.31.
Example 39: (E)-N1-(1-cyclopentylpiperidin-4-yl)-N8-hydroxy-2-
((naphthalen-1-yloxy)methyl)-2-octenediamide
(39-1):(E)-8-(1-cyclopentylpiperidin-4-ylamino)-7-((naphthalen-1-yloxy)
methyl)-8-oxo-6-octene acid methylester
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The procedure of Example (1-1) was repeated except for using 1-
cyclopentylpiperidin-4-ylamine instead of dimethylaminehydrochloride as the
amine to obtain 492 mg of the title compound (yield: 55%).
'H NMR (200 MHz, CDC13) 5 0.83-1.04 (m, 4H), 1.28 (m, 6H), 1.42-1.70 (m,
8H), 1.92-2.59 (m, 6H), 2.85 (m, 1H), 3.62 (s, 3H), 3.94 (m, 1H), 4.92 (s,
2H),
6.39 (d, J = 7.8 Hz, 1H), 6.84 (m, 2H), 7.48 (m, 4H), 7.79 (m, 1H), 8.17 (m,
1 H).
LC/MS (M+H): 493.30.
(39-2):(E)-8-(1-cyclopentylpiperidin-4-ylamino)-7-((naphthalen-1-yloxy)
methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (39-1) as the starting material, to obtain 274
mg of the title compound (yield: 96%).
(39-3):(E)-N1-(1-cyclopentylpiperidin-4-yl)-2-((naphthalen-1-yloxy)
methyl)-N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (39-2) as the starting material, to obtain 257
mg of the title compound (yield: 48%).
1H NMR (200 MHz, CDC13) b 0.82 (m, 2H), 1.25-1.77 (m, 22H), 1.93-2.37
(m, 6H), 2.49 (m, 1 H), 2.90 (m, 2H), 3.61 (br, 1 H), 3.91 (br, 1 H), 4.91 (s,
2H), 6.52 (br, 1 H), 6.89 (m, 2H), 7.50 (m, 4H), 7.79 (m, 1 H), 8.16 (m, 1 H),
8.52 (br, 1H).
LC/MS (M+H): 578.35.
(39-4):(E)-N1-(1-cyclopentylpiperidin-4-yl)-N8-hydroxy-2-((naphthalen-
1-yloxy)methyl)-2-octenediamide
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The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (39-3) as the starting material, to obtain 122
mg of the title compound (yield: 70%).
HPLC purification: 42 mg (purity: 95%)
'H NMR (300 MHz, MeOH-d4) b 1.46 (m, 2H), 1.54-1.78 (m, 12H), 1.99-
2.11 (m, 6H), 2.32 (q, J = 7.4 Hz, 2H), 2.98 (t, J = 12.6 Hz, 2H), 3.39 (m,
1H),
3.57 (d, J = 12.4 Hz, 2H), 3.94 (m, 1 H), 4.96 (s, 2H), 6.47 (t, J = 7.2 Hz, 1
H),
6.92 (d, J= 7.2 Hz, 1H), 7.34 (m, 4H), 7.74 (d, J= 8.0 Hz, 1H), 7.82 (s, 1H),
8.07 (d, J = 7.8 Hz, 1H).
LC/MS (M+H): 494.29.
Example 40: (E)-N1-(1-benzylpyrrolidin-3-yl)-N8-hydroxy-2-
((naphthalen -1-yloxy)methyl)-2-octenediamide
(40-1):(E)-8-(1-benzylpyrrolidin-3-ylamino)-7-((naphthalen-1-yloxy)
methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 1-
2 0 benzylpyrrolidin-3-ylamine instead of dimethylaminehydrochloride as the
amine to obtain 501 mg of the title compound (yield: 70%).
'H NMR (200 MHz, CDC13) 6 0.84 (m, 2H), 1.29 (m, 2H), 1.62 (m, 4H),
2.30 (m, 6H), 2.55 (m, 2H), 3.48 (m,3H), 3.63 (s, 3H), 4.94 (s, 2H), 6.86 (m,
2H), 7.14 (m, 2H), 7.18 (m, 2H), 7.46 (m, 4H), 7.81 (d, J 7.8 Hz, 111), 8.19
(d, J = 7.4 Hz, 1 H).
LC/MS (M+H): 501.27.
(40-2):(E)-8-(1-benzylpyrrolidin-3-ylamino)-7-((naphthalen-1-yloxy)
methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (40-1) as the starting material, to obtain 352
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mg of the title compound (yield: 55%).
(40-3): (E)-N1-(1-benzylpyrrolidin-3-yl)-2-((naphthalen-1-yloxy)methyl)-
N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (40-2) as the starting material, to obtain 188
mg of the title compound (yield: 67%).
'H NMR (200 MHz, CDC13) b 0.86 (m,2H), 1.28 (m, 2H), 1.42-1.77 (m, 8H),
2.08-2.37 (m, 6H), 2.54 (m, 2H), 2.75 (m, 1 H), 3.48 (m, 3H), 3.91 (br, 1 H),
4.53 (br, 1H), 4.85 (m, 1H), 4.92 (s, 2H), 6.94 (m, 3H), 7.16 (m, 4H), 7.40
(m,
4H), 7.84 (d, J = 7.0 Hz, 1 H), 8.21 (d, J = 9.6 Hz, 1 H), 8.60 (br, 1 H).
LC/MS (M+H): 586.32.
(40-4): (E)-N1-(1-benzylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (40-3) as the starting material, to obtain 64
mg of the title compound (yield: 68%).
HPLC purification: 23 mg (purity: 95%)
'H NMR (300 MHz, MeOH-d4) b 1.30 (m, 2H), 1.52 (m, 2H), 1.64 (m, 2H),
2.07 (t, J = 7.0 Hz, 2H), 2.39 (q, J = 7.2 Hz, 2H), 4.32 (m, 3H), 4.94 (m,
3H),
5.47 (s, 2H), 6.57 (t, J = 7.4 Hz, 1H), 7.0 2(d, J = 7.2 Hz, 1H), 7.36-7.44
(m,
8H), 7.77 (d, J = 8.4 Hz, 1 H), 7.86 (m, 1 H), 8.08 (d, J = 6.4 Hz, 1 H), 8.75
(br,
1 H).
LC/MS (M+H): 502.26.
Example 41: (E)-N8-hydroxy-N1-(1-isopropylpyrrolidin-3-yl)-2-
((naphthalen-1-yloxy)methyl)-2-octenediamide
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(41-1):(E)-8-(1-isopropylpyrrolidin-3-ylamino)-7-((naphthalen-1-yloxy)
methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 1-
isopropylpyrrolidin-3-ylamine instead of dimethylaminehydrochloride as the
amine to obtain 452 mg of the title compound (yield: 41%).
'H NMR (200 MHz, CDC13) b 0.84 (m, 2H), 1.0 2(m, 4H), 1.26 (m, 3H),
1.61 (m, 4H), 2.18 (m, 2H), 2.30 (m, 5H), 2.70(t, J = 6.6 Hz, 2H), 3.63 (s,
3H), 4.95 (s, 2H), 6.86 (m, 3H), 7.46 (m, 4H), 7.79 (d, J = 8.2 Hz, 1H), 8.17
(d, J = 8.6 Hz, 1H).
LC/MS (M+H): 453.27.
(41-2):(E)-8-(1-isopropylpyrrolidin-3-ylamino)-7-((naphthalen-l-yloxy)
methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (41-1) as the starting material, to obtain 184
mg of the title compound (yield: 83%).
(41-3):(E)-N1-(1-isopropylpyrrolidin-3-yl)-2-((naphthalen-1-yloxy)
methyl)-N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (41-2) as the starting material, to obtain 122
mg of the title compound (yield: 69%).
'H NMR (200 MHz, CDC13) b 0.83 (m, 4H), 1.05 (m, 6H), 1.25 (m, 4H),
1.59 (m, 6H), 2.09 (m, 2H), 2.34 (m, 4H), 2.76 (d, J = 5.4 Hz, 2H), 3.62 (m,
1H), 3.92 (m, 1 H), 4.94 (s, 2H), 6.79 (t, J = 7.8 Hz, 1 H), 6.94 (d, J = 7.4
Hz,
1 H), 7.14 (m, 1 H), 7.44 (m, 4H), 7.77 (m, 1 H), 8.16 (m, 1 H).
LC/MS (M+H): 538.32.
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(41-4):(E)-N8-hydroxy-N1-(1-isopropylpyrrolidin-3-yl)-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (41-3) as the starting material, to obtain 101
mg of the title compound (yield: 82%).
HPLC purification: 39 mg (purity: 96%)
'H NMR (300 MHz, MeOH-d4) b 1.26 (m, 6H), 1.47 (q, J=7.2Hz, 2H), 1.62
(q, J=7.2Hz, 2H), 2.04 (t, J = 7.0 Hz, 3H), 2.34 (q, J = 7.2 Hz, 3H), 3.25-
3.53
(m, 4H), 3.69 (m, 1H), 4.43 (m, 1H), 4.97 (m, 2H), 6.58 (m, IH), 6.95 (d, J
7.2 Hz, 1 H), 7.34 (m, 4H), 7.74 (d, J = 7.6 Hz, 1 H), 8.06 (d, J = 8.0 Hz, 1
H).
LC/MS (M+H): 454.26.
Example 42: (E)-N1-(1-(cyclohexanecarbonyl)pyrrolidin-3-yl)-N8-
hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide
(42-1):(E)-8-(1-(cyclohexanecarbonyl)pyrrolidin-3-ylamino)-7-
((naphthalen-1-yloxy)methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 1-
(cyclohexanecarbonyl)pyrrol i din- 3 -ylamine instead of
dimethylaminehydrochloride as the amine to obtain 520 mg of the title
compound (yield: 66%).
'H NMR (200 MHz, CDC13) 5 1.17-1.76 (m, 14H), 2.16-2.35 (m, 7H), 3.46
(m, 2H), 3.62 (s, 3H), 3.83 (m, 2H), 4.54 (m, 1 H), 4.93 (s, 2H), 6.60 (m, 1
H),
6.88 (m, 1H), 7.47 (m, 4H), 7.80 (d, J = 7.2 Hz, 1H), 8.12 (d, J = 6.8 Hz,
1H).
LC/MS (M+H): 521.29.
(42-2):(E)-8-(1-(cyclohexanecarbonyl)pyrrolidin-3-ylamino)-7-
((naphthalen-1-yloxy)methyl)-8-oxo-6-octene acid
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The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (42-1) as the starting material, to obtain 342
mg of the title compound (yield: 78%).
(42-3):(E)-N1-(1-(cyclohexanecarbonyl)pyrrolidin-3-yl)-2-((naphthalen-
1-yloxy)methyl)-N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (42-2) as the starting material, to obtain 262
mg of the title compound (yield: 40%).
'H NMR (300 MHz, CDC13) 6 1.20 (m, 4H), 1.42-1.77 (m, 16H), 2.11 (m,
4H), 2.32 (m, 3H), 3.37 (m, 2H), 3.44 (m, 1H), 3.60 (m, 2H), 3.86 (m, 1H),
4.53 (q, J = 5.6 Hz, 1H), 4.93 (s, 2H), 6.89 (m, 3H), 7.45 (m, 4H), 7.80 (d, J
7.4 Hz, 1 H), 8.10 (d, J= 7.6 Hz, 1 H), 8.41 (br, 1 H).
LC/MS (M+H): 606.35.
(42-4):(E)-N1-(1-(cyclohexanecarbonyl)pyrrolidin-3-yl)-N8-hydroxy-2-
((naphthalen-1-yloxy)methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (42-3) as the starting material, to obtain 154
mg of the title compound (yield: 80%).
HPLC purification: 67 mg (purity: 96%)
'H NMR (300 MHz, MeOH-d4) b 1.18-1.69 (m, 14H), 2.03 (m, 4H), 2.32 (q,
J = 7.0 Hz, 3H), 3.49 (m, 2H), 3.80 (m, 1H), 3.93 (s, 1H), 4.40 (m, 1H), 4.98
(s, 2H), 6.48 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 5.4 Hz, 1H), 7.37 (m, 4H),
7.73
(d, J = 7.8 Hz, 1 H), 8.08 (d, J = 8.8 Hz, 1 H).
LC/MS (M+H): 522.29.
Example 43 : (E)-3-(8-(hydroxyamino)-2-((naphthalen-1-yloxy)methyl)-
8-oxo-2-octeneamido)pyrrolidin-l-carboxylic acid t-butylester
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(43-1):(E)-3-(8-methoxy-2-((naphthalen-1-yloxy)methyl)-8-oxo-2-
octeneamido)pyrrolidin-l-carboxylic acid t-butylester
The procedure of Example (1-1) was repeated except for using 3-
aminopyrrolidin-l-carboxylic acid t-butylester instead of
dimethylaminehydrochloride as the amine to obtain 510 mg of the title
compound (yield: 83%).
'H NMR (300 MHz, CDC13) 5 1.33 (m, 2H), 1.39 (s, 9H), 1.60 (m, 2H), 2.15
(m, 2H), 2.31 (m, 4H), 3.36 (m, 4H), 3.62 (s, 3H), 4.93 (s, 2H), 6.66 (br,
1H),
6.90 (m, 2H), 7.3 8 (t, J = 7.8 Hz, 2H), 7.49 (m, 2H), 7.80 (m, 1 H), 8.10 (m,
1 H).
LC/MS (M+H): 511.27.
(43-2):(E)-8-(1-(t-butoxycarbonyl)pyrrolidin-3-ylamino)-7-((naphthalen-
1-yloxy)methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (43-1) as the starting material, to obtain 423
mg of the title compound (yield: 77%).
(43-3):(E)-3-(2-((naphthalen-1-yloxy)methyl)-8-oxo-8-(tetrahydro-2H-
pyran-2-yloxyamino)-2-octeneamido)pyrrolidin-l-carboxylic acid t-
2 5 butylester
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (43-2) as the starting material, to obtain 320
mg of the title compound (yield: 72%).
1H NMR (300 MHz, CDC13) 5 1.25 (m, 2H), 1.39 (s, 9H), 1.45 (m, 2H), 1.50-
1.77 (m, 6H), 1.92 (m, 1H), 2.04 (m, 4H), 2.30 (q, J = 7.2 Hz, 2H), 3.36 (m,
4H), 3.60 (br, 1 H), 3.92 (br, 1 H), 4.92 (s, 2H), 6.74 (br, 1 H), 6.83 (t, J
= 7.6
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Hz, 1 H), 6.92 (d, J = 7.4 Hz, 1 H), 7.46 (m, 4H), 7.80 (m, 1 H), 8.10 (m, 1
H),
8.71 (br, 1 H).
LC/MS (M+H): 596.33.
(43-4):(E)-3-(8-(hydroxyamino)-2-((naphthalen-1-yloxy)methyl)-8-oxo-2-
octeneamido)pyrrolidin-l-carboxylic acid t-butylester
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (43-3) as the starting material, to obtain 255
mg of the title compound (yield: 95%).
HPLC purification: 5 mg (purity: 96%)
'H NMR (300 MHz, MeOH-d4) b 1.29 (m, 2H), 1.42 (s, 9H), 1.62 (m, 2H),
1.89-2.09 (m, 4H), 2.33 (m, 2H), 3.20 (m, 2H), 3.57 (m, 2H), 4.41 (t, J = 5.4
Hz, 1H), 5.48 (s, 2H), 6.52 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 7.2 Hz, 2H),
7.40
(m, 4H), 7.79 (d, J = 8.4 Hz, 1 H), 8.10 (d, J = 7.4 Hz, 1 H).
LC/MS (M+H): 512.27.
Example 44: (E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-
2 0 (pyrrolidin-3-yl)2-octenediamide
(44-1):(E)-3-(8-methoxy-2-((naphthalen-1-yloxy)methyl)-8-oxo-2-
octeneamido)pyrrolidin-l-carboxylic acid t-butylester
The procedure of Example (1-1) was repeated except for using 3-
aminopyrrolidin-l-carboxylic acid t-butylester instead of
dimethylaminehydrochloride as the amine to obtain 510 mg of the title
compound (yield: 83%).
'H NMR (300 MHz, CDC13) 6 1.33 (m, 2H), 1.39 (s, 9H), 1.60 (m, 2H), 2.15
(m, 2H), 2.31 (m, 4H), 3.36 (m, 4H), 3.62 (s, 3H), 4.93 (s, 2H), 6.66 (br,
1H),
6.90 (m, 2H), 7.3 8 (t, J = 7.8 Hz, 2H), 7.49 (m, 2H), 7.80 (m, 1 H), 8.10 (m,
1 H).
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LC/MS (M+H): 511.27.
(44-2):(E)-8-(1-(t-butoxycarbonyl)pyrrolidin-3-ylamino)-7-((naphthalen-
1-yloxy)methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (44-1) as the starting material, to obtain 423
mg of the title compound (yield: 77%).
(44-3):(E)-3-(2-((naphthalen-1-yloxy)methyl)-8-oxo-8-(tetrahydro-2H-
pyran-2-yloxyamino)-2-octeneamido)pyrrolidin-l-carboxylic acid t-
butylester
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (44-2) as the starting material, to obtain 320
mg of the title compound (yield: 72%).
'H NMR (300 MHz, CDC13) 5 1.25 (m, 2H), 1.39 (s, 9H), 1.45 (m, 2H), 1.50-
1.77 (m, 6H), 1.92 (m, 1H), 2.04 (m, 4H), 2.30 (q, J = 7.2 Hz, 2H), 3.36 (m,
4H), 3.60 (br, 1 H), 3.92 (br, 1 H), 4.92 (s, 2H), 6.74 (br, 1 H), 6.83 (t, J
= 7.6
Hz, 1 H), 6.92 (d, J = 7.4 Hz, 1 H), 7.46 (m, 4H), 7.80 (m, 1 H), 8.10 (m, 1
H),
8.71 (br, 1 H).
LC/MS (M+H): 596.33.
(44-4):(E)-3-(8-(hydroxyamino)-2-((naphthalen-1-yloxy)methyl)-8-oxo-2-
octeneamido)pyrrolidin-l-carboxylic acid t-butylester
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (44-3) as the starting material, to obtain 255
mg of the title compound (yield: 95%).
HPLC purification: 5 mg (purity: 96%)
'H NMR (300 MHz, MeOH-d4) 5 1.29 (m, 2H), 1.42 (s, 9H), 1.62 (m, 2H),
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1.89-2.09 (m, 4H), 2.33 (m, 2H), 3.20 (m, 2H), 3.57 (m, 2H), 4.41 (t, J = 5.4
Hz, 1H), 5.48 (s, 2H), 6.52 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 7.2 Hz, 2H),
7.40
(m, 4H), 7.79 (d, J= 8.4 Hz, 1 H), 8.10 (d, J= 7.4 Hz, 1 H).
LC/MS (M+H): 512.27.
(44-5):(E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(pyrrolidin-3-
yl)2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (44-4) as the starting material, to obtain 172
mg of the title compound (yield: 92%).
HPLC purification: 58 mg (purity: 96%)
'H NMR (300 MHz, MeOH-d4) b 1.46 (m, 2H), 1.58 (m, 2H), 2.04 (t, J= 7.0
Hz, 2H), 2.34 (m, 4H), 3.22 (m, 2H), 3.44 (m, 2H), 4.43 (m, 1 H), 4.97 (s,
2H),
6.55 (m, 1 H), 6.95 (d, J = 6.8 Hz, 1 H), 7.3 8(m, 4H), 7.73 (d, J = 7.4 Hz, 1
H),
8.0 8 (d, J = 7.8 Hz, 1H).
LC/MS (M+H): 412.22.
Example 45: (E)-N1-(1-cyclohexylpyrrolidin-3-yl)-N8-hydroxy-2-
((naphthalen-2-yloxy)methyl)-2-octenediamide
(45-1):(E)-8-(1-cyclohexylpyrrolidin-3-ylamino)-7-((naphthalen-2-yloxy)
methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 1-
cyclohexylpyrrolidin-3-ylamine instead of dimethylaminehydrochloride as
the amine to obtain 492 mg of the title compound (yield: 54%).
'H NMR (200 MHz, CDC13) 5 1.08-1.42 (m, 4H), 1.51-1.78 (m, lOH), 1.94
(m, 2H), 2.29 (m, 6H), 2.64 (d, J = 5. 4Hz, 2H), 2.82 (m, 1H), 3.63 (s, 3H),
4.53 (m, 1H), 4.93 (s, 2H), 6.90 (m, 2H), 7.48 (m, 4H), 7.78 (m, 1H), 8.17 (d,
J = 7.2 Hz, 1H).
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LC/MS (M+H): 493.30.
(45-2):(E)-8-(1-cyclohexylpyrrolidin-3-ylamino)-7-((naphthalen-2-yloxy)
methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (45-1) as the starting material, to obtain 269
mg of the title compound (yield: 100%).
(45-3):(E)-N1-(1-cyclohexylpyrrolidin-3-yl)-2-((naphthalen-2-yloxy)
methyl)-N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (45-2) as the starting material, to obtain 269
mg of the title compound (yield: 43%).
'H NMR (200 MHz, CDC13) b 0.83 (m 4H), 1.13-1.42 (m, 6H), 1.56-1.89 (m,
12H), 2.16 (m, 6H), 2.32 (m, 2H), 2.77 (m, 1 H), 3.62 (br, 1 H), 3.94 (br, 1
H),
4.61 (m, 1 H), 4.80 (m, 1H), 4.94 (s, 2H), 6.82 (t, J = 7.8 Hz, 1 H), 6.91 (d,
J
7.6 Hz, 2H), 7.44 (m, 4H), 7.82 (m, 1H), 8.16 (m, 1 H).
LC/MS (M+H): 578.35.
(45-4):(E)-N1-(1-cyclohexylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-
2-yloxy)methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (45-3) as the starting material, to obtain 140
mg of the title compound (yield: 88%).
HPLC purification: 16 mg (purity: 97%)
'H NMR (300 MHz, MeOH-d4) b 1.24-1.34 (m, 8H), 1.47-1.65 (m, 6H), 1.77
(m, 1H), 1.98 (m, 2H), 2.05 (t, J = 7.2 Hz, 2H), 2.11 (s, 2H), 2.34 (m, 2H),
2.76 (br, 1H), 4.41 (m, 1H), 4.99 (s, 2H), 6.59 (t, J = 7.4 Hz, 2H), 6.98 (d,
J
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7.0 Hz, 1 H), 7.3 9 (m, 414), 7.74 (d, J = 7.6 Hz, 1 H), 8.07 (d, J = 8.2 Hz,
1 H).
LC/MS (M+H): 494.29.
Example 46: (E)-N1-(1-cyclopropylpyrrolidin-3-yl)-N8-hydroxy-2-
((naphthalen-1-yloxy)methyl)-2-octenediamide
(46-1):(E)-8-(1-cyclopropylpyrrolidin-3-ylamino)-7-((naphthalen-2-yloxy)
methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 1-
cyclopropylpyrrolidin-3-ylamine instead of dimethylaminehydrochloride as
the amine to obtain 450 mg of the title compound (yield: 78%).
'H NMR (200 MHz, CDC13) b 0.15 (m, 214), 0.28 (m, 2H), 1.28-1.93 (m, 8H),
2.29 (m, 6H), 2.80 (m, 2H), 3.62 (s, 3H), 4.92 (s, 2H), 6.69 (d, J = 7.8 Hz,
1 H), 6.82 (m, 1 H), 7.47 (m, 4H), 7.82 (m, 1 H), 8.15 (m, 1 H).
LC/MS (M+H): 451.25.
(46-2):(E)-8-(1-cyclopropylpyrrolidin-3-ylamino)-7-((naphthalen-2-yloxy)
methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (46-1) as the starting material, to obtain 355
mg of the title compound (yield: 98%).
(46-3):(E)-N1-(1-cyclopropylpyrrolidin-3-yl)-2-((naphthalen-1-yloxy)
methyl)-N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (46-2) as the starting material, to obtain 334
mg of the title compound (yield: 61%).
'H NMR (200 MHz, CDC13) b 0.16 (m, 2H), 0.31 (m, 2H), 1.47-1.83 (m,
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12H), 2.15 (m, 2H), 2.17 (s, 2H), 2.30 (m, 2H), 2.37 (m, 2H), 2.81 (m, 2H),
3.62 (br, 1 H), 3.91 (br, 1 H), 4.90 (m, 1 H), 4.92 (s, 2H), 6.80 (t, J = 7.8
Hz,
1 H), 6.90 (d, J = 7.6 Hz, 1 H), 7.46 (m, 4H), 7.80 (m, 1 H), 8.14 (m, 1 H),
8.44
(br, 1H).
LC/MS (M+H): 536.30.
(46-4): (E)-N1-(1-cyclopropylpyrrolidin-3-yl)-NB-hydroxy-2-
((naphthalen-1-yloxy)methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (46-3) as the starting material, to obtain 154
mg of the title compound (yield: 89%).
HPLC purification: 65 mg (purity: 95%)
'H NMR (300 MHz, MeOH-d4) b 0.42 (m, 4H), 1.44 (q, J = 7.4 Hz, 2H), 1.59
(m, 3H), 1.82 (br, 1 H), 2.02 (t, J = 7.2 Hz, 1 H), 2.09 (s, 1 H), 2.27 (m, 1
H),
2.32 (q, J = 7.2 Hz, 2H), 2.71 (m, 2H), 3.01 (m, 2H), 4.94 (s, 2H), 6.53 (t,
J=
7.4 Hz, 1 H), 6.92 (d, J = 7.2 Hz, 1 H), 7.3 6 (m, 4H), 7.74 (d, J = 7.8 Hz, 1
H),
7.81 (s, 1 H), 8.08 (d, J= 7.8 Hz, 1 H).
Example 47: (E)-N1-(1-cyclopropylpiperidin-4-yl)-N8-hydroxy-2-
((naphthalen-1-yloxy)methyl)-2-octenediamide
(47-1):(E)-8-(1-cyclopropylpiperidin-4-ylamino)-7-((naphthalen-1-yloxy)
methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 1-
cyclopropylpiperidin-4-ylamine instead of dimethylaminehydrochloride as
the amine to obtain 464 mg of the title compound (yield: 47%).
'H NMR (200 MHz, CDC13) b 0.33-0.40 (m, 4H), 1.24-1.73 (m, 9H), 1.88 (m,
2H), 2.17 (m, 1 H), 2.29 (m, 6H), 3.62 (s, 3H), 3.92 (m, 1 H), 4.91 (s, 2H),
6.35 (d, J = 8.0 Hz, 1H), 6.90 (m, 2H), 7.48 (m, 4H), 7.80 (m, 1H), 8.12 (m,
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1 H).
LC/MS (M+H): 465.27.
(47-2): (E)-8-(1-cyclopropylpiperidin-4-ylamin o)-7-((naphtha len-1-yloxy)
methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (47-1) as the starting material, to obtain 221
mg of the title compound (yield: 100%).
(47-3):(E)-N1-(1-cyclopropylpiperidin-4-yl)-2-((naphthalen-1-yloxy)
methyl)-N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (47-2) as the starting material, to obtain 221
mg of the title compound (yield: 51 %).
'H NMR (200 MHz, CDC13) b 0.38 (m, 4H), 1.28-1.94 (m, 18H), 2.10 (m,
2H), 2.32 (m, 4H), 3.64 (m, 1H), 3.95 (m, 1H), 4.88 (m, 1H), 4.92 (s, 2H),
6.40 (d, J = 8.2 Hz, 1 H), 6.92 (m, 2H), 7.48 (m, 4H), 7.84 (m, 1 H), 8.14 (m,
1H), 8.42 (br, 1 H).
LC/MS (M+H): 550.32.
(47-4):(E)-N1-(1-cyclopropylpiperidin-4-yl)-N8-hydroxy-2-((naphthalen-
2 5 1-yloxy)methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (47-3) as the starting material, to obtain 150
mg of the title compound (yield: 90%).
HPLC purification: 107 mg (purity: 95%)
'H NMR (300 MHz, MeOH-d4) b 0.89 (m, 4H), 1.25 (m, 4H), 1.46 (m, 2H),
1.62 (m, 2H), 2.04 (t, J = 7.2 Hz, 2H), 2.10 (m, 2H), 2.33 (q, J = 7.4, 2H),
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2.73 (m, 1 H), 3.59 (m, 2H), 3.99 (m, 1 H), 4.98 (s, 2H), 6.49 (m, 1 H), 6.94
(d,
J = 7.2 Hz, 1H), 7.3 6(m, 4H), 7.73 (d, J= 7. 8Hz, 1 H), 8.06 (d, J= 7.8 Hz,
1 H).
LC/MS (M+H): 466.26.
Example 48: (E)-N1-(1-ethylpiperidin-4-yl)-N8-hydroxy-2-((naphthalen-
1-yloxy)methyl)-2-octenediamide
(48-1):(E)-8-(1-ethylpiperidin-4-ylamino)-7-((naphthalen-1-yloxy)methyl)
-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 1-
ethylpiperidin-4-ylamine instead of dimethylaminehydrochloride as the amine
to obtain 452 mg of the title compound (yield: 62%).
'H NMR (200 MHz, CDC13) 5 1.02 (t, J = 7.4, 3H), 1.26-1.74 (m, 8H), 1.92-
2.17 (m, 4H), 2.32 (m, 4H), 2.72 (m, 2H), 3.63 (s, 3H), 4.92 (s, 2H), 6.38 (d,
J
= 8.0 Hz, 1 H), 6.80 (t, J = 7.8 Hz, 1 H), 6.90 (d, J= 7.6 Hz, 1 H), 7.48 (m,
4H),
7.82 (m, 1 H), 8.14 (m, 1 H).
LC/MS (M+H): 453.27.
(48-2):(E)-8-(1-ethylpiperidin-4-ylamino)-7-((naphthalen-1-yloxy)methyl)
-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (48-1) as the starting material, to obtain 279
mg of the title compound (yield: 100%).
(48-3):(E)-N1-(1-ethylpiperidin-4-yl)-2-((naphthalen-1-yloxy)methyl)-N8-
3 0 (tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (48-2) as the starting material, to obtain 279
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mg of the title compound (yield: 80%).
'H NMR (200 MHz, CDC13) b 0.84 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H), 1.27 (m,
2H), 1.44-1.79 (m, 10H), 1.94-2.26 (m, 4H), 2.35 (m, 4H), 2.90 (m, 2H), 3.62
(m, 1 H), 3.93 (m, 1 H), 4.94 (s, 2H), 4.97 (m, 1 H), 6.46 (d, J= 7.8 Hz, 1
H),
6.84 (t, J = 7.8 Hz, 1 H), 6.92 (d, J = 7.0 Hz, 1 H), 7.4 8(m, 4H), 7.82 (m, 1
H),
8.14 (m, 111), 8.43 (br, 1 H).
LC/MS (M+H): 538.32.
(48-4):(E)-N1-(1-ethylpiperidin-4-yl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (48-3) as the starting material, to obtain 146
mg of the title compound (yield: 94%).
HPLC purification: 114 mg (purity: 95%)
'H NMR (300 MHz, MeOH-d4) b 1.24 (t, J = 7.2 Hz, 3H), 1.45-1.81 (m, 7H),
1.93-2.10 (m, 5H), 2.32 (q, J = 7.2 Hz, 2H), 2.98 (m, 2H), 3.09 (q, J = 7.2
Hz,
2H), 3.51 (m, 1 H), 4.97 (s, 2H), 6.46 (t, J = 7.6 Hz, 1 H), 6.94 (d, J= 7.0
Hz,
1 H), 7.3 8 (m, 4H), 7.72 (d, J = 7.6 Hz, 1 H), 8.05 (d, J = 7.8 Hz, 1 H).
LC/MS (M+H): 454.26.
Example 49: (E)-N1-(1-ethylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-
2 5 1-yloxy)methyl)-2-octenediamide
(49-1):(E)-8-(1-ethylpyrrolidin-3-ylamino)-7-((naphthalen-1-yloxy)
methyl)-8-oxo-6-octene acid methylester
The procedure of Example (1-1) was repeated except for using 1-
ethylpyrrolidin-3-ylamine instead of dimethylaminehydrochloride as the
amine to obtain 438 mg of the title compound (yield: 52%).
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'H NMR (200 MHz, CDC13) b 0.99 (t, J= 7.2 Hz, 3H), 1.26-1.73 (m, 6H),
2.16-2.47 (m, 8H), 2.60 (m, 2H), 2.80 (m, 1H), 3.63 (s, 3H), 4.95 (s, 2H),
6.81 (t, J = 7.6 Hz, 1 H), 6.90 (d, J = 7.4 Hz, 1 H), 7.46 (m, 4H), 7.79 (m, 1
H),
8.16 (m, 1H).
LC/MS (M+H): 469.30.
(49-2):(E)-8-(1-ethylpyrrolidin-3-ylamino)-7-((naphthalen-1-yloxy)
methyl)-8-oxo-6-octene acid
The procedure of Example (1-2) was repeated except for using the
compound obtained in Example (49-1) as the starting material, to obtain 224
mg of the title compound (yield: 100%).
(49-3):(E)-N1-(1-ethylpyrrolidin-3-yl)-2-((naphthalen-1-yloxy)methyl)-
N8-(tetrahydro-2H-pyran-2-yloxy)-2-octenediamide
The procedure of Example (4-3) was repeated except for using the
compound obtained in Example (49-2) as the starting material, to obtain 224
mg of the title compound (yield: 69%).
'H NMR (200 MHz, CDC13) b 0.82 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H), 1.24 (m,
4H), 1.41-2.20 (m, 8H), 2.31 (m, 4H), 2.51 (m, 3H), 2.57 (m, 1H), 2.62 (m,
1 H), 3.61 (br, 1 H), 3.92 (br, 1 H), 4.91 (m, 1 H), 4.94 (s, 2H), 6.79 (t, J
= 7.8
Hz, 1 H), 6.94 (d, J = 7.0 Hz, 1 H), 7.44 (m, 4H), 7.82 (m, 1 H), 8.20 (m, 1
H).
LC/MS (M+H): 524.30.
(49-4):(E)-N1-(1-ethylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-l-
yloxy)methyl)-2-octenediamide
The procedure of Example (4-4) was repeated except for using the
compound obtained in Example (49-3) as the starting material, to obtain 184
mg of the title compound (yield: 91 %).
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HPLC purification: 128 mg (purity: 96%)
'H NMR (300 MHz, MeOH-d4) b 1.22 (m, 4H), 1.46-1.62 (m, 6H), 1.79 (m,
1 H), 2.03 (m, 3H), 2.3 3(m, 6H), 4.97 (s, 2H), 6.54 (m, 1 H), 6.94 (d, J =
6.4
Hz, 1 H), 7.3 8 (m, 4H), 7.73 (d, J = 7.8 Hz, 1 H), 8.04 (d, J = 8.2 Hz, 1 H).
LC/MS (M+H): 440.25.
It should be understood that Examples, while indicating preferred
embodiments of the invention, are given by way of illustration only. From the
above Examples, one skilled in the art can ascertain the essential
characteristics of this invention, and without departing from the spirit and
scope thereof, can make various changes and modifications of the invention
to adapt it to various usage and conditions.
Test example 1
HDAC activity was analyzed using BIOMOL QuantizymeTM Assay
system which comprised two steps of 1) enzyme reaction between HDAC and
a substrate and 2) determination of the level of HDAC inhibitory activity. In
step 1), 42 ,u,e of a buffer solution (25 mM Tris-HCl [pH 8.0], 137 mM
NaCl, 2.7 mM KCI, 1 mM MgCl2) and 50 of 250 M Fluor de LysTM
substrate were added to each well of a 96-well plate, to which 2.5 /a of a
test compound (compounds of Example 1 to 49) was added. 0.5 0 of
HeLa nuclear extract(10 M) (a source of HDAC enzymes) was then added
thereto to a final concentration of 100 nM. The enzyme reaction was carried
out for 1 hr. Subsequently, in step 2), 2 M tricostatin A was added to 50
,ut of Flour de LysTM developer, followed by allowing the mixture to react at
room temperature for 15 minutes. The light excited at 355 nm and emitted
at 460 nm from the fluorophore was measured with a fluorometric plate
reader. The intensity of the fluorescence increases as the enzyme activity is
higher. The HDAC inhibitory activity of each of the test compounds was
determined and compared with that of the control. And suberoylanilide
hydroxamic acid (SAHA) (Biomol) was used at the same level with the test
compounds as a comparative control.
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The HDAC inhibitory concentrations (IC50) of the compounds
according to the present invention are shown in Table 1.
Table 1
compound IC50 compound IC50 compound IC50
(PM/ml) (PM/ml) (PM/ml)
Example Example Example
2 0.015 26 0.005 39 0.013
Example Example Example
4 0.014 27 0.020 40 0.007
Example Example Example
6 0.014 28 0.014 41 0.012
Example Example Example
7 0.012 29 0.027 42 0.022
Example Example Example
8 0.025 30 0.016 44 0.012
Example Example Example
0.020 0.006 0.010
31 45
Example Example Example
13 0.015 32 0.006 46 0.011
Example Example Example
21 0.023 33 0.024 47 0.016
Example Example Example
22 0.009 35 0.008 48 0.013
Example Example Example
23 0.021 36 0.017 49 0.010
Example Example
0.009 0.007 SAHA 0.100
24 37
Example 0.017 Example 0.010
25 38
5
As shown in Table l, each of the inventive alkylcarbamoyl
naphthalenyloxyoctenoyl hydroxyamide derivatives of formula (1) has a
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markedly higher inhibitory activity against HDAC than SAHA which is
known as a HDAC inhibitor.
Test Example 2
Inhibitory activities of the compounds synthesized in Examples
against proliferation of cancer cells were examined by SRB (Sulforhodamine
B) analysis using cervix adenocarcinoma Hela (Korean Cell Line Bank,
KCLB 10002) and colon cancer cells HCT116 (Korean Cell Line Bank,
KCLB 10247) as followed:
Cancer cells were inoculated into a 96-well microplate at a
concentration of 1 x 103-3 x 103 cells/well and incubated under the condition
of
37 C, 5% CO2 for 24 hrs. After the incubation was completed, 0.2, 1, 5, 25,
or 100 pM of each of the compounds of Examples was added to the plate, and
then the reactant was incubated again. After the substrate was stained, the
anti-cancer activity was determined by comparing the amount of protein in
the cells treated with compound of Examples with that of protein in non-
treated cells.
Specificially, after the incubation was completed, the culture medium
was removed from each well, and the cells were washed 3 times with PBS
(pH7.4). Then, a solution of 50% trichloroacetic acid (TCA) was added to
each well in an amount of 50 ,ul/well at 4 C for 1 hr to fix them. Then, the
microplate was washed 5 times with distilled water and dried at room
temperature.
50 ,ut of a staining solution prepared by dissolving 0.4% SRB in 1%
acetic acid was added to the wells, and the microplate was kept at room
temperature for 1 hr. The well plate was then washed 5 times with 1%
acetic acid to remove unbound SRB and dried at room temperature.
The stained cells were treated with 150 ,ut/well of 10 mM Tris-HCl
solution (pH 10.5) to elute SRB from the cells, and the absorbance of each
well at 520 nm was measured.
The ED50 value representing inhibition of the cancer cell growth by
the extent of 50% was calculated from the measured absorbance, and the
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results are shown in Table 2.
When cancer cells were treated with a HDAC inhibitor, histone
deacetylation would be inhibited, leading to an increase in the amount of
acetyl-histone. In this test, the increased amount of acetyl-histone in the
cancer cells was determined by using Western blotting, after the treatment
with each of the compounds of Examples.
Hela cells were inoculated into a 6-well microplate at a concentration
of 1.5 x 108 cells/well and incubated overnight under the condition of 371C,
5% CO2.
10 pM of each compound of Examples, and suberoylanilide
hydroxamic acid (SAHA) as a control was added to the plate and the plate
was incubated again for 24 hrs.
The cells were harvested in the presence of the test compound and
were subjected to fractionation to separate the nuclei from the cells. The
cells were allowed to swell in a hypotonic solution, lysed by several rounds
of
freezing-thawing cycles, and then centrifuged of 1,300 rpm for 5 min to
collect the nuclei. The nuclei was lysed in a lysis buffer solution (20 mM
HEPES (pH 7.9), 25% glycerol, 420 mM KCI, 1.5 mM MgCl2, 0.2 mM
EDTA) to obtain a protein extract.
The resulting protein extract was subjected to SDS-PAGE to separate
the proteins by the size and transferred onto the nitrocellulose membrane
according to the conventional method.
The amount of acetylated histon H4 was measured using anti-acetyl
histone H4 antibody (Upstate, USA) and evaluated the HDAC inhibitory
activity of the inventive compounds by comparing the degree of increase of
acetylated histone H4 relative to the control (SAHA).
The results are shown in Table 2.
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Table 2
Inhibitory conc.
against the cancer cell Effect on increase of acetylated
growth (EC50 PM)
histon H4 compared with SAHA
HCT116
Example 1 1.0 ++
Example 2 0.3 ++
Example 4 0.4 ++
Example 5 0.6 ++
Example 6 0.4 ++
Example 7 0.2 ++
Example 8 0.6 +
Example 13 1.3 ++
Example 24 1.1 +
Example 25 1.3 +
Example 26 0.8 +
Example 27 1.2 +
Example 28 0.7 +
Example 31 0.6 +
Example 32 0.5 +
Example 33 0.6 +
Example 34 0.8 +
Example 35 0.4 +
Example 36 0.7 +
Example 39 0.8 +
Example 40 0.9 +
Example 41 1.0 +
Example 45 0.5 +
Example 46 < 0.2 +
Example 47 0.32 +
Example 48 1.2 +
Example 49 0.9 +
SAHA 1.6 +
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As shown in Table 2, the inventive alkylcarbamoyl
naphthalenyloxyoctenoyl hydroxyamide derivatives of formula (1) has a
markedly enhanced inhibitory activity against HDAC, which leads to
effective suppression of the cancer cell proliferation.
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