Note: Descriptions are shown in the official language in which they were submitted.
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NOVEL ARYLALKENE DERIVATIVES AND USE THEREOF AS SELECTIVE
ESTROGEN RECEPTOR MODULATORS
FIELD OF THE INVENTION
[001] The present invention relates to a series of ethylene derivatives which
are selective estrogen
receptor modulators (SERMs), a pharmaceutical composition thereof, use thereof
in the preparation of
a medicament, and a method for preventing and/or treating estrogen-dependent
diseases and conditions
in mammals, especially humans, by using the same.
BACKGROUND OF THE INVENTION
[002] Estrogen receptor (ER) is an important transcription factor which plays
a key role in
reproductive, cardiovascular and central nervous systems and bone tissue. In
female body, there are
more than 400 tissues or organs containing ER, including for example uterus,
vagina, breast, pelvic
cavity (anadesma and connective tissues), skin, urocyst, urethra, ossature and
brain. During the
menopause, the secretion of estrogens is dramatically decreased, and the
tissues, organs and systems
related to estrogen change accordingly. Subsequently, elderly women develop
commonly climacteric
symptoms including hot flashes, sweating, insomnia, depression, headache,
vaginal dryness,
cardiovascular symptoms, urinary incontinence, swelling feeling, breast
tenderness and fatigue (Payer,
L: The menopause in various cultures. In: A portrait of the menopause. Expert
reports on medical and
therapeutic strategies for the 1990s. Ed. Burger H & Boulet M, Parthenon
Publishing, Park Ridge, NJ,
USA, 1991. pp 3-22; and Rekers H: Mastering the menopause. In: A portrait of
the menopause. Expert
reports on medical and therapeutic strategies for the 1990s. Ed. Burger H &
Boulet M, Parthenon
Publishing, Park Ridge, NJ, USA, 1991. pp 23-43). Long-term estrogen
deficiency would also induce
osteoporosis, senile dementia and cardiovascular disorders.
[003] Estrogen replacement therapy is increasingly used for the treatment of
climacteric symptoms
in women. Estrogen replacement therapy is also shown to be beneficial in
decreasing the risk of
osteoporotic bone fractures, preventing Alzheimer's disease (Henderson VW:
Estrogen, cognition, and
as woman's risk of Alzheimer's disease. Am J Med 103 (3A): 11S-18S, 1997) and
lowering
LDL-cholesterol values and thus preventing cardiovascular diseases (Grodstein
F, Stampfer, MJ:
Estrogen for women at varying risk of coronary disease. Maturitas 30: 19-26,
1998). However, use of
estrogen replacement therapy increases the risk of uterine and breast cancers
(Lobo RA: Benefits and
risks of estrogen replacement therapy. Am J Obstet Gynecol 173:982-990, 1995).
[004] Selective estrogen receptor modulators (SERMs) show different activities
to ER in different
tissues. They mimic estrogen in some tissues and have anti-estrogen activity
in others. It would be most
desirable to develop tissue-specific estrogens, which could be ER agonists in
bone tissue,
cardiovascular system and central nervous system, while being ER antagonists
in tissues like breast and
uterus, and without estrogenic adverse effects.
[005] As the first SERMs drug approved for the treatment of osteoporosis,
Raloxifene exhibits ER
antagonism in breast and uterus and ER agonism in bone tissue and
cardiovascular system. However,
Raloxifene has no advantage over Tamoxifen in terms of therapeutic effect on
breast cancer, while it
has adverse effects such as hot flashes, leg cramps, headache and weight gain
(Davies GC, et al.,
Obstet Gynecol 193: 558-565(1999)).
[006] Obviously, it would be desirable to develop more potent and safer drugs
in preventing and
treating estrogen-dependent diseases and conditions.
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SUMMARY
[007] In one aspect, the present disclosure provides a compound of formula I,
A (R2)m
R1
_
R0
B (R3),,
Formula I
wherein:
R and R1 are independently selected from the group consisting of hydrogen,
halogen, alkyl,
cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl,
heterocyclyl, aryl and
heteroaryl are each optionally substituted with one or more groups selected
from the group consisting
of halogen, -OH, -NH2, -SH, alkyl, halogenated alkyl, and alkoxy, and the
carbon atoms on the ring of
the cycloalkyl, the heterocyclyl and the heteroaryl are optionally oxidized;
ring A and ring B are each independently selected from aryl, heteroaryl and
heterocyclyl, wherein
the carbon atoms on the ring of the heterocyclyl and the heteroaryl are
optionally oxidized;
R2 and R3 are independently selected from the group consisting of halogen, -
OH, -NH2, -CN, -SH,
-COOH, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkoxy,
alkylsulfanyl, cycloalkyloxy,
heterocyclyloxy, monoalkylamino, dialkylamino, -5(0)-alkyl and -S(0)2-alkyl,
wherein the alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkoxy, alkylsulfanyl,
cycloalkyloxy, heterocyclyloxy,
monoalkylamino, dialkylamino, -5(0)-alkyl and -S(0)2-alkyl are each optionally
substituted with
halogen, -OH, heterocyclyl, or -NR4R5, wherein R4 and R5 are each
independently hydrogen, alkyl or
cycloalkyl, or R4 and R5, together with the nitrogen atom to which they
attach, form a heterocyclyl
which is optionally substituted with alkyl;
m and n are the number of group R2 on ring A and the number of group R3 on
ring B, respectively,
and m and n are each independently 0, 1, 2 or 3,
or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph,
tautomer or prodrug
thereof.
[008] In another aspect, the present invention provides a compound of formula
I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof, for
modulating estrogen activities.
[009] In another aspect, the present invention provides a compound of formula
I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof, for
preventing and/or treating estrogen-dependent diseases and conditions.
[010] In another aspect, the present invention provides a pharmaceutical
composition which
comprises a compound of formula I, or a pharmaceutically acceptable salt,
stereoisomer, solvate,
polymorph, tautomer or prodrug thereof, as well as a pharmaceutically
acceptable carrier.
[011] In another aspect, the present invention provides use of a compound of
formula I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof, in the
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manufacture of a medicament for modulating estrogen activities.
[012] In another aspect, the present invention provides use of a compound of
formula I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof, in the
manufacture of a medicament for preventing and/or treating estrogen-dependent
diseases and
conditions.
[013] In another aspect, the present invention provides a method for
modulating estrogen activities
in mammals, especially in humans, which method comprises administering to a
mammal, especially a
human, in need thereof a therapeutically effective amount of a compound of
formula I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof.
[014] In another aspect, the present invention provides a method for
preventing and/or treating
estrogen-dependent diseases and conditions in mammals, especially in humans,
which method
comprises administering to a mammal, especially a human, in need thereof a
therapeutically effective
amount of a compound of formula I, or a pharmaceutically acceptable salt,
stereoisomer, solvate,
polymorph, tautomer or prodrug thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[015] Figure 1 shows weight change of nude mice during anti-tumor (MCF-7)
test.
MODES FOR CARRING OUT THE INVENTION
[016] Unless defined otherwise, all technical and scientific terms used herein
have the same
meanings as are commonly understood by one of skilled in the art to which the
claimed subject matter
belongs. All patents, patent applications, published materials referred to
throughout the entire
disclosure herein, unless noted otherwise, are incorporated by reference in
their entirety.
[017] It is to be understood that the foregoing general description and the
following detailed
description are exemplary and explanatory only and are not restrictive of any
subject matter claimed. In
this application, the use of the singular includes the plural unless
specifically stated otherwise. It must
be noted that, as used in the specification and the appended claims, the
singular forms "a", "an" and
"the" include plural referents unless the context clearly dictates otherwise.
It should also be noted that
use of "or" means "and/or" unless stated otherwise. Furthermore, use of the
term "including" as well as
other forms, such as "include", "includes", and "included" is not limiting.
Likewise, use of the term
"comprising" as well as other forms, such as "comprise", "comprises", and
"comprised" is not limiting.
[018] Definition of standard chemistry terms may be found in reference works,
including Carey
and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001),
Plenum
Press, New York. Unless otherwise indicated, conventional methods of mass
spectroscopy, NMR,
HPLC, IR and UVNis spectroscopy and pharmacology, within the skill of the art
are employed. Unless
specific definitions are provided, the nomenclature employed in connection
with, and the laboratory
procedures and techniques of, analytical chemistry, synthetic organic
chemistry, and medicinal and
pharmaceutical chemistry described herein are those known in the art. Standard
techniques can be used
for chemical syntheses, chemical analyses, pharmaceutical preparation,
formulation, and delivery, and
treatment of patients. Reactions and purification techniques can be performed
e.g., using kits of
manufacturer's specifications or as commonly accomplished in the art or as
described herein. The
foregoing techniques and procedures can be generally performed of conventional
methods well known
in the art and as described in various general and more specific references
that are cited and discussed
throughout the present specification. Throughout the specification, groups and
substituents thereof can
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be chosen by one skilled in the field to provide stable moieties and
compounds.
[019] Where substituent groups are specified by their conventional chemical
formulas, written
from left to right, they equally encompass the chemically identical
substituents that would result from
writing the structure from right to left. As a non-limiting example, -CH20- is
equivalent to -OCH2-.
[020] The section headings used herein are for organizational purposes only
and are not to be
construed as limiting the subject matter described. All documents, or portions
of documents, cited in
the application including, without limitation, patents, patent applications,
articles, books, manuals, and
treatises are hereby expressly incorporated by reference in their entirety for
any purpose.
[021] Certain chemical groups named herein may be preceded by a shorthand
notation indicating
the total number of carbon atoms that are to be found in the indicated
chemical group. For example;
C1-C6 alkyl describes an alkyl group, as defined below, having a total of 1 to
6 carbon atoms. The total
number of carbons in the shorthand notation does not include carbons that may
exist in substituents of
the group described.
[022] In addition to the foregoing, as used in the specification and appended
claims, unless
specified to the contrary, the following terms have the meaning indicated.
[023] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.
[024] The term "aromatic" as used herein, refers to a planar, cyclic or
polycyclic, ring moiety
having a delocalized at-electron system containing 4n+2 n electrons, where n
is an integer. Aromatic
rings can be formed by five, six, seven, eight, nine, or more than nine atoms.
Aromatics can be
optionally substituted and can be monocyclic or fused- ring polycyclic. The
term aromatic encompasses
both all carbon containing rings (e.g., phenyl) and those rings containing one
or more heteroatoms (e.g.,
pyridine).
[025] The terms "heteroatom" or "hetero" as used herein, alone or in
combination, refer to an atom
other than carbon and hydrogen. Heteroatoms are independently selected from
among oxygen, nitrogen,
sulfur, phosphor, silicon, selenium and tin but are not limited to these
atoms. In embodiments in which
two or more heteroatoms are present, the two or more heteroatoms can be the
same as each another, or
some or all of the two or more heteroatoms can each be different from the
others.
[026] The term "fused" as used herein, alone or in combination, refers to
cyclic structures in which
two or more rings share one or more bonds.
[027] As used alone or as a part of another moiety, such as in halogen-
substituted alkyl, the term
"alkyl" refers to a straight or branched mono-valent hydrocarbon chain radical
consisting solely of
carbon and hydrogen atoms, containing no unsaturation, having from one to
twelve carbon atoms,
preferably one to eight carbon atoms and more preferably one to six carbon
atoms, and which is
attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-
propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl, tert-butyl, n-pentyl, hexyl, heptyl, 2-methylhexyl, 3-
methylhexyl, octyl, nonyl,
decyl, and the like.
[028] As used herein, the term "alkoxy" refers to a radical of the formula -
0Ra where Ra is an alkyl
radical as defined above. Examples of the alkoxy radical include, but not
limited to, methoxy, ethoxy,
iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
[029] As used herein, the term "alkylsulfanyl" refers to a radical of the
formula -SRa where Ra is an
alkyl radical as defined above. Examples of the alkylsulfanyl radical include,
but not limited to,
methylsulfanyl, ethylsulfanyl, iso-propylsulfanyl, and the like.
[030] As used herein, the term "monoalkylamino" refers to a radical of the
formula -NHRa where
Ra is an alkyl radical as defined above. Examples of the monoalkylamino
radical include, but not
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[031] As used herein, the term "dialkylamino" refers to a radical of the
formula -NRaRb where R.
and Rb are each independently an alkyl radical as defined above. Examples of
the dialkylamino radical
include, but not limited to, dimethylamino, diethylamino, dipropylamino,
methylethylamino, and the
like.
[032] As used alone or as a part of another moiety, the term "alkenyl" refers
to a straight or
branched mono-valent hydrocarbon chain radical group consisting solely of
carbon and hydrogen
atoms, containing at least one double bond, having from two to fourteen carbon
atoms, preferably from
two to ten carbon atoms, more preferably form two to six carbon atoms, and
which is attached to the
rest of the molecule by a single bond, e.g., ethenyl, prop-1-enyl, allyl, but-
1-enyl, but-2-enyl,
pent-l-enyl, penta-1,4-dienyl, and the like.
[033] As used alone or as a part of another moiety, the term "alkynyl" refers
to a straight or
branched mono-valent hydrocarbon chain radical group comprising solely of
carbon and hydrogen
atoms, containing at least one triple bond, optionally containing more or more
double bonds, having
from two to fourteen carbon atoms, preferably from two to ten carbon atoms,
more preferably from two
to six carbon atoms, and which is attached to the rest of the molecule by a
single bond, for example,
ethynyl, prop- 1 -ynyl, but- 1 -ynyl, pent- 1 - en-4-ynyl, and the like.
[034] As used alone or as a part of another moiety, the term "cycloalkyl"
refers to a stable
mono-valent non-aromatic monocyclic or polycyclic hydrocarbon radical
consisting solely of carbon
and hydrogen atoms, which may include fused or bridged ring systems, having
from three to fifteen
carbon atoms, preferably having from three to ten carbon atoms, more
preferably having from three to
eight carbon atoms, and which is saturated or unsaturated and attached to the
rest of the molecule by a
single bond. Examples of cycloalkyl include, but not limited to, cyclopropyl,
cyclobutyl, cyclopentyl,
cyclohexyl, cyclohexanonyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydro-
indenyl,
1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-
benzocyclohepten-6-yl,
6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-
benzocyclooctenyl, fluorenyl,
dicyclo[2.2.1]heptyl, 7,7-dimethyl-dicyclo[2.2.1]heptyl,
dicyclo[2.2.1]heptenyl, dicyclo[2.2.2]octyl,
dicyclo[3.1.1]heptyl, dicyclo[3.2.1]octyl, dicyclo[2.2.2]octenyl,
dicyclo[3.2.1]octenyl, adamantyl,
octahydro-4,7-methylene-1H-indenyl, octahydro-2,5-methylene-pentalinyl,
norbornyl, decalinyl, and
the like. In the present application, the heterocyclyl comprises preferably
three to eitht carbon atoms,
and is more preferably cyclopentyl, cyclohexyl, cyclohexanonyl, or
cycloheptyl.
[035] As used herein, the term "cycloalkyloxy" refers to a radical of the
formula -ORb where Rb is
a cycloalkyl radical as defined above.
[036] As used alone or as a part of another moiety, the term "heterocyclyl"
refers to a stable 3- to
18-membered mono-valent non-aromatic ring radical which consists of two to
twelve carbon atoms and
from one to six heteroatoms selected from the group consisting of nitrogen,
oxygen and sulfur. Unless
stated otherwise specifically in the specification, the heterocyclyl radical
may be a monocyclic, bicyclic,
tricyclic or tetracyclic ring system, which may include fused or bridged ring
systems; and the nitrogen,
carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized;
the nitrogen atom may
be optionally quaternized; and the heterocyclyl radical may be partially or
fully saturated. A
heterocyclyl may be connected to the rest of the molecule by a single bond via
a carbon atom or a
heteroatom on the ring. In a heterocyclyl comprising a fused ring, one or more
of the rings may be an
aryl or heteroaryl, provided that the site for connecting to the rest of the
molecule is a non-aromatic
ring atom. For the purpose of the present application, the heterocyclyl is
preferably a stable 4- to
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11-membered mono-valent non-aromatic mono- or di-cyclic ring radical which
comprises one to three
heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur,
and more preferably a
stable 4- to 8-membered mono-valent non-aromatic mono-cyclic ring radical
which comprises one to
three heteroatoms selected from the group consisting of nitrogen, oxygen and
sulfur. Examples of
heterocyclyl radicals include, but are not limited to, azepanyl, azetidinyl,
decahydroisoquinolyl,
dihydrofuranyl, dihydroindolyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl,
imidazolidinyl, imidazolinyl,
isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,
octahydroisoindolyl, oxazinyl,
oxazolidinyl, 1-oxo-thiomorpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-
oxopyrrolidinyl,
phthalimido, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl,
pyrrolidinyl, quinolizinyl,
quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolyl,
tetrahydropyranyl, thiazolidinyl,
thienyl[1,3]dithianyl, thiomorpholinyl, trithianyl, and the like.
[037] As used herein, the term "heterocyclyloxy" refers to a radical of the
formula -0R6 where R6
is a heterocyclyl radical as defined above.
[038] As used alone or as a part of another moiety, the term "aryl" or the
prefix "ar-" (such as in
"aralkyl") refers to a hydrocarbon ring system radical comprising hydrogen, 6
to 18 carbon atoms,
preferably 6 to 10 carbon atoms, and at least one aromatic ring. For purposes
of this invention, the aryl
radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system,
which may included fused or
bridged ring systems. An aryl may be connected to the rest of the molecule by
a single bond via an
aromatic ring atom. Aryl radicals include, but are not limited to, phenyl,
naphthyl, anthracenyl,
phenanthrenyl, fluorenyl, 2-benzooxazolinonyl, 2H-1,4-benzooxazon-3(4H)-on-7-
yl, and the like. In
the present application, the aryl is preferably a C6-C10 aryl, and more
preferably phenyl.
[039] As used alone or as a part of another moiety, the term "heteroaryl"
refers to a 5- to
16-membered ring system radical comprising one to fifteen carbon atoms,
preferably one to ten carbon
atoms, one to four heteroatoms selected from the group consisting of nitrogen,
oxygen and sulfur, and
at least one aromatic ring. Unless specified otherwise in the Specification,
the heteroaryl radical may be
a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may
include fused or bridged ring
systems, provided that the site for connection to the rest of the molecule is
an aromatic ring atom. The
nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally
oxidized; the nitrogen atom
may be optionally quaternized. For purposes of this invention, the heteroaryl
is preferably a stable 4- to
11-membered aromatic mono-cyclic ring radical which comprises one to three
heteroatoms selected
from the group consisting of nitrogen, oxygen and sulfur, and more preferably
a stable 5- to
8-membered aromatic mono-cyclic ring radical which comprises one to three
heteroatoms selected
from the group consisting of nitrogen, oxygen and sulfur. Examples of
heteroaryl radicals include, but
are not limited to, acridinyl, azepinyl, benzimidazolyl, benzindolyl, 1,4-
benzodioxanyl,
benzo[6][1,4]dioxepinyl, benzodioxinyl,
benzodioxolyl, benzofuranonyl, benzofuranyl,
benzo[4,6]imidazo[1,2-a]pyridinyl, benzonaphthofuranyl,
benzopyranonyl, benzopyranyl,
benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl
(benzothiophenyl), benzotriazolyl,
benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, dibenzofuranyl,
dibenzothiophenyl, furanonyl, furanyl,
imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, isoindazolyl,
isoindolinyl, isoindolyl,
isoquinolinyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl,
oxadiazolyl, oxatriazolyl, oxazolyl,
1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl,
oxiranyl, 2-oxoazepinyl,
oxopyridinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,
phenoxazinyl,
1-pheny1-1H-pyrrolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl,
pyridazinyl,
1H-pyridin-2-onyl, 1H-pyridin-4-onyl, 1H-pyridin-2-on-4-yl, pyridinyl,
pyrimidinyl, pyrrolyl,
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quinazolinyl, quinolinyl, quinolyl, quinoxalinyl, quinuclidinyl,
tetrahydroquinolinyl,
4,5,6,7-tetrahydrobenzo[b]thiophenyl, tetrazolyl, thiadiazolyl, thiazolyl,
thiophenyl (i.e. thienyl),
triazinyl, triazolyl, and the like. In the present application, the heteroaryl
is preferably a 5- to
8-membered heteroaryl comprises one to three heteroatoms selected from the
group consisting of
nitrogen, oxygen and sulfur, and more preferably pyridinyl, pyrimidinyl,
thiazolyl, oxo-pyridinyl,
1H-pyridin-2-on-4-y1 or thienyl.
[040] "Optional" or "optionally" as used herein means that the subsequently
described event or
circumstances may or may not occur, and that the description includes
instances where said event or
circumstance occurs and instances in which it does not. For example,
"optionally substituted aryl"
means that the aryl radical may or may not be substituted and that the
description includes both
substituted aryl radicals and aryl radicals having no substitution.
[041] The terms "moiety", "chemical moiety", "group" and "chemical group", as
used herein, refer
to a specific segment or functional group of a molecule. Chemical moieties are
often recognized
chemical entities embedded in or appended to a molecule.
[042] A "stereoisomer" refers to a compound made up of the same atoms bonded
by the same
bonds but having different three-dimensional structures. The present invention
contemplates various
stereoisomers and mixtures thereof.
[043] As the compounds described herein contain olefinic double bonds, unless
specified
otherwise, it is intended that the compounds include both E and Z geometric
isomers.
[044] A "tautomer" refers to an isomer resulted from a proton shift from one
atom of a molecule
to another atom of the same molecule. The present invention includes tautomers
of any said
compounds.
[045] The term "polymorph" or "polymorphism" as used herein refers to a
compound of this
invention present in different crystal lattice forms. Some of the compounds of
the present invention
may have more than one crystal forms, and the present invention tends to
encompass all the
polymorphs or mixtures thereof.
[046] Also within the scope of the invention are intermediate compounds of
formula (I) and all
polymorphs of the aforementioned species and crystal habits thereof. Likewise,
all tautomeric forms
are also intended to be included.
[047] The compounds of the invention, or their pharmaceutically acceptable
salts may contain one
or more asymmetric centers and may thus give rise to enantiomers,
diastereomers, and other
stereoisomeric forms that may be defined, in terms of absolute
stereochemistry, as (R)- or (S)-. The
present invention is meant to include all such possible isomers, as well as
their racemic and optically
pure forms. Optically active (+) and (-), or (R)- and (S)- isomers may be
prepared using chiral synthons
or chiral reagents, or resolved using conventional techniques, for example,
chromatography and
fractional crystallization.
[048] Conventional techniques for the preparation/isolation of individual
enantiomers include
chiral synthesis from a suitable optically pure precursor or resolution of the
racemate (or the racemate
of a salt or derivative) using, for example, chiral high pressure liquid
chromatography (HPLC). See, for
example, Gerald Giibitz and Martin G Schmid (Eds.), Chiral Separations,
Methods and Protocols,
Methods in Molecular Biology, Vol. 243, 2004; A.M. Stalcup, Chiral
Separations, Annu. Rev. Anal.
Chem. 3:341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL
ORGANIC CHEMISTRY 5TH ED., Longman Scientific and Technical Ltd., Essex,
1991,
809-816; Heller, Acc. Chem. Res. 1990, 23, 128.
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[049] As used herein, the term "pharmaceutically acceptable salt" includes
both acid and base
addition salts.
[050] "Pharmaceutically acceptable acid addition salt" refers to those salts
which retain the
biological effectiveness and properties of the free bases, which are not
biologically or otherwise
undesirable, and which are formed with inorganic acids such as, but are not
limited to, hydrochloric
acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the
like, and organic acids such
as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid,
alginic acid, ascorbic acid,
aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,
camphoric acid,
camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic
acid, cinnamic acid, citric
acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,
ethanesulfonic acid,
2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid,
gentisic acid, glucoheptonic
acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-
glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic
acid, lactobionic acid, lauric
acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic
acid, mucic acid,
naphthalene-1 ,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-
naphthoic acid, nicotinic
acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,
propionic acid, pyroglutamic acid,
pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic
acid, succinic acid, tartaric acid,
thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic
acid, and the like.
[051] "Pharmaceutically acceptable base addition salt" refers to those salts
which retain the
biological effectiveness and properties of the free acids, which are not
biologically or otherwise
undesirable. These salts are prepared from addition of an inorganic base or an
organic base to the free
acid. Salts derived from inorganic bases include, but are not limited to, the
sodium, potassium, lithium,
ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts
and the like. Preferred
inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium
salts. Salts derived
from organic bases include, but are not limited to, salts of primary,
secondary, and tertiary amines,
substituted amines including naturally occurring substituted amines, cyclic
amines and basic ion
exchange resins, such as ammonia, isopropylamine, trimethylamine,
diethylamine, triethylamine,
tripropylamine, diethanolamine, ethanolamine, deanol, 2-
dimethylaminoethanol,
2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,
caffeine, procaine, hydrabamine,
choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine,
methylglucamine,
theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-
ethylpiperidine,
polyamine resins and the like. Particularly preferred organic bases are
isopropylamine, diethylamine,
ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
[052] Crystallizations often produce a solvate of the compound of the
invention. As used herein,
the term "solvate" refers to an aggregate that comprises one or more molecules
of a compound of the
invention with one or more molecules of solvent. The solvent may be water, in
which case the solvate
may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus,
the compounds of the
present invention may exist as a hydrate, including a monohydrate, dihydrate,
hemihydrate,
sesquihydrate, trihydrate, tetrahydrate and the like, as well as the
corresponding solvated forms. The
compound of the invention may be true solvates, while in other cases, the
compound of the invention
may merely retain adventitious water or be a mixture of water plus some
adventitious solvent. The
compounds of the present invention may react in a solvent or deposit or
crystallize from a solvent. The
solvates of the compounds of the present invention are also encompassed in the
scope of the present
invention.
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9
[053] The present invention also contemplates prodrugs of the compounds of the
present invention.
"Prodrugs" is meant to indicate a compound that may be converted under
physiological conditions or
by solvolysis to a biologically active compound of the invention. Thus, the
term "prodrug" refers to a
metabolic precursor of a compound of the invention that is pharmaceutically
acceptable. A prodrug
may be inactive when administered to a subject in need thereof, but is
converted in vivo to an active
compound of the invention. Prodrugs are typically rapidly transformed in vivo
to yield the parent
compound of the invention, for example, by hydrolysis in blood. The prodrug
compound often offers
advantages of solubility, tissue compatibility or delayed release in a
mammalian organism. Prodrugs
include amino protective groups and carboxy protective groups which are known
to persons skilled in
the art. Methods for preparing specific prodrugs are provided in e.g.
Saulnier, M. G, et al., Bioorg. Med.
Chem. Lett. 1994, 4, 1985-1990; Greenwald, R. B., et al., J. Med. Chem. 2000,
43, 475.
[054] As used herein, "pharmaceutical composition" refers to a formulation of
a compound of the
invention and a medium generally accepted in the art for the delivery of the
biologically active
compound to mammals, e.g., humans. Such a medium includes all pharmaceutically
acceptable carriers
therefor.
[055] The term "acceptable" as used herein, with respect to a formulation,
composition or
ingredient, means having no persistent detrimental effect on the general
health of the subject being
treated.
[056] The term "pharmaceutically acceptable" as used herein, refers to a
material, such as a carrier
or diluent, which does not abrogate the biological activity or properties of
the compounds described
herein, and is relatively nontoxic, i.e., the material may be administered to
an individual without
causing undesirable biological effects or interacting in a deleterious manner
with any of the
components of the composition in which it is contained.
[057] "Pharmaceutically acceptable carrier" includes without limitation any
adjuvant, carrier,
excipient, glidant, sweetening agent, diluent, preservative, dye/colorant,
flavor enhancer, surfactant,
wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent,
solvent, or emulsifier
which has been approved by relevant government administration as being
acceptable for use in humans
or domestic animals.
[058] The term "SERMs" as used herein, refers to selective estrogen receptor
modulators, which
are compounds that exhibit estrogen receptor agonism in one or more target
tissues, and estrogen
receptor antagonism in one or more other target tissues.
[059] The term "subject", "patient" or "individual" as used herein in
reference to individuals
suffering from a disease, a disorder, a condition, and the like, encompasses
mammals and
non-mammals. Examples of mammals include, but are not limited to, any member
of the Mammalian
class: humans, non-human primates such as chimpanzees, and other apes and
monkey species; farm
animals such as cattle, horses, sheep, goats, swine; domestic animals such as
rabbits, dogs, and cats;
laboratory animals including rodents, such as rats, mice and guinea pigs, and
the like. Examples of
non- mammals include, but are not limited to, birds, fish and the like. In one
embodiment of the
methods and compositions provided herein, the mammal is a human.
[060] The terms "prevention of', "prophylaxis" and "prevent" includes reducing
the likelihood of a
patient incurring or developing breast cancer.
[061] "Treating" or "treatment" as used herein covers the treatment of the
disease or condition of
interest in a mammal, preferably a human, having the disease or condition of
interest, and includes:
(i) preventing the disease or condition from occurring in a mammal, in
particular, when such
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mammal is predisposed to the condition but has not yet been diagnosed as
having it;
(ii) inhibiting the disease or condition, i.e., arresting its development;
(iii) relieving the disease or condition, i.e., causing regression of the
disease or condition; or
(iv) relieving the symptoms resulting from the disease or condition.
[062] As used herein, the terms "disease" and "condition" may be used
interchangeably or may be
different in that the particular malady or condition may not have a known
causative agent (so that
etiology has not yet been worked out) and it is therefore not yet recognized
as a disease but only as an
undesirable condition or syndrome, wherein a more or less specific set of
symptoms have been
identified by clinicians.
[063] The terms "effective amount", "therapeutically effective amount" or
"pharmaceutically
effective amount" as used herein, refer to a sufficient amount of at least one
agent or compound being
administered which will relieve to some extent one or more of the symptoms of
the disease or condition
being treated. The result can be reduction and/or alleviation of the signs,
symptoms, or causes of a
disease, or any other desired alteration of a biological system. For example,
an "effective amount" for
therapeutic uses is the amount of the composition comprising a compound as
disclosed herein required
to provide a clinically significant decrease in a disease. An appropriate
"effective" amount in any
individual case may be determined using techniques, such as a dose escalation
study.
[064] The terms "administer", "administering", "administration", and the like,
as used herein, refer
to the methods that may be used to enable delivery of compounds or
compositions to the desired site of
biological action. These methods include, but are not limited to oral routes,
intraduodenal routes,
parenteral injection (including intravenous, subcutaneous, intraperitoneal,
intramuscular, intravascular
or infusion), topical and rectal administration. Those of skill in the art are
familiar with administration
techniques that can be employed with the compounds and methods described
herein, e.g., as discussed
in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.;
Pergamon; and
Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co.,
Easton, Pa. In preferred
embodiments, the compounds and compositions described herein are administered
orally.
[065] The term "agonist", as used herein, refers to a molecule such as a
compound, a drug, an
enzyme activator or a hormone modulator which enhances the activity of another
molecule or the
activity of a receptor site.
[066] The term "antagonist", as used herein, refers to a molecule such as a
compound, a drug, an
enzyme inhibitor, or a hormone modulator, which diminishes, or prevents the
action of another
molecule or the activity of a receptor site.
[067] The term "modulate", as used herein, means to interact with a target
either directly or
indirectly so as to alter the activity of the target, including, by way of
example only, to enhance the
activity of the target (up-regulate), to inhibit the activity of the target
(down-regulate), to limit the
activity of the target, or to extend the activity of the target.
[068] The term "modulator", as used herein, refers to a molecule that
interacts with a target either
directly or indirectly. The interactions include, but are not limited to, the
interactions of an agonist and
an antagonist.
[069] The terms "enhance" or "enhancing," as used herein, means to increase or
prolong either in
potency or duration of a desired effect. Thus, in regard to enhancing the
effect of therapeutic agents, the
term "enhancing" refers to the ability to increase or prolong, either in
potency or duration, the effect of
other therapeutic agents on a system.
[070] An "enhancing-effective amount," as used herein, refers to an amount
adequate to enhance
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the effect of another therapeutic agent in a desired system.
[071] The terms "pharmaceutical combination", "administering an additional
therapy",
"administering an additional therapeutic agent" and the like, as used herein,
refer to a pharmaceutical
therapy resulting from mixing or combining more than one active ingredient and
includes both fixed
and non-fixed combinations of the active ingredients. The term "fixed
combination" means that at least
one of the compounds described herein, and at least one co-agent, are both
administered to a patient
simultaneously in the form of a single entity or dosage. The term "non-fixed
combination" means that
at least one of the compounds described herein, and at least one co-agent, are
administered to a patient
as separate entities either simultaneously, concurrently or sequentially with
variable intervening time
limits, wherein such administration provides effective levels of the two or
more compounds in the body
of the patient. These also apply to cocktail therapies, e.g. the
administration of three or more active
ingredients.
[072] The terms "co-administration", "administered in combination with" and
their grammatical
equivalents or the like, as used herein, are meant to encompass administration
of the selected
therapeutic agents to a single patient, and are intended to include treatment
regimens in which the
agents are administered by the same or different route of administration or at
the same or different
times. In some embodiments the compounds described herein will be co-
administered with other agents.
These terms encompass administration of two or more agents to an animal so
that both agents and/or
their metabolites are present in the animal at the same time. They include
simultaneous administration
in separate compositions, administration at different times in separate
compositions, and/or
administration in a composition in which both agents are present. Thus, in
some embodiments, the
compounds of the invention and the other agent (s) are administered in a
single composition.
[073] The term "metabolite," as used herein, refers to a derivative of a
compound which is formed
when the compound is metabolized.
[074] The term "active metabolite," as used herein, refers to a biologically
active derivative of a
compound that is formed when the compound is metabolized.
[075] The term "metabolized," as used herein, refers to the sum of the
processes (including, but not
limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which
a particular substance is
changed by an organism. Thus, enzymes may produce specific structural
alterations to a compound.
For example, cytochrome P450 catalyzes a variety of oxidative and reductive
reactions while uridine
diphosphate glucuronyltransferases catalyze the transfer of an activated
glucuronic-acid molecule to
aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free
mercapto groups. Further
information on metabolism may be obtained from The Pharmacological Basis of
Therapeutics, 9th
Edition, McGraw-Hill (1996).
[076] In one aspect, the present invention provides a compound of formula I,
A (R2)m
R1
_
R
B (R3)n
Formula I
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wherein:
R and R1 are independently selected from the group consisting of hydrogen,
halogen, alkyl,
cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl,
heterocyclyl, aryl and
heteroaryl are each optionally substituted with one or more groups selected
from the group consisting
of halogen, -OH, -NH2, -SH, alkyl, halogenated alkyl and alkoxy, and the
carbon atoms on the ring of
the cycloalkyl, the heterocyclyl and the heteroaryl are optionally oxidized;
ring A and ring B are each independently selected from aryl, heteroaryl and
heterocyclyl, wherein
the carbon atoms on the ring of the heterocyclyl and the heteroaryl are
optionally oxidized;
R2 and R3 are independently selected from the group consisting of halogen, -
OH, -NH2, -CN, -SH,
-COOH, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkoxy,
alkylsulfanyl, cycloalkyloxy,
heterocyclyloxy, monoalkylamino, dialkylamino, -S(0)-alkyl and -S(0)2-alkyl,
wherein the alkyl,
alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkoxy, alkylsulfanyl,
cycloalkyloxy, heterocyclyloxy,
monoalkylamino, dialkylamino, -S(0)-alkyl and -S(0)2-alkyl are each optionally
substituted with
halogen, -OH, heterocyclyl, or -NR4R5, wherein R4 and R5 are each
independently hydrogen, alkyl or
cycloalkyl, or R4 and R5, together with the nitrogen atom to which they
attach, form a heterocyclyl
which is optionally substituted with alkyl;
m and n are the number of group R2 on ring A and the number of group R3 on
ring B, respectively,
and m and n are each independently 0, 1, 2 or 3,
or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph,
tautomer or prodrug
thereof.
[077] In one embodiment, the present invention provides a compound of formula
I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
wherein:
R and R1 are independently selected from the group consisting of alkyl,
cycloalkyl, heterocyclyl,
aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and
heteroaryl are each optionally
substituted with one or more groups selected from the group consisting of
halogen, -OH, alkyl,
halogenated alkyl and alkoxy, and the carbon atoms on the ring of the
cycloalkyl, the heterocyclyl, and
the carbon atoms on the ring of the cycloalkyl or the heteroaryl are
optionally oxidized.
[078] In another embodiment, the present invention provides a compound of
formula I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
wherein:
R and R1 are independently selected from the group consisting of alkyl,
cycloalkyl, aryl and
heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl are each
optionally substituted with one or
more groups selected from the group consisting of halogen, -OH, alkyl and
alkoxy, and the carbon
atoms on the ring of the cycloalkyl or the heteroaryl are optionally oxidized.
[079] In another embodiment, the present invention provides a compound of
formula I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
wherein:
one of R and R1 is alkyl, and the other of R and R1 is selected from the
group consisting of
cycloalkyl, aryl and heteroaryl, each optionally substituted with one or more
groups independently
selected from the group consisting of halogen, -OH, -NH2, -SH, alkyl, alkoxy,
and halogen-substituted
alkyl, wherein the carbon atoms on the ring of the cycloalkyl or the
heteroaryl are optionally oxidized.
[080] In one embodiment, the present invention provides a compound of formula
I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
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13
wherein:
one of R and R1 is alkyl or halogen-substituted alkyl, and the other of R
and R1 is selected from
the group consisting of:
a) 5-membered heteroaryl comprising at least one heteroatom selected from the
group
consisting of nitrogen, sulfur and oxygen, optionally substituted with one or
more groups
independently selected from the group consisting of halogen, -OH, alkyl,
alkoxy, and
halogen-substituted alkyl; preferably thiophenyl optionally substituted with
one or more
halogen;
b) 6-membered heteroaryl comprising one or two heteroatoms selected from the
group
consisting of nitrogen, sulfur and oxygen, optionally substituted with one or
more groups
independently selected from the group consisting of halogen, -OH, alkyl,
alkoxy, and
halogen-substituted alkyl, wherein the carbon atoms on the ring of the
heteroaryl are optionally
oxidized; preferably pyridinyl optionally substituted with one or more -OH;
c) 5- or 6-membered cycloalkyl optionally substituted with one or more groups
independently selected from the group consisting of halogen, -OH, alkyl,
alkoxy, and
halogen-substituted alkyl, wherein the carbon atoms on the ring of the
cycloalkyl are optionally
oxidized; preferably cyclohexanonyl or cyclohexyl optionally substituted with
one or more
-OH; and
d) phenyl optionally substituted with one or more groups independently
selected from the
group consisting of halogen, -OH, alkyl and alkoxy.
[081] In one embodiment, the present invention provides a compound of formula
I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
wherein:
one of R and R1 is selected from the group consisting of hydrogen, halogen
and alkyl, wherein
the alkyl is optionally substituted with one or more groups independently
selected from the group
consisting of halogen, -OH, -NH2, alkoxy; or is alkyl optionally substituted
with one or more halogen;
and
the other of R and R1 is represented by the following Formula II:
_.....x
Y-----
,
\ (
Wµ .
*
Formula II
wherein the dashed line in Formula II indicates that the 5-membered ring
formed by X, Y and W
together with the carbon atoms to which they attach is saturated or
unsaturated, wherein:
X, Y and W are each independently selected from the group consisting of C, N,
0 and S; and said
5-membered ring is optionally substituted with one or more groups
independently selected from the
group consisting of halogen, -OH, -SH, alkyl, cycloalkyl, alkoxy and
alkylsulfanyl, wherein the alkyl,
cycloalkyl, alkoxy and alkylsulfanyl are each optionally substituted with one
or more groups
independently selected from the group consisting of halogen, -OH, -NH2,
monoalkylamino,
dialkylamino and heterocyclyl.
[082] In another embodiment, the present invention provides a compound of
formula I, or a
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14
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
wherein:
at least one of X, Y and W is a heteroatom selected from the group consisting
of N, 0 and S; and
said 5-membered ring is optionally substituted with one or more groups
independently selected from
the group consisting of halogen and alkyl;
[083] In another embodiment, the present invention provides a compound of
formula I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
wherein:
Formula II is selected from:
H
0
' N N------.
0
\\ \\
I/ \ . * \ e
N---- \
HN = N = N =
*
*
* . ..
[084] In one embodiment, the present invention provides a compound of formula
I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
wherein:
ring A and ring B are each independently selected from aryl and heteroaryl,
wherein the carbon
atoms on the ring of the heteroaryl are optionally oxidized.
[085] In another embodiment, the present invention provides a compound of
formula I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
wherein:
ring A and ring B are each independently selected from aryl and a 6-membered
heteroaryl
comprising 1 or 2 nitrogen atoms, wherein the carbon atoms on the ring of the
heteroaryl are optionally
oxidized.
[086] In another embodiment, the present invention provides a compound of
formula I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
wherein:
ring A and ring B are each independently selected from phenyl and pyridinyl.
[087] In one embodiment, the present invention provides a compound of formula
I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
wherein:
R2 and R3 are independently selected from the group consisting of halogen, -
OH, -NH2, -CN, alkyl,
alkenyl, alkynyl, alkoxy, alkylsulfanyl, heterocyclyloxy, monoalkylamino and
dialkylamino, wherein
the alkyl, alkenyl, alkynyl, alkoxy, alkylsulfanyl, heterocyclyloxy,
monoalkylamino and dialkylamino
are each optionally substituted with halogen, -OH, heterocyclyl or -NR4R5,
wherein R4 and R5 are each
independently hydrogen, alkyl or cycloalkyl, or R4 and R5, together with the
nitrogen atom to which
they attach, form a heterocyclyl which is optionally substituted with alkyl.
[088] In another embodiment, the present invention provides a compound of
formula I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
wherein:
R2 and R3 are independently selected from the group consisting of halogen, -
OH, -NH2, -CN, alkyl,
alkenyl, alkynyl, alkoxy, alkylsulfanyl, heterocyclyloxy, monoalkylamino and
dialkylamino, wherein
the alkyl, alkenyl, alkynyl, alkoxy, alkylsulfanyl, heterocyclyloxy,
monoalkylamino and dialkylamino
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are each optionally substituted with heterocyclyl or -NR4R5, wherein R4 and R5
are each independently
hydrogen or alkyl, or R4 and R5, together with the nitrogen atom to which they
attach, form a
heterocyclyl which is optionally substituted with alkyl.
[089] In one embodiment, the present invention provides a compound of formula
I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
wherein:
ring A is selected from phenyl and a 6-membered heteroaryl, and R2 is at least
at para-position of
the phenyl or the 6-membered heteroaryl;
or
ring B is selected from phenyl and a 6-membered heteroaryl, and R3 is at least
at para-position of
the phenyl or the 6-membered heteroaryl.
[090] In one embodiment, the present invention provides a compound of formula
I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
wherein:
m and n are each independently 1 or 2.
[091] In one embodiment, the present invention provides a compound of formula
I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof,
wherein the compound is selected from the group consisting of:
/
CI j-N
\ OH
0
HCI
N /-
el
I 411 N \
/ N
-
OH li I
N CI
OH
OH /
4. = HCI 0,N / \
NH
_
N'
\_
=
OH
N
\ OH
/
0-\ N I
N '-NH \ .\.N
-/ \ \ N- HCI 0
- 1
0 ---
11 41
11
OH
OH SOH
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16
/
/¨NH
0" ON
0
N . . N
I I
0 : 0 :
/
,_\ N
0
= OH OH OH
N/"---- r-N- r-
...___
o o ..,.)
C)N
N N
I I /
* 0 / 0
OH OH = OH
/
NH ro
N.,..,) \ N NH
0
* / \ N . /
N
I /
* 0
0 *
OH
OH OH
OH
=. * /N
/
\¨N/
0 \ S
\ / \
_
\ /N
*
*
7¨\_
OH
NH OH
\
/
/¨NH HO 0¨\
OH 0 0' 'NH
s 0 = * = * \
CI \ \
S(:)FNI * *
OH
OH
0 OH
0 \ OH
. * 0 \N \ . ¨\_
NH
\ 0 N
\ *
*
* *
0¨\
0¨\_
'NH OH NH
\ \
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17
HO 0¨\ / HO 0¨\ /
_P\I\
¨N
\/ = 'NH
\¨/N . 'NH
* =
0
* *
OH OH *
OH
NT"-
N/"---- /
NH \----
\---
F //
= = . = . =
* * *
OH OH OH
0¨\¨ 0¨\¨ ONH
= = Br NH
CN
\ . 40 NII
. i¨
:
* *
*OH OH
OH
o....01H
_CH /
0 _/¨NH
HO
0 * .0
* * *
OH OH OH
/ / HO OH
/¨NH /¨NH
F
= 41 F * 4.0
*
*
OH OH NH
\
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18
/ /
/¨NH
0¨/ 0 0¨\ //¨NH
"NH 0 F 0'
4. 41
OH 41
OH OH
/
0 N0¨\ NH H
_
/¨
. 0oN
411 'NH
\ õN
s"
N241, 41
0
N¨
HNI
*
411 0 SOHO
H
OH
i
/ r.-N OH
r.-N 0¨\ / II
OH
II 'NH N
HNI1¨ 0 N . 41 * *
110 / 0
. *
o...-...õ,,N
Hõ
0¨\
OH 'NH
\
0 0¨\_ 0 H 0¨\_ /
CI 0 0¨\ /
= 41 N
\ 1 41, 441 NH
* 41 'NH
CI, 40 41
OH
OH OH
CI 0 OH
CI 0 O\_/
CI 0 0¨\ /
1 * 41 NH * * * = 'NH
4. *
41
0¨\
OH "NH OMe
\
CI 0¨\ 0 CI¨\_ /---- CI 0 0
'NH N ¨\¨ND
* / "N \ \ * . \--- *
0 .
4. . .
OH OH OH
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19
a = (3-\_ a = o /¨
N
II 41 N
\ = N\_
OH
CI 0 CI 0
CI 0
NH /10
\ 40 NO
=
OH OH OH
N \ /NH 0 0
NH
CI 0 0 CI 0 H
41\ N
=
OH OH
OH
\NJ¨NH
CI 0 CI 0
N
=
OH OH =
[092] In another aspect, the present invention provides a compound of formula
I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof, for
modulating estrogen activities.
[093] In another aspect, the present invention provides use of a compound of
formula I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof, in the
manufacture of a medicament for modulating estrogen activities.
[094] In another aspect, the present invention provides a compound of formula
I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof, for
preventing and/or treating estrogen-dependent diseases and conditions.
[095] In another aspect, the present invention provides use of a compound of
formula I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof, in the
manufacture of a medicament for preventing and/or treating estrogen-dependent
diseases and
conditions.
[096] In another aspect, the present invention provides a pharmaceutical
composition which
comprises a compound of formula I, or a pharmaceutically acceptable salt,
stereoisomer, solvate,
polymorph, tautomer or prodrug thereof, as well as a pharmaceutically
acceptable carrier.
[097] Normally, a compound of the invention, or a pharmaceutically acceptable
salt thereof, may
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be administered by formulating it into an appropriate pharmaceutical
composition with one or more
pharmaceutically acceptable carrier can. The pharmaceutical composition of the
invention may be
formulated into preparations in solid, semi-solid, liquid or gaseous forms,
such as tablets, capsules,
powders, granules, ointments, solutions, suppositories, injections, inhalants,
gels, microspheres, and
aerosols.
[098] The pharmaceutical composition of the invention may be prepared by
methodology well
known in the pharmaceutical art. For example, a pharmaceutical composition
intended to be
administered by injection can be prepared by combining a compound of the
invention with sterile,
distilled water so as to form a solution. A surfactant may be added to
facilitate the formation of a
homogeneous solution or suspension. Actual methods of preparing such dosage
forms are known, or
will be apparent, to those skilled in this art; for example, see The Science
and Practice of Pharmacy,
20th Edition (Philadelphia College of Pharmacy and Science, 2000).
[099] Typical routes of administering such pharmaceutical compositions
include, without
limitation, oral, topical, transdermal, inhalation, parenteral, sublingual,
rectal, vaginal, and intranasal.
For example, dosage forms suitable for oral administration include capsules,
tablets, granules, and
syrups. The compound of the present invention included in these dosage forms
may be solid powders
or granules; solutions or suspensions in aqueous or non-aqueous liquids;
emulsions of oil-in-water type
of water-in-oil type; and the like. The above mentioned dosage forms may be
prepared from active
compounds and one or more carriers or auxiliaries through common
pharmacological methods. The
carriers shall be compatible with the active compounds or the other
auxiliaries. For solid formulation,
commonly used non-toxic carriers include, but are not limited to, mannitol,
lactose, starch, magnesium
stearate, cellulose, glucose, sucrose, and the like. Carriers for liquid
formulations include, but are not
limited to, water, physiological saline, aqueous solution of glucose, ethylene
glycol, polyethylene
glycol, and the like. The active compound may form a solution or a suspension
with the above carriers.
The specific route of administration and dosage form depend on the
physical/chemical properties of the
compound per se and the severity of the disease to be treated, and can be
routinely determined by a
person skilled in the art.
[0100] In another aspect, the present invention provides a method for
modulating estrogen activities
in mammals, especially in humans, which method comprises administering to a
mammal, especially a
human, in need thereof a therapeutically effective amount of a compound of
formula I, or a
pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer
or prodrug thereof.
[0101] In one embodiment of the present invention, estrogen receptor is up-
regulated by a
compound of formula I, or a pharmaceutically acceptable salt, stereoisomer,
solvate, polymorph,
tautomer or prodrug thereof in bone tissue, cardiovascular system and central
nervous system, and
down-regulated by a compound of formula I, or a pharmaceutically acceptable
salt, stereoisomer,
solvate, polymorph, tautomer or prodrug thereof in tissues like breast and
uterus.
[0102] In another aspect, the present invention provides a method for
preventing and/or treating
estrogen-dependent diseases and conditions in mammals, especially in humans,
which method
comprises administering to a mammal, especially a human, in need thereof a
therapeutically effective
amount of a compound of formula I, or a pharmaceutically acceptable salt,
stereoisomer, solvate,
polymorph, tautomer or prodrug thereof.
[0103] As used herein, estrogen-dependent diseases and conditions refer to
diseases and conditions
in which the regulation of estrogen receptor is involved. In one embodiment of
the present invention,
estrogen-dependent diseases and conditions are selected from the group
consisting of menopausal or
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21
postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal
atrophy, atrophic
vaginitis, endometriosis, female sexual dysfunction, cancers (e.g. uterine
cancer, breast cancer, etc.),
depressive symptoms, diabetes, bone demineralization, and osteoporosis.
[0104] The compound of the invention, or a pharmaceutically acceptable salt,
stereoisomer, solvate,
polymorph, tautomer or prodrug thereof, is administered in a therapeutically
effective amount, which
will vary depending upon a variety of factors including the activity of the
specific compound employed;
the metabolic stability and length of action of the compound; the age, body
weight, general health, sex,
and diet of the patient; the mode and time of administration; the rate of
excretion; the drug combination;
the severity of the particular disorder or condition; and the subject
undergoing therapy. Generally, a
therapeutically effective daily dose is from about 0.001 mg/Kg body weight to
about 100 mg/Kg body
weight; preferaby a therapeutically effective dose is from about 0.01 mg/Kg
body weight to about 50
mg/Kg body weight; more preferably a therapeutically effective dose is from
about 1 mg/Kg body
weight to about 25 mg/Kg body weight. In particular, the parenteral dose of
the compound of the
present invention may be from about 1 mg/Kg body weight to about 100 mg/Kg
body weight; the oral
dose may be from about 1 mg/Kg body weight to about 500 mg/Kg body weight.
[0105] The ranges of effective doses provided herein are not intended to be
limiting and represent
preferred dose ranges. However, the most preferred dosage will be tailored to
the individual subject, as
is understood and determinable by one skilled in the relevant arts (see, e.g.,
Berkowet al., eds., The
Merck Manual, 16th edition, Merck and Co., Rahway, N.J., 1992).
[0106] The total dose required for each treatment can be administered by
multiple doses or in a
single dose over the course of the day, if desired. Generally, treatment is
initiated with smaller dosages,
which are less than the optimum dose of the compound. Thereafter, the dosage
is increased by small
increments until the optimum effect under the circumstances is reached. The
diagnostic pharmaceutical
compound or composition can be administered alone or in conjunction with other
diagnostics and/or
pharmaceuticals directed to the pathology, or directed to other symptoms of
the pathology. The
recipients of administration of compounds and/or compositions of the invention
can be any mammals.
The preferred recipients are mammals of the Orders Primate (including humans,
apes and monkeys),
Arteriodactyla (including horses, goats, cows, sheep, pigs), Rodenta
(including mice, rats, rabbits, and
hamsters), and Camivora (including cats, and dogs). The most preferred
recipients are humans.
Preparation of the Compound of the Invention
[0107] The following Reaction Schemes illustrate methods to make compounds of
this invention.
[0108] It is understood that in the following description, combinations of
substituents and/or
variables of the depicted formulae are permissible only if such contributions
result in stable
compounds.
[0109] It will also be appreciated by those skilled in the art that in the
process described below the
functional groups of intermediate compounds may need to be protected by
suitable protecting groups.
Such functional groups include hydroxyl, amino, mercapto and carboxylic acid.
Suitable protecting
groups for hydroxyl include trialkylsilyl or diarylalkylsilyl (e.g., t-
butyldimethylsilyl,
t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the
like. Suitable protecting
groups for amino, amidino and guanidino include t-butoxycarbonyl,
benzyloxycarbonyl, and the like.
Suitable protecting groups for mercapto include -C(0)-R" (where R" is alkyl,
aryl or arylalkyl),
p-methoxybenzyl, trityl and the like. Suitable protecting groups for
carboxylic acid include alkyl, aryl
or arylalkyl esters.
[0110] Protecting groups may be added or removed in accordance with standard
techniques, which
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22
are known to one skilled in the art and as described herein.
[0111] The use of protecting groups is described in detail in Greene, T.W. and
P. G M. Wuts,
Greene 's Protective Groups in Organic Synthesis (2006), 4th Ed., Wiley. The
protecting group may also
be a polymer resin.
[0112] The compound of formula I of the present invention may be prepared
following the
procedures illustrated in Scheme 1.
Scheme 1
A (R2),, A (R2)rn
Rai Ri
Zn, TiC14
0 + 0
R0 THF, ref lux R0
B (R3), B (R3)II III I
[0113] In Scheme 1, McMurry coupling is carried out between compounds II and
III to provides the
ethylene derivative I. Compounds II and III are either commercially available
or may be prepared by
synthetic methods appreciated by those skilled in the art.
Examples
[0114] The following experiments, preparation methods and the intermediates
involved are
provided as an illustration of the present invention, and are not intended as
a limitation on the scope of
the invention.
Example 1
(Z)-4-(1-(6-chloropyridin-3-y1)-2-phenylbut-1-enyl)phenol
CI
N
/16
OH
[0115] Step A: (6-chloropyridin-3-y1)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)
methanone
CI N Or=
,
lel 0
0
Mg (1.67 g, 1.2 eq) was added to dry THF (50 mL). The mixture was heated to 55
C, then 12 was
added in one lot followed by EtBr. 2-(4-Bromophenoxy)tetrahydro- 2H-pyran (16
g, 1.1 eq) was
dissolved in THF. Part of this solution was added at once to the Mg-THF
mixture. After the initiation
after about 30min and reflux started, the remaining above solution was added,
and the resulting mixture
was refluxed for 2 h to give a MgBr-THF solution, which will be used in the
next step.
To a solution of 6-chloronicotinoyl chloride (10.0 g, 1.0 eq) in dry THF at 0
C under N2, was
added dropwise the above MgBr-THF solution over 20 min. The resulting mixture
was warmed to rt,
and stirred overnight.
Water was added and the resulting mixture was extracted with Et0Ac. The
extract was dried,
concentrated, and purified by column chromatography with petroleum ether:Et0Ac
= 5:1 to give the
desired product (13.6 g, 76% yield). 1H NMR (400 MHz, CDC13) 6 8.78 (s, 1H),
8.05 (d, J = 8.4 Hz,
1H), 7.78 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.0 Hz,
2H), 5.56 (t, J = 3.2 Hz,
1H), 3.83-3.90 (m, 1H), 3.63-3.67 (m, 1H), 2.02-2.05 (m, 1H), 1.89-1.92 (m,
2H), 1.69-1.75 (m, 2H),
1.59-1.65 (m, 1H).
[0116] Step B: (Z)-4-(1-(6-chloropyridin-3-y1)-2-phenylbut-1-enyl)phenol
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23
CI
N
I
1.1 to
IW OH
To a stirred mixture of Zn powder (8.06 g, 6 eq) in dry THF at rt under N2 was
slowly added TiC14
(6.8 mL, 3 eq). The resulting mixture was heated to 80 C and refluxed for 1
h. After cooling to rt, a
mixture of propiophenone (8.2 g, 3.0 eq) and
(6-chloropyridin-3-y1)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (6.5 g,
1.0 eq) in dry THF
was added. The resulting mixture was refluxed for additional 2 h, then
quenched with saturated aq.
Na2CO3 solution, extracted with Et0Ac. The extract was dried, concentrated,
and purified by column
chromatography to give a Z/E mixture of the product (6.3 g, 92%, Z/E = 1/1).
The Z/E mixture was
recrystallized in petroleum ether/CH2C12 to give the pure Z-isomer (2.8 g, 41%
yield). 1H NMR (400
MHz, CDC13) 6 7.85 (s, 1H), 7.06-7.25 (m, 8H), 6.97 (d, J = 8.4 Hz, 1H), 6.83
(d, J = 8.0 Hz, 2H),
2.51 (q, J = 7.6 Hz, 2H), 0.94 (t, J = 7.6 Hz, 3H); m/z = 336 [M+1] '.
Example 2
[0117] (E)-4-(1-(6-ehloropyridin-3-y1)-2-phenylbut-1-enyl)phenol
OH
Si
I
N CI
The title compound was obtained (3.0 g, E-isomer) via recrystallization from
the Z/E mixture
(example 1, step B) in Me0H. 1H NMR (400 MHz, CDC13) 6 8.34 (s, 1H), 7.07-7.48
(m, 7H), 6.70 (d,
J = 8.4 Hz, 2H), 6.50 (d, J = 8.0 Hz, 2H), 2.45 (q, J = 7.2 Hz, 2H), 0.94 (t,
J = 7.6 Hz, 3H); m/z = 336
[M+1]+.
Example 3
[0 1 1 8] (Z)-4-(1-(6-(2-(methylamino)ethoxy)pyridin-3-y1)-2-phenylbut-1-enyl)
phenol
-\-NH
4I0 r7 \ ,
_
41
OH
To a stirred solution of 2-(methylamino)ethanol (672 mg, 10 eq) in 20 mL
anhydrous THF was
added NaH (373 mg, 8.0 eq) at 0 C. The mixture was stirred at rt for 1 h,
then to the mixture was
added (Z) -4-(1-(6-chloropyridin-3-y1)-2- phenylbut-l-enyl)phenol (300 mg, 1
eq, made from example
1). The reaction was heated at reflux for 16 h, cooled, quenched with sat.
NH4C1, and extracted with
CH2C12. The extract was dried, concentrated, and purified by column
chromatography to give the
desired product (200 mg, 60% yield). 1H NMR (400 MHz, CDC13) 6 7.59 (s, 1H),
7.18-7.20 (m, 2H),
7.08-7.16 (m, 3H), 7.01-7.06 (m, 3H), 6.77(d, J = 8.4 Hz, 2H), 6.28 (d, J =
8.4 Hz, 1H), 4.28 (t, J =
5.2 Hz, 2H), 2.93 (t, J = 5.2 Hz, 2H), 2.46-2.55 (m, 5H), 0.92 (t, J = 7.6 Hz,
3H); m/z = 375 [M+1]'.
Example 4
[0119] (E)-4-(1-(6-(2-(methylamino)ethoxy)pyridin-3-y1)-2-phenylbut-1-enyl)
phenol
0-\
N 'NH
/ \ \
_
_
IP =
OH
Following the same procedure as described in
example 3,
(E)-4-(1-(6-chloropyridin-3-y1)-2-phenylbut-1-enyl)phenol (100 mg, prepared
from example 2) were
used as starting material to get the desired product (53 mg, 48%). 1H NMR (400
MHz, CDC13) 6 8.09
(s, 1H), 7.31-7.7.34 (m, 1H), 7.09-7.10 (m, 5H), 6.68 (d, J = 8.8 Hz, 2H),
6.62 (d, J = 8.4 Hz, 1H),
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24
6.47 (d, J = 8.4 Hz, 2H), 4.44 (t, J = 5.2 Hz, 2H), 3.01 (t, J = 5.2 Hz, 2H),
2.46-2.52 (m, 5H), 0.9 (t, J
= 7.2 Hz, 3H); m/z = 375 [M+1]'.
Example 5
[0120] (Z)-4-(1-(6-(2-(dimethylamino)ethoxy)pyridin-3-y1)-2-phenylbut-1-enyl)
phenol
I
N
(:)
N
1
0 / la
LW OH
Following the same procedure as described in example 3, 2-
(dimethylamino)ethanol (798 mg, 10
eq) and (Z)-4-(1-(6-chloropyridin-3-y1)-2- phenylbut-l-enyl)phenol (300 mg, 1
eq, prepared from
example 1) were reacted to get the desired product (260 mg, 75% yield). 1H NMR
(400 MHz, CDC13) 6
7.54 (s, 1H), 7.14-7.20 (m, 2H), 7.01-7.09 (m, 5H), 6.93 (d, J = 8.0 Hz, 1H),
6.78 (d, J = 8.0 Hz, 2H),
5.84 (d, J = 8.8 Hz, 1H), 4.22 (t, J = 5.2 Hz, 2H), 2.70 (t, J = 5.2 Hz, 2H),
2.50 (q, J = 7.2 Hz, 2H),
2.35 (s, 6H), 0.91 (t, J = 7.6 Hz, 3H); m/z = 389 [M+1]'.
Example 6
[0121] (S,Z)-4-(2-pheny1-1-(6-(pyrrolidin-3-yloxy)pyridin-3-yl)but-1-enyl)
phenol
r-T
N
1
110 / 16
W OH
Following the same procedure as described in example 3, (S)-pyrrolidin-3-ol
(558 mg, 10 eq) was
reacted with (Z)-4-(1-(6-chloropyridin-3-y1)-2-phenylbut-1- enyl)phenol (100
mg, 1 eq, prepared from
example 1) to give the desired product (87 mg, 76% yield). 1H NMR (400 MHz,
DMSO-d6) 6 9.50 (s,
1H), 6 7.54 (s, 1H), 7.20-7.23 (m, 2H), 7.10-7.16 (m, 4H), 7.00(d, J = 8.4 Hz,
2H), 6.77 (d, J = 8.4 Hz,
2H), 6.49 (d, J = 8.4 Hz, 1H), 5.28 (bs, 1H), 3.15-3.32 (m, 2H), 2.94-3.05 (m,
2H), 2.43 (q, J = 7.6 Hz,
1H) 1.90-2.10 (m, 1H), 1.79-1.89 (m, 1H), 0.86 (t, J = 7.6 Hz, 3H); m/z = 387
[M+1]'.
Example 7
[0122] (Z)-4-(2-pheny1-1-(6-(2-(pyrrolidin-1-yDethoxy)pyridin-3-yl)but-1-enyl)
phenol
o.....,. NO
N
1
0 / la
W OH
Following the same procedure as described in example 3, 2-(pyrrolidin-1-y1)
ethanol (343 mg, 10
eq) and (Z)-4-(1-(6-chloropyridin-3-y1)-2-phenylbut-1-enyl) phenol (100 mg, 1
eq, prepared from
example 1) were used as starting material to get the desired product (140 mg,
95%). 1H NMR (400
MHz, CDC13) 6 7.53 (s, 1H), 7.15-7.20 (m, 2H), 7.01-7.13 (m, 6H), 6.92(d, J =
8.0 Hz, 1H), 6.76 (d, J
= 8.4 Hz, 2H), 5.68 (brs, 1H), 4.26 (bs, 2H), 2.91 (brs, 2H), 2.72 (brs, 4H),
2.50 (q, J = 7.2 Hz, 2H),
1.89 (brs, 4H), 0.91 (t, J = 7.6 Hz, 3H); m/z = 415 [M+1]'.
Example 8
[0123] (Z)-4-(1-(6-(2-(4-methylpiperazin-1-yDethoxy)pyridin-3-y1)-2-phenyl but-
l-enyl)phenol
r-N
o...--..,.N.,)
N '-
1
110 /10
W OH
Following the same procedure as described in example 3, 2-(4-methylpiperazin -
1-yl)ethanol (430
mg, 10 eq) was reacted with (Z)-4-(1- (6-chloropyridin- 3-y1)-2-phenylbut-1-
enyl)phenol (100 mg, 1 eq,
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prepared from example 1) to give the desired product (160 mg, 95% yield). 1H
NMR (400 MHz, CDC13)
6 7.57 (s, 1H), 7.17-7.22 (m, 2H), 7.00-7.15 (m, 5H), 6.97 (d, J = 8.0 Hz,
1H), 6.76 (d, J = 8.8 Hz, 2H),
6.03 (d, J = 8.8 Hz, 1H), 4.27 (t, J = 5.6 Hz, 2H), 2.75 (t, J = 5.6 Hz, 2H),
2.48-2.57 (m, 12H), 2.32 (s,
3H), 0.92 (t, J = 7.6 Hz, 3H); m/z = 444 [M+1]'.
Example 9
[0124] (Z)-4-(2-pheny1-1-(6-(2-(piperidin-1-yDethoxy)pyridin-3-yl)but-1-enyl)
phenol
r.
O'N
N
I
0 / a
'W OH
Following the same procedure as described in example 3, 2-(piperidin-1-y1)
ethanol (385 mg, 10
eq) was reacted with (Z)-4-(1-(6-chloropyridin-3-y1)-2-phenyl but-l-
enyl)phenol (100 mg, 1 eq,
prepared from example 1) to give the desired product (106 mg, 83% yield). 1H
NMR (400 MHz, CDC13)
6 7.53 (s, 1H), 7.16-7.21 (m, 2H), 7.01-7.15 (m, 6H), 6.88 (d, J = 8.8 Hz,
1H), 6.77 (d, J = 8.8 Hz, 2H),
5.63 (d, J = 8.0 Hz, 1H), 4.25 (t, J = 5.6 Hz, 2H), 2.73 (t, J = 5.6 Hz, 2H),
2.40-2.62 (m, 6H),
1.63-1.75 (m, 4H), 1.44-1.56 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); m/z = 429
[M+1]'.
Example 10
[0125] (Z)-4-(1-(6-(2-morpholinoethoxy)pyridin-3-y1)-2-phenylbut-1-enyl)
phenol
ro
N
I
110 a
'W OH
Following the same procedure as described in example 3,2-morpholinoethanol
(391 mg, 10 eq)
was reacted with (Z)-4-(1-(6-chloropyridin-3-y1)-2- phenylbut-l-enyl) phenol
(100 mg, 1 eq, prepared
from example 1) to give the desired product (110 mg, 86% yield). 1H NMR (400
MHz, CDC13) 6 7.59
(s, 1H), 7.01-7.18 (m, 8H), 6.79 (d, J = 8.8 Hz, 2H), 6.27 (d, J = 8.4 Hz,
1H), 4.29 (t, J = 5.6 Hz, 2H),
2.70 (t, J = 5.6 Hz, 2H), 2.46-2.52 (m, 6H), 1.29-1.40 (m, 4H), 0.92 (t, J =
7.6 Hz, 3H); m/z =
431 [M+1] '.
Example 11
4-(1-(4-(2-(Methylamino)ethoxy)pheny1)-2-(thiophen-3-yl)but-1-enyl)phenol
0¨\
¨
OH
[0126] Step A: N-methoxy-N-methylthiophene-3-carboxamide
\ /
N-0
SO µ0
To a stirred solution of thiophene-3-carboxylic acid (20 g, 1.0 eq) in CH2C12
at 0 C was added
SOC12 (59 mL, 5.2 eq). After gas evolution became less vigorous, the reaction
mixture was refluxed for
3 h at 50 C. The mixture was then concentrated and the residue was used
directly in the next step
without further purification.
N, 0-dimethylhydroxylamine hydrochloride (16.8 g, 1.1 eq) was added to a
solution of the above
residue in CH2C12 at 0 C, then to the resulting solution was added dropwise
Et3N (44 mL, 2.0 eq). The
mixture was stirred at rt for 3 h, washed with water, and extracted by CH2C12.
The extract was dried,
concentrated, and purified by column chromatography with petroleum ether:Et0Ac
= 5:1 to give the
desired product as a yellow solid (17.2 g, 64% yield). 1H NMR (400 MHz, CDC13)
6 8.07 (s, 1H), 7.57
(d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 3.65 (s, 3H), 3.36 (s, 3H).
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26
[0127] Step B: 1-(thiophen-3-yl)propan-1-one
0 _________________________________ Z
EtMgBr (3 M, 1.2 eq, 18.6 mL) was added to a solution of N-methoxy-
N-methylthiophene-3-carboxamide (8 g, 1.0 eq) in dry THF. Once the addition
was complete, the
mixture was stirred at rt overnight. The reaction mixture was washed with
saturated NH4C1 (aq), dried,
concentrated, and purified by column chromatography with petroleum ether:Et0Ac
= 5:1 to give the
desired product as a yellow oil (3.4 g, 52% yield). 1H NMR (400 MHz, CDC13) 6
8.05 (s, 1H), 7.56 (d,
J = 8.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 2.92 (q, J = 7.6 Hz, 2H), 1.21 (t,
J = 7.6 Hz, 3H).
[0128] Step C: 4-(1-(4-(2-chloroethoxy)pheny1)-2-(thiophen-3-yl)but-1-enyl)
phenol
0¨\
S /\ \¨oi
\ / W
¨
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
1-(thiophen-3-yl)propan-1-one (0.5 g, 1.0 eq) was reacted
with (4-(2-
chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (1.5 g, 1.5 eq) to give 1.3 g
desired product (95%
yield, Z/E = 1/1). 1H NMR (400 MHz, CDC13) 6 7.10-7.14 (m, 1H), 7.02-7.09 (m,
2H), 6.76-6.92 (m,
5H), 6.68-6.71 (m, 1H), 6.60-6.66 (m, 1H), 6.55-6.59 (m,1 H), 4.62 (s, 1H),
4.49 (s, 1H), 4.24 (t, J =
6.0 Hz, 1H), 4.14 (t, J = 6.0 Hz, 1H), 3.82 (t, J = 6.0 Hz, 1H), 3.76 (t, J =
6.0 Hz, 1H), 2.43-2.49 (m,
2H), 0.98 (t, J = 7.6 Hz, 3H).
[0129] Step D: 4-(1-(4-(2-(methylamino)ethoxy)pheny1)-2-(thiophen-3-yObut-1-
enyl)phenol
0¨\
s . \¨NH
\
\ /
¨
OH
To a stirred solution of 4-(1-(4-(2-chloroethoxy)pheny1)-2-(thiophen-3-yl)but-
1- enyl)phenol (0.3
g, 1.0 eq) in 10 mL Me0H was added 10 mL MeNH2 (30% in water). The mixture was
refluxed at 80
C overnight, and purified by column chromatography with CH2C12 : Me0H(NH3)
=10:1 to give the
desired product (185 mg, 63% yield, Z/E = 1/1). 1H NMR (400 MHz, CDC13) 6 7.00-
7.12 (m, 3H),
6.90-6.95 (m, 1H), 6.80-6.89 (m, 2H), 6.72-6.79 (m, 2H), 6.68-6.72 (m, 1H),
6.58 (d, J = 8.8 Hz, 1H),
6.53 (d, J = 8.8 Hz, 1H), 4.09 (t, J = 5.2 Hz, 1H), 3.99 (t, J = 5.2 Hz, 1H),
3.00 (t, J = 5.2 Hz, 1H),
2.94 (t, J = 5.2 Hz, 1H), 2.40-2.54 (m, 5H), 0.98 (t, J = 5.2 Hz, 3H); m/z =
380[M+1].
Example 12
(E)-4-(2-(5-chlorothiophen-3-y1)-1-(4-(2-(methylamino)ethoxy)phenyDbut-1-
enyl)phenol
OH
S 0
CI \ \
H
0
0
[0130] Step A: 5-chloro-N-methoxy-N-methylthiophene-3-carboxamide
\ /
CINsrep µN-0
To a stirred solution of N-methoxy-N-methylthiophene-3-carboxamide (5.0 g, 1.0
eq, prepared
from Example 12 step A) in 50 mL CH3COOH was added N-chlorosuccinimide (3.88
g, 1.0 eq). The
mixture was then reflux at 120 C for 4 h. After quenching with water, the
mixture was extracted with
ethyl acetate. The extract was washed with brine, dried, concentrated, and
purified by column
chromatography to get 3.0 g desried product (40% yield).
[0131] Step B: 1-(5-chlorothiophen-3-yl)propan-1-one
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CI Z
Following the same procedure as described in example 11, step B, the title
compound was
obtained.
[0132] Step C: (E)-4-(1-
(4-(2-chloroethoxy)pheny1)-2-(5-chlorothiophen-3-y1)-
but-l-enyl)phenol
OH
S 1.1
CI \ \
0 CI
0
Following general procedure of McMurry reaction as described in example 1,
step B,
1 - (5- chlorothiophen-3 -yl)propan-1 -one (1.5 g, 1.0 eq)
was reacted with
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (2.0 g, 1.2 eq) to give
0.8 g desired product
(45% yield, E).
[0133] Step D: (E)-4-(2-
(5-chlorothiophen-3-y1)-1-(4-(2-(methylamino)ethoxy)-
phenyl)but-l-enyl)phenol
OH
s 0
CI \ 1
H
So
0
Following the same procedure as described in example 11, step D,
(E)-4-(1-(4-(2-chloroethoxy)pheny1)-2-(5-chlorothiophen-3-yl)but-1-enyl)phenol
(0.8 g, 1.0 eq) was
reacted with MeNH2 (30% wt in water, 10 mL) in Me0H (20 mL) at reflux to give
120 mg desired
product (35% yield, E) . 1H NMR (400 MHz, DMSO-d6) 6 9.30 (bs, 1H), 6.99-7.02
(m, 3H), 6.84-6.89
(m, 2H), 6.62-6.70 (m, 2H), 6.50-6.56 (m, 3H), 3.97 (t, J = 5.6 Hz, 2H), 2.78
(t, J = 5.6 Hz, 2H),
2.26-2.38 (m, 5H), 0.89 (t, J = 7.2 Hz, 3H); m/z = 414[M+1].
Example 13
4-(2-(4-Hydroxycyclohexyl)-1-(4-(2-(methylamino)ethoxy)phenyDbut-1-enyl)
phenol
HO
. 40. T
_
OH
[0134] Step A: 1-(4-hydroxycyclohexyl)propan-1-one
0
HO
EtMgBr (1 M, 3.0 eq, 20 mL) was added to a solution of 4-hydroxy-N-methoxy-
N-methylcyclohexanecarboxamide (1.0g, 1.0eq) in dry THF at 0 C. Once addition
was complete, the
mixture was stirred overnight. The reaction mixture was washed with saturated
NH4C1 (aq), and
extracted by Et0Ac. The extract was dried, concentrated, and purified by
column chromatography with
petroleum ether:Et0Ac = 1:1 to give the desired product (0.6g, 72% yield). 1H
NMR (400 MHz, CDC13)
6 3.50-3.64 (m, 1H), 2.47 (q, J = 7.2 Hz, 2H), 2.28-2.37 (m, 1H), 2.00-2.10
(m, 2H), 1.88-1.94 (m, 2H),
1.70-1.80 (m, 1H), 1.21-1.49 (m, 4H), 1.05 (t, J = 7.2 Hz, 3H).
[0135] Step B: 4-(1-(4-(2-chloroethoxy)pheny1)-2-(4-hydroxycyclohexyDbut-1-
enyl)phenol
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HO 0-\_
_
41
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
1 -(4-hydroxycyclohexyl)propan-1 -one (0.6 g, 1.0 eq) was ..
reacted .. with
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (1.6 g, 1.5 eq) to give
0.8 g desired product
(52% yield, Z/E = 1/1). 1H NMR (400 MHz, CDC13) 6 7.11-7.20 (m, 1H), 7.00-7.10
(m, 2H), 6.90-6.70
(m, 1H), 6.60-6.89 (m, 3H), 6.58 (d, J = 7.6 Hz, 1H), 4.08-4.20 (m, 2H), 3.70-
3.80 (m, 2H), 3.60 (brs,
1H), 2.47 (q, J = 7.6 Hz, 2H), 2.28-2.38 (m, 1H), 2.00-2.08 (m, 2H), 1.86-1.94
(m, 2H), 1.72-1.80 (m,
1H), 1.20-1.49 (m, 4H), 1.04 (t, J = 7.6 Hz, 3H)
[0136] Step C: 4-(2-(4-hydroxycyclohexyl)-1-(4-(2-
(methylamino)ethoxy)-
phenyl)but-l-enyl)phenol
HO
. 40 1\1--1
_
OH
Following the same procedure as described in example 11, step D,
4-(1-(4-(2-chloroethoxy)pheny1)-2-(4-hydroxycyclohexyl)but-1-enyl)phenol (0.8
g, 1.0 eq) was reacted
with MeNH2 (30% wt in water, 10 mL) in Me0H (20 mL) at reflux to give 20 mg
desired product (3%
yield, Z/E = 1/1). 1H NMR (400 MHz, CDC13) 6 7.03 (d, J = 8.4 Hz, 2H), 6.94
(d, J = 8.4 Hz, 2H),
6.78 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 4.04 (t, J = 4.8 Hz, 2H),
2.96 (t, J = 4.8 Hz, 2H),
2.50 (s, 3H), 2.36-2.47 (m, 1H), 2.04 (q, J = 7.6 Hz, 2H), 1.90-2.01 (m, 2H),
1.40-1.80 (m, 6H), 0.87 (t,
J = 7.6 Hz, 3H); m/z = 396[M+1].
Example 14
4-(1-(3-Bromo-4-(2-(methylamino)ethoxy)pheny1)-2-phenylbut-1-enyl)phenol
_
41
OH
[0137] Step A: methyl 3-bromo-4-(2-bromoethoxy)benzoate
0
0 Br
0
0
To a stirred solution of methyl 3-bromo-4-hydroxybenzoate (5.0 g, 1.0 eq) in
20 mL DMF were
added BrCH2CH2Br (11 mL, 6.0 eq) and K2CO3 (6.0 g, 2.0 eq). The mixture was
heated to 60 C for 6
h and purified by column chromatography with petroleum ether:Et0Ac = 3:1 to
give the desired
product (6.0 g, 80% yield). 1H NMR (400 MHz, CDC13) 6 8.24 (s, 1H), 7.96 (d, J
= 8.8 Hz, 1H), 6.90
(d, J = 8.8 Hz, 1H), 4.40 (t, J = 6.8 Hz, 2H), 3.90 (s, 3H), 3.71 (t, J = 6.4
Hz, 2H)
[0138] Step B: 3-bromo-4-(2-bromoethoxy)benzoic acid
0
HO 0 Br
0
To a stirred solution of methyl 3-bromo-4-(2-bromoethoxy)benzoate (4.0 g, 1.0
eq) in Me0H/H20
(v/v 2:1, 60 mL) was added NaOH (0.715 g, 1.5 eq). The mixture was then
refluxed for 25 min, and
concentrated under reduced pressure. The residue was poured into water and
washed with Et0Ac. To
the aqueous layer was added 3 N HC1 to give the desired product as a white
solid (3.4 g, 87% yield). 1H
NMR (400 MHz, DMSO-d6) 6 8.07 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.23 (d, J =
8.4 Hz, 1H), 4.50 (t,
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J = 5.6 Hz, 2H), 3.85 (t, J = 5.6 Hz, 2H)
[0139] Step C: (3-bromo-4-(2-bromoethoxy)phenyl)(4-methoxyphenyl) methanone
0
Br
1010 0 Br
0
To a stirred solution of 3-bromo-4-(2-bromoethoxy)benzoic acid (2.0 g, 1.0 eq)
in 20mL CH2C12,
was added SOC12 (5.0eq, 2.2mL). The mixture was refluxed for 3 h, then
evaporated to give the
benzoyl chloride without further purification.
To a stirred solution of benzoyl chloride, A1C13 (1.65 g, 2.0 eq) in 50mL
CH2C12 was added anisole
(1.34 g, 2.0 eq). The mixture was then stirred at rt overnight and purified by
column chromatography
with petroleum ether:Et0Ac=3:1 to give the desired product (1.47g, 57%). 1H
NMR (400 MHz,
DMSO-d6) 6 8.03 (s, 1H), 7.71-7.84 (m, 3H), 6.91-7.04 (m, 3H), 4.43 (t, J =
6.4 Hz, 2H), 3.90 (s, 3H),
3.74 (t, J = 6.4 Hz, 2H)
[0140] Step D: (3-bromo-4-(2-bromoethoxy)phenyl)(4-hydroxypheny1)- methanone
0
0 1. Br
(:) Br
HO
To a stirred solution of (3-bromo-4-(2-bromoethoxy)phenyl)(4- methoxyphenyl)
methanone (0.6 g,
1.0 e q) in 50 mL CH2C12 was added BBr3 (3.0 eq, 0.4 mL) dropwise. After
addition, the mixture was
stirred at rt overnight, concentrated, and purified by column chromatography
with petroleum
ether:Et0Ac = 2:1 to give the desired product (0.36 g, 62% yield). 1H NMR (400
MHz, CDC13) 6 8.03
(s, 1H), 7.70-7.79 (m, 3H), 6.90-7.00 (m, 3H), 4.43 (t, J = 6.4 Hz, 2H), 3.72
(t, J = 6.0 Hz, 2H).
[0141] Step E: 4-(1-(3-bromo-4-(2-bromoethoxy)pheny1)-2-phenylbut-1-enyl)
phenol
0-\
* 41 Br
_
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
propiophenone (0.2 g, 3.0 eq) was reacted with (3-bromo-4-(2- bromoethoxy)
phenyl)(4-hydroxyphenyl)methanone (0.2 g, 1.0 eq) to give 0.09 g desired
product (36% yield, Z/E =
1/1).1H NMR (400 MHz, CDC13) 6 7.42 (s, 1H), 7.01-7.0 (m, 7H), 6.87 (d, J =
8.4 Hz, 1H), 6.82 (d, J
= 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 4.36 (t, J
= 6.8 Hz, 1H), 4.19 (t, J =
6.4 Hz, 1H), 3.70 (t, J = 6.4 Hz, 1H), 3.59 (t, J = 6.8 Hz, 1H), 2.46 (q, J =
6.4 Hz, 2H), 0.92 (t, J = 6.0
Hz, 3H)
[0142] Step F: 4-(1-(3-bromo-4-(2-(methylamino)ethoxy)pheny1)-2-phenylbut- 1-
enyl)phenol
imk -\-NH
_
4/
OH
Following the same procedure as described in example 11, step D,
4-(1-(3-bromo-4-(2-bromoethoxy)pheny1)-2-phenylbut-1-enyl)phenol (0.09 g, 1.0
eq) was reacted with
MeNH2 (30% wt in water, 10 mL) in Me0H (20 mL) under reflux to give 73 mg
desired product (90%
yield, Z/E = 1/1). 1H NMR (400 MHz, CDC13) 6 7.40 (s, 1H), 6.98-7.20 (m, 7H),
6.87 (d, J = 8.4 Hz,
1H), 6.78 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 6.45 (d, J = 8.4 Hz,
1H), 4.17 (t, J = 5.2 Hz,
1H), 4.01 (t, J = 4.8 Hz, 1H), 3.06 (t, J = 4.8 Hz, 1H), 2.96 (t, J = 5.2 Hz,
1H), 2.40-2.60 (m, 5H), 0.88
(t, J = 5.2 Hz, 3H); m/z = 452 [M+1].
Example 15
[0143] 5-(1-(4-Hydroxypheny1)-2-phenylbut-1-eny1)-2-(2-
(methylamino)ethoxy)benzonitrile
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41, 44I CN
OH
To a stirred solution of 4- (1 -(3 -bromo-4- (2-
(methylamino) ethoxy)pheny1)-
2-phenylbut-l-enyl)phenol (150 mg, 1.0 eq) in 5 mL DMF was added CuCN (36 mg,
1.2 eq) at rt. The
mixture was then heated at 120 C overnight, poured into water, and the
resulting mixture was
extracted with Et0Ac. The extract was washed with water and brine, dried,
concentrated, and purified
by column chromatography with CH2C12 : Me0H(NH3) =1:1 to give the desired
product (10 mg, 6%
yield, Z/E = 1/1). 1H NMR (400 MHz, CDC13) 6 7.36 (s, 1H), 6.99-7.21 (m, 7H),
6.90 (d, J = 8.8 Hz,
1H), 6.81 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 8.8 Hz,
1H), 4.32 (t, J = 5.6 Hz,
1H), 4.20 (t, J = 5.2 Hz, 1H), 3.46 (t, J = 5.6 Hz, 1H), 3.30 (t, J = 5.2 Hz,
1H), 3.29 (s, 3H), 2.40-2.50
(m, 2H), 0.90 (t, J = 5.6 Hz, 3H); m/z = 399 [M+1]'.
Example 16
(S)-4-(2-pheny1-1-(4-(pyrrolidin-2-ylmethoxy)phenyl)but-1-enyl)phenol
ONH
OH
[0144] Step A: (S)-pyrrolidin-2-ylmethanol
OH
To a stirred solution of (S)-pyrrolidine-2-carboxylic acid (11.5 g, 1.0 eq) in
250 mL anhydrous
THF was added LiA1H4 (6 g, 1.6 eq) very slowly at 0 C. The reaction was
stirred at 0 C for 1 h., and
then quenched with 6 mL water slowly at 0 C, After 6 mL 10% NaOH (aq) was
added, the suspension
was filtered and washed with Et0Ac. The filtrate was dried and concentrated to
give a residue, which
was purified by distillation under reduced pressure to give the product (5.75
g, 57% yield). 1H NMR
(400 MHz, DMSO-d6) 6 3.22 (d, J= 1.2 Hz, 2H), 2.95-3.01 (m, 1H), 2.73-2.79 (m,
1H), 2.64-2.70 (m,
1H), 1.53-1.68 (m, 3H), 1.27-1.34 (m, 1H).
[0145] Step B: (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate
Bo c
To a stirred solution of (S)-pyrrolidin-2-ylmethanol (3 g, 1 eq) in 100 mL
THF, was added
(Boc)20 (7.1 g, 1.1 eq) at 0 C. After a solution of NaHCO3 (5 g, 2.0 eq) in
100 mL water was added,
the reaction was stirred overnight at rt. Then added water to the mixture and
extracted with Et0Ac. The
extract was dried, concentrated, and purified by column chromatography to give
the desired product
(5.7 g, 95% yield). 1H NMR (400 MHz, CDC13) 6 4.68 (brs, 1H), 3.96 (brs, 1H),
3.55-3.66 (m, 2H),
3.43-3.49 (m, 1H), 3.28-3.34 (m, 1H), 1.97-2.05 (m, 1H), 1.76-1.85 (m, 2H),
1.47 (s, 9H).
[0146] Step C: 4-(1-(4-hydroxylpheny1)-2-phenylbut-1-enyl)phenol
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OH
4.
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
propiophenone (1.9 g, 3.0 eq) was reacted with bis(4-hydroxypheny1)- methanone
(1.0 g, 1.0 eq) to
give 1.3 g desired product (88% yield).
[0147] Step D: (S)-tert-butyl 24(4-(1-
(4-hydroxypheny1)-2-phenylbut-1-eny1)-
phenoxy)methyl)pyrrolidine-l-carboxylate
O.NBoc
OH
To a stirred mixture of 4-(1-(4-hydroxylpheny1)-2-phenylbut-1-enyl)phenol (500
mg, 1.0 eq),
(S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (480 mg, 1.5 eq) and
PPh3 (625 mg, 1.5 eq)
in 25 mL anhydrous THF under nitrogen was added DIAD (480 mg, 1.5 eq) dropwise
at 0 C. The
reaction was stirred for 48 h at rt. Then the reaction was quenched with water
and extracted with
Et0Ac. The extract was dried, concentrated and purified by column
chromatography to give the desired
product (400 mg, 51% yield, Z/E = 1/1).
[0148] Step E: (S)-4-(2-phenyl-1-(4-(pyrrolidin-2-ylmethoxy)phenyl)but-1-
enyl)phenol
. NH
=
OH
To a stirred solution of
tert-butyl 2 - ((4-(1 - (4-hydroxypheny1)-2 -phenylbut-1 -
enyl)phenoxy)methyl)pyrrolidine- 1 -carboxylate (400 mg, 1.0 eq) in 20 mL
CH2C12 was added 1 mL
TFA dropwise at 0 C. The reaction was stirred at rt for 3 h, then quenched
with sat. NaHCO3, and
extracted with CH2C12. The extract was dried, concentrated and purified by
column chromatography to
give the desired product (210 mg, 68% yield, Z/E = 1/1). 1H NMR (400 MHz,
CDC13) 6 7.07-7.17 (m,
6H), 7.05 (d, J= 8.4 Hz, 1H), 6.84 (d, J= 8.8 Hz, 1H), 6.77 (d, J= 8.8 Hz,
1H), 6.74 (d, J = 8.8 Hz,
1H), 6.68 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 8.4 Hz,
1H), 3.96-4.00 (m, 0.5H),
3.89-3.93 (m, 0.5H), 3.82-3.85 (m, 0.5H), 3.73-3.77 (m, 0.5H), 3.53-3.59 (m,
0.5 H), 3.43-3.49 (m,
0.5H), 2.90-3.11 (m, 2H), 2.44-2.51 (m, 2H), 1.77-1.99 (m, 3H), 1.52-1.66 (m,
1H), 0.92 (t, J= 7.2 Hz,
3H); m/z = 400[M+1].
Example 17
[0149] (R)-4-(2-phenyl-1-(4-(pyrrolidin-3-yloxy)phenyDbut-1-enyl)phenol
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0.¨CH
li 41,
=
OH
Following the same procedure as described in example 16, step D & E,
4-(1-(4-hydroxylpheny1)-2-phenylbut-1-enyl)phenol (150 mg, 0.474 mmol) was
reacted with
(S)-tert-butyl 3-hydroxypyrrolidine- 1 -carboxylate (107 mg, 0.571 mmol),
followed by de-Boc in
condition of TFA/CH2C12, to give the desired product (36 mg, 20% yield, Z/E =
1/1). m/z = 386[M+1].
Example 18
4-(2-Phenyl-1-(4-(pyrrolidin-3-yloxy)phenyl)but-1-enyl)phenol
0¨OH
41 *
OH
[0150] Step A: tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate
OMs
N Boc
To a stirred solution of tert-butyl 3-hydroxypyrrolidine- 1 -carboxylate (16
g, 85.4 mmol) and
triethylamine (19 mL, 129 mmol) in 130 mL CH2C12 was added methanesulfonyl
chloride (10 mL, 129
mmol) in 20 mL CH2C12dropwise at 0 C. After addition, the reaction was stirred
for 2.5 h at rt, then
quenched with sat. NaHCO3 (aq.), and extracted with CH2C12. The extract was
dried and concentrated
to give the desired product (22.7 g, 100% yield) as a yellow solid.
[0151] Step B: tert-butyl 3-(4-(4-hydroxybenzoyl)phenoxy)pyrrolidine-1-
carboxylate
0
HO
0 =N B oc
0
A mixture of tert-butyl 3-(methylsulfonyloxy)pyrrolidine- 1 -carboxylate (0.6
g, 2.26 mmol),
bis(4-hydroxyphenyl)methanone (2.15 g, 10.0 mmol) and K2CO3 (313 mg, 2.26
mmol) in 12 mL DMF
was heated at 100 C for 3.5 h, then quenched with water, and extracted with
Et0Ac. The extract was
washed with water, dried, and concentrated to give a residue, to which was
added CH2C12 and the white
suspension thus formed removed and filtration. The filtrate was concentrated
in vacuo and the residue
was purified by column chromatography (petroleum ether/CH2C12/acetone = 4/2/1)
to give the desired
product (400 mg, 46% yield).
[0152] Step C: 4-(2-phenyl-1-(4-(pyrrolidin-3-yloxy)phenyl)but-1-enyl)phenol
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0 ¨C1N H
= .
OH
Following general procedure of McMurry reaction as described in example 1,
step B, tert-butyl
3-(4-(4-hydroxybenzoyl)phenoxy)pyrrolidine-1-carboxylate (395 mg, 1.03 mmol)
was reacted with
propiophenone (276 mg, 2.06 mmol) to give 340 mg desired product (86% yield,
Z/E = 1/1) as a light
yellow solid. m/z = 386[M+1]'.
Example 19
4-(1-(4-Hydroxypheny1)-1-(4-(2-(methylamino)ethoxy)phenyl)but-1-en-2-y1)-2-
methoxyphenol
/
/0
OH
[0153] Step A: 2-methoxyphenyl propionate
0
0
To a stirred solution of 2-methoxyphenol (4.4 g, 35.4 mmol) and triethylamine
(6.2 mL, 42.3
mmol) in 20 mL CH2C12, was added propionyl chloride (3.3 g, 35.7 mmol)
dropwise at 0 C. After
addition, the reaction was stirred for 5 h at rt, then quenched with sat.
NaHCO3 (aq.), and extracted
with CH2C12. The extract was dried and evaporated in vacuo to give the desired
product (6.0 g, 94%
yield) as a yellow solid.
[0154] Step B: 1-(4-hydroxy-3-methoxyphenyl)propan-1-one
HO
/0 411
0
Powdered anhydrous aluminum chloride (3.0 g, 22.5 mmol) was dissolved in
anhydrous
nitrobenzene (10 mL) at 100 C. The solution was cooled and 2-methoxyphenyl
propionate (2.0 g, 11.1
mmol) was added rapidly. The reaction mixture was heated at 60 C for 1.5 h and
cooled, 3 N NaOH
was added, and the mixture was stirred for 15 min. The suspension was filtered
off, washed with water.
The filtrate was then washed with CH2C12 twice, acidified with 3 N HC1,
extracted with CH2C12. The
extract was dried, concentrated, and purified by column chromatography
(petroleum ether/Et0Ac =
10/1 to 5/1) to give the desired product (874 mg, 44% yield) as a yellow oil.
[0155] Step C: 4-(1-(4-(2-chloroethoxy)pheny1)-1-(4-
hydroxyphenyl)but-1-en-
2-y1)-2-methoxyphenol
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HOCI
/0 41,
OH
Following general procedure of McMurry reaction as example 1, step B
described,
1-(4-hydroxy-3-methoxyphenyl)propan-1-one (207 mg, 1.15 mmol) was reacted with
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (318 mg, 1.15 mmol) to
give 188 mg desired
product (38.5% yield).
[0156] Step D: 4-(1-(4-
hydroxypheny0-1-(4-(2-(methylamino)ethoxy)pheny0-
but-1-en-2-370-2-methoxyphenol
/¨NH
HO 0¨/
OH
To a stirred solution of 4-
(1 - (4- (2-Chloroethoxy)pheny1)-1 - (4-hydroxypheny1)-
but- 1 - en-2 -y1)-2 -methoxyphenol (88 mg, impure) in 10 mL Me0H was added 2
mL CH3NH2 (aq).
After the mixture was heated at 85 C for 24 h., the solvent was removed in
vacuo, Et0Ac was added,
the mixture was washed with water and brine, dried over Na2SO4, filtered and
the filtrate was
evaporated in vacuo. The residue was purified by column chromatography
(CH2C12/Me0H(NH3 gas) =
10/1) to give the desired product (42 mg, 48% yield, Z/E = 1/1) as a white
solid. m/z = 420[M+1].
Example 20
[0157] 4-(1-(4-((1-Methylpyrrolidin-2-yOmethoxy)pheny0-2-phenylbut-1-eny0
phenol
o
4,
OH
Following same procedure of Mitsunobu reaction as described in example 16,
step D,
4,4- (2 -phenylbut-1 - ene-1,1 -diy1)diphenol (220 mg,
0.473 mmol) was reacted with
(1-methylpyrrolidin-2-yl)methanol (82 mg, 0.712 mmol, made from DL-proline
Following Arch.
Pharrn. Phamz. Med. Chem. 1996, 329, 95-104.) to give 65 mg desired product
(33% yield). m/z =
414[M+1]
Example 21
4-(1-(3-Fluoro-4-(2-(methylamino)ethoxy)pheny0-2-phenylbut-1-enyOphenol
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/
F
/-NH
0-/
OH
[0158] Step A: 3-fluoro-4-methoxybenzonitrile
0
0 F
CN
A mixture of 4-bromo-2-fluoro-1-methoxybenzene (30.0 g, 146 mmol) and CuCN
(15.6 g, 174
mmol) in dry DMF (45 mL) was stirred at 120 C overnight. The reaction mixture
was cooled to room
temperature, diluted with water and extracted with ethyl acetate. The extract
was washed with water
and brine, dried, and concentrated to give 20.0 g (91% yield) of the product
as a yellow solid. 1H NMR
(400 MHz, CDC13) 6 7.44 (dd, J= 8.8 Hz, 2.0 Hz, 1H), 7.36 (dd, J= 10.8 Hz, 2.0
Hz, 1H), 7.02 (dd, J
= 8.8 Hz, 8.4 Hz, 1H), 3.96 (s, 3H).
[0159] Step B: 3-fluoro-4-hydroxybenzonitrile
0 H
0 F
C N
BBr3 (20 mL, 0.211 mol) was added to 3-fluoro-4-methoxybenzonitrile (15.6 g,
0.103 mol) in
dichloromethane (100 mL) at 0 C. The mixture was refluxed for 3 days under a
nitrogen atmosphere.
The reaction mixture was quenched with ice water and extracted with
dichloromethane. The organic
layer was washed with water and brine and then dried over sodium sulfate.
Solvent evaporation under
reduced pressure gave 13.3 g (94%) of the product as a gray solid. 1H NMR (400
MHz, CDC13) 6
7.38-7.42 (m, 2H), 7.09 (dd, J= 8.8 Hz, 8.4 Hz, 1H), 5.68 (s, 1H).
[0160] Step C: 4-(2-bromoethoxy)-3-fluorobenzonitrile
Br,..,...õ----...0
s F
CN
A suspension of 3-fluoro-4-hydroxybenzonitrile (1.2 g, 8.76 mmol), anhydrous
K2CO3 (2.43 g,
17.6 mmol) and 1,2-dibromoethane (4.5 mL, 52.0 mmol) in DMF (6 mL) was stirred
at 60 C overnight
under a nitrogen atmosphere. The reaction mixture was filtered and the
filtrate was extracted with ethyl
acetate. The extract was washed with water and brine, dried over sodium
sulfate. Solvent evaporation
under reduced pressure, followed by column chromatography over silica gel
(eluent: petroleum
ether/ethyl acetate = 5/1), gave 1.52 g (71%) of the subtitle compound as a
colorless oil. 1H NMR (400
MHz, CDC13) 6 7.43 (d, J = 9.2 Hz, 1H), 7.40 (d, J = 12.0 Hz, 1H), 7.03 (dd, J
= 8.0 Hz, 8.4 Hz, 1H),
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4.42 (t, J= 6.2 Hz, 2H), 3.68 (t, J= 6.2 Hz, 2H).
[0161] Step D: 4-(2-bromoethoxy)-3-fluorobenzoic acid
Br-....0
0 F
CO2H
4-(2-Bromoethoxy)-3-fluorobenzonitrile (3.78 g, 15.5 mmol) in water (18 mL)
and concentrated
sulfuric acid (18 mL) was heated at 110 C for 12 hours. The solution was then
cooled to room
temperature and neutralized with solid sodium bicarbonate. Acidification with
glacial acetic acid leads
to a white solid precipitate, which was collected by filtration and dissolved
in dichloromethane. The
resulting solution was dried over anhydrous sodium sulfate, filtered, and
concentrated to give the
product as a beige-colored solid (2.65 g, 65% yield). 1H NMR (400 MHz, DMSO-
d6) 6 13.00 (brs, 1H),
7.44 (d, J= 8.4 Hz, 1H), 7.69 (d, J= 12.0 Hz, 1H), 7.29 (dd, J= 8.8 Hz, 8.4
Hz, 1H), 4.48 (t, J= 5.2
Hz, 2H), 3.85 (t, J= 5.2 Hz, 2H).
[0162] Step E: 4-(2-bromoethoxy)-3-fluorobenzoyl chloride
Br-...0
s F
Goa
4-(2-Bromoethoxy)-3-fluorobenzoic acid (1.08 g, 4.1 mmol) and thionyl chloride
(10 mL) were
refluxed for 7 h. The excess of thionyl chloride was removed by repeated
evaporation with dry toluene
in vacuo, giving 1.07 g (93% yield) subtitle compound as a brown oil. 1H NMR
(400 MHz, CDC13) 6
7.93 (d, J= 8.8 Hz, 1H), 7.86 (d, J= 11.2 Hz, 1H), 7.04 (dd, J= 8.4 Hz, 8.4
Hz, 1H), 4.46 (t, J= 6.4
Hz, 2H), 3.70 (t, J= 6.4 Hz, 2H).
[0163] Step F: (4-(2-bromoethoxy)-3-fluorophenyl)(4-methoxypheny1)- methanone
0
1101 0 FoBr
Me0
To a solution of 4-(2-bromoethoxy)-3-fluorobenzoyl chloride (1.07 g, 3.80
mmol) and anhydrous
A1C13 (1.01 g, 7.60 mmol) in dry dichloromethane (18 mL) was added anisole
(822 mg, 7.60 mmol) in
2 mL dichloromethane at 0 C. After stirring at rt for 6 h, the mixture was
poured into 3 N HC1 and
extracted with dichloromethane twice. The extracts were combined, washed with
sat. NaHCO3 and
brine, dried over Na2SO4, filtered, concentrated, and purified by column
chromatography over silica
gel (eluent: petroleum ether/ethyl acetate = 10/1 to 5/1) to give 1.05 g (77%
yield) of the subtitle
compound as a white solid. 1H NMR (400 MHz, CDC13) 6 7.79 (d, J= 8.8 Hz, 2H),
7.58 (d, J= 11.6
Hz, 1H), 7.55 (d, J= 8.4 Hz, 1H), 7.03 (dd, J= 8.0 Hz, 8.4 Hz, 1H), 6.98 (d,
J= 9.2 Hz, 2H), 4.44 (t, J
= 6.4 Hz, 2H), 3.90 (s, 3H), 3.70 (t, J= 6.4 Hz, 2H).
[0164] Step G: (4-(2-bromoethoxy)-3-fluorophenyl)(4-hydroxypheny1)- methanone
0
so 0 F
HO
BBr3 (0.5 mL, 5.29 mmol) was added to (4-(2-bromoethoxy)-3-fluorophenyl)(4-
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methoxyphenyl)methanone (930 mg, 2.63 mmol) in dichloromethane (6 mL) at 0 C.
Stirring was
continued at room temperature for 2 h under a nitrogen atmosphere. The
reaction mixture was
quenched with ice water and extracted with dichloromethane and the white
suspension was filtered off.
The organic layer was washed with water and brine and then dried over sodium
sulfate. Solvent
evaporation under reduced pressure, followed by purification by column
chromatography over silica
gel (eluent: petroleum ether/ethyl acetate = 5/1 to 2/1) gave 536 mg (60%
yield) of the subtitle
compound as a beige solid. 1H NMR (400 MHz, CDC13) 6 7.74 (d, J = 8.4 Hz, 2H),
7.59 (d, J = 12.4
Hz, 1H), 7.56 (d, J= 8.0 Hz, 1H), 7.03 (dd, J= 8.0 Hz, 8.0 Hz, 1H), 6.92 (d,
J= 8.4 Hz, 2H), 5.88 (s,
1H), 4.44 (t, J= 6.4 Hz, 2H), 3.70 (t, J= 6.4 Hz, 2H).
[0165] Step H: 4-(1-(4-(2-bromoethoxy)-3-fluoropheny1)-2-phenylbut-1-enyl)
phenol
/-Br
F 0-/
4. 410
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
(4-(2-bromoethoxy)-3-fluorophenyl)(4-hydroxyphenyl)methanone (311 mg, 0.917
mmol) was reacted
with propiophenone (246 mg, 1.83 mmol) to give 403 mg desired product (99.6%
yield, Z/E = 1/1) as a
beige solid.
[0166] Step I: 4-(1-(3-fluoro-4-(2-(methylamino)ethoxy)pheny1)-2-phenylbut-1-
enyl)phenol
/
/-NH
F 0-/
. .
OH
To a stirred solution of 4-(1-(4-(2-bromoethoxy)-3-fluoropheny1)-2-phenyl but-
l-enyl)phenol (111
mg, 0.25 mmol) in 5 mL Me0H was added 1 mL CH3NH2 (30% aq) and the mixture was
heated at 85
C for 18 h. The mixture was extracted with Et0Ac. The extract was washed with
water and brine,
dried over Na2SO4, filtered, concentrated, and purified by column
chromatography (CH2C12/Me0H
(NH3 gas) = 10/1) to give the desired product (56 mg, 57% yield, Z/E = 1/1) as
a beige solid. 1H NMR
(400 MHz, CDC13) 6 7.08-7.11 (m, 5H), 7.03 & 6.77 (d, J = 8.6 Hz, 2H), 6.91-
6.96 (m, 1H), 6.76 &
6.44(d, J = 8.4 Hz, 2H), 6.51-6.58 (m, 2H), 4.17 & 4.01 (t, J= 5.0 Hz, 2H),
3.03 & 2.93 (t, J= 5.0 Hz,
2H), 2.55 & 2.48 (s, 3H), 2.47 (q, J= 7.6 Hz, 2H), 0.91 (t, J= 7.6 Hz, 3H);
m/z = 392[M+1].
Example 22
(Z)-2-fluoro-4-(1-(4-hydroxypheny1)-1-(4-(2-(methylamino)ethoxy)phenyl)but-1-
en-2-Aphenol
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/
HO
OH
[0167] Step A: 1-(3-fluoro-4-methoxyphenyl)propan-1-one
/
0
F *
0
To a solution of 3-fluoro-4-methoxybenzonitrile (350 mg, 2.32 mmol) in 15 mL
anhydrous THF
was added ethylmagnesium bromide (1 M in Et20, 4.63 mL) at 0 C. The reaction
mixture was stirred
at rt overnight, then quenched with sat. NaHCO3, extracted with Et0Ac, washed
with brine, dried and
evaporated. The residue was purified by column chromatography (eluent:
petroleum ether/Et0Ac = 5/1)
over silica gel to give the product (239 mg, 57% yield) as a yellow solid.
[0168] Step B: 1-(3-fluoro-4-hydroxyphenyl)propan-1-one
HO
F 4I
0
1-(3-Fluoro-4-methoxyphenyl)propan-1 -one (421 mg, 2.31 mmol) in 20 mL 40% HBr
was
refluxed for 1 h., neutralized with solid Na2CO3 at 0 C, and extracted with
Et0Ac. The extract was
washed with brine, dried, concentrated, and purified by column chromatography
(eluent: petroleum
ether/Et0Ac = 5/1) over silica gel to give the product (257 mg, 66% yield) as
a yellow solid.
[0169] Step C: 4-(1-(4-
(2-chloroethoxy)pheny0-1-(4-hydroxyphenyDbut-1-en-2-
y0-2-fluorophenol
HO 0¨/
F * 41
41
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
1 -(3 - fluoro-4-hydroxyphenyl)propan-1 -one (255 mg, 1.52
mmol) was reacted with
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (629 mg, 2.27 mmol) to
give 549 mg desired
product (88% yield).
[0170] Step D: (Z)-2-
fluoro-4-(1-(4-hydroxypheny0-1-(4-(2-(methylamino)-
ethoxy)phenyl)but-l-en-2-yl)phenol
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/
OH
To a stirred solution of 4- (1- (4- (2 - chloroethoxy)pheny1)-
1 - (4-hydroxyphenyl)
but- 1 -en-2-y1)-2-fluorophenol (310 mg, 0.75 mmol) in 10 mL Me0H was added 2
mL CH3NH2 (30%
aq). The reaction mixture was heated at 85 C for 13 h. and extracted with
Et0Ac. The extract was
washed with water and brine, dried over Na2SO4, filtered, concentrated, and
purified by column
chromatography (CH2C12/Me0H(NH3 gas) = 10/1) to give the (Z)-product (39 mg,
white solid) and
(E)-product (14 mg, black brown crystal). m/z = 408[M+1] '.
Example 23
[0171] (E)-2-fluoro-4-(1-(4-hydroxypheny1)-1-(4-(2-(methylamino)ethoxy)
phenyllbut-1-en-2-yllphenol
HO OH
F . *
41/
0¨\
\¨NH
\
The title compound was separated as described in example 22 (14 mg, black
brown crystal). m/z =
408[M+1] '.
Example 24
2-Fuoro-4-(1-(4-(2-(methylamino)ethoxy)pheny1)-2-phenylbut-1-enyllphenol
/
0¨/
41, .
41 F
OH
[0172] Step A: 3-fuoro-4-methoxybenzoic acid
HO2C 0 F
0
3-Fluoro-4-methoxybenzonitrile (2.0 g, 13.2 mmol) in water (5 mL) and
concentrated sulphuric
acid (5 mL) was heated at 110 C for 4 hours. The solution was then cooled to
room temperature and
neutralized with solid sodium carbonate. Acidification with glacial acetic
acid leads to a white
precipitate, which was collected by filtration and dissolved in
dichloromethane. The resulting solution
was dried over sodium sulfate, filtered, and concentrated to give the product
as a beige-colored solid
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(2.03 g, 90% yield).
[0173] Step B: 3-fluoro-4-methoxybenzoyl chloride
0
0 F
CI
0
3-Fluoro-4-methoxybenzoic acid (830 mg, 4.88 mmol) and thionyl chloride (10
mL) were
refluxed for 2 h. The excess thionyl chloride was removed by repeated
evaporation with dry toluene in
vacuo, giving the subtitle compound as a brown solid, which would be used for
the next step directly.
[0174] Step C: (4-(2-chloroethoxy)phenyl)(3-fluoro-4-methoxypheny1)- methanone
0
0 F
CI.....õ......o 110)
0
To a solution of 3-fluoro-4-methoxybenzoyl chloride from the last step and
anhydrous A1C13 (1.30
g, 9.76 mmol) in dry dichloromethane (18 mL) was added (2-chloroethoxy)benzene
(1.53 g, 9.76 mmol)
in 2 mL dichloromethane at 0 C. After stirring at rt for 25 min, the mixture
was poured into 3 N HC1.
The mixture was extracted with dichloromethane. The extract was washed with
sat. NaHCO3 and brine,
dried over Na2SO4, filtered, and concentrated to give the subtitle compound,
which would be used for
the next step directly.
[0175] Step D: (4-(2-chloroethoxy)phenyl)(3-fluoro-4-hydroxypheny1)- methanone
0
0 F
CI o 0
OH
(4-(2-Chloroethoxy)phenyl)(3-fluoro-4-methoxyphenyl)methanone from the
previous step in 20
mL 40% HBr was refluxed for 1 h., neutralized with solid Na2CO3 at 0 C, and
extracted with Et0Ac.
The extract was washed with brine, dried, concentrated, and purified by column
chromatography
(eluent: petroleum ether/Et0Ac = 5/1 to 2/1) over silica gel to give the
subtitle compound (731 mg,
51% yield for 3 steps) as a yellow solid.
[0176] Step E: 4-(1-(4-(2-chloroethoxy)pheny1)-2-phenylbut-1-eny1)-2-fluoro
phenol
¨/
/¨CI
0
41/ .
40 F
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
(4-(2-chloroethoxy)phenyl)(3-fluoro-4-hydroxyphenyl)methanone (350 mg, 1.19
mmol) was reacted
with propiophenone (319 mg, 2.38 mmol) to give the desired product (quant.) as
a yellow solid.
[0177] Step F: 2-fuoro-4-(1-(4-(2-(methylamino)ethoxy)pheny1)-2-phenylbut-1-
enyl)phenol
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41
/
-//-NH
0
. 4I
* F
OH
To a stirred solution of 4-(1-(4-(2-chloroethoxy)pheny1)-2-phenylbut- 1-eny1)-
2-fluorophenol in 5
mL Me0H was added 2 mL CH3NH2 (30% aq) and heated at 85 C overnight. The
mixture was
extracted with Et0Ac, washed with water and brine, dried over Na2SO4,
filtered, concentrated, and
purified by column chromatography (CH2C12/Me0H(NH3 gas) = 10/1) to give the
desired product
(59% yield, Z/E = 1/1 as a white solid. m/z = 392[M+1].
Example 25
(Z)-4-(1-(5-(2-(dimethylamino)ethoxy)pyrimidin-2-y1)-2-phenylbut-1-enyl)phenol
hydrochloride
/
N\
0¨/¨
/ HCI
41 N/¨
\
N
_
=
OH
[0178] Step A: (5-bromopyrimidin-2-y1)(4-(tetrahydro-2H-pyran-2-yloxy)-
phenyl)methanone
0
- N
....
1
Br N 00
N.,,...- N.,
\/
Following same procedure of Grignard reaction as described in example 1, step
A,
2-(4-bromophenoxy)tetrahydro-2H-pyran (2.57 g, 10 mmol) was reacted with
5-bromopyrimidine-2-carbonitrile (0.92 g, 5 mmol) to give 910 mg desired
product (50%).
[0179] Step B: (4-(tetrahydro-2H-pyran-2-yloxy)phenyl)(5-(4,4,5,5-
tetramethyl-
1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)methanone
0
i&
I
0,BN
\
0 0 0
====---= =-=..
A mixture of (5-bromopyrimidin-2-y1)(4-(tetrahydro-2H-pyran-2-yloxy)-phenyl)
methanone (363
mg, 1 mmol), 4,4,4,4,5,5,5,5-octamethy1-2,2-bi(1,3,2- dioxaborolane) (508 mg,
2 mmol),
PdC12(DPPF) (73.1 mg, 0.1 mmol) and KOAc (200 mg, 2 mmol) in 30 mL of dioxane
was heated at 95
C for 5 h and cooled. The reaction was concentrated and purified by column
chromatography to give
the desired product as a yellow oil (329 mg, 80% yield).
[0180] Step C: (5-hydroxypyrimidin-2-y1)(4-(tetrahydro-2H-pyran-2-
yloxy)-
phenyl)methanone
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42
0
I N
HON 0,0
=-..........--
To a solution of (4-
(tetrahydro-2H-pyran-2-yloxy)phenyl)(5-(4,4,5,5-
tetramethy1-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)methanone (410 mg, 1 mmol)
in 20 mL of THF
was added 0.5 mL 33%H202 and the reaction was stirred for 1 h at rt. The
reaction was then quenched
with aq. Na2S03, extracted with Et0Ac, washed with water and brine, dried,
filtered, concentrated, and
purified by column chromatography to give the desired product (240 mg, 80%
yield).
[0181] Step D: (5-(2-
(dimethylamino)ethoxy)pyrimidin-2-y1)(4-(tetrahydro-2H-
pyran-2-yloxy)phenyl)methanone
0
NJ 0I I
..,,N.............------0--N 0 0
=-....--= ====,
To a mixture of (5-hydroxypyrimidin-2-y1)(4-(tetrahydro-2H-pyran-2- yloxy)
phenyl)methanone
(300 mg, 1 mmol), 2-(dimethylamino)ethanol (180 mg, 2 mmol) and PPh3 (524 mg,
2 mmol) in 50 mL
of THF was added DIAD (404 mg, 2 mmol) dropwise and the mixture was stirred
overnight at rt. The
mixture was concentrated and purified by flash chromatography to give the
product (297 mg, 80%
yield)
[0182] Step E: (Z)-4-(1-
(5-(2-(dimethylamino)ethoxy)pyrimidin-2-y1)-2-phenyl
but-l-enyl)phenol hydrochloride
/
0 \
HCI
N
_
lik
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
(5-(2-(dimethylamino)ethoxy)pyrimidin-2-y1)(4-(tetrahydro-2H-pyran-2-yloxy)
phenyl)methanone
(753 mg, 2 mmol) was reacted with propiophenone (800 mg, 6 mmol) to give Z/E
mixed product. The
pure (Z) and (E) isomer were separated by preparative HPLC. Evaporation of the
(Z)-isomer from 3 N
HC1 in Me0H to afford the title compound (16 mg). 1H NMR (400 MHz, CD30D) 6
8.30 (s, 2H),
7.06-7.13 (m, 7H), 6.77 (d, J = 8.4 Hz, 2H), 4.40 (t, J = 4.8 Hz, 2H), 3.57
(t, J = 4.8 Hz, 2H), 2.95 (s,
6H), 2.58 (q, J= 7.2 Hz, 2H), 0.95 (t, J= 7.2 Hz, 3H); m/z = 390[M-HC1+1]'.
Example 26
[0183] (E)-4-(1-(5-(2-(dimethylamino)ethoxy)pyrimidin-2-y1)-2-phenylbut-1-
enyl)phenol
hydrochloride
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OH
. 4*
N
N/
\¨ H CI
0¨\
\
The title compound (16 mg) was obtained in the same way as described in
example 25, step E. 1H
NMR (400 MHz, CD30D) 6 8.62 (s, 2H), 7.14-7.20 (m, 5H), 6.70 (d, J = 8.4 Hz,
2H), 6.43 (d, J= 8.8
Hz, 2H), 4.57 (t, J= 5.2 Hz, 2H), 3.67 (t, J= 5.2 Hz, 2H), 3.02 (s, 6H), 2.32
(q, J = 7.2 Hz, 2H), 0.90 (t,
J= 7.2 Hz, 3H); m/z = 390[M-HC1+1]'.
Example 27
4-(1-(5-(2-(Dimethylamino)ethoxy)pyridin-2-y1)-2-phenylbut-1-enyl)phenol
/
. / \
¨N
_
OH
[0184] Step A: 5-hydroxy-N-methoxy-N-methylpicolinamide
0 H
I I
o_N yN
0
To a suspension of 5-hydroxypicolinic acid (1.0 eq), HATU (1.2 eq) and N-
methoxymethanamine
hydrochloride (1.2 eq) in dry DMF was added DIEt0Ac (2.5 eq) dropwise at rt.
The mixture was then
stirred overnight at rt. After addition with water, the mixture was extracted
with CH2C12. The extract
was dried, concentrated, and purified by column chromatography to give the
desired product (87%
yield).
[0185] Step B: 5-(2-(dimethylamino)ethoxy)-N-methoxy-N-methylpicolinamide
ON
I I I
0
To a stirred solution of 5-hydroxy-N-methoxy-N-methylpicolinamide (1.0 eq),
2-(dimethylamino)ethanol (1.2 eq) and PPh3 (1.2 eq) in 5 mL anhydrous THF
under nitrogen was
added DIAD (1.2 eq) dropwise at 0 C. The reaction was stirred overnight at
rt., quenched with water,
and extracted with Et0Ac. The extract was dried, concentrated, and purified by
column
chromatography to give the desired product (40% yield).
[0186] Step C: (5-(2-(dimethylamino)ethoxy)pyridin-2-y1)(4-
(tetrahydro-2H-
pyran-2-yloxy)phenyl)methanone
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THP0 0,N
0
To a solution of 2-(4-iodophenoxy)tetrahydro-2H-pyran (1.1 eq) in THF was
added a solution of
nbutyllitium in hexane (1.1 eq) at -78 C. The mixture was stirred at -78 C
for 20 min. To the mixture
was added a solution of 5-(2-(dimethylamino)- ethoxy)-N-methoxy-N-
methylpicolinamide (1.0 eq) in
THF at -78 C. After 2 h, isopropanol and water was added to the mixture, and
the cold bath was
removed. The mixture was stirred at room temperature for 20 min. The mixture
was extracted with
ethyl acetate. The extract was washed with 0.5 N HC1, sodium bicarbonate
(sat.), and brine, dried over
sodium sulfate, filtered, concentrated, and pufified by column chromatography
(silica gel) to give the
subtitle compound (47% yield).
[0187] Step D: 4-(1-(5-(2-(dimethylamino)ethoxy)pyridin-2-y1)-2-phenylbut-1-
enyl)phenol
0
¨N
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
(5-(2-(dimethylamino)ethoxy)pyridin-2-y1)(4-(tetrahydro-2H-pyran-2-yloxy)
phenyl)methanone (1 eq)
was reacted with propiophenone (2 eq) to give the desired product (Z/E = 1/1).
m/z = 389[M+11.
Example 28
4-(1-(6-(3-(Dimethylamino)propyl)pyridin-3-y1)-2-phenylbut-1-enyl)phenol
hydrochloride
HCI
41N¨
\
OH
[0188] Step A: (6-chloropyridin-3-y1)(4-methoxyphenyOmethanone
0
0 N CI
To a solution of 6-chloronicotinonitrile (1.39 g, 10 mmol) in 100 mL of THF
was added
(4-methoxyphenyl)magnesium bromide (15 mmol) dropwise at 0 C. The mixture was
then stirred at 0
C for 1 h. and then 50 mL sat. NH4C1 solution was added. The mixture was
extracted with ethyl
acetate and the organic layer was washed with brine, dried over Na2SO4,
filtered, concentrated, and
purified by flash chromatography to give the product (1.24g, 50% yield).
[0189] Step B: (6-(3-(dimethylamino)prop-1-ynyl)pyridin-3-y1)(4-methoxy
phenyl)methanone
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0
, 0 I
1:D N I
N
A 25 ml Schlenk flask was charged with (6-chloropyridin-3-y1)(4-methoxy-
phenyl)methanone
(124 mg, 0.5 mmol), Pd(PPh3)2C12 (18 mg, 0.0 25mmol), CuI (10 mg, 0.05 mmol),
Et3N (10 mL), and
N,N-dimethylpropargylamine (83 mg, 1.0 mmol). The flask was flushed with argon
three times and the
mixture was stirred at 80 C for 24 h. The solvent was evaporated under vacuum
and the residue was
purified by column chromatography to give the product (118 mg, 80% yield).
[0190] Step C: (6-(3-(dimethylamino)propyl)pyridin-3-y1)(4-methoxy-phenyl)
methanone
0
õ
I I 1
0 N=='N
A flask was charged with (6-(3 -
(dimethylamino)prop-1 -ynyl)pyridin-3 -y1)-
(4-methoxyphenyl)methanone (294 mg, 1 mmol) and Riney Ni (0.2 eq), and 20 mL
methanol. The
mixture was stirred under hydrogen at room temperature and atmospheric
pressure for 2 h. The catalyst
was filtered off through a pad of celite, washed with Et0Ac. The filtrate was
concentrated under
reduced pressure to give the product (284 mg, 95% yield).
[0191] Step D: (6-(3-(dimethylamino)propyl)pyridin-3-y1)(4-hydroxy-phenyl)
methanone
0
I
HO NN
To a solution of (6-(3-(dimethylamino)propyl)pyridin-3-y1)(4-methoxy-
phenyl)methanone (298
mg, 1 mmol) in 10 mL of methanol was added 10 mL of 48% HBr at rt and the
mixture was heated to
reflux for 3 h and cooled. The solvent was evaporated to give the crude
product, which was used
without further purification (284 mg, 100% yield).
[0192] Step E: 4-(1-(6-(3-(dimethylamino)propyl)pyridin-3-y1)-2-phenylbut- 1-
enyl)phenol
hydrochloride
/
N
\
HCI
N _
11
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
(6-(3-(dimethylamino)propyl)pyridin-3-y1)(4-hydroxyphenyl)methanone (568 mg, 2
mmol) was
reacted with propiophenone (800 mg, 6 mmol) to give 55 mg desired product (7%
yield, Z/E = 1/1).
m/z = 387[M-HC1+1] '.
[0193] Example 29
6-(1-(4-(2-(Methylamino)ethoxy)pheny1)-2-phenylbut-1-enyl)pyridin-3-ol
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46
_/¨NH
0
N\
OH
[0194] Step A: tert-butyl 2-(4-bromophenoxy)ethyl(methyl)carbamate
40 0 N
Boc
Br
To a stirred solution of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.5 eq),
4-bromophenol (1.0
eq) and PPh3 (1.5 eq) in anhydrous THF under nitrogen was added DIAD (1.5 eq)
dropwise at 0 C.
The reaction was stirred at rt.for 48 h., quenched with water, and extracted
with Et0Ac. The extract
was dried, concentrated, and purified by column chromatography to give the
desired product.
[0195] Step B: tert-butyl 2-(4-(5-hydroxypicolinoyl)phenoxy)ethyl-(methyl)
carbamate
NO I OH
Boc
0
Mg (3.5 eq) was added to a 3-neck round bottom flask containing 50 mL
anhydrous THF. The
mixture was heated to 55 C. Iodine chips (2 grains) were added in one lot
followed by addition of 0.1
mL ethyl bromide. Tert-butyl 2-(4-bromophenoxy)ethyl(methyl)carbamate (3.0 eq)
was dissolved in 30
mL anhydrous THF, 3 mL of this solution was added at once to Mg- THF
suspension. The reaction was
initiated after 30 min and reflux started. The remaining solution of tert-
butyl
2-(4-bromophenoxy)ethyl(methyl)carbamate was added dropwise in such speed that
the reaction
mixture remained reflux. After addition, the reaction mixture was further
reflux for 2 h and cooled to rt.
5-Hydroxy-N-methoxy-N- methylpicolinamide (1.0 eq ) in 20 mL THF was added
dropwise at rt,
stirred for 30 min. at rt., quenched with sat NH4C1 (aq), and extracted with
Et0Ac. The extract was
dried, concentrated, and purified by column chromatography to give the desired
product.
[0196] Step C: 6-(1-(4-(2-(methylamino)ethoxy)pheny1)-2-phenylbut-1-enyl)
pyridin-3-ol
/¨NH
N\
OH
Following general procedure of McMurry reaction as described in example 1,
step B, tert-butyl
2-(4-(5-hydroxypicolinoyl)phenoxy)ethyl(methyl)carbamate (1.0 eq) was reacted
with propiophenone
(3.0 eq) to give the desired product (Z/E = 1/1). m/z = 375[M+1]'.
Example 30
4-(2-Pheny1-1-(6-(3-(pyrrolidin-1-yl)propyl)pyridin-3-yl)but-1-enyl)phenol
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47
/-
N
OH
\----
-
41
OH
[0197] Step A: 2-(4-iodophenoxy)tetrahydro-2H-pyran
0 0 I
0
4-Iodophenol 10.0 g (45.5 mmol) was dissolved in 20 mL 3,4-dihydro-2H-pyran,
then one drop of
concentrated sulfuric acid was added, the reaction mixture was stirred for 30
min, then the mixture was
poured into 1000 mL of n-hexane, filtered and washed with 300 mL (100 mL >< 3)
hexane, dried in
vacuum to afford the desired product as white solid (9.1 g, 65.9% yield).
[0198] Step B: 6-chloro-N-methoxy-N-methylnicotinamide
0
N).
I I
0 NCI
Oxalyl chloride 12.1 g (95.2 mmol) was added dropwise to a solution of 6-
chloronicotinic acid
10.0 g (63.5 mmol) in 100 mL tetrahydrofuran. The reaction mixture was stirred
at room temperature
for 1 h, and then concentrated to give a residue, which was dissolved in 50 mL
dichloromethane. The
solution thus formed was added to a solution of N,O-dimethylhydroxylamine
hydrochloride 12.4 g
(126.9 mmol) and triethylamine 25.7 g (253.9 mmol) in 100 mL dichloromethane,
stirred at room
temperature for 1 h., concentrated, and purified by column chromatography to
afford the desired
product as colorless oil (9.4 g, 73.8% yield).
[0199] Step C: 1-(prop-2-ynyl)pyrrolidine
0
3-Bromoprop-1-yne (60.5 g, 0.50 mol) was slowly added to methylamine (70.1 g,
1.0 mol) at -10
C. After addition, the mixture was stirred at room temperature overnight, and
then distilled on a
rectification column to afford the desired product as a colorless oil (45.5 g,
83.5% yield).
[0200] Step D: (6-chloropyridin-3-34)(4-(tetrahydro-2H-pyran-2-yloxy)-phenyl)
methanone
0
0
I
THPO N CI
2-(4-Iodophenoxy)tetrahydro-2H-pyran (18.2 g, 59.9 mmol) was dissolved in 100
mL dry
tetrahydrofuran and cooled to -78 C under nitrogen atmosphere, and then n-
butyllithium was added
dropwise to the solution. After addition, the solution was stirred at -78 C
for 0.5 h,
6-chloro-N-methoxy-N-methylnicotinamide (8.0 g, 39.9 mmol) in 50 mL
tetrahydrofuran was added
dropwise and keep the temperature under -78 C for 2 h. 100 mL of saturated
aqueous ammonium
chloride was added. The mixture was extracted with ethyl acetate. The extract
was dried, concentrated,
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and purified by column chromatography to give the desired product as yellow
solid (8.4 g, 66.3%
yield).
[0201] Step E: (6-(3-(pyrrolidin-1-yl)prop-1-ynyl)pyridin-3-y1)(4-
(tetrahydro-
2H-pyran-2-yloxy)phenyl)methanone
0
la I
THPO N 0
A 100 mL Schlenk flask was charged with (6-chloropyridin-3-y1)(4-(tetrahydro-
2H-pyran-2-yloxy)phenyl)methanone (4.0 g , 12.6 mmol),
tetrakis(triphenylphosphine) palladium(0)
(1.5 g, 1.3 mmol, 10 mol%), cuprous iodide (0.48 g, 2.5 mmol, 20 mol%),
triethylamine 50 mL and
1-(prop-2-ynyl)pyrrolidine (2.8 g, 25.2 mmol), and then the flask was flushed
with nitrogen three times.
The mixture was stirred at 80 C for 2 h. The solvent was evaporated under
vacuum and the residue was
purified by column chromatography to afford the desired product as a yellow
solid (2.2 g, 44.9% yield).
[0202] Step F: (6-(3-(pyrrolidin-1-yl)propyl)pyridin-3-y1)(4-
(tetrahydro-2H-
pyran-2-yloxy)phenyl)methanone
0
/../.õ
THPOI &N'NCD
Raney nickel (0.3 g, 0.6 mmol, 10 mol%) was added to a solution of
(6-(3 - (pyrrolidin-1 -yl)prop-1 -ynyl)pyridin-3 -y1) (4- (tetrahydro-2H-pyr
an-2-yloxy)phenyl)methanone
(2.2 g, 5.6 mmol) in 20 mL methanol at room temperature, and the reaction
mixture was stirred for 1 h
under hydrogen atmosphere. The nickel was filtered off and the filtrate was
concentrated in vacuo to
afford the desired product as a yellow solid (1.7 g, 77.3% yield).
[0203] Step G: 4-(2-phenyl-1-(6-(3-(pyrrolidin-1-yl)propyl)pyridin-3-yl)but-1-
enyl)phenol
N-----
...--
41 I\I
_ / "
OH
Following the general procedure of McMurry reaction as described in example 1,
step B,
(6-(3 - (pyrrolidin-1 -yl)propyl)pyridin-3 -y1) (4- (tetr ahydro-2H-pyr an-2-
yl- oxy)phenyl)methanone (1.0 g,
2.5 mmol) was reacted with propiophenone (1.0 g, 7.6 mmol) to give 186 mg
desired product (17.8%
yield, Z/E = 3/1). m/z = 413[M+1]'.
Example 31
4-(2-Pheny1-1-(4-(3-(pyrrolidin-1-yl)propyl)phenyl)but-1-enyl)phenol
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49
N7------
\---
. 41
41
OH
[0204] Step A: (4-(3-
(pyrrolidin-1-yl)prop-1-ynyl)phenyl)(4-(tetrahydro-2H-
pyran-2-yloxy)phenyl)methanone
0
0 0
THPO - 0
A 25 mL Schlenk flask was charged with (4-iodophenyl)(4-(tetrahydro-2H-
pyran-2-yloxy)phenyl)methanone (408 mg, 1 mmol), Pd(PPh3)2C12 (18 mg, 0.025
mmol), CuI (10 mg,
0.05 mmol), Et3N (10 ml) and 1-(prop-2-ynyl)pyrrolidine (165 mg, 1.5 mmol).
The flask was flushed
with argon three times and the mixture was stirred at 90 C for 3 h. The
solvent was evaporated under
vacuum and the residue was purified by columnchromatography to give the
desired product (312 mg,
80% yield)
[0205] Step B: (4-(3-
(pyrrolidin-l-yl)propyl)phenyl)(4-(tetrahydro-2H-pyran-
2-yloxy)phenyl)methanone
0
THPOI NO
A flask was charged with
(4-(3 - (pyrrolidin-1 -yl)prop-1 -ynyl)phenyl) (4-
(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (391 mg, 1 mmol), Riney Ni (0.2
eq), and 20 mL of
methanol. The mixture was stirred under hydrogen at room temperature and
atmospheric pressure for 2
h. After complete conversion (TLC monitoring), the catalyst was filtered off
through a pad of celite,
and washed with Et0Ac. The filtrate was concentrated under reduced pressure to
give the product (375
mg, 95% yield).
[0206] Step C: 4-(2-phenyl-1-(4-(3-(pyrrolidin-1-yl)propyl)phenyl)but-1-eny1)-
phenol
7"----
N
\----
= .
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
(4-(3-(pyrrolidin-1-yl)propyl)phenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)
methanone (798 mg, 2
mmol) was reacted with propiophenone (800 mg, 6 mmol) to give 208 mg desired
product (25%, Z/E =
1/1). m/z = 412[M+1] '.
Example 32
4-(1-(6-(3-(Methylamino)propyl)pyridin-3-y1)-2-phenylbut-1-enyl)phenol
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/
NH
_
OH
[0207] Step A: N-methylprop-2-yn-1-amine
H
N---..
=/
Allyl bromide 64.0 g (0.54 mol) was added to 120 mL of anhydrous methylamine
cooled with
solid carbon dioxide. The mixture was sealed in a sealtube and kept at room
temperature overnight. The
tube was opened and the contents heated to 45 C to expel excess methylamine.
Dry ether (100 mL)
was then added and the methylamine hydrochloride was removed by filtration.
Distillation of the
filtrate gave the desired product as a colorless oil (5.0 g, 13.4% yield),
b.p. 82-84 C.
[0208] Step B: tert-butyl methyl(prop-2-ynyl)carbamate
Boc
i\J---.
=/
Di-tertbutyl dicarbonate (2.7 mL, 11.7 mmol) was slowly added to a stirring
solution of
N-methylpropargylamine 0.8 g (1.0 mL, 11.8 mmol) in 20 mL of methanol at 25
C. The mixture was
allowed to stir for 1 h. All volatiles were removed in vacuo to afford crude
Boc-N-methylpropargylamine as a light yellow oil (1.9 g, 97% yield).
[0209] Step C: tert-butyl methyl(3-
(5-(4-(tetrahydro-2H-pyran-2-yloxy)
benzoyD-pyridin-2-34)prop-2-ynyOcarbamate
0
la I
THPO N /
N,Boc
A 25 mL
Schlenk flask was charged with (6- chloropyridin-3 -y1) (4- (tetr ahydro-
2H-pyran-2-yloxy)phenyl)methanone (318 mg, 1.0 mmol), tetrakis(triphenylphos-
phine)Palladium(0)
(116 mg, 0.1 mmol, 10 mol%), cuprous iodide (38g, 0.2 mmol, 20 mol%),
triethylamine (5 mL), and
tert-butyl methyl(prop-2-ynyl)carbamate (169 mg, 1 mmol). The flask was
flushed with nitrogen three
times and the mixture was stirred at 80 C for 2 h. The solvent was evaporated
under vacuum and the
residue was purified by column chomatography to afford the desired product as
yellow solid (180 mg,
40% yield).
[0210] Step D: tert-butyl methyl(3-
(5-(4-(tetrahydro-2H-pyran-2-yloxy)
benzoyD-pyridin-2-34)propy0carbamate
0
-------zz,}1-------\,..,
I
THPO tNN,Boc
Raney nickel (2.4 mg, 0.04 mmol, 10 mol%) was added to a solution of
tert-butylmethyl(3 - (5 - (4- (tetr ahydro-2H-pyr an-2 -yloxy)benzoyl)pyridin-
2 -yl)prop-2 -ynyl) carbamate
(180 mg, 0.4 mmol) in 3 mL methanol at room temperature, and the reaction
mixture was stirred for 1 h
under hydrogen atmosphere. The nickel was filtered off and the filtrate was
concentrated in vacuo to
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afford the desired product as a yellow solid (100 mg, 55.6% yield).
[0211] Step E: 4-(1-(6-(3-(methylamino)propyl)pyridin-3-y1)-2-phenylbut-1-
enyl)phenol
/
NH
_
OH
Following general procedure of McMurry reaction as described in example 1,
step B, tert-butyl
methyl(3-(5-(4-(tetrahydro-2H-pyran-2-yloxy)benzoyl)pyridin-2-
yl)propyl)carbamate (100 mg, 0.22
mmol) was reacted with propiophenone (88 mg, 0.66 mmol) to give 16 mg desired
product (20% yield,
Z/E = 1/1). m/z = 373[M+1] '.
Example 33
4-(1-(4-(3-(Methylamino)propyl)pheny1)-2-phenylbut-1-enyl)phenol
/
NH
. .
OH
[0212] Step A: tert-butyl methyl(3-(4-(4-(tetrahydro-2H-pyran-2-
yloxy)
benzoy1)-phenyl)prop-2-ynyl)earbamate
0
SS
THPO Boc
N
A 25 mL Schlenk flask was charged with (4-iodophenyl)(4-(tetrahydro-
2H-pyran-2-yloxy)phenyl)methanone (408 mg, 1 mmol), Pd(PPh3)2C12 (18 mg, 0.025
mmol), CuI (10
mg, 0.05 mmol), Et3N (10 mL), and tert-butyl methyl(prop- 2-ynyl)carbamate
(255 mg, 1.5 mmol).
The flask was flushed with argon three times and the mixture was stirred at 90
C for 3 h. The solvent
was evaporated under vacuum and the residue was purified by
columnchromatography to give the
desired product (270 mg, 60% yield).
[0213] Step B: tert-butyl methyl(3-(4-(4-(tetrahydro-2H-pyran-2-
yloxy)
benzoy1)-phenyl)propypearbamate
0
I I Boo
THP0
A flask was charged with tert-butyl methyl(3-(4-(4-(tetrahydro-2H-pyran-2-
yloxy)benzoyl)phenyl)prop-2-ynyl)carbamate (450 mg, 1 mmol), Riney Ni (0.2
eq), and 20 mL of
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methanol. The mixture was stirred under hydrogen at room temperature and
atmospheric pressure for 2
h. After complete conversion (TLC monitoring), the catalyst was filtered off
through a pad of celite,
and washed with Et0Ac. The filtrate was concentrated under reduced pressure to
give the product (364
mg, 80% yield).
[0214] Step C: 4-(1-(4-(3-(methylamino)propyl)pheny1)-2-phenylbut-1-eny1)-
phenol
/
NH
41 .
OH
Following general procedure of McMurry reaction as described in example 1,
step B, tert-butyl
methyl(3-(4-(4-(tetrahydro-2H-pyran-2-yloxy)benzoyl)pheny1)- propyl)carbamate
(909 mg, 2 mmol)
was reacted with propiophenone (800 mg, 6 mmol) to give 224 mg desired product
(30%, Z/E = 1/1).
m/z = 372[M+1].
Example 34
4-(1-(3-Fluoro-4-(3-(pyrrolidin-1-yl)prop-1-ynyl)pheny1)-2-phenylbut-1-enyl)
phenol
r----
N
\---
F //
. .
=
OH
[0215] Step A: (4-bromo-3-fluorophenyl)(4-(tetrahydro-2H-pyran-2-yloxy)-
phenyl)methanone
0
so 0 F
THPO Br
To a solution of 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (1.00 g, 3.8
mmol) in dry
tetrahydrofuran at 0 C under nitrogen was
added dropwise
(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)magnesium bromide (7.6 mmol). After
addition, the reaction
mixture was let warm to room temperature, stirred for 2 h., quenched with
saturated ammonium
chloride, and extracted with ethyl acetate. The extract was dried over sodium
sulfate, concentrated, and
purified by column chromatography to give the desired product as a colorless
oil (1.10 g, 76% yield).
[0216] Step B: (3-fluoro-
4-(3-(pyrrolidin-1-yl)prop-1-ynyl)phenyl)(4-
(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone
0
0 0 F
THPO
0
A 100 mL Schlenk flask was charged with (4-bromo-
3 - fluorophenyl) (4-
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(tetr ahydro-2H-pyr an-2 -yloxy)phenyl)methanone (1.10g, 2.90
mmol), tetrakis(tri-
phenylphosphine)Palladium(0) (0.34 g, 0.29 mmol, 10 mol%), cuprous iodide
(0.11 g, 0.58 mmol, 20
mol%), triethylamine (20 mL), and 1-(prop-2-ynyl)pyrrolidine (0.63 g, 5.80
mmol), and the flask was
flushed with nitrogen three times. The mixture was stirred at 80 C for 2 h.
The solvent was evaporated
under vacuum and the residue was purified by column chromatography to afford
the desired product as
a yellow solid (0.43 g, 36.4% yield).
[0217] Step C: 4-(1-(3-
fluoro-4-(3-(pyrrolidin-1-yl)prop-1-ynyl)pheny1)-2-
phenylbut-l-enyl)phenol
/------
N
\---
F //
41 .
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
(3 - fluoro-4- (3 - (pyrrolidin-1 -yl)prop-1 -ynyl)phenyl) (4- (tetrahydro-2H-
pyr an-
2 -yloxy)phenyl)methanone (155 mg, 0.38 mmol) was reacted with propiophenone
(152 mg, 1.13 mmol)
to give 58 g desired product (36% yield, Z/E = 1/1). m/z = 426[M+1]'.
Example 35
(Z)-4-(1-(4-hydroxypheny1)-1-(4-(2-(methylamino)ethoxy)phenyl)but-1-en-2-y1)
cyclohexan one
/
0 o_/¨NH
. 41
41
OH
[0218] Step A: triethyl 4-oxocyclohexane-1,1,3-tricarboxylate
0
Et00C¨
___________________________________ COOEt
COOEt
To a solution of 23.0 g of sodium hydride in 280 mL of anhydrous THF was added
a solution of
40.0 g of diethyl malonate in 80 mL of THF at 40 C over a period of 30
minutes. After addition the
mixture was stirred for one hour, the temperature decreased to 15 C, and a
solution of 52.5 g ethyl
acetate in 80 mL THF, was added. After the mixture was stirred at 45 C for 30
minutes, 100 mL water
was added, and the mixture was extracted with ethyl acetate. The extract was
concentrated and purified
by silica gel chromatography (Et0Ac:petroleum ether=50:1) to give the product
of triethyl
4-oxocyclohexane-1,1,3-tricarboxylate (40 g, 38.1% yield).
[0219] Step B: 4-oxocyclohexanecarboxylic acid
0_)
\--
\
CO2H
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A mixture of triethyl 4-oxocyclohexane-1,1,3-tricarboxylate (31.4 g, 0.1 mol),
concentrate
hydrochloride acid (30 mL), and water (145 mL) was refluxed overnight, and
then extracted with ethyl
acetate. The extract was concentrated and purified by silic gel chromatography
(CH2C12:Me0H=80:1)
to give the product of 4-oxocyclohexanecarboxylic acid (4.2 g, 29% yield).
[0220] Step C: N-methoxy-N-methyl-4-oxocyclohexanecarboxamide
0
/0-N\
To a solution of 4-oxocyclohexanecarboxylic acid (4.2 g, 0.0293 mol) in CH2C12
(20 mL) was
added oxalyl chloride (5.2 g, 0.44 mol) slowly, stirred at room temperature
for 1 hour and concentrated,
then 20 mL CH2C12 was added, followed by addition of Et3N (9 g, 0.116 mol) and
N, 0-dimethylhydroxylamine hydrochloride (3.5 g, 0.0359 mol). The reaction
mixture was stirred for 2
hours, and then 100 mL water was added. The mixture was extracted with ethyl
acetate. The extract
was concentrated and purified by column chromatography to give the desired
product (2.1 g, 39%
yield).
[0221] Step D: N-methoxy-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide
(No
oq0
/o¨N\
A mixture of N-methoxy-N-methyl-4-oxocyclohexanecarboxamide (2.1 g, 0.114
mol), glycol (0.9
g, 0.136 mol) and toluenesulfonate (0.1 g, cat) in toluene (30 mL) was
refluxed overnight and then
concentrated. Water was added, and the mixture was extracted with ethyl
acetate. The extract was
concentrated and purified by silica gel column chromatography
(CH2C12:Me0H=100:1) to give the
desired product (1 g, 38.4% yield).
[0222] Step E: 1-(1,4-dioxaspiro[4.5]decan-8-yDpropan-1-one
(NO
0--t
0
To a solution of N-methoxy-N-methyl-1,4-dioxaspiro[4.5]decane-8-carboxamide (1
g, 0.0043 mol)
in anhydrous Et20 (20 mL) was added EtMgBr (9 g, 0.043 mol). The reaction
mixture was refluxed
overnight, and then 200 mL water was added. The mixture was extracted with
ethyl acetate. The extract
was concentrated and purified by silica gel column chromatography
(CH2C12:Me0H=150:1) to give the
desired product (0.259 g, 26% yield).
[0223] Step F: (Z)-4-(1-(4-(2-chloroethoxy)pheny0-2-(1,4-
dioxaspiro[4.5] decan-
8-yl)but-1-enyl)phenol
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OcI
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
1-(1,4-dioxaspiro[4.5]decan-8-Apropan-1-one (259 mg, 1.3 mmol) was reacted
with
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (360 mg, 1.3 mmol) to
give 90 mg title
compound (Z-isomer, 16% yield) and 110 mg E-isomer (19% yield) as well.
[0224] Step G: (Z)-4-(1-(4-
(2-(methylamino)ethoxy)pheny1)-2-(1,4-dioxaspiro-
[4.5]decan-8-yl)but-l-enyl)phenol
0
OH
A mixture of (Z)-4- (1
- (4- (2- chloroethoxy)pheny1)-2- (1,4-dioxaspiro[4.5] decan-
8-yl)but-1- enyl)phenol (90 mg, 0.20 mol), 30% aqueous of CH3NH2 (5 mL), and
Me0H (5 mL) was
heated at 85 C in a sealed tube overnight, concentrated, and purified by
column chromatography to
give the desired product (90 mg).
[0225] Step H: (Z)-4-(1-(4-
hydroxypheny1)-1-(4-(2-(methylamino)ethoxy)-
phenyl)but-l-en-2-yl)cyclohexanone
/¨NH
0 0¨/
OH
To a solution of (Z)-
4- (1 - (4- (2- (methylamino) ethoxy)pheny1)-2- (1,4-dioxa-
spiro[4.5]decan-8-yl)but- 1 -enyl)phenol (90 mg) in Me0H (10 mL) was added
aqueous of HC1 (3 M,
1.5 mL), the mixture was stirred at room temperature for 2 hours, 20 mL water
was added, pH was
adjusted to 7-8 by addition of aqueous NaHCO3, and the mixture was extracted
with ethyl acetate. The
extract was dried, concentrated, and purified by column chromatography
(CH2C12:Me0H=150:1) to
give the desired product (22 mg, 27.5% yield). m/z = 394[M+1].
Example 36
[0226] (E)-4-(1-(4-hydroxypheny1)-1-(4-(2-(methylamino)ethoxy)phenyl)but-1-en-
2-Acyclohex
anone
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0 0 H
= .
0¨\
\¨NH
\
The title compound (32 mg, 39.5%) was obtained in the same way as described in
example 35,
step F, G & H, from the E-isomer (made from example 35, step F). m/z =
394[M+1].
Example 37
(Z)-4-(1-(4-hydroxypheny1)-1-(4-(2-(methylamino)ethoxy)phenyl)but-1-en-2-y1)-1-
methylpyridin-
2(111)-one
\ 0¨\
0 N_\ 40, \¨N1c1
_
OH
[0227] Step A: 2-oxo-1,2-dihydropyridine-4-carboxylic acid
0y0H
N 0
H
To a stirred solution of 2-chloroisonicotinic acid (15 g, 1.0 eq) in 200 mL
water at 0 C was added
KOH (40 g, 7.5 eq). Then the reaction mixture was heated to reflux for 36 h.,
cooled, and 3 N HC1 (aq)
was added to pH = 1-3. The precipitate was collected by filtration and washed
with water to give the
product as a white solid (13.1 g, 99% yield). 1H NMR (400 MHz, DMSO-d6) 6
12.80 (brs, 2H), 7.47 (d,
J= 6.4 Hz, 1H), 6.79 (s, 1H), 6.50 (dd, J= 6.8 Hz, 1.6 Hz, 1H).
[0228] Step B: methyl 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate
0 0
NO
I
To a solution of 2-oxo-1,2-dihydropyridine-4-carboxylic acid (5 g, 1.0 eq) in
100 mL DMF was
added 60% NaH (4.3 g, 3.0 eq) slowly at 0 C, and the mixture was stirred for
30 min at rt. Then CH3I
(15.3 g, 3.0 eq) was added dropwise at 0 C. After the reaction was stirred at
rt overnight, the reaction
mixture was quenched with water and extracted with Et0Ac. The extract was
dried, concentrated, and
purified by column chromatography to give the desired product (1.5 g, 25%
yield). 1H NMR (400 MHz,
CDC13) 6 7.34 (d, J= 7.2 Hz, 1H), 7.21 (d, J= 2.0 Hz, 1H), 6.65 (dd, J= 6.8
Hz, 2.0 Hz, 1H), 3.91 (s,
3H), 3.57 (s, 3H).
[0229] Step C: 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid
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OOH
To a stirred solution of methyl 1-methy1-2-oxo-1,2-dihydropyridine-4-
carboxylate (1 g, 1.0 eq) in
25 mL Me0H was added a solution of LiOHH20 (755 mg, 3.0 eq) in 5 mL water at
rt. The reaction
was then stirred at rt for 2 h. Then the solvent was removed in vacuo, and
water was added to the
residue, followed by addition of 3N HC1 (aq) to adjust pH=1-3. The product was
collected by filtration
and washed with water to give the product as white solid (540 mg, 60% yield).
1H NMR (400 MHz,
DMSO-d6) 6 13.56 (brs, 1H), 7.80 (d, J= 7.2 Hz, 1H), 6.83 (d, J= 1.6 Hz, 1H),
6.53 (d, J= 6.8 Hz, 1.6
Hz, 1H), 3.46 (s, 3H).
[0230] Step D: N-methoxy-N,1-dimethy1-2-oxo-1,2-dihydropyridine-4- carboxamide
0 N
LN0
A suspension of 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (540 mg,
1.0 eq), EDCI
(811 mg, 1.2 eq) and HOBt (572 mg, 1.2 eq) in 20 mL CH2C12 was stirred at r.t.
for 5 min Then
N-methoxymethanamine hydrochloride (413 mg, 1.2 eq) and Et3N (1.1 g, 3.0 eq)
were added, and the
reaction was stirred at rt overnight. Water was added, and the mixture was
extracted with CH2C12. The
extract was dried, concentrated, and purified by column chromatography to give
the desired product
(555 mg, 80% yield). 1H NMR (400 MHz, CDC13) 6 7.32 (d, J = 6.8 Hz, 1H), 6.78
(s, 1H), 6.32 (dd, J
= 6.8 Hz, 1.6 Hz, 1H), 3.61 (s, 3H), 3.57 (s, 3H), 3.32 (s, 3H).
[0231] Step E: 1-methyl-4-propionylpyridin-2(1H)-one
NO
To a solution of N-methoxy-N,1-dimethy1-2-oxo-1,2-dihydropyridine-4-
carboxamide (200 mg,
1.0 eq) in 10 mL anhydrous THF was added 3 M EtBrMg (0.7 mL, 2 eq) slowly at 0
C. The reaction
was stirred at rt for lh., quenched with sat NH4C1 (aq), and extracted with
CH2C12. The extract was
dried, concentrated, and purified by column chromatography to give the desired
product (105 mg, 62%
yield). 1H NMR (400 MHz, CDC13) 6 7.35 (d, J= 6.8 Hz, 1H), 7.06 (d, J= 2.0 Hz,
1H), 6.61 (dd, J =
6.8 Hz, 1.6 Hz, 1H), 3.57 (s, 3H), 2.89 (q, J = 7.2 Hz, 2H), 1.20 (t, J= 7.2
Hz, 3H).
[0232] Step F: 4-(1-(4-(2-chloroethoxy)pheny1)-1-(4-hydroxyphenyl)but-
l-en-2-
y1)-1-methylpyridin-2(1H)-one
\ 411 0-\
\-C1
0
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
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1 -methyl-4-propionylpyridin-2 (1H)-one (105 mg, 1.0 eq) was
reacted with
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (352 mg, 2.0 eq) to give
the desired product
(Z/E = 1:1).
[0233] Step G: (Z)-4-(1-(4-hydroxypheny1)-1-(4-(2-
(methylamino)ethoxy)
phenyl)but-1-en-2-y1)-1-methylpyridin-2(1H)-one
\ 0-\
N \ ak \-NH
0 \
41
OH
To a stirred solution of 4-
(1 - (4- (2- chloroethoxy)pheny1)-1 - (4-hydroxypheny1)-
but- 1 -en-2-y1)-1-methylpyridin-2(11/)-one (30 mg, 1.0 eq) in 10 mL Me0H was
added 5 mL 30%
CH3NH2 (aq), and the mixture was then heated at 85 C for 36 h. Then the
solvent was removed in
vacuo, water was added to the residue and extracted with Et0Ac. The extract
was dried, concentrated,
and purified by column chromatography to give the desired product (3 mg, Z-
isomer), E-isomer (2 mg),
and Z/E mixture (230 mg, 49% yield) as well. 1H NMR (400 MHz, CDC13) 6 6.96-
6.98 (m, 3H), 6.84
(d, J = 8.8 Hz, 2H), 6.77 (d, J= 8.4 Hz, 2H), 6.57 (d, J= 8.8 Hz, 2H), 6.47
(d, J= 2.0 Hz, 1H), 5.78
(dd, J= 6.8 Hz, 2.0 Hz, 1H), 3.98 (t, J= 5.2 Hz, 2H), 3.47 (s, 3H), 2.96 (t,
J= 5.2 Hz, 2H), 2.52 (s, 3H),
2.36-2.38 (m, 2H), 0.92 (t, J= 7.2 Hz, 3H); m/z = 405[M+1].
Example 38
[0234] (E)-4-(1-(4-hydroxypheny1)-1-(4-(2-(methylamino)ethoxy)phenyl)but-1-
en-2-y1)-1-methylpyridin-2(1H)-one
\ OH
N
0 \ 4110
_
-\-NH
\
The title compound was obtained by example 37. 1H NMR (400 MHz, CDC13) 6 7.08
(d, J = 8.4
Hz, 2H), 6.99 (d, J= 6.8 Hz, 1H), 6.84 (d, J= 8.8 Hz, 2H), 6.79 (d, J= 8.4 Hz,
2H), 6.53 (d, J= 8.4 Hz,
2H), 6.51 (d, J= 1.6 Hz, 1H), 5.83 (dd, J= 7.2 Hz, 2.0 Hz, 1H), 4.08 (t, J=
5.2 Hz, 2H), 2.99 (t, J=
5.2 Hz, 2H), 2.52 (s, 3H), 2.41 (q, J= 7.2 Hz, 2H), 0.97 (t, J= 7.6 Hz, 3H);
m/z = 405[M+1].
Example 39
(Z)-4-(1-(6-(2-(methylamino)ethylthio)pyridin-3-y1)-2-phenylbut-1-enyl)phenol
S-\ /
. \-NH
_
=
OH
[0235] Step A: 2-(methylamino)ethanol hydrochloride
HHCI
HON
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A solution of 2-(methylamino)ethanol (20 g, 1.0 eq) in 50 mL concentrated HC1
was stirred at rt
for 2 h, and then concentrated to give the product (quant). 1H NMR (400 MHz,
DMSO-d6) 6 8.95 (brs,
2H), 3.65 (t, J= 5.2 Hz, 2H), 2.94 (t, J= 5.6 Hz, 2H), 2.50-2.54 (m, 3H).
[0236] Step B: 2-chloro-N-methylethanamine hydrochloride
H HCI
CI N
To a stirred solution of 2-(methylamino)ethanol hydrochloride (29.7 g, 1.0 eq)
in 150 mL CHC13
was added sulfuryl dichloride (41 g, 1.3 eq) dropwise at 0 C. After refluxing
for 3 h, the reaction was
cooled to rt. Then solvent was removed in vacuo, and the residue was stirred
in 100 mL 1:10
CH2C12/petroleum ether to give a suspension. The product was collected by
filtration (28 g, 80% yield).
1H NMR (400 MHz, DMSO-d6) 6 9.24 (brs, 2H), 3.93(t, J= 6.0 Hz, 2H), 3.28 (t,
J= 6.0 Hz, 2H), 2.56
(s, 3H).
[0237] Step C: 2-(methylamino)ethanethiol hydrochloride
HHCI
HS N
To a stirred solution of 2-chloro-N-methylethanamine hydrochloride (15 g, 1.0
eq) in 150 mL
water was added Na2S203 (18.5 g, 1.0 eq), and the mixture was then heated to
reflux for 48 h. After
cooling to rt, the solvent was removed in vacuo. The crude salt was dissolved
in 60 mL 6M HC1 (aq)
and heated at 90 C for 4 h. The solvent was removed in vacuo and the residue
was purified by column
chromatography to give the desired product. 1H NMR (400 MHz, DMSO-d6) 6 4.95
(brs, 2H), 2.90 (s,
4H), 2.37 (s, 3H).
[0238] Step D: (Z)-4-(1-(6-(2-(methylamino)ethylthio)pyridin-3-y1)-2-phenylbut-
1-enyl)phenol
S-\ /
NH
_
=
OH
To a stirred solution of 2-(methylamino)ethanethiol hydrochloride (217 mg, 10
eq) in 20 mL
anhydrous THF was added NaH (120 mg, 12 eq) at 0 C. After the mixture was
stirred at rt for 1 h,
(Z)-4-(1-(6-chloropyridin-3-y1)-2-phenylbut-1-eny1)- phenol (80 mg, 1.0 eq,
made from example 1)
was added. The reaction mixture was heated under reflux for 48 h, cooled,
quenched with sat. NH4C1,
and extracted with CH2C12. The extract was dried, concentrated, and purified
by column
chromatography to give the desired product (75 mg, 81% yield). 1H NMR (400
MHz, CDC13) 6 7.89
(dd, J= 2.4 Hz, 0.8 Hz, 1H), 7.13-7.21 (m, 3H), 7.05-7.10 (m, 4H), 6.95 (dd,
J= 8.4 Hz, 2.4 Hz, 1H),
6.83 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 2H), 3.23 (t, J = 6.4 Hz, 2H),
2.84 (t, J = 6.4 Hz, 2H),
2.50 (q, J= 7.2 Hz, 2H), 2.41 (s, 3H), 0.93 (t, J= 7.2 Hz, 3H); m/z =
391[M+1].
Example 40
[0239] (E)-4-(1-(6-(methyl(2-(methylamino)ethyDamino)pyridin-3-y1)-2-phenylbut-
1-enyl)phe
nol
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OH
41 .
_
_
\ / N
7-\
\-N H
\
Following the same procedure as described in example 39, step D, (E)-4-(1-(6-
chloropyridin-3-y1)-2-phenylbut- 1 -enyl)phenol (100 mg, 1.0 eq, made from
example 2) was reacted
with /V,/V'-dimethylethane-1,2-diamine (262 mg, 10.0 eq) to give the desired
product. 1H NMR (400
MHz, CDC13) 6 8.07 (d, J= 2.4 z, 1H), 7.06-7.14 (m, 6H), 6.69 (d, J= 8.8 Hz,
2H), 6.49 (d, J= 8.8 Hz,
1H), 6.43 (d, J= 8.8 Hz, 2H), 3.71 (t, J= 6.4 Hz, 2H), 3.08 (s, 3H), 2.88 (t,
J= 6.4 Hz, 2H), 2.53 (q, J
= 7.6 Hz, 2H), 2.48 (s, 3H), 0.95 (t, J= 7.6 Hz, 3H); m/z = 388[M+1] '.
Example 41
(Z)-5-(1-(4-hydroxypheny1)-1-(4-(2-(methylamino)ethoxy)phenyl)but-1-en-2-
yl)pyridin-2-ol
HO 0-\ /
\-1\1/ 0, \-NH
OH
[0240] Step A: 6-hydroxy-N-methoxy-N-methylnicotinamide
0 1
I
HON
To a stirred solution of 6-hydroxynicotinic acid (5.0 g, 1.0 eq), EDCI (8.3 g,
1.2 eq) and HOBt
(5.8 g, 1.2 eq) in 150 mL CH2C12 were added N-methoxymethanamine hydrochloride
(4.2 g, 1.2eq) and
Et3N (14.5 g, 4.0 eq) at rt, the mixture was stirred at rt overnight, water
was added, and the mixture was
extracted with CH2C12. The extract was dried, concentrated, and purified by
column chromatography to
give the desired product (3.5 g, 53% yield). 1H NMR (400 MHz, DMSO-d6) 6 11.82
(brs, 1H), 7.87 (d,
J= 2.8 Hz, 1H), 7.72 (dd, J= 9.6 Hz, 2.8 Hz, 1H), 6.32 (d, J= 9.6 Hz, 1H),
3.59 (s, 3H), 3.20 (s, 3H).
[0241] Step B: 1-(6-hydroxypyridin-3-yl)propan-1-one
0
/..).,
I
HO N
To a solution of 6-hydroxy-N-methoxy-N-methylnicotinamide (800 mg, 1.0 eq) in
20 mL
anhydrous THF was added 3 M EtMgBr (6 mL, 4.0 eq) dropwise at 0 C. The
reaction mixture was
stirred at rt for 2 h., quenched with sat NH4C1, and extracted with CH2C12.
The extract was dried,
concentrated, and purified by column chromatography to give the desired
product (320 mg, 48%). 1H
NMR (400 MHz, CDC13) 6 12.13 (brs, 1H), 8.11 (d, J= 2.4 Hz, 1H), 8.05 (dd, J=
10.0 Hz, 2.8 Hz, 1H),
6.60 (d, J= 9.6 Hz, 1H), 2.79 (q, J= 7.2 Hz, 2H), 1.22 (t, J= 7.2 Hz, 3H).
[0242] Step C: (Z)-5-(1-(4-(2-chloroethoxy)pheny1)-1-(4-
hydroxypheny1)-
but-l-en-2-yl)pyridin-2-ol
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HO 0-
= \
-N `-CI
\ /
_
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
1 - (6-hydroxypyridin-3 -yl)propan-1 -one (0.3 g, 1.0 eq) was
reacted with
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (1.37 g, 2.5 eq) to give
the desired Z-product
(Z and E isomer can be separated via column chromatography).
[0243] Step D: (Z)-5-(1-(4-hydroxypheny1)-1-(4-(2-
(methylamino)ethoxy)-
phenyl)but-l-en-2-yl)pyridin-2-ol
HO 0-\ /
-N* `-NH
\ /
_
OH
Following the same procedure as described in example 11, step D, (Z)-5-(1-(4-
(2-chloroethoxy)pheny1)-1-(4-hydroxyphenyl)but-1-en-2-y1)pyridin-2-ol (0.02 g,
1.0 eq) was reacted
with MeNH2(30% wt in water, 10 mL) in Me0H (20 mL) under reflux to give the
desired product. 1H
NMR (400 MHz, DMSO-d6) 6 9.37 (brs, 1H), 7.13 (dd, J= 9.2 Hz, 2.8 Hz, 1H),
6.96 (s, 1H), 6.91 (d, J
= 8.8 Hz, 2H), 6.81 (d, J= 8.4 Hz, 2H), 6.71 (d, J= 8.4 Hz, 4H), 6.12 (d, J=
9.2 Hz, 1H), 3.97 (t, J=
5.6 Hz, 2H), 2.93 (t, J = 5.6 Hz, 2H), 2.40 (s, 3H), 2.29 (q, J = 7.2 Hz, 2H),
0.90 (t, J = 7.2 Hz, 3H);
m/z = 391 [M+l] '.
Example 42
6-(1-(4-Hydroxypheny1)-1-(4-(2-(methylamino)ethoxy)phenyDbut-1-en-2-y1)
pyridin-3-ol
HO 0-\ /
-
\,N \-NH
*
_
OH
[0244] Step A: 5-hydroxy-N-methoxy-N-methylpicolinamide
0 1
I I
HON
Following the same procedure as described in example 41, step A, 5-
hydroxypicolinic acid (6.2 g,
1.0 eq) was reacted with N, 0-dimethylhydroxylamine hydrochloride (5.2 g, 1.2
eq) to get the desired
product with column chromatography (4.25 g, 52% yield).
[0245] Step B: 1-(5-hydroxypyridin-2-yl)propan-1-one
0
HON
Following the same procedure as described in example 11, step B, 5-hydroxy-
N-methoxy-N-methylpicolinamide (0.5 g, 1.0 eq) was reacted with EtMgBr (6.0
mL, 4.0 eq) to get the
desired product (0.2 g, 48% yield).
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[0246] Step C: 6-(1-(4-(2-chloroethoxy)pheny1)-1-(4-hydroxyphenyl)but-1-en-2-
yl)pyridin-3-ol
HO 0¨\
¨ 'CI
\ 1N 41
_
=
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
1 - (5-hydroxypyridin-2-yl)propan-1 -one (0.15 g, 1.0 eq) was
reacted with
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (0.549 g, 2.0 eq) to give
the desired product
(Z/E = 1/1).
[0247] Step D: 6-(1-(4-hydroxypheny1)-1-(4-(2-
(methylamino)ethoxy)pheny1)-
but-l-en-2-yl)pyridin-3-ol
HO 0¨\ /
'
¨
\,N NH41
_
OH
Following the same procedure as described in example 11, step D,
6- (1 - (4- (2- chloroethoxy)pheny1)-1 - (4-hydroxyphenyl)but-1 - en-2-
yl)pyridin-3 -ol (0.22 g, 1.0 eq) was
reacted with MeNH2 (30% wt in water, 10 mL) in Me0H (20 mL) under reflux to
give the desired
product (Z/E = 1/1).1H NMR (400 MHz, DMSO-d6) 6 9.31 (brs, 1H), 8.09 (d, J=
2.4 Hz, 1H), 7.08 (d,
J = 8.0 Hz, 1H), 6.92-6.97 (m, 2H), 6.81 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 8.4
Hz, 1H), 6.55-6.69 (m,
4H), 6.45 (d, J= 8.4 Hz, 1H), 4.06 (t, J= 5.2 Hz, 1H), 3.93 (t, J= 5.2 Hz,
1H), 2.93 (t, J= 5.6 Hz, 1H),
2.85 (t, J= 5.6 Hz, 1H), 2.46-2.50 (m, 2H), 2.40 (s, 1.5 H), 2.35 (s, 1.5H),
0.83 (t, J= 7.2 Hz, 3H); m/z
= 391[M+1]'.
Example 43
1-(3-(Dimethylamino)propy1)-4-(1-(4-hydroxypheny1)-2-phenylbut-1-enyl) pyridin-
2(1H)-one
/ \_ /
N N\
OH / 0 \
_
OH
[0248] Step A: 3-chloro-N,N-dimethylpropan-1-amine hydrochloride
\
N C I
/ HCI
To a stirred solution of 3-(dimethylamino)propan-1-ol (15 g, 1.0 eq) in 150 mL
CHC13 was added
sulfuryl dichloride (21 g, 1.2 eq) dropwise at 0 C. The reaction mixture was
then heated under reflux
for 5 h. After cooling to rt, the solvent was removed in vacuo to give the
crude product, which was
washed with solution of (CH2C12:petroleum ether = 1:10, 50 mL) to give the
desired product (22 g,
98% yield).
[0249] Step B: N-methoxy-N-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide
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63
I
ON,c,
I
NO
H
To a suspension of 2-oxo-1,2-dihydropyridine-4-carboxylic acid (8.0 g, 1.0
eq), EDCI (13.2 g, 1.2
eq) and HOBt (9.3 g, 1.2 eq) in 150 mL CH2C12 were added N-methoxymethanamine
hydrochloride
(6.8 g, 1.2eq) and Et3N (26.2 g, 4.5 eq). The reaction mixture was stirred at
rt overnight, concentrated,
and purified by column chromatography to give the desired product (6.3, 60%
yield). 1H NMR (400
MHz, CDC13) 6 12.79 (s, 1H), 7.40 (d, J= 6.8 Hz, 1H), 6.77 (s, 1H), 6.43 (dd,
J= 6.8 Hz, 1.6 Hz, 1H),
3.62 (s, 3H), 3.34 (s, 3H).
[0250] Step C: 1-(3-
(dimethylamino)propy1)-N-methoxy-N-methyl-2-oxo-1,2-
dihydropyridine-4-carboxamide
I
0 ,N
'0
I
I
NO
N
I
A stirred mixture of N-methoxy-N-methyl-2-oxo-1,2-dihydropyridine-4-carbox-
amide (200 mg,
1.0 eq), 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (350 mg, 2.0 eq)
and K2CO3 (455 mg,
3.0 eq) in 20 mL acetone was heated under reflux overnight. After cooling to
rt, water was added, and
the mixture was extracted with CH2C12. The extract was dried, concentrated,
and purified by column
chromatography to give the desired product (255 mg, 87% yield). 1H NMR (400
MHz, CDC13) 6 7.40
(d, J= 7.2 Hz, 1H), 6.75 (d, J= 1.2 Hz, 1H), 6.30 (dd, J= 6.8 Hz, 2.0 Hz, 1H),
4.02 (t, J= 7.2 Hz, 2H),
3.62 (s, 3H), 3.33 (s, 3H), 2.30 (t, J= 6.8 Hz, 2H), 2.23 (s, 6H), 1.93 (t, J=
7.2 Hz, 2H).
[0251] Step D: 1-(3-
(dimethylamino)propy1)-4-(4-(tetrahydro-2H-pyran-2-yloxy)
benzoyl)pyridin-2(1H)-one
0
I
N
0
0) o
N
--- --...
Mg (440 mg, 3.5 eq) was added to a 3-neck round bottom flask containing 50 mL
anhydrous THF,
and the mixture was heated to 55 C. Iodine chips (2 grains) were added in one
lot followed by 0.1 mL
ethyl bromide. 2-(4-Bromophenoxy)- tetrahydro-2H-pyran (4.0 g, 3.0 eq) was
dissolved in 30 mL
anhydrous THF, and 3 mL of this solution was added at once to the Mg-THF
suspension. The reaction
was initiated after 30 min and reflux started, the remaining solution of
2-(4-bromophenoxy)-tetrahydro-2H-pyran was added dropwise maintaining the
reflux temperature
over 5 min. After addition, the reaction mixture was further reflux for 2 h.,
cooled to rt,
1-(3-(dimethylamino)propy1)-N-methoxy-N-methy1-2-oxo-1,2-dihydro- pyridine-4-
carboxamide (1.4 g,
1.0 eq) in 20 mL THF was added dropwise at rt, stirred at rt for 30 min.,
quenched with sat NH4C1(aq),
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64
and extracted with Et0Ac. The extract was dried, concentrated, and purified by
column
chromatography to give the desired product (1.6g, 80% yield). 1H NMR (400 MHz,
CDC13) 6 7.85 (d, J
= 9.2 Hz, 2H), 7.48 (d, J= 6.8 Hz, 1H), 7.11 (d, J= 9.2 Hz, 2H), 6.75 (d, J=
1.6 Hz, 1H), 6.44 (dd, J=
6.8 Hz, 2.0 Hz, 1H), 5.55 (t, J= 2.8 Hz, 1H), 4.05 (t, J= 7.2 Hz, 2H), 3.82-
3.88 (m, 1H), 3.62-3.66 (m,
1H), 2.32 (t, J= 6.4 Hz, 2H), 2.24 (s, 6H), 1.88-2.08 (m, 5H), 1.62-1.74 (m,
4H).
[0252] Step E: 1-(3-(dimethylamino)propy0-4-(1-(4-hydroxypheny1)-2-
phenyl
but-1-enyl)pyridin-2(1H)-one
N/ \-Ni
* / 0 \
_
41
OH
Following general procedure of McMurry reaction as described in example 1,
step B,
propiophenone (0.838 g, 3.0 eq) was reacted with 1-(3-(dimethylamino)
propy1)-4-(4-hydroxybenzoyl)pyridin-2(1H)-one (0.8 g, 1.0 eq) to give the
desired product (Z was
prepared by preparative HPLC). 1H NMR (400 MHz, DMSO-d6) 6 9.54 (brs, 1H),
7.34 (d, J = 6.8 Hz,
1H), 7.17-7.29 (m, 5H), 7.04 (d, J= 8.4 Hz, 2H), 6.79 (d, J= 8.4 Hz, 2H), 5.83
(d, J= 1.6 Hz, 1H),
5.75 (dd, J= 6.8 Hz, 1.6 Hz, 1H), 3.75 (t, J= 6.8 Hz, 2H), 2.93 (t, J= 6.8 Hz,
2H), 2.73 (s, 6H), 2.37 (q,
J= 7.2 Hz, 2H), 1.86-1.90 (m, 2H), 0.83 (t, J= 7.2 Hz, 3H); m/z = 403[M+1]'.
Example 44
4-(2-(2,3-Dihydrobenzofuran-5-y1)-1-(4-(2-(methylamino)ethoxy)phenyDbut-1-
enyl)phenol
0
4. 4. NH
_
OH
[0253] Step A: 1-(2,3-dihydrobenzofuran-5-yl)propan-1-one
0,
0
To a stirred solution of 2,3-dihydrobenzofuran (10 g, 1.0 eq) in 200 mL CH2C12
at 0 C was added
dropwise a solution of propionyl chloride (14 g, 1.8 eq) and A1C13 (11.1 g,
1.0 eq) in 200 mL CH2C12
while maintaining the temperature at 0 C. After addition was complete, the
reaction was stirred at rt for
1 h. Then ice water was added to quench the reaction and the mixture was
extracted with CH2C12. The
extract was washed with brine, dried and evaporated in vacuo. Hexane (100mL)
was added to the
residue, and cooled to 0 C and stirred for 30 min, then filtered and washed
with cold hexane and dried
to give the product as a white solid (11.8 g, 80%). 1H NMR (400 MHz, CDC13) 6
7.86 (s, 1H), 7.81 (d, J
= 8.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 4.66 (t, J = 8.8 Hz, 2H), 3.25 (t, J
= 8.8 Hz, 2H), 2.94 (q, J = 7.2
Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H).
[0254] Step B: (4-(2-chloroethoxy)phenyl)(4-methoxyphenyl)methanone
0
0 0 oCI
0
To a stirred solution of 1-(2-chloroethoxy)benzene (48 g, 1.0 eq) in 400 mL
CH2C12 at 0 C was
added dropwise a solution of 4-methoxybenzoyl chloride (62 g, 1.2 eq) and
A1C13 (49 g, 1.2 eq) in 400
mL CH2C12 while maintaining the temperature at 0 C. After the addition, the
reaction was stirred at rt
for 1 h. Then added ice water to quench the reaction and extracted with
CH2C12. The extract was
washed with brine, dried and evaporated in vacuo. Hexane (500 mL) was added to
the residue, cooled
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to 0 C and stirred for 30 min, then filtered and washed with cold hexane and
dried to give the product
as a white solid (85 g, 96%). 1H NMR (400 MHz, CDC13) 67.79 (dd, J= 6.8 Hz,
2.0 Hz, 4H), 6.97 (dd, J
= 8.8 Hz, 2.0 Hz, 4H), 4.32 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.86 (t, J =
6.0 Hz, 2H).
[0255] Step C: (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone
0
HO 0 0 c3,C1
To a stirred solution of (4-(2-chloroethoxy)phenyl)(4-methoxyphenyl)methanone
(20 g, 1.0 eq) in
150 mL CH2C12 was added BBr3 (52 g, 3.0 eq) dropwise at 0 C. The reaction was
stirred for 4 h at rt,
then quenched with 500 mL ice water. The suspension was filtered and washed
with water to give the
product (16 g, 85%). 1H NMR (400 MHz, DMSO-d6) 6 10.36 (s, 1H), 7.69 (dd, J =
6.8 Hz, 2.0 Hz, 2H),
7.64 (dd, J = 6.8 Hz, 2.0 Hz, 2H), 7.11 (dd, J = 7.2 Hz, 2.0 Hz, 2H), 6.90
(dd, J = 6.8 Hz, 2.0 Hz, 2H),
4.38 (t, J = 5.2 Hz, 2H), 4.01 (t, J = 5.2 Hz, 2H).
[0256] Step D: 4-(1-(4-(2-
chloroethoxy)pheny1)-2-(2,3-dihydrobenzofuran-5-y1)
but-l-enyl)phenol
0 0-\
* = \-CI
_
4.
OH
To a suspension of Zn (595 mg, 6 eq) in 20 mL anhydrous THF was added TiC14
(0.5 mL, 3 eq)
dropwise at 0 C under nitrogen. The mixture was then heated to reflux for 1 h
and cooled to rt. Then a
solution of 1 - (2,3 -dihydrobenzofur an-5-
yl)propan-1 -one (670 mg, 2.5 eq) and
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (420 mg, 1.0 eq) in 10 mL
anhydrous THF
was added dropwise at 0 C. After the addition, the reaction mixture was heated
to reflex for 1 h, cooled
and quenched with sat. NaHCO3, filtered and the filtrate was extracted with
Et0Ac. The extract was
dried and evaporated under reduced pressure. The residue was purified by
column chromatography to
give the desired product (500 mg, 78%, Z/E = 1/1).
[0257] Step E: 4-(2-(2,3-
dihydrobenzofuran-5-y1)-1-(4-(2-(methylamino)ethoxy)-
phenyl)but-l-enyl)phenol
0 0-\_ /
li = NH
_
OH
To a stirred solution of 4- (1 -
(4- (2- chloroethoxy)pheny1)-2- (2,3 -dihydrobenzo-
furan-5-yl)but- 1 -enyl)phenol (500 mg, 1.0 eq) in 20 mL Me0H, 10 mL CH3NH2
(aq) was added and
heated at 85 C for 24h. The solvent was removed in vacuo, water was added to
the residue and
extracted with Et0Ac. The extract was dried, concentrated, and purified by
column chromatography to
give the desired product (Z/E = 1/1). 1H NMR (400 MHz, CDC13) 6 7.10 & 7.01
(d, J= 8.8 Hz, 2H),
6.92 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.82 & 6.74(d, J = 8.8 Hz, 2H), 6.79 &
6.75 (d, J = 8.8 Hz, 2H),
6.57 (d, J = 8.4 Hz, 1H), 6.51 & 6.45 (d,J = 8.8 Hz, 2H), 4.51 (t,J= 8.4 Hz,
2H), 4.10 & 3.96 (t, J = 4.8
Hz, 2H), 3.09 (t,J= 8.8 Hz, 2H), 3.01 & 2.93 (t,J= 4.8 Hz, 2H), 2.54 & 2.50
(s, 3H), 2.39-2.46 (m, 2H),
0.90-0.94 (m, 3H); m/z = 416 [M+1] '.
Example 45
(Z)-4-(2-(1H-indazol-5-y1)-1-(4-(2-(methylamino)ethoxy)phenyObut-1-enyl)phenol
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66
H
oN
IV¨
Si
H N
OH
[0258] Step A: methyl 4-amino-3-methylbenzoate
CO2Me
'Me
NH2
To a stirred solution of methyl 3-methyl-4-nitrobenzoate (50 g, 1.0 eq) in 1 L
Me0H were added
at rt a solution of NH4C1 (137 g, 10 eq) in 60 mL H20 and Fe power (96 g, 7
eq), and the resulting
mixture is heated at reflux for 4 h. The reaction mixture was allowed to cool
to rt, filtered, and water
was added. The mixture was extracted with Et0Ac. The extract was dried, washed
with water, and
concentrated to give the desired product directly as a white solid (26 g,
62%).
[0259] Step B: 4-(methoxycarbony0-2-methylbenzenediazonium tetrafluoro- borate
0
0 Me
0
N2BF4
To an aqueous solution of NaNO2 (12.54 g, 2.0 eq) in 75 mL H20 at 0 C was
added dropwise
cooled solution of methyl 4-amino-3-methylbenzoate (15 g, 1.0 eq) in
HBF4(aq)(40% in water). After
addition, the mixture was stirred for 15 min at ambient temperature. The
precipitate was filtered,
washed with ice-cold water, and dried, to give the desired product as a white
solid (16 g, 90%).
[0260] Step C: methyl 1H-indazole-5-carboxylate
0
0 0 \N
N
H
A suspension of BF4 salt (12 g, 1.0 eq), potassium acetated (KOAc, 16.6 g, 2.5
eq) and
18-crown-6 (1.8 g, 0.1 eq) in CHC13 (200 mL) was stirred at rt for 24 h, and
the residue was partitioned
between water and Et0Ac. The organic layer was washed with brine, dried with
Na2SO4 and
concentrated to give the desired product (6.5 g, 55%).
[0261] Step D: 1H-indazole-5-carboxylic acid
0
HO 0 \N
N
H
To a stirred solution of methyl 1H-indazole-5-carboxylate (6.5 g, 1.0 eq) in
200 mL Me0H was
added a solution of NaOH (4.4 g, 3.0 eq) in 150 mL H20. The mixture was
refluxed for 1 h. The
organic solvent was removed in vacuo, the remaining aqueous solution was
washed with Et0Ac,
acidified with 3 N HC1 to pH = 5-6, and the precipitate was collected by
filtration, and washed with
water, to give the desired product as a yellow solid (6.2 g, 98%).
[0262] Step E: N-methoxy-N-methyl-1H-indazole-5-carboxamide
0
/ 0 N
N 1
'N 0
H
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To a mixture of 1H-indazole-5-carboxylic acid (6.0 g, 1.0 eq), N, -
dimethylhydr oxylamine
hydrochloride (5.4 g, 1.5 eq), HOBt (6.0 g, 1.2 eq) and EDCI (8.5 g, 1.2 eq)
in 100 mL CH2C12 was
added Et3N (15g, 4.0 eq) dropwise at 0 C. After addition, the mixture was
stirred at rt overnight,
concentrated, and purified by column chromatography to give the desired
product (4.4 g, 58%). 1H
NMR (400 MHz, CDC13) 6 10.40 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.78 (d, J=
8.8 Hz, 1H), 7.52 (d,,/
= 8.8 Hz, 1H), 3.56 (s, 3H), 3.42 (s, 3H).
[0263] Step F: 1-(1H-indazol-5-y0propan-1-one
0
N,/
EtMgBr (3 M, 2.0 eq, 6.5 mL) was added to a solution of N-methoxy-N-methyl-
1H-indazole-5-carboxamide (2 g, 1.0 eq) in dry THF at 0 C. Once addition was
complete, the mixture
was stirred for 2 h, and extracted by Et0Ac. The extract was dried,
concentrated, and purified by
column chromatography with petroleum ether:Et0Ac = 1:1 to give the desired
product (1.8 g, 95%). 1H
NMR (400 MHz, CDC13) 6 11.20 (s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 8.06 (d, J=
8.0 Hz, 1H), 7.27 (d,,/
= 8.0 Hz, 1H), 3.08 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H).
[0264] Step G: 4-(1-(4-(2-chloroethoxy)pheny1)-2-(1H-indazol-5-yObut-1-eny1)-
phenol
o C I
,N1-
H N
4I)
OH
To a stirred mixture of Zn power (1.65 g, 10.0 eq) in dry THF at rt under N2
was slowly added
TiC14 (4.0 eq, 1.1 mL). The resulting mixture was heated at reflux for 1 h and
cooled to rt. A mixture of
1 41H-indazol-5-y1)propan-1 -one (1.3 g, 3.0 eq)
and
(4(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (0.7 g, 1.0 eq) in dry THF
was added,
warmed to 80 C, refluxed for additional 1 h, quenched with Na2CO3(aq), and
extracted with Et0Ac.
The extract was dried, concentrated, and purified by column chromatography to
give the title product
(0.3 g, 70%, Z/E = 1/1). 1H NMR (400 MHz, CDC13) 6 7.96 (s, 1H), 7.53 (s, 1H),
7.18 (d, J = 8.8 Hz,
2H), 7.12 (d,J = 8.4 Hz, 2H), 6.90 (d,J = 8.8 Hz, 2H), 6.71-6.88 (m, 1H), 6.72
(d,J = 8.8 Hz, 2H), 6.43
(d, J = 8.8 Hz, 1H), 4.35 (t, J = 7.2 Hz, 1H), 4.24 (t, J = 7.2 Hz, 1H), 3.83
(t, J = 6.0 Hz, 1H), 3.70 (t, J
= 6.0 Hz, 1H), 2.47-2.54 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).
[0265] Step H: (Z)-4-(2-
(1H-indazol-5-y1)-1-(4-(2-(methylamino)ethoxy)-
phenyl)but-l-enyl)phenol
oN
H N
OH
To a stirred solution of 4-
(241H-indazol-5-y1)-1 - (442- (methylamino) ethoxy)-
phenyl)but-1- enyl)phenol (0.3 g, 1.0 eq) in 20 mL Me0H was added 10 mL MeNH2
(30%wt in water).
The mixture was refluxed overnight. The organic solvent was removed in vacuo,
and the remaining
mixture was extracted with Et0Ac. The extract was dried, concentrated, and
purified by column
chromatography with CH2C12 : Me0H(NH3) =10:1 to give the desired Z-isomer
product (5 mg) and
E-isomer product (11 mg) as well. 1H NMR (400 MHz, DMSO-d6) 6 12.92 (s, 1H),
9.11 (s, 1H), 7.93 (s,
1H), 7.50 (s, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.01-7.19 (m, 2H), 6.88 (d, J =
9.2 Hz, 2H), 6.60 (d, J = 9.2
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Hz, 2H), 6.36 (d, J = 8.8 Hz, 2H), 4.03 (t, J = 6.0 Hz, 2H), 2.85 (t, J = 6.0
Hz, 2H), 2.20-2.40 (m, 5H),
0.81 (t, J = 6.0 Hz, 3H); m/z = 414[M+1] '.
Example 46
(E)-4-(2-(1H-indazol-5-y1)-1-(4-(2-(methylamino)ethoxy)phenyObut-1-enyl)phenol
OH
N-
H NI
0
lel /
H
0 N
0
The title compound (E-isomer, 11 mg) was separated via Example 2. 1H NMR (400
MHz,
DMSO-d6) 6 12.92(s, 1H), 9.41 (s, 1H), 7.92(s, 1H), 7.51 (s, 1H),7.30 (d, J =
8.4 Hz, 1H), 6.98-7.16
(m, 2H), 6.60-6.80 (m, 4H), 6.36 (d, J = 8.8 Hz, 2H), 3.82 (t, J = 6.0 Hz,
2H), 2.67 (t, J = 6.0 Hz, 2H),
2.40-2.50 (m, 5H), 0.79 (t, J = 6.8 Hz, 3H); m/z = 414[M+1].
Example 47
4-(2-(Benzo Id] oxazol-5-y1)-1-(4-(2-(methylamino)ethoxy)phenyObut-1-
enyl)phenol
0VN 0-\
. 41 NH
\
-
OH
[0266] Step A: 4-hydroxy-3-nitrobenzoic acid
0 OH
HOOC NO2
A mixture of 4-chloro-3-nitrobenzoic acid (20 g, 1.0 eq) and NaOH (20.5 g, 2.0
eq) in 100 mL
H20 was reflux at 100 C overnight. After cooling to rt, con. HC1 was added to
pH = 7. The precipitate
thus formed was isolated by filtration, washed with cold water, and dried, to
give the desired product as
a white solid (18.4 g, 98%).
[0267] Step B: 3-amino-4-hydroxybenzoic acid
0 OH
HOOC NH2
A mixture of 4-hydroxy-3-nitrobenzoic acid (10 g, 1.0 eq) and 2 g Pd/C in 100
mL Me0H was
stirred at rt under H2 (1 atm) overnight, and then filtered. The filtrate was
concentrated under reduced
pressure to afford the desired product (8.0 g, 95%). 1H NMR (400 MHz, DMSO-d6)
6 10.00 (brs, 1H),
7.19 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H).
[0268] Step C: benzo Id] oxazole-5-carboxylic acid
=0,>
HOOC N
A mixture of 3-amino-4-hydroxybenzoic acid (8.0 g, 1.0 eq) and 60 mL CH(OEt)3
was heated to
reflux for 3 h, and then cooled to rt,. The remaining CH(OEt)3 was removed
under reduced pressure to
give the desired product (7.8 g, 92%). 1H NMR (400 MHz, DMSO-d6) 6 13.00 (brs,
1H), 8.85 (s, 1H),
8.30 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H).
[0269] Step D: N-methoxy-N-methylbenzo[d]oxazole-5-carboxamide
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0
N N
% el 6
To a solution of benzo[d]oxazole-5-carboxylic acid (7.8 g, 1.0 eq), N,O-
dimethylhydroxylamine
hydrochloride (7.0 g, 1.5 eq), HOBt (7.76 g, 1.2 eq) and EDCI (11 g, 1.2 eq)
in 100 mL CH2C12 was
added Et3N (19 g, 4.0 eq) dropwise at 0 C. The mixture was then stirred at rt
overnight, concentrated,
and purified by column chromatography with petroleum ether:Et0Ac=1:1 to give
the desired product
(6.0 g, 51%). 1H NMR (400 MHz, CDC13) 6 8.18 (s, 1H), 8.16 (1H), 7.80 (d, J =
8.4 Hz, 1H), 7.62 (d, J
= 8.0 Hz, 1H), 3.56 (s, 3H), 3.41 (s, 3H).
[0270] Step E: 1-(benzo[d]oxazol-5-yl)propan-1-one
0
N
0 lei
EtMgBr (1 M, 2.0 eq, 58 mL) was added to a solution of
N-methoxy-N-methylbenzo[d]oxazole-5-carboxamide (6 g, 1.0 eq) in dry THF at 0
C, Once addition
was complete, the mixture was stirred for 2 h. The reaction mixture was
quenched with saturated
NH4C1 and extracted with Et0Ac. The extract was dried, concentrated, and
purified by column
chromatography with petroleum ether:Et0Ac = 1:1 to give the desired product
(0.6 g, 12%)
[0271] Step F: 4-(2-(benzo[d]oxazol-5-y1)-1-(4-(2-chloroethoxy)phenyl)but-1-
enyl)phenol
la 4. 'CI
-
OH
According to general procedure of McMurry reaction as example 1, step D
described,
1-(benzo[d]oxazol-5-yl)propan-1-one (0.6 g, 1.0 eq) was ..
reacted .. with
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (1.42 g, 1.5 eq) to give
0.23 g desired product
(15%, Z/E = 1/1) as a white solid.
[0272] Step G: 4-(2-
(benzo Id] oxazol-5-y1)-1-(4-(2-(methylamino)ethoxy)phe-
nyl)but-1-enyl)phenol
\
_
OH
According to the same procedure as example 1, step E described,
4-(2-(benzo[d]oxazol-5-y1)-1-(4-(2-chloroethoxy)phenyl)but- 1 -enyl)phenol
(0.1 g, 1.0 eq) was reacted
with MeNH2 (30% wt in water, 10 mL) in Me0H (20 mL) under reflux to give 20 mg
desired product
(25%, Z/E = 1/1). 1H NMR (400 MHz, CDC13) 6 7.08 (d, J = 8.4 Hz, 2H), 7.01 (d,
J = 8.8 Hz, 2H), 6.82
(d, J = 8.4 Hz, 2H), 6.68-6.80 (m, 6H), 6.58-6.64 (m, 4H), 6.49-6.55 (m, 4H).
6.46 (d,J= 8.8 Hz, 2H),
5.89 (s, 2H), 4.09 (t,J= 5.6 Hz, 2H), 3.97 (t,J= 5.2 Hz, 2H), 3.00 (t,J= 5.2
Hz, 2H), 2.92 (t,J= 5.6 Hz,
2H), 2.54 (s, 3H), 2.50 (s, 3H), 2.39-2.49 (m, 4H), 0.80-1.00 (m, 6H).
Example 48
4-(4-Chloro-2-(2,3-dihydrobenzofuran-5-y1)-1-(4-(2-
(methylamino)ethoxy)phenyl)but-1-enyl)phe
nol
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0 0¨\
\
_
CI,
OH
[0273] Step A: 3-chloro-1-(2,3-dihydrobenzofuran-5-yl)propan-1-one
0 0
CI
0
To a solution of A1C13 (2.22 g, 1.0 eq) in 50 mL CH2C12 was added 3-
chloropropanoyl chloride
(2.54 g, 1.2 eq) dropwise. The mixture was stirred at rt for 10 min, then 2,3-
dihydrobenzofuran (2.0 g,
1.0 eq) was added. After stirring at rt overnight, the mixture was quenched
with cold water and then
extracted with CH2C12. The extract was dried over Na2SO4, filtered, the
filtrate was concentrated and
purified by column chromatography on silica gel to give the desired product
(1.5 g, 62%), 1H NMR
(400 MHz, CDC13) 6 7.86 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4
Hz, 1H), 4.68(t, J = 8.8 Hz,
2H), 3.92 (t, J = 6.8 Hz, 2H), 3.40 (t, J = 8.8 Hz, 2H), 3.26 (t, J = 6.8 Hz,
2H).
[0274] Step B: (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone
0
SI 0 o...-.........ki.......
HO
According to the same procedure as example 1, step E described,
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (2.0 g, 1.0 eq) was
reacted with MeNH2 (30%
wt in water, 30 mL) in Me0H (30 mL) under reflux to give the desired product
(1.4 g, 65%). 1H NMR
(400 MHz, DM50-d6) 6 7.67 (d,J = 8.8 Hz, 2H), 7.60 (d,J = 8.8 Hz, 2H), 7.06
(d, J = 8.8 Hz, 2H), 6.85
(d, J = 8.8 Hz, 2H), 4.18 (t, J = 5.6 Hz, 2H), 2.89 (t, J = 6.0 Hz, 2H), 2.37
(s, 3H).
[0275] Step C: 4-(4-chloro-2-(2,3-dihydrobenzofuran-5-y1)-1-(4-(2-
(methyl-
amino)ethoxy)phenyl)but-l-enyl)phenol
0 0¨\
\
¨
CI,
OH
According to general procedure of McMurry reaction as example 1, step D
described,
3-chloro-1-(2,3-dihydrobenzofuran-5-yl)propan-1-one (0.85 g, 1.0 eq) was
reacted with
(4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone (1.0 g, 1.0 eq) to
give 1.2 g desired
product (85%, Z/E = 1/1). 1H NMR (400 MHz, DM50-d6) 6 9.87(s, 1H), 7.02-7.54
(m, 6H), 6.70-6.84
(m, 5H), 4.22 (t, J = 8.4 Hz, 2H), 4.03 (t, J = 6.0 Hz, 2H), 3.48 (t, J = 5.6
Hz, 2H), 2.89-3.05 (m, 4H),
2.42 (s, 3H), 2.13 (t, J = 8.4 Hz, 2H); m/z = 450[M+1].
Example 49
4-(2-(2,3-Dihydr obenzofur an-5-y1)-1-(3-fluor o-4-(2-
(methylamino)ethoxy)phenyDbut-1-enyl)phen
ol
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/
j-N H
0 F 0
'-S
OH
[0276] Step A: 3-fluoro-4-methoxybenzonitrile
0
0 F
C N
A mixture of 4-bromo-2-fluoro- 1 -methoxybenzene (30.0 g, 146 mmol) and CuCN
(15.6 g, 174
mmol) in dry DMF (45 mL) was stirred at 120 C overnight. The reaction mixture
was cooled to room
temperature, diluted with water and extracted with ethyl acetate. The organic
layer was washed with
water and brine and then dried over sodium sulfate. Solvent evaporation under
reduced pressure gave
20.0 g (91%) of the subtitle compound as a yellow solid. 1H NMR (400 MHz,
CDC13) 6 7.44 (dd, J=
8.8 Hz, 2.0 Hz, 1H), 7.36 (dd, J= 10.8 Hz, 2.0 Hz, 1H), 7.02 (dd, J= 8.8 Hz,
8.4 Hz, 1H), 3.96 (s, 3H).
[0277] Step B: 3-fluoro-4-hydroxybenzonitrile
0 H
0 F
C N
BBr3 (20 mL, 0.211 mol) was added to 3-fluoro-4-methoxybenzonitrile (15.6 g,
0.103 mol) in
dichloromethane (100 mL) at 0 C. Stirring was continued under reflux for 3
days under a nitrogen
atmosphere. The reaction mixture was quenched with ice water and extracted
with dichloromethane.
The organic layer was washed with water and brine and then dried over sodium
sulfate. Solvent
evaporation under reduced pressure gave 13.3 g (94%) of the subtitle compound
as a gray solid. 1H
NMR (400 MHz, CDC13) 6 7.38-7.42 (m, 2H), 7.09 (dd, J= 8.8 Hz, 8.4 Hz, 1H),
5.68 (s, 1H).
[0278] Step C: 4-(2-bromoethoxy)-3-fluorobenzonitrile
Br-0
is F
CN
A suspension of 3-fluoro-4-hydroxybenzonitrile (1.2 g, 8.76 mmol), anhydrous
K2CO3 (2.43 g,
17.6 mmol) and 1,2-dibromoethane (4.5 mL, 52.0 mmol) in DMF (6 mL) was stirred
at 60 C overnight
under a nitrogen atmosphere. The reaction mixture was filtered and extracted
with ethyl acetate. The
extract was washed with water and brine, dried over sodium sulfate, filtered,
concentrated, and purified
by column chromatography over silica gel (eluent: petroleum ether/ethyl
acetate = 5/1) to give 1.52 g
(71%) of the subtitle compound as a colorless oil. 1H NMR (400 MHz, CDC13) 6
7.43 (d, J= 9.2 Hz,
1H), 7.40 (d, J= 12.0 Hz, 1H), 7.03 (dd, J= 8.0 Hz, 8.4 Hz, 1H), 4.42 (t, J=
6.2 Hz, 2H), 3.68 (t, J= 6.2
Hz, 2H).
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[0279] Step D: 4-(2-bromoethoxy)-3-fluorobenzoic acid
Br-0
I. F
CO2H
4-(2-Bromoethoxy)-3-fluorobenzonitrile (3.78 g, 15.5 mmol) in water (18 mL)
and concentrated
sulfuric acid (18 mL) was heated at 110 C for 12 hours. The solution was then
cooled to room
temperature and neutralized with solid sodium bicarbonate. Acidification with
glacial acetic acid gave
a white solid precipitate, which was collected by filtration and dissolved in
dichloromethane. The
resultant solution was dried over sodium sulfate. The dichloromethane solution
was then filtered and
evaporated to give the product as a beige-colored solid (2.65 g, 65%). 1H NMR
(400 MHz, DMSO-d6) 6
13.00 (brs, 1H), 7.44 (d, J= 8.4 Hz, 1H), 7.69 (d,J= 12.0 Hz, 1H), 7.29 (dd,
J= 8.8 Hz, 8.4 Hz, 1H),
4.48 (t,J= 5.2 Hz, 2H), 3.85 (t,J= 5.2 Hz, 2H).
[0280] Step E: 4-(2-bromoethoxy)-3-fluorobenzoyl chloride
Br-...0
s F
COCI
4-(2-Bromoethoxy)-3-fluorobenzoic acid (1.08 g, 4.1 mmol) and thionyl chloride
(10 mL) were
refluxed for 7 h. The excess thionyl chloride was removed by repeated
evaporation with dry toluene in
vacuo, giving 1.07 g (93%) the subtitle compound as a brown oil. 1H NMR (400
MHz, CDC13) 6 7.93 (d,
J= 8.8 Hz, 1H), 7.86 (d,J= 11.2 Hz, 1H), 7.04 (dd, J= 8.4 Hz, 8.4 Hz, 1H),
4.46 (t,J= 6.4 Hz, 2H), 3.70
(t,J= 6.4 Hz, 2H).
[0281] Step F: (4-(2-bromoethoxy)-3-fluorophenyl)(4-methoxyphenyl)methan- one
0
0 40) F
oBr
M e 0
To a solution of 4-(2-bromoethoxy)-3-fluorobenzoyl chloride (1.07 g, 3.80
mmol) and anhydrous
A1C13 (1.01 g, 7.60 mmol) in dry dichloromethane (18 mL) was added anisole
(822 mg, 7.60 mmol) in
2 mL dichloromethane at 0 C. After stirring at rt for 6 h, the mixture was
poured into 3 N HC1, and
extracted with dichloromethane. The extract was washed with sat. NaHCO3 and
brine, dried over
Na2SO4, filtered, concentrated, and purified by column chromatography over
silica gel (eluent:
petroleum ether/ethyl acetate = 10/1 to 5/1) to give 1.05 g (77%) of the
subtitle compound as a white
solid. 1H NMR (400 MHz, CDC13) 6 7.79 (d,J= 8.8 Hz, 2H), 7.58 (d,J= 11.6 Hz,
1H), 7.55 (d,J= 8.4
Hz, 1H), 7.03 (dd, J= 8.0 Hz, 8.4 Hz, 1H), 6.98 (d,J= 9.2 Hz, 2H), 4.44 (t,J=
6.4 Hz, 2H), 3.90 (s, 3H),
3.70 (t, J= 6.4 Hz, 2H).
[0282] Step G: (4-(2-bromoethoxy)-3-fluorophenyl)(4-hydroxyphenyl)methan- one
0
o
HO 0 0 F B r
BBr3 (0.5 mL, 5.29 mmol) was added to (4-(2-bromoethoxy)-3-fluorophenyl)(4-
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methoxyphenyl)methanone (930 mg, 2.63 mmol) in dichloromethane (6 mL) at 0 C.
Stirring was
continued at room temperature for 2 h under a nitrogen atmosphere. The
reaction mixture was
quenched with ice water and extracted with dichloromethane. The extract was
washed with water and
brine, dried over sodium sulfate, filtered, concentrated, and purified by
column chromatography over
silica gel (eluent: petroleum ether/ethyl acetate = 5/1 to 2/1) to give 536 mg
(60%) of the subtitle
compound as a beige solid. 1H NMR (400 MHz, CDC13) 6 7.74 (d, J= 8.4 Hz, 2H),
7.59 (d, J= 12.4 Hz,
1H), 7.56 (d, J= 8.0 Hz, 1H), 7.03 (dd, J= 8.0 Hz, 8.0 Hz, 1H), 6.92 (d, J=
8.4 Hz, 2H), 5.88 (s, 1H),
4.44 (t,J= 6.4 Hz, 2H), 3.70 (t,J= 6.4 Hz, 2H).
[0283] Step H: 4-(1-(4-(2-bromoethoxy)-3-fluoropheny1)-2-phenylbut-1-eny1)-
phenol
/¨Br
0 F 0"
= .
_
OH
According to general procedure of McMurry reaction as example 1, step D
described,
(4-(2-bromoethoxy)-3-fluorophenyl)(4-hydroxyphenyl)methanone (150 mg, 0.442
mmol) was
reacted with 1-(2,3-dihydrobenzofuran-5-yl)propan-1-one (94 mg, 0.533 mmol,
made by example 1,
step A) to give 145 mg desired product (68%, Z/E = 1/1) as a gray solid.
[0284] Step I: 4-(2-(2,3-dihydrobenzofuran-5-y1)-1-(3-fluoro-4-(2-
(methyl-
amino)ethoxy)phenyl)but-l-enyl)phenol
/
O F 0'
. 41
_
OH
To a stirred solution of 4-(1-(4-(2-bromoethoxy)-3-fluoropheny1)-2-phenylbut-1-
enyl)phenol (111
mg, 0.25 mmol) in 5 mL Me0H was added 1 mL CH3NH2 (30% aq) and heated at 85 C
for 18 h. The
organic solvent was removed in vacuo, and the remaining mixture was extracted
with Et0Ac. The
extract was washed with water and brine, dried over Na2SO4, filtered,
concentrated, and purified by
column chromatography (CH2C12/Me0H(NH3 gas) = 10/1) to give the desired
product (56 mg, 57%,
Z/E = 5/4) as a beige solid. 1H NMR (400 MHz, CDC13) 6 7.04 & 6.71 (d,J= 8.6
Hz, 2H), 6.91-7.00 (m,
2H), 6.82 (m, 1H), 6.79 & 6.49 (d, J= 8.8 Hz, 2H), 6.53-6.63 (m, 3H), 4.52
(t,J= 8.8 Hz, 2H), 4.27 &
4.14 (t,J= 4.8 Hz, 2H), 3.16 & 3.12 (t,J= 4.8 Hz, 2H), 3.09 (t,J= 8.4 Hz, 2H),
2.65 & 2.60 (s, 3H), 2.41
(q, J= 7.4 Hz, 2H), 0.92 (t, J= 7.4 Hz, 3H); m/z = 434[M+1].
Example 50
4-(2-(Benzo [c] [1,2,5] thiadiazol-5-y1)-1-(4-(2-(methylamino)ethoxy)phenyObut-
1-enyl)phenol
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H
N\
0
r\\I ¨11 41
=
OH
[0285] Step A: N-(2-nitro-4-propionylphenyl)acetamide
0
NO2
N HAc
To a solution of N-(4-propionylphenyl)acetamide (1.91 g, 10 mmol) in 20 mL of
concentrated
H2SO4 was added 2 mL 98% HNO3 over 10 minutes while maintain the temperature
at -10 C. After
stirring for 0.5 h, the mixture was poured into 100 mL of cold water. The
precipitate was collected by
filtration and washed with water to give the crude product (1.18 g, 50%),
which was used directly in
the next step.
[0286] Step B: 1-(4-amino-3-nitrophenyl)propan-1-one
0
NO2
N H2
A solution of N-(2-nitro-4-propionylphenyl)acetamide (3.36 g, 10 mmol) in 30
mL 35% HC1 was
heated to reflux for 1 h and cooled. The pH was adjusted to 7 by adding
aqueous ammonia under
stirring. The precipitate was collected by filtration to give the desired
product as a yellow solid (1.75 g,
90%).
[0287] Step C: 1-(3,4-diaminophenyl)propan-1-one
0
N H2
N H2
To a solution of 1-(4-amino-3-nitrophenyl)propan- 1-one (1.94 g, 10 mmol) in
50 mL of methanol
was added 0.5 g 10% Pd/C and the mixture was hydrogenated under H2 (1 atm) at
rt for 1 h. The
mixture was filtered and the filtrated was concentrated to give the desired
product (1.48 g, 90%).
[0288] Step D: 1-(benzo[c][1,2,5hhiadiazol-5-34)propan-1-one
0
SiNj
To a solution of aniline (1.86 g, 20 mmol) in 50 mL of toluene was added SOC12
(2.6 g, 22 mmol)
dropwise at 0 C and the mixture was then refluxed for 2 h. After cooling to
rt,
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1-(3,4-diaminophenyl)propan- 1 -one (1.65 g, 10 mmol) was added. The mixture
was refluxed for 2 h,
cooled, concentrated, and purified by flash chromatography to give the desired
product (960 mg, 50%)
as a yellow solid. 1H NMR (400 MHz, CDC13) 6 8.62 (s, 1H), 8.21 (d, J= 9.2 Hz,
1H), 8.06 (d, J= 9.2
Hz, 1H), 3.15 (q, J= 7.2 Hz, 2H), 1.30 (t, J= 7.2 Hz, 3H).
[0289] Step E: 4-(2-
(benzo[c][1,2,5]thiadiazol-5-y1)-1-(4-(2-chloroethoxy)-
phenyl)but-1-enyl)phenol
-N
\--CI
rµ\1-11 =
OH
According to general procedure of McMurry reaction as example 1, step D
described,
1-(benzo[c][1,2,5]thiadiazol-5-yl)propan-1-one (552 mg, 2 mmol) was reacted
with
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (384 mg, 2 mmol) to give
the desired product
(83 mg, 10%, Z/E = 1/1).
[0290] Step F: 4-(2-
(benzo[c][1,2,5]thiadiazol-5-y1)-1-(4-(2-(methylamino)-
ethoxy)phenyl)but-1-enyl)phenol
/
/-NH
N\ 0-/
S-
OH
To a stirred solution of 4-
(2 - (benzo[c] [1,2,5]thiadiazol-5 -y1)-1 - (4- (2 - chloro-
ethoxy)phenyl)but- 1 -enyl)phenol (83 mg) in 10 mL Me0H was added 3 mL CH3NH2
(30% aq.) and
heated at 85 C for 15 h. The organic solvent was removed in vacuo, and the
remaining mixture was
extracted with Et0Ac. The extract was washed with water and brine, dried over
Na2SO4, filtered,
concentrated, and purified by column chromatography (CH2C12/Me0H(NH3 gas) =
50/1) to give the
desired product (11 mg, Z/E = 1/1) as a yellow solid. 1H NMR (400 MHz, CDC13)
6 7.81 (s, 1H), 7.68
(d, J= 9.2 Hz, 1H), 7.15 & 7.06 (d, J= 8.4 Hz, 2H), 6.86 (d, J= 8.8 Hz, 1H),
6.79 (d, J= 8.4 Hz, 2H),
6.78 & 6.72 (d, J= 8.6 Hz, 2H), 6.48 & 6.42 (d, J= 8.6 Hz, 2H), 4.12 & 3.92
(t, J= 4.8 Hz, 2H), 3.03 &
2.91 (t, J= 4.8 Hz, 2H), 2.60 (q, J = 7.2 Hz, 2H), 2.55 & 2.47 (s, 3H), 0.97
(t, J= 7.2 Hz, 3H); m/z =
432[M+1] '.
Example 51
(Z)-4-(2-(1-methy1-1H-benzo Id] imidazol-5-y1)-1-(4-(2-
(methylamino)ethoxy)phenyl)but-1-enyl)ph
enol
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N 0- \
NH
N
OH
[0291] Step A: 4-(methylamino)-3-nitrobenzoic acid
0 OH
101
NO
NH
A solution of 4-chloro-3-nitrobenzoic acid (30 g, 1.0 eq) in 200 mL CH3NH2
(aq) was stirred at
100 C for 14 h, cooled, and concentrated in vacuo. The residue was poured
into 200 mL 2N HC1 (aq)
at C. The suspension was filtered and washed with water to give the product
as yellow solid (quant).
1H NMR (400 MHz, DMSO-d6) 6 8.58 (d, J= 2.0 Hz, 1H), 8.51 (d, J= 5.2 Hz, 1H),
7.95 (dd,J= 9.2 Hz,
2.0 Hz, 1H), 7.02 (d, J= 9.2 Hz, 1H), 2.98 (s, 3H).
[0292] Step B: 3-amino-4-(methylamino)benzoic acid
0 OH
NH
NH
A mixture of 4-(methylamino)-3-nitrobenzoic acid (29 g, 1.0 eq) and Pd/C (5 g,
10%) in 300 mL
Me0H was stirred at rt under hydrogen for 48 h and filtered. The filtrate was
concentrated in vacuo to
give the product (9 g, 36.5%). 1H NMR (400 MHz, DMSO-d6) 6 7.21 (dd, J= 8.4
Hz, 2.0 Hz, 1H), 7.14
(d, J= 2.0 Hz, 1H), 6.37 (d, J= 8.4 Hz, 1H), 5.28 (brs, 1H), 4.60 (brs, 2H),
2.76 (s, 3H).
[0293] Step C: 1-methyl-1H-benzo[d]imidazole-5-carboxylic acid
0 OH
To a stirred solution of 3-amino-4-(methylamino)benzoic acid (9 g, 1.0 eq) in
50 mL water, was
added 50 mL formic acid and heated at 85 C overnight. The mixture was cooled,
concentrated in
vacuo, and dissolved in water. Then 2N HC1 was added to adjust pH to 1-3. The
suspension was
filtered and washed with water to give the product (9.7 g, 84%). 1H NMR (400
MHz, DMSO-d6) 6 9.48
(s, 1H), 8.37 (s, 1H), 8.12 (d, J= 8.8 Hz, 1H), 8.00 (d, J= 8.8 Hz, 1H), 4.06
(s, 3H).
[0294] Step D: N-methoxy-N,1-dimethy1-1H-benzo[d]imidazole-5-carboxamide
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0 N,
0
A suspension of 1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (9.7 g, 1.0
eq), EDCI (10.5 g,
1.2 eq), and HOBt (7.4 g, 1.2 eq) in 150 mL CH2C12 was stirred at rt for 5
min, and then
N-methoxymethanamine hydrochloride (6.7 g, 1.5 eq) and Et3N (18.5 g, 4.0 eq)
were added. The
reaction mixture was stirred at rt overnight. Water was added and extracted
with CH2C12. The extract
was dried, concentrated, and purified by column chromatography to give the
desired product (9.5 g,
80%). 1H NMR (400 MHz, CDC13) 6 8.20 (d,J= 1.2 Hz, 1H), 7.93 (s, 1H), 7.72
(dd, J= 8.8 Hz,1.6 Hz,
1H), 7.40 (dd, J= 8.4 Hz, 0.8 Hz, 1H), 3.87 (s, 3H), 3.57 (s, 3H), 3.40 (s,
3H).
[0295] Step E: 1-(1-methyl-1H-benzo[d]imidazol-5-yl)propan-1-one
0
To a solution of N-methoxy-N,1-dimethy1-1H-benzo[d]imidazole-5-carboxamide
(900 mg, 1.0 eq)
in 30 mL anhydrous THF was added 3 M EtBrMg (9 mL, 6.0 eq) slowly at 0 C. The
reaction was
stirred at rt overnight, quenched with sat NH4C1 (aq), and extracted with
CH2C12. The extract was dried,
concentrated, and purified by column chromatography to give the desired
product (730 mg, 94%). 1H
NMR (400 MHz, CDC13) 6 8.44 (s, 1H), 8.04 (J= 8.4 Hz, 1.6 Hz, 1H), 7.95 (s,
1H), 7.43 (d, J= 8.4 Hz,
1H), 3.89 (s, 3H), 3.10 (q, J= 7.2 Hz, 2H), 1.27 (t, J= 7.2 Hz, 3H).
[0296] Step F: (Z)-4-(1-(4-(2-ehloroethoxy)pheny1)-2-(1-methyl-1H-
benzo[d]-
imidazol-5-yDbut-1-enyl)phenol
0-\
N 41,
OH
According to general procedure of McMurry reaction as example 1, step D
described,
1-(1-methyl-1H-benzo[d]imidazol-5-y1)propan-1-one (730 mg, 2.2 eq) was reacted
with
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (500 mg, 1.0 eq) to give
the separated
(Z)-isomer and (E)-isomer of the product. (Z)-isomer: 1H NMR (400 MHz, CDC13)
6 7.81 (s, 1H), 7.62
(s, 1H), 7.11-7.15 (m, 3H), 7.01 (dd, J= 8.4 Hz, 1.2 Hz, 1H), 6.83 (dd, J= 6.8
Hz, 2.0 Hz, 2H), 6.79 (dd,
J= 6.8 Hz, 2.0 Hz, 2H), 6.49 (dd,J= 6.8 Hz, 2.0 Hz, 2H), 4.05 (t, J= 5.6 Hz,
2H), 3.79 (s, 3H), 3.69 (t,
J= 6.0 Hz, 2H), 2.53 (q, J= 7.2 Hz, 2H), 0.91 (t, J= 7.2 Hz, 3H).
[0297] Step G: (Z)-4-(2-(1-methy1-1H-benzo Id] imidazol-5-y1)-1-(4-
(2-(methyl-
amino)ethoxy)phenyl)but-1-enyl)phenol
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N
`¨NH
N * 411
411
OH
To a stirred solution of (Z)-4-(1
chloroethoxy)pheny1)-2-(1 -methyl-1H-
benzo[d]imidazol-5-yl)but-1-enyl)phenol (20 mg, 1.0 eq) in 10 mL Me0H was
added 5 mL CH3NH2
(aq) and heated at 85 C for 72 h. The organic solvent was removed in vacuo,
water was added to the
residue, and extracted with Et0Ac. The extract was dried, concentrated, and
purified by column
chromatography to give the desired (Z)-product. 1H NMR (400 MHz, CDC13) 6 7.80
(s, 1H), 7.60 (s,
1H), 7.13 (d, J= 8.4 Hz, 1H), 7.08 (d,J= 8.4 Hz, 2H), 7.01 (d,J= 9.2 Hz, 1H),
6.80 (d,J= 8.4 Hz, 2H),
6.75 (d,J= 8.8 Hz, 2H), 6.45 (d,J= 8.4 Hz, 2H), 3.89 (t,J= 5.2 Hz, 2H), 3.80
(s, 3H), 2.88 (t,J= 5.2 Hz,
2H), 2.52 (q, J= 7.2 Hz, 2H), 2.46 (s, 3H), 0.88 (t, J= 7.2 Hz, 3H); m/z =
428[M+1]
Example 52
(E)-4-(2-(1-methy1-1H-benzo[d]imidazol-5-y1)-1-(4-(2-
(methylamino)ethoxy)phenyl)but-1-enyl)ph
enol
OH
N
¨\¨NH
According to the same procedure as example 1, step E described,
(E)-4-(1
chloroethoxy)pheny1)-2-(1 -methyl-1H-benzo[d] imidazol-5-yl)but-1 -
enyl)phenol (made
by example 8, step F) was reacted with MeNH2 (30% wt in water) in Me0H under
reflux to give the
desired (E)-product. 1H NMR (400 MHz, CDC13) 6 7.78 (s, 1H), 7.63 (s, 1H),
7.18 (d, J= 8.8 Hz, 2H),
7.13 (d,J= 8.4 Hz, 1H), 7.01 (dd, J= 8.4 Hz, 1.2 Hz, 1H), 6.88 (d,J= 8.8 Hz,
2H), 6.72 (d,J= 8.4 Hz,
2H), 6.40 (d,J= 8.4 Hz, 2H), 4.10 (t,J= 5.2 Hz, 2H), 3.77 (s, 3H), 2.99 (t,J=
5.2 Hz, 2H), 2.50-2.55 (m,
5H), 0.91 (t, J= 7.2 Hz, 3H); m/z = 428[M+1].
Example 53
4-(2-(Benzofuran-5-y1)-1-(4-(2-(methylamino)ethoxy)phenyl)but-1-enyl)phenol
0 0¨\
la 41 'NH
OH
[0298] Step A: 1-(benzofuran-5-yl)propan-1-one
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1:) 0
0
A solution
of 1 -(2,3-dihydrobenzofuran-5-yl)propan-1 -one (40 g, 1.0 eq) and
4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (62 g, 1.2 eq) in
400 mL anhydrous
1,4-dioxane was refluxed overnight, cooled, quenched with sat NaHCO3 (aq), and
extracted with
Et0Ac. The extract was washed with brine, dried, concentrated, and purified by
column
chromatography to give the desired product (10.3 g, 26%). 1H NMR (400 MHz,
CDC13) 6 8.27 (d, J=
2.0 Hz, 1H), 7.98 (dd,J= 8.8 Hz, 2.0 Hz, 1H), 7.69 (d,J= 2.0 Hz, 1H), 7.54
(d,J= 8.4 Hz, 1H), 6.86 (d,
J= 2.0 Hz, 1H), 3.07 (q, J= 7.2 Hz, 2H), 1.26 (t, J= 7.2 Hz, 3H).
[0299] Step B: 4-(2-(benzofuran-5-y1)-1-(4-(2-chloroethoxy)phenyl)but-1-
enyl)phenol
0 0-\
1 le = 'CI
OH
According to general procedure of McMurry reaction as example 1, step D
described,
1 -(benzofuran-5-yl)propan-1 -one (250 mg, 1.0 eq) was
reacted with
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (794 mg, 2.0 eq) to give
480 mg desired
product (80%, Z/E = 1/1).
[0300] Step C: 4-(2-(benzofuran-5-y1)-1-(4-(2-(methylamino)ethoxy)pheny1)- but-
l-enyl)phenol
1 . . NH
OH
To a stirred solution of 4-
(2-(benzofuran-5-y1)-1 -(442- chloroethoxy)phenyl)
but- 1-enyl)phenol(480 mg, 1.0 eq) in 15 mL Me0H was added 5 mL CH3NH2 (aq)
and the mixture
was heated at 85 C for 48 h. The organic solvent was removed in vacuo, water
was added to the
residue and extracted with Et0Ac. The extract was dried, concentrated, and
purified by column
chromatography to give the desired product (230 mg, 49%, Z/E = 1/1). 1H NMR
(400 MHz, CDC13) 6
7.55 (d,J= 2.0 Hz, 1H), 7.36 (s, 1H), 7.27 (d,J= 8.8 Hz, 1H), 7.15 (d,J= 8.8
Hz, 1H), 7.08 (d,J= 8.8
Hz, 1H), 7.01 (d,J= 8.8Hz, 1H), 6.87 (d,J= 8.8 Hz, 1H), 6.78 (d,J= 8.4 Hz,
1H), 6.74 (d,J= 8.8 Hz,
1H), 6.69 (d,J= 8.8 Hz, 1H), 6.65 (d,J= 2.0 Hz, 1H), 6.47 (d,J= 8.8 Hz, 1H),
6.41 (d,J= 8.4 Hz, 1H),
4.11 (t, J= 4.8 Hz, 1H), 3.92 (t, J= 4.8 Hz, 1H), 3.01 (t, J= 5.2 Hz, 1H),
2.89 (t, J= 5.2 Hz, 1H),
2.45-2.54 (m, 5H), 0.89-0.94 (m, 3H); m/z = 414[M+1].
Example 54
4-(2-(2-Chlorobenzofuran-5-y1)-1-(4-(2-(methylamino)ethoxy)phenyl)but-1-
enyl)phenol
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CI 0
=
OH
[0301] Step A: 5-(2-ethyl-1,3-dioxolan-2-yObenzofuran
0 0 \
0 0
\__/
A solution of 1-(benzofuran-5-yl)propan-1-one (650 mg, 1.0 eq), ethane-1,2-
diol (3.5 g, 15.0 eq)
and 4-methylbenzenesulfonic acid (65 mg, 0.1 eq) in 20 mL toluene was refluxed
for 72 h, cooled,
quenched with sat. NaHCO3 (aq) and extracted with Et0Ac. The extract was
washed with brine, dried,
concentrated, and purified by column chromatography to give the desired
product (710 mg, 87%). 1H
NMR (400 MHz, CDC13) 6 7.69 (d, J= 2.0 Hz, 1H), 7.62 (d, J= 2.4 Hz, 1H), 7.45
(d, J= 8.4 Hz, 1H),
7.39 (dd, J= 8.4 Hz, 1.6 Hz, 1H), 6.76 (dd, J= 2.4 Hz, 0.4 Hz, 1H), 4.02-4.05
(m, 2H), 3.78-3.81 (m, 2H),
1.96 (q, J= 7.2 Hz, 2H), 0.89 (t, J= 7.2 Hz, 3H).
[0302] Step B: 2-chloro-5-(2-ethyl-1,3-dioxolan-2-yObenzofuran
0 0 CI \
0 0
To a stirred solution of 5-(2-ethyl-1,3-dioxolan-2-yl)benzofuran (350 mg, 1.0
eq) in 20 mL
anhydrous THF was added 2.5 M n-BuLi solution in hexane (1.6 mL, 2.4 eq)
dropwise at 0 C, and the
mixture was stirred at 0 C for 50 min under nitrogen. A solution of
hexachloroethane (915 mg, 2.4
eq) in 10 mL anhydrous THF was added dropwise. The reaction was stirred at rt
for 1 h, quenched with
sat NH4C1 (aq), and extracted with Et0Ac. The extract was dried, concentrated,
and purified by column
chromatography to give the desired product (260 mg, 65%). 1H NMR (400 MHz,
CDC13) 6 7.58 (d, J=
0.4 Hz, 1H), 7.37-7.38 (m, 2H), 6.57 (s, 1H), 4.01-4.05 (m, 2H), 3.77-3.80 (m,
2H), 1.94 (q, J= 7.6 Hz,
2H), 0.88 (t, J= 7.2 Hz, 3H).
[0303] Step C: 1-(2-chlorobenzofuran-5-yl)propan-1-one
0 0 CI \
0
To a stirred solution of 2-chloro-5-(2-ethyl-1,3-dioxolan-2-yl)benzofuran (250
mg, 1.0 eq) in 15
mL Me0H was added 3 mL 3N HC1 (aq) at rt. The reaction was stirred for 30 min
at rt, quenched with
sat NaHCO3 (aq), and extracted with Et0Ac. The extract was washed with brine,
dried, concentrated,
and purified by column chromatography to give the desired product (140 mg,
68%). 1H NMR (400
MHz, CDC13) 6 8.15 (d, J= 1.6 Hz, 1H), 7.95 (dd, J= 8.4 Hz, 1.6 Hz, 1H), 7.48
(d, J= 8.8 Hz, 1H), 6.68
(s, 1H), 3.06 (q, J= 6.8 Hz, 2H), 1.25 (t, J= 6.8 Hz, 3H).
[0304] Step D: 4-(2-(2-chlorobenzofuran-5-y0-1-(4-(2-chloroethoxy)phenyDbut- 1-
enyl)phenol
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CI 0 0-\
_
OH
According to general procedure of McMurry reaction as example 1, step D
described,
1 -(2- chlorobenzofuran-5-yl)propan-1 -one (140 mg, 1.0 eq)
was reacted with
(4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (371 mg, 2.0 eq) to give
220 mg desired
product (72%, Z/E = 1/1). 1H NMR (400 MHz, CDC13) 6 7.23 (s, 1H), 7.21 (d, J=
8.4 Hz, 1H), 7.16 &
7.10 (d,J= 8.6 Hz, 2H), 7.00 & 6.99 (d, J= 8.4 Hz, 1H), 6.90 & 6.81 (d,J= 8.6
Hz, 2H), 6.76 & 6.70 (d,
J= 8.8 Hz, 2H), 6.52 & 6.44 (d, J= 9.0 Hz, 2H), 6.45 (s, 1H), 4.73 & 4.48 (s,
1H), 4.26 & 4.08 (t, J= 6.0
Hz, 2H), 3.83 & 3.72 (t,J= 6.0 Hz, 2H), 2.50 (q, J= 7.2 Hz, 2H), 0.91 (t,J=
7.2 Hz, 3H).
[0305] Step E: 4-(2-(2-
chlorobenzofuran-5-y1)-1-(4-(2-(methylamino)ethoxy)
phenyl)but-l-enyl)phenol
CI 0
=
OH
To a stirred solution of
44242- chlorobenzofuran-5-y1)-1 -(442- chloroethoxy)-
phenyl)but- 1 -enyl)phenol (220 mg, 1.0 eq) in 15 mL Me0H was added 5 mL
CH3NH2 (aq) and heated
at 85 C for 48 h. The organic solvent was removed in vacuo, water was added
to the residue and
extracted with Et0Ac. The extract was dried, concentrated, and purified by
column chromatography to
give the desired product (105 mg, 48%, Z/E = 1/1). 1H NMR (400 MHz, CDC13) 6
7.23 (s, 1H), 7.20 (d,
J= 8.4 Hz, 1H), 7.14 & 7.08 (d,J= 8.4 Hz, 2H), 7.00 (d,J= 8.4 Hz, 1H), 6.87 &
6.78 (d,J= 8.8 Hz, 2H),
6.73 & 6.69 (d, J= 8.8 Hz, 2H), 6.49 & 6.42 (d, J= 8.6 Hz, 2H), 6.45 (s, 1H),
4.10 & 3.92 (t, J= 5.0 Hz,
2H), 3.00 & 2.89 (t,J= 5.0 Hz, 2H), 2.53 & 2.46 (s, 3H), 2.50 (q, J= 7.6 Hz,
2H), 0.91 (t,J= 7.6 Hz, 3H);
m/z = 448[M+1].
Example 55
(Z)-4-(2-(2-Chlorobenzofuran-5-y1)-1-(4-(2-(methylamino)ethoxy)phenyl)but-1-
enyl)phenol
CI 0
1 li = 'N H
OH
The title compound (Z-isomer) was separated by preparative HPLC from the Z/E
mixture made by
example 11. 1H NMR (400 MHz, DMSO-d6) 6 9.43 (brs, 1H), 7.37 (d,J= 8.4 Hz,
1H), 7.32 (s, 1H), 7.04
(d,J= 8.4 Hz, 1H), 6.99 (d,J= 8.4 Hz, 2H), 6.90 (s, 1H), 6.75 (d,J= 8.0 Hz,
2H), 6.70 (d,J= 8.8 Hz,
2H), 6.56 (d, J= 8.4 Hz, 2H), 3.84 (t, J= 5.4 Hz, 2H), 2.73 (t, J= 5.4 Hz,
2H), 2.43 (q, J= 7.4 Hz, 2H),
2.26 (s, 3H), 0.84 (t, J= 7.4 Hz, 3H); m/z = 448[M+1].
Example 56
(E)-4-(2-(2-Chlorobenzofuran-5-y1)-1-(4-(2-(methylamino)ethoxy)phenyl)but-1-
enyl)phenol
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CI 0 0 H
_
*
0¨ \
'N H
\
The title compound (E-isomer) was separated by preparative HPLC from the Z/E
mixture made by
example 11. 1H NMR (400 MHz, CDC13) 6 7.24 (s, 1H), 7.20 (d, J= 8.4 Hz, 1H),
7.13 (d, J= 6.8 Hz,
2H), 7.00 (d, J= 8.6 Hz, 1H), 6.83 (d, J= 8.8 Hz, 2H), 6.66 (d, J= 6.8 Hz,
2H), 6.45 (s, 1H), 6.41 (d, J=
6.4 Hz, 2H), 4.08 (t, J= 5.0 Hz, 2H), 2.99 (t, J= 5.2 Hz, 2H), 2.51 (s, 3H),
2.49 (q, J= 7.4 Hz, 2H), 0.91
(t, J= 7.4 Hz, 3H); m/z = 448[M+1].
Example 57
(Z)-2-(4-(2-(2-chlorobenzofuran-5-y1)-1-(4-methoxyphenyl)but-1-enyl)phenoxy)-N-
methylethana
mine
CI 0 0¨ \ /
_
=
0 Me
[0306] Step A: 2-chloro-
5-(1-(4-(2-chloroethoxy)pheny1)-1-(4-methoxypheny1)-
but-l-en-2-yl)benzofuran
CI 0 0¨ \
\¨C1
_
0 M e
According to general procedure of McMurry reaction as example 1, step D
described,
1 -(2- chlorobenzofuran-5-yl)propan-1 -one (200 mg, 1.0 eq)
was reacted with
(4-methoxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone (418 mg, 1.5 eq,
by example 1, step
B) to give 440 mg desired product (98%, Z/E = 1/1).
[0307] Step B: (Z)-2-(4-
(2-(2-chlorobenzofuran-5-y1)-1-(4-methoxyphenyl)but-
1-enyl)phenoxy)-N-methylethanamine
Cl 0 0¨ \ /
_
=
0 Me
According to the same procedure as example 1, step E described,
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2- chloro-5- (1 - (4- (2- chloroethoxy)pheny1)-1 - (4-methoxyphenyl)but-1 - en-
2-yl)benzofur an (440 mg, 1.0
eq) was reacted with MeNH2 (30% wt in water, 10 mL) in Me0H (20 mL) under
reflux to give the
desired (Z)-product (Z and E isomer can be separated via column
chromatography). 1H NMR (400 MHz,
CDC13) 6 7.24 (d,J= 2.0 Hz, 1H), 7.20 (d,J= 8.4 Hz, 1H), 7.15 (d,J= 8.8 Hz,
2H), 7.01 (dd, J= 8.4 Hz,
2.0 Hz, 1H), 6.88 (d,J= 8.8 Hz, 2H), 6.74 (d,J= 8.8 Hz, 2H), 6.51 (d,J= 8.8
Hz, 2H), 6.45 (s, 1H), 3.92
(t, J= 5.2 Hz, 2H), 3.83 (s, 3H), 2.88 (t, J= 5.2 Hz, 2H), 2.50 (q, J= 7.6 Hz,
2H), 2.45 (s, 3H), 0.92 (t, J
= 7.6 Hz, 3H); m/z = 462[M+1].
Example 58
4-(1-(4-(2-(Azepan-1-yDethoxy)pheny1)-2-(2-chlorobenzofuran-5-yObut-1-
enyl)phenol
CI 0 0¨\ f---N
1 . . 'N
_
OH
According to the same procedure as example 1, step E described,
4-(2-(2-chlorobenzofuran-5-y1)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol
(220 mg, 1.0 eq, made
by example 11, step D) was reacted with azepane (500 mg) in Me0H under reflux
to give the desired
product (105 mg, 48%, Z/E = 1/1). 1H NMR (400 MHz, CDC13) 6 7.22 (d, J= 1.6
Hz, 1H), 7.19 (d,J=
8.4 Hz, 1H), 7.14 (d,J= 8.4 Hz, 1H), 7.07 (d,J= 8.8 Hz, 1H), 6.97-7.01 (m,
1H), 6.87 (d,J= 8.4 Hz, 1H),
6.84 (d, J= 8.4 Hz, 1H), 6.75 (d, J= 8.8 Hz, 1H), 6.76 (d, J= 8.8 Hz, 1H),
6.50 (d, J= 8.4 Hz, 1H), 6.45
(d, J = 8.8 Hz, 1H), 6.43-6.44 (m, 1H), 4.46-4.48 (m, 1H), 4.25-4.27 (m, 1H),
3.00-3.71 (m, 6H),
2.44-2.51 (m, 2H), 1.73-2.00 (m, 8H), 0.91 (t, J= 7.6 Hz, 3H); m/z = 516[M+1].
Example 59
4-(2-(2,3-Dihydrobenzofuran-5-y1)-1-(6-(2-(methylamino)ethoxy)pyridin-3-yDbut-
1-enyl)phenol
0 0¨\
'
4, / \NH N \
_
OH
[0308] Step A: (6-chloropyridin-3-y1)(4-(tetrahydro-2H-pyran-2-yloxy)pheny1)-
methanone
CI N el CD
I
CD
0
Mg (1.67 g, 1.2 eq) was added to dry THF (50 mL), the mixture was heated to 55
C, 12 was added
in one lot followed by EtBr. 2-(4-Bromophenoxy)tetrahydro-2H-pyran (16 g, 1.1
eq) was dissolved in
THF, and part of this solution was added at once to the Mg-THF mixture. After
the reaction was
Initiated, the remaining above solution was added and the mixture was refluxed
for 2 h to give the
MgBr-THF solution, ready for the next step. 6-Chloronicotinoyl chloride (10.0
g, 1.0 eq) was added to
dry THF, cooled to 0 C under N2, and then the above MgBr-THF solution was
added dropwise over 20
min. The mixture was warmed to rt and stirred overnight. Water was added and
extracted by Et0Ac.
The extract was concentrated and purified by column chromatography with
petroleum ether:Et0Ac =
5:1 to give the desired product of the
(6-chloropyridin-3-y1)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (13.6
g) in 76% yield. 1H
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NMR (400 MHz, CDC13) 6 8.78 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.78 (d, J =
8.0Hz, 2H), 7.46 (d, J =
8.4 Hz, 1H), 7.15 (d, J = 8.0Hz, 2H), 5.56 (t, J = 3.2 Hz, 1H), 3.83-3.90 (m,
1H), 3.63-3.67 (m, 1H),
2.02-2.05 (m, 1H), 1.89-1.92 (m, 2H), 1.69-1.75 (m, 2H), 1.59-1.65 (m, 1H).
[0309] Step B: 4-(1-(6-chloropyridin-3-y1)-2-(2,3-dihydrobenzofuran-5-yl)but-1-
enyl)phenol
0 CI
_
=
OH
According to general procedure of McMurry reaction as example 1, step D
described,
1 -(2,3 -dihydrobenzofuran-5-yl)propan-1 -one (610 mg, 1.1 eq)
was reacted with
(6-chloropyridin-3-y1)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (1.0 g,
1.0 eq) to give 440
mg desired product (37%, Z/E = 1/1).
[0310] Step C: 4-(2-(2,3-dihydrobenzofuran-5-y1)-1-(6-(2-
(methylamino)-
ethoxy)pyridin-3-yl)but-l-enyl)phenol
0 0¨\
'
4, / \N H N \
_
OH
To a stirred solution of 2-(methylamino)ethanol (875 mg, 10 eq) in 20 mL
anhydrous THF was
added NaH (373 mg, 8.0 eq) at 0 C, and the mixture was stirred at rt for 1 h,
4-(1-(6-Chloropyridin-3-y1)-2-(2,3-dihydrobenzofuran-5-yl)but-1- enyl)phenol
(440 mg, 1.0 eq) was
added. The mixture was refluxed for 16 h, cooled, quenched with sat. NH4C1,
and extracted with
CH2C12. The extract was dried, concentrated, and purified by column
chromatography to give the
desired product (197 mg, 41%). 1H NMR (400 MHz, CDC13) 6 8.06 (d, J= 2.4 Hz,
0.5H), 7.60 (d, J=
2.0 Hz, 0.5H), 7.32 (dd, J= 8.4 Hz, 2.4 Hz, 0.5H), 7.07 (dd, J= 8.4 Hz, 2.4
Hz, 0.5H), 7.03 (d, J= 8.8 Hz,
1H), 6.93 (d, J= 8.4 Hz, 1H), 6.83 (d, J= 8.4 Hz, 0.5H), 6.78 (d, J= 8.4 Hz,
1.5H), 6.69 (d, J= 8.4 Hz,
1H), 6.65 (d, J= 8.4 Hz, 0.5H), 6.59 (d, J = 8.0 Hz, 1H), 6.49 (d, J= 8.8 Hz,
1H), 6.36 (d, J= 8.4 Hz,
0.5H), 4.53 (t,J= 8.4 Hz, 2H), 4.46 (t,J= 5.2 Hz, 1H), 4.31 (t,J= 5.2 Hz, 1H),
3.10 (t,J= 8.4 Hz, 2H),
3.05 (t,J= 5.2 Hz, 1H), 2.96 (t,J= 5.2 Hz, 1H), 2.55 (s, 1.5H), 2.50 (s,
1.5H), 2.45 (q, J= 7.6 Hz, 2H),
0.94 (t, J= 7.2 Hz, 3H); m/z = 417[M+1] '.
Example 60
4-(2-(2-Chlorobenzofuran-5-y1)-1-(4-(2-(pyrrolidin-1-yDethoxy)phenyl)but-1-
enyl)phenol
CI 0 0¨\ /-,
1 la 41 "N
\----
OH
According to the same procedure as example 1, step E described,
4-(2-(2-chlorobenzofuran-5-y1)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol
(70 mg, 1.0 eq, made
by example 11, step D) was reacted with pyrrolidine (1 mL) in Me0H (3 mL)
under reflux to give the
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desired product (51 mg, 68%, Z/E = 1/2.6) as a yellow solid. 1H NMR (400 MHz,
CDC13) 6 7.24 (s, 1H),
7.20 (d, J= 9.2 Hz, 1H), 7.09 & 7.06 (d, J= 8.4 Hz, 2H), 7.00 (d, J= 8.8 Hz,
1H), 6.78 & 6.72 (d, J= 8.2
Hz, 2H), 6.68 (d, J= 8.6 Hz, 2H), 6.46 & 6.45 (s, 1H), 6.41 & 6.27 (d, J= 8.4
Hz, 2H), 4.10 & 3.89 (t, J
= 5.8 Hz, 2H), 2.94 & 2.83 (t,J= 6.2 Hz, 2H), 2.68 & 2.61 (m, 4H), 2.49 (q, J=
7.4 Hz, 2H), 1.84 & 1.81
(m, 4H), 0.91 (t, J= 7.4 Hz, 3H); m/z = 488[M+1].
Example 61
4-(2-(2-Chlorobenzofuran-5-y1)-1-(4-(2-(piperidin-1-ypethoxy)phenyl)but-1-
enyl)phenol
CI 0 0-\_N I/ __ \
1 . ii \ ____________________________________ /
-
OH
According to the same procedure as example 1, step E described,
4-(2-(2-chlorobenzofuran-5-y1)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol
(70 mg, 1.0 eq, made
by example 11, step D) was reacted with piperidine (1 mL) in Me0H (3 mL) under
reflux to give the
desired product (63 mg, 82%, Z/E = 1/1) as a light yellow solid. 1H NMR (400
MHz, CDC13) 6 7.24 &
7.22 (s, 1H), 7.21 (d, J= 9.2 Hz, 1H), 7.09 & 7.06 (d, J= 8.6 Hz, 2H), 7.01 &
6.99 (d, J= 8.8 Hz, 1H),
6.78 & 6.69 (d, J= 8.2 Hz, 2H), 6.68 & 6.66 (d, J= 8.6 Hz, 2H), 6.47 & 6.45
(s, 1H), 6.42 & 6.25 (d, J=
8.6 Hz, 2H), 4.10 & 3.90 (t, J= 6.0 Hz, 2H), 2.81 & 2.70 (t, J= 6.0 Hz, 2H),
2.48-2.57 (m, 6H),
1.47-1.68 (m, 6H), 0.89-0.93 (m, 3H); m/z = 502[M+1].
Example 62
4-(2-(2-Chlorobenzofuran-5-y1)-1-(4-(2-morpholinoethoxy)phenyl)but-1-
enyl)phenol
CI 0 0-\ /-
1 . . \-N /0
_
411
OH
According to the same procedure as example 1, step E described,
4-(2-(2-chlorobenzofuran-5-y1)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol
(70 mg, 1.0 eq, made
by example 11, step D) was reacted with morpholine (1 mL) in Me0H (3 mL) under
reflux to give the
desired product (61 mg, 79%, Z/E = 1/2) as a light yellow solid. 1H NMR (400
MHz, CDC13) 6 7.23 (s,
1H), 7.21 (d, J= 8.4 Hz, 1H), 7.13 & 7.09 (d, J= 8.6 Hz, 2H), 7.00 (d, J= 8.4
Hz, 1H), 6.83 & 6.80 (d,J
= 8.6 Hz, 2H), 6.72 & 6.69 (d, J= 8.6 Hz, 2H), 6.45 (s, 1H), 6.43 (d, J= 8.8
Hz, 2H), 4.12 & 3.94 (t, J=
5.6 Hz, 2H), 3.76 & 3.71 (t, J= 4.8 Hz, 4H), 2.83 & 2.71 (t, J= 5.6 Hz, 2H),
2.61 & 2.52 (t,J= 4.4 Hz,
4H), 2.49 (q, J= 7.2 Hz, 2H), 0.91 (t, J= 7.2 Hz, 3H); m/z = 504[M+1].
Example 63
4-(2-(2-Chlorobenzofuran-5-y1)-1-(4-(2-(4-methylpiperazin-1-
yDethoxy)phenyl)but-1-enyl)phenol
CI 0,
= 0-\
I \-N N-
-
OH
According to the same procedure as example 1, step E described,
4-(2-(2-chlorobenzofuran-5-y1)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol
(70 mg, 1.0 eq, made
by example 11, step D) was reacted with 1-methylpiperazine (1 mL) in Me0H (8
mL) under reflux to
give the desired product (60 mg, 76%, Z/E = 1/1.7) as a yellow solid. 1H NMR
(400 MHz, CDC13) 6
7.23 (s, 1H), 7.20 (d, J= 8.8 Hz, 1H), 7.12 & 7.08 (d, J= 8.8 Hz, 2H), 7.00
(d, J= 8.8 Hz, 1H), 6.83 &
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6.78 (d, J= 8.8 Hz, 2H), 6.72 & 6.69 (d, J= 8.8 Hz, 2H), 6.45 & 6.44 (s, 1H),
6.42 (d, J= 8.8 Hz, 2H),
4.12 & 3.93 (t,J= 5.6 Hz, 2H), 2.84 & 2.73 (t,J= 5.6 Hz, 2H), 2.40-2.62 (m,
10H), 2.31 & 2.82 (s, 3H),
0.91 (t,J= 7.2 Hz, 3H); m/z = 517[M+1] '.
Example 64
4-(2-(2-Chlorobenzofuran-5-y1)-1-(4-(2-(diethylamino)ethoxy)phenyl)but-1-
enyl)phenol
CI 0
1 le = 'N
\_
-
OH
According to the same procedure as example 1, step E described,
4-(2-(2-chlorobenzofuran-5-y1)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol
(70 mg, 1.0 eq, made
by example 11, step D) was reacted with diethylamine (3 mL) in Me0H (8 mL)
under reflux to give
the desired product (61 mg, 81%, Z/E = 1/1.25) as a brown solid. 1H NMR (400
MHz, CDC13) 6 7.23 (s,
1H), 7.20 (d, J= 8.4 Hz, 1H), 7.12 & 7.09 (d,J= 8.8 Hz, 2H), 7.00 & 6.99 (d,J=
8.4 Hz, 1H), 6.83 &
6.80 (d,J= 8.8 Hz, 2H), 6.71 & 6.69 (d,J= 8.4 Hz, 2H), 6.45 (s, 1H), 6.43
(d,J= 8.8 Hz, 2H), 4.08 &
3.90 (t,J= 5.8 Hz, 2H), 2.92 & 2.80 (t,J= 5.8 Hz, 2H), 2.69 & 2.62 (q, J= 7.0
Hz, 4H), 2.50 (q, J= 7.6
Hz, 2H), 1.10 & 1.04 (q, J= 7.2 Hz, 6H), 0.91 (t,J= 7.6 Hz, 3H); m/z =
490[M+1] '.
Example 65
4-(2-(2-Chlorobenzofuran-5-y1)-1-(4-(2-(ethylamino)ethoxy)phenyl)but-1-
enyl)phenol
CI 0 0-\
1 ID ,-NH
\_
-
OH
According to the same procedure as example 1, step E described,
4-(2-(2-chlorobenzofuran-5-y1)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol
(70 mg, 1.0 eq, made
by example 11, step D) was reacted with ethanamine (3 mL) in Me0H (8 mL) under
reflux to give the
desired product (38 mg, 54%, Z/E = 1/1.2) as a white solid. 1H NMR (400 MHz,
CDC13) 6 7.23 (s, 1H),
7.20 (d, J= 8.4 Hz, 1H), 7.12 & 7.03 (d,J= 8.6 Hz, 2H), 6.99 (d,J= 8.8 Hz,
1H), 6.83 & 6.75 (d,J= 8.8
Hz, 2H), 6.71 & 6.65 (d,J= 8.6 Hz, 2H), 6.44 (s, 1H), 6.45 & 6.40 (d,J= 8.4
Hz, 2H), 4.10 & 3.92 (t,J
= 4.8 Hz, 2H), 3.04 & 2.93 (t, J= 4.8 Hz, 2H), 2.78 & 2.71 (q, J= 7.2 Hz, 2H),
2.50 (q, J= 7.2 Hz, 2H),
1.18 & 1.13 (q, J= 7.2 Hz, 3H), 0.91 (t,J= 7.2 Hz, 3H); m/z = 462[M+1].
Example 66
4-(2-(2-Chlorobenzofuran-5-y1)-1-(4-(2-(dimethylamino)ethoxy)phenyl)but-1-
enyl)phenol
CI
\,\
-
OH
According to the same procedure as example 1, step E described,
4-(2-(2-chlorobenzofuran-5-y1)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol
(70 mg, 1.0 eq, made
by example 11, step D) was reacted with dimethylamine (1 mL) in Me0H (8 mL)
under reflux to give
the desired product (27 mg, 38%, Z/E = 1/1.2) as a white solid. 1H NMR (400
MHz, CDC13) 6 7.23 &
7.21 (s, 1H), 7.20 (d, J= 8.8 Hz, 1H), 7.08 & 7.06 (d, J= 9.2 Hz, 2H), 7.00 &
6.97 (d, J= 8.4 Hz, 1H),
6.79 & 6.67 (d,J= 8.6 Hz, 2H), 6.66 (d,J= 8.4 Hz, 2H), 6.45 & 6.24 (d,J= 8.8
Hz, 2H), 6.43 & 6.41 (s,
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1H), 4.10 & 3.89 (t, J= 5.2 Hz, 2H), 2.86 & 2.75 (t, J= 5.2 Hz, 2H), 2.49 (q,
J= 7.2 Hz, 2H), 2.44 &
2.37(s, 6H), 0.91 (t, J= 7.2 Hz, 3H); m/z = 462[M+1].
Example 67
4-(2-(2-Chlorobenzofuran-5-y1)-1-(4-(2-(piperazin-1-yDethoxy)phenyl)but-1-
enyl)phenol
i¨N\ 7H
CI o o-1
= =
=
OH
According to the same procedure as example 1, step E described,
4-(2-(2-chlorobenzofuran-5-y1)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol
(70 mg, 1.0 eq, made
by example 11, step D) was reacted with tert-butyl piperazine-l-carboxylate
(500 mg) in Me0H (3 mL)
under reflux and separated via column chromatography, followed by treatment
with 1 mL
trifluoroacetic acid in 3 mL CH2C12 and then purified by column chromatography
to give the desired
product (Z/E = 1/1) as a white solid. m/z = 503[M+1]'.
Example 68
4-(2-(2-Chlorobenzofuran-5-y1)-1-(6-(2-(methylamino)ethoxy)pyridin-3-yl)but-1-
enyl)phenol
CI 0
= \ N
OH
According to the same procedure as example 16, step C described,
4-(2-(2-chlorobenzofuran-5-y1)-1-(6-chloropyridin-3-yl)but-1-enyl)phenol (70
mg, 1.0 eq) was reacted
with 2-(methylamino)ethanol (128 mg, 10 eq) to give the desired product (Z/E =
1/1). m/z =
449[M+11.
Example 69
4-(2-(2-Chlorobenzofuran-5-y1)-1-(6-(2-(methylamino)ethylthio)pyridin-3-yl)but-
1-enyl)phenol
H
CI 0
=
OH
[0311] Step A: 2-(methylamino)ethanol hydrochloride
HHCI
H N
A solution of 2-(methylamino)ethanol (20 g, 1.0 eq) in 50 mL concentrated HC1
was stirred at rt
for 2 h and concentrated to give the product (quant). 1H NMR (400 MHz, DMSO-
d6) 6 8.95 (brs, 2H),
3.65 (t, J= 5.2 Hz, 2H), 2.94 (t, J= 5.6 Hz, 2H), 2.50-2.54 (m, 3H).
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[0312] Step B: 2-chloro-N-methylethanamine hydrochloride
HHCI
CI
To a stirred solution of 2-(methylamino)ethanol hydrochloride (29.7 g, 1.0 eq)
in 150 mL CHC13
was added sulfuryl dichloride (41 g, 1.3 eq) dropwise at 0 C. After refluxing
for 3 h, the reaction was
cooled to rt. Then solvent was removed in vacuo, the residue was suspended in
100 mL solution
(CH2C12: petroleum ether = 1: 10), and filtered to give the desired product
(28 g, 80%). 1H NMR (400
MHz, DMSO-d6) 6 9.24 (brs, 2H), 3.93(t, J= 6.0 Hz, 2H), 3.28 (t, J= 6.0 Hz,
2H), 2.56 (s, 3H).
[0313] Step C: 2-(methylamino)ethanethiol hydrochloride
HHCI
HS
To a stirred solution of 2-chloro-N-methylethanamine hydrochloride (15 g, 1.0
eq) in 150 mL
water was added Na2S203 (18.5 g, 1.0 eq), and the mixture was refluxed for 48
h. After cooling to rt,
the solvent was removed in vacuo. The crude salt was dissolved in 60 mL 6 M
HC1 (aq) and heated at
90 C for 4 h. The solvent was removed in vacuo and the residue was purified
by column
chromatography to give the desired product. 1H NMR (400 MHz, DMSO-d6) 6 4.95
(brs, 2H), 2.90 (s,
4H), 2.37 (s, 3H).
[0314] Step D: 4-(2-(2-chlorobenzofuran-5-y1)-1-(6-(2-
(methylamino)ethylthio)-
pyridin-3-yl)but-l-enyl)phenol
CI 0
/
= \ N
OH
According to the same procedure as example 16, step C described,
4-(2-(2-chlorobenzofuran-5-y1)-1-(6-chloropyridin-3-yl)but-1-enyl)phenol (70
mg, 1.0 eq) was reacted
with 2-(methylamino)ethanethiol hydrochloride (217 mg, 10 eq) to give the
desired product (Z/E = 1/1).
m/z = 465 [M+l]
Example 70
4-(2-(2-Chlorobenzofuran-5-y1)-1-(6-(methyl(2-(methylamino)ethyDamino)pyridin-
3-yObut-1-eny
Dphenol
\NJ¨NH
CI 0
' \ N
OH
According to the same procedure as example 16, step C described,
4-(2-(2-chlorobenzofuran-5-y1)-1-(6-chloropyridin-3-yl)but-1-enyl)phenol (70
mg, 1.0 eq) was reacted
with /V,/V'-dimethylethane-1,2-diamine (150 mg, 10 eq) to give the desired
product (Z/E = 1/1). m/z =
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462[M+1]'.
Example 71
4-(2-(2-Chlorobenzofuran-5-y1)-1-(6-(3-(pyrrolidin-1-34)propyl)pyridin-3-yObut-
1-enyl)phenol
CI 0
/
N
OH
[0315] Step A: 2-(4-iodophenoxy)tetrahydro-2H-pyran
0
4-Iodophenol 10.0 g (45.5 mmol) was dissolved in 20 mL 3,4-dihydro-2H-pyran,
then one drop of
concentrated sulfuric acid was added, the reaction mixture was stirred for 30
min, then the mixture was
poured into 1000 mL of n-hexane, filtered, washed with 300 mL (100 mL x 3)
hexane, and dried in
vacuum to afford the desired product as a white solid (9.1 g, 65.9%).
[0316] Step B: 6-chloro-N-methoxy-N-methylnicotinamide
0
N
0 NCI
Oxalyl chloride 12.1 g (95.2 mmol) was added dropwise to a solution of 6-
chloronicotinic acid
10.0 g (63.5 mmol) in 100 mL tetrahydrofuran,. The reaction mixture was
stirred at room temperature
for 1 h, and then concentrated in vacuo to give a residue. The residue was
dissolved in 50 mL
dichloromethane to give a solution, which was added to a solution of N,O-
dimethylhydroxylamine
hydrochloride (12.4 g, 126.9 mmol) and triethylamine (25.7 g, 253.9 mmol) in
100 mL
dichloromethane, stirred at room temperature for another 1 h, concentrated,
and purified by column
chromatography to afford the desired product as a colorless oil (9.4 g,
73.8%).
[0317] Step C: 1-(prop-2-ynyl)pyrrolidine
3-Bromoprop-1-yne (60.5 g, 0.50 mol) was slowly added to methylamine (70.1 g,
1.0 mol) at -10
C. After addition, the mixture was stirred at room temperature overnight. The
mixture was distilled
on a rectification column to afford the desired product as a colorless oil
(45.5 g, 83.5%).
[0318] Step D: (6-chloropyridin-3-y1)(4-(tetrahydro-2H-pyran-2-yloxy)pheny1)-
methanone
0
=IT
THPO N CI
2-(4-Iodophenoxy)tetrahydro-2H-pyran (18.2 g, 59.9 mmol) was dissolved in 100
mL dry
tetrahydrofuran and cooled to -78 C under nitrogen atmosphere, and then n-
butyllithium was added
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dropwise to the solution. After addition, the solution was stirred at -78 C
for 0.5 h,
6-chloro-N-methoxy-N-methylnicotinamide (8.0 g, 39.9 mmol) in 50 mL
tetrahydrofuran was added
dropwise and keep the temperature under -78 C for 2 h. Then 100 mL of aqueous
saturated ammonium
chloride was added. The mixture was extracted with ethyl acetate. The extract
was dried over sodium
sulfate, concentrated in vacuo, and purified by column chromatography to give
the desired product as a
yellow solid (8.4 g, 66.3%).
[0319] Step E: (6-(3-
(pyrrolidin-1-yl)prop-1-ynyl)pyridin-3-y1)(4-(tetrahydro-
2H-pyran-2-yloxy)phenyl)methanone
0
I
THPO N
A 100 mL
Schlenk flask was charge with (6- chloropyridin-3 -y1) (4- (tetrahydro-
2H-pyran-2-yloxy)phenyl)methanone (4.0 g, 12.6 mmol),
tetrakis(triphenylphosphine) palladium(0)
(1.5 g, 1.3 mmol, 10 mol%), cuprous iodide (0.48 g, 2.5 mmol, 20 mol%),
triethylamine 50 mL and
1-(prop-2-ynyl)pyrrolidine (2.8 g, 25.2 mmol). The flask was flushed with
nitrogen three times and the
mixture was stirred at 80 C for 2 h. The solvent was evaporated under vacuum
and the residue was
purified by column chromatography to afford the desired product as a yellow
solid (2.2 g, 44.9%).
[0320] Step F: (6-(3-
(pyrrolidin-1-yl)propyl)pyridin-3-y1)(4-(tetrahydro-
2H-pyran-2-yloxy)phenyl)methanone
0
THP0 NN J
Raney nickel (0.3 g, 0.6 mmol, 10 mol%) was added to the solution of
(6-(3 - (pyrrolidin-1 -yl)prop-1 -ynyl)pyridin-3 -y1) (4- (tetrahydro-2H-pyr
an-2-yloxy)phenyl)methanone
(2.2 g, 5.6 mmol) in 20 mL methanol at room temperature, and the reaction
mixture was stirred for 1 h
under hydrogen atmosphere. Filtered off the nickel and the filtrate was
concentrated in vacuo to afford
the desired product as a yellow solid (1.7 g, 77.3%).
[0321] Step G: 4-(2-(2-
chlorobenzofuran-5-y1)-1-(6-(3-(pyrrolidin-1-yl)propy1)-
pyridin-3-yl)but-l-enyl)phenol
CI 0
\ N
OH
According to general procedure of McMurry reaction as example 1, step D
described,6- (3 - (pyrrolidin-l-yl)propyl)pyridin-3 -y1)(4-(tetrahydro-2H-
pyran-2-yloxy)phenyl)methanon
e was reacted with 1-(2-chlorobenzofuran-5-yl)propan- 1 -one to give the
desired product (Z/E = 1/1).
m/z = 487[M+1].
Biological Activity
Generation of IC50 Data
In vitro growth inhibitory potency of anti-estrogen activity in MCF- 7 cells:
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[0322] The estrogen receptor a (ERa) high expression human breast cancer MCF-7
cells (#HTB-22,
A.T.C.C.) were cultured in DMEM medium supplemented by 10% fetal bovine serum
(Gibco0) and 10
1.1g/m1 bovine insulin (Sigma ). The cells were maintained in 75cm2 cell
culture flask (Corning )
filled with 15 ml medium, 95% air and 5% CO2. Cells were split twice a week in
a single layer cell
culture.
[0323] For experiments related to 1713-Estradiol (E2), cells at logarithm
growing stage were
pretreated for two days without E2, the phenol red DMEM medium was replaced by
the phenol red free
DMEM/F12 medium, and FBS was replaced by 10% charcoal stripped FBS to remove
the steroid and
greatly decrease the hormone levels. Cells were seeded in 96 well cell culture
plates (Corning ) with 4
x 103/well density, cultured in E2 free DMEM/F12 medium at 37 C for 24 hours,
95% air and 5% CO2.
All the compounds were stocked in DMSO as 0.01 M, serial diluted by the
culture medium and added
to the cells in the presence of proper E2 concentration. The final
concentrations of compounds and
DMSO were 3x10-10-1x10-5 M and 0.1%. Cells were incubated at 37 C for 7 days,
medium
containing E2 and compounds were changed every two days to maintain the
chemical activity.
[0324] 7 Days later, the viable cell numbers were calculated by the ATP amount
from the luciferase
quantity measurement (Cell Titre Glo0 luciferase kit, Promega0). This method
can be used to evaluate
the stimulating estrogenicity of estrogen dependent cell growth under the
condition of E2 free. The
estrogenicity was tested by percentage compared to the maximum growth
stimulation (100%) by E2. In
this study, the percentage antagonist effects were evaluated by compared to
the complete inhibition
(100%) at the dose of 1x10-5 M. The inhibition curves were generated by the
reading numbers with the
program Prism 5, ICso values were calculated.
Biological Data for Selected Compounds
[0325] Selected compounds prepared as described above were assayed following
the biological
procedures described herein. The results are given in the table below:
Growth inhibitory Growth inhibitory
potency in MCF-7 potency in MCF-7
Structure Structure
cells cells
ICso (nM) ICso (nM)
/
0-\_
\
N NH 0
ilfr ,_\ \
. / \
_
<100 -N <500
_
41
OH
OH
/
0-\
N
\
N 'NH
41
/ \ \ N- HCI
_
\ /
- <100 <100
. =
*
OH
OH
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I
ON
0
N
1: . (*.
<100 <100
ii
0
4111AP" *
OH
OH
L.,
N
0 O
N N
1 <100 I <100
0 :di 0 dal
4111PA IP
OH OH
/-----
N r-N-
õ _
oõN.,...)
N
<100 I<100
* 0 : 0
OH OH
/----
N
\---
4. 41 N
<100 I: <100
. 0
SOH
OH
/
NH ro
oõN.,....)
40 / \ N N
<100 I: <100
I.
41
SOHO
H
/
NH 0- \
S
41\-NH
411 410 \ / \
<100 _
<100
41 41
OH
OH
N
OH
F //
= . <100 s 0 <500
CI \
. 0 oiRli=
OH
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/-NH HO 0-\
`-NH
=
<100 <500
=
OH
OH
40 Br NH
NH
<100 <100
=
OH OH
OH
0-CHNH
<100 I, = <100
/N
OH
0.-OH
411
<100 <100
=
OH OH
/ /-NH
N
0 \ HO
/0
<500 <500
=
OH
OH
/-NH /-NH
=
= F
<100 <500
=
OH OH
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HO OH /
o_/¨NH
. 41
. <500 <100
0¨\ 40 F
"¨NH
\ OH
/
0 O_\/
F 0_rNH
. 4.
<100 <100
41
41
OH
OH
/
/¨NH
H
0¨/
¨11 ii pi¨ 0
<100 HN iiii <100
41 11111 --- *OH
OH
0 0¨\
OH . . "¨NH
\
HniN¨ 0
0 4 &
'-
i, ci
H <100 <100
1
n
c)
OH
CI 0
0 0¨\ / 0¨\ /
. . \¨NH . . \¨NH
<100 <100
41 41
OH
OH Z/E = 1/1
a o OH
CI 0
. 41 \¨NH
<100 <100
41 II
o¨\_
OH Z NH
\ E
CI 0 O_\/ 0 0¨\_
. 41 \¨NH
. / \ N NH
\
<500 <100
41 41
OMe OH
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CI 0 0-\ CI 0 0
-NO -\
= = -ND
* .
<100 <100
* *
OH OH
a = (3- \_ i¨\ a = 0-
N \_ /¨
\
* 4. 0 / * 4. N /N-
\
<100 <100
* *
CI 0 0-\ /¨ a 0 0\\_
* 411 "N NH
\_
<100 <100
* *
OH OH
CI 0 0-\ / CI 0 0-\
I. . N\
<100 <100
* *
O
OH H
/
/¨\ j¨NH
CI 0 0
_
<100_ <100
*
*
OH
OH
/
/ N
\N HI-
CI 0 S-I a 0
= /
' \ N
_
<100 I =
/ \ N
_
<100
_ _
* *
OH
OH
/----
N
Cl 0
./ 'N
_
_ <100
*
OH
[0326] The representative compounds of the present invention show potent anti-
estrogen activities
in MCF-7 cells.
Toxicity
[0327] Studies further show that the compounds of the present invention have
relatively low
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96
toxicities.
[0328] As shown in Figure and the table below, 21 days after the nude mouse
was administered with
Tamoxifen (20 mg/kg), the weight dropped by 20%, and a higher dose of 30 mg/kg
of an exemplary
compound of the present application, shown below as CT-946-01, led to a weight
gain of 7%.
1 ro
# N
I /
(01 * 0
0 OH
Tamoxifen CT-946-01
Anti-tumor (MCF-7) effect and weight change:
Compound Dose (PO, QD) TGI (%) 21 days BW (% of vehicle)
Tamoxifen 20 mg/kg 22.4 80.0
CT-946-01 10 mg/kg 108 104
CT-946-01 30 mg/kg 104 107
PO: per os; QD: quapua die; TGI: Target Group Index; BW: Body Weight
[0329] While preferred embodiments of the present invention have been shown
and described
herein, such embodiments are provided by way of example only. It should be
understood that various
alternatives to the embodiments of the invention described herein may be
employed in practicing the
invention. Those ordinary skilled in the art will appreciate that numerous
variations, changes, and
substitutions are possible without departing from the invention. It is
intended that the following claims
define the scope of aspects of the invention and that methods and structures
within the scope of these
claims and their equivalents be covered thereby.
