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CA 02454613 2003-12-22
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SUBSTITUTED ANILINIC PIPERIDINES AS MCH SELECTIVE
ANTAGONISTS
BACKGROUND OF THE INVENTION
This application is a continuation-in-part of U.S.
Serial No. 10/042,582, filed January 9, 2002, and of
U.S. Serial No. 09/899,794, filed July 5, 2001, the
contents of both of which are hereby incorporated by
reference into the subject application.
Throughout this application, various publications are
referenced in parentheses by author and year. Full
citations for these references may be found at the end
of the specification immediately preceding the sequence
listings and the claims. The disclosure of these
publications in their entireties are hereby incorporated
by reference into this application to describe more
fully the state of the art to which this invention
pertains. Melanin-concentrating hormone (MCH) is a
cyclic peptide originally isolated from salmonid
(teleost fish) pituitaries (Kawauchi et al., 1983). In
fish the 17 amino acid peptide causes aggregation of
melanin within the melanophores and inhibits the release
of ACTH, acting as a functional antagonist of a-MSH.
Mammalian MCH (19 amino acids) is highly conserved
between rat, mouse, and human, exhibiting 1000 amino
acid identity, but its physiological roles are less
clear, MCH has been reported to participate in a
variety of processes including feeding, water balance,
energy metabolism, general arousal/attention state,
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2
memory and cognitive functions, and psychiatric
disorders (for reviews, see Baker, 1991; Baker, 1994;
Nahon, 1994; Knigge et al., 1996). Its role in feeding
or body weight regulation is supported by a recent
Nature publication (Qu et al., 1996) demonstrating that
MCH is overexpressed in the hypothalamus of ob/ob mice
compared with ob/+ mice, and that fasting further
increased MCH mRNA in both obese and normal mice during
fasting. MCH also stimulated feeding in normal rats
when injected into the lateral ventricles (Rossi et al.,
1997). MCH also has been reported to functionally
antagonize the behavioral effects of a-MSH (Miller et
al., 1993; Gonzalez et al, 1996; Sanchez et al., 1997);
in addition, stress has been shown to increase POMC mRNA
levels while decreasing the MCH precursor preproMCH
(ppMCH) mRNA levels (Presse et al., 1992). Thus MCH may
serve as an integrative neuropeptide involved in the
reaction to stress, as well as in the regulation of
feeding and sexual activity (Baker, 1991; Knigge et al.,
1996) .
Although the biological effects of MCH are believed to
be mediated by specific receptors, binding sites for MCH
have not been well described. A tritiated ligand ( [3H] -
MCH) was reported to exhibit specific binding to brain
membranes but was unusable for saturation analyses, so
neither affinity nor Bm~ were determined (Drozdz and
Eberle, 1995). Radioiodination of the. tyrosine at
position thirteen resulted in a ligand with dramatically
reduced biological activity (see Drozdz and Eberle,
1995). In contrast, the radioiodination of the MCH
analogue [Phel3, Tyrl9] -MCH was successful (Drozdz et al . ,
1995); the ligand retained biological activity and
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3
exhibited specific binding to a variety of cell lines
including mouse melanoma (B16-F1, G4F, and G4F-7), PC12,
and COS cells. In G4F-7 cells, the KD = 0.118nM and the
Bm~ 1100 sites/cell. Importantly, the binding was not
inhibited by a-MSH but was weakly inhibited by rat ANF
(Ki - 116 nM vs. 12 nM for native MCH) (Drozdz et al.,
1995). More recently specific MCH binding was reported
in transformed keratinocytes (Burgaud et al., 1997) and
melanoma cells (Drozdz et al., 1998), where photo-
crosslinking studies suggest that the receptor is a
membrane protein with an apparent molecular weight of
45-50 kDaltons, compatible with the molecular weight
range of the GPCR superfamily of receptors. No
radioautoradiographic studies of MCH receptor
localization using this ligand have been reported as
yet.
The localization and biological activities of MCH
peptide suggest that the modulation of MCH receptor
activity may be useful in a number of therapeutic
applications. The role of MCH in feeding is the best
characterized of its potential clinical uses. MCH is
expressed in the lateral hypothalamus, a brain area
implicated in the regulation of thirst and hunger
(Grillon et al.; 1997); recently orexins A and B, which
are potent orexigenic agents, have been shown to have
very similar localization to MCH in the lateral
hypothalamus (Sakurai et al., 1998). MCH mRNA levels in
this brain region are increased in rats after 24 hours
of food-deprivation (Nerve and Fellman, 1997); after
insulin injection, a significant increase in the
abundance and staining intensity of MCH immunoreactive
perikarya and fibres was observed concurrent with a
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4
significant increase in the level of MCH mRNA
(Bahjaoui-Bouhaddi et al., 1994). Consistent with the
ability of MCH to stimulate feeding in rats (Rossi et
al., 1997) is the observation that MCH mRNA levels are
upregulated in the hypothalami of obese ob/ob mice (Qu
et al., 1996), and decreased in the hypothalami of rats
treated with leptin, whose food intake and body weight
gains are also decreased (Sahu, 1998). MCH appears to
act as a functional antagonist of the melanocortin
system in its effects on food intake and on hormone
secretion within the HPA (hypothalamopituitary/adrenal
axis) (Ludwig et al., 1998). Together these data suggest
a role for endogenous MCH in the regulation of energy
balance and response to stress, and provide a rationale
for the development of specific compounds acting at MCH
receptors for use in the treatment of obesity and
stress-related disorders.
In all species studied to date, a major portion of the
neurons of the MCH cell group occupies a rather constant
location in those areas of the lateral hypothalamus and
subthalamus where they lie and may be a part of some of
the so-called "extrapyramidal" motor circuits. These
involve substantial striato- and pallidofugal pathways
involving the thalamus and cerebral cortex, hypothalamic
areas, and reciprocal connections to subthalamic
nucleus, substantia nigra, and mid-brain centers
(Bittencourt et al., 1992). In their location, the MCH
cell group may offer a bridge or mechanism for
expressing hypothalamic visceral activity with
appropriate and coordinated motor activity. Clinically
it may be of some value to consider the involvement of
this MCH system in movement disorders, such as
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Parkinson's disease and Huntingdon's Chorea in
which extrapyramidal circuits are known to be involved.
Human genetic linkage studies have located authentic
5 hMCH loci on chromosome 12 (12q23-24) and the variant
hMCH loci on chromosome 5 (5q12-13) (Pedeutour et al.,
1994). Locus 12q23-24 coincides with a locus to which
autosomal dominant cerebellar ataxia type II (SCA2) has
been mapped (Auburger et al., 1992; Twells et al.,
1992). This disease comprises neurodegenerative
disorders, including an olivopontocerebellar atrophy.
Furthermore, the gene for Darier's disease, has been
mapped to locus 12q23-24 (Craddock et al., 1993).
Dariers' disease is characterized by abnormalities I
keratinocyte adhesion and mental illnesses in some
families. In view of the functional and neuroanatomical
patterns of the MCH neural system in the rat and human
brains, the MCH gene may represent a good candidate for
SCA2 or Darier's disease. Interestingly, diseases with
high social impact have been mapped to this locus.
Indeed, the gene responsible for chronic or acute forms
of spinal muscular atrophies has been assigned to
chromosome 5q12-13 using genetic linkage analysis (Melki
et al., 1990; Westbrook et al., 1992). Furthermore,
independent lines of evidence support the assignment of
a major schizophrenia locus to chromosome 5q11.2-13.3
(Sherrington et al., 1988; Bassett et al., 1988; Gilliam
et al., 1989). The above studies suggest.that MCH may
play a role in neurodegenerative diseases and disorders
of emotion.
Additional therapeutic applications for MCH-related
compounds are suggested by the observed effects of MCH
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6
in other biological systems. For example, MCH
may regulate reproductive functions in male and female
rats. MCH transcripts and MCH peptide were found within
germ cells in .testes of adult rats, suggesting that MCH
may participate in stem cell renewal and/or
differentiation of early spermatocytes (Hervieu et al.,
1996). MCH injected directly into the medial preoptic
area (MPOA) or ventromedial nucleus (VMN) stimulated
sexual activity in female rats (Gonzalez et al . , 1996) .
In ovariectomized rats primed with estradiol, MCH
stimulated luteinizing hormone (LH) release while anti-
MCH antiserum inhibited LH release (Gonzalez et al.,
1997). The zona incerta, which contains a large
population of MCH cell bodies, has previously been
identified as a regulatory site for the pre-ovulatory LH
surge (MacKenzie et al., 1984). MCH has been reported
to influence release of pituitary hormones including
ACTH and oxytocin. MCH analogues may also be useful. in
treating epilepsy. In the PTZ seizure model, injection
of MCH prior to seizure induction prevented seizure
activity in both rats and guinea pigs, suggesting that
MCH-containing neurons may participate in the neural
circuitry underlying PTZ-induced seizure (Knigge and
Wagner, 1997). MCH has also been observed to affect
behavioral correlates of cognitive functions. MCH
treatment hastened extinction of the passive avoidance
response in rats (McBride et al., 1994), raising the
possibility that MCH receptor antagonists may be
beneficial for memory storage. and/or retention. A
possible role for MCH in the modulation or perception of
pain is supported by the dense innervation of the
periaqueductal grey (PAG) by MCH-positive fibers.
Finally, MCH may participate in the regulation of fluid
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7
intake. ICV infusion of MCH in conscious sheep
produced diuretic, natriuretic, and kaliuretic changes
in response to increased plasma volume (Parkes, 1996).
Together with anatomical data reporting the presence of
MCH in fluid regulatory areas of the brain, the results
indicate that MCH may be an important peptide involved
in the central control of fluid homeostasis in mammals.
The identification of a G-protein coupled receptor for
MCH has recently been published (Chambers et al., 1999;
Saito et al., 1999). These groups identified MCH as the
endogenous ligand for the human orphan G-protein coupled
receptor SLC-1 (Lakaye et al., 1998). The rat homologue
of this receptor (now called MCH-1) was reported to be
localized in regions of the rat brain associated with
feeding behavior (e. g. dorsomedial and ventromedial
hypothalamus). The link between MCH-1 and the effects
of MCH on feeding has been strengthened by recent
reports on the phenotype of MCH-1 knockout mice. Two
groups have shown independently (Marsh et al, 2002; Chen
et a1, 2002) that the targeted disruption of the MCH-1
receptor gene (MCH-1 knockout) in mice results in
animals that are hyperphagic but are lean and have
decreased body mass relative to wild-type littermates.
The decrease in body mass is attributed to an increase
in metabolism. Each group demonstrated that the MCH-1
knockout mice are resistant to diet-induced obesity, and
generally exhibit weights similar to. littermates
maintained on regular chow.
Finally, synthetic antagonist molecules for the MCH-1
receptor have now been described in the literature.
Bednarek et al. (2002) have reported on the synthesis of
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8
high affinity peptide antagonists of MCH-1. In
addition, a small molecule antagonist of MCH-1 has been
described by Takekawa et al. (Takekawa et al., 2002).
This compound, T-226296, exhibits high affinity for the
MCH-1 receptor (-. 5-9 nM for rat and human MCH-1), and
was shown to inhibit food intake induced by the
intracerebroventricular application of MCH. These data
validate the strategy of using an MCH-1 receptor
antagonist to treat obesity.
Furthermore, in our own studies, we have tested MCH1
antagonists in several animal models that are well known
as predictive for the efficacy of compounds in humans
(Borowsky, et al., in press; unpublished data). These
experiments indicate that MCH1 antagonists are useful to
treat obesity, depression, anxiety, as well as urinary
disorders.
As used in this invention, the term "antagonist" refers
to a compound which binds to, and decreases the activity
of, a receptor in the presence of an agonist. In the
case of a G-protein coupled receptor, activation may be
measured using any appropriate second messenger system
which is coupled to the receptor in a cell or tissue in
which the receptor is expressed. Some specific, but by
no means limiting, examples of well-known second
messenger systems are adenylate cyclase, intracellular
calcium mobilization, ion channel activation, guanylate
cyclase and inositol phospholipid hydrolysis.
Conversely, the term "agonist" refers to a compound
which binds to, and increases activity of, a receptor as
compared with the activity of the receptor in the
absence of any agonist.
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In one embodiment of this invention, the synthesis of
novel compounds which bind selectively to the cloned
human melanin-concentrating hormone-1 (MCH1) receptor,
compared to other cloned G-protein coupled receptors,
and inhibit the activation of the cloned receptors as
measured in in vitro assays is disclosed. The in vitro
receptor binding assays described hereinafter were
performed using various cultured cell lines, each
transfected with and expressing only a single cloned
receptor.
Furthermore, the compounds of the present invention may
also be used to treat abnormal conditions such as
feeding disorders (obesity, bulimia and bulimia
nervosa), sexual/reproductive disorders, depression,
anxiety, depression and anxiety, epileptic seizure,
hypertension, cerebral hemorrhage, congestive heart
failure, sleep disturbances, or any condition in which
antagonism of an MCH1 receptor may be beneficial. In
addition, the compounds of the present invention may be
used to reduce the body mass of a subject. Furthermore,
the compounds of the present invention may be used to
treat urinary disorders.
30
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Summary of the Invention
This invention provides a compound having the structure:
R,-x~n .
~n
R3
5 wherein R1 chained branched
is hydrogen, or
straight
C1-C~ alkyl, monofluoroalkyl polyfluoroalkyl,
or aryl or
heteroaryl, wherein the aryl heteroaryl is optionally
or
substituted with one or more -Cl, -Br, -I, -CN,
-F,
-N02, -CH3, -CF3, -CORD, -COaRa, phenoxy or
phenyl,
10 straight chained or branched Cl-C~ alkyl;
wherein R2 is straight-chained or branched C3-C4 alkyl or
cyclopropyl;
wherein R3 is aryl or heteroaryl, wherein the aryl or
heteroaryl is optionally substituted with one or more
-F, -C1, -Br, -I, -CN, -NO2, straight chained or
branched C1-C~ alkyl;
wherein A is -H, -F, -Cl, -Br, -CN, -N02, -COR3, -CO2R3,
straight chained or branched C1-C~ alkyl, monofluoroalkyl
or polyfluoroalkyl;
wherein X is O or NH; and
wherein n is an integer from 0 to 5 inclusive.
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In one embodiment, R1 is aryl optionally substituted
with one or more -F, -Cl, -Br, -I, -CN, -N02, -COR2,
-COZR2, straight chained or branched C1-C~ alkyl;
wherein R3 is phenyl;
wherein A is H; and
wherein X is O.
In one embodiment, R~ is isopropyl.
In one embodiment, the compound has the structure:
O
O N
N
O
In one embodiment, compound has the structure:
O-
O N
N
O
In one embodiment, R1 is hydrogen, straight chained or
branched C1-C~ alkyl; and wherein R3 is aryl.
In one embodiment, R2 is isopropyl; and A is hydrogen.
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In one embodiment, the compound has the structure:
.O N
N
O
In one embodiment, the compound has the structure:
HO N
N
O
The present invention also provides a compound having
the structure:
A
-H
wherein R1 is aryl or heteroaryl optionally substituted
with one or more -F, -C1, -Br, -I, -CN, -NO2, -OCH3,
phenoxy, fused cyclopentanyl, straight chained or
branched C1-C., alkyl, monofluoroalkyl or polyfluoroalkyl;
wherein R2 is straight-chained or branched C1-C4 alkyl or
cyclopropyl;
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wherein A is -H, -F, -Cl, - Br, -CN, -NOZ, straight
chained or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; and
wherein n is an integer from 1 to 5 inclusive.
In one embodiment, Rl is aryl optionally substituted with
one or more -F, -C1, -Br, -I or straight chained or
branched C1-C4 alkyl ; and
wherein A is H.
In one embodiment, Rz is isopropyl; and
wherein n is 2.
In one embodiment, the compound has the structure:
N
N
O O
2.0 In one embodiment, the compound has the structure:
N
CI ~ ~ N
O O
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14
In one embodiment, the compound has the structure:
O
O
F ~ N N~ .
In one embodiment, R1 is-thienyl; and wherein A is H.
In one embodiment, R2 is isopropyl.
In one embodiment, the compound has the structure:
O
O
N N
The invention provides a compound having the structure:
A
W N ~ ~ .
N-H
O
R2 .
wherein W is
A
or I ~ X-Y
N R~ T
H
wherein each R1 is independently hydrogen, methyl or
ethyl;
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wherein R~ is straight- chained or branched C3-C4
alkyl or cyclopropyl;
wherein R3 is hydrogen, aryl or heteroaryl, wherein the
5 aryl or heteroaryl is optionally substituted with one or
more -H, -F, -C1, -Br, -I, -CN, -NOa, straight chained
or branched C1-C~ alkyl.
wherein each A is independently -H, -F, -C1, -Br, -CN,
10 -N02, -COR3, -CO2R3, straight chained or branched C1-C~
alkyl, monofluoroalkyl or polyfluoroalkyl;
wherein X is O, NR3, CO or may be absent; and
15 wherein Y is hydrogen, aryl or heteroaryl, wherein the
aryl or heteroaryl is optionally substituted with one ox
more -F, -C1, -Br, -I, -CN, -N02, straight chained or
branched C1-C~ alkyl.
In one embodiment, W is
H A
X-Y
H ;
and wherein X is O or may be absent.
In one embodiment, RZ is isopropyl.
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16
In one embodiment, the compound has the structure:
N \ /
O
N
O
/ \
F F
In one embodiment, the compound has the structure:
In one embodiment, W is
N R~
R~
In one embodiment, A is -H, -F, -C1, -Br.
In one embodiment, R~ is isopropyl; and A is hydrogen.
In one embodiment, the compound has the structure:
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17
N
N / ~ N O
J
This invention provides a compound having the structure:
A
W
~--N
N-H
O
R2
wherein W is
B\ w ~B B~ ~w iB
~~N
N
R~ R~
wherein R1 is hydrogen, straight chained or branched
C1-C~ alkyl, aryl or heteroaryl, wherein the aryl or
heteroaryl is optionally substituted with one or more
-F, -Cl, -Br, -CN, -N02, -OCH3, -COaCH3, -CF3, phenyl,
straight chained or branched Cl-C~ alkyl;
wherein Ra is straight-chained or branched C3-C4 alkyl or
cyclopropyl;
wherein A is -H, -F, -C1, -Br, -CN, -N02, -COR1, -COZR1,
straight chained or branched C1-C~ alkyl, monofluoroalkyl
or polyfluoroalkyl or phenyl.
wherein each B is independently -H, -F, -C1, -Br, -I,
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-CN, -N02, -COR1, -CO~Rl, - OCH3, -OCF3, -CF3, straight
chained or branched Cl-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl or aryl, phenoxy or benzyloxy, wherein
the aryl, phenoxy or benzyloxy is optionally substituted
with one or more -F, -C1, -Br, -CN, -NO~, -COR1, -CO2R1,
-OCH3, -OCF3, -CF3 or straight chained or branched C1 -C3
alkyl.
In one embodiment, W is
B
N
In one embodiment, R1 is hydrogen or phenyl optionally
substituted with one or more -F, -C1, -Br, -CN, -N02,
straight chained or branched C1-C~ alkyl.
In one embodiment, Rz is isopropyl.
In one embodiment, the compound has the structure:
N
N
O
. . C~ ~ N
25
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19
In one embodiment, the compound has the structure:
N',
N
N
This invention provides a compound having the structure:
A
nn
Rs \ ' ~ R _H ;
N
i
R~
wherein R1 is hydrogen, straight chained or branched
C1-C~ alkyl, aryl or heteroaryl, wherein the aryl or
heteroaryl is optionally substituted with one or more
-F, -Cl, -Br, -CN, -N02, -CF3, -OCH3, straight chained or
branched C1-C3 alkyl;
wherein RZ is straight-chained or branched C3-C4 alkyl or
cyclopropyl;
wherein R3 is -H, -F, -C1, -Br, -I, -CN, -N02, -CF3,
-OCH3, or straight chained or branched C1-C3 alkyl,
monofluoroalkyl or polyfluoroalkyl, or a. phenyl ring
fused to C6 and C~ of the indole moiety;
wherein R4 is hydrogen or aryl optionally substituted
with one or more -F, -C1, -Br, -I, -CN, -NO2, -CF3,
straight chained or branched C1-C3 alkyl;
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wherein A is -H, -F, -Cl, -Br, -CN, -N02, straight.
chained or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; and
5
wherein n is an integer from 2 to 4 inclusive.
In one embodiment, R3 is -H, -F, -C1, -Br, -I, -CN, -N02,
-OCF3 or -OCH3 ; and
wherein R4 is hydrogen or phenyl optionally substituted
with one or more -F, -Cl or -CF3.
In one embodiment, R1 is hydrogen or phenyl optionally
substituted with one or more -F, -C1, -Br, -CN, -NO2,
-CF3, -OCH3 or straight chained or branched Cs-C3 alkyl;
In one embodiment, Rz is isopropyl.
In one embodiment, the compound has the structure:
N ~ J
N
O
O
I \
N
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In one embodiment, the compound has the structure:
FF
FRO
N
N N
O
CI
In one embodiment, the compound has the structure:
This invention provides a compound having the structure:
A
R~ Rs ~I~
R~
~N X
O
\\O
wherein each R1 is independently hydrogen or CH3;
wherein R~ is straight-chained or branched C1-C4 alkyl or
cyclopropyl;
wherein R3 is benzyl or phenyl, wherein the benzyl or
phenyl is optionally substituted with a methylenenedioxy
group or one or more -F or -C1;
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22
wherein A is -H, -F, -C1, - Br, -CN, -N02, straight
chained or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl;
wherein X is (CHz) 2, COCHz or CONH;
In one embodiment, R3 is phenyl optionally' substituted
with one or more -F; and
wherein A is hydrogen.
In one embodiment, X is CONH.
In one embodiment, RZ is methyl.
In one embodiment, the compound has the structure:
F \ F
O
~ O
~N~N~N
O~ \ N
O
In one embodiment, the compound has the structure:
F
Y
Y
R~ R~ ~N
~N-X N-H
O~ O
wherein each Y is independently hydrogen or -F.
In one embodiment, the compound has the structure:
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23
F
F ~ F
/
O
O
N
O~ w N
O
In one embodiment, the compound has the structure:
F
F
I/
'O'
~ N OI
O \\ w N
O
In one embodiment, R3 is benzyl optionally substituted
with a methylenedioxy group or one or more -F or -Cl.
In one embodiment, the compound has the structure:
F~ Y
C/~/
Y~ /
R R1
1
O~N-X ~ _H
O
O ;
wherein each Y is independently hydrogen or -F.
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In one embodiment, the compound has the structure:
/~/~ N O
N
N ,
In one embodiment, the compound is enantiomerically
pure.
In one embodiment, the compound is diastereomerically
pure.
In one embodiment, the compound is enantiomerically and
diastereomerically pure.
This invention also provides a pharmaceutical
composition comprising a therapeutically amount of a
compound of the invention and a pharmaceutically
acceptable carrier.
In one embodiment, the amount of the compound is from
about O.Olmg to about 500mg.
In one embodiment, the amount of the compound is from
about 0.lmg to about 60mg~.
In one embodiment, the amount of the compound is from
about 1mg to about 20mg.
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In one embodiment, the pharmaceutical composition
consists of a carrier which is a liquid and the
composition is a solution.
5 In one embodiment, the pharmaceutical composition
consists of a carrier which is a solid and the
composition is a tablet.
In one embodiment, the pharmaceutical composition
10 consists of a carrier which is a gel and the composition
is a suppository.
The invention also provides a process for making a
pharmaceutical composition comprising admixing a
15 therapeutically effective amount of the compound of any
of the invention and a pharmaceutically acceptable
carrier.
This invention also provides the method of treating a
20 subject suffering from a disorder selected from the
group consisting of depression, anxiety, urge
incontinence, or obesity comprising administering to the
subject a therapeutically effective amount of the
compound of the invention.
In one embodiment, the therapeutically effective amount
is between about 0.03 and about 1000 mg per day.
In one embodiment, the therapeutically effective amount
is between about 0.30 and about 300 mg per day.
In one embodiment, the therapeutically effective amount
is between about 1.0 and about 100 mg per day.
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In one embodiment, the disorder is depression.
In one embodiment, the disorder is anxiety.
In one embodiment, the disorder is obesity.
In one embodiment, the disorder is urge incontinence.
The invention provides the method of reducing the body
mass of a subject, which comprises administering to the
subject an amount of a compound of the invention
effective to reduce the body mass of the subject.
The invention provides the method of treating a subject
suffering from depression, which comprises administering
to the subj ect an amount of a compound of any of claims
of the invention effective to treat the subject's
depression.
The invention'provides the method of treating a subject
suffering from anxiety, which comprises administering to
the subject an amount of a compound of the invention
effective to treat the subject's anxiety.
The invention provides the method of alleviating urge
urinary incontinence in a subject suffering from an
overactive bladder, which comprises administering to the
subject an amount of the compound of the invention
effective to alleviate the subject's urge urinary
incontinence.
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The invention provides the method of managing obesity
in a subject in need of weight loss, which comprises
administering to the subj ect an amount of a .,compound of
the invention effective to induce weight loss in the
subject.
The invention provides the method of managing obesity in
a subject who has experienced weight loss, which
comprises administering to the subject an amount of a
compound of the invention effective to maintain such
weight loss in the subject.
The invention provides the method of treating overactive
bladder in a subject, which comprises administering to
the subject an amount of a compound of any of the
invention effective to treat the subject's overactive
bladder.
The invention provides the method of treating a disorder
in a subject, wherein the symptoms of the subject can be
alleviated by treatment with an MCH1 antagonist, wherein
the MCH1 antagonist is the compound of the invention.
The invention provides the method of alleviating the
symptoms of a disor4der in a subject, which comprises
administering to the subject an amount of an MCHl
antagonist effective to alleviate the symptoms, wherein
the MCH1 antagonist is the compound of the invention.
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Detailed Description of the Invention
This invention provides a compound having the structure:
R6
R m V~N~Z~R6
W n N
~m
V ~ R R5
X
R6
R m V~N~Z~R6
v
~m
5
Y
R6
V
R m~~ V/N'z/R6 ; or
V N
~m
R5
Y
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R6
R m V~N~Z~R6
X
~m
Y
wherein each V is independently phthalimide, aryl,
phenoxy or heteroaryl, wherein the aryl, phenoxy or
5 heteroaryl is optionally substituted with one or more F;
C1; Br; I; CORs; COzRs; -OCORs; -CON (Rs) z; -N (Rs) CORs; CN;
-NOz ; -N ( Rs ) z ~ -ORs ; - SRs 1 ( CHz ) qORs 1 ( CHz ) qRs 7 ( CHa ) qSRs
I
straight chained or branched Cl-C~ alkyl,
monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched Cz-C~
alkenyl, Cz-C~ alkynyl; aryl; phenoxy; C~-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein each W is independently aryl or heteroaryl,
wherein the aryl or heteroaryl is optionally substituted
wi th one or more F; Cl ; Br; I ; COR3 ; -OCOR3 ; COzR3 ;
-CON (R3) z t -N (R3) COR3; CN; -NOz; -N (R3) zT -OR3; -SR3 J
(CHz) qOR3; (CHz) qSR3; straight chained or branched C1-C~
alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched Cz-C~
alkenyl, Cz-C~ alkynyl; aryl; phenoxy; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
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wherein X is hydrogen or - OR3, provided that when X
is -OR3 the V geminal to X cannot be phthalimide;
wherein Y is hydrogen, =O (carbonyl oxygen), OR3, OV,
5 COV, =NNHV, =NNRS, NZRS, NZV, NCONV (ureas) , NCONRS, NR3,
carbazole, indole or phthalimide;
wherein each R is independently -H; -F; straight chained
or branched C1-C~ alkyl, monofluoroalkyl or
10 polyfluoroalkyl; straight chained or branched Cz-C~
alkenyl or alkynyl ; -N ( R3 ) z ; -NOz ; -CN; -COzR3 ; -OCOR3 ;
-OR3; or -N (R3) COR3; -CON (R3) z:
wherein each R3 is independently -H; straight chained or
15 branched C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched Cz-C~ alkenyl or alkynyl;
C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
20 wherein each RS is -H; -NOz; -N3; -CN; straight chained
or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched Cz-C~
alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or
25 cycloalkenyl; -N(R3)z; -OR3; -(CHz)pOR3; -COR3; -COzR3;
-OCOR3; -CUN (R3) z; -N (R3) COR3; aryl or heteroaryl, wherein
the aryl or heteroaryl is optionally substituted with
one or more F ; Cl ; Br ; I ; CORE ; COzR3 ; -OCOR3 ; - CON ( R3 ) z ;
-N (R3) COR3; CN; -NOz; -N (R3) z; -OR6; -SR6; (CHz) qOR6;
30 (CHz) qSR6; straight chained or branched Cl-C~ alkyl,
monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or
carboxamidoalkyl; straight chained or branched Cz-C~
alkenyl, Cz-C~ alkynyl; C3-C~ cycloalkyl,
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monofluorocycloalkyl, polyfluorocycloalkyl or
cycloalkenyl;
wherein R6 is. -H; straight chained or branched C1-C~
alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C~-C~ alkenyl or alkynyl; C3-C-,
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl; -N (R3) ~; -OR3; - (CHI) POR3; -COR3; -C02R3;
-OCOR3; -CON(R3)a; -N(R3)COR3; aryl, benzyl or heteroaryl,
optionally substituted with one or more F; Cl; Br; I;
COR3 ; C02R3 ; - OCOR3 ; - CON ( R3 ) ~ ; -N ( R3 ) COR3 , CN ; -NOa ;
-N (R3) a; -OR3; -SR3; (CHZ) qOR3; (CHZ) qSR3; straight chained
or branched C1-C~ alkyl, monofluoroalkyl,
polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; aryl;
benzyl; straight chained or branched C2-C~ alkenyl, CZ-C~
alkynyl; C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
wherein 2 is CO, SOZ or SO~NR6;
wherein each m is independently an integer from 0 to 3
inclusive;
wherein each' n is independently an integer from 0 to 5
inclusive;
wherein each p is independently an integer from 1 to 7
inclusive; and
wherein q is an integer from 1 to 3 inclusive;
or a pharmaceutically acceptable salt thereof.
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As used in the present invention, the term "cycloalkyl"
includes C3-C~ cycloalky moities which may be
substituted with one or more of the following: F; CN;
-N02; straight chained or branched Cl-C~ alkyl, straight
chained or branched C1-C~ monofluoroalkyl,straight
chained or branched C1-C~ polyfluoroalkyl, straight
chained or branched CZ-C~ alkenyl, straight chained or
branched Cz-C~ alkynyl; C3-C~ cycloalkyl, C3-C~
monofluorocycloalkyl, C3-C~ polyfluorocycloalkyl, C5-C~
cycloalkenyl, -N (R3) 2; -OR3; -NCOR3; -COR3; -COaR3;
-CON (R3) ~ Or (CHz) p-O- (CH3) n,-CH3.
In the present invention, the term "cycloalkenyl"
includes CS-C~ cycloalkenyl moities which may be
substituted with one or more of the following: -F;
-C1; -Br, -I; CN; -NO~; straight chained or branched
C1-C~ alkyl, straight chained or branched C1-C~
monofluoroalkyl, straight chained or branched C1-C~
polyfluoroalkyl, straight chained or branched C2-C~
alkenyl, straight chained or branched Ca-C~ alkynyl; C3-C~
cycloalkyl, C3-C~ monofluorocycloalkyl, C3-C~
polyfluorocycloalkyl, C5-C~ cycloalkenyl, -N (R3) ~; -OR3;
-NCOR3; -COR3; -CO~R3; -CON (R3) 2 or (CHz) p-O- (CH3) m-CH3.
As used in the present invention, the term "heteroaryl"
is used to include five and six membered unsaturated
rings that may contain one or more oxygen, sulfur, or
nitrogen atoms. Examples of heteroaryl groups include,
but are not limited to, furanyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, triazzolyl, thiadiazolyl,
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pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and
triazinyl.
In addition, the term "heteroaryl" is used to include
fused bicyclic ring systems that may contain one or more
heteroatoms such as oxygen, sulfur and nitrogen.
Examples of such heteroaryl groups include, but are not
limited to, indolizinyl, indolyl, isoindolyl,
benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,
benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl,
benzo[b]thiazolyl, imidazo[2,1-b]thiazolyl, cinnolinyl,
quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,
pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and
2,1,3-benzothiazolyl.
The term "heteroaryl" also includes those chemical
moieties recited above which may be substituted with one
or more of the following: -F; -C1; -Br, -I; CN;
-NOz; straight chained or branched C1-C~ alkyl, straight
chained or branched C1-C~ monofluoroalkyl, straight
chained or branched C1-C-, polyfluoroalkyl, straight
chained or branched Cz-C~ alkenyl, straight chained or
branched Cz-C~ alkynyl; C3-C~ cycloalkyl, C3-C~
monofluorocycloalkyl, C3-C~ polyfluorocycloalkyl, CS-C~
cycloalkenyl, -N (R3) z; -OR3; -NCOR3; -COR3; -COzR3; -
CON (R3) z Or (CHz) p-O- (CH3) m-CH3 .
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In still another embodiment of the above described
invention, the compound has the structure:
H O
R / ~NwS~R 6
'\
V nN
R
y H
R N~C~R6
/ ,,/ ;
V nN
R.
Y H O
R N~IS~R6
W nN / '~ ~ ; o r
V
R
y H
R wC~R6
W / ' ,
nN
V R.
Y
In a further embodiment of the instant invention, R6 is
straight chained or branched Cl-C~ alkyl; C3-C~
cycloalkyl; -N (R3) 2; -OR3; - (CHZ) POR3; aryl, benzyl or
heteroaryl, optionally substituted with one or more F;
C1; Br; I; -OR3; .- (CHZ) qOR3; or straight chained or
branched Cl-C~ alkyl.
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In an embodiment of the present invention, the
compound has the structure:
0
R N~I I/' R6
S
Or
N
O
I R
O
H
R ~ N~C~ R6
,,e .
N
0
I R
O
5 In a further embodiment of the present invention, at
least one V is phenyl optionally substituted with one or
more F; Cl; Br; -OR3; (CH~)qOR3; straight chained or
branched Cl-C-, alkyl; C1-C~ polyfluoroalkyl; or phenoxy.
10 In one embodiment of the present invention, the compound
is:
N
N
,O. O
In one embodiment, the compound is:
N
CI ~ ~ N
15 O O
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In one embodiment, the compound is:
O N
O ~ ~ HN
~O O
In another embodiment of the present invention, the
compound has the structure:
O
R
S
or
v N
0
OR3
H
R N~C~ R6
O
v
OR3
In a further embodiment of the present invention, at
least one V is phenyl optionally substituted with one or
more F; Cl; Br; -OR3; (CH2)qOR3; straight chained or
branched C1-C~ alkyl; C1-C~ polyfluoroalkyl; or phenoxy.
In another embodiment of the present invention, the
compound is
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In one embodiment, the compound is
In a further embodiment of the present invention, the
compound has the structure:
O
R N~~~~R6
S
or
V N
O
ov
H
R N~C~R6
V N
0
OV
In another embodiment of the present invention, at least
one V is phenyl optionally substituted with one or more
F; Cl; Br; -OR3; -COR3; (CHz) qOR3; straight chained or
branched C1-C~ alkyl; C1-C~ polyfluoroalkyl; aryl or
phenoxy.
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In yet another embodiment of the present invention,
the compound is
In one embodiment, the compound is
In one embodiment, the compound is
In one embodiment, the compound is
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In one embodiment, the compound is
In one embodiment, the compound is
O
O; N
O
HN /
In an embodiment of the present invention, the compound
has the structure:
0
R N~~I~R6
' or
V n N
U
R
H
R . N~ ~R6
C
N / ~~
V n
R
10~
In a further embodiment of the present invention, at
least one V is phenyl optionally substituted with one or
more F; C1; Br; -OR3; (CH2)qOR3; straight chained or
branched C1-C~ alkyl; C1-C~ polyfluoroalkyl; or phenoxy.
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In yet another embodiment of the present invention, the
compound is
5 In one embodiment, the compound has the structure:
In one embodiment, the compound has the structure:
In one embodiment, the compound has the structure:
J-H
20
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In one embodiment, the compound has the structure:
O
~ _
CI CI
In one embodiment, the compound has the structure:
In one embodiment, the compound has the structure:
N
N-H
N O
I , \
In one embodiment, the compound has the structure:
N
N-H
N'N CI
O
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In one embodiment, the compound has the structure:
J-H
F
In an additional embodiment of the present invention, Y
is hydrogen and V is phthalimide.
In an additional embodiment of the present invention, R6
is straight chained or branched C1-C~ alkyl; C3-C~
cycloalkyl; -N(R3)2; -OR3; -(CH~)pOR3; aryl, benzyl or
heteroaryl, optionally substituted with one or more F;
Cl; Br; I; -OR3; -(CH2)qOR3; or straight chained or
branched C1-C~ alkyl.
In a further embodiment of the present invention, the
compound is
_.. . ~ . ..
.. . . ~ . ~ ~ o ~ . .
~ ~N O
H
N N a
O
In one embodiment, the compound has the structure:
/ N Rs
i
"N
. U ~ 'R
N~
NH
V
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In one embodiment of the compound, at least one V is
phenyl or heteroaryl optionally substituted with one or
more F; Cl; Br; I; RS; -ORS; - (CHZ) qORS; - (CH2) qRS;
straight chained or branched Cl-C~ alkyl; Cl-C~
monoflouroalkyl or polyflouroalkyl; or phenoxy.
In one embodiment, the compound has the structure:
~N
N,N-H W I N~H
I
NJ O
In one embodiment, the compound has the structure:
R
O --~ N R6
R5~ n N ~ ~ O
eN R
H V
In one embodiment of the compound, V is phenyl which is
optionally substituted with one or more F; C1; Br; -ORS;
- ( CH2 ) qORS ; - ( CHz ) qR5 ; straight chained or branched C1-C~
alkyl ; C1-C~ monoflouroalkyl or polyf louroalkyl ; ~ or
phenoxy.
In one embodiment, the compound has the structure:
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In one embodiment, the compound has the structure:
H
i
R / N Rs
N ~ / O
X Ft
Y
In one embodiment, the compound has the structure:
R H
i
N R6
nN ~ / O
VZN
In one embodiment, the compouiZd has the structure:
~-H
In one embodiment, the compound has the structure:
R H
N R6
H nN ~ / O
R5~N
R
O
In one embodiment of the compound, R5 is straight chained
or branched C1-C~ alkyl; C3-C~ cycloalkyl;
-N (Rs) z: -OR6; - (CHz) qOR6; -CH (R6) z 1 - (CHz) qRs : or aryl,
benzyl or heteroaryl, wherein the aryl, benzyl or
heteroaryl is optionally.substituted with one or' more F;
C1; I; R6; -N (R6) z; -OR6; - (CHz) qOR~; - (CHz) qR6.; or straight
chained or branched Cl-C~ alkyl.
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In one embodiment, the compound has the structure:
~ HN~N ~ / O
N
'p H
In one embodiment, the compound has the structure:
CI N1O N
N
NH H
CI O
5
In one embodiment of the compound, X is hydrogen and Y
is carbazole optionally substituted with one or more F;
C1; Br; R5; -ORS; - (CH2) qORs; - (CHZ) qRs ; straight chained
or branched Cl - C~ alkyl; or C1-C~ monoflouroalkyl or
10 polyflouroalkyl; or phenoxy.
In one embodiment, the compound has the structure:
,H
N \ / N
i O
N
15 In one embodiment, the compound has the structure:
N
O
H~N
N~
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In one embodiment of the compound, Y is hydrogen and
V is an indole, which can be optionally substituted with
one or more F; C1; Br; Rs; -CO~Rs; -ORs; -(CHa)qORs; -
(CH2? qRs: straig~.t chained or branched C1 - C~ alkyl; C1-C~
monoflouroalkyl or polyflouroalkyl; or phenoxy on the 1,
2, 3, 4 , 5, 6 or 7 positions.
In one embodiment, the compound has the structure:
R
N
n
R N-H
0
In one embodiment, the compound has the structure:
In one embodiment, the compound has the structure':
N
N.H
N O
In one embodiment, the compound has the structure:
_ N \
CI \ ~ ~ N-H
N-H O
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In one embodiment, the compound has the structure:
In one embodiment, the compound has the structure:
_ N
N~H
N O
w
In one embodiment, the compound has the structure:
In one embodiment, the compound has the structure:
/
N-H
In one embodiment, the compound has the structure:
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In one embodiment, the compound has the structure:
O~ _
N ~ ~ .H
N N
O
H/
a
In one embodiment, the compound has the structure:
R
nN
N,H
N
In one embodiment, the compound has the structure:
N
I O N~H
N
a
In one embodiment, the compound has the structure:
N S
N-H
I ~ ~ O
N
,\
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In one embodiment, the compound has the structure:
N \ /
N-H
I \ / O
N
O-
In one embodiment, the compound has the structure:
-I
O
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The present invention provides a compond having the
srucuture:
X X
R
X N
R1 ~ ~ 1
Rz ~~~ Rz Rz ~~~ Rz
q ~ q
Rs R4 Rs R4
X
or / R1
N
I
Rz '.~.~ q Rz
5 Rs R4
wherein each X is independently O or S;
wherein q is 1 or 2;
10 wherein each RZ is independently H; - (CHz) tXR3;
- (CHZ) tC (X) N (R3) 2; - (CHI) tCO2R3; -COZR3; straight cliained or
branched C1-C~ alkyl optionally substituted with
-N (R3) z; -CON (R3) 2 or -N (R3) C (0) R3; straight chained or
branched Cz-C~ alkenyl, or alkynyl; or C3-C~ cycloalkyl or
15 Cs-C~ cycloalkenyl;
wherein each t is independently an integer from 1 to 4
inclusive;
20 wherein each R3 is independently H; straight chained or
branched Cl-C., alkyl, straight chained or branched Cz-C~
alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C~
cycloalkenyl;
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wherein R4 is aryl, heteroaryl, C1-C~ alkyl substituted
with one or two aryl, or C1-C~ alkyl substituted with one
or two heteroaryl; wherein the aryl or heteroaryl may be
substituted with one or more of F, Cl, Br, I,
-CN, -NOz, -N (R3) z ~ -COR3, - (CHz) nXR3 i - (CHz) nC (X) NR3
- (CHz) nN (R3) C (X) R3, - (CHz) llCOzR3, - (CHz) nOCOR3, Straight
chained or branched Cl-C~ alkyl, monofluoroalkyl OR
polyfluoroalkyl or straight chained or branched Cz-C~
aminoalkyl, alkenyl or alkynyl, or C3-C~ cycloalkyl or
CS-C~ cycloalkenyl;
wherein each n independently is an integer from 0 to 7
inclusive;
wherein R5 is H; aryl, C1-C~ alkyl substituted with aryl,
heteroaryl, or C1-C~ alkyl substituted with heteroaryl;
wherein the aryl or heteroaryl may be substituted with
one or more of F, C1, Br, I, -CN, -NOz, -N (R3) z, -COR3, -
(CHz) nXR3, - (CHz) nC (X) NR3, - (CHz) nCO2R3, straight chained or
branched C1-C~ alkyl, monofluoroalkyl, polyfluoroalkyl or
carboxamidoalkyl, or straight chained or branched Cz-C~
aminoalkyl, alkenyl or alkynyl, or C3-C~ cycloalkyl or
C,-C~ cycloalkenyl;
where RS and one Rz on adjacent carbon atoms together may
form aryl, heteroaryl, indane or tetrahydronaphthyl, C3-
C~ cycloalkyl, or heterocycloalkyl wherein. one or two
heteroatoms may be O, N or S; .
wherein R1 is
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52
Rs
s
Rs m ~V/Y'B/R , or
/Z-N . ,
m R7
Rs
Rs
R~
Rs ~'~ / Re
B
Z-
RE
Rs
- . . ,
wherein- each V is independently aryl, phens~xy or
heteroaryl, wherein the aryl, phenoxy or heteroaryl is
optionally substituted with one or more F; Cl; Br; I;
CORS; C02R5; ~ -OCORS; -CON (R5) z.; -N (R5) CORS; CN; -N02; -
N (R5) 2; -ORS; -SRS; (CHz) qORS; (CH2) qSRs; straight chained
or branched C1-C~ alkyl optionally substituted with -
CON (RS) z, -N (RS) C (0) R3 or N (R3) z, straight chaff ned or
branched monofluoroalkyl or polyfluoroalkyl, straight
chained or branched Cz-C~ alkeny:l, C2-C~ alkynyl;
phenoxy; or C3-C~ cycloalkyl, monofluorocycloalkyl,
polyfluorocycloalkyl or cycloalkenyl;
wherein each R6 is independently H; (CHz) tXR3;
2 0 ( CHz ) cC ( X ) NRa . ( CHz ) tN ( Ra ) C ( X ) Ra ; ( CHz ) tCOzR3 : (
CHz ) r.OCOR3 ;
straight chained or branched Cl-C~ alkyl optionally
substituted with -CON(R3)z or -NC(O)R3; straight chained
or branched Cz-C~ alkyl substituted with -N(R3)z; straight
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chained or branched Cz-C-, alkenyl or alkynyl; or C3-C~
cycloalkyl or C5-C~ cycloalkenyl;
where each R~ is independently H; F; C1; Br; I; -COR3; -
COZR3; - (CHz) nXRa; - (CHz) nN (R3) C (0) R3; (CHz) nC (X) N (R3) z; -
(CHz)~nCO2R3; -CN; -NOz; -N (R3) z; straight chained or
branched C1-C~ alkyl, hydroxyalkyl, aminoalkyl,
carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or
polyfluoroalkyl; straight chained or branched Cz-C~
alkenyl or alkynyl; C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or C5-C~
cycloalkenyl, wherein the alkyl, aminoalkyl,
carboxamidoalkyl., hydroxyalkyl, alkoxyalkyl, alkenyl,
alkynyl, cycloalkyl or cycloalkenyl may be substituted
with one or more ar~.~1 or heteroaryl, wherein the aryl or
heteroaryl may be substituted with one or more of F, C1,
Br, I, - (CHz) nXRa ~ -COR3, - (CHz) nC (X) N (R3) z ~ - (CHz) nCOzR3, -
CN, -NOz, - (CHz) nN (R3) C (O) R3; -N' (R3) z, -SO2R3, straight
chained or branched Cl-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl, straight chained or branched Cz-C~
alkenyl or alkynyl, or C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or C5-C~
cycloalkenyl; aryl or heteroaryl, wherein the aryl or
heteroaryl may be substituted with one or more of F, C1,
Br, I, - (CHz) nXR3, -COR3, - (CHz) nC (X) N (R3) z
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- (CHZ) nCO~R3, - (CH2) nN (R3) C (O) R3 ~ -CN, -NO2.
-N (R3) 2, -SOzR3, straight chained or branched C1-C~ alkyl,
straight chained or branched C1-C~ monofluoroalkyl or
polyfluoroalkyl, straight chained or branched CZ-C~
alkenyl or alkynyl, or C3-C~ cycloalkyl,
monofluorocycloalkyl, polyfluorocycloalkyl or C5-C~
cycloalkenyl;
wherein B is CO, S02 or SO2NR6;
wherein R8 is -H; straight chained or branched C1-C~
alkyl, monofluoroalkyl or polyfluoroalkyl; straight
chained or branched C2-C~ alkenyl or alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl
or cycloalkenyl; -N (R3) 2; -NR3C (O) R3; -OR3; - (CH~)pOR3; -
COR3; -CO~R3; -OCOR3;-CON(R3)~; aryl or heteroaryl,
optionally substituted with one or more F; Cl; Br; I;
COR3; COzR3; -OCOR3; -NR3C (O) R3; -CON (R.3) ~; CN; -N02; -
N ( R3 ) ~ ; -OR3 ; - SR3 ; ( CHI ) qOR3 ; ( CH2 ) qSR3 ; straight chained
or branched Cl-C~ alkyl optionally substituted with
CON (R3) 2, -NR3C (O) R3 or -N (R3) 2; straight chained or
branched monofluoroalkyl, polyfluoroalkyl; straight
chained or branched C~-C~ alkenyl, C~-C~ alkynyl; C3-C~
cycloalkyl, monofluorocycloalkyl, po7.yfluorocycloalkyl
or cycloalkenyl;
wherein each m independently is an integer from 0 to 3
inclusive;
wherein Z is
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O Rz Rs
R9
t t
Y I ~n
Rz Rs
R9
Rz Rs
t R9 t
n
Rz ~ Rs
R9
O
Rz Rs
R9
t t
'n
Rz ~ Rs
R9
Rs O R9
Rz Rs
t n
s
Rs Y ~ t R9 ~ t
R2 Rs
Rz
O R
9
n m ~R9
y ~ n
Rz m Rs
R9
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R Rs
6
m ~R10
-N ~ a_
R
R6 R6 RS 6
O R2 R6
R2 R9
yt yte or
n '
R2 R6
R~ R9
or C2-C~ alkenyl, wherein the C2-C~ alkenyl may be
unsubstituted or substituted with one or more R9 groups;
wherein each R9 is independently H; F; C1; Br; I;
- (CHZ) mXR3; (CHz) ",C (X) NR3; (CHz) mCOzR3; straight chained or
branched Cl-C~ alkyl, monofluoroalkyl, polyfluoroalkyl,
aminoalkyl, or carboxamidoalkyl; straight chained or
branched Cz-C-, alkenyl, or alkynyl; or C3-C-, cycloalkyl or
CS-C~ cycloalkenyl;
O R~ R
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wherein Rlo is H; (CHz) tXR3; (CHz) tC (X) NR3; (CHz) tCOzR3;
straight chained or branched Cl-C~ alkyl,
carboxamidoalkyl; straight chained or branched Cz-C.,
aminoalkyl, alkenyl,.or alkynyl; or C3-C~ cycloalkyl or
Cs-C~ cycloalkenyl;
wherein Y is S, O, or NRlo:
wherein each p is independently an integer from 1 to 7
inclusive;
or a pharmaceutically acceptable salt thereof.
In a further embodiment of the present invention, the
compound has the following structure:
X X
.o Rl ' .~ Rl
X _N N _N
R ~~~~ R or_ R -o° ~~ R
2 ~ ~ Z 2 ~ 2
H
Rs R4 Rs R4
In an additional embodiment of the present invention,
the compound has the structure:
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O Rs
O ~ R~
N-Z-N
R v/Y~Rs : or
Ra Ra Rs Rs 0O
O Rs
O ~R~
N-Z-N ~ O
Rz V/Y~SI/Re
RZ R R6~ II
a Rs O
In an additional embodiment of the present invention,
the compound has the structure:
0
0
~N-Z-N
~ / N\ /Re
Rz
Rz 'R4 ~ / O
In one embodiment of the present invention, Z is:
O R2 R6
R9
t t
Y n '
20
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In one embodiment of the present invention, Z is:
F
_ \ F
O
N N
~~''N
O~ N NN
O
In an additional embodiment of the present .invention,
the compound has the structure:
R9
Rs
In one embodiment of the present invention, the compound
has the strucuture:
F
F
N N
~ I
O~O ~ ~ N
O
20
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This invention provides a compound having the structure:
A
R~ X~N
~n ,
R3 ~N-H
O
R2
wherein R1 is hydrogen, straight chained or branched
5 C1-C~ alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or
heteroaryl, wherein the aryl or heteroaryl is optionally
substituted with one or more -F, -C1, -Br, =I, -CN,
-N02, -CH3, -CF3, -COCH3, -COaR2, phenyl, phenoxy or
straight chained or branched Cl-C~ alkyl;
wherein RZ is straight-chained or branched C3-C4 alkyl or
cyclopropyl;
wherein R3 is aryl or heteroaryl, wherein the aryl or
heteroaryl is optionally substituted with one or more
-F, -C1, -Br, -I, -CN, -N02, straight chained or
branched C1-C~ alkyl;
wherein A is -H, -F, -Cl, -Br, -CN, -N02, -COR3, -CO2R3,
straight chained or branched C1-C~ alkyl, monofluoroalkyl
or polyfluoroalkyl;
wherein X is O or NH;
wherein n is an integer from 0 to 5 inclusive;
In one embodiment, R1 is aryl optionally substituted with
one or more -F, -Cl, -Br, -I, -CN, -N02, -COCH3,
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-COZR~, straight chained or branched C1-C~ alkyl;
wherein R3 is phenyl;
wherein A is H; and
wherein X is 0.
In one embodiment, Rz is isopropyl.
In a preferred embodiment, X is NH, R1 is alkyl and n is
1 or 2.
In the most preferred embodiment, X is O, R1 is 3-acetyl
phenyl, R2 is isopropyl, R3 is phenyl and n is 1.
In one embodiment, the compound has the structure:
O
N
N
O
In one embodiment, compound has the structure:
0-
O: N
N
O-
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In one embodiment, R1 is hydrogen, straight chained
or branched C1-C~ alkyl; and wherein R3 is aryl.
In one embodiment, R~.is isopropyl; and A is hydrogen.
In one embodiment,. the compound has the structure:
O N
N
O
In one embodiment, the compound has the structure:
HO
The present invention also provides a compound having
the structure:
A
wherein R1 is aryl or heteroaryl optionally substituted
with one or more -F, -Cl, -Br, -I, -CN, -NOz, -OCH3,
phenoxy, fused cyclopentanyl, straight chained or
branched C1-C-, alkyl, monofluoroalkyl or polyfluoroalkyl;
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wherein R~ is straight-chained or branched C1-C4 alkyl or
cyclopropyl;
wherein A is -H, -F, -C1, -Br, -CN, -N02, straight
chained or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; and
wherein n is an integer from 1 to 5 inclusive.
In one embodiment, R~_ is aryl optionally substituted with
one or more -F, -C1, -Br, -I or straight chained or
branched C1-C4 alkyl ; and
wherein A is H.
In one embodiment, Rz is isopropyl; and
wherein n is 2.
In a preferred embodiment, n is 2 and Rz is isopropyl.
In one embodiment, the compound has the structure:
l
N
N
O O
In one embodiment, the compound has the structure:
N
CI ~ ~ N
O O
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In one embodiment, the compound has the structure:
O
O
N N
In one embodiment, R1 is thienyl; and wherein A is H.
In one embodiment, RZ is isopropyl.
In one embodiment, the compound has the structure:
O i
w ~ / o
g N N
The invention provides a compound having the structure:
A
_I_
w N \ / .
N-H
O
R2
wherein W is
H A
N R~ ~
wherein each R1 is independently hydrogen, methyl or
ethyl;
wherein Rz is straight-chained or branched C3-C4 alkyl or
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wherein Rz is straight- chained or branched C3-C4
alkyl or cyclopropyl;
wherein R3 is hydrogen, aryl or heteroaryl, wherein the
5 aryl or heteroaryl is optionally substituted with one or
more -H, -F, -C1, -Br, -I, -CN, -N02, straight chained
or branched C1-C~ alkyl.
wherein each A is independently -H, -F, -C1, -Br, -CN,
10 -NO2, -COR3, -COaR3, straight chained or branched C1-C~
alkyl, monofluoroalkyl or polyfluoroalkyl;
wherein X is O, NR3, CO or may be absent; and
15 wherein Y is hydrogen, aryl or heteroaryl, wherein the
aryl or heteroaryl is optionally substituted with one or
more -F, -C1, -Br, -I, -CN, -NOZ, straight chained or
branched C1-C~ alkyl.
20 In one embodiment, W is
H A
X-Y
H
and wherein X is O or may be absent.
25 In one embodiment, R2 is isopropyl.
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In one embodiment, the compound has the structure:
N \ /
O
\ / N
O
/ \
F F
In one embodiment, the compound has the structure:
In one embodiment, W is
N R~
R~
In one embodiment, A is -H, -F, -C1, -Br.
In one embodiment, R~ is isopropyl; and A is hydrogen.
In one embodiment, the compound has the structure:
N
~ ~ / ~ N O
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This invention provides a compound having the structure:
W
A
-H
wherein W is
B
B~, ~ ~>g I ~ y B
or ~
~~N
R~
wrerein R1 is hydrogen, straight chained or branched
C1-C~ alkyl, aryl or heteroaryl, wherein the aryl or
hete.roaryl is optionally substituted with one or more
-F, -Cl, -Br, -CN, -NO2, -OCH3, -C02CH3, -CF3, phenyl,
'straight chained or branched Cl-C~ alkyl;
wherein RZ is straight-chained or branched C3-C4 alkyl or
cyclopropyl;
wherein A is -H, -F, -Cl, -Br, -CN, -N02, -COR1, -CO~R1,
straight chained or branched C1-C~ alkyl, monofluoroalkyl
or polyfluoroalkyl or phenyl.
wherein each B is independently -H, -F, -Cl, -Br, -I,
-CN, -N02, -COR1, -C02R1, -OCH3, -OCF3, -CF3, straight
chained or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl or aryl, phenoxy or benzyloxy, wherein
the aryl, phenoxy or benzyloxy is optionally substituted
with one or more -F, -C1, -Br, -CN, -N02, -COR1, -CO~Rl,
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-OCH3, -OCF3, -CF3 or straight chained ~ or
branched C1 -C3 alkyl,
In one embodiment, W is
B~ ~ ~~B
N
R~ .
In one embodiment, R1 is hydrogen or phenyl optionally
substituted with one or more -F, -C1, -Br, -CN, -NO~,
straight chained or branched C1-C~ alkyl.
In one embodiment, R~ is isopropyl.
In one embodiment, the compound has the structure:
N
N
\ o
CI ~ N
In one embodiment, the compound has the structure:
N
N
w U
N
f
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This invention provides a compound having the structure:
A
nN
R3 \ ' ~ R4
N O
R~ R2
wherein R1 is hydrogen, straight chained or branched
C1-C~ alkyl, aryl or heteroaryl, wherein the aryl or
heteroaryl is optionally substituted with one or more
-F, -C1, -Br, -CN, -N02, -CF3, -OCH3, straight chained or
bunched C~-C3 alkyl;
wherein Rz is straight-chained or branched C3-C4 alkyl or
cyclopropyl;
wherein R3 is -H, -F, -Cl, -Br, -I, -CN, -NO~, -CF3,
-OCH3, or straight chained or branched C1-C3 alkyl,
monofluoroalkyl or polyfluoroalkyl, or a phenyl ring
fused to C6 and C~ of the indole moiety;
wherein Ra is hydrogen or aryl optionally substituted
with one or more =F, -C1, -Br, -I, -CN, -N02, -CF3,
straight chained or branched C1-C3 alkyl;
wherein A is -H, -F, -Cl, -Br, -CN, -N02, straight
chained or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl; and
wherein n is an integer from 2 to 4 inclusive.
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In one embodiment, R3 is - H, -F, -Cl, -Br, -I, -CN, -
NO2 , -OCF3 or -OCH3 ; and
wherein R4 is hydrogen or phenyl optionally substituted
5 with one or more -F, -Cl or -CF3.
In one embodiment, R1 is hydrogen or phenyl optionally
substituted with one or more -F, -Cl, -Br, -CN, -NO~,
-CF3, -OCH3 or straight chained or branched C1-C~ alkyl;
In one embodiment, R2 is isopropyl.
In one embodiment, the compound has the structure:
..
N
N
O
O ja
I
N
In one embodiment, the compound has the structure:
FF
FRO
N N
~ ~ ~J O
CI
In one embodiment, the compound has the structure:
~ ~ .
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This invention provides a compound having the structure:
A
R1 R3 ~N ~
R1
~N X N-H
O
R2
wherein each R1 is independently hydrogen or CH3;
wherein RZ is straight-chained or branched Cl-C4 alkyl or
cyclopropyl;
wherein R3 is benzyl or phenyl, wherein the benzyl or
1p phenyl is optionally substituted with a methylenenedioxy
group .or-one or more -F or -C1;
. wherein A is -H, -F, -Cl, -Br, -CN, -NOa, straight
chained or branched C1-C~ alkyl, monofluoroalkyl or
polyfluoroalkyl;
wherein X is (CH2) 2, COCH2 or CONH;
.In one embodiment, R3 is phenyl optionally substituted
with one or more -F; and
wherein A is hydrogen.
In one embodiment, X is CONH.
In one embodiment, Ra is methyl.
In one embodiment, the compound has the structure:
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F ~ F
O
~ O
~N~N~~N
O~ ~ N
O
In one embodiment, the compound has the structure:
F
YW
R1 R~ Y~N
O~N_X ~ _H
O
O
wherein each Y is independently hydrogen or -F.
Tn one embodiment, the compound has the structure:
F
F ~ F
~/
O
~ O
~N~N~N
N
O
In one embodimerit, the compound has the structure:
F
~~ F
/
IOI
N~N~N O I
O~ N
O
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In one embodiment, R3 is benzyl optionally substituted
with a methylenedioxy group or one or more -F or -Cl.
In one embodiment, the compound has the structure:
H
wherein each Y is independently hydrogen or -F.
In one embodiment, the compound has the structure:
F
IOI
N~N/~/~N O
O \\ N
O
In one embodiment, the compound is enantiomerically
pure.
In one embodiment, the compound is diastereomerically
pure.
In one embodiment, the compound is enantiomerically and
diastereomerically pure.
This invention also provides a pharmaceutical
composition comprising a therapeutically amount of a
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compound of the invention and a pharmaceutically
acceptable carrier.
In_ one embodiment, the amount of the compound is from
about O.Olmg to about 500mg.
In one embodiment, the amount of the compound is from
about O.lmg to about 60mg.
In one embodiment, the amount of the compound is from
about lmg to about 20mg.
In one embodiment, the pharmaceutical composition
consists of_ a carrier which is a liquid and the
composition is a solution.
In one embodiment, the pharmaceutical composition
consists of a carrier which is a solid and the
composition is a tablet.
In one embodiment, the pharmaceutical composition
consists of a carrier which is a gel and the composition
is a suppository. .
The invention also provides a process for making a
pharmaceutical composition comprising admixing a
therapeutically effective amount of the compound of any
of the invention and a pharmaceutically acceptable
'carrier.
This invention also provides the method of treating a
subject suffering from a disorder selected from the
group consisting of depression, anxiety, urge
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incontinence, or obesity comprising administering to
the subject a therapeutically effective amount of the
compound of the invention.
5 In one embodiment, the therapeutically effective amount
is. between about 0.03 and about 1000 mg per day.
In one embadiment, the therapeutically effective amount
is between about 0.30 and about 300 mg per day.
In one embodiment, the therapeutically effective amount
is between about 1.0 and about 100 mg per day.
In one embodiment, the disorder is depression. _
. . , .
In one embodiment, the disorder is anxiety.
In one embodiment, the disorder is obesity.
In one embodiment, the disorder is urge incontinence.
The invention provides the method of reducing the body
mass of a subject, which comprises administering to the
subject an amount of a compound of the invention
effective to reduce the body mass of the subject.
The invention provides the method of treating a subject
suffering from depression, which comprises administering
to the subj ect an amount of a compound of any of claims
of the invention effective to treat the subject's
depression.
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The invention provides the method of treating a
subject suffering from anxiety, which comprises
administering to the subject an amount of a compound of
the invention .effective to treat the subject's anxiety.
5:
The 'invention provides the method of alleviating urge
urinary incontinence in a subject suffering from an
overactive bladder, which comprises administering to the
subject an amount of the compound of the invention
effective to alleviate the subject's urge urinary
incontinence.
The inventiori-provides the method of managing obesity in
a subject in need of weight loss, which comprises
administering to the subj ect an amount of a compound of
'the invention effective to induce weight loss in the
subject.
The invention provides the method of managing obesity in
a subject who has experienced weight loss, which
comprises administering to the subject an amount of a
compound of the invention effective to maintain such
weight loss in the subject.
The inventibn provides the method of treating overactive
bladder in a subject, which comprises administering to
:the subject an amount of a compound of any of the
invention effective to treat the subject'.s overactive
bladder.
The invention provides the method of treating a disorder
in a subject, wherein the symptoms of the subject can be
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alleviated by treatment with an MCH1 antagonist,
wherein the MCH1 antagonist is the compound of the
invention.
The invention provides the method of. alleviating the
symptoms of a disor4der in a subject, which comprises
administering to the subject an amount sof an MCH1
antagonist effective to alleviate the symptoms,~wherein
the MCH1 antagonist is the compound of the invention
As used in the present invention, the term "heteroaryl"
is used to include five and six membered unsaturated
rings that may contain one or more oxygen, sulfur, or
nitrogen. atoms. Examples of heteroaryl groups include,
but are not limited to, carbazole, furanyl, thi.enyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,
isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, and triazinyl.
In addition, the term "heteroaryl" is used to include
fused bicyclic ring systems that may contain one or more
heteroatoms such as oxygen, sulfur and nitrogen.
Examples of such,heteroaryl groups include, but are not
limited to, indolizinyl, indolyl, isoindolyl,
benzo [b] furanyl, benzo [b] thiophenyl, i.ndazolyl,
benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl,
benzo [b] thiazolyl, imidazo [2, 1-b] thiazolyl,. cinnolinyl,
quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,
pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and
2,1,3-benzothiazolyl.
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The term "heteroaryl" also includes those chemical
moieties recited above which may be substituted with one
or more of the following: -F, -CI, -Br, -I, CN, -N02,
straight chained or branched C1-C~ alkyl, straight
5~ ~ chained or branched C1-C~ monofluoroalkyl, straight
chained or branched C1-C~ polyfluoroalkyl, straight
chained or branched C2-C~ alkenyl, straight chained or
branched C2-C~ alkynyl; C3-C~ cycloalkyl, C3-C~
monofluorocycloalkyl, C3-C~ polyfluorocycloalkyl, C5-C~
cycloalkenyl,
The term °'heteroaryl" further includes the N-oxides of
those chemical moieties recited above which include at
least one nitrogen atom.
In the present invention, the term "aryl" is phenyl or
naphthyl.
The invention provides for each pure stereoisomer of any
of the compounds described herein. Such stereoisomers
may include enantiomers, diastereomers, or E or Z alkene
or imine isomers. The invention also provides for
stereoisomeric ' mixtures, including racemic mixtures,
diastereomeric mixtures, or E/Z isomeric mixtures.
25~ Stereoisomers can be synthesized in pure form (Nogradi;
' M.; Stereoselective Synthesis, (1987) VCH Editor Ebel,
H. and Asymmetric Synthesis, Volumes 3'B 5, (1983)
Academic Press, Editor Morrison, J.) or they.' can be
resolved by a variety of methods such as crystallization
and chromatographic techniques (Jaques, J.; Collet, A.;
Wilen, S.; Enantiomer, Racemates, and Resolutions, 1981,
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John Wiley and Sons and Asymmetric Synthesis, Vol.
2, 1983, Academic Press, Editor Morrison, J).
In addition the compounds of the present invention may
be present as enantiomers, diasteriomers, isomers or two
or~ more of the compounds may be present to, form a
racemic or diastereomeric mixture.
The compounds of the present invention are preferably
80% pure, more preferably 90% pure, and most preferably
95% pure. Included in this invention are
pharmaceutically acceptable salts and complexes of all
of the compounds described herein. The acids and bases
from which these salts are prepared include but, are not
limited to the acids and bases listed herein. The acids
include but are not limited to, the following inorganic
acids: hydrochloric acid, hydrobromic acid, hydroiodic
acid, sulfuric acid and boric acid. The acids include;
but are not limited to, the following organic acids:
acetic acid, malonic acid, succinic acid; fumaric acid,
tartaric acid, malefic acid, citric acid, methanesulfonic
acid, benzoic acid, glycolic acid, lactic acid and
mandelic acid. The bases include, but are not limited
to ammonia, methylamine, ethylamine, propylamine,
dimethylamine, ' diethylamine, trimethylamine,
triethylamine, ethylenediamine, hydroxyethylamine,
morpholine, piperazine .and guanidine. This invention
further provides'for the hydrates and polymorphs of all
of the compounds described herein.
The present invention includes within its scope prodrugs
of the compounds of the invention. In general, such
prodrugs will be functional derivatives of the compounds
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of the invention which are readily convertible in vivo
into the required compound. Thus, in the present
invention, the term "administering" shall encompass the
treatment of the various conditions described with the
5 compound specifically disclosed or with a compound which
may not be specifically disclosed, but which converts to
the specified compound in vivo after,administration to
" the patient. Conventional procedures for the selection..
and preparation of suitable prodrug derivatives are
. : ' 10 ' - 'described, for example, in Design of Prodrugs,. ed. .I3..
. ~' Bundgaard, Elsevier, 1985. . ..
The present invention further includes metabolites of
the compounds of the present invention. Metabolites
15 include active species produced upon introduction of
compounds of this invention into the biological milieu.
This. invention ~furtner provides a pharmaceutical
composition comprising a therapeutically effective
2.0 amount of the compound of the invention and a
pharmaceutically acceptable carrier. In one embodiment,
the amount of the compound is from about 0.01 mg to
about 8 0 0 mg . In another embodiment , the amount of the
compound is from about 0.01 mg to about 500 mg. In yet
25 another embodiment, the amount of the compound is from
about 0:1 mg to about 250 mg. In another embodiment,
the amount of the compound is from about 0.1 mg to about
60 mg. In yet another embodiment, the amount of the
compound is -from about 1 mg to about 20 mg. In a
30 further. embodiment, the carrier is a liquid and the
composition is a solution. In another embodiment, the
carrier is a solid and the composition is a tablet. In
another embodiment, the carrier is a gel and the
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composition is a capsule, suppository or a cream. In
a further embodiment the compound may be formulated as a
part of a pharmaceutically acceptable transdermal patch.
In yet a further embodiment, the compound may be
delivered to. 'the ' subject by means of a spray or
inhalant.
This invention a7_so provides a pharmaceutical
composition made by combining a therapeutically
effective amount of the compound of this invention and a
pharmaceut~_cally acceptable carrier.
.This ~inveritibn. provides a process for making a
pharmaceutical composition comprising combining a
therapeutically 'effective amount of the compound, of. this
invention and a pharmaceutically acceptable carrier.
A-solid carrier can include one or more substances which
may also act as .endogenous carriers (e.g. nutrient. or
micronutrient carriers), flavoring agents, lubricants,
solubilizers, suspending agents, fillers, glidants,
compression aids, binders or tablet-disintegrating
agents; it can also be an encapsulating material. In
powdexs~, the carrier is a finely divided solid which is
W adWixture with the finely divided active ingredient.
In tablets, - the active ingredient is mixed with a
carrier having the necessary compression properties in
suitable proportions and compacted in the shape and size
desired. The powders and tablets preferably contain up
to 99% of the active ingredient. Suitable solid carriers
include, for example, calcium phosphate, magnesium
stearate, talc, sugars, lactose, dextrin, starch,
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gelatin, cellulose, polyvinylpyrrolidine, low
melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions,
suspensions, emulsions, syrups, elixirs and pressurized.,
compositions . The active ingredient Can be dissolved or
suspended in ~ a pharmaceutically acceptable liquid
carrier such as water, an organic solvent, a mixture of
bath or pharmaceutically acceptable oils or fats. The
liquid carrier can contain other suitable pharmaceutical
additives such as solubilizers, emulsifiers, buffers,
preservatives; s~nieeteners, flavoring agents, suspending
agents, thickening agents, coloring agents, viscosity
regulators, stabilizers or osmoregulators. Suitable;
.examples of liquid carriers for oral and parenteral
administration include water (partially containing
additives as above, e.g. cellulose derivatives,
preferably sodium carboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric
alcohols, e.g. glycols) and their derivatives, and oils
(e.~g. fractionated coconut oil and arachis oil). .For
parenteral administration, the .carrier can also be an
oily ester such as ethyl oleate or isopropyl myristate.
Sterile liquid carriers are useful in sterile liquid
form compositions for parenteral administration. .The
liquid carrier for pressurized compositions can be a
halogenated hydrocarbon or other pharmaceutically
acceptable propellent.
Liquid pharmaceutical compositions which are sterile
solutions or suspensions can be utilized by for example,
intramuscular, intrathecal, epidural, intraperitoneal or.
subcutaneous injection. Sterile solutions can also be
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administered intravenously. The compounds may be
prepared as a sterile solid composition which may be
dissolved or suspended at the time of administration
using sterile water, saline, or other appropriate
sterile injectable medium. Carriers are intended to
include,. necessary and inert binders, suspending agents,
lubricants, flavorants, sweeteners, preservatives, dyes,
and coatings. The compound can be administered orally
in- the form of a s_ile _ solution:;-~ or suspension- ,
containing other solutes or suspending agents (for
example, enough-saline or glucose to make the solution
isotonic), bil a salts, acacia, gelatin, sorbitan
monoleate, polysorbate 80 (oleate esters of sorbitol and
its anhydrides copolymerized with ethylene oxide) and
the lil~.e.
The compound can also be administered orally either in
liquid. or solid composition form. Compositions suitable
for oral administration include solid forms, such as
pills, capsules, granu_, tablets, and powders, and
liquid forms, such as solutions, syrups, elixirs, and
suspensions. Forms useful for parenteral administration
include -sterile olutions, emulsions, and suspenions.
Cp.timal dosages to be administered may be -determined by
those skilled in the art, and will vary with the
particular compound in use, the strength of the
preparation, the mode of administration, and the
advancement of the disease condition. Additional
factors depending on the particular subject being
treated will result is meed to adjust dosages,
including subject age, weight, gender, diet, and time of
administration.
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In the subject application a "therapeutically effective
amount" is any amount of a compound which, when
administered to a subject suffering from a disease
against which the compounds are effective, causes
reduction, remission, or regression of the disease. In
a subject application, a "subject" is a vertebrate, a
mammal or a human.
This invention provides a method of treating a subject
suffering from an abnormality wherein the abnormality i.s
alleviated by decreasing the activity of an MCH1
receptor which comprises administering to the subject an
amount of a compound of the invention which is an MCH1
receptor antagonist effective to treat the subject=s
abnormality.
In separate embodiments, the abnormality is a regulation
of a steroid or pituitary hormone disorder, an
epinephrine release disorder, a gastrointestinal
disorder, a cardiovascular disorder, an electrolyte
balance disorder, hypertension, diabetes, a respiratory
disorder, asthma, a reproductive function disorder, an
immune disorder, an endocrine disorder, a
musculoskeletal disorder, a neuroendocrine disorder, a
cognitive disorder, a memory disorder such as
Alzheimer=s disease, a sensory modulation and
transmission disorder, a motor coordination disorder, a
sensory integration disorder,. a motor integration
disorder, a dopaminergic function disorder such as
Parkinson=s disease, a sensory transmission disorder, an
olfaction disorder, a sympathetic innervation disorder,
an affective disorder such as depression and anxiety, a
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stress-related disorder, a fluid-balance disorder, a
seizure disorder, pain, psychotic behavior such as
schizophrenia, morphine tolerance, opiate addiction,
migraine or a urinary disorder such as urinary
5 incontinence.
The following description of depressive .and anxiety
disorders is for the purpose of illustrating the utility
of the compounds of this invention. The definitions of
10 depressive and anxiety disorders given below are those
listed in Diagnostic and Statistical Manual of Mental
Disorders. 4th ed. (DSM-IV; American Psychiatric
Association, 1994a) or Diagnostic and Statistical Manual
of Mental Disorders. 3rd ed. Revised (DSM-III-R;
15 American Psychiatric Association, 1987). Additional
information regarding these disorders can be found in
this reference, as well as the others cited below, all
of which are incorporated herein by reference.
20 Depressive disorders include major depressive disorder
and dysthymic disorder (American Psychiatric
Association, 1994a; American Psychiatric Association,
1994b). Major depressive disorder is characterized by
the occurrence of one or more major depressive episodes
25 without manic or hypomanic episodes. A major depressive
episode is defined as a prominent and relatively
persistent depressed or dysphoric mood that usually
interferes with daily functioning (nearly every day for
at least 2 weeks); it should include at least 4 of the
30 following 8 symptoms: change in appetite, change in
sleep, psychomotor agitation or retardation, loss of
interest in usual activities or decrease in sexual
drive, increased fatigue, feelings of guilt or
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worthlessness, slowed thinking or impaired
concentration, and a suicide attempt or suicidal
ideation (Medical Economics Company, 2002). Dysthymic
disorder involves a type of depression that is not
' severe enough to be called a major depressive episode,
but that lasts much longer than major depressive
disorder, without high phases.
It is contemplated that the compounds of this invention
will be effective in treating depression in patients who
have been diagnosed with depression by administration of
any of the following tests: Hamilton Depression Rating
Scale (HDRS), Hamilton depressed mood item, Clinical
Global Impressions (CGI)-Severity of Illness. It is
further contemplated that the compounds of the invention
will be effective in inducing improvements in certain of
the factors measured in these tests, such as the HDRS
subfactor scores, including the depressed mood item,
sleep disturbance factor and anxiety factor, and the
CGI-Severity of Illness rating. It is also contemplated
that the compounds of this invention will be effective
in preventing relapse of major depressive episodes.
Anxiety disorders include panic disorder, agoraphobia
with or without history of panic disorder, specific
phobia, social phobia, obsessive-compulsive disorder,
post-traumatic stress disorder, acute stress disorder
and generalized anxiety disorder. It is. contemplated
that the compounds of this invention will be effective
in treating any of all of these disorders in patients
who have been diagnosed with these disorders.
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Obsessive compulsive disorder is characterized
by recurrent and persistent ideas, thoughts, impulses or
images (obsessions) that are ego-dystonic and/or
repetitive, purposeful and intentional behaviors
(compulsions) that are recognized by the person as
excessive or unreasonable (American Psychiatric
Association, 1994a). The obsessions or compulsions
cause marked distress, are time-consuming, or
significantly interfere with social or occupational
functioning.
It is contemplated that the compounds of this invention
will be effective in treating obsessions and compulsions
in patients who have been diagnosed with obsessive
compulsive disorder by administration of appropriate
tests, which may include, but are not limited to any of
the following: Yale Brown Obsessive Compulsive Scale
(YBOCS) (Goodman, 1989) (for adults), National Institute
of Mental Health Global OCD Scale (NIMH GOCS), CGI-
Severity of Illness scale. It is further contemplated
that the compounds of the invention will be effective. in
inducing improvements in certain of the factors measured
in these tests, such as a reduction of several points in
the YBOCS total score. It is also contemplated that the
compounds of this invention will be effective in
preventing relapse of obsessive compulsive disorder.
Panic disorder is characterized by recurrent unexpected
panic attacks and associated concern about having
additional attacks, worry about the implications or
consequences of the attacks, and/or a significant change
in behavior related to the attacks (American Psychiatric
Association, 1994a). A panic attack is defined as a
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discrete period of intense fear or discomfort in which
four (or more) of the following symptoms develop
abruptly and reach a peak within 10 minutes: (1)
palpitations, pounding heart, or accelerated heart rate;
(2) sweating; (3) trembling or shaking; (4) sensations
of shortness of breath or smothering; (5) feeling of
choking; (6) chest pain or discomfort; (7) nausea or
abdominal distress; (8) feeling dizzy, unsteady,
lightheaded, or faint; (9) derealization (feelings of
unreality) or depersonalization (being detached from
oneself); fear of losing control; (11) fear of dying;
(12) paresthesias (numbness or tingling sensations);
(13) chills or hot flushes. Panic disorder may or may
not be associated with agoraphobia, or an irrational and
often disabling fear of being out in public.
It is contemplated that the compounds of this invention
will be effective in treating panic disorder in patients
who have been diagnosed with panic disorder on the basis
of frequency of occurrence of panic attacks, or by means
of the CGI-Severity of Illness scale. It is further
contemplated that the compounds of the invention will be
effective in inducing improvements in certain of the
factors measured in these evaluations, such as a
reduction in frequency or elimination of panic attacks,
an improvement in the CGI-Severity of Illness scale or a
CGI-Global Improvement score of 1 (very much improved),
2 (much improved) or 3 (minimally improved).. It is also
contemplated that the compounds of this invention will
be effective in preventing relapse of panic disorder.
Social anxiety disorder, also known as social phobia, is
characterized by a marked and persistent fear of one or
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more social or performance situations in which the
person is exposed to unfamiliar people or to possible
scrutiny by others (American Psychiatric Association,
1994a). Exposure to the feared situation almost
invariably provokes anxiety, which may approach the
intensity of a panic attack. The feared situations are
avoided or endured with intense anxiety or distress.
The avoidance, anxious anticipation, or distress in the
feared situations) interferes significantly with the
person's normal routine, occupational or academic
functioning, or social activities or relationships, or
there is marked distress about having the phobias.
Lesser degrees of performance anxiety or shyness
generally do not require psychopharmacological
treatment.
It is contemplated that the compounds of this invention
will be effective in treating social anxiety disorder in
patients who have been diagnosed with social anxiety
disorder by administration of any of the following
tests: the Liebowitz Social Anxiety Scale (LSAS), the
CGI-Severity of Illness scale, the Hamilton Rating Scale
for Anxiety (HAM-A), the Hamilton Rating Scale for
Depression (HAM-D), the axis V Social and Occupational
Functioning Assessment Scale of DSM-IV, the axis II
(ICD-10) World Health Organization Disability
Assessment, Schedule 2 (DAS-2), the Sheehan Disability
Scales, the Schneier Disability Profile., the World
Health Organization Quality of Life-100 (WHOQOL-100) , or
other tests as described in Bobes, 1998, which is
incorporated herein by reference. It is further
contemplated that the compounds of the invention will be
effective in inducing improvements as measured by these
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tests, such as the a change from baseline in the
Liebowitz Social Anxiety Scale (LSAS), or a CGI- Global
Improvement score of 1 (very much improved), 2 (much
improved) or 3 (minimally improved). It is also
5 contemplated that the compounds of this invention will
be effective in preventing relapse of social anxiety
disorder.
Generalized ~ anxiety disorder is characterized by
10 excessive anxiety and worry (apprehensive expectation)
that is persistent for at least 6 months and which the
person finds difficult to control (American Psychiatric
Association, 1994a). It must be associated with at
least 3 of the following 6 symptoms: restlessness or
15 feeling keyed up or on edge, being easily fatigued,
difficulty concentrating or mind going blank,
irritability, muscle tension, sleep disturbance. The
diagnostic criteria for this disorder are described in
further detail in DSM-IV, which is incorporated herein
20 by reference (American Psychiatric Association, 1994a).
It is contemplated that. the compounds of this invention
will be effective in treating generalized anxiety
disorder in patients who have been diagnosed with this
25 disorder according to the diagnostic criteria described
iri DSM-IV. It is further contemplated that the
compounds of the invention will be effective in reducing
symptoms of this disorder, such as the following:
excessive worry and anxiety, difficulty controlling
30 worry, restlessness or feeling keyed up or on edge,
being easily fatigued, difficulty concentrating or mind
going blank, irritability, muscle tension, or sleep
disturbance. It is also contemplated that the compounds
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of this invention will be effective in preventing
relapse of general anxiety disorder.
Post-traumatic stress disorder (PTSD), as defined by
DSM-III-R/IV (American Psychiatric Association, 1987,
American Psychiatric Association, 1994a), requires
exposure to a traumatic event that involved actual or
' threatened death or serious injury, or threat to the
physical integrity of self or others, and a response
which involves intense fear, helplessness, or horror.
Symptoms that occur as a result of exposure to the
traumatic event include re-experiencing of the event in
the form of .intrusive thoughts, flashbacks or dreams,
and intense psychological distress and physiological
reactivity on exposure to cues to the event; avoidance
of situations reminiscent of the traumatic event,
inability to recall details of the event, and/or numbing
of general responsiveness manifested as diminished
interest in significant activities, estrangement from
others, restricted range of affect, or sense of
foreshortened future; and symptoms of autonomic arousal
including hypervigilance, exaggerated startle response,
sleep disturbance, impaired concentration, and
irritability or outbursts of anger. A PTSD diagnosis
requires that the symptoms are present for at. least a
month and that they cause clinically significant
distress or impairment in social, occupational, or other
important areas of functioning. '
It is contemplated that the compounds of this invention
will be effective in treating PTSD in patients who have
been diagnosed with PTSD by administration of any of the
' following tests: Clinician-Administered PTSD Scale Part
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2 (CAPS), the patient-rated Impact of Event Scale (IES)
(Medical Economics Company, 2002, p. 2752). It is
further contemplated that the compounds of the invention
will be effective in inducing improvements in the scores
of the CAPS, IES, CGI-Severity of Illness or CGI-Global
Improvement tests. It is also contemplated that the
compounds of this invention will be effective in
preventing relapse of PTSD.
In a preferred embodiment, the subject invention
provides a method of treatment or management of the
following indications: depressive disorders, anxiety
disorders, eating/body weight disorders, and urinary
disorders. Examples of depressive disorders are major
depressive disorder or dysthymic disorder. Examples of
anxiety disorders are panic disorder, agoraphobia
without history of panic disorder, specific phobia,
social phobia, obsessive-compulsive disorder, post-
traumatic stress disorder, acute stress disorder or
generalized anxiety disorder. Examples of eating/body
weight disorders are obesity, weight gain, bulimia,
bulimia nervosa or anorexia nervosa. Examples of
urinary disorders include, but are not limited to
urinary incontinence overactive bladder, urge
incontinence, urinary frequency, urinary urgency,
nocturia or enuresis. Overactive bladder and urinary
urgency may or may not be associated with benign
prostatic hyperplasia.
This invention provides a method of modifying the
feeding behavior of a subject, which comprises
administering to the subject an amount of a compound of
the invention effective to decrease the consumption of
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food by the subject. This invention also provides a
method of treating an eating disorder in a subject,
which comprises administering to the subject an amount
of a compound of the invention effective to treat the
eating disorder. In an embodiment of the present
invention, the eating disorder is obesity, bulimia,
bulimia nervosa or anorexia nervosa.
The present invention further provides a method of
reducing the body mass of a subject, which comprises
administering to the subject an amount of a compound of
the invention effective to reduce the body mass of the
subject. This invention also provides a method of
managing obesity in a subject in need of weight loss,
which comprises administering to the subject an amount
of a compound of the invention effective to induce
weight loss in the subject. This invention also
provides a method of managing obesity in a subject who
has experienced weight loss, which comprises
administering to the subject an amount of a compound of
the invention effective to maintain such weight loss in
the subject.
The present invention also provides a method of treating
depression in a subject, which comprises administering
to the subject an amount of a compound of the invention
effective to treat the subject's depression. This
invention also provides a method of treating anxiety in
a subject, which comprises administering to the subject
an amount .of a compound of the invention effective to
treat the subject's anxiety. This invention also
provides a method of treating depression and anxiety in
a subject, which comprises administering to the subject
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an amount of a compound of the invention effective to
treat the subject's depression and anxiety. This
invention also provides a method of treating major
depressive disorder in a subject, which comprises
administering to the subj ect an amount of a compound of
the invention effective to treat the subject's major
depressive disorder. This invention also provides. a
method of treating dysthymic disorder in a subject,
which comprises administering to the subject an amount
of a compound of the invention effective to treat the
subject's dysthymic disorder. This invention also
provides a method of treating obsessions and compulsions
in a subject with obsessive compulsive disorder, which
comprises administering to the subject an amount of a
compound of the invention effective to treat the
subject's obsessions and compulsions. This invention
also provides a method of treating panic disorder, with
or without agoraphobia, in a subject, which comprises
administering to the subj ect an amount of a compound of
the invention effective to treat the subject's panic
disorder. This invention also provides a method of
treating social anxiety disorder in a subject, which
comprises administering to the subject an amount of a
compound of the invention effective to treat the
subject's social anxiety disorder. This invention also
provides a method of treating generalized anxiety
disorder in a subject, which comprises administering to
the subject an amount of a compound of the invention
effective to treat the subject's generalized anxiety
disorder. This invention also provides a method of
treating post-traumatic stress disorder in a subject,
which comprises administering to the subject an amount
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of a compound of the invention effective to
treat the subject's post-traumatic stress disorder.
It is contemplated that the compounds of this invention
5 will be effective in treating obesity, including weight
loss and maintenance of weight loss in patients, who
have been diagnosed with obesity by the one or more of
the following measurements: an increased body mass
index, increased waist circumference (an indicator of
10 intra-adominal fat), Dual Energy X-Ray Absorptiometry
(DEXA) and trucal (android) fat mass. It is further
contemplated that the compounds of the invention will be
effective in inducing improvements in certain factors
-measured in~these tests.
It is contemplated that the compounds of this invention
will be effective in treating urinary disorders in
patients who have urge or mixed (with a predominance of
urge) incontinence as evidenced by the number of
unnecessary episodes per week, the number of unnecessary
micturitions per day and a low volume voided per
micturition. It is further contemplated that the
compounds of the invention will be effective in inducing
' improvements in certain factors measured in these tests.
The present invention also provides a method of treating
a subject suffering from bipolar I or .II disorder,
schizoaffective disorder, a cognitive disorder with
depressed mood, a personality disorder, insomnia,
hypersomnia, narcolepsy, circadian rhythm sleep
disorder, nightmare disorder, sleep terror disorder or
sleepwalking disorder.
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The present invention provides a method of treating
overactive bladder with symptoms of urge urinary
incontinence, urgency and/or frequency in a subject,
which comprises administering to the subject an amount
of a compound of the invention effective to treat .the
subject's overactive bladder. This invention also
provides a method of alleviating urge urinary
incontinence in a subject suffering .from overactive
bladder, which comprises administering to the subject an
amount of a compound of the invention effective to
alleviate the subject's urge urinary incontinence. This
invention further provides a method of alleviating
urinary urgency in a subject suffering from overactive
bladder, which comprises administering to the subject an
amount of a compound of the invention effective to
alleviate the subject's urinary urgency. Additionally,
this invention provides a method of alleviating urinary
frequency in a subject suffering from overactive
bladder, which comprises administering to the subject an
amount of a compound of the invention effective to
alleviate the subject's urinary frequency.
The present invention also provides a method of treating
a subject suffering from a urinary disorder, which
comprises administering to the subject an amount of a
compound of the invention effective to treat the
subject's urinary disorder. In some embodiments the
urinary disorder is urinary incontinence, overactive
bladder, urge incontinence, urinary frequency, urinary
urgency, nocturia or enuresis.
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The present invention provides a method of
alleviating the symptoms of a disorder in a subject,
which comprises administering to the subject an amount
of an MCH1 antagonist effective to alleviate the
symptoms, wherein the MCH1 antagonist is any of the
compounds of the invention.
In an embodiment of the invention, the subject is a
vertebrate, a mammal, a human or a canine. In another
embodiment, the compound is administered orally. In yet
another embodiment, the compound is administered in
combination with food.
This invention will be better understood from the
Experimental Details In a preferred embodiment, the
subject invention provides a method of treatment for the
following indications: depression, anxiety, eating/body
weight disorders, and urinary disorders. Examples of
eating/body weight disorders are obesity, bulimia, or
bulimia nervosa. Examples of urinary disorders include,
but are not limited to, urinary incontinence, overactive
bladder, urge incontinence, urinary frequency, urinary
urgency, nocturia, or enuresis. Overactive bladder and
urinary urgency may or may not be associated with benign
prostatic hyperplasia.
This invention provides a method of modifying the
feeding behavior of a subject which comprises
administering to the subject an amount of a compound of
the invention effective to decrease the consumption of
food by the subject.
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This invention also provides a method of
treating an eating disorder in a subject which comprises
administering to the subj ect an amount of a compound of
this invention effective to decrease the consumption of
food by the subject. In an embodiment of the present
invention, the eating disorder is bulimia, obesity or
bulimia nervosa. In an embodiment of the present
invention, the subject is a vertebrate, a mammal, a
human or a canine. In a further embodiment, the
. compound is administered in combination with food.
The present invention further provides a method of
reducing the body mass of a subject which comprises
administering to the subj ect an amount of a compound of
the invention effective to reduce the body mass of the
subj ect .
The present invention also provides a method of treating
a subject suffering from depression which comprises
administering to the subject an amount of a compound of
this invention effective to treat the subject's
depression. The present invention further provides a
method of treating a subject suffering from anxiety
which comprises administering to the subject an amount
of a compound of this invention effective to treat the
subject's anxiety. The present invention also provides
a method of treating a subject suffering from depression
and anxiety which comprises administering to the subject
an amount of a compound of this invention effective to
treat the subject's depression and anxiety.
The present invention also provides a method of treating
a subject suffering from major depressive disorder,
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dysthymic disorder, bipolar I and II disorders,
schizoaffective disorder, cognitive disorders with
depressed mood, personality disorders, insomnia,
hypersomnia, .narcolepsy, circadian rhythm sleep
disorder, nightmare disorder, sleep terror disorder,
sleepwalking disorder, obsessive-compulsive disorder,
panic disorder, with or without agoraphobia,
posttraumatic stress disorder, social anxiety disorder,
social phobia and generalized anxiety disorder.
The present invention also provides a method of treating
a subject suffering from a urinary disorder which
comprises administering to the subject an amount of a
compound of this invention effective to treat the
subject's a urinary disorder. In some embodiments, the
urinary disorder is urinary incontinence, overactive
bladder, urge incontinence, urinary frequency, urinary
urgency, nocturia, or enuresis.
This invention will be better understood from the
Experimental Details which follow. However, one skilled
in the. art will readily appreciate that the specific
methods and results discussed are merely illustrative of
the invention as described more fully in the claims
25' which follow thereafter.
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Experimental Section
I. Synthetic Methods for Examples
General Methods: All reactions (except for those done by
parallel synthesis reaction arrays) were performed under
an Argon atmosphere and the reagents, neat or in
appropriate solvents, were transferred to the 'reaction
vessel via syringe and cannula techniques. The parallel
synthesis reaction arrays were performed in vials
(without an inert atmosphere) using J-KEM heating
shakers (Saint Louis, MO). Anhydrous solvents were
purchased from Aldrich Chemical Company and used as
received. The examples described in the patent were
named using ACD/Name program (version 2.51, Advanced
Chemistry Development Inc., Toronto, Ontario, M5H2L3,
Canada). Unless otherwise noted, the 1H spectra were
recorded at 300 and 400 MHz (QE Plus and Briiker
respectively) with tetramethylsilane as internal
standard. s - ringlet; d - doublet; t - triplet; q -
quartet; p - pentet; seat; rcpt; br - broad; m -
multiplet. Elemental analyses were performed by
Robertson Microlit Laboratories, Inc. Unless otherwise
noted, mass spectra were obtained using low-resolution
electrospray (ESMS) and MH+ is reported. Thin-layer
chromatography (TLC) was carried out on glass plates
precoated with silica gel 60 F254 (0.25 mm, EM
Separations Tech.). Preparative . thin-layer
chromatography was carried out on glass sheets precoated
with silica gel GF (2 mm, Analtech). Flash column
chromatography was performed on Merck silica gel 60 (230
- 400 mesh). Melting points (mp) were determined in
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open capillary tubes on a Mel-Temp apparatus and are
uncorrected.
Piperidine Side Chain Intermediates
TERT-BUTYL 4-~[(TRIFLUOROMETHYL)SULFONYL]OXY~-1,2,3,6
-TETRAHYDRO-1-PYRIDINECARBOXYLATE: n-Butyl lithium (17.6
mL, 44.2 mmol, 2.5 M in hexanes) was added to a solution
of diisopropyl amine (96.2 mL, 44.2 mmol) in 40 mL of
dry THF at 0 °C and stirred for 20 minutes. The reaction
mixture was cooled to -78 °C and tert-butyl
4-oxo-1-piperidinecarboxylate (Aldrich Chemical Company,
40.0 mmol) in THF (40 mL) was added dropwise to the
'reaction mixture and stirred for 30 minutes. TfZNPh
(42,0 mmol, 15.0 g) in THF (40 mL) was added dropwise to
the reaction mixture and stirred at °C overnight. The
reaction mixture was concentrated in vacuo, re-dissolved
in hexanes:EtOAc (9:1), passed through a plug of alumina
and the alumina plug was washed. with hexanes:EtOAc
(9:1). The combined extracts were concentrated to yield
16.5 g of the desired product that was contaminated with
some starting Tf2NPh.
1H NMR (400 MHz, 400 MHz, CDC13) ~ 5.77 (s, 1 H), 4.05
(dm, 2 H, J=3 . 0 Hz) , 3 .63 (t, 2 H, J=5.7 Hz) , 2 .45 (m, 2
H) , 1.47 (s, 9 H) .
TERT-BUTYL 4-[3-(AMINO)PHENYL]-1,2,3,6-TETRAHYDRO-1-
PYRIDINECARBOXYLATE: A mixture of 2 M aqueous Na~C03
solution (4.2 mL), tert-butyl
4-~[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-
1-pyridine-carboxylate (0.500 g, 1.51 mmol),
3-aminophenylboronic acid hemisulfate (0.393 g, 2.11
mmol), lithium chloride (0.191 g, 4.50 mmol) and
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tetrakis- triphenylphosphine
palladium (0) (0.080 g, 0.075 mmol) in dimethoxyethane
(5 mL) was heated at reflux temperature for 3 hours,
under an inert atmosphere (an initial degassing of the
mixture is recommended to prevent the formation of
triphenylphosphine oxide). The organic layer of the
cooled reaction mixture was separated and the aqueous
layer was washed with ethyl acetate (3X) . The combined
organic extracts were dried and concentrated in vacuo.
The crude product was chromatographed (silica,
hexanes:EtOAc:dichloromethane (6:1:1) with 1% added
isopropylamine to protect the BOC group from hydrolysis)
to give 0.330 g of the desired product in 81% yield. 1H
NMR (400 MHz, CDC13) S 7.12 (t, 1H, J= 7.60 Hz) , 6.78 (d,
1H, J= 8.4 Hz), 6.69 (t, 1H, J= 2.0 Hz), 6.59 (dd, 1H,
J= 2.2, 8.0 Hz), 6.01 (m, 1H), 4.10 - 4.01 (d, 2H, J=
2.4 Hz), 3.61 (t, 2H, J= 5.6 Hz), 2.52 - 2.46 (m, 2H),
1.49 (s, 9H) ; ESMS m/e . 275.2 (M + H)+. Anal. Calc. for
CisHz4NzOa: C~ 70.04; H, 8.08; N, 10.21. Found: C, 69.78;
H, 7.80; N, 9.92.
TERT-BUTYL 4-[3-(AMINO)PHENYL]-1-PIPERIDINECARBOXYLATE:
A mixture of 3.10 g of tert-butyl 4-(3-aminophenyl)-
1,2,3,6-tetrahydropyridine-1-carboxylate (11.3 mmol) and
1.0 g of 10a Pd/C in 200 mL of ethanol was hydrogenated
at room temperature using the balloon method for 2 days.
The reaction mixture was filtered and washed with
ethanol. The combined ethanol extracts were
concentrated in vacuo and the residue was
chromatographed on silica (dichloromethane: methanol
95:5 with 1% isopropylamine added to protect the BOC
group from hydrolysis) to give 2.63 g of the desired
product (84 0) . 1H NMR (400 MHz, CDC13) 8 7.10 (t, 1H, J=
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7.60 Hz), 6.62 (d, 1H, J= 8.4 Hz), 6.60 - 6.59 (m,
2H), 4.27 - 4.18 (m, 2H), 3.62 - 3.58 (m, 2H), 2.80 -
2 . 72 (m, 2H) , 2 , 62 - 2 . 59 (m, 1H) , 1 . 89 - 1 . 52 (m, 4H) ,
1.49 (s, 9H); ESMS m/e . 277.2 (M + H)+.
TERT-BUTYL 4-[3-(ACETYLAMINO)PHENYL]-1,2,3,6-TETRAHYDRO-
1-PYRIDINECARBOXYLATE: A mixture of saturated aqueous
Na~C03 solution (25 mL) , tent-butyl
4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-
1-pyridine-carboxylate (20 mmol),
3-acetamidophenylboronic acid (30 mmol) and tetrakis-
triphenylphosphine palladium (0) (1.15 g) and
dimethoxyethane (40 mL) was heated at reflux temperature
overnight. The organic layer of the cooled reaction
mixture was separated and the aqueous layer was washed
with ethyl acetate (3X). The combined organic extracts
were dried and concentrated in vacuo. The crude product
was chromatograghed, giving the desired product: 1H NMR
(CDC13) ~ 8.11 (br s, 1 H) , 7.57 (br s, 1 H) , 7.41 (br d
, 1 H, J=7.8 Hz), 7.25 (apparent t, 1 H, J=7.8 Hz), 7.08
(br d, 1 H, J=7. 8 Hz) , 5.99 (br s, 1 H) , 4. 03 (br m, 2
H, J=2. 7 Hz) , 3. 59 (t, 2 H, J=5.7 Hz) , 2.46 (m, 2 H, ) ,
2.16 (s, 3 H) , 1.49 (s, 9 H) .
Nl-j3-(1,2,3,6-TETRAHYDRO-4-PYRIDINYL)PHENYh]ACETAMIDE:
A solution of 4 M HC1 in dioxane (10 mL) was added to
tert-butyl 4-[3-(acetylamino)phenyl]-1,2,3,6-tetrahydro-
1-pyridinecarboxylate (8.25 mmol) in dichloromethane (30
mL). The reaction mixture was stirred at room
temperature overnight, concentrated in vacuo, giving the
desired product as the hydrochloride salt (2.1 g): 1H NMR
(CDC13) ~ 7.41-7.00 (m, 4 H), 6.10 (br, 1 H), 3.55 (m, 2
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H) , 3 .16 (t, 2 H, J = 5.7 Hz) , 2 .44 (m, 2 H) , 2 .19
(s, 3 H) .
TERT-BUTYL N-(3-,BROMOPROPYL)CARBAMATE: Prepared from
3-bromopropylamine hydrobromide and BOC~O in the presence
of base in dichloromethane, 9.89 mmol: 1H NMR (CDC13) 8
5.07 (br, 1 H) , 3 .31 (t, 2 H, J=6.6 Hz) , 3 .12 (apparent
br q, 2 H, J=6.0 Hz) , 1.92 (p, 2 H, J=6.6 Hz) , 1.30 (s,
9H) .
TERT-BUTYL N-(3-~4-[3-(ACETYLAMINO)PHENYL]-1,2,3,
6-TETRAHYDRO-1-PYRIDINYL~PROPYL)CARBAMATE: A solution of
N1-[3-(1,2,3,6-tetrahydro-4-
pyridinyl)phenyl]acetamide.HCl (8.24 mmol), tert-butyl
N-(3-bromopropyl)carbamate and potassium carbonate (33
mmol) in dry diox.ane (30 mL) was heated at reflux
temperature overnight. The solids were removed by
filtration, the solution was concentrated in vacuo and
the product was chromatograghed, giving the desired
product (110 mg) . 1H NMR (CDC13) b 7.65 (s, 1 H) , 6.98
(s, 1 H), 7.45 (d, 1 H, J=7.8 Hz), 7.16 (apparent t, 1
H, J=7. 8 Hz) , 7.10 (d, 1 H, J=7.8 Hz) , 6. 02 (s, 1 H) ,
5 . 23 (b, 1' H) , 3 . 40 (b, 2 H) , 3 . 30-1 . 80 (m, 10 H) , 2 . Z8
(s, 3 H) , 1.'45 (s, 9 H) .
N1-~3-[1-(3-AMINOPROPYL)-1,2,3,6-TETRAHYDRO-4-
PYRIDINYL]PHENYL~ACETAMIDE: A 1:1 solution of TFA:CH2C12
(5 mL) was added to tert-butyl
N- (3-~4- [3- (acetylamino)phenyl] -1,'2, 3, 6-tetrahydro-1-
pyridinyl~propyl)carbamate in dichloromethane (5 mL).
The resulting solution was stirred at room temperature
for 1-3 days, saturated NaHC03 was added until pH > 6,
the organic layer was separated, and dried in vacuo,
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giving 1H NMR (CDC13)
the 8
desired
product
(45
mg)
:
7.6 8 (br, 1 H) , 7.35 (dm, J=7. 8 , 7.25 (apparent
1 H, Hz)
t, 1 H, J=7. 8 Hz) , 7.15 H, J=7. Hz) , 6.12 (m,
(dm, 1 8 l
H), 3.22 (m, 2 H), 3.03 (t, H, J=7.3 Hz), 2.78 (t,
2 2
H, J=5.5 Hz), 2.70-2.50 (m, H), 2.10 (s, 3 H), 1.87
4
(p, 2 H, J=7.3 Hz) .
TERT-BUTYL 4-[3-(ACETYLAMINO)PHENYL]-1
PIPERIDINECARBOXYLATE: A mixture tart-butyl 4-[3
(acetylamino)phenyl]-1,2,3,6-tetrahydro-1
pyridinecarboxylate (710 mg) and 5o Pd/C (100 mg) in
EtOH (10 mL) was hydrogenated (balloon technique) at
room temperature overnight. The reaction mixture was
passed through a pad of Celite 545 and the pad of Celite
was washed with ethanol. The combined ethanol extracts
were concentrated and chromatograghed, giving the
desired product (660 mg) : 1H NMR (CDC13) 8 7 . 80 (s, 1 H) ,
7 .41-7 . 20 (m, 3 H) , 6 . 94 (d, 1 , H, J=7 . 5 Hz) , 4 . 21 (m, 2
H), 2.75 (m, 2 H), 2.62 (m, 1 H), 2.16 (s, 3 H), 1.78
(m, 2 H), 1.56 (m, 2 H), 1.48 (s, 9 H).
N1-[3-(4-PIPERIDYL)PHENYL]ACETAMIDE: A solution of HC1
in dioxane (4N, 5 mL) was added to tart-butyl 4-[3-
(acetylamino)phenyl]-1-piperidinecarboxylate (60'0 mg)
in dry dichloromethane (15 mL). The reaction mixture
was stirred at room temperature overnight and
concentrated in vacuo, giving the desired product. (550
mg) : mp 102-104 °C; 1H NMR (CDC13) 8 2.02 (d, J=13.2 Hz,
2H), 2.11-2.45 (m, 5H), 2.67-2.77 (m, 1H), 3.00-3.10 (m,
2H), 3.51 (d, J=10.5 Hz, 2H), 6.94 (d, J=7.5 Hz, 1H),
7.20-7.46 (m, 3H), 7.60 (s, 1H); Anal. Calcd. For
Ci3H19N~OC1+0.86 CHZCl~: C, 50,78; H, 6.37; N, 8.55. Found:
C, 50.80; H, 7.55; N, 7.01.
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TERT-BUTYL
N- (3-~4- [3-
(ACETYLAMINO)PHENYL~PIPERIDINO~PROPYL)CARBAMATE: A
solution of N1- [3- (4-piperidyl)phenyl] acetamide (550 mg,
0.210 mmol), tert-butyl N-(3-bromopropyl)carbamate (550
mg, 0.230 mmol), KZC03 (1.10 g, 0.$90 mmol),
diisopropylethyl amine (1.50 mL) and a few crystals of
KI in dioxane (20 mL) was heated at reflux temperature
for 2 days. The precipitated salts were removed by
filtration, concentrated in vacuo and the crude product
was chromatographed, giving the desired product (340
mg) ; 1H NMR (CDCl3) 8 8.15 (s, 1 H) , 7.47-7.44 (m, 2 H) ,
7.22 (t, 1 H, J=7.8 Hz), 6.94 (d, 1 H, J=7.8 Hz), 5.53
(b, 1 H) , 3.23 (b, 6 H) , 2.80-1.60 (m, 9 H) , 2.20 (s, 3
H) , 1 .45 (s, 9 H) .
Nl-~3-L~.-(3-AMINOPROPYL)-4-PIPERIDYL]PHENYL~ACETAMIDE:
TFA (1.0 mL) was added to a solution of tert-butyl
N- (3-~4- [3-
(acetylamino)phenyl]piperidino~propyl)carbamate (340 mg)
in dry dichloromethane (10 mL) and stirred at room
temperature for 5 h. A 10% aqueous solution of KOH was
added to the reaction mixture until pH > 6 and then the
dichloromethane was removed in vacuo. The aqueous layer
was frozen and lyophilized to give a solid, which was
extracted with methanol. Removal of the solvent gave
the desired product (120 mg) as an oil: iH NMR (CDC13) S
7.23-7.16 (apparent t, 1H, J=7.5 Hz), 6.95-6.92 (m, 1H),
3 . 03-2. 99 (m, 2H) , 2. 77-2.73 (t, 2H, J = 6.6 Hz) , 2 . 50-
1.60 (m, 10 H) , 2.13 (s, 3 H) .
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TERT-BUTYL ~ 4-(3-NITROPHENYL)-3,6-DIHYDRO-1(2H)-
PYRIDINECARBOXYLATE: According to the procedure used for
the synthesis of tert-butyl 4- [3- (amino) phenyl] -1, 2, 3, 6-
tetrahydro-1-pyridinecarboxylate,a mixture of 2 M
aqueous Na~C03 solution (2.2 mL), tert-butyl
4-{[(trifluoromethyl)sulfonyl]oxy~-1,2,3,6-tetrahydro-1-
pyridine-carboxylate (0.5.00 g, 1.51 mmol),
3-nitrophenylboronic acid (0.353 g, 2.11 mmol), lithium
chloride (0.191 g, 4.50 mmol) and tetrakis-
triphenylphosphine palladium (0) (0.080 g, 0.075 mmol)
in dimethoxyethane (5 mL) afforded 0.3808 of the desired
product.
1H NMR (400 MHz, CDC13) 8 8.23 (s, 1H), 8.11 (d, 1H,
J=8.0 Hz), 7.69 (d, 1H, J=8.0 Hz), 7.51 (t, 1H, J=8.0
Hz) , 6.20 (m, 1H) , 4 . 17-4.08 (m, 2H) , 3 . 67 (t, 2H, J=5. 6
Hz), 2.61-2.52 (m, 2H), 1.50 (s, 9H); ESMS m/e . 249.1
(M + H - C4H8)~.
1,2,3,6-TETRAHYDRO-4-(3-NITROPHENYL)PYRIDINE: Into a
stirred solution of 5.00 g (16.0 mmol) of tert-butyl
1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine-1-
carboxylate in 100 ml of 1,4-dioxane at 0°C was bubbled
HC1 gas for 10 minutes. The reaction mixture was
allowed to warm to room temperature and the bubbling of
the HC1 gas was continued for an additional 1 hour. The
solvent was removed in vacuo, the residue was dissolved
in 50. mL of water and was neutralized by the addition of
KOH pellets. The aqueous solution was extracted with 3
X 80 mL of dichloromethane and the combined organic
extracts were dried (MgS04), filtered and concentrated in
vacuo. The residue was purified by column
chromatography (silica, 9 . 1 ,dichloromethane
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methanol + to isopropyl amine) to afford 2.85 g
(87.5 o yield) of the desired product: 1H NMR (400 MHz,
CDC13) 8 8.24 (s, 1H) , 8.09 (d, 1H, J=8.4 Hz) , 7.71 (d,
1H, J=8.0 Hz), 7.49 (t, 1H, J=8.0 Hz), 6.35-6.25 (m,
1H), 3.58 (apparent q, 2H, J=3.0 Hz), 3.14 (t, 2H, J=5.6
Hz) , 2.54-2.46 (m, 2H) .
TERT-BUTYL 3-(4-(3-NITROPHENYL)-3,6-DIHYDRO-1(2H)-
PYRIDTNYL)PROPYLCARBAMATE: A mixture of 2.80 g (14.0
mmol) of 1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine,
3.60 g (15.0 mmol) of tent-butyl
N- ( 3 -bromopropyl ) carbamate , 11 . 6 g ( 84 . 0 mmol ) of KaC03 ,
14.6 mL (84.0 mmol) of diisopropylethylamine and 0.78 g
(2.00 mmol) of tetrabutylammonium iodide in 250 mL of
1,4-dioxane was heated at reflux temperature for 14 .
hours. The reaction mixture was filtered and the
filtrate was dried (MgS04), concentrated in vacuo and the
residue was purified by column chromatography (silica,
9:1, dichloromethane: methanol + 1% isopropyl amine) to
afford 4.35 g (85.7% yield) of the desired product: 1H
NMR (400 MHz, CDC13) 8 8.24 (t, 1H, J=1 .9 Hz) , 8.09 (dd,
1H, J=1.9, 8.0 Hz), 7.70 (apparent d, 1H, J=8.0 Hz),
7.49 (t, 1H, J=8. 0 Hz) , 6.23 (m, 1H) , 3 .29-3.18 (m, 4H) ,
2.75 (t, 2H, J=5.6 Hz), 2.64-2.54 (m, 4H), 1.82-1.70 (m,
2H), 1.44 (s, 9H); ESMS m/e . 362.2 (M + H)~.
3- (4- (3-NITROPHENYL) -3, 6-DIHYDRO-Z (2H) -PYRIDINYL) -1-
PROPANAMINE: Into a stirred solution of 4.35 (12.0 mmol)
of tert-butyl
3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-
pyridinyl)propylcarbamate in 100 ml of 1,4-dioxane at
0°C was bubbled HC1 gas for 10 minutes. The reaction
mixture was allowed to warm to room temperature and. the
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bubbling was continued for an additional 1 hour. The
solvent was removed in vacuo, the residue was dissolved
in 50 mL of water and was neutralized by the addition of
KOH pellets. .The aqueous solution was extracted with 3
X 80 mL of dichloromethane, the combined organic
extracts were dried (MgS04), filtered and concentrated in
vacuo. The residue was purified by column
chromatography (silica, 9 . 1 ,dichloromethane
methanol + 1% isopropyl amine) to afford 3.05 g (97.0%
yield) of the desired product: 1H NMR (400 MHz, CDC13) 8
8.24 (t, 1H, J=1.8 Hz), 8.09 (dd, 1H, J=1.8, 8.2 Hz),
7.69 (dd, 1H, J=1.8, 8.2 Hz), 7,48 (t, 1H, J=8.2 Hz),
6.24 (m, 1H) , 3 .21 (d, 2H, J=3 .6 Hz) , 2.84 (t, 2H, J=6.6
Hz) , 2 .75 (t, 2H, J=5.8 Hz) , 2.64-2.54 (m, 4H) , 1 .76 (m,
2H); ESMS m/e . 262.2 (M + H)+; Anal. Calc. for
C14H19N3Oz (0.06 CHC13) : C, 62.90; H, 7.16; N, 15.65.
Found: C, 63.20; H, 7.16; N, 15.65.
METHYL (4S) -3- [ ( f 3- [4- (3-AMINOPHENYL) -Z-
PIPERIDINYL]PROPYL~AMINO)CARBONYL]-4-(3,4-
DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4-
TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: A mixture of 3.02 g
(6.33 mmol) 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-
difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-
1,5(2FI)-pyrimidinedicarboxylate, 1.50 g (5.80 mmol) of
3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)-1-
propanamine, 7.94 g (75.5 mmol) of KzC03 and 1.00 mL of
methanol in 200 mL dichloromethane (under argon) was
stirred at room temperature for I hour. The reaction
mixture was filtered and concentrated in vacuo. The
residue was dissolved in 100 mL of ethyl acetate and
washed 3 X 50 mL of 5o aqueous NaOH solution, the
organic layer was dried (PdgS04) and concentrated in
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vacuo. The residue was dissolved in 100 mL of
anhydrous ethanol containing 0.50 g 10% Pd/C and the
reaction mixture was stirred under a hydrogen balloon
for 24 hours. The reaction mixture was passed through a
column of Celite 545 filtering agent, washed with
ethanol, the filtrate was dried (MgS04) and concentrated
in vacuo. The residue was purified, by column
chromatography (silica, 9.5 . 0.5 ,dichloromethane
methanol + to isopropyl amine) to afford 1.65 g (52.0%
yield) of the desired product: 1H NMR (400 MHz, CDC13) S
7.80 (s, 1H), 7.22-7.02 ~(m, 2H), 6.95 (t, J = 8.70 Hz,
1H), 6.63-6.44 (m, 4H), 4.56 (Abq, 2H), 3.62 (s, 3H),
3.33 (s, 3H), 3.32-3.20 (m, 4H), 2.96 (br s, 2H), 2.33
(t, J - 7.50 Hz, 2H), 2.11-1.94 (m, 3H), 1.81-1.64 (m,
4H); ESMS m/e . 572.3 (M + H)+;
TERT-BUTYL 4-[3-(ISOBUTYRYLAMINO)PHENYL]-3,6-DIHYDRO-
1(2H)-PYRIDINECARBOXYLATE: Into a solution of 4.00 g
(16.0 mmol) of tert-butyl 4-(3-aminophenyl)-3,6-dihydro-
1(2H)-pyridinecarboxylate and 5.60 mL (32.0 mmol) of
diisopropylethylamine in 100 mL dichloromethane was
slowly added 1.90 mL (19.0 mmol) of isobutyryl chloride.
The reaction mixture was stirred at room temperature for
2 hours, washed with water, dried (MgS04), and
concentrated in vacuo. The residue was purified by
column chromatography (silica, 50 . 46 . 3 . 1, hexanes
dichloromethane . methanol . isopropyl amine) to
afford 2.90 g (52.0o yield) of the desired product: 1H
NMR (400 MHz, CDC13) ~ 7.69 (s, 1 H) , 7.34 (d, 1 H, J=7. 8
Hz), 7.27 (t, 1H, J=7.8 Hz), 7.11 (d, 1H, J=7.8 Hz),
6.04 (s, 1H) , 4.05 (s, 2H) , 3.62 (apparent t, 2 H, J=4.9
Hz) , 2.51 (m, 3H) , 1.49 (s, 9H) , 1.25 (d, 6H, J=7.4 Hz) ;
ESMS m/e: 345.5 (M + H)+. Anal. Calc. for
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CaoHasNaOs+0 .175 CHC13: C, 66 . 33 ; H, 7 . 77; N, 7 . 67 ,
Found: C, 66.20; H, 7.41; N, 7.88
TERT-BUTYL 4-[3-(ISOBUTYRYLAMINO)PHENYL]-1
-PIPERIDINECARBOXYLATE: A mixture of 2.90 g (8.40 mmol)
of text-butyl 4-(3-(isobutyrylamino)phenyl]-3,6-dihydro-
1(2H)-pyridinecarboxylate and 0.80 g of loo yield Pd/C
in 100 mL of ethanol was stirred under a hydrogen
balloon for 24 hours. The reaction mixture was passed
through a column of Celite 545 filtering agent, the
filtrate was dried (MgS04) and concentrated in vacuo.
The residue was purified by column chromatography
(silica, 9.5 . 0.5 ,dichloromethane . methanol + to
isopropyl amine) to afford 2.40 g (84.0% yield) of the
desired product: 1H NMR (400 MHz, CDC13) b 7.49-7.44 (m,
2H), 7.24 (t, 1H, J=7.6 Hz), 6.93 (d, 1H, J=7.6 Hz),
4.20-4.10 (m, 2H), 2.86-2.45 (m, 4H), 1.86-1.75 (m, 4H),
1.48 (s, 9H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e . 345.2
(M + H) +; Anal. Calc. for CapH30N2~3'~O . 3Ha0: C, 68. 27; H,
8.77; N, 7.96. Found: C, 68.25; H, 8.54; N, 7.84.
2-METHYL-N-[3-(4-PIPERIDINYL)PHENYL]PROPANAMIDE: Into a
stirred solution of 2.20 (6.50 mmol) of tent-butyl 4-[3-
(isobutyrylamino)phenyl]-1-piperidinecarboxylate in 100
ml of 1,4-dioxane at 0 °C was bubbled HC1 gas for 10
minutes. The reaction mixture was allowed to warm to
room temperature and the bubbling of the HCl gas was
continued for 1 hour The solvent was removed in vacuo,
the residue was dissolved in 50 mL of water and was
neutralized by the addition of KOH pellets. The aqueous
solution was extracted with 3 X 80 mL of
dichlorotriethane, the combined organic extracts were
dried (MgSO4), filtered and concentrated in vacuo. The
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residue was purified by column chromatography
(silica, 9 . 1 ,dichloromethane . methanol + 10
isopropyl amine) to afford 0.700 g (46.0% yield) of the
desired product: 1H NMR (400 MHz, CDC13) 8 7.47 (s, 1H) ,
7.40 (d, 1H, J=7.8 Hz) , 7.24 (t, 1H, J=7. 8 Hz) , 7. 00 (d,
1H, J=7.8 Hz), 3.23-3.14 (m, 5H), 2.82-2.57 (m, 4H),
1.20 (d, 6H, J=6. 8 Hz) ; ESMS m/e . 247 . 2 (M + H) +; The
hydrochloride salt was used for the combustion analysis:
Anal. Calc. for C15H~ZN20+HCl+0.15 CHC13: C, 60.51; H,
7.76; N, 9.32. Found: C, 60.57; H, 7.83; N, 8.88.
3-(4-PIPERIDINYL)ANILINE: A solution of 4 M HC1 in
dioxane (25 mL) was added to tert-butyl 4- [3-
(amino)phenyl]-1-piperidinecarboxylate (2.60 g, 9.00
mmol) in dichloromethane (250 mL). The reaction mixture
was stirred at room temperature overnight, concentrated
in vacuo, and the residue was dissolved in water (50
mL). The mixture was nuetralized using KOH pellets and
extracted with methylene chloride (3 X 50 mL). The
combined organic extracts were dried (MgS04),
concentrated and chromatographed to give the desired
product (1.03 g) . 1H NMR (400 MHz, CDC13) 8 7.01 (t, 1H,
J=7.6 Hz), 6.62-6.54 (m, 3H), 3.16 (br d, 2H, J=10.3
Hz) , 2.75 (dt, 2H, J=2.7, 12 .3 Hz) , 2.56 (tt, 1H, J=3.6,
12.3 Hz), 1.81 (br d, 2H, J=12.3 Hz), 1.65 (dq, 2H,
J=4.0, 12.3 Hz); ESMS m/e . 177.2 (M + H)+.
TERT-BUTYL 4- (4-NITROPHENYL) -3, 6-DTHYDRO-1 (2H') -
PYRIDINECARBOXYLATE: To a 25-mL RB flask, equipped with
a condensor, was added tert-butyl 4-
f [ (trifluoromethyl) sulfonyl] oxy}-3, 6-dihydro-1 (2H) -
pyridinecarboxylate (1.0 g), 4-nitrophenylboronic acid
(0.71 g), sodium carbonate (0.430 mL of 2M solution),
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lithium chloride (0.382 g),
tetrakis(triphenylphosphine)- palladium (0) (0.173 g)
and ethylene glycol dimethyl ether (10 mL). The
reaction mixture was flushed with Argon three times,
then the reaction mixture was heated to 100 °C for 3 hrs.
After cooling to room temperature, the reaction mixture
was diluted with methylene chloride (30 mL) and water
(30 mL) and the organic layer was separated. The
aqueous layer was extracted with methylene chloride
(3x20 mL) and the combined organic extracts were washed
with sat NH4C1 (20 mL) and brine (20 mL), dried over
MgS04 and concentrated under reduced pressure. The
residue was purified by chromatography (6:1=hexane: ethyl
acetate with 1% NH3) to afford the product (0.55 g,
59.9%) as a yellow oil. The compound is not stable at
room temperature and should be used as promptly as
practical: 1H NMR (400 MHz, CDC13) ~ 8.20 (d, 2H, J=8.6
Hz) , 7.51 (d, 2H, J=8. 6 Hz) , 6.24 (m, 1H) , 4. 13 (m, 2H) .
3 .67 (apparent t, 2H, J=5.5 Hz) , 2.55 (m, 2H) , 1.49 (s,
9H) .
4-(4-NITROPHENYL)-1,2,3,6-TETRAHYDROPYRIDINE: 4-(4-
Nitrophenyl)-1,2,3,6-tetrahydropyridine was prepared by
a similar procedure to that used for the preparation of
2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide using
HCl gas and tert-Butyl 4-(4-Nitrophenyl)-3,6-dihydro-
1 (2H) -pyridinecarboxylate (130 mg) in dioxane (5. 0 mL)
at room temperature. The reaction mixture was
concentrated in vacuo to give the crude product (69.8
mg) which used in the next reaction without further
purification.
Oxazolidinone Intermediates:
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AMINO-(3,4-DIFLUOROPHENYL)-ACETONITRILE: Through a
solution of 3,4-difluorobenzaldehyde (25.0 g, 0.176 mol)
in MeOH (500 mL) in a round bottom flask, was bubbled
ammonia gas for two hours at room temperature. The flask
was then cooled to 0 °C and trimethylsilyl cyanide was
then added slowly. The reaction mixture was stirred for
2 h, at which time TLC analysis indicated that the
reaction was complete (Rf = 0.35, 3:2 hexane/EtOAc). The
solvent was removed in vacuo and the residue was
subjected to flash column chromatography on silica gel
to obtain the desired product, which was used in the
next step without purification.
AMINO-(3,4-DIFLUOROPHENYL)-ACETIC ACID METHYL ESTER:
Into a well-stirred solution of amino-(3,4-
difluorophenyl)-acetonitrile (22.0 g, 0.130 mol), a
solution of HC1 in MeOH (200 mL) was added at room
temperature. The resulting yellow solution was stirred
20- at room temperature for 10 h and was heated at reflux
temperature for 1.5 h. After cooling, the solvent was
removed in vacuo and the resulting yellow solid was
dissolved in water (200 mL). The aqueous solution was
then carefully basified with 20% NaOH solution to pH 9.
The aqueous layer was extracted with CHZC12 (3 x 100 mL).
The organic layer was separated and dried over NaZS04,
filtered and the solvent was removed in vacuo to obtain
the desired product which was used in the next step
without purification.
2-AMINO-2-(3,4-DIFLUOROPHENYL)-ETHANOL: Into a well-
stirred suspension of LiAlH4 (4.7 g, 0.125 mol) in THF
(120 mL) in a 3-necked round bottom flask fitted with a
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condenser and a dropping funnel, was added a
solution of amino-(3,4-difluorophenyl)-acetic acid
methyl ester (10.0 g, 0.05 mol) in THF (100 mL) dropwise
at 0 °C. The resulting greenish brown suspension was
heated at reflux temperature for 2 h. The reaction
mixture was cooled to 0 °C and then carefully quenched
sequentially with 5 mL of water, 5 mL >of 3N NaOH
followed by 15 mL of water. The resulting suspension
was filtered through a fritted glass funnel. To the
filter cake was added 100 mL Et~O and the suspension was
heated at reflux temperature for 20 min. The suspension
was filtered and the combined filtrates were dried over
MgS04, filtered and the solvent was removed in vacuo. 2-
Amino-2-(3,4-difluorophenyl)-ethanol was obtained as a
yellow glassy syrup which was used in the next step
without further purification.
[1-(3,4-DIFLUOROPHENYL)-2-HYDROXY-ETHYL]-CARBAMIC ACID-
TERT-BUTYL ESTER: Into a solution of 2-amino-2-(3,4-
difluorophenyl) -ethanol (8. 6 g, 49.7 mmol) in CHC13 (150
mL) at 0 °C was added a solution of di-tert-butyl
dicarbonate (11.4 g, 52.0 mmol),in CHC13 (50 mL) in one
portion and the resulting solution was stirred overnight
at room temperature. The solvent was removed in vacuo
and the residue was subjected to column chromatography
on silica gel (2:1 hexane-EtOAc followed by EtOAc) to
obtain [1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic
acid-tert-butyl ester as a white solid (10.0 g, 74%
yield) .
(+)-4-(3,4-DIFLUOROPHENYL)-OXAZOLIDIN-2-ONE: Into a
well-stirred suspension of NaH (1.1 g, 45.8 mmol) in THF
(40 mL) at R.T. was added a solution of [1-(3,5-
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difluorophenyl)-2-hydroxy- ethyl]-carbamic acid-tert-
butyl ester (5.0 g, 18.3 mmol) in THF (20 mL) via a
dropping funnel at room temperature. The resulting
suspension was stirred for 3 h and then quenched
carefully with 10 mL of water. The biphasic mixture was
extracted with 100 mL of Et20, washed with brine,
filtered and the solvent was removed in vacuo. The
gummy residue thus obtained was purified by column
chromatography over silica gel (Rf - 0.15, 3:2 hexane-
EtOAc) to obtain 4-(3,5-difluorophenyl)-oxazolidin-2-one
as a white flaky solid (2.8 g, 77o yield) . M.P. 81-83
°C; 1H NMR (300 MHz, CDC13) 8 7.23-7. 03 (m, 3H) , ...6. 08. (br
s, 1H), 4.94 (dd, J=6.6 Hz, J=8.7 Hz, 1 H), 4.73 (t,
J=8.7 Hz, 1 H), 4.13 (dd, J=6.6 Hz, J=8.7 Hz, 1 H). The
enantiomers were separated by HPLC on a Chiralcel OD (20
x 250 mm) column using 80o hexane/20% isopropyl alcohol
as the eluting system at 12.0 mL/min (U.V. 254 nm). The
retention times for the two isomers were 16.19 min and
20.08 min respectively.
4-NITROPHENYL (4S)-4-(3,4-DIFLUOROPHENYL)-2-OXO-1,3-
OXAZOLIDINE-3-CARBOXYLATE: Into a suspension of NaH
(0.14 g, 5.30 mmol) in 20 mL of anhydrous THF under
argon, a solution of (+) -4- (3, 4-difluorophenyl) -
oxazolidin-2-one (0.88 g, 4.42 mmol) in THF was added
dropwise (dropping funnel). The resulting suspension
was stirred at room temperature for 30 min. This
suspension was then added dropwise via ~cannula into
another round bottom flask containing a solution of 4-
nitrophenylchloroformate (1.11 g, 5.30 mmol) in 25 mL of
THF and cooled at -78 °C over a period of 15 min. The
stirring~was continued for 2 h after which the solvent
.was removed and the residue was purified by column
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chromatography on silica gel with 1:1 hexane/CHZClz
followed by CHzClz (Rf= 0.4, CH2Clz) to obtain the desired
- . product as a white solid (1.55 g, 86% yield).
Similarly, following the above procedure, 4-(3,5-
difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-
nitro-phenyl ester and 4-(3,4,5-trifluorophenyl)-2-oxo-
oxazolidine-3-carboxylic acid-4-nitro-phenyl ester were
obtained by substituting 3,4-diflourobenzaldehyde in the
first step with 3,5-diflourobenzaldehyde or 3,4,5
triflourobenzaldehyde, respectively. The oxazolidinone
enantiomers were resolved by HPLC on a Chiralcel OD
column (as in the previous example) and the 4-nitro
phenyl carbamates were prepared using 4-nitrophenyl
chloroformate.
4-NITROPHENYL (4S)-4-(3,5-DIFLUOROPHENYL)-2-OXO-1,3-
OXAZOLIDINE-3-CARBOXYLATE: Following the procedure for
the synthesis of 4-(3,4-difluorophenyl)-2-oxo-
oxazolidine-3-carboxylic acid-4-nitro-phenyl ester, 3,5
diflourobenzaldehyde yielded the desired product.
1H NMR (400 MHz, CDC13) 8 8.26 (d, 2H, J= 9.3 Hz) , 7.33
- 6.81 (m, 5H), 5.41 (dd, 1H, J=4.1, 8.7 Hz), 4.81 (t,
1H, J=9.3 Hz) , 4.33 (dd, 1H, J=4.1, 9.3 Hz) ; Anal. Calc.
for Cl6HioFzNzOs+0.2EtOAc: C, 52.84; H, 3.06; N, 7.34.
Found: C, 53.26; H, 2.83; N, 7.73
4-NITROPHENYL (4S)-2-OXO-4-(3,4,5-TRIFLUOROPHENYL)-1,3-
OXAZOLIDINE-3-CARBOXYLATE: Following the procedure for
the synthesis of 4-(3,4-difluorophenyi)-2-oxo-
oxazolidine-3-carboxylic acid-4-nitro-phenyl ester,
3,4,5-triflourobenzaldehyde yielded the desired product.
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1H NMR (400 MHz, CDC13) 8 8.27 (d, 2H, J=9.0 Hz) ,
7.31 (d, 2H, J=9.0 Hz), 7.11-7.02 (m, 2H), 5.37 (dd, 1H,
J=4.1, 9.0 Hz), 4.51 (apparent t, 1H, J=9.0 Hz), 4.33
(dd, 1H, J=4.1, 9.0 Hz) ; Anal. Calc. for Cl6HgF3N~O6: C,
50.27; H, 2.37; N, 7.33. Found: C, 50.56; H, 2.50; N,
7.49.
1-(3,4-DIFLUOROPHENYL)-2-METHYL-2-HYDROXYPROPYLAMINE: .
Into a well-stirred solution of methyl 2-amino-2-(3,4-
difluorophenyl)acetate (10.5 g, 52.19 mmol) in anhydrous
ether (200 mL) at 0 °C a solution of methylmagnesium
bromide (3 M, 87 mL, 261 mmol) in ether was added over
10 minutes. The reaction mixture was stirred at 0 °C for
2.5 h and allowed to warm to room temperature. After 12
h, the reaction mixture was carefully poured onto a
mixture of ice (300 g) and saturated aqueous ammonium
chloride (50 g). The ether layer was separated and the
aqueous layer was extracted with more ether (4 X 200
mL). The combined extracts were dried with magnesium
sulfate and the solvent evaporated. The crude product
was purified by column chromatography on silica gel
using chloroform/methanol/2M ammonia in methanol
(1000:20:10, 1000:40:20, 1000:80:40) as the eluent to
give the product as an oil (6.5 g, 62% yield) which was
used in the next step without further purification.
4-(3,4-DIFLUOROPHENYL)-5,5-DIMETHYL-2-OXO-OXAZOLIDINE: A
mixture of 1-(3,4-difluorophenyl~)-2-methyl-2-
hydroxypropylamine (3.00 g, 14.9 mmol) and
carbonyldiimidazole (2.418 g, 14.9 mmol) in
dichloromethane (150 mL) was heated at reflux
temperature for 36 h and the solvent evaporated. The
residue was purified by column chromatography on silica
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gel using chloroform/ethyl acetate (9:1) to give the
product as a viscous oil which solidified on standing
(1.80 g, 50% yield). The product was used in the next
step without further characterization.
4-NITROPHENYL 4-(3,4-DIFLUOROPHENYL)-5,5-DIMETHYL-2-OXO-
1,3-OXAZOLIDINE-3-CARBOXYLATE: Into a stirred suspension
of sodium hydride (60% suspension in paraffin 203 mg,
1.4 eq.) in THF (20 mL) at 0 °C, a solution of 4-(3,4-
difluorophenyl)-5,5-dimethyl-2-oxo-oxazolidine (870 mg,
3.622 mmol) in THF (5 mL) was added followed by stirring
for 30 minutes. This suspension was added to a solution
of 4-nitrophenyl chloroformate (950 mg, 4.71 mmol) in
THF (20 mL) at -78 °C under argon and the stirring was
continued for 2 h. It was slowly warmed to room
temperature and after 4 h the solvent was evaporated.
The residue was mixed with dichloromethane (150 mL),
washed with 0.05 N sodium hydroxide (3 X l0 mL), and
dried (sodium sulfate). The solvent was evaporated and
the residue was purified by column chromatography on
silica gel using chloroform/ethyl acetate (9:1) as the
eluent to give the product as a white powder (860 mg,
59% yield).
1H NMR (400 MHz, CDC13) 8 8.24 (d, 2H, J=9 Hz), 7.29
6.97 (m, 5H), 5.04 (s, 1H), 1.09 (s, 6H); Anal. Calc.
for C18H14FaN2O6+0.2% H20: C, 54.61; H, 3.67; N, 7.08.
Found: C, 54.89; H, 3.59; N, 7.41.
(3,4-DIFLOUROPHENYL)-N(DIPHENYLMETHYLENE)METHANAMINE:
Into a solution of 3,4-difluorobenzylamine (9.8 g, 69
mmol) and benzophenone (13.0 g, 71.0 mmol) in toluene
(200 mL) was added a catalytic amount of BF3.OEt~ and the
resulting solution was heated at reflux temperature for
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12 h. The reaction mixture was concentrated
in vacuo, yielding >950), which was
an oil
(21
g,
characterized NMR analysis and subjected to the
by
following reactionwithout any further purification.
~H
NMR (CDC13) ~ 4.57 (s, ZH), 7.80-6.80(m, 13H).
1-(3.4-DIFLOUROPHENYL)-1-
[(DIPHENYLMETHYLENE)AMINO]PROPAN-2-OL: Into a solution
of the benzhydrylindene-(3,4-difluoro-benzyl)-amine (21
g, 69 mmol) in 250 ml of dry THF was added tert-
butyllithium (1.7 M, 60 ml) dropwise and the resulting
solution was stirred at -78 °C for 0.5 h. To the
solution was added acetaldehyde (10 ml, 180 mmol) in 100
ml of THF and the solution was stirred at -78 °C for 2 h
and 25 °C for 1 h. The reaction mixture was quenched by
addition of brine. The reaction mixture was diluted
with 500 ml of Et20 and washed with brine. The organic
layer was dried over NazS04 and concentrated in vacuo to
give an oil, which was taken to the next step without
any further purification. 1H NMR (CDCl3) b 1.04 (d, 3H),
2 . 77 (broad s . 1H) , 4 . 08 (m, 1H) , 4 . 25 (d, 1H) , 7, 80-6. 80
(m, 13H) .
1-AMINO-1-(3,4-DIFLUORO-PHENYL)-PROPAN-2-OL: A solution
of crude product from the previous procedure and
MeONH2.HC1 (10 g, 120 mmol) was diluted in 200 ml of MeOH
and stirred for 12 h. The reaction mixture was
concentrated in vacuo, yielding an oily residue, which
was re-dissolved in 200 ml of EtOAc and washed with
brine. The organic layer was concentrated in vacuo to
produce an oily mixture, which was subjected to column
chromatography [5% NH3 (2.0 M in MeOH) in CHC13] to yield
the desired product (8.8 g, 68% yield from 3,4-
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difluorobenzylamine) as a mixture of diastereomers.
1H NMR (CDC13) (~ 4:1 mixture of the diastereomers) S
1.02 (d, J=6.0 Hz, 3 H), 1.04 (d, J=6.3 Hz, 3 H), 2.10
(br, 6 H), 3.56-3.69 (m, 2 H), 3.88-3.92 (m, 2 H), 7.02-
7.17 (m, 6 H) .
(1-(3,4-DIFLUOROPHENYL)-2-HYDROXY-PROPYL~-CARBAMIC ACID-
TERT-BUTYL ESTER: Into a solution of 1-amino-1-(3,4-
difluorophenyl)-propan-2-of (13.1 g, 70.1 mmol) in CHC13
(150 mL) at 0 °C was added a solution of di-tert-butyl
dicarbonate (19.3 g, 87.6 mmol) in CHC13 (50 mL) in one
portion and the resulting solution was stirred overnight
at room temperature. The solvent was removed in vacuo
and the residue was subjected to column chromatography.
on silica gel (2:1 hexane-EtOAc followed by EtOAc) to
obtain [1- (3, 4-difluorophenyl) -2-hydroxy-propyl] -
carbamic acid-tert-butyl ester as a viscous oil (18.4 g,
91 o yield) . 1H NMR ( CDC13 ) ( ~ 4 : 1 mixture of the
diastereomers) ~ 1.05 (d, J=6.6 Hz, 3 H), 1.25 (d, J=6.0
Hz, 3 H), 1.41 (br, 20 H), 3.92-4.19 (br, 2 H), 4.45-
4.60 (m, 2 H), 5.41-5.49 (br, 2 H), 7.02-7.17 (m, 6 H).
4-(3,4-DIFLUOROPHENYL)-5-METHYL-OXAZOLIDIN-2-ONE: Into a
well-stirred solution of [1-(3,4-difluorophenyl)-2-
hydroxy-propyl]-carbamic acid-tert-butyl ester (0.43 g,
1 .5 mmol) in THF (20 mL) was added 95 o NaH (0.09 g, 3 . 8
mmol) at room temperature. When the reaction was
carried out on a larger (> 5 g) scale, 1.0 equivalent of
KH and 1.5 eq. of NaH was used as the base. The
resulting suspension was stirred for 3 h at about 35 °C
(warm water bath) and then quenched carefully with ice.
The biphasic mixture was extracted with 100 mL of EtOAc,
washed with brine, dried over Na2S04, filtered and the
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solvent was removed in vacuo. The two
diastereomers were separated by column chromatography
over silica gel (First isomer: 0.16 g, Rf - 0.6, 3:1
hexane-EtOAc; second isomer: 0.18 g, Rf - 0.5, 3:1
hexane-EtOAc). NOE experiments suggested that the first
diastereomer had the methyl and the aryl group in trans
configuration while the second diastereomer had cis
relationship between the two groups. The 1H NMR spectrum
fox the trans diastereomer is as follows. 1H NMR (CDC13)
~ 1.49 (d, J = 6.0 Hz, 3H), 4.37 (dq, J = 6.0 Hz, J =
7.2 Hz, 1H) , 4.45 (d, J = 7.2 Hz, 1H) , 6.63 (br S, 1H) ,
7.08-7.28 (m, 3H) .
The 1H NMR spectrum f or the cis diastereomer is as
follows. 1H NMR (CDC13) b 0.96 (d, J = 6. 6 Hz, 3H) , 4.91
(d, J = 8. 1 Hz, 1H) , 4. 99 (dq, J = 6. 6 Hz, J = 8 . 1 Hz,
1H), 6.63 (br s, 1H), 7.08-7.28 (m, 3H).
4-(3,4-DIFLUOROPHENYL)-5-METHYL-2-OXO-OXAZOLIDINE-3-
CARBOXYLIC ACID-4-NITRO-PHENYL ESTER . Into a solution
- of one of the two diastereomers of 4-(3,4-
difluorophenyl)-5-methyl-oxazolidin-2-one (0.97 g, 4.55
mmol) in 60 mL THF was added a solution of n-
butyllithium in hexane (3.06 mmol, 4.9 mmol) dropwise
via a syringe under argon atmosphere at -78 °C. The
resulting yellow solution was stirred at -78 °C for 40
min. This solution was then added dropwise via a
cannula into another round bottom flask .containing a
solution of 4-nitrophenylchloroformate (1.03 g, 5.1
mmol) in 60 mL of THF, cooled at -78 °C, over a period of
15 min. After five minutes, the flask was removed from
the cooling bath and stirring was continued for 1 h. The
reaction mixture was quenched by adding ice and it was
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extracted with EtOAc. The organic extracts were
washed with brine and the organic layer was dried over
Na2S04. The solvent was removed after filtration and the
residue was purified by column chromatography on silica
gel with 1:1 hexane/CHZC12 followed by CHzCl~ to give the
desired product.
The relative configurations of the cis and trans isomers
were assigned on the basis of 1H NMR analysis of the
respective p-nitrophenyloxycarbonyl derivatives. For
the trans isomer, an NOE was observed between the
protons of the C-5 methyl group and the proton at C-4.
No NOE was observed between the protons at the C-4 and
C-5 positions of this isomer, which was thus assigned
traps stereochemistry. For the cis isomer, no NOE was
observed between the protons of the C-5 methyl group and
the proton at C-4. However, a NOE was observed between
the protons at the C-4 and C-S positions, leading us to
assign this isomer cis stereochemistry. The vicinal
coupling constants of the C-4 protons of cis (J = 7.8
Hz) and traps (J = 5.1 Hz) are also consistent with the
values reported for similar oxazolidinones, and were
thus helpful in making the stereochemical assignments
(Dondoni, A.; Perrone, D.; Semola, T. Synthesis 1995,
181) .
Enantiomers of the diastereomers were separated by HPLC
by using a Chiralcel OD column (20 x 250 mm) with 80%
hexane/20% isopropyl alcohol/ 0.1 o diethylamine as the
eluting system (12 mL/min) under isocratic conditions
(U. V. 254 nm).
In order to assign the absolute configurations at the
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stereogenic centers of the oxazolidinone rings, a new
synthetic route was designed which employed an
enantiomerically pure substrate derived from the chiral
pool. .Commercially available (S)-(+)-methyl lactate was
converted into its pyrrolidine amide according to the
method of Martin et al (Martin, R. ; Pascual, O. ; Romea,
P.; Rovira, R.; Urpi, F.; Vilarrasa, J. Tetrahedron
Lett. 1997, 38, 1633) . Following the protection of the
hydroxy group of (2S)-1-oxo-1-(1-pyrrolidinyl)-2-
propanol to a TBDMS group, treatment of tert-
butyl(dimethyl)silyl (1S)-1-methyl-2-oxo-2-(1-
pyrrolidinyl)ethyl ether with 3,4-difluorophenyllithium
yielded (2S) -2- f [tent-butyl (dimethyl) silyl] oxy}-1- (3, 4-
difluorophenyl)-1-propanone as the sole product, which
was then converted to (2S)-2-~[tert-
butyl(dimethyl)silyl]oxy}-1-(3,4-difluorophenyl)-1-
propanone oxime. Reduction of the (2S)-2-{[tert-
butyl (dimethyl) silyl] oxy}-1- (3, 4-difluorophenyl) -1-
propanone oxime with LiAlH4, N-acylation, and base
induced cyclization provided oxazolidinone
diastereomers, which were separated by flash column
chromatography. The enantiomeric purity of these
isomers was confirmed by chiral HPLC analysis and their
relative configurations were assigned by comparison of
their 1H NMR spectra with those of the racemic isomers.
As the absolute configuration at C-5 of the lactic acid
derived oxazolidinone described above is (S), the C-4
center in traps compounds also has the (S)
configuration. Accordingly, the. absolute configurations
for the stereogenic centers in the cis compounds are
assigned accordingly (4R,5S).
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4-NITROPHENYL (4S,5R)-4- (3.4-DIFLUOROPHENYL)-5-
METHYL-2-OXO-1,3-OXAZOLIDINE-3-CARBOXYLATE: 1H NMR (400
MHz, CDC13) 8 8.25 (d, 2H, J=8.8 Hz), 7.30 - 6.99 (m,
5H), 5.35 (d, 1H, J.=7.7 Hz), 5.07 (apparent quintet,
1H), 1.17 (d, 3H, J=6.5 Hz); Anal. Calc. for
C1~H12F2Nz06+0.5H20: C, 52.72; H, 3.38; N, 7.23. Found: C,
53.09; H, 3.19; N, 7.50. .
(+)-2-AMINO-3-(3,4-DIFLUORO)-PHENYL-PROPAN-1-OL: (+)-
3,4-difluorophenyl alanine (1.0 g, 5.0 mmol) was added
in small portions to a stirring suspension of LiAlH4
(0.480 g, 12.5 mmol) in THF (30 mL) at 0 °C. The
resulting gray suspension was then heated at reflux for
2 h. The reaction mixture was cooled to 0 °C and then
Z5 carefully quenched sequentially with water (0.5 mL), 3 N
NaOH (0.5 mL), and water (1.50 mL). The resulting
suspension was filtered through a fritted glass funnel.
Ether (50 ~mL) was added to the filter cake and the
suspension was heated at reflux temperature for 20 min.
The suspension was filtered and was combined with the
previous filtrate. The combined organics were dried
over MgS04, filtered and the solvent was removed in
vacuo. 2-Amino-3-(3,4-difluoro)-phenyl-propan-1-of was
obtained as a white solid (0.500 g, 1000) which was used
in the next step without further purification.
(+)-[1-(3,4-DIFLUOROBENZYL)-Z-HYDROXY-ETHYL -CARBAMIC
ACID-TERT-BUTYL ESTER: A solution of di-tert-butyl
dicarbonate (0.640 g, 2.90 mmol) in CHC13 (10 mL) was
added in one portion to a solution of (+)-2-amino-3-
(3,4-difluoro)-phenyl-propan-1-of (0.500 g, 2.62 mmol)
in CHC13 (20 mL) at 0 °C and the resulting solution was
stirred overnight at room temperature. The solvent was
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removed in vacuo and the residue was
chromatographed (2:1 hexane-EtOAc, followed by EtOAc),
giving (+) - [1- (3, 4-difluorobenzyl) -2-hydroxy-ethyl] -
carbamic acid-tert-butyl ester as a white solid (0.640
g, 99a) .
(+)-4-(3,4-DIFLUORO-BENZYL)-OXAZOLIDIN-2-ONE: A solution
of (+)-[1-(3,4-difluorobenzyl)-2-hydroxy-ethyl]-carbamic
acid-tert-butyl ester (1.00 g, 4.00 mmol) in THF (10 mL)
was added via a dropping funnel to a stirring suspension
of 95o NaH (0.12 g, 5.0 mmol) in THF (20 mL) at room
temperature. The resulting suspension was stirred for 3
'- h and then quenched carefully with water (10 mL). The
biphasic mixture was extracted with Et~O (50 mL), washed
with brine, filtered and the solvent was removed in
vacuo. The resulting gummy residue was purified by
column chromatography (Rf - 0.25, 3:2 hexane-EtOAc), to
giT,re the desired product as a white solid (0.320 g,
760) .
(+)-4-(3,4-DIFLUORO-BENZYL)-OXAZOLIDIN-2-ONE-3-
CARBOXYLIC ACID-4-NITRO-PHENYL ESTER: A solution of.(+)-
4-(3,4-difluoro-benzyl)-oxazolidin-2-one (0.210 g, 1.0
mmol) in THF (10 mL) was added dropwise via a dropping
funnel to a stirring suspension of NaH (30.0 mg, 1.30
mmol) in anhydrous THF (10 mL) under argon. The
resulting suspension was stirred at room temperature for
min. This suspension was then added .dropwise via
cannula to a solution of 4-nitrophenylchloroformate
30 (0.300 g, 1.50 mmol) in THF (20 mL) at -78 °C over 15
min. Stirring was continued for 2 h after which the
solvent was removed and the residue was purified by
column chromatography (1:1 hexane/CHaCl2, followed by
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CHZC12; Rf= 0.4, CH2Cla) , to give the desired product
as a yellow solid (0.350 g, 820).
Similarly, following the above procedure, 4-nitrophenyl
4-(4-fluorobenzyl)-2-oxo-1,3-oxazolidine-3-carboxylate
was obtained by substituting (+)-3,4-diflourophenyl
alanine with p-fluorophenyl alanine:
4-NITROPHENYL 4-(4-FLUOROBENZYL)-2-OXO-1,3-OXAZOLIDINE-
3-CARBOXYLATE: H (d, 2H,
1 NMR
(400
MHz,
CDC13)
8
8.32
J=9.3 Hz), 7.42 (d, 2H, J=8.9 Hz), 7.24-6.99(m, 4H),
4.69 - 4.59 (m, 1H), 4.35 (t, 1H, J=8.6 Hz), 4.23
(dd,
1H, J=2 .7, 9 .3 Hz) 3 (dd, 1H, J=3 . 8, Hz) ,
, .37 13 . 6 2 .94
(dd, 1H, J=9.3, 13.6 Hz) Anal.- Calc. for 3FNa06:
; C1~H1 C,
56.67; H, 3.64; N, 7.77.Found: C, 56.94; 3.76;
H, N,
7.71.
2-[6-(4-PHENYL-1-PIPERIDINYL)HEXYL]-1H-ISOINDOLE-
1,3(2H)-DIONE: To the 500 ml RB-flask was added 4-
phenylpiperidine hydrochloride (5 g, 25 mmol), N-(6-
bromohexyl)phthalimide (15.5 g, 50 mmol), N,N-
diisopropylethylamine (21.8 ml, 125 mniol),
tetrabutylammonium iodide (0.2 g), and dioxane (250 ml)
at room temperature. The reaction mixture was stirred
at 100 °C for 72 h. fihe solvent was removed in vacuo and
the crude product was purified by flash chromatography
(98:2 - Chloroform . 2N ammonia in methanol) to afford
7 . 67 g of the desired product (77 o yield) :~ 1H NMR (400
MHz, CDC13) ~ 7.78-7.79 (m, 2H), 7.74-7.65 (m, 2H), 7.32-
7.14 (m, 5H), 3.69 (t, 2H, J=7.35 Hz), 3.06 (d, 2H,
J=11.0 Hz), 2.49 (quintet, 1H, J=7.6 Hz), 2.36 (t, 2H,
J=7.6 Hz) , 2.02 (t, 2H, J=12.5 Hz) , 1.82 (br s, 4H) ,
1.69 (t, 2H, J=6.3 Hz), 1.54 (br s, 2H), 1.37 (br s,
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4H); ESMS m/e: 391.3 (M + H)+; Anal. Calc. for
C~SH3oN20Z+0.2Ha0: C, 76.19; H, 7.77; N, 7.11. Found: C,
76.14; H, 7.38; N, 7.13.
METHOD I. General procedure for the Preparation of the
substituted 4-[4-(3-aminophenyl)-1-piperidinyl]-1-
(phenyl)-1-butanones: A mixture of 4-(3-
aminophenyl)piperidine (2.0 mmol), 2.4 mmol of the
appropriate substituted phenyl butyryl chloride (e.g. 4-
chloro-4'-phenoxybutyrophenone, 4-chloro-3',4'-
dimethylbutyrophenone, 4-chloro-4'-chlorobutyrophenone,
'y-chlorobutyrophenone, 4-chloro-3',4'-
dimethoxybutyrophenone) , 3.0 mmol of KZC03, and 10 mg of
18-crown.-6 in 5 mL of toluene were heated at 110 °C for
2.5 days. The reaction mixture was concentrated and
chromatographed on silica (5% methanol in .
dichloromethane) to give the desired compound:
4- [4- (3-AMINOPHENYL) -1-PIPERIDINYL] -1- (4-PHENOXYPHENYL) -
1-BUTANONE: Using Method I, the desired product was
obtained. 305 mg; ESMS m/e . 415.4 (M + H)+.
4- [4- (3-AMINOPHENYL) -1-PIPERIDINYL] -1- (3, 4-
DIMETHYLPHENYL)-1-BUTANONE: Using Method I, the desired
product was obtained. 320 mg; ESMS m/e . 351.3 (M + H)+.
4-[4-(3-AMINOPHENYL)-1-PIPERIDINYL]-1-(4-CHLOROPHENYL)-
1-BUTANONE: Using Method I, the desired product was
obtained. 500 mg; Anal. Calc for Cz1H25C1N~0+0.3H~0: C,
69.62; H, 7.12; N, 7.73. Found: C, 69.63; H, 7.34; N,
7.60; ESMS m/e . 357.3 (M + H)+.
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4- [4- (3-AMINOPHENYL) -1- PIPERIDINYL] -1-PHENYL-3.-
BUTANONE: Using Method I, the desired product was
obtained. 250 mg; Anal. Calc for C2lHzsNzO+0.2H20: C,
77.36; H, 8.16; N, 8.59. Found: C, 77.55; H, 8.12; N,
8.75; ESMS m/e . 323.3 (M + H)+.
4-[4-(3-AMTNOPHENYL)-1-PIPERIDINYL]-1-(2,4-
DIMETHOXYPHENYL)-1-BUTANONE: Using Method I, the desired
product was obtained. 330 mg; Anal. Calc for
C23HaoNaOs+O.5H20: C, 70.56; H, 7.98; N, 7.16. Found: C,
70.69; H, 7.87; N, 6.99; ESMS m/e . 383.3 (M + H)+.
METHOD II. General Procedure for the Acylation or
Sulfonylation of the Substituted 4-[4-(3-Aminophenyl)-1-
piperidinyl]-1-(4-phenyl)-1-butanones: A mixture of 1
equivalent of a substituted 4-[4-(3-aminophenyl)-1-
piperidinyl]-1-(4-phenyl)-1-butanone., 1.5 equivalent of
an acid chloride or a sulfonyl chloride, and 5
equivalents of diisopropylethylamine, in dichloromethane
was stirred at room temperature for two days. The
reaction mixture was applied to a preparative TLC plate
and eluted with dichloromethane: methanol (15:1,
containing 1°s isopropyl amine) to give the desired
product.
METHOD III. General procedure for the Preparation of
the substituted 4-N- (3-{1- [4- (phenyl) -4-oxobutyl] -4-
pip.eridinyl~phenyl) acetamides: A mixture . of N- [3- (4-
piperidinyl)phenyl]acetamide (1.0 eq) and an aryl
substituted chlorobutyrophenone (2.0 eq), KaC03 (5.0 eq),
diisopropylethylamine (3.0 eq) and tetrabutylammonium
iodide (cat. 5-l00) in dioxane (0.5 to 1.0 M) were
heated at reflux temperature for 16 h. The reaction
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mixture was filtered and concentrated in vacuo.
The crude product was chromatographed using silica
preparative TLC (chloroform . methanol containing 0.5%
isopropyl amine) to give the desired product.
Example 1
N-(3-~1-[4-(3,4-DIMETHYLPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)ACETAMIDE: Using Method III, the
desired product was obtained. iH NMR (CDC13) S 7.75 (s,
1H), 7.71 (d, 1H, J=7.6 Hz), 7.45 (d, 2H, J=7.2 Hz),
7.35 (s, 1H) , 7.26-7.22 (m, 2H) , 6.93 (d, 1H, J=7.6 Hz) ,
3.24-3.21 (m, 2H), 3.04 (t, 2H, J=7.0 Hz), 2.67-2.63 (m,
2H), 2.59-2.48 (m, 1H), 2.32 (s, 6H), 2.30-2.27 (m, 2H),
2.18 (s, 3H), 2.14-2.06 (m, 2H), 2.00-1.80 (m, 4H); ESMS
m/e . 393.3 (M + H)+.
Example 2
N- (3-~1- [4- (3,4-DIMETHYLPHENYL) -4-OXOBUTYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of
0.0500 g (0.200 mmol) of 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide, 0.100 g (0.480 mmol) of
4-chloro-3',4'-dimethylbutyrophenone, 0.080 g (0.600
mmol) of KaC03 and 0.090 g (0.600 mmol) of NaI in 5 mL of
DMF was heated at reflux temperature for 18 hours. The
reaction mixture was filtered, the filtrate was poured
into 5 mL of water and washed with 3 X 5 mL of ethyl
acetate. The combined organic extracts were dried
(MgS04), concentrated in vacuo and purified by
preparative TLC (silica; 9.5 . 0.5, dichloromethane
methanol + 1 o isopropyl amine) to afford 0 . 067 g (80. 0%
yield) of the desired product: 1H NMR (400 MHz, CDC13) b
7.72 (d, 1H, J=8.0 Hz), 7.44 (s, 1H), 7.38 (d, 1H, J=8.0
Hz) , 7.23-7.20 (m, 2H) , 7.16 (s, 1H) , 6.95 (d, 1H, J=6.8
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Hz), 3.13-3.11 (m, 2H), 3.02 (t, 2H, J=7.0 Hz),
2.56-2.40 (m, 4H), 2.32 (s, 6H), 2.17-2.15 (m, 2H),
2,04-1.78 (m, 6H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e .
421 . 3 (M + H) +.
Example 3
N- (3-~1- j4- (3~4-DIMETHYLPHENYL) -4-OXOBUTYL] -4-
PIPERIDINYL~PHENYL)CYCLOHEXANECARBOXAMIDE: Using Method
II, the desired compound was obtained. 1H NMR (400 MHz,
CDC13) 8 7.80-6.81 (m, 7H) , 3 .41-3 .00 (m, 4H) , 2.95-2.41
- (m, 4H), 2.32 (s, 6H), 2.22-1.05 (m, 18H); ESMS m/e .
461 . 4 (M + H) +.
Example 4
N-(3-~1-[4-(3,4-DIMETHYLPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)-2-PHENYLACETAMIDE: Using Method II,
the desired product was obtained. 1H NMR (400 MHz, CDC13)
8 7.85-7.65 (m, 2H), 7.45-6.92 (m, 10H), 3.76 (s, 2H),
3.10-2.90 (m, 4H), 2.50-2.35 (m, 3H), 2.32 (s, 6H),
2.10-1.85 (m, 4H), 1.80-1.60 (m, 4H); ESMS m/e . 469.4
(M + H)+.
Example 5
N-(3-~1-[4-(3,4-DIMETHYLPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)-2-(3-METHOXYPHENYL)ACETAMIDE: Using
Method II, the desired product was obtained. 1H NMR (400
MHz, CDC13) b 7.76-7.65 (m, 2H), 7.38-7.12 (m, 6H), 6..95
6.80 (m, 3H) , 3 .82 (s, 3H) , 3 .70 (s, 2H) , 3.10-2 .90 (m,
4H) , 2.50-2 .38 (m, 3H) , 2.32 (s, 6H) , 2 .10-1 . 85 (m, 4H) ,
1.80 -1.60 (m, 4H); ESMS m/e . 499.4 (M + H)+.
Example 6
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N- (3-~1- [4- (3, 4- DIMETHYLPHENYL) -4-
OXOBUTYL]-4-PIPERIDINYL~PHENYL)-2-METHOXYACETAMIDE:
Using Method II, the desired product was obtained. 1H NMR
(400 MHz, CDC13) b 7.80-7.75 (m, 2H) , 7.50-7.38 (m, 2H) ,
7.34-6.90 (m, 3H) , 4.00 (s, 2H) , 3 .51 (s, 3H) , 3.30-2.95
(m, 4H) , 2.70-2.50 (m, 3H) , 2.32 (s, 6H) , 2.15 -1.80 (m,
8H); ESMS m/e . 423.3 (M + H)+.
Example 7
N- (3-~1- [4- (3, 4-DIMETHYLPHENYL) -4-OXOBUTYL] -4-
PIPERIDINYL~PHENYL)METHAN'ESULFONAMIDE: Using Method II,
the desired product was obtained. 1H NMR (400 MHz, CDC13)
8 7.82-7.10 (m, 7H), 3.41 (s, 3H), 3.40-2.85 (m, 4H),
2 . 82-2 .35 (m, 5H) , 2 .32 (s, 6H) , 2 .22-1 . 80 (m, '6H) ; . ESMS
m/e . 429.3 (M + H)+.
Example 8
N-(3-~1-[4-(3,4-DIMETHYLPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)ETHANESULFONAMIDE: Using Method II,
the desired product was obtained. 1H NMR (400 MHz, CDC13)
8 7.75 (s, 1H), 7.71 (d, 1H, J=7.6 Hz), 7.30-7.09 (m,
4H), 7.02 (d, 1H, J=7.2 Hz), 3.36-3.05 (m, 6H), 2.77-
2.52 (m, 3H) , 2 .32 (s, 6H) , 2.15-1. 82 (m, 8H) , 1.37 (t,
3H, J=7.4 Hz); ESMS m/e . 443.3 (M + H)+
Example 9
N- ( 3 - f 1- [ 4 - ( 4 - CHLOROPHENYL ) - 4 - OXOBUTYL] - 4 -
PIPERIDINYL~PHENYL)ACETAMIDE: Using Method III, the
desired product was obtained. 1H NMR (400 MHz, CDC13) 8
7.92 (d, 2H, J=8. 8 Hz) , 7.55-7.40 (m, 3H) , 7.35 (s, 1H) ,
7.22 (t, 1H, J=8.0 Hz), 6.92 (d, 1H, J=8.0 Hz), 3.30-
3.27 (m, 2H) , 3 .09 (t, 2H, J=7.0 Hz) , 2.76-2.39 (m, 5H) ,
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2.20 (s, 3H), 2.17-1.85 (m, 6H); ESMS m/e . 399.3
(M + H) +.
Example 10
N- (3-~l- [4- (4-CHLOROPHENYL) -4-OXOBUTYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Using Method
II, the desired product was obtained. 1H NMR (400 MHz,
CDC13) 8 7.93 (d, 2H, J=8.6 Hz) , 7.45 (d, 2H, J=8.6 Hz) ,
7.39 (d, 1H, J=7.2 Hz) , 7.32 (s, 1H) , 7.24 (t, 1H, J=7.8
Hz) , 6.94 (d, 1H, J=8.4 Hz) , 3.21-3 .18 (m, 2H) , 3.05 (t,
2H, J=7.0 Hz), 2.64-2.51 (m, 4H), 2.28-1.86 (m, 8H),
1.26 (d, 6H, J=6.8 Hz),- ESMS m/e . 427.3 (M + H)+.
Example 11
N-(3-~1-[4-(4-CHLOROPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)CYCLOHEXANECARBOXAMIDE: Using Method
II, the desired product was obtained. 1H NMR (400 MHz,
CDC13) 8 7.93 (d, 2H, J=8.4 Hz), 7.55-7.19 (m, 5H), 6.93
(d, 1H, J=7.6 Hz) , 3 .25-3 .00 (m, 4H) , 2.65-2.45 (m, 4H) ,
2.30-1.50 (m, 18H); ESMS m/e . 467.3 (M + H)+.
Example 12
N- (3-~1- [4- (4-CHLOROPHENYL) -4-OXOBUTYL] -4-
PIPERIDINYL~PHENYL)-2-PHENYLACETAMIDE: Using Method II,
the desired product was obtained. ''H NMR (400 MHz, CDC13)
b 7.92 (d, 2H, J=8.4 Hz), 7.46-7.26 (m, 9H), 7.20 (t,
' 1H, J=7.6 Hz), 6.92 (d, 1H, J=7.6 Hz), 3.75 (s, 2H),
3.15-3.13 (m, 2H), 3.03 (t, 2H, J=7.0 Hz), 2.64-2.46 (m,
3H), 2.22-1.60 (m, 8H); ESMS m/e . 475.3 (M + H)+.
Example 13
N-(3-~1-[4-(4-CHLOROPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)-2-(3-METHOXYPHENYL)ACETAMIDE: Using
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Method II, the desired product was obtained. IH
NMR (400 MHz, CDC13) 8 7.92 (d, 2H, J=8.4 Hz) , 7.44 (d,
2H, J=8.4 Hz) 7.38 (s, 1H), 7.35-7.25 (m, 3H), 7.19 (t,
1H, J=7.8 Hz),~6.94-6.86 (m, 3H), 3.81 (s, 3H), 3.72 (s,
2H), 3.12-3.09 (m, 2H), 3.02 (t, 2H, J=6.8 Hz), 2.57-
2.44 (m, 3H), 2.20-1.60 (m, 8H); ESMS m/e . 505.3 (M +
H)+.
Example 14
N-(3-~1-[4-(4-CHLOROPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)-2-METHOXYACETAMIDE: Using Method II, ,
the desired product was obtained. 1H NMR (400 MHz,
CDC13) 8 7. 93 (d, 2H, J=8.4 Hz) , 7.50-7.25 (m, 5H) , 6. 98
(d, 1H, J=7.8 Hz), 4.01 (s, 2H), 3.57 (s, 3H), 3.30-3.15
(m, 2H), 3.06 (t, 2H, J=6.8 Hz), 2.70-2.50 (m, 3H),
2.35-1.80 (m, 8H); ESMS m/e . 429.3 (M + H)+.
Example 15
N-(3-~1-[4-(4-CHLOROPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)METHANESULFONAMIDE: Using Method II,
the desired product was obtained. 1H NMR (400 MHz,
CDC13) 8 7.95-6.96 (m, 8H), 3.48 (s, 3H), 3.28-2.90 (m,
6H), 2.80-2.57 (m, 3H), 2.38-1.86 (m, 6H); ESMS m/e .
435.2 (M + H)+.
Example 16
N- (3-~l- [4- (4-CHLOROPHENYL) -4-OXOBUTYL] -4-
PIPERIDINYL~PHENYL)ETHANESULFONAMIDE: Using Method II,
the desired product was obtained. 1H NMR (400 MHz,
CDC13) 8 7.93 (d, 2H, J=8.2 Hz) , 7.45 (d, 2H, J=8.2 Hz) ,
7.30-7.08 (m, 3H), 6.99 (d, 1H, J=7.6 Hz), 3.26-3.02 (m,
6H), 2.69-2.45 (m, 3H), 2.32-1.75 (m, 8H), 1.36 (t, 3H,
J=7.4 Hz); ESMS m/e . 449.3 (M + H)+.
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Example 17
N-~3- [1- (4-OXO-4-PHENYLBUTYL) -4-
PIPERIDINYL]PHENYL~ACETAMIDE: Using Method III, the
desired product was obtained. 1H NMR (400 MHz, CDC13) 8
8.10-6.80 (m, 9H), 3.40-2.95 (m, 4H), 2.85-2.20 (m, 3H),
2.19 (s, 3H), 2.15-1.70 (m, 8H); ESMS m/e . 365.3 (M +
H)+.
Example 18
2-METHYL-N-~3-[1-(4-OXO-4-PHENYLBUTYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Using Method II, the
desired product was obtained. 1H NMR (400 MHz, CDC13) 8
7.99 (d, 2H, J=7.4 Hz) , 7.57 (t, 1H, J=7.4 Hz) , 7.48 (t,
2H, J=7.4 Hz), 7.45-7.20 (m, 2H), 7.24 (t, 1H, J=8.0
Hz) , 6 . 94 (d, 1H, 8.0 Hz) , 3 .24-3 .21 (m, 2H) , 3.. 09 (t,
2H, J=7.0 Hz), 2.57-2.25 (m, 4H), 2.31-1.84 (m, 8H),
1.26 (d, 6H, J=7.2 Hz); ESMS m/e . 393.3 (M + H)+.
Example 19
N-~3-[1-(4-OXO-4-PHENYLBUTYL)-4-PIPERIDINYL]PHENYL-2-
PHENYLACETAMIDE: Using Method II, the desired product
was obtained. 1H NMR (400 MHz, CDC13) 8 7.98 (d, 2H, ,
J=7.6 Hz), 7.65-7.15 (m, 11H), 6.92 (d, 2H, J=7.2 Hz),
3.74 (s, 2H), 3.20-2.95 (m, 4H), 2.65-2.40 (m, 3H),
2.25-1.70 (m, 8H); ESMS m/e . 441.3 (M + H)+.
Example 20
2-(3-METHOXYPHENYL)-N-~3-[1-(4-OXO-4-PHENYLBUTYL)-4-
PIPERIDINYL]PHENYL~ACETAMIDE: Using Method II, the
desired product was obtained. 1H NMR (400 MHz, CDC13) 8
7.98 (d, 2H, J=7.6 Hz), 7.56 (t, 1H, J=7.62 Hz), 7.46
(t, 2H, J=7.6 Hz), 7.40 (s, 1H), 7.37-7.26 (m, 2H), 7.19
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(t, 1H, J=7.8 Hz), 6.94- 6.86 (m, 3H), 3.8I (s,
3H), 3.71 (s, 3H), 3.12-3.03 (m, 4H), 2.57-2.44 (m, 3H),
2.16-1.77 (m, 8H) ; ESMS m/e . 471.3 (M + H)+.
Example 21
N- ( 3 - f 1- [ 4 - ( 2 , 4 -DIMETHOXYPHENYL ) - 4 - OXOBUTYL] - 4 -
PIPERIDINYL~PHENYL)ACETAMIDE: Using Method III, the
desired product was obtained. 1H NMR (400 MHz, CDC13) 8
7.82 (d, 1H, J=8.8 Hz), 7.54 (d, 1H, J=7.6 Hz), 7.33 (s,
1H), 7.22 (t, 1H, J=7.6 Hz), 6.93 (d, 1H, J=7.6 Hz),
6.53 (d, 1H, J=8. 8 Hz) , 6.46 (s, 1H) , 3 .90 (s, 3H) , 3 .86
(s, 3H), 3.48-3.27 (m, 2H), 3.05 (t, 2H, J=6.8 Hz),
2.90-2 .68 (m, 2H) , 2.65-2.38 (m, 3H) , 2.25 -(s, 3H) ,
2.18-1.80 (m, 6H); ESMS m/e . 425.3 (M + H)+.
Example 22
N-(3-~1-[4-(2,4-DIMETHOXYPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Using Method
II, the desired product was obtained. 1H NMR (400 MHz,
CDC13) 8 7.98 (d, 1H, J=8.6 Hz) , 7.41-7.37 (m, 2H) , 7.24
(t, 1H, J=7.8 Hz), 6.96 (d, 1H, J=7.8 Hz), 6.54 (d, 1H,
J=8.6 Hz), 6.46 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H),
3 .11-3 .08 (m, 2H) , 2.98 (t, 2H, J=7.2 Hz) , 2.53-2.46 (m,
4H) , 2.13-1.79 (m, 8H) , 1 .25 (d, 6H, J=6.8 Hz) ; ESMS m/e
. 453.3 (M + H)+.
Example 23
N-(3-~1-[4-(2,4-DIMETHOXYPHENYL)-4-OXOBUTYL]'-4-
PIPERIDINYL~PHENYL)-2-PHENYLACETAMIDE: Using Method II,
the desired product was obtained. 1H NMR (400 MHz,
CDC13) 8 7.85 (m, 12H) , 3 .89 (s, 3H) , 3 .86 (s, 3H) , 3 .74
(s, 2H), .3.22-2.90 (m, 4H), 2.64-2.40 (m, 3H), 2.25-1.70
(m, 8H); ESMS m/e . 501.3 (M + H)+.
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Example 24
N-(3-fl-(4-(2,4-DIMETHOXYPHENYL)-4-OXOBUTYL]-4-
PTPERIDINYL~PHENYL)-2-(3-METHOXYPHENYL)ACETAMIDE:Using
.Method II, the desired product was obtained. 1H NMR (400
MHz, CDC13) 8 7 . 82 (d, 1H, J=8. 8 Hz) , 7.48-7 .15 (m, 5H) ,
6.95-6.80 (m, 3H), 6.58-6.45 (m, 2H), 3.89 (s, 3H), 3.86
(s, 3H) , 3 .81 (s, 3H) , 3.72 (s, 2H) , 3.25-2.95 (m, 4H) ,
2.65-2.40 (m, 3H), 2.30-1.95 (m, 4H), 1.93-1.72 (m, 4H);
ESMS m/e . 531.3 (M + H)+.
Example 25
N-(3-~1-[4-OXO-4-(4-PHENOXYPHENYL)BUTYL]-4-
PIPERIDINYL~PHENYL)ACETAMIDE: Using Method III, the
desired product was obtained.
1H NMR (400 MHz, CDC13) 8 8.15-6.75 (m, 13H), 3.30-2.80
(m, 4H) , 2.75-2 .10 (m, 5H) , 2 .03 (s, 3H) , 2.00-1 .60 ~(m,
6H); ESMS m/e . 457.3 (M + H)+.
Example 26
2-METHYL-N-(3-~1-[4-OXO-4-(4-PHENOXYPHENYL)BUTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Using Method II, the
desired product was obtained. 1H NMR (400 MHz, CDC13)
7.96 (d, 2H, J=8.8 Hz), 7.43-7.15 (m, 6H), 7.10-6.93 (m,
5H), 3.42-2.95 (m, 4H), 2.80-2.45 (m, 4H), 2.20-1.80 ~(m,
8H), 1.14 (d, 6H, J=6.8 Hz); ESMS m/e . 485.4 (M + H)+.
Example 27
2-(3-METHOXYPHENYL)-N-(3-~1-[4-OXO-4-(4-
PHENOXYPHENYL)BUTYL]-4-PIPERIDINYL~PHENYL)ACETAMIDE:
Using Method II, the desired product was obtained. 1H
NMR (400 MHz, CDC13) 8 7.97 (d, 2H, J=8.8 Hz), 7.41-7.18
(m, 7H) , 7.08-6.99 (m, 5H) , 6.94-6.87 (m, 3H) , 3 . 82 (s,
3H), 3.70 (s, 2H), 3.10-2.95 (m, 4H), 2.55-2.40 (m, 3H),
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2.15-1.95 (m, 4H), 1.81- 1.70 (m, 4H); ESMS m/e
563 . 4 (M + H) +.
Example 28
N'-(3-{1-[4-(4-CHLOROPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)-N,N-DIMETHYLSULFAMIDE: Using Method
II, the desired product was obtained. 1H NMR (400 MHz,
CDC13) ~ 7.93 (d, 2H, J=8.8 Hz) , 7.44 (d, 2H, J=8. 8 Hz) ,
7.27 (s, 1H) , 7.25-7.10 (m, 2H) , 6.94 (d, 1H, J=7.6 Hz) ,
3 .30-3 .10 (m, 2H) , 3 .04 (t, 2H, J=6. 8 Hz) , 2.83 (s, 6H) ,
2.68-2.45 (m, 3H), 2.30-1.75 (m, 8H); ESMS m/e . 464.3
(M + H)+.
Exaxnp 1 a 2 9
N- (3-~1- [4-OXO-4- (2-THIENYL) BUTYL] -4-
PIPERIDINYL}PHENYL)ACETAMIDE: Using Method III, the
desired product was obtained. 1H NMR (400 MHz, CDC13) S
7.90-6.78 (m, 7H), 3.22-2.88 (m, 4H), 2.69-2.25 (m, 5H),
2.02 (s, 3H), 2.00-1.64 (m, 6H); ESMS m/e . 371.2 (M +
H)+.
Example 30
N-(3-~1-[4-(4-ISOPROPYLPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)ACETAMIDE: Using Method III, the
desired product was obtained. 1H NMR (400 MHz, CDC13) b
8.00-6.78 (m, 8H), '3.15-2.98 (m, 4H), 2.77-2.15 (m, 4H),
2.03 (s, 3H), 2.00-1.62 (m, 8H), 0.927 (d, 6H, J=6.0
Hz); ESMS m/e . 407.3 (M + H)+.
Example 31
N-(3-~1-[4-(4-METHYLPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)ACETAMIDE: Using Method III, the
desired product was obtained. 1H NMR (400 MHz, CDC13) 8
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7.90-6.80 (m, 8H), 3.10- 2.45 (m, 7H), 2.32 (S,
3H), 2.02 (s, 3H), 2.01-1.68 (m, 8H); ESMS m/e . 379.3
(M + H)+.
Example 32
N- (3-~l- [4- (4-BROMOPHENYL) -4-OXOBUTYL] -4-
PIPERIDINYL~PHENYL)ACETAMIDE: Using Method III, the
desired product was obtained. 1H NMR (400 MHz, CDC13) 8
7.90-6.80 (m, 8H), 3.30-.05 (m, 4H), 2:70-2.45 (m, 3H),
2.05 (s, 3H), 1.98-1.65 (m, 8H); ESMS m/e . 444.0 (M +
H)+.
EXAMPLE 33
N-(3-~1-[4-(3,4-DIMETHYLPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)-2-PROPANESULFONAMIDE: Using Method
II, the desired product was obtained. 1H NMR (400 MHz,
CDC13) b 7.75 (s, 1H) , 7.71 (d, 1H, J=7.6 Hz) , 7.27-7.00
(m, 5H), 3.32-3.24 (m, 3H), 3.10-3.02 (m, 2H), 2.78-2.50
(m, 3H), 2.32 (s, 6H), 2.19-1.84 (m, 8H), 1.39 (d, 6H,
J=6.8 Hz) ; ESMS m/e . 4.4 (M + H)+.
Example 34
N- (3-~1- [4-OXO-4- (4-PHENOXYPHENYL) BUTYL] -4-
PIPERIDINYL~PHENYL)-2-PROPANESULFONAMIDE: Using Method
II, the desired product was obtained. 1H NMR (400 MHz,
CDC13) 8 7.97 (d, 2H, J=7.6 Hz) , 7.44 (t, 2H, J=7.6 Hz) ,
7 .27-7 . 00 (m, 9H) , 3 .35-2. 96 (m, 5H) , 2 .69-2 .45 (m, 3H) ,
2.14-1.79 (m, 8H), 1.39 (d, 6H, J=6.8 Hz); ESMS m/e .
521.4 (M + H)+.
Example 35
N-(3-{1-[3-(4-CHLOROPHENYL)-3-METHOXYPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of 3-
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methoxy-3-(p- chlorophenyl)-1-
chloropropane (27.4 mg, 0.125 mmol), 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide (28.3 mg, 0.125 mmol),
diisopropylethylamine (0.50 mL) and catalytic amount of
tetrabutylammonium iodide in dioxane (2.0 mL) was
stirred at 90 °C for 72 hrs. The reaction mixture was
concentrated to a small volume and chromatographed using
preparative TLC plates [2.5% of NH3 (2.0 M in methanol)
in CHC13] gave N- (3-{1- [3- (4-chlorophenyl) -3-
methoxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide
(39.5 mg, 73.80 yield) as a thick oil: 1H NMR b 7.48 (S,
1 H), 7.34-7.3 (m, 2H), 7.25 (m, 4H), 6.96 (d, 1H, J=7.4
Hz) , 4.20 (apparent dd, 1H, J=5. 9, 7. 6 Hz) , 3.2 (s, 3H) ,
3.04 (d, 1H, J=10.1 Hz), 2.99 (d, 1H, J=10.1 Hz), 2.49
(h, 4H, J=6.6 Hz), 2.20-2.10 (m, 4H), 1.82 (m, 4H), 1.25
(d, 6H, J=7.1 Hz); ESMS m/e: 429.4 (M + H)+.
Example 36
N-(3-~1-[6-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-
YL)HEXYL]-4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: The
synthetic method is the same as described for 2-[6-(4-
phenyl-1-piperidinyl)hexyl]-1H-isoindole-1,3(2H)-dione.
N-(3-~l-[6-(1,3-dioxo-2,3-dihydro-2H-isoindol-2-
yl)hexyl]-4-piperidinyl~phenyl)-2-methylpropanamide: 506
mg (56 o yield) ; 1H NMR (400 MHz, CDC13) 8 7 . 86-7 . 80 (m,
2H), 7.73-7.68 (m, 2H), 7.44 (s, 1H), 7.37 (d, 1H, J=8.3
Hz), 7.22 (t, 1H, J=7.7~Hz), 6.96 (d, 1H, J=7.7 Hz),
3.69 (t, 2H, J=7.2 Hz), 3.01 (apparent d, 2H, J=11.3
Hz), 2.58-2.40 (m, 2H), 2.33 (m, 2H) 1.98 (dt, 2H,
J=3.2, 11.3 Hz), 1.84-1.64 (m, 4H), 1.51 (q, 2H, J=7.1
Hz), 1.43-1.30 (m, 6H), 1.24 (d, 6H, J=6.8 Hz); ESMS
m/e: 476.4 (M + H)~.
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Example 37
N-{3-(1-(3-METHOXY-3-PHENYLPROPYL)-4-
. PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: A mixture of 3
methoxy-3-phenyl-1-chloropropane (23.1 mg, 0.126 mmol),
2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3
mg, 0.126 mmol), diisopropylethylamine (0.50 mL) and
catalytic amount of tetrabutylammonium iodide in dioxane
(2.0 mL) was stirred at 90 °C for 72 hrs. Chromatography
using silica preparative TLC plates [2.5% of NH3 (2.0 M
in methanol) in CHC13] gave N-~3-[1-(3-methoxy-3-
phenylpropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
(45.4 mg, 91.2% yield) as a thick oil: 1H NMR (400 MHz,
CDC13) 8 7.45 (S, 1 H) , 7.34-7.25 (m, 5H) , 7.25 (m, 2H) ,
6.96 (d, 1H, J=7.4 Hz), 4.20 (apparent dd, 1H, J=5.9,
7.6 Hz) , 3 .2 (s, 3H) , 3 .04 (d, 1H, J=10.1 Hz) , 2 .99 (d,
1H, J=10.1Hz), 2.49 (apparent sept, partially hidden,
4H, J=6.6 Hz), 2.3-2.1(m, 4H), 1.82 (m, 4H), 1.25 (d,
6H, J=7.1 Hz); ESMS m/e: 395.4 (M + H)+.
Example 38
N-(3-~1-[4-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-
YL)BUTYL]-4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: The
synthetic method is the same as described for 2-[6-(4-
phenyl-1-piperidinyl)hexyl]-1H-isoindole-1,3(2H)-dione.
N-(3-{1-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-
yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 664
mg (74 o yield) ; 1H NMR (400 MHz, CDC13) S 7. 87-7 .78 (m,
2H) , 7. 76-7.64 (m, 2H) , 7.47 (s, 1H) , 7.39 ~(d, 1H, J=7.6
Hz), 7:21 (t, 1H, J=8.1 Hz), 6.94 (d, 1H, J=7.6 Hz),
3.72 (t, 2H, J=6.8 Hz), 3.37-3.22 (m, 2H), 3.0 (apparent
d, 2H, J=10.7 Hz), 2.75 (q, 2H, J=7.0 Hz), 2.64-2.33 (m,
4H), 1.99 (dt, 2H, J=2.6, 11.7 Hz), 1.86-1.65 (m, 2H),
1.63-1.50 (m, 2H), 1.23 and 1,21 (two d, 6H, J=5.5 Hz);
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ESMS m/e: 448.4 (M + H)+; Anal. Calc. for
C2~H34N3C103+0.4H~0: C, 66.02; H, 7.14; N, 8.55. Found: C,
66.07; H, 6.78; N, 8.65.
Example 39
N-(3-~1-[4-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-
YL)BUTYL]-4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: The
synthetic method is the same as described for 2-[6-(4-
phenyl-1-piperidinyl)hexyl]-1H-isoindole-1,3(2H)-dione.
N-(3-{1-[5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-
yl)pentyl]-4-piperidinyl}phenyl)-2-methylpropanamide:
614 mg (64% yield); 1H NMR (400 MHz, CDC13) 8 7.87-7.8
(m, 2H), 7.76-7.68 (m, 2H), 7.48 (s, 1H), 7.41 (d, 1H,
J=7.6 Hz), 7.21 (t, lH, J=7.6 Hz), 6.95 (d, 1H, J=7.6
Hz), 3.69 (t, 2H, J=7.2 Hz), 3.39-3.28 (m, 2H), 3.02
(apparent d, 2H, J=11.6 Hz), 2.78 (q, 2H, J=7.2 Hz),
2.64-2.52 (m, 1H), 2.52-2.40 (m, 1H), 2.40-2.31 (m, 2H),
2.01 (dt, 2H, J=3.7, 11.1 Hz), 1.85-1.64 (m, 2H), 1.58
(q, 2H, J=7.6 Hz) , 1.45-1.32 (m, 2H) , 1.23 (d, 6H, J=6. 9
Hz); ESMS m/e: 462.4 (M + H)+; Anal. Calc. for
CZ8H36N3C1O3: C, 67.52; H, 7.29; N, 8.44. Found: C, 67.04;
H, 7.06; N, 8.38.
Example 40
2-METHYL-N-~3- (1- (4-PT3ENYLBUTYL) -4-
PIPERIDINYL]PHENYL~PROPANAMIDE: A mixture of 2-methyl-
N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.100
mmol), 4-phenyl-1-chlorobutane (21.1 mg, 0.125 mmol-),
diisopropylethylamine (0.50 mL), catalytic amount of
tetrabutylammonium iodide and dioxane (2.0 mL) was
heated at reflux temperature for 3 days. The reaction
mixture was concentrated and chromatographed using
preparative TLC plates [2 . 5 0 of NH3 (2 . 0 M in methanol)
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in CHC13] afforded the product, 2-methyl-N-{3-[1-
(4-phenylbutyl)-4-piperidinyl]phenyl}propanamide (9.50
mg, 25.1% yield) as a thick oil: 1H NMR S 7.37 (s, 1H) ,
7.29 (apparent d, 1H,. J=7.9 Hz), 7.18 (m, 3H), 7.11 (m,
3H) , 6.90 (apparent d, 1H, J=7.9 Hz) , 3 .02 (d, 2H, J=6.8
Hz) , 2.41 (m, 4H, partially hidden) , 2 . O1 (m, 2H) , 1 . 78
(m, 4H) , 1 .57 ' (m, 4H) , 1.18 (d, 6H, J=7. 7 Hz,) ; ESMS m/e:
379.4 (M + H)+.
Example 41
N-(3-~1-(3-(1,3-DIOXO-l,3-DIHYDRO-2H-ISOINDOL-2-
YL)PROPYL]-4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE:
The synthetic method is the same as described for 2-[6-
(4-phenyl-1-piperidinyl)hexyl]-1H-isoindole-1,3(2H)-
dione. N-(3-{1-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-
yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide:
8l0 mg. (93a yield); 1H NMR (400 MHz, CDC13) 8 7.87-7.82
(m, 2H), 7.73-7.68 (m, 2H), 7..57 (s, 1H), 7.36, (d, 1H,
J=8.5 Hz), 7.18 (t, 1H, J=7.7 Hz), 6.79 (d, 1H, J=7.1
Hz) , 3 .78 (t, 2H, J=6.8 Hz) , 3.06 (quintet, 2H, J=6 Hz) ,
2.95 (apparent d, 2H, J=12.2 Hz), 2.58-2.31 (m, 4H),
1.96-1.83 (m, 2H), 1.70 (apparent d, 2H, J=12.1 Hz),
1.52 (dt, 2H, J=3.5, 12.5 Hz), 1.03 (d, 6H, J=6.5 Hz);
ESMS m/e: 434.4 (M + H)~.
Example 42
N- (3-~1- j (3S) -3-HYDROXY-3-PHENYLPROPYL] -4-
PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A' mixture of
(S)-(-)-3-chloro-1-phenyl-1-propanol (0.426 g, 2.50
mmol, 99%ee), 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide (0.565 g, 2.00 mmol),
diisopropylethylamine (1.29 g, 10.0 mmol), dioxane (5.0
mL) and catalytic amount of tetrabutylammonium iodide
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was stirred at 90 °C for 72 hrs. Chromatography using
silica preparative TLC plates [2.5% of NH3 (2.0 M in
methanol) in CHC13] gave the desired product (306 mg,
39.3 % yield) as a thick oil: 1H NMR (400 MHz, CDC13) 8
7.46 (S, 1 H), 7.42 (d, 4H, J=8.1 Hz), 7.35 (m, 1 H),
7.30 (d, 1 H, J=8.0 Hz), 7.23 (t, 1H, J=8.1 Hz), 7.12
(s, 1H) , 6.96 (apparent dd, 1H, J=8.0 Hz) , 5.0 (apparent
dd, 1H, J=4.4, 8.3 Hz), 3.18 (apparent dd, 2H, J=2.5,
12.5 Hz) , 2.74 (m, 2 H) , 2.50 (m, 2H) , 2.3-2.1 (m, 6H) ,
1.8 (m, 2H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 389.2 (M
+ H)+.
Example 43 _
N-(3-~1-[3-METHOXY-3-(4-METHYLPHENYL)PROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of
3-methoxy-3-(p-tolyl)-1-chloropropane (24.9 mg, 0.126
mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide
(28.3 mg, 0.126 mmol), diisopropylethylamine (0.50 mL)
and catalytic amount of tetrabutylammonium iodide in
dioxane (2.0 mL) was stirred at 90 °C for 72 hrs.
Chromatography using silica preparative TLC plates [2.5%
of NH3 (2.0 M in methanol) in CHC13] gave the desired
product (10.9 mg, 21.2 % yield) as a thick oil: 1H NMR
(400 MHz, CDC13) 8 7.44 (s, 1 H) , 7.38 (m, 1H) , 7.3-7.1
(m, 5 H) , 6.96 (d, 1H, J=7.4 Hz) , 4.18 (apparent dd, 1H,
J=5.6, 7.9 Hz), 3.24- (d, 1H, J=8.2 Hz), 3.2 (s, 3H),
3.11 (m, 2H, J=10.1Hz), 2.49 (m, 4H), 2.35 (s, 3H), 2.3-
2.1(m, 3H), 1.92 (d, 4H), 1.25 (d, 6H, J=7.1 Hz); ESMS
m/e: 409.4 (M + H)+.
Example 44
N-~3-[1-(3-ISOPROPOXY-3-PHENYLPROPYL)-4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: A mixture of 3-
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isopropyl-3'-phenyl-1- chloropropane (26.6 mg,
0.126 mmol) , 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide (28.3 mg, 0.126 mmol),
diisopropylethylamine (0.50 mL) and catalytic amount of
tetrabutylammonium iodide in dioxane (2.0 mL) was
stirred at 90 C for 72 hrs. Chromatography using
silica
preparative TLC plates [2.5% of NH3 (2.0 M in methanol)
in CHC13] gave the desired product (14.1 mg, 26.5% yield)
as a thick oil: 1H NMR (400 MHz, CDC13) S 7.46 (s,
1H) ,
7.43-7.37 (m, 2H) , 7.33 (m, 3H) , 7.23 (m, 2H) , 6.95
(d,
1H, J=8.4 Hz), 4.46 (apparent dd, 1H, J=5.0,
8.3 Hz),
3.49 (apparent sept, 1H, J=7.1 Hz), 3.10 (s, 2H),
2.70
(m, 2H), 2.52 (apparent sept, partially hidden, 4H,
J=6.6 Hz), 2.30-2.10 (m, 2H), 1.90-1.80 (d, 4H),
1.25
(d, 6H, J=7.1 Hz) , 1.15 (d, 3H, J=6.4 Hz) 1. 08 (d,
, 3H,
J=6 . 4 Hz) ; ESMS m/e: 423 . 4 (M + H) +.
Example 45
N- (3-~1- [4, 4-BIS (4-FLUOROPHENYL) BUTYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of
4,4-bis(4-fluoro-phenyl)-1-chloro-butane (39.0 mg, 0.126
mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide
(28.3 mg, 0.126 mmol), diisopropylethylamine (0.50 mL)
and catalytic amount of tetrabutylammonium iodide in
dioxane (2.0 mL) was stirred at 90 °C for 72 hrs.
Chromatography using silica preparative TLC plates [2.50
of NH3 (2.0 M in methanol) in CHC13] gave the desired
product (15.9 mg, 25.2 % yield) as a thick oil: 1H NMR
(400 MHz, CDC13) 8 8.02 (s, 1H), 7.41 (s, 1H), 7.3-7.15
(m, 4H), 7.10 (m, 3H), 6.89 (apparent t, 5H), 3.81 (t,
1H, J=7.8 Hz), 3.30 (s, 1H), 2.91 (d, 1H, J=12,5 Hz),
2.80 (m, 1H) , 2 .40 (m, 2H) , 2.31 (t, 1H, J=8.0 Hz) , 1.93
(apparent q, 3H, J=8.0 Hz) , 1.72 (m, 3H) , 1.40 (m, 2H) ,
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1.20 (m, 2H), 1.15 (d, 6H, J=8.1 Hz); ESMS m/e: 491.4
(M + H)+
EXAMPLE 46
N-~3- [1- (3-METHOXYBENZYL) -4-PIPERIDINYL] PHENYL-2-
METHYLPROPANAMIDE: A mixture of 2-methyl-N-[3-(4-
piperidinyl) phenyl] propanamide (28 . 3 mg, 0 .100 mmol) , 3-
methoxybenzyl chloride (19.6 mg, 0.125 mmol),
diisopropylethylamine (0.50 mL), catalytic amount of
tetrabutylammonium iodide and dioxane (2.0 mL).
Chromatography using silica preparative TLC plates [2.5%
of NH3 (2.0 M in methanol) in CHC13] afforded the desired
product (10.2 mg, 27.9% yield) as a yellow solid: 1H NMR
(400 MHz, CDC13) ~ 7.46 (s, 1H), 7.35 (apparent d, 1H,
J=8.3 Hz), 7.27-7.21 (m, 2H), 6.95 (apparent t, 3H,
J=6.9 Hz), 6.82 (apparent dd, 1H, J=2.4, 8.3 Hz), 3.84
(m, 3H) , 3 .56 (s,~ 2H) , 3 .05 (d, 2H, J=10 .5 Hz) , 2 .51
(apparent sept, partially hidden, 4H, J=7.2 Hz), 2.13
(apparent t, 2H, J=9.7 Hz), 1.88 (m, 2H), 1.25 (d, 6H,
J=6.7 Hz); ESMS m/e: 367.3 (M + H)+.
Example 47
N- (3-~l- [3, 5-BIS (TRIFLUOROMETHYL) BENZYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg,
0.100 mmol), 3,5-bis(trifluoromethyl)benzyl bromide
(38.4 mg, 0.125 mmol), diisopropylethylamine (0.50 mL),
catalytic amount of tetrabutylammonium ~ iodide and
dioxane (2.0 mL). Chromatography using silica
preparative TLC plates [2.5% of NH3 (2.0 M in methanol)
in CHC13] gave the desired product (12.2 mg, 25.80 yield)
as a thick oil: 1H NMR (400 MHz, CDC13) 8 7.83 (s, 2H) ,
7.77 (s, 1H) , 7.53 (s, 1H) , 7.30-7.21 (m, 2H) , 7.16 (s,
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1H), 6.98 (apparent d, 1H, J=7.6 Hz), 3.62 (s, 2H),
2.94 (d, 2H, J=9.4 Hz), 2.51 (apparent sept, partially
hidden, 2H, J=6.6 Hz) , 2.14 (m, 2H) , 1.82 (m, 4H) , 1 .25
(d, 6H, J=6.6 Hz); ESMS m/e: 473.2 (M + H)+.
Example 48
N- (3-~1- [ (3R) -3- (3, 4-DIMETHOXYPHENOXY) -3-PHENYLPROPYL] -
4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE
Method A
4-~[(1R)-3-chloro-1-phenylpropyl]oxy~-1,2-
dimethoxybenzene: A mixture of 3,4-dimethoxyphenol (4.07
g, 26.4 mmol), (S)-(-)-3-chloro-phenyl-1-propanol (4.50
g, 26.4 mmol, 99oee, Aldrich Chemical Co.),
triphenylphosphine (6.92 g, 26.4 mmol) and diethyl
azodicarboxylate (4.59 g, 26.4 mmol) in THF (110 mL) was
stirred at room temperature for 24 h. The reaction
mixture was concentrated in vacuo. At this point, the
residue can either be washed with pentane (x3) and the
combined pentane extracts were concentrated and
chromatographed (silica with hexanes-EtOAc 8:1 as the
eluent) to give the desired product (as described as a
general procedure by: Srebnik, M.; Ramachandran, P.V.;
Brown, H.C. J. Org. Chem. 1988, 53, 2916-2920). This
procedure was performed on a smaller scale reaction and
only a 40o yield of the product was realized.
Alternatively, on a larger scale (26.4 mmol) , the crude
product was triturated with , a small amount of
dichloromethane and the precipitated triphenylphosphine
oxide was filtered. The filtrate was concentrated and
the crude product was chromatographed to give the
desired product as a thick yellow oil (7.30 g, 88.9%
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yield) : 1H NMR (400 MHz, CDC13) 8 7.39-7.32 (m, 4H) ,
7.20 (m, 1H) , 6.64 (d, 1H, J=8.7 Hz) , 6.51 (d, 1H, J=2.7
Hz), 6.30 (dd, 1H, J=2.7, 8.7 Hz), 5.27 (apparent dd,
1H, J=4.5, 8.7 Hz) , 3.79 (s, 3H) , 3.77 (s, 3H) , 3.61 (m,
1H), 2.45 (m, 1 H), 2.20 (m, 1H), 1.80 (s, 1H); ESMS
m/e: 307.11 (M+H)+.
N- (3-~l- [ (3R) -3- (3, 4-DIMETHOXYPHENOXY) -3-PHENYLPROPYL~ -
4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of
potassium carbonate (321 mg, 2.32 mmol), sodium iodide
(522 mg, 3.48 mmol), 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide (570 mg, 2.32 mmol) and
4-~[(1R)-3-chloro-1-phenylpropyl]oxy}-1,2-
dimethoxybenzene (712 mg, 2.32 mmol) in DMF (5.0 mL) was
stirred at 100 °C for 3 hrs, at which time TLC indicated
that the reaction was complete. The reaction mixture
was poured into water (50 mL) and the aqueous layer was
extracted with methylene chloride (3x30 mL). The
combined-organic extracts were washed with brine (30
mL), dried over MgS04 and concentrated under reduced
pressure. The crude product was purified by Prep-TLC
plates [2.5% of NH3 (2.0 M in methanol) in CHC13] to
afford the product (970 mg, 90.1%) as a thick oil.
Method B
Into a 25-mL RB-flask was added triphenylphosphine (9.80
mg, 0.0375 mmol), diethyl azodicarboxylate (5.22 mg,
0 . 0 3 0 0 mmo 1 ) , N- ( 3 - { 1- [ ( 3 S ) - 3 -hydroxy- 3 -phei~.ylpropyl
] -4 -
piperidinyl~phenyl)-2-methylpropanamide (9.53 mg, 0.0250
mmol), 3,4-dimethoxyphenol (7.70 mg, 0.050 mmol) and THF
(1.0 mL) at room temperature. The reaction mixture was
stirred at room temperature overnight (16 hrs). The
solvent was removed under reduced pressure and the
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residue was purified by preparative TLC plates
[2 . 5 0 of NH3 (2 . 0 M in methanol) in CHC13] to afford the
desired product (4.4 mg, 34.1 a yield) as a thick oil: 1H
NMR (400 MHz, CDC13) 8 7.46 (s, 1 H) , 7.40-7.30 (m, 4H) ,
7.25 (m, 3H) , 6.97 (d, 1H, J=7.8 6.64
Hz) , (d,
1H,
J=9.1
Hz), 6.51 (d, 1H, J=2.6 Hz), 6.29 (d, 1H, J=2.6,
9.1
Hz), 5.20 (apparent dd, 1H, J=4.4, 8.5 Hz), 3.80 (s,
3H) , 3 . 77 (s, 3H) , 3.23 (m, 2H) (m, 2 H) , 2.5
, 2 .77 (m,
2H), 2.3-2.1(m, 6H), 1.80 (m, 2H), 1.25(d, 6H, J=7.9
Hz); ESMS m/e: 517.4 (M + H)+.
Example 49
2-METHYL-N-(3-~1-((3S)-3-PHENOXY-3-PHENYLPROPYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: A mixture of N-(3-fl-
[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70
mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375
mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300
mmol) in THF (1.0 mL) was stirred at room temperature
for 3 days. Chromatography using silica preparative TLC
plates [2.5 0 of NH3 (2 . 0 M in methanol) in CHC13] gave
the desired product (2.7 mg, 23.6 % yield) as a thick
oil: 1H NMR 8 7.46 (s, 2H), 7.40-7.30 (m, 4H), 7.25 (m,
3 H), 7.20 (m, 2H), 6.97 (apparent d, 1H, J=7.4 Hz),
6.89 (apparent tt, 1H, J=0.8, 7.6 Hz), 6.84 (apparent
dt, 1H, J=0.8, 8.0 Hz), 5.20 (apparent dd, 1H, J=4.4,
8.5 Hz) , 3 .35 ~(m, 2H) , 2.91 (m, 2H) , 2. 60 (m, 2H) , 2.30-
2.10 (m, 6H) , 1.90 (m, 2H) , 1.25 (d, 6H, J=7.9 Hz) ; ESMS
m/e: 457 . 4 (M + H) +;
Example 50
N- (3-~l- [~(3S) -3- (4-METHOXYPHENOXY) -3-PHENYLPROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of N-
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(3-{1- [ (3R) -3-hydroxy-3- phenylpropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250
mmol), 4-methoxyphenol (6.20 mg, 0.050 mmol),
triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl
azodicarboxylate (5.2 mg, 0.0300 mmol) in THF (1.0 mL)
was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates [2.50
of NH3 (2.0 M in methanol) in CHC13] gave the desired
product (4.6 mg, 37.9 % yield) as a thick oil. 1H NMR
(400 MHz, CDC13) 8 7.38-7.14 (m, 8H), 6.90 (apparent d,
1H, J=7. 7 Hz) , 6.72-6.46 (m, 4H) , 5 .09 (apparent dd, 1H,
J=4.8, 8.1 Hz), 3.64 (s, 3H), 3.18 (m, 2H), 2.73 (m,
2H) , 2 . 50 (m, 2H) , 2.37-I . 72 (m, 8H) , 1 .25 (d, 6H, J=7.4
Hz); ESMS m/e: 487.4 (M + H)+.
Example 51
N- (3-~1- [ (3S) -3- (3-CHLOROPHENOXY) -3-PHENYLPROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of N-
(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-
piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250
mmol), 3-chlorophenol (6.40 mg, 0.050 mmol),
triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl
azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL)
was stirred at room temperature for 3 days.
Chromatography using~silica preparative TLC plates [2.5%
of NH3 (2.0 M in methanol) in CHC13] gave the desired
product (4.9 mg, 40.0 0 yield) as a thick oil: 1H NMR
(400 MHz, CDC13) 8 7.39 (s, 1H), 7.35-7.10 '(m, 7H), 7.02
(t, 1H, J=8.0 Hz) , 6.90 (d, 1H, J=7.6 Hz) , 6.84-6.75 (m,
2H), 6.65 (m, 1H), 5.09 (apparent dd, 1H, J=4.99, 8.1
Hz) , 3 .10 (m, 2H) , 2 . 60 (m, 2H) , 2 .50 (m, 2H) , 2 .30-1 .70
(m, 8H), 1.18 (d, 6H, J=6.8 Hz); ESMS m/e: 491.4 (M +
H)+.
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Example 52
N- (3-~1- [ (3S) -3- (4-CHLOROPHENOXY) -3-PHENYLPROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A rnixture of N-
(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-
.piperidinyl~phenyl)-2-methylpropanamide (9.53 mg, 0.0250
mmol), ~4-chlorophenol (6.40 mg, 0.050 mmol),
triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl
azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL)
was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates [2.50
of NH3 (2.0 M in methanol) in CHC13] gave the desired
product (3.3 mg, 26.9 o yield) as a thick oil: 1H NMR 8
7.36 (s, 1H), 7.35-7.22 (m, 7H), 7.12 (m, 2H), 6.97
(apparent d, 1H, J=7.2 Hz) , 6.77 (m, 2H) , 5 .23 (m, 1H) ,
3 .18 (m, 2H) , 2.70 (m, 2H) , 2.50 (m, 2H) , 2.40-1 .80 (m,
8H) , 1 .25 (d, 6H, J=6 . 8 Hz) ; ESMS m/e: 491 .4 (M + H) +.
Example 53
2-METHYL-N- [3- (1-{ (3S) -3-PHENYL-3- [4-
(TRIFLUOROMETHYL)PHENOXY]PROPYL~-4-
PIPERIDINYL)PHENYL]PROPANAMIDE: A mixture of N-(3-{1-
[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide (9.53 mg, 0.0250 mmol), 4-
trifluoromethylphenol (8.100 mg, 0.050 mmol),
triphenylphosphine (9.8 mg, 0.0375 mmol) and diethyl
azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL)
was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates [2.50
of NH3 (2.0 M in methanol) in CHC13] gave the desired
product (5.10 mg, 38.9 o yield) as a thick oil: 1H NMR 8
8.06 (s, 1H), 7.49 (s, 1H), 7.44 (apparent d, 2H, J=.6
Hz), 7.38-7.30 (m, 4H), 7.30-7.20 (m, 3H), 6.96
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(apparent d, 1H, J=7.6 Hz), 6.91 (apparent d, 2H,
J=8.6 Hz), 5.34 (m, 1H), 3.19 (m, 2H), 2.72 (m, 2H),
2.53 (m, 2H), 2.40-1.80 (m, 8H), 1.25 (d, 6H, J=6.8 Hz);
ESMS m/e: 525.4 (M + H)+.
Example 54
N- (3-~1- [ (3R) -3- (2, 5-DIFLUOROPHENOXY) -3-PHENYLPROPYL~ -4-
PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of N-
(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-
piperidinyl)phenyl)-2-methylpropanamide (9.53 mg, 0.0250
mmol), 2,5-difluorophenol (6.50 mg, 0.050 mmol),
triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl
azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL)
was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates [2.5%
of NH3. (2.0 M in methanol) in CHC13] gave the desired
product (3.60 mg, 29.3 % yield) as a thick oil: 1H NMR 8
7.46 (s, 1H), 7.40-7.32 (m, 4H), 7.31-7.20 (m, 2H), 7.17
(s, 1H), 7.01-6.92 (m, 2H), 6.65-6.42 (m, 2H), 5.27 (m,
1H), 3.13 (m, 2H), 2.64 (m, 2H), 2.51 (m, 2H), 2.28-1.80
(m, 8 H) , 1.25 (d, 6H, J=7.1 Hz) ; ESMS m/e: 493.4 (M +
H)~.
Example 55
N-(3-~1-[(3R)-3-(3,4-DICHLOROPHENOXY)-3-PHENYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of N-
(3-{.1- [ (3S) -3-hydroxy-3-phenylpropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250
mmol), 3,4-dichlorophenol (8.20 mg, 0.050 mmol),
triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl
azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL)
was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates [2.5%
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of NH3 (2.0 M in methanol) CHC13]gave the des ired
in
product (5.20 mg, 39.7% yield) as thick oil: NMR
a 1H
(CDC13) cS 7.70-7.63 (m, 2H), 7.55(m, 1H), 7.47-7.43(m,
3H) , 7.40-7 .19 (m, 3H.)7 .00-6.50 2H) , 6.69 1H,
, (m, (dd,
J=2.2, 8.8 Hz), 5 .25 (m, 1H), 3.20 (m, 2H), 2.70 (m,
2H), 2.53 (m, 2H), 2.40-2.20 4H), 2.10-1.80 (m, 4H),
(m,
1.25 (d, 6H, J=7.1 Hz);ESMS m/e:525.4
(M
+-H)+.
Example 56
2-METHYL-N-(3-~1-[(3R)-3-PHENOXY-3-PHENYLPROPYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: A mixture of N-(3-(1-
[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70
mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375
mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300
mmol) in THF (1.0 mL) was stirred at room temperature
for 3 days. Chromatography using silica preparative TLC
plates [2.5% of NH3 (2.0 M in methanol) in CHC13] gave
the desired product (4.1 mg, 36.0 % yield) as a thick
oil: 1H NMR (400 MHz, CDC13) 8 7.45 (s, 2H), 7.40-7.15
~(m, 10H), 6.97 (d, 1H, J=7.6 Hz), 6.88-6.82 (m, 2H),
5.26 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H), 2.53 (m, 2H),
2.40-2.10 (m, 4H), 2.10-1.80 (m, 4H), 1.25 (d, 6H, J=6.9
Hz); ESMS m/e: 457.4 (M + H)+.
Example 57
N-(3-~1-[(3R)-3-HYDROXY-3-PHENYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE
Method A
Into a 25-mL RB-flask was added (R)-(+)-3-chloro-1-
phenyl-1-propanol (0.545 g, 3.19 mmol, 99%ee, Aldrich
Chemical Co.), 2-methyl-N-j3-(4-
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piperidinyl)phenyl]propanamide (0.748 g, 3.04 mmol),
potassium carbonate (0.420 g, 3.04 mmol) and sodium
iodide (0.684 g, 4.56 mmol) and DMF (6.0 mL) at room
temperature. After stirring at 100 °C for 3 hrs, the TLC
showed the reaction was complete. The reaction mixture
was poured into water (50 mL) and the ac~.ieous layer was
extracted with methylene chloride (3x20 mL). The
combined organic extracts were washed with brine (20
mL), dried over Na2SOg and concentrated under reduced
pressure. The residue was purified by flash
chromatography (1:1= hexane: ethyl acetate with 1%
isopropylamine) to afford the desired product (1.09 g,
94.3 % yield) as light-yellow solid: 1H NMR (400 MHz,
CDC13) 8 8.10 (s, 1H) , 7.46-7.35 (m, 6H) , 7.27 (m, 2H) ,
6.98 (apparent d, 1H, J=7.6 Hz), 5.02 (apparent dd, 1H,
J=4.4, 8.1 Hz), 3.18 (apparent dd, 2H, J=2.5, 12.5 Hz),
2 .74 (m, 2 H) , 2 . 50 (m, 2H) , 2 .30-2 . 10 (m, 6H) , 1 . 80 (m,
2H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 381.2 (M + H)+.
The hydrochloric salt was prepared by addition of a
slight excess of 1 N HC1 in ether (1.2 eq.) to a
solution of the free base in dichloromethane. The
solvent was removed under reduced pressure, the residue
was washed with ether and dried under reduced pressure:
Anal. Calc. for C24H3~N202+HCl+0.8H~0: C, 66.82; H, 8.08;
N, 6.49; C1, 8.22. Found: C, 66.90; H, 7.78; N, 6.63;
Cl, 8.52.
Me thod B
Into a 25-mL RB-flask was added (R)-(+)-3-chloro-1-
phenyl-1-propanol (0.426 g, 2.50 mmol), 2-methyl-N-[3-
(4-piperidinyl)phenyl]propanamide (0.565 g, 2.00 mmol),
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diisopropylethylamine (1.29 g, 10.0 mmol),
dioxane (5.0 mL) and catalytic amount of
tetrabutylammonium iodide at room temperature. After
stirring at 90 °C for 72 hrs, the reaction mixture was
poured into water (50 mL) and the aqueous layer was
extracted with methylene chloride (3x20 mL). The
combined organic extracts were washed with brine (20
mL), dried over NazS04 and concentrated under reduced
pressure. The residue was purified by preparative TLC
plates (1:5:100=isopropylamine:methanol: ethyl acetate)
to afford the desired product (0.260 g, 34.2 % yield)
as light-yellow solid.
Example 58
N-(3-~1-[(3S)-3-(4-CYANO-PHEONXY)-3-PHENYLPROPYL]-4-
PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: N-(3-~1-[(3S)-
3-(4-cyanophenoxy)-3-phenylpropyl]-4-
pi.peridinyl~phenyl)-2-methylpropanamide
A mixture of N-(3-f1-[(3R)-3-hydroxy-3-phenylpropyl]-4-
piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 4-cyanophenol (100 mg), triphenylphosphine (30,0
mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg,
0.0426 mmol) in THF (0.50 mL) was stirred at room
temperature for 3 days. Chromatography using silica
preparative TLC plates [2.50 of NH3 (2.0 M in methanol)
in CHC13] gave the desired product (4.70 mg, 71.3 0
yield) as a thick oil: 1H NMR (400 MHz, CDC13) b 7.54
(m, 2H), 7.48 (d, 2H, J=8.4 Hz), 7.30-7.20 '(m, 3H), 7.20
(m, 3H) , 6.97 (apparent d, 1H, J=8.4 Hz) , 6.92 (apparent
d, 2H, J=8.4 Hz), 5.36 (apparent dd, 1H, J=3.9, 7.6 Hz),
3.12 (m, 2H), 2.61 (m, 2H), 2.53 (apparent sept,
partially hidden, 2H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.82
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(m, 2H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 482.2
(M + H) +.
Example 59
N-(3-~1-[(3S)-3-(4-FLUOROPHENOXY)-3-PHENYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of N-
(3-{1- [ (3R) -3-hydroxy-3-phenylpropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol ) , 4 - f luorophenol ( 10 0 mg ) , triphenylphosphine ( 3 0 . 0
IO mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg,
0.0426 mmol) in THF (0.50 mL) was stirred at room
temperature for 3 days. Chromatography using silica
preparative TLC plates [2.5% of NH3 (2.0 M in methanol)
in CHC13] gave the desired product (4.20 mg, 64.7% yield)
as a thick oil : 1H ~NMR (400 MHz, CDC13) 8 7.40 (m, 2H) ,
7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (apparent d, 1H,
J=7.7 Hz), 6.87 (m, 1H), 6.76 (m, 1H), 5.26 (apparent
dd, 1H, J=4.0, 8.1 Hz), 3.09 (m, 2H), 2.66 (m, 2H), 2.51
(m, 2H), 2.3-2.1 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H,
overlapped); ESMS m/e: 475.2 (M + H)+.
Example 60
N- (3-~1- [ (3S) -3- (4-BROMOPHENOXY) -3-PHENYLPROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROP,ANAMIDE: A mixture of N-
(3-{1- [ (3R) -3-hydroxy-3-phenylpropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 4-bromophenol (100 mg), triphenylphosphine (30.0
mg, 0.115 mmol) and diethyl azodicarboxyla~te (7.42 mg,
0.0426 mmol) in THF (0.50 mL) was stirred at room
temperature for 3 days. Chromatography using silica
preparative TLC plates [2.5% of NH3 (2.0 M in methanol)
in CHC13] the desired product (0.70 mg, 9.6% yield) as a
thick oil: 1H NMR (400 MHz, CDC13) 8 8. 06 (s, 1H) , 7.48
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(m, 2H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97
(apparent d, 1H, J=8.5 Hz), 6.73 (apparent d, 2H, J=8.5
Hz), 5.22 (apparent dd, 1H, J=4.9, 7.8 Hz), 3.15 (m,
2H), 2.65 (m, 2H), 2.51 (apparent sept, partially
hidden, 2H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H),
1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 535.1 (M + H)+.
Example 61
N- ( 3 - ~ 1- [ ( 3 S ) - 3 - ( 3 -METHOXYPHENOXY) - 3 - PHENYLPROPYL] - 4 -
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of N-
(3-{1- [ (3R) -3-hydroxy-3-phenylpropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 3-methoxyphenol (100 mg), triphenylphosphine
(30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42
mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room
temperature for 3 days. Chromatography using silica
preparative TLC plates [2 .5 a of NH3 (2 . 0 M in methanol)
in CHC13] gave the desired product (3.1 mg, 46.6 a yield)
as a thick oil: 1H NMR (400 MHz, CDC13) ~ 7.47 (d, 1H,
J=6.7 Hz), 7.42 (s, 1H), 7.3-7.20 (m, 3H), 7.20 (m, 3H),
7.07 (t, 1H, J=8.4 Hz) , 6.97 (apparent d, 1H, J=6.7 Hz) ,
6.40 (m, 3H), 5.27 (apparent dd, 1H, J=5.3, 8.0 Hz),
3.74 (s, 3H) , 3.38 (m, 2H) , 2.93 (m, 2H) , 2.61 (s, 1H) ,
2.53 (apparent sept, partially hidden, 1H, J=6.5 Hz),
2.30-2 .10 (m, 6H) , 1 .82 (m, 2H) , 1 .25 (d, 6H, J=6.9 Hz) ;
ESMS m/e: 487.3 (M + H)'~.
Example 62
N- (3-~1- [ (3S) -3- (4-CYANO-2-METHOXYPHENOXY) -3-
PHENYLPROPYL]-4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-
piperidinyl~phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 2-methoxy-4-cyanophenol (100 mg),
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triphenylphosphine (30.0 mg, 0.115 mmol) and
diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF
(0.50 mL) was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates [2.5%
of NH3 (2.0 M in methanol) in CHC13] gave the desired
product (5.50 mg, 76.5 % yield) as a thick oil: 1H NMR
(400 MHz, CDC13) b 7.51 (s, 1H) , 7.38 (s, 1H) , 7.37 (d,
2H, J=2.4 Hz), 7.20 (m, 4H), 7.10 (d, 1H, J=2.4 Hz),
7.08 (s, 1H), 6.99 (apparent d, 1H, J=8.3 Hz), 6.76
(apparent d, 1H, J=8.3 Hz), 5.43 (apparent dd, 1H,
J=5.1, 8.0 Hz), 3.91 (s, 3H), 3.34 (m, 2H), 2.63 (m,
2H), 2.63 (s, 1H), 2.53 (apparent sept, partially
hidden, 1H,~ J=7.7 Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H),
1.28 (d, 6H, J=6.8 Hz); ESMS m/e: 512.2 (M + H)+.
Example 63
N-(3-~l-((3S)-3-(5-ACETYL-2-METHOXYPHENOXY)-3- .
PHENYLPROPYL]-4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-
piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 2-methoxy-5-acetylphenol (100 , mg),
triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl
azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL)
was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates [2.5%
of NH3 (2.0 M in methanol) in CHC13] gave the desired
product (1.60 mg, 22.2 o yield) as a thick oil: 1H NMR
(400 MHz, CDC13) 8 7.52 (d, 2H, J=2.4 Hz) ,' 7.3-7~.2 (m,
5H) , 7.20 (m, 3H) , 6.97 (apparent d, 1H, J=6.7 Hz) , 6.69
(apparent d, 1H, J=8.0 Hz), 5.47 (apparent dd, 1H,
J=4.3, 7.8 Hz), 3.95 (s, 3H), 3.38 (m, 2H), 2.93 (m,
2H), 2.61 (s, 1H), 2.53 (apparent sept, partially
hidden, 1H, J=7.6 Hz) , 2.50 (s, 3H) , 2.30-2.10 (m, 6H)',
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1.82 (m, 2H) , 1.25 (d, 6H, J=6.8 Hz) ; ESMS m/e: 529.6
(M + H)+.
Example 64
N- (3-~1- [ (3R) -3- (2-ACETYLPHENOXY) -3-PHENYLPROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of N-
(3-{1- [ (35) -3-hydroxy-3-phenylpropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide (5.2 mg, 0.0137
mmol), 2-acetylphenol (100 mg), triphenylphosphine (30.0
~ mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg,
0.0426 mmol) in THF (0.50 mL) was stirred at room
temperature for 3 days. Chromatography using silica
preparative TLC plates [2.5% of NH3 (2.0 M in methanol)
in CHC~13] gave the desired product (1.70 mg, 24.9
yield) as a thick oil: 1H NMR (400 MHz, CDC13) 8 7.65 (m,
1H) , 7.55 (s, 1H) , 7.30-7.20 (m, 5H) , 7.20 (m, 3H) , 6.97
(m, 2H), 6.76 (apparent d, 1H), 5.49 (apparent dd, 1H,
J=4.3, 8.0 Hz), 3.38 (m, 2H), 2.93 (m, 2H), 2.71 (s,
3H), 2.60 (s, 1H), 2.53 (apparent sept, partially
hidden, 1H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H),
1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 498.8 (M+).
Example 65
N- [3- (1-~ (3R) -3- [2-FLUORO-5- (TRIFLUOROMETHYL) PHENOXY] -3-
PHENYLPROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
A mixture of N-(3-f1-[(3S)-3-hydroxy-3-phenylpropyl]-4-
piperidinyl)phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 2-fluoro-5-trifluoromethylphenol ~ (100 mg),
triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl
azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL)
was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates [2.50
of NH3 (2.0 M in methanol) in CHC13] gave the desired
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product (2.50mg, 33.7 o yield) as
a thick oil: 1H
NMR (400 MHz, CDC13) 8 8.07 (s, 1H),
7.67 (m, 1H), 7.54
(m, 1H), 7.45 (m, 2H), 7.30-7.10 (m, 6H), 7.14 (d,
1H,
J=7.4 Hz ), .97 (apparent d, 1H, J=7.7 Hz), 5.37
6
(apparent dd, 1H, J=5.0, 8.5 Hz), (m, 2H), 2.8 (m,
3.4
2H), 2.6 (s, H), 2.53 (apparent sept,partially hidden,
1
1H, J=7.4 Hz) 2.30-2.10 (m, 6H) , (m, 2H) , 1.25
, 1.80 (d,
6H, J=7.1 Hz, overlapped); ESMS m/e: 542.6 (M+), 543.54
(M + H) ''~ .
Example 66
N- [3- (1-~ (3S) -3- [2-FLUORO-5- (TRIFLUOROMETHYL) PHENOXY] -3-
PHENYLPROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
A mixture of N- (3-{1- [ (3R) -3-hydroxy-3-phenylpropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 2-fluoro-5-trifluoromethylphenol (100 mg),
triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl
azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL)
was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates [2.50
of NH3 (2.0 M in methanol) in CHC13] gave the desired
product (3.00 mg, 40.40 yield) as a thick oil: 1H NMR
(400 MHz, CDC13) 8 8.06 (s, 1H), 7.67 (m, 2H), 7.55 (m,
2H), 7.50-7.40 (m, 3H), 7.30-7.10 (m, 3H), 7.17 (d, 1H,
J=8.9 Hz), 7.07 (apparent d, 1H, J=6.7 Hz), 6.97
(apparent d, 1H, J=7.8 Hz), 5.37 (apparent dd, 1H,
J=4.2, 8.1 Hz), 3.37 (m,' 2H), 2.93 (m, 2H), 2.63 (s,
1H), 2.50 (apparent sept, partially hidden, 1H, J=7.9
Hz) , 2.30-2.10 (m, 6H) , 1 .85 (m, 2H) , 1 .25 (d, 6H, J=6.9
Hz); ESMS m/e: 542.7 (M + H)+.
Example 67
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N-(3-~1-[(3S)-3-(2,5- DIFLUOROPHENOXY)-3-
PHENYLPROPYL]-4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE:
A mixture of N- (3-{1- [ (3R) -3-hydroxy-3-phenylpropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 2,5-difluorophenol (100 mg), triphenylphosphine
(30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42
mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room
temperature for 3 days. Chromatography using silica
preparative TLC plates [2. 5 0 of NH3 (2 . 0 M in methanol)
in CHC13] gave the desired product (2.70 mg, 40.1
yield) as a thick oil: 1H NMR (400 MHz, CDC13) 8 7.46. (s,
1H), 7.40-7.30 (m, 4H), 7.20 (m, 2H), 7.17 (s, 1H), 6.97
(m, 2H), 6.58 (m, 1H), 6.51 (m, 1H), 5.27 (apparent dd,
1H, J=5.1, 8.2 Hz), 3.13 (apparent d, J=9.7 Hz,~ 2H),
2.64 (m, 2H), 2.51 (m, 2H), 2.34 (apparent sept,
partially hidden, J=7.1 Hz, 1H), 2.17 (m, 3H), 1.90-1.80
(m, 4H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 493.1 (M +
H)+.
Example 68,
N- (3-~1- [ (3R) -3- (3-CHLOROPHENOXY) -3-PHENYLPROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of N-
(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-
piperidinyl~phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 3-chlorophenol (100 mg), triphenylphosphine (30.0
mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg,
0.0426 mmol) in THF (0.50 mL) was stirred at room
temperature for 3 days. Chromatography using. silica
preparative TLC plates [2 . 5 0 of NH3 (2 . 0 M in methanol)
in CHC13] gave the desired product (2.4 mg, 35.8% yield)
as a thick oil : 1H NMR (400 MHz, CDC13) b 7.30 (m, 2H) ,
7.30-7.20 (m, 3H), 7.20 (m, 3H), 6.90 (apparent d, 1H,
J=7.7 Hz), 6.71 (apparent d, 1H, J=2.9 Hz), 6.69
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(apparent t, 1H, J=2.9 Hz), 6.67 (apparent t, 1H,
J=2.9 Hz), 6.65 (apparent d, 1H, J=2.9 Hz), 5.09
(apparent dd, 1H, J=4.8, 8.1 Hz), 3.18 (m, 2H), 2.73 (m,
2H), 2.50 (apparent sept, partially hidden, 2H, J=7.1
Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.25 (d, 6H,
overlapped); ESMS m/e: 491.1 (M + H)+.
Example 69
(1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-Z-PIPERIDINYL~-1-
PHENYLPROPYL 1-NAPHTHOATE: Into a 25-mL RB-flask was
added N- (3-~1- [ (3S) -3-hydroxy-3-phenylpropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 1-naphthalenecarbonyl chloride (100 mg),
diisopropylethylamine (0.30 mL) in THF (0.50 mL) at room
temperature. After stirring for 16 hrs at room
temperature, the reaction mixture was concentrated under
reduced pressure. The residue was purified using
preparative TLC plates [2.5% of NH3 (2.0 M in methanol)
in CHC13] gave the desired product (4.70 mg, 71.3
yield) as a thick oil: 1H NMR (400 MHz, CDC13) ~ 8.90 (d,
1H, J=8.9 Hz')', 8.28 (apparent dd, 1H, J=1.5, 7.2 Hz),
8.03 (d, 1H, J=8.7 Hz), 7.88 (dm, 2H, J=8.7 Hz), 7.60-
7.48 (m, 7H), 7.40-7.32 (m, 3H), 7.25 (m, 1H), 6.90
(apparent d, 1H, J=7.4 Hz), 6.18 (apparent dd, 1H,
J=5.7, 7.8 Hz), 3.42 (m, 2H), 2.84 (m, 2H), 2.53 (m,
2H), 2.44 (apparent sept, partially hidden, 4H, J=7.5
Hz), 2.30-2.10 (m, 2H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.8
Hz); ESMS m/e: 535.6 (M + H)+.
Example 70
N- (3- f 1- [ (3S) -3- (3-ACETYLPHENOXY) -3-PHENYLPROPYL] -4-
PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of N-
(3-{1- [ (3R) -3-hydroxy-3-phenylpropyl] -4-
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piperidinyl}phenyl)-2- methylpropanamide (5.20
mg, 0.0137 mmol), 2-acetylphenol (100 mg),
triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl
azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL)
was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates [2.50
of NH3 (2.0 M in methanol) in CHC13] gave ..the desired
product (1.50 mg, 22.0% yield) as a thick oil: 1H NMR
(400 MHz, CDC13) 8 7.65 (m, 1H) , 7.55 (s, 1H) , 7.30-7.20
(m, 5H), 7.20 (m, 3H), 6.97 (m, 2H), 6.76 (apparent d,
1H), 5.49 (apparent dd, 1H, J=4.3, 8.0 Hz), 3..38 (m,
2H), 2.93 (m, 2H), 2.75 (s, 3H), 2.53 (apparent sept,
partially hidden, 2H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.92
(m, 2H) , 1.25 (d, 6H, J=6.9 Hz) ; ESMS m/e: 498.81 (M+) ,
499.6 (M + H)+.
Example 71
N- (3-~1- [ (3S) -3- (2-FLUOROPHENOXY) -3-PHENYLPROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of N-
(3-{1- [ (3R) -3-hydroxy-3-phenylpropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 2-fluorophenol (100 mg), triphenylphosphine (30.0
mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg,
0.0426 mmol) in THF (0.50 mL) was stirred at room
temperature for 3 days. Chromatography using silica
preparative TLC plates [2.5% of NH3 (2.0 M in methanol)
in CHC13] gave the desired product (3.5 mg, 53.9% yield)
as a thick oil : 1H NMR (400 MHz, CDC13) 8 8.07 (s, 1H) ,
7.65 (m, 1H) , 7.41 (s, 1H) , 7.40-7.10 (m, 5H) , 7.05 (m,
2H), 6.97 (apparent d, 1H, J=8.7 Hz), 6.86 (m, 2H), 6.79
(apparent dt, 1H, J=2.4, 7.9 Hz), 5.31 (apparent dd, 1H,
J=4.5, 8.0 Hz), 3.39 (m, 2H), 2.97 (m, 2H), 2.53
(apparent sept, partially hidden, 2H, J=7.5 Hz), 2.3-2.1
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(m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.7 Hz);
ESMS m/e: 475.7 (M + H)+.
Example 72
(4S) -N- (3-~4- [3- (ACETYLAMINO) PHENYL] -1-
PIPERIDINYL~PROPYL)-4-(3,5-DIFLUOROPHENYL)-2-OXO-1,3-
OXAZOLIDINE-3-CARBOXAMIDE
Method: Into a 20 ml vial was added N1-~3-[1-(3-
aminopropyl)-4-piperidyl]phenyl}acetamide (15 mg, 0.054
mmol), (4S)-4-(3,5-difluorophenyl)-2-oxo-oxazolidine-3-
carboxylic acid-4-nitro-phenyl ester (39.3 mg, 1.08
mmol, 2 eq) and dichloromethane with 0.6% of methanol (3
ml) at room ~ temperature. After stirring at room
temperature for 3 hrs, the reaction mixture was
filtered, and purified by preparative silica TLC (19:1 =
chloroform . methanol) to afford the desired product
(18.3 mg, 68% yield) ; 1H NMR (400 MHz, CDC13) 8 8.09 (br
s, 1H), 7.40 (d, 1H, J=8.0 Hz), 7.36-7.28 (m, 2H), 7.24
(t, 1H, J=8.0 Hz), 6.99 (d, 1H, J=8.0 Hz), 6.86-6.82 (m,
2H), 5.41 (dd, 1H, J=4.1, 9.0 Hz), 4.72 (t, 1H, J=9.0
Hz), 4.22 (dd, 1H, J=3.9, 9.1 Hz), 3.42-3.29 (m, 2H);
3.02 (d, 2H J=11.1 Hz), 2.52-2.38 (m, 3H), 2.16 (s, 3H),
2.08-1.98 (m, 2H) , 1.86-1.70 (m, 6H) ; ESMS m/e: 501.2 (M
+ H) +; Anal . Calc . for C26H30FzN4~4+0 . 5H20: C, 60 . 64; H,
6.18; N, 10.88. Found: C, 60.67; H, 5.79; N, 10.86.
Example 73
The synthetic method is the same as described for the
synthesis of (4S) -N- (3- f 4- [3- (acetylamino)phenyl] -1-
piperidinyl~propyl)-4-(3,5-difluorophenyl)-2-oxo-1,3-
oxazolidine-3-carboxamide.
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(4S,) -N- (3-~4- [3- (ACETYLAMINO) PHENYL] -1-
PIPERIDINYL~PROPYL)-2-OXO-4-(3,4,5-TRIFLUOROPHENYL)-1,3-
OXAZOLIDINE-3-CARBOXAMIDE: 18.8 mg (67o yield); 1H NMR
(400 MHz, CDC13) 8 8.09 (br s, 1H), 7.41-7.20 (m, 3H),
7.02-6.91 (m, 3H), 5.37 (dd, 1H, J=3.8, 8.9 Hz), 4.71
(t, 1H, J=9 Hz), 4.21 (dd, 1H, J=4, 9.3 Hz), 3.43-3.27
(m, 2H), 3.02 (d, 2H, J=11.0 Hz), 2.53-2.37 (m, 3H),
2.16 (s, 3H), 2.08-1.97 (m, 2H), 1.85-1.69 (m, 6H); ESMS
m/e : 519 . 2 (M + H) +; Anal . Calc . for C26H29F3N4O4+0 . 5H20:
C, 59.20; H, 5.73; N, 10.62. Found: C, 59.40; H, 5.35;
N, 10.65.
Example 74
The synthetic method is the same as described for the
synthesis of (4S) -N- (3- ~4- [3- (acetyl amino) phenyl] -1-
piperidinyl~propyl)-4-(3,5-difluorophenyl)-2-oxo-1,3-
oxazolidine-3-carboxamide.
N- (3-~4- [3- (ACETYLAMINO) PHENYL] -1-PIPERIDINYL~PROPYL) -4-
(3,4-DIFLUOROPHENYL)-5,5-DTMETHYL-2-OXO-1,3-OXAZOLIDINE-
3-CARBOXAMIDE: 19.6 mg (68% yield); ~H NMR (400 MHz,
CDC13) ~ 8.18 (t, 1H, J=5.9 Hz) , 7.41 (d, 1H, J=8.
8 Hz) ,
7.33 (s, 1H), 7.27-7.14 (m, 2H), 7.02-6.88 (m, 3H),
5.04
(s, 1H), 3.34 (qm, 2H, J=6.3 Hz), 3.02 (dm, 2H, J=10.9
Hz), 2.53-2.38 (m, 3H), 2.16 (s, 3H), 2.07-1.96 (m,
2H),
1.87-1.69 (m, 6H) , 1.62 (s, 3H) , 1.02 (s, 3H) ; ESMS
m/e:
529.3 (M + H) ~ ; Anal . Calc. for CzeH34F2N4O4: C, 63
.62; H,
6.48; N, 10.60 . Found: C, 63.15; H, 6.27; N; 10.48.
Example 75
The synthetic method is the same as described for the
synthesis of (4S) -N- (3-{4- [3- (acetylamino)phenyl] -1-
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piperidinyl~propyl)-4- (3,5-difluorophenyl)-2-
oxo-1,3-oxazolidine-3-carboxamide.
(4S.5R) -N- (3- f 4- (3- (ACETYLAMINO) PHENYL] -1-
PIPERIDINYL~PROPYL)-4-(3,4-DIFLUOROPHENYL)-5-METHYL-2-
OXO-1,3-OXAZOLIDINE-3-CARBOXAMIDE: 20.5 mg (74% yield);
1H NMR (400 MHz, CDC13) 8 8.14 (t, 1H, J=5.5 Hz) , 7.40
(d, 1H, J=7.8 Hz) , 7.37-6.89 (m, 6H) , 5.35 (d, 1H, J=7.5
Hz), 5.02-4.93 (m, 1H), 3.41-3.25 (m, 2H), 3.02 (d, 2H,
J=10.8 Hz), 2.53-2.37 (m, 3H), 2.16 (s, 3H), 2.07 (m,
2H), 1.89-1.68 (m, 6H), 1.04 (d, 3H, J=6.4 Hz); ESMS
m/e : 515 . 3 (M + H) +; Anal . Calc . for CZ~H3zFaN404+0 . 5H20
C, 61.94; H, 6.35; N, 10.70. Found: C, 61.90; H, 6.13;
N, 10.64.
Example 76
The synthetic method is the same as described for the
synthesis of (4S) -N- (3- {4- [3- (acetyl amino) phenyl] -1-
piperidinyl~propyl)-4-(3,5-difluorophenyl)-2-oxo-1,3-
oxazolidine-3-carboxamide.
N-(3-{4-I3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL~PROPYL)-4-
(4-FLUOROBENZYL)-2-OXO-1,3-OXAZOLIDINE-3-CARBOXAMIDE:
17.4 mg (65% yield) ; 1H NMR (400 MHz, CDC13) 8 8. 08 (t,
1H, J=5.6 Hz), 7.4 (d, 1H, J=7.2 Hz), 7.34 (s, 1H),
7.28-7.14 (m, 3H), 7.05-6.95 (m, 3H), 4.69-4.60 (m, 1H),
4.26 (t, 1H, J=8. 8 Hz) , 4.15 (dd, 1H, J=3 .2, 9 Hz) 3
, .43
(q, 2H, J=6.2 Hz) , 3.3 (dm 1H, J=13 .6 Hz) , '3 .04 2H,
(dm,
J=11 Hz), 2.87 (dd, 1H, J=9.3, 14.4 Hz), 2.53-2.42 (m,
3H), 2.16 (s, 3H), 2.09-1.99 (m, 2H), 1.87-1.65 (m, 6H);
ESMS m/e: 497.3 (M + H)+; Anal. Calc. for
Ca~H33FN404+0.5H20: C, 64.14; H, 6.78; N, 11.08. Found :
C,
64.26; H, 6.39; N, 11.12.
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Example 77
2-METHYL-N- (3-~l- [ (.3R) -3- (2-NITROPHENOXY) -3-
FHENYLPROPYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE: A
mixture of N- ( 3 - ( 1- [ ( 3 S ) - 3 -hydroxy- 3 -phenylp ropyl ] - 4 -
piperidinyl~phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 2-nitrophenol (100 mg), triphenylphosphine (30.0
mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg,
0.0426 mmol) in THF (0.50 mL) was stirred at room
temperature for 3 days. Chromatography using silica
preparative TLC plates [2 . 5 0 of NH3 (2 . 0 M in methanol)
in CHC13] gave the desired product (2.37 mg, 34.50 yield)
as a thick oil: 1H NMR (400 MHz, CDC13) 8 7. 84 (d, 1H) ,
7.90 (m; 1H), 7.45 (m 1H), 7.30-7.20 (m, 5H), 7.20 (m,
2H) , 6.98 (m, 2H) , 6. 89 (apparent d, 1H, J=7.7 Hz) , 5.62
(apparent dd, 1H, J=4.1, 8.9 Hz) , 3 .10 (m, 2H) , 2.60 (m,
2H) , 2 .53 (m, 2H) , 2.30-2.10 (m, 6H) , 1.90 (m, 2H) , 1.25
(d, 6H, overlapped); ESMS m/e: 502.3 (M + H)+.
Example 78
N- (3-~1- [ (35) -3- ( [l, 1' -BIPHENYL] -4-YLOXY) -3-
PHENYLPROPYL]-4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE:
A mixture of N- (3-(1- [ (3R) -3-hydroxy-3-phenylpropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 4-phenylphenol (100 mg), triphenylphosphine (30.0
mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg,
0.0426 mmol) in THF (0.50 mL) was stirred at room
temperature for 3 days. Chromatography using silica
.preparative TLC plates [2 . 5 0 of . NH3 (2 . 0 M in methanol)
in CHC13] gave the desired product (3.00 mg, 41.2% yield)
as a thick oil: 1H NMR (400 MHz, CDC13) b 8.06 (s, 1H) ,
7.48 (m, 2H), 7.40-7.30 (m, 8H), 7.30-7.25 (m, 4H), 6.97
(apparent d, 1H, J=7.6 Hz), 6.91 (apparent d, 2H, J=8.7
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Hz), 5.34 (apparent dd, 1H, J=4.4, 8.0 Hz), 3.40
(m, 2H), 2.98 (m, 2H), 2.53 (apparent sept, partially
hidden, 1H, J=8.1 Hz), 2.44 (m, 1H), 2.30-2.10 (m, 6H),
1.93 (d, 2H) , 1.26 (d., 6H, J=6.9 Hz) ; ESMS m/e: 533.4 (M
+ H)+.
Example 79
2-METHYL-N-(3-~1-[(3R)-3-(3-NITROPHENOXY)-3-
PHENYLPROPYL]-
4-PIPERIDINYL~PHENYL)PROPANAMIDE: A mixture of N-(3-~1-
[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide (5.20 mg, 0.0137 mmol), 3-nitrophenol
(100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and
diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF
(0.50 mL) was stirred at room temperature for 3 days.
Chromatography using silica preparative TLC plates [2.5%
of NH3 (2.0 M in methanol) in CHC13] gave the desired
product (2.80 mg, 40.8 % yield) as a thick oil: 1H NMR
(400 MHz, CDC13) 8 7.76 (dm, 1H), 7.71 (t, 1H, J=1.8 Hz),
7.50-7.40 (m, 2H), 7.40-7.25 (m, 7H), 7.17 (apparent dd,
1H, J=2.4, 8.2), 6.97 (apparent d, 1H, J=7.7 Hz), 5.45
(apparent dd, 1H, J=5.0, 8.1 Hz), 3.45 (m, 2H), 2.89 (m,
2H), x.53 (apparent sept, partially hidden, 2H, J=8.3
Hz) , 2 .30-2.10 (m, 6I-i) , 1.92 (m, 2H) , 1 .25 (d, 6H, J=6.8
Hz) ; ESMS m/e: 502.3 (M + H)+.
Example 80
N-(3-~1-[(3S)-3-(2-ETHOXYPHENOXY)-3-PHENYLPROPYL]-4-
PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of N-
(3-{1- [ (3R) -3-hydroxy-3-phenylpropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 2-ethoxyphenol (100 mg), triphenylphosphine (30.0
mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg,
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0.0426 mmol) in THF (0.50 mL) was stirred at room
temperature for 3 days. Chromatography using silica
preparative TLC plates [2.5% of NH3 (2.0 M in methanol)
in CHC13] gave the desired product (1.16 mg, 15.50 yield)
as a thick oil: 1H NMR (400 MHz, CDC13) b 8.06 (s, 1H),
7.52 (s, 1H), 7.40-7.33 (m, 4H), 7.30-7.20 (m, 3H), 6.97
(apparent d, 1H, J=7.7 Hz) , 6. 88 (m, 2H) , 6.68 (m, 2H) ,
5.21 (m, 1H), 4.11 (q, 2H, J=7.3 Hz), 3.37 (m, 2H), 2.71
(m, 2H), 2.53 (apparent sept, partially hidden, 2H,
J=7.6 Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.49 (t, 3H,
J=7.3 Hz) , 1.25 (d, 6H, J=6. 8. Hz) ; ESMS m/e: 501.4 (M +
H)+.
Example 81
2-METHYL-N-(3-~1-[(3S)-3-(1-NAPHTHYLOXY)-3-
PHENYLPROPYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE: A
mixture of N- (3-{1- [ (3R) -3-hydroxy-3-phenylpropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide (5.20 mg, 0.0137
mmol), 1-naphthol (100 mg), triphenylphosphine (30.0 mg,
0.115 mmol) and diethyl azodicarboxylate (7.42 mg,
0.0426 mmol) in THF (0.50 mL) was stirred at room
temperature for 3 days. Chromatography using silica
preparative TLC plates [2.5% of NH3 (2.0 M in methanol)
in CHC13] gave the desired product (4 .30 mg, 66.2 o yield)
as a thick oil: 1H NMR (400 MHz, CDC13) b 8.06 (s, 1H),
7 .72 (d, 1H, J=8. 5 Hz) , 7 . 59 (d, 1H, J=8 .5 Hz) , 7.5 (m,
2H) , 7.45-7.30 (m, 6H) , 7.25 (m, 3H) , 7. 17 (apparent dd,
1H, J=2.6, 9.0 Hz), 7.01 (apparent d, 1H, J=2.6 Hz),
6.97 (apparent d, 1H, J=7.9 Hz), 5.46 (apparent dd, 1H,
J=4.5, 8.1 Hz), 3.12 (m, 2H), 2.61 (m, 2H), 2.53
(apparent sept, partially hidden, 2H, J=7.9 Hz), 2.30-
2.10 (m,~ 6H), 1.90 (m, 2H), 1.25 (d, 6H, J=7.3 Hz,
overlapped); ESMS m/e: 507.2 (M + H)+.
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Example 82
N-(3-f1-[(3S)-3-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-
YL)-3-PHENYLPROPYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE
Step 1:
2-[(1S)-3-CHLORO-1-PHENYLPROPYL]-1H-ISOINDOLE-1,3(2H)-
DIONE: According to the general procedure des~cibed in
Srebnik, M.; Ramachandran, P.V.; Brown, H.C. J. Org.
Chem. 1988, 53, 2916-2920, a mixture of phthalimide
(0.147 g, 1.0 mmol), (R)-(+)-3-chloro-phenyl-1-propanol
(0.171 g, 1.0 mmol), triphenylphosphine (0.262 g, 1.0
mmol) and diethyl azodicarboxylate (0.174 g, 1.0 mmol)
in 5.0 mL of THF was stirred at room temperature for 24
h. The reaction mixture was concentrated in vacuo. The
residue was washed with pentane (x3) and the combined
pentane extracts were concentrated and chromatographed
(silica with hexanes-EtOAc 8:1 as the eluent) to give
the desired product (0.121 g, 50.2 0) as a yellow solid:
1H NMR (400 MHz, CDC13) 8 7.82 (apparent dd, 2H, J=2.9
Hz), 7.70 (apparent dd, 2H, J=2.9 Hz), 7.56 (m, 2H),
7.39-7.27 (m, 3H),~5.64 (apparent dd, 1H, J=7.0, 9.2
Hz), 3.57 (m, 2H), 3.05 (m, 1H), 2.82 (apparent sept,
1H, J=7.0 Hz); ESMS m/e: 300.13 (M+H)+.
Step 2:
N-(3-{1-[(3S)-3-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-
YL)-3-PHENYLPROPYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE: A mixture of potassium carbonate
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(29.2 mg, 0.211 mmol), sodium iodide (47.5 mg,
0.317 mmol) , 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide (51.8 mg, 0.211 mmol) 2-
[ (1S) -3-chloro-1-phenylpropyl] -1H-isoindole-1, 3 (2H) -
dione (63.1 mg, 0.211 mmol) in DMF (5.0 mL) was stirred
at~100 °C for 3 hrs, at which time TLC indicated that the
reaction was complete. The reaction mixture was poured
into water (50 mL) and the aqueous layer was extracted
with methylene chloride (3x30 mL). The combined organic
extracts were washed with brine (30 mL), dried over MgS04
and concentrated under reduced pressure. The crude
product was purified by Prep-TLC plates [2.50 of NH3 (2.0
M in methanol) in CHC13] to give the desired product
(74.1 mg, 77.1 %) as a thick oil: 1H NMR (400 MHz,
CDC13) 8 7.83 (apparent dd, 2H, J=2.9 Hz), 7.69 (apparent
dd, 2H, J=2.9 Hz), 7.56 (apparent dt, 3H, J=2.9, 7.3
Hz) , 7 .33 (m, 4H) , 7.21 (t, 1H, J=7 . 8 Hz) , 7 .09 (s, 1H) ,
6.81 (apparent d, 1H, J=7.8 Hz), 5.49 (apparent dd, 1H,
J=5.5, 9.5 Hz), 2.98 (d, 1H, J=9.5 Hz), 2.87 (m, 2H),
2.50 (apparent sept, 1H, J=6.7 Hz), 2.40-2.35 (m, 4H),
1.94 (m, 2H) , 1.70-1.50 (m, 4H) , 1.25 (d, 6H, J=7.9 Hz) ;
ESMS m/e: 510.37 (M+H)+.
Example 83
2-METHYL-N-(3-~1-[(3S)-3-(4-PHENOXYPHENOXY)-3-
PHENYLPROPYL]-4-PTPERIDINYL~PHENYL)PROPANAMIDE
STEP 1:
4-~[(1S)-3-CHLORO-1-PHENYLPROPYL]OXY~-(4-
PHENOXY)BENZENE: A mixture of 4-phenoxyphenol (1.86 g,
10.0 mmol), (R)-(-)-3-chloro-phenyl-1-propanol (1.70 g,
10.0 mmol), triphenylphosphine (2.62 g, 10.0 mmol),
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diethyl azodicarboxylate (1.57 mL, 10.0 mmol) in
5.0 mL of THF was stirred at room temperature for 24 h.
The reaction mixture was concentrated in vacuo. The
residue was washed with pentane (x3) and the combined
pentane extracts were concentrated and chromatographed
(silica with hexanes-EtOAc 97:3 as the eluent) to give
the desired product as a thick oil which solidified on
standing (2.51 g, 75.7 %) : zH NMR (400 MHz, CDCI3) 8 7.4-
7.23 (m, 7H), 7.03 (apparent t, 1H, J=7.3 Hz), 6.91
(apparent dm, 2H, J=7.8 Hz), 6.93 (apparent q, 4H, J=7.8
Hz), 5.31 (apparent dd, 1H, J=4.5, 8.6 Hz), 3.82 (m,
1H), 3.62 (apparent quintet, 1H, J=5.6 Hz), 2.47 (m,
1H), 2.20 (m, 1H).
Step 2:
2-METHYL-N-(3-~1-[(3S)-3-(4-PHENOXYPHENOXY)-3-
PfiENYLPROPYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE: A
mixture of 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide (65.5 mg, 0.266 mmol), 4-
[ (1S) -3-chloro-1-phenylpropyl] oxy}- (4-phenoxy)benzene
(0.100 mg, 0.296 mmol), potassium carbonate (40.9 mg,
0.296 mmol) and sodium iodide (67.0 mg, 0.444 mmol) in
DMF (1.0 mL) at '100 °C for 3 hours. The reaction mixture
was poured into water (50 mL) and the aqueous layer was
extracted with methylene chloride (3x30 mL). The
combined organic extracts were washed with brine (30
mL), dried over MgS04 and concentrated under reduced
pressure. The crude product was purified by Prep-TLC
plates [2.5% of NH3 (2.0 M in methanol) in CHC13] to give
the desired product (0.109 g, 74.6 %) as a thick oil: 1H
NMR (400 MHz, CDC13) 8 7.48 (s, 1H), 7.40-7.30 (m, 4H),
7.20-7.10 (m, 6 H), 7.09 (s, 1H), 6.99 (apparent d, 1H,
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J=7.8 Hz), 6.98 (apparent t, 1H, J=7.8 Hz), 6.93
(apparent d, 2H, J=8.4 Hz) , 6.84 (m, 2H) , 5.20 (apparent
dd, 1H, J=4.4, 8.5 Hz), 3.03 (m, 2H), 2.51 (m, 4H), 2.24
(apparent sept, 1H, J=7.8 Hz), 2.20-2.10 (m, 3H), 1.90
(m, 4H), 1.25 (d, 6H, J=7.9 Hz); ESMS m/e: 549.41 (M+H)+;
Anal. Calc. for C36H4nNaO3: C, 78.80; H, 7.35; N, 5.11.
Found: C, 78.58; H, 7.48; N, 5.09.
Example 84
N-(4-~1-[(3R)-3-(3,4-DIMETHOXYPHENOXY)-3-PHENYLPROPYL]-
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE
Step 1:
1- [ (3R) -3- (3,4-DIMETHOXYPHENOXY) -3-PHENYLPROPYL] -4- (4-
NITROPHENYL)-1,2,3,6-TETRAHYDROPYRIDINE: A mixture of
potassium carbonate (24.0 mg, 0.174 mmol), sodium iodide
(39.0 mg, 0.260 mmol), 4-(4-nitrophenyl)-1,2,3,6-
tetrahydropyridine (35.4 mg, 0.174 mmol) and 4-~[(1R)-3-
chloro-1-phenylpropyl]oxy~-1,2-dimethoxybenzene (53.4
mg, 0.174 mmol) in DMF (0.5 mL) was stirred at 100 °C for
3 hrs, at which time TLC indicated that the reaction was
complete. The reaction mixture was poured into water
(5.0 mL) and the aqueous layer was extracted with
methylene chloride (3x30 mL). The combined organic
extracts were washed with brine (30 mL), dried over MgS04
and concentrated under reduced pressure. The crude
product was purified by Prep-TLC plates
[1:1=hexane:ethyl acetate with 1% NH3] afforded the
product (63.1 mg, 76.6 %) as a yellow oil. The product
was used in next reaction without further purification.
Step 2:
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4-~1-[(3R)-3-(3,4-DIMETHOXYPHENOXY)-3-PHENYLPROPYL]-4-
PIPERIDINYL~ANILINE: A 25-mL RB flask, equipped with a
hydrogen-filled balloon, was charged with 1-[(3R)-3-
(3,4-dimethoxyphenoxy)-3-phenylpropyl]-4-(4-
nitrophenyl)-1,2,3,6-tetrahydropyridine (63.0 mg, 0.133
mmol), palladium on carbon (5.0 mol-eq%, 0.00665 mmol,
7.04 mg) and ethanol (2.0 mL) at room temperature.
After 1 hr the reaction mixture was filtered through a
plug of Celite 545 and concentrated under reduced
pressure. The crude pxoduct (54.1 mg, 89.4%) was used
in next reaction without further purification.
STEP 3:
N- (4-~1- [ (3R) -3-~(3, 4-DIMETHOXYPHENOXY) -3-PHENYLP,ROPYL] -
4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of
4-{1-[(3R)-3-(3,4-dimethoxyphenoxy)-3-phenylpropyl]-4-
piperidinyl}aniline (5.31 mg, 0.0119 mmol), isobutyryl
chloride (2.08 mg, 0.019 mmol), N,N-
diisopropylethylamine (8.40 mg, 0.0650 mmol) in
methylene chloride (1.0 mL) was stirred at room
temperature for 24 hours. The reaction mixture was
concentrated and chromatographed using a preparative TLC
plate [2 . 5 0 of NH3 (2 . 0 M in methanol) in CHC13] to give
the product (3.5 mg, 56.5 %) as a thick oil: 1H NMR (400
MHz, CDC13) ~ 7.38 (d, 1H, J=8.6 Hz) , 7.30-7.20 (m, 4H) ,
7.20(m, 1H), 7.11 (d, 2H, J=8.6 Hz), 7.04 ~(s, 1H), 6.57
(d, 1H, J=8.3 Hz), 6.44 (d, 1H, J=2.6 Hz), 6.22 (dd, 1H,
J=2.6, 8.3 Hz), 5.09 (apparent dd, 1H, J=4.4, 8.1 Hz),
3 . 72 (s, 3H) , 3 . 70 (s, 3H) , 3 . 08 (m, 2H) , 2.57 (m, 2 H) ,
2.43 (apparent sept, partially hidden, 2H, J=6.8 Hz),
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2.30-2.10 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H,
J=7.9 Hz); ESMS m/e: 517.3 (M+H)+.
Example 85
N- (3-~1- [ (3S) -3- (3-ACETYLPHENOXY) -3-PHENYLPROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Into a 25-mL
RB-flask was added triphenylphosphine (9.80 mg, 0.0375
mmol), diethyl azodicarboxylate (5.22 mg, 0.0300 mmol),
N- (3-~l- [ (3R) -3-hydroxy-3-phenylpropyl] -4-
piperidinyl~ph.enyl)-2-methylpropanamide (9.53 mg, 0.0250
mmol), 3-hydroxyacetophenone (100 mg) and THF (1.0 mL)
at room temperature. The reaction mixture was stirred
at room temperature overnight (16 hrs). The solvent was
removed under reduced pressure and the residue was
purified by preparative TLC plates [2.50 of NH3 (2.0 M in
methanol) in CHC13] to afford the desired product (2.73
mg, 39. 9 0) as a thick oil : 1H NMR {CDC13) 8 7 .70-7 .64 (m,
2H), 7.54 (m, 2H), 7.49-7.44 (m, 6H), 7.25 (m, 1H), 7.05
(d, 1H, J=8.3 Hz), 6.96 (apparent d, 1H, J=7.7 Hz), 5.34
(apparent dd, 1H, J=4.8, 8.2 Hz), 3.15 (m, 2H), 2.67 {m,
2H), 2.52 (s, 3H), 2.53 (apparent sept, partially
hidden, 2H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H),
1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 499.4 (M + H)+.
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Scheme A. Synthesis of tert-Butyl 4-(3-aminophenyl)-1-piperidinecarboxylate
F' /F
O OS~F
O ~O
a ~ b
--
N
O O O
~ NH2 I ~ NH2
c
o~o~ o
a. n-BuLi, diisopropylamine, THF, PhN(Tf)2, -78 °C to room temperature,
81
b. 3-aminophenylboronic acid hemisulfate, LiCI, tetrakis-triphenylphosphine
-palladium (0), Na2C03, DME-H20, reflux, 81
c. 10% Pd/C, ethanol, H2, room temperature, baNoon method, 84°!°
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Scheme B1, A General Synthesis of the MCH Antagonists
OTf (Ph3P)4Pd(0), NazC03, LiCI, ~ NHz
o-,m- or p-NOz
HzO, dimethoxyethane, reflux
NHz ~ W or
BOC ~ / ~ / o-,m- or p-NOz
or N N
BOC BOC
B(OH)z B(OH)z 2 3
1
H
NHz 1. R~X(=O)CI ~ N,X~R~
2. Hz, PdlC, EtOH ~ / O
3. HCI in dioxane _
4. Rz-halide, cat. Bu4Nl, dioxane, reflux 4
N or Rz-halide, cat. 18-crown-6, toluene, reflux
N
BOC or Rz-halide, cat. Nal, NazC03, DMF, 100 °C
H
NHz 1. H2, Pd/C, EtOH ~ N, ,R~
2. NCI in dioxane ' ~ X
O
3. Rz-halide, cat. Bu4Nl, dioxane, reflux
2 or Rz-halide, cat. 18-crown-6, toluene, reflux
N or Rz-halide, cat. Nal, NazC03, DMF, 100 °C
i
BOC 4. R~X(=O)CI N
R2
Scheme B2, A General Synthesis of the MCH Antagonists
1. NCI in dioxane ~ H
/~ o-,m- or p-NOz 2. R -halide, cat. Bu NI, dioxane, reflux I ~I N~X~R~
2 4
or Rz-halide, cat. 18-crown-6, toluene, reflux O
or Rz-halide, cat. Nal, NazC03, DMF, 100 °C '
N~ 3. Hz, PdlC, EtOH N'
(30C 4. RiX(=O)CI Rz
1. Hz, PdIC, EtOH ~ H
~ o_,m_ or P_NOz ~ ~ N.X.R~
2. HCI in dioxane ~ ii
3. Rz-halide, cat. Bu4Nl, dioxane, reflu . O
or Rz-halide, cat. 18-crown-6, toluene, reflux ~ 4
N or Rz-halide, cat. Nal, NazC03, DMF, 100 °C N
BOC 4. RiX(=O)CI Rz
X = C, S(=O) halide = CI, Br
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178
Scheme C1. Specific Examples of the Syntheses of the MCH Antagonists
H
'[~~_N
NHZ 1. isobutyryl chloride, dichloromethane
/ 2. Hz, 10°lo PdIC, EtOH ' / O
3. NCI in dioxane 5A
4. Rz-CI (or Br), cat. 8u4N1, dioxane, reflux
N or R~-CI (or Br), cat. Nal, Na2C03, DMF, >90 °C N
BOC OH ,
CI ,. I
-O
HO N \ / -
diethylazodicarboxylate j0 / ~ O N \ /
NH THF, PPh
/ 5g O~ 3 0 ~ H \ / s O NH
Scheme C2. Specific Examples of the Syntheses of the MCH Antagonists
HO N \ / / \ / -
NH d°sopropylethylamine O O N \ /
O THF, ' - NH
\ / 5B ~ ~ \ O Cl 7 \ / O
retention of the absolute~'~
HO CI 1, diethylazodicarboxylate O / \ O N \ /
THF, 4-phenylphenol, PPh3 \ / NH
2. DMF, heat, K2C03, KI \ / 8
commercially HN ~ i ~ inversion of sterochemistry
available HN
HO CI 1 _ diethylazodicarboxylate ~ /=
_ THF, phthalimide, PPh3~ O~N N'
\ / 2. DMF, heat, KZC03, KI _ ~l
HN v/~ \ / g
HN O inversion of sterochemistry
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Scheme D1. Specific Examples of the Syntheses of the MCH Antagonists
H
j~ 'N
I/ o
I ~ NHz 1. Hz, 10% PdlC, EtOH
2. HCf in dioxane
N
3. cat. 18-crown-6, toluene, reflux, O
Cf
N 4. isobutyryl chloride,
BOC dichloromethane O
O ~Br
I, N
BOC O
NHz 1. isobutyryl chloride, dichloromethane
2. H2, Pd/C, EtOH
3. NCI in dioxane
4. cat. Bu4Nl, dioxane, reflux,
N
Scheme D2. Specific Examples of the Syntheses of the MCH Antagonists
NO 1. HCI in dioxane ~ ~ I O
z
2, cat. Nal, NazC03, DMF, 100 °C, f , CI
I / 3. Hz, 10% Pd/C, EtOH
4. isobutyryl chloride,
dichloromethane
,O
N ~
BOC ~O~O
N.
O
N
H
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Scheme E: General Synthesis of the MCH Antagonists
O - O -
CI + N ~ / O ~ Ri' v v N ~ /
R~ 1 2 N-X 3 N-~O
Rz Rz
O - O
CI + N ~ / ~ Ri' v v N
R~
1 4 NHz 5 NHz
O - O
~ ~ R2COCI b j~ ~
R~~N ~ / ~. RzSOzCI R1~N ~ / O
NH2 6 HN-X-R2
a. dioxane, diisopropylethylamine, Bu4Nl, reflux
or DMF, lCi, NazC03, 90-100 °C
or toluene, 110 °C, 18-crown-6
b. diisopyropylethylamine, dichloromethane
X = S(=O), C
Ri = Aromatic, substituted aromatic or heterocyclic
Rz = aliphatic oraromatic
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Scheme F. General Synthesis of the MCH Antagonists
R-halide;
_ diisopropylethylamine _
H-N \ ~ or Na2C03; R-N
/~O Bu4Nl, or KI; O
N~ dioxane, toluene, N
or DMF; heat 50-90%
If R = (CHZ)~CHOH-Ar, then,
HO N
- !/O DEAD, Ph3P,
N~ THF, R-PhOH
inversion of the absolute
or the other enantiomer stereochemistry
R
HO N \ ~ ~O -
N O acid chloride, Hunig's base O N
\ / ~ retention of the absolute ~ NH
or the other enantiomer stereochemistry \ / / "O
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Scheme G. General Synthesis of the MCH Antagonists
R\ \ I ~
o
HO CI p CI O N CI
DEAD, Ph3P,
THF, R-phOH or or
\ ~ \
phthalimide
H-N~ \ ~ R \ \
~O
N XR O N \
,.O
~N
diisopropylethylamine ~ ~ R
or Na2C03;
Bu4Nl, or KI;
dioxane, toluene, or
or DMF; heat
I
O
N N
O ~ / ,.O
.J~N
R
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Scheme H: Synthesis of Oxazolidinones
a Ar b Ar c
ArCHO
NC~NHz Me02C~NH2
O
Ar d Ar II
a O~NH f
HO~NH2 HO~NHtBoc
Ar
OI OII
O~NH + O~NH
U
~Ar . ~Ar
O NOa O'' OI,
O~NH ~ ~ J''O ~ ~ ~ O~N~N~N
O N ~ H
Ar Ar
~Ar
~NH
a. NH3, then TMS-CN; b. HCI in MeOH (room temperature to reflux);
c. LAN, THF, reflux; d. (BOC)20, chloroform; e. NaH, THF; f. Chiralcel OD
column
g. NaH, p-nitrophenyl chloroformate, THF;
h. an amine such as N-(3-[1-(3-aminopropyl)-4-piperidinyl)phenyi)acetamide
Ar = 3,4-difluorophenyl, 3,5-difluorophenyl or 3,4,5-trifluorophenyl
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Scheme f: Synthesis of gem-Dialkyl Substituted Oxazofidinones
F F
F I ~ F O
/ / II
a b O~NH
H N OMe ---~. H2N OH ~ n",.
2
p ' / \ F
O O
yI 'I F
c d O~N~N~N
2 _ u",. H
/ \ F
F \/NH
~O
a. methyl magnesium bromide, THF; b. N,N-carbonyldiimidazole, DCM; c. NaH,
THF,
p-nitrophenylchioroformate; d. an amine such as
N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide
J
Scheme J: Synthesis and Chiral Resolution of Oxazolidinones
O
OH
N Ph a,b c,d O NH
I / ~ NHz 4 .---
F P
F F / ~ ~ F
F
F
OII
O~NH f g
F
F
a (a) t-BuLi, THF, RCHO (b) CH30NHz.HCI, MeOH, 50-68% over 2 steps (c) Boc20,
CHCI3, >90% (d)
NaH,THF, 76-92% (e) separate diastereomers by column chromatography and
separate enantiomers by chiral
phase HPLC, 10-16% (f) n-BuLi, THF, 4-nitrophenylchloroformate, -75%
(g) THF, >80%, an amine such as N-{3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl)acetamide
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Scheme K: Synthesis Oxazolidinones from Amino Acids
_ O
Ar a Ar b, c O~NH d
OOH ~ H N' v OH
H2N C
Ar
O O
O O ~ NOZ O~N~N~N
h H
p N p
J
F (H) l R
Ar
F
a. LAN, THF; b. (BOC)20, CHC13; c. NaH, THF; d. p-nitrophenylchloroformate,
NaH, THF;
h, an amine such as N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide
Ar = aromatic such as 4-tluorophenyl or 3,4-difluorophenyf
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Scheme L: Determination of the Absolute Stereochemistry of the Di-Substituted
Oxazoiidinones
Using Lactic Acid Derivatives
O
O O
a b ~N~
--~ ~N~ -~ Si~O
OH OH
O HON
F ~ NH2
j F ~ \./O I % F ~ ~ ~ F
~S ~ \ 'Si F OH
F
F F F
\ F ~ \ F ~ \ F
g ~ h
l, -~ ise + ~
',,O NH 'I0 NH ' ~0 NH
O O O
pyrrolidine, methanol, heat; b. t-butyldimethylsilyl chloride; c. LAN, ether,
reflux
(BOC)~O, chloroform; e. NaH, THF; h. silica gel chromatography
For more details, See: Lagu, B.; Wetzel, J. M.; Forray, C.; Patane, M. A.;
Bock, M. G.
"Determination of the Relative and Absolute Stereochemistry of a Potent a1A
Selective
Adrenoceptor Antagonist" Bioorg. Med. Chem. Lett. 2000, 10, 2705.
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Scheme M
/ 3
n .H
.~. R2 \ ZnClp, HOAc
'R1 ~ / ~R4 NH2 75 °C, 10 hrs
Example
R3 R3 ~ H
n H + R2~ \ I ZnCl2. HOAc ~ ~ O
\ N I n-1
NHz 75 °C, 10 hrs
\,
~2 ~ ~~t
n=2, R1=H, R2=Ph, R3=H
n=5, R1=H, R2=H, R3=5-OMe
n=1, R1=H, R2=Ph, R3=H
n=4, R1=H, R2=H, R3=5-OMe
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Scheme N
H
s ~ ~l
y H
\,
\ t O t dioxane/HOAc \ \ O s
H~ rt, 5 hrs ~~~,,,'
~W2z R
/ Rz ,
H
Example
H
N
~~.~~r~~(~H
t ~ t dioxane/HOAc \ \ O
\ H rt, 5 hrs ~
~ R2 Fii R
N z
H
R1=6-CI, R2=H
Ri=H, R2=4'-tolyl
10
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Scheme P
R \ ~ 1. NaH, DMF R' i \ ~ KZC03, NaI, 3
i
/ / N DMF, 90 °C, l2 h
N 2. BrCH2(CH2)nCH2C1
H CHz(CHz)~CHZCI
3. H.N~~NH
O R
z
~ ~N ~R
I' z
O
R~~ N N
'-(CHz)~
Example
\ 1. NaH, DMF ~ \ ~ KzC03, NaI, 3
R~ I \ R~ ~ o
/ N 2. BrCH2(CHZ)3CHZC1 ~~~ DMF, 90 C, 12 h
H 2a: n=3 CHz(CHz)nCH2Ci , ~
2b: n=4 3v H N N
O
\ NH
r ~ \ O
w N N
~(CHp)n~ 4a:n=3
4b:n=4
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Scheme O
i
Cu, K2C03, NMP
~2 _ /
/ N / 150 °C, 12 hrs R~
R~ H ~~~2
R1=H, R2=4'-Me
Scheme Q
KZC03, CuBr, 6, N H
H
I ~N /N~O NMP, I50°C, 12h I N I / N'/O
N ~ / RR2 / \ / I ~R'z
I R~
R~
Example
KZC03, CuBr, 6, ~ N
N N O NMP, I50 °C, 12 h I N I / I ~ N O
~~ i
N~ ~ / ~ 6a: I / \ ~ /
6b: I / \ F R~ 7a: R1 = p-OMe
gc: I /-\ COZMe _ - 76: Rl = p_p '
7c: R1 =p-COZMe
6d: I / \ 7d: Rl= p-Me
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Scheme R
NaBH(OAc)3
1,2-dichloroethane
R1 CH0 + NN ~ ~ ~--N
N HOAc, rt overnight R~ N
O
R2 R2
Example
NaBH(OAc)3
1,2-dichloroethane
R1 CHO +
HOAc, rt overnight
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192
The following additional abbreviations are used: HOAc,
acetic acid; DMF, N,N-dimethylformamide; EtOAc, ethyl
acetate; MeOH, methanol; NMP, 1-methyl-2-pyrrolidinone;
TEA, triethylamine; THF, tetrahydrofuran; All solvent
ratios are volume/volume unless stated otherwise.
1-(4-METHYLPHENYL)1H-INDOLE: A mixture of 1-H-indole
(58.5 mg, 0.500 mmol), 1-(iodo)-4-methylbenzene (0.218
g, 1 .00 mmol) , copper powder (32 .0 mg, 0.500 mmol) , and
K2C03 (0.138 g, 1.00 mmol) in 1-methyl-2-pyrrolidinone (1
mL) was heated at 150 °C for 12 h under argon. The
resulting mixture was diluted with HBO (6 mL). The
aqueous layer was extracted with CH2C12 (3 X 10 mL) . The
combined organic extracts were washed with brine (10
mL), dried over MgS04, and concentrated in vacuo. The
residue was purified by preparative TLC using
EtOAc/hexane (1:4) to give the desired product (82 mg,
790) . 1H NMR (400 MHz, CDC13) 8 7.67 (d, 1H, J =
7.7 Hz), 7.52 (d, 1H, J = 7.4 Hz), 7.38 (d, 2H, J = 8.4
Hz) , 7. 34-7 .29 (m, 3H) , 7.21 (t, 1H, J = 7 . 0 Hz) , 7. 15
(t, 1H, J = 7.0 Hz) , 6.66 (d, 1H, 3 .3 Hz) , 2 .43 (s, 3H) ;
ESMS m/e: 208.0 (M + H)+.
Examgle 86
N-(3-~1-[(6-CHLORO-1H-INDOL-3-YL)METHYL]-4-.
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A solution of
2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.369
g, 1.50 mmol) and 37 wt % aqueous formaldehyde (30.0
mg, 1.50 mmol) in 1 mL of HOAc:dioxane (1:4) was added
to 6-chloro-1-H-indole (0.152 g, 1.00 mmol) and the
reaction mixture was stirred for 12 h at room
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temperature. The resulting mixture was diluted with
Hz0 (10 mL). The aqueous layer was extracted with CHZC12
(3 X '100 mL). The combined organic extracts were washed
with brine (10 mL), dried over MgS04, and concentrated in
vacuo. The residue was purified by preparative TLC on
silica using 5% of NH3 (2.0 M in methanol) in CHZC12 to
give the desired product (79 mg, 42 0) . 1H NMR (400 MHz,
CDC13) 8 9.14 (s, 1H), 8.04 (s, 1H), 7.52 (t, 2H, J = 8.1
Hz) , 7.35 (d, 2H, J = 13 .3 Hz) , 7.18 (t, 1H, J = 7.9
Hz), 7.09 (dd, 1H, J = 1.9, 8.5 Hz), 6.85 (d, 1H, J =
7.4 Hz) , 5.18 (s, 1H) , 4.01 (s, 2H) , 2.55 (septet, 1H, J
- 6.8 Hz), 2.48-2.34 (m, 3H), 2.08-1.95 (m, 4H), 1.78
(d, 2H, J = 12.8 Hz), 1.22 (d, 6H, J = 6.8 Hz); ESMS
m/e: 410.1 (M + H)+.
Example 87
2-METHYL-N-[3-(1-~Ll-(4-METHYLPHENYL)-1H-INDOL-3- .
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: According
to the procedure used for the synthesis of N-(3-~1-[(6-
chloro-1H-indol-3-yl)methyl]-4-piperidinyl~phenyl)-2-
methylpropanamide, 1-(4-methylphenyl)-1H-indole (0.207
g, 1.00 mmol) provided 2-methyl-N-[3-(1-f[1-(4-
methylphenyl)-1H-indol-3-yl]methyl}-4-
piperidinyl)phenyl]propanamide (0.441 g, 780). 1H NMR
(400 MHz, CDC13) 8 7.90 (s, 1H), 7.73 (d, 1H, J = 7.2
Hz), 7.58-7.51 (m, 2H), 7.43-7.36 (m, 3H), 7.35-7.29 (m,
3H) , 7.26-7.15 (m, 3H) , 6.89 (d, 1H, J = 7.7 Hz) , 4.07
(s, 2H), 3.36 (d, 2H, J = 11.6 Hz), 2.59-2.39 (m, 6H),
2.55 (sept, 1H, J = 6.7 Hz), 2.10-1.98 (m, 2H), 1.83 (d,
30~ 2H, J = 12.9 Hz), 1.23 (d, 6H, J = 6.9' Hz); ESMS m/e:
466.2 (M + H)+.
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2-[(1S)-3-CHLORO-1- PHENYLPROPYL]-1H-
ISOINDOLE-1,3(2H)-DIONE: Triphenylphosphine (5.25 g,
20.0 mmol) and diethyl azodicarboxylate (3.58 g, 20.0
mmol) were added to a solution of (1R)-3-chloro-1-
phenyl-1-propanol (3.42 g, 20.0 mmol) and phthalimide
(2.94 g, 20.0 mmol) in THF (100 mL). The reaction
mixture was stirred for 4 h at room temperature. The
solvent was removed under reduced pressure and the
residue was triturated with pentane (3 X 50 mL). The
combined pentane fractions were concentrated in vacuo
and the crude product was purified by chromatography on
silica using EtOAc/hexane (3:97) to give the desired
product (4 .40 g, 74 0) . 1H NMR (400 MHz, CDC13) 8 7 . 82
(d, 1H, J = 5.7 Hz) , 7.81 (d, 1H, J = 5.5 Hz) , 7.70 (d,
1H, J = 5 .4 Hz) , 7 .69 (d, 1H, J = 5 . 8 Hz) , 7.55 (d, 2H,
J = 7.2 Hz), 7.38-7.28 (m, 3H), 5.64 (dd, 1H, J = 6.8,
9.2 Hz), 3.56 (t, 2H, J = 6.4 Hz), 3.11-3.02 .(m, 1H),
2.85-2.75 (m, 1H) ; ESMS m/e: 300.1 (M + H)'~.
N-(3-~1-[(3S)-3-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-
YL)-3-PHENYLPROPYL]-4-PIPERIDINYL}PHENYL)-2-
METHYLPROPANAMIDE: A mixture of 2-[(1S)-3-chloro-1-
phenylpropyl] -1H-isoindole-1, 3 (2H) -dione (4 .50 g, 15 . 0
mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide
(4.26 g, 15.0 mmol) , KzC03 (4.16 g, 30. 0 mmol) , and NaI
(3.40 g, 20.0 mmol) in DMF (40 mL) was stirred at 90 °C
for 12 hrs. The reaction mixture was diluted with water
(50 mL) , extracted with CH2Clz (3 X 50 mL) , and the
combined organic extracts were washed with brine (50
"30 mL), dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by chromatography on
silica using 5% of NH3 (2.0 M in methanol) in CH2C12 to
give the desired product (5.10 g, 74%). 1H NMR (400 MHz,
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CDC13) 8 7.83 (d, 1H, J = 5.5 Hz), 7.82 (d, 1H, J =
5.5 Hz) , 7.71 (d, 1H, J = 5.5 Hz) , 7.70 (d, 1H, J = 5.4
Hz), 7.56 (d, 2H, J = 7.1 Hz), 7.35-7.27 (m, 5H), 7.22
(t, 1H, J = 7.5 Hz) , 7 .09 (s, 1H) , 6.81 (d, 1H, J = 7 .8
Hz), 5.49 (dd, 1H, J = 5.5, 9.6 Hz), 2.97 (d, 1H, J =
10.1 Hz), 2.92-2.82 (m, 2H), 2.44 (sept, 1H, J - 6.7
Hz), 2.40-2.29 (m, 3H), 2.00-1.83 (m, 2H), 1.79-1.39 (m,
5H), 1.26 (d, 6H, J = 6.9 Hz); ESMS m/e: 510.4 (M + H)+.
N-(3-~1-[(3S)-3-AMINO-3-PHENYLPROPYL~-4- .
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of N-
(3-~1- [ (3S) -3- (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) -
3-phenylpropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide (4.60 g, 9.06 mmol) and hydrazine
(3.62 g, 72.4 mmol) in ethanol (150 mL) was refluxed for
12 h. The resulting white precipitate was filtered out
and the filtrate was concentrated under vacuum. The
residue was washed with CH2Clz/EtOAc (1:1, 3 X 50 mL) and
the combined organic fractions were concentrated in
vacuo to give the desired product (2.90 g, 950) . 1H NMR
(400 MHz, CDC13) 8 7.45 (s, 1H), 7.39-7.30 (m; 6H), 7.29-
7.19 (m, 2H), 6.95 (d, 1H, J = 7.2), 4.01 (t, 1H, J =
6.8 Hz), 3.04 (t, 2H, J = 10.6 Hz), 2.62-2.30 (m, 6H),
2.05-1.70 (m, 8H), 1.24 (d, 6H, J = 6.8 Hz); ESMS m/e:
380.4 (M + H)+.
Example 88
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2-METHYL-N-(3-~1-[(3S)-3- PHENYL-3-
(PROPIONYLAMINO)PROPYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: According to the
procedure used for the synthesis of N- (3-{1- [ (3S) -3
(acetylamino)-3-phenylpropyl]-4-piperidinyl}phenyl)-2
methylpropanamide, N-(3-{1-[(3S)-3-amino-3-
phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide
(11.0 mg, 0.0280 mmol) and propionyl chloride (3.,80 mg,
0.0420 mmol) provided 2-methyl-N- (3-~1- [ (3S) -3-phenyl-3-
(propionylamino)propyl]-4-piperidinyl}phenyl)propanamide
(12 mg, 97 o yield) . 1H NMR (400 MHz, CDC13) 8 8. 05 (s,
1H), 7.59 (s, 1H), 7.40-7.20 (m, 7H), 6.96 (s, 1H),
5.19-5.12 (m, 1H) , 3 .18 (d, 1 H, J = 12.0 Hz) , 2.99 (d,
1H, J = 10.4 Hz), 2.93-2.86 (m, 1H), 2.61-2.40 (m, 3H),
2.38-2.23 (m, 3H), 2.19-1.75 (m, 8H), 1.25 (d, 6H, J =
6.9 Hz), 1.22-1.08 (m, 3H); ESMS m/e: 436.4 (M + H)+.
Example 89
N-~3- [1- ( (3S) -3-~ [ (4-FLUOROPHENYL)ACETYL]AMINO}-3-
PHENYLPROPYL)-4-PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE:
A mixture of N- (3-~1- [ (3S) -3-amino-3-phenylpropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide (11.0 mg, 0.0280
mmol) and (4-fluorophenyl)acetyl chloride (7.20 mg,
0.0420 mmol) in THF (5 mL) was stirred at room
temperature for 4 h. The solvent was removed under
reduced pressure and the residue was purified by
preparative TLC using Hexane:EtOAc (2:1) to give the
desired product (13 mg, 90% yield). 1H NMR (400 MHz,
CDC13) 8 7. 89 (d, 1H, J = 8.4 Hz) , 7.59 (s, 1H) , 7.31-
6.93 (m, 13H), 5.13 (q, 1H, J = 6.0 Hz), 3.56 (s, 2H),
3.07 (d, 1H, J = 11.7 Hz), 2.91 (d, 1H, J = 11.0 Hz),
2.62-2.42 (m, 2H), 2.40-2.30 (m, 1H), 2.12-1.54 (m, 9H),
1.24 (d, 6H, J = 6.7 Hz); ESMS m/e: 515.3 (M + H)~.
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Example 90
N-(3-{1-[3-(1,2-DIPHENYL-1H-INDOL-3-YL)PROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of
1,1-diphenylhydrazine hydrochloride (10.3 mg, 0.0470
mmol), 2-methyl-N-~3-[1-(5-oxo-5-phenylpentyl)-4-
piperidinyl]phenyl)propanamide (14.7 mg, 0.0362 mmol),
ZnCl2 (14.85 mg, 0.109 mmol), and HOAc (0.5 mL) was
heated for 4 h at 80 °C. The resulting crude mixture was
diluted with water (10 mL), the aqueous layer was
neutralized with saturated IC2C03 and extracted with CHZCla
(3 X 20 mL). The combined organic layers were
concentrated in vacuo and the residue was purified by
preparative TLC using 5% of NH3 (2.0 M in methanol) in
CH2C12 to give the desired product N-(3-{l-[3-(1,2-
diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-
methylpropanamide (4.1 mg, 37%) . 1H NMR (400 MHz, CDC13)
8 7. 71-7 . 65 (m, 1H) , 7. 42 (d, 1H, J = 7.4 Hz) , 7.39 (s,
1H) , 7.36-7.15 (m, 15H) , 6.94 (d, 1H, J = 7.8 Hz) , 3.12
(d, 2H, J = 11.2 Hz), 2.90 (t, 2H, J = 7.8 Hz),
2.59-2.45 (m, 3H), 2.19-1.91 (m, 7H), 1.82 (d, 2H, J =
13 .5 Hz) , 1.24 (d, 6H, J = 6.9 Hz) ; ESMS m/e: 555.3 (M +
H)+.
Example 91
N-(3-~1-[3-(5-METHOXY-2-PHENYL-1H-INDOL-3-YL)PROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: According to
the procedure used for the synthesis of
N- (3-{1- [3- (1, 2-diphenyl-1H-indol-3-yl) propyl] -4-
piperidinyl~phenyl)-2-methylpropanamide, 2-methyl-N-{3-
[1-(5-oxo-5-phenylpentyl)-4-
piperidinyl]phenyl~propanamide (15.6 mg, 38.2 mmol), and
1-(4-methoxyphenyl)hydrazine hydrochloride (8.00 mg,
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0.0458 mmol) provided N- (3-{1-[3-(5-methoxy-2-
phenyl-1H-indol-3-yl)propyl]-4-piperidinyl~phenyl)-2-
methylpropanamide (3.9 mg, 200) . 1H NMR (400 MHz, CDC13)
8 8 . 06 (s, 1H) , 7.55 . (d, 2H, J = 7.4 Hz) , 7.43-7.39 (m,
3H), 7.38-7.35 (m, 2H), 7.27-7.19 (m, 3H), 7.08 (d, 1H,
J = 7.4 Hz) , 6.94 (d, 1H, J = 7.6 Hz) , 6.87 (dd, 1H, J =
4.0, 6. 6 Hz) , 3 .88 (s, 3H) , 3 .80-3 .69 (m, 1H) , 2.99 (d,
2H, J = 11.7 Hz), 2.89 (t, 2H, J = 7.3), 2.55-2.39 (m,
4H), 2.02-1.88 (m, 3H), 1.82-1.68-.(m, 4H), 1.24 (d, 6H,
J = 6.9 Hz); ESMS m/e: 510.3 (M + H)+.
Example 92
N-(3-{1-[4-(5-METHOXY-2-PHENYL-1H-INDOL-3-YL)BUTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: According to
the procedure used for the synthesis of N-(3-{1-[3-(1,2-
diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl~phenyl)-2-
methylpropanamide, 2-methyl-N-{3-[1-(6-oxo-6-
phenylhexyl)-4-piperidinyl]phenyl~propanamide (14.3 mg,
0.0339 mmol) and 1-(4-methoxyphenyl)hydrazine
hydrochloride (7.10 mg, 0.0407 mmol) provided N-(3-{1-
[4-(5-methoxy-2-phenyl-1H-indol-3-yl)butyl]-4-
piperidinyl}phenyl)-2-methylpropanamide (5.8 mg, 33%).
1H NMR (400 MHz, CDC13) b 7.95 (d, 2H, J = 7. 8 Hz) , 7.61-
7.15 (m, 11H), 6.97 (d, 1H, J = 7.0 Hz), 3.88 (s, 3H),
3.09 (d, 2H, J = 11.3 Hz), 2.99 (t, 2H, J = 7.0 Hz),
2 .55-2 .35 (m, 4H) , 2 .12-1 . 70 (m, 6H) , 1 . 68-1 .52 (m, 2H) ,
1.48-1.34 (m, 2H), 1.25 (d, 6H, J = 6.7 Hz); ESMS m/e:
524.3 (M + H)+.
Example 93 .
2-METHYL-N-(3-~1-[(1-PHENYL-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: According to the
procedure used for the synthesis of N-(3-{1-[3-(1,2-
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diphenyl-1H-indol-3- yl)propyl]-4-
piperidinyl~phenyl)-2-methylpropanamide, N-{3-[1-(3,3-
dimethoxypropyl)-4-piperidinyl]phenyl -2-
methylpropanamide (15.2 mg, 0.0436 mmol) and 1,1
diphenylhydrazine hydrochloride (11.6 mg, 0.0524 mmol)
provided 2-methyl-N-(3-~1-[(1-phenyl-1H-indol-3
yl)methyl]-4-piperidinyl~phenyl)propanamide (11 mg,
560) . 1H NMR (400 MHz, CDC13) 8 7.79 (d, 1H, J = 7.8
Hz), 7.57 (d, 1H, J = 7.7 Hz), 7.54-7.47 (m, 4H), 7.43
7..32 (m, 4H), 7.25-7.16 (m, 4H), 6.95 (d, 1H, J = 7.8
Hz) , 3 . 87 (s, 2H) , 2 .53-2.47 (m, 2H) , 2.21 (dt, 2H, J _
' 3.0, 10.5 Hz), 2.12-1.77 (m, 6H), 1.24 (d, 6H, J = 6.9
Hz); ESMS m/e: 451.3 (M + H)+.
Example 94 .
2-METHYL-N-(3-~1-[(4E)-4-PHENYL-4-(2-
PYRIDINYLHYDRAZONO)BUTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: According to the
procedure used for the synthesis of N-(3-(1-[3-(1,2-
diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-
methylpropanamide, 2-methyl-N-{3-[1-(4-oxo-4-
phenylbutyl)-4-piperidinyl]phenyl~propanamide (8.70 mg,~
0.0223 mmol) and 2-hydrazinopyridine (2.92 mg, 0.0268
mmol) provided 2-methyl-N- (3-{1- [ (4E) -4-phenyl-4- (2-.
pyridinylhydrazono) butyl] -4- .
piperidinyl }phenyl) propanamide ( 2 . 5 mg, 24 0 ) . 1H NMR
(400 MHz, CDC13) b 7.97 (d, 1H, J = 8.6 Hz), 7.85 (d, 1H,
J = 7.3 Hz), 7.64-7.27 (m, 9H), 7.09 (d, '1H, J = 8.0
Hz), 6.97 (d, 1H, J = 8.4 Hz), 6.73 (q, 1H, J = 6.6 Hz),
3.52-3.48 (m, 2H), 3.20-3.10 (m, 2H), 2.85-1.75 (m,
13H) , 1.26 (d, 6H, J = 6.8 Hz) ; ESMS m/e: 484.4 (M + H)+.
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Example 95
N- (3-~1- [3- (5-METHOXY-1H-INDOL-3-YL) PROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: According = to
the procedure used for the synthesis of N-(3-{1-[3-(1,2-
diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-
methylpropanamide, N- (3-{1- [4- (1, 3-dioxolan-2-yl) butyl] -
4-piperidinyl~phenyl) -2-methylpropanamide (23.5 mg,
0 . 0628 mmol) ' and _ - 1- (4-methoxyphenyl) hydrazir~e
hydrochloride (13.2 mg, 0.0774 mmol) provided N-(3-~1-
[3-(5-methoxy-1H-indol-3-yl)propyl]-4-
piperidinyl~phenyl)-2-methylpropanamide (11 mg, 42%). 1H
NMR (400 MHz, CDC13) 8 7.86 (s, 1H), 7.45 (s, 1H), 7.32
(d, 1H, J = 8.4 Hz), 7.28-7.21 (m, 2H), 7.10 (s, 1H),
7.05 (d, 1H, J = 2.3 Hz), 7.00-6.91 (m, 2H), 6.85 (dd,
1H, J = 2.7, 9.0 Hz), 3.87 (s, 3H), 3.06 (d, 2H, J =
11.6 Hz) , 2.75 (t, 2H, J = 7.2 Hz) , 2 .55-2 .42 (m, 4H) ,
2.08-1.90 (m, 4H), 1.88-1.74 (m, 4H), 1.25 (d, 6H, J =
6.9 Hz) ; ESMS m/e: 434.2 (M + H)+.
2 0 " ''~~'
TERT-BUTYL 4- [3- (PROPIONYLAMINO) PHENYL] -1-
PIPERIDINECARBOXYLATE: Propionyl chloride (5.53 g,
0.0597 mol) was added dropwise to a solution of tert-
butyl 4-(3-aminophenyl)-1-piperidinecarboxylate (15.0 g,
0.0543 mol) and TEA ~ (16.5 g, 0.163 mol) in THF (200 mL)
and the mixture was stirred at room temperature for 3 h.
Water (50 mL) was added to the reaction mixture, the
aqueous layer was extracted with CH2C1~ (3 X 100 mL), and
the combined organic extracts were washed with brine (50
mL), dried over Na~S04 and concentrated under reduced
pressure. The residue v~a'~- purified by chromatography on
silica using hexane/EtOAc (10:1) to afford the product
(18.8 g, 99 0) . 1H NMR (400 MHz, CDC13) b 7.48 (s, 1H) ,
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7.34-7.21 (m, 3H), 6.93 (d, 1H, J = 7.4 Hz), 2.77
(t, 2H, J = 11.5 Hz) , 2.68-2.58 (m, 1H) , (q, 2H,
2.38 J
- 7.6 Hz), 1.87-1.67 (m, 4H), 1.67-1.54 (m, 2H), 1.48
(s, 9H) , 1.25 (t, 3H, J = 7.5 Hz) ; ESMS m/e:333.4(M
+
H)+.
N-(3-(4-PIPERIDINYL)PHENYL]PROPANAMIDE: Into a stirred
solution of tert-butyl 4-[3-(propionylamino)phenyl]-1-
piperidinecarboxylate (18.8 g, 0.0543 mmol) in dioxane
(100 mL) at 5 °C was bubbled HC1 gas for 2 h. The
solvent was removed in vacuo, the residue was dissolved
in water (100 mL) and neutralized by adding 10% KOH
aqueous solution. The aqueous layer was extracted (3 X
200 mL) with a mixture of CHC13/isopropyl alcohol (3 :1) ,
and the combined organic layers were washed with brine
(100 mL), dried over Na~S04, filtered and concentrated in
vacuo. The residue was purified by column
chromatography on silica using 50 of NH3 (2.0 M in
methanol) in CH~C12 to afford the desired product (12.6
g, 99a). 1H NMR b 7.44 (s, 1H),7.32 (d,
(400
MHz,
CDC13)
1H, J 7.2 Hz), 7.28-7.21 1H), 7.09 (s, 1H), 6.97
= (m,
(d, 1H, J = 7.6 Hz), 3.18 2H, J = 12.6 Hz), 2.73
(d,
(dt, 2H, J = 2.2, 11.2 Hz) , 5-2 .57 (m, 2.38 (q,
2.6 1H) ,
2H, J 7.4 Hz), 1.83 (d, 2H, J = 12.1 Hz), 1.70-1.61
=
(m, 3H) 1.25 (t, 3H, J = 7.5 (M
, Hz) ; ESMS
m/e: 233.1
H)+.
TERT-BUTYL 4-~3-[(CYCLOPROPYLCARBONYL)AMINO]PHENYL-1-
PIPERIDINECARBOXYLATE: According to the procedure used
for the synthesis of tert-butyl 4-[3-
(propionylamino)phenyl]-1-piperidinecarboxylate, tert-
butyl 4-('3-aminophenyl)-1-piperidinecarboxylate (16.47 g
0.0596 mol) and cyclopropanecarbonyl chloride (6.27 g,
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0.0597 mol) provided the tent-butyl 4-{3-
[(cyclopropylcarbonyl)amino]phenyl}-1-
piperidinecarboxylate (18.1 g, 100%). 1H NMR (400 MHz,
CDC13) 8 7.55-7.46 (m, 2H) , 7.29-7.21 (m, 2H) , 6.96-6.89
(m, 1H), 2.79 (t, 2H, J = 12.1 Hz), 2.68-2.58(m, 1H),
1.84 (d, 2H, J = 12.6 Hz), 1.83-1.76 (m, 4H), 1.48 (s,
9H) , 1 . 19-1 .12 (m, 1H) , 1. 09-1 .05 (m, 2H) , 0 . 89-0 .75 (m,
2H); ESMS m/e: 345.5 (M + H)+.
N-[3-(4-PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE:
According to the procedure used for the synthesis of N-
[3-(4-piperidinyl)phenyl]propanamide, tert-butyl 4-~3-
[(cyclopropylcarbonyl)amino]phenyl}-1-
piperidinecarboxylate (18.9 g, 0.0543 mol) provided N-
[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide (13.2
g, 100 0) . 1H NMR (400 MHz, CDC13) 8 7.46 (s, 1H) , 7.36-
7.22 (m, 3H) , 7 .23 (d, 1H, J = 6. 9 Hz) , 3 . 17 (d, 2H, J =
11.9 Hz), 2.72 (dt, 2H, J = 2.6, 12.2 Hz), 2.65-2.55 (m,
1H) , 1 . 82 (d, 2H, J = 13 .9 Hz) , 1.63 (dt, 3H, J = 4.1,
12.5 Hz), 1.53-1.45 (m, 1H), 1.11-1.06 (m, 2H), 0.87-
0.81 (m, 2H); ESMS m/e: 245.03 (M + H)+.
1-(6-CHLOROHEXYL)-1H-INDOLE: To a mixture of NaH (0.249
g, 10.0 mmol) in DMF (5 mL) at 0 °C was added a solution
of 1-H-indole (0.585 g, 5.00 mmol) in DMF (2 mL) . The
reaction mixture was stirred for 30 minutes and warmed
up to room temperature. Then 1-bromo-6-chlorohexane
(0.998 g, 5.00 mmol) was added dropwise by syringe and
the reaction mixture was stirred overnight. The
reaction mixture was diluted with EtOAc (30 mL), washed
with water (3 X 10 mL), dried over MgS04, concentrated in
vacuo and purified by chromatography using hexane/EtOAc
(97.5:2.5) to give the desired product (0.900 g, 76 0).
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1H NMR (CDCl3) 8 7.76-7.54 (m, 1H), 7.47-6.96 (m,
4H), 6.60-6.34 (m, 1H), 4.13 (t, 2H, J = 6.8 Hz), 3.50
(t, 2H, J = 5.6 Hz), 1.98-1.79 (m, 2H), 1.79-1.64 (m,
2H) , 1 . 54-1 .17 (m, 4H) .
1-(5-CHLOROPENTYL)-1H-INDOLE: According to the procedure
used for the synthesis of 1-(6-chlorohexyl)-1H-.indole,
1-H-indole (0.585 g, 5.00 mmol) and 1-bromo-5-
chloropentane (0.928 g, 5.00 mmol) gave the desired
product (0.890 g, 80%) . 1H NMR (CDC13) b 7.76-7.51 (m,
1H), 7.44-6.96 (m, 4H), 6.60-6.38 (m, 1H), 4.11 (t, 2H,
J = 6.8 Hz), 3.47 (t, 2H, J = 6.4 Hz), 1.97-1.79 (m,
2H), 1.79-1.61 (m, 2H), 1.58-1.32 (m, 2H).
Example 96
N- (3-~1- [6- (1H-INDOL-1-YL) HEXYL] -4-PIPERIDINYL~PHENYL) -
2-METHYLPROPANAMIDE: 1-(6-Chlorohexyl)-1H-indole (23.6
mg, 0.100 mmol) , 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide (24.6 mg, 0.100 mmol),
KZC03 (27.6 mg, 0.200 mmol), NaI (22.5 mg, 0.150 mmol)
and DMF (1.00 mL) were combined and stirred overnight at
100 C. The reaction cooled to room
mixture
was
temperatu re and the crude material was purified by
preparati ve TLC M in methanol)
using in
5 0
of NH3
(2.0
- CH2C12 give desired product a yellow solid
to the as (40
mg, 900) . 1H NMR (400 MHz, CDC13)
8 8.08-6.52 (m,
11H) ,
4.17 (t, 2H, J 7.2 Hz), 3.26 (d, 2H, J = 11.6 Hz),
=
2.74-2.52 (m, 4H),2.44-2.28 (m, 2H), 2.20-2.02 (m, 2H),
1.98-1.82 (m,4H), 1.78-1.62 (m, 2H), 1.43-1.28 (m, 4H),
1.28 (d, 6H, J :8 Hz); ESMS m/e: 6.5 (M + H)+.
= 6 44
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Example 97
N-(3-~1-[5-(1H-INDOL-1-YL)PENTYL]-4-PIPERIDINYL~PHENYL)-
2-METHYLPROPANAMIDE: Prepared as above, using 1-(5-
chloropentyl)-.1H-indole (22.2 mg, 0.100 mmol), 2-methyl-
N-[3-(4-piperidinyl)phenyl]propanamide (24.6 mg, 0.100
mmol), K2C03 (27.6 mg, 0.200 mmol), NaI (23.0 mg, 0.150
mmol) and DMF (1.00 mL), giving the desired product as a
yellow oil (36 mg, 81%) . 1H NMR (400 MHz, CDC13) 8
8.08-6.52 (m, 11H), 4.19 (t, 2H, J = 7.2 Hz), 3.26-3.10
(m, 2H), 2.71-2.55 (m, 2H), 2.55-2.42 (m, 2H), 2.35-2.12
(m, 2H) , 2. 12-1 .80 (m, 6H) , 1.80-1 .57 (m, 2H) , 1 .51-1 .34
(m, 2H) , 1.31 (d, 6H, J = 6. 8 Hz) ; ESMS m/e: 432 . 2 (M +
H)+.
Example 98
N-(4-~1-[(9-ETHYL-9H-CARBAZOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: According to
the procedure used for the synthesis of N- (3-~l- [4- (4-
CHLOROPHENOXY)BENZYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE (Example 108) N-(3-fl-[3-(1,2-
diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl~phenyl)-2-
methylpropanamide, 9-ethyl-9H-carbazole-3-carbaldehyde
(22.3 mg, 0.100 mmol) and 2-methyl-N-[4-(4-
piperidinyl)phenyl]propanamide (24.6 mg, 0.100 mmol)
provided N-(4-~1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-
piperidinyl}phenyl)-2-methylpropanamide. The product was
obtained as a white crystalline solid (20 mg, 44%). 1H
NMR (400 MHz, CDC13) 8 8.21-7.09 (m, 12H) , 4'.38 (q, 2H, J
- 7.2 Hz), 3.81 (s, 2H), 3.25=3.03 (m, 2H), 2.60-2.38
(m, 2H) , 2.31-2.09 (m, 2H) , 1 .98-1.69 (m, 4H) , 1.44 (t,
3H, J = 7.2 Hz), 1.23 (d, 6H, J = 6.8 Hz); ESMS m/e:
454.3 (M + H)+.
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Example 99
N- (3-~1- [ (9-ETHYL-9H-CARBAZOL-3-YL)METHYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: According to
the procedure used for the synthesis of N-(3-{1-[4-(4-
CHLOROPHENOXY)BENZYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE (Example 108) N-(4-{1-[(9-ethyl-9H-
carbazol-3-yl)methyl]-4-piperidinyl}phenyl)-2-
methylpropanamide, 9-ethyl-9H-carbazole-3-carbaldehyde
and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide
afforded N-(3-{1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-
piperidinyl}phenyl)-2-methylpropanamide (37 mg, 95%).
1H NMR (400 MHz, CDC13) 8 8.24-6.29 (m, 12H), 4.37 (q,
2H, J = 7.2 Hz) , 3 .82 (s, 2H) , 3 .23-3 . 06 (m, 2H) , 2.65-
2.38 (m, 2H), 2.31-2.11 (m, 2H), 2.01-1.73 (m, 4H), 1.43
(t, 3H, J = 7.2 Hz), 1.25 (d, 6H, J = 4.0 Hz); ESMS m/e:
454.3 (M + H)+.
Example 100
N- [3- (1-~ [1- (4-METHOXYPHENYL) -1H-INDOL-5-YL] METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: According to
the procedure used for the synthesis of 1-(4-
methylphenyl)1H -indole, N-{3-[1-(1H-indol-5-ylmethyl)-
4-piperidinyl]phenyl}-2-methylpropanamide (37.5 mg,
0.100 mmol) and 1-iodo-4-methoxybenzene (46.8 mg, 0,200
mmol) gave the desired product (27 mg, 560). 1H NMR (400
MHz, CDC13) s 7.70-6.58 (m, 14H) , 3 . 88 (s, 3H) , 3 .67 (s,
2H), 3.14-3.01 (m, 2H), 2.57-2.41 (m, 2H), 2.25-2.01 (m,
2H), 1.93-1.69 (m, 4H), 1.24 (d, 6H, J = 7.2 Hz); ESMS
m/e: 482.2 (M + H)+.
Example 101
N- [3- (1-{ [1- (4-FLUOROPHENYL) -1H-INDOL-5-YL] METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: According to
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the procedure used for the synthesis of . 1- (4-
methylphenyl)1H-indole, N-{3-[1-(1H-indol-5-ylmethyl)-4-
piperidinyl]phenyl -2-methylpropanamide (37.5 mg, 0.100
mmol) and 1-fluoro-4-iodobenzene (44.4 mg, 0.200 mmol)
gave the desired product (21 mg, 45%) . 1H NMR (400 MHz,
CDC13) 8 7.71-6.60 (m, 14H) , 3 .69 (s, 2H) , 3.19-2.99 (m,
2H), 2.62-2.41 (m, 2H), 2.22-2.07 (m, 2H), 1.94-1.70 (m,
4H) , 1.24 (d, 6H, J = 6.-8 Hz) ; ESMS m/e: 470.2 (M + H)+.
Example 102
METHYL-4-[5-(~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
IPERIDINYL~METHYL)-1H-INDOL-1-YL]BENZOATE: According to
the procedure used for the synthesis of 1-(4-
methylphenyl)1H-indole, N-f3-[1-(1H-indol-5-ylmethyl)-
4-piperidinyl]phenyl -2-methylpropanamide (37.5 mg,
0.100 mmol) and methyl 4-iodobenzoate (52.4 mg, 0.200
mmol) gave the desired product (11 mg, 22%). 1H NMR (400
MHz, CDC13) b 8.31-6.64 (m, 14H) , 3 .96 (s, 3H) , 3. 67 (s,
2H), 3.16-2.96 (m, 2H), 2.57-2.41 (m, 2H), 2.18-2.02 (m,
2H), 1.91-1.73 (m, 4H), 1.24 (d, 6H, J = 6.8 Hz); ESMS
m/e: 510.2 (M + H)+.
Example 103
2-METHYL-11T- [3- (1-~ (1- (3-METHYLPHENYL) -1H-INDOL-5-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: According
to the procedure used for the synthesis of 1-(4-
methylphenyl)1H-indole, N-~3-[1-(1H-indol-5-ylmethyl)-4-
piperidinyl]phenyl}-2-methylpropanamide (37.5 mg, 0.100
mmol) and 1-iodo-3-methylbenzene (43.6 mg, 0.200 mmol)
gave the desired product (28 mg, 60 0) . 1H NMR (400 MHz,
CDC13) 8 7.68-6.60 (m, 14H) , 3 .66 (s, 2H) , 3 .16-2.96 (m,
2H), 2.59-2.44 (m, 2H), 2.44 (s, 3H), 2.18-2.01 (m, 2H),
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1.91-1.68 (m, 4H), 1.24 (d, 6H, J = 6.8 Hz); ESMS
m/e: 466.2 (M + H)+.
Example 104
N-~3- [1- (3-{ [ (4-CHLORO-3-
NITROPHENYL)SULFONYL]AMINO~PROPYL)-4-
PIPERIDINYL] PHENYL-2-METHYLPROPANAMIDE: A mixture of N-
{3[1-(2-aminopropyl)-4-piperidinyl]phenyl -2-
methylpropanamide (10.0 mg, 0.0350 mmol), 4-chloro-3-
nitrobenzenesulfonyl chloride (9.90 mg, 0.0380 mmol),
and TEA (7.OO~mg, 0.0700 mmol) in THF (2 mL) was stirred
for 12 h at room temperature. The crude product was
purified by preparative TLC (CHaCl2/MeOH/isopropyl amine
- 19:1:0.2) to give the desired product (16 mg, 86%). 1H
NMR (400 MHz, CDC13) 8 8.45-8.38 (m, 1H) , 8.02 (d, 1H, J
- 8.4 Hz) , 7.72 (d, 1H, J = 8.8 Hz) , 7.48-7.40 (m, 3H) ,
7.29-7.24 (m, 2H), 6.96 (d, 1H, J = 7.5 Hz), 3.17-3.09
(m, 4H), 2.63-2.48 (m, 4H), 2.15 (t, 2H, J = 11.8 Hz),
1.96-1.72 (m, 6H), 1.25 (d, 6H, J = 6.9 Hz); ESMS m/e:
523.2 (M + H)+.
Example 105
N-[3-(1-~5-[4-(3,4-DIFLUOROPHENYL)-2-OXO-1,3-OXAZOLIDIN-
3-YL]PENTYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
A mixture of 3-(5-bromopentyl)-4-(3,4-difluorophenyl)-
1,3-oxazolidin-2-one (38.0 mg, 0.110 mmol), 2-methyl-N-
[3- (4-piperidinyl)phenyl]~propanamide (26.0 mg, 0.100
mmol) , NaI (23 .0 mg, 0.150 mmol) , and K2C03 (14. 0 mg,
0.100 mmol) in DMF (2 mL) was heated for 1 h at 50°C.
The crude product was purified by preparative TLC using
CH2C12/MeOH/isopropyl amine (19:1:0.2) to give the
desired product (21 mg, 410) . 1H NMR (400 MHz, CDC13) 8
7.49 (s, 1H), 7.39-7.32 (m, 2H), 7.26-7.20 (m, 2H),
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7.18-7.11 (m, 1H), 7.10- 7.03 (m, 1H), 6.96 (d, 1H,
J = 7.6 Hz), 4.80-4.73 (m, 1H), 4.62 (t, 1H, J = 7.9
Hz) , 4. 09-4.04 (m, 1H) , 3 .51-3 .42 (m, 1H) , 3 .03 (d, 2H,
J = 11.7 Hz), 2.82-2.72 (m, 1H), 2.51-2.42 (m, 2H), 2.32
(t, 2H, J = 7.9 Hz), 2.11 (s, 1H), 2.03-1.97 (m, 2H),
1:85-1.70 (m, 4H), 1.49 (m, 4H), 1.31-1.27 (m, 1H), 1.24
(d, 6H, J = 6.9 Hz); ESMS m/e: 514.4 (M + H)+.
Example 106
3- (2, 6-DICHLOROPHENYL) -N- (5-~4- (3-
(ISOBUTYRYLAMINO)PHENYLJ-1-PIPERIDINYL~PENTYL)-5-METHYL-
4-ISOXAZOLECARBOXAMIDE: A mixture of 3-(2,6-
dichlorophenyl)-4-formyl-5-isoxazolecarbonyl chloride
(69.0 mg, 0.250 mmol), N-f3-(1-(5-aminopentyl)-4-
piperidinyl]phenyl -2-ethylpropanamide (44.0 mg, 0.150
mmol), TEA (30.0 mg, 0.300 mmol) in THF (2 mL) was
stirred for 12 h at room temperature. The crude product
was purified by preparative TLC using CH2C12/MeOH/
isopropyl amine (19:1:0.2) to give the desired product
(52 mg, 67%) . 1H NMR (400 MHz, CDC13) 8 7.52-7.49 (m,
2H) , 7.49-7.41 (m, 2H) , 7.39-7.31 (m, 2H) , 7.29-7.21 (m,
2H) , 6. 92 (d, 1H, J = 7.6 Hz) , 3 .25-3.11 (m, 5H) , 2.81-
2.74 (m, 4H) , 2.58-2 .44 (m, 4H) , 2.30-2.19 (m, 2H) ,
1,93- 1.78 (m, 4H), 1.56-1.44 (m, 2H), 1.31-1.28 (m,
2H), 1.24 (d, 6H, J = 6.6 Hz); ESMS m/e: 585.2 (M + H)+.
Example 107
N- [3- (1-~2- ( (DIPHENYLACETYL)AMINO] ETHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: A mixture of N-
f3(1-(2-aminoethyl)-4-piperidinyl)phenyl)-2-
methylpropanamide (20.0 mg, 0.0700 mmol), diphenylacetyl
chloride (23.0 mg, 0.110 mmol), and TEA (20.0 mg, 0.140
mmol) in THF (2 mL) was stirred overnight at 23 °C. The
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crude product was purified by preparative TLC using
CH2C1~/MeOH/isopropyl amine (19:1:0.2) to give the
desired product (8.0 mg, 47%) . 1H NMR (400 MHz, CDCT3) 8
7.53 (s, 1H),' 7.37-7.20 (m, 13H), 6.97-6.92 (m, 1H),
6.67 (s, 1H), 4.98 (s, 1H), 3.43 (q, 2H, J = 5.9 Hz),
2.90 (d, 2H, J = 11.6 Hz), 2.57-2.42 (m, 4H), 2.11 (t,
2H, J = 10.4 Hz), 1.75 (d, 2H, J = 12.4 Hz), 1.70-1.58
(m, 2H) , 1.25 (d, 6H, J = 6.7 Hz) ; ESMS m/e: 484.2 (M +
H)+.
Example 108
N-(3-~1-[4-(4-CHLOROPHENOXY)BENZYL~-4-
PIPERIDTNYL~PHENYh)-2-METHYLPROPANAMIDE: 4-(4-
chlorophenoxy)benzaldehyde (0.11 9 g, 0.510 mmol) and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.126 g,
0.510 mmol) were mixed in 1,2-dichloroethane (5 mL) and
then treated with sodium triacetoxyborohydride (0.424 g,
2.00 mmol) and HOAc (0.03 mL, 0.5 mmol). The mixture
was stirred overnight at room temperature. The reaction
mixture was neutralized with saturated NaHC03 aqueous
solution and the aqueous layer was extracted with CH~Clz
(3 X 10 mL). The combined organic layers were washed
with brine, dried over MgS04, concentrated in vacuo, and
purified by preparative TLC using 50 of NH3 (2.0 M in
methanol) in CHZC12 to give the desired product (53 mg,
230) . 1H NMR (400 MHz, CDC13) b 7.50 (s, 1H) , 7.34-7.19
(m, 7H) , 6.98-6.87 (m, 5H) , 3 .50 (s, 2H) , 2.98 (d, 2H, J
- 11.8 Hz) , 2.58-2.44 (m, 2H) , 2.10-1.98 (in, 2H) , 1.83
1 .76 (m, 4H) , 1 .24 (d, 6H, J = '6.8 Hz) ; ESMS m/e: 463 .2
(M + H)+.
Example 109
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N-~3-[1-(~2,5-DIMETHYL-1- [3-
(TRIFLUOROMETHYL)PHENYL]-1H-PYRROL-3-YL~METHYL)-4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by the
procedure described in example 108, substituting 2,5-
dimethyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3-
carbaldehyde (0.136 g, 0.510 mmol) for 4-(4-
chlorophenoxy)benzaldehyde. 1H NMR (400 MHz,. CDC13) 8
7.69-7.56 (m,~2H), 7.53-7.32 (m, 4H), 7.28-7.18 (m, 2H),
6.99 (s, 1H), 5.98 (s, 1H), 3.43 (s, 2H), 3.16-3.06 (m,
2H), 2.57-2.42 (m, 2H), 2.07-1.95 (m, 8H), 1.89-1,76 (m,
4H), 1.24 (d, 6H, J = 6.8 Hz); ESMS m/e: 498.2 (M + H)+.
Example 110
N- (3-~1- [4- (3, 4-DIFLUOROPHENOXY) BENZYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by the
procedure described in example 108, substituting 4-(3,4-
difluorophenoxy)benzaldehyde (0.119 g, 0.510 mmol) for
4-(4-chlorophenoxy)benzaldehyde. 1H NMR (400 MHz, CDC13)
b 7.52 (s, 1H), 7.32 (d, 2H, J = 8.4 Hz), 7.28-7.21 (m,
2H), 7.14-7.06 (m, 2H), 6.98-6.94 (m, 3H), 6.86-6.79 (m,
1H), 6.76-6.69 (m; 1H), 3.51 (s, 2H), 2.99 (d, 2H, J =
11.7 Hz), 2.55-2.44 (m, 2H), 2.12-2.02 (m, 2H), 1.86-
1.74 (m, 4H), 1.25 (d, 6H, J = 7.0 Hz); ESMS m/e: 465.2
(M + H)+.
Example 111
N-(3-~1-[(5-CHLORO-3-METHYL-1-PHENYL-1H-PYRAZOL-4-
YL)METHYL]-4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE:
Prepared by the procedure described in example 108,
substituting 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-
carbaldehyde (0.113 g, 0.510 mmol) for 4-(4-
chlorophenoxy)benzaldehyde. 1H NMR (400 MHz, CDC13) S
7.62-7.19 (m, 9H), 6.97 (s, 1H), 3.43 (s, 2H), 3.08-2.98
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(m, 2H), 2.58-2.43 (m, 2H), 2.39-2.32 (m, 3H),
2.18-1.71 (m, 6H), 1.24 (d, 6H, J = 6.9 Hz); ESMS m/e:
451.2 (M + H)~.
Example 112
N- (3-~1- [4- (3, 4-DICHLOROPHENOXY) BENZYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by the
procedure described in example 108, substituting 4-(3,4-
dichlorophenoxy)benzaldehyde (0.236 g, 0.510 mmol) for
4-(4-chlorophenoxy)benzaldehyde. 1H NMR (400 MHz, CDC13)
8 7.53 (s, 1H), 7.36-7.18 (m, 6H), 7.08 (d, 1H, J = 1.8
Hz) , 6.96 (d, 3H, J = 6.8 Hz) , 6. 84 (dd, 1H, J = 2. 8,
8.9 Hz) , 3 .51 (s, 2H) , 2.99 (d, 2H, J = 11.5 Hz) , 2.55
2.42 (m, 2H), 2.12-2.02 (m, 2H), 1.84-1.73 (m, 4H), 1.24
(d, 6H, J = 7.0 Hz); ESMS m/e: 497.1 (M + H)+.
Example 113
2-METHYL-N-(3-~1-[(2-PHENYL-1H-IMIDAZOL-4-YL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by the
procedure described in example 108, substituting 2-
phenyl-1H-imidazole-4-carbaldehyde (88.0 mg, 0.510 mmol)
for 4-(4-chlorophenoxy)benzaldehyde. 1H NMR (400 MHz,
CDC13) 8 7.92 (d, 2H, J = 7.4 Hz), 7.65-7.31 (m, 6H),
7.28-7.18 (m, 2H), 7.12-7.05 (m, 1H), 6.95-6.88 (m, 1H),
3 .69 (s, 2H) , 3.17-3 .05 (m, 2H) , 2 .62-2.45 (m, 2H) ,
2.28-2.18 (m, 2H), 1.88-1.70 (m, 4H), 1.25 (d, 6H, J =
6.8 Hz); ESMS m/e: 403.2 (M + H)+.
Example 114
N- (3-~1- [4- (DIPHENYLAMINO) BENZYL] -4-PIPERIDINYL~PHENYL) -
2-METHYLPROPANAMIDE: Prepared by the procedure described
in ~ example 108, substituting 4-
(diphenylamino)benzaldehyde (0.139 g, 0.510 mmol) for 4-
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212
chlorophenoxy)benzaldehyde. iH NMR (400 MHz, CDC13) 8
7.49 (s, 1H), 7.39-6.92 (m, 18H), 3.49 (s, 2H), 3.02-
2.99 (m, 2H), 2.59-2.43 (m, 2H), 2.15-2.03 (m, 2H),
1.92-1.76 (m, 4H), 1.23 (d, 6H, J = 6.8 Hz); ESMS m/e:
504.2 (M + H)+.
Example 115
N-[3-(1-f[4-BROMO-l-(4-CHLOROBENZYL)-1H-PYRAZOL-5-
YL]METHYL-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by the procedure described in example 108,
substituting 4-bromo-1-(4-chlorobenzyl)-1H-pyrazole-5-
carbaldehyde (0.153 g, 0.510 mmol) for 4-(4-
chlorophenoxy)benzaldehyde. 1H NMR (400 MHz, CDC13) 8
7.41 (s, 1H), 7.36 (d, 1H, J = 8.8 Hz), 7.34-7.30 (m,
3H), 7.29-7.26 (m, 1H), 7.22 (t, 1H, J = 7.8 Hz), 7.16
(d, 2H, J = 8.6 Hz) , 6.95 (d, 1H, J = 7.5 Hz) , 5.24 (s,
2H) , 3 . 61 (s, 2H) , 3 . 09 (d, 2H, J = 11.9 Hz) , 2.55-2 .42
(m, 2H) , 2.19 (dt, 2H, J = 4.4, 11.4 Hz) , 1.89-1.76 (m,
4H), 1.24 (d, 6H, J = 6.7 Hz); ESMS m/e: 529.1 (M + H)~.
1-(3-[~(1R)-3-CHLORO-PHENYLPROPYL]OXY~PHENYL)ETHANONE:
Azodicarboxylate (5.37 g, 0.0310 mol) was added to a
solution of triphenylphosphine (8.09 g, 0.0308 mol), 15-
3-chloro-1-phenyl-1-propanol (4.20 g, 0.031 mol) and, 1-
(3-hydroxyphenyl)ethanone in THF (150 mL). The reaction
mixture was stirred for 4~ days at 23 °C. The solvent was
removed under reduced pressure and the residue was
triturated with ether/hexane (1:2, (3 X 100 mL). The
combined organic fractions were concentrated in vacuo
and the crude product was purified by chromatography
using EtOAc/hexane (1:14) to give the desired product
(6.55 g, 74 0) . 1H NMR (400 MHz, CDC13) 8 7.48-7.31 (m,
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6H) , 7.26 (t, 2H, J = 8.2 Hz) , 7.04 (d, 1H, J = 8.1
Hz), 5.44 (dd, 1H, J = 4.4, 8.1 Hz), 3.83-3.74 (m, 1H),
3.63-3.56 (m, 1H), 2.51 (s, 3H), 2.51-2.45 (m, 1H),
2.29-2.17 (m, 1H); ESMS m/e: 289.0 (M + H)+.
Example 116
N-(3-~1-[(3R)-3-(3-ACETYLPHENOXY)-3-PHENYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of 1-
(3-{[(1R)-3-chloro-1-phenylpropyl]oxy}phenyl)ethanone
(58.5 mg, 0.200 mmol), 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide (56.8 mg, 0.200 mmol),
NaI (34.0 mg, 0.200 mmol) and K2C03 (55.5 mg, 0.400
mmol)in DMF (1 mL) was stirred at 100 °C for 3 h. The
solvent was removed under reduced pressure and the
residue was purified by chromatography on silica using 5
of NH3 (2.0 M in methanol) in CHZC12 to give the desired
product (98 mg, 98%) . 1H NMR (400 MHz, CDC13) 8 8.01 (s,
1H), 7.49-7.21 (m, 11H), 7.09-7.03 (m, 1H), 6.96 (d, 1H,
J = 7.9 Hz), 5.32 (dd, 1H, J = 5.0, 7.9 Hz), 3.08-2.98
(m, 2H), 2.57-2.43 (m, 6H), 2.11-1.72 (m, 9H), 1.25 (d,
6H, J = 6.8 Hz); ESMS m/e: 499.4 (M + H)+.
Procedures:
Procedure A (see also example 48)
N-(3-~1-[(3R)-3-(3,4-DIMETHOXYPHENOXY)-3-PHENYLPROPYL]-
4-PIPERIDINYIr~PHENYL)-2-METHYLPROPANAMIDE:
O/ 0-
O N
N
/ O
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Method A
4-~ [ (7.R) -3-CHLORO-1-PHENYLPROPYL~ OXY~-1, 2-
DIMETHOXYBENZENE: A mixture of 3,4-dimethoxyphenol (4.07
g, 26.4 mmol), (S)-(-)-3-chloro-phenyl-1-propanol (4.50
g, 26.4 mmol, 99% ee, Aldrich Chemical Co.),
triphenylphosphine (6.92 g, 26.4 mmol) and diethyl
azodicarboxylate (4.59 g, 26.4 mmol) in THF (110 mL) was
stirred at room temperature for 24 h. The reaction
mixture was concentrated in vacuo. At this point, the
residue can either be washed with pentane and the
combined pentane extracts were concentrated and
chromatographed with hexane:EtOAc (8:1) as the eluent to
give the desired product (as described as a general
procedure by: Srebnik, M.; Ramachandran, P.V.; Brown,
H.C. J. Org. Chem. 1988, 53, 2916-2920) . This procedure
was performed on a smaller scale reaction and only a 400
yield of the product was realized.
Alternatively, on a larger scale (26.4 mmol), the erode
product was triturated with a small amount of
dichloromethane and the precipitated triphenylphosphine
oxide was filtered. The filtrate was concentrated and
the crude product was chromatographed to give the
desired product as a thick yellow oil (7.30 g, 88.9%
yield) : 1H NMR (400 MHz, CDC13) b 7.39-7.32 (m, 4H) , 7.20
(m, 1H) , 6.64 (d, 1H, J = 8.7 Hz) , 6.51 (d, 1H, J = 2.7
Hz) , 6 .30 (dd, 1H, J = 2 . 7, 8 .7 Hz) , 5.27 . (apparent dd,
1H, J = 4.5, 8.7 Hz) , 3 .79 (s, .3H) , 3.77 (s, 3H) , 3.61
(m, 1H), 2.45 (m, 1 H), 2.20 (m, 1H), 1.80 (s, 1H); ESMS
m/e: 307.1 (M + H)+.
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N- (3- f 1- [ (3R) -3- (3, 4- DIMETHOXYPHENOXY) -3-
PHENYLPROPYL]-4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE:
A mixture of potassium carbonate (321 mg, 2.32 mmol),
sodium iodide (522 mg, 3 .48 mmol) , 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide (570 mg, 2.32 mmol) and
4-~[(1R)-3-chloro-1-phenylpropyl]oxy~-1,2-
dimethoxybenzene (712 mg, 2.32 mmol) in DMF (5.00 mL)
was stirred at 100 °C for 3 h, at which time TLC
indicated that the reaction was complete. The reaction
mixture was poured into water (50 mL) and the aqueous
layer was extracted with methylene chloride (3 x 30 mL).
The combined organic extracts were washed with brine (30
mL), dried over MgS04 and concentrated under reduced
pressure. The crude product was purified by Preparatory
TLC [2.5% of NH3 (2.0 M in methanol) in CHC13] to afford
the product (970 mg, 90.1%) as a thick oil.
Method B
Into a 25-mL RB-flask was added triphenylphosphine (9.80
mg, 0.0375 mmol), diethyl azodicarboxylate (5.22 mg,
0.0300 mmol), N-(3-~l-[(3S)-3-hydroxy-3-phenylpropyl]-4
piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250
mmol), 3,4-dimethoxyphenol (7.70 mg, 0.0500 mmol) and
THF (1.00 mL) at room temperature. The reaction mixture
was stirred at room temperature overnight (16 h). The
solvent was removed under reduced pressure and the
residue was purified by preparative TLC plates [2 .5 0 of
NH3 (2.0 M in methanol) in CHC13] to afford the desired
product (4.40 mg, 34.1 o yield) as a thick oil: 1H NMR
(400 MHz, CDC13) ~ 7.46 (s, 1 H), 7.40-7.30 (m, 4H), 7.25
(m, 3H) , 6.97 (d, lH, J = 7. 8 Hz) , 6.64 (d, 1H, J = 9.1
Hz) , 6.51 (d, 1H, J - 2.6 Hz) , 6.29 (d, 1H, J = 2.6,
9.1 Hz), 5.20 (apparent dd, 1H, J = 4.4, 8.5 Hz), 3.80
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(s, 3H) , 3 .77 (s, 3H) , 3 .23 (m, 2H) , 2.77 (m,
2H) , 2.5 (m, 2H) , 2 .3-2.1 (m, 6H) , 1. 80 (m, 2H) , 1 .25
(d, 6H, J = 7.9 Hz); ESMS m/e: 517.4 (M + H)+.
Procedure B (see also example 49)
2-METHYL-N-(3-~1-[(3S)-3-PHENOXY-3-PHENYLPROPYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: A mixture of N-(3-~l-
[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70
mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375
mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300
mmol) in THF (1.00 mL) was stirred at room temperature
for 3 days. Chromatography using silica preparative TLC
plates [2.5% of NH3 (2.0 M in methanol) in CHC13] gave
the desired product (2.70 mg, 23.6 % yield) as a thick
oil: 1H NMR b 7.46 (s, 2H) , 7.40-7.30 (m, 4H) , 7.25 (m,
3H), '7.20 (m, 2H), 6.97 (apparent d, 1H, J - 7.4 Hz),
6.89 (apparent tt, 1H, J = 0.8, 7.6 Hz) , 6.84 (apparent
dt, 1H, J - 0.8, 8.0 Hz), 5.20 (apparent dd, 1H, J -
4.4, 8.5 Hz) , 3 .35 (m, 2H) , 2.91 (m, 2H) , 2 .60 (m, 2H) ,
2.30-2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, J - 7.9
Hz) ; ESMS m/e: 457.4 (M + H)+;
Procedure C
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Scheme O
_ . I w
Cu, KZC03, NMP
I \~ ~ \ R
1 . '~- 2 /
R L~~i~ ~ ~ 150 °C, 12 h R
H ~ ~ Rz
R1=N, Rz=4'-Me
1-(4-METHYLPHENYL)1H-INDOLE: A mixture of 1-H-indole
(58.5 mg, 0.500 mmol), 1-iodo-4-methylbenzene (0.218 g,
1.00 mmol), copper powder (32.0 mg, 0.500 mmol), and
KzC03 (0.138 g, 1.00 mmol) in 1-methyl-2-pyrrolidinone
(1.00 mL) was heated at 150 °C for 12 h under argon.' The
resulting mixture was diluted with H20 (6 mL). The
aqueous layer was extracted with CHZC12 (3 X 10 mL) . The
combined organic extracts were washed with brine (10
mL), dried over MgS04, and concentrated in vacuo. The
residue was purified by preparative TLC using
EtOAc:hexane (1:4) to give the desired product (82.0 mg,
79.0 %) : 1H NMR (400 MHz, CDC13) d 7.67 (d, 1H, J = 7.7
Hz), 7.52 (d, 1H, J = 7.4 Hz), 7.38 (d, 2H, J = 8.4 Hz),
7.34-7.29 (m, 3H), 7.21 (t, 1H, J - 7.0 Hz), 7.15 (t,
1H, J = 7.0 Hz) , 6.66 (d, 1H, J = 3.3 Hz) , 2.43 (s, 3H) ;
ESMS m/e: 208.0 (M + H)+.
Procedure D (see also example 86)
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Scheme N
H
~~N~R3 \ ~NH
O N
I ~ ~ ~ ~, ~ + dioxane/HOAc ~ ~ O R3
l
'~ H H rt 5 h I
N
.~Rt ,R2 , Rt~ R
N z
H
Example
H
NN
I o
I ~ \ "F ~ ,~ dioxane/HOAc
H H rt 5 h
R1 Rz ,
N
H
R~=6-C1, Rz=H
R~=H, Rz=4'-tolyl
N-(3-~1-[(6-CHLORO-1H-INDOL-3-YL)METHYL'-4- .
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A solution of
2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.369
g, 1.50 mmol) and 37 wt % aqueous formaldehyde (30.0
mg, 1.50 mmol) in 1.00 mL of HOAc:dioxane (1:4) was
added to 6-chloro-1-H-indole (0.152 g, 1.00 mmol) and
the. reaction mixture was stirred for 12 h at room
temperature. The resulting mixture was diluted with HZO
(10 mL) , The aqueous layer was extracted with CH2Clz (3
X 100 mL). The combined organic extracts were washed
with brine (10 mL), dried over MgS04, and concentrated in
vaeuo. The residue was purified by preparative TLC
plates using 5% of NH3 (2.0 M in methanol) in CHzClz to
give the desired product (79.0 mg, 42.0 %): 1H NMR (400
MHz, CDC13) 5 9.14 (s, 1H) , 8.04 (s, 1H) , 7.52 (t, 2H, J
- 8.1 Hz) , 7.35 (d, 2H, J = 13 .3 Hz) , 7.18 (t, 1H, J =
7.9 Hz) , 7.09 (dd, 1H, J = 1.9, 8.5 Hz) , 6.85 (d, 1H, J
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- 7.4 Hz) , 5.18 (s, 1H) , 4.01 (s, 2H) , 2 .55
(septet, 1H, J = 6.8 Hz), 2.48-2.34 (m, 3H), 2.08-1.95
(m, 4H), 1.78 (d, 2H, J = 12.8 Hz), 1.22 (d, 6H, J = 6.8
Hz); ESMS m/e:.410.1 (M + H)+.
Procedure E (see also example 90)
scheme M
° i~Rs ~~r
w n N H i
I N R4 + R2.N W ZnCla, HOAc ~ ~ N~ O'
-\ -- ~
R~ I / 0 NH2 75 °C, 10 h R3 ' ~ n-1
R2 I ~ R,
Example
° Rs
N H i ~I
n N~ + R2. W ZnCl2, HOAc
N ->
\R1 I / O NHZ 75 °C. 10 h
N-(3-~1-[3-(I,2-DIPHENYL-1H-INDOL-3-YL)PROPYL]-4-
PIPERIDINYL~PHEN'YL)-2-METHYLPROPANAMIDE: A mixture of
1,1-diphenylhydrazine hydrochloride (10.3 mg, 0.0470
mmol), 2-methyl-N-~3-[1-(5-oxo-5-phenylpentyl)-4-
piperidinyl]phenyl}propanamide (14.7 mg, 0.0362 mmol),
ZnCl2 (14.8 mg, 0.109 mmol), and HOAc (0.500 mL) was
heated for 4 h at 80 °C. The resulting crude mixture was
diluted with water (10 mL), the aqueous layer was
neutralized with saturated KzC03 (10 mL) and extracted
with CHzCl2 (3 X 20 mL) . The combined organic layers
were concentrated in vacuo and the residue was purified
n=2, R~=H, R2=Ph, R3=H
n=5, R~=H, R2=H, Rg=5-OM
n=1, R~=H, R2=Ph, R3=H
n=4, R1=H, R2=H, R3=5-OM
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by preparative TLC plates using 50 of NH3 (2.0 M in
methanol) in CHzCla to give the desired product N-(3-{1-
[3-(1,2-diphenyl-1H-indol-3-yl)propyl]-4-
piperidinyl}phenyl)-2-methylpropanamide (4.10 mg, 37.0
%) : 1H NMR (400 MHz, CDC13) ~ 7.71-7.65 (m, 1H) , 7.42 (d,
1H, J = 7.4 Hz), 7.39 (s, 1H), 7.36-7.15 (m, 15H), 6.94
(d, 1H, J = 7.8 Hz) , 3.12 (d, 2H, J = 11.2 Hz) , 2. 90 (t,
2H, J - 7.8 Hz), 2.59-2.45 (m, 3H), 2.19-1.91 (m, 7H),
1.82 (d, 2H, J - 13.5 Hz), 1.24 (d, 6H, J - 6.9 Hz);
ESMS m/e: 555.3 (M + H)+.
Procedure F (see also example 108)
Scheme R
NaBH(OAc)3
1,2-dichloroethane
R CHO + HN ~ N
~ ~N HOAc, rt, overnight R~ ~ ~N
R2 R2
Example
NaBH(OAc)3
1,2-dichloroethane
R~CHO + HN ~ / ~N
HOAc, rt, overnight R~
NH NH
O O
N- (3-~1- (4- (4-CHLOROPHENOXY) BENZYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A solution of
4-(4-chlorophenoxy)benzaldehyde (0.129 g, 0.510 mmol)
and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide
(0.126 g, 0.510 mmol) in 1,2-dichloroethane (5.00 mL)
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was treated with sodium triacetoxyborohydride
(0.424 g, 2.00 mmol) and HOAc (0.0300 mL, 0.500 mmol) at
room temperature. The mixture was stirred overnight at
room temperature. The reaction mixture was neutralized
with saturated NaHC03 aqueous solution (10 mL) and the
aqueous layer was extracted with CHzCl2 (3 x 10 mL). The
combined organic layers were washed with brine, dried
over MgS04, concentrated in vacuo and purified by
preparative TLC plates using 50 of NH3 (2.0 M in
methanol) in CH2Clz to give the desired product (53.0 mg,
23 . 0 %) : 1H NMR (400 MHz, CDC13) 5 7 .50 (s, 1H) , 7 .34
7.19 (m, 7H) , 6.98-6. 87 (m, 5H) , 3 .50 (s, 2H) , 2 . 98 (d,
2H, J = 11. 8 Hz) , 2.58-2.44 (m, 2H) , 2.10-1.98 (m, 2H) ,
1.83-1.76 (m, 4H), 1.24 (d, 6H, J = 6.8 Hz); ESMS m/e:
463.2 (M + H)+.
Procedure G (see also example 116)
Scheme F
R-halide;
_ diisopropylethylamine _
H-N ~ ~ or Na2C03; R-N ~ /
O Bu4Nl, or KI; O
~N dloxane, toluene, N
or DMF; heat 50-90%
N- (3-~1- [ (3R) -3- (3-ACETYLPHENOXY) -3-PHENYLPROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A mixture of 1-
(3-{[(1R)-3-chloro-1-phenylpropyl]oxy}phenyl)ethanone
(58.5 mg, 0.200 mmol) , 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide (56.8 mg, 0.200 mmol),
NaI (34.0 mg, 0.200 mmol) and KZC03 (55.5 mg, 0.400 mmol)
in DMF (1.00 mL) was stirred at 100 °C for 3 h. The
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solvent was removed under reduced pressure and the
residue was purified by chromatography on silica using 5
of NH3 (2.0 M in methanol) in CHzCl2 to give the desired
product (98.0 mg, 98.0 %): 1H NMR (400 MHz, CDC13) S
8.01 (s, 1H), 7.49-7.21 (m, 11H), 7.09-7.03 (m, 1H),
6.96 (d, 1H, J = 7.9 Hz), 5.32 (dd, 1H, J - 5.0, 7.9
Hz) , 3.08-2.98 (m, 2H) , 2.57-2 .43 (m, 6H) , 2.11-1.72 (m,
9H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m/e: 499.4 (M + H)+.
Scheme S
O _~/~ N N ~ -
~O
O ~ R2 ZnCI2~HOAc
R~.N
80 °C, 10 h
H NHS
N
O
/ I I n N ~ /
RZ~J
n=0-3
R~
Procedure H
N
/ OO ' N
\ ZnCl2, HOAc ~NH
O
/ N/ ~- N 80 °C, 12 h ~ \
N
N H~
O~
2-METHYL-N-(3-~1-[3-(1-METHYL-1H-INDOL-3-YL)PROPYL]-4-
PIPERIDINYL~PHENYL) PROPANAMIDE: A mixture of N- (3- {1- [4-
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(1,3-dioxolan-2-yl)butyl]- 4-piperidinyl~phenyl)-2-
methylpropanamide (100 mg, 0.270 mmol), 1-methyl-1-
phenylhydrazine (106 mg, 0.870 mmol), ZnClz (119 mg,
0.870 mmol), and HOAc (1.00 mL) was heated for 12 h at
80 °C. The resulting crude mixture was diluted with
water (20 mL), the aqueous layer was neutralized with
saturated K~C03 solotion (10 mL) and extracted with CH2Cla
(3 X 20 mL). The combined organic layers were
concentrated in vacuo and the residue was purified by
preparative TLC using 3 % of NH3 (2.0 M in methanol) in
CH2C12 to give the desired product 2-methyl-N- (3-~1- [3-
(1-methyl-1H-indol-3-yl)propyl]-4-
piperidinyl~phenyl)propanamide (20.7 mg, 18.7 0):
1H NMR (400 MHz, CDC13) ~ 7. 60 (d, 1H, J = 8 .1 Hz) , 7 . 45
(s, 1H), 7.35 (d, 1H, J - 7.4 Hz), 7.26-7.24 (m, 4H),
7. 09 (t, 1H, J = 7.3 Hz) , 6.97 (d, 1H, J = 7.3 Hz) , 6. 86
(s, 1H) , 3 . 75 (s, _ 3H) , 3 . 11 (d, 2H, J = 11 . 6 Hz) , 2 . 79
(t, 2H, J - ~7.3 Hz), 2.51-2.50 (m, 4H), 2.12-1.81 (m,
8H), 1.25 (d, 6H, J - 7.1 Hz); Anal. Calcd for
Cz~H35N30+0.225CHC13: C, 73.57; H, 7.99; N, 9.45. Found:
C, 73.93; H, 7:90; N, 9.23; ESMS m/e: 418.2 (M + H)+.
Procedure I
Scheme T
j (OH)~ Pd(PPh3)4, Na2C03, LiCI,
Br- +
DME/H20, 90 °C R N
N H
R
H
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HO~ ,OH I \
B
\ ~ \ F Pd(PPh3)4, LiCI, Na2C03 / N
/ (
N ~ / DME, 75 °C,12 h
Br
7-(2-FLUOROPHENYL)-1H-INDOLE: A mixture of 2-
fluorophenylboronic acid (83.4 mg, 0.600 mmol), 7-bromo-
1H-indole (98.0 mg, 0.500 mmol), LiCl (42.0 mg, 1.00
mmol) , Na~C03 (2. 0 M, 0.100 mL) , Pd (PPh3) mg, 0.
4 (115 100
mmol) and DME (2.00 mL) was heated at 75 C for 12
h
under Argon. The resulting crude mixture was diluted
with water (40 mL), the aqueous layer was extracted
with
CHzCl2 (3 X 20 mL). The combined organic la yers were
washed with brine (30 mL), dried over Na2S04, filtered,
and concentrated in vacuo. The residue was purified
by
preparative TLC using hexane:EtOAc (8:1) to give the
desired product 7-(2-fluorophenyl)-1H-indole (108 mg,
100 %) : 1H NMR (400 MHz, CDC13) 8.21 (br s, 1H) , 7.71
(dm, 1H, J = 7.3), 7.55 (dt, 1H, J = 7,3, 1.6 Hz), 7.39
(m, 1 H), 7.30-7.19 (m, 5H), 6.62 (dd, 1H, J = 2.1-3.3
Hz); ESMS m/e: 211.9 (M + H)~.
Procedure J
Scheme U
OH
Br / , Cu, K2C03 \ O\
° I ~ \ N
N \J NMP, 160 C
H R R
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.
Br ~ \ I ~ Cu, KZC03
°
DMF, 160 C O
O
N
5-(4-METHYLPHENOXY)-~.H-INDOLE: A mixture of 5-bromo-1H-
indole (98.0 mg, 0.500 mmol), p-cresol (108 mg, 1.00
mmol) ; Cu (32 .0 mg, 0.500 mmol) , K~C03 (138 mg, 1.00 mL)
and DMF (1.00 mL) was heated at 160 °C for 12 h. The
resulting crude mixture was diluted with water (40 mL),
the aqueous layer was extracted with CHzCl2 (3 X 20 mL) .
The combined organic layers were washed with brine (30
mL), dried over NaaSO4, filtered, and concentrated in
vacuo. The residue was purified by preparative TLC
using hexane:EtOAc (4:1) to give the desired product 5-
(4-methylphenoxy) -1H-indole (57.5 mg, 51.5 0) : ESMS m/e:
224.0 (M + H)+.
Procedure K
O ~ N~ Nal, IfZC03, DMF O _
90 °C, 12 h R j n N ~
N
O
N
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Scheme AN
226
O w N~ O
~ CI I i [O~ ' Nal, K2C03, DMF R , ~ n N ~ /
R- n + i
NH
O
N
NaBH4, MeOH
OH
DEAD, PPh3, ArOH
R-',', / n N ~ /
NH
O
N- (3-~1- (7- (2-FLUOROPHENYL) -7-OXOHEPTYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: A 50-mL round-
s bottom flask was charged with a solution
of 7-chloro-1-oxo-1(2-fluorophenyl)heptane (2.42 g, 10.0
mmol), 2-methyl-N-[3-(4-piperidyl)phenyl] propanamide
(2.46 g, 10.0 mmol) , KZC03 (2.76 g, 20.0 mmol) and NaI
(2.25 g, 15.0 mmol) in DMF (25.0 mL) . The mixture was
stirred for 10 min at 25 ~C and then heated at 100 °C for
12 h, cooled to 25 ~C and diluted with EtOAc (100 mL).
The reaction mixture was washed with water (4 X 50 mL)
and the aqueous layer was extracted with EtOAc (100 mL).
The organic layers were washed with brine (50 mL), dried
over MgS04, concentrated in vacuo and the crude product
was purified by chromatography (EtOAc:MeOH 97:3) to give
the desired product (3.70 g, 82.0 0).
Procedure L
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OH
O
N -~ / NaBH4, MeOH R I / N \ /
_ ~ / NH
NH
O
Scheme AN
O w N~ O _
~ i O Nal, K~C03, DMF R i j n N \ /
n +
NH
O
N
NaBH4, MeOH
oAr
O _ OH
N DEAD, PPh3, ArOH
n \ / R ~ / ~ N \
NN NH
O
n=1-4
N-(3-~l-[7-(2-FLUOROPHENYL)-7-HYDROXYHEPTYL]-4-
PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: To a 50-mL
round-bottomed flask charged with N-(3-~1-[7-(2-
fluorophenyl)-7-oxoheptyl]-4-piperidinyl~phenyl)-2-
methylpropanamide (5.0 mmol) and methanol (20 mL) was
added NaBH4 (7.5 mmol) at 0 °C in an ice-bath. The
reaction mixture was warmed to 25 °C and stirred for 2 h.
The reaction was monitored by TLC (EtOAc:MeOH 95:5). If
necessary, another 5.0 mmol of NaBH4 was added to the
reaction mixture and the reaction mixture was refluxed
for 1 h. The reaction was quenched with water (5.0 mL)
and diluted with EtOAc (10 mL). The organic layer was
separated, washed with saturated NaHC03 solution (10 mL),
dried over MgS04 and concentrated in vacuo. The crude
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product was purified by chromatography
(EtOAc:MeOH 97:3) to give the desired product (900).
Procedure M
Scheme A
NH2
OII (1) TEA, THF ~ N~O
R~CI (2) HCI or TFA I / R
N
0~'0
N
i
H
Step 1: If reacted individually, a solution of the amine
or aniline (1.00 eq), diisopropylethylamine or TEA (2.00
eq) and an electrophile (1.50 eq) in CH2Clz was stirred
for 24 h at 23 °C. The solvent was removed in vacuo and
the crude product was chromatographed (silica) to give
the final product.
NH2 ' ~ N O
CI O
N~ TEA, THF ~ CI
N
O"O CI
O O
TERT-BUTYL 4 - ~ 3 - [ ( 4 - CHLOROBUTANOYL) AMINO ] PHENYL -1-
PIPERIDINECARBOXYLATE (3.32 g, 87.4 0) was synthesized
according to Scheme A and Procedure M: 1H NMR (400 MHz,
CDC13) b 7.55 (s, 1H), 7.47 (s, 1H), 7.37 (m, 1H), 7.28
(m, 1H), 6.97 (d, 1H, J = 7.6 Hz), 3.89 (t, 1H, J = 6.4
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Hz), 3.74 (m, 2H), 2.79- 2.75 (m, 4H), 2.64 (m,
2H), 1.88-1.77 (m, 4H), 1.60-1.59 (m, 4H), 1.48 (s, 9H).
o~ o
r~N
HCI or TFA
N N
BOC
Step B:
TERT-BTJTYL 4- [3- (2-OXO-1-PYRROLIDINYL) PHENYL] -1-
PIPERIDINECARBOXYLATE: To a solution of tert-butyl 4-[3-
(2-oxo-1-pyrrolidinyl)phenyl]-1-piperidinecarboxylate
(0.429 g, 16.9 mmol) in dioxane (100 mL) was bubbled HC1
gas for 1 h at 25 °C. The resulting crude mixture was
basified with 10% KOH solution (100 mL), the aqueous
layer was extracted with 3:1 CHCl3:iso-propyl alcohol (3
X 150 mL). The combined organic layers were washed with
brine (100 mL) , dried over Na~S04, filtered, and
concentrated in vacuo. The residue was purified by
preparative TLC using 20% NH3 (2.0 M in MeOH) in CH2Cla
solution to give the desired product tert-butyl 4-[3-(2-
oxo-1-pyrrolidinyl)phenyl]-1-piperidinecarboxylate (245
mg, 78.7 a) : 1H NMR (400 MHz, CDC13) 8 7.52 (t, 1H, J =
1. 8 Hz) , 7.41 (ddd, 1H, J = 8.1, 2.3, 0.9 Hz) , 7.30 (t,
1H, J = 7.9 Hz) , 7.02 (d, 1H, J = 7.9 Hz) , 3 .86 (t, 2H,
J = 7.3 Hz) , 3 .21 (dt, 2H, J = 11 . 9, 2 .9 Hz) , 2 . 76 (dt,
2H, J = 12.1, 2 .4 Hz) , 2.65 (tt, 1H, J = 11.9, 3 .5 Hz) ,
. 2.61 (t, 2H, J = 8.3 Hz) , 2.22 (br s, 1H) , 2 .16 (qt, 2H,
J = 7.5 Hz) , 1.85 (d, 2H, J = 12.4 Hz) , 1.67 (dq, 2H, J
- 12.5, 4.0 Hz).
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I \ NHz I / N R ( / N R
RCOCI, EI3N, THF, r.t., 2 h TFA, CHZCIZ, r.t., 6 h
R = Et, i-Pr, n-Bu, cyc-Pr, etc.
N
boc boc H
TERT-BUTYL 4-(4-AMINOPHENYL)-1-PIPERIDINECARBOXYLATE:
Available from Arch Chemical Company, NJ.
2-METHYL-N-[4-(4-PIPERIDINYL)PHENYL~PROPANAMIDE: To a
solution of tart-butyl 4-(4-aminophenyl)-1-
piperidinecarboxylate (8.20 g, 29.7 mmol) and
triethylamine (8.4 mL, 60 mmol) in dry THF (100 mL) at 0
°C was slowly added a solution of 2-methylpropanoyl
chloride (3.84 g, 36.0 mmol) in THF (50 mL). The
reaction mixture was then warmed up to room temperature
and stirred for 2 h. After removing the solvent in
vacuo, the crude product, was purified by
recrystallization (hexane/THF), affording the desired
amide, tart-butyl 4- [4- (isobutyrylamino) phenyl] -1-
piperidinecarboxylate, as a white solid (8.60 g, 840).
The tart-butyl 4- [4- (isobutyrylamino) phenyl] -1-
piperidinecarboxylate was dissolved in CH~C12 (50 mL) at
room temperature, TFA (13.68 g, 120 mmol, 5 equiv.) was
added by syringe. The reaction mixture was stirred for
3 or 4 h and another 5 equivalents of TFA was added and
the mixture was stirred for 2 or 3 more hours. The
reaction solution was then basified to pH > 14 by KOH
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(aq, 2 M). The solution was extracted with CHzCl~
(8 x 200 mL). The combined organic layer was dried over
KzC03. Removal of solvent under reduced pressure gave the
free amine, 2-methyl-N- [4- (4-
piperidinyl)phenyl]propanamide, as a brownish solid
(5.99 g, 98%) . 1H NMR (400 MHz, CDC13) 8 7.55-7.35 (m,
2H), 7.35-6.9 (m, 3H), 3.26-2.98 (m, 2H), 2.84-2.64 (m,
2H), 2.64-2.53 (m, 1H), 2.53-2.32 (m, 1H), 1.90-1.68 (m,
2H), 1.68-1.36 (m, 3H), 1.22 (d, 6H, J = 6.0 Hz); ESMS
m/e: 247.1 (M + H)+.
N-[4-(4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by
the procedure for 2-methyl-N- [4- (4-
piperidinyl)phenyl]propanamide using tert-butyl 4-(4-
aminophenyl)-1-piperidinecarboxylate and propanoyl
chloride: ESMS m/e: 233.1 (M + H)+.
N-[4-(4-PIPERIDINYL)PHENYL]BUTANAMIDE: Prepared by the
procedure for 2-methyl-N-[4-(4-
piperidinyl)phenyl]propanamide using tert-butyl 4-(4-
aminophenyl)-1-piperidinecarboxylate and butanoyl
chloride: ESMS m/e: 247.2 (M + H)+.
N-[3-(4-PIPERIDINYL)PHENYL]GYCLOPROPANECARBOXAMIDE:
Prepared by the procedure for 2-methyl-N-[4-(4-
piperidinyl)phenyl]propanamide using tent-butyl 4-(3-
aminophenyl)-1-piperidinecarboxylate ~ and
cyclopropanecarbonyl chloride: Anal. Calcd for
ClSH~oN20+0.15CH2C12: C, 70.8; H, 7.87; N, 10.9. found: C,
70.9; H, 7.68; N, 11.1; ESMS m/e: 245.0 (M + H)+.
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N-[3-(4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by the
procedure for 2-methyl-N- [4- (4-
piperidinyl)phenyl]propanamide using tert-butyl 4-(3-
aminophenyl)-1-piperidinecarboxylate and propanoyl
chloride : Anal . Calcd for Cl4HzoNzO: C, 72 . 2 ; H, 8 . 63 ; N,
12.1. found: C, 72.4; H, 8.68; N, 12.1; ESMS m/e:
233.1.
Procedure N
Scheme AV
PS-TBD resin
benz I bromide
r ~N~R2 + or benzyl iodide ~H3CN
R~ RT, 16 h
r k
'N R2
R1
The library was constructed in polypropylene Robbins 46
well plates Reactor Blocks. In the initial incubation
period, each well was charged with PS-TBD resin (from
Argonaut Technologies, 0.280 mmol, 2.50 eq, 200 mg) and
piperidine (0.120 mm~l, 1.10 eq) in acetonitrile (0.500
mL) and agitated for 1 h. A solution of benzyl iodide
or bromide (0.110 mmol, 1.00 eq) in acetonitrile (0.500
mL) was added to each well followed by additional
acetonitrile (1.00 mL) to make a total volume of 2.00 mL
and the mixture was rotated in a Bobbins rotating oven
at room temperature for 16 h. Then AP-Isocyanate resin
(Argonaut Technologies, 250 mg, 0.430 mmol, 4.00 eq) was
added to each well and reacted further at room
temperature for another 12 h. The mixture was filtered
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and the filtrate was concentrated in vacuo to
obtain the desired product that was characterized via
LC-MS.
Procedure O
Alkylation of Piperidines Using Alcohols and PS-TSCl
Resin in Robbins 48 well "Reactor Blocks"
Scheme W
HN ~ ~ O - ~ l O
P SOZCI R-~ P S03R N~R2 R N N~R2
R'~ ~ R1
The library was constructed in polypropylene Bobbins
"Reactor Blocks", 46 well plates. PS-TSCl resin (100
mg, 1.00 eq, purchased from Argonaut Technologies) was
placed in each well of the "Reactor Blocks" 46 well
plates. To each well was added an alcohol (1.50 mmol)
in 3.00 mL of CH2C12 and pyridine (1:1). The mixture was
stirred for 5 h and the resin was washed with CHzCl2 (3 x
4mL) , DMF (5 x 4.0 mL) , DMF/Hz0 (3 :1, 5 x 4. 0 mL) , THF (3
x 4.0 mL), CH2C12 (3 x 4.0 mL), acetonitrile (2 x 4.0 mL)
and dried under reduced pressure. A solution of an
amine (0.0750 mmol, 0.500 eq) and N,N-diisopropylethyl
amine (19.0 mg, 0.150 mmol, 1.00 eq) in acetonitrile
(3.00 mL) was added to the well containing the
derivatized resin and the mixture was reacted at 70 °C
for 16 h. Finally, AP-Isocyanate resin (120 mg, 0.150
mmol, 1.00 eq) and THF (2.00 mL) was added to the
reaction vessel and reacted at room temperature for
another 3 h. The solution was filtered into the Bobbins
receiving plates and concentrated in vacuo to give the
desired tertiary amine, which was analyzed via LC-MS.
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Procedure P
Scheme AB
R~ Ra
H 'R3 THF, RT, 12 h i w X
+ ~N i ~~
~N=C=X R2 N~N-Ra
H
X=OorS R2
O
N~N~ ~N~N~N
O I i ~ i
~~ J
N o~N ' o N
N-~3- [1- (3-~ [ (4-FLUOROANILINO) CARBONYL]AMINO~PROPYL) -4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: A solution of
N-~3- [1- (3-aminopropyl) -4-piperidinyl]phenyl-2-
methylpropanamide (26.4 mg, 0.0870 mol), 1-fluoro-4-
isocyanatobenzene (11.9 mg, 0.0870 mmol), in THF (1.00
mL) was stirred for 12 h at 25 °C. The resulting crude
mixture was diluted with water (10 mL), the aqueous
layer was extracted with CH2Clz (3 X 20 mL) . The
combined organic layers were concentrated in vacuo and
the residue was purified by preparative TLC using 2.5
of NH3 (2.0 M in methanol) in CH~Clz to give the desired
product N-~3-[1-(3-{[(4-fluoroanilino)carbonyl]amino}
propyl)-4-piperidinyl]phenyl}-2-methylpropanamide (4.18
mg, 10.9 %) : 1H NMR (400 MHz, CDC13) 7.45 (q, 2H, J =
4.7 Hz), 7.23-7.21 (m, 4H), 7.05 (t, 4H, J - 7.8 Hz),
6.75 (m, 1H) , 4 . 05 (m, 1H) , 3 . 19 (s, 1H) , 2 .71 (m, 1H) ,
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2.53 (m, 1H), 2.26-2.21 (m, 3H), 1.80-1.60 (m,
9H) , 1.25 (d, 6H, J = 6.4 Hz) ; ESMS m/e: 439.4 (M + H)+.
Procedure Ql
Scheme AT
H2N~-N ~ ~°j electrophile, base R -NH~N
~ ~ N' 'R ~N
I2
R~
If reacted individually, a solution of the amine (1.0
eq), an electrophile (1.5 eq), diisopropylethylamine
(2.0 eq) in CHzCl2 was stirred for 1 day. The solvent
was removed in vacuo and the crude product was
chromatographed to give the final product.
Q. ,O
N~ . I ~ S:N~N
.,o
s i
ci I ,
O~N
2-METHYL-N-{3- [1- (3-~ [ (4-
METHYLPHENYL)SULFONYL]AMINO~PROPYL)-4-PIPERID=NYL]
PHENYL~PROPANAMIDE: A solution of 4-
methylbenzenesulfonyl chloride (16.6 mg, 0.0870 mmol),
N-{3- [1- (3-aminopropyl) -4-piperidinyl]phenyi~-2-
methylpropanamide (26.4 mg, 0.0870 mmol), TEA (10.0 mg,
0.174 mmol) in THF (1.00 mL) was stirred for 12 h at 25
°C. The resulting crude mixture was diluted with water
(20 mL), the aqueous layer was extracted with CH~C12 (2 X
20 mL). The combined organic layers were concentrated
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in vacuo and the residue was purified by
preparative TLC using 2.5 % of NH3 (2.0 M in methanol) in
CHaCl2 to give the desired product 2-methyl-N-{3-[1-(3-
{ [ (4-methylphenyl) sulfonyl] amino} propyl) -4-
piperidinyl]phenyl~propanamide (17.3 mg, 43.6 %) : 1H NMR
(400 MHz, CDC13) 8 8.19 (s, 1H), 7.53 (s, 1H), 7.41 (s,
1H), 7.32-7.21 (m, 4H), 7.16 (s, 1H), 6.97 (d, 1H, J =
7.9 Hz) , 3.44 (t, 2H, J = 6.3 Hz) , 3.15 (d, 2H, J = 9.8
Hz), 2.62-2.45 (m, 4H), 2.15 (m, 3H), 2.05 (s, 3H),
1.95-1.71 (m, 5H), 1.26 (d, 6H, J = 6.6 Hz); ESMS m/e:
458.2 (M + H)+.
Procedure QZ
The Capture and Release Method for the Synthesis and
Purification of the Piperidine Library
The commercially obtained Amberlyst 15 exchange resin
(Aldrich) was activated using the following procedure:
1. The resin was shaken in methanol for 24 hr.
2. The resin was filtered and washed with methanol on a
fritted funnel.
3. The resin was neutralized with 2N NH3 in MeOH (pH
checked) - shaken for 1 hr.
4. The neutralized resin was acidified with 3M HC1 in
MeOH (pH checked) - shaken for 1 hr.
5. The resin was captured on a fritted funnel and washed
with MeOH.
6. The resin was dried in vacuo and stored.'
Synthesis (Acylation of the Amines):
The library was constructed in polypropylene Bobbins
'°Reactor Blocks", 46 well plates. In each plate an
array of 5 amines (0.10 mmol) and 8 electrophiles (acid
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chlorides, sulfonyl chlorides, 1.5 eq.) in the
presence of triethylamine (2.0 eq) in THF/DCM 3:1 (2.0
mL) were reacted overnight to give 40 compounds/plate.
The reactions were rigorously monitored via TLC to the
depletion of the starting amine due to the ensuing
purification methodology via the acidic Amberlyst 15
resin. Following the disappearance of the starting
amine, the desired products were captured and then
released using the process outlined below.
to
Purification of the Piperidine Products: Activated
Amberlyst 15 ion-exchange resin (0.90 g, Aldrich) was
added to each well, and the plates were rotated for 2
hours in a Robbins rotating oven to capture the desired
final product from the reaction mixture. The solvent was
filtered and the resin was washed with CH30H and CH2Cla
(x 3) alternately with each of the solvents (for 10
minutes each time). After the last filtration, 2 N
ammonia in methanol was added to the resin (2 mL to each
well) and the reaction blocks were rotated fox 2 hours
to release the desired compounds from,the resin. The
final compounds were filtered into Robbins' "Receiving
Blocks", the solvent was removed and the compounds were
analyzed via LC-MS.
Procedure R
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Scheme Z
X
X TEA, THF
+ Br CI
12 h, RT S CI
SH
n = 1-4
n=1-4.
X = F, CI, Br, I
[(3-CHLOROPROPYL)SULFANYL]BENZENE: A mixture of
benzenethiol (0.550 g, 5.00 mmol), 1-bromo-3-
chloropropane (106 mg, 5.50 mmol), TEA (1.01 g, 10.0
mmol) and THF (10.0 mL) was stirred for 12 h at 25 °C.
The resulting crude mixture was diluted with water (40
mL) , the aqueous layer was extracted with CHaClz (3 X 30
mL). The combined~organic layers were concentrated in
vacuo and the residue was purified by preparative TLC
using hexane:EtOAc (10:1) to give the desired product
[ (3-chloropropyl) sulfanyl] benzene (1. 05 g, 100 %) .
Scheme AA
X X
m-CPBA, CHZCI2
S CI
S'~CI 4 h, RT
\/ n O
n=1-4 n=1-4
X = F, CI, Br, I
Procedure S
3-CHLOROPROPYL 4-FLUOROPHENYL SULFOXIDE: A solution of
3-chloropropyl 4-fluorophenyl sulfide (77.5 mg, 0.380
mmol) in CH2C12 (2.00 mL) was cooled to 0 °C. To this
solution m-CPBA (78.7 mg, 0.460 mmol) was added. Th.e
reaction mixture was stirred at 0 °C for 30 min, then at
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239
23 °C for 4 h. The resulting crude mixture
was diluted with 10% aqueous Na2S03 (10 mL), the aqueous
layer was extracted with CH~C12 (2 X 15 mL). The combined
organic layers were washed with brine (10 mL), dried
over NazS04, filtered, and concentrated in vacuo. The
residue was purified by preparative TLC using 2.5 % of
NH3 (2.0 M in methanol) in CH2C12 to give the desired
product 3-chloropropyl 4-fluorophenyl sulfoxide (47.8
mg, 57.0 %).
Procedure T
Scheme AD
room temp.
R- ---
Base, THF, CH31
N \ ~ Mel, Base, THF ~ ~ N
N-~ --~' N-
° ° ° ~ °
N-(3-{1-[4-(3,4-DIMETHYLPHENYL)-4-OX08UTYLj-4-
PIPERIDINYL~PHENYL)-N,2-DIMETHYLPROPANAMIDE: A mixture
of N- (3-~1- [4- (3,4-dimethylphenyl) -4-oxobutyl] -4-
piperidinyl}phenyl)-2-methylpropanamide (15.0 mg, 0.0357
mmol), MeI (5.07 mg, 0.0357 mmol), NaOtBu (6.86 mg,
0.0714 mmol) and THF (1.00 mL) was stirred for 5 h at 25
°C. The resulting crude mixture was diluted with water
(10 mL), the aqueous layer was extracted with CH2Cla (3 X
20 mL). The combined organic layers were concentrated
in vacuo and the residue was purified by preparative TLC
using 4.0 % of NH3 (2.0 M in methanol) in CHaCl2 to
afford the desired product N- (3-~1- [4- (3,4-
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dimethylphenyl)-4- oxobutyl]-4-
piperidinyl~phenyl)-N,2-dimethylpropanamide mg,
(13.8
89.1 0) : 1H NMR (400 MHz, CDC13) 7.76 (s, 1H) 7.72
,
(dd., 1H, J = 1. 8, 7. 7. Hz) , 7.33 (t, 1H, 8. Hz) 7.22
J = 8 ,
(d, 1H, J = 7. 8 Hz) , 7.18 (d, 1H, J = 8. Hz) 7 . (m,
8 , 0l
2H), 3.24 (s, 3H), 3.10 (d, 1H, J = 10.6 Hz),3.00 (t,
1H, J - 7.6 Hz), 2.49-2.44 (m, 4H), 2.33(s, 6H),
2.112.10 (m, 2H), 1.99 (m, 1H), 1.79-1.77 (m, 4H), 1.26
(t, 2H, J = 7.6 Hz), 1.02 (d, 6H, J = 7.6 Hz);ESMS m/e:
435.2 (M + H)+.
Procedure U
Scheme AK
X NaH, DMF X
+ Br' M 'CI
n o
95 C, 12 h O CI
OH
n = 1-4
X = F, CI, Br, I , n = 1-4
O O
Br~CI NaH, DMF, 95 °C I ~ O~Ci
1- [3- (3-CHLOROPROPOXY) PIiENYL] ETHANONE: To a suspension
of NaH (50.5 mg, 2.00 mmol) in DMF (1.00 mL) was added 1-
(3-hydroxyphenyl)ethanone (136 mg, 1.00 mmol) at 0 °C.
The reaction mixture was stirred at room temperature for
1 h. To this mixture was added a solution of 1-bromo-3-
chloropropane (188 mg, 1.20 mmol) in DMF (0.500 mL). The
reaction mixture was stirred at room temperature for 5
h. The resulting crude mixture was diluted with water
(20 mL), the aqueous layer was extracted with CH2C12 (3 x
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20 mL). The combined organic layers were washed
with brine (20 mL) , dried over NaaS04, filtered, and
concentrated in vacuo. The residue was purified by
preparative TLC using hexane:EtOAc (4:1) to afford the
desired product 1-[3-(3-chloropropoxy)phenyl]ethanone
(235 mg, 55.2 0) : 1H NMR (400 MHz, CDC13) b 7.7 (d, 1H,
J = 6.6 Hz) , 7.52 (s, 1H) , 7.25 (t, 1H, J = 6.6 Hz) , 7.01
(m, 1H) , 4. 11 (t, 2H, J =~ 7 .9 Hz) , 3 .69 (t, 2H, J = 7 . 9
Hz), 2.61 (s, 3H), 1.95-1.92 (m, 2H).
Procedure V
Scheme AE
OTf O\ ,O
B
N
BOC N
I
BOC
1-[(2,2-DIMETHYLPROPANOYL)OXY]-4-(4,4,5,5-TETRAMETHYL-
1,3,2-DIOXABOROLAN-2-YL)-1,2,3,6-TETRAHYDROPYRIDINE:
To a 50-mL RB-flask, charged with bis(pinacolato)diboron
(422 mg; "1.66 mmol), KOAc (444 mg, 4.53 mmol) and
PdCl2dppf (37.0 mg, 3.00 molo), dppf (25.0 mg, 3.00
mol%), was added a solution of 1-[(2,2-
dimethylpropanoyl)oxy]-1,2,3,6-tetrahydro-4-pyridinyl
trifluoromethanesulfonate (500 mg, 1.51 mmol) in 1,4-
dioxane (10.0 mL) at room temperature under. argon. The
mixture' was heated at 80 °C overnight. After cooled to
room temperature, the mixture was filtered through
celite and the celite was washed with EtOAc (3 x 20 mL).
The filtrates were concentrated in vacuo. The resulting
residue was dissolved in EtOAc and washed with Hz0 and
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brine, dried over MgS04, filtered and concentrated
in vacuo. The crude material was purified by flash
chromatography (1:9 EtOAc:hexane) to give 1-[(2,2-
dimethylpropanoyl)oxy]-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (355 mg,
76.0 0) .
Procedure W
Scheme AF
O
Br ~ N
H N
O
O\B O
N
BOC
N
I
BOC
TERT-BUTYL 4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-3,o'-
DIHYDRO-1(2H)-PYRIDINEOARBOXYLATE: To a 50-mL RB flask
containing 1-[(2',2-dimethylpropanoyl)oxy]-4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-
tetrahydropyridine (500 .mg, 1.62 mmol), K2C03 (670 mg,
4.86 mmol) and PdCl2dppf (155 mg) was added.a solution of
N-(3-bromo-4-methylphenyl.)-2-methylpropanamide (415mg,
1.62 mmol) in DMF (10.0 mL) at room temperature under
argon. The mixture was heated to 80 °C under argon
overnight. After cooled to room temperature, the
mixture was filtered through celite and the celite was
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243
washed with EtOAc (3 x 20 mL). The filtrates were
washed with Hz0 (20 mL), brine (20 mL), dried over MgS04,
filtered and concentrated in vacuo. The crude material
was purified flash chromatography (20% EtOAc/ hexane) to
give tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-
3,6-dihydro-1(2H)-pyridinecarboxylate (360 mg, 62.0 0).
Scheme AG
H H
N ~ ~ \~~'N
/ OO ' ~ / O
N/
aoc aOc
Procedure X
TERT-BUTYL 4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-
PIPERIDINECARBOXYLATE: A solution of tert-butyl 4-[5-
(isobutyrylamino)-2-methylphenyl]-3,6-dihydro-1(2H)-
pyridinecarboxylate (335 mg, 0.93 mmol) and loo Pd/C
(35.0 mg) in EtOH (20.0 mL) was hydrogenated at room
temperature overnight using the hydrogen balloon method.
The reaction mixture was filtered through celite and
washed with ethanol (3 x 10 mL) . The combined extracts
were concentrated in vacuo to afford tert-butyl 4-[5-
(isobutyrylamino)-2-methylphenyl]-1-
piperidinecarboxylate (335 mg, 100 0).
Procedure Y
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Scheme AH
244
H H
I \ N . I \ N \
O / O
N~ N~
BOC H
2-METHYL-N- [4-ME'PHYL-3- (4-PIPERIDINYL) PHENYL]
PROP.ANAMIDE: Into a solution of tert-butyl 4-[5-
(isobutyrylamino)-2-methylphenyl]-1-
piperidinecarboxylate (335 mg, 0.930 mmol) in CH2Cla
(10.0 mL) was added TFA (10.0 mL) at room temperature.
The reaction mixture was stirred for 2 h and
concentrated in vacuo. The residue was dissolved in 20
mL of CHC13/i-PrOH (3:1) and was basified with 5% KOH
solution (10 mL). The aqueous layer was extracted with
CHC13/i-PrOH (3:1, 3 x 10 mL). The combined organic
extracts were washed with brine, dried over MgS04,
filtered and concentrated in vacuo to give 2-methyl-N
[4-methyl-3-(4-piperidinyl)phenyl]propanamide (190 mg,
78.0 %) .
Procedure Z
Scherr~e A!
H
R ~~N~Rz s R~
Nal, ICzC03, DMF, R N
0 95 °C, overnight
~ L ~X
'' ~ R3~C~ ~X ~\
-' NH
N X = C, N Rz
H
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245
N F / F
i
i ~ ~ ~ CI
~i
N '
F
N-(3-~l-~4,4-BIS(4-FLUOROPHENYL)BUTYL]-4-PIPERIDINYL~-4-
METHYLPHENYL)-2-METHYLPROPANAMIDE: A solution of 2-
methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide
(49.0 mg, 0.190 mmol), 1-[4-chloro-1-(4-
fluorophenyl)butyl]-4-fluorobenzene (58.0 mg, 0.210
mmol) , NaI (42'.0 mg, 0.280 mmol) and K2CO3 (52.0 mg,
0.380 mmol) in DMF (10.0 mL) was heated at 95 °C
overnight. The mixture was diluted with water (20 mL)
and the aqueous layer was extracted with EtOAc (3 x 20
mL). The combined organic layers were washed with
brine, dried over MgS04 and concentrated in vacuo. The
crude product was purified by flash chromatography [5~
NH3 (2.0 M in MeOH) in CHaClz] to afford N- (3-(1- [4, 4
bis(4-fluorophenyl)butyl]-4-piperidinyl~-4
methylphenyl)-2-methylpropanamide (37.0 mg, 38.0
Procedure AA
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246
Scheme AJ
H H
N RZ N RZ
1,2-Dichloroethane, NaBH(OAc)3, ~'~~ O
R~ l ~ j( O AcOH, RT, overnight Ri l ~ X
R3CH0
N X=C,N N
H
R3
H
N~ ~ ~ O N ~ /
O 0 w ~' N
\ ~ r I. ,
O O/
N F \
F
F
N-(3-~1-[4-(3,4-DIFLUOROPHENOXY)BENZYL~-4-PIPERIDINYL~-
4-METHYLPHENYL)-2-METHYLPROPANAMIDE: To a solution of
4-(3,4-Difluorophenoxy)benzaldehyde (41.0 mg, 0.170
mmol) and 2-methyl-N-[4-methyl-3-(4-
piperidinyl)phenyl]propanamide (45.0 mg, 0.170 mmol) in
1,2-dichloroethane (5.00 mL) was added sodium
triacetoxyborohydride (110 mg, 0.520 mmol) and AcOH
(10.0 uL, 0.170 mmol) at room temperature. The mixture
was stirred overnight. The reaction mixture was
quenched by saturated NaHC03 solution (10 mL) and
extracted with CH2C12 ( 3 x 10 mL) . The combined organic
layers were washed with brine, dried over MgS04,
concentrated in vacuo. The crude product was purified
by preparative TLC using 5% NH3 ~2.0 M in MeOH) in CHzCla
to give the desired product N- (3-~1- [4- (3, 4-
difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-
2-methylpropanamide (44.0 mg, 54.0 %).
Procedure AC
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247
Scheme AT: Synthesis of Amides using PS-
Carbodiimide Resin
. ~I O
O ~ I ~ PS-Carbodiimide H \ N~R~
+ N R2 R~~N~N H
R~ CI H2N~N H DCM/DMF 10/ ''1
O
25 °C, 12 h
F
F . F
F I
I ~ ~ I O PS-Carbodiimide_ ° O
+ \ N~ DCM/DMF 10/1 NON
H2N~N H O N ~ s
0 N 25 °C, 12 h H N O
H
A mixture of a carboxylic acid (0.0800 mmol) and PS-
Carbodiimide Resin (2.00 eq, 80.0 mg, 1.34 mmol/g) in
DCM:DMF (10:1, 3.00 mL) was shaken for 30 min. To the
reaction mixture was added amine (0.0540 mmol) and the
resulting mixture was shaken for 12 h at room
temperature. The reaction mixture was filtered and the
resin was washed with CHzCla. The combined organic
extracts were concentrated to a small volume, applied to
a preparative TLC plate and eluted with 6 % NH3 (2.0 M in
MeOH) in CH~Clz to give the desired product.
Procedure AD
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Scheme X
248
bromopropyiamine.FiBr
+ (BOC)20 + base
HN / r ~N~RZ BOC-N~Br BOC-N~N ~ !/ N' \R2
I H ~ ~H
TFA, CH2Ch H2N~-N
~H R2
R1
TERT-BUTYL N-(3-BROMOPROPYL)CARBAMATE: Prepared from 3-
bromopropylamine hydrobromide and BOC20 in the presence
of base in CHaCl2: ' 1H NMR (300 MHz) c5 5.07 (br, 1 H) ,
3.31 (t, 2 H, J = 6.6 Hz), 3.12 (apparent br q, 2 H, J =
6.0 Hz), 1.92 (p, 2 H, J = 6.6 Hz), 1.30 (s, 9H).
i
O
~N~N N~O
O
Step 1. To a solution of piperidine (19.3 mmol) in
dioxane (20.0 mL) was N-(tert-butoxycarbonyl)-3-
bromopropylamine (21.2 mmol) and potassium carbonate
(38.7 mmol) at room temperature and the mixture was
heated at reflux temperature for 24 h. The reaction
mixture was cooled to room temperature, concentrated in
vacuo and partitioned between CHC13 (40 mL)~ and water (5
mL). The organic layer was washed with brine, dried
over sodium sulfate, filtered and concentrated in vacuo.
The crude product was purified by column chromatography
(ethyl acetate: methanol 9:1) to yield the required
product tert-butyl 3- f 4- [3- (acetylamino)phenyl] -1-
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piperidinyl}propylcarbamate as a colorless oil: ESMS
m/e: 376.2 [M+H]+.
Step 2. HC1 gas was bubbled into a solution of the boc-
protected amine (12.1 mmol) in dioxane (5.00 mL) for 10-
20 minutes at 0-5 °C. The resulting solution was stirred
at 0-5 °C for 1 h, concentrated, neutralized with 10
KOH solution (10 mL) and extracted into CH2Clz (25 mL).
The organic extract was washed with brine, dried over
sodium sulfate and concentrated in vacuo. The crude
product was chromatographed to give the desired product
N-~3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide:
ESMS m/e: 276.1 [M+H]+.
Procedure AE
Scheme Y
0
O ~ - O
N
\ O ~~ ~~ N N
o e~ \ ~ J N
HN f ~N~ p H R
H R~ THF, DIPEA ~ / R~
O
hydrazine, EtOH, reflex, HzN N
'/ N R2
H
R~
O ~ - O
N N ~[
O \ '~ N~RZ
Step 1: A mixture of piperidine (1. 00 eq, 0.0226 mmol) ,
N-(bromoalkyl)phthalimide (1.50 eq, 0.0338 mmol), Bu4NI
(200 mg) and diisopropylethylamine (5.00 eq, 0.113 mmol)
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in dioxane (200 mL) was heated at 99 °C for 24 h.
The reaction was followed by TLC analysis (95:5
CHZCI2:methanol). If necessary additional 0.0113 mmol of
the appropriate bromoalkylphthalimides was added to each
reaction mixture and the heating was continued for
additional 48 h. The reaction mixture was cooled to
room temperature, the ammonium salts were.filtered out
and the solvent was removed under reduced pressure. The
crude product was chromatographed to give the desired
product.
O
O
NON N
~N J N O
O ~ N O
O
ESMS m/e: 420.2 ESMS m/e: 434.4
[M+H] + [M+H] +
_ /
O /~ N ~ ~ ~ ~ O ~ I N O
N-' N N N
O
O O
ESMS m/e : 448 . 4 ESMS m/e : 4x2.4
[M+H] + [M+H] +
ESMS m/e: 476.4
[M+H] +
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Step 2: Deprotection of the resulting phthalimides
was conducted by heating a solution of phthaliamide-
protected amines with excess hydrazine hydrate (10 eq)
in ethanol (0.5-1.0 M) at 90 °C for 4 h. The reaction
mixture was monitored by TLC to completion. Upon- the
reaction was completed, the mixture was cooled to room
temperature, the insoluble by-products were filtered out
through celite and the solvent was removed in vacuo.
The crude product was chromatographed (dichloromethane
methanol-isoprpylamine) to give the desired products.
HaN~N I
N HaN \
W w ~N~ .N O
O
ESMS m/e : 290 . 2 [M+H] + ESMS m/e : 304 . 1 [M+H] +
N O
Hz
HEN N
ESMS m/e: 318.2 [M+H]+ ESMS m/e: 332.2 [M+H]+
H~
ESMS m/e: 346.3 [M+H]+
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Procedure AF
F F
F F
p
u+ ~+
a + ~ I ~ N.O- LDA, THF, - 78 ~C 1 A ~ \ I N'O +
N~ CI O~ N O
O~O O~O
F
F
NON N ~C03, DCM/MeOH 1 ~ O
I N~N ~N
0 N
0~0 w
/ 0
Scheme H
~~R O ~~R O
+ O ~ ~t~lo_ LDA, THF, - 78 °C ~ a O , No-
II I +
NH C~~O I i N~O
O~O O~O
KZC03 , ~~R
H2N~N DCM/MeOH a O
n ~ N~ N~N~N
[ n
I i O O~O ~ w N
n = 0-4
(4R) -4- (3, 4-DIFLUOROPHENYL) -N- (3-~4- [3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~PROPYL)-2-OXO-
1,3-OXAZOLIDINE-3-CARBOXAMIDE was synthesized according
to Scheme H and Procedure AF: To a solution of (4R)-4-
(3,4-difluorophenyl)-1,3-oxazolidin-2-one (this compound
and analogs were prepared according to J. Med. Chem
2000, 43, 2775) (0.300 mol, 60.0 mg) in THF (5.00 mL)
was added LDA (2.0 M in THF, 0.390 mmol, 0.200 mL) at -
78 °C under argon. After 30 min at -78 °C, to the
mixture was added a solution of 4-nitrophenyl
chloroformate (0.330 mmol, 51.2 mg) in THF (0.500 mL) at
-78 °C. After stirring for 30 min at -78 °C the reaction
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mixture was diluted with a saturated Na2C03 solution
(5.0 mL) and the aqueous layer was extracted with CHzCIz
(3 x 10 mL). The combined organic layers were washed
with brine (10 mL), dried over Na2S04 and concentrated in
vacuo. The residue was purified by preparative TLC
plates (10:1 hexane:ethyl acetate) to afford 4-
nitrophenyl (4R)-4-(3,4-difluorophenyl)-2-oxo-1,3-
oxazolidine-3-carboxylate (51.5 mg, 54.0 %).
4-Nitrophenyl (4R)-4-(3,4-difluorophenyl)-2-oxo
1,3-oxazolidine-3-carboxylate (169 mg, 0.465 mmol), N
{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2
methylpropanamide (141 mg, 0.465 mmol), KaC03 (0.193 g,
1.39 mmol), CHaCl2 (10 mL), and methanol (0.1 mL) were
combined in a flask. The mixture was stirred overnight
at room temperature, the solvent was removed in vacuo,
and the residue was purified by chromatography [2.5% of
NH3 (2.0 M in methanol) in CHzCl2] to afford the desired
product (26.1 mg, 10.6 %): 1H NMR (400 MHz, CDC13) ~
8.08 (t, 1H, J = 5.5 Hz), 7.45 (S, 2H), 7.38 (d, 1H, J =
8.6 Hz) , 7.24-7.12 (m, 3H) , 7.06 (m, 1H) , 6. 97 (d, IH, J
- 8.6 Hz), 5.40 (dd, 1H, J = 3.9-8.8 Hz), 4.71 (t, 1H, J
- 8.8 Hz) , 4.23 (dd, 1H, J = 4.4, 9.1 Hz) , 3 .32 (qt, 2H,
J = 6.1 Hz) , 2.99 (d, 2H, J = 11. 0 Hz) , 2.49 (qt, 2H, J
- 7 . 0 Hz) , 2 .41 (t, 2H, J = 7 . 0 Hz) , 1 . 99-1 . 97 (m, 2H) ,
1.82-1.68 (m, 6H), 1.23 (d, 6H, J - 7.3 Hz); Anal.
Calcd. for CagH34F''2N4~4+'HC1+o.185CHC13: C, 57.6; H, 6.04;
N, 9.54. Found: C, 58.5; H, 6.08; N, 9.47; ESMS m/e:
529.1 (M + H)+. .
Procedure AG
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Scheme AR:
y
CHO o~o I ~ R~
O O R3NH30Ac, HOAc O
R~ + . O~O + R~O~R4 127 °C, 18 h
J\i
O N R~
R3
i R~ ~ 1 R~
O if R4 = benzyl, then ~ O
O~R4 10% Pd/C, HZ
'O H
methanol, ~
O N R2 room temperture O N"R2
R3 i
R3
Step 1: A solution of ketoester (10 mmol), Meldrum's
acid (10 mmol), aldehyde (10 mmol) and an ammonium
acetate (11 mmol) in HOAc (10 mL) was heated at reflux
temperature for 18 h.1 The cooled reaction mixture was
poured over ice (100 g). The precipitated oils were
collected and dried under reduced pressure. The benzyl
ester protected analogs solidified upon trituration with
a mixture of ether/hexane.
l0
F F
F w
0
0
~OBn I OBn
O N O N
H
1.05 g, 29.0 % 523 mg, 15.0%
1 MORALES, A.; OCHOA, E.; SUAREZ, M.; VERDECIA, Y.;
GONZALEZ, L.; MARTIN, N.; QUINTEIRO, M.; SEOANE, C.;
SOTO, J. L. ; J. Heterocycl . Chem. [JHTCAD) 1996, 33 (1) ,
103-107.
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Step 2: A mixture of a benzyl ester and 10% Pd/C
in methanol was hydrogenated using the balloon method at
room temperature. The reaction mixture was monitored
(TLC) to completion, filtered through Celite 545 and the
Celite filter cake was washed with methanol (3 x 10 mL).
The combined methanol extracts were concentrated in
vacuo to give the desired carboxylic acid that was used
in the next step without any further purification,
F
F ~ O
~OH
O N
4-(2,4-DIFLUOROPHENYL)-2-METHYL-6-OXO-1,4,5,6-
TETRAHYDRO-3-PYRIDINECARBOXYLIC ACID was synthesized
according to Procedure AG and Scheme AR: 1H NMR (CDC1~,
400 MHz) 8 7.82 (s, 1H) , 7.00-.6.72 (m, 3H) , 4.51 (d, 1H,
J = 8.4 Hz), 2.90 (dd, 1H, J = 8.4, 16.3 Hz), 2.68 (d,
1H, J = 16.3 Hz), 2.46 (s, 3H).
F
F
0
-OH
O N
4-(3,4-DTFLUOROPHENYL)-2-METHYL-6-OXO-1,4,5,6-
TETRAHYDRO-3-PYRIDINECARBOXYLIC ACTD was synthesized
according to Procedure AG and Scheme AR: 1H NMR (CDC13,
300MHz) 8 7.40-6.80 (m, 4 H), 4.23(d, 1 H, J - 7.5
avg.Hz), 2.93 (dd, H, J = 16.8, 7,5 avg. Hz), 2.68
1
(d,1 H, J = 16.5 avg.Hz),2.45 (s, H).
3
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Procedure AH
256
KzC03, Nal
1. NaH, DMF ~ \ DMF, 90 °C, 12 h
N r CH CH CI ~~~!~
H 2. B CHz( z)n z ~ _ ~I
CHz(CHz)nCHzCI ,~'~NN
H H N Y 'O
w ~ IN
/ N O~ n~3,4
N
L-- (CHz)n .-/
1-(6-CHLOROHEXYL)-1H-INDOL: To a mixture--of NaH (0.249
g, 10.0 mmol) in DMF (5.00 mL) was added a solution of
1-H-indole (0.585 g, 5.00 mmol) in DMF (2.00 mL) at 0 °C.
The reaction mixture was stirred for 30 minutes at 0 °C
and warmed up to room temperature. To the reaction
mixture 1-bromo-6-chlorohexane (0.998 g, 5.00 mmol) was
added dropwise via syringe and the reaction mixture was
stirred overnight. The reaction mixture was diluted
with EtOAc (30 mL), washed with water (3 X 10 mL), brine
(10 mL), dried over MgS04, concentrated in vacuo and
purified by chromatography using hexane:EtOAc (97.5:2.5)
to give the desired prod~~-t (0.900 g, 76.0 0) : 1H NMR
(400 MHz, CDC13) 8 7.76-7.54 (m, 1H) , 7.47-6.96 (m, 4H) ,
6.60-6.34 (m, 1H), 4.13 (t, 2H, J = 6.8 Hz), 3.50 (t,
2H, J = 5,6 Hz), 1.98-1.79 (m, 2H), 1.79-1.64 (m, 2H),
1.54-1.17 (m, 4H).
N- (3-~1- [6- (1H-INDOL-1-YL) HEXYL] -4-PIPERIDINYL~PHENYL) -
2-METHYLPROPANAMTDE: A mixture of 1-(6-Chlorohexyl)-1H-
indole (23.6 mg, 0.100 mmol), 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide (24.6 mg, 0.100 mmol),
K~C03 (27.6 mg, 0.200 mmol), NaI (22.5 mg, 0.150 mmol)
and DMF (1.00 mL) was hu ed at 100 °C for 12 h. .The
reaction mixture was cooled to room temperature and the
crude material was purified by preparative TLC using 5 0
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257
of NH3 (2.0 M in methanol) CHZC12 to g ive the
in
desired product as a yellow solid ~H NMR
(40 mg, 90
%):
(400 MHz, CDC13) 8 8.08-6.52 11H), 4.17 (t, 2H, J
(m, =
7.2 Hz), 3.26 (d, 2H, J = 11.6 Hz), 2.74-2.52 (m, 4H),
2.44-2.28 (m, 2H), 2.20-2.02 2H), 1.98-1.82 (m, 4H),
(m,
1:78-1.62 (m, 2H), 1.43-1.28 4H), 1.28 (d, 6H, J
(m, =
6.8 Hz); ESMS m/e: 446.5 (M + .
H)+
Procedure AI:
Seheme AU: Preparation of tert-Piperdines Usingd PS-S02C1 Resin
/ ~ O
~P -S02C1 R'OH ~ P~--SO3R HN ~ ~N~Rz
i
O
R_rv / ~ ,N~
R2
R~
The library was constructed in polypropylene Bobbins
"Reactor Blocks", 48 well plates. PS-TSC1 resin (100
mg, 1.00 eq, purchased from Argonaut Technologies) was
placed in each well of the "Reactor Blocks" 48 well
plates. To each well was added 2-10 eq of an alcohol in
dichloromethane:pyridine (1:1, 3.00 mL). The mixture
was stirred at room temperature for 5 h and the resin
was washed with dichloromethane (3 x 4.00 mL), DMF (5 x
4.00 mL) , DMF/Hz0 (3 :1, 5 x 4.00 mL) , THF (3 x 4. 00 mL) ,
dichloromethane (3 x 4.00 mL), acetonitrile (2 x 4.00
mL) and dried under reduced pressure. A solution of an
amine (0.0750 mmol, 0.500 eq) and N,N-diisopropylethyl
amine (19.0 mg, 0.150 mmol, 1.00 eq) in acetonitrile
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258
(3.00 mL) was added to the well containing the
derivatized resin and the mixture was reacted at 70 °C
for 16 h in the Bobbins rotating oven. After cooling,
AP-isocyanate. resin (120 mg, 0.150 mmol, 1.00 eq) and
THF (2.00 mL) was added to the each reaction vessel and
reacted at room temperature for additional 3 h. The
solution was filtered into the Robbins~ receiving plates
and concentrated in vacuo to give the desired tertiary
amines which were analyzed via LC-MS.
Procedure AJ:
Scheme AV: Preparation of tert-Piperidines Using Piperdines,
p PS-TBD resin
benzyl bromide
'N~R2 + or benzyl iodide ~HsCN
Ri RT, 16 h
ANN
R2
R~
The library was constructed in polypropylene Robbins~ 48
~ well plates Reactor Blocks. In the initial incubation
period, each well was charged with PS-TBD resin (from
Argonaut Technologies, 200 mg, 0.280 mmol, 2.50 eq) and
piperidine (0.120 mmol, 1.10 eq) in acetonitrile (0.500
mL) and agitated for 1 h. A solution of ,benzyl iodide
or bromide (0.110 mmol, 1.00 eq) in acetonitrile (0.500
mL) was added to each well followed by additional
acetonitrile (1.00 mL) to make a total volume of 2 mL
and the mixture was rotated in a Bobbins rotating oven
at room temperature for 16 h. Then AP-Isocyanate resin
(Argonaut Technologies, 250 mg (0.430 mmol, 4.00 eq) was
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259
added to each well and reacted further at room
temperature for another 12 h. The mixture was filtered
and the filtrate was concentrated in vacuo to obtain the
desired product that.was characterized via LC-MS.
Scheme AX
O ZnCi2, HOAc
R2 R3
n N~R4 + ~ i ~ 75 °C, 10 h
NH2 N,
i
Exat~zple 117
N-(3-~1-[3-(4-BROMOPHENYL)-3-OXOPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Procedure K
(KI) and Scheme E (K~C03) using 1-(4-bromophenyl)-3-
chloro-1-propanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 457.1 (M +
H)+.
Example 118
N-(3-~1-[3-(4-CHLOROPHENYL)-3-OXOPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Procedure K
(KI) and Scheme E (KzC03) using 3-chloro-1-(4-
chlorophenyl)-1-propanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 413.1 (M +
H)+. .
Example 119
N-(3-~1-[3-(4-METHOXYPHENYL)-3-OXOPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Procedure K
(KI) and Scheme E (KaC03) using 3-chloro-1-(4-
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methoxyphenyl)-1-propanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 409.2 (M +
H)+.
Example 120
N-(3-~L-[3-(2,3-DIHYDRO-1H-INDEN-5-YL)-3-OXOPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Procedure K
(KT) and Scheme E (K2C03) using 3-chloro-1-(2,3-dihydro-
1H-inden-5-yl)-1-propanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 419.2 (M +
H)+.
Example 121
2-METHYL-N-~3-[1-(3-OXO-3-PHENYLPROPYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Procedure K (KI) and
Scheme E (KzC03) using 3-chloro-1-phenyl-1-propanone and
2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS
m/e: 379.2 (M + H)+.
Example 122
2-METHYL-N-(3-{1-(3-(4-METHYLPHENYL)-3-OXOPROPYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Procedure K (KI) and
Scheme E (KzC03) using 3-chloro-1-(4-methylphenyl)-1-
propanone and 2 -methyl -N- [ 3 - ( 4 -
piperidinyl)phenyl]propanamide: ESMS m/e: 393.2 (M +
H)+.
Example 123 .
N-(3-~1-[3-(4-FLUOROPHENYL)-3-OXOPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Procedure K
(KI) and Scheme E (K2C03) using 3-chloro-1-(4-
fluorophenyl)-1-propanone and 2-methyl-N-[3-(4-
mL) was added to ea
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261
piperidinyl)phenyl]propanamide: ESMS m/e: 397.2 (M +
H)+.
Example 124
N-(3-~1-[3-(4-CHLOROPHENYL)-3-HYDROXYPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN using N- (3-~1- [3- (4-
chlorophenyl)-3-oxopropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide: ESMS m/e: 415.1 (M + H)+.
Example 125
N-(3-~1- [3- (4-CHLOROPHENYL) -3- (3,4-
DIFLUOROPHENOXY)PROPYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN
using N-(3-~1-[3-(4-chlorophenyl)-3-hydroacypropyl]-4-
piperidinyl~phenyl)-2-methylpropanamide and 3,4-
difluorophenol: ESMS m/e: 526.8 (M + H)+.
Example 126
N- (3- f 1- [3- (4-CHLOROPHENYL) -3- (2-METHYLPHENOXY) PROPYL] -
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-fl-[3-(4-
chlorophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and o-cresol: ESMS m/e: 505.4 (M +
H)*.
Example 127
N-(3-~1-[3-(4-FLUOROPHENYL)-3-HYDROXYPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN using N- (3- f 1- [3- (4-
fluorophenyl)-3-oxopropyl]-4-piperidinyl~phenyl)-2
methylpropanamide: ESMS m/e: 399.2 (M + H)+.
Example 128
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N-(3-~1-[3-HYDROXY-3-(4- METHOXYPHENYL)PROPYL]-4-
PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN using N- (3-{1- [3- (4-
methoxyphenyl)-3-oxopropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide: ESMS m/e: 411.2 (M + H)+~.
Example 129
N-(3-~1-[3-(4-BROMOPHENYL)-3-HYDROXYPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN using N- (3-~1- [3- (4-
bromophenyl)-3-oxopropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide: ESMS m/e: 459.1 (M + H)~.
Example 130
N-(3-fl-[3-(4-CHLOROPHENYL)-3-(4-METHOXYPHENOXY)PROPYL]-
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N- (3- ~l- [3- (4-
chlorophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-methoxyphenol: ESMS m/e: 520.8
(M + H)+.
Example 131
N-(3-{1-[3-(4-CHLOROPHENOXY)-3-(4-FLUOROPHENYL)PROPYL]-
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-~1-[3-(4-
fluorophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-chlorophenol: ESMS m/e: 509.1
(M + H)+.
Example 132
N-(3-~1-[3-(4-FLUOROPHENYL)-3-(2,3,4,5,6-
PENTAFLUOROPHENOXY)PROPYL]-4-PIPERIDINYL}PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN
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263
using N- (3- f 1- [3- (4- fluorophenyl) -3-
hydroxypropyl]-4-piperidinyl~phenyl)-2-methylpropanamide
and 2,3,4,5,6-pentafluorophenol: ESMS m/e: 564.7 (M +
H)+. .
Example 133
N-(3-~1- [3- (4-BROMOPHENYL) -3- (2-METHYLPHENOXY) PROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N- (3- f 1- [3- (4-
bromophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 2-methylphenol: ESMS m/e: 548.8
(M + H)+.
Example 134
N-(3-~1-[3-(3,4-DIFLUOROPHENOXY)-3-(4-
FLUOROPHENYL)PROPYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN
using N- (3-(1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide and 3,4-
difluorophenol: ESMS m/e: 511.1 (M + H)~.
Example 135
N-(3-~1-[3-(4-BROMOPHENOXY)-3-(4-FLUOROPHENYL)PROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N- (3-{1- [3- (4-
fluorophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-bromophenol: ESMS m/e: 553.0 (M
+ H)+.
Example 136
N-(3-~1-[3-(3,4-DICHLOROPHENOXY)-3-(4-
FLUOROPHENYL)PROPYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN
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using N- (3-{1- [3- (4- fluorophenyl) -3-
hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide
and 3,4-dichlorophenol: ESMS m/e: 542.7 (M + H)+.
Example 137
N- [3- (1- f 3- (4-FLUOROPHENYL) -3- [4-
(TRIFLUOROMETHYL)PHENOXY]PROPYL}-4-PIPERIDINYL)PHENYL]-
2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme
AN using N- (3-{1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide and 4
(trifluoromethyl)phenol: ESMS m/e: 543.1 (M + H)+.
Example 138
N-(3-{1- [3- (3-BROMOPHENOXY) -3- (4-FLUOROPHENYL) PROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-{1- [3- (4-
fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-.
methylpropanamide and 3-bromophenol: ESMS m/e: 552.7 (M
+ H) +.
Example 139
N-(3-{1-[3-(4-FLUOROPHENOXY)-3-(4-FLUOROPHENYL)PROPYL]-
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-{1-[3-(4-
fluorophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-fluorophenol: ESMS m/e: 493.2
(M + H)+.
Example 140
N-(3-{1-[3-(3-FLUOROPHENOXY)-3-(4-FLUOROPHENYL)PROPYL]-
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-{1-[3-(4-
fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-
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methylpropanamide and 3- fluorophenol: ESMS m/e:
492.9 (M + H)+.
Example 141
N-(3-~1-[3-(2,6-DICHLOROPHENOXY)-3-(4-
FLUOROPHENYL)PROPYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN
using N- (3-{1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide and 2,6-
dichlorophenol: ESMS m/e: 543.0 (M + H)+.
Example 142
N-(3-~1-[3-(2,5-DIFLUOROPHENOXY)-3-(4-
FLUOROPHENYL)PROPYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN
using N- (3-{1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide and 2,5-
difluorophenol: ESMS m/e: 511.5 (M + H)+.
Example 143
N-(3-~1- [3- (3-CHLOROPHENOXY) -3- (4-FLUOROPHENYL) PROPYL] -
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-{1-[3-(4-
fluorophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 3-chlorophenol: ESMS m/e: 509.1
(M + H)+.
Example 144 .
N-(3-~1-[3-(4-BROMOPHENYL)-3-(3-METHYLPHENOXY)PROPYL]-4-
PIPERIDINYLj~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-{1-[3-(4-
bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-
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methylpropanamide and 3- methylphenol: ESMS m/e:
549.1 (M + H)~.
Example 145
N-(3-~1- [3- ( [1, 1' -BIPHENYL] -4-YLOXY) -3- (4-
BROMOPHENYL)PROPYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN
using N- (3- f 1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide and 4-
phenylphenol: ESMS m/e: 611.2 (M + H)+.
Example 146
N-(3-~1-[3-(2,4-DIFLUOROPHENOXY)-3-(4-
FLUOROPHENYL)PROPYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN
using N- (3-{1- [3- (4-fluorophenyl) -3-hydroxypropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide and 2,4-
difluorophenol: ESMS m/e: 511.1 (M + H)+.
Example 147
N-(3-~1-[3-(4-BROMOPHENYL)-3-(3-METHOXYPHENOXY)PROPYL]-
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N- (3-{1- [3- (4-
bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 3-methoxyphenol: ESMS m/e: 564.6
(M + H)+.
Example 148
METHYL 4- (1- (4-BROMOPHENYL) -3-~4- [3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~PROPOXY)BENZOATE:
Prepared by Procedure A and Scheme AN using N- (3-{1- [3-
(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-
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2-methylpropanamide and methyl 4-hydroxybenzoate:
ESMS m/e: 593.0 (M + H)+.
Example 149
N-(3-~1-[3-(4-BROMOPHENYL)-3-(4-PHENOXYPHENOXY)PROPYL]-
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N- (3-{1- [3- (4-
bromophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-phenoxyphenol: ESMS m/e: 626.6
(M + H) +.
Example 150
N-(3-~7.- [3- (4-BROMOPHENYL) -3- (2-CHLORO-4-
METHYLPHENOXY)PROPYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN
using N- (3- f 1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide and 2-chloro-4-
methylphenol: ESMS m/e: 583.0 (M + H)+.
Example 151
N-(3-~1-[3-(4-BROMOPHENYL)-3-PHENOXYPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N- (3-{1- [3- (4-
bromophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and phenol: ESMS m/e: 535.0 (M + H)+.
Example 152
N- [3- (1-~3- (4-BROMOPHENYL) -3- [4-
(TRIFLUOROMETHYL)PHENOXY]PROPYL~-4-PIPERIDINYL)PHENYL]-
2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme
AN using N- (3-~1- [3- (4-bromophenyl) -3-hydroxypropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide and 4-
(trifluoromethyl)phenol: ESMS m/e: 603.1 (M + H)+.
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Example 153
N-(3-~l- [3- (2-ACETYLPHENOXY) -3- (4-BROMOPHENYL) PROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A .and Scheme AN using N-(3-~1-[3-(4-
bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 2-acetylphenol: ESMS m/e: 576.6
(M + H)+.
Example 154
N- (3-~1- [3- (3-ACETYLPHENOXY) -3- (4-BROMOPHENYL) PROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N- (3- f 1- [3- (4-
bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 3-acetylphenol: ESMS m/e: 576.9
(M + H)+.
Example 155
N-(3-~1-[3-(3-ACETYLPHENOXY)-3-(2,3-DIHYDRO-1H-INDEN-5-
YL)PROPYL]-4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE:
Prepared by Procedure A and Scheme AN using N- (3- f 1- [3-
(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-
piperidinyl~prlenyl)-2-methylpropanamide and 3-
acetylphenol: ESMS m/e: 539.2 (M + H)+.
Example 156
N-(3-fl-[3-(2,3-DIHYDRO-1H-INDEN-5-YL)-3-PHENOXYPROPYL]-
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-~1-[3-(2,3-dihydro-
1H-inden-5-yl)-3-hydroxypropyl]-4:piperidinyl}phenyl)-2-
methylpropanamide and phenol: ESMS m/e: 497.2 (M + H)+.
Example 157
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N-(3-~1- [3- (2- ACETYLPHENOXY) -3- (2, 3-
DIHYDRO-1H-INDEN-5-YL)PROPYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE:
Prepared by Procedure . A and Scheme AN using N- (3- f 1- [3-
(2,3-dihydro-1H-inden-5-yI)-3-hydroxypropyl]-4-
piperidinyl~phenyl)-2-methylpropanamide 2-acetylphenol:
ESMS m/e: 539.1 (M + H)+. .
Example 158
N-(3- f 1- [3- (4-BROMOPHENOXY) -3- (4-BROMOPHENYL) PROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N- (3-~1- [3- (4-
bromophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-bromophenol: ESMS m/e: 612.7 (M
+ H)+.
Example 159
N-(3-{1- [3- (4-BROMOPHENYL) -3- (4-CHLOROPHENOXY) PROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N- (3-~1- [3- (4-
bromophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-chlorophenol: ESMS m/e: 568.7
(M + H)+.
Example 160
N-(3-~1-[3-(4-BROMOPHENYL)-3-(4-FLUOROPHENOXY)PROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-.(3- f 1- [3- (4-
bromophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-fluorophenol: ESMS m/e: 552.8
(M + H)+.
Example 161
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N-(3-~1- L3- (2, 3-DIHYDRO- 1H-INDEN-5-YL) -3- (4-
METHOXYPHENOXY)PROPYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN
using N-(3-{1-[3-{2,3-dihydro-1H-inden-5-yl)-3-
hydroxypropyl]-4-piperidinyl~phenyl)-2-methylpropanamide
and 4-methoxyphenol: ESMS m/e: 527.3 {M + H)+.
Example 162
N-(3-~1- [3- (2,3-DIHYDRO-1FI-INDEN-5-YL) -3- (4-
FLUOROPHENOXY)PROPYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN
using N-(3-{1-[3-{2,3-dihydro-1H-inden-5-yl)-3-
hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide
and 4-fluorophenol: ESMS m/e: 515.2 (M + H)+.
Example 163
N-(3-~1-[3-(2,3-DIHYDRO-1H-INDEN-5-YL)-3-HYDROXYPROPYL]-
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE
Prepared by Procedure L and Scheme AN using N- (3- f 1- [3-
(2,3-dihydro-1H-inden-5-yl)-3-oxopropyl]-4-
piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 421.2
(M + H)+.
Example 164
N- [3- (1-~3- (2, 3-DIHYDRO-1H-INDEN-5-YL) -3- (4-
(TRIFLUOROMETHYL)PHENOXY]PROPYL~-4-PIPERIDINYL)PHENYL]-
2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme
AN using N- (3- f 1- [3- (2, 3-dihydro-1H-inden-5-yl) -3-
hydroxypropyl]-4-piperidinyl~phenyl)-2-methylpropanamide
and 4-trifluoromethylphenol: ESMS m/e: 565.0 (M + H)+.
Example 165
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N-(3-~1- [3- (4- BROMOPHENOXY) -3- (2,3-
DIHYDRO-1H-INDEN-5-YL)PROPYL]-4-PIPERIDINYL~PHENYL)-2-
METHYLPROPANAMIDE:
Prepared by Procedure A and Scheme AN using N- (3-{1- [3-
(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-
piperidinyl~phenyl)-2-methylpropanamide and 4-
bromophenol:
ESMS m/e: 577.4 (M + H)+.
Example 166
N- ( 3 - { 1- C 3 - ( 3 -ACETYLPHENOXY) - 3 - ( 4 - CHLOROPHENYL ) PROPYL ] -
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-{1-[3-(4-
chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 3-acetylphenol: SMS m/e: 533.1 (M
+ H)+.
Example 167
' N-(3-~1- [3- (4-METHOXYPHENOXY) -3- (4-
METHOXYPHENYL)PROPYL]-4-PIPERTDINYL~PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN
using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-
piperidinyl}phenyl)-2-methylpropanamide and 4-
methoxyphenol: ESMS m/e: 517.4 (M + H)+.
Example 168
N-(3-{1-[3-(4-CHLOROPHENOXY)-3-(2,3-DIHYDRO-1H-INDEN-5-
YL)PROPYL]-4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE:
Prepared by Procedure A and Scheme AN using N- (3-{1- [3-
(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-
piperidinyl}phenyl)-2-methylpropanamide and 4-
chlorophenol: ESMS m/e: 531.1 (M + H)~.
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Example 169
N-(3-~1- [3- (2-ACETYLPHENOXY) -3- (4-CHLOROPHENYL) PROPYL] -
.4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-~l-[3-(4-
chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 2-acetylphenol: ESMS m/e: 533.4
(M + H)+.
Example 170
N-(3-{1- [3- (4-BROMOPHENYL) -3- (4-METHOXYPHENOXY) PROPYL] -
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N- (3-{1- [3- (4-
bromophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-methoxyphenol: ESMS m/e: 565.0
(M + H) + . ,
Example 171
N-(3-~l- [3- (4-BROMOPHENOXY) -3- (4-CHLOROPHENYL) PROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-fl-[3-(4-
chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 4-bromophenol: ESMS m/e: 568.8 (M
+ H)+.
Example 172
N-(3-~l- [3- (4-CHLOROPHENOXY) -3- (4-CHLOROPHENYL) PROPYL] -
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-.(3-{1- [3- (4-
chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 4-chlorophenol: ESMS m/e: 525.0
(M + H) +.
Example 173
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N-(3-~l-[3-(4- METHOXYPHENYL)-3-
PHENOXYPROPYL]-4-PIPERTDINYL~PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure A and Scheme AN
using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-
piperidinyl}phenyl)-2-methylpropanamide and phenol:
ESMS m/e: 487.4 (M + H)+.
Example 174
N-(3-~l-[3-(4-FLUOROPHENYL)-3-PHENOXYPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N- (3-~1- [3- (4-
fluorophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and phenol: ESMS m/e: 475.6 (M + H)+.
Example 175
N-(3-fl-[3-(2-ACETYLPHENOXY)-3-(4-FLUOROPHENYL)PROPYL]-
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-~1-[3-(4-
fluorophenyl)-3-hydroxypropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 2-acetylphenol: ESMS m/e: 517.1
(M + H)+.
Example 176
N-(3-~l-[3-(3-ACETYLPHENOXY)-3-(4-FLUOROPHENYL)PROPYL]-
4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N- (3-{1- [3- (4-
fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 3-acetylphenol: ESMS m/e: 516.9
(M + H)+.
Example 177
N- ( 3 - ~ 1- [ 3 - ( 4 - FLUOROPHENYL) - 3 - ( 4 -METHOXYPHENOXY) PROPYL] -
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
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Procedure A and Scheme AN using N-(3-fl-[3-(4-
fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 4-methoxyphenol: ESMS m/e: 505.2
(M + H)+.
Example 178
N-(3-~1-[3-(4-CHLOROPHENOXY)-3-(4-METHOXYPHENYL)PROPYL]-
4-PIPERIDZNYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-~l-[3-hydroxy-3-(4-
methoxyphenyl)propyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-cholorophenol: ESMS m/e: 521.5
(M + H)+.
Example 179
N-(3-~1-[3-(3-ACETYLPHENOXY)-3-(4-METHOXYPHENYL)PROPYL]-
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-f1-[3-hydroxy-3-(4-..
methoxyphenyl)propyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 3-acetylphenol: ESMS m/e: 529.0
(M + H)+.
Example 180
N-(3-{1-[3-(4-CHLOROPHENYL)-3-PHENOXYPROPYL]-4-
PIPERTDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-~1-[3-(4-
chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and phenol. ESMS m/e: 490.9 (M + H)+.
Example 181
N-(3-~l- [3- (4-BROMOPHENOXY) -3- (4-METHOXYPHENYL) PROPYL] -
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-f1-[3-hydroxy-3-(4-
methoxyphenyl)propyl]-4-piperidinyl~pheny1)-2-
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methylpropanamide and 4- bromophenol: ESMS m/e:
564 . 9 (M + H) + .
Example 182
N- [3- (1-{3- (4-METHOXYPHENYL) -3- [4-
(TRIFLUOROMETHYL)PHENOXY]PROPYL~-4-PIPERIDINYL)PHENYL]-
2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme
AN using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-
4-piperidinyl~phenyl)-2-methylpropanamide and 4-
trifluoromethyphenol: ESMS m/e: 555.1 (M + H)+.
Example 183
N-(3-~1- [3- (4-CHLOROPHENYL) -3- (4-FLUOROPHENOXY) PROPYL] -
4-PTPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N-(3-{1-[3-(4-
chlorophenyl)-3-hydroxypropyl]-4-piperidinyl)phenyl)-2-
methylpropanamide and 4-fluorophenol: ESMS m/e: 509.1
(M + H) ~ .
Example 184
N-(3-{1-[3-(4-FLUOROPHENOXY)-3-(4-METHOXYPHENYL)PROPYL]-
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using N- (3- (1- [3-hydroxy-3- (4-
methoxyphenyl)propyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 4-fluorophenol: ESMS m/e: 505.5
(M + H)+.
Example 185
N-(3-{1-[3-(2-ACETYLPHENOXY)-3-(4-METHOXYPHENYL)PROPYL]-
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared . by
Procedure A and Scheme AN using N- (3-{1- [3-hydroxy-3- (4-
methoxyphenyl)propyl]-4-piperidinyl~phenyl)-2-
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methylpropanamide and 2- acetylphenol: ESMS m/e:
529 : 2 (M + H) +.
Example 186
N- [3- (1-~3- (4-CHLOROPHENYL) -3- [4-
(TRIFLUOROMETHYL)PHENOXY]PROPYL~-4-PIPERIDINYL)PHENYL]-
2-METHYLPROPANAMIDE: Prepared by Procedure A and Scheme
AN using N- (3-{1- [3- (4-chlorophenyl) -3-hydroxypropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide and 4-
trifluoromethylphenol: SMS m/e: 559.1 (M + H)~.
Example 187
N-(3-~1-[(3S)-3-(3-ACETYLPHENOXY)-3-PHENYLPROPYL]-4-
PIPERIDINYL~-4-METHYLPHENYL)-2-METHYLPROPANAMIDE:
Prepared by Procedure G and Scheme AI using 1-(3-{[(1S)-
3-chloro-1-phenylpropyl]oxy~phenyl)ethanone and 2-
methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 513.0 (M + H)+.
Z-(ISOPENTYLOXY)-1-NAPHTHALDEHYDE: 2-Hydroxy-1-
naphthaldehyde (1.72 g, 10.0 mmol) and THF (50 .ml) were
combined in a flask. NaH (312 mg, 13 mmol) was added,
followed by 1-bromo-3-methylbutane (1.20 mL, 10.0 mmol).
The solution was stirred at room temperature overnight,
the solvent was removed in vacuo, and the residue was
purified by chromatography (5-10 o ethyl acetate /
hexane): 1H NMR (400 MHz, CDC13) b 10.9 (s, 1H), 9.28
(dd, 1H, J = 0.7 Hz, 8.6 Hz) , 8.02 (d, 1H, J = 9.1 Hz) ,
7.75 (d, 1H, J = 8.1 Hz), 7.63-7.59 (m, 1H), 7.43-7.39
(m, 1H), 7.27 (d, 1H, J = 9.2 Hz), 4.25 (t, 2H, J = 6.5
Hz), 1.98-1.84 (m, 1H), 1.80-1.75 (m, 2H), 0.99 (d, 6H,
J = 6.6 Hz); ESMS m/e: 242.8 (M + H)+.
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Example 188
N- [3- (1-~ (2- (ISOPENTYLOXY) -1-NAPHTHYL] METHYL-4-
.PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 2-(isopentyloxy)-1-
naphthaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 473.3 (M + H)+.
2-PROPOXY-1-NAPHTHALDEHYDE: Prepared according to the
Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 2
hydroxy-1-naphthaldehyde and 1-bromopropane.
Example 189
2-METHYL-N-(3-~l-[(2-PROPOXY-1-NAPHTHYL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 2-propoxy-1-naphthaldehyde and 2-
methyl-N-[3-(4-piperidinyl)phenyl)propanamide: ESMS m/e:
445.2 (M + H)+.
4-~[(1-FORMYL-2-NAPHTHYL)OXY]METHYL~BENZONITRILE:
Prepared according to the Procedure for 2
(isopentyloxy)-1-naphthaldehyde using 2-hydroxy-1-
naphthaldehyde and 4-(bromomethyl)benzonitrile.
Example 190
N-~3- [1- (~2- [ (4-CYANOBENZYL) OXY] -1-NAPHTHYL~METHYL) -4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 4-{[(1-formyl-2-
naphthyl)oxy]methyl~benzonitrile and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 518.2 (M + H)+.
[(1-FORMYL-2-NAPHTHYL)OXY]ACETONITRILE: Prepared
according to the Procedure for 2-(isopentyloxy)-1-
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naphthaldehyde using 2- hydroxy-1-naphthaldehyde
and bromoacetonitrile.
Example 191 .
N- [3- (1-~ [2- (CYANOMETHOXY) -1-NAPHTHYL] METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using [(1-formyl-2-
naphthyl) oxy] acetonitrile and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 442.2 (M + H)+.
2-[(3-CHLOROBENZYL)OXY]-1-NAPHTHALDEHYDE: Prepared
according to the Procedure for 2-(isopentyloxy)-1~-
naphthaldehyde using 2-hydroxy-1-naphthaldehyde and 1-
(bromomethyl)-3-chlorobenzene.
Example 192
N-~3- [1- ( f 2- [ (3-CHLOROBENZYL) OXY] -1-NAPHTHYL~METHYL) -4-
PIPERIDINYL]PHENYL -2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 2- [ (3-chlorobenzyl) oxy] -
1-naphthaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 527.2 (M + H)+.
Example 193
N-(3-~1-[4-(4-CHLOROPHENOXY)BENZYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 4-(4-
chlorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDC13) S
7.50 (s, 1H), 7.34-7.19 (m, 7H),.6.98-6.87 (m, 5H), 3.50
(s, 2H) , 2.98 (d, 2H, J = 11 .8 Hz) , 2.58-2 .44 (m, 2H) ,
2.10-1.98 (m, 2H), 1.83-1.76 (m, 4H), 1.24 (d, 6H, J =
6.8 Hz); ESMS m/e: 463.2 (M + H)+.
Example 194
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N-(3- f 1- [4- (3, 4- DIFLUOROPHENOXY) BENZYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 4-(3,4-
difluorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 465.2 (M +
H)+.
4-(ISOPENTYLOXY)-1-NAPHTHALDEHYDE: Prepared according
to the Procedure for 2-(isopentyloxy)-1-naphthaldehyde
using 4-hydroxy-1-naphthaldehyde and 1-bromo-3-
methylbutane.
Example 195
N- [3- (1-~ [4- (ISOPENTYLOXY) -1-NAPHTHYL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 4-(isopentyloxy)-1-
naphthaldehyde and 2-methyl-N-[3-(4-..
piperidinyl)phenyl]propanamide: ESMS m/e: 473.3 (M + H)+.
Example 196
N-(3-{1-[4-(4-METHOXYPHENOXY)BENZYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 4-(4-
methoxyphenoxy)benzaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e; 459.2 (M + H)+.
4-PROPOXY-1-NAPHTHALDEHYDE: Prepared according to the
Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 4-
hydroxy-1-naphthaldehyde and 1-bromopropane.
Example 197
2-METHYL-N-(3-~1-[(4-PROPOXY-1-NAPHTHYL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
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and Scheme R using 4- propoxy-1-naphthaldehyde
and 2-methyl-N-[3-{4-piperidinyl)phenyl]propanamide:
ESMS m/e: 445.2 (M + H)+.
Example 198
N-(3-~1-[4-(3,4-DICHLOROPHENOXY)BENZYL?-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 4-(3,4-
dichlorophenoxy)benzaldehyde and 2-methyl-N-[3-{4-
piperidinyl)phenyl]propanamide: ESMS m/e:497.1 (M + H)+.
Example 199
N-(3-{1-[4-(DIPHENYLAMINO)BENZYL]-4-PIPERIDINYL~PHENYL)-
2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme
R using 4- (diphenylamino) benzaldehyde and 2-methyl-N- [3-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 504.2 {M +
H)+.
Example 200
N-~3-[1-{~2,5-DIMETHYL-1-[3-(TRIFLUOROMETHYL)PHENYL]-1H-
PYRROL-3-YL~METHYL)-4-PIPERIDINYL]PHENYL-2-
METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R
using 2,5-dimethyl-1-[3-(trifluoromethyl)phenyl]-1H-
pyrrole-3-carbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 498.2 (M + H)+.
Example 201
2-METHYL-N-(3-f1-[1-(2-PHENYL-1,3-THIAZOL-4-YL)ETHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 1-(2-phenyl-1,3-thiazol-4-yl)ethanone
and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e:~434.2 (M + H)+.
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Example 202
N-(3-~1-[(5-CHLORO-3-METHYL-1-PHENYL-1H-PYRAZOL-4-
YL)METHYL]-4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE:
Prepared by Procedure F and Scheme R using 5-chloro-3-
methyl-1-phenyl-1H-pyrazole-4-carbaldehyde and 2-methyl-
N-[3-(4-piperidinyl)phenyl~propanamide: ESMS m/e: 451.2
(M + H)+.
Example 203
2-METHYL-N-(3-~1-[(2-PHENYL-1H-IMIDAZOL-4-YL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 2-phenyl-1H-imidazole-4-carbaldehyde
and 2-methyl-N-(3-(4-piperidinyl)phenyl]propanamide:
ESMS ,m/e: 403.2 (M + H)+.
Example 204
N-[3-(1-~[4-BROMO-1-(4-CHLOROBENZYL)-1H-PYRAZOL-5-
YL]METHYL-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure F and Scheme R using 4-bromo-1-(4-
chlorobenzyl)-1H-pyrazole-5-carbaldehyde and 2-methyl-N-
[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 529.1
(M + H) + .
Example 205
2-METHYL-N-~3-[1-(3-PHENOXYBENZYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure F
and Scheme R using 3-phenoxybenzaldehyde and 2-methyl-N-
[3- (4-piperidinyl)phenyl~propanamide: ESMS m./e: 429.2 (M
+ H)+.
Example 206
N- ( 3 - ~ 1- [ 3 - ( 3 , 4 -DICHLOROPHENOXY) BENZYL] - 4 -
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
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Procedure F and Scheme R using 3-(3,4-
dichlorophenoxy)benzaldehyde and 2-methyl-N-j3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 497.15 (M +
H)+.
Example 207
N-(3-~1-[3-(3,5-dichlorophenoxy)benzyl]-4-
piperidinyl~phenyl)-2-methylpropanamide: Prepared by
Procedure F and Scheme R using 3-(3,5-
dichlorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 497.2 (M + H)+.
Example 208
2-METHYL-N-(3-~1-[3-(4-METHYLPHENOXY)BENZYL]-4- .
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 3-(4-methylphenoxy)benzaldehyde and
2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS
m/e: 443.2 (M + H)+.
Example 209
2-METHYL-N-[3-(1-~3-[3-(TRIFLUOROMETHYL)PHENOXY]BENZYL~-
4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure
F and Scheme R using' 3-[3-
(trifluoromethyl)phenoxyJbenzaldehyde and 2-methyl-N-[3-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 497.2 (M +
H) t .
Example 210
N-(3-~1-[3-(4-CHLOROPHENOXY)BENZYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 3-(4-
chlorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 463.2 (M + H)+.
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Example 211
N-(3-~1-[3-(DIMETHYLAMINO)BENZYL]-4-PIPERIDINYL~PHENYL)-
2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme
R using 3-(dimethylamino)benzaldehyde and 2-methyl-N-[3-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 380.2 (M +
H)+.
Example 212
N-(3-~1-[3-(4-METHOXYPHENOXY)BENZYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 3-(4-
methoxyphenoxy)benzaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 459.2 (M +
H)+.
Example 213
N-(3-~1-[3-(4-TERT-BUTYLPHENOXY)BENZYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 3-(4-tert-
butylphenoxy)benzaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 485.3 (M +
H)+.
Example 214
2-METHYL-N-(3-~1-[3-NITRO-4-(1-PIPERIDINYL)BENZYL]-4-
PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 3-nitro-4-(1-piperidinyl).benzaldehyde
and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 465.2 (M + H)+.
Example 215
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N-(3-~1-[(3,4- DIMETHYLTHIENO[2,3-
B]THIEN-2-YL)METHYL]-4-PIPERIDTNYL~PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R
using 3,4-dimethylthieno[2,3-b]thiophene-2-carbaldehyde
and 2-methyl-N- [3- (4-piperidinyl)phenyl]propanamide:
ESMS m/e: 427.1 (M + H)+.
Example 216
2-METHYL-N-~3-[1-(~3-[4-(TRIFLUOROMETHYL)PHENYL]-1H-
PYRAZOL-4-YL~METHYL)-4-PIPERIDINYL]PHENYL~PROPANAMIDE:
Prepared by Procedure F and Scheme R using 3-[4-
(tritluoromethyl)phenyl]-1H-pyrazole-4-carbaldehyde and
2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS
m/e: 471.1 (M + H)+.
Example 217
2-METHYL-N-(3-~1-[4-(1FI-1,2,4-TRIAZOL-1-YL)BENZYL]-4-
PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 4-(1H-1,2,4-triazol-1-yl)benzaldehyde
and 2-methyl-N- [3- (4-piperid.inyl)phenyl]propanamide:
ESMS m/e: 404.1 (M + H)+.
Example 218
2-METHYL-N-(3-~1-[(5-METHYL-1-PHENYL-1H-PYRAZOL-4-
YL)METHYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by
Procedure F and Scheme R using 5-methyl-1-phenyl-1H-
pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 417.1 (M +
H)+. .
Example 219
2-METHYL-N-(3-~1-[4-(4-MORPHOLINYL)-3-NITROBENZYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 4-(4-morpholinyl)-3-nitrobenzaldehyde
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and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 467.1 (M + H)+.
Example 220
N-~3-[1-(~5-[2-CHLORO-4-(TRIFLUOROMETHYL)PHENYL]-2-
FURYL~METHYL)-4-PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE:
Prepared by Procedure F and Scheme R using 5- [2-chloro-
4-(trifluoromethyl)phenyl]-2-furaldehyde and 2-methyl-N-
[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 505.0 (M
+ H)+.
Example 221
ETHYL 4-(~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~METHYL)-2,5-DIMETHYL-1-PHENYL-1H-PYRROLE-3-
CARBOXYLATE: Prepared by Procedure F and Scheme R using
ethyl 4-formyl-2,5-dimethyl-1-phenyl-1H-pyrrole-3-
carboxylate and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 502.2 (M + H)~.
Example 222
ETHYL 5- (4-CHLOROPHENYL) -2- (~4- [3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~METHYL)-3-
FUROATE: Prepared by Procedure F and Scheme R using
ethyl 5-(4-chlorophenyl)-2-formyl-3-furoate and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
509.0 (M + H)+.
Example 223 .
N-~3-[1-(2,3-DIHYDRO-1,4-BENZODIOXIN-6-YLMETHYL)-4-
PIPERIDINYL]PHENYL -2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 2,3-dihydro-1,4-
benzodioxine-6-carbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 395.1 (M + H)+.
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Example 224
2-METHYL-N-(3-~1-[(6-PHENOXY-3-PYRIDINYL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 6-phenoxynicotinaldehyde and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
430.1 (M + H)+.
Example 225
2-METHYL-N- [3- (1-~ [5- (2-PYRIDINYL) -2-THIENYL] METHYL-4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure F
and Scheme R using 5-(2-pyridinyl)-2-
thiophenecarbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 420.1 (M + H)+.
Example 226 .
2-METHYL-N-~3-[1-(~5-[1-METHYL-3-(TRIFLUOROMETHYL)-1H-
PYRAZOL-5-YL]-2-THIEN'YL~METHYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure F
and Scheme R using 5-[1-methyl-3-(trifluoromethyl)-1H-
pyrazol-5-yl]-2-thiophenecarbaldehyde and 2-methyl-N-[3-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 491.0 (M +
H)+.
Example 227
2-METHYL-N-[3-(1-~[1-(PHENYLSULFONYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by
Procedure F and Scheme R using 1-(phenylsulfonyl)-1H-
indole-3-carbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 516.1 (M + H)+.
Example 228
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N-(3-fl-[(1,5-DIMETHYL-3- OXO-2-PHENYL-2,3-DIHYDRO-
1H-PYRAZOL-4-YL)METHYL]-4-PIPERTDINYL~PHENYL)-2-
METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R
using 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-
p.iperidinyl)phenyl]propanamide: ESMS m/e: 447.2 (M + H)+.
Example 229
N-(3-fl-[4-(4-TERT-BUTYL-1,3-THIAZOL-2-YL)BENZYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 4-(4-tent-butyl-1,3-
thiazol-2-yl) benzaldehyde and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide.
Example 230
N-~3-[1-(2,3-DTHYDRO-1-BENZOFURAN-5-YLMETHYL)-4-
PTPERIDINYL~PHENYL~-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 2,3-dihydro-1-benzofuran-
5-carbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 379.1 (M + H)+.
Example 231
2-METHYL-N-(3-~1-((4-METHYL-2-PHENYL-5-
PYRIMIDINYL)METHYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE:
Prepared by Procedure F and Scheme R using 4-methyl-2-
phenyl-5-pyrimidinecarbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 429.2 (M + H)'".
Example 232
N-~3-[1-(2,1,3-BENZOTHIADIAZOL-5-YLMETHYL)-4-
PIPERTDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 2,1,3-benzothiadiazole-5-
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carbaldehyde and 2-methyl- N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 395.1 (M + H)+.
Example 233 .
2-METHYL-N-(3-~1-((5-PHENYL-2-THIENYL)METHYL]-4-
PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 5-phenyl-2-thiophenecarbaldehyde and
2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS
m/e: 419.1 (M + H)+.
Example 234
N-~3-(1-(3,4-DIHYDRO-2H-1,5-BENZODIOXEPIN-7-YLMETHYL)-4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 3,4-dihydro-2H-1,5-
benzodioxepine-7-carbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 409.2 (M +
H)+.
Example 235
2-METHYL-N-(3-(1-~(3-(2-THIENYL)-1H-PYRAZOL-4-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by
Procedure F and Scheme R using 3-(2-thienyl)-1H-
pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 409.1 (M + H)+.
Example 236
N-~3- (1- ( (1, 1' -BITHIENYL] -4-YLMETHYL) -4-
PIPERIDINYL~PHENYL~-2-METHYLPROPANAMIDE: .Prepared by
Procedure F and Scheme R using 2,2'-Bithiophene-5-
carboxaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 425.0 (M + H)+.
Example 237
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N-(3-~1-((2,2-DIMETHYL- 3,4-DIHYDRO-2H-CHROMEN-6-
YL)METHYL]-4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE:
Prepared by Procedure F and Scheme R using 2,2-dimethyl-
6-chromanecarbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 421.2 (M + H)+.
Example 238
2-METHYL-N-~(3-[1-(~5-(1-METHYL-5-(TRIFLUOROMETHYL)-1H-
PYRAZOL-3-YL]-2-THIENYL~METHYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure F
and Scheme R using 5-[1-methyl-5-(trifluoromethyl)-1H-
pyrazol-3-yl]-2-thiophenecarbaldehyde and 2-methyl-N-[3-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 491.1 (M +
H)+
Example 239
2-METHYL-N-(3-f1-[(2-PHENYL-1,3-THIAZOL-4-YL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 2-phenyl-1,3-thiazole-4-carbaldehyde
and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 420.0 (M + H)+.
Example 240
2-METHYL-N-(3-~l-[(3-PHENOXY-2-THIENYL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 3-phenoxy-2-thiophenecarbaldehyde and
2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS
m/e: 435.0 (M + H)+.
Example 241
N- f 3- (1- (~2- [ (4-CHLOROPHENYL) SULFANYL] -3-
THIENYL~METHYL)-4-PIPERIDINYL]PHENYL-2-
METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R
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using 2- [ (4- chlorophenyl) sulfanyl] -3-
thiophenecarbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 485.0 (M + H)+.
Example 242
N-[3-(1-~[1-(4-CHLOROPHENYL)-1H-PYRROL-2-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 1-(4-chlorophenyl)-1H-
pyrrole-2-carbaldehyde and 2-methyl-N-[3-(4-
piperidinyl) phenyl] propanamide : ESMS m/e: 436 . 0 (M + H) ~'' .
Example 243
2-METHYL-N-{3-(1-(~5-[2-(TRIFLUOROMETHOXY)PHENYL]-2-
FURYL~METHYL)-4-PIPERIDINYL]PHENYL~PROPANAMIDE:
Prepared by Procedure F and Scheme R using 5-[2-
(trifluoromethoxy)phenyl]-2-furaldehyde and 2-methyl-N-
[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 487.1 (M
+ H)+.
Example 244
2 -METHYL-N- ( 3 - ~ 1- [ 2 - ( 4 -MORPHOLINYL ) BENZYL ] - 4 -
PIFERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 2-(4-morpholinyl)benzaldehyde and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS
m/e: 422 . 2 (M + H) +.
Example 245
N- [3- (1-{ L3- (4-METHOXYPHENYL) -1H-PYRAZOL-4-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 3-(4-methoxyphenyl)-1H-
pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 433.1 (M +
H)+.
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Example 246
2-METHYL-N-(3-~1-[4-(1H-PYRAZOL-1-YL)BENZYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 4-(1H-pyrazol-1-yl)benzaldehyde and
2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS
m/e: 402.8 (M + H)'~.
Example 247
2-METHYL-N-~3-[1-(4-QUINOLINYLMETHYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure F
and Scheme R using 4-quinolinecarbaldehyde and 2-methyl-
N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 388.1
(M + H)+.
Example 248
2-METHYL-N-(3-~1-[4-(4-MORPHOLINYL)BENZYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 4- (4-morpholinyl) benzaldehyde and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
422.5 (M + H)+.
Example 249
2-METHYL-N-(3-~1- [4- (2-THIENYL)BENZYL] -4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 4-(2-thienyl)benzaldehyde and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
419.1 (M + H)+.
Example 250
2-METHYL-N-(3-~l-[(2-METHYL-5-PHENYL-3-FURYL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 2-methyl-5-phenyl-3-furaldehyde and
2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS
m/e: 417.2 (M + H)+.
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Example 251
. N- ( 3 - ~ 1- [ 3 - ( CYCLOPENTYLOXY) - 4 -METHOXYBENZYL] -4 -
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 3-(cyclopentyloxy)-4-
methoxybenzaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 451.1 (M +
H)+.
Example 252
2-METHYL-N-~3-(1-(~5-[4-(TRIFLUOROMETHOXY)PHENYL]-2-
FURYL~METHYL)-4-PIPERIDINYL]PHENYL~PROPANAMIDE:
Prepared by Procedure F and Scheme R using 5-[4-
(trifluoromethoxy)phenyl]-2-furaldehyde and 2-methyl-N-
[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 487.1
(M + H)+.
Example 253
N-~3-[1-(1-BENZOTHIEN-2-YLMETHYL)-4-PIPERIDINYL]PHENYL~-
2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme
R using 1-benzothiophene-2-carbaldehyde and 2-methyl-N-
[3- (4-piperidinyl)phenyl]propanamide: ESMS m/e: 393.2 (M
+ H)+.
Example 254
2-METHYL-N-~3-[1-(~5-(3-(TRIFLUOROMETHOXY)PHENYL]-2-
FURYL~METHYL)-4-PIPERIDINYL]PHENYL~PROPANAMIDE:
Prepared by Procedure F and Scheme R~ using 5-[3-
(trifluoromethoxy)phenyl]-2-furaldehyde and 2-methyl-N-
[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 487.2 (M
+ H)+.
Example 255
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2-METHYL-N-~3-[1-(2- QUINOLINYLMETHYL)-4
PIPERIDINYL~PHENYL~PROPANAMIDE: Prepared by Procedure F
and Scheme R using 2-quinolinecarbaldehyde and 2-methyl
N- [3- (4-piperi.dinyl) phenyl] propanamide: ESMS m/e: 388 , 1
(M + H)+.
Example 256
N-(3-~1- [4- (1H-IMIDAZOL-1-YL) BENZYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using 4-(1H-imidazo.l-1-
yl)benzaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 403.2 (M + H)+.
Example 257
N-~3-[1-(9H-FLUOREN-2-YLMETHYL)-4-PIPERIDINYL]PHENYL-2-
METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R
using 9H-fluorene-2-carbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 425.1 (M + H)~.
Example 258
METHYL 3- [5- ( f 4- [3- (ISOBUTYRYLAMINO) PHENYL] -1-
PIPERIDINYL}METHYL)-2-FURYL]-2-THIOPHENECARBOXYLATE:
Prepared by Procedure F and Scheme R using methyl 3-(5-
formyl-2-furyl)-2-thiophenecarboxylate and 2-methyl-N-
[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 467.1 (M
+ H)+.
Example 259
2-METHYL-N-{3-[1-(4-PHENOXYBENZYL)-4- .
PIPERIDINYL]PHENYL~PROPANAMIDE: .Prepared by Procedure F
and Scheme R using 4-phenoxybenzaldehyde and 2-methyl-N-
[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.2
(M + H)~.
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Example 260
N-~3-[1-([1,1'-BIPHENYL]-4-YLMETHYL)-4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R using [1,1'-biphenyl]-4-
carbaldehyde and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M +
H)+. .
Example 261
N-(3-~l-[4-(DIBUTYLAMINO)BENZYL]-4-PIPERIDINYL~PHENYL)-
2-METHYLPROPANAMIDE: Prepared by Procedure F and Scheme
R using 4-(dibutylamino)benzaldehyde and 2-methyl-N-[3-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 464.6 (M +
H)+.
Example 262
2 -METHYL-N- [ 3 - ( 1- ~ 4 - [ ( 4 -METHYLPHENYL ) SULFANYL ] - 3 -
NITROBENZYL~-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared
by Procedure F and Scheme R using 4-[(4-
methylphenyl)sulfanyl]-3-nitrobenzaldehyde and 2-methyl-
N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/:e 504.2
(M + H)+.
Example 263
2-METHYL-N-(3-~1-[4-(1,2,3-THIADIAZOL-4-YL)BENZYL]-4-
PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R using 4-(1,2,3-thiadiazol-4-yl)benzaldehyde
and 2-methyl-N- [3- (4-piperidinyl)phenyl]propanamide:
ESMS m/e: 421.1 (M + H)+.
1-(3-~[(IS)-3-CHLORO-1-PHENYLPROPYL]OXY~PHENYL)ETHANONE:
(1R)-3-Chloro-1-phenyl-1-propanol (1.000 g, 5.86 mmol),
1-(3-hydroxyphenyl)ethanone (0.797 g, 5.86 mmol),
triphenylphosphine (1.54 g, 5.86 mmol) and
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diethylazodicarboxylate (1.53 g, 8.79 mmol) were
combined in a flask, which was immediately flushed with
argon. THF (20 mL) was added and the mixture was
stirred overnight under argon. THF was removed in
vacuo, the crude product was dissolved in 50 mL of
CHZC12/Ha0 (1:1) and the organic layer was separated and
dried over MgS04. After removing the solvent in vacuo,
the residue was purified by flash chromatography using
o ethyl acetate/hexane to yield the desired product
10 (900 mg, 76.0 0) : 1H NMR (400 MHz, CDC13) ~ 7.49-7.46 (m,
2H), 7.40-7.26 (m, 6H), 7.07-7.04 (m, 1H), 5.46-5.43
(dd, 1H, J = 4.4 Hz, 8.8 Hz), 3.84-3.78 (m, 1H), 3.64-
3 .59 (m, 1H) , 2.52 (s, 3H) , 2.51-2 .46 (m, 1H) , 2 .29-2:22
(m, 1H) .
4-(3,4-DIFLUOROPHENOXY)BENZALDEHYDE: 4-
Fluorobenzaldehyde (5.32 mL, 49.6 mmol), 3,4-
difluorophenol (7.10 g, 54.6 mmol) and K2C03 (8.31 g,
60.1 mmol) were combined in a flask, which was
immediately flushed with argon. DMF (50.0 mL) was added
and the mixture was heated at reflux under argon for 6
h. Upon cooling to room temperature, EtOAc (100 mL) and
H20 (100 mL) were added; the ethyl acetate layer was
separated and washed with HBO (2 X 100 mL). The combined
organic layers were washed with brine, dried over MgS04,
and the solvent was removed in vacuo. The desired
product was obtained (11.4 g, 98.0 %): 1H NMR (400 MHz,
CDC13) b 9.95 (s, 1H), 7.88 (dd, 2H, J = 0.8 Hz, 8.8 Hz),
7.24-7.17 (m, 1H), 7.07 (d, 2H, J = 8.8 Hz), 6.97-6.92
(m, 1H), 6.86-6.82 (m, 1H); ESMS m/e: 235.0 (M + H)+.
TERT-BUTYL 4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-
YL)-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE: To a flask
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were added bis(pinacolato)diboron
(422 mg, 1.66 mmol), KOAc (444 mg, 4.53 mmol), PdCl2dppf
(37.0 mg, 3.00 mol%), dppf (25.0 mg, 3.00 mol%) and the
flask was flushed with argon. A solution of tert-butyl
4-~[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-
pyridinecarboxylate (500 mg, 1.51 mmol) in 1,4-dioxane
(10.0 ml) was added and the mixture was stirred at 80 °C
overnight. The mixture was filtered through Celite and
the filtrate was evaporated in vacuo. The resulting
residue was dissolved in EtOAc and washed with H20,
followed by brine. The organic layer was dried over
MgS04, filtered and concentrated in vacuo. The crude
material was purified by flash chromatography (10%
EtOAC/hexane) to give tert-butyl 4-(4,4,5,5-tetramethyl
1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)
pyridinecarboxylate (355 mg, 76.0o): 1H NMR (400 MHz,
CDC13) 5 6.44 (br s, 1H), 3.93 (br s, 2H), 3.42 (br s,
2H) , 2.21 (br s, 2H) , 1.45 (s, 9H) , 1.25 (s, 12H) ; ESMS
m/e: 310.4 (M + H)+.
N-(6-BROMO-2-PYRIDINYL)-2-METHYLPROPANAMIDE: Prepared
by Procedure Q1 using 2-methylpropanoyl chloride and 6-
bromo-2-pyridinamine: ESMS m/e: 242.8 (M + H)+.
TERT-BUTYL 4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-3,6-
DIHYDRO-1(2H)=PYRIDINECARBOXYLATE: Prepared by
Procedure W and Scheme AF using N-(6-bromo-2-pyridinyl)-
2-methylpropanamide and tert-butyl . 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-
pyridinecarboxylate: ESMS m/e: 245.8 (M - 100)+.
2-METHYL-N-[6-(4-PIPERIDINYL)-2-PYRIDINYL]PROPANAMIDE:
Prepared by Procedures X and Y, Schemes AG and AH,
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respectively using tent- butyl 4-[6-
(isobutyrylamino)-2-pyridinyl]-3,6-dihydro-1(2H)-
pyridinecarboxylate: ESMS m/e: 248.1 (M + H)+.
Example 264
N-(6-~1-[4-(3,4-DIMETHYLPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~-2-PYRIDINYL)-2-METHYLPROPANAMIDE: Prepared
by Procedure G and Scheme AI using 4-chloro-1-(3,4-
dimethylphenyl)-1-butanone and 2-methyl-N-[6-(4-
piperidinyl)-2-pyridinyl]propanamide: ESMS m/e: 422.1 (M
+ H)+.
Example 265
N-(6-~1-[4,4-BIS(4-FLUOROPHENYL)BUTYL]-4-PIPERIDINYL~-2-
PYRIDTNYL)-2-METHYLPROPANAMIDE: Prepared by Procedure G
and Scheme AI using 1-[4-chloro-1-(4-
fluorophenyl)butyl] -4-fluorobenzene and 2-methyl-N- [6-
(4-piperidinyl)-2-pyridinyl]propanamide: ESMS m/e: 492.2
(M + H)+.
Example 266
N-(6-~1-[4-(3,4-DIFLUOROPHENOXY)BENZYL]-4-PIPERIDINYL~-
2-PYRIDINYL)-2-METHYLPROPANAMIDE: Prepared by Procedure
AA and Scheme AJ using 4-(3,4-
difluorophenoxy)benzaldehyde and. 2-methyl-N- [6- (4-
piperidinyl)-2-pyridinyl]propanamide: ESMS m/e: 466.0 ,(M
+ H)+.
N-(3-BROMO-4-METHYLPHENYL)-2-METHYLPROPANAMIDE:
Prepared by Procedure Q1 using 2-methylpropanoyl
chloride and 3-bromo-4-methylaniline: ESMS m/e: 255.9 (M
+ H)+.
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TERT-BUTYL 4-[5- (ISOBUTYRYLAMINO)-2-
METHYLPHENYL]-3,6,-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE:
Prepared by Procedure W and Scheme AF using N- (3-bromo-
4-methylphenyl)-2-methylpropanamide and tent-butyl 4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-
dihydro-1(2H)-pyridinecarboxylate: ESMS m/e: 259.1 (M -
100)+.
2-METHYL-N-[4-METHYL-3-(4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedures
X and Y, Schemes AG and AH, respectively using tert-
butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-3,6-
dihydro-1(2H)-pyridinecarboxylate: ESMS m/e: 261.0 (M +
H)~.
Example 267
N-(3-~l-[4-(3,4-DIFLUOROPHENOXY)BENZYL]-4-PIPERIDINYL~-
4-METHYLPHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure AA and Scheme AJ using 4-(3,4-
difluorophenoxy)benzaldehyde and using 2-methyl-N-[4-
methyl-3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
479 . 1 (M + H) +.
N-(5-BROMO-2-METHYLPHENYL)-2-METHYLPROPANAMIDE:
Prepared by Procedure Q1 using 2-methylpropanoyl
chloride and 5-bromo-2-methylaniline: ESMS m/e: 255.9 (M
+ H)+.
TERT-BUTYL 4-[3-(ISOBUTYRYLAMINO)-4-METHYLPHENYL]-3,6-
DIHYDRO-1(2H)-PYRIDINECARBOXYLATE: Prepared by
Procedure W and Scheme AF using N-(5-bromo-2-
methylphenyl)-2-methylpropanamide and tert-butyl 4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-
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dihydro-1(2H)- pyridinecarboxylate: ESMS
m/e: 259.1 (M - 100)+.
2-METHYL-N-[2-METHYL-5-(4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedures
X and Y, Schemes AG and AH, respectively using tert-
butyl 4-[3-(isobutyrylamino)-4-methylphenyl]-3,6-
dihydro-1(2H)-pyridinecarboxylate: ESMS m/e: 261.0 (M +
H)+.
Example 268
N-(5-~1-[(9-ETHYL-9H-CARBAZOL-3-YL)METHYL]-4-
PIPERIDINYL~-2-METHYLPHENYL)-2-METHYLPROPANAMIDE:
Prepared by Procedure AA and Scheme AJ using 9-ethyl-9H-
carbazole-3-carbaldehyde and 2-methyl-N-[2-methyl-5-(4-
piperidinyl)phenyllpropanamide: ESMS m/e: 468.1 (M + H)+.
Example 269 .
N-(5-~l-[4-(3,4-DIFLUOROPHENOXY)BENZYL]-4-PIPERIDINYL~-
2-METHYLPHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure AA and Scheme AJ using 4-(3,4-
difluorophenoxy)benzaldehyde and 2-methyl-N-[2-methyl-5-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 479.2 (M +
H)+.
Example 270
N-(3-~1-[(9-ETHYL-9H-CARBAZOL-3-YL)METHYL]-4-
PIPERIDINYL~-4-METHYLPHENYL)-2-METHYLPROPANAMIDE:
Prepared by Procedure AA and Scheme AJ using 9-ethyl-9H-
carbazole-3-carbaldehyde and 2-methyl-N-[4-methyl-3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 468.1 (M + H)+.
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Example 271
2-METHYL-N-[2-METHYL-5-(4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure G
and Scheme AI using 1- [4-chloro-1- (4-
fluorophenyl)butyl] -4-fluorobenzene and 2-methyl-N- [2-
methyl-5-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
505.1 (M + H)+.
Example 272
N-(3-~1-[(3S)-3-(3-ACETYLPHENOXY)-3-PHENYLPROPYL]-4-
PIPERIDINYL~-4-METHYLPHENYL)-2-METHYLPROPANAMIDE:
Prepared by Procedure G and Scheme AI using 1-(3-~[(1S)-
3-chloro-1-phenylpropyl]oxy~phenyl)ethanone and 2-
methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 513.0 (M + H)+.
Example 273
N-(5-fl-I(3S)-3-(3-ACETYLPHENOXY)-3-PHENYLPROPYL]-4-
PIPERIDINYL~-2-METHYLPHENYL)-2-METHYLPROPANAMIDE:
Prepared by Procedure G and Scheme AI using 1-(3-f[(1S)-
3-chloro-1-phenylpropyl]oxy}phenyl)ethanone and 2-
methyl-N-[2-methyl-5-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 512.9 (M + H)~.
N-(2-IODOPHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure Q1 using 2-methylpropanoyl chloride and 2-
iodoaniline: ESMS m/e: 289.9 (M + H)+.
TERT-BUTYL 4-[2-(ISOBUTYRYLAMINO)PHENYL]-3,6-DIHYDRO-
1(2FI)-PYRIDINECARBOXYLATE: Prepared by Procedure W and
Scheme AF using N-(2-iodophenyl)-2-methylpropanamide and
tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
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yl)-3,6-dihydro-1(2H)- pyridinecarboxylate: ESMS
m/e: 245.1 (M - 100)+.
2-METHYL-N-[2-(4-PIPERIDINYL)PHENYL]PROPANAMIDE:
Prepared by Procedures X and Y, Schemes AG and AH,
respectively using tert-butyl 4-[2-
(isobutyrylamino)phenyl] -3, 6-dihydro-1 (2H) -
pyridinecarboxylate: ESMS m/e: 247.1 (M + H)+.
Example 274
N-(2-~1-[(9-ETHYL-9H-CARBAZOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure AA and Scheme AJ using 9-ethyl-9H-carbazole-3-
carbaldehyde and 2-methyl-N-[2-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 454.1 (M + H)+.
Example 275
N-(3-~1-[4,4-BIS(4-FLUOROPHENYL)BUTYL]-4-PIPERIDINYL}-4-
METHYLPHENYL)-2-METHYLPROPANAMTDE: Prepared by
Procedure G and Scheme AI using 1-[4-chloro-1-(4-
fluorophenyl)butyl]-4-fluorobenzene and 2-methyl-N-(4-
methyl-3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
505.0 (M + H)+.
2 5 Example 276
N-(2-~1- [4, 4-BIS (4-FLUOROPHENYL) BUTYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme AI using 1-[4-chloro-1-(4-
fluorophenyl)butyl]-4-fluorobenzene and 2-methyl-N-[2-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 490.9 (M +
H)+.
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N-[2-BROMO-4- (TRIFLUOROMETHOXY)PHENYL]-
2-METHYLPROPANAMIDE: Prepared by Procedure Q1 using 2-
methylpropanoyl chloride and 2-bromo-4-
(trifluoromethoxy)aniline: ESMS m/e: 325.9 (M + H)+.
TERT-BUTYL 4-[2-(ISOBUTYRYLAMINO)-5-
(TRIFLUOROMETHOXY)PHENYL]-3,6-DIHYDRO-1(2H)-
PYRIDINECARBOXYLATE: Prepared by Procedure W and Scheme
AF using N- [2-bromo-4- (trifluoromethoxy)phenyl] -2-
methylpropanamide and tert-butyl 4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-
pyridinecarboxylate: ESMS m/e: 329.0 (M - 100)+.
2-METHYL-N-[2-(4-PIPERIDINYL)-4-
(TRIFLUOROMETHOXY)PHENYL]PROPANAMIDE: Prepared by
Procedures X and Y, Schemes AG and AH, respectively
using tert-butyl 4-[2-(isobutyrylamino)-5-
(trifluoromethoxy)phenyl]-3,6-dihydro-1(2H)-
pyridinecarboxylate: ESMS m/e: 330.9 (M + H)+. .
Example 277
N-[2-fl-[4,4-BIS(4-FLUOROPHENYL)BUTYL]-4-PIPERIDINYL~-4-
(TRIFLUOROMETHOXY)PHENYL]-2-METHYLPROPANAMIDE: Prepared
by Procedure G and Scheme AI using 1-[4-chloro-1-(4-
fluorophenyl)butyl]-4-fluorobenzene and 2-methyl-N-[2-
(4-piperidinyl)-4-(trifluoromethoxy)phenyl]propanamide:
ESMS m/e: 574.8 (M + H)+.
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10
20
N-~3-(1-(4-HYDROXYBUTYL)- 4-PIPERIDINYL]PHENYL}-2-
METHYLPROP,ANAMIDE: Prepared by Procedure G and Scheme
B1 using 4-chloro-1-butanol and 2-methyl-N-[3-(4-
piperidinyl)ghenyl]propanamide: ESMS m/e: 319.3 (M + H)+.
N-~3-[1-(5-HYDROXYPENTYL)-4-PIPERIDINYL]PHENYL-2-
METHYLPROPANAMIDE: Prepared by Procedure G and Scheme
B1 using 5-chloro-1-pentanol and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 333.3 (M + H)+.
N-~3-[1-(6-HYDROXYHEXYL)-4-PIPERIDINYL]PHENYL-2-
METHYLPROPANAMIDE: Prepared by Procedure G and Scheme
B1 using 6-chloro-1-hexanol and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 347.3 (M + H)+.
N-~3-[1-(3-HYDROXYPROPYL)-4-PIPERIDINYL]PHENYL-2-
METHYLPROP,ANAMIDE: Prepared by Procedure G and Scheme
B1 using 3-chloro-1-propanol and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 305.3 (M + H)+.
N-(3-~1-((2S)-2-HYDROXY-2-PHENYLETHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using (1S)-2-chloro-1-
phenylethanol and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 367.2 (M + H)+.
N-(3-~1-[(2R)-2-HYDROXY-2-PHENYLETHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: .
Prepared by Procedure G and.Scheme B1 using (1R)-2
chloro-1-phenylethanol and 2-methyl-N-[3-(4
piperidinyl)phenyl]propanamide: ESMS m/e: 367.2 (M + H)+.
N-(3-{1-((2S)-3-HYDROXY-2-METHYLPROPYLJ-4
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
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Procedure G and Scheme B1 using (2R)-3-chloro-2-
methyl-1-propanol and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 319.2 (M + H)+.
N-(3-~1-[(2R)-3-HYDROXY-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using (2S)-3-chhoro-2-methyl-
1-propanol and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 319.2.(M + H)+.
Example 278
N-(3-fl-[(3R)-3-HYDROXY-3-PHENYLPROPYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE:
Prepared by Procedure G and Scheme Bl using (1R)-3-
chloro-1-phenyl-1-propanol and N-[3,-(4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
379.2 (M + H)+.
Example 279
N-~3-[1-(4-HYDROXY-4-PHENYLBUTYL)-4-PIPERIDINYL]PHENYL~
2-METHYLPROPANAMIDE: Prepared by Procedure L and Scheme
AN, Step 1 using 2-methyl-N-~3-[1-(4-oxo-4-phenylbutyl)
4-piperidinyl]phenyl}propanamide: Anal. Calcd for
C25H34N202+0.08CHC13: C, 74.5; H, 8.50; N, 6.93. Found:
C, 74.5; H, 8.63; N, 6.81; ESMS m/e: 395.2 (M + H)+.
Example 280
N-~3-[1-(5-HYDROXY-5-PHENYLPENTYL)-4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN, Step 1 using 2-methyl-N-~3-
[1-(5-oxo-5-phenylpentyl)-4-
piperidinyl]phenyl~propanamide: Anal. Calcd for
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C26H36N202+0.25CHC13: C, 71.9; H, 8.33; N, 6.39.
Found: C, 71.3; H, 8.96; N, 6.86; ESMS m/e: 409.2 (M +
H)+.
Example 281
N-~3-[1-(6-HYDROXY-6-PHENYLHEXYL)-4-PIPERIDINYL]PHENYL~-
2-METHYLPROPANAMIDE: Prepared by Procedure L and Scheme
AN, Step 1 using 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-
4-piperidinyl]phenyl~propanamide: Anal. Calcd for
C27H38N202+O.1CHC13: C, 75.5; H, 8.93; N, 6.50. Found:
C, 75.3; H, 8.52; N, 6.00; ESMS m/e: 423.2 (M + H)+.
Example 282
N-~3-[1-(7-HYDROXY-7-PHENYLHEPTYL)-4-
PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN, Step 1 using 2-methyl-N-{3-
[1-(7-oxo-7-phenylheptyl)-4-
piperidinyl]phenyl}propanamide: Anal. Calcd for
C28H40N202+O.1CHC13: C, 75.8; H, 9.10; N, 6.29. Found:
C, 75.1; H, 9.24; N, 6.51; ESMS m/e: 437.1 (M + H)+.
Example 283
N-(3-~1-[4-(4-FLUOROPHENYL)-4-HYDROXYBUTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN, Step 1 using N-(3-~1-[4-(4-
fluorophenyl)-4-oxobutyl]-4-piperidinyl}phenyl)-2-
methylpropanamide: ESMS m/e: 413.1 (M + H)+.
Example 284
4-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-1-
PHENYLBUTYL 3-(2,6-DICHLOROPHENYL)-5-METHYL-4-
ISOXAZOLECARBOXYLATE: Prepared by Procedure Q1 and
Scheme C2 (TEA) using N-f3-[1-(4-hydroxy-4-phenylbutyl)-
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4-piperidinyl]phenyl -2- methylpropanamide and
3-
(2,6-dichlorophenyl)-5-methyl-4-isoxa zolecarbonyl
chloride: 1H NMR (400 MHz, CDC13) ~ 7.56 (m, 1H) 7.47
,
(m, 2H), 7.44-7.39 (m, 3H), 7.25 (m, 2H), 7.09 (s, 1H),
7. 03 (m, 2H) , 6.95 (m, 1H) , 6. 83 (m, 1H) 5.75 (t, 1H,
, J
- 7.1 Hz), 3.03 (t, 2H, J = 7.2 Hz), 2.93 (m, 2H),2.78
(s, 3H) , 2 .48 (m, 3H) , 2.25 (m, 2H) , 1 (m, 3H) 1.
.48 , 77
(m, 2H), 1.54 (m, 2H), 1.25 (d, 6H, J 7.3 Hz);ESMS
-
m/e: 647.7 (M + H)''-.
Example 285
4-f4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-1-
PHENYLBUTYL (4-FLUOROPHENYL)ACETATE: Prepared by
Procedure Q1 and Scheme C2 (TEA) using N-~3-[1-(4-
hydroxy-4-phenylbutyl)-4-piperidinyl]phenyl -2-
methylpropanamide and (4-fluorophenyl)acetyl chloride: 1H
NMR (400 MHz, CDC13) 5 7.45 (s, 1H), 7.34-7.19 (m, 8H),
7.11 (m, 1H), 6.98 (m, 3H), 5.75 (t, 1H, J - 6.8 Hz),
3.61 (s, 2H), 2.92 (d, 2H, J = 8.1 Hz), 2.48 (m, 2H),
2.31 (m, 2H), 1.99-1.84 (m, 4H), 1.84-1.67 (m, 5H),
1.55-1.35 (m, 2H), 1.25 (d, 6H, J - 6.9 Hz); ESMS .m/e:
531.1 (M + H)+.
Example 286
3-~4--[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~PROPYL
(4-FLUOROPHENYL)ACETATE: Prepared by Procedure Q1 and
Scheme C2 (TEA) using N-~3-[1-(3-hydroxypropyl)-4-
piperidinyl]phenyl}-2-methylpropanamide ~ and (4-
fluorophenyl)acetyl chloride: ESMS m/e: 441.3 (M + H)~.
Example 287
3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~PROPYL 3-
(2-CHLORO-6-FLUOROPHENYL)-5-METHYL-4-
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ISOXAZOLECARBOXYLATE; Prepared by Procedure Q1
and Scheme C2 (TEA) using N-{3-[1-(3-hydroxypropyl)-4-
piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chloro-
6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride:
ESMS m/e: 542.2 (M + H)+.
Example 288
3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~PROPYL 3-
(2,6-DICHLOROPHENYL)-5-METHYL-4-ISOXAZOLECARBOXYLATE:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-
[ 1- ( 3 -hydroxypropyl ) - 4 -p iperidinyl ] phenyl - 2 -
methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-
isoxazolecarbonyl chloride: ESMS m/e: 558.2 (M + H)+.
Example 289
3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~PROPYL 3-
(2--CHLOROPHENYL)-5-METHYL-4-ISOXAZOLECARBOXYLATE:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-
[1-(3-hydroxypropyl)-4-piperidinyl]phenyl}-2-
methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-
isoxazolecarbonyl chloride: ESMS m/e: 524.2 (M + H)+.
Example 290
(1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-1-
PHENYLPROPYL 3-(2,6-DICHLOROPHENYL)-5-METHYL-4-
ISOXAZOLECARBOXYLATE: Prepared by Procedure Q1 and
Scheme C2 (TEA) using N- (3-{1- [ (3S) -3-hydroxy-3-
phenylpropyl]-4-piperidinyl~phenyl)-2-methylpropanamide
and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl
chloride: ESMS m/e: 633.6 (M + H)+.
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Example 291
4-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~BUTYL 3-
(2-CHLORO-6-FLUOROPHENYL)-5-METHYL-4-
ISOXAZOLECARBOXYLATE: Prepared by Procedure Q1 and
Scheme C2 (TEA) using N-f3-[1-(4-hydroxybutyl)-4-
piperidinyl]phenyl -2-methylpropanamide and 3-(2-chloro-
6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride:
Anal. Calcd for C30H35C1FN304+CH2C12: C, 63.3; H, 6.23;
N, 7.33. Found: C, 63.0; H, 6.39; N, 7.03; ESMS m/e:
556.2 (M + H)+.
Example 292
4-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~BUTYL 3-
(2-CHLOROPHENYL)-5-METHYL-4-ISOXAZOLECARBOXYLATE:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-
[1- (4-hydroxybutyl) -4-piperidinyl]phenyl-2-
methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-
isoxazolecarbonyl chloride: ESMS m/e: 538.2 (M +.H)+.
2 0 Example 293
3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~PROPYL 5-
METHYL-3-PHENYL-4-ISOXAZOLECARBOXYLATE: Prepared by
Procedure Q1 and Scheme C2 (TEA) using N-f3-[1-(3-
hydroxypropyl)-4-piperidinyl]phenyl -2-methylpropanamide
and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS
m/e: 490'.3 (M + H)+.
Example 294
4-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-~1-PIPERIDINYL~BUTYL 3-
(2,6-DICHLOROPHENYL)-5-METHYL-4-ISOXAZOLECARBOXYLATE:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-~3-
[1-(4-hydroxybutyl)-4-piperidinyl]phenyl}-2-
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methylpropanamide and 3- (2,6-dichlorophenyl)-5-
methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 572.2 (M
+ H)+.
Example 295
4-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-1-
PHENYLBUTYL 3-(2-CHLORO-6-FLUOROPHENYL)-5-METHYL-4-
ISOXAZOLECARBOXYLATE: Prepared by Procedure Q1 and
Scheme C2 (TEA) using N-{3-[1-(4-hydroxy-4-phenylbutyl)-
4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-
chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl
chloride: Anal. Calcd for C36H39C1FN304+0.54CHC13: C,
63.0; H, 5.72; N, 6.03. Found: C, 63.0; H, 5.54; N,
6.05; ESMS m/e: 632.2 (M + H)+.
Example 296
4-f4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~BUTYL 5-
METHYL-3-PHENYL-4-ISOXAZOLECARBOXYLATE: Prepared by
Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-
hydroxybutyl)-4-piperidinyl]phenyl -2-methylpropanamide
and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS
m/e: 504.3 (M + H)+.
Example 297
6-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~HEXYL 3-
(2,6-DICHLOROPHENYL)-5-METHYL-4-ISOXAZOLECARBOXYLATE:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-
[1-(6-hydroxyhexyl)-4-piperidinyl]phenyl}-2-
methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-
isoxazolecarbonyl chloride: ESMS m/e: 600.0 (M + H)+.
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Example 298
6-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~HEXYL 5-
METHYL-3-PHENYL-4-ISOXAZOLECARBOXYLATE: Prepared by
Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(6-
hydroxyhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS
m/e: 532.1 (M + H)+.
Example 299
4-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~BUTYL (4-
FLUOROPHENYL)ACETATE: Prepared by Procedure Q1 and
Scheme C2 (TEA) using N-{3-[1-(4-hydroxybutyl)-4-
piperidinyl]phenyl}-2-methylpropanamide and (4-
fluorophenyl)acetyl chloride: ESMS m/e: 455.3 (M + H)+.
Example 300
4-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-1-
PHENYLBUTYL 3-(2-CHLOROPHENYL)-5-METHYL-4-
ISOXAZOLECARBOXYLATE: Prepared by Procedure Q1 and
Scheme C2 (TEA) using N-{3-[1-(4-hydroxy-4-phenylbutyl)-
4-piperidinyl]phenyl -2-methylpropanamide and 3-(2-
chlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride:
ESMS m/e: 614.2 (M + H)+.
2 5 Example 301
4-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-1-
PHENYLBUTYL 5-METHYL-3-PHENYL-4-ISOXAZOLECARBOXYLATE:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-
[1-(4-hydroxy-4-phenylbutyl)-4-piperidinyl]phenyl}-2-
methylpropanamide and 5-methyl-3-phenyl-4-
isoxazolecarbonyl chloride: ESMS m/e: 580.0 (M + H)+.
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Example 302
(1S) -3-~4- [3- (ISOBUTYRYIrAMINO) PHENYL] -1-PIPERIDINYL~-1-
PHENYLPROPYL (4-FLUOROPHENYL)ACETATE: Prepared by
Procedure Q1 and Scheme C2 (TEA) using N- (3-~1- [ (3S) -3-
hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-~-
methylpropanamide and (4-fluorophenyl)acetyl chloride:
Anal. Calcd for C32H37FN203+0.07CHC13: C, 73.4; H, 7.12;
N, 5.34. Found: C, 73.4; H, 6.96; N, 5.14; ESMS m/e:
517.1 (M + H)+.
Example 303
N-((1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-
1-PHENYLPROPYL)BENZAMIDE: Prepared by Procedure Q1 and
Scheme AC using N- (3-~l- [ (3S) -3-amino-3-phenylpropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide and benzoyl
chloride: Anal. Calcd for C31H37N302+0.55CHC13: C, 69.0;
H, 6.89; N, 7.65. Found: C, 69.7; H, 6.73; N, 6.03;
ESMS m/e: 484.4 (M + H)+.
2 0 Example 304
N- [3- (1-~ (3S) -3- [ (DIPHENYLACETYL)AMINO] -3-PHENYLPROPYL~-
4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure Q1 and Scheme AC using N- (3-{1- [ (3S) -3-amino-
3-phenylpropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide arid diphenylacetyl chloride; ESMS m/e:
574 . 3 (M + H) + .
Example 305
3-CHLORO-N-((1S)-3-f4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~-1-PHENYLPROPYL)BENZAMIDE: Prepared by
Procedure Q1 and Scheme AC using N- (3- ~ 1- [ ( 3 S) -3 -amino-
3-phenylpropyl]-4-piperidinyl~phenyl)-2-
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methylpropanamide and 3- chlorobenzoyl chloride:
ESMS m/e: 518.3 (M + H)+.
Example 306
3,5-DICHLORO-N-((1S)-3-~4-(3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL}-1-PHENYLPROPYL)BENZAMIDE: Prepared by
Procedure Q1 and Scheme AC using N- (3-~1- [ (3S) -3-amino-
3-phenylpropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 3,5-dichlorobenzoyl chloride: ESMS
m/e: 552.3 (M + H)+.
Example 307
2-(ETHYLSULFANYL)=N-((1S)-3-~4-[3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}-1-
PHENYLPROPYL)NICOTINAMIDE: Prepared by Procedure Q1 and
Scheme AC using N- (3-{1- [ (3S) -3-amino-3-phenylpropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide and 2-
(ethylsulfanyl)nicotinoyl chloride: ESMS m/e: 545.3 (M +
H)+.
Example 308
N-((1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-
1-PHENYLPROPYL)[1,1'-BIPHENYL]-4-CARBOXAMIDE: Prepared
by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-
amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and [1,1'-biphenyl]-4-carbonyl
chloride: ESMS m/e: 560.3 (M + H)+.
Example 309
N-((1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PTPERIDINYL~-
1-PHENYLPROPYL)-2-PYRIDINECARBOXAMIDE: Prepared by
Procedure Q1 and Scheme AC using N- (3- { 1- [ ( 3 S) -3 -amino-
3-phenylpropyl]-4-piperidinyl}phenyl)-2-
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methylpropanamide and 2- pyridinecarbonyl chloride:
ESMS m/e: 484.6 (M + H)+.
Example 310
N-( (1S) -3-~4- [3- (ISOBUTYRYLAMINO) PHENYL -1-PIPERIDINYL~-
1-PHENYLPROPYL)-2-METHOXYBENZAMIDE: Prepared by
Procedure Q1 and Scheme AC using N- (3-~1- [ (3S) -3-amino-
3-phenylpropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 2-methoxybenzoyl chloride: ESMS
m/e: 514.1 (M + H)+.
Example 311
N-((1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-
1-PHENYLPROPYL)-1-NAPHTHAMIDE: Prepared by Procedure Q1
and Scheme AC using N-(3-{1-[(3S)-3-amino-3-
phenylpropyl]-4-piperidinyl~phenyl)-2-methylpropanamide
and 1-naphthoyl chloride: ESMS m/e: 533.7 (M + H)+.
Example 312
2,4-DIFLUORO-N-((1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~-1-PHENYLPROPYL)BENZAMIDE: Prepared by
Procedure Ql .and Scheme AC using N- (3- f 1- [ (3S) -3-amino-
3-phenylpropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 2,4-difluorobenzoyl chloride: ESMS
m/e: 520.2 (M + H)+.
Example 313
3-(2-CHLORO-6-FLUOROPHENYL)-N-((1S)-3-~4-[3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-1-PHENYLPROPYL)-
5-METHYL-4-ISOXAZOLECARBOXAMIDE: Prepared by Procedure
Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-
phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide
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and 3-(2-chloro-6- fluorophenyl)-5-methyl-4-
isoxazolecarbonyl chloride: ESMS m/e: 617.2 (M + H)+.
Example 314
3-CHLORO-N-((1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~-1-PHENYLPROPYL)-2-THIOPHENECARBOXAMIDE:
Prepared by Procedure Ql and Scheme AC using N-(3-~1-
[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 3-chloro-2-thiophenecarbonyl
chloride: ESMS m/e: 524.2 (M + H)+.
Example 315
N-((1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-
1-PHENYLPROPYL)-2-PHENOXYNICOTINAMIDE: Prepared by
Procedure Q1 and Scheme AC using N- (3-~1- [ (3S) -3-amino-
3-phenylpropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 2-phenoxynicotinoyl chloride: ESMS
m/e: 577.3 (M + H)+.
2 0 Example 316
1- (4-CHLOROPHENYL) -N-( (1S) -3-~4- [3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-1-PHENYLPROPYL)-
3-PROPYL-1H-PYRAZOLE-4-CARBOXAMIDE: Prepared by
Procedure Q1 and Scheme AC using N- (3-{1- [ (3S) -3-amino-
3-phenylpropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-(4-chlorophenyl)-3-propyl-1H-
pyrazole-4-carbonyl chloride: ESMS m/e: 626.3 (M + H)+.
Example 317
4-CHLORO-N-((1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~-1-PHENYLPROPYL)-1,3-DIMETHYL-1H-
PYRAZOLO[3,4-B]PYRIDINE-5-CARBOXAMIDE: Prepared by
Procedure Q1 and Scheme AC using N- (3-~1- [ (3S) -3-amino-
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3-phenylpropyl]-4- piperidinyl~phenyl)-2-
methylpropanamide and 4-chloro-1,3-dimethyl-1H-
pyrazolo[3,4-b]pyridine-5-carbonyl chloride: ESMS m/e:
587.3 (M + H)+.
Example 318
5-(3,5-DICHLOROPHENOXY)-N-((1S)-3-{4-[3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-1-PHENYLPROPYL)-
1H-PYRROLE-2-CARBOXAMIDE: Prepared by Procedure Q1 and
Scheme AC using N- (3- f 1- [ (3S) -3-amino-3-phenylpropyl] -4-
piperidinyl)phenyl)-2-methylpropanamide and 5-(3,5-
dichlorophenoxy)-1H-pyrrole-2-carbonyl chloride: ESMS
m/e: 634.2 (M + H)+.
Example 319
N-((1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-
1-PHENYLPROPYL)NICOTINAMIDE: Prepared by Procedure Q1
and Scheme AC using N-(3-~1-[(3S)-3-amino-3-
phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide
and nicotinoyl chloride: ESMS m/e: 485.3 (M + H)+.
Example 320
3,4-DIFLUORO-N-((1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~-Z-PHENYLPROPYL)BENZAMIDE: Prepared by
Procedure Ql and Scheme AC using N-(3-f1-[(3S)-3-amino-
3-phenylpropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 3,4-difluorobenZOyl chloride: ESMS
m/e: 520.3 (M + H)+.
3 0 Example 321
N-((1S)-3-~4-[3-(ISQBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-
1-PHENYLPROPYL)-1-PHENYL-3-PROPYL-1H-PYRAZOLE-4-
CARBOXAMIDE: Prepared by Procedure Q1 and Scheme AC
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using N- (3-{1- [ (3S) -3- amino-3-phenylpropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide and 1-phenyl-3-
propyl-1H-pyrazole-4-carbonyl chloride: ESMS m/e: 592.2
(M + H)+.
Example 322
4-(DIMETHYLAMINO)-N-((1S)-3-f4-[3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-1-
PHENYLPROPYL)BENZAMIDE: Prepared by Procedure Ql and
Scheme AC using N- (3-~1- [ (3S) -3-amino-3-phenylpropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide and 4-
(dimethylamino)benzoyl chloride: ESMS m/e: 527.3 (M +
H)+.
Example 323
N-((1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-
1-PHENYLPROPYL)-2-THIOPHENECARBOXAMIDE: Prepared by
Procedure Q1 and Scheme AC using N- (3-~1- [ (3S) -3-amino-
3-phenylpropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 2-thiophenecarbonyl chloride: ESMS
m/e: 490.2 (M + H)+.
Example 324
N-((1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-
1-PHENYLPROPYL)-5-NITRO-2-FURAMIDE: Prepared by
Procedure Q1 and Scheme AC using N- (3- ~ 1- [ ( 3 S) -3 -amino-
3-phenylpropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 5-nitro-2-furoyl chloride: ESMS
m/e: 519.2 (M + H)+.
Example 325
N-(3-~4-(3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~PROPYL)-5-METHYL-3-PHENYL-4-
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ISOXAZOLECARBOXAMIDE: Prepared by Procedure Q1
and Scheme AC using N-(3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl}-2-methylpropanamide and 5-methyl-3-
phenyl-4-isoxazolecarbonyl chloride: ESMS m/e: 489.1 (M
+ H)+.
Example 326
N-((1S)-3-f4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~-
1-PHENYLPROPYL)-2-FURAMIDE: Prepared by Procedure Ql
and Scheme AC using N-(3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl}-2-methylpropanamide and 2-furoyl
chloride: ESMS m/e: 474.2 (M + H)+.
Example 327
N-((1S)-3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}-
1-PHENYLPROPYL)-1-(4-NITROPHENYL)-5-(TRIFLUOROMETHYL)-
1H-PYRAZOLE-4-CARBOXAMIDE: Prepared by Procedure Q1 and
Scheme AC using N- (3-(1- [ (3S) -3-amino-3-phenylpropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide and 1-(4-
nitrophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl
chloride: ESMS m/e: 663.2 (M + H)+.
Example 328
3-(2-CHLORO-6-FLUOROPHENYL)-N-(3-~4-[3-
(ISOBUTYRYLAMINO)PHENYL -1-PIPERIDINYL}PROPYL)-5.-METHYL-
4-ISOXAZOLECARBOXAMIDE: Prepared by Procedure Q1 and
Scheme AC using N-~3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chloro-
6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride:
ESMS m/e: 541 .2 (M + H)+.
Example 329
N-[3-(1-~3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
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Procedure Q1 and Scheme AC using N-(3-[1-(3-
aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and diphenylacetyl chloride: 1H NMR (400 MHz, CDC13) ~
7.51 (s, 1H) , 7..33-7.21 (m, 13H) , 6.94 (m, 2H) , 4.88 (s,
1H), 3.39 (t, 2H, J - 5.6 Hz), 2.93 (d, 2H, J - 11.3
Hz) , 2.52-2.36 (m, 4H) , 1.97 (t, 2H, J = 11.3 Hz) , 1.83-
1 .58 (m, 6H) , 1 .24 (d, 6H, J = 7.6 Hz) ; Anal. Calcd for
C32H39N302+HC1+0.19CHC13: C, 69.44; H, 7.27; N, 7.55.
Found: C, 69.44; H, 7.43; N, 7.43; ESMS m/e: 498.4 (M +
H)+.
Example 330
N-(3-~4-C3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~PROPYL)-1-BENZOTHIOPHENE-3-CARBOXAMIDE:
Prepared by Procedure Q1 and Scheme AC using N-~3-[1-(3-
aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and 1-benzothiophene-3-carbonyl chloride: ESMS m/e:
464.2 (M + H)+.
2 0 Example 331
3 - ( 2 - CHLOROPHENYL ) -N- ( 3 - ~ 4 - [ 3 - ( I SOBUTYRYLAMINO ) PHENYL] -
1-PIPERIDINYL~PROPYL)-5-METHYL-4-ISOXAZOLECARBOXAMIDE:
Prepared by Procedure Q1 and Scheme AC using N-f3-[1-(3-
aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarbonyl
chloride: ESMS m/e: 523.1 (M + H)+.
Example 332
3-(2,6-DICHLOROPHENYL)-N-(3-~4-[3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERTDINYL~PROPYL)-5-METHYL-
4-ISOXA.ZOLECARBOXAMIDE: Prepared by Procedure Q1 and
Scheme AC using N-~3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl}-2-methylpropanamide and 3-(2,6-
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dichlorophenyl)-5-methyl- 4-isoxazolecarbonyl
chloride: 1H NMR (400 MHz, CDC13) b 7.50 (d, 1H, J = 2.3
Hz), 7.48 (s, 1H), 7.4 (m, 1H), 7.39 (s, 1H), 7.37 (m,
2H) , 7.24 (t, 1H, J = ,7.2 Hz) , 6.92 (d, 1H, J = 7.9 Hz) ,
5' 6.06 (s, 1H) , 3.31 (q, 2H, J = 6.4 Hz) , 2.94 (d, 2H, J =
10.8 Hz), 2.79 (s, 3H), 2.53 (q, 1H, J = 6.1), 2.47 (tt,
1H, J = 4.2, 11.4 Hz), 2.29 (t, 2H, ,J - 7.2 Hz), 1.99
(t, 2H, J - 11.4 Hz), 1.81 (m, 2H), 1.69 (dt, 2H, J
2.4, 11.6), 1.59 (q, 2H, J = 6.6 Hz), 1.24 (d, 6H, J =
6.5 Hz) ; ESMS m/e: 557.0 (M + H)+.
1- [3- (3-CFiLOROPROPOXY) PHENYL] E'THANONE: Prepared by
Procedure U and Scheme AK using 1-(3-
hydroxyphenyl)ethanone and 1-bromo-3-chloropropane.
1-(3-CHLOROPROPOXY)-2-FLUOROBENZENE: Prepared by
Procedure U and Scheme AK using 2-fluorophenol and 1-
bromo-3-chloropropane.
1-CHLORO-3-(3-CHLOROPROPOXY)BENZENE: Prepared by
Procedure U and Scheme AK using 3-chlorophenol and 1-
bromo-3-chloropropane.
1-CHLORO-4-(3-CHLOROPROPOXY)BENZENE: Prepared by
Procedure U and Scheme AK using 4-chlorophenol and 1
bromo-3-chloropropane.
I-(3-CHLOROPROPOXY)-3-FLUOROBENZENE: Prepared by
Procedure U and Scheme AK using 3-fluorophenol and 1
bromo-3-chloropropane.
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1-(3-CHLOROPROPOXY)-4- FLUOROBENZENE: Prepared
by Procedure U and Scheme AK using 4-fluorophenol and 1-
bromo-3-chloropropane.
1-CHLORO-2-(3-CHLOROPROPOXY)BENZENE: Prepared by
Procedure U and Scheme AK using 2-chlorophenol and 1-
bromo-3-chloropropane.
4-(3-CHLOROPROPOXY)-1,2-DIMETHYLBENZENE: Prepared by
Procedure U and Scheme AK using 3,~-dimethylphenol and
1-bromo-3-chloropropane.
1-BROMO-2-(3-CHLOROPROPOXY)BENZENE: Prepared by
Procedure U and Scheme AK using 2-bromophenol and 1-
bromo-3-chloropropane.
1-BROMO-3-(3-CHLOROPROPOXY)BENZENE: Prepared by
Procedure U and Scheme AK using 3-bromophenol and 1-
bromo-3-chloropropane.
1-BROMO-4-(3-CHLOROPROPOXY)BENZENE: _ Prepared by
Procedure U and Scheme AK using 4-bromophenol and 1-
bromo-3-chloropropane.
1-(3-CHLOROPROPOXY)-4-METHYLBENZENE: Prepared by
Procedure U and Scheme AK using p-cresol and 1-bromo-3
chloropropane.
4-BROMOPHENYL (2R)-3-CHLORO-2-METHYLPROPYL ETHER:
Prepared by Procedure U and Scheme AK using 4-
bromophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
1-~[(2R)-3'-CHLORO-2-METHYLPROPYL~OXY~-2,4,5-
TRIFLUOROBENZENE: Prepared by Procedure U and Scheme AK
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using 2,4,5- trifluorophenol and (2S)-
1-bromo-3-chloro-2-methylpropane.
1-CHLORO-3-~((2R)-3-CHLORO-2-METHYLPROPYL]OXY~BENZENE:
Prepared by Procedure U and Scheme AK using 3-
chlorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
1-~[(2R)-3-CHLORO-2-METHYLPROPYL]OXY~-4-FLUOROBENZENE:
Prepared by Procedure U and Scheme AK using 4-
fluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
1-~[(2R)-3-CHLORO-2-METHYLPROPYL]OXY~-3-FLUOROBENZENE:
Prepared by Procedure U and Scheme AK using 3-
fluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
1-CHLORO-2-~((2R)-3-CHLORO-2-METHYLPROPYL]OXY~BENZENE:
Prepared by Procedure U and Scheme AK using 2-
chlorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
.- 20 1-~[(2R)-3-CHLORO-2-METHYLPROPYL]OXY~-2-FLUOROBENZENE:
Prepared by Procedure U and Scheme AK using 2-
fluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
1-CHLORO-4-{~[(2R)-3-CHLORO-2-METHYLPROPYL]OXY~BENZENE:
Prepared by Procedure U and Scheme AK using 4-
chlorophenol and (2S)'-1-bromo-3-chloro-2-methylpropane.
3-BROMOPHENYL (2R)-3-CHLORO-2-METHYLPROPYL ETHER:
Prepared by Procedure U and Scheme AK using 3-
bromophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
2-BROMOPHENYL (2R)-3-CHLORO-2-METHYLPROPYL ETHER:
Prepared by Procedure U and Scheme AK using 2-
bromophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
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1-~[(2S)-3-CHLORO-2-METHYLPROPYL]OXY~-3-FLUOROBENZENE:
Prepared by Procedure U and Scheme AK using 3-
fluorophenol and (2R)-1-bromo-3-chloro-2-methylpropane.-.
1-{[(2S)-3-CHLORO-2-METHYLPROPYL]OXY~-4-FLUOROBENZENE:
Prepared by Procedure U and Scheme AK using 4-
fluorophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
_.
1-~[(2S)-3-CHLORO-2-METHYLPROPYL]OXY~-2-FLUOROBENZENE:
Prepared by Procedure U and Scheme AK using 2-
fluorophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
1-CHLORO-2-~[(2S)-3-CHLORO-2-METHYLPROPYL]OXY~BENZENE:
Prepared by Procedure U and Scheme AK using 2-
chlorophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
1-CHLORO-4-~[(2S)-3-CHLORO-2-METHYLPROPYL]OXY~BENZENE:
Prepared by Procedure U and Scheme AK using 4-
chlorophenol and (2R)-1-boo-3~-chloro-2-methylpropane.
4-BROMOPHENYL (2S)-3-CHLORO-2-METHYLPROPYL ETHER:
Prepared by Procedure U and Scheme AK using 4-
bromophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
3-BROMOPHENYL (2S)-3-CHLORO-2-METHYLPROPYL ETHER:
Prepared by Procedure U and Scheme AK using 3-
bromophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
2-BROMOPHENYL (2S)-3-CHLORO-2-METHYLPROPYL ETHER:
Prepared by Procedure ~3-- and Scheme - ~AK using - 2-
bromophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
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1-CHLORO-3-~[(2S)-3- CHLORO-2-
METHYLPROPYL]OXY~BENZENE: Prepared by Procedure U and
Scheme AK using 3-chlorophenol and (2R)-1-bromo-3-
chloro-2-methylpropane.
1-[3-(4-CHLOROBUTOXY)PHENYL]ETHANONE: Prepared by
Procedure U and Scheme AK using 1-(3-
hydroxyphenyl)ethanone and 1-bromo-4-chlorobutane.
1-(3-(4-CHLOROBUTOXY)PHENYL]ETHANONE: Prepared by
Procedure U and Scheme AK using 1-(3-
hydroxyphenyl)ethanone and 1-bromo-4-chlorobutane.
1-(4-CHLOROBUTOXY)-3-METHOXYBENZENE: Prepared by
Procedure U and Scheme AK using 3-methoxyphenol and 1
bromo-4-chlorobutane.
1-(4-CHLOROBUTOXY)-4-METHOXYBENZENE: Prepared by
Procedure U and Scheme AK using 4-methoxyphenol and 1
bromo-4-chlorobutane.
1-(4-CHLOROBUTOXY)-2-METHOXYBENZENE: Prepared by
Procedure U and Scheme AK using 2-methaxyphenol and 1-
bromo-4-chlorobutane.
4-(4-CHLOROBUTOXY)-1,2-DIMETHYLBENZENE: Prepared by
Procedure U and Scheme AK using 3,4-dimethylphenol and
1-bromo-4-chlorobutane.
1-~3-[(5-CHLOROPENTYL)OXY]PHENYL~ETHANONE:. Prepared by
Procedure U and Scheme AK using 1-(3-
hydroxyphenyl)ethanone and 1-bromo-5-chloropentane.
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1_~3_t(5_
CHLOROPENTYL)OXY]PHENYL~ETHANONE: Prepared by Procedure
U and Scheme AK using 1-(3-hydroxyphenyl)ethanone and 1-
bromo-5-chloropentane.
1-~3-[(6-CHLOROHEXYL)OXY]PHENYL~ETHANONE: Prepared by
Procedure U and Scheme AK using 1-(3-
hydroxyphenyl)ethanone and 1-bromo-6-chlorohexane.
1-~3-[(6-CHLOROHEXYL)OXY]PHENYL~ETHANONE: Prepared by
Procedure U and Scheme AK using 1-(3-
hydroxyphenyl)ethanone and 1-bromo-6-chlorohexane.
Example 333
N-(3-~1-[(2S)-2-(3-ACETYLPHENOXY)-2-PHENYLETHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure B and Scheme B1 using 1-(3-
hydroxyphenyl)ethanone and N-(3-{1-[(2R)-2-hydroxy-2-
phenylethyl]-4-piperidinyl~phenyl)-2-methylpropanamide:
ESMS m/e: 485.0 (M + H)+.
Example 334
N-(3-~1-[(2S)-2-(2-ACETYLPHENOXY)-2-PHENYLETHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure B and Scheme B1 using 1-(2-
hydroxyphenyl)ethanone and N-(3-~1-[(2R)-2-hydroxy-2-
phenylethyl]-4-piperidinyl~phenyl)-2-methylpropanamide:
ESMS m/e: 485.2 (M + H)+.
3 0 Example 335
N-(3-{1-[(2S)-2-(3-CHLOROPHENOXY)-2-PHENYLETHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure B and Scheme B1 using 3-chlorophenol and N-(3-
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{1- [ (2R) -2-hydroxy-2- phenylethyl] -4-
piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 477.1
(M + H)+. .
Example 336
N-(3-{1-[(2S)-2-(3,4-DIMETHOXYPHENOXY)-2-PHENYLETHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure B and Scheme B1 using 3,4-dimethoxyphenol and
N- (3-{1- [ (2R) -2-hydroxy-2-phenylethyl] -4-
piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 503.2
(M + H)+.
Example 337
N-(3-~1-[(2R)-2-(4-FLUOROPHENOXY)-2-PHENYLETHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure B and Scheme Bl using 4-fluorophenol and N-(3-
{1-[(2S)-2-hydroxy-2-phenylethyl]-4-piperidinyl~phenyl)-
2-methylpropanamide: ESMS m/e: 461.2 (M + H)+.
2 0 Example 338
N-(3-~1-[(2R)-2-(3-METHOXYPHENOXY)-2-PHENYLETHYL~-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure B and Scheme B1 using 3-methoxyphenol and N-
(3-{1-[(2S)-2-hydroxy-2-phenylethyl]-4-
piperidinyl~phenyl)-2-methylpropanamide: ESMS m/e: 472.9
(M + H)+.
Example 339 '
N-(3-fl-[(2R)-2-(3-CHLOROPHENOXY)-2-PHENYLETHYL]-4
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure B and Scheme B1 using 3-chlorophenol and N-(3-
{1-[(2S)-2-hydroxy-2-phenylethyl]-4-piperidinyl~phenyl)-
2- methylpropanamide: ESMS m/e: 478.5 (M + H)+.
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N-~3-[1-(3,3-DIMETHOXYPROPYL)-4-PIPERIDINYL]PHENYL-2-
METHYLPROPANAMIDE: Prepared by Procedure G and Scheme
B1 using 3-bromo-1,1-dimethoxypropane and 2-methyl-N-[3-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 349.2 (M +
H ) +.
Example 340
N-(3-~l-[(3S)-3-(3-ACETYLPHENOXY)-3-PHENYLPROPYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure B and Scheme B1 using 1-(3-
hydroxyphenyl ) ethanone and N- (3 - f 1- [ ( 3 R) - 3 -hydroxy- 3 -
phenylpropyl]-4-
piperidinyl}phenyl)cyclopropanecarboxamide: ESMS m/e:
497.1 (M + H)+.
Example 341
N-(3-~1- [3- (3-ACETYLPHENOXY) PROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-[3-(3-
chloropropoxy)phenyl] ethanone and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 423.2 (M + H)+.
Example 342
N- (3-~1- [3- (3-ACETYLPHENOXY) PROPYL] -4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure G
and Scheme B1 using 1- [3- (3-
chloropropoxy)phenyl]ethanone and ~ N-[3-(4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
421.2 (M + H)+.
Example 343
N-(3-~1- [3- (2-FLUOROPHENOXY) PROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
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Procedure G and Scheme B1 using 1-(3-chloropropoxy)-
2-fluorobenzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 399.2 (M + H)+.
Example 344
N-(3-~1-[3-(3-CHLOROPHENOXY)PROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-chloro-3-(3-
chloropropoxy)benzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 415.2 (M + H)+.
Example 345
N-(3-~l-[3-(4-CHLOROPHENOXY)PROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-chloro-4-(3-
chloropropoxy)benzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDC13) ~
7.71 (dd, 1H, J = 3 .2, 5.7 Hz) , 7.53 (dd, 1H, J = 3.2,
5.7 Hz) , 7.50 (m,. 1H) , 7.31 (m, 1H) , 7.24-7.20 (m, 2H) ,
6.94 (d, 1H, J - 7.9 Hz), 6.85-6.82 (m, 2H), 4.00 (t,
2H, J - 6.1 Hz), 3.07 (d, 2H, J - 10.9 Hz), 2.55 (m,
3H), 2.50 (sept, 1H, J = 6.2 Hz), 2.08 (dt, 2H, J = 3.1,
10.9 Hz), 2.00 (m, 2H), 1.83 (m, 3H), 1.69 (qt, 1H, J =
6.2 Hz), 1.24 (d, 6H, J - 6.8 Hz); Anal. Calcd for
C24H31C1N202+HC1: C, 63.8; H, 7.09; N, 6.21. Found: C,
63.3; H, 7.04; N, 6.27; ESMS m/e: 415.2 (M + H)+.
Example 346
N-(3-~l-[3-(3-FLUOROPHENOXY)PROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-(3-chloropropoxy)-3-
fluorobenzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 399.2 (M + H)+.
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Example 347
. N-(3-~1- (3- (4-FLUOROPHENOXY) PROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-(3-chloropropoxy)-4-
fluorobenzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 399..2 (M + H)+.
Example 348
N-(3-~1-(3-(2-CHLOROPHENOXY)PROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-chloro-2-(3-
chloropropoxy)benzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 415.2 (M + H)+.
Example 349
N-(3-~l- (3- (3,4-DIMETHYLPHENOXY) PROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 4-(3-chloropropoxy)-1,2-
dimethylbenzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 409.2 (M + H)+.
Example 350
N-(3-~1m(3-(2-BROMOPHENOXY)PROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-bromo-2-(3-
chloropropoxy)benzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDC13) ~
7.53 (dd, 1H, J = 1.6, 7.9 Hz), 7.48 (s, 1H), 7.32 (m,
1H), 7.28-7.22 (m, 3H), 7.17 (s, 1H), 6.98 (d, 1H, J =
7.7 Hz), 6.93 (dd, 1H, J = 1.4, 8.4 Hz), 6.82 (dt, 1H, J
- 7.6, 1 .4 Hz) , 4.11 (t, 2H, J = 6.3 Hz) , 3 .07 (d, 2H, J
- 11.3 Hz), 2.61 (t, 2H, J = 6.9 Hz), 2.50 (m, 3H), 2.07
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(m, 1H), 1.8-1.75 (m, 5H), 1.25 (d, 6H, J - 6.7 Hz);
Anal. Calcd for Cz4H31BrN~O2.HC1+0.2 CHC13: C, 55.9; H,
6.24; N, 5.39. Found: C, 55.8; H, 6.23; N, 5.47; ESMS
m/e: 459.1 (M + H)+.
Example 351
N-(3-{1- [3- (3-BROMOPHENOXY) PROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-bromo-3-(3-
chloropropoxy)benzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl~propanamide: ESMS m/e: 459.1 (M + H)+.
Example 352
N- (3-~1- [3- (4-BROMOPHENOXY) PROPYL] -4-
PTPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-bromo-4-(3-
chloropropoxy)benzene and 2-methyl-N-L3-(4-
piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDC13) ~
7.51 (s, 1H), 7.37 (d, 2H, J = 7.6 Hz), 7.26 (m, 3H),
6.97 (d, 1H, J = 7.7 Hz), 6.79 (d, 2H, J = 7.7 Hz), 4.01
(t, 2H, J = 5.6 Hz) , 3 .08 (d, 2H, J = 9.4 Hz) , 2 .53 (m,
4H), 2.05 (m, 4H), 1.84 (m, 4H), 1.24 (d, 6H, J - 5.9
Hz) ; Anal. Calcd for Ca4H31BrN20a.HCl+0.34CHC13: C, 54.5;
H, 6.08; N, 5.22. Found: C, 54.5; H, 6.22; N, 5.22;
ESMS m/e: 459.1 (M + H)+.
Example 353
N-(3-~l-[(3R)-3-(3,4-DIMETHOXYPHENOXY)-3-PHENYLPROPYL]-
4-PIPERIDINYL~PHENYL)-N,2-DIMETHYLPROPANAMIDE: Prepared
by Procedure T and Scheme AD using N- (3- f 1- [ (3R) -3- (3, 4-
dimethoxyphenoxy)-3-phenylpropyl]-4-piperidinyl}phenyl)-
2-methylpropanamide and methyl iodide: ESMS m/e: 531.2
(M + H) + .
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Example 354
N-(3-~1-[(3R)-3-(3-ACETYLPHENOXY)-3-PHENYLPROPYL]-4-
PIPERIDINYL~PHENYL)-N,2-DIMETHYLPROPANAMIDE: Prepared
by Procedure T and Scheme AD using N- (3- f 1- [ (3R) -3- (3-
acetylphenoxy)-3-phenylpropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and methyl iodide: ESMS m/e: 513.2 (M
+ H)+.
Example 355
N-(3-~1-[(3S)-3-(3-ACETYLPHENOXY)-3-PHENYLPROPYL]-4-
PIPERIDINYL~PHENYL)-N,2-DIMETHYLPROPANAMIDE: Prepared
by Procedure T and Scheme AD using N- (3-(1- [ (3S) -3- (3-
acetylphenoxy)-3-phenylpropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and methyl iodide: ESMS m/e: 513.2 (M
+ H)+.
Example 356
N-(3-fl-[(2S)-3-(4-BROMOPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 4-bromophenyl (2R)-3-
chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M + H)~.
2 5 Example 357
2-METHYL-N-(3-~1-[(2S)-2-METHYL-3-(2,4,5-
TRIFLUOROPHENOXY)PROPYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure G
and Scheme B1 using 1-{ [ (2R) -3-chloro-2-
methylpropyl]oxy~-2,4,5-trifluorobenzene and 2-methyl-N-
[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 449.2 (M
+ H)+.
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Example 358
N-(3-~1-[(2S)-3-(3-CHLOROPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-chloro-3-{[(2R)-3-
chloro-2-methylpropyl]oxy~benzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 429.2 (M + H)+.
Example 359
N-(3-~1-[(2S)-3-(4-FLUOROPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-([(2R)-3-chloro-2
methylpropyl]oxy}-4-fluorobenzene and 2-methyl-N-[3-(4
piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M + H)+.
Example 360
N-(3-~1-[(2S)-3-(3-FLUOROPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-~[(2R)-3-chloro-2-
methylpropyl]oxy}-3-fluorobenzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M + H)+.
Example 361
N-(3-~l-[(2S)-3-(2-CHLOROPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-chloro-2-{[(2R)-3-
chloro-2-methylpropyl]oxy}benzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 429.1 (M + H)+.
Example 362
N-(3-~1-[(2S)-3-(2-FLUOROPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-{[(2R)-3-chloro-2-
methylpropyl]oxy~-2-fluorobenzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M + H)+.
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Example 363
N-(3-~1-[(2S)-3-(4-CHLOROPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-chloro-4-~[(2R)-3-
chloro-2-methylpropyl]oxy}benzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 429.2 (M + H)+.
Example 364
N-(3-~1-[(2S)-3-(3-BROMOPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 3-bromophenyl (2R)-3-
chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 474.0 (M + H)+.
Example 365
N-(3-~1-[(2S)-3-(2-BROMOPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 2-bromophenyl (2R)-3-
chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M + H)+.
Example 366
N-(3-~1-[(2R)-3-(3-FLUOROPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme Bl using 1-~[(2S)-3-chloro-2
methylpropyl]oxy~-3-fluorobenzene and 2-methyl-N-[3-(4
piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M + H)+.
Example 367
N-(3-~1-[(2R)-3-(4-FLUOROPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-~[(2S)-3-chloro-2-
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methylpropyl]oxy~-4- fluorobenzene and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
413.8 (M + H)+.
Example 368
N-(3-~1-[(2R)-3-(2-CHLOROPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-chloro-2-{[(2S)-3-
chloro-2-methylpropyl]oxy}benzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS in/e: 429.1 (M + H)+.
Example 369
N-(3-{1-[(2R)-3-(4-CHLOROPHENOXY)-~-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-chloro-4-{[(2S)-3-
chloro-2-methylpropyl]oxy~benzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 429.1 (M + H)+.
Example 370
N-(3-{1-[(ZR)-3-(4-BROMOPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 4-bromophenyl (2S)-3-
chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M + H)~.
Example 371
N-(3-{1-[(2R)-3-(3-BROMOPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 3-bromophenyl (2S)-3-
chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M + H)~.
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Example 372
N-(3-~1-[(2R)-3-(2-BROMOPHENOXY)-2-METHYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1'using 2-bromophenyl (2S)-3-
chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M + H)+.
Example 373
N-(3-{1- [ (2R) -3- (3-CHLOROPHENOXY) -2-METHYLPROPYL] -4-
PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-chloro-3-([(2S)-3
chloro-2-methylpropyl]oxy~benzene and 2-methyl-N-[3-(4
piperidinyl)phenyl]propanamide: ESMS m/e: 429.1 (M + H)+.
Example 374
N-(3-~1-[3-(5,5-DIMETHYL-1,3-DIOXAN-2-YL)PROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 2-(3-bromopropyl)-5,5-
dimethyl-1,3-dioxane and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 403.2 (M + H)+
Example 375
N-(3-~1- [4- (3-ACETYLPHENOXY)BUTYL] -4-
PIPERIDTNYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-[3-(4-
chlorobutoxy)phenyl]ethanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 437.2 (M + H)+.
Example 376
N-(3-~I-[4-(3-METHOXYPHENOXY)BUTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-(4-chlorobutoxy)-3-
methoxybei~.zene and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M + H)+.
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Example 377
N-(3-~1-[4-(4-METHOXYPHENOXY)BUTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-(4-chlorobutoxy)-4-
methoxybenzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M + H)+.
Example 378
N- ( 3 - ~ 1- [ 4 - ( 2 -METHOXYPHENOXY) BUTYL] - 4 -
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-(4-chlorobutoxy)-2-
methoxybenzene and 2-methyl-N-[3-(4-'
piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M + H)+.
Example 379
N-(3-~1- [4- (3,4-DIMETHYLPHENOXY)BUTYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 4-(4-chlorobutoxy)-1,2-
dimethylbenzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 423.2 (M + H)+.
Example 380
N-(3-~1-[4-(1,3-DIOXOLAN-2-YL)BUTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 2-(4-chlorobutyl)-1,3-
dioxolane and. 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 375.2 (M + H)+
3 0 Example 381
N-(3-~1-[5-(3-ACETYLPHENOXY)PENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-{3-[(5-
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chloropentyl)oxy]phenyl}ethanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 451.3 (M + H)+.
Example 382
N-(3-~1-[5-(3-ACETYLPHENOXY)PENTYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure G and Scheme B1 using 1-~3-[(5-
chl oropentyl ) oxy] phenyl } ethanone and N- [ 3 - ( 4 -
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
449.2 (M + H)+.
Example 383
N-(3-~1-[6-(3-ACETYLPHENOXY)HEXYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-~3-[(6-
chlorohexyl)oxy]phenyl}ethanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 465.-3 (M + H)+.
Example 384
N-(3-~1-[6-(3-ACETYLPHENOXY)HEXYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure G and Scheme B1 using 1-~3-[(6-
chlorohexyl)oxy]phenyl~ethanone and N-[3-(4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
463.3 (M + H)+.
Example 385 .
N-(3-~1- [4- (4-CHLOROPHENOXY) -4- (4-CHLOROPHENYL) BUTYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure B and Scheme AN using 4-chlorophenol and N-(3-
{1-[4-(4-chlorophenyl)-4-hydroxybutyl]-4-
piperidinyl~phenyl)-2-methylpropanamide: ESMS m/e: 562.9
(M + 23)+.
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Example 386
2-METHYL-N-(3-~1-[2-(1-METHYL-2-PHENYL-1H-INDOL-3-
YL)ETHYL]-4-PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-~3-[1-(4-oxo-
4-phenylbutyl)-4-piperidinyl]phenyl~propanamide and 1-
methyl-1-phenylhydrazine: ESMS m/e: 480.3 (M + H)+.
Example 387
2-METHYL-N-(3-~1-[2-(2-PHENYL-1H-BENZO[G]INDOL-3-
YL)ETHYL]-4-PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-{3-[1-(4-oxo-
4-phenylbutyl)-4-piperidinyl]phenyl~propanamide and 1-
(1-naphthyl)hydrazine hydrochloride: ESMS m/e: 516.4 (M
+ H)+
Example 388
2-METHYL-N-(3-~1-[3-(2-PHENYL-1H-BENZO[G]INDOL-3-
YL)PROPYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared
by Procedure E and Scheme M using 2-methyl-N-f3-[1-(5-
oxo-5-phenylpentyl)-4-piperidinyl]phenyl)propanamide and
1-(1-naphthyl)hydrazine hydrochloride: ESMS m/e: 530..2
(M + H)''.
Example 389
2-METHYL-N-[3-(1-~3-[2-PHENYL-5-(TRIFLUOROMETHOXY)-1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]PROPANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
{3-[1-(5-oxo-5-phenylpentyl)-4- .
piperidinyl]phenyl~propanamide and 1-[4-
(trifluoromethoxy)phenyl]hydrazine hydrochloride: ESMS
m/e . 564.2 (M + H)+.
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Example 390
2-METHYL-N- [3- (1-{4- [2-PHENYL-5- (TRIFLUOROMETHOXY) -1H-
IN~OL-3-YL]BUTYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
{3-[1-(6-oxo-6-phenylhexyl)-4-
piperidinyl]phenyl~propanamide and 1-[4-
(trifluoromethoxy)phenyl]hydrazine hydrochloride: ESMS
m/e: 578.2 (M + H)+.
Example 391
_ ~ 2-METHYL-N-(3-{1-[3-(1-METHYL-2-PHENYL-1H-INDOL-3-
YL)PROPYL]-4-PIPERIDINYL~PHENYL)PROP.ANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-{3-[1-(5-oxo-
5-phenylpentyl)-4-piperidinyl]phenyl~propanamide and 1-
methyl-1-phenylhydrazine: ESMS m/e: 495.3 (M + H)+.
Example 392
N-(3-{1-[4-(1,2-DIPHENYL-1H-INDOL-3-YL)BUTYL]-4-
PIPERIDINYL}PI~ENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-~3-[1-(6-oxo-
6-phenylhexyl)-4-piperidinyl]phenyl~propanamide and
1,1-diphenylhydrazine hydrochloride: ESMS m/e: (M + H)+.
570.3
Example 393
2-METHYL-N-[3-(1-{5-[2-PHENYL-5-(TRIFLUOROMETHOXY)-1H-
INDOL-3-YL]PENTYL}-4-PIPERIDINYL)PHENYL]PROPANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
{3-[1-(7-oxo-7-phenylheptyl)-4-
piperidinyl]phenyl~propanamide and 1-[4-
(trifluoromethoxy)phenyl]hydrazine hydrochloride: ESMS
m/e: 592.3 (M + H)+.
Example 394
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N- (3-{1- [5- (1,2-DIPHENYL- 1H-INDOL-3-YL) PENTYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-~3-[1-(7-oxo-
7-phenylheptyl)-4-piperidinyl~phenyl~propanamide and
1,1-diphenylhydrazine hydrochloride: ESMS m/e: 584.3 (M
+ H)+.
Example 395
2-METHYL-N-(3-{1-[5-(1-METHYL-2-PHENYL-1H-INDOL-3-
YL)PENTYL]-4-PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-~3-[1-(7-oxo-
7-phenylheptyl)-4-piperidinyl]phenyl~propanamide and 1-
methyl-1-phenylhydrazine: ESMS m/e: 522.3 (M + H)+.
Example 396
2-METHYL-N- (3-{1- [4- (2-PHENYL-1H-BENZO [G] INDOL-3-
YL)BUTYL]-4-PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-{3-[1-(6-oxo-
6-phenylhexyl)-4-piperidinyl~phenyl~propanamide and 1-
(1-naphthyl)hydrazine hydrochloride: ESMS m/e: 544.3 (M
+ H)+.
Example 397
2-METHYL-N-(3-~1-[4-(1-METHYL-2-PHENYL-1H-INDOL-3-
YL)BUTYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-{3-[1-(6-oxo-
6-phenylhexyl)-4-piperidinyl]phenyl~propanamide and 1-
methyl-1-phenylhydrazine: ESMS m/e: 508.3 (M.+ H)+.
Example 398
2-METHYL-N- (3-{1- [5- (2-PHENYL-1H-BENZO [G] INDOL-3-
YL)PENTYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared
by Procedure E and Scheme M using 2-methyl-N-{3-[1-(7-
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oxo-7-phenylheptyl)-4-
piperidinyl]phenyl~propanamide and 1-(1-
naphthyl)hydrazine hydrochloride: ESMS m/e: 558.2 (M +
H) +.
Example 399
2-METHYL-N-(3-f1-[2-(5-METHYL-2-PHENYL-1H-INDOL-3-
YL)ETHYL]-4-PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-~3- [1- (4-oxo-
4-phenylbutyl)-4-piperidinyl]phenyl~propanamide and 1-
(4-methylphenyl)hydrazine hydrochloride: ESMS m/e: 480.2
(M + H)+.
Example 400
N-(3-~1-[2-(7-METHOXY-2-PHENYL-1H-INDOL-3-YL)ETHYL]-4-
PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-f3-[1-(4-oxo-
4-phenylbutyl)-4-piperidinyl]phenyl~propanamide and 1-
(2-methoxyphenyl)hydrazine hydrochloride: ESMS m/e:
496.2 (M + H)+.
Example 401
2-METHYL-N-(3-~1-C2-(7-METHYL-2-PHENYL-1H-INDOL-3-
YL)ETHYL]-4-PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-~3-[1-(4-oxo-
4-phenylbutyl)-4-piperidinyl]phenyl~propanamide and 1-
(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 480.2
(M + H)+. .
Example 402
N-(3-f1-[3-(7-METHOXY-2-PHENYL-1H-INDOL-3-YL)PROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-~3-[1-(5-oxo-
5-phenylpentyl)-4-piperidinyl]phenyl~propanamide and 1-
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5-phenylpentyl)-4-
piperidinyl]phenyl}propanamide and 1-(2-
methoxyphenyl)hydrazine hydrochloride: ESMS m/e: 510.2
(M + H)+.
Example 403
2-METHYL-N-(3-~1-[4-(7-METHYL-2-PHENYL-1H-INDOL-3-
YL)BUTYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared
by Procedure E and Scheme M using 2-methyl-N-(3-[1-(6-
oxo-6-phenylhexyl)-4-piperidinyl]phenyl~propanamide and
1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e:
508.3 (M + H)+.
Example 404
N-(3-~1-[2-(5-METHOXY-2-PHENYL-1H-INDOL-3-YL)ETHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-~3-[1-(4-oxo-
4-phenylbutyl)-4-piperidinyl]phenyl~propanamide and 1-
(4-methoxyphenyl)hydrazine hydrochloride: ESMS m/e:
496.2 (M + H)+.
Example 405
2-METHYL-N-(3-~1-[3-(5-METHYL-2-PHENYL-1H-INDOL-3-
YL)PROPYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared
by Procedure E and Scheme M using 2-methyl-N-{3-[1-(5-
oxo-5-phenylpentyl)-4-piperidinyl]phenyl)propanamide and
1-(4-methylphenyl)hydrazine hydrochloride: ESMS m/e:
494 . 3 (M + H) +.
Example 406
N-(3-{1-[4-(7-METHOXY-2-PHENYL-1H-INDOL-3-YL)BUTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE
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Prepared by Procedure E and Scheme M using 2-
methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-
piperidinyl]phenyl}propanamide and 1-(2-
methoxyphenyl)hydrazine hydrochloride: ESMS m/e: 524.3
(M + H)+.
Example 407
2-METHYL-N-(3-~1-[3-(1-PHENYL-1H-INDOL-3-YL)PROPYL~-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure H
and Scheme S using N- (3-{1- [4- (1, 3-dioxolan-2-yl) butyl] -
4-piperidinyl)phenyl)-2-methylpropanamide and l,l-
diphenylhydrazine hydrochloride: ESMS m/e: 480.2 (M +
H)+.
Example 408
2-METHYL-N-(3-f1-[2-(1-PHENYL-1H-INDOL-3-YL)ETHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure H
and Scheme S using N-(3-{1-[3-(1,3-dioxolan-2-
yl)propyl]-4-piperidinyl~phenyl)-2-methylpropanamide and
1,1-diphenylhydrazine hydrochloride: ESMS m/e: 466.2 (M
+ H)+.
Example 409
2-METHYL-N-(3-~1-[2-(7-METHYL-1H-INDOL-3-YL)ETHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure H
and Scheme S using N-(3-{1-[3-(1,3-dioxolan-2-
yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and
1-(2-methylphenyl)hydrazine hydrochloride:. ESMS m/e:
404.2 (M + H)+.
Example 410
2-METHYL-N-(3-~1-[2-(1-METHYL-1H-INDOL-3-YL)ETHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure
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H and Scheme S using N- (3- ~1- [3- (l, 3-dioxolan-2-
yl)propyl]-4-piperidinyl~phenyl)-2-methylpropanamide and
1-methyl-1-phenylhydrazine: ESMS m/e: 404.2 (M + H)+.
Example 411
2-METHYL-N-(3-{1-[2-(5-METHYL-1H-INDOL-3-YL)ETHYL]-4-
PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure
H and Scheme S using N-(3-~1-[3-(1,3-dioxolan-2-
yl)propyl]-4-piperidinyl~phenyl)-2-methylpropanamide and
1-(4-methylphenyl)hydrazine hydrochloride: ESMS m/e:
404.2 (M + H)+.
Example 412
2-METHYL-N-[3-(1-~2-[5-(TRIFLUOROMETHOXY)-1H-INDOL-3-
YL]ETHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by
Procedure H and Scheme S using N-(3-~1-[3-(1,3-dioxolan-
2-yl)propyl]-4-piperidinyl~phenyl)-2-methylpropanamide
and 1- [4- (trifluoromethoxy) phenyl] hydrazine
hydrochloride: ESMS m/e: 474.2 (M + H)~.
Example 413
N- (3-~1- [3- (1H-BENZO [G] INDOL-3-YL) PROPYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure H and Scheme S using N-(3-{1-[4-(1,3-dioxolan-
2-yl)butyl]-4-piperidinyl~phenyl)-2-methylpropanamide
and 1-(1-naphthyl)hydrazine hydrochloride: ESMS 454.2
m/e: (M + H)+.
Example 414
2-METHYL-N-(3-~1-[3-(1-METHYL-1H-INDOL-3-YL)PROPYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure H
and Scheme S. A mixture of N-(3-~1-[4-(1,3-dioxolan-2-
yl)butyl]-4-piperidinyl~phenyl)-2-methylpropanamide (100
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mg, 0.270 mmol), 1-methyl- 1-phenylhydrazine (106 mg,
0.870 mmol), ZnCl2 (119 mg, 0.870 mmol) and HOAc (1.00
mL) was heated for 12 h at 80 °C. The resulting crude
mixture was diluted with water (20 mL), the aqueous
layer was neutralized with a saturated KzC03 solution (10
mL) and extracted with CHZCla (3 X 20 mL) . The combined
organic layers were concentrated in vacuo and the
residue was purified by preparative TLC using 3 % of NH3
(2.0 M in methanol) in CHZC1~ to give the desired product
2-methyl-N-(3-f1-[3-(1-methyl-1H-indol-3-yl)propyl]-4-
piperidinyl}phenyl)propanamide (20.7 mg, 18.7 o): 1H NMR
(400 MHz, CDC13) 5 7.60 (d, 1H, J - 8.1 Hz), 7.45 (s,
1H) , 7.35 (d, 1H, J - 7.4 Hz) , 7.25 (m, 4H) , 7.09 (t,
1H, J = 7.3 Hz) , 6.97 (d, 1H, J = 7.3 Hz) , 6.86 (s, 1H) ,:
3 .75 (s, 3H) , 3 .11 (d, 2H, J = 11.6 Hz) , 2.79 (t, 2H, J
- 7.3 Hz), 2.51 (m, 4H), 2.12-1.81 (m, 8H), 1.25 (d, 6H,
J - 7.1 Hz) ; Anal. Calcd for CZ~H35N3O+0.225 CHC13: C,
73.57; H, 7.99; N, 9.45. Found: C, 73.93; H, 7.90; N,
9.23; ESMS m/e: 418.2 (M + H)+.
Example 415
2-METHYL-N-(3-~1-[3-(5-METHYL-1H-INDOL-3-YL)PROPYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure
H and Scheme S using N-(3-~1-[4-(1,3-dioxolan-2-
yl)butyl]-4-piperidinyl~phenyl)-2-methylpropanamide and
1-(4-methylphenyl)hydrazine hydrochloride: ESMS m/e:
418.2 (M + H)'".
Example 416
2-METHYL-N-[3-(1-f3-[5-(TRIFLUOROMETHOXY)-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by
Procedure'H and Scheme S using N-(3-~1-[4-(1,3-dioxolan-
2-yl)butyl]-4-piperidinyl~phenyl)-2-methylpropanamide
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and 1- [4-
(trifluoromethoxy)phenyl]hydrazine hydrochloride: ESMS
m/e: 488.2 (M + H)+.
Example 417
2-METHYL-N-(3-~1-[3-(7-METHYL-1H-INDOL-3-YL)PROPYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure H
and Scheme S using N- (3- f 1- [4- (1, 3-dioxolan-2-yl)butyl] -
4-piperidinyl~phenyl)-2-methylpropanamide and 1-(2
IO methylphenyl)hydrazine hydrochloride: ESMS m/e: 418.2 (M
+ H)~.
Example 418
N-(3-~1-[3-(7-METHOXY-1H-INDOL-3-YL)PROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure H and Scheme S using N-(3-~1-[4-(1,3-dioxolan-
2-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide
and 1-(2-methoxyphenyl)hydrazine hydrochloride: ESMS
m/e: 434.0 (M + H)+.
Example 419
N- (3-~1- [2- (7-METHOXY-1H-INDOL-3-YL) ETHYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure H and Scheme S using N- (3-~l- [3- (l, 3-dioxolan-
2-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide
and 1-(2-methoxyphenyl)hydrazine hydrochloride: ESMS
m/e: 420.2 (M + H)+.
Example 420
N-(3-~1-[2-(5-METHOXY-1H-INDOL-3-YL)ETHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure H and Scheme S using N- (3- f 1- [3- (1, 3-dioxolan-
2-yl)propyl]-4-piperidinyl~phenyl)-2-methylpropanamide
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and 1-(4- methoxyphenyl)hydrazine
hydrochloride: ESMS m/e: 420.2 (M + H)+.
Example 421
2-METHYL-N-(3-~1-[4-(5-METHYL-2-PHENYL-1H-INDOL-3-
YL)BUTYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-~3-[1-(6-oxo-
6-phenylhexyl)-4-piperidinyl]phenyl}propanamide and 1-
(4-methylphenyl)hydrazine hydrochloride: ESMS m/e: 508.3
(M + H)+.
Example 422
2-METHYL-N-[4-(1-~[1-(4-METHYLPHENYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by
Procedure D and Scheme N using 2-methyl-N-[4-(4-
piperidinyl)phenyl]propanamide and 1-(4-methylphenyl)-
1H-indole: ESMS m/e: 466.2 (M + H)+.
Example 423
N-[4-(1-~[1-(4-METHYLPHENYL)-1H-INDOL-3-YL]METHYL-4-
PIPERIDINYL)PHENYL]BUTANAMIDE; Prepared by Procedure D
and Scheme N using N-[4-(4-piperidinyl)phenyl]butanamide
and 1-(4-methylphenyl)-1H-indole: ESMS m/e: 466.2 (M +
H)+.
Example 424
N- [3- (1-~ [2- (2-AMINOPHENYL) -1H-INDOL-3-YL] METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide and 2-(1H-indol-2-
yl)aniline: ESMS m/e: 467.2 (M + H)+.
Example 425
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ETHYL 3-(~4-[3- (ISOBUTYRYLAMINO)PHENYL]-
1-PIPERIDINYL~METHYL)-1H-INDOLE-2-CARBOXYLATE: Prepared
by Procedure D and Scheme N using 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide and ethyl 1H-indole-2-
carboxylate: ESMS m/e: 448.2 (M + H)+.
Example 426
2-METHYL-N-(3-~1-[(1-METHYL-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure D
and Scheme N using 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide and 1-methyl-1H-indole:
ESMS m/e: 390.2 (M + H)+.
Example 427
N-(3-~1-[(5-METHOXY-2-METHYL-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 2-methyl-N-[3-(4-
piperidiriyl)phenyl]propanamide and 5-methoxy-2-methyl-
1H-indole: ESMS m/e: 420.2 (M + H)+.
Example 428 .
2-METHYL-N-(3-~l-[(1-METHYL-2-PHENYL-1H-INDOL-3-
YL)METHYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by
Procedure D and Scheme N using 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide and 1-methyl-2-phenyl-1H-
indole: ESMS m/e: 466.2 (M + H)+.
Example 429 .
2-METHYL-N-(3-~1-[(5-NITRO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure D
and Scheme N using 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide and 5-nitro-1H-indole:
ESMS m/e: 421.1 (M + H)+.
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Example 430
2-METHYL-N-(3-~1-[(2-METHYL-1H-INDOL-3-YL)METHYL]-4-
PIPERIDTNYL~PHENYL)PROPANAMIDE: Prepared by Procedure D
and Scheme N using 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide and 2-methyl-1H-indole:
ESMS m/e.: 390.2 (M + H)+. .
Example 431
N-(3-fl-[(4-BROMO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide and 4-bromo-1H-indole:
ESMS m/e: 455.0 (M + H)+.
Example 432
N- [3- (1-~ [2- (4-FLUOROPHENYL) -1H-INDOL-3-YL] METHYL}-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide and 2-(4-fluorophenyl)-
1H-indole: ESMS m/e: 470.0 (M + H)+.
Example 433
N-(3-~1-[(1,2-DIPHENYL-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide and 1,2-diphenyl-1H-
indole: ESMS m/e: 528.2 (M + H)+. .
Example 434
N- [3- (1-~ [2- (4-CHLOROPHENYL) -1-ETHYL-1H-INDOL-3-
YL]METHYL}-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure D and Scheme N using 2-methyl-N-
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[3- (4-
piperidinyl)phenyl]propanamide and 2-(4-chlorophenyl)-1-
ethyl-1H-indole: ESMS m/e: 514.1 (M + H)+.
Example 435
N-(3-~l-[(5-CHLORO-2-METHYL-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide and 5-chloro-2-methyl-1H-
indole: ESMS m/e: 424.1(M + H)+.
Example 436
N-(3-{1-[(5-CYANO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide and 1H-indole-5-
carbonitrile: ESMS m/e: 401.1 (M + H)+.
Example 437
2-METHYL-N-(3-{1-[(5-METHYL-2-PHENYL-1H-INDOL-3-
YL)METHYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by
Procedure D and Scheme N using
2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 5-
methyl-2-phenyl-1H-indole: ESMS m/e: 466.2 (M + H)+.
Example 438
2-METHYL-N-[3-(1-~[1-(4-NITROPHENYL)-1H-INDOL-3-
YL] METHYL-4-PIPERIDINYL) PHENYL] PROPANAMIDE:. Prepared by
Procedure D and Scheme N using 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide and 1-(4-nitrophenyl)-1H-
indole: ESMS m/e: 497.2 (M + H)+.
Example 439
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N- [3- (1-~ [1- (2- FLUOROPHENYL) -1H-INDOL-3-
YL]METHYL}-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure D and Scheme N using 2-methyl-N-
[3-(4-piperidinyl)phenyl]propanamide and 1-(2-
fluorophenyl)-1H-indole: ESMS m/e: 470.1 (M + H)+.
Example 440
N-(3-fl-[(5,6-DIMETHOXY-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL}PHENYL)-2-METHYLPROP,ANAMIDE: Prepared by
Procedure D and Scheme N using 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide and 5,6-dimethoxy-1H-
indole: ESMS m/e: 436.2 (M + H)+.
Example 441
2-METHYL-N-[3-(1-~[1-(3-METHYLPHENYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by
Procedure D and Scheme N using 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide and 1-(3-methylphenyl)-
1H-indole: ESMS m/e: 466.2 (M + H)'".
Example 442
2-METHYL-N-~3-[1-(~l-[3-(TRIFLUOROMETHYL)PHENYL]-1H-
INDOL-3-YL~METHYL)-4-PIPERIDINYL]PHENYL~PROPANAMIDE:
Prepared by Procedure D and Scheme N using 2-methyl-N-
[3-(4-piperidinyl)phenyl]propanamide and 1-[3-
(trifluoromethyl)phenyl]-1H-indole: ESMS m/e: 520.2 (M +
H)+.
Example 443
N- [3- (1-{ [l- (4-METHOXYPHENYL) -1H-INDOL-3-YL]METHYL}-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 2-methyl-N-[3-(4-
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piperidinyl)phenyl]propanamide and 5-methoxy-2-phenyl-
1H-indole: ESMS m/e: 482.2 (M + H)+.
Example 445
2-METHYL-N-(3-f1-[(5-METHYL-1H-INDOL-3-YL)METHYL]-4-
PIPERTDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure D
and ' Scheme N using 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide and 5-methyl-1H-indole:
ESMS m/e: 390.2 (M + H)+.
Example 446
N-[3-(1-~[1-(2-NITROPHENYL)-1H-INDOL-3-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 1-(2-nitrophenyl)-1H-
indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 497.2 (M~+ H)+.
Example 447
N- [3- (1-~ [1- (2-METHOXYPHENYL) -1H-INDOL-3-YL] METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using l-(2-methoxyphenyl)-1H-
indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 482.2 (M + H)+.
Example 448
2-METHYL-N-~3-[1-(~1-[2-(TRIFLUOROMETHYL)PHENYL]-1H-
INDOL-3-YL~METIiYL)-4-PIPERIDINYL]PHENYL~PROPANAMIDE:
Prepared by Procedure D and Scheme N using 1-[2-
(trifluoromethyl)phenyl] -1H-indole, and 2-methyl-N- [3-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 520.2 (M +
H)+
Example 449
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N-(3-~1-[(5-METHOXY-1H- INDOL-3-YL)METHYL]-4-
PIPERTDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 1H-indol-5-yl methyl
ether and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 406.2 (M + H)+.
Example 450
N- [3- (1-~ [1- (4-FLUOROPHENYL) -1H-INDOL-3-YL] METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 1-(4-fluorophenyl)-1H-
indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 470.2 (M + H)+.
Example 451
N-[3-(1-{[1-(3-METHOXYPHENYL)-1H-INDOL-3-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 1-(3-methoxyphenyl)-1H-
indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 482.2 (M + H)+.
Example 452
2-METHYL-N-[3-(1-~[1-(2-METHYLPHENYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE; Prepared by
Procedure D and Scheme N using 1-(2-methylphenyl)-1H-
indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 466.2 (M + H)+.
Example 453
ETHYL 3-(~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~METHYL)-5-METHOXY-1H-INDOLE-2-CARBOXYLATE:
Prepared by Procedure D and Scheme N using ethyl 5-
methoxy-1H-indole-2-carboxylate and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 478.2 (M + H)+.
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Example 454
N-(3-~l-[(5-FLUORO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 5-fluoro-1H-indole and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
394 .2 (M + H) +.
1-PHENYL-1H-INDOLE: Prepared by Procedure C and Scheme O
using 1H-indole and iodobenzene: ESMS m/e: 193.9 (M +
H)+.
1-(4-CHLOROPHENYL)-1H-INDOLE: Prepared by Procedure C
and Scheme O using 1H-indole and 1-chloro-4-iodobenzene:
ESMS m/e: 227.9 (M + H)+.
1-(3-CHLOROPHENYL)-1H-INDOLE: Prepared by Procedure C
and Scheme O using 1H-indole and 1-chloro-3-iodobenzene:
ESMS m/e: 227.9 (M + H)+.
1-(2-CHLOROPHENYL)-1H-INDOLE: Prepared by Procedure C
and Scheme O using 1H-indole and 1-chloro-2-iodobenzene:
ESMS m/e: 227.9 (M + H)+.
1-[2-(TRIFLUOROMETHYL)PHENYL]-1H-INDOLE: Prepared by
Procedure C and Scheme O using 1H-indole and 1-iodo-2
(trifluoromethyl)benzene: ESMS m/e: 262.0 (M + H)+.
4-(1H-INDOL-1-YL)BENZONITRILE: Prepared by Procedure C
and Scheme O using 1H-indole and 4-iodobenzonitrile:
ESMS m/e: 219.0 (M + H)+.
1-(4-NITROPHENYL)-1H-INDOLE: Prepared by Procedure C
and Scheme O using 1H-indole and 1-iodo-4-nitrobenzene:
ESMS m/e: 238.2 (M + H)+.
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1-(2-NITROPHENYL)-1H-INDOLE: Prepared by Procedure C
and Scheme O using 1H-indole and 1-iodo-2-nitrobenzene:
ESMS m/e: 238.2 (M + H)+.
Example 455 .
N-[3-(1-~[1-(4-CHLOROPHENYL)-1H-INDOL-3-YL]METHYL-4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure D
and Scheme N using 1-(4-chlorophenyl)-1H-indole and N-
[3-(4-piperidiriyl)phenyl]propanamide: ESMS m/e: 472.1 (M
+ H)+.
Example 456
N-[3-(1-~[1-(3-CHLOROPHENYL)-1H-INDOL-3-YL]METHYL-4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure D
and Scheme N using 1-(3-chlorophenyl)-1H-indole and N-
[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 472.1 (M
+ H)+.
Example 457
N- [3- (1-~ [1- (2-CHLOROPHENYL) -1H-INDOL-3-YL]METHYL}-4-
PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure D and Scheme N using 1-(2-chlorophenyl)-.1H-
indole and N- [3- (4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
484.1 (M + H)+.
Example 458
N-[3-(1-~[1-(3-CHLOROPHENYL)-1H-INDOL-3-YL]METHYL-4-
PTPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 1-(3-chlorophenyl)-1H-
indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 486.1 (M + H)+.
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Example 459
N- [3- (1-{ [1- (4-CHLOROPHENYL) -1H-INDOL-3-YL] METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 1-(4-chlorophenyl)-1H-
indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 486.2 (M + H)+.
Example 460
N-[3-(1-f[1-(2-CHLOROPHENYL)-1H-INDOL-3-YL]METHYL}-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 1-(2-chlorophenyl)-1H-
indole and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 486.2 (M + H)+.
Example 461
N- [3- (1-~ [1- (2-CHLOROPHENYL) -1H-INDOL-3-YL] METHYL-4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure D
and Scheme N using 1-(2-chlorophenyl)-1H-indole and N-
[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 472.1 (M
+ H)+.
Example 462
N-[3-(1-~[1-(4-CHLOROPHENYL)-1H-INDOL-3-YL]METHYL}-4-
PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure D and Scheme N using 1-(4-chlorophenyl)-1H-
indole and N- [3- (4-
piperidinyl)phenyl]cyclopropanecarboxamide: . ESMS m/e:
484.1 (M + H)+.
Example 463
N- [3- (1-~ [1- (3-CHLOROPHENYL) -1H-INDOL-3-YL] METHYL-4-
PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE: Prepared by
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Procedure D and Scheme N using 1-(3-chlorophenyl)-
1H-indole and N-[3-(4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
484.1 (M + H)".
Example 464
N-(3-~l-[(1-PHENYL-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure D
and Scheme N using 1-phenyl-1H-indole and N-(3-(4-
piperidinyl)phenyl]propanamide: ESMS rn/e: 438.2 (M + H)+.
Example 465
N-(3-~2-[(1-PHENYL-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL}PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure D and Scheme N using 1-phenyl-1H-indole and N-
[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS
m/e: 450.2 (M + H)+.
6-CHLORO-1-(4-NITROPHENYL)-1H-INDOLE: Prepared by
Procedure C and Scheme O using 6-chloro-1H-indole and 1
iodo-4-nitrobenzene: ESMS m/e: 272.6 (M + H)+.
6-CHLORO-1-(2,3-DICHLOROPHENYL)-1H-INDOLE: Prepared by
Procedure C and Scheme O using 6-chloro-1H-indole and
1,2-dichloro-3-iodobenzene: ESMS m/e: 296.5 (M + H)+.
6-CHLORO-1-(3-METHYLPHENYL)-1H-INDOLE: Prepared by
Procedure C and Scheme O using 6-chloro-1H-indole and 1-
iodo-3-methylbenzene: ESMS m/e: 241.9 (M + H)+.
6-CHLORO-1-~(2-METHYLPHENYL)-1H-INDOLE: Prepared by
Procedure C and Scheme O using 6-chloro-1H-indole and 1-
iodo-2-methylbenzene: ESMS m/e: 241.9 (M + H)+.
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2-(6-CHLORO-1H-INDOL-1-YL)PHENYL METHYL ETHER: Prepared
by Procedure C and Scheme O using 6-chloro-1H-indole and
1-iodo-2-methoxybenzene: ESMS m/e: 257.9 (M + H)+.
6-CHLORO-1-[3-(TRIFLUOROMETHYL)PHENYL]-1H-INDOLE:
Prepared by Procedure C and Scheme O using 6-chloro-1H-
indole and 1-iodo-3-(trifluoromethyl)benzene: ESMS m/e:
295.6 (M + H)+.
6-CHLORO-1-(2-FLUOROPHENYL)-1H-INDOLE: Prepared by
Procedure C and Scheme O using 6-chloro-1H-indole and 1-
fluoro-2-iodobenzene: ESMS m/e: 245.9 (M + H)+.
6-CHLORO-1-(3-CHLOROPHENYL)-1H-INDOLE: Prepared by
Procedure C and Scheme O using 6-chloro-1H-indole and 1-
chloro-3-iodobenzene: ESMS m/e: 261.9 (M + H)+.
6-CHLORO-1-(4-CHLOROPHENYL)-1H-INDOLE: Prepared by
Procedure C and Scheme O using 6-chloro-1H-indole and 1
chloro-4-iodobenzene: ESMS m/e: 262.9 (M + H)+.
6-CHLORO-1-(2-CHLOROPHENYL)-1H-INDOLE: Prepared by
Procedure C and Scheme O using 6-chloro-1H-indole and 1
chloro-2-iodobenzene: ESMS m/e: 262.9 (M + H)+.
3-(6-CHLORO-1H-INDOL-1-YL)PHENYL METHYL ETHER: Prepared
by Procedure C and Scheme O using 6-chloro-1H-indole and
1-iodo-3-methoxybenzene: ESMS m/e: 257.9 (M + H)+.
6-CHLORO-1-[4-(TRIFLUOROMETHYL)PHENYL]-1H-INDOLE:
Prepared by Procedure C and Scheme O using 6-chloro-1H-
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indole and 1-iodo-4- (trifluoromethyl)benzene
ESMS m/e: 295.6 (M + H)+.
6-CHLORO-1-(4-METHYLPHENYL)-1H-INDOLE: Prepared by
Procedure C and Scheme O using 6-chloro-1H-indole and 1
iodo-4-methylbenzene: ESMS m/e: 241.9 (M + H)+.
6-CHLORO-1-(4-FLUOROPHENYL)-1H-INDOLE: Prepared by
Procedure C and Scheme O using 6-chloro-1H-indole and 1
fluoro-4-iodobenzene: ESMS m/e: 245.9 (M + H)+.
Example 466
N-[3-(1-~[6-CHLORO-1-(4-FLUOROPHENYL)-1H-INDOL-3-
YL]METHYL -4-PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE:
Prepared by Procedure D and Scheme N using 6-chloro-1-
(4-fluorophenyl) -1H-indole and N- [3- (4-
piperidinyl)'phenyl]cyclopropanecarboxamide: ESMS m/e:
502 . 1 (M + H) +.
Example 467
N-[3-(1-~[6-CHLORO-1-(4-FLUOROPHENYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYLJPROPANAMIDE: Prepared by
Procedure D and Scheme N using 6-chloro-1-(4-
fluorophenyl) -1H-indole and N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 490.1 (M + H)+.
Example 468
N-(3-~1-[(6-FLUORO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure D
and Scheme N using 6-fluoro-1H-indole and N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 380.1 (M + H)+.
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Example 469
N-(3-~1-[(6-FLUORO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure D and Scheme N using 6-fluoro-1H-indole and N-
[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS
m/e: 392.1 (M + H)+.
Example 470
N-(3-~1-[(6-FLUORO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 6-fluoro-1H-indole and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
394.1 (M + H)+.
Example 471
N- [3- (1-~ [6-CHLORO-1- (4-FLUOROPHENYL) -1FI-INDOL-3-
YL]METHYL -4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure D and Scheme N usir~g 6-chloro-1-
(4-fluorophenyl) -1H-indole and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 504.1 (M + H)+.
Example 472
N-[3-(1-~[6-CHLORO-1-(2-FLUOROPHENYL)-1H-INDOL-3-
YL] METHYL-4-PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared
by Procedure D and Scheme N using 6-chloro-1-(2-
fluorophenyl)-1H-indole and N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 490.1 (M + H)+.
Example 473
N- [3- (1-{ [6-CHLORO-1- (2-FLUOROPHENYL) -1FI-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE:
Prepared by Procedure D and Scheme N using 6-chloro-1-
(2-fluorophenyl) -1H-indole and N- [3- (4-
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piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
502.1 (M + H)+.
Example 474
N- [3- (1-~ [6-CHLORO-1- (2-FLUOROPHENYL) -1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure D and Scheme N using 6-chloro-1-
(2-fluorophenyl)-1H-indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide ESMS m/e: 504.1 (M + H)+.
Example 475
N-[3-(1-~[6-CHLORO-1-(4-CHLOROPHENYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared
by Procedure D and Scheme N using 6-chloro-1-(4-
chlorophenyl) -1H-indole and N- [3- (4-
piperidinyl)phenyl]propanamide ESMS m/e: 506.1 (M + H)~.
Example 476
N- [3- (1- f [6-CHLORO-1- (4-CHLOROPHENYL) -1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE:
Prepared by Procedure D and Scheme N using 6-chloro-1-
(4-chlorophenyl) -1H-indole and N- [3- (4-
piperidinyl)phenyl]cyclopropanecarboxamide ESMS m/e:
518.1 (M + H)+.
Example 477
N- [3- (1-~ [6-CHLORO-1- (4-CHLOROPHENYL) -1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure D and Scheme N using 6-chloro-1-
(4-chlorophenyl)-1H-indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide ESMS m/e: 520.1 (M + H)+.
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Example 478
N- [3- (1-~ [6-CHLORO-I- (3-CHLOROPHENYL) -1H-INDOL-3-
YL] METHYL-4-PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared
by Procedure .D and Scheme N using 6-chloro-1-(3
chlorophenyl) -1H-indole and N- [3- (4
piperidinyl)phenyl]propanamide: ESMS m/e: 506.1 (M + H)+.
Example 479
N-[3-(1-~[6-CHLORO-1-(3-CHLOROPHENYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE:
Prepared by Procedure D and Scheme N using 6-chloro-1-
(3-chlorophenyl) -1H-indole and N- [3- (4-
piperidinyl)phenyl]cyclopropanecarboxamide: 1H NMR (400
MHz, CDC13) b 7.72 (d, 1H, J = 8.4 Hz), 7.68 (s, 1H),
7.49 (m, 2H), 7.44 (d, 2H, J - 7.9 Hz), 7.49-7.25 (m,
4H) , 7.21 (d, 1H, J = 7.9 Hz) , 7.17 (d, 1H, J = 7. 9 Hz) ,
6. 93 (d, 1H, J = 7. 9 Hz) , 3 . 79 (s, 2H) , 3 . 13 (d, 2H, J =
9.4 Hz), 2.48 (sept, 1H, J = 7.5 Hz), 2.16 (m, 2H), 1.80
(m, 4H), 1.51 (s, 1H), 1.06 (m, 2H), 0.806 (m, 2H);
Anal. Calcd for C3oH29C1zN30+HC1+l.4Ha0: C, 62.11; H,
5.70; N, 7.24. Found: C, 62.19; H, 6.21; N, 7.06; ESMS
m/e: 519.2 (M + H)+.
Example 480
N-[3-(1-~[6-CHLORO-1-(3-CHLOROPHENYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYLI-2-METHYLPROPANAMIDE: '
Prepared by Procedure D and Scheme N using 6-chloro-1-
(3-chlorophenyl) -1H-indole and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 520.1 (M + H)+.
Example 481
N-(3-~l-[(5-FLUORO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
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Procedure D and Scheme N using 5-fluoro-1H-indole
and N- [3- (4-piperidinyl)phenyl] cyclopropanecarboa~amide:
ESMS m/e: 392.1 (M + H)+.
Example 482
N- [3- (1-~ [6-CHLORO-1- (2-CHLOROPHENYL) -1H-INDOL-3-
YL] METHYL-4-PIPERIDINYL) PHENYL] -2-METHYLPROP,ANAMIDE:
Prepared by Procedure D and Scheme N using 6-chloro-1-
(2-chlorophenyl) -1H-indole and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 520.2 (M + H)+.
Example 483
N-[3-(1-f[6-CHLORO-1-(3-METHOXYPHENYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure D and Scheme N using 3-(6-chloro-
1H-indol-1-yl)phenyl methyl ether and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 516.2 (M + H)+..
Example 484
N-[3-(1-~[6-CHLORO-I-(2-METHOXYPHENYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure D and Scheme N using 2-(6-chloro-
1H-indol-1-yl)phenyl methyl ether and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 516.2 (M + H)+.
Example 485
N-[3-(1-~[6-CHLORO-1-(2,3-DICHLOROPHENYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure D and Scheme N using 6-chloro-1-
(2,3-dichlorophenyl)-1H-indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 555.1 (M + H)+.
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Example 486
N- [3- (1- f [6-CHLORO-1- (4-METHYLPHENYL) -1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure D and Scheme N using 6-chloro-1-
(4-methylphenyl)-1H-indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 500.2 (M + H)+.
Example 487
N-~3-[1-(~6-CHLORO-1-[3-(TRIFLUOROMETHYL)PHENYL]-1H-
INDOL-3-YL~METHYL) -4-PIPERIDINYL] PHENYL-2-
METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N
using 6-chloro-1- [3- (trifluoromethyl)phenyl] -IH-indole
and 2-methyl-N- [3- (4-piperidinyl)phenyl] propanamide:
ESMS m/e: 554.2 (M + H)+.
Example 488
N-~3-[1-(~6-CHLORO-1-[4-(TRIFLUOROMETHYL)PHENYL]-1H-
INDOL-3-YL~METHYL)-4-PIPERIDINYL]PHENYL -2-
METHYLPROPANAMIDE: Prepared by Procedure D and Scheme N
using 6-chloro-1-[4-(trifluoromethyl)phenyl]-1H-indole
and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 554.2 (M + H)+.
Example 489
N-[3-(1-~[6-CHLORO-I-(2-METHYLPHENYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure D and Scheme N using 6-chloro-1-
(2-methylphenyl)-1H-indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 500.2 (M + H)+.
Example 490
N-[3-(1-~[6-CHLORO-1-(3-METHYLPHENYL)-1H-INDOL-3-
YL]METHYLr~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure D and Scheme N using 6-chloro-1-
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(3-methylphenyl)-1H-indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 500.2 (M + H)+.
Example 491
N-(3-~1-[(7-CHLORO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure D and Scheme N using 7-chloro-1H-indole and N-
[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS
m/e: 408.1 (M + H)+.
Example 492
N-(3-{1-[(7-CHLORO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 7-chloro-1H-indole and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
410.1 (M + H)+.
Example 493
N-(3-~1-[(4-FLUORO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure D
and Scheme N using 4-fluoro-1H-indole and N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 380.2 (M + H)+.
Example 494
N-(3-{1-[(7-CHLORO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure D
and Scheme N using 7-.chloro-1H-indole and N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 39.6.1 (M + H)+.
Example 495
2-METHYL-N-(3-~1-[(6-METHYL-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure D
and Scheme N using 6-methyl-1H-indole and 2-methyl-N-[3-
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(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 390.2 (M + H)+
Example 496
N- [3- (1-~ [6- (BENZYLOXY) -1H-INDOL-3-YL] METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 6-(benzyloxy)-1H-indole
and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 482.2 (M + H)+.
Example 497
N-(3-{1-[(6-METHOXY-1H-INDOL-3-YL)METHYL~-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 1H-indol-6-yl methyl
ether and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 406.2 (M + H)+.
Example 498
METHYL 3-(~4-(3-(ISOBUTYRYLAMINO)PHENYL]-1
PIPERIDINYL~METHYL)-1H-INDOLE-6-CARBOXYLATE: Prepared by
Procedure D and Scheme N using methyl 1H-indole-6
carboxylate and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 434.2 (M + H)+.
Example 499
2-METHYL-N-[3-(1-~(6-(TRIFLUOROMETHYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared
by Procedure D and Scheme N using 6-(trifluoromethyl)-
1H-indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDC13) b
8.11 (s, 1H) , 7.66 (s, 1H) , 7.63 (s, 2H) , 7.44 (d, 1H, J
- 8.4 Hz) , 7.39 (s, 2H) , 7.32 (d, 1H, J = 8.4 Hz) , 7. 16
(t, 1H, J = 8.4 Hz) , 6.84 (d, 1H, J = 8.4 Hz) , 4.06 (s,
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2H), 3.27 (d, 2H, J = 11.6 Hz), 2.56 (sept, 1H, J
-
6. 8 Hz) , 2 .37 (m, 3H) , 1 (m, ) , 1 .75 (m, 1
. 93 2H 2H) , .22
(d, 6H, J - 6. 8 Hz) P.nal . Calcd for
;
Ca5H28F3N30+2HC1+0.5EtOAc: C, 57.8; H, 6.11; N, 7.50.
Found: C, 56.5; H, 6.46; N, 7.77; ESMS m/e: 444.2 (M
+
H)+.
1-(2-PYRIDINYL)-1H-INDOLE: Prepared by Procedure C and
Scheme O using 2-iodopyridine and 1H-indole: ESMS m/e:
195.0 (M + H)+.
1-(3-PYRIDINYL)-1H-INDOLE: Prepared by Procedure C and
Scheme O using 3-iodopyridine and 1H-indole: ESMS m/e:
195.0 (M + H)+.
Example 500
2-METHYL-N-[3-(1-~(1-(3-PYRIDINYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared
by Procedure D and Scheme N using 1-(3-pyridinyl)-1H-
indole and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 453.2 (M + H)+.
Example 501
2-METHYL-N-L3-(1-~[1-(2-PYRIDINYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared
by Procedure D and Scheme N using 1-(2-pyridinyl)-1H-
indole and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 453.2 (M + H)+.
Example 502
N-(3-~l-[(6-FLUORO-1-PHENYL-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 6-fluoro-1-phenyl-1H-
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indole and 2-methyl-N-[3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 470.2 (M + H)+.
Examp7.e 503 .
N-(3-~1-L(6-CHLORO-1-PHENYL-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure D. and Scheme N using 6-chloro-.1-phenyl-1H-
indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 486.2 (M + H)~.
7-METHYL-1-PHENYL-1H-INDOLE: Prepared by Procedure C
and Scheme O using 7-methyl-1H-indole and iodobenzene:
ESMS m/e: 208.1 (M + H)+.
METHYL 1-PHENYL-1H-INDOLE-6-CARBOXYLATE: Prepared by
Procedure C and Scheme 0 using methyl 1H-indole-6-
carboxylate and iodobenzene: ESMS m/e: 252.0 (M + H)+.
6-METHYL-1-PHENYL-1H-INDOLE: Prepared by Procedure C
and Scheme O using 6-methyl-1H-indole and iodobenzene:
ESMS m/e: 208.0 (M + H)+.
7-CHLORO-1-PHENYL-1H-INDOLE: Prepared by Procedure C
and Scheme O using 7-chloro-1H-indole and iodobenzene:
ESMS m/e: 228.0 (M + H)+.
6-NITRO-1-PHENYL-1H-INDOLE: Prepared by Procedure C and
Scheme 0 using 6-nitro-1H-indole and iodobenzene: ESMS
m/e: 238.2 (M + H)+.
6-METHOXY-1-PHENYL-1H-INDOLE: Prepared by Procedure C
and Scheme O using 1H-indol-6-yl methyl ether and
iodobenzene: ESMS m/e: 224.0 (M + H)+.
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BENZYL 1-PHENYL-1H-INDOL- 6-YL ETHER: Prepared by
Procedure C and Scheme O using 6-(benzyloxy)-1H-indole
and iodobenzene: ESMS m/e: 300.0 (M + H)+.
1-PHENYL-1H-INDOL-6-YL TRIFLUOROMETHYL ETHER: Prepared
by Procedure C and Scheme O using 6-(trifluoromethoxy)-
1H-indole and iodobenzene: ESMS m/e: 278.0 (M + H)+.
7-METHOXY-1-PHENYL-1H-INDOLE: Prepared by Procedure C
and Scheme O using 1H-indol-7-yl methyl ether and
iodobenzene: ESMS m/e: 224.0 (M + H)+.
Z-PHENYL-6-(TRIFLUOROMETHYL)-1H-INDOLE: Prepared by
Procedure C and Scheme O using 6-(trifluoromethyl)-1H
indole and iodobenzene: ESMS m/e: 262.0 (M + H)+.
1-(4-PYRIDINYL)-1H-INDOLE: Prepared by Procedure C and
Scheme O using 1H-indole and 4-iodopyridine: ESMS m/e:
195 (M + H)+.
Example 504
N-j3-(1-~j6-(BENZYLOXY)-1-PHENYL-1H-INDOL-3-YL]METHYL~-
4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using benzyl 1-phenyl-1H-indol-
6-yl ether and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 558.0 (M + H)+.
Example 505
2-METHYL-N-(3-~l-j(6-METHYL-1-PHENYL-1H-TNDOL-3-
YL)METHYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared
by Procedure D and Scheme N using- 6-methyl-1-phenyl-1H-
indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDC13) b
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7.66 (s, 1H), 7.64 {d, 1H, J - 7.8 Hz), 7.51 1H,
(d,
J - 3.9 Hz), 7.50 {m, 3H), 4 (m, 2H), 7.36-7.32(m,
7.
2H) , 7.31 1H) , 7.19 (t, J= 7.8 Hz) , 4 1H,
(s, 1H, 7.0 {d,
J - 7.8 Hz), 6.91 (d, 1H, J 7.8 Hz), 3.94 (s, 2H),
-
3.25 (d, 2H, J = 9.2 Hz), 2.52(sept, 1H, J 6.4 Hz),
=
2.46 (s, 3H) 2.28 (dt, 2H, 11.8, 2.6 Hz) 1.89 (dq,
, J = ,
2H, J 2.9 z), 1.80 (m, 3H),1.22 (d, 6H, 6.9 Hz);
= H J =
Anal . lcd H,
Ca for 7.41;
C3lHasN30+HC1+0.6Et0Ac:
C,
72.2;
N, 7.57. Found: 7.40; N, 7.66; ESMS m/e:
C,
71.0;
H,
466 (M H)+.
+
Example 506
METHYL 3 - ( ~ 4 - [ 3 - ( I S OBUTYRYLAMINO ) PHENYL ] -1-
PIPERIDINYL~METHYL)-1-PHENYL-1H-INDOLE-6-CARBOXYLATE:
Prepared by Procedure D and Scheme N using methyl 1-
phenyl-1H-indole-6-carboxylate and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 510.0 (M + H)+.
Example 507
2-METHYL-N-(3-~l-[(6-NITRO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure D
and Scheme N using 6-nitro-1H-indole and 2-methyl-N-[3-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 421.0 (M +
H)+.
Example 508
2-METHYL-N-[3-(1-~[1-PHENYL-6-(TRIFLUOROMETHYL)-1H-
INDOL-3-YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE:
Prepared by Procedure D and Scheme N using 1-phenyl-6-
(trifluoromethyl) -1H-indole and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 520.0 (M + H)+.
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Example 509
2-METHYL-N-(3-{1-[(7-METHYL-1-PHENYL-1H-INDOL-3-
YL)METHYL]-4-PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared
by Procedure D and Scheme N using 7-methyl-1-phenyl-1H-
indole and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 466.0 (M + H)+.
Example 510
N-(3-~1- [ (7-METHOXY-1H-II~DOL-3-YL)METHYL]~-4-
PIPERIDINYL~PHENYL)-2-METHYLPROP,ANAMIDE: Prepared by
Procedure D and Scheme N using 1H-indol-7-yl methyl
ether and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 406.0 (M + H)+.
Example 511
N-(3-~1-[(7-METHOXY-1-PHENYL-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure -D and Scheme N using 7-methoxy-1-phenyl-1H-
indole and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propa~samide:-ESMS m/e: 482.0 (M + H)~.
Example 512
N-(3-{1-[(7-CHLORO-1-PHENYL-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 7-chloro-1-phenyl-1H-
:indole . and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 488.6 (M + H)+.
Example 513
2-METHYL-N-(3-~1-[(7-NITRO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPA~&MI~E: Prepared by Procedure D
and Scheme N using 7-nitro-1H-indole and 2-methyl-N- [3-
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(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 421.1 (M + H)+.
Example 514 ,
N-(3-~l- [ (7-NITRO-1H-INDOL-3-YL)METHYL] -4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure D and Scheme N using 7-nitro-1H-i-ndole and N-
[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS
m/e: 419.5 (M + H)~.
Example 515
N-(3-~1-[(7-NITRO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure D
and Scheme N using 7-vitro-1H-indole and N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 407.3 (M + H)+.
7-(2-FLUOROPHENYL)-1H-INDOLE: Prepared by Procedure T
and Scheme T using 7-bromo-1H-indole and 2-
fluorophenylboronic acid: ESMS m/e: 211.9 (M + H)+.
Example 516
N- [3- (1-~ [7- (2-FLUOROPHENYL) -1H-INDOL-3-YL] METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N. A solution of 2-methyl-N- [3-
(4-piperidinyl)phenyl]propanamide (23.3 mg, 0.0948 mmol)
and 37 wt % aqueous formaldehyde (11.4 mg, 0.142 mmol)
in 1.00 mL of HOAc:dioxane (1:4) was added to 7-(2-
fluorophenyl)-1H-indole (20.0 mg, 0.0948 mmol) and the
reaction mixture was stirred for 12 h at room
temperature. The resulting mixture was diluted with H20
(10 mL). The aqueous layer was extracted with CHZC12 (3
X 10 mL). The combined organic extracts were washed
with brine (10 mL), dried over MgS04, and concentrated in
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vacuo. The residue was purified by preparative
TLC on silica using 4 % of NH3 (2.0 M in methanol) in
CHzCla to give the desired product (56.1 mg, 100 0) : 1H
NMR (400 MHz, CDC13) b 8.58 (s, 1H), 7.73 (dd, 1H, J =
2.8, 6.3 Hz), 7.69 (s, 1H), 7.53 (dt, 1H, J = 1.8, 7.6
Hz), 7.44 (d, 1H, J - 8.1 Hz), 7.38 (m, 2H), 7.32 (s,
1H) , 7 .27-7.21 (m, 4H) , 7 . 17 (t, 1H, J = 7. 6 Hz) , 6 . 88
(d, 1H, J = 7.6 Hz), 3.92 (s, 2H); 3.20 (d, 1H, J = 11.6
Hz) , 2.51 (qt, 1H, J = 6.7 Hz) , 2.42 (m, 1H) , 2.25 (dt,
2H, J = 2 .2, 21 .6 Hz) , 1.89-1. 72 (m, 5H) , 1 .22 (d, 6H, J
- 7.3 Hz); ESMS m/e: 470.1 (M + H)+.
7-(4-ETHYLPHENYL)-1H-INDOLE: Prepared by Procedure I and
Scheme T using 7-bromo-1H-indole and 4
ethylphenylboronic acid: ESMS m/e: 222.0 (M + H)+.
7-(2-NAPHTHYL)-1H-INDOLE: Prepared by Procedure I and
Scheme T using 7-bromo-1H-indole and 2-naphthylboronic
acid: ESMS m/e: 244.0 (M + H)+.
7-(3-CHLOROPHENYL)-1H-INDOLE: Prepared by Procedure I
and Scheme T using 7-bromo-1H-indole and 3-
chlorophenylboronic acid: ESMS m/e: 227.9 (M + H)~.
6-(2-FLUOROPHENYL)-1H-INDOLE: Prepared by Procedure I
and Scheme T using 6-bromo-1H-indole and 2-
fluorophenylboronic acid: ESMS m/e: 211.9 (M + H)+.
7-(3-NITROPHENYL)-1H-INDOLE: Prepared by Procedure I and
Scheme T using 7-bromo-1H-indole and 3
nitrophenylboronic acid: ESMS m/e: 238.9 (M + H)+.
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1- [4- (1H-INDOL-7- YL) PHENYL] ETHANONE:
Prepared by Procedure I and Scheme T using 7-bromo-1H-
indole and 4-acetylphenylboronic acid: ESMS m/e: 235.2
(M + H)+.
6-(2-METHYLPHENYL)-1H-INDOLE: Prepared by Procedure I
and Scheme T using 6-bromo-1H-indole and 2-
methylphenylboronic acid: ESMS m/e: 207.9 (M + H)+.
6-(3-CHLOROPHENYL)-1H-INDOLE: Prepared by Procedure I
and Scheme T using 6-bromo-1H-indole and 3-
chlorophenylboronic acid: ESMS m/e: 227.9 (M + H)+.
1-[4-(1H-TNDOL-6-YL)PHENYL]ETHANONE: Prepared by
Procedure I and Scheme T using 6-bromo-1H-indole and 4
acetylphenylboronic acid: ESMS m/e: 235.8 (M + H)+.
7-(2-METHYLPHENYL)-1H-INDOLE: Prepared by Procedure I
and Scheme T using 7-bromo-1H-indole and 2
methylphenylboronic acid: ESMS m/e: 208 (M + H)+.
6-(4-ETHYLPHENYL)-1H-INDOLE: Prepared by Procedure I and
Scheme T using 6-bromo-1H-indole and 4-
ethylphenylboronic acid: ESMS m/e: 221.9 (M + H)+.
Example 517
2-METHYL-N-[3-(1-~[7-(2-NAPHTHYL)-1H-INDOL-3-YL]METHYL~-
4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared. by Procedure
D and Scheme N using 7-(2-naphthyl)-1H-indole and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
502.2 (M + H)+.
Example 518
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N- [3- (1-~ [7- (4- ETHYLPHENYL) -1FI-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure D and Scheme N using 7-(4-
ethylphenyl)-1H-indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 480.2 (M + H)+.
Example 519
2-METHYL-N-[3-(1-~[6-(2-METHYLPHENYL)-1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared
by Procedure D and Scheme N using 6-(2-methylphenyl)-1H-
indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDC13) b
8.2 (s, 1H), 7.53 (m, 4H), 7.41 (d, 1H, J - 8.4 Hz),
7.34 (m, 2H), 7.27-7.12 (m, 5H), 6.81 (d, lH, J - 8.4
Hz), 4.09 (s, 2H), 3.32 (d, 2H, J = 11.4 Hz), 2.57 (q,
2H, J - 7.6 Hz), 2.43 (m, 3H), 2.08 (s, 3H), 1.98 (m,
1H), 1.75 (m, 2H), 1.22 (d, 6H, J = 6.3 Hz); Anal. Calcd
for C3lHssNaO+CHC13+DMF: C, 57.0; H, 6.09; N, 8.06.
Found: C, 56.5; H, 5.94; N, 7.76; ESMS m/e: 466.2 (M +
H) +.
Example 520
N- [3- (1-~ [7- (3-CHLOROPHENYL) -1H-INDOL-3-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROP.ANAMIDE: Prepared by
Procedure D and Scheme N using 7-(3-chlorophenyl)-1H-
indole and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 486.1 (M + H)+.
Example 521
2-METHYL-N-[3-(1-{[7-(3-NITROPHENYL)-1H-INDOL-3-
YL] METHYL-4-PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared
by Procedure D and Scheme N using 7- (3-nitrophenyl) -1H-
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indole and 2-methyl-N-[3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 497.0 (M + H)+.
Example 522
N- [3- (1-~ L7- (4-ACETYLPHENYL) -1H-INDOL-3-YL] METHYL}-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 1-[4-(1H-indol-7-
yl)phenyl]ethanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 493.6 (M + H)+.
Example 523
N- [3- (1-~ [6- (4-ETHYLPHENYL) -1FI-INDOL-3-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 6-(4-ethylphenyl)-1H-
indole and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e; 480.1 (M + H)+.
Example 524
2-METHYL-N- [3- (1-~ [7- (2-METHYLPHENYL) -1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared
by Procedure D and Scheme N using 7-(2-methylphenyl)-1H-
indole and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 466.1 (M + H)~.
Example 525
N- [3- (1-~ [6- (2-FLUOROPHENYL) -1H-TNDOL-3-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 6-(2-fluorophenyl)-1H-
indole and . 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 470.2 (M + H)+.
5-(4-METHYLPHENOXY)-1H-INDOLE: Prepared by Procedure J
and Scheme U using 5-bromo-1H-indole and p-cresol; ESMS
m/e: 224.0 (M + H)+.
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Example 526
N-(3-~1-[(5-BROMO-1H-INDOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure D and Scheme N using 5-bromo-1H-indole and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
454.0 (M + H)~. .
1-(4-PYRIDINYL)-6-(TRIFLUOROMETHYL)-1H-INDOLE: Prepared
by Procedure C and Scheme O using 6-(trifluoromethyl)-
1H-indole and 4-iodopyridine: ESMS m/e: 262.9 (M + H)+.
Example 527
2-METHYL-N- [3- (1-~ [5- (4-METHYLPHENOXY) -1H-INDOL-3-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared
by Procedure D and Scheme N using 5-(4-methylphenoxy)-
1H-indole and 2-methyl-N- [3- (4.-
piperidinyl)phenyl~propanamide: ESMS m/e: 481.9 (M + H)+.
1-(4-METHYLPHENYL)-1H-INDOLE: Prepared by Procedure C
and Scheme O using 1H-indole and 1-iodo-4-methylbenzene:
ESMS m/e: 208.0 (M + H)+.
1-(3-METHYLPHENYL)-1H-INDOLE: Prepared by Procedure C
and Scheme O using 1H-indole and 1-iodo-3-methylbenzene:
ESMS m/e: 208.0 (M + H)+.
1- [3- (TRIFLUOROMETHYL) PHENYL] -1H-INDOLE: . Prepared by
Procedure C and Scheme O using 1H-indole and 1-iodo-3
(trifluoromethyl)benzene: ESMS m/e: 262.0 (M + H)+.
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1-(4-METHOXYPHENYL)-1H- INDOLE: Prepared by
Procedure C and Scheme O using 1H-indole and 1-iodo-4-
methoxybenzene: ESMS m/e: 224.0 (M + H)+.
1-(2-METHOXYPHENYL)-1H-INDOLE: Prepared by Procedure C
and Scheme O using 1H-indole and 1-iodo-2-
methoxybenzene: ESMS m/e: 224.0 (M + H)+.
1-(3-METHOXYPHENYL)-1H-INDOLE: Prepared by Procedure C
and Scheme O using 1H-indole and 1-iodo-3
methoxybenzene: ESMS m/e: 224.0 (M + H)'".
1-(2-METHYLPHENYL)-1H-INDOLE: Prepared by Procedure C
and Scheme O using 1H-indole and 1-iodo-2-methylbenzene:
ESMS m/e: 208.0 (M + H)+.
6-FLUORO-1-PHENYL-1H-INDOLE: Prepared by Procedure C and
Scheme O using 6-fluoro-1H-indole and iodobenzene: ESMS
m/e: 212Ø (M + H)+.
6-CHLORO-1-PHENYL-1H-INDOLE: Prepared lay Procedure C
and Scheme O using 6-chloro-1H-indole and iodobenzene:
ESMS m/e: 228.0 (M + H)+.
7-CHLORO-1-PHENYL-1H-INDOLE: Prepared by Procedure C
and Scheme O using 7-chloro-1H-indole and iodobenzene:
ESMS m/e: 228.0 (M + H)+.
6-(2-FLUOROPHENYL)-1H-INDOLE: Prepared by Procedure I
and Scheme T using 6-bromo-1H-indole and 2
fluorophenylboronic acid: ESMS m/e: 211.9 (M + H)+.
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Example 528
2-METHYL-1J-~3- (1- (7-OXO-7-PHENYLHEPTYL) -4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 7-chloro-1-phenyl-1-heptanone and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
435.1 (M + H)+.
Example 529
2-METHYL-N-~3-(1-(6-OXO-6-PHENYLHEXYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure K
and Scheme BI using 6-chloro-1-phenyl-1-hexanone and 2
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: Anal.
Calcd for C27H36N202+0.1CHC13: C, 75.3; H, 8.39; N, 6.46.
Found: C, 75.4; H, 7.89; N, 6.18; ESMS m/e: 421.1 (M +
H)+.
Example 530
2-METHYL-N-~3-(1-(5-OXO-5-PHENYLPENTYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE; Prepared by Procedure K
and Scheme B1 using 5-chloro-1-phenyl-1-pentanone and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
407.1 (M + H)+.
Example 531
N-(3-~1-(4-(4-METHOXYPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using .4-chloro-1-(4-methoxyphenyl)-1-
butanone and N- [3- (4-piperidinyl)phenyl]propanamide:
ESMS m/e: 409.2 (M + H)+.
3 o Example 532
N-(3-~1-(4-(4-CHLOROPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 4-chloro-1-(4-chlorophenyl)-1-
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but anone and N- [ 3 - ( 4 -
piperidinyl)phenyl]propanamide: ESMS m/e: 413.1 (M + H)+.
Example 533
N-(3-~1-[4-(4-BROMOPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme Bl using 1-(4-bromophenyl)-4-chloro-1-
butanone and N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 457.1 (M + H)+.
Example 534
N-(3-~l-[4-(4-TERT-BUTYLPHENYL)-4-OXOBUTYLj-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 1-(4-tert-butylphenyl)-4-chloro-1-
butanone and N- [3- (4-piperidinyl) phenyl] propanamide
ESMS m/e: 435.2 (M + H)+.
Example 535
N-(3-~l-[4-(4-FLUOROPHENYL)-4-OXOBUTYLj-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 4-chloro-1-(4-fluorophenyl)-1-
butanone and N-[3-{4-piperidinyl)phenyl]propanamide:
ESMS m/e: 397.2 (M + H)+.
2 5 Example 536
N-(3-tl-[4-OXO-4-(4-PHENOXYPHENYL)BUTYLj-4-
PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme Bl using 4-chloro-1-(4-phenoxyphenyl)-1-
butanone and N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 471.2 (M + H)+.
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Example 537
N-(3-{1-[4-(4-ISOPROPYLPHENYL)-4-OXOBUTYL~-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K- and Scheme B1 using 4-chloro-1-(4-
isopropylphenyl)-1-butanone and N-[3-(4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
433.2 (M + H)+.
Example 538
N-(3-~1-[4-(4-METHOXYPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 4-chloro-1-(4-
methoxyphenyl) -1-butanone and N- [3- (4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
421.2 (M + H)+.
Example 539
N-(3-~l-[4-OXO-4-(4-PHENOXYPHENYL)BUTYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme Bl using 4-chloro-1-(4-
phenoxyphenyl ) -1-but anone and N- [ 3 - ( 4 -
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
483.2 (M + H)+.
2 5 Example S40
N-(3- f 1- [4- (4-ISOPROPYLPHENYL) -4-OXOBUTYL] -4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 4-chloro-1-(4-isopropylphenyl)-1-
butanone and N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 421.3 (M + H)+.
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Example 541
N-(3-~1-(4-(4-TERT-BUTYLPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 1-(4-tert-butylphenyl)-
4-chloro-1-butanone and N- [3- (4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
447.2 (M + H)+.
Example 542
N- ( 3 - ~ 1- [ 4 - ( 4 -METHYLPHENYL ) - 4 - OXOBUTYL] - 4 -
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 4-chloro-1-(4-methylphenyl)-1-
butanone and N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 393.2 (M + H)+.
Example 543
N-(3-~1-[4-(3,4-DIMETHYLPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 4-chloro-1-(3,4-dimethylphenyl)-1-
butanone and N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 407.2 (M + H)+.
Example 544
N-(3-~l-[4-(4-BROMOPHENYL)-4-OXOBUTYLj-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 1-(4-bromophenyl)-4-
chloro-1-butanone and N-[3-(4-
piperidinyl)phenyl]cyclopropanecarboxamide:~ ESMS m/e:
469.1 (M + H)+.
3 0 Example 545
N-(3-~l-[5-(4-FLUOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL}PHENYL)PROP.ANAMIDE: Prepared by Procedure K
and Scheme B1 using 5-chloro-1-(4-fluorophenyl)-1-
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pentanone and N- [ 3 - ( 4 -
piperidinyl)phenyl]propanamide: ESMS m/e: 411.2 (M + H)+.
Example 546
N-(3-~l-[4-(3,4-DIMETHYLPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 4-chloro-1-(3,4-
dimethylphenyl)-1-butanone and N-[3-(4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
419 . 2 (M + H) +.
Example 547
N-(3-~1- (4- (4-METHYLPHENYL) -4-OXOBUTYL] -4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 4-chloro-1-(4-
methylphenyl ) -1-but anone and N- [ 3 - ( 4 -
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
405.2 (M + H)+.
2 0 Example 548
N-(3-~1- (4- (4-FLUOROPHENYL) -4-OXOBUTYL] -4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 4-chloro-1-(4-
fluorophenyl) -1-butanone and N- [3- (4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
409.2 (M + H)+.
Example 549
N-(3-~1- [5- (3-FLUOROPHENYL) -5-OXOPENTYL] -4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 5-chloro-1-(3-
fluorophenyl) -1-pentanone and N- [3- (4-
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piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
- 423.2 (M + H)+.
Example 550
N- [3- (1.-~5-OXO-5- [4- (TRIFLUOROMETHYL) PHENYL] PENTYL~-4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 5-chloro-1-[4-
(trifluoromethyl)phenyl] -1-pentanone and N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 461.2 (M + H)+.
Example 551
N-(3-~l-[5-(4-FLUOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 5-chloro-1-(4-
fluorophenyl)-1-pentanone and N-[3-(4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
423.2 (M + H)+.
Example 552
N-(3-~1- [5- (3-NITROPHENYL) -5-OXOPENTYL] -4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 5-chloro-1-(3-nitrophenyl)-1-
pentanone and N- [3- (4-piperidinyl) phenyl] propanamide:
ESMS m/e: 438.2 (M + H)+.
Example 553
N-(3-~1- [5- (3-NITROPHENYL) -5-OXOPENTYL] -4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 5-chloro-1-(3-
nitrophenyl)-1-pentanone and N-[3-(4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
450.2 (M + H)+.
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Example 554
N-(3-~1-[5-(2-FLUOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 5-chloro-1-(2-fluorophenyl)-1-
pentanone and N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 411.2 (M + H)+.
Example 555
N-(3-~1-[5-(3-FLUOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 5-chloro-1-(3-fluorophenyl)-1-
pentanone and N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 411.2 (M + H)+.
Example 556
N-(3-~1-[5-(4-NITROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 5-chloro-1-(4-nitrophenyl)-1-
pentanone and N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 438.1 (M + H)+.
Example 557
N-(3-~2-[5-(4-NITROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 5-chloro-1-(4-
nitrophenyl)-1-pentanone and N-[3-(4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
450.1 (M + H)+.
3 0 Example 558
N-(3-~1-[5-(4-CHLOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDTNYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 5-chloro-1-(4-
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chlorophenyl)-1-pentanone and N-[3-(4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
439.1 (M + H)+.
Example 559
N-[3-(1-~5-OXO-5-[2-(TRIFLUOROMETHYL)PHENYL]PENTYL~-4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 5-chloro-1-[2-
(trifluoromethyl)phenyl]-1-pentanone and N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 461.2 (M + H)+.
Example 560
N-[3-(1-{5-OXO-5-[2-(TRIFLUOROMETHYL)PHENYL]PENTYL~-4-
PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 5-chloro-1-[2-
(trifluoromethyl)phenyl]-1-pentanone and N-[3-(4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
473 . 2 (M + H) +.
2 0 Example 561
N-(3-~l-[5-(4-CHLOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 5-chloro-1-(4-chlorophenyl)-1-
pentanone and N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 427.1 (M + H)+.
Example 562
N-(3-~1-[5-(3-CHLOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: . Prepared by Procedure K
and Scheme B1 using S-chloro-1-(3-chlorophenyl)-1-
pentanone and N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 427.1 (M + H)+.
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Example 563
N-(3-~1-[5-(2-FLUOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and .Scheme B1. using 5-chloro-1-(2-
f luorophenyl ) -1-pentanone and N- [ 3 - ( 4 -
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
423.1 (M + H)+.
Example 564
N-(3-~1-[5-(3-CHLOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 5-chloro-1-(3-
chlorophenyl) -1-pentanone and N- [3- (4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
439.1 (M + H)~.
Example 565 _
N-[3-(1-~5-OXO-5-[4-(TRIFLUOROMETHYL)PHENYL]PENTYL}-4-
PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 5-chloro-1-[4-
(trifluoromethyl)phenyl]-1-pentanone and N-[3-(4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
473.2 (M + H)+.
2 5 Example 566
N-(3-~l- [5- (2-CHLOROPHENYL) -5-OXOPENTYL] -4-
PIPERTDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 5-chloro-1-(2-chlorophenyl)-1-
pentanone and N-[3-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 427.1 (M + H)+.
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Example 567
N-(3-~1- [5- (2-CHLOROPHENYL) -5-OXOPENTYL] -4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 5-chloro-1-(2-
chlorophenyl)-1-pentanone and N-[3-(4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
439.1 (M + H)+.
Example 568
N- [3- (1-~5-OXO-5- [3- (TRIFLUOROMETHYL) PHENYL] PENTYL~-4-
PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure K and Scheme B1 using 5-chloro-1-[3-
(trifluoromethyl) phenyl] -1-pentanone and N- [3- (4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
473.2 (M + H)+.
Example 569
N-(3-~1-[4-(3,4-DIMETHYLPHENYL)-4-OXOBUTYL]-4-
PIPERIDINYL~PHENYL)-N,2-DIMETHYLPROPANAMIDE: Prepared
by Procedure T and Scheme AD using N-(3-{1-[4- (3,4-
dimethylphenyl)-4-oxobutyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and methyl iodide: 1H NMR (400 MHz,
CDC13) b 7.76 (s, 1H), 7.72 (dd, 1H, J = 1.5, 7.7 Hz),
7.33 (t, 1H, J = 8.8 Hz), 7.22 (d, 1H, J = 7.8 Hz), 7.18
(d, 1H, J - 8.8 Hz), 7. O1 (m, 2H), 3.24 (s, 3H), 3.10
(d, 1H, J = 10.6 Hz), 3.00 (t, 1H, J = 7.6 Hz), 2.49 (m,
4H) , 2.33 (s, 6H) , 2.11 (m, 3H) , 1. 99 (m, 1H) , 1 .79 (m,
4H), 1.26 (t, 2H, J = 7.6 Hz), 7..02 (d, 6H,~ J = 7.6 Hz);
ESMS m/e: 435.2 (M + H)+.
Example 570
2-METHYL-N-~3-[1-(1-METHYL-4-OXO-4-PHENYLBUTYL)-4-
PIPERIDINYL]PHENYL}PROPANAMIDE: Prepared by Procedure K
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and Scheme B1 using 4- chloro-1-phenyl-1-
pentanone and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 407.2 (M + H)+.
Example 571
N- (3- (1-~5-OXO-5- [3- (TRIFLUOROMETHYL) PHENYL] PENTYL~-4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure K
and Scheme B1 using 5-chloro-1-[3-
(trifluoromethyl)phenyl] -1-pentanone and N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 461.2 (M + H)+
3-(5-CHLOROPENTANOYL)-4-(3,4-DIFLUOROPHENYL)-1,3-
OXAZOLIDIN-2-ONE: Prepared by Procedure AF and Scheme H
using 4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and
5-chloropentanoyl chloride.
3-(5-CHLOROPENTYL)-4-(3,4-DIFLUOROPHENYL)-1,3-
OXAZOLIDIN-2-ONE: Prepared by Procedure G and Scheme C1
using 4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and 1-
bromo-5-chloropentane.
Example 572
N-[3-(1-~5-[(4R)-4-(3,4-DIFLUOROPHENYL)-2-OXO-1,3-
OXAZOLIDIN-3-YL]-5-OXOPENTYL~-4-PIPERIDINYL)PHENYL]-2-
METHYLPROPANAMIDE: ' Prepared by Procedure G and Scheme
B1 using (4R)-3-(5-chloropentanoyl)-4-(3,4-
dif luorophenyl)-1,3-oxazolidin-2-one and 2-methyl-N-[3-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 528.2 (M +
H)+.
Example 573
(4R) -4- (3,4-DIFLUOROPHENYL) -N-(3-~4- [3-
(ISOBUTYRYLAMINO)PHENYL]-Z-PIPERIDINYL~PROPYL)-2-OXO-
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1,3-OXAZOLIDINE-3- CARBOXAMIDE: Prepared by
Procedure AF and Scheme H using 4-nitrophenyl (4R)-4-
. (3,4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-carboxylate
and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2
methylpropanamide: 1H NMR (400 MHz, CDC13) ~ 8.08 (t, 1H,
J ~ - 5 .5 Hz) , 7.45 (S, 2H) , 7.38 (d, 1H, J - 8. 6 Hz) ,
7.24-7.12 (m, 3H), 7.06 (m, 1H), 6.97 (d, 1H, J - 8.6
Hz), 5.40 (dd, 1H, J = 3.9,8.8 Hz), 4.71 (t, 1H, J = 8.8
Hz), 4.23 (dd, 1H, J = 4.4, 9.1 Hz), 3.32 (qt, 2H, J =
6.1 Hz), 2.99 (d, 2H, J - 11.0 Hz), 2.49 (qt, 2H, J -
7. 0 Hz) , 2.41 (t, 2H, J = 7.0 Hz) , 1.99 (m, 2H) , 1.82-
1 . 68 (m, 6H) , 1 .23 (d, 6H, J = 7.3 Hz) ; ESMS m/e: 529. 1
(M + H)+.
(4S)-3-(5-CHLOROPENTYL)-4-(3,4-DIFLUOROPHENYL)-1,3-
OXAZOLIDIN-2-ONE: Prepared by Procedure G and Scheme C1
using (4S)-4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one
and 1-bromo-5-chloropentane.
2 0 Example 574
N- [3- (1-~5- [ (4S) -4- (3, 4-DIFLUOROPHENYL) -2-OXO-1, 3-
OXAZOLIDIN-3-YLJPENTYL~-4-PIPERIDINYL)PHENYL]-2-
METHYLPROPANAMIDE: Prepared by Procedure G and Scheme
B1 using (4S) -3- (5-chloropentyl) -4- (3, 4-difluorophenyl) -
1,3-oxazolidin-2-one and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDC13) c
7.48 (s, 1H), 7.32 (d, 1H, J - 8.6 Hz), 7.26-7.21 (m,
2H), 7.20-7.12 (m, 2H), 7.06 (m, 1H), 6.97 (d, 1H, J =
6.96 Hz) , 4.76 (dd, 1H, J = 6.3, 8.3 Hz) , 4.62 (t, 1H, J
- 9.0 Hz), 4.06 (dd, 1H, J = 6.4, 8.7 Hz), 3.46 (m, 1H),
3 .0 (d, 2H, J = 9.0 Hz) , 2 .77 (q, 1H, J = 6.8 Hz) , 2.50
(q, 2H, J = 6. 8 Hz) , 2 . 31 (t, 2H, J = 6. 8 Hz) , 2 . 0l (m,
4H), 1.81 (m, 4H), 1.48 (m, 4H), 1.26 (d, 6H, J - 7.3
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Hz) ; Anal . Calcd for C28H3~FZN303+HCl+0 .25CHC13:
C, 60.6; H, 6.65; N, 7.25. Found: C, 60.7; H, 6.91; N,
7.05; ESMS m/e: 514.2 (M + H)+.
Example 575
N- [3- (1-~5- [ (4S) -4- (3,4-DIFLUOROPHENYL)~-2-OXO-1,3-
OXAZOLIDIN-3-YL]-5-OXOPENTYL}-4-PIPERIDINYL)PHENYL]-2-
METHYLPROPANAMIDE: Prepared by Procedure G and Scheme
B1 using (4S)-3-(5-chloropentanoyl)-4-(3,4-
l0 difluorophenyl)-1,3-oxazolidin-2-one and 2-methyl-N-[3-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 528.1 (M +
H)+
Example 576
(4S)-4-(3,4-DTFLUOROPHENYL)-N-(3-{4-[3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~PROPYL)-2-OXO-
1,3-OXAZOLIDINE-3-CARBOXAMIDE: Prepared by Procedure AF
and Scheme H using 4-nitrophenyl (4S)-4-(3,4-
difluorophenyl)-2-oxo-1,3-oxazolidine-3-carboxylate and
N-{3- [1- (3-aminopropyl)-4-piperidinyl]phenyl-2-
methylpropanamide: ESMS m/e: 529.1 (M + H)+.
Example 577
(4S) -N-(3-~4- [3- (ISOBUTYRYLAMINO) PHENYL] -1-
PIPERIDINYL~PROPYL)-2-OXO-4-(3,4,5-TRIFLUOROPHENYL)-1,3-
OXAZOLIDINE-3-CARBOXAMIDE: Prepared by Procedure AF and
Scheme H using 4-nitrophenyl (4S)-4-(3,4-
difluorophenyl)-2-oxo-1,3-oxazolidine-3-carboxylate and
N-{3- [1- (3-aminopropyl) -4-piperidinyl] phenyl~~-2-
methylpropanamide: ESMS m/e: 547.1 (M + H)+.
Example 578
(4S) -4- (3, 5-DIFLUOROPHENYL) -N-(3-~4- [3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~PROPYL)-2-OXO-
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1,3-OXAZOLIDINE-3- CARBOXAMIDE: Prepared by
Procedure AF and Scheme H using 4-nitrophenyl (4S)-4-
(3,4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-carboxylate
and N-~3-[1-(3-aminopropyl)-4-piperidinyl]phenyl -2-
methylpropanamide: ESMS m/e: 529.2 (M + H)+.
Example 579
N-(3-{1- L3- (PHENYLSULFANYL) PROPYL] -4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure
G
and Scheme B1 using [(3-chloropropyl)sulfanyl]benzene
and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
382.9 (M + H)+.
Example 580
N-(3-~1-[3-(PHENYLSULFANYL)PROPYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared
by
Procedure G and Scheme B1 using [(3-
chloropropyl) sulfanyl]benzene and N- [3- (4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
395.1 (M + H)+.
Example 581
2-METHYL-N-(3-~1-[3-(PHENYLSULFANYL)PROPYL]-4-
PTPE RIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure
G
and Scheme B1 using [(3-chloropropyl)sulfanyl]benzene
and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide:
1H
NMR (400 MHz, CDC13) ~ 7.63 (s, 1H), 7.48 (s, 1H),
7.33
(m, 3H) , 7.27 (t, 2H, J = 7.5 Hz) , 7.20 (t, lH,
J = 7.9
Hz) , 7.15 (tt, 1H, J - 7.2, 1.4 Hz) , 6. 95~ (d, 1H,
J =
7.6 Hz), 2.97 (t, 4H, J - 7.3 Hz), 2.46 (m, 4H), 1.99
(dt, 2H, J = 11.4, 3.0 Hz) , 1.84 (qt, 2H, J = 7.3
Hz) ,
1 .77 (m, 4H) , 1 .21 (d, 6H, J = 6. 8 Hz) ; ESMS m/e:
396. 8
(M + H)+.
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Example 582
N-(3-~l-[6-(PHENYLSULFANYL)HEXYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure G and Scheme B1 using [(6-
chlorohexyl) sulfanyl] benzene and N- [3- (4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
437.4 (M + H)+.
Example 583
N-(3-~1-[4-(PHENYLSULFANYL)BUTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure G
and Scheme B1 using [ (4-chlorobutyl) sulfanyl] benzene and
N- [3- (4-piperidinyl) phenyl] propanamide: ESMS m/e: 396. 8
(M + H)+.
Example 584
N-(3-~l-[4-(PHENYLSULFANYL)BUTYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure G and Scheme B1 using [(4-
chlorobutyl) sulfanyl] benzene and N- [3- (4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
409.5 (M + H)+.
Example 585
2-METHYL-N-(3-~1-[4-(PHENYLSULFANYL)BUTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure G
and Scheme B1 using [ (4-chlorobutyl) sulfanyl] benzene and
2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide,: ESMS
m/e: 410.6 (M + H)+.
Example 586
2-METHYL=N-(3-~l-[5-(PHENYLSULFANYL)PENTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure G
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and Scheme B1 using [(5-
chloropentyl) sulfanyl]benzene and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 425.1 (M + H)~.
Example 587
N-(3-~l-[5-(PHENYLSULFANYL)PENTYL~-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure G and Scheme BI using [(5-
chloropentyl) sulfanyl] benzene and N- [3- (4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
423 . 1 (M + H) + .
[(6-CHLOROHEXYL)SULFANYL]BENZENE: Prepared by Procedure
R and Scheme Z using benzenethiol and 1-bromo-6
chlorohexane.
[(4-CHLOROBUTYL)SULFANYL]BENZENE: Prepared by Procedure
R and Scheme Z using benzenethiol and 1-bromo-4-
chlorobutane.
Example 588
N- ( 3 - ~ 1- [ 6 - ( PHENYL SULFANYL ) HEXYL ] - 4 -
PIPERIDINYL}PHENYL)PROPANAMIDE: Prepared by Procedure G
and Scheme B1 using [(6-chlorohexyl)sulfanyl]benzene and
N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.4
(M + H)+.
[(5-CHLOROPENTYL)SULFANYL]BENZENE: Prepared by
Procedure R and Scheme Z using benzenethiol and 1-bromo
5-chloropentane.
[(3-CHLOROPROPYL)SULFANYL]BENZENE: Prepared by
Procedure R and Scheme Z using benzenethiol and 1-bromo-
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3-chloropropane: 1H NMR (400 MHz, CDC13) ~ 7.37-
7.34 (m, 2H), 7.32-7.26 (m, 2H), 7.19 (tt, 1H, J = 1.4,
7.3 Hz) , 3 . 67 (t, 2H, J = 6.6 Hz) , 3 . 08 (t, 2H, J = 6. 6
Hz) , 2.06 (qt, 2H, J = 6.6 Hz) .
Example 589
N-(3-~l- [5- (PHENYLSULFANYL) PENTYL] -4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure G
and Scheme B1 using [(5-chloropentyl)sulfanyl]benzene
and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
411.1 (M + H)+.
3-CHLOROPROPYL 4-FLUOROPHENYL SULFIDE: Prepared by
Procedure R and Scheme Z using 4-fluorobenzenethiol and
1-bromo-3-chloropropane.
1-BROMO-2-[(3-CHLOROPROPYL)SULFANYL]BENZENE: Prepared by
Procedure R and Scheme Z using 2-bromobenzenethiol and
1-bromo-3-chloropropane.
3-CHLOROPROPYL 4-FLUOROPHENYL SULFOXIDE: Prepared by
Procedure S and Scheme AA using 3-chloropropyl 4
fluorophenyl sulfide and 1 eq m-CPBA: 1H NMR (400 MHz,
CDC13) b 7.65-7.62 (m, 2H), 7.28-7.21 (m, 2H), 3.65 (m,
2H), 2.94 (m, 2H), 2.28 (m, 1H), 2.06 (m, 1H); ESMS~m/e:
220.9 (M + H)+.
3-CHLOROPROPYL 3-FLUOROPHENYL SULFIDE: Prepared by
Procedure R and Scheme Z using 3-fluorobenzenethiol and
1-bromo-3-chloropropane.
3-CHLOROPROPYL 2-FLUOROPHENYL SULFIDE: Prepared by
Procedure R and Scheme Z using 2-fluorobenzenethiol and
1-bromo-3-chloropropane.
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1-BROMO-2-[(3-CHLOROPROPYL)SULFINYL]BENZENE: Prepared
by Procedure S and Scheme AA using 1-bromo-2-[(3
chloropropyl)sulfanyl]benzene and 1 eq m-CPBA: ESMS m/e:
282.8 (M + H)+.
1-CHLORO-2-[(3-CHLOROPROPYL)SULFANYL]BENZENE: Prepared
by Procedure R and Scheme Z using 2-chlorobenzenethiol
and 1-bromo-3-chloropropane.
1-CHLORO-3-[(3-CHLOROPROPYL)SULFANYL]BENZENE: Prepared
by Procedure R and Scheme Z using 3-chlorobenzenethiol
and 1-bromo-3-chloropropane.
1-CHLORO-4-[(3-CHLOROPROPYL)SULFANYL]BENZENE: Prepared
by Procedure R and Scheme Z using 4-chlorobenzenethiol
and 1-bromo-3-chloropropane.
1-BROMO-3-[(3-CHLOROPROPYL)SULFANYL]BENZENE: Prepared
by Procedure R and Scheme Z using 3-bromobenzenethiol
and 1-bromo-3-chloropropane.
1-BROMO-4-[(3-CHLOROPROPYL)SULFANYL]BENZENE: Prepared
by Procedure R and Scheme Z using 4-bromobenzenethiol
and 1-bromo-3-chloropropane.
3-CHLOROPROPYL 3,4-DIMETHYLPHENYL SULFIDE: Prepared by
Procedure R and Scheme Z using 3,4-dimethylbenzenethiol
and 1-bromo-3-chloropropane. .
3 0 Example 590
N-[3-(1-~3-[(4-FLUOROPHENYL)SULFINYL]PROPYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 3-chloropropyl 4-
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fluorophenyl sulfoxide and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDC13) b
7.64 (m, 2H) , 7.53 (s, 1H) , 7.24 (m, 5H) , 6. 94 (d, 1H, J
_ 7.7 Hz), 2.89 (m, 4H), 2.45 (m, 4H ), 1.99 (m, 3H),
1. 77 (m, 5H) , 1 .24 (d, 6H, J = 6.8 Hz) ; Anal . Calcd for
C24H3iFN2O2S+0.6EtOAc: C, 65.5; H, 7.45; N, 5.79.
Found: C, 65.4; H, 7.30; N, 5.73; ESMS m/e: 431.1 (M +
H)+.
Example 591
N-(3-(1-~3-((2-SROMOPHENYL)SULFINYL]PROPYL~-4-
PIPERIDINYL)PHENYL =2-METHYLPROPANAMIDE: Prepared by
Procedure G and Scheme B1 using 1-bromo-2-[(3-
chloropropyl)sulfinyl]benzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: Anal. Calcd for
C~4H31BrN202S+0.3CHC13: ESMS m/e: 491.0 (M + H)+.
Example 592
N-~3-(1-((3S)-3-~((3,4-DIFLUOROPHENYL)SULFONYL]AMINO-3-
PHENYLPROPYL)-4-PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE:
Prepared by Procedure Q1 and Scheme AC using 3,4-
difluorobenzenesulfonyl chloride and N- (3-{1- [ (3S) -3-
amino-3-phenylpropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide: ESMS m/e: 556.2 (M + H)+.
Example 593
3-CHLORO-N-((1S)-3-~4-(3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~-1-PHENYLPROPYL)-2-THIOPHENECARBOXAMIDE:
Prepared by Procedure Q1 and Scheme AC using 3-chloro-2-
thiophenecarbonyl chloride and N-(3-{1-[(3S)-3-amino-3-
phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide:
ESMS m/e: 524.2 (M + H)+.
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Example 594
N-(3-~l- [ (3S) -3- (~ [5- (DIMETHYLAMINO) -1-
NAPHTHYL]SULFONYL~AMINO)-3-PHENYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure Q1 and Scheme AC using 5-(dimethylamino)-1-
naphthalenesulfonyl chloride and N- (3-{1- [ (3S) -3-amino-
3-phenylpropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide: ESMS m/e: 613.3 (M + H)+.
Example 595
2-METHYL-N-~3- [1- ( (3S) -3-~ [ (4-
METHYLPHENYL) SULFONYL]AMINO-3-PHENYLPROPYL) -4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure
Q1 and Scheme AC using 4-methylbenzenesulfonyl chloride
and N- (3-{1- [ (3S) -3-amino-3-phenylpropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 534.2
(M + H)+.
Example 596
N-~3- [1- ( (3S) -3-~ [ (3, 5-DICHLORO-2-
HYDROXYPHENYL) SULFONYL] AMINO-3-PHENYLPROPYL) -4-
PTPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared
Procedure Q1 and Scheme AC using 3,5-dichloro-2-
hydro~ybenzenesulfonyl chloride and N- (3-{1- [ (3S) -3-
amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide: ESMS m/e: 605.4 (M + H)~.
Example 597
2-METHYL-N- [3- (1-~ (3S) -3- C (METHYLSULFONYL) AMINO] -3-
PHENYLPROPYL~-4-PIPERIDINYL)PHENYL]PROPANAMIDE:
Prepared by Procedure Q1 and Scheme AC using
methanesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-
phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide:
ESMS m/e: 458.6 (M + H)+.
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Example 598
N-~3- [1- ( (3S) -3-~ [ (4-FLUOROPHENYL) SULFONYL]AMINO-3-
PHENYLPROPYL)-4-PIPERIDINYL]PHENYL -2-METHYLPROPANAMIDE:
Prepared by Procedure Q1 and Scheme AC using 4-
fluorobenzenesulfonyl chloride and N-(3-{1-[(3S)-3-
amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide: ESMS m/e: 538.1 (M + H)+.
Example 599
N-~3- [1- ( (3S) -3-~ [ (4-TERT-BUTYLPHENYL) SULFONYL]AMINO-3-
PHENYLPROPYL)-4-PIPERTDINYL]PHENYL-2-METHYLPROPANAMIDE:
Prepared by Procedure Q1 and Scheme AC using 4-tert-
butylbenzenesulfonyl chloride and N-(3-{1-[(3S)-3-amino-
3-phenylpropyl)-4-piperidinyl~phenyl)-2-
methylpropanamide: ESMS m/e: 576.2 (M + H)+.
Example 600
N-~3-[1-((3S)-3-~[(2,5-DICHLOROPHENYL)SULFONYL]AMIN03-3-
PHENYLPROPYL)-4-PIPERIDINYL]PHENYL -2-METHYLPROPANAMIDE:
Prepared by Procedure Q1 and Scheme AC using 2,5-
dichlorobenzenesulfonyl chloride and N-(3-{1-[(3S)-3-
amino-3-phenylpropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide: ESMS m/e: 588.0 (M + H)+.
2 5 Example 601
2-METHYL-N- [3- (1-~ (3S) -3-PHENYL-3-
[(PROPYLSULFONYL)AMINO]PROPYL~-4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared ~by Procedure
Q1 and Scheme AC using 1-propanesulfonyl chloride and N-
(3-{1- [ (3S) -3-amino-3-phenylpropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide: ESMS m/e: 486.2
(M + H)+.
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Example 602
N-~3- [1- ( (3S) -3-~ [ (3, 5-DIMETHYL-4-
ISOXAZOLYL) SULFONYL]AMINO-3-PHENYLPROPYL) -4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Prooedure Q1 and Scheme AC using 3,5-dimethyl-4-
isoxazolesulfonyl chloride and N- (3-{1- [ (3S) -3-amino-3-
phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide:
1H NMR (400 MHz, CDC13) ~ 7 .53 (s, 2H) , 7.3-7.1 (m, 5H) ,
7.05 (t, 2H, J = 6.5 Hz) , 6.81 (d, 1'H, J = 7.1 Hz) , 4. 65
(dd, 1H, J = 6.3, 2 .2 Hz) , 3 .11 (t, 2H, J = 7.2 Hz) , 2.4
(m, 4H), 2.2 (s, 3H), 2.05 (m, 2H), 2.01 (s, 3H), 2.0-
1.8 (m, 7H), 1.21 (d, 6H, J = 7.1 Hz); ESMS m/e: 539.5
(M + H)+.
Example 603
METHYL 3-~[(3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~PROPYL)AMINO]SULFONYL~-2-
THIOPHENECARBOXYLATE: Prepared Procedure Q1~ and Scheme
AC using methyl 3-(chlorosulfonyl)-2-
thiophenecarboxylate and N-f3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl -2-methylpropanamide: Anal. Calcd for
Cz4H33N3O5S . HCl : C, 6 . 0 0 ; H, 5 . 3 0 ; N, 7 . 72 . Found: C,
52.9; H, 6.04; N, 7.59; ESMS m/e: 508.2 (M + H)+.
Example 604
2-METHYL-N-~3- [1- ( (3S) -3-~ [ (4-
PHENOXYANILINO)CARBONYL]AMINO-3-PHENYLPROPYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure P
and Scheme AB using 1-isocyanato-4-phenoxybenzene and N-
(3-{1- [ (3S) -3-amino-3-phenylpropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide: ESMS m/e: 591.3
(M + H)+.
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PIPERIDINYLIPHENZ.'L~-2- METHYLPROPANAMIDE:
Prepared by Procedure Q1 and Scheme AC using 3,5-
dimethyl-4-isoxazolesulfonyl chloride and N- (3-{1- [ (3S) -
3-amino-3-phenylpropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide: 1H NMR (400 MHz, CDC13) b 7.53 (s,
2H), 7.3-7.1 (m, 5H), 7.05 (t, 2H, J = 6.5 Hz), 6.81 (d,
1H, J - 7.1 Hz), 4.65 (dd, 1H, J = 6.3, 2.2 Hz), 3.11
(t, 2H, J = 7.2 Hz) , 2.4~ (m, 4H) , 2.2 (s, 3H) , 2.05 (m,
2H) , 2 .01 (s, 3H) , 2.0-1.8 (m, 7H) , 1.21 (d, 6H, J = 7.1
Hz); ESMS m/e: 539.5 (M + H)+.
Example 603
METHYL 3-~[(3-~4-[3-(ISOBUTYRYLAMINO)PHENYLJ-1-
PIPERIDINYL~PROPYL)AMINO]SULFONYL~-2-
THIOPHENECARBOXYLATE: Prepared Procedure Q1 and Scheme
AC using methyl 3-(chlorosulfonyl)-2
thiophenecarboxylate and N-~3-[1-(3-aminopropyl)-4
piperidinyl]phenyl -2-methylprapanamide: Anal~ Calcd for.
C24H33N305S.HC1: C, 6.00; H, 5.30; N, 7.72. Found: C,
52.9; H, 6.04; N, 7.59; ESMS m/e: 508.2 (M + H)~.
Example 604
2-METHYL-N-~3- [1- ( (3S) -3-~ [ (4-
PHENOXYANILINO)CARBONYL]AMINO -3-PHENYLPROPYL)-4-
PIPERIDINYL]PHENYL}PROPANAMIDE: Prepared by Procedure P
and Scheme AB using 1-isocyanato-4-phenoxybenzene and N-
(3-(1-[(3S)-3-amino-3-phenylpropyl]-4-
piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 591.3
(M + H)+.
Example 605
N- [3- (1-~ (3S) -3- [ (ANILINOCARBONYL)AMINO] -3-
PHENYLPROPYL~-4-PIPERIDINYL)PHENYL -2-METHYLPROPANAMIDE:
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Prepared by Procedure P and Scheme AB using
isocyanatobenzene and N-(3-{1-[(3S)-3-amino-3-
phenylpropyl]-4-piperidinyl~phenyl)-2-methylpropanamide:
ESMS m/e: 499.2 (M + H)+.
Example 606
N-~3- [1- ( (3S) -3- f [ (TERT-BUTYLAMINO) CARBOTHIOYL]AMINO-3-
PHENYLPROPYL)-4-PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE:
Prepared by Procedure P id Scheme AB using 2-
isothiocyanato-2-methylpropane and N-(3-~1-[(3S)-3-
amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-
methylpropanamide: ESMS m/e: 495.1 (M + H)+.
Example 607
N-{3- [1- ( (3S) -3-~ L (2-FLUOROANILINO) CARBONYL] AMINO-3-
PHENYLPROPYL)-4-PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE:
Prepared by Procedure P and Scheme AB using 1-fluoro-2.-
isocyanatobenzene and ~ N- (3- f 1- [ (3S) -3-amino-3-
phenylpropyl]-4-piperidinyl~phenyl)-2-methylpropanamide:
ESMS m/e: 517.0 (M + H)+.~~
Example 608
2-METHYL-N- [3- (1-{ (3S) -3-PHENYL-3- [ (2-
TOLUIDINOCARBOTHIOYL)AMINO]PROPYL~-4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure P
and Scheme AB using 1-isothiocyanato-2-methylbenzene and
N- (3- f 1- [ (3S) -3-amino-3-phenylpropyl] -4-
piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 529.1
(M + H)+.
Example 609 W w
Y
N-~3- [I- ( (3S) -3-~ [ (BENZYLAMINO) CARBONYL]AMINO-3-
PHENYLPROPYL)-4-PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE:
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phenylpropyl]-4- piperidinyl~phenyl)-2-
methylpropanamide: 1H NMR (400 MHz, CDC13) b 8.44 (s,
1H), 7.67 (d, 1H, J = 7.9 Hz), 7.31-7.13 (m, 13H), 6.38
(s, 1H), 6.80 (d, 1H, J = 7.9 Hz), 5.54 (m, 1H), 4.81
~(m, 1H), 4.41 (dd, 1H, J = 14.8, 6.2 Hz), 4.29 (dd, 1H,
J = 14.9, 5.4 Hz) , 2.99 (d, 1H, J = 11.2 Hz) , 2 .87 (d,
1H, J = 11.2 Hz) , 2.67 (q, 1H, J = 6.2 Hz) , 2 .3 (m, 3H) ,
2.0-1.5 (m, 7H), 1.23 (d, 6H, J - 6.7 Hz); ESMS m/e:
513.2 (M + H)+.
Example 610
2-METHYL-N-~3-[1-((3S)-3-~[(2-
NITROANILINO)CARBONYL]AMINO-3-PHENYLPROPYL)-4-
PIPERIDINYL]PHENYL}PROPANAMIDE: Prepared by Procedure P
and Scheme AB using 1-isocyanato-2-nitrobenzene and N-
(3-{1- [ (3S) -3-amino-3-phenylpropyl] -4-
piperidinyl~phenyl)-2-methylpropanamide: ESMS m/e: 543.6
(M + H)+.
2 0 Example 611
N- f 3- [1- ( (3S) -3-~ [ (3, 4-DICHLOROANILINO) CARBONYL] AMINO-
3-PHENYLPROPYL)-4-PIPERIDINYL]PHENYL-2-
METHYLPROPANAMIDE: Prepared by Procedure P and Scheme
AB using 1,2-dichloro-4-isocyanatobenzene and N-(3-~1-
[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl~phenyl)-2-
methylpropanamide: ESMS m/e: 567.1 (M + H)+.
Example 612
2-METHYL-N-(3-~l- [ (3S) -3- (~ [2- .
(METHYLSULFANYL)ANILTNO]CARBONYL~AMINO)-3-PHENYLPROPYL]-
4-PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure
P and Scheme AB using 1-isocyanato-2-
(methylsulfanyl)benzene and N- (3-(1- [ (3S) -3-amino-3-
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phenylpropyl]-4- piperidinyl~phenyl)-2-
methylpropanamide: ESMS m/e: 545.0 (M + H)~.
Example 613
N-~3- [1- (3-~ [ (4-FLUOROANILINO) CARBONYL] AMINO~PROPYL) -4-
PIPERIDINYLjPHENYL~-2-METHYLPROPANAMIDE: Prepared by
Procedure P and Scheme AB using. 1-fluoro-4-
isocyanatobenzene and N-{3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl -2-methylpropanamide: 1H NMR (400
MHz, CDC13) b 7.45 (q, 2H, J = 4.7 Hz), 7.23 (m, 4H),
7.05 (t, 4H, J = 7.8 Hz) , 6.75 (m, 1H) , 4 .05 (m, 1H) ,
3 .19 (s, 1H) , 2.71 (m, 1H) , 2.53 (m, 1H) , 2 .25 (m, 3H) ,
1.8 (m, 9H) , 1.25 (d, 6H, J = 6.4 Hz) ; ESMS m/e: 441.1
(M + H)+.
Example 614
N- f 3- Ll- (3-~ [ (3,4- .
DICHLOROANILINO) CARBONYL] AMINO~PROPLrL) -4-
PIPERIDINYLjPHENYL~-2-METHYLPROPANAMIDE: Prepared by
Procedure P and Scheme AB using 1,2-dichloro-4-
isocyanatobenzene and N-f3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 493.2
(M + H)+.
2 5 Example 615
2-METHYL-N-[3-(1-{3-[(2-
TOLUIDINOCARBOTHIOYL)AMINOjPROPYL~-4-
PIPERIDINYL)PHENYLjPROPANAMIDE: Prepared by Procedure P
and Scheme AB using 1-isothiocyanato-2-methylbenzene and
N-{3- [1- (3-aminopropyl) -4-piperidinyl]phenyl}-2-
methylpropanamide: ESMS m/e: 453.2 (M + H)+.
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Example 616
N-{3-[1-(3-~[(BENZYLAMINO)CARBONYL]AMINO}PROPYL)-4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure P and Scheme AB using
(isocyanatomethyl)benzene and N-{3-[1-(3-aminopropyl)-4-
piperidinyl)phenyl -2-methylpropanamide: ESMS m/e: 437.2
(M + H)+.
Example 617
N-~3-[1-(3-{[(4-ETHOXYANILINO)CARBONYL]AMINO~PROPYL)-4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure P and Scheme AB using 1-ethoxy-4-
isocyanatobenzene and N-{3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 467.2
(M + H)+.
Example 618 _
N- [3- (1-~3- [ (ANILINOCARBONYL)AMINO] PROPYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure P and Scheme AB using isocyanatobenzene and N-
~3- [1- (3-aminopropyl) -4-piperidinyl]phenyl-2-
methylpropanamide: ESMS m/e: 422.9 (M + H)+.
Example 619
2-METHYL-N-(3-~1-[3-(~[2-
(METHYLSULFANYL)ANILINO]CARBONYL~AMINO)PROPYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure P
and Scheme AB using 1-isocyanato-2-
(methylsulfanyl)benzene and N-~3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 469.1
(M + H)+.
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Example 620
N-~3-(1-(3-~((TERT-BUTYLAMINO)CARBOTHIOYL]AMINO~PROPYL)-
4-PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure P and Scheme AB using 2-isothiocyanato-2-
methylpropane and N-(3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 419.0
(M + H)+.
Example 621
2-METHYL-N- f 3- (1- (3-~ ( (4-
PHENOXYANILINO)CARBONYL]AMINO~PROPYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure P
and Scheme AB using 1-isocyanato-4-phenoxybenzene and N-
{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-
methylpropanamide: ESMS m/e: 515.5 (M + H)+.
Example 622
N-(3-~4-(3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL~PROPYL)-4-
(2,4-DIFLUOROPHENYL)-2-METHYL-6-OXO-1,4,5,6-TETRAHYDRO-
3-PYRIDINECARBOXAMIDE: Prepared by Procedure AC and
Scheme AM using N- f 3- [1- (3-aminopropyl) -4-
piperidinyl]phenyl}acetamide and 4-(2,4-difluorophenyl)-
2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylic
acid: ESMS m/e: 525.2 (M + H)+.
Example 623
N-(3-~4-(3-(ACETYLAMINO)PHENYL]-1-PTPERIDZNYL~PROPYL)-4-
(3,4-DIFLUOROPHENYL)-2-METHYL-6-OXO-1,4,5,6-TETRAHYDRO-
3-PYRIDINECARBOXAMIDE: Prepared by Procedure AC and
Scheme AM using N-~3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl}acetamide and 4-(3,4 -
difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-
pyridinecarboxylic acid: ESMS m/e: 525.2 (M + H)+.
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Example 624
N-(6-~4-(3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~HEXYL)-1-(4-NITROPHENYL)-5-
(TRIFLUOROMETHYL)-1H-PYRAZOLE-4-CARBOXAMIDE: Prepared by
Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-
aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and 1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-
carbonyl chloride: ESMS m/e: 629.2 (M + H)+.
Example 625
N- [3- (1-~6- [ (DIPHENYLACETYL)AMINO]HEXYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure Q1 (THF) and Scheme AT using N-~3-[1-(6-
aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide,
and diphenylacetyl chloride: ESMS m/e: 540.3 (M + H)+.
Example 626
5- (3, 5-DICHLOROPHENOXY) -N-(6-~4- [3-
(ISOBUTYRYLAMTNO)PHENYL]-1-PIPERIDINYL~HEXYL)-2-
FURAMIDE:
Prepared by Procedure Ql (THF) and Scheme AT using N-~3-
[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-
methylpropanamide and 5-(3,5-dichlorophenoxy)-2-furoyl
chloride: ESMS m/e: 600.2 (M + H)+.
Example 627
N-(6-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~HEXYL)-2-PHENOXYNICOTINAMIDE: Prepared by
Procedure Q1 (THF) and Scheme AT using N- f 3- [1- (6-
aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and 2-phenoxynicotinoyl chloride: ESMS m/e: 543.3 (M +
H)+.
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Example 628
N-(6-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~HEXYL)-2-NAPHTHAMIDE: Prepared by Procedure
Q1 (THF) and Scheme AT using N- f 3- [1- (6-aminohexy=1) -4-
piperidinyl]phenyl -2-methylpropanamide and 2-naphthoyl
chloride: ESMS m/e: 500.3 (M + H)+.
Example 629
1-BENZYL-3-TERT-BUTYL-N-(6-f4-(3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~HEXYL)-1H-
PYRAZOLE-5-CARBOXAMIDE: Prepared by Procedure Q1 (THF)
and Scheme AT using N-~3-[1-(6-aminohexyl)-4-
piperidinyl]phenyl}-2-methylpropanamide and 1-benzyl-3-
tert-butyl-1H-pyrazole-5-carbonyl chloride: ESMS m/e:
586.3 (M + H)+.
Example 630
3-CHLORO-N-(6-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~HEXYL)-4-(ISOPROPYLSULFONYL)-2-
THIOPHENECARBOXAMIDE: Prepared by Procedure Q1 (THF) and
Scheme AT using N-{3- [1- (6- aminohexyl) -4-
piperidinyl]phenyl -2-methylpropanamide and 3-chloro-4-
(isopropylsulfonyl)-2-thiophenecarbonyl chloride: ESMS
m/e: 596.2 (M + H)+.
Example 63I
N- [3- (1- f 6- [ (ANILINOCARBONYL)AMTNO] HEXYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure Q1 (THF) and Scheme AT using N-~3-[1-(6-
aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and phenyl isocyanate . ESMS m/e: 465.2 (M + H)+.
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Example 632
N-{3-[1-(6-~[(2,4-DICHLOROANILINO)CARBONYL]AMINO}HEXYL)-
4-PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-
aminohexyl)-4-piperidinyl]phenyl -2-methylpropanamide
and 2,4-dichlorophenyl isocyanate: ESMS m/e: 533.2 (M +
H)+.
Example 633
N-(6-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDTNYL~HEXYL)-1-PHENYL-5-PROPYL-1H-PYRAZOLE-4-
CARBOXAMIDE: Prepared by Procedure Q1 (THF) and Scheme
AT using N-~3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-
methylpropanamide and 1-phenyl-5-propyl-1H-pyrazole-4-
carbonyl chloride: ESMS m/e: 558.3 (M + H)+.
Example 634
2-METHYL-N-~3-[1-(6-~[(1-
NAPHTHYLAMINO)CARBONYL]AMINO~HEXYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure Ql
(THF) and Scheme AT using N-~3-[1-(6-aminohexyl)-4-
piperidinyl]phenyl -2-methylpropanamide and 1-naphthyl
isocyanate: ESMS m/e: 515.3 (M + H)+.
Example 635
N-~3-[1-(6-~[([1,1'-BIPHENYL]-4-
YLAMINO)CARBONYL]AMINO~HEXYL)-4-PIPERIDINYL]PHENYL-2-
METHYLPROPANAMIDE: Prepared by Procedure Q1 (THF) and
Scheme AT using N-f3-[1-(6-aminohexyl)-4-
piperidinyl]phenyl}-2-methylpropanamide and 4-biphenyl
isocyanate: ESMS m/e: 541.3 (M + H)+.
Example 636
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2-METHYL-N-{3-[1-(6-~[(2-
NAPHTHYLAMINO)CARBONYL]AMINO~HEXYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure Q1
(THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-
piperidinyl]phenyl -2-methylpropanamide and 2-naphthyl
isocyanate: ESMS m/e: 515.3 (M + H)+.
Example 637
N-~3- [1- (3- f [ (3, 4-
DIMETHOXYPHENYL)SULFONYL]AMINO}PROPYL)-4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-
aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and 3,4-dimethoxybenzenesulfonyl chloride; ESMS m/e:
504.2 (M + H)+.
Example 638
N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~PROPYL)-5-METHYL-3-PHENYL-4-
ISOXAZOLECARBOXAMIDE: Prepared by Procedure Q1 (THF) and
Scheme AT using N-{3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl}-2-methylpropanamide and 5-methyl-3-
phenyl-4-isoxazolecarbonyl chloride: ESMS m/e: 489.3 (M
+ H)+.
Example 639
N-~3-[1-(3-~[(4-FLUOROPHENYL)ACETYL]AMINO~PROPYL)-4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-
aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and (4-fluorophenyl)acetyl chloride: ESMS m/e: 440.3 (M
+ H)+.
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Example 640
N-~3- [1- (3-~ [ (4-CHLORO-3-
NITROPHENYL) SULFONYL] AMINO~PROPYL) -4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure Q1 (THF) and Scheme AT using N- f 3- [1- (3-
aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and 4-chloro-3-nitrobenzenesulfonyl chloride: ESMS m/e:
523.1 (M + H)+
Example 641
2-(4-CHLOROPHENOXY)-N-(3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-
1-PIPERIDINYL~PROPYL)NICOTINAMIDE: Prepared by Procedure
Q1 (THF) and Scheme AT using N-f3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl -2-methylpropanamide and 2-(4-
chlorophenoxy)nicotinoyl chloride: ESMS m/e: 535.2 (M +
H)+.
Example 642
5-(3,S-DICHLOROPHENOXY)-N-(3-~4-[3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~PROPYL)-2-
FURAMIDE:
Prepared by Procedure Ql (THF) and Scheme AT using N-~3-
[1- (3-aminopropyl) -4-piperidinyl]phenyl}-2-
methylpropanamide and 5-(3,5-dichlorophenoxy)-2-furoyl
chloride: ESMS m/e:'558.2 (M + H)+.
Example 643
N-~3-[1-(3-~[(2-FLUOROPHENYL)SULFONYL]AMINO~PROPYL)-4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure Q1 (THF) and Scheme AT using N-~3-[1-(3-
aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and 2-fluorobenzenesulfonyl chloride: ESMS m/e: 462.2 (M
+ H)+.
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Example 644
N-~3-[1-(3-~[(3,5-DIMETHYL-4-
ISOXAZOLYL)SULFONYL]AMINO~PROPYL)-4-PIPERIDINYL]PHENYL~-
2-METHYLPROPANAMIDE: Prepared by Procedure Q1 (THF) and
Scheme AT using N-f3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl -2-methylpropanamide and 3,5-
dimethyl-4-isoxazolesulfonyl chloride: ESMS m/e: 463.2
(M + H)+.
Example 644
N-~3- [1- (3-~ [ (4-TERT-BUTYLPHENYL) SULFONYL]AMINO~PROPYL) -
4-PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure Q1 (THF) and Scheme AT using N-f3-[1-(3-
aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and 4-tert-butylbenzenesulfonyl chloride: ESMS m/e:
500.3 (M + H)+.
Example 646
N-~3-[1-(6-AMINOHEXYL)-4-PIPERIDINYL]PHENYL -2-
METHYLPROPANAMIDE: Prepared by Procedure AE and Scheme Y
using N-(3-f1-[6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-
yl)hexyll-4-piperidinyl~phenyl)-2-methylpropanamide and
hydrazine hydrate: ESMS m/e: 346.2 (M + H)+.
Example 647
N-~3- [1- (2-~ [ ( [l, 1' -BIPHENYL] -4-
YLAMINO) CARBONYL] AMINO~ETHYL) -4-PIPERIDINYL].PHENYL-2-
METHYLPROPANAMIDE: Prepared by Procedure Ql (THF) and
Scheme AT using N-(3-[1-(2-aminoethyl)-4-
piperidinyl]phenyl -2-methylpropanamide and 4-biphenyl
isocyanate: ESMS m/e: 485.2 (M + H)+.
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Example 648
412
5- (3, 5-DICHLOROPHENOXY) -N-(2-~4- [3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~ETHYL)-3-
FURAMIDE:
Prepared by Procedure Q1 (THF) and Scheme AT using N-(3-
[1- (2-aminoethyl) -4-piperidinyl]phenyl~-2-
methylpropanamide and 5-(3,5-dichlorophenoxy)-3-furoyl
chloride: ESMS m/e: 544.1 (M + H)+.
Example 649
N- [3- (1-~2- [ (DIPHENYLACETYL)AMINO] ETHYL-4-
PTPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure Q1 (THF) and Scheme AT using N-~3- [1- (2-
aminoethyl)-4-piperidinyl]phenyl -2-methylpropanamide
and diphenylacetyl chloride: ESMS m/e: 484.2 (M + H)+.
Example 650
N-(2-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PTPERIDINYL~ETHYL)-2-NAPHTHAMIDE: Prepared by Procedure
Q1 (THF) and Scheme AT using N-~3-[1-(2-aminoethyl)-4-
piperidinyl]phenyl}-2-methylpropanamide and 2-naphthoyl
chloride: ESMS m/e: 444. 2 (M + H)+.
Example 651
3- (2, 6-DICHLOROPHENYL) -N-(4- f 4- [3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}BUTYL)-5-METHYL-
4-ISOXAZOLECARBOXAMIDE:
Prepared by Procedure Q1 (THF) and Scheme AT using N-~3-
[1- (4-aminobutyl) -4-piperidinyl].phenyl-2-
methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-
isoxazolecarbonyl chloride: ESMS m/e: 571.2 (M + H)+.
Example 652
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3- (2, 6-DICHLOROPHENYL) -N- (5-~4- [3-
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~PENTYL)-5-METHYL-
4-ISOXAZOLECARBOXAMIDE:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-
[1- (5-aminopentyl) -4-piperidinyl]phenyl-2-
methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-
isoxazolecarbonyl chloride. ESMS m/e: 585.2.(M + H)+.
Example 653
N- (3- (1-{4- [ (DIPHENYLACETYL) AMINO] BUTYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure Q2(THF/DCM, 1:3)) and Scheme AT using N-{3-
[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-
methylpropanamide and diphenylacetyl chloride: ESMS m/e:
512.0 (M + H)+.
Example 654
N-[3-(1-{5-[(DIPHENYLACETYL)AMINO]PENTYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure Q2(THF/DCM, 1:3)) and Scheme AT using N-{3-
[1-(5-aminopentyl)-4-piperidinyl]phenyl}-2-
methylpropanamide and diphenylacetyl chloride: ESMS
m/e: 526.0 (M + H)+.
Example 655
3,5-DICHLORO-N-(4-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-Z-
PIPERIDINYL~BUTYL)BENZAMIDE: Prepared by Procedure Q2
(THF/DCM, 1:3) and Scheme AT using . N-{3-[1-(4-
aminobutyl)-4-piperidinyl]phenyl -2-methylpropanamide
and 3,5-dichlorobenzoyl chloride: ESMS m/e: 490.0 (M +
H)+.
Example 656
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- ( 3 , 5 -DICHLOROPHENOXY) -N- ( 4 - ~ 4 - [ 3 -
(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL~BUTYL)-2-
FURAMIDE:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT
5 using N-{3- [1- (4-aminobutyl) -4-piperidinyl]phenyl-2
methylpropanamide and 5-(3,5-dichlorophenoxy)-2-furoyl
chloride: ESMS m/e: 572.0 (M + H)+.
Example 657
3-CHLORO-N-(4-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~BUTYL)BENZAMIDE: Prepared by Procedure Q2
(THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-
aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and 3-chlorobenzoyl chloride: ESMS m/e: 456.0 (M + H)+.
Example 658
3,4-DIFLUORO-N-(4-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~BUTYL)BENZAMIDE: Prepared by Procedure Q2
(THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-
aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and 3,4-difluorobenzoyl chloride: ESMS m/e: 458.0 (M +
H)+.
Example 659
N-~3- [1- (4-~ [ (3, 5-DICHLOROANILINO) CARBONYL] AMINO~BUTYL) -
4-PIPERIDINYL]PHENYL -2-METHYLPROPANAMIDE: Prepared by
Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-(3-
{1- [4- (formylamino)butyl] -4-piperidinyl~phenyl) -2-
methylpropanamide and 3,5-dichlorophenyl isocyanate:
ESMS m/e: 505.0 (M + H)+.
Example 660
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N-~3- [1- (4-{ [ ( [1~ 1' - BIPHENYL] -4-
YLAMINO) CARBONYL] AMINO~BUTYL) -4-PIPERIDINYL] PHENYL-2-
METHYLPROPANAMIDE: Prepared by Procedure Q2 (THF/DCM,
1:3) and Scheme AT using N-~3-[1-(4-aminobutyl)-4-
piperidinyl]phenyl -2-methylpropanamide and 4-biphenyl
isocyanate: ESMS m/e: 513.0 (M + H)+.
Example 661
2-METHYL-N-(3-{1-[5-(4-NITROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 (KZC03) using 5-chloro-1- (4-nitrophenyl) -
1-pentanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 452.2 (M + H)+.
Example 662
N-(3-~l-[5-(4-FLUOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme B1 (KZCO3) using 5-chloro-1-(4-
fluorophenyl)-1-pentanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M + H)+.
Example 663
2-METHYL-N- [3- (1-~5-OXO-5- [2-
(TRIFLUOROMETHYL)PHENYL]PENTYL~-4-
PIPERTDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure K
and Scheme Bl (K2C03) using 5-chloro-1- [2-
(trifluoromethyl) phenyl] -.1-pentanone and 2-methyl-N- [3-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 475.2 (M +
H)+
Example 664
N-(3-~l- [5- (3-BROMOPHENYL) -5-OXOPENTYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
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Procedure K and Scheme B1 (KaCO3) using 1- (3-
bromophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 485,1 (M + H)+.
Example 665
2-.METHYL-N-(3-~1-[5-(3-NITROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure K
and Scheme B1 (K2CO3) using 5-chloro-1-(3-nitrophenyl)-
1-pentanone and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 452.2 (M + H)+.
Example 666
N-(3-~1-(5-(3-CHLOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme B1 (K2CO3) using 1-(3-
chlorophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 441.1 (M + H)+.
Example 667
N-(3-~1- [5- (4-BROMOPHENYL) -5-OXOPENTYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme Bl (KaC03) using 1- (4-
bromophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 485.1 (M + H)+.
Example 668
N-(3-~1-(5-(2-IODOPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme B1 (KzC03) using 1-(2-
iodophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 533.0 (M + H)+.
Example 669
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N-(3-~1-[5-(3- FLUOROPHENYL)-5-
OXOPENTYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE:
Prepared by Procedure K and Scheme B1 (K~C03) using 1-
(3-fluoropheny~.) -5-chloro-1-pentanone and 2-methyl-N- [3-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M +
H)+
Example 670
2-METHYL-N- [3- (1-~5-OXO-5- [3-
(TRIFLUOROMETHYL)PHENYL]PENTYL~-4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure K
and Scheme B1 (KzC03) using 1- [3-
(trifluoromethyl)phenyl]-5-chloro-1-pentanone and 2
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
475.2 (M + H)+.
Example 671
N-(3-~1-[5-(2-FLUOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme B1 (KZC03) using 1-(2-
fluorophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M + H)+.
Example 672
N-(3-~1-[5-(3-IODOPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme B1 (K~C03) using 1- (3-
iodophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 533.0 (M + H)+.
Example 673
N-(3-~1-[5-(2-CHLOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
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Procedure K and Scheme B1 (KzC03) using 1- (2-
chlorophenyl)-5-chloro-1-pentanone and 2-methyl-N-C3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 441.1 (M + H)+.
Example 674
2-METHYL-N-[3-(1-~5-OXO-5-[4-
(TRTFLUOROMETHYL)PHENYL]PENTYL~-4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure K
and Scheme B1 (KZC03) using 1- [4-
(trifluoromethyl)phenyl]-5-chloro-1-pentanone and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
475.2 (M + H)+.
Example 675
N-(3-~1-[5-(4-CHLOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme B1 (K2C03) using 1- (4-
chlorophenyl)-5-chloro-1-pentanone and 2-methyl-N-C3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 441.1 (M + H)+.
Example 676
N-(3-~l-[5-(4-IODOPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme B1 (K~C03) using 1- (4-
iodophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 533 (M + H)+.
Example 677 .
N-(3-~1- [5- (2-BROMOPHENYL) -5-OXOPENTYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme B1 (KzC03) using 1- (2-
bromophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 485.1 (M + H)+.
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Example 678
2 - ( 4 - CHLOROPHENOXY) -N- ( 4 - ~ 4 - [ 3 - ( I SOBUTYRYLAMINO) PHENYL ] -
1-PIPERIDINYL~BUTYL)NICOTINAMIDE: Prepared by Procedure
Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-
aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide
and 2-(4-chloropher_oxy)nicotinoyl chloride: ESMS m/e:
549.0 (M + H)+.
l0 Example 679
N-(4-{4-[3-(TSOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~BUTYL)-3,4-DIMETHOXYBENZAMIDE: Prepared by
Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-
[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-
methylpropanamide and 3,4-dimethoxybenzoyl chloride:
ESMS m/e: 482.0 (M + H)+.
Example 680
3 - ( 2 - CHLOROPHENYL ) -N- ( 4 - { 4 - [ 3 - ( I SOBUTYRYLAMINO ) PHENYL] -
1-PIPERIDINYL~BUTYL)-5-METHYL-4-ISOXAZOLECARBOXAMIDE:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT
using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl)-2-
methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-
isoxazolecarbonyl chloride: ESMS m/e: 537.0 (M + H)+.
Example 681
3-(2-CHLOROPHENYL)-N-(5-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-
1-PIPERIDINYL~PENTYL)-5-METHYL-4-ISOXAZOLECARBOXAMIDE:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT
using N-{3-[1-(5-aminopentyl)-4-piperidinyl]phenyl}-2-
methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-
isoxazolecarbonyl chloride: ESMS m/e: 551.0 (M + H)+.
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Example 682
2-METHYL-N-~3-[1-(3-~1-METHYL-2-[4-
(TRIFLUOROMETHYL)PHENYL]-1H-INDOL-3-YL~PROPYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure E
and Scheme M using 2-methyl-N-[3-(1-f5-oxo-5-[4-
(trifluoromethyl)phenyl]pentyl}-4-
piperidinyl)phenyl]propanamide and 1-methyl-1-
phenylhydrazine: ESMS m/e: 562.2 (M + H)+.
Example 683
2-METHYL-N-~3-[1-(3-~1-METHYL-2-[4-
(TRIFLUOROMETHYL)PHENYL]-1H-INDOL-3-YL~PROPYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure E
and Scheme M using 2-methyl-N-[3-(1-~5-oxo-5-[4-
(trifluoromethyl)phenyl]pentyl~-4-
piperidinyl)phenyl]propanamide and 4-
(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
. m/e: 632.2 (M + H)+.
Example 684
2-METHYL-N-~3-[2-(3-~2-[4-(TRIFLUOROMETHYL)PHENYL]-1H-
INDOL-3-YL~PROPYL)-4-PIPERIDINYL]PHENYL}PROPANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
[3- (1-{5-oxo-5- [4- (trifluoromethyl)phenyl]pentyl}--4-
piperidinyl)phenyl]propanamide and phenylhydrazine: ESMS
m/e: 548.2 (M + H)+.
Example 685 .
2-METHYL-N-~3-[1-(3-~1-PHENYL-2-[4-
(TRIFLUOROMETHYL)PHENYL]-1H-INDOL-3-YL~PROPYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure E
and Scheme M using 2-methyl-N-[3-(1-~5-oxo-5-[4-
(trifluoromethyl)phenyl]pentyl~-4-
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piperidinyl)phenyl]propanamide and 1,1-diphenylhydrazine
hydrochloride: ESMS m/e: 624.2 (M + H)+.
Example 686
2-METHYL-N-~3-[1-(3-~2-[4-(TRIFLUOROMETHYL)PHENYL]-1H-
BENZO[G]INDOL-3-YL~PROPYL)-4-
PIPERIDINYL~PHENYL~PROPANAMIDE: Prepared by Procedure E
and Scheme M using 2-methyl-N-.[3- (1- f 5-oxo-5- [4-
(trifluoromethyl)phenyl]pentyl~-4-
piperidinyl)phenyl]propanamide and 1-naphthylhydrazine
hydrochloride: ESMS m/e: 598.2 (M + H)+.
Example 687
2-METHYL-N-~3-[1-(3-f7-METHYL-2-[4-
(TRIFLUOROMETHYL)PHENYL]-1H-INDOL-3-YL~PROPYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure E
and Scheme M using 2-methyl-N-[3-(1-~5-oxo-5-[4-
(trifluoromethyl)phenyl]pentyl~-4-
piperidinyl)phenyl]propanamide and 1-(2
methylphenyl)hydrazine hydrochloride: ESMS m/e: 562.2(M
+ H)+.
Example 688
2-METHYL-N-~3-[1-(3-f5-METHYL-2-[4-
(TRIFLUOROMETHYL)PHENYL]-1H-INDOL-3-YL~PROPYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure E
and Scheme M using 2-methyl-N-[3-(1-~5-oxo-5-[4-
(trifluoromethyl)phenyl]pentyl}-4-
piperidinyl)phenyl]propanamide and 4-
methylphenylhydrazine hydrochloride: ESMS m/e: 562.2(M +
H)+.
Example 689
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N-~3-[1-(3-~5-METHOXY-2-
(TRTFLUOROMETHYL)PHENYL]-1H-INDOL-3-YL~PROPYL)-4-
PIPERIDINYL]PHENYL-2-METHYLPROPANAMIDE: Prepared by
Procedure E and Scheme M using 2-methyl-N-[3-(1-~5-oxo-
5- [4- (trifluoromethyl) phenyl] pentyl ~ -4-
piperidinyl)phenyl]propanamide and 4-
methoxyphenylhydrazine hydrochloride: ESMS m/e: 578.2 (M
+ H)+.
Example 690
N- [3- (1-~3- [2- (3-FLUOROPHENYL) -7-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-(2-methylphenyl)hydrazine
hydrochloride: ESMS m/e: 512.2 (M + H)~.
Example 691
N-[3-(1-~3-[2-(4-CHLOROPHENYL)-1-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS
m/e: 528.2 (M + H)+.
Example 692
N-[3-(1-~3-(2-(4-FLUOROPHENYL)-5-METHOXY-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-methoxyphenylhydrazine
hydrochloride: ESMS m/e: 528.2(M + H)+.
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Example 693
N- [3- (1-~3- [2- (2-FLUOROPHENYL) -1H-INDOL-3-YL] PROPYL}-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure E and Scheme M using N-(3-{1-[5-(2-
fluorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and phenylhydrazine: ESMS m/e: 498.2
(M + H)+.
Example 694
N- [3- (1-~3- [2- (3-FLUOROPHENYL) -5- (TRIFLUOROMETHOXY) -1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-
METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M
using N- (3- f 1- [5- (3-fluorophenyl) -5-oxopentyl] -4-
piperidinyl}phenyl)-2-methylpropanamide and 4-
(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
m/e: 582 .2 (M + H) +.
Example 695
N- [3- (1-~3- [2- (2-FLUOROPHENYL) -5- (TRIFLUOROMETHOXY) -1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-
METHYLPROPAN.AMIDE: Prepared by Procedure E and Scheme M
using N- (3-{1- [5- (2-fluorophenyl) -5-oxopentyl] -4
piperidinyl~phenyl)-2-methylpropanamide and 4
(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
m/e: 582.2 (M + H)~.
Example 696
N-[3-(1-~3-[2-(4-FLUOROPHENYL)-1-PHENYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(4-f luorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1,1-diphenylhydrazine
hydrochloride: ESMS m/e: 548.2 (M + H)+.
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Example 697
N- [3- (1-~3- [2- (2-FLUOROPHENYL) -1H-BENZO [G] INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-naphthylhydrazine hydrochloride:
ESMS m/e: 547.7 (M + H)+.
Example 698
N-[3-(1-~3-[2-(2-FLUOROPHENYL)-5-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2.-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-methylphenylhydrazine
hydrochloride: ESMS m/e: 512.2( M + H)+.
Example 699
N- [3- (1-~3- [2- (3-FLUOROPHENYL) -1H-BENZO [G] INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-naphthylhydrazine hydrochloride:
ESMS m/e: 548.2 (M + H)+.
Example 700
N-[3-(1-~3-[2-(4-FLUOROPHENYL)-1-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS
m/e: 512.2 (M + H)+.
Example 701
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N- [3- (1-~3- [2- (3- FLUOROPHENYL) -5-METHOXY-
1H-INDOL-3-YL]PROPYL}-4-PIPERIDINYL)PHENYL]-2-
METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 4-methoxyphenylhydrazine
hydrochloride: ESMS m/e: 528.2 (M + H)+.
Example 702
N-[3-(1-~3-[2-(3-FLUOROPHENYL)-1-PHENYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1,1-diphenylhydrazine
hydrochloride: ESMS m/e: 574.2 (M + H)+.
Example 703
N- [3- (1-~3- [2- (4-CHLOROPHENYL) -5- (TRIFLUOROMETHOXY) -1H-
INDOL-3-YL]PROPYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure E and Scheme M using N-(3-fl-[5-(4-
chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 4
(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
m/e: 598 . 2 (M + H) +.'
Example 704
N- [3- (1-~3- [2- (3-FLUOROPHENYL) -1H-INDOL-3-YL] PROPYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure E and Scheme M using N-(3-fl-[5-(3-
fluorophenyl)-5-oxopentyl]-4-piperidinyl)phenyl)-2-
methylpropanamide and phenylhydrazine: ESMS m/e: 498.2
(M + H) +.
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Example 705
N-[3-(1-~3-[2-(3-FLUOROPHENYL)-1-METHYL-1H-INDOL-3-
YLJPROPYL}-4-PIPERIDINYL)PHENYLJ-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS
m/e: 512.2 (M + H)+.
Example 706
N-[3-(1-~3-[2-(3-FLUOROPHENYL)-5-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYLJ-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-methylphenylhydrazine
hydrochloride: ESMS m/e: 512.2 (M + H)+.
Example 707
N- [3- (1-~3- [2- (4-CHLOROPHENYL) -1H-BENZO [G] INDOL-3-
YLJPROPYL~-4-PIPERIDINYL)PHENYLJ-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-naphthylhydrazine hydrochloride:
ESMS m/e: 564.2 (M + H)+.
Example 708
N-[3-(1-~3-[2-(4-CHLOROPHENYL)-1H-INDOL-3-YL]PROPYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure E and Scheme M using N-(3-{1-[5-(4-
chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-phenylhydrazine hydrochloride:
ESMS m/e: 514.2 (M + H)+.
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Example 709
N-[3-(1-~3-[2-(2-FLUOROPHENYL)-I-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-methyl-1-phenylhydrazine: ESM
m/e: 512.2 (M + H)+.
Example 710
N-[3-(1-~3-[2-(2-FLUOROPHENYL)-7-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-(2-methylphenyl)hydrazine
hydrochloride: ESMS m/e: 512.2 (M + H)~.
Example 711
N-[3-(1-~3-[2-(2-FLUOROPHENYL)-1-PHENYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1,1-diphenylhydrazine
hydrochloride: ESMS m/e: 574.2 (M + H)+.
Example 712
N- [ 3 - ( 1- ~ 3 - [ 2 - ( 2 - FLUOROPHENYL ) - 5 -METHOXY-1FI- INDOL- 3 -
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{l-[5-
(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl)phenyl)-2-
methylpropanamide and 4-methoxyphenylhydrazine
hydrochloride: ESMS m/e: 528.2 {M + H)+,
Example 713
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N- [3- (1-~3- [2- (4- CHLOROPHENYL) -5-METHOXY-
1H-INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-
METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 4-methoxyphenylhydrazine
hydrochloride: ESMS m/e: 544.2 (M + H)+. .
Example 714
N- [3- (1-~3- [2- (4-FLUOROPHENYL) -1H-BENZO [G] INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-naphthylhydrazine hydrochloride:
ESMS m/e: 548 .2 (M + H) +.
Example 715
N- [3- (1-~3- [2- (4-FLUOROPHENYL) -5- (TRIFLUOROMETHOXY) -1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-
METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-(1-[5-
(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4
(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
m/e: 582.9 (M + H)+.
Example 716
N-[3-(1-~3-[2-(4-FLUOROPHENYL)-7-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-f1-[5-
(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl)phenyl)-2-
methylpropanamide and 1-(2-methylphenyl)hydrazine
hydrochloride: ESMS m/e: 512.2 (M + H)~.
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Example 717
N- [3- (1-~3- [2- (4-FLUOROPHENYL) -1H-INDOL-3-YL] PROPYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure E and Scheme M using N- (3- ~ 1- [5- (4-
fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and phenylhydrazine: ESMS m/e: 498.2
(M + H)+.
Example 718
N-[3-(1-~3-[2-(4-FLUOROPHENYL)-5-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PZPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-methylphenylhydrazine
hydrochloride: ESMS m/e: 512.2 (M + H)+.
Example 719
N-[3-(1-~3-[2-(4-CHLOROPHENYL)-7-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-(1-[5-
(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-(2-methylphenyl)hydrazine
hydrochloride: ESMS m/e: 528.2 (M + H)+.
Example 720
N- [3- (1-~3- [2- (4-CHLOROPHENYL) -5-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-fl-[5-
(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 4-methylphenylhydrazine
hydrochloride: ESMS m/e: 528.2 (M + H)+.
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Example 721
N-[3-(1-~3-[2-(4-CHLOROPHENYL)-1-PHENYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-(1-[5-
(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1,1-diphenylhydrazine
hydrochloride: ESMS m/e: 590.2 (M + H)+.
Example 722
N- [3- (1- f 3- [2- (3-CHLOROPHENYL) -7-METHYL-1FI-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-(2-methylphenyl)hydrazine
hydrochloride: ESMS m/e: 528.1 (M + H)+.
Example 723
N- [3- (1- f 3- [2- (3-CHLOROPHENYL) -5- (TRIFLUOROMETHOXY) -1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-
METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4
(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
m/e: 598.2 (M + H)+.'
Example 724
N-[3-(1-~3-[2-(3-CHLOROPHENYL)-1-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS
m/e: 528.2 (M + H)+.
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Example 725
. N-[3-(1-~3-[2-(3-CHLOROPHENYL)-1-PHENYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl)phenyl)-2-
methylpropanamide and 1,1-diphenylhydrazine
hydrochloride: ESMS m/e: 590.3 (M + H)+.
Example 726
N-[3-(1-~3-[2-(3-CHLOROPHENYL)-5-METHOXY-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 4-methoxyphenylhydrazine
hydrochloride: ESMS m/e: 544.3 (M + H)+.
Example 727
N-[3-(1-~3-[2-(3-CHLOROPHENYL)-5-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-fl-[5-
(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-methylphenylhydrazine
hydrochloride : ESMS m/e: 528 . 2 (M + H) '~ .
Example 728
N- [3- (1-~3- [2- (3-CHLOROPHENYL) -1H-BENZO [G] INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-naphthylhydrazine hydrochloride:
ESMS m/e: 564.2 (M + H)+.
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Example 729
N- [3- (1-~3- [2- (3-CHLOROPHENYL) -1H-INDOL-3-YL] PROPYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and phenylhydrazine: ESMS m/e: 514.2
(M + H) + .
Example 730
N-[3-(1-~3-[2-(2-CHLOROPHENYL)-1H-INDOL-3-YL]PROPYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(2- chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and phenylhydrazine: ESMS m/e: 514.2
(M + H)+.
Example 731
N- [3- (1-{3- [2- (2-CHLOROPHENYL) -5- (TRIFLUOROMETHOXY) -1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-
METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M
using ' N- (3-{1- [5- (2-chlorophenyl) -5-oxopentyl] -4-
piperidinyl~phenyl)-2- methylpropanamide and 4-
(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
m/e: 598.2 (M + H)+.
Example 732
N- [3- (1-~3- [2- (2-CHLOROPHENYL) -1H-BENZO [G] INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N- (3- { 1- [5-
(2-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-naphthylhydrazine hydrochloride:
ESMS m/e: 564.2 (M + H)+.
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Example 733
N- [3- (1-~3- [2- (2-CHLOROPHENYL) -7-METHYL-1FI-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-fl-[5-
(2-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-(2-methylphenyl)hydrazine
hydrochloride: ESMS m/e: 528.2 (M + H)+. ,
Example 734
N- [3- (1-~3- [2- (2-CHLOROPHENYL) -1-PHENYL-1FI-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(2-chlorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1,1-diphenylhydrazine
hydrochloride: ESMS m/e: 590.2 (M + H)+.
Example 735
N-[3-(1-f3-[2-(2-CHLOROPHENYL)-1-METHYL-1H-INDOL-3-
YL]PROPYL}-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(2-chlorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS
m/e: 528.2 (M + H)+.
Example 736
N-[3-(1-~3-[2-(2-CHLOROPHENYL)-5-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-f1-[5-
(2-chlorophenyl)-5-o.xopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-methylphenylhydrazine
hydrochloride: ESMS m/e: 528.2 (M + H)+.
Example 737
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N- [3- (1-~3- (2- (3- IODOPHENYL) -1H-INDOL-3-
YL]PROPYL~-4-PIPERTDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N- (3- ~ 1- [5-
(3-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and phenylhydrazine: ESMS m/e: 606.2
(M + H)+.
Example 738
N-[3-(1-~3-[2-(3-IODOPHENYL)-1-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(3-iodophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS
m/e: 620.2 (M + H)+.
Example 739
N-(3-(1-~3-[2-(3-IODOPHENYL)-1-PHENYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(3-iodophenyl)-5-oxopentyl]-4-piperidinyl)phenyl)-2-
methylpropanamide and 1,1-diphenylhydrazine
hydrochloride: ESMS m/e: 682.2 (M + H)+.
Example 740
N- [3- (1-~3- [2- (3-TODOPHENYL) -1H-BENZO [G] INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-(1-[5-
(3-iodophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-naphthylhydrazine hydrochloride:
ESMS m/e: 656.2 (M + H)+.
Example 741
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N- [3- (1-{3- [2- (3- IODOPHENYL) -5-
(TRIFLUOROMETHOXY)-1H-INDOL-3-YL]PROPYL}-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N- (3-(1- [5-
(3-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 4-
(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
m/e: 690.2 (M + H)~.
Example 742
N-[3-(1-~3-[2-(3-IODOPHENYL)-5-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-(1-[5-
(3-iodophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-methylphenylhydrazine
hydrochloride: ESMS m/e: 620.2 (M + H)+.
Example 743
N- [3- (1-~3- [2- (3-IODOPHENYL) -7-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(3-iodophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-(2-methylphenyl)hydrazine
hydrochloride: ESMS m/e: 620.2 (M + H)+.
Example 744
N- [3- (1- f 3- [2- (4-IODOPHENYL) -5- (TRIFLUOROMETHOXY) -1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-.
METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-f1-[5-
(4-iodophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-
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(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
m/e: 690.1 (M + H)+.
Example. 745
N- [3- (1-~3- [2- (4-IODOPHENYL) -5-METHYL-1H-INDOL-3-
YL]PROPYL}-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 4-methylphenylhydrazine
hydrochloride: ESMS m/e: 620.1 (M + H)+.
Example 746
N-[3-(1-~3-[2-(4-IODOPHENYL)-7-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-(2-methylphenyl)hydrazine
hydrochloride: ESMS m/e: 620.1 (M + H)+.
Example 747
N-[3-(1-~3-[2-(4-IODOPHENYL)-1-PHENYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1,1-diphenylhydrazine
hydrochloride: ESMS m/e: 682.1 (M + H)+.
Example 748
N-[3-(1-~3-[2-(4-IODOPHENYL)-1-METHYL-1H-INDOL-3-
YL]PROPYL}-4-PIPERIDINYL)PHENYL]-2-METHYLPROP.ANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
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methylpropanamide and 1- methyl-1-phenylhydrazine:
ESMS m/e: 620.1 (M + H)+.
Example 749 .
N- [3- (1-~3- [2- (4-IODOPHENYL) -1H-BENZO [G] TNDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(4-iodophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-naphthylhydrazine hydrochloride:
ESMS m/e: 656.1 (M + H)+.
Example 750
N- [3- (1-{3- [2- (4-IODOPHENYL) -1H-INDOL-3-YL] PROPYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~l-[5-
(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and phenylhydrazine: ESMS m/e: 606.1
(M + H)+.
Example 751
N- [3- (3.-~3- [2- (3-BROMOPHENYL) -5- (TRIFLUOROMETHOXY) -1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-
METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M
using N- (3-~1- [5- (3-bromophenyl) -5-oxopentyl] -4-
piperidinyl)phenyl)-2-methylpropanamide and 4-
(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
m/e: 642.0 (M + H)+.
Example 752
N- [3- (1-~3- [2- (4-BROMOPHENYL) -1H-BENZO [G] INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(4-bromophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
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methylpropanamide and 1- naphthylhydrazine
hydrochloride: ESMS m/e: 608.0 (M + H)+.
Example 753 ,
N-[3-(1-~3-[2-(4-BROMOPHENYL)-7-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using. N-(3-~1-[5-
(4-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-(2-methylphenyl)hydrazine
hydrochloride: ESMS m/e: 572 (M + H)+.
Example 754
N-[3-(1-~3-[2-(4-BROMOPHENYL)-5-(TRIFLUOROMETHOXY)-1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-
METHYLPROPANAMIDE: Prepared by Procedure E and Scheme M
using N- (3-{1- [5- (4-bromophenyl) -5-oxopentyl] -4-
piperidinyl}phenyl)-2-methylpropanamide and 4-
(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
m/e: 642 (M + H)+.
Example 755
N- [3- (1-~3- [2- (3-BROMOPHENYL) -1FI-BENZO [G] INDOL-3-
YL]PROPYL}-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(3-bromophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-naphthylhydrazine hydrochloride:
ESMS m/e: 608.0 (M + H)+.
Example 756
N-[3-(1-~3-[2-(4-BROMOPHENYL)-1H-INDOL-3-YL]PROPYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure E and Scheme M using N-(3-fl-[5-(4-
bromophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
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methylpropanamide and phenylhydrazine: ESMS m/e:
558.1 (M + H)+.
Example 757
N-[3-(1-~3-[2-(3-BROMOPHENYL)-1-PHENYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N- (3- ~.1- [5-
(3-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1,1-diphenylhydrazine
hydrochloride: ESMS m/e: 634.0 (M + H)+.
Example 758
N-[3-(1-~3-[2-(3-BROMOPHENYL)-1-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(3-bromophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS
m/e: 572.0 (M + H)+.
Example 759
N-[3-(1-~3-[2-(4-BROMOPHENYL)-1-METHYL-1H-INDOL-3-
YL]PROPYL}-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-f1-[5-
(4-bromophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS
m/e: 572.0 (M + H)+.
Example 760
N- [3- (1-~3- [2- (4-BROMOPHENYL) -1-PHENYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(4-brcmophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
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methylpropanamide and 1,1- diphenylhydrazine
hydrochloride: ESMS m/e: 634.0 (M + H)+.
Example 761
N-[3-(1-~3-[2-(4-BROMOPHENYL)-5-METHOXY-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(4-bromophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-methoxyphenylhydrazine
hydrochloride: ESMS m/e: 588.1 (M + H)+.
Example 762
N-[3-(1-~3-[2-(3-BROMOPHENYL)-7-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(3-bromophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-(2-methylphenyl)hydrazine
hydrochloride: ESMS m/e: 572 (M + H)+.
Example 763
N-[3-(1-~3-[2-(3-BROMOPHENYL)-5-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(3-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide ~ and 4-methylphenylhydrazine
hydrochloride: ESMS m/e: 572 (M + H)~.
Example 764
N- [3- (1-~3- I2- (4-BROMOPHENYL) -5-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(4-bromophenyl)-5-oacopentyl]-4-piperidinyl~phenyl)-2-
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methylpropanamide and 4- methylphenylhydrazine
hydrochloride: ESMS m/e: 572.0 (M + H)+.
Example 765
N-[3-(1-~3-[2-(3-BROMOPHENYL)-5-METHOXY-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROP.ANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-f1-[5-
(3-bromophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-methoxyphenylhydrazine
hydrochloride: ESMS m/e: 588.0 (M + H)+.
Example 766
2-METHYL-N-[3-(1-~3-[2-(3-NITROPHENYL)-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]PROPANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
(3-~l-[5-(3-nitrophenyl)-5-oxopentyl]-4-
piperidinyl~phenyl)propanamide and phenylhydrazine: ESMS
m/e: 525.2 (M + H)+.
Example 767
2-METHYL-N- [3- (1-~3- [2- (3-NITROPHENYL) -1H-BENZO [G] INDOL-
3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]PROPANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
(3-(1- [5- (3-nitrophenyl) -5-oxopentyl] -4-
piperidinyl~phenyl)propanamide and 1-naphthylhydrazine
hydrochloride : ESMS m/e: 575 . 1 (M + H) '~ .
Example 768
2-METHYL-N-[3-(1-~3-[2-(3-NITROPHENYL)-5-
(TRIFLUOROMETHOXY)-1H-INDOL-3-YL]PROPYL~-4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure E
and Scheme M using 2-methyl-N-(3-{1-[5-(3-nitrophenyl)-
5-oxopentyl]-4-piperidinyl~phenyl)propanamide and 4-
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(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
m/e: 609.1 (M + H)+.
Example 769
2-METHYL-N-[3-(1-~3-[5-METHYL-2-(3-NITROPHENYL)-1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]PROPANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
(3-~l-[5-(3-nitrophenyl)-5-oxopentyl]-4-
piperidinyl~phenyl)propanamide ~ and 4-
methylphenylhydrazine hydrochloride: ESMS m/e: 539.2 (M
+ H)+.
Example 770
N-[3-(1-~3-[5-METHOXY-2-(3-NITROPHENYL)-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
(3-~1- [5- (3-nitrophenyl) -5-oxopentyl] -4- -
piperidinyl}phenyl)propanamide and 4-
methoxyphenylhydrazine hydrochloride: ESMS m/e: 555.2 (M
+ H)+.
Example 771
2-METHYL-N-[3-(1-~3-[2-(3-NITROPHENYL)-1-PHENYL-1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]PROP.ANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
(3- { 1- [5- (3-nitrophenyl) -5-oxopentyl] -4-
piperidinyl}phenyl)propanamide and l,l-diphenylhydrazine
hydrochloride: ESMS m/e: 601.1 (M + H)~.
Example 772
2-METHYL-N-[3-(1-~3-[1-METHYL-2-(3-NITROPHENYL)-1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]PROPANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
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(3-fl-[5-(3-nitrophenyl)- 5-oxopentyl]-4-
piperidinyl}phenyl)propanamide and 1-methyl-1-
phenylhydrazine: ESMS m/e: 539.2 (M + H)+.
Example 773
2-METHYL-N-[3-(1-~3-[7-METHYL-2-(3-NITROPHENYL)-1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]PROPANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
(3-{1- [5- (3-nitrophenyl) -5-oxopentyl] -4-
piperidinyl~phenyl)propanamide and 1-(2-
methylphenyl)hydrazine hydrochloride: ESMS m/e: 539.2 (M
+ H)+.
Example 774
N-[3-(1-~3-[5-METHOXY-2-(4-NITROPHENYL)-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
(3- f 1- [5- (4-nitrophenyl) -5-oxopentyl] -4-
piperidinyl}phenyl)propanamide and 4-
methoxyphenylhydrazine hydrochloride: ESMS m/e: 555.6 (M
+ H)+.
Example 775
N-[3-(1-~3-[2-(2-BROMOPHENYL)-1H-INDOL-3-YL]PROPYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure E and Scheme M using N-(3-{1-[5-(2-
bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and phenylhydrazine: ESMS m/e: 557.9
(M + H) ~ .
Example 776
2-METHYL-N-[3-(1-~3-[5-METHYL-2-(4-NITROPHENYL)-1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYh]PROPANAMIDE:
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Prepared by Procedure E and Scheme M using 2-
methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-
piperidinyl~phenyl)propanamide and 4-
methylphenylhydrazine hydrochloride: ESMS m/e: 539.1 (M
+ H)+.
Example 777
2-METHYL-N- [3- (1-~3- [2- (4-NITROPHENYL) -1H-BENZO [G] INDOL-
3-YLIPROPYL~-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared
by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-
(4-nitrophenyl)-5-oxopentyl]-4-
piperidinyl}phenyl)propanamide and 1-naphthylhydrazine
hydrochloride: ESMS m/e: 574.7 (M + H)+.
Example 778
2-METHYL-N-(3-~1-[(5E)-5-(4-NITROPHENYL)-5-
(PHENYLHYDRAZONO)PENTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE:
Prepared by Procedure E and Scheme AX using 2-methyl-N-
(3-{1- [5- (4-nitrophenyl) -5-oxopentyl] -4-
piperidinyl~phenyl)propanamide and phenylhydrazine: ESMS
m/e: 542.4 (M + H)+.
Example 779
2-METHYL-N-[3-(1-f3-[7-METHYL-2-(4-NITROPHENYL)-1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]PROPANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4- .
piperidinyl~phenyl)propanamide and 1-(2-
methylphenyl)hydrazine hydrochloride: ESMS m/e: 538.8 (M
+ H)+.
Example 780
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2-METHYL-N-~3- [1- ( (5E) -5- (4-NITROPHENYL) -5-~ [4-
(TRIFLUOROMETHOXY)PHENYL]HYDRAZONO~PENTYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure E
and Scheme M using 2-methyl-N- (3-{1- [5- (4-nitrophenyl) -
5-oxopentyl]-4-piperidinyl~phenyl)propanamide and 4-
(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
m/e: 626.2 (M + H)+.
Example 781
N- [3- (1-~3- [2- (2-BROMOPHENYL) -1H-BENZO [G] INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-fl-[5-
2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-naphthylhydrazine hydrochloride:
ESMS m/e: 608.0 (M + H)+.
Example 782
N- [3- (1-~3- [2- (2-BROMOPHENYL) -5- (TRIFLUOROMETHOXY) -1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-
METHYLPROPANAMIDE:Prepared by Procedure E and Scheme M
using N- (3- f 1- [5- (2-bromophenyl) -5-oxopentyl] -4-
piperidinyl)phenyl)-2-methylpropanamide and . 4-
(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
m/e: 641.9 (M + H)+.
Example 783
N- [3- (1-~3- [2- (2-BROMOPHENYL) -7-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(2-bromophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-(2-methylphenyl)hydrazine
hydrochloride: ESMS m/e: 572.0 (M + H)+.
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Example 784
N-[3-(1-~3-[2-(2-BROMOPHENYL)-1-PHENYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-fl-[5-
(2-bromophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1,1-diphenylhydrazine
hydrochloride: ESMS m/e: 634 (M + H)+.
Example 785
N-[3-(1-{3-[2-(2-BROMOPHENYL)-5-METHYL-1H-INDOL-3-
YL]PROPYL}-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-fl-[5-
(2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 4-methylphenylhydrazine
hydrochloride: ESMS m/e: 572.0 (M + H)+.
Example 786
N- [3- (1-~3- [2- (2-IODOPHENYL) -5- (TRIFLUOROMETHOXY) -1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-
METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~l-[5-
(2-iodophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4
(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS
m/e: 690.0 (M + H)+.
Example 787
N- [3- (1-~3- [2- (2-IODOPHENYL) -5-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(2-iodophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 4-methylphenylhydrazine
hydrochloride: ESMS m/e: 620.2 (M + H)+.
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Example 788
2-METHYL-N-[3-(1-~3-[1-METHYL-2-(4-NITROPHENYL)-1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]PROPANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
(3-{1- [5- (4-nitrophenyl) -5-oxopentyl] -4-
piperidinyl}phenyl)propanamide and 1-methyl-1-
phenylhydrazine: ESMS m/e: 539.6 (M + H)+.
Example 789
2-METHYL-N- [3-'(1-~3- [2- (4-NITROPHENYL) -1-PHENYL-1H-
INDOL-3-YL]PROPYL~-4-PIPERIDINYL)PHENYL]PROPANAMIDE:
Prepared by Procedure E and Scheme M using 2-methyl-N-
(3-{1- [5- (4-nitrophenyl) -5-oxopentyl] -4-
piperidinyl~phenyl)propanamide and 1,1-diphenylhydrazine
hydrochloride: ESMS m/e: 601.6 (M + H)+.
Example 790
N- [3- (1- f 3- [2- (2-IODOPHENYL) -1H-INDOL-3-YL] PROPYL~-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-~1-[5-
(2-iodophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and phenylhydrazine: ESMS m/e: 606.1
(M + H)+.
Example 791
N- [3- (1-~3- [2- (2-IODOPHENYL) -1H-BENZO [G] INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPRtOPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(2-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-naphthylhydrazine hydrochloride:
ESMS m/e: 656.1 (M + H)+.
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448
N- [3- (1-~3- [2- (2-IODOPHENYL) -1-PHENYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-fl-[5-
(2-iodophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1,1-diphenylhydrazine
hydrochloride: ESMS m/e: 682.1 (M + H)+.
Example 793
N-[3-(1-f3-[2-(2-IODOPHENYL)-7-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-
(2-iodophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide and 1-(2-methylphenyl)hydrazine
hydrochloride: ESMS m/e: 619.6 (M + H)+.
Example 794
N-[3-(1-~3-[2-(2-BROMOPHENYL)-1-METHYL-1H-INDOL-3-
YL]PROPYL~-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
Prepared by Procedure E and Scheme M using N- (3-~1- [5-
(2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide and 1-methyl-1-phenylhydrazine: ESM
m/e: 572 (M + H) * .
2 5 Example 795
4-(3,4-DIFLUOROPHENYL)-N-(3-~4-[3-
(ISOBUTYRYLAMINO)PHENYL]-.1-PIPERIDINYL}PROPYL)-2-METHYL-
6-OXO-1,4,5,6-TETRAHYDRO-3-PYRIDINECARBOXAMIDE:
Prepared by Procedure AC and Scheme AM using 4-(3,4-
difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-
pyridinecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-
piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e:
553.0 (M + H)+.
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Example 796
4-(2,4-DIFL
UOROPHENYL)-N-(3-~4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL~PROPYL)-2-METHYL-6-OXO-1,4,5,6-TETRAHYDRO-3-
PYRIDINECARBOXAMTDE: Prepared by Procedure AC and
Scheme AM using 4-(2,4-difluorophenyl)-2-methyl-6-oxo-
1,4,5,6-tetrahydro-3-pyridinecarboxylic acid and N-(3-
[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-
methylpropanamide: ESMS m/e: 553.0 (M + H)+.
Example 797
N-(3-~1-[4-(4-METHOXYPHENYL)BUTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure O and Scheme W using 4-(4-methoxyphenyl)-1-
butanol and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 409 (M + H)+.
Example 798
N-(4-~1-[3-(1,2-DIPHENYL-1H-INDOL-3-YL)PROPYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure O
and Scheme W using 3-(1,2-diphenyl-1H-indol-3-yl)-1-
propanol and N-[4-(4-piperidinyl)phenyl]propanamide:
ESMS m/e: 542.0 (M + H)+.
Example 799
N-~4-[1-(3,3-DIPHENYLPROPYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure O
and Scheme W using 3,3-diphenyl-1-propanol and
N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 427.0
(M + H)+.
Example 800
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2-METHYL-N-(3-~1-[4-(4- NITROPHENYL)BUTYL]-4-
PIPERIDINYL~PHENYL): Prepared by Procedure 0 and Scheme
W using 4-(4-nitrophenyl)-1-butanol and 2-methyl-N-[3-
(4-piperidinyl).phenyl]propanamide: ESMS m;~e: 424.2 (M +
H)~.
Example 801
2-METHYL-N-(3-~1-[2-(1-NAPHTHYL)ETHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE Prepared by Procedure O
l0 and Scheme w using 2-(1-naphthyl)ethanol and 2-methyl-N-
[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 401.2 (M
+ H)+.
Example 802
N-~3-[1-(3,3-DIPHENYLPROPYL)-4-PIPERIDINYL]PHENYL -2-
METHYLPROPANAMIDE: Prepared by Procedure 0 and Scheme W
using 3,3-diphenyl-1-propanol and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 441.2 (M + H)+.
Example 803
N-(3-~1-[3-(3,4-DIMETHOXYPHENYL)PROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure 0 and Scheme W using 3-(3,4-dimethoxyphenyl)-
1-propanol and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M + H)+.
Example 804
2-METHYL-N-~3-[1-(3-PHENYLPROPYL)-4- .
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure 0
and Scheme W using 3-phenyl-1-propanol and
2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS
m/e: 365.2 (M + H)~.
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Example 805
2-METHYL-N-(3- f 1- [3- (4-PYRIDINYL) PROPYL] -4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure O
and Scheme W using .3-(4-pyridinyl)-1-propanol and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
366.2 (M + H)+.
Example 806
N-~3-[1-(4-TERT-BUTYLBENZYL)-4-PTPERIDINYL]PHENYL}-2-
METHYLPROPANAMIDE: Prepared by Procedure AJ and Scheme
AV using 1-bromomethyl)-4-tert-butylbenzene and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
393.0 (M + H)+.
Example 807
N-~3-[1-(4-BENZOYLBENZYL)-4-PIPERIDINYL]PHEN'YL~-2-
METHYLPROP.ANAMIDE: Prepared by Procedure AJ and Scheme
AV using [4- (bromomethyl) phenyl] (phenyl) methanone and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
441.0 (M + H)+.
1,2-DICHLORO-4-~[(1S)-3-CHLORO-1-
PHENYLPROPYL]OXY~BENZENE: Prepared by Procedure A using
3,4-dichlorophenol and (1R)-3-chloro-1-phenyl-1-
propanol.
Example 808
N-(3-~l-[(3S)-3-(3,4-DICHLOROPHENOXY)-3-PHENYLPROPYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A using 1,2-dichloro-4-([(1S)-3-chloro-1-
phenylpropyl]oxy}benzene and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 525.3 (M + H)+.
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Example 809
N-(3-~1-[6-(2-FLUOROPHENYL)-6-HYDROXYHEXYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN using N- (3- f 1- [6- (2-
fluorophenyl)-6-oxohexyl]-4-piperidinyl~phenyl)-2-
methylpropanamide: ESMS m/e: 441.3 (M + H)+.
Example 810
N- [3- (1-~5-HYDROXY-5- [4- (TRIFLUOROMETHYL) PHENYL] PENTYL~-
4-PIPERIDINYL)PHENYL]-2-METHYLPROP.ANAMIDE: Prepared by
Procedure L and Scheme AN using 2-methyl-N-[3-(1-~5-oxo-
5- [4- (trifluoromethyl)phenyl]pentyl)-4-
piperidinyl)phenyl]propanamide: ESMS m/e: 477.2 (M + H)+.
Example 811
N-(3-~1-[5-(4-FLUOROPHENYL)-5-HYDROXYPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN using N-(3-~1-[5-(4-
fluorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2
methylpropanamide: ESMS m/e: 427.2 (M + H)+.
Example 812
N-(3-~1-[7-(2-FLUOROPHENYL)-7-HYDROXYHEPTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN using N-(3-~1-[7-(2-
fluorophenyl)-7-oxoheptyl]-4-piperidinyl~phenyl)-2-
methylpropanamide: ESMS m/e: 455.2 (M + H)+.
3 0 Example 813
N-(3-{1-[6-(3-FLUOROPHENYL)-6-HYDROXYHEXYL]-4-
PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN using N-(3-{1-[6-(3-
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fluorophenyl)-6-oxohexyl]- 4-piperidinyl}phenyl)-2-
methylpropanamide: ESMS m/e: 441.2 (M + H)+.
Example 814
N-(3-~l-j5-(2-FLUOROPHENYL)-5-HYDROXYPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN using N- (3-~1- [5- (2-
fluorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2-
methylpropanamide: ESMS m/e: 427.2 (M + H)+.
Example 815
N-(3-{1-[5-(3-FLUOROPHENYL)-5-HYDROXYPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN using N- (3- f 1- [5- (3-
fluorophenyl)-5-oxopentyl]-4-piperidinyl~phenyl)-2
methylpropanamide: ESMS m/e: 427.2 (M + H)+.
Example 816
N-(3-~1-[5-(3-CHLOROPHENYL)-5-HYDROXYPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN using N-(3-~l-[5-(3-
chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide: ESMS m/e: 443.1 (M + H)+.
2 5 Example 817
N-(3-~1-[6-(4-FLUOROPHENYL)-6-HYDROXYHEXYL]-4-
PIPERIDINYL~PHENYL)-2-MET~HYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN using N-(3-~l-[6-(4-
fluorophenyl)-6-oxohexyl]-4-piperidinyl~phenyl)-2-
methylpropanamide: ESMS m/e: 441.2 (M + H)+.
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Example 818
N-(3-~1-[6-(4-CHLOROPHENYL)-6-HYDROXYHEXYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme PST using N- (3-~1- [6- (4-
chlorophenyl)-6-oxohexyl]-4-piperidinyl~phenyl)-2
methylpropanamide: ESMS m/e: 456.9 (M + H)~.
Example 819
N-(3-{1-[5-(4-CHLOROPHENYL)-5-HYDROXYPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure L and Scheme AN using N- (3-(I- [5- (4-
chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-
methylpropanamide: ESMS m/e: 443.0 (M + H)+.
Example 820
N-(4-~1-[(9-ETHYL-9H-CARBAZOL-3-YL)METHYL)-4-
PIPERIDINYL~PHENYL)BUTANAMIDE: Prepared by Procedure F
and Scheme R, without HOAc, using 9-ethyl-9H-carbazole-
3-carbaldehyde and N- [4- (4-
piperidinyl)phenyl]butanamide: ESMS m/e: 454.2 (M + H)+.
Example 821
N-(3-~1-[(9-ETHYL-9H-CARBAZOL-3-YL)METHYL]-4-
PIPERrDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R, without HOAc, using 9-ethyl-9H-carbazole-
3-carbaldehyde and N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 440.5 (M + H)+.
Example 822
N-(3-~l-[(1,9-DIMETHYL-9H-CARBAZOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure F and Scheme R, without HOAc, using 1,9-
dimethyl-9H-carbazole-3-carbaldehyde and 2-methyl-N-[3-
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(4-
piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDC13) b
8.05-6.77 (m, 10H), 5.20-5.12 (m, 1H), 4.04 (s, 3H),
3.93 (s, 2H), 3.34-3.24 (m, 2H), 2.79 (s, 3H), 2.56-2.38
(m, 2H), 2.38-2.26 (m, 2H), 2.08-1.88 (m, 2H), 1.82-1.70
(m, 2H) , 1.16 (d, 6H, J = 6.8 Hz) ; ESMS .m/e: 454.2 (M +
H)+.
Example 823
N-(3-~1-[(9-ETHYL-9H-CARBAZOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)CYCLOPROPANECARBOXAMIDE: Prepared by
Procedure F and Scheme R, without HOAc, using 9-ethyl-
9H-carbazole-3-carbaldehyde and N-[3-(4-
piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e:
452.6 (M + H)+.
Example 824
1-(3-~1-[(9-ETHYL-9H-CARBAZOL-3-YL)METHYL]-4-
PIPERIDINYL~PHENYL)-2-PYRROLIDINONE: Prepared by Scheme
R and Procedure F. A solution of 1-(9-ethyl-9H-
carbazol-3-yl)ethanone (22.3 mg, 0.100 mmol) and 1-[3-
(4-piperidinyl)phenyl]-2-pyrrolidinone (27.2 mg, 0.100
mmol) in 1,2-dichloroethane (1.00 mL) was treated with
sodium triacetoxyborohydride (63.6 mg, 0.300 mmol) and
HOAc (5.70 uL, 0.100 mmol). The mixture was stirred
overnight at room temperature. The reaction mixture was
treated with a saturated aqueous NaHC03 solution (10 mL).
The aqueous layer was extracted with CH2C12 (3 X 10 mL)
and the combined organic layers were washed with brine
(10 mL), dried over MgS04 and concentrated in vacuo. The
residue was purified by preparative TLC using 5% of NH3
(2.0 M in methanol) in CH2Cla to give the desired product
1-(3-~1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-
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piperidinyl)phenyl)-2- pyrrolidinone (4.60 mg,
9.43 %) : 1H NMR (400 MHz, CDC13) b 8.04 (d, 1H, J = 7.4
Hz), 7.99 (s, 1H), 7.43-7.28 (m, 5H), 6.96 (d, 1H, J =
7.4 Hz) , 4.31 (q, 2H,. J = 6.8 Hz) , 3 .77 (t, 2H, J = 7.3
Hz) , 3 .70 (s, 2H) , 3 . 06 (d, 2H, J = 10 . 6 Hz) , 2 .56-2 .42
(m, 3H) , 2.07 (m, 4H) , 1.77 (m, 4H) , 1.36 (m, 3H);
ESMS m/e: 452.5 (M + H)+.
N-~3-[1-(1H-INDOL-5-YLMETHYL)-4-PIPERIDINYL]PHENYL -2-
METHYLPROPANAMIDE: Prepared by Procedure F and Scheme
R, without HOAc, using 1H-indole-5-carbaldehyde and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
376.2 (M + H)+.
1-(4-CHLOROBUTYL)-1H-INDOLE: Prepared by Procedure AH,
and Scheme P using 1H-indole and 1-bromo-4-chlorobutane:
1NMR (400 MHz, CDC13) b 7.72-7.02 (m, 5H) , 6.49 (d, 1H, .J
- 2 .8 Hz) , 4.13 (t, 2H, J = 6.8 Hz) , 3 .48 (t, 2H, J =
6.8 Hz) , 2.06-1.92 (m, 2H) , 1.80-1.70 (m, 2H) .
1-(3-CHLOROPROPYL)-1H-INDOLE: Prepared by Procedure AH,
and Scheme P using 1H-indole and 1-bromo-3
chloropropane: 1H NMR (400 MHz, CDC13) b 7.70-7.04 (m,
5H), 6.50 (d, 1H, J = 2.8 Hz), 4.31 (t, 2H, J = 6.8 Hz),
3.42 (t, 2H, J = 6.4 Hz), 2.28-2.20 (m, 2H).
Example 825
N-(4- f 1- [5- (1H-INDOL-1-YL) PENTYL] -4-PIPERIDINYL~PHENYL) -
2-METHYLPROPANAMIDE: Prepared by Procedure AH and
Scheme P using 1-(5-chloropentyl)-1H-indole and 2-
methyl-N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
432:3 (M + H)+.
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Example 826
N-(4-~1- [5- (1H-INDOL-1-YL) PENTYL1 -4-
PIPERIDINYL~PHENYL)BUTANAMIDE: Prepared by Procedure AH
and Scheme P using 1-(5-chloropentyl)-1H-indole and N-
[4-(4-piperidinyl)phenyl]butanamide: ESMS m/e: 432.3 (M
+ H)+.
Example 827
N-(4-~1-[5-(1H-INDOL-1-YL)PENTYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure
AH and Scheme P using 1-(5-chloropentyl)-1H-indole and
N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 418.2
(M + H)+.
Example 828
N- (4- f 1- [6- (IH-INDOL-1-YL) HEXYL] -4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure
AH and Scheme P using 1-(6-chlorohexyl)-1H-indole and N-
[4- (4-piperid.inyl)phenyl]propanamide: ESMS m/e: 432.3 (M
+ H)+.
Example 829
2-METHYL-N-(3-~1-[(1-METHYL-1H-INDOL-2-YL)METHYL]-4-
PIPERIDINYL~PHENYL)PROPANAMIDE: Prepared by Procedure F
and Scheme R, without HOAc, using 1-methyl-1H-indole-2-
carbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 390.3 (M + H)+.
Example 830
N-~3-[1-(1H-INDOL-4-YLMETHYL)-4-PIPERIDINYLJPHENYL~-2-
METHYLPROPANAMIDE: Prepared by Procedure F and Scheme
R, without HOAc, using 1H-indole-4-carbaldehyde and 2-
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methyl-N- [3- (4-
piperidinyl)phenyllpropanamide: ESMS m/e: 376.2 (M + H)+.
Example 831
N-(4-~1- [6- (1FI-INDOL-1-YL)HEXYL] -4-PIPERIDINYL~PHENYL) -
2-METHYLPROPANAMIDE: Prepared by Procedure AH and
Scheme P using 1-(6-chlorohexyl)-1H-indole and 2-methyl-
N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 446.3
(M + H)+.
Example 832
N-~3- [1- (1FI-INDOL-7-YLMETHYL) -4-PIPERIDINYL] PHENYL-2-
METHYLPROPANAMIDE: Prepared by Procedure F and Scheme
R, without HOAc, using 1H-indole-7-carbaldehyde and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
376 . 2 (M + H) +.
Example 833
N-[3-(1-~[1-(4-METHOXYPHENYL)-1H-INDOL-5-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-iodo-4-methoxybenzene and N-f3-[1-(1H-indol-5-
ylmethyl)-4-piperidinyl]phenyl -2-methylpropanamide:
ESMS m/e: 482.0(M + H)+.
Example 834
METHYL 4 - [ 4 - ( ~ 4 - [ 3 - ( I SOBUTYRYLAMINO ) PHENYL ] -1-
PIPERIDINYL~METHYL)-1H-INDOL-1-YL]BENZOATE: ~ Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using methyl 4-iodobenzoate and N-~3-[1-(1H-indol-4-
ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 510.3 (M + H)+.
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Example 835
2-METHYL-N- [3- (1-~ [1- (3-METHYLPHENYL) -1FI-INDOL-5-
. YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared
by Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-iodo-3-methylbenzene and N-f3-[1-(1H-indol-5
ylmethyl)-4-piperidinyl]phenyl -2-methylpropanamide:
ESMS m/e: 466.3 (M + H)+.
Example 836
N- [3- (1-~ [1- (4-FLUOROPHENYL) -1H-INDOL-4-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-fluoro-4-iodobenzene and N-~3-[1-(1H-indol-4-
ylmethyl)-4-piperidinyl]phenyl -2-methylpropanamide: 1H
NMR (400 MHz, CDC13) 8 7.66-6.92 (m, 12H) , 6.65 (d, 1H, J
- 3.2 Hz), 3.69 (s, 2H), 3.15-3.02 (m, 2H), 2.58-2.40
(m, 2H) , 2.20-2. 04 (m, 2H) , 1 . 94-1.76 (m, 4H) , 1 .25 (d,
6H, J = 6.8 Hz); ESMS m/e: 470.6 (M + H)+.
2 0 Example 837
N-(3-~1-[4-(1H-INDOL-1-YL)BUTYL]-4-PIPERIDINYL~PHENYL)-
2-METHYLPROPANAMIDE: Prepared by Procedure AH and
Scheme P using 1-(4-chlorobutyl)-1H-indole and 2-methyl-
N- [3- (4-piperidinyl)phenyl] propanamide: ESMS m/e: 418.3
(M + H) +.
Example 838
N-[3-(1-f[1-(4-CHLOROPHENYL)-1H-INDOL-5-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-chloro-4-iodobenzene and N-{3-[1-(1H-indol-5-
ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 486.2 (M + H)+.
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Example 839
N- [3- (1-~ [1- (3-METHOXYPHENYL) -1H-INDOL-5-YL] METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-iodo-3-methoxybenzene and N-{3-[1-(1H-indol-5-
ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 482.2 (M + H)+.
1 o Example 840
N-(4-{1-[4-(1H-INDOL-1-YL)BUTYL]-4-
PIPERIDINYL~PHENYL)BUTANAMIDE: Prepared by Procedure AH
and Scheme P using 1-(4-chlorobutyl)-1H-indole and N-[4-
(4-piperidinyl)phenyl]butanamide: ESMS m/e: 418.2 (M +
H)+.
Example 84I
N-[3-(1-~[1-(2-METHOXYPHENYL)-1H-INDOL-5-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-iodo-2-methoxybenzene and N-(3-[1-(1H-indol-5-
ylmethyl)-4-piperidinyl]phenyl -2-methylpropanamide:
ESMS m/e: 482.2 (M + H)~.
2 5 Example 842
N-[3-(1-~[1-(3-CHLOROPHENYL)-1H-INDOL-5-YL]METHYL-4-
PIPERIDINYL)PHENYLj-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-chloro-3-iodobenzene and N-f3-[1-(1H-indol-5-
ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 486 .2 (M + H) +.
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Example 843
METHYL 2 - [ 5 - ( ~ 4 - [ 3 - ( I SOBUTYRYLAMINO ) PHENYL ] -1-
PIPERIDINYL~METHYL)-1H-INDOL-1-YL]BENZOATE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using methyl 2-iodobenzoate and N-{3-[1-(1H-indol-5-
ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 510.2 (M + H)+.
Example 844
' N-(3-~1-[3-(1H-INDOL-1-YL)PROPYL]-4-PIPERIDINYL~PHENYL)-
2-METHYLPROPANAMIDE: Prepared by Procedure AH and
Scheme P using 1-(3-chloropropyl)-1H-indole and 2-
methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e:
404.2 (M + H)+.
Example 845
2-METHYL-N-~3-[1-({1-[4-(TRIFLUOROMETHYL)PHENYL]-1H-
INDOL-5-YL~METHYL)-4-PIPERIDINYL]PHENYL~PROPANAMIDE:
Prepared by Procedure C and Scheme Q1, with CuBr in
place of Cu, using 1-iodo-4-(trifluoromethyl)benzene and
N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-
methylpropanamide: ESMS m/e: 520.2 (M + H)+.
Example 846
N-(3-~l-[(1-[1,1'-BIPHENYL]-2-YL-1H-INDOL-5-YL)METHYL]-
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 2-iodo-1,1'-biphenyl and N-{3-[1-(1H-indol-5-
ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 528.3 (M + H)+.
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Example 847
2-METHYL-N-[3-(1-~[1-(2-METHYLPHENYL)-1H-INDOL-5-
YL] METHYL-4-PIPERIDINYL) PHENYL] PROPANAMIDE: Prepared
by Procedure C and Scheme Q1, with CuBr in place of ,Cu,
using 1-iodo-2-methylbenzene and N-{3-[1-(1H-indol-5-
ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 466.2 (M + H)+.
Example 848
2-METHYL-N-[3-(1-~[1-(4-METHYLPHENYL)-1H-INDOL-5-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared
by Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-iodo-4-methylbenzene and N-{3-[1-(1H-indol-5-
ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 466.3 (M + H)+.
Example 849
N- [3- (1-~ [I- (2-CHLOROPHENYL) -1H-INDOL-5-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-chloro-2-iodobenzene and N-{3-[1-(1H-indol-5-
ylmethyl)-4-piperidinyl]phenyl -2-methylpropanamide:
ESMS m/e: 486.2 (M + H)+.
2 5 Example 850
2-METHYL-N-~3-[1-(~1-[3-(TRIFLUOROMETHYL)PHENYL]-1H-
INDOL-5-YL~METHYL)-4-PIPERIDINYL]PHENYL~PROPANAMIDE:
Prepared by Procedure C and Scheme Q1, with CuBr in
place of Cu, using 1-iodo-3-(trifluoromethyl)benzene and
N-{3- [1- (1H-indol-5-ylmethyl) -4-piperidinyl]phenyl-2-
methylpropanamide: 1H NMR (400 MHz, CDC13) b 7.80-6.94
(m, 12H) , 6.69 (d, 1H, J = 3 .6 Hz) , 3 .36 (s, 2H) , 3.10-
3.00 (m, 2H) , 2.58-2.42 (m, 2H) , 2.16-2 .02 (m, 2H) ,
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1.85-1.75 (m, 4H), 1.25 (d, 6H, J - 7.2 Hz); ESMS
m/e: 520.2 (M + H)+.
Example 851
2-METHYL-N-[3-(1-~[1-(2-NITROPHENYL)-1H-INDOL-5-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared
by Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-iodo-2-nitrobenzene and N-~3-[1-(1H-indol-5-
ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 497.2 (M + H)+.
Example 852
N-[3-(1-~[1-(2-FLUOROPHENYL)-1H-INDOL-5-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Ql, with CuBr in place of Cu,
using 1-fluoro-2-iodobenzene and N-{3-[1-(1H-indol-5-
ylmethyl)-4-piperidinyl]phenyl -2-methylpropanamide:
ESMS m/e: 470.2 (M + H)+.
2 0 Example 853
2-METHYL-N-[3-(1-~[1-(1-NAPHTHYL)-1H-INDOL-5-YL]METHYL~-
4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure
C and Scheme Q1, with CuBr in place of Cu, using 1-
iodonaphthalene and N-{3-[1-(1H-indol-5-ylmethyl)-4-
piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 502.2
(M + H)+.
Example 854
N-[3-(1-~[1-(2,3-DICHLOROPHENYL)-1H-INDOL-5-YL]METHYL~-
4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1,2-dichloro-3-iodobenzene and N-{3-[1-(1H-indol-
5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H
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NMR (400 MHz, CDC13) 8 7.68-6.94 (m, 12H), 6.68
(d, 1H, J - 2.8 Hz), 3.69 (s, 2H), 3.15-3.02 (m, 2H),
2.54-2.42 (m, 2H), 2.18-2.02 (m, 2H), 1.88-1.76 (m, 4H),
1.25 (d, 6H, J = 6.8 Hz); ESMS m/e: 520.1 (M + H)+.
Example 855
N- [3- (1-~ [1- (2, 3-DICHLOROPHENYL) -1H-INDOL-7-YL] METHYL~-
4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1,2-dichloro-3-iodobenzene and N-~3-[1-(1H-indol-
7-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 520.2 (M + H)+.
Example 856
N-[3-(1-~[1-(3-METHOXYPHENYL)-1H-INDOL-4-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-iodo-3-methoxybenzene and N-{3-[1-(1H-indol-4-
ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 482.3 (M + H)+.
Example 857
N-[3-(1-~[1-(2,3-DICHLOROPHENYL)-1H-INDOL-4-YL]METHYL~-
4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1,2-dichloro-3-iodobenzene and N-{3-[1-(1H-indol-
4-ylmethyl)-4-piperidinyl]phenyl -2-methylpropanamide:
ESMS m/e: 520.2 (M + H)+. '
3 0 Example 858
N- [3- (1- f [1- (3-CHLOROPHENYL) -1H-INDOL-4-YL] METHYL-4-
PIPERTDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Ql, with CuBr in place of Cu,
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using 1-chloro-3- iodobenzene and N-{3-[1-
(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-
methylpropanamide: ESMS m/e: 486.2 (M + H)+.
Example 859
2-METHYL-N-[3-(1-~[1-(3-METHYLPHENYL)-1H-INDOL-4-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared
by Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-iodo-3-methylbenzene and N-{3-[1-(1H-indol-4-
ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 466.3 (M + H)+.
Example 860
N-[3-(1-~[1-(3-METHOXYPHENYL)-1H-INDOL-7-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-iodo-3-methoxybenzene and N-{3-[1-(1H-indol-7-
ylmethyl)-4-piperidinyl]phenyl -2-methylpropanamide:
ESMS m/e: 482.3 (M + H)+.
Example 861
2-METHYL-N-~3-[1-(~1-[3-(TRIFLUOROMETHYL)PHENYL]-1H-
INDOL-4-YL~METHYL)-4-PIPERIDINYL]PHENYL~PROPANAMIDE:
Prepared by Procedure C and Scheme Q1, with CuBr in
place of Cu, using 1-iodo-3-(trifluoromethyl)benzene and
N-{3- [1- (1H-indol-4-ylmethyl) -4-piperidinyl]phenyl-2-
methylpropanamide: ESMS m/e: 520.2 (M + H)+.
Example 862 .
N- [3- (1-{ [1- (3,4-DIMETHYLPHENYL) -1H-INDOL-4-YL]METHYL~-
4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using N-{3-[1-(1H-indol-4-ylmethyl)-4-
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piperidinyl]phenyl}-2- methylpropanamide and 4-
iodo-1,2-dimethylbenzene: ESMS m/e: 4.80.0 (M + H)t.
Example 863
N-[3-(1-{[1-(3,4-DIFLUOROPHENYL)-1H-INDOL-4-YL]METHYL~-
4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1,3-dichloro-5-iodobenzene and N-{3-[1-(1H-indol-
4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 520.0 (M + H)+.
Example 864
N-(3-(1-{[1-(3~4-DICHLOROPHENYL)-1H-INDOL-4-YL]METHYL}-
4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1,2-dichloro-4-iodobenzene and N-{3-[1-(1H-indol-
4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: .
ESMS m/e: 520.0 (M + H)+.
2 0 Example 865
N- [3- (1-~ [1- (2-CHLORO-4-FLUOROPHENYL) -1H-INDOL-4-
YL]METHYL-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:
,Prepared by Procedure C and Scheme Ql, with CuBr in
place of Cu, using 2-chloro-4-fluoro-1-iodobenzene and
N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-
methylpropanamide: ESMS m/e: 504.0 (M + H)+.
Example 866
N- [3- (1-{ [1- (2, 4-DIFLUOROPHENYL) -1H-INDOL-4-YL]METHYL~-
4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 2,4-difluoro-1-iodobenzene and N-{3-[1-(1H-indol-
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4-ylmethyl)-4- piperidinyl]phenyl)-2-
methylpropanamide: ESMS m/e: 488.0 (M + H)+.
Example 867
2-METHYL-N-[3-(1-~[1-(3-PYRIDINYL)-1H-INDOL-7-
YL]METHYL-4-PIPERIDINYL)PHENYL~PROPANAMIDE: Prepared
by Procedure C and Scheme Q1, with CuBr in place of Cu,
using 3-iodopyridine and N-{3-[1-.(1H-indol-7-ylmethyl)-
4-piperidinyl]phenyl -2-methylpropanamide: ESMS m/e:
453,1 (M + H)+.
Example 868
N-~3-[1-(1H-INDOL-6-YLMETHYL)-4-PIPERIDINYL]PHENYL~-2-
METHYLPROPANAMIDE: Prepared by Procedure F and Scheme R
using 1H-indole-6-carbaldehyde and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 376.2 (M + H)_
Example 869
2-METHYL-N-[3-(1-~[1-(4-PYRIDINYL)-1H-INDOL-4-
YL]METHYL-4-PIPERIDINYL)PHENYL~PROPANAMIDE: Prepared
by Procedure C and Scheme Q1, with CuBr in place of Cu,
using 4-iodopyridine and N-{3-[1-(1H-indol-4-ylmethyl)-
4-piperidinyl]phenyl -2-methylpropanamide: ESMS m/e:
453.2 (M + H)+.
Example 870
2-METHYL-N-[3-(1-~[1-(2-PYRIDINYL)-1H-INDOL-4-
YL)METHYL-4-PIPERIDINYL) PHENYL] PROP.ANAMIDE: Prepared
by Procedure C and Scheme Q1, with CuBr in place of Cu,
using 2-iodopyridine and N-{3-[1-(1H-indol-4-ylmethyl)-
4-piperidinyl]phenyl -2-methylpropanamide: ESMS m/e:
453.2 (M '+ H)+.
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Example 871
N-[3-(1-~[1-(2-FLUOROPHENYL)-1H-INDOL-4-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-fluoro-2-iodobenzene and N-{3-[1-(1H-indol-4-
ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 470.1 (M + H)+.
Example 872
N-[3-(Z-~[1-(4-CHLOROPHENYL)-1H-INDOL-4-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-chloro-4-iodobenzene and N-f3-[1-(1H-indol-4-
ylmethyl)-4-piperidinyl]phenyl -2-methylpropanamide:
~SMS m/e: 486.1 (M + H)+.
Example 873
2-METHYL-N-[3-(1-~[1-(3-PYRIDINYL)-1H-INDOL-4-
YL]METHYL-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared
by Procedure C and Scheme Q1, with CuBr in place of Cu,
using 3-iodopyridine and N-~3-[1-(1H-indol-4-ylmethyl)-
4-piperidinyl]phenyl -2-methylpropanamide; ESMS m/e:
453.2 (M + H)+.
2 5 Example 874
N- [3- (1-~ [1- (2, 3-DIMETHYLPHENYL) -IH-INDOL-4-YL] METHYL}-
4-PIPERIDINYL)PHENYL]-2-METHYLPROP.ANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-iodo-2,3-dimethylbenzene and N-{3-[1-(1H-indol-
4-ylmethyl)-4-piperidinyl]phenyl -2-methylpropanamide:
ESMS m/e: 480.1 (M + H)+.
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Example 875
N- [3- (1-~ [1- (3-FLUOROPHENYL) -1H-INDOL-4-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-fluoro-3-iodobenzene and N-{3-[1-(1H-indol-4-
ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 470.1 (M + H)+.
Example 876
2-METHYL-N-~3- [1- (~l- [2- (TRIFLUOROMETHYL) PHENYL] -1H-
INDOL-4-YL~METHYL)-4-PIPERIDINYL]PHENYL~PROPANAMIDE:
Prepared by Procedure C and Scheme Q1, with CuBr in
place of Cu, using 1-iodo-2- (trifluoromethyl)benzene and
N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-
15~ inethylpropanamide: ESMS m/e: 520.1 (M + H)+.
Example 877
N-[3-(1-~[1-(2-CHLOROPHENYL)-1H-INDOL-4-YL]METHYL-4-
PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in place of Cu,
using 1-chloro-2-iodobenzene and N-{3-[1-(1H-indol-4-
ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide:
ESMS m/e: 486.1 (M + H)+.
2 5 Example 878
N-[3-(1-~[1-(2,3-DIMETHYLPHENYL)-1H-INDOL-7-YL]METHYL~-
4-PIPERIDINYL)PHENYL]-2-METHYLPROPAN,AMIDE: Prepared by
Procedure C and Scheme Q1, with CuBr in .place of Cu,
using 1-iodo-2,3-dimethylbenzene and N-{3-[1-(1H-indol-
7-ylmethyl)-4-piperidinyl]phenyl -2-methylpropanamide:
ESMS m/e: 480.0 (M + H)+.
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2-METHYL-N-[3-(2-~5-OXO-5-
(TP,IFLUOROMETHYL) PHENYL] PENTYL~-4-
PIPERIDINYL)PHENYL]PROPANAMIDE: Prepared by Procedure K
and Scheme E using 5-chloro-1-[4-
(trifluoromethyl)phenyl]-1-pentanone and 2-methyl-N-[3-
(4-piperidinyl)phenyl]propanamide: ESMS m/e: 475.1 (M +
H)+.
N-(3-~l-[5-(4-FLUOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme E using 5-chloro-1-(4-
fluorophenyl) -1-pentanone and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M + H)+.
N-(3-~1-[5-(3-FLUOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme E using 5-chloro-1-(3-
fluorophenyl)-1-pentanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M + H)+.
N-(3-~1-[5-(3-CHLOROPHENYL)-5-OXOPENTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme E using 5-chloro-1-(3-
chlorophenyl) -1-pentanone and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 441.1 (M + H)+.
N-(3-{1- [5- (4-CHLOROPHENYL) -5-OXOPENTYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE; .Prepared by
Procedure K and Scheme E . using 5-chloro-1-(4-
chlorophenyl)-1-pentanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide; ESMS m/e: 441.1 (M + H)~.
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Example 879
2-METHYL-N-f3-[l-(3-OXO-3-PHENYLPROPYL)-4-
PIPERIDINYL]PHENYL~PROPANAMIDE: Prepared by Procedure K
and Scheme E using KzC03 instead of Na~C03 and NaI instead
of KI and 3-chloro-1-phenyl-l-propanone and 2-methyl-N-
[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 379.3 (M
+ H)+.
Example 880
N-(3-~l-[7-(2-FLUOROPHENYL)-7-OXOHEPTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme E using KaC03 instead of Na2CO3 and
NaI instead of KI and 7-chloro-1-(2-fluorophenyl)-1-
heptanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDC13),
$ 8.17 (s, br, 1H), 8.06-6.88 (m, 8H), 3.08-2.94 (m,
4H) , 2.62-2 .48 (m, 1H) , 2.48-2 .38 ~ (m, 1H) , 2 .38-2.15 (m~,
2H) , 2 . 02-1 . 92 (m, 2H) , 1 . 84-1..77 (m, 4H) , 1 .77-1 . 66 (m,
2H) , 1 .62-1.46 (m, 2H) , 1.46-1.29 (M, 4H) , I.21 (d, 6H,
J = 6.8 Hz); ESMS m/e: 453.2 (M + H)+.
Example 881
N-(3-~l- [5- (2-FLUOROPHENYL) -5-OXOPENTYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme E using KzC03 instead of Na2CO3 and
NaI instead of KT and 5-chloro-1-(2-fluorophenyl)-1-
pentanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl7propanamide: ESMS m/e: 425.2 (M + H)+.
3 0 Example 882
N- ( 3 - ~ 1- [ 6 - ( 3 - FLUOROPHENYL ) - 6 - OXOHEXYL] - 4 -
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme E using KzC03 instead of Na2C03 and
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NaI instead of KI and 6- chloro-1-(3-fluorophenyl)-
1-hexanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 439.2 (M + H)+.
Example 883
N-(3-~1-[6-(2-FLUOROPHENYL)-6-OXOHEXYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme E using KzC03 instead of Na~C03 and
NaI instead of KI and 6-chloro-1-(2-fluorophenyl)-1-
20 hexanone and 2-methyl-N-[3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 439.2 (M + H)+.
Example 884
N-(3-~1- [7- (4-FLUOROPHENYL) -7-OXOHEPTYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme E using K2C03 instead of NaaC03 and
NaI instead of KI and 7-chloro-1-(4-fluorophenyl)-1-
heptanone and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 453.2 (M + H)+.
Example 885
N-(3-~Z-[6-(4-CHLOROPHENYL)-6-OXOHEXYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme E using KZC03 instead of NazC03 and
NaI instead of KI and 6-chloro-1-(4-chlorophenyl)-1-
hexanone and 2-methyl-N-[3-(4-
piperid:inyl)phenyl]propanamide: ESMS m/e: 455.1 (M + H)+.
Example 886
N-(3-~1-[7-(4-CHLOROPHENYL)-7-OXOHEPTYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure' K and Scheme E using KZC03 instead of Na2C03 and
NaI instead of KI and 7-chloro-1-(4-chlorophenyl)-1-
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heptanone and 2-methyl-N- [3-(4-
piperidinyl)phenyl]propanamide: ESMS m/e: 469.1 (M + H)+.
Example 887
N-(3-~1-[6-(4-FLUOROPHENYL)-6-OXOHEXYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure K and Scheme E using KzC03 instead of Na2C03 and
NaI instead of KI and 6-chloro-1-(4-fluorophenyl)-1-
hexanone and 2-methyl-N- [3- (4-
piperidinyl)phenyl]propanamide: ESMS m/e: 439.1 (M + H)+.
Example 888
N-(3-~1-[6-(3-ACETYLPHENOXY)-6-(2-FLUOROPHENYL)HEXYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using 1-(3-
hydroxyphenyl ) ethanone and N- (3- ~ Z - [ 6- ( 2 -f luorophenyl ) -
6-hydroxyhexyl~-4-piperidinyl~phenyl)-2-
methylpropanamide: ESMS m/e: 559.5 (M + H)+.
2 0 Example 889
N-(3- f 1- [6- (2-FLUOROPHENOXY) -6- (2-FLUOROPHENYL) HEXYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using 2-fluorophenol and N-(3-
f 1- [6- (2-fluorophenyl) -6-hydroxyhexyl] -4-
piperidinyl~phenyl)=2-methylpropanamide: ESMS m/e: 535.1
(M + H)+.
Example 890
N-(3-~1- [6- (4-FLUOROPHEN'OXY) -6- (2-FLUOROPHENYL) HEXYL] -4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using 4-fluorophenol and N-(3-
fl-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-
piperidinyl~phenyl)-2-methylpropanamide: 1H NMR (400 MHz,
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CDC13), HC1 salt 8 7.72- 6.72 (m, 12H), 5.42-5.34
(m, 1H), 3.68-3.58 (m, br, 2H), 3.02-2.92 (m, 2H), 2.80-
2.46 (m, 6H), 2.05-1.78 (m, 6H), 1.68-1.56 (m, 1H),
1.56-1.38 (m, 3H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m/e:
535.1 (M + H)+.
Example 891
N- ( 3 - ~ 1- [ 6 - ( 2 - FLUOROPHENYL ) - 6 - ( 2 -METHOXYPHENOXY) HEXYL] -
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using 2-methoxyphenol and N-
(3-{1- [6- (2-fluorophenyl) -6-hydroxyhexyl] -4-
piperidinyl~phenyl)-2-methylpropanamide: ESMS m/e: 547.0
(M + H)+.
Z 5 . . Example 892
N- ( 3 - { 1- [ 6 - ( 2 - FLUOROPHENYL ) - 6 - ( 4 -METHOXYPHENOXY) HEXYL ] -
4-PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using 4-methoxyphenol and N-
(3- { Z- [6- (2-fluorophenyl) -6-hydroxyhexyl] -4-
piperidinyl~phenyl)-2-methylpropanamide: ESMS m/e: 547.1
(M + H)+.
Example 893
N-(3-~1-[6-(4-ACETYLPHENOXY)-6-(2-FLUOROPHENYL)HEXYL]-4-
PIPERIDINYL~PHENYL)-2-METHYLPROPANAMIDE: Prepared by
Procedure A and Scheme AN using 1-(4-
hydroxyphenyl)ethanone and N-(3-{1-[6-(2-fluorophenyl)-
6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-
methylpropanamide: ESMS m/e: 559.2 (M + H)+.
Example 894
N-(3-~1- [6- (3,4-DIMETHOXYPHENOXY) -6- (2-
FLUOROPHENYL)HEXYL]-4-PIPERIDINYL~PHENYL)-2-
DEMANDE OU BREVET VOLUMINEUX
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