Note: Descriptions are shown in the official language in which they were submitted.
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DESCRIPTION
STEREOISOMERIC PYRIDYL AND PYRIDONYL COMPOUNDS AND METHODS
FOR THE TREATMENT OF GASTROINTESTINAL AND CENTRAL NERVOUS
SYSTEM DISORDERS
Background of Invention
Cisapride is one of a class of compounds known as benzamide derivatives, the
parent
compound of which is metoclopramide. U.S. Patent Nos. 4,962,115 and 5,057,525
(collectively "Van Daele" and incorporated by reference in their entireties)
disclose N-(3-
hydroxy-4-piperidenyl) benzamides of cisapride. Van Daele discloses that these
compounds,
the pharmaceutically acceptable acid addition salts thereof and the
stereochemically isomeric
forms thereof, stimulate the motility of the gastrointestinal system.
As a class, these benzamide derivatives have several prominent pharmacological
actions. The prominent pharmacological activities of the benzamide derivatives
are due to
their effects on the neuronal systems which are modulated by the
neurotransmitter serotonin.
The role of serotonin, and thus the pharmacology of the benzamide derivatives,
has been
broadly implicated in a variety of conditions for many years. Thus, research
has focused on
locating the production and storage sites of serotonin as well as the location
of serotonin
receptors in the human body in order to determine the connection between these
sites and
various disease states or conditions.
In this regard, it was discovered that a major site of production and storage
of
serotonin is the enterochromaffin cell of the gastrointestinal mucosa. It was
also discovered
that serotonin has a powerful stimulating action on intestinal motility by
stimulating intestinal
smooth muscle, speeding intestinal transit, and decreasing absorption time, as
in diarrhea.
This stimulating action is also associated with nausea and vomiting.
Because of their modulation of the serotonin neuronal system in the
gastrointestinal
tract, many of the benzamide derivatives are effective anti-emetic agents and
are commonly
used to control vomiting during cancer chemotherapy or radiotherapy,
especially when highly
emetogenic compounds such as cisplatin are used. This action is almost
certainly the result of
the ability of the compounds to block the actions of serotonin (5HT) at
specific sites of
action, called the 5HT3-receptor, which was classically designated in the
scientific literature
as the serotonin M-receptor. Chemotherapy and radiation therapy may induce
nausea and
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voiniting by the release of serotonin from damaged enterochromaffin cells in
the
gastrointestinal tract. Release of the neurotransmitter serotonin stimulates
both afferent vagal
nerve fibers (thus initiating the vomiting reflex) and serotonin receptors in
the chemoreceptor
trigger zone of the area postrema region of the brain. The anatomical site for
this action of the
benzamide derivatives, and whether such action is central (CNS), peripheral,
or a
combination thereof, remains unresolved (Barnes et al., J. Pharm. Pharmacol.
40: 586-588,
1988). Cisapride, like the other benzamide derivatives would appear to be an
effective anti-
emetic agent based on its ability to modulate the activity of serotonin at the
5HT3 receptor.
A second prominent action of the benzamide derivatives is in augmenting
gastrointestinal smooth muscle activity from the esophagus through the
proximal small
bowel, thus accelerating esophageal and small intestinal transit as well as
facilitating gastric
emptying and increasing lower esophageal sphincter tone (Decktor et al., Eur.
J. Pharmacol.
147: 313-316, 1988). Although the benzamide derivatives are not cholinergic
receptor
agonists per se, the aforementioned smooth muscle effects may be blocked by
muscarinic
receptor blocking agents such as atropine or neuronal transmission inhibitors
of the
tetrodotoxin type which affect sodium channels. Similar blocking activity has
been reported
for the contractile effects of serotonin in the small intestine. It is
currently believed that the
primary smooth muscle effects of the benzamide derivatives are the result of
an agonist
action upon a new class of serotonin receptors referred to as 5HT4 receptors
which are
located on interneurons in the myenteric plexus of the gut wall. Activation of
these receptors
subsequently enhances the release of acetylcholine from parasympathetic nerve
terminals
located near surrounding smooth muscle fibers, and it is the combination of
acetylcholine
with its receptors on smooth muscle membranes which is the actual trigger for
muscle
contraction.
A discussion of various 5HT receptors, including the 5HT4 receptor can be
found in,
for example, U.S. Patent Nos. 6, 331,401 and 6,632,827, which are incorporated
by reference
herein in their entirety.
Cisapride has been used primarily to treat gastroesophageal reflux disease
(GERD).
This disease is characterized as the backward flow of the stomach contents
into the
esophagus. One of the most important factors in the pathogenesis of
gastroesophageal reflux
disease is a reduction in the pressure barrier due to the failure of the lower
esophageal
sphincter. Failure of the lower esophageal sphincter can arise due to a low
basal pressure,
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sphincter relaxation, or to a non-compensated increase in intragastric
pressure. Other factors
in the pathogenesis of the disease are delayed gastric emptying, insufficient
esophageal
clearing due to impaired peristalsis and the corrosive nature of the reflux
material which can
damage esophageal mucosa. Cisapride is thought to strengthen the anti-reflux
barrier and
improve esophageal clearance by increasing the lower esophageal sphincter
pressure and
enhancing peristaltic contractions.
Because of its activity as a prokinetic agent, cisapride would also appear to
be useful
to treat dyspepsia, gastroparesis, constipation, post-operative ileus, and
intestinal pseudo-
obstruction. Dyspepsia is a condition characterized by an impairment of the
power or
function of digestion that can arise as a symptom of a primary
gastrointestinal dysfunction or
as a complication due to other disorders such as appendicitis, gallbladder
disturbances, or
malnutrition. Gastroparesis is a paralysis of the stomach brought about by a
motor
abnormality in the stomach or as a complication of diseases such as diabetes,
progressive
systemic sclerosis, anorexia nervosa or myotonic dystrophy. Constipation is a
condition
characterized by infrequent or difficult evacuation of feces resulting from
conditions such as
lack of intestinal muscle tone or intestinal spasticity. Post-operative ileus
is an obstruction in
the intestine due to a disruption in muscle tone following surgery. Intestinal
pseudo-
obstruction is a condition characterized by constipation, colicky pain, and
vomiting, but
without evidence of physical obstruction.
Drug toxicity is an important consideration in the treatment of humans and
animals.
Toxic side effects (adverse effects) resulting from the administration of
drugs include a
variety of conditions which range from low grade fever to death. Drug therapy
is justified
only when the benefits of the treatment protocol outweigh the potential risks
associated with
the treatment. The factors balanced by the practitioner include the
qualitative and quantitative
impact of the drug to be used as well as the resulting outcome if the drug is
not provided to
the individual. Other factors considered include the physical condition of the
patient, the
disease stage and its history of progression, and any known adverse effects
associated with a
drug.
Drug elimination is typically the result of metabolic activity upon the drug
and the
subsequent excretion of the drug from the body. Metabolic activity can take
place within the
vascular supply and/or within cellular compartments or organs. The liver is a
principal site of
drug metabolism. The metabolic process can be categorized into synthetic and
nonsynthetic
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reactions. In nonsynthetic reactions, the drug is chemically altered by
oxidation, reduction,
hydrolysis, or any combination of the aforementioned processes. These
processes are
collectively referred to as Phase I reactions.
In Phase II reactions, also known as synthetic reactions or conjugations, the
parent
drug, or intermediate metabolites thereof, are combined with endogenous
substrates to yield
an addition or conjugation product. Metabolites formed in synthetic reactions
are, typically,
more polar and biologically inactive. As a result, these metabolites are more
easily excreted
via the kidneys (in urine) or the liver (in bile). Synthetic reactions include
glucuronidation,
amino acid conjugation, acetylation, sulfoconjugation, and methylation.
More than 90% of a dose of cisapride is metabolized by oxidative N-
dealkylation at
the piperidine nitrogen or by aromatic hydroxylation occurring on either the 4-
fluorophenoxy
or benzamide rings.
The administration of cisapride to a human has been found to cause serious
adverse
effects including CNS disorders, increased systolic pressure, interactions
with other drugs,
diarrhea, and abdominal cramping. Further, it has been reported that
intravenous
administration of cisapride demonstrates the occurrence of additional adverse
effects not
experienced after oral administration of cisapride (Stacher et al. [1987]
Digestive Diseases
and Sciences 32(11):1223-1230). It is believed that these adverse effects are
caused by the
metabolites that result from the oxidative dealkylation or aromatic
hydroxylation of the
compound which occurs in the cytochrome P450 detoxification system. Cisapride
is also
subject to a number of undesirable drug/drug interactions that are also a
result of metabolism
by the cytochrome P450 system.
Between July 1993 and December 1999, cisapride (PROPULSID, Janssen
Pharmaceutica Products, L.P.) was reportedly associated with at least 341
serious cardiac
arrhythmias. These arrhythmias include ventricular tachycardia, ventricular
fibrillation,
torsades de pointes, and QT prolongation. Eighty (80) deaths have been
reported. As a result
of these adverse effects, the product was voluntarily withdrawn from the open
market in the
United States; however, the drug is available through an investigational
limited access
program.
The safety of 5HT4 receptor agonists with gastrointestinal (GI) prokinetic
activity has
been limited due to cardiac effects (prolongation of QTc intervals,
tachycardia, torsades de
pointes) and adverse drug interactions due to hepatic cytochrome P-450
metabolism. A GI
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prokinetic agent of this class that lacks these liabilities would be very
valuable in several
therapeutic areas including GERD and gastric emptying disorders. Certain
cisapride
derivatives have been described in U.S. Pat. No. 6,552,046 and WO 01/093849
(incorporated
by reference herein in their entireties), however further compounds with even
more
advantageous properties would be desirable.
It has now been discovered that certain stereoisomers of one such esterified
structural
and/or functional analogs of cisapride have distinct and particularly
advantageous properties.
Brief Summary
The subject invention provides compounds and compositions of formulae Xa and
Xb,
which are stereoisomeric, functional and/or structural analogs of cisapride,
for the safe and
effective treatment of various gastrointestinal disorders including, but not
limited to,
gastroparesis, gastroesophageal reflux and related conditions. The compounds
of the subject
invention are also useful in treating a variety of conditions involving the
central nervous
system.
The compounds of the invention comprise compounds of formulae Xa and/or Xb:
O N1.11 L 5
Ri 4
N 3
R~ N O R4 R20
2 H
Formula Xa
O N~ R5
R\~ 43
N
R~N ORR4 R20
2 3
Formula Xb
and pharmaceutically acceptable salts thereof, wherein
the bonds at positions 3 and 4 are cis relative to each other;
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L is -(Cl-C6 alkyl)- (in one aspect, -(C3-C5 alkyl)-), -(CI-C6 alkyl)-C(O)-,
or -C(O)-
(Cl-C6 alkyl)-, wherein each of the alkyl groups is optionally substituted
with 1 or 2 groups
that are independently halogen, C1-C4 alkoxy, or OH and wherein one carbon in
the alkyl
portion of L may be replaced by N(R9)-; or
L is -(C1-C4 alkyl)-NR9-(Ci-C4 alkyl)-, -(CI-C4 alkyl)-C(O)NR9-, -(CI-C4
alkyl)-,
-(C1-C4 alkyl)-NRgC(O)- or -C(O)NR9-(Cl-C4 alkyl)-;
Rl is halogen;
R2 is amino, NH(Cl-C4 alkyl) or N(C1-C4 alkyl)(C1-C4 alkyl);
R3 is H, C1-C4 alkyl, Cl-C4 alkoxy, or OH;
R4 is H or C1-C4 alkyl, and in one preferred aspect, methyl; and
R5 is -O-CI-C6-alkyl, -O-C3-C$ cycloalkyl, -0-heterocycloalkyl,
heterocycloalkyl,
aryl, -O-aryl, -N(Rg)-(Co-C6 alkyl)-C(O)-aryl, or N(Rg)-Co-C6 alkyl-aryl, -0-
heteroaryl, -
N(R9)-CI-C6(O)-heteroaryl, or N(R9)-Co-C6 alkyl-heteroaryl, wherein each of
the cyclic
groups is unsubstituted or substituted at one or more substitutable positions
with C1-C6 alkyl,
C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, hydroxy-C1-
C4-alkyl,
amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -(Co-C6 alkyl)-C(O)Rl
l, -O-(Co-C6
alkyl)-C(O)Rl l, methylsulfone, Co-C6-sulfonamide, NO2, -CO2Rlo, or -(C1-C4
alkyl)-
C02RIO; wherein
R9 at each occurrence is independently H or Cl-C4 alkyl;
Rlo at each occurrence is independently H, C1-C4 alkyl optionally substituted
with one
group that is selected from a 5 or 6 membered monocyclic heterocycloalkyl
ring, and OH,
quinuclidinyl, -C(O)NH2, -C(O)NH(C1-C~ alkyl), -C(O)N(Cl-C4 alkyl)(C1-C4
alkyl) or
piperidinyl optionally substituted with Cl-C4 alkyl;
Rll is C1-C6 alkyl, or OH; or
Rl l is NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)(Cl-C6 alkyl); or
R11 is C1-C6 alkoxy, optionally substituted with 1 or 2 groups that are
independently
CI-C4 alkoxy, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl),
heterocycloalkyl, OH,
-(Co-C6 alkyl)-C(O)N(R9)-heterocycloalkyl, -0-heterocycloalkyl, -C1-C6(O)N(R9)-
heteroaryl,
or heteroaryl, wherein
the heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups
that are independently halogen, Cl-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxy CI-
C6
allcyl, C1-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3,
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the heteroaryl group is optionally substituted with 1, 2, or 3 groups that are
independently halogen, Cl-C6 alkyl, CI-C6 alkoxy, hydroxy, hydroxy CI-C6
alkyl, C1-
C6 alkoxycarbonyl, -CO2H, CF3, or OCF3; or
Rl l is heterocycloalkyl or -0-heterocycloalkyl wherein the heterocycloalkyl
is
optionally substituted with 1, 2, or 3 groups that are independently halogen,
C1-C6 alkyl, Cl-
C6 alkoxy, hydroxy, hydroxy Cl-C6 alkyl, Cl-C6 alkoxycarbonyl, -COaH, CF3, or
OCF3; and
Rzo is -H, Cl-C6 alkoxy (preferably C1-C4 alkoxy, more preferably methoxy), or
OH.
The invention also encompasses compositions comprising at least one compound
of
formulae Xa and Xb and at least one pharmaceutically acceptable excipient,
adjuvant, carrier,
or solvent.
The compounds of formulae Xa and Xb are useful in the treatment or prevention
of
gastroesophageal reflux disease and substantially reduce adverse effects
associated with the
administration of cisapride. These adverse effects include, but are not
limited to, diarrhea,
abdominal cramping and elevations of blood pressure and heart rate.
Additionally, the compounds and compositions of the invention are useful in
treating
emesis and other conditions, including but not limited to dyspepsia,
gastroparesis,
constipation, post-operative ileus and intestinal pseudo-obstruction. As an
added benefit,
adverse effects associated with the administration of cisapride are also
reduced in these
methods of treatment.
Advantageously, the compounds of the subject invention are ligands for the
5HT4
receptor and, accordingly, can be used to treat conditions mediated through
this receptor.
These receptors are located in several areas of the central nervous system and
the modulation
of these receptors can be used to effect desired modulations of the CNS.
Advantageously, the subject invention provides stereoisomeric compounds which
contain an ester moiety that does not detract from the ability of these
compounds to provide a
therapeutic benefit, but which makes them more susceptible to degradation by
serum and/or
cytosolic esterases, thereby avoiding the cytochrome P450 drug detoxification
system
associated with adverse effects caused by cisapride and reducing the incidence
of such
adverse events.
The subject invention further provides methods of treatment comprising the
administration of the compounds of formulae Xa and Xb and therapeutically
effective
amounts to individuals in need of treatment for gastroesophageal reflux
disease, dyspepsia,
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gastroparesis, constipation, post-operative ileus, and intestinal pseudo-
obstruction; and
related conditions.
Advantageously, the therapeutic compounds of the subject invention are stable
in
storage and provide for safer metabolism of the drugs as compared to other
drugs; therefore,
the compounds of the subject invention can be used with a lower incidence of
side effects and
toxicity.
In a further aspect, the subject invention pertains to the breakdown products
(preferably metabolic breakdown products) which are formed when the
therapeutic
compounds of the subject invention are acted upon by esterases. These
breakdown products
can be used as described herein to monitor the clearance of the therapeutic
compounds from a
patient.
In yet a further aspect, the subject invention provides methods for
synthesizing the
therapeutic stereoisomeric compounds of the subject invention, as well as
intermediates
useful in preparing the compounds of interest.
Detailed Disclosure
In a further aspect, the invention provides compounds of Formulae Xa and Xb,
wherein
R5 is -O-C1-C6-alkyl, -O-C3-C8 cycloalkyl, -0-heterocycloalkyl,
heterocycloalkyl,
wherein the heterocycloalkyl group is selected from piperidinyl, piperazinyl,
pyrrolidinyl,
aza-bicyclo-octyl, in certain embodiments aza-bicyclo[2.2.2]octyl, aza-
bicyclo[3.2.1]octyl,
aza-bicyclo-nonyl, aza-bicyclo-decyl, indolinyl, morpholinyl, thiomorpholinyl,
S,S-
dioxothiomorpholinyl, and imidazolidinyl, -0-aryl, -N(R9)-C(O)-aryl, or N(R9)-
Co-C6,alkyl-
aryl, wherein each of the cyclic groups is unsubstituted or substituted at one
or more
substitutable positions with C1-C6 alkyl, C1-C6 alkoxy, halogen, CI-C6
haloalkyl, C1-C6
haloalkoxy, hydroxyl, hydroxy-C1-C4-alkyl, amino, -NH(C1-C6 alkyl), -N(C1-C6
alkyl)(C1-C6
alkyl), -C(O)Rl 1, or NO2; wherein
R9 at each occurrence is independently H or Cl-C4 alkyl; and
R11 is Cl-C6 alkyl, OH, or
Rll is Cl-C6 alkoxy, optionally substituted with 1 or 2 groups that are
independently
C1-C4 alkoxy, amino, -NH(CI-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -
C(O)N(R9)-
heterocycloalkyl, heterocycloalkyl or heteroaryl, wherein
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the heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl,
piperazinyl, morpholinyl, aza-bicyclo-octyl, in certain embodiments aza-
bicyclo[2.2.2]octyl, aza-bicyclo[3.2.1]octyl, aza-bicyclo-nonyl and aza-
bicyclo-decyl,
wherein the heterocycloalkyl groups are optionally substituted with 1, 2, or 3
groups
that are independently halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxy C1-
C6
alkyl, C1-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3,
the heteroaryl group is selected from pyridyl, pyrimidyl, quinolinyl,
isoquinolinyl, and indolyl, wherein the heteroaryl groups are optionally
substituted
with 1, 2, or 3 groups that are independently halogen, C1-C6 alkyl, C1-C6
alkoxy,
hydroxy, hydroxy C1-C6 alkyl, C1-C6 alkoxycarbonyl, -COZH, CF3, or OCF3; or
Rll is -0-heterocycloalkyl wherein the heterocycloalkyl is selected from
piperidinyl,
pyrrolidinyl, imidazolidinyl, morpholinyl, aza-bicyclo-octyl, in certain
embodiments aza-
bicyclo[2.2.2]octyl, aza-bicyclo[3.2.1]octyl, aza-bicyclo-nonyl, aza-bicyclo-
decyl, and
tetrahydrofuranyl, and wherein each heterocycloalkyl group is optionally
substituted with 1,
2, or 3 groups that are independently halogen, CI-C6 alkyl, C1-C6 alkoxy,
hydroxy, hydroxy
C1-C6 alkyl, C1-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3.
In another aspect, the invention provides compounds of Formulae Xa and Xb,
wherein
Rl is chloro.
In yet another aspect, the invention provides compounds of Formulae Xa and Xb,
wherein R2 is amino.
In still another aspect, the invention provides compounds of Formulae Xa and
Xb,
wherein R3 is methyl.
In another aspect, the invention provides compounds of Formulae Xa and Xb,
wherein
R4 is H or methyl.
In still yet another aspect, the invention provides compounds of Formulae Xa
and Xb,
wherein RI is chloro; R2 is amino; R3 is methyl; and R4 is H or methyl.
In yet another aspect, the invention provides compounds of Formulae Xa and Xb,
wherein Rl is chloro; R2 is amino; R3 is methyl; R4 is H, and L is -(C4-C6
alkyl)-C(O)-.
In another aspect, the invention provides compounds of Formulae Xa and Xb,
wherein
two or more previously described aspects are combined.
In another aspect, the invention provides compounds of Formulae XIa and XIb,
which
are compounds of Formulae Xa and Xb wherein R2o is OCH3 and L is -(CH2)5-C(O)-
:
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R5
O
Rl1~ 3 O
- N
o\ R4 OCH3
R2 ~ 0
Formula XIa
R5
0
Rl~ 4 3 O
N
R N ORR4 OCH3
z
Forrnula XIb
In yet still another aspect, the invention provides compounds of Formulae Xla
and
XIb, wherein Rl is chloro; R2 is amino; R3 is methyl; and R4 is H or methyl.
In still another aspect, the invention provides compounds of Formulae XIa and
Xlb,
wherein R5 is-O-heterocycloalkyl, wherein the heterocycloalkyl group is
selected from aza-
bicyclo-octyl, in certain embodiments 1-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-
bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza
nitrogen, is
optionally substituted with methyl or ethyl; and R4 is H or methyl.
In still yet another aspect, the invention provides compounds of Formulae XIa
and
Xlb, wherein R5 is -O-heterocycloalkyl, wherein the heterocycloalkyl group is
selected from
piperidinyl, piperazinyl, or pyrrolidinyl, each of which is unsubstituted or
substituted at one
or two positions with groups that are independently Cl-C4 alkyl, C1-C4 alkoxy,
halogen, C1-
C4 haloalkyl (in one aspect, CF3), C1-C4 haloalkoxy (in one aspect OCF3),
hydroxyl, hydroxy
C1-C4 alkyl, ainino, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(CI-C4 alkyl), -(C1-C6
alkyl)-C(O)Rll,
or NO2i and R4 is H or methyl.
In yet another aspect, the invention provides compounds of Formulae XIa and
XIb,
wherein R5 is -0-heterocycloalkyl, wherein the heterocycloalkyl group is
selected from
indolinyl, morpholinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl, and
imidazolidinyl, each
of which is unsubstituted or substituted at one or two positions with groups
that are
independently C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl (in one
aspect, CF3), C1-
C4 haloalkoxy (in one aspect OCF3), hydroxyl, hydroxy C1-C4 alkyl, amino, -
NH(CI-C4
alkyl), -N(Cl-C~ alkyl)(Cl-C4 alkyl), -(Co-C6 alkyl)-C(O)Rl l, or NOz; and R4
is H or methyl.
In yet another aspect, the invention provides compounds of Formulae Xla and
XIb,
wherein R5 is -0-phenyl, N(R9)-(Co-C6 alkyl)-C(O)-phenyl, or -N(Rq)-Co-C4
alkyl-phenyl,
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wherein the phenyl group is substituted with one or two groups that are
independently C1-C4
alkyl, CI-C4 alkoxy, halogen, Cl-C4 haloalkyl (in one aspect, CF3), C1-C4
haloalkoxy (in one
aspect OCF3), hydroxyl, hydroxy C1-C4 alkyl, amino, -NH(C1-C4 alkyl), -N(C1-C4
alkyl)(C1-
C4 alkyl), -(Co-C6 alkyl)-C(O)R11, or NO2; and R4 and R9 are independently H
or methyl.
In another aspect, the invention provides compounds of Formulae XIa and XIb,
wherein R4 is H.
In yet another aspect, the invention provides compounds of Formulae XIa and
XIb,
wherein Rl l is C1-C6 alkoxy, optionally substituted with 1 or 2 groups that
are independently
C1-C4 alkoxy, amino, -NH(C1-C6 alkyl), -N(Cl-C6 alkyl)(C1-C6 alkyl), -(Co-C6
alkyl)-
C(O)N(R9)-heterocycloalkyl, or heterocycloalkyl wherein the heterocycloalkyl
group is
selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein
the
heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that
are
independently halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxy C1-C6
alkyl, C1-C6
alkoxycarbonyl, -CO2H, CF3, or OCF3.
In another aspect, the invention provides compounds of Formulae XIa and XIb,
wherein two or more previously described aspects are combined.
In another aspect, the invention provides compounds of Formulae XIIa and XIIb,
i.e.,
compounds of Formulae Xa and Xb, of the formulae:
R9
I
O N~N
4 3 O R~s
I R15 (Co-Csalkyl)-C(O)Rjj
R4
OCH3
R2 H O
Formula Xlla
R9
I
N ~
4 3 O I J R l s
N 1,!~
I R15 (Co-Csalkyl)-C(O)Rjj
R2 ORR4 OCH3
2 3
Formula XIIb
wherein R15 is H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl (in one
aspect CF3),
C1 -Cg haloalkoxy ( in one aspect OCF3), hydroxyl, hydroxy C1-C4 alkyl, amino,
-NH(CI-C6
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alkyl), -N(C1-C6 alkyl)(CI-C6 alkyl), methylsulfone, Co-C6-sulfonamide or NOa,
and R16 is H
or -O-(Co-C6 alkyl)-C(O)RI 1. In another aspect, R15 is H.
In yet another aspect, the invention provides compounds of Formulae XIIa and
XIIb,
wherein R4 and R9 are independently H or methyl and Rl l is OH.
In still yet another aspect, the invention provides compounds of Formulae XIIa
and
XIIb, wherein R4 and R9 are independently H or methyl and Rll is C1-C6 alkoxy,
optionally
substituted with 1 or 2 groups that are independently C1-C4 alkoxy, amino, -
NH(C1-C6 alkyl),
-N(C1-C6 alkyl)(C1-C6 alkyl), -(Cn-C6 alkyl)-C(O)N(R9)-heterocycloalkyl, or
heterocycloalkyl wherein the heterocycloalkyl group is selected from aza-
bicyclo-octyl, in
certain embodiments 1-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-
yl, aza-
bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally
substituted with methyl
or ethyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein the
heterocycloalkyl
groups are optionally substituted with 1, 2, or 3 groups that are
independently halogen, C1-C6
alkyl, C1-C6 alkoxy, hydroxy, hydroxy C1-C6 alkyl, C1-C6 alkoxycarbonyl, -
CO2H, CF3, or
OCF3, and R4 and R9 are independently H or methyl. In another aspect, R4, R9,
and Rl I are as
previously defined and R15 is H, Rl is chloro; R2 is amino; and R3 is methyl.
In yet still another aspect, the invention provides compounds of Formulae XIIa
and
XIIb, wherein R4 and R9 are independently H or methyl and Ril is Cl-C6 alkoxy,
optionally
substituted with 1 or 2 groups that are independently C1-C4 alkoxy, amino, -
NH(C1-C6 alkyl),
-N(C1-C6 alkyl)(C1-C6 allcyl), or heteroaryl, wherein the heteroaryl group is
selected from
pyridyl, pyrimidyl, quinolinyl, isoquinolinyl, and indolyl, wherein the
heteroaryl groups are
optionally substituted witli 1, 2, or 3 groups that are independently halogen,
C1-C6 alkyl, C1-
C6 alkoxy, hydroxy, hydroxy C1-C6 alkyl, C1-C6 alkoxycarbonyl, -CO2H, CF3, or
OCF3; and
R4 and R9 are independently H or methyl. In another aspect, R4, R9, and R11
are as previously
defined and R15 is H, Rl is chloro; R2 is amino; and R3 is methyl.
In still another aspect, the invention provides compounds of Formulae XIIa and
XIIb,
wherein at least one of R4 and R9 is H.
In another aspect, the invention provides compounds of Formulae XIIa and XIIb,
wherein two or more previously described aspects are combined.
In another aspect, the invention provides compounds of Formulae XIIIa and
XIIIb,
i.e., compounds of Formula XIIa and XIIb, of the formulae:
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R9
O N~N
R1\ 4 3 O j R1s
N /1----~(Co-C6a1ky1)-C(O)R11
R eI~N O R4 OCH3 R15
2 H
Formula XIIIa
Ry
I
O N~N ~
R1l 4 3 O I ' R1s
N ~~(Co-Csalkyl)-C(O)R11
R1
R N OR R4 OCH3 5
z 3
Formula XIIIb
wherein R15 is H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl (in one
aspect CF3),
C1-C6 haloalkoxy ( in one aspect OCF3), hydroxyl, hydroxy CI-C4 alkyl, amino, -
NH(C1-C6
alkyl), -N(CI-C6 alkyl)(C1-C6 alkyl), or methylsulfone, Co-C6-sulfonamide,
NO2, and R16 is H
or -O-(Co-C6 alkyl)-C(O)R11. In another aspect, R15 is H.
In yet another aspect, the invention provides compounds of Formulae XIIIa and
XIIIb,
wherein, R4 and R9 are independently H or methyl, and Rl l is OH, CI-C4 alkoxy
(in another
aspect, Cl-C3 alkoxy), or C1-C2 alkoxy-C1-C3 alkoxy-. In another aspect, R4,
R9, and Rl l are
as previously defined and Rl is chloro; R2 is amino; and R3 is methyl.
In still yet another aspect, the invention provides compounds of Formulae
XIIIa and
XIIIb, wherein R4 and R9 are independently H or methyl, and Rl j is CI-C4
alkoxy substituted
with ainino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), aza-bicyclo-
octyl, in certain
embodiments 1-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza-
bicyclo-nonyl,
aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with
methyl or ethyl; and
R4 is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(Co-C6
alkyl)-C(O)NH-
pyrid-4-yl. In another aspect, R4, R9, and Rl 1 are as previously defined and
Rl is chloro; R2 is
amino; and R3 is methyl.
In still another aspect, the invention provides compounds of Formulae XIIIa
and
XIIIb, wherein R4 and R9 are independently H or methyl, and R11 is Cl-C4
alkoxy substituted
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with amino, -NH(CI-C6 alkyl), or -N(C1-C6 alkyl)(CI-C6 alkyl). In another
aspect, R4, R9, and
R11 are as previously defined and Ri is chloro; R2 is amino; and R3 is methyl.
In yet another aspect, the invention provides compounds of Formulae XIIIa and
XIIIb,
wherein R4 and R9 are independently H or methyl, and Rll is C1-C4 alkoxy
substituted with
pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(Co-C6 alkyl)-C(O)NH-
pyrid-4-yl. In
another aspect, R4, R9, and Rl l are as previously defined and Rl is chloro;
R2 is amino; and
R3 is methyl.
In still another aspect, the invention provides compounds of Formulae XIIIa
and
XIIlb, wherein at least one of R4 and R9 is H.
In another aspect, the invention provides compounds of Formulae XIIla and
XIIIb,
wherein two or more previously described aspects are combined.
In another aspect, the invention provides compounds of Fonnulae XIVa and XIVb,
i.e., compounds of Formulae Xa and Xb, of the formulae:
/R1s
R
9 \ (Co-C6a1kyl)-C(O)R11
O
R1 R15
~~ N 3
R~~N 0 R4 OCH3
z H
Formula XIVa
/R1s
R9
N \ (Co-C6a1kyl)-C(0)R11
O N
R1 R15
a-:' RSORR4 OCH3
2 3
Formula XIVb
wherein R15 is H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl (in one
aspect CF3),
C1-C6 haloalkoxy ( in one aspect OCF3), hydroxyl, hydroxy C1-Cd alkyl, amino, -
NH(C1-C6
alkyl), -N(CI-C6 alkyl)(CI-C6 alkyl), methylsulfone, Co-C6-sulfonamide, or
NOZ, and R16 is H
or -O-(Co-C6 alkyl)-C(O)Rl I. In another aspect, R15 is H.
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In still another aspect, the invention provides compounds of Formulae XIVa and
XIVb, wherein R4 and R9 are independently H or methyl, and Rll is OH, Cl-C4
alkoxy (in
another aspect, C1-C3 alkoxy) or C1-Ca alkoxy-C1-C3 alkoxy-. In another
aspect, R4, R9, and
RI1 are as previously defined and Rl is chloro; R2 is amino; and R3 is methyl.
In still another
aspect, at least one of R4 and R9 is H.
In yet still another aspect, the invention provides compounds of Formulae XIVa
and
XIVb, wherein R4 and R9 are independently H or methyl, and Rll is C1-C4 alkoxy
substituted
with amino, -NH(CI-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), aza-bicyclo-octyl,
in certain
embodiments 1-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza-
bicyclo-nonyl,
aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with
methyl or ethyl; and
R4 is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(Co-C6
alkyl)-C(O)NH-
pyrid-4-yl. In another aspect, R4, R9, and Rl l are as previously defined and
Rl is chloro; R2 is
amino; and R3 is methyl.
In still another aspect, the invention provides compounds of Formulae XIVa and
XIVb, wherein R4 and Rg are independently H or methyl, and Rll is Cl-C4 alkoxy
substituted
with amino, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)(Ci-C6 alkyl). In another
aspect, R4, R9, and
Rl l are as previously defined and Rl is chloro; R2 is amino; and R3 is
methyl.
In yet another aspect, the invention provides compounds of Formulae XIVa and
XIVb, wherein R4 and R9 are independently H or methyl, and Rll is Cl-C4 alkoxy
substituted
with pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -(Co-C6 alkyl)-C(O)NH-
pyrid-4-yl. In
another aspect, R4, R9, and Rl l are as previously defined and RI is chloro;
R2 is amino; and
R3 is methyl.
In still another aspect, the invention provides compounds of Formulae XIVa and
XIVb, wherein at least one of R4 and R9 is H.
In another aspect, the invention provides compounds of Formulae XIVa and XIVb,
wherein two or more previously described aspects are combined.
In another aspect, the invention provides compounds of Formulae XVa and XVb,
i.e.,
compounds of Formulae Xa and Xb of the formulae:
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N (C0-C6a1ky1)-C(O)Rjj
O N n
R~ 4 3 O
N
R4 OCH3
O 3 N Formula XVa
N (C0-C6a1ky1)-C(O)Rjj
O N n
R,\ 4
N 3 O
R I~Ir1 N ORR4 OCH3
2 3
Formula XVb
wherein n is 1 or 2.
In still another aspect, the invention provides compounds of Formulae XVa and
XVb,
wherein R4 is H or methyl, and Rl l is OH, C1-C4 alkoxy (in another aspect, Cl-
C3 alkoxy) or
CI-C2 alkoxy-C1-C3 alkoxy-. In another aspect, R4 and Rll are as previously
defined and Rl is
chloro; R2 is amino; and R3 is methyl. In still another aspect, at least one
of R4 and R9 is H.
In yet still another aspect, the invention provides compounds of Formulae XVa
and
XVb, wherein R4 and R9 are independently H or methyl, and Rl l is Cl-C4 alkoxy
substituted
with amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), aza-bicyclo-octyl,
in certain
embodiments 1-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza-
bicyclo-nonyl,
aza-bicyclo-decyl, where the aza nitrogen is optionally substituted with
methyl or ethyl; and
R4 is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, or -C(O)NH-
pyrid-4-yl. In
another aspect, R4, R9, and Rll are as previously defined and Rl is chloro; R2
is amino; and
R3 is methyl.
In still another aspect, the invention provides compounds of Formulae XVa and
XVb,
wherein R4 and R9 are independently H or methyl, and Rl l is C1-C4 alkoxy
substituted with
amino, -NH(C1-C6 allcyl), or -N(C1-C6 alkyl)(C1-C6 alkyl). In another aspect,
R4, R9, and Rl1
are as previously defined and Rl is chloro; R2 is amino; and R3 is methyl.
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In yet another aspect, the invention provides compounds of Formulae XVa and
XVb,
wherein R4 is H or methyl, and Rll is C1-C4 alkoxy substituted with aza-
bicyclo-octyl, in
certain embodiments 1-aza-bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-
yl, aza-
bicyclo-nonyl, aza-bicyclo-decyl, where the aza nitrogen is optionally
substituted with methyl
or ethyl; and R4 is H or methyl, pyrrolidinyl, piperidinyl, morpholinyl,
pyridyl, or -(Co-C6
alkyl)-C(O)NH-pyrid-4-yl. In another aspect, R4, R9, and Rl l are as
previously defined and
Rl is chloro; R2 is amino; and R3 is methyl.
In another aspect, the invention provides compounds of Formulae XVa and XVb,
wherein two or more previously described aspects are combined.
In another aspect, the invention provides compounds according to any one of
Formulae Xa, Xb, Xla, XIb, XIIa, Xllb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb,
wherein Rl,
and R2 are oriented on the pyridyl and pyridonyl ring as follows:
O
R~ \ ~ .
R2 N OR3
O
::'
~
H
In another aspect, the invention provides compounds according to any one of
Formulae Xa, Xb, Xla, XIb, XIIa, Xllb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb,
wherein
bond 3 of the core piperidine ring has the "S" configuration and bond 4 has
the "R"
configuration.
In still another aspect, the invention provides compounds according to any one
of
Formulae Xa, Xb, XIa, Xlb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb,
wherein Rl
and R2 are oriented on the pyridyl and pyridonyl ring as follows:
O
R~
R2 N O R3
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O
RiI ~
R2 H O
and bond 3 of the core piperidine ring has the "S" configuration and bond 4
has the "R"
configuration.
In another aspect, the invention provides compounds according to any one of
Formulae Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or XVb,
wherein
bond 3 has the "R" configuration and bond 4 has the "S" configuration.
In another aspect, the invention provides compounds according to any one of
Formulae Xa, Xb, XIa, XIb, XIIa, Xllb, XIIIa, XIIlb, XIVa, XIVb, XVa or XVb,
wherein Rl
and R2 are oriented on the pyridyl and pyridonyl ring as follows:
O
R~
R2 N OR3
O
R,
R2 H O
and bond 3 of the core piperidine ring has the "R" configuration and bond 4
has the "S"
configuration.
In still another aspect, the invention provides compounds of Formulae Xa and
Xb,
wherein:
Rl is chloro; R2 is amino; R3 (for Xb) is methyl; R4 is H, and Rl and R2 have
the following
orientation on the pyridyl and pyridonyl ring:
O
R,
R2 N O R3
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O
:;xc' H O
, and
L is -(C3-C5 alkyl)- wherein one carbon may be replaced by N(R9)-, or -(C2-C6
alkyl)-C(O)-. In yet another aspect, the Rl, R2, and R3 (R3 for the pyridyl
ring) are as defined
and oriented on the pyridyl and pyridonyl rings as previously described, R4 is
as previously
defined and R5 is-O-heterocycloalkyl, wherein the heterocycloalkyl group is
selected from
aza-bicyclo-octyl, in certain embodiments 1-aza-bicyclo[2.2.2]oct-3-yl or 8-
aza-
bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the aza
nitrogen is
optionally substituted with methyl or ethyl, piperidinyl, piperazinyl, and
pyrrolidinyl, wherein
the piperidinyl, piperazinyl, and pyrrolidinyl groups are unsubstituted or
substituted at one or
two positions with groups that are independently C1-C4 alkyl, Cl-C4 alkoxy,
halogen, C1-C4
haloalkyl, C1-C4 haloalkoxy, hydroxyl, hydroxy C1-C4 alkyl, amino, -NH(C1-C4
alkyl),
-N(C1-C4 alkyl)(C1-C4 alkyl), -(Co-C6 alkyl)-C(O)Rll, or NOZ, wherein
Rl l is C1-C6 alkoxy, optionally substituted with 1 or 2 groups that are
independently
C1-C4 alkoxy, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -(Co-C6
alkyl)-
C(O)N(Rg)-heterocycloalkyl, or heterocycloalkyl wherein the heterocycloalkyl
group is
selected from aza-bicyclo-octyl, in certain embodiments 1-aza-
bicyclo[2.2.2]oct-3-yl or 8-
aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-bicyclo-decyl, where the
aza nitrogen is
optionally substituted with methyl or ethyl; and R4 is H or methyl,
pyrrolidinyl, piperidinyl,
piperazinyl, and morpholinyl, wherein the heterocycloalkyl groups are
optionally substituted
with 1, 2, or 3 groups that are independently halogen, C1-C6 alkyl, C1-C6
alkoxy, hydroxy,
hydroxy C1-C6 alkyl, C1-C6 alkoxycarbonyl, -CO2H, CF3, or OCF3.
In still yet another aspect, the invention provides compounds of Formulae Xa
and Xb,
wherein:
Rl is chloro; R2 is amino; R3 (for Xb) is methyl; R4 is H, and Rl, R2, and R3
have the
following orientation on the pyridyl and pyridonyl rings:
O
R~
/
R2 N O R3
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O
R,
I
R2 H O
, and
L is -(C3-C5 alkyl)- wherein one carbon may be replaced by N(R9)-, or -(C2-C6
alkyl)-C(O)-. In yet another aspect, the Rl, R2, and R3 are as defined and
oriented on the
pyridyl and pyridonyl ring as previously described, R4 is as previously
defined and R5 is
heterocycloalkyl, which is selected from aza-bicyclo-octyl, in certain
embodiments 1-aza-
bicyclo[2.2.2]oct-3-yl or 8-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo-nonyl, aza-
bicyclo-decyl,
where the aza nitrogen, is optionally substituted with methyl or ethyl.
In still yet another aspect, the invention provides compounds of Formulae Xa
and Xb,
wherein
Rl is chloro; R2 is amino; R3 (for Xb) is methyl; R4 is H, and Rl, R2, and R3
have the
following orientation on the pyridyl and pyridonyl rings:
O
R~
R2 N OR3
O
R,
x
R2 H O
, and
L is -(C3-C5 alkyl)- wherein one carbon may be replaced by N(R9)-, or -(C2-C6
alkyl)-C(O)-. In yet another aspect, the Rl, R2, and R3 are as defined and
oriented on the
pyridyl and pyridonyl ring as previously described, R4 is as previously
defined and R5 is-
N(R9)-Co-C4 alkyl-aryl or -N(R9)-(Co-C6 alkyl)-C(O)-aryl, wherein the aryl
group is
unsubstituted or substituted at one or more substitutable positions with C1-C6
alkyl, C1-C6
alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, hydroxyalkyl,
amino, -NH(Cl-
C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -(Co-C6 alkyl)-C(O)R11, or NOa. In
still another
aspect, the aryl group is a phenyl substituted with -(Co-C6 alkyl)-C(O)Rl l
and optionally
substituted with 1 or 2 groups independently selected from C1-C6 alkyl, C1-C6
alkoxy,
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halogen, CF3, OCF3, hydroxyl, hydroxyalkyl, amino, -NH(Cl-C4 alkyl), -N(C1-C4
alkyl)(Cl-
C4 alkyl), or NO2, wherein
Rll is C1-C6 alkoxy, optionally substituted with 1 or 2 groups that are
independently
C1-C4 alkoxy, amino, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -(Co-C6
alkyl)-
C(O)N(R9)-heterocycloalkyl, or heterocycloalkyl wherein the heterocycloalkyl
group is
selected from pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, wherein
the
heterocycloalkyl groups are optionally substituted with 1, 2, or 3 groups that
are
independently halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, hydroxy C1-C6
allcyl, C1-C6
alkoxycarbonyl, -CO2H, CF3, or OCF3. In a preferred aspect the -(Co-C6 alkyl)-
C(O)RI1
group is attached to position 4 of the phenyl ring.
In still another aspect, the orientation of bonds 3 and 4 of the core
piperidine ring is as
follows:
N
,Z,r 3
OCH3
In a preferred aspect, the orientation of bonds 3 and 4 of the core piperidine
ring is as
follows:
OCH3
The compounds of the invention comprise compounds of formulas XX-a or XX-b,
i.e., compounds of formulas Xa and/or Xb having the formulas:
,L-R5
P43
R, 0 R
2 ~\\ N Rzo
R3
XX-a, or
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,L-R5
O O
P43
Ri H ~\ ~ ~0
R,
XX-b
or pharmaceutically acceptable salts thereof, wherein
L is -(C1-C4 alkyl)-NR9-(C1-C4 alkyl)-, -(C1-C4 alkyl)-C(O)NR9-, -(C1-C4
alkyl)-, -(C1-C4
alkyl)-NR9C(O)- or -C(O)NR9-(C1-C4 alkyl)-;
Rl is halogen;
R2 is amino or mono or di(Cl-C4 alkyl)amino;
R3 is C1-C4 alkyl, CI-C4 alkoxy, or OH;
R4 is H or C1-C4 alkyl;
R5 is phenyl or naphthyl, each of which is substituted with 1 or 2 groups that
are
independently C1-C4 alkyl, C1-C4 alkoxy, OH, -O-C2-C4 alkanoyl, halogen, halo
CI-
C4 alkyl, halo C1-C4 alkoxy, -CO2RIo, -(CI-C4 alkyl)-CO2Rlo;
R9 is H or Cl-C4 alkyl;
Rio at each occurrence is independently H, C1-C4 alkyl optionally substituted
with one group
that is selected from a 5 or 6 membered monocyclic heterocycloalkyl ring, and
OH,
quinuclidinyl, -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(Cl-C4 alkyl)(C1-C4
alkyl)
or piperidinyl optionally substituted with C1-C4 alkyl; and
R20 is C1-C4 alkyl, or C1-C4 alkoxy.
In yet another aspect, the invention provides compounds of Formula (XX-2a) or
Formula (XX-2b) i.e., compounds of Formula (XX-a) or Formula (XX-b) having the
formula:
R17
R3 O
P43
R18
\
nl R20
R2
R~
Formula XX-2a, or
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R17
Nj LxJ
O O
'} 3 R18
HN
R2o
R1
Formula XX-2b
where
R17 is C1-C4 alkyl, C1-C4 alkoxy, OH, -O-C2-C4 alkanoyl, halogen, halo C1-C4
alkyl, halo C1-
C4 alkoxy, -C02Rl0, or -(C1-C4 alkyl)-CO2Rlo; and
R18 is H, C1-C4 alkyl, C1-C4 alkoxy, OH, -O-C2-C4 alkanoyl, halogen, halo C1-
C4 alkyl (such
as CF3), halo C1-C4 alkoxy (such as OCF3), -C02Rlo, or -(C1-C4 alkyl)-CO2Rlo.
In still another aspect, the invention provides compounds of either Formula
(XX-2a)
or Formula (XX-2b) wherein the bonds at positions 3 and 4 of the piperidinyl
ring are cis to
each other.
In still another aspect, the orientation of bonds 3 and 4 is as follows:
R20
In a preferred aspect, the orientation of bonds 3 and 4 is as follows:
Ni~
4 3
R20
In yet still another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(C1-Cz alkyl)-NR9-(C1-C2 alkyl)-;
RI7 is C1-C4
alkyl, C1-C4 alkoxy, or halogen; and R18 is H, C1-C4 alkyl, C1-C4 alkoxy, OH,
or -O-C2-C4
alkanoyl. Preferably, one of R17 or R18 is at the 4-position of the phenyl
group.
In still yet another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(C1-C2 alkyl)-NR9-(C1-C2 alkyl)-;
R17 is
halogen, halo C1-C4 alkyl, or halo CI-C4 alkoxy; and R18 is H, Cl-C4 alkyl, C1-
C4 alkoxy, OH.
Preferably, one of R17 or R18 is at the 4-position of the phenyl group.
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In another aspect, the invention provides compounds of either of Formula (XX-
2a) or
Formula (XX-2b), wherein L is -(C1-C2 alkyl)-NR9-(Cl-C2 alkyl)-; R17 is OH, or
-0-C2-C4
alkanoyl; and R18 is H, C1-C4 alkyl, C1-C4 alkoxy, or OH. Preferably, one of
R17 or R18 is at
the 4-position of the phenyl group.
In yet another aspect, the invention provides compounds of either of Formula
(XX-2a)
or Formula (XX-2b), wherein L is -(C1-C2 alkyl)-NR9-(C1-C2 alkyl)-; R17 is OH,
or -O-C2-C4
alkanoyl; and R18 is O-C2-C4 alkanoyl, halogen, halo C1-C4 alkyl, or halo CI-
C4 alkoxy.
Preferably, one of R17 or R18 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula
(XX-
2a) or Formula (XX-2b), wherein L is -(C1-C2 alkyl)-NR9-(Cl-CZ alkyl)-; Rlo is
H, C1-C4
alkyl optionally substituted with one group that is selected from morpholinyl,
pyrrolidinyl,
and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-
C3 alkyl; R17
is -CO2Rlo, or -(CI-C4 alkyl)-CO2Rlo; and R18 is C1-C4 alkyl, C1-C4 alkoxy, or
OH.
Preferably, one of R17 or R18 is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(Cl-C2 alkyl)-NR9-(C1-C2 alkyl)-;
Rlo is H, C1-
C4 alkyl optionally substituted with one group that is selected from
morpholinyl, pyrrolidinyl,
and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-
C3 alkyl; RI7
is -CO2Rlo; and R18 is C1-C4 alkyl (such as methyl), C1-C4 alkoxy (such as
methoxy), or OH.
Preferably, one of Rl7 or R18 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula
(XX-
2a) or Formula (XX-2b), wherein L is -(CI-C2 alkyl)-NR9-(C1-C2 alkyl)-; Rlo is
H, C1-C4
alkyl optionally substituted with one group that is selected from morpholinyl,
pyrrolidinyl,
and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-
C3 alkyl; R17
is-(Cl-C4 alkyl)-COzRIo; and R18 is C1-C4 alkyl, CI-C4 alkoxy, or OH.
Preferably, one of R17
or R18 is at the 4-position of the phenyl group.
In yet another aspect, the invention provides compounds of either of Formula
(XX-2a)
or Formula (XX-2b), wherein
L is -(C1-C3 alkyl)-NR9-(C1-C3 alkyl)-;
Rlo is H, CI-C4 alkyl optionally substituted with one group that is selected
from a 5 or 6
membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, or
piperidinyl optionally substituted with C1-C3 alkyl;
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R17 is OH, -O-C2-C4 alkanoyl, -C02Rl0, or -(C1-C4 alkyl)-CO2Rlo; and
R18 is H; and
R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein
L is -(C1-C3 alkyl)-NR9-(C1-C3 alkyl)-;
RIO is H, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with
C1-C3 alkyl;
R17 is OH, -O-C2-C4 alkanoyl, -C02Rl0, or -(C1-C4 alkyl)-CO2Rlo; and
R18 is H; and
R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(C1-C3 alkyl)-NR9-(CI-C3 alkyl)-;
Rlo is H; R17
is -CO2RIo, or -(Cl-C4 alkyl)-CO2Rlo; and R18 is H.
In still another aspect, the invention provides compounds of either of Formula
(XX-
2a) or Forinula (XX-2b), wherein L is -(C1-C3 alkyl)-NR9-(C1-C3 alkyl)-; R17
is OH, or -0-
C2-C4 alkanoyl; and R18 is H, methyl, methoxy, OH, F, or Cl.
In yet still another aspect, the invention provides compounds of Formula (XX-
3a) or
Formula (XX-3b), i.e., compounds of Formula (XX-2a) or Formula (XX-2b) having
the
formula:
R17
Rs
N ~ ~
~
O O
4 g
N ~ IV '
H R20
t-I2N
a
XX-3a, or
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R17
R9
~~/N
C3N ~ ~
O O HN I f~j~
H R20
H2N
a
XX-3b.
In still yet another aspect, the invention provides compounds of Formula (XX-3
a) or
Formula (XX-3b), wherein R17 is -CO2R10, or -(Cl-C4 alkyl)-CO2Rlo; R9 is H or
methyl; and
Rlo is H, C1-C4 alkyl optionally substituted with one group that is selected
from morpholinyl,
pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally
substituted with Cl-
C2 alkyl.
In another aspect, the invention provides compounds of Formula (XX-2a) or
Formula
(XX-2b), wherein
L is -(C2-C4 alkyl)-;
Rlo is H, C1-C4 alkyl optionally substituted with one group that is selected
from a 5 or 6
membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, or
piperidinyl optionally substituted with C1-C3 alkyl;
R17 is OH, -O-C2-C4 alkanoyl, -C02Rlo, or -(C1-C4 alkyl)-CO2Rlo;
R18 is H; and
R2o is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; R17 is Cl-C4 alkyl,
C1-C4 alkoxy,
or halogen; and R18 is H, C1-C4 alkyl, C1-C4 alkoxy, OH, or -O-C2-C4 alkanoyl.
Preferably,
one of R17 or R18 is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; R17 is halogen, halo
CI-C4 alkyl,
or halo C1-C4 alkoxy; and R18 is H, C1-C4 alkyl, C1-C4 alkoxy, OH. Preferably,
one of R17 or
R18 is at the 4-position of the phenyl group.
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In another aspect, the invention provides compounds of either of Formula (XX-
2a) or
Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; Rl7 is OH, or -O-C2-C4
alkanoyl; and Rl$ is
H, C1-C4 alkyl, C1-Cd alkoxy, or OH. Preferably, one of R17 or R18 is at the 4-
position of the
phenyl group.
In yet another aspect, the invention provides compounds of either of Formula
(XX-2a)
or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; R17 is OH, or -O-C2-C4
alkanoyl; and R18
is O-C2-C4 alkanoyl, halogen, halo C1-C4 alkyl, or halo Cl-C4 alkoxy.
Preferably, one of R17
or R18 is at the 4-position of the phenyl group.
In still another aspect, the invention provides coinpounds of either of
Formula (XX-
2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; Rlo is H, C1-C4 alkyl
optionally
substituted with one group that is selected from morpholinyl, pyrrolidinyl,
and OH,
quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Cl-C3
alkyl; R17 is -
CO2R10, or-(C1-C4 alkyl)-CO2Rlo; and R18 is C1-C4 alkyl, C1-C4 alkoxy, or OH.
Preferably,
one of RI7 or R18 is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; RIO is H, Cl-C4
alkyl optionally
substituted with one group that is selected from morpholinyl, pyrrolidinyl,
and OH,
quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Cl-C3
alkyl; R17 is
-C02Rlo; and RI$ is C1-C4 alkyl (such as methyl), C1-C4 alkoxy (such as
methoxy), or OH.
Preferably, one of Rl7 or R18 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula
(XX-
2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; Rlo is H, C1-C4 alkyl
optionally
substituted with one group that is selected from morpholinyl, pyrrolidinyl,
and OH,
quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-C3
alkyl; R17 is-(C1-
C4 alkyl)-CO2Rlo; and R18 is C1-C4 alkyl, C1-C4 alkoxy, or OH. Preferably, one
of R17 or R18
is at the 4-position of the phenyl group.
In yet another aspect, the invention provides compounds of either of Formula
(XX-2a)
or Formula (XX-2b), wherein
L is -(C2-C4 alkyl)-;
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Rlo is H, C1-C4 alkyl optionally substituted with one group that is selected
from a 5 or 6
membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, or
piperidinyl optionally substituted with C1-C3 alkyl;
R17 is OH, -O-C2-C4 alkanoyl, -C02Rlo, or -(C1-C4 alkyl)-CO2Rlo; and
R18 is H; and
R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein
L is -(C2-C4 alkyl)-;
Rlo is H, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with
C1-C3 alkyl;
R17 is OH, -O-C2-C4 alkanoyl, -C02Rlo, or -(C1-C4 alkyl)-COZRIo; and
R18 is H; and
R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; Rlo is H; R17 is -
C02RIo, or -(C1-
C4 alkyl)-CO2Rlo; and R18 is H.
In still another aspect, the invention provides compounds of either of Formula
(XX-
2a) or Formula (XX-2b), wherein L is -(C2-C4 alkyl)-; R17 is OH, or -O-C2-C4
alkanoyl; and
R18 is H, methyl, methoxy, OH, F, or Cl.
In another aspect, the invention provides compounds of either of Formula (XX-
2a) or
Formula (XX-2b), wherein
L is -(C1-C3 alkyl)-C(O)NR9-;
Rlo is H, C1-C4 alkyl optionally substituted with one group that is selected
from a 5 or 6
membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, or
piperidinyl optionally substituted with C1-C3 alkyl;
R17 is OH, -O-C2-C4 alkanoyl, -C02Rlo, or -(Cl-C4 alkyl)-CO2Rlo;
Rls is H; and
Rao is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(CI-CZ alkyl)-C(O)NR9-; R17 is C1-C4
alkyl, C1-
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C4 alkoxy, or halogen; and R18 is H, Cl-C4 alkyl, CI-C4 alkoxy, OH, or -O-C2-
C4 alkanoyl.
Preferably, one of R17 or R1$ is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(Cl-Ca alkyl)-C(O)NR9-; R17 is
halogen, halo
C1-C4 alkyl, or halo C1-C4 alkoxy; and Rl$ is H, C1-C4 alkyl, C1-C4 alkoxy,
OH. Preferably,
one of RI7 or R18 is at the 4-position of the phenyl group.
In another aspect, the invention provides compounds of either of Formula (XX-
2a) or
Formula (XX-2b), wherein L is -(C1-C2 alkyl)-C(O)NR9-; R17 is OH, or -O-Ca-C4
alkanoyl;
and R18 is H, C1-C4 alkyl, C1-C4 alkoxy, or OH. Preferably, one of R17 or R18
is at the 4-
position of the phenyl group.
In yet another aspect, the invention provides compounds of either of Formula
(XX-2a)
or Formula (XX-2b), wherein L is -(C1-C2 alkyl)-C(O)NR9-; R17 is OH, or -O-C2-
C4
alkanoyl; and R18 is O-C2-C4 alkanoyl, halogen, halo CI-C4 alkyl, or halo C1-
C4 alkoxy.
Preferably, one of R17 or R18 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula
(XX-
2a) or Formula (XX-2b), wherein L is -(C1-C2 alkyl)-C(O)NR9-; Rlo is H, C1-C4
alkyl
optionally substituted with one group that is selected from morpholinyl,
pyrrolidinyl, and
OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-C3
alkyl; R17 is -
CO2Rlo, or-(Cl-C4 alkyl)-CO2R10i and R18 is C1-C4 alkyl, C1-C4 alkoxy, or OH.
Preferably,
one of R17 or R18 is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(C1-C2 alkyl)-C(O)NR9-; Rlo is H, C1-
C4 alkyl
optionally substituted with one group that is selected from morpholinyl,
pyrrolidinyl, and
OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with C1-C3
alkyl; R17 is
-CO2Rlo; and Rlg is C1-C4 alkyl (such as methyl), C1-C4 alkoxy (such as
methoxy), or OH.
Preferably, one of R17 or R18 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula
(XX-
2a) or Formula (XX-2b), wherein L is -(C1-C2 alkyl)-C(O)NR9-; Rln is H, C1-C4
alkyl
optionally substituted with one group that is selected from morpholinyl,
pyrrolidinyl, and
OH, quinuclidinyl, -C(O)NHZ, or piperidinyl optionally substituted with CI-C3
alkyl; Rl7 is-
(C1-C4 alkyl)-CO2Rlo; and R18 is C1-C4 alkyl, C1-C4 alkoxy, or OH. Preferably,
one of R17 or
R18 is at the 4-position of the phenyl group.
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In yet another aspect, the invention provides compounds of either of Formula
(XX-2a)
or Formula (XX-2b), wherein
L is -(Cl-C2 alkyl)-C(O)NR9-;
Rlo is H, Cl-C4 alkyl optionally substituted with one group that is selected
from a 5 or 6
membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, or
piperidinyl optionally substituted with C1-C3 alkyl;
Rl7 is OH, -O-C2-C4 alkanoyl, -COzRIo, or -(CI -C4 alkyl)-CO2Rlo; and
R18 is H; and
R2o is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein
L is -(C1-C2 alkyl)-C(O)NR9-;
Rlo is H, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with
C1-C3 alkyl;
R17 is OH, -O-C2-C4 alkanoyl, -CO2Rlo, or -(C1-C4 alkyl)-CO2R1O; and
R18 is H; and
R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(C1-C2 alkyl)-C(O)NR9-; Rlo is H;
R17 is
-CO2RIo, or -(C1-C4 alkyl)-CO2Rlo; and Rl$ is H.
In still another aspect, the invention provides compounds of either of Formula
(XX-
2a) or Formula (XX-2b), wherein L is -(C1-C3 alkyl)-C(O)NR9-; R17 is OH, or -O-
C2-C4
alkanoyl; and Rl$ is H, methyl, methoxy, OH, F, or Cl.
In yet still another aspect, the invention provides compounds of Formula (XX-
4a) or
Formula (XX-4b), i.e., compounds of Formula (XX-2a) or Formula (XX-2b) having
the
formula:
R9
~ N ~
'O O N \O ' ~ R~~
~43
N
R2NzN H 0
a
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XX-4a, or
Rs
N
O O N~ \ / R17
' 4 3
HN I N
H R2o
, H2N
XX-4b.
In still yet another aspect, the invention provides compounds of Formula (XX-
4a) or
Formula (XX-4b), wherein R17 is -C02Rlo, or -(Cl-C4 alkyl)-CO2Rlo; R9 is H or
methyl; and
Rlo is H, C1-C4 alkyl optionally substituted with one group that is selected
from morpholinyl,
pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally
substituted with Cl-
C2 alkyl.
In yet still another aspect, the invention provides compounds of Formula (XX-
5a) or
Formula (XX-5b), i.e., compounds of Formula (XX-2a) or Formula (XX-2b) having
the
formula:
N ~ / RV
\O O
~ 4 3
N ~ N' '
H R20
HZN
a
XX-5a or
N ~ / RV
O O C43
HN I N '
R20
HZN
a
XX-5b.
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In still yet another aspect, the invention provides compounds of Formula (XX-
5a) or
Formula (XX-5b), wherein R17 is -C02R,o, or -(Cl-C4 alkyl)-COZRIO; R9 is H or
methyl; and
RIo is H, Cl-C4 alkyl optionally substituted with one group that is selected
from morpholinyl,
pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally
substituted with C1-
CZ alkyl.
In another aspect, the invention provides compounds of Formula (XX-2a) or
Formula
(XX-2b), wherein
L is -(C1-C4 alkyl)-NR9C(O)-;
Rlo is H, C1-C4 alkyl optionally substituted with one group that is selected
from a 5 or 6
membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, or
piperidinyl optionally substituted with Cl-C3 alkyl;
R17 is OH, -O-C2-C4 alkanoyl, -C02Rlo, or -(Cl-C4 alkyl)-C02Rlo;
Rl$ is H; and
R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(C1-C4 alkyl)-NR9C(O)-; R17 is C1-C4
alkyl, C1-
C4 alkoxy, or halogen; and R18 is H, C1-C4 alkyl, C1-C4 alkoxy, OH, or -O-Cz-
C~ alkanoyl.
Preferably, one of R17 or R18 is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(Cl-C4 a1ky1)-NR9C(O)-; R17 is
halogen, halo
C1-C4 alkyl, or halo C1-C4 alkoxy; and R18 is H, Cl-C4 alkyl, C1-C4 alkoxy,
OH. Preferably,
one of R17 or R18 is at the 4-position of the phenyl group.
In another aspect, the invention provides compounds of either of Formula (XX-
2a) or
Formula (XX-2b), wherein L is -(C1-C4 alkyl)-NR9C(O)-; R17 is OH, or -O-C2-C4
alkanoyl;
and R18 is H, C1-C4 alkyl, C1-C4 alkoxy, or OH. Preferably, one of RI7 or R18
is at the 4-
position of the phenyl group.
In yet another aspect, the invention provides compounds of either of Formula
(XX-2a)
or Formula (XX-2b), wherein L is -(C1-C4 alkyl)-NRgC(O)-; R17 is OH, or -O-C2-
C4
alkanoyl; and R18 is O-C2-C4 alkanoyl, halogen, halo CI-C4 alkyl, or halo C1-
C4 alkoxy.
Preferably, one of R17 or R18 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula
(XX-
2a) or Formula (XX-2b), wherein L is -(C1-C4 alkyl)-NR9C(O)-; Rlo is H, C1-C4
alkyl
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optionally substituted with one group that is selected from morpholinyl,
pyrrolidinyl, and
OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Cl-C3
alkyl; R17 is -
C02Rlo, or -(C1-C4 alkyl)-CO2Rlo; and R18 is C1-C4 alkyl, Cl-C4 alkoxy, or OH.
Preferably,
one of R17 or R18 is at the 4-position of the phenyl group.
In still yet another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(CI-C4 alkyl)-NR9C(O)-; Rlo is H, C1-
C4 alkyl
optionally substituted with one group that is selected from morpholinyl,
pyrrolidinyl, and
OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Cl-C3
alkyl; R17 is
-CO2Rlo; and R18 is C1-C4 alkyl (such as methyl), Cl-C4 alkoxy (such as
methoxy), or OH.
Preferably, one of R17 or R18 is at the 4-position of the phenyl group.
In still another aspect, the invention provides compounds of either of Formula
(XX-
2a) or Formula (XX-2b), wherein L is -(C1-C4 alkyl)-NR9C(O)-; Rlo is H, C1-C4
alkyl
optionally substituted with one group that is selected from morpholinyl,
pyrrolidinyl, and
OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with Cl-C3
alkyl; R17 is-
(CI-C4 alkyl)-CO2Rio; and R18 is C1-C4 alkyl, C1-C4 alkoxy, or OH. Preferably,
one of R17 or
R18 is at the 4-position of the phenyl group.
In yet another aspect, the invention provides compounds of either of Formula
(XX-2a)
or Formula (XX-2b), wherein
L is -(C1-C4 alkyl)-NR9C(O)-;
Rlo is H, C1-C4 alkyl optionally substituted with one group that is selected
from a 5 or 6
membered monocyclic heterocycloalkyl ring, and OH, quinuclidinyl, -C(O)NH2, or
piperidinyl optionally substituted with C1-C3 alkyl;
R17 is OH, -O-C2-C4 alkanoyl, -CO2R10, or-(C1-C4 alkyl)-CO2R10;
R18 is H; and
R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
In yet still another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein
L is -(C1-C4 alkyl)-NR9C(O)-;
RlO is H, quinuclidinyl, -C(O)NH2, or piperidinyl optionally substituted with
C1-C3 alkyl;
R17 is OH, -O-C2-C4 alkanoyl, -CO2Rlo, or -(CI -C4 alkyl)-CO2R10; and
Rl8 is H; and
R20 is methoxy or ethoxy (in one aspect, methoxy is preferred.)
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In yet still another aspect, the invention provides compounds of either of
Formula
(XX-2a) or Formula (XX-2b), wherein L is -(Cl-C4 alkyl)-NR9C(O)-; Rlo is H;
R17 is -
C02Rlo, or -(CI-C4 alkyl)-CO2Rlo; and R18 is H.
In still another aspect, the invention provides compounds of either of Formula
(XX-
2a) or Formula (XX-2b), wherein L is -(C1-C4 alkyl)-NR9C(O)-; R17 is OH, or -O-
C2-C4
alkanoyl; and R18 is H, methyl, methoxy, OH, F, or Cl.
In yet still another aspect, the invention provides compounds of Formula (XX-
6a) or
Formula (XX-6b), i.e., compounds of Formula (XX-2a) or Formula (XX-2b) having
the
formula:
/ R17
~O O N ~ I
4 g
" - O
N
H R20
HZN
a
XX-6a, or
7
a R1
O O N HN '~ 3 -rr
H ~N" R O
2o
H2N
a
XX-6b.
In still yet another aspect, the invention provides compounds of Formula (XX-
6a) or
Formula (XX-6b), wherein R17 is -COzRIo, or -(Cl-Cd alkyl)-CO2Rlo; R9 is H or
methyl; and
Rlo is H, Cl-C4 alkyl optionally substituted with one group that is selected
from morpholinyl,
pyrrolidinyl, and OH, quinuclidinyl, -C(O)NH2, or piperidinyl optionally
substituted with Cl-
C2 alkyl.
In yet another aspect, the invention provides compounds of Formula (XX-6a) or
Formula (XX-6b), wherein R17 is -COzRIo, and Rlo is H, or C1-C4 alkyl
optionally substituted
with one group that is selected from morpholinyl, pyrrolidinyl. and OH,
In still another aspect, the invention provides compounds of Formula (XX-6a)
or
Formula (XX-6b), wherein R17 is -C02Rlo, and Rlo is quinuclidinyl, -C(O)NH2,
or
piperidinyl optionally substituted with C1-C2 alkyl.
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In a further aspect, the invention provides compounds of Formula Formula (XX-
6a)
or Formula (XX-6b), wherein R17 is -C02Rlo, and Rlo is H or piperidinyl
substituted with Cl-
Ca alkyl.
The invention further provides methods for treating emesis, dyspepsia,
gastroparesis,
constipation, intestinal pseudo-obstruction, gastroesophageal reflux, or post-
operative ileus,
the method comprising administering a therapeutically effective amount of a
compound or
salt according of Formulae Xa and Xb to a patient in need of such treatment.
The subject invention provides compounds that are more susceptible to
degradation
by serum and/or cytosolic esterases than cisapride, thus avoiding the adverse
effects
associated with metabolism by cytochrome P450.
Advantageously, the therapeutic compounds of the subject invention are stable
in
storage but have a relatively short half-life in the physiological
environment; therefore, the
compounds of the subject invention can be used with a lower incidence of side
effects and
toxicity.
In a preferred aspect of the subject invention, therapeutic stereoisomeric
compounds
are provided that are useful in the treatment of gastroesophageal reflux
disease and that
contain an ester group, which is susceptible to degradation by esterases,
thereby breaking
down the compound and facilitating its efficient removal from the treated
individual. In a
preferred aspect, the therapeutic stereoisomeric compounds are metabolized by
the Phase I
drug detoxification system.
A further aspect of the subject invention pertains to the breakdown products
(preferably metabolic breakdown products, i.e., metabolites, generally acids
of parent esters)
that are produced when the therapeutic compounds of the subject invention are
acted upon by
an esterase. The presence of these breakdown products in the urine or serum
can be used to
monitor the rate of clearance of the therapeutic compound from a patient.
Degradation of the compounds of the subject invention by esterases is
particularly
advantageous for drug metabolism because these enzymes are ubiquitously
distributed and
their activity is not dependent on age, gender, or disease state to the same
extent as oxidative
hepatic drug metabolism.
The subject invention further provides methods of treating disorders, such as
gastroesophageal reflux disease comprising the administration of a
therapeutically effective
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amount of at least one stereoisomeric structural and/or functional analog of
cisapride to an
individual in need of treatment. In a specific aspect, the subject invention
provides
stereoisomeric structural and/or functional analogs of cisapride and
pharmaceutical
compositions of these esterified compounds.
The subject invention further provides materials and methods for the treatment
of
emesis and such other conditions, including but not limited to dyspepsia,
gastroparesis,
constipation, and intestinal pseudo-obstruction, while substantially reducing
adverse effects
associated with the administration of cisapride.
In a preferred aspect of the subject invention, therapeutic stereoisomeric
compounds
are provided which are useful in the treatment of gastroesophageal reflux,
dyspepsia,
gastroparesis, constipation, post-operative ileus, and intestinal pseudo-
obstruction and which
contain an ester group which is acted upon by esterases thereby breaking down
the compound
and facilitating its efficient removal from the treated individual.
The subject invention further provides methods of synthesizing the unique and
advantageous compounds of the subject invention. Particularly, methods of
producing and
purifying such stereoisomeric compounds are taught. Methods of adding such
ester moieties
and of producing and purifying stereoisomers, are well known to the skilled
artisan and can
be readily carried out utilizing the guidance provided herein.
Preferred Compounds
In a preferred aspect, the present invention provides isolated stereoisomers
of
Compound I, which contains three chiral centers.
O N
CI 4 3 O
X H N
H2N H O
quinuclidin-3-yl 6-(4-(6-amino-5-chloro-2-oxo-1,2-
dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-
yl)hexanoate Ia
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O N If 3,
CI N 4 3 O N
H
H2N N i
quinuclidin-3-yl 6-(4-(6-amino-5-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-1-yl)hexanoate lb
Compound Ia and lb
Two of the chiral centers exist in cisapride and norcisapride and are in the
cis
configuration in the active drugs:
O NH
F
O N
CI ~ N
CI ~ N H
I H O
HzN S i o H2N / i
(:L)-Cisapride (:L)-Norcisapride
Thus, for example, pharmaceutically active norcisapride is a racemic mixture
of the
two cis enantiomers:
O NH O NH
CI ~ CI N~~,,.=
I H H =
H2N ~ O O H2N O O~
I
(-) Norcisapride (+) Norcisapride
In one aspect, the current invention is particularly concerned with the
configuration at
the third chiral center, in the quinuclidinol moiety, of the structural and/or
functional analogs
of cisapride. This group is eliminated in the conversion to the acid
metabolite referred to
herein as Compounda IIa and Ilb:
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OH
O N 3,
CI N J4 3 O
X
H2N H O
6-(4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-
carboxamido)-3-inethoxypiperidin-1-yl)hexanoic acid IIa
OH
O N 3,
CI 4 3 O
H
ON-I
H2N N O
1
6-(4-(6-amino-5-chloro-2-methoxynicotinamido)-3-
methoxypiperidin-1-yl)hexanoic acid IIb
Compound IIa and IIb
The preferred Compound Ia and Ib stereoisomers of the present invention are
made by
conjugating R or S quinuclidinol to a structural/functional analog of (+)- or
(-)-norcisapride
characterized by the substitution of a pyridyl or pyridonyl moiety for the
phenyl moiety of
norcisapride, giving Compounds IIIa, IIIb, IVa, IVb, Va, Vb, Vla and VIb.
Oo,,
O N (R)'
X
CI N (R) O ON
H2N H O
(R)-quinuclidin-3-yl 6-((3R,4S)-4-(6-amino-5-chloro-2-oxo-1,2-
dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-
yl)hexanoate IIIa
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O N
CI (R) O (R) eN
N
H
H2N N O O
1
(R)-quinuclidin-3-yl 6-((3R,4,S)-4-(6-amino-5-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-1-yl)hexanoate IIIb
Compounds IIIa and IIIb: (-)(R -compounds of Ia and lb
O [(3R
CI NO
(
R)
eN
H =
Q\
H2N H O
(R)-quinuclidin-3-y16-((3S,4R)-4-(6-amino-5-chloro-2-oxo-1,2-
dihydropyridine-3 -carboxamido)-3-methoxypiperidin-l-
yl)hexanoate IVa
O
(R)
N (R)
CI
~
( N
H =
H2N N O O
1
(R)-quinuclidin-3-yl 6-((3 S,4R)-4-(6-amino-5-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-1-yl)hexanoate IVb
Compounds IVa and IVb: (+)(R -com op unds
O N
CI N (R) O N
I
O\
H2N H O
(S)-quinuclidin-3-y16-((3R,4S)-4-(6-amino-5-chloro-2-oxo-1,2-
dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-
yl)hexanoate Va
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O N O
CI (R) O
N (~ N
H
o
H2N N i
(S)-quinuclidin-3 -y16-((3R,4S)-4-(6-amino-5-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-1-yl)hexanoate Vb
Compounds Va and Vb: (-)(S)-compounds
O (~
N
CI ~ ~~,,,== (R~~ O
H N
H2N x
H O
(S)-quinuclidin-3-yl 6-((3S,4R)-4-(6-amino-5-chloro-2-oxo-1,2-
dihydropyridine-3-carboxamido)-3-methoxypiperidin-l-
yl)hexanoate VIa
O N O
(R~ (S)
cl S) ~ o
NN
H =
H2N N~ O O~
1
(S)-quinuclidin-3 -y16-((3S,4R)-4-(6-amino-5-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-1-yl)hexanoate VIb
Compounds VIa and VIb: (+)(S)-compounds
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In a preferred aspect, the subject invention pertains to stereoisomerically
isolated
compounds, and compositions comprising the compounds. The isolated
stereoisomeric forms
of the compounds of the invention are substantially free from one another
(i.e., in
stereoisomeric excess). In other words, the "R" forms of the compounds are
substantially free
from the "S" forms of the compounds and are, thus, in stereoisomeric excess of
the "S"
forms. Conversely, "S" forms of the compounds are substantially free of "R"
forms of the
compounds and are, thus, in stereoisomeric excess of the "R" forms. In one
aspect of the
invention, the isolated stereoisomeric compounds are in at least about 80%
stereoisomeric
excess. In a preferred aspect, the compounds are in at least about 90%
stereoisomeric excess.
In a more preferred aspect, the compounds are in at least about 95%
stereoisomeric excess. In
an even more preferred aspect, the compounds are in at least about 97.5%
stereoisomeric
excess. In a most preferred aspect, the compounds are in at least about 99%
stereoisomeric
excess. Similarly, the "(+)" and "(-)" forms of the compounds are also
provided in
stereoisomeric excess.
As described herein, the various stereoisomers have particular unexpected
properties
that, advantageously, can be used to customize treatment for a particular set
of circumstances.
Thus, for example, compounds containing the (3'R)-isomer in the quinuclidinyl
ester moiety,
i.e., compounds IIIa, IIIb, IVa and IVb, can be rapidly metabolized by
esterases in human
plasma, whereas compounds containing the (3'S)-isomer of quinuclidinol, i.e.,
compounds
Va and Vb and Vla and VIb, can undergo a much slower metabolism.
Thus, the (3'R)-isomers of compounds Ia and Ib can be used, for example, when
a
short-duration of action is preferred, for example stimulation of gastric
motility in an acute
episode, such as pulsatile administration to patients with acute
gastroparesis, or in acute
gastroesophageal reflux. Another advantage of rapid metabolism by esterases to
an
substantially less active metabolites, i.e., compound IIa or IIb, is the very
low probability of
drug-drug interactions and toxicity. Therefore these shorter-acting (R)-
isomers can be
advantageously used, for example, as intravenous formulations for treating
gastroesophageal
reflux in premature newborn who notoriously are not able to metabolize drugs
as well as
adults because their CYP450 system is not fully developed. In these newborn, a
drug having
rapid metabolism by a system other than CYP450, e.g., esterases, is a great
advantage. On the
other hand, the (3'S)-isomers of compound I are best used in chronic
situations of the same
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ailments, for example gastroparesis in diabetic patients or cancer patients
under opiates, or in
chronic gastroesophageal reflux in patients who need 24-hour coverage.
In addition to their differences in metabolic fate, these separate isomers
also can have
different binding affinities for the 5-HT4 receptor, thus suggesting different
activities as well,
and therefore different therapeutic uses.
As a conclusion to these considerations: when the 3 and 4 positions are cis
relative to
each other, each compound (e.g., compound Ia) is a mixture of 4 isomers,
consisting of 2
pairs of enantiomers. The first pair of enantiomers is (+)(R)-compound Ia and
(-)(S)-
compound Ia (compounds IVa and Va, respectively), the second pair of
enantiomers is (-)(R)-
compound I and (+)(S)-compound I (compounds IIIa and VIa, respectively).
Within each
enantiomeric pair, each separate enantiomer has different properties regarding
both their rate
of hydrolysis by esterases and regarding their affinity at the 5-HT4 receptor.
These different
properties give them separately advantageous therapeutic uses which are not
interchangeable,
i.e., which are specific to each isomer, and which are not applicable to the
racemic mixture.
These differences of affinity at the receptor and these differences in
metabolic rates are not
predictable and neither is it possible to dissect these properties when
testing the racemic
mixture.
Definitions
As used herein, the term "alkyl" includes those alkyl groups of a designed
number of
carbon atoms. Alkyl groups may be straight, or branched. Examples of "alkyl"
include
methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl,
hexyl, heptyl, 3-
ethylbutyl, and the like. If the number of carbon atoms is not specified, the
subject "alkyl"
moiety has from 1 to 6 carbons.
The term "alkoxy" represents an alkyl group of indicated number of carbon
atoms
attached to the parent molecular moiety through an oxygen bridge. Examples of
alkoxy
groups include, for example, methoxy, ethoxy, propoxy and isopropoxy.
By "aryl" is meant an aromatic carbocyclic group having a single ring (e.g.,
phenyl)
that is optionally fused or otherwise attached to other aromatic hydrocarbon
rings or non-
aromatic hydrocarbon rings. "Aryl" includes multiple condensed rings in which
at least one is
aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl), wherein each ring is
optionally mono-,
di-, or trisubstituted with the groups identified below, as well as multiple
rings that are not
fused, such as, for example, biphenyl or binaphthyl. Preferred aryl groups of
the present
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invention are phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl,
dihydronaphthyl, fluorenyl,
tetralinyl or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. More preferred are
phenyl,
biphenyl, and naphthyl. Most preferred is phenyl. The aryl groups herein are
unsubstituted or,
as specified, substituted in one or more substitutable positions with various
groups. For
example, such aryl groups may be optionally substituted with, for example, Cl-
C6 alkyl, Cl-
C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-C6)alkylamino, di(C1-
C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy,
amino(C1-
C6)alkyl, mono(Cl-C6)alkylamino(C1-C6)alkyl or di(C1-C6)alkylamino(C1-
C6)alkyl.
The term "haloalkoxy" refers to an alkoxy group substituted with at least one
halogen
atom and optionally further substituted with at least one additional halogen
atom, where each
halogen is independently F, Cl, Br or I. Preferred halogens are F or Cl.
Preferred haloalkoxy
groups contain 1-6 carbons, more preferably 1-4 carbons, and still more
preferably 1-2
carbons. "Haloalkoxy" includes perhaloalkoxy groups, such as OCF3 or OCF2CF3.
The term "heteroaryl" refers to an aromatic ring system containing at least
one
heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl ring may
be fused or
otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic
hydrocarbon
rings or heterocycloalkyl rings. Examples of heteroaryl groups include, for
example, pyridyl,
pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl,
pyrazinyl, isoindolyl,
isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,
pyrazolyl,
oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,
benzofuranyl,
furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, benzo[1,4]oxazinyl,
triazolyl, tetrazolyl,
isothiazolyl, naphthyridinyl, isochromanyl, chromanyl,
tetrahydroisoquinolinyl, isoindolinyl,
isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,
benzoxazolyl,
pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl,
benzodioxolyl,
triazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl,
dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl,
benzopyranyl, benzothiopyranyl, chromonyl, chromanonyl, pyridinyl-N-oxide,
tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,
dihydroisoquinolinonyl,
dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl,
benzoxazolinonyl,
pyrrolyl N-oxide,, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-
oxide, quinolinyl
N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl
N-oxide,
quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-
oxide, oxazolyl
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N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide,
benzothiazolyl N-oxide,
benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-
oxide,
triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide,
benzothiopyranyl S,S-
dioxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl,
indolyl, pyrrolyl,
furanyl, thienyl, and imidazolyl. More preferred heteroaryl groups include
pyridyl, pyrrolyl,
and indolyl. The heteroaryl groups herein are unsubstituted or, as specified,
substituted in one
or more substitutable positions with various groups. For example, such
heteroaryl groups may
be optionally substituted with, for example, Cl-C6 alkyl, C1-C6 alkoxy,
halogen, hydroxy,
cyano, nitro, amino, mono(CI-C6)alkylamino, di(Cl-C6)alkylamino, C2-C6alkenyl,
C2-
C6alkynyl, Cl-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono(Cl-
C6)alkylamino(C 1-C6)alkyl or di(C 1-C6)alkylamino(C 1-C6)alkyl.
The term "heterocycloalkyl" refers to a ring or ring system containing at
least one
heteroatom that is preferably selected from nitrogen, oxygen, and sulfur,
wherein said
heteroatom is in a non-aromatic ring. The heterocycloalkyl ring is optionally
fused to or
otherwise attached to other heterocycloalkyl rings and/or non-aromatic
hydrocarbon rings
and/or phenyl rings. Preferred heterocycloalkyl groups have from 3 to 7
members. More
preferred heterocycloalkyl groups have 5 or 6 members. Examples of
heterocycloalkyl groups
include, for example, aza-bicyclo[2.2.2]octyl (in each case also
"quinuclidinyl" or a
quinuclidine derivative), aza-bicyclo[3.2.1]octyl, morpholinyl,
thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,
homopiperazinyl,
pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl,
tetrahydrothienyl,
homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-
dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,
dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,
tetrahydrothienyl S-
oxide, tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide.
Preferred
heterocycloalkyl groups include aza-bicyclo[2.2.2]octyl, aza-
bicyclo[3.2.1]octyl, piperidinyl,
piperazinyl, pyrrolidinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl,
morpholinyl, and
imidazolidinyl. More preferred are aza-bicyclo[2.2.2]octyl, aza-
bicyclo[3.2.1]octyl,
piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, and morpholinyl. The
heterocycle
groups herein are unsubstituted or, as specified, substituted in one or more
substitutable
positions with various groups. For example, such heterocycle groups may be
optionally
substituted with, for example, C1-C6 allcyl, Cl-C6 alkoxy, halogen, hydroxy,
cyano, nitro,
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amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, C2-C6 alkenyl, C2-C6
alkynyl, C1-C6
haloalkyl, Cl-C6 haloalkoxy, amino(CI-C6)alkyl, mono(Cl-C6)alkylamino(CI-
C6)alkyl, di(C1-
C6)alkylamino(C1-C6)alkyl or =0.
The term "pharmaceutically acceptable salts" or "a pharmaceutically acceptable
salt
thereof' refer to salts prepared from pharmaceutically acceptable non-toxic
acids or bases
including inorganic acids and bases and organic acids and bases. Since the
'compound of the
present invention is basic, salts may be prepared from pharmaceutically
acceptable non-toxic
acids. Suitable pharmaceutically acceptable acid addition salts for the
compound of the
present invention include acetic, benzenesulfonic (besylate), benzoic,
camphorsulfonic, citric,
ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,
isethionic, lactic,
maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,
phosphoric,
succinic, sulfuric, tartaric, p-toluenesulfonic, and the like. Preferred acid
addition salts are the
chloride and sulfate salts. In the most preferred aspect, structural and/or
functional analogs of
cisapride are administered as the free base or as the mono or dihydrochloride
salt.
As used herein, the terms "treatment" and "treating" encompass prophylactic
administration of the compound or a pharmaceutical composition comprising the
compound
("prophylaxis") as well as remedial therapy to reduce or eliminate a disease
or disorder
mentioned herein. Prophylactic administration is intended for prevention of
disorders and
may be used to treat a subject that is at risk of having or suffering from one
or more disorders
mentioned herein. Thus, as used herein, the term "treatment", or a derivative
thereof,
contemplates partial or complete inhibition of the stated disease state, when
an active
ingredient of the invention is administered prophylactically or following the
onset of the
disease state for which such active ingredient of the is administered.
"Prophylaxis" refers to
administration of the active ingredient(s) to a mammal to protect the mammal
from any of the
disorders set forth herein, as well as others.
The term "therapeutically effective amount" refers to an amount necessary to
achieve
a derived therapeutic effect such as: 1) an amount sufficient to alleviate
reflux disease, 2) an
amount sufficient to alleviate nausea and vomiting, or 3) an amount sufficient
to alleviate a
condition caused by gastrointestinal motility dysfunction. Therapeutically
effective amounts
of structural and/or functional analogs of cisapride are encompassed by the
above-described
dosage amounts and dose frequency schedule.
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A "mammal" may be, for example, a mouse, rat, pig, horse, rabbit, goat, cow,
cat,
dog, or human. In a preferred aspect, the mammal is a human.
The term "individual(s)" is defined as a single mammal to which is
administered a
compound of the present invention. The mammal may be, for example, a mouse,
rat, pig,
horse, rabbit, goat, cow, cat, dog, or human. In a preferred aspect, the
individual is a human.
The term "esterified cisapride" means therapeutic compounds of the subject
invention
that are structural and/or functional analogs of cisapride, which contain a
hydrolysable group,
generally an ester, that does not detract from the ability of these compounds
to provide a
therapeutic benefit, but which makes these compounds more susceptible to
degradation by
hydrolases, particularly serum and/or cytosolic esterases, and which reduces
the interaction of
the cytochrome P-450 drug detoxification system with the cisapride compounds.
Esterase-
mediated metabolism of esterified cisapride compounds reduces the role of the
cytochrome P-
450 drug detoxification system in cisapride metabolism and reduces or
eliminates adverse
effects caused by cisapride.
The term "structural analog" as used herein means that a described compound
shares
structural characteristics with a parent compound. For example, a structural
analog of
cisapride may share one or more structural characteristics with the parent
cisapride
compound, such as a substituted aryl ring connected to a piperdine ring
through an amide
linker, but differ structurally in other ways, such as the inclusion or
deletion of one or more
other chemical moieties. Another example is the substitution of a pyridyl or
pyridonyl ring
for cisapride's phenyl ring.
The term "functional analog" as used herein means that a described compound
shares
a functional characteristic with a parent compound. For example, a functional
analog of
cisapride may share few, if any, structural characteristics with cisapride,
but affect a similar
function, for example, 5-HT4 agonism.
The term "adverse effects" includes, but is not limited to, gastrointestinal
disorders
such as diarrhea, abdominal cramping, and abdominal grumbling; tiredness;
headache;
increased systolic pressure; death; ventricular tachycardia; ventricular
fibrillation; torsades de
pointes; QT prolongation; increased heart rate; neurological and CNS
disorders; and
interaction of cisapride with other drugs given concurrently such as but not
limited to
digoxin, diazepam, ethanol, acenocoumarol, cimetidine, ranitidine,
paracetamol, and
propranolol.
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The term "gastroesophageal reflux disease" as used herein means the incidence
of,
and the symptoms of, those conditions causing the backward flow of the stomach
contents
into the esophagus.
The terms "eliciting an anti-emetic effect" and "anti-emetic therapy" as used
herein
mean providing relief from or preventing the symptoms of nausea and vomiting
induced
spontaneously or associated with emetogenic cancer chemotherapy or irradiation
therapy.
The term "treating a condition caused by gastrointestinal motility
dysfunction" as used
herein means treating the symptoms and conditions associated with this
disorder which
include, but are not limited to, gastroesophageal reflux disease, dyspepsia,
gastroparesis,
constipation, post-operative ileus, and intestinal pseudo-obstruction.
The term "prokinetic" as used herein means the enhancement of peristalsis in,
and
thus the movement through the gastrointestinal tract.
The term "dyspepsia" as used herein means a condition characterized by an
impairment of the power or function of digestion that can arise as a symptom
of a primary
gastrointestinal dysfunction or as a complication due to other disorders such
as appendicitis,
gallbladder disturbances, or malnutrition.
The term "gastroparesis" as used herein means a paralysis of the stomach
brought
about by a motor abnormality in the stomach or as a complication of diseases
such as
diabetes, progressive systemic sclerosis, anorexia nervosa, or myotonic
dystrophy.
The term "constipation" as used herein means a condition characterized by
infrequent
or difficult evacuation of feces resulting from conditions such as lack of
intestinal muscle
tone or intestinal spasticity.
The term "post-operative ileus" as used herein means an obstruction in the
intestine
due to a disruption in muscle tone following surgery.
The term "intestinal pseudo-obstruction" as used herein means a condition
characterized by constipation, colicky pain, and vomiting, but without
evidence of physical
obstruction.
Preparation of Compounds
The chemical synthesis of various analogs of cisapride can be performed by the
methods described in European Patent Application No. 0,076,530 A2 published
Apr. 13,
1983, U.S. Pat. Nos. 4,962,115 and 5,057,525 and in Van Daele et al., Drug
Development
Res. 8: 225-232 (1986), the disclosures of which are incorporated herein by
reference in their
47
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WO 2007/005951 PCT/US2006/026166
entireties. Such syntheses can be modified, for example, by the incorporation
of an ester
group at a point convenient in the synthesis and by the substitution of an
optionally
0 0
R1~ R1~ N>~
N~
H
H
N
substituted pyridyl- R2 "N~ OR3 or pyridonyl-containing R2 ll H 0
0
cl /X
H
moiety for the substituted phenyl moiety H2N OCH3 of native cisapride.
Exemplary, non-limiting synthesis schemes for certain esterified cisapride
analogs of the
subject invention are provided in WO 01/093849.
The invention is illustrated further by the following examples, which are not
to be
construed as limiting the invention in scope or spirit to the specific
procedures described in
them. Those having skill in the art will recognize that the starting materials
may be varied
and additional steps employed to produce compounds encompassed by the
invention, as
demonstrated by the following examples. Those skilled in the art will also
recognize that it
may be necessary to utilize different solvents or reagents to achieve some of
the above
transformations. In some cases, protection of reactive functionalities may be
necessary to
achieve the above transformations. In general, such need for protecting
groups, as well as the
conditions necessary to attach and remove such groups, will be apparent to
those skilled in
the art of organic synthesis. When a protecting group is employed,
deprotection step may be
required. Suitable protecting groups and methodology for protection and
deprotection such as
those described in Protecting Groups in Organic Synthesis by T. Greene are
well known and
appreciated in the art.
Unless otherwise specified, all reagents and solvents are of standard
commercial
grade and are used without further purification. The appropriate atmosphere to
run the
reaction under, for example, air, nitrogen, hydrogen, argon and the like, will
be apparent to
those skilled in the art.
(R)-quinuclidin-3-yl 6-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3 -
methoxypiperidin-1-yl)hexanoate dihydrochloride salt is a small molecule
structurally and/or
functionally related to the 5-HT4 receptor agonist, cisapride, which has been
designed to
reduce and/or eliminate QT prolongation and CYP450-dependent metabolism at
anticipated
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therapeutically relevant concentrations.
Example 1
Preparation of (R)-quinuclidin-3-y16-((3S,4R)-4-(6-amino-5-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-1-yl)hexanoate, dihydrochloride salt
(also
referred to as N-7505 dihydrochloride)
O N If 3~
CI N j 3 0 N
H
H N N O C~ =2HC1
2 I
N-7505 dihydrochloride contains three chiral centers and can be chemically
synthesized as an enantiomerically and diastereomerically pure product. The
chiral purities of
key starting materials can be assessed by, for example, chiral HPLC or chiral
GC methods to
assure the diastereomeric purity of N-7505 dihydrochloride and other compounds
of the
invention with one or more chiral centers.
An exemplary synthetic process for (R)-quinuclidin-3-y16-((3S,4R)-4-(6-amino-5-
chloro-2-methoxynicotinamido)-3-methoxypiperidin-1-yl)hexanoate
dihydrochloride salt (N-
7505 dihydrochloride) is illustrated below. Racemic 6-amino-5-chloro-2-methoxy-
N-(3-
methoxypiperidin-4-yl)nicotinamide can be used as the starting material for
the synthesis. An
efficient chemical resolution process can be used to produce enantiomerically
pure 6-amino-
5-chloro-2-methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide. The chiral purity
of
enantiomerically pure 6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-4-
yl)nicotinamide can be assessed by a chiral HPLC method to assure greater than
or equal to,
for example, 98% enantiomeric excess (e.e.) quality. Enantiomerically pure 6-
amino-5-
chloro-2-inethoxy-N-(3-methoxypiperidin-4-yl)nicotinamide can then be reacted
with ethyl
6-bromohexanoate under basic conditions to make the corresponding alkylated
ethyl ester. A
transesterification reaction between the ethyl ester and (R)-(-)-3-
quinuclidinol (preferably
greater than or equal to 98% e.e. by chiral GC), is used to make N-7505
dihydrochloride. The
final product is isolated as a dihydrochloride salt.
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L-DBT
O NH (dibenzoyl-L- 0 NH
tartaric acid) CI R S
CI
I \ H H
H2N N OCH3 OCH3 H2N N OCH3
0 OBz
6-amino-5-chloro-2-methoxy-N-(3-
methoxYP~ eridin-4-Y1)nicotinamide Crude (+)-6-amino-5- ~~OH
1P chloro-2-methoxy-N- ~..10
((3S,4R)-3-
methoxypiperidin-4- OBz 0
yl)nicotinamide DBT salt
1. Recrystallization 0 NH
2. Salt breakup R
CI Ns
H =
H2N N OCH3 O
6-amino-5-chloro-2-methoxy-N-((3S,4R)-
3-methoxypiperidin-4-yl)nicotinamide
OEt OEt
Br O N
0 CI N,. R s O
H =
H2N N OCH3 O
ethyl6-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-methoxypiperidin-
l-yl)hexanoate
HOii,,,.. R R
O G
N CI \ N'"''=' 0 S
-
~ I H = N
H2N N OCH3
(R)-quinuclidin-3-y16-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-
methoxypiperidin-1-yl)hexanoate
R
O
HCl CI R O
\ Ns
H =2xcl GN
H2N N OCH3 O
(R)-quinuclidin-3-y16-((3S,4R)-4-(6-amino-5-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-1-yl)hexanoate dihydrochloride
Step 1: Resolution of Racemic 6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-
4-
yl)nicotinamide
(-)-Dibenzoyl-L-tartaric acid ((-)-DBT, about 1 part by weight) was dissolved
in
ethanol and filtered to remove residual particulates. Separately, racemic 6-
amino-5-chloro-2-
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methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide (about 0.8 part by weight) was
dissolved
in a mixture of ethanol and water and then filtered. The filtrate was heated
to about 75 C
before adding the (-)-DBT solution. After stirring at this temperature for
about 30 minutes,
the mixture was slowly cooled for several hours to about 5 C and the product
salt was
collected under vacuum filtration and washed with EtOH/H20 mixture. The
wetcake was
recrystallized from EtOH/H2O by heating to about 79 C and slow cooling to
about 5 C as
before. The product was collected on a vacuum filter and washed with EtOH/HzO
to give a
wetcake.
The wetcake was suspended in water and the pH was adjusted to about 12 using
7%
(W/W) aq. NaOH. The resulting suspension was stirred for about 3 hours at room
temperature before filtering under vacuum and washing the solid material with
water and
drying under vacuum. The product was then retreated with (-)-DBT to form the
salt by the
same general procedure described above. The isolated salt was then neutralized
with aq.
NaOH as described above. The product was isolated on a filter and dried as
before to provide
(+)-6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide base
(about 0.25
parts by weight). The e.e. by chiral HPLC analysis was about 100% (+)-6-amino-
5-chloro-2-
methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide. The optical rotation was
about +5
(methanol; 25 C and 589 nm), confirming the positive isomer of 6-amino-5-
chloro-2-
methoxy-N-(3 -methoxypiperidin-4-yl)nicotinamide.
Step 2: Coupling with Ethyl 6-bromohexanoate
O HBr OEt O N OEt
CI UN
O CI ~ Ns O
H
H
H2N I N OCH3 OCH3 K2CO3, Ethanol H2N I N OCH3 OCH3
6-amino-5-chloro-2- ethyl 6-((3S,4R)-4-(6-amino-5-chloro-2-
methoxy-N-((3S,4R)-3- methoxynicotinamido)-3-methoxypiperidin-
methoxypiperidin-4- 1-yl)hexanoate
yl)nicotinamide
(+)-6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide (about
1 part by weight), potassium carbonate (about 0.48 part by weight) and
potassium iodide
(about 0.063 part by weight) were suspended in anhydrous USP ethanol. Ethyl 6-
bromohexanoate (about 0.76 part by weight) was added slowly to the suspension
at room
temperature. The mixture was heated to reflux until completion of the
reaction. Subsequent
cooling to room temperature the reaction mixture was filtered to remove, e.g.,
inorganic
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solids, and the filtrate was concentrated under reduced pressure to about one-
half the volume.
The product was precipitated by slowly adding the crude material to cold water
(about 13
parts by weight) with rapid stirring. The precipitate was filtered under
vacuum and washed
with water and then reprecipitated twice more by dissolution in anhydrous
ethanol and slow
addition into cold water as before. The resulting wetcake was washed with n-
heptane and
resuspended in ethyl acetate and n-heptane (1:9; v/v) and stirred for about 1
hour and before
filtering and drying under vacuum to yield 0.73 parts by weight of the coupled
product.
Step 3: Coupling with (R)-3-Quinuclidinol and Dihydrochloride Salt Formation
O ~N OEt
1. Ti(OEt)4, Toluene
0 2. HCl (EtOH, i-PrOH)
CI N HO,,..'R
H2N I N OCH3 OCH3 + f' N
ethyl 6-((3S,4R)-4-(6-amino-5-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-
1-yl)hexanoate
O N 0,,,. R
CI ~ N,.= U 0 G
N
i H OCH3 =2HC1
HZN N OCH3
(R)-quinuclidin-3-yl 6-((3S,4R)-4-(6-amino-5-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-l-
yl)hexanoate
The ester product of step (1 part by weight) and (R)-3-Quinuclidinol (about
1.12 part by
weight) were suspended in toluene before slowly adding titanium (IV) ethoxide
(about 0.5
part by weight) to the stirred suspension. The mixture was heated to about 91
C under a
stream of nitrogen, and partial vacuum was applied to the flask through a
distillation
apparatus in order to azeotropically remove the ethanol. Additional toluene
was added as
needed to maintain a minimum solvent volume in the flask. The reaction was
considered
complete after about 33 hours.
The mixture was cooled to about room temperature and extracted five times with
water. The organic layer was concentrated under reduced pressure and the
resulting residue
was redissolved in EtOH/iPrOH (about 1:1 v/v) and then filtered through a 0.45
micron
membrane filter to remove any particulates. Concentrated hydrochloric acid was
added
slowly to the stirred filtrate to precipitate out the desired product, (R)-
quinuclidin-3-yl 6-
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((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-methoxypiperidin-1-
yl)hexanoate
as the dihydrochloride salt. The resulting suspension was stirred for several
hours at room
temperature and collected under vacuum filtration and rinsed with EtOH/zPrOH
(1:1; v/v) to
provide 0.53 part by weight of the crude product salt.
Crude (R)-quinuclidin-3-y16-((3S,4R)-4-(6-amino-5-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-1-yl)hexanoate dihydrochloride salt
was
resuspended in ethanol and heated to reflux before cooling to room temperature
over about 1
hour. The product was collected under vacuum filtration and rinsed with
ethanol and then air-
dried. The solids were resuspended in ethanol and warmed to about 55 C to
give a clear
solution before adding warm isopropanol and the product was allowed to
precipitate by slow
cooling to room temperature. The resulting suspension was stirred for several
hours before
vacuum filtering and rinsing with, e.g., isopropanol. The product was vacuum
dried, initially
at room temperature for several hours and then at about 55 C until a constant
weight was
achieved.
Example 2
Preparation of (R)-quinuclidin-3-yl 6-((3S,4R)-4-(6-amino-4-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-l-yl)hexanoate
Step 1: Synthesis of ethyl4-(dibenzylamino)-3-methoxypiperidine-l-carboxylate
(1):
O O
'k OEt BnBr, K2CO3, KI N~OEt
H2N J? DMF,A Bn2N
OCH3 OCH3
racemic I
To a solution of racemic ethyl4-amino-3-methoxypiperidine-l-carboxylate (1
part by
mole) in DMF were added benzyl bromide (about 2.2 part by mole), potassium
carbonate
(about 2.4 part by mole) and potassium iodide (about 0.2 part by mole)
respectively. The
reaction was heated to about 80 C. After about 6 hours, the reaction was
slowly diluted with
water (about 12 parts by volume) and extracted with, for example, ethyl
acetate. The organic
layer was washed with brine and then dried over aszhylz. Na2SO4. Subsequent
filtration and
concentration of the solvent provided the 1 as the yellow-orange oil (1 part
by mole).
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Step 2. Synthesis of N,N-dibenzyl-3-methoxypiperidin-4-amine (2):
O
N~OEt NaOH, iPrOH NH
Bn2N 0 Bn2N
OCH3 OCH3
1 2
To a solution of 1 was added NaOH (about 10 part by mole) in isopropanol and
the
mixture was stirred and heated to reflux. After about 3 to about 5 hours, the
reaction was
cooled to room temperature and the alcoholic solvent was removed via rotary
evaporation.
The mixture was diluted with water and extracted with ethyl acetate. The
organic layer was
brined washed before drying over anhyh. Na2SO4. Subsequent filtration and
concentration of
the solvent provided a crude oil which was purified over Si02 (CH2C12 : MeOH:
NH4OH;
(about) 15:1:0.01) to furnish 2.
Step 3. Synthesis of (3S,4R)-N,N-dibenzyl-3-methoxypiperidin-4-amine (3):
NH 1. (-)-DBT, EtOH/H20 NH
Bn2N 2, aq. NaOH Bn2N'~
OCH3 OCH3
2 3
(-)-Dibenzoyl-L-tartaric acid (about 1.2 part by weight) is dissolved in
ethanol before
slowly adding to a solution of 2 (about 1 part by weight). The solution is
gently warmed and
then allowed to cool to room temperature to crystallize the salt product. The
salt is filtered
and washed with EtOH/H2O before suspending in water and basifying by adding
aq. NaOH
(7%, wt/wt) until the pH reaches about 12. The suspension is stirred
vigorously at rt and the
solid is filtered away, washed with water and vacuum dried to furnish the cis-
isomer 3.
Step 4. Synthesis of ethyl 6-((3S,4R)-4-(dibenzylamino)-3-methoxypiperidin-1-
yl)hexanoate
(4):
NH Ethyl bromohexanoate OEt
'G K2C03, KI, DMF, A Bn2N"' O
Bn2N _
OCH3 OCH3
3 4
To a solution of 3 (1 part by mole) in DMF are added ethyl bromohexanoate
(about
1.2 part by mole), potassium carbonate (about 1.4 part by mole) and potassium
iodide (about
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0.2 part by mole) respectively. The reaction is then heated to 80 C. After
about 8 h, the
reaction is slowly diluted with water (about 12 part by volume) and extracted
with ethyl
acetate. The organic layer is washed with brine and then dried over anhyd.
Na2SO4.
Subsequent filtration and concentration of the solvent furnishes the crude
material.
Purification over Si02 and gives the alkylated material 4.
Step 5. Synthesis of (R)-quinuclidin-3-yl 6-((3S,4R)-4-(dibenzylamino)-3-
methoxypiperidin-
1-yl)hexanoate (5):
GN OEt Ti(OEt)4, (R)-Quinuclidinol ~N 0,,,~
BnZN _ 0 toluene, A BnZN O N
OCH3 OCH3
4 5
Titanium tetraethoxide is added to a mixture of 4 (1 part by mole) and (R)-(-)-
3-
quinuclidinol (1 part by mole) in toluene. The reaction mixture is equipped
with a dean-stark
apparatus before heating to about 90 C and partial vacuum is then applied
(additional toluene
is added as needed to main the requisite solvent level). The mixture is then
cooled to rt and
the reaction is diluted with ethyl acetate and then water is added to the
resulting mixture. The
organic layer is separated, brine washed, dried over anhyd. Na2SO4, filtered
and concentrated.
Purification over Si02 gives the enantiomerically enriched 5.
Step 6. Synthesis of (R)-quinuclidin-3-yl 6-((3S,4R)-4-amino-3-
methoxypiperidin-l-
yl)hexanoate (6):
GN 0,,~
GN O,~~ H2, Pd/C, EtOH O
HZN N
BnzN _ 0
N OCH3
OCH3
6
A solution of 5 (1 part by mole) in EtOH is added to a reaction flask
containing
palladium on carbon (about 0.2 part by mole). The mixture is then evacuated of
air before
subjecting to hydrogenolysis condition by using atmospheric H2. Upon
completion of the
reaction, the palladium is filtered off under a pad of celite followed by EtOH
washes. The
filtrated is concentrated via rotary evaporation to furnish 6.
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Step 7. Synthesis of (R)-quinuclidin-3-yl 6-((3S,4R)-4-(6-amino-4-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-1-yl)hexanoate (7):
CI O
OH
H2N N OCH3
N
R S O
H2N 6 N EtOCOCI, THF
OCH3
(R)-quinuclidin-3-y16-((3S,4R)-4-amino-
3-methoxypiperidin-1-yl)hexanoate
CI O
S O
N~~" N
H
7
3
H2N N OCH3 OCH
(R)-quinuclidin-3-yl 6-((3S,4R)-4-(6-amino-4-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-1-yl)hexanoate
To a solution of, for example, ethyl chloroformate (1 part by mole) in THF at
about 0
C is added the (optionally substituted) nicotinic acid (1 part by mole) in
portions. The
mixture is warmed to room temperature (rt) for about 1 hour before cooling to
about 0 C and
adding dropwise a solution of compound 6 (1 part by mole). The reaction is
then warmed to
rt. Upon completion of the reaction, reaction is quenched by addition of a
saturated solution
of NaHCO3 and extracting over EA (ethyl acetate). The organic layer is brine
washed, dried
over anhydrous Na2SO4, filtered and concentrated to furnish the desired
product 7(R)-
quinuclidin-3-yl 6-((3S,4R)-4-(6-amino-4-chloro-2-methoxynicotinamido)-3-
methoxypiperidin-1-yl)hexanoate.
Example 3
Alternate synthesis of (R)-quinuclidin-3-yl 6-((3S,4R)-4-(6-amino-5-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-1-yl)hexanoate dihydrochloride salt (N-
7505
dihydrochloride):
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0 N
CI &zz~ N~~,,.== R s O N
II =2HC1
H2N OCH3 O
(R)-quinuclidin-3-yl 6-((3S,4R)-4-(6-amino-5-chloro-2-
methoxynicotinamido)-3-methoxypiperidin-1-yl)hexanoate dihydrochloride
Under acidic conditions, 1-benzylpiperidin-4-one (1) and hydrobromic acid are
reacted in the presence of acetic acid to generate N-benzyl-3-bromopiperidin-4-
one (2).
Treatment of 2 with a sodium methoxide and methanol solution provides 1-benzyl-
4,4-
dimethoxypiperidin-3-ol (3). [The presence of the beta-amino group negates the
possibility of
a Favorskii-type reaction.] Methylation of the hydroxyl group is done using a
hydride base
followed by treatment with iodomethane in the presence of DMF
(dimethylformamide) as the
solvent to furnish compound 4.
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NBn AcOH, HBr (ag) N Bn NaOMe/MeOH, rt N Bn
p p H3CO -ry
H3CO
1 2 Br 3 OH
NaH,Mel NBn 1%H2SO4,heat fjNBn NaNH3CN,NHqOAc NBn
~ -~
DMF MeOH, heat
H3CO p H2N
H3CO
4 OCH3 5 OCH3 6 OCH3
NH
(-)-DBT 0NBn BOCZO, NBn Pd/C,MeOH,H2
EtOH/H20
= ' BocHN
H2NBocHN"
7 OCH3 8 OCH3 9 OCH3
N CN HO,,,,~
6-bromohexanenitrile _
K2C03, DMF, heat ~~.='' 1 Q N
BocHN
_ H+
OCH3
TFA
O
BocHN~" 11 N
OCH3 0
CI.~OH
~ N-7505
II H2N N OCH3 dihydrochloride
H2Nv 12 0 N EtOCOCI, TEA, THF 13
OCH3
Subsequent acetal hydrolysis using 1% sulfuric acid in the presence of heat
yields a
piperidine 5, which can then undergo a reductive amination using, for example,
sodium
cyanoborohydride and ammonium acetate in methanol to yield 1-benzyl-3-
methoxypiperidin-
4-amine (6). At this stage, 6 can undergo a chiral resolution technique. This
can be
accomplished, for example, using (-)-DBT or other variant of tartaric acid in
the presence of
the suitable solvent to afford exclusively asymmetrically pure compound 7. Boc
group
protection of the primary amine in 7 can be accomplished using Boc anhydride
in the
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presence of THF solvent to obtain 8. A debenzylation reaction by
hydrogenolysis using Pd/C
in methanol in the presence of atmospheric hydrogen gas set the stage for the
alkylation step.
Treatment of 6-bromohexanenitrile in the presence of mild base and DMF
generates
compound 10. A nitrile to ester conversion using (R)-quinuclidinol in the
presence of dilute
acid generates 11. Subsequent removal of the Boc group using TFA furnishes the
free amine,
which can undergo a coupling reaction with requisite nicotinic acid in the
presence of a
coupling reagent such as ethyl chloroformate to afford N-7505 dihydrochloride
as an
enantiomerically pure material.
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1. Ethy16-bromohexanoate
O,
N H K2C03, DMF, heat N \/
BocHN"" 2. TFA ~~~
HzN,.== 14 O
9 OCH3 OCH3
HO,,,,,
i. ~
N '\\,:
Ti(OEt)q, Tol., heat H2N 15 N
OCH3
O Ooo,,,
ci I oH O
HZN N~ OCH3 CI N16 O
EtOCOCI, TEA, THF X7" H2N OCH3 OCH3
racemic mixture
O
CI ~ N~.= 17 O N
H
I / OCH3
H2N N OCH3
Carlsburg
esterase
N-7505
dihydrochloride
18
Alternatively, compound 9 can be alkylated using ethyl 6-bromohexanoate in the
presence of
mild base. Subsequent removal of the Boc group yields compound 14. Titanium
mediated
transesterification of 14 using (R)-quinuclidinol and titanium tetraethoxide
in toluene solvent
generates 15 (R)-quinuclidin-3-yl 6-((3S,4R)-4-amino-3-methoxypiperidin-1-
yl)hexanoate.
The free amine of 15 can undergo a coupling reaction with requisite nicotinic
acid, in this
exemplary case 6-amino-5-chloro-2-methoxynicotinic acid, in the presence of a
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reagent such as ethyl chloroformate to afford 16, N-7505 dihydrochloride, as
an
enantiomerically pure material. Carlsburg esterase hydrolyzes esters that are
of the S-
configuration, therefore leaving intact esters that are of the R
configuration. Therefore
treatment of diasteriomeric mixtures of 17 with the Carlsburg esterase may
also yield 18, (R)-
quinuclidin-3-yl 6-((3S,4R)-4-(6-amino-5-chloro-2-methoxynicotinamido)-3-
methoxypiperidin-1-yl)hexanoate dihydrochloride.
Example 4
(+) and (-)-6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-4-yl)nicotinamide
or
(+) and (-)-6-amino-5-chloro-N-(3-methoxypiperidin-4-yl)-2-oxo-1,2-
dihydropyridine-3-
carboxamide can be made from their racemic mixtures by resolution of the
enantiomers using
conventional means such as optically resolving acids, according to the method
described in
US Patent 6,147,093, or in "Enantiomers, Racemates and Resolutions", by J.
Jacques, A.
Collet, and S.H. Wilen (Wiley-Interscience, New York, NY), or in S.H. Wilen et
al.,
Tetrahedron (1977) 33:2725.
The 4 isomers of each of the above compounds can easily be obtained in low-
milligram amounts by using preparative column chromatography followed by
evaporation of
the solvent. This method is useful for preparing small amounts for analytical
and
characterization purposes. This is a standard separation method used routinely
in analytical
labs in order to isolate and characterize metabolites.
Exemplary synthetic routes to Compound IVb, Compound VIb and (+)-Compound IIb
are described below using (+)-6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-
4-
yl)nicotinamide as a starting material. The routes to Compound IIIb, Compound
Vb and (-)-
Compound IIb are identical except that they use (-)-6-amino-5-chloro-2-methoxy-
N-(3-
methoxypiperidin-4-yl)nicotinamide as a starting material.
Example 5
Production of (+)-Coinpound IIb, ethyl ester
A equimolar mixture of (+)-6-amino-5-chloro-2-methoxy-N-(3-methoxypiperidin-4-
yl)nicotinamide and ethyl 6-bromohexanoate (1 equivalent each), a catalytic
amount of KI,
and K2C03 (2 equivalents) in DMF (dimethylformamide) is heated at about 60 C
for several
hours or until TLC analysis indicates that the reaction is over. After cooling
to room
temperature, water is added and the mixture is extracted with EtOAc. The
combined organic
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extracts are washed successively with water, 10% LiCl(aa) solution and brine,
then dried over
Na2SO4. Concentration gives (+)-compound Ilb, ethyl ester.
Production of (+)-Compound IIb
A mixture of crude (+)-compound IIb, ethyl ester, from above (1 eq.), KOH (2M,
5
eq.) in MeOH (methanol) and THF (tetrahydrofuran; enough to dissolve) is
stirred at room
temperature for approximately 1 to 2 hours. The MeOH and THF are removed under
vacuum,
and the residue is diluted with water. Wash with an organic solvent such as
EtOAc. The
aqueous layer is acidified to pH -5 using HCI. The precipitate is filtered off
and dried to give
(+)-Compound IIb.
Production of Compound IVb and Compound VIb
A mixture of (+)-Compound IIb (1 eq.), (R)-(-)-3-quinuclidinol HCl salt (1
eq.),
EDAC (1-ethyl-3-(3-dimethylpropyl)-carbodiimide; 1 eq.) and DMAP (4-
dimethylaminopyridine; 1 eq.) in DMF is heated at around 50 C overnight. After
cooling and
diluting with water, the mixture is purified by chromatography or by
crystallization to
provide Compound IVb. Similarly, using (S)-(+)-quinuclidinol, Compound VIb is
obtained.
The following compounds are prepared essentially according to methods and
procedures described above. The compound names were generated using either
ChemDraw
Ultra version 8.03 and/or 9.0, which is available from Cambridgesoft
Corporation or ACD
Namepro software, version 6Ø
ci 0
H2N
::r-" H
I H O 6-((3S,4R)-4-(6-amino-5-chloro-2-
N N' , methoxynicotinamido)-3-
~,. N methoxypiperidin-l-yl)hexanoic acid
,o 0 0
I
ci 0
H2N
H OH 6-((3S,4R)-4-(6-amino-5-chloro-2-
HN )yN//I"'.O oxo-1,2-dihydropyridine-3-carboxamido)-
0 0 0~õ== 3-methoxypiperidin-1-yl)hexanoic acid
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CI 0
HZN ~ I H OH
6-((3R,4S)-4-(6-amino-5-chloro-2-
N N methoxynicotinamido)-3-
0 o N methoxypiperidin-1-yl)hexanoic acid
0
I
ci 0
HZN / I OH
HN N 6-((3R,4S)-4-(6-amino-5-chloro-2-
oxo-1,2-dihydropyridine-3-carboxamido)-
O 0 N 3-methoxypiperidin-1-yl)hexanoic acid
0
o (R)-quinuclidin-3-y16-((3S,4R)-4-
c~ rN~) N o N (6-amino-5-chloro-2-
HZN o" o methoxynicotinamido)-3-
I methoxypiperidin-l-yl)hexanoate
cl o 0o ~ (R)-quinuclidin-3-y16-((3S,4R)-4-
~ N (6-amino-5-chloro-2-oxo-1,2-
C o dihydropyridine-3-carboxamido)-3-
H2N H methoxypiperidin- 1 -yl)hexanoate
o (R)-quinuclidin-3-y16-((3R,4S)-4-
c' r N o N (6-amino-5-chloro-2-
HaN No H o-' methoxynicotinamido)-3-
I methoxypiperidin-1-yl)hexanoate
~
o (R)-quinuclidin-3-y16-((3R,4S)-4-
ci N o N (6-amino-5-chloro-2-oxo-1,2-
~ " o dihydropyridine-3-carboxamido)-3-
"2" ,"1 0 methoxypiperidin-l-yl)hexanoate
ci
o (S)-quinuclidin-3-y16-((3S,4R)-4-
HaN ~ ~ (6-amino-5-chloro-2-oxo-1,2-
HN HN CN-,, O HuN dihydropyridine-3-carboxamido)-3-
0 o methoxypiperidin-l-yl)hexanoate
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ci
o (S)-quinuclidin-3-y16-((3S,4R)-4-
HZN ~ (6-amino-5-chloro-2-
1HN
N methoxynicotinamido)-3-
% methoxypiperidin- 1 -yl)hexanoate
ci
o (S)-quinuclidin-3-y16-((3R,4S')-4-
HZN (6-amino-5-chloro-2-oxo-1,2-
HN HN N
0
dihydropyridine-3-carboxamido)-3-
_o methoxypiperidin-l-yl)hexanoate
ci
o (S)-quinuclidin-3-yl 6-((3R,4S)-4-
HZN (6-amino-5-chloro-2-
N- HN N 0 N methoxynicotinamido)-3-
% _o o methoxypipcridin-1-yl)hexanoa.te
ci
o (S)-quinuclidin-3-y16-((3R,4S)-4-
HZN (6-amino-5-chloro-2-oxo-1,2-
-~D
HN HN N 0 0 0
N dihydropyridine-3-carboxamido)-3-
_0 methoxypiperidin- 1 -yl)hexanoate
ci
o (5)-quinuclidin-3-y16-((3R,4S')-4-
H2N (6-amino-5-chloro-2-
N- HN --P N 0
H"" N methoxynicotinamido)-3-
% _o o methoxypipcridin-l-yl)hexanoate
ci
0 (S)-quinuclidin-3-y16-((3S,4R)-4-
H2N (6-amino-5-chloro-2-oxo-1,2-
HN HN, ,...CN y0 ,,,...
dihydropyridine-3-carboxamido)-3-
_o methoxypiperidin-1-yl)hexanoate
ci
o (S)-quinuclidin-3-y16-((3S,4R)-4-
HaN (6-amino-5-chloro-2-
N- HN11.11...CN 0 H,
~N' methoxynicotinamido)-3-
% o methoxypiperidin- 1 -yl)hexanoate
ci
~ (R)-quinuclidin-3-y16-((3R,4S)-4-
H2N (6-amino-5-chloro-2-
N- HN~{ N O H N methoxynicotinamido)-3-
/O _OY methoxypiperidin-l-yl)hexanoate
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F.
~ o (R)-quinuclidin-3-y16-((3R,4S)-4-
HZN (6-amino-5-fluoro-2-oxo-1,2-
HN HN~N N dihydropyridine-3-carboxamido)-3-
o -o methoxypiperidin- 1-yl)hexanoato
ci
o (R)-quinuclidin-3-yl6-((3S,4R)-4-
H2N /~~ (6-amino-5-chloro-2-
N- HNII.I. ( N O H N
\_/ methoxynicotinamido)-3-
% -o' o' methoxypiperidin- 1 -yl)hexanoate
F
o (R)-quinuclidin-3-y16-((3S,4R)-4-
HZN CN H (6-amino-5-fluoro-2-oxo-1,2-
HN HN, o dihydropyridine-3-carboxamido)-3-
O :
-o' methoxypiperidin-1-yl)hexanoate
ci
~ ~ 0 N/ 8-methyl-8-azabicyclo[3.2.1]octan-
HzN /~ 3-yl 6-((3S,4R)-4-(6-amino-5-chloro-2-
N- HNI"---==( N O
~~// methoxynicotinamido)-3-
% methoxypiperidin-l-yl)hexanoate
ci
o N 8-methyl-8-azabicyclo[3.2.1]octan-
HZN / 3-y16-((3S,4R)-4-(6-amino-5-chloro-2-
HN HN ~N O
~~~/// oxo-1,2-dihydropyridine-3-carboxamido)-
0
3-methoxypiperidin-l-yl)hexanoate
ci
o N/ 8-methyl-8-azabicyclo [3.2. 1 ] octan-
H2N ~ 3-yl6-((3R,4S)-4-(6-amino-5-chloro-2-
N- HN DN-\ o methoxynicotinamido)-3-
% _o o methoxypiperidin-1-yl)hexanoate
ci
0 N/ 8-methyl-8-azabicyclo[3.2.1]octan-
HZN 3-y16-((3R,4S)-4-(6-amino-5-chloro-2-
HN HN N o oxo-1,2-dihydropyridine-3-carboxamido)-
0
0 3-methoxypiperidin-1-yl)hexanoate
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ci 0
HaN OH 4-(2-((3S,4R)-4-(6-amino-5-chloro-
N\ N ( / 2-methoxynicotinamido)-3-
HN methoxypiperidin-1-yl)acetamido)benzoic
0 0 ' ' --,~o acid
ci 0
H2N OH 4-(2-((3S,4R)-4-(6-amino-5-chloro-
HN N,,,, ~/ 2-oxo-1,2-dihydropyridine-3-
H j carboxamido)-3-methoxypiperidin-l-
0 o i,, N"/'o yl)acetamido)benzoic acid
ci 0
H2N OH 4-(2-((3R,4S)-4-(6-amino-5-chloro-
N N N I/ 2-methoxynicotinamido)-3-
methoxypiperidin-l-yl)acetamido)benzoic
o 0 o DH
- -I~o acid
ci 0
H2N
oH 4-(2-((3R,4S)-4-(6-amino-5-chloro-
Y
HN N D:D HN ~/ 2-oxo-1,2-dihydropyridine:3:
carboxamido)-3 -methoxypiperidin-l-
0 0 o -,~o yl)acetamido)benzoic acid
H
"
methyl4-(2-((3R,4S)-4-(6-amino-5-
cl N o o chloro-2-methoxynicotinamido)-3-
HaN I N~ o 0 o methoxypiperidin-l-
" ~ yl)acetamido)benzoate
(
H
o methyl4-(2-((3R,4S)-4-(6-amino-5-
cl ~ N 0 chloro-2-oxo-1,2-dihydropyridine-3-
~ " carboxamido)-3-methoxypiperidin-l-
HzN H o 0 0 yl)acetamido)benzoate
ci 0
H2N o methyl4-(2-((3S,4R)-4-(6-amino-5-
N\ N,,,,, I, I chloro-2-methoxynicotinamido)-3-
H j methoxypiperidin-l-
o 0 0,,, IDNyl)acetamido)benzoate
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CI 0
H2N
o methyl 4-(2-((3S,4R)-4-(6-amino-5-
N
Y
H I NHN ~/ I chloro-2-oxo-1,2-dihydropyridine-3-
carboxamido)-3 -methoxypiperidin-l-
0 0 0,,,.. Nyl)acetamido)benzoate
ci o~
~
H2N o ethyl4-(2-((3S,4R)-4-(6-amino-5-
~ H chloro-2-methox nicotinamido)3
N~ N,,,,.. I/ Y - -
: ~ methoxYp eridin-l-
ip
0 0 N yl)acetamido)benzoate
ci o~
H2N
o ethyl4-(2-((3S,4R)-4-(6-amino-5-
HN ni~/ chloro-2-oxo-1,2-dihydropyridine-3-
~ HN carboxamido)-3-methoxypiperidin-l-
0 0 o,, Nl'-~o yl)acetamido)benzoate
ci o~
H2N o ethyl4-(2-((3R,4S)-4-(6-amino-5-
~ N ~ / chloro-2-methoxynicotinamido)-3-
HN methoxypiperidin-l-
0 0 o N-,-~o yl)acetamido)benzoate
ci o~
H2N o ethyl4-(2-((3R,4S)-4-(6-amino-5-
HN rHi ~/ chloro-2-oxo-1,2-dihydropyridine-3-
HN carboxamido)-3-methoxypiperidin-l-
0 0 o N~o yl)acetamido)benzoate
CI O1~,
H2N / ~ isopropyl4-(2-((3S,4R)-4-(6-
~ H I O amino-5-chloro-2-methoxynicotinamido)-
N,,, HN / 3-methoxypiperidin-l-
~O O ~,.=N~ yl)acetamido)benzoate
O
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CI Oil" iso ro 14- 2- 3S,4R -4- 6-
H2N P pY ( (( ) (
O amino-5-chloro-2-oxo-1,2-
HN ~ N, ~ e dihydropyridine-3-carboxamido)-3-
HN methoxypiperidin-l-
O O 0~,,.= N~O yl)acetamido)benzoate
CI o/\
H2N , O isopropyl4-(2-((3R,4S)-4-(6-
H I amino-5-chloro-2-methoxynicotinamido)-
N HN / 3-methoxypiperidin-l-
O N~ yl)acetamido)benzoate
O O
CI oj-" isopropY14-(2-((3R,4S)-4-(6-
H2N , O amino-5-chloro-2-oxo-1,2-
HN N ~, dihydropyridine-3-carboxamido)-3-
HN methoxypiperidin-l-
O O O N-~O yl)acetamido)benzoate
cI o,-~o-,
H2N 0 2-methoxyethyl4-(2-((3S,4R)-4-(6-
N~ N~ ~ ~ amino-5-chloro-2-methoxynicotinamido)-
HN 3-methoxypiperidin-l-
~10 0 N,,),,o yl)acetamido)benzoate
CI
2-methoxyethyl4-(2-((3S,4R)-4-(6-
2 o amino-5-chloro-2-oxo-1,2-
HN N,,,= dihydropyridine-3-carboxamido)-3-
0 0 0,,.= N HN~
-,-~-o methoxypiperidin-l-
I yl)acetamido)benzoate
CI
HZN , 0 2-methoxyethyl4-(2-((3R,4S)-4-(6-
N~ ~ N ~ amino-5-chloro-2-methoxynicotinamido)-
HN 3-methoxypiperidin-l-
0 o N,,J,,o yl)acetamido)benzoate
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CI
2-methoxyethyl4-(2-((3R,4S')-4-(6-
H2N ~ ~ o amino-5-chloro-2-oxo-1,2-
HN I N HN ~ i dihydropyridine-3-carboxamido)-3-
0 00 methoxypiperidin-l-
~ yl)acetamido)benzoate
H2N CI
N 2-(pyrrolidin-1-yl)ethyl4-(2-
-0 NH ((3S,4R)-4-(6-amino-5-chloro-2-
o ' N methoxynicotinamido)-3-
o ON o ~- methoxypiperidin-l-
N O yl)acetamido)benzoate
O
O
H2N CI
HN 2-(pyrrolidin-1-yl)ethyl4-(2-
O NH ((3S,4R)-4-(6-amino-5-chloro-2-oxo-1,2-
0 dihydropyridine-3-carboxamido)-3-
O ~ O-~ methoxypiperidin-l-
~N () yl)acetamido)benzoate
\\ o
0
H2N CI
N~ 2-(pyrrolidin-1-yl)ethyl4-(2-
-0 NH ((3R,4.S')-4-(6-amino-5-chloro-2-
o N methoxynicotinamido)-3-
0- / ~ o-~ methoxypiperidin-l-
N~ ~ yl)acetamido)benzoate
0
0
H2N CI
HN 2-(pyrrolidin-1-yl)ethyl4-(2-
0 NH ((3R,4S)-4-(6-amino-5-chloro-2-oxo-1,2-
o N dihydropyridine-3-carboxamido)-3-
o- methoxypiperidin-l-
NHN -~ yl)acetamido)benzoate
0
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ci 0 1-methylpiperidin-4-yl 4-(2-
H N ((3S,4R)-4-(6-amino-5-chloro-2-
2 ~ H ~\ o methoxynicotinamido)-3-
N- N,, ' HN methoxypiperidin-l-
.110 0 .N,,,~,o yl)acetamido)benzoate
ci 1-methylpiperidin-4-yl 4-(2-
H N ((3S,4R)-4-(6-amino-5-chloro-2-oxo-1,2-
~ H ~\ o dihydropyridine-3-carboxamido)-3-
HN N,,, HN methoxypiperidin-l-
0 0 0,,==Nll~--o yl)acetamido)benzoate
N
ci 0 1-methylpiperidin-4-y14-(2-
H N ((3R,4S)-4-(6-amino-5-chloro-2-
2 \ N ~ o methoxynicotinamido)-3-
HN methoxypiperidin-l-
,10 0 oDCN,,,I,,o yl)acetamido)benzoate
cl 1-methylpiperidin-4-y14-(2-
H2N o ((3R,4S)-4-(6-amino-5-chloro-2-oxo-1,2-
HN N ~ dihydropyridine-3-carboxamido)-3-
HN methoxypiperidin-l-
0 00, N,~,,o yl)acetamido)benzoate
H2N CI
N~ 2-(pyridin-2-yl)ethyl4-(2-((3S,4R)-
-0 NH 4-(6-amino-5-chloro-2-
0 methoxynicotinamido)-3-
~ ~ ...0 0 N methoxypiperidin-l-
~ 0 yl)acetamido)benzoate
H2N CI
HN 2-(pyridin-2-yl)ethyl4-(2-((3S,4R)-
0 NH _ 4-(6-amino-5-chloro-2-oxo-1,2-
0 dihydropyridine-3-carboxamido)-3-
~ /
j /~ o N methoxypiperidin-l-
N~ ~~ yl)acetamido)benzoate
0
0
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H2N CI
N~ ~ 2-(pyridin-2-yl)ethyl4-(2-((3R,4S)-
-o NH _ 4-(6-amino-5-chloro-2-
o }-~ ~ methoxynicotinamido)-3-
0 ~ ~~ 0 N~ methoxypiperidin-l-
N~ H 0 yl)acetamido)benzoate
H2N CI
HN ~ 2-(pyridin-2-yl)ethyl4-(2-((3R,4S)-
o NH _ 4-(6-amino-5-chloro-2-oxo-1,2-
o ~ dihydropyridine-3-carboxamido)-3-
0 N ~ inethoxypiperidin-l-
NHN yl)acetamido)benzoate
O
O
H2N CI
N\ / 2-(dimethylamino)ethyl4-(2-
-0 NH ((3S,4R)-4-(6-amino-5-chloro-2-
o N methoxynicotinamido)-3-
/ ~ OO ~- methoxypiperidin-l-
N HN- yl)acetamido)benzoate
O
HZN CI
HN / 2-(dimethylamino)ethyl4-(2-
O NH ~ ((3S,4R)-4-(6-amino-5-chloro-2-oxo-1,2-
0 N dihydropyridine-3-carboxamido)-3-
O~~ ~ / ~ O~- methoxypiperidin-l-
'--N HN yl)acetamido)benzoate
O
HzN CI
N~ / 2-(dimethylamino)ethyl4-(2-
-0 NH ~ ((3R,4S)-4-(6-amino-5-chloro-2-
0 N methoxynicotinamido)-3-
~ o~ ~ methoxypiperidin-l-
N HN~ yl)acetamido)benzoate
~ O
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H2N CI
HN 2-(dimethylamino)ethyl4-(2-
O NH ~ ((3R,4S)-4-(6-amino-5-chloro-2-oxo-1,2-
N dihydropyridine-3-carboxamido)-3-
0 O-~ methoxypiperidin-l-
N HN~ yl)acetamido)benzoate
O
ci oN~, 1-methylpiperidin-3-yl 4-(2-
H N ((3S,4R)-4-(6-amino-5-chloro-2-
2 ~ H X-L0 methoxynicotinamido)-3-
N~ N,,,. HN methoxypiperidin-l-
1.10 0 0,,,.=N,, Lo yl)acetamido)benzoate
ci ON,, 1-methylpiperidin-3-y14-(2-
H N ((3S,4R)-4-(6-amino-5-chloro-2-oxo-1,2-
2
HN rHV,,= c(L0 \ dihydropyridine-3-carboxamido)-3-
HN methoxYp eridin-l-
ip
0 0 0õ= N~o yl)acetamido)benzoate
ci oN, 1-methylpiperidin-3-y14-(2-
H N ((3R,4S)-4-(6-amino-5-chloro-2-
z \ N ~ o methoxynicotinamido)-3-
HN methoxypiperidin-l-
~o 0 oN,,--o yl)acetamido)benzoate
ci oN,, 1-methylpiperidin-3-y14-(2-
H2N ((3R,4S)-4-(6-amino-5-chloro-2-oxo-1,2-
HN N ~, o dihydropyridine-3-carboxamido)-3-
HN methoxypiperidin-l-
0 0 o No yl)acetamido)benzoate
H2N CI
N~ 2-morpholinoethyl4-(2-((3S,4R)-4-
-0 NH (6-amino-5-chloro-2-
0 o0 ~N0 methoxynicotinamido)-3-
~ ~ ~ ~ methoxypiperidin-l-
N~ ~ yl)acetamido)benzoate
0
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H2N CI
HN / 2-morpholinoethyl4-(2-((3S,4R)-4-
0 NH (6-amino-5-chloro-2-oxo-1,2-
0 o dihydropyridine-3-carboxamido)-3-
o~ methoxypiperidin-l-
~ N~ ~ yl)acetamido)benzoate
0
0
H2N CI
N~ 2-morpholinoethyl4-(2-((3R,4S)-4-
-0 NH (6-amino-5-chloro-2-
o N o methoxynicotinamido)-3-
o- o~ U methoxypiperidin-l-
~ N~ f ~ yl)acetamido)benzoate
0
0
H2N CI
HN / 2-morpholinoethyl4-(2-((3R,4S)-4-
0 NH (6-amino-5-chloro-2-oxo-1,2-
0 p dihydropyridine-3-carboxamido)-3-
0- o~ ~--~ inethoxypiperidin-l-
~ NHN--a yl)acetamido)benzoate
0
0
--N
O
1,4-dimethylpiperidin-4-y14-(2-
- ((3S,4R)-4-(6-amino-5-chloro-2-
\ /~ methoxynicotinamido)-3-
N, ) NH N methoxypiperidin-l-
HN~ ~/ o \ ~ NH2
yl)acetamido)benzoate
CI
--N
1,4-dimethylpiperidin-4-yl4-(2-
- ((3S,4R)-4-(6-amino-5-chloro-2-oxo-1,2-
\ ~ ~\' dihydropyridine-3-carboxamido)-3-
HN~N= ) NH NH methoxypiperidin-l-
0 ~/ o ""z yl)acetamido)benzoate
CI
'N
\ 1,4-dimethylpiperidin-4-y14-(2-
- o ~ ((3R,4S)-4-(6-amino-5-chloro-2-
\ ~ methoxynicotinamido)-3-
/-" (~- "" " methoxypiperidin-l-
HN\o o \ ""Z yl)acetamido)benzoate
CI
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--N
1,4-dimethylpiperidin-4-y14-(2-
_ o ((3R,4S)-4-(6-amino-5-chloro-2-oxo-1,2-
~ dihydropyridine-3-carboxamido)-3-
N N5:\ NmethoxYpiperidin-l- \,_5 HN~ NHZ yl)acetamido)benzoate
0
CI
ci 0
H2N -- oH 4-(2-((3S,4R)-4-(6-amino-5-chloro-
N I N I/ 2-methoxynicotinamido)-3-
HN methoxypiperidin-1-yl)acetamido)benzoic
Oo,,... N acid
Ci 0
H2N / oH 4-(2-((3S,4R)-4-(6-amino-5-chloro-
HN ~ ri,, ~/ 2-oxo-1,2-dihydropyridine-3-
HN carboxamido)-3-methoxypiperidin-l-
0 0 0,,.. N--~o yl)acetamido)benzoic acid
Ci 0
H2N OH 4-(2-((3R,4S)-4-(6-amino-5-chloro-
N~ I N HN I/ 2-methoxynicotinamido)-3-
methoxypiperidin-l-yl)acetamido)benzo ic
o 0 o N~o acid
ci o
H2N / 4-(2-((3R,4S)-4-(6-amino-5-chloro-
HN HN ((OH
/ 2-oxo-1,2-dihydropyridine-3-
carboxamido)-3 -methoxypiperidin-l-
0 0 o D:D-,-~o yl)acetamido)benzoic acid
H2N CI
N~ ~ NH 2-oxo-2-(piperidin-4-ylamino)ethyl
-o NH 0 4-(2-((3S,4R)-4-(6-amino-5-chloro-2-
0 ~-NH methoxynicotinamido)-3-
oi o methoxypiperidin-l-
~ N~ 0 yl)acetamido)benzoate
0
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H2N CI
HN / QN H 2-oxo-2-(piperidin-4-ylamino)ethyl
o NH o 4-(2 -((3S,4R)-4-(6-amino-5-chloro-2-oxo-
___,-NH 1,2-dihydropyridine-3-carboxamido)-3-
0
methoxypiperidin-l-
0" ~ ~ ~ o0
~ ~ yl)acetamido)benzoate
0
H2N CI
N~ ~ NH 2-oxo-2-(piperidin-4-ylamino)ethyl
-o NH 4-(2-((3R,48)-4-(6-amino-5-chloro-2-
0 ~-NH methoxynicotinamido)-3-
0 o0 methoxypiperidin-l-
~ N~ / ~ yl)acetamido)benzoate
0
H2N CI
HN / NH 2-oxo-2-(piperidin-4-ylamino)ethyl
o NH o 4-(2-((3R,4S)-4-(6-amino-5-chloro-2-oxo-
0 ~ ~-NH 1,2-dihydropyridine-3-carboxamido)-3-
0 o methoxypiperidin-l-
/ ~ yl)acetamido)benzoate
0
0
O OH
CI
H2N /
1-(2-((3S,4R)-4-(6-amino-5 -chloro-
H 2-methoxynicotinamido)-3-
N ~ NN methoxypiperidin-1-yl)acetyl)piperidine-
O O O\~~,,= N 4-carboxylic acid
O OH
CI
H2N ~ 1-(2-((3S,4R)-4-(6-amino-5-chloro-
HN I N,, 2-oxo-1,2-dihydropyridine-3-
N carboxamido)-3-methoxypiperidin-l-
yl)acetyl)piperidine-4-carboxylic acid
O N
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O OH
CI
H2N ~ I 1-(2-((3R,4S)-4-(6-amino-5-chloro-
N N 2-methoxynicotinamido)-3-
N methoxypiperidin-1-yl)acetyl)piperidine-
O O N 4-carboxylic acid
O
I
O OH
CI
H2N ~ 1-(2-((3R,4S)-4-(6-amino-5-chloro-
HN N 2-oxo-1,2-dihydropyridine-3-
N carboxamido)-3-methoxypiperidin-l-
0 O N yl)acetyl)piperidine-4-carboxylic acid
O O
/O O
CI
H2N
methyl 1-(2-((3S,4R)-4-(6-amino-5-
H chloro-2-methoxynicotinamido)-3-
N N,,, N methoxypiperidin-l-yl)acetyl)piperidine-
O 0K N-4-~O 4-carboxylate
/O O
CI
H2N /
methyl 1-(2-((3S,4R)-4-(6-amino-5 -
H chloro-2-oxo-1,2-dihydropyridine-3-
HN N,,,, N carboxamido)-3-methoxypiperidin-1-
0 0 \~~,: N~ yl)acetyl)piperidine-4-carboxylate
O O
CI /O 0
H2N
methyl 1-(2-((3R,4S)-4-(6-amino-5-
N N chloro-2-methoxynicotinamido)-3-
N methoxypiperidin-l-yl)acetyl)piperidine-
4-carboxylate
N
O
O O
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/O O
cl
H2N /
methyl 1-(2-((3R,4S)-4-(6-amino-5-
HN I N chloro-2-oxo-1,2-dihydropyridine-3-
N carboxamido)-3-methoxypiperidin-l-
0 N yl)acetyl)piperidine-4-carboxylate
O O
cl ethyl 1-(2-((3S,4R)-4-(6-amino-5-
,..~
H
~ \ "m
HZN chloro-2-methoxynicotinamido)-3-
N- 0 0 methoxypiperidin-1-yl)acetyl)piperidine-
~ 4-carboxylate
cl ethyl1-(2-((3S,4R)-4-(6-amino-5-
~ ~ HN ~ -~ chloro-2-oxo-1,2-dihydropyridine-3-
H2N carboxamido)-3 -methoxypiperidin-l-
H" o 0 1 yl)acetyl)piperidine-4-carboxylate
0 o
ethyl 1-(2-((3R,4S)-4-(6-amino-5-
ci pd
HN HZN o~ chloro-2-methoxynicotinamido)-3-
N- o o methoxypiperidin-1-yl)acetyl)piperidine-
/ 0 \ 4-carboxylate
o
ci --~-"~ ethyl 1 -(2-((3R,4S)-4-(6-amino-5-
~ HN N 0-\ chloro-2-oxo-1,2-dihydropyridine-3-
HZN carboxamido)-3-methoxypiperidin-l-
HN o
o ~ yl)acetyl)piperidine-4-carboxylate
O O
c' _-
"\-/ _/ 2-methoxyethyl 1-(2-((3S,4R)-4-(6-
HZN
N- HN ~N amino-5-chloro-2-methoxynicotinamido)-
o 3-methoxypiperidin-l-
/ yl)acetyl)piperidine-4-carboxylate
\\ -0
2-methoxyethyl1-(2-((3S,4R)-4-(6-
cl amino-5-chloro-2-oxo-1,2-
HN O ~
/ \ ...~
H2N dihydropyridine-3-carboxamido)-3-
HN o methoxypiperidin-l-yl)acetyl)piperidine-
4-carboxylate
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0 0
c' HN d-No-/-o 2-methoxyethyl1-(2-((3R,48)-4-(6-
H2N amino-5-chloro-2-methoxynicotinamido)-
N- o o~ 3-methoxypiperidin-l-
/o yl)acetyl)piperidine-4-carboxylate
ci c N~~( c a 2-methoxyethyll-(2-((3R,4.')-4-(6-
/ HN ~of- amino-5-chloro-2-oxo-1,2-
HzN \ ~ dihydropyridine-3-carboxamido)-3-
HN o ~ methoxypiperidin-l-yl)acetyl)piperidine-
0 4-carboxylate
/
0 0 0 -N 4-(((2-((3S,4R)-4-(6-amino-5-
\ / NHZ chloro-2-methoxynicotinamido)-3-
o _ N_~N~ "NH methoxypiperidin-l-
cl yl)ethyl)(methyl)amino)methyl)benzoic
Ho \ / acid
0
,o o NH 4-(((2-((3S,4R)-4-(6-amino-5-
//~\ NH2 chloro-2-oxo-1,2-dihydropyridine-3-
0 N~-N\ IINH carboxamido)-3-methoxypiperidin-l-
~J c~ yl)ethyl)(methyl)amino)methyl)benzoic
Ho acid
/
0 0 0 4-(((2-((3R,4S')-4-(6-amino-5-
NH2 chloro-2-methoxynicotinamido)-3-
o N~-N NH ~i methoxypiperidin-l-
yl)ethyl)(methyl)amino)methyl)benzoic
acid
Ho
Y
0
0 0 NH 4-(((2-((3R,4S)-4-(6-amino-5-
/ NH2 chloro-2-oxo-1,2-dihydropyridine-3-
0 N~N NH cl carboxamido)-3-methoxypiperidin-l-
yl)ethyl)(methyl)amino)methyl)benzoic
Ho acid
o/
-N
0 0 NHZ
: methyl 4-(((2-((3S,4R)-4-(6-amino-
o N_~No ~-IINH 5-chloro-2-methoxynicotinamido)-3-
ci methoxypiperidin-l-
\\ yl)ethyl)(methyl)amino)methyl)benzoate
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o
O O NH
/ c~ NH2 methyl4-(((2-((3S,4R)-4-(6-amino-
o 5-chloro-2-oxo-1,2-dihydropyridine-3-
~J carboxamido)-3-methoxypiperidin-l-
o yl)ethyl)(methyl)amino)methyl)benzoate
\ o
0 0 -N methyl4-(((2-((3R,4S)-4-(6-amino-
-N NH NHZ 5-chloro-2-methoxynicotinamido)-3-
o N--' ci methoxypiperidin-l-
\ yl)ethyl)(methyl)amino)methyl)benzoate
o
O O NH
NH2 methyl4-(((2-((3R,4S)-4-(6-amino-
~N NH \ / 5-chloro-2-oxo-1,2-dihydropyridine-3-
0 \N ci carboxamido)-3-methoxypiperidin-l-
0 yl)ethyl)(methyl)amino)methyl)benzoate
\
ci
H2N
methyl 4-((2-((3S,4R)-4-(6-amino-
N~ w,,,, 5-chloro-2-methoxynicotinamido)-3-
\ I ~ methoxypiperidin-l-
~o o ,,, N J HN yl)ethylamino)methyl)benzoate
ci
H2N ~ methyl4-((2-((3S,4R)-4-(6-amino-
5-chloro-2-oxo-1,2-dihydropyridine-3-
HN N,,, N HN )
o carboxamido)-3-methoxypiperidin-l-
0 o o K' J yl)ethylamino)methyl)benzoate
~ 0
ci
H2N
methyl4-((2-((3R,4,S')-4-(6-amino-
N~ N HN / 5-chloro-2-methoxynicotinamido)-3-
lmethoxypiperidin-l-
o o N J yl)ethylamino)methyl)benzoate
~ 0
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ci
H2N /
I methyl4-((2-((3R,4,S)-4-(6-amino-
HN N , 5-chloro-2-oxo-l,2-dihydropyridine-3-
HN
0 o iN o carboxamido)-3-methoxypiperidin-l-
i yl)ethylamino)methyl)benzoate
ci
H2N isopropyl4-((2-((3S,4R)-4-(6-
N-_ I N,,, HN amino-5-chloro-2-methoxynicotinamido)-
0 0 N 3-methoxypiperidin-l-
o ==. ~ yl)ethylamino)methyl)benzoate
0 ci
HZN s isopropyl4-((2-((3S,4R)-4-(6-
HN N,,, amino-5-chloro-2-oxo-1,2-
HN dihydropyridine-3-carboxamido)-3-
0 0 NJ o methoxypiperidin-l-
o Y yl)ethylamino)methyl)benzoate
Ci
H2N isopropyl4-((2-((3R,4S)-4-(6-
N-_ N HN , amino-5-chloro-2-methoxynicotinamido)-
0 J
0 0 N ) 0 3-methoxypiperidin-l-
~ yl)ethylamino)methyl)benzoate
0
ci
HZN e isopropyl4-((2-((3R,4S)-4-(6-
HN N amino-5-chloro-2-oxo-1,2-
HN dihydropyridine-3-carboxamido)-3-
0 0 o N J o methoxypiperidin-l-
1 0 "r yl)ethylamino)methyl)benzoate
cl
H2N o
H ethyl4-((2-((3S,4R)-4-(6-amino-5-
N- I N,,,., HN chloro-2-methoxynicotinamido)-3-
~10 0 0~,.N~ o,_" methoxypiperidin-l-
yl)ethylamino)methyl)benzoate
H ~ H'~I dihydrochloride
CI
CI
H2N /
H ethyl 4-((2-((3S,4R)-4-(6-amino-5-
HN I N,,, HN chloro-2-oxo-1,2-dihydropyridine-3-
0 0 0~,,.=NJ o, carboxamido)-3-methoxypiperidin-l-
yl)ethylamino)methyl)benzoate
H o HcI dihydrochloride
cl
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CI
H2N /
ethyl4-((2-((3R,4S)-4-(6-amino-5-
N~ N HN / chloro-2-methoxynicotinamido)-3-
1~o 00 N J o,_,., methoxypiperidin-l-
yl)ethylamino)methyl)benzoate
H o H'c~ dihydrochloride
ci
ci
H2N /
ethyl 4-((2-((3R,4S)-4-(6-amino-5-
HN I H
HN ~ chloro-2-oxo-1,2-dihydropyridine-3-
0 0 oNJ o,~, carboxamido)-3-methoxypiperidin-l-
1 yl)ethylamino)methyl)benzoate
H o H'cl dihydrochloride
ci
01 0 0 H (R)-quinuclidin-3-y14-(2-((3S,4R)-
/ ~ ,,,.. 4-(6-amino-5-chloro-2-
H2N /~ ~
HN = ( N~ N methoxynicotinamido)-3-
% o~~~/// N methoxypiperidin-l-
\ yl)ethylcarbamoyl)benzoate
c~ o / \ H (R)-quinuclidin-3-y14-(2-((3S,4R)-
W~ ,-,,... 4-(6-amino-5-chloro-2-oxo-1,2-
--
HN HN==CN dihydropyridine-3-carboxamido)-3-
HZN
o N methoxypiperidin-l-
yl)ethylcarbamoyl)benzoate
ci o 0 H (R)-quinuclidin-3-y14-(2-((3R,4S)-
NH ,,... 4-(6-amino-5-chloro-2-
HZN / \ 0
N- HN N--/ N methoxynicotinamido)-3-
/ methoxypiperidin-l-
yl)ethylcarbamoyl)benzoate
ci 0 0 H (R)-quinuclidin-3-y14-(2-((3R,4S)-
HZN ~NH~O,,=,.. 4-(6-amino-5-chloro-2-oxo-1,2-
HN HN N ~ dihydropyridine-3-carboxamido)-3-
O N
methoxypiperidin-l-
yl)ethylcarbamoyl)benzoate
The following compounds may be prepared essentially according to methods and
procedures described above. The compound names were generated using either
ChemDraw
Ultra version 8.03 and/or 9.0, which is available from Cambridgesoft Corp.
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"1 O 0
N NH ~ benzyl 3-((3S,4R)-4-(6-amino-5-
H,N ~ O chloro-2-methoxynicotinamido)-
CI ~ 3-methoxypiperidin-l-
N ~ yl)propanoate
YO
O
O
O isopropyl 3-((3R,4S)-4-(6-
amino-5-chloro-2-
CI N methoxynicotinamido)-3-
HZN I N O H O~ methoxypiperidin-l-
yl)propanoate
0
O 4-(methylsulfonyl)benzyl 3-
O ((3R,4S)-4-(6-amino-5-chloro-2-
CI N S\ methoxynicotinamido)-3-
HZN N O H ~O O methoxypiperidin-l-
yl)propanoate
0 (tetrahydro-2H-pyran-2-
O N~O O yl)methyl 3-((3R,4S)-4-(6-
CI ~ amino-5-chloro-2-
N methoxynicotinamido)-3-
HaN I 7" O H O~ methoxypiperidin-l-
yl)propanoate
~l\ ~ cyclohexyl 3-((3R,4S)-4-(6-
0 N O amino-5-chloro-2-
CI N methoxynicotinamido)-3-
~ H methoxypiperidin-l-
HzN N O yl)propanoate
O 0
N NH ~ neopentyl 3-((3S,4R)-4-(6-
H,N I O amino-5-chloro-2-
CI methoxynicotinamido)-3-
N o methoxypiperidin-l-
\/' yl)propanoate
O I
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0
O 4-methoxybenzyl 3-((3R,4S)-4-
(6-amino-5-chloro-2-
CI N p methoxynicotinamido)-3-
~ H methoxypiperidin-l-
HZN N O yl)propanoate
0
O O pyridin-4-ylmethyl3-((3R,4S)-4-
~ N (6-amino-5-chloro-2-
N N methoxynicotinamido)-3-
HN H methoxypiperidin-l-
~ CI yl)propanoate
O 0
2-((3S,4R)-4-(6-amino-5-chloro-
y:--- NH
H2N 2-methoxynicotinamido)-3-
CI N methoxypiperidin-l-yl)acetic
l/OH acid
~p(
0
N~ 2-(pyrrolidin-1-yl)ethyl 4-(((2-
N ((3S,4R)-4-(6-amino-5-chloro-2-
0 ~N methoxynicotinamido)-3-
CI N" methoxypiperidin-l-
~ H yl)ethyl)(methyl)amino)methyl)b
H2N N O enzoate
1-methylpiperidin-4-yl 4-(((2-
~~N ((3S,4R)-4-(6-amino-5-chloro-2-
O N methoxynicotinamido)-3-
CI methoxypiperidin-l-
~ HN yl)ethyl)(methyl)amino)methyl)b
H'N N 0 enzoate
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O rO
i~N 2-morpholinoethyl 4-(((2-
N O ((3S,4R)-4-(6-amino-5-chloro-2-
0 methoxynicotinamido)-3-
c i methoxypiperidin-l-
~ H o yl)ethyl)(methyl)amino)methyl)b
H2N N O ~ enzoate
O 0
N NH
I, u 4-fluorobenzyl 2-((3 S,4R)-4-(6-
H2N amino-5-chloro-2-
CI (N) F methoxynicotinamido)-3-
y methoxypiperidin-l-yl)acetate
0
O 0
N NH I
H2N ~ O benzyl 2-((3S,4R)-4-(6-ainino-5-
~I chloro-2-methoxynicotinamido)-
N / I 3-methoxypiperidin-1-yl)acetate
0
O 0
N NH o 4-methylbenzyl 2-((3S,4R)-4-(6-
H2N amino-5-chloro-2-
CI CJN" methoxynicotinamido)-3-
O methoxypiperidin-l-yl)acetate
O
O 0
N ~ NH
, p 2-methoxybenzyl 2-((3 S,4R)-4-
H2N (6-amino-5-chloro-2-
CI N methoxynicotinamido)-3-
yO p methoxypiperidin-1-yl)acetate
0 O1-1
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'1-, O 0
N ~ NH
I u 4-chlorobenzyl 2-((3 S,4R)-4-(6-
H2N amino-5-chloro-2-
CI (N'~ CI methoxynicotinamido)-3-
O methoxypiperidin-l-yl)acetate
0
O,"
0
O ~ I 4-methoxybenzyl 2-((3R,4R)-4-
(6-amino-5-chloro-2-
CI X NO
methoxynicotinamido)-3-
HzN N0 H O methoxypiperidin-l-yl)acetate
I
O 0
N NH
a,o piperidin-4-yl 2-((3S,4R)-4-(6-
H2N amino-5-chloro-2-
CI methoxynicotinamido)-3-
O methoxypiperidin-1-yl)acetate
O NH
O 0
N NH
I, aI#o 2-methoxyethyl 2-((3 S,4R)-4-(6-
H,N ~ amino-5-chloro-2-
CI N methoxynicotinamido)-3-
yO\~O~ methoxypiperidin-l-yl)acetate
0
O 0
N ~ NH
cJ,Q 2-hydroxyethyl 2-((3 S,4R)-4-(6-
HZN amino-5-chloro-2-
CI N methoxynicotinamido)-3-
y O'-methoxypiperidin-1-yl)acetate
~OH
0
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o 2-chlorobenzyl 2-((3R,4S)-4-(6-
CI 0 CI amino-5-chloro-2-
H methoxynicotinamido)-3-
H2N N 0 O methoxypiperidin-l-yl)acetate
0
H OH 4-((2-((3S,4R)-4-(6-amino-5-
0 N chloro-2-methoxynicotinamido)-
CI 3-methoxypiperidin-l-
N" yl)ethylamino)methyl)benzoic
H2N N 0 H 0 acid
0
H O-~OH 3-hydroxypropyl 4-((2-((3S,4R)-
0 N 4-(6-amino-5-chloro-2-
CI methoxynicotinamido)-3-
X7,xl H methoxypiperidin-l-
H,N O yl)ethylamino)methyl)benzoate
O ~NH
H O piperidin-4-yl 4-((2-((3S,4R)-4-
0 (6-amino-5-chloro-2-
CI methoxynicotinamido)-3-
~ methoxypiperidin-l-
H2N N 0 H 1-10 yl)ethylamino)methyl)benzoate
F F
O F 4-(trifluoromethyl)benzyl 2-
O ~ ((3R,4S)-4-(6-amino-5-chloro-2-
CI N 0 methoxynicotinamido)-3-
~ H 0 methoxypiperidin-1-yl)acetate
HaN N 0
O 3-methylbenzyl 2-((3R,4S)-4-(6-
CI N O amino-5-chloro-2-
H methoxynicotinamido)-3-
H,N N 0 O~ methoxypiperidin-l-yl)acetate
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/
O N~-O ~ I CI 3-chlorobenzyl 2-((3R,4S)-4-(6-
CI O amino-5-chloro-2-
N methoxynicotinamido)-3-
HZN I ~ N 0 H O'~, methoxypiperidin-1-yl)acetate
O N--yO 2-(trifluoromethyl)benzyl 2-el: CI 0 F F ((3R,4S)-4-(6-amino-5-chloro-
2-
N methoxynicotinamido)-3-
F
H
HzN N O Oll, methoxypiperidin-l-yl)acetate
O 2-morpholinoethyl 2-((3R,4S)-4-
CI N O ~O (6-amino-5-chloro-2-
HZN N O H O~ methoxynicotinamido)-3-
I methoxypiperidin-1-yl)acetate
O~ (tetrahydro-2H-pyran-2-
yl)methyl N~ O 2-((3R,4S)-4-(6-
CI ~ N O amino-5-chloro-2-
~ H O methoxynicotinamido)-3-
HaN N O N O methoxypiperidin-1-yl)acetate
O N~O ~ I 2-fluorobenzyl 2-((3R,4S)-4-(6-
CI O F amino-5-chloro-2-
N methoxynicotinamido)-3-
HZN I N O H 0111. methoxypiperidin-1-yl)acetate
0
/ OH
N ~ ~ 4-(2-((3 S,4R)-4-(6-amino-5-
O chloro-2-methoxynicotinamido)-
CI '-~z N,. N 0 3-methoxypiperidin-1-
H = yl)ethylcarbamoyl)benzoic acid
H2N N O Oll,
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H O Oj::)H
piperidin-4-yl 4-(2-((3S,4R)-4-
0 N (6-amino-5-chloro-2-
methoxynicotinamido)-3-
CI N~,' 0 methoxypiperidin-l-
H N N O H "lO yl)ethylcarbamoyl)benzoate
Z
O N~O ~ I F 3-fluorobenzyl 2-((3R,4S)-4-(6-
CI 17, H O amino-5-chloro-2-
methoxynicotinamido)-3-
HZN 0 O methoxypiperidin- 1 -yl)acetate
0 O 3-methoxybenzyl 2-((3R,4S)-4-
CI 0 (6-amino-5-chloro-2-
N methoxynicotinamido)-3-
H,N I ~ N 0 H 01*11 methoxypiperidin-l-yl)acetate
0
O N~O oS~ 2-(methylsulfonyl)ethyl 2-
CI N O ((3R,4S)-4-(6-amino-5-chloro-2-
~ H O methoxynicotinamido)-3-
H2N N O ~ O ~ methoxypiperidin- 1 -yl)acetate
0
isopropyl 2-((3R,4S)-4-(6-
CI O
N amino-5-chloro-2-
C H 011-1 methoxynicotinamido)-3-
HaN N O methoxypiperidin-1-yl)acetate
CI I H O ethyl 2-((3R,4S)-4-(6-amino-5-
chloro-2-methoxynicotinamido)-
H2N N O O1~1 3-methoxypiperidin-1-yl)acetate
O JJN~ I\ 2-(pyridin-2-yl)ethyl 2-((3R,4S)-
CI N O N~ 4-(6-amino-5-chloro-2-
HZN N 0 H methoxynicotinamido)-3-
methoxypiperidin-l-yl)acetate
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/ I
o N~O ~N pyridin-2-ylmethyl2-((3R,4S)-4-
(6-amino-5-chloro-2-
CI N O methoxynicotinamido)-3-
HaN N 0 H O~ methoxypiperidin-1-yl)acetate
O N~O ~ N pyridin-3-ylmethyl2-((3R,4S)-4-
CI O (6-amino-5-chloro-2-
N methoxynicotinamido)-3-
H2N I N O H O'-, methoxypiperidin-1-yl)acetate
O,NH piperidin-3-ylmethyl 2-((3R,4S)-
O
CI O 4-(6-amino-5-chloro-2-
N inethoxynicotinamido)-3-
HZN I N O H O'-, methoxypiperidin-1-yl)acetate
O N~O
cyclohexyl 2-((3R,4S)-4-(6-
CI ~ N O amino-5-chloro-2-
~ ~ H o methoxynicotinamido)-3-
H2N N O ll,
methoxypiperidin-l-yl) acetate
H
O NN O 2-(4-(2-((3S,4R)-4-(6-amino-5-
chloro-2-methoxynicotinamido)-
CI ~ N . ,.=G O OH
~ H 0 3-methoxypiperidin-l-
HZN N O O yl)acetamido)phenyl)acetic acid
H
0 ON N O ethyl 2-(4-(2-((3S,4R)-4-(6-
CI ~ O amino-5-chloro-2-
N O~ methoxynicotinamido)-3-
HaN I N O H 6 methoxypiperidin-
yl)acetamido)phenyl)acetate
H
ONN O 1-methylpiperidin-4-yl 2-(4-(2-
0
CI O ((3S,4R)-4-(6-amino-5-chloro-2-
N~ methoxynicotinamido)-3-
HZN N O H 0 methoxypiperidin-l-
yl)acetamido)phenyl)acetate
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H
0 N,~yN 3-hydroxypropyl 2-(4-(2-
CI O I ((3S,4R)-4-(6-amino-5-chloro-2-
~ N'~= O-~~OH methoxynicotinamido)-3-
HZN x N O H 1-10 methoxypiperidin-l-
yl)acetamido)phenyl)acetate
H
CI ~ quinuclidin-3-yl 2-(4-(2-
N O
O
()N
0 ~j L ~N ((3S,4R)-4-(6-amino-5-chloro-2-
~ N, 0 ~ methoxynicotinamido)-3-
H~N I N O HO methoxypiperidin-l-
~ -
~ yl)acetamido)phenyl)acetate
O O 1-methoxypropan-2-yl 2-
CI N O ((3R,4S)-4-(6-amino-5-chloro-2-
H~N N O H methoxynicotinamido)-3-
methoxypiperidin-l-yl)acetate
O*-,
0 N~O I O,- 2,3,4-trimethoxybenzyl 2-
((3R,4S)-4-(6-amino-5-chloro-2-
CI N O O1-1 methoxynicotinamido)-3-
HzN I ~N O H i0 methoxypiperidin-1-yl)acetate
I
O Ny O 0-1 2,3-dimethoxybenzyl2-((3R,4S)-
CI O O~ 4-(6-amino-5-chloro-2-
N methoxynicotinamido)-3-
HZN N 0 H O1-1 methoxypiperidin-1-yl)acetate
F
O N~O ~ I 1-(4-fluorophenyl)ethyl 2-
((3R,4S)-4-(6-amino-5-chloro-2-
CI N O methoxynicotinamido)-3-
17: H O methoxypiperidin-l-yl)acetate
H2N N 0
3-(4-fluorophenoxy)propyl 2-
0
CI N O F ((3R,4S)-4-(6-amino-5-chloro-2-
HZN N O H O~ methoxynicotinamido)-3-
I methoxypiperidin-l-yl)acetate
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1-1 O 0
0 3-fluoro-4-methylbenzyl 2-
y:r---r NH
HaN ((3S,4R)-4-(6-amino-5-chloro-2-
CI N , methoxynicotinamido)-3-
y O ~ methoxypiperidin-1-yl)acetate
F
0
O 0
N/ NH CljO 4-fluoro-3-methylbenzyl 2-
H2N ((3S,4R)-4-(6-amino-5-chloro-2-
CI N / F methoxynicotinamido)-3-
O methoxypiperidin-l-yl)acetate
~
0
O 0
N ~ NH
, u 2-fluoro-6-methylbenzyl 2-
HzN ((3S,4R)-4-(6-amino-5-chloro-2-
CI I C N F methoxynicotinamido)-3-
0 methoxypiperidin- 1 -yl)acetate
0
O N~O
tetrahydro-2H-pyran-4-yl 2-
CI N O O ((3R,4S)-4-(6-amino-5-chloro-2-
H2N I N O H O1-1 methoxynicotinamido)-3-
methoxypiperidin-1-yl)acetate
H
O N 6-amino-5-chloro-N-((3S,4R)-1-
CI O (2-(4-hydroxyphenylamino)-2-
~ H OH oxoethyl)-3-methoxypiperidin-4-
H,N N O yl)-2-methoxynicotinamide
H
O O 4-(2-((3 S,4R)-4-(6-amino-5-
CI ~ O chloro-2-methoxynicotinamido)-
~ ~ H 3-methoxypiperidin-l-
H2N N 0 O yl)acetamido)phenyl acetate
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O
2-(2-methoxyethoxy)ethyl 2-
CI N O ((3R,4S)-4-(6-amino-5-chloro-2-
~ H O methoxynicotinamido)-3-
HzN N O O methoxypiperidin-l-yl)acetate
O 2-(2-(2-
CI O methoxyethoxy)ethoxy)ethyl 2-
N ((3R,4S)-4-(6-amino-5-chloro-2-
HaN N O H Oll, methoxynicotinamido)-3-
~ methoxypiperidin- 1 -yl)acetate
,-~O 0
N/ NH neopentyl 2-((3S,4R)-4-(6-
H,N amino-5-chloro-2-
CI methoxynicotinamido)-3-
methoxypiperidin-1-yl)acetate
0
'-1O 0
N ~ NH
HaN I (1x0 2-(piperazin-2-yl)ethyl 2-
CI ((3S,4R)-4-(6-amino-5-chloro-2-
N H methoxynicotinamido)-3-
y O N methoxypiperidin-l-yl)acetate
O ~ J
N
H
0 --y O pyridin-4-ylmethyl2-((3R,4S)-4-
O (6-amino-5-chloro-2-
methoxynicotinamido)-3-
CI 17:1 H
tate
HZN N O O~ methoxypiperidin-l-yl)acetate
CI O ~ ~ OH 4-(3-((3S,4R)-4-(6-amino-5-
N"' chloro-2-methoxynicotinamido)-
~ H p 3-methoxypiperidin-l-
H2N N 0 yl)propyl)benzoic acid
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O 2-morpholinoethyl 4-(3-
ci ll~l 011-~"N ((3S,4R)-4-(6-amino-5-chloro-2-
~ H = methoxynicotinamido)-3-
H,N N O O 0 methoxypiperidin-l-
I yl)propyl)benzoate
O ON 2-(pyrrolidin-l-yl)ethyl 4-(3-
CI O~, N ((3S,4R)-4-(6-amino-5-chloro-2-
I H O 0 methoxynicotinamido)-3-
H2N N O methoxypiperidin-l-
I yl)propyl)benzoate
*~, O 0
N NH
H2N O 1-methylpiperidin-4-yl 4-(3-
CI ((3S,4R)-4-(6-amino-5-chloro-2-
N methoxynicotinamido)-3-
methoxypiperidin-l-
yl)propyl)benzoate
O ON~
0
N' v 'OH (R)-3-((3R,4S)-4-(6-amino-5-
O 0
N N chloro-2-methoxynicotinamido)-
I / H 3-methoxypiperidin-1-yl)-2-
HZN methylpropanoic acid
CI
0
O O --~AO (R)-methyl 3-((3R,4S)-4-(6-
amino-5-chloro-2-
N N methoxynicotinamido)-3-
H2N H Oll, methoxypiperidin-l-yl)-2-
CI methylpropanoate
0
O O 4-(methylsulfonyl)benzyl 3-
I /O ((3R,4S)-4-(6-amino-5-chloro-2-
N N ,/S"l methoxynicotinamido)-3-
HaN H O methoxypiperidin-1-yl)-2-
CI methylpropanoate
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0
~O O N *LO 4-fluorobenzyl 3-((3R,4S)-4-(6-
amino-5-chloro-2-
N N methoxynicotinamido)-3-
/ H ~O methoxypiperidin-1-yl)-2-
H~N methylpropanoate
CI
0
O O N' Y 'O ~ (S)-4-(methylsulfonyl)benzyl 3-
0 ((3R,4S)-4-(6-amino-5-chloro-2-
N N SNI methoxynicotinamido)-3-
HZN H 1-10 O methoxypiperidin-1-yl)-2-
CI methylpropanoate
0
O 0 OH (S)-3-((3R,4S)-4-(6-amino-5-
N chloro-2-methoxynicotinamido)-
H O 3-methoxypiperidin-l-yl)-2-
HZN methylpropanoic acid
CI
0
O O ' Y 'O (S)-methyl 3-((3R,4S)-4-(6-
1 amino-5-chloro-2-
N N methoxynicotinamido)-3-
HZN H 0~1 methoxypiperidin-l-yl)-2-
methylpropanoate
CI
O OH
4-((3R,4S)-4-(6-amino-5-chloro-
CI O
N 2-methoxynicotinamido)-3-
H,N I N O H O~ methoxypiperidin-l-yl)butanoic
acid
O 0
N NH
I 0 4-fluorobenzyl 6-((3S,4R)-4-(6-
HZN amino-5-chloro-2-
CI N methoxynicotinamido)-3-
O methoxypiperidin- 1 -yl)hexanoate
0
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O H \O
~-O 2-methoxyethyl 6-((3 S,4R)-4-(6-
~ amino-5-chloro-2-
N ~ / N O methoxynicotinamido)-3-
CI methoxypiperidin-1-yl)hexanoate
H2N 1~1 O 0
N NH
I ~ neopentyl 6-((3 S,4R)-4-(6-
HZN amino-5-chloro-2-
CI L methoxynicotinamido)-3-
0 methoxypiperidin-1-yl)hexanoate
0 O 0
\
N / NH o pyridin-2-ylmethyl6-((3S,4R)-4-
H,N (6-amino-5-chloro-2-
CI N methoxynicotinamido)-3-
O methoxypiperidin-l-yl)hexanoate
N
0
O 0
NN H ~ 2-(piperazin- 1 -yl)ethyl 6-
HZN CJ10 ((3S,4R)-4-(6-amino-5-chloro-2-
CI methoxynicotinamido)-3-
N methoxypiperidin-l-yl)hexanoate
N~ hydrochloride
0 ~NH
O N ~ N 2-(dimethylamino)ethyl 6-
CI \ O ((3S,4R)-4-(6-amino-5-chloro-2-
~ N H H methoxynicotinamido)-3-
H,N N O methoxypiperidin-l-yl)hexanoate
O 1-adamantylmethyl 6-[(3S,4R)-4-
0 N {[(6-amino-5-chloro-2-
CI ~ N,,= O methoxypyridin-3-
H '- yl)carbonyl]amino}-3-
H2N N 0 i0 methoxypiperidin-1-yl]hexanoate
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O
N
cyclohexyl 6-((3 S,4R)-4-(6-
CI O
N~,= O amino-5-chloro-2-
H - methoxynicotinamido)-3-
nc,
HzN N O O~ O~ methoxypiperidin-l-yl)hexanoate
O N O 2-adamantyl 6-[(3S,4R)-4-{[(6-
CI N~,=G O amino-5-chloro-2-
I H = methoxypyridin-3-
HaN N O i0 yl)carbonyl]amino}-3-
methoxypiperidin-1-yl]hexanoate
0
O ON bicyclo[2.2.1]heptan-2-yl 6-
CI O ((3S,4R)-4-(6-amino-5-chloro-2-
~ H - methoxynicotinamido)-3-
HzN N O -O methoxypiperidin-1-yl)hexanoate
O 0
N ~ NH
HZN c1x ~ 2-(2-((3S,4R)-4-(6-amino-5-
CI chloro-2-methoxynicotinamido)-
N 3-methoxypiperidin-l-
0 yl)ethoxy)acetic acid
Ov 'OH
0
O --,OJ~O methyl 2-(2-((3R,4S)-4-(6-
CI ~ amino-5-chloro-2-
~ N methoxynicotinamido)-3-
~ ~ H O methoxypiperidin-l-
HZN N 0
yl)ethoxy)acetate
I
O 0
N NH ~ cyclohexyl 2-(2-((3S,4R)-4-(6-
H~N CX0 amino-5-chloro-2-
CI methoxynicotinamido)-3-
N methoxypiperidin-l-
O yl)ethoxy)acetate
O v 'O
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,,,pJ~0,10 cyclohexyl 2-(2-((3R,4S)-4-(6-
0 N amino-5-chloro-2-
CI 11-~ N methoxynicotinamido)-3-
~ H 0 methoxypiperidin-l-
HZN N O yl)ethoxy)acetate
o N H
O N OvJ~'p piperidin-4-yl 2-(2-((3R,4S)-4-
(6-amino-5 -chloro-2-
CI ~ N methoxynicotinamido)-3-
~ H 0 methoxypiperidin-l-
HzN N O ~ O ~ yl)ethoxy)acetate hydrochloride
H
O CjN~ N ~ 2-hydroxyethyl 4-(2-((3 S,4R)-4-
CI O O~~ (6-amino-5-chloro-2-
N OH methoxynicotinamido)-3-
H N N O H i0 0 methoxypiperidin-l-
Z I yl)acetamido)benzoate
O 0
N ~ NH ~
HZN 2-amino-2-oxoethyl 4-(2-
((3 S,4R)-4-(6-amino-5-chloro-2-
CI N methoxynicotinamido)-3-H y N methoxypiperidin-l-
yl)acetamido)benzoate
O I 0
O---~-NH,
0
H
O NN 2-(piperazin-1-yl)ethyl 4-(2-
CI O O~~ ((3S,4R)-4-(6-amino-5-chloro-2-
~ N"G N methoxynicotinamido)-3-
HN I N O H i0 0 ~NH methoxypiperidin-1-
a ~ yl)acetamido)benzoate
O O
N ~ NH 1-(2-((3S,4R)-4-(6-amino-5-
H2N ~ p chloro-2-methoxynicotinamido)-Ar ':~ CI CN OH yl)acetyl)piperidine-4-
carboxylic
~yN acid
0
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'1-, O 0
N NH methyl1-(2-((3S,4R)-4-(6-
~ , u amino-5-chloro-2-
H2N O methoxynicotinamido)-3-
CI N O methoxypiperidin-l-
~ N ~ yl)acetyl)piperidine-4-
carboxylate
0
O 0
N ~ NH ethyll-(2-((3S,4R)-4-(6-amino-
I , o 5-chloro-2-
H2N O methoxynicotinamido)-3-
CI
CJ" f N O-' methoxypiperidin-1-
~ N yl)acetyl)piperidine-4-
carboxylate
0
O 0
N NH 2-methoxyethyl1-(2-((3S,4R)-4-
I u (6-amino-5-chloro-2-
HzN O methoxynicotinamido)-3-
CI N O~~O~ methoxypiperidin-l-
N yl)acetyl)piperidine-4-
carboxylate
0
O N/~OH
6-amino-5-chloro-N-((3R,4S)-1-
CI N (2-hydroxyethyl)-3-
HZN I N O H O~ methoxypiperidin-4-yl)-2-
methoxynicotinamide
I
O NH
CI N 6-amino-5-chloro-2-methoxy-N-
H ((3R,4S)-3-methoxypiperidin-4-
HaN N 0 ONI yl)nicotinamide
6-amino-5-chloro-N-((3R,4S)-1-
0 N O
CI (3-(4-fluorophenoxy)propyl)-3-
N methoxypiperidin-4-yl)-2-
H2N I N 0 H O~ methoxynicotinamide
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O O
H\ I NH o benzyl3-((3S,4R)-4-(6-amino-5-
H2N chloro-2-oxo-1,2-dihydropyridine-
CI / 3-carboxamido)-3-
N~ ,p ~ I methoxypiperidin-l-yl)propanoate
~O
0
isopropyl 3-((3R,4S)-4-(6-amino-
0 N' v 'O 5-chloro-2-oxo-1,2-
CI N dihydropyridine-3-carboxamido)-
~ H 3-methoxypiperidin-l-
HZN H O yl)propanoate
0
4-(methylsulfonyl)benzyl3-
0 N O I~ O ((3R,4S)-4-(6-amino-5-chloro-2-
CI N S oxo-1,2-dihydropyridine-3-
( H O carboxamido)-3-
H~N H O ~ methoxypiperidin-1-yl)propanoate
0
O (tetrahydro-2H-pyran-2-yl)methyl
0 N ~ 3-((3R,4S)-4-(6-amino-5-chloro-2-
CI N oxo-1,2-dihydropyridine-3-
H carboxamido)-3-
H,N H O methoxypiperidin- 1 -yl)propanoate
0
~-~~ cyclohexyl3-((3R,4S)-4-(6-amino-
O O 5-chloro-2-oxo-1,2-
CI N dihydropyridine-3-carboxamido)-
H O 3-methoxypiperidin-l-
H2N H N 0 yl)propanoate
O O
HN I NH ~ neopentyl3-((3S,4R)-4-(6-amino-
HZN O 5-chloro-2-oxo-1,2-
CI dihydropyridine-3-carboxamido)-
N 0 3-methoxypiperidin-l-
L"'O~ yl)propanoate
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0
4-methoxybenzyl 3-((3R,4S)-4-(6-
O N O amino-5-chloro-2-oxo-1,2-
CI N Oi dihydropyridine-3-carboxamido)-
~ H O 3-methoxypiperidin-l-
HZN H N 0 ~ yl)propanoate
0
O 0 pyridin-4-ylmethyl3-((3R,4S)-4-
~ (6-amino-5-chloro-2-oxo-1,2-
HN N dihydropyridine-3-carboxamido)-
HZN ~ H 3-methoxypiperidin-l-
CI yl)propanoate
O O
HZN HN NH
p 2-((3 S,4R)-4-(6-amino-5-chloro-2-
"" oxo-1,2-dihydropyridine-3 -
CI N carboxamido)-3-
OH methoxypiperidin-1-yl)acetic acid
0
O
2-(pyrrolidin-1-yl)ethyl4-(((2-
~ O~~ N ((3 S,4R)-4-(6-amino-5-chloro-2-
O N oxo-1,2-dihydropyridine-3-
CI carboxamido)-3-
r,N H methoxypiperidin-l-
HH O yl)ethyl)(methyl)amino)methyl)be
nzoate
O N 1-methylpiperidin-4-yl4-(((2-
~ O ((3S,4R)-4-(6-amino-5-chloro-2-
0 N oxo-1,2-dihydropyridine-3-
CI carboxamido)-3-
I H methoxypiperidin-l-
~p yl)ethyl)(methyl)amino)methyl)be
H2N N O nzoate
O rO 2-morpholinoethyl4-(((2-
i ((3S,4R)-4-(6-amino-5-chloro-2-
0 N oxo-1,2-dihydropyridine-3-
CI carboxamido)-3-
I H' methoxypiperidin-l-
p yl)ethyl)(methyl)amino)methyl)be
HaN H O nzoate
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O O
HN NH
4-fluorobenzyl 2-((3 S,4R)-4-(6-
H2N amino-5-chloro-2-oxo-1,2-
CI N F dihydropyridine-3-carboxamido)-
O 3-methoxypiperidin-1-yl)acetate
O
O O
HN NH
benzyl 2-((3S,4R)-4-(6-amino-5-
H2N chloro-2-oxo-1,2-dihydropyridine-
CI N 0;---
y 3-carboxamido)-3-
O methoxypiperidin-l-yl)acetate
0
O O
HNH
p 4-methylbenzyl 2-((3S,4R)-4-(6-
H,N amino-5-chloro-2-oxo-1,2-
CI N dihydropyridine-3-carboxamido)-
O 3-methoxypiperidin-1-yl)acetate
O
O O
HN I NH
p 2-methoxybenzyl 2-((3S,4R)-4-(6-
H,N r ':~ amino-5-chloro-2-oxo-1,2-
CI N dihydropyridine-3-carboxamido)-
y O 3-methoxypiperidin-1-yl)acetate
O Oll,
O O
HN NH
p 4-chlorobenzyl 2-((3S,4R)-4-(6-
H2N amino-5-chloro-2-oxo-1,2-
CI N CI dihydropyridine-3-carboxamido)-
O 3-methoxypiperidin-1-yl)acetate
0
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O ~ I 4-methoxybenzyl2-((3R,4R)-4-(6-
0 N~
amino-5-chloro-2-oxo-1,2-
CI r H, O dihydropyridine-3-carboxamido)-
HZN N O O~ 3-methoxypiperidin-1-yl)acetate
O O
HN NH ~
H~N c1x0 piperidin-4-y12-((3S,4R)-4-(6-
amino-5-chloro-2-oxo-1,2-
CI N dihydropyridine-3-carboxamido)-
y0 3-methoxypiperidin-1-yl)acetate
0 NH
O O
HN NH
c3o 2-methoxyethyl 2-((3S,4R)-4-(6-
H2N "' amino-5-chloro-2-oxo-1,2-
CI N dihydropyridine-3-carboxamido)-
yO\~O~ 3 -methoxypiperidin- 1 -yl)acetate
0
O O
NH
O\ 2-hydroxyethyl2-((3S,4R)-4-(6-
H2NHN amino-5-chloro-2-oxo-1,2-
CI N dihydropyridine-3-carboxamido)-
I-r 0"~3-methoxypiperidin-1-yl)acetate
OH
0
O O 2-chlorobenzyl2-((3R,4S)-4-(6-
amino-5-chloro-2-oxo-1,2-
CI H O CI dihydropyridine-3-carboxamido)-
H2N H O O~ 3-methoxypiperidin-1-yl)acetate
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0
OH 4-((2-((3S,4R)-4-(6-amino-5-
H 0 NN chloro-2-oxo-1,2-dihydropyridine-
CI 3-carboxamido)-3-
I H' methoxypiperidin-l-
HZN N 0 yl)ethylamino)methyl)benzoic acid
0
3-hydroxypropyl4-((2-((3S,4R)-4-
H 0 N (6-amino-5-chloro-2-oxo-1,2-
CI dihydropyridine-3-carboxamido)-
rN:] N3-methoxypiperidin-l-
HZN O yl)ethylamino)methyl)benzoate
O JDNH
piperidin-4-y14-((2-((3 S,4R)-4-(6-
N amino-5-chloro-2-oxo-1,2-
CI O dihydropyridine-3-carboxamido)-
N 3-methoxypiperidin-l-
H ~~ yl)ethylamino)methyl)benzoate
HZN H 0 O
F F
F 4-(trifluoromethyl)benzyl2-
0 O ((3R,4S)-4-(6-amino-5-chloro-2-
oxo-1,2-dihydropyridine-3 -
CI H 0 carboxamido)-3-
H,N N 0 O methoxypiperidin-1-yl)acetate
O I 3-methylbenzyl2-((3R,4S)-4-(6-
O
amino-5-chloro-2-oxo-1,2-
CI r H 0 dihydropyridine-3-carboxamido)-N HZN N 0 O 3-methoxypiperidin-1-
yl)acetate
3-chlorobenzyl2-((3R,4S)-4-(6-
O N~O CI
CI H O amino-5-chloro-2-oxo-1,2-
dihydropyridine-3-carboxamido)-
H, N H N:] 0 O~ 3-methoxypiperidin-1-yl)acetate
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2-(trifluoromethyl)benzyl2-
o ((3R,4S)-4-(6-amino-5-chloro-2-
CI N 0 F F oxo-1,2-dihydropyridine-3-
~ H p F carboxamido)-3-
H2 N H N:] O methoxypiperidin-1-yl)acetate
O 2-morpholinoethyl2-((3R,4S)-4-
C N O ~O (6-amino-5-chloro-2-oxo-1,2-
H p dihydropyridine-3-carboxamido)-
HaN H O
3 -methoxypiperidin-l-yl) acetate
~ (tetrahydro-2H-pyran-2-yl)methyl
O N~ O 2-((3R,4S)-4-(6-amino-5-chloro-2-
CI rN: N O oxo-1,2-dihydropyridine-3-
H p carboxamido)-3-
HZN H O methoxypiperidin-l-yl)acetate
O N~O 2-fluorobenzyl2-((3R,4S)-4-(6-
CI O F amino-5-chloro-2-oxo-1,2-
H dihydropyridine-3-carboxamido)-
3-methoxypiperidin-l-yl)acetate
H2 N H N O
0
H / OH 4-(2-((3S,4R)-4-(6-amino-5-
O N~~N chloro-2-oxo-1,2-dihydropyridine-
CI " Gp 3-carboxamido)-3-
H methoxypiperidin-l-
H,N H O O yl)ethylcarbamoyl)benzoic acid
O NH
/ O piperidin-4-y14-(2-((3S,4R)-4-(6-
O N ( amino-5-chloro-2-oxo-1,2-
dihydropyridine-3-carboxamido)-
CI r H O 3-methoxypiperidin-l-
~p yl)ethylcarbamoyl)benzoate
HZN H O
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O N~O ~ I F 3-fluorobenzyl2-((3R,4S)-4-(6-
amino-5 -chloro-2-oxo-1,2-
CI r H O dihydropyridine-3-carboxamido)-
H2N H O O~ 3-methoxypiperidin-1 -yl)acetate
O O 3-methoxybenzyl2-((3R,4S)-4-(6-
amino-5 -chloro-2-oxo-1,2-
dihydropyridine-3-carboxamido)-
CI r H 0
3-methoxypiperidin-1-yl)acetate
H2N H 0
2-(methylsulfonyl)ethyl2-
O S0
~ ((3R,4S)-4-(6-amino-5-chloro-2-
CI H 0 oxo-1,2-dihydropyridine-3-
O1-1 carboxamido)-3-
methoxypiperidin-1-yl)acetate
HZN H 0
O
isopropyl2-((3R,4S)-4-(6-amino-
CI N 0
5-chloro-2-oxo-1,2-
H O dihydropyridine-3-carboxamido)-
HzN H O O
3 -methoxypiperidin-l-yl) acetate
O
ethyl2-((3R,4S)-4-(6-amino-5-
CI ~ N 0
chloro-2-oxo-1,2-dihydropyridine-
~ H 3-carboxamido)-3-
HZN H 0 methoxypiperidin-1-yl)acetate
CI O N, 2-(pyridin-2-yl)ethyl2-((3R,4S)-4-
~ N (6-amino-5-chloro-2-oxo-1,2-
H O dihydropyridine-3-carboxamido)-
HZN H O 3-methoxypiperidin-1-yl)acetate
O N1O pyridin-2-ylmethyl2-((3R,4S)-4-
(6-amino-5-chloro-2-oxo-1,2-
CI 0
~ N dihydropyridine-3-carboxamido)-
HZN N 0 O~ 3-methoxypiperidin-1-yl)acetate
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O " - ~, r O )",
pyridin-3-ylmethyl 2-((3R,4S)-4- oj:: (6-amino-5-chloro 2 oxo 1,2
CI H O dihydropyridine-3-carboxamido)-
H2N N O 3-methoxypiperidin-l-yl)acetate
O,_NH piperidin-3-ylmethyl 2-((3R,4S)-4-
O
CI H O (6-amino-5-chloro-2-oxo-1,2-
dihydropyridine-3-carboxamido)-
H,N N O 3-methoxypiperidin-1-yl)acetate
cyclohexyl 2-((3R,4S)-4-(6-amino-
O - - - -
CI r N O 5 chloro-2 oxo 1,2
H O'-, dihydropyridine-3-carboxamido)-
H2N H N O 3-methoxypiperidin-1-yl)acetate
H
O N~N O 2-(4-(2-((3S,4R)-4-(6-amino-5-
CI 0 chloro-2-oxo-1,2-dihydropyridine-
I H'' OH 3-carboxamido)-3-
methoxypiperidin-l-
HZN H 0
yl)acetamido)phenyl)acetic acid
H
O 0 ethyl 2-(4-(2-((3 S,4R)-4-(6-amino-
CI O 5-chloro-2-oxo-1,2-
I H O~ dihydropyridine-3-carboxamido)-
~O 3-methoxypiperidin-l-
H2N H 0 yl)acetamido)phenyl)acetate
H 1-methylpiperidin-4-y12-(4-(2-
O N~N ::~ j ((3S,4R)-4-(6-amino-5-chloro-2-
CI G O oxo-1,2-dihydropyridine-3-
~ H carboxamido)-3-
HZN H O methoxypiperidin-l-
yl)acetamido)phenyl)acetate
H
0 -hydroxypropyl2-(4-(2-((3S,4R)-
O N N 3
~ 4-(6-amino-5-chloro-2-oxo-1,2-
CI O i~/~
H O OH dihydropyridme-3-carboxamido)-
0 3-methoxypiperidin-l-
H,N N O yl)acetamido)phenyl)acetate
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H
~ O quinuclidin-3-y12-(4-(2-((3S,4R)-
0 CjN~ 4-(6-amino-5-chloro-2-oxo-1,2-
CI H\'' O O dihydropyridine-3-carboxamido)-
~p 3-methoxypiperidin-l-
HaN H N:] 0 yl)acetamido)phenyl)acetate
O N~ O-r O 1-methoxypropan-2-y12-((3R,4S)-
CI N O 4-(6-amino-5-chloro-2-oxo-1,2-
~ H O dihydropyridine-3-carboxamido)-
HZN H N:: 0 ~
3 -methoxypiperidin-l-yl)acetate
2,3,4-trimethoxybenzyl2-
0 N~ O ((3R,4S)-4-(6-amino-5-chloro-2-
ci rN:: N O oxo-1,2-dihydropyridine-3-
H carboxamido)-3-
HzN O methoxypiperidin- 1 -yl)acetate
O N~O O~ 2,3-dimethoxybenzyl 2-((3R,4S)-
4(6 amino-5-chloro-2-oxo-1,2-
CI H N O O~ dihydropyridine-3-carboxamido)-
H,N H N O O~ 3-methoxypiperidin-1-yl)acetate
/ F
O 1-(4-fluorophenyl)ethyl2-
0 N~ ((3R,4S)-4-(6-amino-5-chloro-2-
CI N O oxo-1,2-dihydropyridine-3-
H carboxamido)-3-
HZN H N O O~ methoxypiperidin-1-yl)acetate
0 3-(4-fluorophenoxy)propyl2-
((3R,4S)-4-(6-amino-5-chloro-2-
CI 0
rN N F oxo-1,2-dihydropyridine-3-
O~ carboxamido)-3-
HzN H O methoxypiperidin- 1 -yl)acetate
O O
HN I NH ~ 3-fluoro-4-methylbenzyl2-
H2N O ((3S,4R)-4-(6-amino-5-chloro-2-
CI oxo-1,2-dihydropyridine-3-
N ~ carboxamido)-3-
y O ~ I F methoxypiperidin-1-yl)acetate
0
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0 0
H\ NH o 4-fluoro-3-methylbenzyl2-
H,N ((3S,4R)-4-(6-amino-5-chloro-2-
oxo-1,2-dihydropyridine-3-
CI F
carboxamido)-3-
~O methoxypiperidin-1-yl)acetate
0
O 0
HN I NH ~ 2-fluoro-6-methylbenzyl2-
H,N ~ O ((3S,4R)-4-(6-amino-5-chloro-2-
CI F oxo-1,2-dihydropyridine-3-
N carboxamido)-3-
y O methoxypiperidin-l-yl)acetate
0
O N O tetrahydro-2H-pyran-4-y12-
CI ~ O ((3R,4S)-4-(6-amino-5-chloro-2-
I H oxo-1,2-dihydropyridine-3-
HZN N O O~ carboxamido)-3-
H methoxypiperidin-1-yl)acetate
H
O N 6-amino-5-chloro-N-((3 S,4R)-1-
CI 0 (2-(4-hydroxyphenylamino)-2-
I H OH oxoethyl)-3-methoxypiperidin-4-
p yl)-2-oxo-1,2-dihydropyridine-3-
HZN H N 0 \ carboxamide
H
O N O 4-(2-((3S,4R)-4-(6-amino-5-
O chloro-2-oxo-1,2-dihydropyridine-
CI
111~ H 3-carboxamido)-3-
~p methoxypiperidin-l-
HaN H N O yl)acetamido)phenyl acetate
0 2-(2-methoxyethoxy)ethyl2-
CI 0 ((3R,4S)-4-(6-amino-5-chloro-2-N H oxo-1,2-dihydropyridine-3-
HZN N O carboxamido)-3-
H methoxypiperidin-l-yl)acetate
O 2-(2-(2-
methoxyethoxy)ethoxy)ethyl2-
CI I H O ((3R,4S)-4-(6-amino-5-chloro-2-
HZN N O 0~ oxo-1,2-dihydropyridine-3-
H carboxamido)-3-
methoxypiperidin-1-yl)acetate
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O O
HN NH
O\ neopentyl 2-((3S,4R)-4-(6-amino-
H2N 5-chloro-2-oxo-1,2-
CI N dihydropyridine-3-carboxamido)-
0 1 3-methoxypiperidin-1-yl)acetate
y ~\\
0
O O
HN NH I
H2N ClJ0 2-(piperazin-2-yl)ethyl2-((3S,4R)-
CI 4-(6-amino-5-chloro-2-oxo-1,2-
N H dihydropyridine-3-carboxamido)-
YO N 3-methoxypiperidin-1-yl)acetate
O ~ J
N
H
0 N~O I pyridin-4-ylmethyl2-((3R,4S)-4-
(6-amino-5-chloro-2-oxo-1,2-
CI rN:] H O dihydropyridine-3-carboxamido)-
0 3-methoxypiperidin-1-yl)acetate
HZN H O
0 4-(3-((3S,4R)-4-(6-amino-5-
CI ~ N,, ~ OH chloro-2-oxo-1,2-dihydropyridine-
~ H = 3-carboxamido)-3-
methoxypiperidin-l-
HZN N O 0
H yl)propyl)benzoic acid
O N I 2-morpholinoethyl4-(3-((3S,4R)-
CI ~ 4-(6-amino-5-chloro-2-oxo-1,2-
~ H dihydropyridine-3-carboxamido)-
HZN N O ~O O ~O 3-methoxypiperidin-l-
H yl)propyl)benzoate
O 2-(pyrrolidin-1-yl)ethyl4-(3-
CI ((3S,4R)
H N -4-(6-amino-5-chloro-2-
rN:] oxo-l,2-dihydropyridine-3-
O
carboxamido)-3-
HzN O ~O O methoxypiperidin-l-
yl)propyl)benzoate
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O O
HN NH
a,o 1-methylpiperidin-4-y14-(3-
HZN ((3 S,4R)-4-(6-amino-5-chloro-2-
CI N oxo-1,2-dihydropyridine-3-
carboxamido)-3-
methoxypiperidin-l-
~ O yl)propyl)benzoate
O N~
0
0 0 N~OH (R)-3-((3R,4S)-4-(6-amino-5-
chloro-2-oxo-1,2-dihydropyridine-
HN N 3-carboxamido)-3-
H2N ~ H methoxypiperidin-l-yl)-2-
CI methylpropanoic acid
0
0 0 (R)-methyl3-((3R,4S)-4-(6-
amino-5-chloro-2-oxo-1,2-
HN N dihydropyridine-3-carboxamido)-
HZN I H 3-methoxypiperidin-l-yl)-2-
CI methylpropanoate
0 4-(methylsulfonyl)benzyl3- .
0 0 N" Y'O ((3R,4S)-4-(6-amino-5-chloro-2-
I oxo-1,2-dihydropyridine-3-
HH O p~s~ carboxamido)-3-
H2N methoxypiperidin-1-yl)-2-
CI methylpropanoate
0
O 0 N' Y'O 4-fluorobenzyl3-((3R,4S)-4-(6-
I amino-5-chloro-2-oxo-1,2-
HN H F dihydropyridine-3-carboxamido)-
~O 3-methoxypiperidin-l-yl)-2-
HaN methylpropanoate
CI
0 (S)-4-(methylsulfonyl)benzyl3-
0 0 N' Y'O ((3R,4S)-4-(6-amino-5-chloro-2-
1 iO i oxo-1,2-dihydropyridine-3-
H\ H carboxamido)-3-
H2N methoxypiperidin-1-yl)-2-
CI methylpropanoate
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0
(S)-3-((3R,4S)-4-(6-amino-5-
O 0 N OH chloro-2-oxo-1,2-dihydropyridine-
HN I H 3-carboxamido)-3-
O~ methoxypiperidin-l-yl)-2-
HZN methylpropanoic acid
CI
0
O 0 N~O~ (S)-methyl3-((3R,4S)-4-(6-amino-
5-chloro-2-oxo-1,2-
HN H dihydropyridine-3-carboxamido)-
O~ 3-methoxypiperidin-1-yl)-2-
H~N methylpropanoate
CI
0 ,,~OH 4-((3R,4S)-4-(6-amino-5-chloro-2-
CI H O oxo-1,2-dihydropyridine-3-
carboxamido)-3-
methoxypiperidin-1-yl)butanoic
HZN H 0
acid
O O
HNH 4-fluorobenzyl 6-((3S,4R)-4-(6-
H2N O amino-5-chloro-2-oxo-1,2-
CI F dihydropyridine-3-carboxamido)-
N ~ 3-methoxYP eridin-l-
iP
O ~ I yl)hexanoate
0
\
0 N O 2-inethoxyethyl6-((3 S,4R)-4-(6-
0 O\ amino-5-chloro-2-oxo-1,2-
~ N ~ dihydropyridine-3-carboxamido)-
HN ~ O 3-methoxypiperidin-l-
HZN CI yl)hexanoate
O O
HN I NH ~ neopentyl6-((3S,4R)-4-(6-amino-
HZN O 5-chloro-2-oxo-1,2-
CI dihydropyridine-3-carboxamido)-
N ~ 3-methoxypiperidin-l-
O yl)hexanoate
0
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O O
HN NH pyridin-2-ylmethyl6-((3S,4R)-4-
H2N O (6-amino-5-chloro-2-oxo-1,2-
CI dihydropyridine-3-carboxamido)-
N 3-methoxypiperidin-l-
O N yl)hexanoate
0
O O
HNH o 2-(piperazin-1-yl)ethyl6-((3S,4R)-
H2N 4-(6-amino-5-chloro-2-oxo-1,2-
CI dihydropyridine-3-carboxamido)-
N 3-methoxypiperidin-l-
O"/-'N~ yl)hexanoate hydrochloride
0 ~NH
O 2-(dimethylamino)ethyl6-
CI 0 ((3S,4R)-4-(6-amino-5-chloro-2-
I H\ = oxo-1,2-dihydropyridine-3-
O~ carboxamido)-3-
H2 N H O methoxypiperidin-1-yl)hexanoate
O 1-adamantylmethyl6-[(3S,4R)-4-
0 {[(6-amino-5-chloro-2-oxo-1,2-
CI ,,=G O dihydropyridin-3-
' H yl)carbonyl]amino}-3-
HZN N 0 methoxypiperidin-1-yl]hexanoate
H
O cyclohexyl 6-((3S,4R)-4-(6-amino-
CI O =O 5-chloro-2-oxo-1,2-
H dihydropyridine-3-carboxamido)-
0 H
O~ 3-methoxypiperidin-1-
~N N
r
H yl)hexanoate
O 2-adamantyl6-[(3S,4R)-4-{ [(6-
O
CI O amino-5-chloro-2-oxo-1,2-
I H\ dihydropyridin-3-
yl)carbonyl]amino}-3-
H2N H CO methoxypiperidin-1-yl]hexanoate
O bicyclo[2.2.1]heptan-2-yl 6-
O
CI O ((3S,4R)-4-(6-amino-5-chloro-2-
( H~ oxo-1,2-dihydropyridine-3-
carboxamido)-3-
H2N H 0
methoxypiperidin- 1 -yl)hexanoate
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O O
H\ NH O 2-(2-((3S,4R)-4-(6-amino-5-
H2N chloro-2-oxo-1,2-dihydropyridine-
CI C N 3-carboxamido)-3-
~ methoxypiperidin-l-
p yl)ethoxy)acetic acid
O,/'OH
0
O methyl2-(2-((3R,4S)-4-(6-amino-
5-chloro-2-oxo-1,2-
CI N dihydropyridine-3-carboxamido)-
~ H 3-methoxypiperidin-l-
H,N H O yl)ethoxy)acetate
O O
HNH o cyclohexyl2-(2-((3S,4R)-4-(6-
H2N amino-5-chloro-2-oxo-1,2-
CI 'T dihydropyridine-3-carboxamido)-
3-methoxypiperidin-l-
0 yl)ethoxy)acetate
O,A O
,-~0J~cyclohexyl2-(2-((3R,4S)-4-(6-
O O~ amino-5-chloro-2-oxo-1,2-
CI N dihydropyridine-3-carboxamido)-
~ H 3-methoxypiperidin-l-
HZN N O yl)ethoxy)acetate
0 JDH piperidin-4-y12-(2-((3R,4S)-4-(6-
0 O amino-5-chloro-2-oxo-1,2-
CI N dihydropyridine-3-carboxamido)-
H 0~1 3-methoxypiperidin-l-
H,N H N'j 0 yl)ethoxy)acetate hydrochloride
H
~ 2-hydroxyethyl4-(2-((3 S,4R)-4-
CI O GN~ ~/ p (6-amino-5-chloro-2-oxo-1,2-
I H''' ~~OH dihydropyridine-3-carboxamido)-
HZN N O O 0 3-methoxypiperidin-l-
H yl)acetamido)benzoate
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O O
HN NH (
H~N ~ O 2-amino-2-oxoethyl4-(2-((3 S,4R)-
CI 4-(6-amino-5-chloro-2-oxo-1,2-
N H dihydropyridine-3-carboxamido)-
N ~ 3-methoxypiperidin-l-
~/ O yl)acetamido)benzoate
O O---~-NHz
0
H 2-(piperazin-l-yl)ethyl 4-(2-
0 ((3S,4R)-4-(6-amino-5-chloro-2-
CI N O O'-'--.'N oxo-1,2-dihydropyridine-3-
H O 0 ~ NH carboxamido)-3-
methoxypiperidin-l-
H ~
N 0
2N H
yl)acetamido)benzoate
O O
HN I NH ~ 1-(2-((3S,4R)-4-(6-amino-5-
HaN O 0 chloro-2-oxo-1,2-dihydropyridine-
3-carboxamido)-3-
CI N OH methoxypiperidin-l-
~ N yl)acetyl)piperidine-4-carboxylic
acid
0
O O
H\ I NH o methyl 1-(2-((3S,4R)-4-(6-amino-
H,N 0 5-chloro-2-oxo-1,2-
ci dihydropyridine-3-carboxamido)-
N O 3-methoxypiperidin-l-
y N yl)acetyl)piperidine-4-carboxylate
0
O O
I NH o ethyl 1-(2-((3S,4R)-4-(6-amino-5-
H2N O chloro-2-oxo-1,2-dihydropyridine-
YHNY CI r ':~ 3-carboxamido)-3-
N N O-,~--, methoxypiperidin-l-
ly N yl)acetyl)piperidine-4-carboxylate
0
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O O
H\ NH o 2-methoxyethyl1-(2-((3S,4R)-4-
H2N 0 (6-amino-5-chloro-2-oxo-1,2-
ci dihydropyridine-3-carboxamido)-
N 3-methoxypiperidin-l-
ly N yl)acetyl)piperidine-4-carboxylate
0
0 N~~OH
6-amino-5-chloro-N-((3R,4S)-l-
N CI I H (2-hydroxyethyl)-3-
p~ methoxypiperidin-4-yl)-2-oxo-1,2-
H2N H 0 dihydropyridine-3-carboxamide
0 NH
CI N 6-amino-5-chloro-N-((3R,4S)-3-
~ H p methoxypiperidin-4-yl)-2-oxo-1,2-
H2N H 0 dihydropyridine-3-carboxamide
6-amino-5-chloro-N-((3R,4S)-1-
CI O N O (3-(4-fluorophenoxY)ProPY1)-3
-
N methoxypiperidin-4-yl)-2-oxo-1,2-
H
HzN N O O~ dihydropyridine-3-carboxamide
Formulation, Administration, and Uses
Dosage rates and routes of administration of the disclosed compounds are
similar to
those already used in the art and known to the skilled artisan (see, for
example, Physicians'
Desk Reference, 54th Ed., Medical Economics Company, Montvale, NJ, 2000).
The magnitude of a prophylactic or therapeutic dose of structural and/or
functional
analog of cisapride in the acute or chronic management of diseases and/or
disorders described
herein will vary with the severity of the condition to be treated, and the
route of
administration. The dose, and perhaps the dose frequency, will also vary
according to the age,
body weight, and response of the individual patient. In general, the total
daily dose range for
structural and/or functional analogs of cisapride, for the conditions
described herein, is from
about 1 mg to about 200 mg, in single or divided doses. Preferably, a daily
dose range should
be between about 5 mg to about 100 mg, in single or divided doses, while most
preferably, a
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daily dose range should be between about 5 mg to about 75 mg, in single or
divided doses. It
is preferred that the doses are administered from 1 to 4 times a day. In
managing the patient,
the therapy should be initiated at a lower dose, perhaps about 5 mg to about
10 mg, and
increased up to about 50 mg or higher depending on the patient's global
response. It is further
recommended that children, and patients over 65 years, and those with impaired
renal or
hepatic function, initially receive low doses, and that they be titrated based
on individual
response(s) and blood level(s). It may be necessary to use dosages outside
these ranges in
some cases as will be apparent to those skilled in the art. Further, it is
noted that the clinician
or treating physician will know how and when to interrupt, adjust, or
terminate therapy in
conjunction with individual patient response.
The compounds of the subject invention can be formulated according to known
methods for preparing pharmaceutically useful compositions. Formulations are
described in
detail in a number of sources which are well known and readily available to
those skilled in
the art. For example, Remington's Pharmaceutical Science by E.W. Martin
describes
formulations which can be used in connection with the subject invention. In
general, the
compositions of the subject invention are formulated such that an effective
amount of the
bioactive compound(s) is combined with a suitable carrier in order to
facilitate effective
administration of the composition.
The compositions of the subject invention include compositions such as
suspensions,
solutions and elixirs; aerosols; or carriers such as starches, sugars,
microcrystalline cellulose,
diluents, granulating agents, lubricants, binders, disintegrating agents, and
the like, in the case
of oral solid preparations (such as powders, capsules, and tablets) with the
oral solid
preparations being preferred over the oral liquid preparations. A preferred
oral solid
preparation is capsules. The most preferred oral solid preparation is tablets.
Preferred
amounts of active ingredient (i.e., an structural and/or functional analog of
cisapride) in a
solid dosage form are about 5 mg, 10 mg, and 25 mg.
Further, acceptable carriers can be either solid or liquid. Solid form
preparations
include powders, tablets, pills, capsules, cachets, suppositories and
dispersible granules. A
solid carrier can be one or more substances which may act as diluents,
flavoring agents,
solubilizers, lubricants, suspending agents, binders, preservatives, tablet
disintegrating agents
or encapsulating materials.
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The disclosed pharmaceutical compositions may be subdivided into unit doses
containing appropriate quantities of the active component. The unit dosage
form can be a
packaged preparation, such as packeted tablets, capsules, and powders in paper
or plastic
containers or in vials or ampules. Also, the unit dosage can be a liquid based
preparation or
formulated to be incorporated into solid food products, chewing gum, or
lozenge.
In addition to the common dosage forms set out above, the compounds of the
present
invention may also be administered by controlled release means and/or delivery
devices such
as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809;
3,598,123; and
4,008,719, the disclosures of which are hereby incorporated by reference in
their entirety.
Any suitable route of administration may be employed for providing the patient
with
an effective dosage of a structural and/or functional analog of cisapride. For
example, oral,
rectal, parenteral (subcutaneous, intramuscular, intravenous), transdennal,
and like forms of
administration may be employed. Dosage forms include tablets, troches,
dispersions,
suspensions, solutions, capsules, patches, and the like.
One aspect of the invention provides a method of treating gastroesophageal
reflux
disease in a mammal, while substantially reducing the concomitant adverse
effects associated
with the administration of cisapride, which comprises administering to a human
in need of
such treatment, a therapeutically effective amount of a structural and/or
functional analog of
cisapride, or a pharmaceutically acceptable salt thereof. A preferred aspect
is the treatment of
gastroesophageal reflux disease in humans.
Another aspect of the invention provides a composition for the treatment of a
human
suffering from gastroesophageal reflux disease, which comprises a
therapeutically effective
amount of a structural and/or functional analog of cisapride, or a
pharmaceutically acceptable
salt thereof.
Yet another aspect of the present invention provides a method of eliciting an
anti-
emetic effect in a mammal, while substantially reducing the adverse effects
associated with
the administration of cisapride, which comprises administering to a mammal in
need of such
anti-emetic therapy, a therapeutically effective amount of structural and/or
functional analogs
of cisapride, or a pharmaceutically acceptable salt thereof. Preferably, the
mammal is a
human.
In an additional aspect, the present invention encompasses an anti-emetic
composition
for the treatment of a mammal in need of anti-emetic therapy, which comprises
a
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therapeutically effective amount of a structural and/or functional analog of
cisapride, or a
pharmaceutically acceptable salt thereof.
A further aspect of the present invention includes a method of treating a
condition
caused by gastrointestinal motility dysfunction in a mammal which comprises
administering
to a mammal in need of treatment for gastrointestinal motility dysfunction, a
therapeutically
effective amount of a structural and/or functional analog of cisapride, or a
pharmaceutically
acceptable salt thereof. Conditions caused by gastrointestinal motility
dysfunction include,
but are not limited to, dyspepsia, gastroparesis, constipation, post-operative
ileus, and
intestinal pseudo-obstruction. Preferably, the mammal is a human.
The observation that cisapride enters the central nervous system and binds to
5HT4
receptors indicates that cisapride may have centrally-mediated effects.
Cisapride is a potent
ligand at 5HT4 receptors, and these receptors are located in several areas of
the central
nervous system. Modulation of serotonergic systems has a variety of behavioral
effects.
Accordingly, the compounds of the subject invention can be used in the
treatment of: 1)
cognitive disorders, including but not limited to Alzheimer's disease; 2)
behavioral disorders,
including but not limited to schizophrenia, mania, obsessive-compulsive
disorder, and
psychoactive substance use disorders; 3) mood disorders, including but not
limited to
depression and anxiety; and 4) disorders of control of autonomic function,
including but not
limited to essential hypertension and sleep disorders.
Accordingly, the present invention also provides methods of treating
cognitive,
behavioral, mood, or autonomic function control disorders in a mammal
comprising the
administration of a therapeutically effective ainount of structural and/or
functional analog of
cisapride, or a pharmaceutically acceptable salt thereof. Preferably, the
mammal is a human.
It should be understood that the examples and aspects described herein are for
illustrative purposes only and that various modifications or changes in light
thereof will be
suggested to persons skilled in the art and are to be included within the
spirit and purview of
this application and the scope of the appended claims. Further, all patents,,
patent
applications, provisional applications, and publications referred to or cited
herein are
incorporated by reference in their entirety to the extent they are not
inconsistent with the
explicit teachings of this specification.
The invention and the manner and process of making and using it, are now
described
in such full, clear, concise and exact terms as to enable any person skilled
in the art to which
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it pertains, to make and use the same. It is to be understood that the
foregoing describes
preferred aspects of the invention and that modifications may be made therein
without
departing from the spirit or scope of the invention as set forth in the
claims. To particularly
point out and distinctly claim the subject matter regarded as invention, the
following claims
conclude this specification.
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