Note: Descriptions are shown in the official language in which they were submitted.
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CARBOXAMIDE DERIVATIVES AS ION CHANNEL MODULATORS
This application claims the benefit of U.S. Provisional Application Ser. No.
60/874,206, filed December 11, 2006, the entire disclosure of which is
incorporated
herein by reference, and of U.S. Provisional Application Ser. No. 60/874,102,
filed
December 11, 2006.
FIELD OF THE INVENTION
The present teachings relate to certain substituted benzamides and related
derivatives, processes for their preparation, and their use in therapeutic
treatments.
BACKGROUND OF THE INVENTION
All cells rely on the regulated movement of inorganic ions across cell
membranes to
perform essential physiological functions. Electrical excitability, synaptic
plasticity,
and signal transduction are examples of processes in which changes in ion
concentration play a critical role. In general, the ion channels that permit
these
changes are proteinaceous pores consisting of one or multiple subunits, each
containing two or more membrane-spanning domains. Most ion channels have
selectivity for specific ions, primarily Na+, K+, Ca2+, or CI-, by virtue of
physical
preferences for size and charge. Electrochemical forces, rather than active
transport,
drive ions across membranes, thus a single channel may allow the passage of
millions of ions per second. Channel opening, or "gating" is tightly
controlled by
changes in voltage or by ligand binding, depending on the subclass of channel.
Ion
channels are attractive therapeutic targets due to their involvement in so
many
physiological processes, yet the generation of drugs with specificity for
particular
channels in particular tissue types remains a major challenge.
Voltage-gated ion channels open in response to changes in membrane potential.
For
example, depolarization of excitable cells such as neurons results in a
transient influx
of Na+ ions, which propagates nerve impulses. This change in membrane
potential is
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sensed by voltage-gated K+ channels, which then allow an efflux of K+ ions.
The
efflux of K+ ions repolarizes the membrane. Other cell types rely on voltage-
gated
Ca2+ channels to generate action potentials. Voltage-gated ion channels also
perform important functions in non-excitable cells, such as the regulation of
secretory, homeostatic, and mitogenic processes. Ligand-gated ion channels can
be
opened by extracellular stimuli such as neurotransmitters (e.g., glutamate,
serotonin,
and acetylcholine), or intracellular stimuli (e.g., cAMP, Ca2+, and
phosphorylation).
The Cav2 family of voltage-gated calcium channels consists of 3 main subtypes
Cav2.1 (P or Q-type calcium currents), Cav2.2 (N-type calcium currents), and
Cav2.3
(R-type calcium currents). These currents are found almost exclusively in the
central
nervous system (CNS), peripheral nervous system (PNS) and neuroendocrine
cells,
and constitute the predominant forms of presynaptic voltage-gated calcium
current.
Presynaptic calcium entry is modulated by many types of G-protein coupled
receptors (GPCRs) and modulation of Cav2 channels is a widespread and highly
efficacious means of regulating neurotransmission. The subunit composition of
the
Cav2 channels is defined by their a, subunit, which forms the pore and
contains the
voltage-sensing gates (a12.1, a12.2, and a12.3, also known as a,A, a,B, and
alE,
respectively) and the P and a2 subunits.
Genetic or pharmacological perturbations in ion channel function can have
dramatic
clinical consequences. Long QT syndrome, epilepsy, cystic fibrosis, and
episodic
ataxia are a few examples of heritable diseases resulting from mutations in
ion
channel subunits. Toxic side effects such as arrhythmia and seizure, which can
be
triggered by certain drugs, can be due to interference with ion channel
function
(Sirois, J.E. and Atchison, W.D. (1996), Neurotoxicology, 17(1): 63-84;
Keating, M.T.
(1996), Science, 272: 681-685). Drugs are useful for the therapeutic
modulation of
ion channel activity, and have applications in treatment of many pathological
conditions, including hypertension, angina pectoris, myocardial ischemia,
asthma,
bladder overactivity, alopecia, pain, heart failure, dysmenorrhea, type II
diabetes,
arrhythmia, graft rejection, seizure, convulsions, epilepsy, stroke, gastric
hypermotility, psychoses, cancer, muscular dystrophy, and narcolepsy (Coghlan,
M.J. et al. (2001), J. Med. Chem., 44: 1627-1653; Ackerman, M.J. and Clapham,
-2-
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D.E. (1997), N. Eng. J. Med., 336: 1575-1586). The growing number of
identified ion
channels and understanding of their complexity will assist in future efforts
at
therapies, that can modify ion channel function.
Therapeutic modulation of Ca,2 channel activity has applications in treatment
of
many pathological conditions. All primary sensory afferents provide input to
neurons
in the dorsal horns of the spinal cord and in dorsal root ganglia neurons in
the dorsal
horn, and calcium influx through Cav2.2 channels triggers the release of
neurotransmitters from presynaptic nerve terminals in the spinal cord. Hence,
blockade of Cav2.2 channels is expected to be broadly efficacious because
these
channels are in a common pathway downstream from the wide variety of receptors
that mediate pain (Julius, D. and Basbaum, A.I. (2001), Nature, 413: 203-216).
Indeed, intrathecal injection of the Cav2.2-selective conotoxin ziconitide
(SNX-111)
has been shown to be effective against both neuropathic pain and inflammatory
pain
in animals and man (Bowersox, S.S. et al. (1996), J. Pharmacol. Exp. Ther.,
279:
1243-1249). Ziconotide has also been shown to be effective as a
neuroprotective
agent in rat models of global or focal ischemia (Colburne, F. et al. (1999),
Stroke, 30:
662-668). Thus, it is reasonable to conclude that modulation of Cav2.2 can
have
implications in the treatment of neuroprotection and/or stroke.
Cav2.2 channels are found in the periphery and mediate catecholamine release
from
sympathetic neurons and adrenal chroffin cells. Some forms of hypertension
result
from elevated sympathetic tone. Cav2.2 modulators could be particularly
effective in
treating this disorder. Although complete block of Cav2.2 channels can cause
hypotension or impair baroreceptor reflexes, partial inhibition by Cav2.2
modulators
might reduce hypertension with minimal reflex tachycardia (Uneyama, O.D.
(1999),
Int. J. Mol. Med., 3: 455-466).
Overactive bladder (OAB) is characterized by storage symptoms such as urgency,
frequency, and nocturia, with or without urge incontinence, resulting from the
overactivity of the detrusor muscle in the bladder. OAB can lead to urge
incontinence. The etiology of OAB and painful bladder syndrome is unknown,
although disturbances in nerves, smooth muscle and urothelium can cause OAB
-3-
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(Steers, W., Rev. Urol., 4: S7-S18). There is evidence to suggest that
reduction of
bladder hyperactivity may be indirectly effected by inhibition of Cav2.2
and/or Cav1
channels.
The localization of Cav2.1 channels in the superficial laminae of the dorsal
horn of the
spinal cord suggests involvement of these channels in the perception and
maintenance of certain forms of pain (Vanegas, H. and Schaible, H. (2000),
Pain, 85:
9-18). Complete elimination of Cav2.1 calcium currents alters synaptic
transmission,
resulting in severe ataxia. Gabapentin has been used clinically for many years
as an
add-on therapy for the treatment of epilepsy. In recent years, it has emerged
as a
leading treatment of neuropathic pain. Clinical trials have shown gabapentin
to be
effective for the treatment of post-herpetic neuralgia, diabetic neuropathy,
trigeminal
neuralgia, migrane and fibromyalgia (Mellegers, P.G. et al. (2001), Clin. J.
Pain, 17:
284-295). Gabapentin was designed as a metabologically stable GABA mimetic,
but
most studies find no effect on the GABA receptors. The a2b subunit of voltage-
gated
calcium channels has been identified as a high affinity binding site for
gabapentin in
the CNS. There is evidence that suggests that gabapentin could inhibit
neurotransmission in the spinal cord by interfering with the function of the
a2b
subunits, thereby inhibiting presynaptic calcium currents.
SUMMARY OF THE INVENTION
The present teachings relate to compounds of formula (I):
-4-
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3
R ~ /-(CH2)p /R
N -Ar
X O
A
~ ~ (1)
(R~)n
and pharmaceutically acceptable salts, hydrates, and esters thereof, wherein
Ar, R1,
R2, R3, X, p and n are defined as described herein.
The present teachings also provide methods of making the compounds of formula
(I),
and methods of using the compounds of formula (I) for the therapeutic
modulation of
ion channel function, and treatment of one or more conditions, particularly
those
mediated by certain calcium channel subtype targets. The methods of using the
compounds generally include administering a therapeutically effective amount
of a
compound of formula (I) to a mammal.
DETAILED DESCRIPTION OF THE INVENTION
Embodiments of the present invention provide compounds that can modulate the
activity of ion channels in a mammal, for example, Cav2.2 voltage-gated
calcium
channels, and can treat a variety of pathological conditions, states,
disorders or
diseases.
Unless otherwise indicated, the following terms are held to have the following
meanings as used herein.
The term "mammal" refers to any warm blooded species, such as a human. The
term "ion channel" includes at least voltage-gated calcium channels and
voltage-
gated sodium channels such as, without limitation, Cav1.1, Cav1.2, Cav1.3,
Cav2.1,
-5-
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Ca,2.2, Ca,2.3, Ca,3.1, Ca,3.2, Na,1.1, Na,1.2, Na,1.3, Na,1.7, Na,1.8, and
Na,1.9.
As used herein, "Ca,2.2 voltage-gated calcium channel" refers to a voltage-
gated
calcium channel containing at least one Cav2.2 a, subunit. The phrase "ion
channel
mediated condition" refers to any condition or pathological state of a mammal
or any
disease present in a mammal that can be treated, or the symptoms of which can
be
alleviated, by modulation of the activity of one or more ion channels such as
Cav2.2
voltage-gated calcium channels.
As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
As used herein, "oxo" refers to a double-bonded oxygen (i.e., =0).
As used herein, "alkyl" refers to a straight-chain or branched saturated
hydrocarbon
group. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g.,
n-
propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl),
pentyl groups
(e.g., n-pentyl, isopentyl, neopentyl), and the like. A lower alkyl group
typically has
up to 6 carbon atoms. In various embodiments, an alkyl group has 1-6 carbon
atoms, and is referred to as a"C,_6 alkyl group." Examples of C,_6 alkyl
groups
include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and
isopropyl), and
butyl groups (e.g., n-butyl, isobutyl, s-butyl, t-butyl). A branched alkyl
group has at
least 3 carbon atoms (e.g., an isopropyl group) and up to 6 carbon atoms, e.g.
it is a
C3_6 alkyl group, i.e., a branched lower alkyl group. Examples of branched
lower alkyl
groups include, but are not limited to:
isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and tert-
pentyl.
-6-
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As used here, a divalent C1_6 alkyl group can be a straight chain or branched
alkyl
group, which as a linking group is capable of forming a covalent bond with two
other
moieties. Examples of a divalent C1_6 alkyl group include, for example, a
methylene
group, an ethylene group, an ethylidene group, an n-propylene group, an
isopropylene group, an isobutylene group, a s-butylene group, an n-butylene
group,
and a t-butylene group.
As used herein, "alkenyl" refers to a straight-chain or branched alkyl group
having
one or more carbon-carbon double bonds. Examples of alkenyl groups include,
but
are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl,
pentadienyl, hexadienyl groups, and the like. The one or more carbon-carbon
double
bonds can be internal (such as in 2-butene) or terminal (such as in 1-butene).
A
branched alkenyl group has at least 3 carbon atoms, and in various
embodiments,
has up to 6 carbon atoms, e.g. it is a C3_6 alkenyl group,.
The term "alkynyl" refers to a straight-chain or branched alkyl group having
one or
more carbon-carbon triple bonds. Examples of alkynyl groups include, but are
not
limited to, ethynyl, propynyl, butynyl, pentynyl, and the like. The one or
more carbon-
carbon triple bonds can be internal (such as in 2-butyne) or terminal (such as
in 1-
butyne). The alkynyl group is suitably a C3_6 alkynyl group,
As used herein, "alkoxy" refers to an -0-alkyl group wherein the alkyl group
may be
a straight or branched chain. Examples of alkoxy groups include, but are not
limited
to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy
groups, and
the like.
A divalent alkoxy group means an alkoxy group which, as a linking group, is
capable
of forming a covalent bond with two other moieties (-O-alkyl-).
As used herein, "haloalkyl" refers to an alkyl group having one or more
halogen
substituents. Examples of haloalkyl groups include, but are not limited to, -
CF3,
-C2F5, -CHF2, -CH2F, -CC13, -CHC12, -CH2CI, -C2C15, and the like. Perhaloalkyl
-7-
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groups, i.e., alkyl groups wherein all of the hydrogen atoms are replaced with
halogen atoms (e.g., CF3 and C2F5), are included within the definition of
"haloalkyl."
As used herein, "haloalkoxy" refers to an alkoxy group having one or more
halogen
substituents. Examples of haloalkoxy groups include, but are not limited to, -
OCF3,
-OC2F5, -OCHF2, and the like.
As used herein, "cycloalkyl" refers to a non-aromatic carbocyclic group
including
cyclized alkyl, alkenyl, and alkynyl groups. A cycloalkyl group can be
monocyclic
(e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or
spiro ring
systems), wherein the carbon atoms are located inside or outside of the ring
system.
Any suitable ring position of the cycloalkyl group can be covalently linked to
the
defined chemical structure. In various embodiments, a cycloalkyl group has 3-6
carbon atoms, and is referred to as a"C3_6 cycloalkyl group." Examples of C3_6
cycloalkyl groups include, but are not limited to, cyclopropyl,
cyclopropylmethyl,
cyclopropylethyl, cyclopropylpropyl, cyclobutyl, cyclobutylmethyl,
cyclobutylethyl,
cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and
cyclohexadienyl groups, as well as their homologs, isomers, and the like.
As used herein, "heteroatom" refers to an atom of any element other than
carbon or
hydrogen and includes, for example, nitrogen, oxygen, sulfur, phosphorus, and
selenium.
As used herein, "cycloheteroalkyl" refers to a non-aromatic cycloalkyl group
having 5-
7 ring atoms, among which 1 to 3 ring atoms are heteroatoms independently
selected
from oxygen (0), nitrogen (N) and sulfur (S), and that optionally contains one
or
more, e.g., two, double or triple bonds. One or more N or S atoms in a
cycloheteroalkyl ring can be oxidized (e.g., morpholine N-oxide,
thiomorpholine S-
oxide, thiomorpholine S,S-dioxide). Cycloheteroalkyl groups can also contain
one or
more oxo groups, such as piperidone, oxazolidinone, pyrimidine-2,4(1 H,3H)-
dione,
pyridin-2(1 H)-one, and the like. Examples of cycloheteroalkyl groups include,
among
others, morpholine, thiomorpholine, pyran, imidazolidine, imidazoline,
oxazolidine,
pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran,
tetrahydrothiophene,
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piperidine, piperazine, and the like. A cycloheteroalkyl group can be
optionally
substituted. For example, in some embodiments, one or more carbon ring atoms
of a
cycloheteroalkyl group can bear a substituent independently selected from a
halogen, a C,_6 alkyl group, -C(O)-NRdRei -Y-OR, -Y-NRdRe, a -Y-phenyl group,
a -Y-(5-7 cycloheteroalkyl) group, a -Y-(5-9 membered heteroaryl) group, or a-
Y-
O-(5-7 membered heteroaryl) group, and/or one or more nitrogen ring atoms of a
cycloheteroalkyl group can bear a substituent independently selected from a
halogen, a Cl_6 alkyl group, -C(O)Rc, -C2_6 alkyl-ORc, -C2_6 alkyl-NRdRe, -Y-
C(O)NRdRei an -S(O)2-Cl_6 alkyl group, a-C2_6 alkyl-(5-7 membered
cycloheteroalkyl) group, or a 5-7 membered heteroaryl group, wherein Y, Rc,
Rd, and
R. are as defined hereinbelow. Further, each of the phenyl substituents
immediately
above can be optionally substituted with 1 to 3 substituents independently
selected
from a halogen, a C,_6 alkyl group, a C,_6 haloalkyl group, and a C,_6 alkoxy
group, and
each of the 5-7 membered cycloheteroalkyl substituents, the 5-7 membered
heteroaryl substituents, and the 5-9 membered heteroaryl substituents
immediately
above can be optionally substituted with 1 to 3 substituents independently
selected
from a halogen and a C,_6 alkyl group.
As used herein, "aryl" refers to an aromatic monocyclic hydrocarbon ring
system or a
polycyclic ring system in which two or more aromatic hydrocarbon rings are
fused
(i.e., having a bond in common with) together or at least one aromatic
monocyclic
hydrocarbon ring is fused to one or more cycloalkyl and/or cycloheteroalkyl
rings. An
aryl group can have from 6 to 14 carbon atoms in its ring system, which can
include
multiple fused rings. In some embodiments, a polycyclic aryl group can have
from 7
to 14 carbon atoms. Any suitable ring position of the aryl group can be
covalently
linked to the defined chemical structure. Examples of aryl groups having only
aromatic carbocyclic ring(s) include, but are not limited to, phenyl, 1-
naphthyl
(bicyclic), 2-naphthyl (bicyclic), anthracenyl (tricyclic), phenanthrenyl
(tricyclic) and
like groups. Examples of polycyclic ring systems in which at least one
aromatic
carbocyclic ring is fused to one or more cycloalkyl and/or cycloheteroalkyl
rings
include, among others, benzo derivatives of cyclopentane (i.e., an indanyl
group,
which is a 5,6-bicyclic cycloalkyl/aromatic ring system), cyclohexane (i.e., a
tetrahydronaphthyl group, which is a 6,6-bicyclic cycloalkyl/aromatic ring
system),
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imidazoline (i.e., a benzimidazolinyl group, which is a 5,6-bicyclic
cycloheteroalkyl/aromatic ring system), and pyran (i.e., a chromenyl group,
which is a
6,6-bicyclic cycloheteroalkyl/aromatic ring system). Other examples of aryl
groups
include, but are not limited to, benzodioxanyl, benzodioxolyl, chromanyl,
indolinyl
groups, and the like. In some embodiments, aryl groups optionally contain up
to
three independently selected substitution groups. For example, a phenyl group,
in
some embodiments, can be optionally substituted with 1 to 3 substituents
independently selected from a halogen, CN, -C(O)OR, -NRdRei a C,_6 alkyl
group, a
Cl_6 haloalkyl group, and a C,_6 alkoxy group, wherein Rc, Rd, and R. are as
defined
hereinbelow.
As used herein, "heteroaryl" refers to an aromatic monocyclic ring system or a
polycyclic ring system where at least one of the rings present in the ring
system is
aromatic, containing 5-7 or 5-9 ring atoms, among which 1 to 3 ring atoms are
heteroatoms independently selected from oxygen (0), nitrogen (N) and sulfur
(S).
Polycyclic heteroaryl groups include two or more heteroaryl rings fused
together, and
monocyclic heteroaryl rings fused to one or more aromatic carbocyclic rings,
non-
aromatic carbocyclic rings, and/or non-aromatic cycloheteroalkyl rings. The
heteroaryl group can be attached to the defined chemical structure at any
heteroatom
or carbon atom that results in a stable structure. Generally, heteroaryl rings
do not
contain 0-0, S-S, or S-O bonds. However, one or more N or S atoms in a
heteroaryl
group can be oxidized (e.g., pyridine N-oxide, thiophene S-oxide, thiophene
S,S-
dioxide). Examples of heteroaryl groups include, for example, the 5-membered
monocyclic and 5-6 bicyclic ring systems shown below:
-10-
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QN N-N (-y - N \\
K K KN ~K~N N~K~ `K NK~
N
N / I \ ol \N N N \N N
K K K K K K
N (PN N~ (fN I ~
I\ ~ I " N I\ N~ N~ \
K K K K K K
N
cQNflj?
N K where K is 0, S, NH, or NR'; and R' can be selected from a halogen, a C1_6
alkyl
group, a C(O)Rc group, a C2_6 alkyl-ORc group, a C2_6 alkyl-NRdRe group, a-Y-
C(O)NRdRe group, an S(O)2-C1_6 alkyl group, a 5-7 membered heteroaryl group,
and
a C2_6 alkyl-(5-7 membered cycloheteroalkyl) group, where Y, Rc, Rd and R. are
as
defined hereinbelow. Examples of such heteroaryl rings include, but are not
limited
to, pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine,
triazole,
tetrazole, pyrazole, imidazole, isothiazole, thiazole, thiadiazole, isoxazole,
oxazole,
oxadiazole, indole, isoindole, benzofuran, benzothiophene, quinoline, 2-
methylquinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole,
benzimidazole,
benzothiazole, benzisothiazole, benzisoxazole, benzoxadiazole, benzoxazole,
cinnoline, 1 H-indazole, 2H-indazole, indolizine, isobenzofuran,
naphthyridine,
phthalazine, pteridine, purine, oxazolopyridine, thiazolopyridine,
imidazopyridine,
furopyridine, thienopyridine, pyridopyrimidine, pyridopyrazine,
pyridopyridazine,
thienothiazole, thienoxazole, and thienoimidazole. Further examples of
heteroaryl
groups include, but are not limited to, 4,5,6,7-tetrahydroindole,
tetrahydroquinoline,
benzothienopyridine, benzofuropyridine, and the like. In some embodiments,
heteroaryl groups can be substituted with up to three independently selected
substitution groups. For example, in some embodiments, one or more nitrogen
atoms can be substituted with independently selected R' groups as defined
above,
and/or one or more carbon ring atoms of a cycloheteroalkyl group can bear a
substituent independently selected from a halogen, a C,_6 alkyl group, -C(O)-
NRdRei
-Y-OR, -Y-NRdRei a -Y-phenyl group, a -Y-(5-7 cycloheteroalkyl) group, a-Y-(5-
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9 membered heteroaryl) group, or a -Y-O-(5-7 membered heteroaryl) group,
wherein Y, Rc, Rd, and R. are as defined hereinbelow. Further, each of the
phenyl
substituents immediately above can be optionally substituted with 1 to 3
substituents
independently selected from a halogen, a C,_6 alkyl group, a C,_6 haloalkyl
group, and
a C,_6 alkoxy group, and each of the 5-7 membered cycloheteroalkyl
substituents, the
5-7 membered heteroaryl substituents, and the 5-9 membered heteroaryl
substituents immediately above can be optionally substituted with 1 to 3
substituents
independently selected from a halogen and a C,_6 alkyl group.
Aa "divalent group" is defined herein as a linking group capable of forming a
covalent
bond with two other moieties. As used herein, a "leaving group" ("LG") refers
to a
charged or uncharged atom (or group of atoms) that can be displaced as a
stable
species as a result of, for example, a substitution or elimination reaction.
Examples
of leaving groups include, but are not limited to, halide (e.g., Cl, Br, I),
tosylate
(toluenesulfonyl group, TsO), mesylate (methanesulfonyl group, MsO), brosylate
(p-
bromobenzenesulfonyl group, BsO), nosylate (4-nitrobenzenesulfonyl group,
NsO),
water (H20), ammonia (NH3), and triflate (trifluoromethanesulfonyl group,
OTf).
As used herein, a "protecting group" ("PtG") refers to modification of a
functional
group that reduces the reactivity of the functional group in an unwanted
reaction.
Examples of protecting groups for amines include, but are not limited to, tert-
butyloxycarbonyl (t-BOC), benzyl (Bn), and carbobenzyloxy (Cbz) groups.
Examples
of protecting groups for carbonyls include, but are not limited to, acetals
and ketals.
Examples of protecting groups for carboxylic acids include, but are not
limited to,
methyl esters, benzyl esters, tert-butyl esters, and silyl esters. See Greene,
et al.,
Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991, the
entire
disclosure of which is incorporated by reference herein for all purposes.
At various places in the present specification, substituents of compounds are
disclosed in groups or in ranges. It is specifically intended that the
description
include each and every individual subcombination of the members of such groups
and ranges. For example, the term "C,_6 alkyl" is specifically intended to
individually
disclose C,, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-
C5, C2-C4,
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C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl. By way of another
example, the term "5-9 membered heteroaryl group" is specifically intended to
individually disclose a heteroaryl group having 5, 6, 7, 8, 9, 5-9, 5-8, 5-7,
5-6, 6-9, 6-
8, 6-7, 7-9, 7-8, and 8-9 ring atoms.
The present teachings provide compounds of formula (I):
3
R `11~ 111*1 (CH2)p /R
N Ar
X O
A
~ ~ (1)
(R~)n
and pharmaceutically acceptable salts, hydrates and esters thereof, wherein:
/ A \
is selected from
and O
X is selected from -NRc-,-0-, -CRaRb-, a divalent C,_6 alkoxy group, a
divalent C,_6 alkyl group, a divalent C2_6 alkenyl group, and a covalent bond;
-13-
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R1, at each occurrence, is independently selected from a halogen, -CN, -
ORc, -C(O)OR, -NRdRei -S(O)mNRdRe, -N(Rc)C(O)Rc, -NO2, a phenyl group,
a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, a C1-6
haloalkoxy group;
R2 is C3-6 cycloalkyl, benzyl, indole, phenyl, or a bicyclic aryl group,
wherein
wherein the phenyl, benzyl, and cycloalkyl is optionally substituted with 1 to
3
substituents independently selected from halogen, phenyl, C1-6 alkyl, a C1-6
alkoxy group, C1-6 haloalkyl, C1-6 haloalkoxy, -OCH2-phenyl, -CN, -C(O)OR,
-OH, -C(O)NH2, NHCORc, and -NRdRei
Ar-R3 is selected from:
~ I\ Rs ~ I\ ~ I N~ N R 3
\% ~ 3 3 3
R N R R
Cx3 ~ I / R3 RS N
and
R3 is selected from a halogen, a a piperidin-4-yl group, C1-1o alkyl group, a
C1-
1o alkoxy group, a C1-1o haloalkyl group, a C1-1o haloalkoxy group, a-C(O)Rc
group,, C3-6 cycloalkyl, and -Y-NRfRg, wherein
the C1-1o alkyl group and the C1-1o alkoxy group are optionally substituted
with
from 1-3 substitutents selected from a halogen, a phenyl group, and -OH;
wherein the nitrogen ring atom of the piperidin-4-yl is optionally substituted
with -C(O)O-C1-6 alkyl;
Y, at each occurrence, is independently a divalent C1-6 alkyl group or a
covalent bond;
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Ra and Rb taken together with the carbon atom to which they are bonded form
a C3_6 cycloalkyl group;
Rc, Rd and Rei at each occurrence, independently are H, C,_6 haloalkyl, or a
C,_6 alkyl group;
Rf and Rg, at each occurrence, independently are selected from H, -C(O)Rc, -
C2_6 alkyl-ORc, -C2_6 alkyl-NRdRe, a C,_,o alkyl group, a C3_6 cycloalkyl
group,
a -Y-phenyl group, a -C(O)-phenyl group, a -Y-(5-7 membered
cycloheteroalkyl), a -Y-(5-7 membered heteroaryl) group, and a-C2_6 alkyl-
O-Y-(5-7 membered heteroaryl) group,
alternatively, Rf and Rg taken together with the nitrogen atom to which they
are bonded form a 5-7 membered cycloheteroalkyl group or a 5-7 membered
heteroaryl group, the 5-7 membered cycloheteroalkyl group and the 5-7
membered heteroaryl group containing up to two ring heteroatoms
independently selected from nitrogen, oxygen, and sulfur, wherein
a sulfur atom in the ring optionally is substituted with 1 or 2 oxo
groups;
one or more nitrogen atoms in the ring optionally are independently
substituted with -C(O)Rc, -C2_6 alkyl-ORc, -C2_6 alkyl-NRdRe, -Y-
C(O)NRdRei-S(O)2-Cl_6 alkyl, -C2_6 alkyl-(5-7 membered
cycloheteroalkyl), Cl_6 alkyl, C3_$ cycloalkyl, -Y-(phenyl)q, or 5-7
membered heteroaryl,
one or more carbon atoms in the ring optionally are independently
substituted with -C(O)-NRdRe, -Y-OR, -Y-NRdRe, a -Y-phenyl
group, a -Y-(5-7 cycloheteroalkyl) group, a -Y-(5-9 membered
heteroaryl) group, or a -Y-O-(5-7 membered heteroaryl) group,
wherein
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each of the phenyl groups appearing anywhere in said Rf and Rg is
optionally substituted with 1 to 3 substituents independently selected
from halogen, C,_6 alkyl, C,_6 haloalkyl, and C,_6 alkoxy;
and each of the 5-7 membered cycloheteroalkyl groups, the 5-7
membered heteroaryl groups, and the 5-9 membered heteroaryl
groups appearing anywhere in said Rf and Rg is optionally substituted
with 1 to 3 substituents independently selected from halogen and C1_6
alkyl;
m is 0, 1, or 2;
n is 0, 1, 2, or 3;
p is 1, 2, 3, or 4; and
qis1,2,or3;
&~- w
ith the proviso when is
~nl~
R2 is cycloalkyl and p is 2, then Ar-R3 is not N R3
In some embodiments, X can be selected from -CH2-, -CH2-O-, -O-CH2-,
-CH2CH2CH2-O-, -CH2CH2-, and -CH=CH-.
In accordance with other embodiments, X can be selected from -NH-, -0-, and a
covalent bond.
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In accordance with some embodiments, X can be selected from -CH(CH3)-, -
C(CH3)2-, and a cyclobutylgroup.
In certain embodiments, R' can be selected from a halogen, a C,_6 alkyl group,
a C,_6
haloalkyl group, a phenyl group, and a C,_6 alkoxy group. In particular
embodiments,
R' can be selected from F, Cl, CH3, CF3, OH, -O-CH3, a phenyl group, and a t-
butyl
group.
In certain embodiments, R' can be selected from a hydroxyl group, CN, -
S(O)2NH2, -
C(O)OH, -C(O)CH3, -NHC(O)-C1_6 alkyl group, and a nitro group. In accordance
with some embodiments, R' can be -NO2, -CN, -CO2CH3, -S(O)2NH2, or -
NHC(O)CH3.
In some embodiments, R2 can be a phenyl group optionally substituted with 1-2
substituents independently selected from a halogen, a C,_6 alkyl group, a
phenyl
group, a C,_6 alkoxy group, a C,_6 haloalkyl group, and a -OCH2-phenyl group.
For
example, R2 can be a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-
methylphenyl group, a 3-methylphenyl group, a 2-methylphenyl group, a 4-fluoro-
2-
methylphenyl group, a 5-chloro-2-methyl group, a 3,5-dichlorophenyl group, a
2,3-
dichlorophenyl group, a 3,5-dimethylphenyl group, a 2,6-dimethylphenyl group,
a 3-
cyanophenyl group, a 3-tert-butylphenyl group, a 2-isopropyl-phenyl group, a 3-
isopropyl-phenyl group, a biphenyl-2-yl group, a biphenyl-4-yl group, a 4-
benzyloxyphenyl group, a 3-chloro-2-methoxyphenyl group, a 3-
trifluoromethylphenyl
group, or a 4-trifluoromethylphenyl group.
In some embodiments, R2 can be a phenyl group optionally substituted with 1-2
substituents independently selected from, -CN, -C(O)OR, -OH, -C(O)NH2, NHCORC,
and -NRdRe wherein Rc, Rd and R. are as defined above. For example, R2 can be
a
2-carbamoylphenyl group, a 3-carbamoylphenyl group, a 4-carbamoylphenyl group,
a
4-hydroxyphenyl, 3-acetamidophenyl, a 3-tert-butoxycarbonylphenyl group, a 4-
tert-
butoxycarbonylphenyl group, or a 3-carboxylphenyl group.
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In other embodiments, R2 can be selected from a cyclopropyl group, a
cyclobutyl
group, a cyclopentyl group, and a cyclohexyl group.
In accordance with some embodiments, R2 can be a 1-naphthyl group, a 1 H-indol-
5-
yl group, or a quinolin-6-yl group.
In certain embodiments, Ar-R3 can be:
R 3 N
R 3 3 ~ 3 ~
R N R R s and
Q_R3
wherein R3 is as defined above.
In some embodiments, R3 can be NRfRg, wherein Rf and Rg are as defined above.
In
particular embodiments, R3 can be selected from NH2, an NH-C1_6 alkyl group,
an
N(C,_6 alkyl)2 group wherein the C,_6 alkyl groups do not need to be the
same,, an
NH-C3_6 cycloalkyl group, an N(C,_6 alkyl)-C3_6 cycloalkyl group, an N(C,_6
alkyl)-C2_6
alkyl-ORc group, a -C(O)-phenyl group, an N(C,_6 alkyl)-Y-(5-7 membered
cycloheteroalkyl), an N(C,_6 alkyl)-phenyl group, an N(phenyl)2 group, an
N(C,_6
alkyl)-Y-(5-7 membered heteroaryl) group, and an N(C,_6 alkyl)-C2_6 alkyl-O-Y-
(5-7
membered heteroaryl) group, wherein each of the phenyl group, the 5-7 membered
cycloheteroalkyl group, and the 5-7 membered heteroaryl group immediately
above
is optionally substituted with 1 to 3 substituents independently selected from
a
halogen and a C,_6 alkyl group, and Y and Rc are as defined above. For
example, R3
can be a diethylamino group, a diphenylamino group, a methyl(2-pyridin-2-
ylethyl)amino group, a methyl(2-morpholin-4-ylethyl)amino group, a methyl(4-
chlorobenzoyl)amino group, a 2-(dimethylamino)ethyl](methyl)amino, or a
cyclopropyl(ethyl)amino group.
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In other embodiments, R3 can be an optionally substituted 5-7 membered
cycloheteroalkyl group or an optionally substituted 5-7 membered heteroaryl
group
as described herein. In certain embodiments, R3 can be selected from a
diazepanyl
group, an imidazolyl group, a morpholinyl group, a piperidinyl group, a
piperazinyl
group, a pyridyl group, a pyrrolidyl group, and a thiomorpholinyl group,
wherein each
of these groups can include a nitrogen ring atom optionally substituted with -
C(O)Rc,
-C2-6 alkyl-ORc, -C2-6 alkyl-NRdRe, -Y-C(O)NRdRe, an -S(O)2-C1-6 alkyl group,
a-
C2-6 alkyl-(5-7 membered cycloheteroalkyl) group, a -Y-(phenyl)q group, a C1-6
alkyl
group, or a 5-7 membered heteroaryl group, a carbon ring atom optionally
substituted
with -C(O)-NRdRei -Y-OR, -Y-NRdRe, a -Y-phenyl group, a -Y-(5-7
cycloheteroalkyl) group, a -Y-(5-9 membered heteroaryl) group, or a -Y-O-(5-7
membered heteroaryl) group, and/or a sulfur ring atom optionally substituted
with 1 or
2 oxo groups, wherein each of the phenyl groups immediately above is
optionally
substituted with 1 to 3 substituents independently selected from a halogen, a
C1-6
alkyl group, a C1-6 haloalkyl group, and a C1-6 alkoxy group, and each of the
5-7
membered cycloheteroalkyl groups, the 5-7 membered heteroaryl groups, and the
5-
9 membered heteroaryl groups immediately above is optionally substituted with
1 to 3
substituents independently selected from a halogen and a C1-6 alkyl group,
wherein
Y, Rc, Rd and Re are as defined above.
In particular embodiments, R3 can be selected from a 1-[1,4]diazepanyl group,
a 1-
imidazolyl group, a 4-morpholinyl group, a 1-piperidinyl group, a 1-
piperazinyl group,
a 4-pyridyl group, a 1-pyrrolidyl group, and a 4-thiomorpholinyl group,
wherein each
of these groups can be optionally substituted as described above.
In some embodiments, R3 can be a 1-piperazinyl group having a nitrogen atom in
the
ring optionally substituted with -C(O)Rc, -C2-6 alkyl-ORc, -C2-6 alkyl-NRdRe, -
C1-6
alkyl-C(O)NRdRe, an S(O)2-C1-6 alkyl group, a-C2-6 alkyl-(5-7 membered
cycloheteroalkyl) group, a C1-6 alkyl group, a -Y-(phenyl)q group, or a 5-7
membered
heteroaryl group. For example, R3 can be a 4-methylpiperazin-1-yl group, a 4-
(4-
fluorophenyl) piperazin-1-yl group, a 4-[bis(4-fluorophenyl)methyl]piperazin-1-
yl
group, a 4-pyridin-2-ylpiperazin-1-yl group, or a 4-(methylsulfonyl)piperazin-
1-yl
group.
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In other embodiments, R3 can be a 1-piperidinyl group having a carbon atom in
the
ring optionally substituted with -NRdRei -C(O)-NRdRe, -Y-OR, a 5-7
cycloheteroalkyl group, a 5-9 membered heteroaryl group, or a -Y-O-(5-7
membered heteroaryl) group. For example, R3 can be a 4-
(hydroxymethyl)piperidin-
1-yl group
In accordance with some embodiments, R3 can be a trifluoromethyl group,
chloro, a
2,2,2-trifluoroethoxy group, or a cyclohexyl group
According to some embodiments, R3 can be an optionally substituted piperidin-4-
yl
group, such as, for example, a 1-tert-butoxycarbonyl-piperidin-4-yl group
Representative compounds of formula (I) in accordance with embodiments of the
present invention include, but are not limited to, the compounds presented in
Table 1
below.
TABLE 1
Cpd Structure
No. Chemical Name
1 F O
N 4-Chloro-N-(4-fluoro-phenyl)-N-[6-(4-methyl-
o N N piperazin-1-yl)-pyridin-3-ylmethyl]-benzamide
N
2
N I ~ 4-Chloro-N-(6-diethylamino-pyridin-3-
I~ 0 N N~ ylmethyl)-N-(4-fluoro-phenyl)-benzamide
Ci 3 F I
~S
N ~- N 4-Chloro-N-(4-fluoro-phenyl)-N-(2-pyrrolidin-l-
I o N yl-thiazol-5-ylmethyl)-benzamide
ci
-20-
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Cpd Structure
No. Chemical Name
4 F~
/ NNrN 4-Chloro-N-(4-fluoro-phenyl)-N-(2-piperidin-1-
I o s yl-thiazol-4-ylmethyl)-benzamide
cl /
... /
N 2-Methyl-N-(4-methyl-phenyl)-N-(4-amino-
phenylmethyl)-benzamide
NH 2
Me
6 aN 4-Chloro-N-cyclopentyl-N-[6-(4-methyl-
o N N"') piperazin-1 -yl)-pyridin-3-ylmethyl]-benzamide
~, N
N ~ 4-Chloro-N-cyclobutyl-N-[6-(4-methyl-
~ o N N~ piperazin-1-yl)-pyridin-3-ylmethyl]-benzamide
CI / N
8 '0
N N-Cyclopentyl-N-[6-(4-methyl-piperazin-1-yl)-
N N o ~ pyridin-3-ylmethyl]-benzamide
/N \
9
N
N-Cyclopentyl-3,4,5-trimethoxy-N-{[6-(4-
A N U methylpiperazin-1-yl)pyridin-3-
~NJ yl]methyl}benzamide
F~
/ N 5-Fluoro-N-(4-fluoro-phenyl)-2-methyl-N-[6-(4-
F " methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
I ~ o N N benzamide
/ CH3 ON",
11 F~
N 4-Chloro-N-(4-fluoro-phenyl)-N-{6-[methyl-(2-
~ ~ pyridin-2-yl-ethyl)-amino]-pyridin-3-ylmethyl}-
o N i benzamide
12 F~
N N-(4-Fluoro-phenyl)-2-methoxy-N-[6-(4-
~ methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
benzamide
o N ON"
-21-
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Cpd Structure
No. Chemical Name
13 F /
\ N \ N-(4-Fluoro-phenyl)-N-[6-(4-methyl-piperazin-
1-yl)-pyrid in-3-yl methyl]-benzamid e
O N N__)
N
14 F /
N N
-(4-Fluoro-phenyl)-3-methoxy-N-[6-(4-
O N~ methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
y N benzamide
o\
15 F /
N N-(4-Fluoro-phenyl)-2-methyl-N-[6-(4-methyl-
~ piperazin-1-yl)-pyridin-3-ylmethyl]-benzamide
\ O N
/ /
16 F / N 2-Fluoro-N-(4-fluoro-phenyl)-N-[6-(4-methyl-
O N N--') piperazin-1-yl)-pyridin-3-ylmethyl]-benzamide
N
17 F /
\ N \ N-(4-Fluoro-phenyl)-4-methyl-N-[6-(4-methyl-
O N N' piperazin-1-yl)-pyridin-3-ylmethyl]-benzamide
N
18 F~
/ N 5-Fluoro-N-(4-fluoro-phenyl)-2-methoxy-N-[6-
F ' (4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
benzamide
I\ O N ON,
/ O/ 19
N N-(4-Fluoro-phenyl)-2,4-dimethyl-N-[6-(4-
~ methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
benzamide
I\ O N ON
/
2
0 F~
/ N 4-Chloro-N-(4-fluoro-phenyl)-2-methoxy-N-[6-
~ ~ (4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
benzamide
O N ON
i
2
1 F
N N-(4-Fluoro-phenyl)-2,5-dimethoxy-N-[6-(4-
/o CIN~ methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
benzamide
O N ON"
-22-
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Cpd Structure
No. Chemical Name
22 Fla
N 4-Chloro-N-(4-fluoro-phenyl)-N-{6-[4-(2-
~ hydroxy-ethyl)-piperazin-1-yl]-pyridin-3-
o N N ylmethyl}-benzamide
23
N N-(4-Fluoro-phenyl)-4-methoxy-N-[6-(4-
~ methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
o N N__') benzamide
~,N
24 F / I
N
N-(4-Fluoro-phenyl)-3-methyl-N-[6-(4-methyl-
- o N N~ piperazin-1 -yl)-pyridin-3-ylmethyl]-benzamide
y
25 F / I
N
3-Chloro-N-(4-fluoro-phenyl)-N-[6-(4-methyl-
piperazin-1-yl)-pyridin-3-ylmethyl]-benzamide
o N ON
y
2
6 ~
/ N 4-Chloro-N-(4-fluoro-phenyl)-N-{6-[(2-hydroxy-
" oH ethyl)-methyl-amino]-pyridin-3-ylmethyl}-
o N i~~ benzamide
27
N 4-Chloro-N-(4-fluoro-2-methyl-phenyl)-N-[6-(4-
~ methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
benzamide
o N ON
CI
2
8 F) N 0 4-Chloro-N-(4-fluoro-phenyl)-N-{6-[methyl-(2-
~ N~ morpholin-4-yl-ethyl)-amino]-pyridin-3-
o N i ylmethyl}-benzamide
29
N N-(4-Fluoro-phenyl)-N-[6-(4-methyl-piperazin-
~ ~ 1-yl)-pyridin-3-ylmethyl]-4-trifluoromethyl-
0 N N benzamide
F3C N
30 F /
N 4-Cyano-N-(4-fluoro-phenyl)-N-[6-(4-methyl-
~ o N N~ piperazin-1-yl)-pyridin-3-ylmethyl]-benzamide
( / N
-23-
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Cpd Structure
No. Chemical Name
31 F I
N 4-Acetylamino-N-(4-fluoro-phenyl)-N-[6-(4-
~ methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-N"I /~
0N o N benzamide
N
H
32 F
N 4-Chloro-N-(4-fluoro-phenyl)-N-(6-morpholin-
~ o N N 4-yl-pyridin-3-ylmethyl)-benzamide
33
4-Chloro-N-{6-[(2-methoxylethyl)-methyl-
amino]-pyridin-3-ylmethyl}-N-(4-fluoro-
~ \ `} ~ phenyl)-benzamide
N \ N
~
34 F I
N N-(4-Fluoro-phenyl)-N-[6-(4-methyl-piperazin-
C o N N 1-yl)-pyridin-3-ylmethyl]-4-sulfamoyl-
benzamide
O`S N
H2N~ ~~
35 F) N 4-Chloro-N-(4-fluoro-phenyl)-N-[6-(4-methyl-
~ ~ [1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-
o N N' benzamide
~12
36 F,,o 0 4-Chloro-N-(4-fluoro-phenyl)-N-[6-(4-
~ chlorobenzoyl-methyl-amino)-pyridin-3-
I~ o N i ylmethyl]-benzamide
ci ci
37 N
4-Chloro-N-[6-(4-methyl-piperazin-1-yl)-
o N N__) pyridin-3-ylmethyl]-N-m-tolyl-benzamide
N
38 4-Chloro-N-[6-(4-methyl-piperazin-1-yl)-
o N N) pyridin-3-ylmethyl]-N-o-tolyl-benzamide
-24-
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Cpd Structure
No. Chemical Name
39
LN~ 4-Chloro-N-(3,5-dimethyl-phenyl)-N-[6-(4-
methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
o N N benzamide
CI v N~
i
4-Chloro-N-(2-isopropyl-phenyl)-N-[6-(4-
N I methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
o N~N__~ benzamide
NN,
41 F
4-Chloro-N-(4-fluoro-phenyl)-N-[6-(4-pyridin-2-
~ o N N yl-piperazin-1-yl)-pyridin-3-ylmethyl]-
~ ~N benzamide
CI ~
I
N /
42 F
4-Chloro-N-(4-fluoro-phenyl)-N-(6-piperazin-1-
~ o N N yl-pyridin-3-ylmethyl)-benzamide
CI ~NH
43
N 4-Chloro-N-(4-fluoro-phenyl)-N-(6-
thiomorpholin-4-yl-pyridin-3-ylmethyl)-
benzamide
o N os
44 F I
N N-(4-Fluoro-phenyl)-2-hydroxy-N-[6-(4-methyl-
o N N_') piperazin-1-yl)-pyridin-3-ylmethyl]-benzamide
N
F~
N ~ 4-Chloro-N-(4-fluoro-phenyl)-N-{6-[4-(2-
~ methoxy-ethyl)-piperazin-1-yl]-pyridin-3-
o N N~ ylmethyl}-benzamide
N,
46 F
N 4-Chloro-N-[6-(4-dimethylcarbamoylmethyl-
piperazin-1-yl)-pyridin-3-ylmethyl]-N-(4-fluoro-
I o N N') o phenyl)-benzamide
CI ~,N
~
-25-
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Cpd Structure
No. Chemical Name
47
N 4-Chloro-N-{6-[(2-dimethylamino-ethyl)-
methyl-amino]-pyridin-3-ylmethyl}-N-(4-fluoro-
O N N") phenyl)-benzamide
48 F
/ N 4-Chloro-N-[6-(1,1-dioxo-1\6-thiomorpholin-4-
yl)-pyridin-3-ylmethyl]-N-(4-fluoro-phenyl)-
I O N ~'o benzamide
cl SO
49 cl /
4-Chloro-N-(4-chloro-phenyl)-N-[6-(4-methyl-
O o N N~ piperazin-1-yl)-pyridin-3-ylmethyl]-benzamide
N
CII
\ N
I 4-Chloro-N-[6-(4-methyl-piperazin-1-yl)-
O N N'') pyridin-3-ylmethyl]-N-p-tolyl-benzamide
N
51 cl
N-(4-Chloro-phenyl)-4-methyl-N-[6-(4-methyl-
O N N piperazin-1-yl)-pyridin-3-ylmethyl]-benzamide
N
52 F /
N N-[6-(4-Acetyl-piperazin-1-yl)-pyridin-3-
ylmethyl]-4-chloro-N-(4-fluoro-phenyl)-
I o N ~ benzamide
cl ~
53 Fa N 4-Chloro-N-(4-fluoro-phenyl)-N-{6-[methyl-(2-
N pyridin-3-yl-ethyl)-amino]-pyridin-3-ylmethyl}-
I~ O N i benzamide
CI /
54
4-Chloro-N-(3-isopropYI-phenYI)-N-[6-(4-
~
N methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
benzamide
O N ON
CI /
5
5
N~ 4-Chloro-N-(2,6-dimethyl-phenyl)-N-[6-(4-
~ methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
I~ 0 N N~ benzamide
/ ~, N"1 -26-
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Cpd Structure
No. Chemical Name
56 F N N~ 4-Chloro-N-{6-[4-(2-dimethylamino-ethyl)-
piperazin-1 o N phenyl)-benzamide
CI NN
~
57 F
N 5'-{[(4-Chloro-benzoyl)-(4-fluoro-phenyl)-
o N N amino]-methyl}-3,4,5,6-tetrahydro-2H-
NH2 [1,2']bipyridinyl-4-carboxylic acid amide
cl
58 F I
N
4-(5-{[(4-Chloro-benzoyl)-(4-fluoro-phenyl)-
o N N amino]-methyl}-pyridin-2-yl)-piperazine-l-
~ ~,N o carboxylic acid ethylamide
cl y
HN,_/
59 F
N 4-Chloro-N-(4-fluoro-phenyl)-N-[6-(4-
~ isopropyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
o N N
CI benzamide
/ ~N I
60 F \
~ N 4-Chloro-N-(4-fluoro-phenyl)-N-{6-[4-(2-
~o N N~ morpholin-4-yl-ethyl)-piperazin-1-yl]-pyridin-3-
cl ~,Nylmethyl}-benzamide
061
N N-(6-Piperazin-1-yl-pyridin-3-ylmethyl)-N-p-
o N N" tolyl-benzamide
~NH
62
\ N
N-[6-(4-Methanesulfonyl-piperazin-1-yl)-
I o N ~\/o pyridin-3-ylmethyl]-N-p-tolyl-benzamide
~~
63 F I
\ N ~
N-[4-(1 H-Benzoimidazol-2-yl)-3,4,5,6-
0 N tetrahydro-2H-[1,2']bipyridinyl-5'-ylmethyl]-4-
N
cl ~N chloro-N-(4-fluoro-phenyl)-benzamide
H~N'
-27-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
64
~
I ~ N-[6-(4-Acetyl-piperazin-1-yl)-pyridin-3-
o N N--) ylmethyl]-N-p-tolyl-benzamide
~,NO
65 \
N I 4-Chloro-N-[6-(4-methyl-piperazin-1-yl)-
O N NN pyridin-3-ylmethyl]-N-phenyl-benzamide
N
66 F
N 4-Chloro-N-(4-fluoro-phenyl)-N-(6-pyrrolidin-1-
O N N yl-pyridin-3-ylmethyl)-benzamide
CI
67 F N I ~ 4-Chloro-N-(4-fluoro-phenyl)-N-[6-(4-
O N' N~ methanesulfonyl-piperazin-1-yl)-pyridin-3-
1 ~N O ylmethyl]-benzamide
CI
0
68 F
N I 4-Chloro-N-(4-fluoro-phenyl)-N-(6-imidazol-1 -
I N ~~ yl-pyridin-3-ylmethyl)-benzamide
CI N
69
N 4-Chloro-N-(4-fluoro-phenyl)-N-[6-(3-
~N methylamino-pyrrolidin-l-yl)-pyridin-3-
~ Q
ylmethyl]-benzamide
CI
NH
70 F N 4-Chloro-N-(6-diethylaminomethyl-pyridin-3-
O N' ylmethyl)-N-(4-fluoro-phenyl)-benzamide
CI
71 F
N I 4-Chloro-N-(6-dimethylamino-pyridin-3-
ylmethyl)-N-(4-fluoro-phenyl)-benzamide
O N N
CI
72
N~ I N~CH3 4-Chloro-N-(4-fluoro-phenyl)-N-(2-methyl-
o `S thiazol-4-ylmethyl)-benzamide
-28-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
73 F
\~
N I \ 4-Chloro-N-(4-fluoro-phenyl)-N-(6-
O N NH methylamino-pyridin-3-ylmethyl)-benzamide
ci 74
N I \ 4-Chloro-N-(6-cyclopropylamino-pyridin-3-
O N NH ylmethyl)-N-(4-fluoro-phenyl)-benzamide
ci 75 F
N \ 4-Chloro-N-[6-(cyclopropyl-methyl-amino)-
~ pyridin-3-ylmethyl]-N-(4-fluoro-phenyl)-
O N benzamide
ci 76 F a~_ N~ N~ N~o 4-Chloro-N-(4-fluoro-phenyl)-N-(2-morpholin-
\ o s 4-yl-thiazol-4-ylmethyl)-benzamide
ci 77 F \
I~ N
N N o N-(4-Fluoro-phenyl)-N-(2-morpholin-4-yl-
':I
0 thiazol-4-ylmethyl)-benzamide
78
~N
N_ (4-Fluoro-phenyl)-4-methyl-N-(2-morpholin-
N 0
LS 4 yl thiazol 4 ylmethyl) benzamide
o
79 F
SN N- 4-Chloro-N-(4-fluoro-phenyl)-N-[2-(4-methyl-
N piperazin-1-yl)-thiazol-5-ylmethyl]-benzamide
I \ o
ci
80 F
N'N\ ~N 4-Chloro-N-(4-fluoro-phenyl)-N-(2-pyridin-4-yl-
o S thiazol-4-ylmethyl)-benzamide
ci
81 F a
N~ N N 4-Chloro-N-(2-diethylamino-thiazol-4-
\ o `s ~ ylmethyl)-N-(4-fluoro-phenyl)-benzamide -29-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
82 F I
N \
3-(4-Chloro-phenyl)-1-(4-fluoro-phe nyl)-1-[6-
HN'~O N N (4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
urea
~ y
83 F \
NI\
3-(3,4-Dimethoxy-phenyl)-1-(4-fluoro-phenyl)-
HN' ~O N N 1-[6-(4-methyl-piperazin-1-yl)-pyridin-3-
i ~, N ylmethyl]-urea
OCH3
OCH3
84 F \
N' 3-(5-Chloro-2-methoxy-phenyl)-1-(4-fluoro-
o55 'NH N' N phenyl)-1-[6-(4-methyl-piperazin-1-yl)-pyridin-
~ \ 3-ylmethyl]-urea
85 F I
N
(4-Fluoro-phenyl)-[6-(4-methyl-piperazin-1-yl)-
OO N N-') pyridin-3-ylmethyl]-carbamic acid 4-chloro-
i I N phenyl ester
\
ci
86
N I \ N-Cyclopentyl-N-[6-(4-methyl-piperazin-1-yl)-
o N N) pyridin-3-ylmethyl]-3-phenyl-propionamide
N
87
N ~ \ N-Cyclopropyl-N-[6-(4-methyl-piperazin-1-yl)-
O N N") pyridin-3-ylmethyl]-3-phenyl-propionamide
I~ ~N
88
N I \
N-Cyclopentyl-N-[6-(4-methyl-piperazin-1-yl)-
0 N N pyridin-3-ylmethyl]-2-phenyl-acetamide
a N-30-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
89
\ N \ N-(4-Fluoro-phenyl)-N-[6-(4-methyl-piperazin-
1 -yl)-pyridin-3-ylmethyl]-3-phenyl-
~ o N propionamide
ON,
90 F
ci N MN~z 3-(2-Chloro-phenyl)-N-(4-fluoro-phenyl)-N-[6-
(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
acrylamide 9
O-o N ON
1 F /
N \
~ 2-(4-Chloro-phenyl)-N-(4-fluoro-phenyl)-N-[6-
0 N N (4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
/ N acetamide
92 F a
NSN ~No N-(4-Fluoro-phenyl)-2-phenyl-N-(2-piperidin-1-
o yl-thiazol-4-ylmethyl)-acetamide
93
\ ~ N \ 2-(4-Chloro-phenoxy)-N-(4-fluoro-phenyl)-N-
[6-(4-methyl-piperazin-1-yl)-pyridin-3-
o
1"~o N N ylmethyl]-acetamide
F~
N
2-(4-Chloro-phenyl)-N-(4-fluoro-phenyl)-N-[6-
N N (4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
/ N isobutyramide
94 ci
F~
\ N \
' 1-(4-Chloro-phenyl)-cyclobutanecarboxylic
o N N acid (4-fluoro-phenyl)-[6-(4-methyl-piperazin-
/ N 1-yl)-pyridin-3-ylmethyl]-amide
-31 -
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
F~
N \
~ ~ 2-(4-Chloro-phenyl)-N-(4-fluoro-phenyl)-N-[6-
o N N~ (4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
/ propionamide
96
Fa~, ~ N-(4-Fluoro-phenyl)-N-[6-(4-methyl-piperazin-
0 N C 1- yl)-pyridin-3-ylmethyl]-3-phenyl-butyramide
97 I /
\ N \
2-(4-Chloro-phenyl)-N-[6-(4-methyl-piperazin-
0 N Nl~ 1-yl)-pyridin-3-ylmethyl]-N-phenyl-
/ N isobutyramide
98 ci
F~
~
/ N I \
1-(4-Methoxy-phenyl)-cyclopentanecarboxylic
o N N acid (4-fluoro-phenyl)-[6-(4-methyl-piperazin-
N N 1-yl)-pyridin-3-ylmethyl]-amide
99 01~
F \
/ \ N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-
0 luorophenyl)benzamide
/ \
100
F azzz~
N-{[6-(diethylamino)pyridin-3-yl]methyl}-2-fluoro-
N-(4-fluorophenyl)benzamide 101
CC
-32-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
F
\
o N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-
\ luorophenyl)-2-methoxybenzamide
102
I \ N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-
a ~ luorophenyl)-2-methylbenzamide
103 F \
\ o ~ ~ N-{[6-(diethylamino)pyridin-3-yl]methyl}-3-fluoro-
N-(4-fluorophenyl)benzamide
104
F \
\ o ~ ~ N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-
luorophenyl)-3-methoxybenzamide
~
105
F \
/
N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-
I \ o ~ luorophenyl)-3-methylbenzamide
106
F~
~ \ N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-
\ n,^ luorophenyl)-4-methoxybenzamide
\ i ~
107
F
4-tert-butyl-N-{[6-(diethylamino)pyridin-3-
I wl-11 yl]methyl}-N-(4- fluorophenyl)benzamide
108
-33-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
F,,
N-
{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-
~
CO- luorophenyl)-4-methylbenzamide
a~N----'
109
F \
4-cyano-N-{[6-(diethylamino)pyridin-3-yl]methyl}-
o N---, N-(4-fluorophenyl)benzamide
N
110
F
N I ~ N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-
i o N N^ luorophenyl)-2-naphthamide
111
F~
N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-
luorophenyl)-9-oxo-9H-fluorene-4- carboxamide
Z
112 F I \
luorophenyl)carbamoyl]benzoate methyl 4-[{[6-
~ 0 "- (diethylamino)pyridin-3-yl]methyl}(4-
~o
113 0
N N-(2-isopropylphenyl)-N-[(2-piperidin-1-yl-1,3-
N, - No thiazol-4-yl)methyl]benzamide
114
N 2-fluoro-N-(2-isopropylphenyl)-N-[(2-piperidin-1-
~"~ yl-1,3-thiazol-4- yl)methyl]benzamide
CF
115
-34-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
~ " N-(2-isopropylphenyl)-2-methoxy-N-[(2-
cLo p iperidin-l-yl-l,3-thiazol-4- yl)methyl]benzamide
,
116
" N-(2-isopropylphenyl)-2-methyl-N-[(2-piperidin-
\ "o 1-yl-1,3-thiazol-4- yl)methyl]benzamide
117
cI~
"C3-fluoro-N-(2-isopropylphenyl)-N-[(2-piperidin-1-
yl-1,3-thiazol-4- yl)methyl]benzamide
118 F
N-(2-isopropylphenyl)-3-methyl-N-[(2-piperidin-
I 1-yl-1,3-thiazol-4-yl)methyl]benzamide
119
4-chloro-N-(2-isopropylphenyl)-N-[(2-piperidin-1 -
\ yl-1,3-thiazol-4- yl)methyl]benzamide
120 c
N-(2-isopropylphenyl)-4-methoxy-N-[(2-
\ piperidin-l-yl-l,3-thiazol-4- yl)methyl]benzamide
121
~~~N~ N-(4-methylphenyl)-N-[(2-pyrrolidin-l-yl-1,3-
N thiazol-5-yl)methyl]benzamide
122
-35-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
/ s
No 2-fluoro-N-(4-methylphenyl)-N-[(2-pyrrolidin-1-yl-
I 0 1,3-thiazol-5-yl)methyl]benzamide
F
123
/ s
~N 2-methoxy-N-(4-methylphenyl)-N-[(2-pyrrolidin-
o I N ~ 1-yl-1,3-thiazol-5-yl)methyl]benzamide
o-11
124
S 2-methyl-N-(4-methylphenyl)-N-[(2-pyrrolidin-1-
~
N y1-1,3-thiazol-5-yl)methyl]benzamide
125
3-fluoro-N-(4-methylphenyl)-N-[(2-pyrrolidin-1-yl-
~ 1,3-thiazol-5-yl)methyl]benzamide
F
126
3-methoxy-N-(4-methylphenyl)-N-[(2-pyrrolidin-
~ 1-yl-1,3-thiazol-5-yl)methyl]benzamide
127 -1
L />NC] 3-methyl-N-(4-methylphenyl)-N-[(2-pyrrolidin-1-
" y1-1,3-thiazol-5-yl)methyl]benzamide
128
N s
No 4-fluoro-N-(4-methylphenyl)-N-[(2-pyrrolidin-1-yl-
o N~ 1,3-thiazol-5-yl)methyl]benzamide
F /
129
-36-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
N
N 4-chloro-N-(4-methylphenyl)-N-[(2-pyrrolidin-l-
o N ~ y1-1,3-thiazol-5-yl)methyl]benzamide
ci
130
N S
~N 4-methoxy-N-(4-methylphenyl)-N-[(2-pyrrolidin-
o I N ~ 1-yl-1,3-thiazol-5-yl)methyl]benzamide
\ /
131
~/"~ N-(4-methylphenyl)-N-[(2-pyrrolidin-l-yl-1,3-
thiazol-5-yl)methyl]biphenyl-4- carboxamide
132
"~N~ 4-tert-butyl-N-(4-methylphenyl)-N-[(2-pyrrolidin-
" 1-yl-1,3-thiazol-5-yl)methyl]benzamide
133
S N 4-methyl-N-(4-methylphenyl)-N-[(2-pyrrolidin-1-
~
o N 0 y1-1,3-thiazol-5-yl)methyl]benzamide
134
4-cyano-N-(4-methylphenyl)-N-[(2-pyrrolidin-1-
I \ o y1-1,3-thiazol-5-yl)methyl]benzamide
N~
135
F /
\
N ~N N-(4-fluoro-2-methylphenyl)-N-[(2-piperidin-1-
ylpyrimidin-5-yl)methyl]benzamide
136
-37-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
F
N 2-fluoro-N-(4-fluoro-2-methylphenyl)-N-[(2-
Ke~-. u piperidin-1-ylpyrimidin-5- yl)methyl]benzamide
I \ o
137
N \ N N-(4-fluoro-2-methylphenyl)-2-methyl-N-[(2-
piperidin-1-ylpyrimidin-5- yl)methyl]benzamide
I \ O N N~
138
F /
\ ~'" 3-fluoro-N-(4-fluoro-2-methylphenyl)-N-[(2-
~ ~ piperidin-1-ylpyrimidin-5- yl)methyl]benzamide
139 F
F / I
N-(4-fluoro-2-methylphenyl)-3-methoxy-N-[(2-
~ piperidin-1-ylpyrimidin-5- yl)methyl]benzamide
140 ~
\ N 4-fluoro-N-(4-fluoro-2-methylphenyl)-N-[(2-
~ piperidin-1-ylpyrimidin-5- yl)methyl]benzamide
I \ o ~
141
F /
\ ~\N 4-chloro-N-(4-fluoro-2-methylphenyl)-N-[(2-
I\ o piperidin-1-ylpyrimidin-5- yl)methyl]benzamide
ci
142
F / I
\ ~ N N-(4-fluoro-2-methylphenyl)-4-methoxy-N-[(2-
piperidin-1-ylpyrimidin-5- yl)methyl]benzamide
\ o n~
\ I i lvJ
143
-38-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
~N
4-tert-butyl-N-(4-fluoro-2-methylphenyl)-N-[(2-
I\ o I^ piperidin-1-ylpyrimidin-5- yl)methyl]benzamide
144
N-(4-fluoro-2-methylphenyl)-4-methyl-N-[(2-
145 piperidin-1-ylpyrimidin-5- yl)methyl]benzamide
\ ~N
4-cyano-N-(4-fluoro-2-methylphenyl)-N-[(2-
I\ o piperidin-1-ylpyrimidin-5- yl)methyl]benzamide
N~
146
F a
N-(4-fluoro-2-methylphenyl)-N-[(2-piperidin-1-
~ ylpyrimidin-5-yl)methyl]-2- naphthamide
147
F
N-(4-fluoro-2-methylphenyl)-9-oxo-N-[(2-
piperidin-1-ylpyrimidin-5-yl)methyl]-9H- fluorene-
4-carboxamide 148
ZO-
F
methyl4-{(4-fluoro-2-methylphenyl)[(2-piperidin-
1-ylpyrimidin-5- yl)methyl]carbamoyl}benzoate
o
149
~ ~_ND N-(2-isopropylphenyl)-3-methoxy-N-[(2-
~ piperidin-1-yl-1,3-thiazol-4-yl)methyl]benzamide
~
150
-39-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
" 4-fluoro-N-(2-isopropylphenyl)-N-[(2-piperidin-1-
\\,--""
yl-1,3-thiazol-4- yl)methyl]benzamide
151 F
N-(2-isopropylphenyl)-N-[(2-piperidin-1-yl-1,3-
thiazol-4-yl)methyl]biphenyl-4- carboxamide
152
4-tert-butyl-N-(2-isopropylphenyl)-N-[(2-
I piperidin-l-yl-l,3-thiazol-4-yl)methyl]benzamide
153
N-(2-isopropylphenyl)-4-methyl-N-[(2-piperidin-
\ "D 1-yl-1,3-thiazol-4- yl)methyl]benzamide
154
4-cyano-N-(2-isopropylphenyl)-N-[(2-piperidin-1 -
I yl-1,3-thiazol-4-yl)methyl]benzamide
155 N~
No N-(2-isopropylphenyl)-N-[(2-piperidin-1 -yl-1,3-
thiazol-4-yl)methyl]-2- naphthamide
156
IY
---CN ~-No N-(2-isopropylphenyl)-9-oxo-N-[(2-piperidin-1 -yl-
1,3-thiazol-4-yl)methyl]-9H- fluorene-4-
carboxamide
o -_j
157
-40-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
3-cyano-N-(2-isopropylphenyl)-N-[(2-piperidin-1-
yl-1,3-thiazol-4- yl)methyl]benzamide
158 "
methyl4-{(2-isopropylphenyl)[(2-piperidin-1-yl-
1,3-thiazol-4- yl)methyl]carbamoyl}benzoate
159
\ s~~ N-(4-methylphenyl)-N-[(2-pyrrolidin-1 -yl-1,3-
thiazol-5-yl)methyl]-2-naphthamide
160
ci-
",,-,,, N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin-
~ 2-yl]methyl}benzamide
o
161
al~
~ N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin-
I~ 2-yl]methyl}-2-fluorobenzamide
F
162
a\
FN "~ N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin-
2-yl]methyl}-2-methoxybenzamide
163
ci ~
~ ,
" ~N,,-,,,, N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin-
2-yl]methyl}-2-methylbenzamide
164
-41-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
" N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin-
~ O 2-yl]methyl}-3-fluorobenzamide
165 F
I/ ",,/
N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin-
~ 2-yl]methyl}-3-methoxybenzamide
166 0-1
l
"-,,,-
N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin-
I o 2-yl]methyl}-3-methylbenzamide
167
a\ ^ /
N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin-
o 2-yl]methyl}-4-fluorobenzamide
F I /
168
a\ ^
~I'/\ 4-chloro-N-(4-chlorophenyl)-N-{[6-
~ (diethylamino)pyridin-2-yl]methyl}benzamide
a
169
a,
N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin-
~ 2-yl]methyl}-4-methoxybenzamide
170
i
N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin-
~ 2-yl]methyl}biphenyl-4- carboxamide 171
-42-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
cl
4-tert-butyl-N-(4-chlorophenyl)-N-{[6-
I (diethylamino)pyridin-2- yl]methyl}benzamide
172
ci,
N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin-
~ 2-yl]methyl}-4-methylbenzamide
173
CI
N-(4-chlorophenyl)-4-cyano-N-{[6-
I (diethylamino)pyridin-2-yl]methyl}benzamide
N~
174
ci
N ",,-,,,, N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin-
~ o 2-yl]methyl}-2-naphthamide
175
N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin-
I 2-yl]methyl}-9-oxo-9H-fluorene-4- carboxamide
176 a
r
N-(4-chlorophenyl)-3-cyano-N-{[6-
I (diethylamino)pyridin-2-yl]methyl}benzamide
I
177 N
cl all "r'~ \ "~ methyl 4-[(4-chlorophenyl){[6-
~ (diethylamino)pyridin-2-
0r
~ yl]methyl}carbamoyl]benzoate
178 ~
-43-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
F~
N-(4-fluoro-2-methylphenyl)-2-methoxy-N-[(2-
~ piperidin-1-ylpyrimidin-5- yl)methyl]benzamide
179
\ N
N-(4-fluoro-2-methylphenyl)-3-methyl-N-[(2-
I \ o ~^~ piperidin-1-ylpyrimidin-5- yl)methyl]benzamide
180
\ ~N
4-carboxamide N-(4-fluoro-2-methylphenyl)-N-
~ [(2-piperidin-1 -ylpyrimidin-5-yl)methyl]biphenyl-
-ylpyrimidin-5-yl)methyl]biphenyl-
\
181
F
N-{[6-(diethylamino)pyridin-3-yl]methyl}-4-fluoro-
~ n,l~- N-(4-fluorophenyl)benzamide
\
182
FI~ ~
N-{3-[cyclopropyl(ethyl)amino]benzyl}-2-fluoro-
N-(4-fluorophenyl)benzamide
aF
183
S >-No N-(4-methylphenyl)-9-oxo-N-[(2-pyrrolidin-1 -yl-
~ 0 " 1,3-thiazol-5-yl)methyl]-9H-fluorene-4-
fluorene-4-
carboxamide
184
F
\ ~ \ 4-chloro-N-(4-fluorophenyl)-N-{[6-(4-
~ \ I ~ \ c' methylpiperazin-1 -yl)pyridin-3-
~v yl]methyl}benzamide
185 c
-44-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
N-cYclopentYI-3,4,5-trimethoxY-N-{[6-(4-
~
~ methylpiperazin-1-yl)pyridin-3-
~~ ~ yl]methyl}benzamide
186 o"
5-fluoro-N-(4-fluorophenyl)-2-methyl-N-{[6-(4-
0 methylpiperazin-1-yl)pyridin-3-
F \ / N / \ /--\ yl]methyl}benzamide
NN-
187
F
0 ~ \
_ H G N'-(4-chlorophenyl)-N-(4-fluorophenyl)-N-{[6-(4-
~ methylpiperazin-1-yl)pyridin-3- yl]methyl}urea
04-
1
88
F
N-(4-fluorophenyl)-4-methyl-N-{[6-(4-
"~ methylpiperazin-1-yl)pyridin-3-
~ yl]methyl}benzamide
0
189
ci
0 4-chloro-N-(4-fluorophenyl)-2-methoxy-N-{[6-(4-
methylpiperazin-1-yl)pyridin-3-
/ ~ yl]methyl}benzamide
F~
190
o N J N-(4-fluorophenyl)-4-methoxy-N-{[6-(4-
methylpiperazin-1-yl)pyridin-3-
191 Fi I " yl]methyl}benzamide
~
N-(4-fluorophenyl)-3-methyl-N-{[6-(4-
_ o methylpiperazin-1 -yl)pyridin-3-
F\ / N N yl]methyl}benzamide
/ ~ N 192
-45-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
" 4-(acetylamino)-N-(4-fluorophenyl)-N-{[6-(4-
I ~ methylpiperazin-1-yl)pyridin-3-
N ~ ~ yl]methyl}benzamide
193 F
F
4-chloro-N-(4-fluorophenyl)-N-{[6-(4-methyl-14-
diazepan-1-yl)pyridin-3- yl]methyl}benzamide
194 aa
4-chloro-N-{[6-(diethylamino)pyridin-3-
~ yl]methyl}-N-(4-fluorophenyl)benzamide
195
F
4-chloro-N-({6-[[2-
(dimethylamino)ethyl](methyl)amino]pyridin-3-
.~I yl}methyl)-N-(4- fluorophenyl)benzamide
0-- i
ci
196
F
4-chloro-N-{[6-(1,1-dioxidothiomorpholin-4-
~ yl)pyridin-3-yl]methyl}-N-(4-
~~~ luorophenyl)benzamide
0
197
i
4-chloro-N-(2,6-dimethylphenyl)-N-{[6-(4-
methylpiperazin-1-yl)pyridin-3-
~ N N yl]methyl}benzamide
198
0
\ I \ ~" 4-(5-{[(4-chlorobenzoyl)(4-
c, n'-luorophenyl)amino]methyl}pyridin-2-yl)-N-
~ Iethylpiperazine-1-carboxamide
199 F 0
-46-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
a
4-chloro-N-(4-fluorophenyl)-N-({6-[4-(2-
~ ~ morpholin-4-ylethyl)piperazin-l- yl]pyridin-3-
F N \ N~--~ yl}methyl)benzamide
200
o N-(4-methylphenyl)-N-[(6-piperazin-1-ylpyridin-
3-yl)methyl]benzamide
N CYN\_/ NH
201
CI
(4-fluorophenyl)benzamide N-({6-[4-(1 H-
o benzimidazol-2-yl)piperidin-1-yl]pyridin-3-
~ C\\ I~ yl}methyl)-4-chloro-N-
202 N ~
F
ON cl 4-chloro-N-(4-fluorophenyl)-N-[(6-pyrrolidin-1-
11 ylpyridin-3-yl)methyl]benzamide
N / N I /
203 0
cl
4-chloro-N-(4-fluorophenyl)-N-({6-[4-
o (methylsulfonyl)piperazin-1-yl]pyridin-3-
FC) N & o yl}methyl)benzamide
NN-S-
204 0
F CI
4-chloro-N-(4-fluorophenyl)-N-({6-[3-
(methylamino)pyrrolidin 1 yl]pyridin 3-
~ o yl}methyl)benzamide
205 H
G
S 4-chloro-N-(4-fluorophenyl)-N-[(2-piperidin-l-yl-
~ ~~ 1,3-thiazol-4-yl)methyl]benzamide
~/
206
-47-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
F
N-benzyl-N-({2-[cyclopropyl(ethyl)amino]-1,3-
o "-N thiazol-4-yl}methyl)-4- fluorobenzamide
\
207 ~ ~
o
NN N-benzyl-N-({2-[cyclopropyl(ethyl)amino]-1,3-
S ",> thiazol-4-yl}methyl)-2- phenylacetamide
208
0
N
~_N o N-cyclohexyl-4-fluoro-N-[(2-morpholin-4-yl-1,3-
F thiazol-4-yl)methyl]benzamide
209
F
N-benzyl-4-fluoro-N-[(2-morpholin-4-yl-1,3-
\ N~s~N o thiazol-4-yl)methyl]benzamide
210 ~
~s
0 4-chloro-N-[(2-cyclohexyl-1,3-thiazol-4-
F / \ N ~
yl)methyl]-N-(4-fluorophenyl)benzamide
\ /
211 c~
0
1
"~p
o ~--~ N-(4-fluorophenyl)-N-[(2-morpholin-4-yl-1,3-
\ ~thiazol-4-yl)methyl]-2- nitrobenzamide
212
F
FtF
F ~ N-(4-fluorophenyl)-N-[(2-morpholin-4-yl-1,3-
F -"o thiazol-4-yl)methyl]-3,5-
F ~Q bis(trifluoromethyl)benzamide
213 F-48-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
0-~
N-(4-fluorophenyl)-3,5-dimethoxy-N-[(2-
~~ ~ >,No morpholin-4-yl-1,3-thiazol-4-
" yl)methyl]benzamide
214
s
o tert-butyl 4-(4-{[(4-chlorobenzoyl)(4-
N N \/
_ Y luorophenyl)amino]methyl}-1,3-thiazol-2-
\ ~o yl)piperidine-l-carboxylate
215 c
0
N 4-chloro-N-cyclohexyl-N-({2-
~ ~N [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
s \> yl}methyl)benzamide
216 6
/ \ N ~ s
~NH 4-chloro-N-(4-fluorophenyl)-N-[(2-piperidin-4-yl-
1,3-thiazol-4- yl)methyl]benzamide
217 c
0
11
0~ N~ N-(4-fluorophenyl)-N-[(2-morpholin-4-yl-1,3-
I/ N~"U thiazol-4-yl)methyl]-4- nitrobenzamide
218
N-(4-fluorophenyl)-4-methoxy-N-[(2-morpholin-
N ~ 4-yl-1,3-thiazol-4- yl)methyl]benzamide
F
219
/>N o N-(4-fluorophenyl)-3-methoxy-N-[(2-morpholin-
~ N ~ 4-yl-1,3-thiazol-4- yl)methyl]benzamide
220
-49-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
F
\ N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-
~- yl}methyl)-4-fluoro-N-(4-
c s luorophenyl)benzamide
F
221
F
\ 4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
}- thiazol-4-yl}methyl)-N-(4-
I o s luorophenyl)benzamide
ci
222
ci 0
N N 2-chloro-N-cyclohexyl-N-({2-
~ ~ [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
yl}methyl)benzamide
223 1 6
0
N N 3-chloro-N-cyclohexyl-N-({2-
~ ~ [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
yl}methyl)benzamide
224
,-~o 0
~-N/ N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-
N
s 1,3-thiazol-4-yl}methyl)-2- methoxybenzamide
225
0
N
N N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-
I s 1,3-thiazol-4-yl}methyl)-3- methoxybenzamide
226
0
ci ~ ~ 3,5-dichloro-N-cyclohexyl-N-({2-
S [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
yl}methyl)benzamide
ci
227
-50-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
0
N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-
~ 1,3-thiazol-4-yl}methyl)-3,5-
dimethoxybenzamide
o,'
228
0
N% N~~ 3-cyano-N-cyclohexyl-N-({2-
~ J- ~ [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
s yl}methyl)benzamide
229
0
N
~- N N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-
s 1,3-thiazol-4-yl}methyl)-1- naphthamide
230
F - ~p
'6-r 4-chloro-N-(4-fluorophenyl)-N-[2-(2-morpholin-4-
\S yl-1,3-thiazol-4- yl)ethyl]benzamide
G / \
231
F
4-chloro-N-(4-fluorophenyl)-N-[3-(2-morpholin-4-
s v yl-1,3-thiazol-4-yl)propyl]benzamide
I o
a ~
232
II
4-chloro-N-(3-cyanophenyl)-N-({2-
~ [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
0 S ~ yl}methyl)benzamide
l~
233 a
0
""2 N N-(2-carbamoylphenyl)-4-chloro-N-({2-
~~N [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
I o s yl}methyl)benzamide
234
-51 -
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
H, O
N-(3-carbamoylphenyl)-4-chloro-N-({2-
~ [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
I o s yl}methyl)benzamide
235 a 0
H" N N-(4-carbamoylphenyl)-4-chloro-N-({2-
~[cyclopropyl(ethyl)amino]-1,3-thiazol-4-
I o s yl}methyl)benzamide
236 cl
/I
~
N-biphenyl-2-yl-4-chloro-N-({2-
N
)-N [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
I o yl}methyl)benzamide
237
N-biphenyl-4-yl-4-chloro-N-({2-
~ [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
I o s yl}methyl)benzamide
238 ci
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
\ I ~" thiazol-4-yl}methyl)-N-1- naphthylbenzamide
o
239
H
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
~~ thiazol-4-yl}methyl)-N-1 H-indol-5- ylbenzamide
o
240
i I
~ I \ I N-[4-(benzyloxy)phenyl]-4-chloro-N-({2-
~ [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
I ~ o S yl}methyl)benzamide
~
241
-52-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
~~ -ni 4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
~s thiazol-4-yl}methyl)-N-(4-
I hydroxyphenyl)benzamide
a
242
o
N N-(3-acetamidophenyl)-4_chloro-N-({2 _
" [cyclopropyl(ethyl)amino] 1,3 thiazol 4
yl}methyl)benzamide
ci
243
o ~ 1 4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
thiazol-4-yl}methyl)-N-(2,6-
/ dimethylphenyl)benzamide
244 c
N-(3-tert-butylphenyl)-4-chloro-N-({2-
~ [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
I yl}methyl)benzamide
245
ci
\ ~ 4-chloro-N-(3-chloro-2-methoxyphenyl)-N-({2-
N---C
C~N [cyclopropyl(ethyl)amino]-1,3- thiazol-4-
I ~ o s yl}methyl)benzamide
246 ci /
c ~ N N 4-chloro-N-(5-chloro-2-methylphenyl)-N-({2-
~ [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
I yl}methyl)benzamide
c
247
ci
c 4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
~ ~N thiazol-4-yl}methyl)-N-(2,3-
I dichlorophenyl)benzamide
248 c~
-53-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
ci
N 4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
ci thiazol-4-yl}methyl)-N-(3,5-
I s dichlorophenyl)benzamide
249
0
tert-butyl 3-[(4-chlorobenzoyl)({2-
~ ~ [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
I s yl}methyl)amino]benzoate
250
0-~
o tert-butyl 4-[(4-chlorobenzoyl)({2-
N [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
N~" yl}methyl)amino]benzoate
251 ql~
a~N
N 4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
~-N thiazol-4-yl}methyl)-N-pyridin-2- ylbenzamide
\>
252
N 4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
~ S-N thiazol-4-yl}methyl)-N-pyridin-3- ylbenzamide
I>
a
253
4-chloro-N-(6-chloropyridin-3-yl)-N-({2-
" [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
~
o ~ S \ yl}methyl)benzamide
ci/ ~% D
254
ci
4-chloro-N-(2-chloropyridin-4-yl)-N-({2-
~ [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
~ _" yl}methyl)benzamide
a i ~
255
-54-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
\ \ N 4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
~ ~N thiazol-4-yl}methyl)-N-quinolin-6- ylbenzamide
a S I>
256
N , -1,3-
4-chloro-N-({2-[cYclopropYI(ethYI)amino]
\ \
~ thiazol-4-yl}methyl)-N-quinolin-3- ylbenzamide
a S I>
257
O-N
-N 4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
thiazol-4-yl}methyl)-N-(5- methylisoxazol-3-
I\ o I S/ \> yl)benzamide
a
258
O OH
~ 3-[(4-chlorobenzoyl)({2-
~ [cyclopropyl(ethyl)amino]-1,3-thiazol-4-
I~ o l- ~ yl}methyl)amino]benzoic acid
259 a
N-[(6-chloropyridin-3-yl)methyl]-N-cyclopentyl-
3,4,5-trimethoxybenzamide
260
C,
co" N-[(6-chloropyridin-3-yl)methyl]-N-cyclohexyl-
3,4,5-trimethoxybenzamide
261 o"
~ N-cyclohexyl-3,4,5-trimethoxy-N-{[6-(4-
I c~õ' methylpiperazin-1-yl)pyridin-3-
~ yl]methyl}benzamide
262 0-1
-55-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
N-cyclohexyl-N-({6-[4-(hydroxymethyl)piperidin-
I o 1-yl]pyridin-3-yl}methyl)-3,4,5-
~ trimethoxybenzamide
O\ OH
263
F,,
-chloro-N-[(6-chloropyridin-3-yl)methyl]-N-(4-
I a luorophenyl)benzamide
z 4
o
G 264
" N-[(6-chloropyridin-3-yl)methyl]-3-cyano-N-(4-
<1 0 c luorophenyl)benzamide
265
o s N-(4-fluorophenyl)-N-[(2-morpholin-4-yl-1,3-
I N/ 0 thiazol-4-yl)methyl]-1-naphthamide
266
F~
~ ~ F F 3-cyano-N-(4-fluorophenyl)-N-{[6-
F (trifluoromethyl)pyridin-3-yl]methyl}benzamide
I
267 N
F~
4-chloro-N-(4-fluorophenyl)-N-{[6-
I
I ~ o F (trifluoromethyl)pyridin-3-yl]methyl}benzamide
F
a
268
F /
\ 3-cyano-N-(4-fluorophenyl)-N-({6-[4-(4-
N~ I \ ~ luorophenyl)piperazin-1-yl]pyridin-3-
~ I \ yl}methyl)benzamide
~ ~
269
-56-
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WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
3-cyano-N-(4-fluorophenyl)-N-{[6-(4-pyridin-2-
~ ylpiperazin-1-yl)pyridin-3- yl]methyl}benzamide
270
3-cyano-N-(4-fluorophenyl)-N-({6-[4-(2-
0 N phenylethyl)piperazin-1-yl]pyridin-3-
yl}methyl)benzamide
271
o N~ F N-(4-fluorophenyl)benzamide N-[(6-{4-[bis(4-
~~ luorophenyl)methyl]piperazin-1-yl}pyridin-3-
yl)methyl]-3-cyano-
272 F
F I
\ I ~ ~ I 4-chloro-N-{[6-(diphenylamino)pyridin-3-
~ \ yl]methyl}-N-(4-fluorophenyl)benzamide
i ~ i I
273 \
F
F
N-[(6-chloropyridin-3-yl)methyl]-3-cyano-N-[3-
(trifluoromethyl)phenyl]benzamide
N~
o ~ a
274
F F
F N-[(6-chloropyridin-3-yl)methyl]-3-cyano-N-[4-
N N(trifluoromethyl)phenyl]benzamide
o \N(^ci
275
F /
3-cyano-N-(4-fluorophenyl)-N-{[6-(2,2,2-
Cr'~ ~ j~F trifluoroethoxy)pyridin-3- yl]methyl}benzamide
F'
276
-57-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
F F
3-cyano-N-{[6-(4-methylpiperazin-1-yl)pyridin-3-
\ yl]methyl}-N-[3-
N~ (trifluoromethyl)phenyl]benzamide
I\ o
277
F
3-cyano-N-{[6-(4-methylpiperazin-1-yl)pyridin-3-
\~~i\\
yl]methyl}-N-[4-
"~ (trifluoromethyl)phenyl]benzamide
co
\/"\
278
F
4-chloro-N-(4-fluorophenyl)-N-({6-[methyl(2-
pyridin-2-ylethyl)amino]pyridin-3-
I 'N c ~ yl}methyl)benzamide
vv ~ a
279
4-chloro-N-(4-fluoro-2-methylphenyl)-N-{[6-(4-
~ methylpiperazin-1-yl)pyridin-3-
I yl]methyl}benzamide
~.v a
280
F
2-(4-chlorophenoxy)-N-(4-fluorophenyl)-N-{[6-(4-
~ \ \ \ c' methylpiperazin-1-yl)pyridin-3-
~ yl]methyl}acetamide
0
281
F
1-(4-chlorophenyl)-N-(4-fluorophenyl)-N-{[6-(4-
- methylpiperazin-1-yl)pyridin-3-
-N/-\ o \ ~ yl]methyl}cyclobutanecarboxamide
282
ci
2-(4-chlorophenyl)-N-(4-fluorophenyl)-N-{[6-(4-
' methylpiperazin-1-yl)pyridin-3-
~ yl]methyl}propanamide
283 F
-58-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
Cpd Structure
No. Chemical Name
o ci 2-(4-chlorophenyl)-2-methyl-N-{[6-(4-
methYIpi perazin-1-YI)pYridin-3-YI]methYI}- N-
~
-N ~ phenylpropanamide
N
284
0IJ
~~N N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-
S \~> 1,3-thiazol-4-yl}methyl)-2- phenylacetamide
285
~ I 0-1
N-(4-fluorophenyl)-2-(3-methoxyphenyl)-N-[(2-
0 s morpholin-4-yl-1,3-thiazol-4-
I -N/o yl)methyl]acetamide
286
I \
N
~-N N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-
yl}methyl)-N-(4-fluorophenyl)-2-
~ phenylacetamide
\I
287
YU N-(4-fluorophenyl)-N-[(2-morpholin-4-yl-1,3-
thiazol-4-yl)methyl]-4- phenoxybutanamide
288 F
3oo
s ~ N-(4-fluorophenyl)-N-[(2-morpholin-4-yl-1,3-
~N thiazol-4-yl)methyl]-2-
I phenoxyacetamide
289
F
N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-
o yl}methyl)-N-(4-fluorophenyl)-2-
pyridin-3-ylacetamide
290
-59-
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Cpd Structure
No. Chemical Name
F / I
~N N-- N-(4-fluorophenyl)-N-{[2-(4-methylpiperazin-1-
0 s yl)-1,3-thiazol-4-yl]methyl}-2-
pyridin-3-ylacetamide
291
Pharmaceutically acceptable salts of the compounds of formula (I), which can
have
an acidic moiety, can be formed using organic and inorganic bases. Both mono
and
polyanionic salts are contemplated, depending on the number of acidic
hydrogens
available for deprotonation. Suitable salts formed with bases include metal
salts,
such as alkali metal or alkaline earth metal salts, for example sodium,
potassium, or
magnesium salts; ammonia salts and organic amine salts, such as those formed
with
morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower
alkylamine (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-,
tributyl- or
dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g.,
mono-, di-
or triethanolamine). Specific non-limiting examples of inorganic bases include
NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4,
and Na3PO4. Internal salts also can be formed. Similarly, when a compound
disclosed herein contains a basic moiety, salts can be formed using organic
and
inorganic acids. For example, salts can be formed from the following acids:
acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, dichloroacetic,
ethenesulfonic,
formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,
isethionic,
lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic,
napthalenesulfonic,
nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic,
succinic, sulfuric,
tartaric, toluenesulfonic, and as well as other known pharmaceutically
acceptable
acids.
Pharmaceutically acceptable esters in the present invention refer to non-toxic
esters
of the compounds of formula (I), preferably the alkyl esters such as methyl,
ethyl,
propyl, isopropyl, butyl, isobutyl or pentyl esters, of which the methyl ester
is
preferred. However, other esters such as phenyl-C,_5 alkyl may be employed if
-60-
CA 02672239 2009-06-10
WO 2008/073936 PCT/US2007/087077
desired. Examples of pharmaceutically acceptable esters include, but are not
limited
to, C2-C6 alkyl esters such as methyl esters and ethyl esters.
Pharmaceutically
acceptable esters include esters made with aliphatic carboxylic acids,
preferably
those with a linear chain of between two and six carbon atoms, preferably
acetic
acid, and made with aromatic carboxylic acids, e.g. C7_12 acids such as
benzoic acid.
The aliphatic and aromatic acids may optionally be substituted by one or more
C,_a
alkyl groups.
Also provided in accordance with the present teachings are prodrugs of the
compounds disclosed herein. As used herein, "prodrug" refers to a moiety that
produces, generates or releases a compound of the present teachings when
administered to a mammalian subject. Prodrugs can be prepared by modifying
functional groups present in the compounds in such a way that the
modifications are
cleaved, either by routine manipulation or in vivo, from the parent compounds.
Examples of prodrugs include compounds as described herein that contain one or
more molecular moieties appended to a hydroxyl, amino, sulfhydryl, or carboxyl
group of the compound, and that when administered to a mammalian subject, is
cleaved in vivo to form the free hydroxyl, amino, sulfhydryl, or carboxyl
group,
respectively. Examples of prodrugs can include, but are not limited to,
acetate,
formate and benzoate derivatives of alcohol and amine functional groups in the
compounds of the present teachings. Preparation and use of prodrugs is
discussed
in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of
the
A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed.
Edward
B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, the
entire disclosures of which are incorporated by reference herein for all
purposes.
Carboxylic acid amide compounds of formula (I) in accordance with the present
invention can be prepared as outlined in the schemes below and as illustrated
in the
examples, from (a) commercially available starting materials, (b) compounds
known
in the literature, or readily prepared intermediates using literature
procedures, or (c)
new intermediates described in the schemes and experimental procedures herein.
-61 -
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Standard synthetic methods and procedures for the preparation of organic
molecules
and functional group transformations and manipulations can be readily obtained
from
the relevant scientific literature or from standard textbooks in the field. It
will be
appreciated that where typical or preferred process conditions (i.e., reaction
temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are
given,
other process conditions can also be used unless otherwise stated. Optimum
reaction conditions may vary with the particular reactants or solvent used,
but one
skilled in the art can determine such conditions by routine optimization
procedures.
Those skilled in the art of organic synthesis will recognize that the nature
and order
of the synthetic steps presented may be varied for the purpose of optimizing
the
formation of the compounds described herein.
Reactions are performed in a solvent appropriate to the reagents and materials
employed and suitable for the transformation being effected. Suitable solvents
typically are substantially nonreactive with the reactants, intermediates,
and/or
products at the temperatures at which the reactions are carried out, i.e.,
temperatures that can range from the solvent's freezing temperature to the
solvent's
boiling temperature. A given reaction can be carried out in one solvent or a
mixture
of more than one solvent. Depending on the particular reaction step, suitable
solvents for a particular reaction step can be selected. One skilled in the
art of
organic synthesis can readily selected suitable solvents.
It is understood by those skilled in the art of organic synthesis that the
various
functionalities present on the molecule must be consistent with the chemical
transformation proposed. This may necessitate routine judgment as to the order
of
synthetic steps, and the need for protecting groups for remote
functionalities. One
skilled in the art can readily determine the need for protection and
deprotection and
select appropriate protecting groups. The chemistry of protecting groups can
be
found, for example, in Greene, et al., Protective Groups in Organic Synthesis,
2d.
Ed., Wiley & Sons, 1991, the entire disclosure of which is herein incorporated
by
reference.
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The processes described herein can be monitored according to any suitable
method
known in the art. For example, product formation can be monitored by
spectroscopic
means, such as nuclear magnetic resonance spectroscopy (e.g., 'H or13C),
infrared
spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or
by
chromatography such as high performance liquid chromatograpy (HPLC) or thin
layer
chromatography.
In the schemes provided herein, unless expressed to the contrary, variables in
chemical formulae are as defined in other formulae herein. For example, Ar,
R1, R2,
R3, X and n in the schemes are defined as in any of the formulae herein,
except
where defined otherwise in the schemes.
One method for preparing compounds of formula (I) where X is a covalent bond
involves the coupling of an aryl acid or acid derivative (II) with an
appropriate amine
(III) as shown in Scheme 1 below:
SCHEME 1
R2
\i(CH2)p
O Acid Activation ~R~ )n N ~Ar R3
A A
/ R \ 2
/(C~ p R3
(Rl)n OH H Ar ~ 0
(II) (III) (I)
An aryl acid (II), or alternatively an activated acid derivative, is coupled
with the
desired amine (III) to provide a compound of Formula (I). Many aryl acids and
their
derivatives are commercially available or can otherwise be prepared by
literature
methods.
Examples of activated acid derivatives include, for example, acid chlorides,
esters,
acylimidazoles, anhydrides; these activated acid derivatives can be generated
in situ
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or as isolated compounds. Representative activating agents include, but are
not
limited to, sulfuryl chloride, thionyl chloride, 2-chloro-4,6-dimethoxy-1,3,5-
triazine,
and carbodiimides such as 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide and
dicyclohexyl carbodiimide; for examples of amide bond formation and acid
activation,
see Montalbetti C.A.G.N. and Falque, V. (2005), Tetrahedron, 61(46): 10827-
10852,
the entire disclosure of which is herein incorporated by reference.
Scheme 2 illustrates a method for preparing compounds of formula (I) where X
is
-NRc- and Rc is H, by coupling an optionally substituted isocyanatobenzene
compound (IV) with the desired amine (III).
SCHEME 2
/ \ N (R1)n
A A NH
(R1) / \ R ~2 N~(Cp ~R3 N
n H Ar
(IV) ~~ (III) 0 (CH2)p
(I) ~
Ar
\ R3
Scheme 3 illustrates a method for preparing compounds of formula (I) where X
is
-0-, by coupling an optionally substituted phenyl formate (V) with the desired
amine
(III).
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SCHEME 3
(RI )n \
Acid Activation A O
/A\ O 2
H
(R~) / O R \N/(C~Ar R N
H
(V) O (CH2)p
(111) (1)
/
Ar
\ R3
Alternatively the R3 group can be incorporated in the last step of the
synthesis, as
illustrated in Scheme 4 below.
SCHEME 4
RZ 2
X 0 ~ Z R NH LG~Ar-LG R2 R 3
Z-NH2 O'- X~ D. ~ X 0 Nv Ar-LG R ~XUNvAr-R
(R1 %/ )n p (vIII)cir ~ 10
(R')n~~ IGI
)n
(VI) (ViI) (IX) (1)
Z: e.g., halide or acetate
LG: e.g.,Cl, Br, or I
In this scheme, an acid halide, anhydride or activated acid derivative (VI) is
reacted
with the appropriate amine (R2-NH2) to provide the amide (VII). Alkylation of
the
resulting amide (VII) with a compound of formula (VIII) provides the
substituted
amide (IX). Compounds of formula (VIII) are either commercially available or
can
otherwise be readily synthesized. Displacement of the leaving group on the
substituted amide (IX) with the desired R3 group provides a compound of
Formula (I).
The amine (III) can be synthesized as described in Scheme 5 below.
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SCHEME 5
z LG Ar-LG z "R R2-NH R -N Ar-LG R3
PtG - PtG ~
(VIIIa)
z
(X) (Xl) N^Ar R3 o Rz_N^Ar-R3
PtG I
PtG: e.g., t-Butyloxycarbonyl Ng H
LG: e.g., Cl, Br, or I Rz~PtG LG~Ar-R3 (XII) (III)
(X) (VIIIb)
In this scheme, alkylation of a protected amine (X) with a compound of formula
(Vllla)
provides the protected alkylated amine (XI). Displacement of the leaving group
on
compound (XI) with the appropriate amine (R3, wherein R3 is NRfRg) provides
the
amine-substituted aryl derivative (XII). Alternatively, alkylation of the
protected amine
(X) with a compound of formula (Vlllb) provides the amine-substituted aryl
derivative
(XII) directly. Removal of the protecting group (PtG) under standard
conditions
provides the desired amine (III).
Alternatively, the amine (III) can be synthesized from commercially available
substituted acid halides, anhydrides or other activated carboxylic acid
derivatives
(Vllla or Vlllb), as illustrated in Scheme 6 below.
SCHEME 6
O
~ z z 0 Reduction z
Z Ar-R3 R-NHz R'NkAr-R3 RNAr-R3
(XHIa) H (XIVa) H (HI)
Z: e.g., halide, acetate R
0 2 0
Z~Ar-LG R2-NHz R~Njl~'Ar-LG
(XIIIb) (XIVb)
LG: e.g., Cl, Br or I
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In this scheme, a substituted acid halide, anhydride or activated carboxylic
acid
derivative (Xllla or Xlllb) is reacted with the appropriate amine R2-NH2 to
provide the
amide (XIVa or XIVb). In the case of amide (XIVb), displacement of the leaving
group (LG) with the appropriate amine (R3, wherein R3 is NRfRg) provides amide
(XIVa). Finally, the amide (XIVa) is reduced under standard conditions to
provide the
desired amine (III).
A third approach commences with a substituted aryl compound (XV), as
illustrated in
Scheme 7 below.
SCHEME 7
0 Reductive 2
LG~ Me2NCH0 ~ Amination R, N~Ar-R3
Ar-R 3 0- H Ar-R3 i
R2-NH2 H
(XV) (III)
(XVI)
More specifically, conversion of a compound of formula (XV) to the
corresponding
organometallic derivative and treatment with dimethylformamide (Me2NCHO)
provides the aryl aldehyde (la). Reductive amination with the appropriate
amine (R2-
NH2) provides the desired amine (III).
Evaluation of representative compounds according to embodiments of this
invention
indicated that the compounds of the present teachings can modulate the
activity of
ion channels in a mammal, for example, Cav2.2 voltage-gated calcium channels.
A variety of pathological conditions, states, disorders or diseases can be
treated by
modulating the activity of certain ion channels. As used herein, "ion channel
mediated condition" refers to any condition or pathological state of a mammal
or any
disease present in a mammal that can be treated, or the symptoms of which can
be
alleviated, by modulation of the activity of one or more ion channels such as
Cav2.2
voltage-gated calcium channels. An ion channel mediated condition can be
attributed to the abnormal functioning of one or more ion channels. An ion
channel
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can be functioning abnormally when, for example, the ion channel exhibits
abnormally increased or decreased activation.
By way of non-limiting examples, ion channel mediated conditions include
conditions
associated with neuronal hyperexcitability, conditions associated with
abnormal
glutamate regulation, pain, convulsions, epilepsy, stroke, anxiety disorders,
neuronal
disorders, traumatic brain injury, angina, hypertension, congestive heart
failure,
myocardial ischemia, arrhythmia, diabetes, urinary incontinence, hot flush,
thermal
disregulation, and combinations thereof.
Examples of conditions associated with neuronal hyperexcitability include, but
are not
limited to, convulsions, including neonatal convulsions, epilepsy, episodic
ataxia,
myokymia, cerebral ischemia, cerebral palsy, stroke, traumatic brain injury,
traumatic
spinal cord injury, asphyxia, anoxia, prolonged cardiac surgery, and
combinations
thereof.
Examples of conditions associated with the abnormal regulation of glutamate
include,
but are not limited to, hypoglycemia or diseases associated with abnormal
glutamate
regulation such as, without limitation, Parkinson's disease, Huntingdon's
disease,
Alzheimer's disease, amyotrophic lateral sclerosis, AIDS-related dementia, and
combinations thereof.
Examples of anxiety disorders include, but are not limited to, agoraphobia,
panic
disorder, specific phobia, social phobia, obsessive compulsive disorder,
posttraumatic stress disorder, acute stress disorder, generalized anxiety
disorder,
separation anxiety disorder, substance-induced anxiety disorder, and anxiety
disorder not otherwise specified.
Examples of pain include, but are not limited to various types of nociceptic
or
neuropathic pain, such as, without limitation, inflammatory pain,
musculoskeletal
pain, bony pain, lumbosacral pain, neck or upper back pain, visceral pain,
somatic
pain, pain associated with diabetic neuropathy, cancer pain, pain caused by
injury or
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surgery such as burn pain, headaches such as migraines or tension headaches,
and
combinations of these pains. One skilled in the art will recognize that these
pain
types can overlap one another. For example, a pain caused by inflammation can
also be visceral or musculoskeletal in nature. Other examples of pain include
those
related to conditions of hyperalgesia, allodynia, or both. The types of pain
listed
above can be acute (short duration) or chronic (regularly reoccuring or
persistent),
centralized or peripheral, and can be with or without peripheral or central
sensitization.
Accordingly, the compounds of the present teachings can be useful for the
treatment
of a pathological condition, disorder or disease, and the alleviation of a
symptom
thereof, in a mammal, for example, a human. The pathological condition,
disorder or
disease, or a symptom thereof, can be, but is not limited to, one of the
various ion
channel mediated conditions described above. In some embodiments, the
compounds of the present teachings can be used for pain therapy, including
treating,
by way of non-limiting examples, the various types of pain described above. As
used
herein, "treating" refers to partially or completely alleviating, inhibiting,
preventing
and/or ameliorating the condition. The present teachings therefore include use
of the
compounds disclosed herein as active therapeutic substances for the treatment
of a
variety of ion channel mediated conditions as well as for pain therapy.
For example, the compounds disclosed herein can be useful for treating the
various
conditions associated with neuronal hyperexcitability, the various conditions
associated with abnormal glutamate regulation, the various anxiety and
neuronal
disorders, angina, hypertension, congestive heart failure, myocardial
ischemia,
arrhythmia, diabetes, urinary incontinence, and combinations thereof, as
described
above.
The compounds disclosed herein also can be useful for treating pain, including
chronic pain that is neuropathic pain associated with damage to or
pathological
changes in the peripheral nervous system or the central nervous system;
visceral
pain associated with, by way of non-limiting examples, the abdominal, pelvic,
and/or
perineal regions or pancreatitis;, musculoskeletal pain; bony pain associated
with, by
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way of non-limiting examples, bone or joint degenerating disorders such as
osteoarthritis, rheumatoid arthritis, or spinal stenosis; cancer pain;
musculoskeletal
pain associated with, by way of non-limiting examples, the lower or upper
back,
spine, fibromylagia, temporomandibular joint, or myofascial pain syndrome;
headaches such migraine or tension headaches; pain associated with infections
such
as HIV or shingles, sickle cell anemia, autoimmune disorders, multiple
sclerosis, and
inflammation in accordance with the methods described herein.
Inflammatory pain can be associated with a variety of medical conditions such
as
osteoarthritis, rheumatoid arthritis, surgery, or injury. Neuropathic pain may
be
associated with, for example, diabetic neuropathy, peripheral neuropathy, post-
herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies,
fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy,
casualgia,
thalamic syndrome, nerve root avulsion, or nerve damage cause by injury
resulting in
peripheral and/or central sensitization such as phantom limb pain, reflex
sympathetic
dystrophy or postthoracotomy pain, cancer, chemical injury, toxins,
nutritional
deficiencies, or viral or bacterial infections such as shingles or HIV, or
combinations
thereof. The methods of use for compounds of this invention further include
treatments in which the neuropathic pain is a condition secondary to
metastatic
infiltration, adiposis dolorosa, burns, or central pain conditions related to
thalamic
conditions.
Chronic pain may be associated with diabetes, post traumatic pain of
amputation,
lower back pain, spinal cord damage, cancer, chemical injury, chemotherapy
induced
peripheral neuropathy, toxins, major surgery, peripheral nerve damage due to
traumatic injury, post-herpetic neuralgia, trigeminal neuralgia, lumbar or
cervical
radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic
dystrophy, causalgia, thalamic syndrome, nerve root avulsion, reflex
sympathetic
dystrophy or post thoracotomy pain, nutritional deficiencies, viral infection,
bacterial
infection, metastatic infiltration, adiposis dolorosa, burns, central pain
conditions
related to thalamic conditions; and any combination thereof.
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As used herein, the term "chronic pain" refers to centralized or peripheral
pain that is
intense, localized, sharp, or stinging, and/or dull, aching, diffuse, or
burning in nature
and that occurs for extended periods of time (i.e., persistent and/or
regularly
reoccurring), including, for the purpose of the present invention, neuropathic
pain and
cancer pain. Chronic pain includes neuropathic pain, hyperalgesia, and/or
allodynia.
One skilled in the art will also recognize that at least some of the types of
pain
described above can be attributed to a condition associated with the abnormal
activity of one or more ion channels such as, but not limited to, the abnormal
regulation of glutamate.The present teachings therefore include methods of
administering to a mammal a therapeutically effective amount of a compound
disclosed herein. As used herein, "administer" or "administering" refers to
either
directly administering a compound of the present teachings or a pharmaceutical
composition containing the compound, or administering the compound or
pharmaceutical composition indirectly via a prodrug derivative or analog which
will
form an equivalent amount of the active compound or substance within the body.
The methods also can include identifying a mammal in need of such treatment,
and
administering a therapeutically effective amount of a compound disclosed
herein to
the mammal in need thereof. As used herein, "therapeutically effective" refers
to a
substance or an amount that elicits a desirable biological activity or effect.
In some embodiments, the method includes administering to a mammal a
pharmaceutical composition that comprises a compound disclosed herein in
combination or association with a pharmaceutically acceptable carrier. The
compound of the present teachings can be administered alone or in combination
with
other therapeutically effective compounds or therapies for the treatment of
such
condition(s). For example, the other therapeutically effective compounds can
include
a cardiovascular disease agent and/or a nervous system disease agent. A
nervous
system disease agent can be a peripheral nervous system (PNS) disease agent
and/or a central nervous (CNS) disease agent.
The present teachings also relate to in vitro or in vivo methods of modulating
the
activity of ion channels including, but not limited to, Cav2.2 voltage-gated
calcium
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channels. In some embodiments, such methods include contacting a Ca,2.2
voltage-
gated calcium channel with a compound disclosed herein. In certain
embodiments,
the methods include monitoring the activity of ion channels. In various
embodiments,
the present teachings relate to methods of modulating the activity of an ion
channel
such as a Cav2.2 voltage-gated calcium channel that include in vitro or in
vivo
administration of a pharmaceutically effective amount of one or more compounds
of
formula (I). As used herein, "pharmaceutically effective" refers to an amount
that can
elicit an intended biological activity or effect.
When administered for the treatment or inhibition of a particular disease
state or
disorder, it is understood that an effective dosage can vary depending upon
the
particular compound utilized, the mode of administration, and severity of the
condition being treated, as well as the various physical factors related to
the
individual being treated. In therapeutic applications, a compound of the
present
teachings can be provided to a patient already suffering from a disease in an
amount
sufficient to treat the symptoms of the disease and its complications. The
dosage to
be used in the treatment of a specific individual typically must be
subjectively
determined by the attending physician. The variables involved include the
specific
condition and its state as well as the size, age and response pattern of the
patient.
The present teachings also provide pharmaceutical compositions comprising at
least
one compound described herein and one or more pharmaceutically acceptable
carriers, excipients, or diluents. Examples of such carriers are well known to
those
skilled in the art and can be prepared in accordance with acceptable
pharmaceutical
procedures, such as, for example, those described in Remington's
Pharmaceutical
Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company,
Easton,
PA (1985), the entire disclosure of which is incorporated by reference herein
for all
purposes. As used herein, "pharmaceutically acceptable" refers to a substance
that
is acceptable for use in pharmaceutical applications from a toxicological
perspective
and does not adversely interact with the active ingredient. Accordingly,
pharmaceutically acceptable carriers are those that are compatible with the
other
ingredients in the formulation and are biologically acceptable. Supplementary
active
ingredients can also be incorporated into the pharmaceutical
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compositions.Compounds of the present teachings can be administered orally or
parenterally, neat or in combination with conventional pharmaceutical
carriers.
Applicable solid carriers can include one or more substances which can also
act as
flavoring agents, lubricants, solubilizers, suspending agents, fillers,
glidants,
compression aids, binders or tablet-disintegrating agents, or encapsulating
materials.
The compounds can be formulated in conventional manner, for example, in a
manner
similar to that used for known antiinflammatory agents. Oral formulations
containing
an active compound disclosed herein can comprise any conventionally used oral
form, including tablets, capsules, buccal forms, troches, lozenges and oral
liquids,
suspensions or solutions. In powders, the carrier can be a finely divided
solid, which
is an admixture with a finely divided active compound. In tablets, an active
compound can be mixed with a carrier having the necessary compression
properties
in suitable proportions and compacted in the shape and size desired. The
powders
and tablets can contain up to about 99% or greater of the active compound.
Capsules can contain mixtures of active compound(s) with inert filler(s)
and/or
diluent(s) such as the pharmaceutically acceptable starches (e.g., corn,
potato or
tapioca starch), sugars, artificial sweetening agents, powdered celluloses
(e.g.,
crystalline and microcrystalline celluloses), flours, gelatins, gums, and the
like.
Useful tablet formulations can be made by conventional compression, wet
granulation or dry granulation methods and utilize pharmaceutically acceptable
diluents, binding agents, lubricants, disintegrants, surface modifying agents
(including surfactants), suspending or stabilizing agents, including, but not
limited to,
magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars,
lactose, dextrin,
starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose,
sodium
carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine,
alginic
acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium
carbonate,
glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,
kaolin,
mannitol, sodium chloride, low melting waxes, and ion exchange resins. Surface
modifying agents can include nonionic and anionic surface modifying agents.
Representative examples of surface modifying agents include, but are not
limited to,
poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol,
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cetomacrogol emulsifying wax, sorbitan esters, colloidol silicon dioxide,
phosphates,
sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral
formulations herein can utilize standard delay or time-release formulations to
alter the
absorption of the active compound(s). The oral formulation can also consist of
administering an active compound in water or fruit juice, containing
appropriate
solubilizers or emulisifiers as needed.
Liquid carriers can be used in preparing solutions, suspensions, emulsions,
syrups,
and elixirs. An active compound described herein can be dissolved or suspended
in
a pharmaceutically acceptable liquid carrier such as water, an organic
solvent, or a
mixture of both, or pharmaceutically acceptable oils or fats. The liquid
carrier can
contain other suitable pharmaceutical additives such as solubilizers,
emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending agents,
thickening
agents, colors, viscosity regulators, stabilizers, and osmo-regulators.
Examples of
liquid carriers for oral and parenteral administration include, but are not
limited to,
water (particularly containing additives as described above, e.g., cellulose
derivatives
such as a sodium carboxymethyl cellulose solution), alcohols (including
monohydric
alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and
oils (e.g.,
fractionated coconut oil and arachis oil). For parenteral administration, the
carrier
can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile
liquid
carriers are used in sterile liquid form compositions for parenteral
administration.
The liquid carrier for pressurized compositions can be halogenated hydrocarbon
or
other pharmaceutically acceptable propellants.
Liquid pharmaceutical compositions, which are sterile solutions or
suspensions, can
be utilized by, for example, intrathecal, intramuscular, intraperitoneal or
subcutaneous injection. Sterile solutions can also be administered
intravenously.
Compositions for oral administration can be in either liquid or solid form.
Preferably the pharmaceutical composition is in unit dosage form, for example,
as
tablets, capsules, powders, solutions, suspensions, emulsions, granules, or
suppositories. In such form, the pharmaceutical composition can be sub-divided
in
unit dose(s) containing appropriate quantities of the active compound. The
unit
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dosage forms can be packaged compositions, for example, packeted powders,
vials,
ampoules, prefilled syringes or sachets containing liquids. Alternatively, the
unit
dosage form can be a capsule or tablet itself, or it can comprise the
appropriate
number of any such compositions in package form. Such unit dosage form may
contain from about 1 mg/kg of active compound to about 500 mg/kg of active
compound, and can be given in a single dose or in two or more doses. Such
doses
can be administered in any manner useful in directing the active compound(s)
to the
recipient's bloodstream, including orally, via implants, parenterally
(including
intravenous, intraperitoneal and subcutaneous injections), rectally,
vaginally, and
transdermally. Such administrations can be carried out using the compounds of
the
present teachings including pharmaceutically acceptable salts thereof, in
lotions,
creams, foams, patches, suspensions, solutions, and suppositories (e.g.,
rectal and
vaginal).
In some cases, it may be desirable to administer a compound directly to the
airways
of the patient in the form of a dry powder or an aerosol. For administration
by
intranasal or intrabronchial inhalation, the compounds of the present
teachings can
be formulated, for example, into an aqueous or partially aqueous solution.
Compounds described herein can be administered enterally or parenterally (such
as,
without limitation, interperitoneal, intramuscular, intravascular,
intrathecal, intra-
articular or subcuteaneous injection or infusion). Solutions or suspensions of
these
active compounds or pharmaceutically acceptable salts thereof can be prepared
in
water suitably mixed with a surfactant such as hydroxyl-propylcellulose.
Dispersions
can also be prepared in glycerol, liquid polyethylene glycols, and mixtures
thereof in
oils. Under ordinary conditions of storage and use, these preparations
typically
contain a preservative to inhibit the growth of microorganisms.
The pharmaceutical forms suitable for injection can include sterile aqueous
solutions
or dispersions and sterile powders for the extemporaneous preparation of
sterile
injectable solutions or dispersions. In preferred embodiments, the form is
sterile and
its viscosity permits it to flow through a syringe. The form preferably is
stable under
the conditions of manufacture and storage and can be preserved against the
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contaminating action of microorganisms such as bacteria and fungi. The carrier
can
be a solvent or dispersion medium containing, for example, water, ethanol,
polyol
(e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable
mixtures
thereof, and vegetable oils.
Compounds described herein can be administered transdermally, i.e.,
administered
across the surface of the body and the inner linings of bodily passages
including
epithelial and mucosal tissues. Such administration can be carried out using
the
compounds of the present teachings including pharmaceutically acceptable salts
thereof, in lotions, creams, foams, patches, suspensions, solutions, and
suppositories (e.g., rectal and vaginal). Topical formulations that deliver
active
compound(s) through the epidermis can be useful for localized treatment of
inflammation and arthritis.
Transdermal administration can be accomplished through the use of a
transdermal
patch containing an active compound and a carrier that can be inert to the
active
compound, can be non-toxic to the skin, and can allow delivery of the active
compound for systemic absorption into the blood stream via the skin. The
carrier can
take any number of forms such as creams and ointments, pastes, gels, and
occlusive
devices. The creams and ointments can be viscous liquid or semisolid emulsions
of
either the oil-in-water or water-in-oil type. Pastes comprised of absorptive
powders
dispersed in petroleum or hydrophilic petroleum containing the active compound
can
also be suitable. A variety of occlusive devices can be used to release the
active
compound into the blood stream, such as a semi-permeable membrane covering a
reservoir containing the active compound with or without a carrier, or a
matrix
containing the active compound. Other occlusive devices are known in the
literature.
Compounds described herein can be administered into a body cavity, (e.g.,
rectally
or vaginally) in the form of a conventional suppository. Suppository
formulations can
be made from traditional materials, including cocoa butter, with or without
the
addition of waxes to alter the suppository's melting point, and glycerin.
Water-soluble
suppository bases, such as polyethylene glycols of various molecular weights,
can
also be used.
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Lipid formulations or nanocapsules can be used to introduce compounds of the
present teachings into host cells either in vitro or in vivo. Lipid
formulations and
nanocapsules can be prepared by methods known in the art. For example, the
compounds described herein can be administered in the form of liposomes. As is
known in the art, liposomes are generally derived from phospholipids or other
lipid
substances, and are formed by mono or multilamellar hydrated liquid crystals
that are
dispersed in an aqueous medium. Any nontoxic, pharmacologically acceptable
lipid
capable of forming liposomes can be used.
To increase the effectiveness of compounds of the present teachings, it can be
desirable to combine a compound with other agents effective in the treatment
of the
target disease. For inflammatory diseases, other active compounds (i.e., other
active
ingredients or agents) effective in their treatment, and particularly in the
treatment of
asthma and arthritis, can be administered with active compounds of the present
teachings. The other agents can be administered at the same time or at
different
times than the compounds disclosed herein.
Throughout the description, where compositions are described as having,
including,
or comprising specific components, or where processes are described as having,
including, or comprising specific process steps, it is contemplated that
compositions
of the present teachings also can consist essentially of, or consist of, the
recited
components, and that the processes of the present teachings also consist
essentially
of, or consist of, the recited processing steps.
In the application, where an element or component is said to be included in
and/or
selected from a list of recited elements or components, it should be
understood that
the element or component can be any one of the recited elements or components
and can be selected from a group consisting of two or more of the recited
elements
or components.
The use of the singular herein includes the plural (and vice versa) unless
specifically
stated otherwise. In addition, where the use of the term "about" is before a
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quantitative value, the present teachings also include the specific
quantitative value
itself, unless specifically stated otherwise.
It should be understood that the order of steps or order for performing
certain actions
is immaterial so long as the present teachings remain operable. Moreover, two
or
more steps or actions may be conducted simultaneously.
Compounds described herein can contain an asymmetric atom (also referred as a
chiral center), and some of the compounds can contain one or more asymmetric
atoms or centers, which can thus give rise to optical isomers (enantiomers)
and
diastereomers. The present teachings and compounds disclosed herein include
such optical isomers (enantiomers) and diastereomers (geometric isomers), as
well
as the racemic and resolved, enantiomerically pure R and S stereoisomers, as
well
as other mixtures of the R and S stereoisomers and pharmaceutically acceptable
salts thereof. Optical isomers can be obtained in pure form by standard
procedures
known to those skilled in the art, which include, but are not limited to,
diastereomeric
salt formation, kinetic resolution, and asymmetric synthesis. The present
teachings
also encompass cis and trans isomers of compounds containing alkenyl moieties
(e.g., alkenes and imines). It is also understood that the present teachings
encompass all possible regioisomers, and mixtures thereof, which can be
obtained in
pure form by standard separation procedures known to those skilled in the art,
and
include, but are not limited to, column chromatography, thin-layer
chromatography,
and high-performance liquid chromatography.
Throughout the specification, structures may or may not be presented with
chemical
names. Where any question arises as to nomenclature, the structure prevails.
Aspects of the present teachings can be further understood in light of the
following
examples, which should not be construed as limiting the scope of the present
teachings in any way.
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More specifically, the following examples illustrate various synthetic routes
that can
be used to prepare reagents and intermediates, including appropriate amines
and
carboxylic acids, that can be used to prepare compounds of formula (I).
EXAMPLES
Amines of formula R2NH(CH2)pArR3, including those provided in the following
examples and others commercially available or prepared according to procedures
known in the art, can be coupled with various carboxylic acids and acid
derivatives to
provide compounds of formula (I). Useful carboxylic acids and activated
derivatives
include those provided in the following examples as well as those that are
commercially available or prepared according to procedures known in the art.
Compound Numbers 1-291 were prepared in accordance with Representative
Schemes 1-18 and the following specific examples of analogous compounds using
the appropriate starting materials. Selected compounds are shown in Table 2
below.
It is understood by those skilled in the art of organic synthesis that the
substitution
patterns of the starting materials determines the substitution patterns of the
products,
and the skilled practioner will be able to exercise routine judgment for the
selection of
suitable starting materials in order to prepare specific products, the order
of synthetic
steps, and the need for protecting groups for remote functionalities.
While certain acyl chlorides are illustrated in the representative schemes as
examples of activated acid derivatives useful for acylation of amines, other
reagents
for amide bond formation as known in the art can be utilized in the
preparation of
compounds of formula (I) in accordance with the teachings herein.
In some cases, the compounds were isolated as hydrochloride salts prepared via
standard protocols using anhydrous hydrogen chloride as a gas, or as a
solution in
dioxane or diethyl ether. Those skilled in the art will also appreciate that
the
protonation state of the test compound is in accordance with the pH of the
assay
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conditions, typically buffered as specified in the assay protocols, and not of
the salt
form or free base of the compound as synthesized.
One of skill in the art of organic chemistry would recognize that reference to
R in the
following representative schemes is a generic representation, that R wherever
it
appears does not have to be the same at each occurrence, and R can be selected
from, for example, Rf, Rg, and substitutents on R2 and R3, among others as
appropriate and in accordance with the teachings herein. In the following
schemes,
Ar represents an aryl group in accordance with the teachings herein, and any
of the
alkyl, aryl and cylcloalkyl groups may be substituted in accordance with the
teachings
herein.
When reference is made to HPLC retention time, the following HPLC conditions
were
used:
HPLC A: Waters Xterra RP18, 3.5u, 150 x 4.6 mm; Temperature 40 C; Flow
Ratel.2 mL/min; Mobile Phase Comp. 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10min, hold 4min; Injection Volume 5 L; Detector
Wavelength 210-370 nM.
HPLC B: Nucleodur C18 EC, 4.6 x 250 mm, Mobile phase: A = MeCN, B = 0.1%
aqueous formic acid, Time/%B: 0/90, 3/90, 8/20, 15/20, 18/90, 20/90;Flow: 1.0
mL/min; Temperature 50 C; Diluent: MeOH; and
HPLC C: Mobile phase gradient = 5% acetonitrile / 95% ammonium acetate (10 mM)
to 95% acetonitrile / 5% ammonium acetate (10 mM) over 2.5 min, hold for 1.5
min,
then re-equilibrate. Column = Keystone AquasilTM C18 column (2 x 50 mm, 5 mM).
Detection = 214 nm and 254 nm.
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REPRESENTATIVE SCHEME 1
0
cl I \
~ / 0
N CI R- ~ AcCI, Nal
R I / NH2 \ H
NI \ CI
Oi' RN \ Et2NH R O \ NaAIH(OCH2CH2OMe)2
H I N I K2CO3, NMP H N
I i N' R
R
R \ I R / I
Ar-COCI
H Et3N N
R R
N N A r O N NR R
REPRESENTATIVE SCHEME 2
R o Ri
H2NUN`R CI CI CI~ N R /NH2 R
II ~
g EtOH S R H~SR
i
I ~
-~-- R I \
Ar-X O N N R
Ar-X'O S R
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REPRESENTATIVE SCHEME 3
R / N BOC
HO S SOCI2 H
~ N~CI CI~S~CI
N NaH, (nBu)4N1, THF
HN"R
R \ S R TFA
R\ R
~
BOC ` /~CI BOC ` N
N N R
R \ I R S R ArCOCI, Et3N N S R
H~ /N '
N R Ar O N R
REPRESENTATIVE SCHEME 4
Br
I~ N THF, Br N nBuLi, THF, DMF O~ I~ I
NCl HN NN NN
R i \ CI
~
NH2 R Ar---O R
N N ~N
Na(Ac0)3BH H~~ R3N ~
AcOH, DCM N N Ar O N N
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REPRESENTATIVE SCHEME 5
~ \
R i-/ /
NHBOC R- ~
HO N Br S02CI2 N Br \
CHCI3 CI NaH, (nBu)4N1 BOC Br
1. mCPBA, CHCI3
2. R2NH R- I R- ~
Ar-COCI \ N NR2
3. PCI3 \ N N\ NR2 ,,
~~
4. HCI(g) / Ar O
REPRESENTATIVE SCHEME 6
NaH, THF / Cul, K2CO3, L-proline
I
R
R I /NHBOC Br \ I \ N I\ I H2N~
BOC /
0 Me
R/ H R/ TFA
\ N I\ N H \ N \ N
BOC / NaACO3BH BOC
AcOH, DCM
Me
~ Ar-COCI ~Me
R\ I N N R\ N
~ N
H Ar
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REPRESENTATIVE SCHEME 7
\
O
~
~ I Ar-COCI
R\ N CI R- Et3N
NH2
Na(OAc)3BH H ~ ~
AcOH, DCM N CI
R\ HN' R R\ I
\ R ~~
N N \
THF ~ I i .R
Ar O N CI microwave Ar O N N
R
REPRESENTATIVE SCHEME 8
O' I \
Ar-COCI
N CI cycloalkyl, Et3N
cycloalkyl.NH
2 Na(OAc)3BH H
AcOH, DCM N CI
HN"R
cycloalkyl,N I\ R _ cycloalkyl,N I\
THF R
Ar O N CI microwave Ar O N N
R
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REPRESENTATIVE SCHEME 9
CIN R
~ N Ar-COCI
Alkyl, S R AIkyI-N`\~N R Et3N
NH2 H L N
Et3N S R
AIkyI-N
~~ N R
Ar O S R
REPRESENTATIVE SCHEME 10
R
R
0
S R CI\/Cl CI N R ~ NH2 N N R
~ H~-<
H2N R s R K2CO3, EtOH S R
R
ArCOCI aZz,/l
Et3N N I ~N/ R
Ar O S R
REPRESENTATIVE SCHEME 11
O~ N
L Br F
F I~ S F HNR2 \
N
~ NH2 Na(OAc)3BH N R
AcOH H~Br H
S ~S NR
CI F
Ar-X O /
N N R
~
R3N Ar-X~O S R
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REPRESENTATIVE SCHEME 12
/ R /. R
N O HCI
~~ \~N \ N C N NH
Ar O S O
Ar~ ~
~ O S
REPRESENTATIVE SCHEME 13
S R
i ~
R~
R
~ O O Br H2N R /O~ICH2)n N R NH2 / NH CHZ)n
"
O (CH2)n v O ~j ~N i~ ~N`\rNR
`S R Me3AI o S R
I ArCOCI R~
R~
L'IA~ NH (CH2N R N~(CH2) N R
~S~NR Ar~O ~S~N`R
REPRESENTATIVE SCHEME 14
O~ I ~
Ar-COCI
N CI cycloalkyl, Et3N
cycloalkyl.NH
2 Na(OAc)3BH H
AcOH, DCM N CI
HN"R
cycloalkyl,N cycloalkyl,N I~
THF R
Ar O N CI microwave Ar O N N
R
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REPRESENTATIVE SCHEME 15
\
O
~
Ar-COCI
R\ N CI R-
Et3N
NH2
Na(OAc)3BH H ~ ~
AcOH, DCM N CF3
R-
~ I i
Ar O N CF3
REPRESENTATIVE SCHEME 16
cl I \
~
R R
O N CI i \ ArCOCI
NH2 Et3N, THF / H
N CI
~ R
R i HN' i \
IR
N
Ar O N CI microwave, THF Ar~O I N N"R
R
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REPRESENTATIVE SCHEME 17
CI
i \ N CI
Ri Ri
~ NH2 Et3N, THF H I\
N CI
CI
R L / Ar---O R
N
H I ~ ^ N I \
N O CF3
Ar 0 N O CF3
REPRESENTATIVE SCHEME 18
\
R; /
HO N Br g~ CI N Br NHBOC R~ N Br
N
CHCI3 I/ NaH, (nBu)4N1 BOC
1. mCPBA, CHC13 MeO N CI
2. R2NH R/ N N ~O R I
3. PCI3 N\ NR2 Me'NJ \ N N NR2
4. HCI(g) H ~ OMe
OH R Y-l-- O
R~ NRBOC
O
NRBOC
TFA, DCM R N N NR2
or
HCI, dioxane O
NHR
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EXAMPLE 1A: PREPARATION OF {5-[(4-FLUOROPHENYLAMINO)-METHYL]-
PYRI D I N-2-YL}-D I ETHYLAM I N E
0
CI
CI
AcCI, Nal
F NH2 I N F O
H ~ ~
N CI
F / O F /
N Et2NH \ ~ \ NaAIH(OCH2CH2oMe)2
H N I K2CO3, NMP H ~
N NI^Me
`Me
F
N
H
N NI^Me
`Me
Part I: Preparation of 6-chloro-N-(4-fluorophenyl)-nicotinamide
To a solution of 4-fluoroaniline (15.8 g, 142 mmol) in dichloromethane (450
mL) at
0 C was slowly added a solution of 6-chloro-nicotinoyl chloride (25 g, 142
mmol) in
dichloromethane (50 mL), followed by triethylamine (23.7 mL, 170 mmol). After
the
addition was complete, the reaction was stirred at 0 C for 30 minutes,
followed by
warming to room temperature. After stirring for 30 minutes, the resulting
solid was
filtered, washed with water and dried under reduced pressure to provide 6-
chloro-N-
(4-fluorophenyl)-nicotinamide (35 g, 139.6 mmol) as a white solid.
Part II: Preparation of N-(4-fluorophenyl)-6-iodo-nicotinamide
To a solution of 6-chloro-N-(4-fluorophenyl)-nicotinamide (6.4 g, 25.5 mmol)
in
acetone (130 mL) was added sodium iodide (38.2 g, 255.3 mmol) followed by the
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dropwise addition of acetyl chloride (7.3 mL, 102 mmol). The yellow mixture
was
heated at reflux for 1 hour. The reaction mixture was cooled to room
temperature
and concentrated to dryness under reduced pressure. The residue was
partitioned
between ethyl acetate (10 mL) and 1 N sodium hydroxide (10 mL). The organic
phase was washed with brine, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to provide N-(4-fluorophenyl)-6-iodo-
nicotinamide (6.76 g, 19.8 mmol) as a white solid.
Part III: Preparation of 6-diethylamino-N-(4-fluorophenyl)-nicotinamide
A mixture of N-(4-fluorophenyl)-6-iodo-nicotinamide (684 mg, 2 mmol),
diethylamine
hydrochloride (0.326 g, 4 mmol), and potassium carbonate (911 mg, 6.6 mmol) in
1-
methyl-2-pyrrolidinone (2 mL) was heated at 140 C in a sealed tube for 65
hours.
After cooling to room temperature, a saturated aqueous sodium bicarbonate
solution
(5 mL) was added, followed by extraction into ethyl acetate (5 mL). The
organic
phase was dried over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to provide 6-diethylamino-N-(4-fluorophenyl)-nicotinamide as
a
solid which was used directly in the next reaction without further
purification.
Part IV: Preparation of {5-[(4-fluorophenylamino)-methyl]-pyridin-2-yl}-
diethyl-amine
The 6-diethylamino-N-(4-fluorophenyl)-nicotinamide was suspended in a mixture
of
toluene (5 mL) and tetrahydrofuran (10 mL) and stirred at 0 C. To the reaction
was
slowly added sodium bis(2-methoxyethoxy)aluminum hydride (65 wt.% in toluene,
1.8
mL). The reaction was allowed to warm to room temperature and stirred for 15
minutes followed by heating at 50 C for 1 hour. The mixture was cooled to room
temperature and quenched by the slow addition of an aqueous saturated sodium
bicarbonate solution (10 mL) and 6N sodium hydroxide (10 mL) followed by
extraction into ethyl acetate (30 mL). The organic phase was dried over
anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to provide {5-
[(4-
fluorophenylamino)-methyl]-pyridin-2-yl}diethyl-amine (300 mg, 1.2 mmol) as an
oil.
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EXAMPLE 1 B: ALTERNATIVE PREPARATION OF {5-[(4-
FLUOROPH ENYLAMI NO)-METHYL]-PYRI DI N-2-YL}-DI ETHYL-AMI N E
DIHYDROCHLORIDE
~ mCPBA ~ Et2NH
N N
tBu ~ I ~ tBu
O O N CI O O N CI
F F
N PCI3, CHC13 HCI(g)
+ --
tBu, 0 0 N N Me tBu, 00 N N"N' Me
-00 `Me ~Me
F
H
N N1~11 Me
Me
Part I: Preparation of (6-chloro-l-oxy-pyridin-3-ylmethyl)-(4-fluorophenyl)-
carbamic
acid tert-butyl ester
To a solution of (6-chloro-pyridin-3-ylmethyl)-(4-fluorophenyl)-carbamic acid
tert-butyl
ester (1 g, 2.97 mmol) in chloroform (10 mL) was added m-chloroperbenzoic acid
(1
g, 4.5 mmol) and the reaction heated at 50 C for 6 hours. (6-Chloro-pyridin-3-
ylmethyl)-(4-fluorophenyl)-carbamic acid tert-butyl ester can be prepared
analogously
to (6-bromo-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic acid tert-butyl
ester
following the procedures described in Example 3 infra. The reaction was cooled
to
room temperature, diluted with dichloromethane (6 mL), and washed with 3N
sodium
hydroxide (6 mL). The organic layer was dried over anhydrous sodium sulfate,
filtered and evaporated to dryness under reduced pressure. Purification by
chromatography (silica gel; 3:7 ethyl acetate:hexane) provided (6-chloro-l-oxy-
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pyridin-3-ylmethyl)-(4-fluorophenyl)-carbamic acid tert-butyl ester (1 g, 2.8
mmol) as
a colorless oil.
Part II: Preparation of (6-diethylamino-l-oxy-pyridin-3-ylmethyl)-(4-
fluorophenyl)-
carbamic acid tert-butyl ester
(6-Chloro-l-oxy-pyridin-3-ylmethyl)-(4-fluorophenyl)-carbamic acid tert-butyl
ester (1
g, 2.8 mmol) and diethyl amine (2.9 mL, 28.4 mmol) were combined in a sealed
tube.
The reaction was heated at 130 C overnight. The reaction was cooled to room
temperature and concentrated under reduced pressure. Purification by
chromatography (silica gel; ethyl acetate) provided (6-diethylamino-1-oxy-
pyridin-3-
ylmethyl)-(4-fluorophenyl)-(4-fluorophenyl)-carbamic acid tert-butyl ester (1
g, 2.5
mmol) as a brown oil.
Part III: Preparation of (6-diethylamino-pyridin-3-ylmethyl)-(4-fluorophenyl)-
carbamic
acid tert-butyl ester
(6-Diethylamino-1-oxy-pyridin-3-ylmethyl)-(4-fluorophenyl)-(4-fluorophenyl)-
carbamic
acid tert-butyl ester (1 g, 2.5 mmol) was dissolved in chloroform (10 mL).
Phosphorous trichloride (336 pL, 3.85 mmol) was added, and the reaction was
stirred
at room temperature for 45 minutes. The reaction mixture was diluted with
dichloromethane (10 mL) and washed with 3N sodium hydroxide (20 mL). The
organic layer was dried over anhydrous sodium sulfate, filtered and evaporated
to
dryness under reduced pressure. Purification by chromatography (silica gel;
1:9
ethyl acetate:hexane) provided (6-diethylamino-pyridin-3-ylmethyl)-(4-
fluorophenyl)-
carbamic acid tert-butyl ester (920 mg, 2.5 mmol) as a colorless oil.
Part IV: Preparation of {5-[(4-fluorophenylamino)-methyl]-pyridin-2-yl}-
diethyl-amine
dihydrochloride
To a solution of (6-diethylamino-pyridin-3-ylmethyl)-(4-fluorophenyl)-carbamic
acid
tert-butyl ester (900 mg, 2.4 mmol) in methanol (10 mL) was added gaseous
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hydrochloric acid at 0 C. The reaction was allowed to warm to room temperature
and stirred for 30 minutes. The reaction was concentrated to provide {5-[(4-
fluorophenylamino)-methyl]-pyridin-2-yl}-diethyl-amine dihydrochloride (665
mg, 2.4
mmol) as a white solid.
EXAMPLE 2: PREPARATION OF CYCLOPROPYL-{5-[(4-
F LU O RO P H E NYLAM I N O)-M ETHYL]-PYRI D I N-2-YL}-ETHYL-AM I N E
DIHYDROCHLORIDE
O o O
EtO H2 Et0 NaH, Etl EtO I\ ~
N CI N N N N
Me
Me3AI F\ I O F\
F/ H Na(OCH2CH2OMe)2AIH H
N N N N
NH2
Me Me
Part I: Preparation of 6-cyclopropylamino-nicotinic acid ethyl ester
A mixture of ethyl-6-chloro-nicotinate (10 g, 53.9 mmol) in cyclopropyl amine
(10 mL)
was heated in a sealed tube at 80 C for 12 hours. The reaction was cooled and
the
mixture purified by chromatography (silica gel; ethyl acetate : hexane
gradient
elution) to provide 6-cyclopropylamino-nicotinic acid ethyl ester (6.9 g, 32.2
mmol) as
an oil.
Part II: Preparation of 6-(cyclopropyl-ethyl-amino)-nicotinic acid ethyl ester
To a solution of 6-cyclopropylamino-nicotinic acid ethyl ester (6.9 g, 32.2
mmol) in
anhydrous tetrahydrofuran (80 mL) containing dimethyl formamide (50 pL) at 0 C
was added sodium hydride (60% dispersion in mineral oil, 1.85 g, 48.3 mmol).
The
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reaction was allowed to warm to room temperature and stirred for 30 minutes.
The
reaction was treated with ethyl iodide (3.0 mL, 48.3 mmol) and the reaction
allowed
to stir overnight. The reaction was quenched by the addition of water (10 mL),
followed by extraction with ethyl acetate (2 x 50 mL). The organic phases were
combined, washed with saturated sodium bicarbonate, dried over anhydrous
sodium
sulfate, filtered and concentrated under reduced pressure. Purification by
chromatography (silica gel; ethyl acetate:hexane gradient elution) provided 6-
(cyclopropyl-ethyl-amino)-nicotinic acid ethyl ester (6.45 g, 27.5 mmol) as an
oil.
Part III: Preparation of 6-(cyclopropyl-ethyl-amino)-N-(4-fluorophenyl)-
nicotinamide
To a solution of 4-fluoroaniline (4.65 mL, 35.8 mmol) in toluene (50 mL) was
slowly
added 2M trimethylaluminum in toluene (16.5 mL, 33 mmol) and the reaction
allowed
to stir for 1 hour. A solution of 6-(cyclopropyl-ethyl-amino)-nicotinic acid
ethyl ester
(6.45g, 27.5 mmol) in toluene (25 mL) was added and the reaction heated to 60
C.
After 12 hours, the reaction was cooled to room temperature and quenched by
the
dropwise addition of methanol. The reaction was concentrated under reduced
pressure and the residue taken up into ethyl acetate (100 mL). The organic
phase
was washed with saturated sodium bicarbonate (25 mL), saturated potassium-
sodium tartrate (25 mL), dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. Purification by chromatography (silica
gel;
ethyl acetate:hexane gradient elution) provided 6-(cyclopropyl-ethyl-amino)-N-
(4-
fluorophenyl)-nicotinamide (7.25 g, 24.1 mmol).
Part IV: Preparation of cyclopropyl-{5-[(4-fluorophenylamino)-methyl]-pyridin-
2-yl}-
ethyl-amine dihydrochloride
To a mixture of 6-(cyclopropyl-ethyl-amino)-N-(4-fluorophenyl)-nicotinamide
(7.25 g,
24.1 mmol) in toluene (20 mL) and anhydrous tetrahydrofuran (40 mL) at 0 C was
slowly added sodium bis(2-methoxyethoxy)aluminum hydride (65 wt.% in toluene,
16
mL). The reaction was allowed to warm to room temperature and stirred for 15
minutes followed by heating at 50 C for 1 hour. The mixture was cooled to room
temperature and quenched by the slow addition of an aqueous saturated sodium
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bicarbonate solution (20 mL) and 6N sodium hydroxide (20 mL) followed by
extraction into ethyl acetate (60 mL). The organic phase was dried over
anhydrous
sodium sulfate, filtered and concentrated under reduced pressure. Purification
by
chromatography (silica gel; ethyl acetate:hexane gradient elution) provided
cyclopropyl-{5-[(4-fluorophenylamino)-methyl]-pyridin-2-yl}-ethyl-amine (8.0
g, 23.1
mmol).
The free base was treated with ethereal hydrochloric acid to provide
cyclopropyl-{5-
[(4-fluorophenylamino)-methyl]-pyridin-2-yl}-ethyl-amine dihydrochloride (6.8
g, 23.1
mmol) as a white solid.
EXAMPLE 3: PREPARATION OF DIETHYL-{6-[(4-FLUOROPHENYLAMINO)-
METHYL]-PYRIDIN-2-YL}-AMINE DIHYDROCHLORIDE
F
F
HO N Br gp2C12> CI N Br NHBOC N N Br
CHCI3 NaH, (nBu)4N1 BOC
1. mCPBA, CHCI3 F
2. Et2NH
3. PCI3 N N NEt2
H I /
4. HCI(g)
Part I: Preparation of 2-bromo-6-chloromethyl-pyridine
To a solution of (6-bromo-pyridin-2-yl)-methanol (1.5 g, 8.0 mmol) in
chloroform (10
mL) was added dropwise sulfuryl choride (1.29 mL, 16 mmol) and the reaction
stirred
overnight. The reaction was concentrated under reduced pressure to provide a
yellow semi-solid. The material was triturated with diethyl ether/hexanes and
the
solid collected to provide 2-bromo-6-chloromethyl-pyridine (900 mg, 4.37 mmol)
as a
sticky white solid.
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Part II: Preparation of (6-bromo-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic
acid
tert-butyl ester
To a solution of (4-fluorophenyl)-carbamic acid tert-butyl ester (60144-53-8,
750 mg,
3.55 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (60% dispersion
in
mineral oil, 150 mg, 3.9 mmol). After 30 minutes, tetra-n-butylammonium iodide
(51
mg, 0.36 mmol) and 2-bromo-6-chloromethyl-pyridine (804 mg, 3.9 mmol) was
added
to the reaction and the mixture was heated to 70 C. After 1 hour, the reaction
was
cooled to room temperature, quenched with saturated sodium bicarbonate (10 mL)
and extracted with ethyl acetate (2 x 15 mL). The organic phases were
combined,
dried over anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. Flash chromatography (silica gel; 10% ethyl acetate in hexanes)
provided
(6-bromo-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic acid tert-butyl ester
(700 mg,
1.84 mmol) as an oil which solidified upon standing.
Part III: Preparation of (6-bromo-l-oxy-pyridin-2-ylmethyl)-(4-fluorophenyl)-
carbamic
acid tert-butyl ester
To a solution of (6-bromo-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic acid
tert-butyl
ester (700 mg, 1.84 mmol) in chloroform (8 mL) was added m-chloroperbenzoic
acid
(477 mg, 2.76 mmol) and the reaction heated to 50 C. After stirring overnight,
the
reaction was cooled to room temperature, diluted with chloroform (10 mL) and
washed with 3N sodium hydroxide (5 mL). The layers were separated and the
organic phase was dried over anhydrous sodium sulfate, filtered and
concentrated
under reduced pressure to provide a yellow solid upon standing. Purification
by
chromatography (silica gel; 10-20% ethyl acetate in chloroform) provided (6-
bromo-l-
oxy-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic acid tert-butyl ester (400
mg, 1.0
mmol) as a white solid.
Part IV: Preparation of (6-diethylamino-l-oxy-pyridin-2-ylmethyl)-(4-
fluorophenyl)-
carbamic acid tert-butyl ester
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A suspension of (6-bromo-l-oxy-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic
acid
tert-butyl ester (400 mg, 1.0 mmol) in diethylamine (7 mL) was heated to 130 C
in a
sealed tube. After stirring overnight, the reaction was cooled to room
temperature
and partitioned between brine (10 mL) and ethyl acetate (15 mL). The layers
were
separated and the organic phase was dried over anhydrous sodium sulfate,
filtered
and concentrated under reduced pressure to provide a dark liquid. Flash
chromatography (silica gel; 30-75% ethyl acetate in chloroform) provided (6-
diethylamino-l-oxy-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic acid tert-
butyl ester
(230 mg, 0.59 mmol) as a light yellow oil.
Part V: Preparation of diethyl-{6-[(4-fluorophenylamino)-methyl]-pyridin-2-yl}-
amine
dihydrochloride
To a solution of (6-diethylamino-l-oxy-pyridin-2-ylmethyl)-(4-fluorophenyl)-
carbamic
acid tert-butyl ester (230 mg, 0.59 mmol) in chloroform (2 mL) was added
phosphorous trichloride (121 mg, 0.89 mmol). After stirring for 1 hour, the
reaction
was diluted with chloroform (10 mL) and washed with 3N sodium hydroxide (5
mL).
The organic phase was dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to provide a yellow oil. The oil was
dissolved
in chloroform (2 mL) and treated with trifluoroacetic acid (1 mL) and allowed
to stir for
1 hour. The reaction was concentrated under reduced pressure and the residue
treated with ethereal hydrochloric acid. The resulting solid was collected to
provide
diethyl-{6-[(4-fluorophenylamino)-methyl]-pyridin-2-yl}-amine dihydrochloride
(182
mg, 0.59 mmol) as a white solid.
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EXAMPLE 4: PREPARATION OF ETHYL-CYCLOPROPYL-{[4-(4-
FLUOROPHENYLAMINO)-METHYL]-PHENYL}-AMINE
F I~ BOC2O, PhMe F Br NaH, \ F
NH2 NH ~ N I-~
BOC BOC /
F O F
Cu(1)I, K2CO3, L-proline Me
N N
~
H2N~ DMSO BOC H/-~ DCMcOAcOH BOC N
Me
FN~
~ /
TFA H
NI
Me
Part I: Preparation of (4-fluorophenyl)-carbamic acid tert-butyl ester
A mixture of 4-fluoroaniline (4.2 mL, 44.1 mmol) and carbonic acid di-tert-
butyl ester
(11.55 g, 52.9 mmol) in toluene (100 mL) was heated at reflux overnight. The
reaction was cooled to room temperature and the solvent was removed under
reduced pressure. The residue was triturated with hexanes to provide (4-
fluorophenyl)-carbamic acid tert-butyl ester (8.4 g, 39.8 mmol) as an off-
white solid.
Part II: Preparation of (4-fluorophenyl)-(4-iodo-benzyl)-carbamic acid tert-
butyl ester
A solution of (4-fluorophenyl)-carbamic acid tert-butyl ester (9.98 g, 47.3
mmol) in
anhydrous tetrahydrofuran (150 mL) was cooled to 0 C and treated with sodium
hydride (60% dispersion in mineral oil, 2.3 g, 56.8 mmol). The mixture was
warmed
to room temperature and stirred for 30 minutes. To the reaction was added 1-
bromomethyl-4-iodo-benzene (14.0 g, 47.3 mmol) and the mixture was allowed to
stir
at room temperature overnight. The reaction was diluted with water (50 mL) and
extracted with ethyl acetate (3 x 50 mL). The organic phases were combined,
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washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. Purification by chromatography (silica
gel; 5%
ethyl acetate in hexanes) provided (4-fluorophenyl)-(4-iodo-benzyl)-carbamic
acid
tert-butyl ester (18 g, 42.1 mmol) as a colorless oil.
Part III: Preparation of (4-cyclopropylamino-benzyl)-(4-fluorophenyl)-carbamic
acid
tert-butyl ester
A mixture of (4-fluorophenyl)-(4-iodo-benzyl)-carbamic acid tert-butyl ester
(10 g,
23.4 mmol), cyclopropylamine (4.86 mL, 70.2 mmol), copper (I) iodide (445 mg,
2.34
mmol), potassium carbonate (6.5 g, 46.8 mmol), and L-proline (540 mg, 4.68
mmol)
were combined in dimethylsulfoxide (100 mL) and heated at 80 C for 5 hours.
The
reaction mixture was cooled, diluted with water (50 mL), and extracted with
ethyl
acetate (2 x 100 mL). The combined organic layers were washed with brine,
dried
over anhydrous sodium sulfate, filtered and evaporated to dryness under
reduced
pressure. The (4-cyclopropylamino-benzyl)-(4-fluorophenyl)-carbamic acid tert-
butyl
ester was used in the next step without further purification.
Part IV: Preparation of [4-(cyclopropyl-ethyl-amino)-benzyl]-(4-fluorophenyl)-
carbamic
acid tert-butyl ester
To the (4-cyclopropylamino-benzyl)-(4-fluorophenyl)-carbamic acid tert-butyl
ester
from the previous step in dichloromethane (100 mL) was added acetaldehyde
(1.44
mL, 25.7 mmol) and acetic acid (1.6 mL, 28.1 mmol). The solution was stirred
at
room temperature for 30 minutes, followed by the addition of sodium
triacetoxyborohydride (2.0 g, 9.4 mmol). After 30 minutes, another portion of
sodium
triacetoxyborohydride (2.0 g, 9.4 mmol) was added. A third portion of sodium
triacetoxyborohydride (2.0 g, 9.4 mmol) was added and the reaction stirred for
30
minutes. The reaction mixture was basified with 1 N sodium hydroxide to pH 10
and
extracted with dichloromethane (2 x 50 mL). The organic phases were combined,
dried over anhydrous sodium sulfate, filtered and the solvent removed under
reduced
pressure to provide a yellow oil. Flash chromatography (silica gel; 10% ethyl
acetate
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in hexanes) provided [4-(cyclopropyl-ethyl-amino)-benzyl]-(4-fluorophenyl)-
carbamic
acid tert-butyl ester a yellow oil, which was used directly in the next
reaction.
Part V: Preparation of ethyl-cyclopropyl-{[4-(4-fluorophenylamino)-methyl]-
phenyl}-
amine
To a solution of [4-(cyclopropyl-ethyl-amino)-benzyl]-(4-fluorophenyl)-
carbamic acid
tert-butyl ester from the previous step in dichloromethane (20 mL) was added
trifluoroacetic acid (20 mL) at 0 C. The solution was warmed up to room
temperature
and stirred for 30 minutes. The reaction was concentrated to dryness under
reduced
pressure and the residue was dissolved in dichloromethane (20 mL). The organic
layer was washed with 3N sodium hydroxide (10 mL), dried over anhydrous sodium
sulfate, filtered and evaporated to dryness under reduced pressure. Flash
chromatography (silica gel; 10% ethyl acetate in hexanes) provided ethyl-
cyclopropyl-{[4-(4-fluorophenylamino)-methyl]-phenyl}-amine (6 g, 21.1 mmol)
as a
yellow oil.
EXAMPLE 5: PREPARATION OF DIETHYL-{[4-(4-FLUOROPHENYLAMINO)-
METHYL]-PHENYL}-AMINE DIHYDROCHLORIDE
HO2C EDCI, Py F O
/ Et I / BH3THF
~
N F \
i i
Et H I/ NEt
NH2
Et
F
N
H NEt
Et
Part I: Preparation of 4-diethylamino-N-(4-fluorophenyl)-benzamide
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To a solution of 4-diethylamino-benzoic acid (1.0 g, 5.2 mmol) and N-(3-
dimethylaminopropyl)-N'-ethylcarbodiimide (1.4 g, 9.4 mmol) in pyridine (10
mL) was
added 4-fluoroaniline (446 pL, 4.7 mmol) and the reaction stirred overnight.
The
reaction was concentrated under reduced pressure to provide a red oil, which
was
partitioned between saturated sodium bicarbonate, and hexanes and flash ethyl
acetate. The resulting precipitate was collected and dried under reduced
pressure to
provide 4-diethylamino-N-(4-fluorophenyl)-benzamide (1.2 g, 4.2 mmol) as a
white
solid.
Part II: Preparation of diethyl-{[4-(4-fluorophenylamino)-methyl]-phenyl}-
amine
dihydrochloride
To a solution of 4-diethylamino-N-(4-fluorophenyl)-benzamide (600 mg, 2.1
mmol) in
anhydrous tetrahydrofuran (10 mL) was added dropwise 1 M borane
tetrahydrofuran
complex (6.3 mL, 6.3 mmol). The reaction was heated to reflux and stirred for
3
hours. The reaction was cooled to room temperature and treated with saturated
hydrochloric acid in methanol (6 mL) and heated to reflux for 3 hours. The
reaction
was cooled to room temperature and the resulting precipitate filtered and
dried to
provide diethyl-{[4-(4-fluorophenylamino)-methyl]-phenyl}-amine
dihydrochloride (622
mg, 1.8 mmol) as a white solid.
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EXAMPLE 6: PREPARATION OF ETHYL-CYCLOPROPYL-{[3-(4-
FLUOROPHENYLAMINO)-METHYL]-PHENYL)}AMINE
F NaH, THF F /
I Cul, K2CO3, L-proline
\ I \ \ I
NHBOC Br N~ H2N~
BOC
F O F Me
H ~ TFA
N H N N
BOC NaAc03BH BOC ~
AcOH, DCM
F ~Me
\ I \ N
H 'IV
Part I: Preparation of (4-fluorophenyl)-(3-iodo-benzyl)-carbamic acid tert-
butyl ester
A solution of (4-fluorophenyl)-carbamic acid tert-butyl ester (5 g, 47.3 mmol)
in
anhydrous tetrahydrofuran (80 mL) was cooled to 0 C and treated with sodium
hydride (60% dispersion in mineral oil, 1.1 g, 28.4 mmol). The mixture was
warmed
to room temperature and stirred for 30 minutes. To the reaction was added 1-
bromomethyl-3-iodo-benzene (7.0 g, 23.7 mmol) and the mixture was allowed to
stir
at room temperature overnight. The reaction was diluted with water (50 mL) and
extracted with ethyl acetate (3 x 50 mL). The organic phases were combined,
washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. Purification by chromatography (silica
gel; 5%
ethyl acetate in hexanes) provided (4-fluorophenyl)-(3-iodo-benzyl)-carbamic
acid
tert-butyl ester (9 g, 21.1 mmol) as a colorless oil, which was contaminated
with
residual (4-fluorophenyl)-carbamic acid tert-butyl ester.
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Part II: Preparation of (3-cyclopropylamino-benzyl)-(4-fluorophenyl)-carbamic
acid
tert-butyl ester
A mixture of (4-fluorophenyl)-(3-iodo-benzyl)-carbamic acid tert-butyl ester
(5.8 g,
13.6 mmol), cyclopropylamine (3.8 mL, 54.4 mmol), copper (I) iodide (260 mg,
1.36
mmol), potassium carbonate (7.5 g, 54.4 mmol), and L-proline (313 mg, 2.72
mmol)
were combined in dimethylsulfoxide (60 mL) and heated at 80 C for 4 hours. The
reaction mixture was cooled, diluted with water (50 mL), and extracted with
ethyl
acetate (2 x 100 mL). The combined organic layers were washed with brine,
dried
over anhydrous sodium sulfate, filtered and evaporated to dryness under
reduced
pressure. The (3-cyclopropylamino-benzyl)-(4-fluorophenyl)-carbamic acid tert-
butyl
ester was used in the next step without further purification.
Step III: Preparation of [3-(cyclopropyl-ethyl-amino)-benzyl]-(4-fluorophenyl)-
carbamic acid tert-butyl ester
To the (3-cyclopropylamino-benzyl)-(4-fluorophenyl)-carbamic acid tert-butyl
ester
from the previous step in dichloromethane (30 mL) was added acetaldehyde (840
pL,
15 mmol) and acetic acid (933 pL, 16.3 mmol). The solution was stirred at room
temperature for 30 minutes, followed by the addition of sodium
triacetoxyborohydride
(3.5 g, 16.32 mmol). After 30 minutes, another portion of sodium
triacetoxyborohydride (3.5 g, 16.32 mmol) was added. A third portion of sodium
triacetoxyborohydride (3.5 g, 16.32 mmol) was added and the reaction stirred
for 30
minutes. The reaction mixture was basified with 1 N sodium hydroxide to pH 10
and
extracted with dichloromethane (2 x 50 mL). The organic phases were combined,
dried over anhydrous sodium sulfate, filtered and the solvent removed under
reduced
pressure to provide a yellow oil. Flash chromatography (silica gel; 10% ethyl
acetate
in hexanes) provided (3-(cyclopropyl-ethyl-amino)-benzyl)-(4-fluorophenyl)-
carbamic
acid tert-butyl ester a yellow oil, which was used directly in the next
reaction.
Part IV: Preparation of ethyl-cyclopropyl-{[3-(4-fluorophenylamino)-methyl]-
phenyl}-
amine
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To a solution of [3-(cyclopropyl-ethyl-amino)-benzyl]-(4-fluorophenyl)-
carbamic acid
tert-butyl ester from the previous step in dichloromethane (20 mL) was added
trifluoroacetic acid (20 mL) at 0 C. The solution was warmed to room
temperature
and stirred for 30 minutes. The reaction was concentrated to dryness under
reduced
pressure and the residue was dissolved in dichloromethane (20 mL). The organic
layer was washed with 3N sodium hydroxide (10 mL), dried over anhydrous sodium
sulfate, filtered and evaporated to dryness under reduced pressure. Flash
chromatography (silica gel; 10% ethyl acetate in hexanes) provided ethyl-
cyclopropyl-{[3-(4-fluorophenylamino)-methyl]-phenyl}-amine (3.4 g, 12 mmol)
as a
yellow oil.
EXAMPLE 7: PREPARATION OF (4-FLUOROPHENYL)-[4-(4-METHYL-PIPERAZIN-
1-YL)-BENZYL]-AMINE
O F \ F/ O
~ \ \ NaAIH(OCH2CH2OMe)2, PhMe
CI I\ / NH2_ H
ON, E t3N, DCM N,
Me Me
F~
H
N')
v N, Me
Part I: Preparation of N-(4-fluorophenyl)-4-(4-methyl-piperazin-1-yl)-
benzamide
To a solution of 4-fluoroaniline (15.8 g, 142 mmol) in dichloromethane (200
mL) at
0 C was added dropwise a solution of 4-(4-methylpiperazin-1-yl)-benzoyl
chloride (25
g, 142 mmol). As a precipitate formed, the reaction was slowly diluted with
additional
dichloromethane (300 mL). Triethylamine (23.7 mL, 170 mmol) was added and the
reaction was stirred for 30 minutes. The reaction was then warmed to room
temperature and stirred for 30 minutes. The resulting precipitate was filtered
and
washed with water. The filtrate was treated with water, upon which additional
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precipitates formed. The precipitate was collected and combined with the
previously
obtained precipitate. The material was dried under reduced pressure overnight
to
provide N-(4-fluorophenyl)-4-(4-methyl-piperazin-1-yl)-benzamide (35 g, 140
mmol)
as a white solid.
Part II: Preparation of (4-fluorophenyl)-[4-(4-methyl-piperazin-1-yl)-benzyl]-
amine
To a solution of N-(4-fluorophenyl)-4-(4-methyl-piperazin-1-yl)-benzamide (7.6
g,
24.2 mmol) in anhydrous toluene (50 mL) and anhydrous terahydrofuran (25 mL)
at
0 C was added dropwise sodium bis(2-methoxyethoxy)aluminum hydride (65 wt.% in
toluene, 22 mL). After the addition was complete the reaction was heated to
reflux
and stirred for 1 hour. The reaction was cooled to 0 C and treated by dropwise
addition of 6N sodium hydroxide (50 mL). The reaction was warmed to room
temperature, diluted with toluene (50 mL) and stirred for 2 hours. The layers
were
separated and the aqueous phase washed with toluene (50 mL). The organic
phases were combined, washed with saturated sodium bicarbonate (30 mL), water
(30 mL), and brine (30 mL). The organic phase was filtered through a pad of
Celite
and the Celite pad washed with ethyl acetate. The organic filtrates were
combined
and concentrated under reduced pressure to provide a yellow solid. The
material
was treated with dichloromethane and hexanes to provide (4-fluorophenyl)-[4-(4-
methyl-piperazin-1-yl)-benzyl]-amine (5.7 g, 19 mmol) as a white solid.
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EXAMPLE 8: PREPARATION OF (4-FLUOROPHENYL)-(2-PIPERIDIN-1-YL-
PYRI M I D I N-5-YLM ET HYL)-AM I N E
Br
I%~, THF, Br I~ N nBuLi, THF, DMF 0~ I/
N CI HN NN NN
F
F
NH2 ~~
~
Na(AcO)3BH H II N
AcOH, DCM ~NJ~N
Part I: Preparation of 5-bromo-2-piperidin-1-yl-pyrimidine
To solution of 5-bromo-2-chloro-pyrimidine (3.0 g, 15.5 mmol) in
dichloromethane (30
mL) at room temperature was added piperidine (1.53 mL, 15.5 mmol) followed by
the
dropwise addition of triethylamine (3.23 mL, 23.3 mmol). The reaction was
stirred at
room temperature overnight. The reaction was diluted with dichloromethane (20
mL),
washed with a saturated aqueous sodium bicarbonate solution (50 mL), followed
by
brine (50 mL). The organic phase was dried with anhydrous sodium sulfate,
filtered
and concentrated under reduced pressure. Flash chromatography (silica gel; 5%
ethyl acetate in hexanes) provided 5-bromo-2-piperidin-1-yl-pyrimidine as a
white
solid (3.74g, 15.5 mmol).
Part II: Preparation of 2-piperidin-1-yl-pyrimidine-5-carbaldehyde
To a solution of 5-bromo-2-piperidin-1-yl-pyrimidine (1.3 g, 5.4 mmol) in
anhydrous
tetrahydrofuran (30 mL) at -78 C was added 1.6 M n-butyl lithium in hexanes
(3.7
mL, 5.93 mmol). The mixture was stirred at a temperature below -70 C for 1
hour.
Dimethylformamide (4.2 mL, 53.9 mmol) was added dropwise and the reaction was
stirred at a temperature below -70 C for 1 hour. The reaction was quenched
with
saturated ammonium chloride (10 mL), diluted with water (20 mL) and extracted
with
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ethyl acetate (2 x 20 mL). The organic phases were combined, dried over
anhydrous
sodium sulfate, filtered and the solvent removed under reduced pressure to
provide a
viscous brown oil. Flash chromatography (silica gel; 5-30% ethyl acetate in
hexanes)
provided 2-piperidin-1-yl-pyrimidine-5-carbaldehyde (0.76 g, 4.0 mmol) as a
white
solid.
Part III: Preparation of (4-fluorophenyl)-(2-piperidin-1-yl-pyrimidin-5-
ylmethyl)-amine
2-Piperidin-1-yl-pyrimidine-5-carbaldehyde (0.76 g, 4.0 mmol), 4-fluoroaniline
(0.76
mL, 8.0 mmol), and acetic acid (0.25 mL, 4.4 mmol) were combined in
dichloromethane (8 mL). The solution was stirred at room temperature for 30
minutes, followed by the addition of sodium triacetoxyborohydride (0.28 mg,
1.32
mmol). After 30 minutes, another portion of sodium triacetoxyborohydride (0.28
mg,
1.32 mmol) was added. A third portion of sodium triacetoxyborohydride (0.28
mg,
1.32 mmol) was added and the reaction stirred for 30 minutes. The reaction
mixture
was basified with 1 N sodium hydroxide to pH 10 and extracted with
dichloromethane
(2 x 50 mL). The organic phases were combined, dried over anhydrous sodium
sulfate, filtered and the solvent removed under reduced pressure to provide a
yellow
oil. Flash chromatography (silica gel; 5-30% ethyl acetate in hexanes)
provided (4-
fluorophenyl)-(2-piperidin-1-yl-pyrimidin-5-ylmethyl)-amine (0.93 g, 3.25
mmol) as a
yellow oil.
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EXAMPLE 9: PREPARATION OF (4-FLUOROPHENYL)-(2-PYRROLIDIN-1-YL-
THIAZOL-5-YLMETHYL)-AMINE DIHYDROCHLORIDE
F
NH F
~~ N SOCI2, CHCI3
HO CI BOC
II S~CI -> ~ ~CI N
` S NaH, THF BO ~CI
S
F ^
1. HNJ
N
NJ
2. TFA H S
Part I: Preparation of 2-chloro-5-chloromethyl thiazole
To a solution of 2-chloro-thiazol-5-yl-methanol (1 g, 6.7 mmol) in chloroform
(10 mL)
was added thionyl chloride (1.6g, 13.4 mmol), and the reaction was allowed to
stir at
room temperature overnight. The solvent was removed under reduced pressure to
afford a cloudy oil (1.1g, 6.5 mmol) which was used directly in the next
reaction
without further purification.
Part II: Preparation of 2-chloro-thiazol-5-ylmethyl-4-fluorophenylcarbamic
acid tert-
butyl ester
To a solution of 4-fluorophenylcarbamic acid tert-butyl ester (1.3 g, 6.2
mmol) in
anhydrous tetrahydrofuran (15 mL) was added sodium hydride (60% dispersion in
mineral oil, 261 mg, 6.8 mmol). After the initial gas evolution had ceased,
the
reaction was allowed to stir for 15 minutes. Tetra-n-butylammonium iodide (227
mg,
0.6 mmol) was then added followed by addition of the 2-chloro-5-chloromethyl
thiazole prepared above. The mixture was heated to reflux for 1 hour. After
cooling,
the reaction was carefully neutralized with cold saturated sodium bicarbonate
(10
mL) and extracted with ethyl acetate (2 x 20 mL). The organic layers were
combined, dried over anhydrous sodium sulfate, filtered and the solvent
removed
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under reduced pressure to provide a dark oil. Flash chromatography (silica
gel; 5%-
10% ethyl acetate in hexanes) provided 2-chloro-thiazol-5-ylmethyl-4-
fluorophenylcarbamic acid tert-butyl ester (1.5 g, 4.4 mmol) as a yellow oil.
Part III: Preparation of 4-fluorophenyl-2-pyrrolidin-1-yl-thiazol-5-
ylmethylcarbamic
acid tert-butyl ester
A solution of 2-chloro-thiazol-5-ylmethyl-4-fluorophenylcarbamic acid tert-
butyl ester
(1.5 g, 4.4 mmol) in pyrrolidine (1.6 mL, 22 mmol) was heated in a sealed tube
to
130 C and stirred overnight. After cooling, the reaction was partitioned
between
water and ethyl acetate. The organic layer was separated, dried over anhydrous
sodium sulfate, filtered and the solvent removed under reduced pressure to
provide
4-fluorophenyl-2-pyrrolidin-1-yl-thiazol-5-ylmethylcarbamic acid tert-butyl
ester as a
yellow oil.
Part IV: Preparation of (4-fluorophenyl)-(2-pyrrolidin-1-yl-thiazol-5-
ylmethyl)-amine
dihydrochloride
To the free base of 4-fluorophenyl-2-pyrrolidin-1-yl-thiazol-5-
ylmethylcarbamic acid
tert-butyl ester in dichloromethane (10 mL) was added trifluoroacetic acid (4
mL) and
the reaction was stirred at room temperature for 3 hours. After removing the
solvent
under reduced pressure, the resulting oil was dissolved in diethyl ether and
treated
with excess ethereal hydrochloric acid. The resulting solid was collected by
filtration
and dried to provide (4-fluorophenyl)-(2-pyrrolidin-1-yl-thiazol-5-ylmethyl)-
amine
dihydrochloride (274 mg, 1.2 mmol) as a white solid.
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EXAMPLE 10: PREPARATION OF (4-FLUOROPHENYL)-(2-PIPERIDIN-1-YL-
THIAZOL-4-YLMETHYL)-AMINE DIHYDROCHLORIDE
F
0
S CI~~CI CI I/ N,BOC
\\ N
H
H2N EtOH S NaH, (nBu)4N1, THF
F
F
TFA
N
" N
BOC I ND H ~ND
S S
Part I: Preparation of 1-(4-chloromethyl-thiazol-2-yl)-piperidine
A suspension of piperidine-l-carbothioamide (1.0 g, 6.9 mmol) and 1,3-dichloro-
propan-2-one (876 mg, 6.9 mmol) in ethanol (10 mL) was heated to 80 C and the
reaction monitored by liquid chromatography (LC)/mass spectrometry (MS). After
1
hour, the reaction was cooled and the solvent was removed under reduced
pressure
to provide a pinkish-violet liquid. The liquid was dissolved into ice water
(10 mL) and
slowly treated with solid sodium bicarbonate, upon which a white precipitate
formed.
The solid was collected by filtration and dried under reduced pressure. The
solid was
triturated with hexane and filtered. The filtrate was collected, dried over
anhydrous
sodium sulfate, filtered and the solvent removed under reduced pressure to
afford 1-
(4-chloromethyl-thiazol-2-yl)-piperidine (1.1 g, 5.1 mmol) as an off-white
solid.
Part II: Preparation of (4-fluorophenyl)-(2-piperidin-1-yl-thiazol-4-ylmethyl)-
carbamic
acid tert-butyl ester
To a solution of 4-fluorophenylcarbamic acid tert-butyl ester (1.02 g, 4.6
mmol) in
tetrahydrofuran (15 mL) was added sodium hydride (60% dispersion in mineral
oil,
206 mg, 5.1 mmol). After the initial gas evolution had ceased, the reaction
was
allowed to stir for 15 minutes. Tetra-n-butylammonium iodide (189 mg, 0.5
mmol)
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was then added followed by the addition of 1-(4-chloromethyl-thiazol-2-yl)-
piperidine
(1.1 g, 5.1 mmol) prepared above. The mixture was heated to reflux for 1 hour.
After
cooling, the reaction was carefully neutralized with cold saturated sodium
bicarbonate (10 mL) and extracted with ethyl acetate (2 x 20 mL). The organic
layers
were combined, dried over anhydrous sodium sulfate, filtered and the solvent
removed under reduced pressure to provide an oil. Flash chromatography (silica
gel;
10% ethyl acetate in hexanes) provided (4-fluorophenyl)-(2-piperidin-1-yl-
thiazol-4-
ylmethyl)-carbamic acid tert-butyl ester (1.25 g, 3.2 mmol) as a white solid.
Part III: Preparation of (4-fluorophenyl)-(2-piperidin-1-yl-thiazol-4-
ylmethyl)-amine
dihydrochloride
To a solution of (4-fluorophenyl)-(2-piperidin-1-yl-thiazol-4-ylmethyl)-
carbamic acid
tert-butyl ester (1.25 g, 3.2 mmol) in dichloromethane (15 mL) was added
trifluoroacetic acid (4 mL) and the reaction was stirred at room temperature
for 1.5
hours. After removing the solvent under reduced pressure, the resulting oil
was
dissolved in diethyl ether and treated with excess ethereal hydrochloric acid.
The
resulting solid was collected by filtration and dried to provide (4-
fluorophenyl)-(2-
piperidin-1-yl-thiazol-4-ylmethyl)-amine dihydrochloride (1.05 g, 3.2 mmol) as
a white
solid.
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EXAMPLE 11: PREPARATION OF (4-FLUOROPHENYL)-(2-PIPERIDIN-1-YL-
THIAZOL-5-YLMETHYL)-AMINE DIHYDROCHLORIDE
F \
N,BOC
HO S SOCI2 CI S H
~ /CI ~ ~CI
N N NaH, (nBu)4N1, THF
F HN F
HN S TFA
BOC T S
BOC ~N~
N N
F
S /~
/N )
H N ~/
Part I: Preparation of (2-chloro-thiazol-5-ylmethyl)-(4-fluorophenyl)-carbamic
acid
tert-butyl ester
To a solution of 2-chloro-thiazol-5-yl-methanol (1 g, 6.7 mmol) in chloroform
(10 mL)
was added thionyl chloride (1.6 g, 13.4 mmol), and the reaction was allowed to
stir at
room temperature overnight. The solvent was removed under reduced pressure to
afford a cloudy oil (1.1 g, 6.5 mmol) which was used directly in the next
reaction
without further purification.
To a solution of (4-fluorophenyl)-carbamic acid tert-butyl ester (1.3 g, 6.2
mmol) in
anhydrous tetrahydrofuran (15 mL) was added sodium hydride (60% dispersion in
mineral oil, 261 mg, 6.8 mmol). After the initial gas evolution had ceased,
the
reaction was allowed to stir for 15 minutes. Tetra-n-butylammonium iodide (227
mg,
0.6 mmol) was then added followed by addition of 2-chloro-5-chloromethyl
thiazole
prepared above. The mixture was heated to reflux for 1 hour. After cooling,
the
reaction was carefully neutralized with cold saturated sodium bicarbonate (10
mL)
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and extracted with ethyl acetate (2 x 20 mL). The organic layers were
combined,
dried over anhydrous sodium sulfate, filtered and the solvent removed under
reduced
pressure to provide a dark oil. Flash chromatography (silica gel; 5%-10% ethyl
acetate in hexanes) provided (2-chloro-thiazol-5-ylmethyl)-(4-fluorophenyl)-
carbamic
acid tert-butyl ester as a yellow oil (1.5 g, 4.4 mmol).
Part II: Preparation of (4-fluorophenyl)-(2-piperidin-1-yl-thiazol-5-ylmethyl)-
carbamic
acid tert-butyl ester
A solution of (2-chloro-thiazol-5-ylmethyl)-(4-fluorophenyl)-carbamic acid
tert-butyl
ester (1.5 g, 4.4 mmol) in piperidine (10 mL) was heated in a sealed tube to
130 C
and stirred overnight. After cooling, the reaction was partitioned between
water and
ethyl acetate. The organic layer was separated, dried over anhydrous sodium
sulfate, filtered and the solvent removed under reduced pressure to obtain a
yellow
oil. Flash chromatography (silica gel; 10%-20% ethyl acetate in hexanes)
provided
(4-fluorophenyl)-(2-piperidin-1-yl-thiazol-5-ylmethyl)-carbamic acid tert-
butyl ester as
a light yellow oil (981 mg, 2.6 mmol).
Part III: Preparation of (4-fluorophenyl)-(2-piperidin-1-yl-thiazol-5-
ylmethyl)-amine
dihydrochloride
To a solution of (4-fluorophenyl)-(2-piperidin-1-yl-thiazol-5-ylmethyl)-
carbamic acid
tert-butyl ester (981 mg, 2.6 mmol) in dichloromethane (10 mL) was added
trifluoroacetic acid (4 mL) and the reaction was stirred at room temperature
for 3
hours. After removing the solvent under reduced pressure, the resulting oil
was
dissolved in diethyl ether and treated with excess ethereal hydrochloric acid.
The
resulting solid was collected by filtration and dried to provide (4-
fluorophenyl)-(2-
piperidin-1-yl-thiazol-5-ylmethyl)-amine dihydrochloride as a white solid (472
mg, 1.7
mmol).
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EXAMPLE 12: 4-((1 H-INDOL-5-YLAMINO)METHYL)-N-CYCLOPROPYL-N-
ETHYLTH IAZO L-2-AM I N E
H
~
~
H ~-N
S \>
To a stirred solution of 2-[cyclopropyl(ethyl)amino]-1,3-thiazole-4-
carbaldehyde (0.19
g, 0.97 mmol) and 5-aminoindole (0.13 g, 1.00 mmol) in THF (3 mL) was added
acetic acid (0.1 mL) and the resulting solution was stirred overnight at room
temperature. Sodium triacetoxyborohydride (0.41 g, 1.95 mmol) was added and
the
solution was stirred an additional hour. The reaction was quenched with sat.
sodium
bicarbonate solution and extracted with ethyl acetate. The organic layer was
concentrated and flash column separation using 10-50% ethyl acetate / hexane
gave
N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-1 H-indol-5-amine as
a white
solid. (0.21 g, 56%).
EXAMPLE 13: 4-FLUORO-N-((6-(TRIFLUOROMETHYL)PYRIDIN-3-
YL)METHYL)ANILINE
F
H
N CF3
To a stirred solution of 6-(trifluoromethyl)pyridine-3-carboxaldehyde (1.0 g,
5.71
mmol) and 4-fluoroaniline (0.64 g, 5.71 mmol) in dichloromethane (2 mL) was
added
acetic acid (1.2 mL) and the resulting solution was stirred overnight at room
temperature. Sodium triacetoxyborohydride (2.4 g, 11.4 mmol) was added and the
solution was stirred an additional hour. The reaction was quenched with 1 N
NaOH
solution and extracted with dichloromethane. The organic layer was
concentrated
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and flash column separation using 0-20% ethyl acetate/ hexane to give 4-fluoro-
N-
{[6-(trifluoromethyl)pyridin-3-yl]methyl}aniline as an oil. (0.98 g, 64%)
EXAMPLE 14: 4-FLUORO-N-((6-(2,2,2-TRIFLUOROETHOXY)PYRIDIN-3-
YL)METHYL)ANILINE
F ~
H
N OCF3
Step 1: To a stirred solution of 6-chloronicotinaldehyde (3.0 g, 21.2 mmol)
and 4-
fluoroaniline (2.0 mL, 21.2 mmol) in dichloromethane (70 mL) was added acetic
acid
(3.6 mL) and the resulting solution was stirred overnight at room temperature.
Sodium triacetoxyborohydride (9.0 g, 42.4 mmol) was added and the solution was
stirred an additional hour. The reaction was quenched with 1 N NaOH solution
and
extracted with dichloromethane. The organic layer was concentrated and flash
column separation using 10-30% ethyl acetate/ hexane gave N-[(6-chloropyridin-
3-
yl)methyl]-4-fluoroaniline as a white solid. (4.29 g, 86%)
Step 2: To a stirred solution of 2,2,2-trifluoroethanol (0.42 g, 4.2 mmol) in
DMF (3
mL) at 0 C was added sodium hydride (0.17 g, 4.20 mmol) and the resulting
solution
was stirred 15 minutes. To this was added N-[(6-chloropyridin-3-yl)methyl]-4-
fluoroaniline (0.20 g, 0.85 mmol) and the resulting solution was heated over 3
days at
60 C. The reaction was allowed to cool, diluted with water and extracted
several
times with ethyl acetate. The combined organic phase was concentrated and
flash
column separation using 0-20% ethyl acetate/ hexane gave 4-fluoro-N-((6-(2,2,2-
trifluoroethoxy)pyridin-3-yl)methyl)aniline as an oil. (0.16 g, 65%)
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EXAMPLE 15: 4-FLUORO-N-(2-(2-MORPHOLINOTHIAZOL-4-YL)ETHYL)ANILINE
F ~
O O EtOH, TEA N ~\ I~ NHZ N N
CI O ~N O O I _N
S S ~~ trimethylaluminum S
Toluene
NH2
LiAlH4 / N NN
diethylether
F / )-N-- ~
S
Part I: Preparation of ethyl (2-morpholin-4-yl-1,3-thiazol-4-yl)acetate
A mixture of ethylmalonylchloride (4.76 mL, 35 mmol) and morpholine-4-
carbothioic
acid amide (5.0 g, 34.2 mmol) in ethanol (40 mL) was heated to 80 C for 3
hours.
The mixture was cooled, ethanol evaporated, and diluted with saturated sodium
bicarbonate, and extracted with ethyl acetate. The organic layers were dried
over
magnesium sulfate and the reaction mixture purified by chromatography (silica
gel;
ethylacetate/hexane, 1:1) to provide ethyl (2-morpholin-4-yl-1,3-thiazol-4-
yl)acetate
(9 g, quantitative)
Part II: Preparation of N-(4-fluorophenyl)-2-(2-morpholin-4-yl-1,3-thiazol-4-
yl)acetamide
A mixture of ethyl (2-morpholin-4-yl-1,3-thiazol-4-yl)acetate (1.0 g, 4.65
mmol) and 4-
fluoroaniline(0.55 mL, 5.8 mmol) was dissolved in toluene (13 mL) at room
temperature. 2M Trimethylaluminum (2.5 mL, 5 mmol) was added dropwise, and the
mixture was heated to 60 C for 3 hours. The mixture was cooled, quenched with
methanol, and the solvent evaporated under reduced pressure. The residue was
partitioned between saturated sodium bicarbonate and ethyl acetate. The
organic
layer was collected, washed with saturated potassium-sodium tartrate, dried
over
magnesium sulfate, and concentrated. The residue was purified by
chromatography (silica gel; 10%-50% ethylacetate/hexane, gradient elution) to
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provide N-(4-fluorophenyl)-2-(2-morpholin-4-yl-1,3-thiazol-4-yl)acetamide
(0.930g,
62%).
Part III: Preparation of 4-fluoro-N-[2-(2-morpholin-4-yl-1,3-thiazol-4-
yl)ethyl]aniline
To a mixture of N-(4-fluorophenyl)-2-(2-morpholin-4-yl-1,3-thiazol-4-
yl)acetamide
(0.900g, 2.8 mmol) in anhydrous diethylether (30 mL) at 0 C was slowly added
1M
lithium aluminum hydride (5 mL). The reaction was allowed to warm to room
temperature and stirring continued 7 hours. The mixture was quenched
sequentially
with water (0.2 mL), 2N NaOH (.2 mL), and water (0.6 mL). The mixture was
filtered
through celite and the filtrate concentrated. The residue was purified by
chromatography (silica gel; 20%-50% ethylacetate/hexane, gradient elution) to
provide 4-fluoro-N-[2-(2-morpholin-4-yl-1,3-thiazol-4-yl)ethyl]aniline
(0.520g, 60%).
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EXAMPLE 16: 4-(CHLOROMETHYL)-N-CYCLOPROPYL-N-ETHYL-1,3-THIAZOL-
2-AMINE
BOC2O, NaH, DMF, Me
Et3N, DCM ~ Etl N~
H2N~ HN O=< 0=<
~ O
O
HCI, Et20 ~Me 1. THF, TEA CI~CI
reflux
HN H2NN~
O EtOH
S
.HCI 0)NCO
2. 2N NaOH
reflux, 48 hrs.
CI N
~-N />
S
Step 1. tert-butyl cyclopropylcarbamate
To a solution of cylcopropylamine (6.0 g, 0.10 mol) and triethylamine (14.6
ml, 0.10
mol) in dichloromethane (250 mL) was slowly added di-tertbutyldicarbonate
(22.9 g,
0.10 mol) in dichloromethane (100 mL). After stirring overnight at room
temperature,
the mixture was poured into water, the organic layer was separated, washed
with
water, dried (MgS04) and evaporated to afford the product (15.48 g, 0.098
mol).
Step 2. tert-butyl cyclopropyl(ethyl)carbamate
tert-butyl cyclopropylcarbamate (14.24 g, 0.092 mmol) in dry DMF (100 mL) was
cooled to 0 oC, and treated with sodium hydride (60% dispersion in oil, 3.79
g, 0.095
mol). After the addition was complete, ethyl iodide (8.0 mL, 100 mmol) was
added
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dropwise. The mixture was then stirred overnight at room temperature, then
pured
into water, extracted with diethyl ether, the organic layer was washed with
water,
dried (MgSO4) and evaporated to afford the product as an oil (17.74 g, 0.092
mol).
Step 3. N-ethylcyclopropanamine hydrochloride
tert-butyl cyclopropyl(ethyl)carbamate (15 g, 0.081 mol) was treated with
hydrogen
chloride (4N in dioxane, 200 mL). After 16 h, the reaction was evaporated and
the
residue triturated with diethylether, then hexane. The solid was then dried
under
vacuum to afford the product (8.67 g, 72 mmol).
Step 4. 1-cyclopropyl-1-ethylthiourea
To a mixture of cyclohexylethylamine hydrochloride (10.5 g, 87.5 mmol) and
triethylamine (12.2 mL, 87.7 mmol) in tetrahydrofuran was added
benzoylisothiocyanate (11.9 mL, 90.4 mmol) and reluxed 3 hours. The mixture
was
cooled, and partitioned between water and ethyl acetate. The organic layer was
collected, dried over magnesium sulfate, and evaporated. The residue was
dissolved
in tetrahydrofuran/ethanol (300 mL); 2N NaOH (60 mL) was added and the mixture
refluxed 48 hours. The mixture was partitioned between water and ethyl
acetate.
The organic layer was collected, dried over magnesium sulfate, and evaporated.
The
resultant oil was scratched with hexanes/ether to provide 1-cyclopropyl-l-
ethylthiourea (9.5 g, 75 %).
Step 5. 4-(chloromethyl)-N-cyclopropyl-N-ethyl-1,3-thiazol-2-amine
A mixture of 1-cyclopropyl-l-ethylthiourea (9.5 g, 66.2 mmol) and 1,3
dichloroacetone (8.6 g, 68 mmol) in ethanol (100 mL) was refluxed 8 hours. The
solvent evaporated under reduced pressure and the residue was partitioned
between
saturated sodium bicarbonate and ethyl acetate. The organic layer was
collected,
dried over magnesium sulfate, and concentrated. The residue was purified by
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chromatography (silica gel; 1/5 ethylacetate/hexane) to provide 4-
(chloromethyl)-N-
cyclopropyl-N-ethyl-1,3-thiazol-2-amine (8.0 g, 56 %).
EXAMPLE 17 PREPARATION OF 4-CHLORO-N-(4-FLUOROPHENYL)-N-[6-(4-
METHYL-PI PERAZI N-1-YL)-PYRI DI N-3-YL-METHYL]-BENZAMI DE
HYDROCHLORIDE (COMPOUND NO. 1)
CI
CI
O HN ~ ~ F NaH
F ~ ~ NH2 CI ~ ~ 0
0 CI
CI
N
/ F
/
N F
N N ~ HNN- \ I
~ N
CI O ~ \~
~ / r N O ~
CI ~NJ I ~ CI
Part I: A: Preparation of 4-chloro-N-(4-fluorophenyl)-benzamide
To a solution of 4-fluoroaniline (2.58 g, 23.2 mmol) in dichloromethane (30
mL) at
0 C was added 4-chlorobenzoyl chloride (2.98 mL, 23.2 mmol), followed by the
dropwise addition of triethylamine (3.9 mL, 27.9 mmol). The reaction was
allowed to
warm to room temperature and stirred for 30 minutes. The reaction was diluted
with
dichloromethane (20 mL), washed with a saturated aqueous sodium bicarbonate
solution (50 mL), followed by brine (50 mL). The organic phase was dried with
anhydrous sodium sulfate, filtered and concentrated under reduced pressure to
provide a solid. The solid was washed with hexanes to provide 4-chloro-N-(4-
fluorophenyl)-benzamide (5.38 g, 21.5 mmol) as a white solid.
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Part II: Preparation of 4-chloro-N-(6-chloro-pyridin-3-yl-methyl)-N-(4-
fluorophenyl)-
benzamide
To a solution of 4-chloro-N-(4-fluorophenyl)-benzamide (1.0 g, 4 mmol) in
dimethylformamide (10 mL) at room temperature was added sodium hydride (60%
oil
dispersion, 241 mg, 6 mmol). The reaction was stirred for 15 minutes or until
gas
evolution ceased. The reaction temperature was raised to 90 C for 15 minutes
followed by addition of 2-chloro-5-chloromethyl pyridine (0.98 g, 6 mmol).
After
stirring at 90 C for 30 minutes, the mixture was cooled to room temperature
and then
slowly poured into a 2N sodium hydroxide solution (10 mL). The aqueous medium
was extracted with ethyl acetate (3 x 20 mL). The organic phases were
combined,
dried over anhydrous sodium sulfate, filtered and the solvent removed under
reduced
pressure to provide a viscous brown oil (0.8 g, 2.1 mmol). This material was
used
directly in the next reaction without further purification.
Part III: Preparation of 4-chloro-N-(4-fluorophenyl)-N-[6-(4-methyl-piperazin-
1-yl)-
pyridin-3-yl-methyl]-benzamide hydrochloride
4-Chloro-N-(6-chloropyridin-3-yl-methyl)-N-(4-fluorophenyl)-benzamide (0.8 g,
2.1 mmol, crude) was dissolved in N-methylpiperazine (4 mL). The resulting
mixture
was heated at 130 C overnight in a sealed tube. The reaction was cooled,
diluted
with brine (20 mL), and extracted with ethyl acetate (3 x 20 mL). The organic
phases
were combined, dried over anhydrous sodium sulfate, filtered and the solvent
removed under reduced pressure to provide a dark brown oil. Flash
chromatography
(silica gel; 5-20% methanol in dichloromethane) provided a light yellow oil.
The resulting oil was dissolved in diethyl ether (10 mL) and a saturated
hydrochloric
acid solution in diethyl ether (6 mL) was added. The solvent was removed under
reduced pressure to provide 4-chloro-N-(4-fluorophenyl)-N-[6-(4-methyl-
piperazin-l-
yl)-pyridin-3-yl-methyl]-benzamide hydrochloride (0.4 g, 0.9 mmol) as a white
solid.
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EXAMPLE 18 PREPARATION OF 4-CHLORO-N-(6-DIETHYLAMINO-PYRIDIN-3-
YL-METHYL)-N-(4-FLUOROPHENYL)-BENZAMIDE TRIFLUOROACETATE
(COMPOUND NO. 2)
\1 CI / I F
CI
N O N N \
F NH
~
~ Et3N N O
CI
To a solution of {5-[(4-fluorophenylamino)-methyl]-pyridin-2-yl}-diethylamine
(407 mg,
1.49 mmol) in anhydrous tetrahyrofuran (7.5 mL) at 0 C was added 4-
chlorobenzoyl
chloride (230 pL, 1.79 mmol) and triethylamine (250 pL, 1.79 mmol). The
reaction
was warmed to room temperature and stirred for 1 hour. The reaction was
quenched
with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (2
x 10
mL). The organic phases were combined, washed with brine (10 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
Purification by chromatography (silica gel; 1:2 ethyl acetate in hexane)
provided 4-
chloro-N-(6-diethylamino-pyridin-3-yl-methyl)-N-(4-fluorophenyl)-benzamide
(594 mg,
1.44 mmol).
The free base (309 mg, 0.75 mmol) was treated with 1% aqueous trifluoroacetic
acid,
and lyophilized to provide 4-chloro-N-(6-diethylamino-pyridin-3-yl-methyl)-N-
(4-
fluorophenyl)-benzamide trifluoroacetate (394 mg, 1.44 mmol) as a gummy solid.
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EXAMPLE 19: PREPARATION OF 4-CHLORO-N-(4-FLUOROPHENYL)-N-(2-
PYRROLIDIN-I-YL-THIAZOL-5-YL-METHYL)-BENZAMIDE HYDROCHLORIDE
(COMPOUND NO. 3)
CI F
CI
F
S / CI
NH~" 'N~ N
N-~ ~ N Et3N CS5
To a solution of (4-fluorophenyl)-(2-pyrrolidin-1-yl-thiazol-5-yl-methyl)-
amine (180 mg,
0.65 mmol) in dichloromethane (7.5 mL) was added 4-chlorobenzoyl chloride (125
pL, 0.98 mmol) and triethylamine (270 pL, 1.95 mmol). The reaction was stirred
for
30 minutes. The reaction was quenched with saturated sodium bicarbonate (10
mL)
and extracted with ethyl acetate (2 x 10 mL). The organic phases were
combined,
washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. Purification by chromatography (silica
gel;
10% methanol in dichloromethane) provided 4-chloro-N-(4-fluorophenyl)-N-(2-
pyrrolidin-l-yl-thiazol-5-yl-methyl)-benzamide (229 mg, 0.55 mmol).
Treatment of the free base with ethereal hydrochloric acid provided 4-chloro-N-
(4-
fluorophenyl)-N-(2-pyrrolidin-l-yl-thiazol-5-yl-methyl)-benzamide
hydrochloride (250
mg, 0.55 mmol) as a white solid.
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EXAMPLE 20: PREPARATION OF 4-CHLORO-N-(4-FLUOROPHENYL)-N-(2-
PIPERIDIN-1-YL-THIAZOL-4-YL-METHYL)-BENZAMIDE HYDROCHLORIDE
(COMPOUND NO. 4)
F
- ON N
CI HN \~ F CI N O
O \~
/ N
NaH, (nBu)4N1, THF Cc1
To a solution of 4-chloro-N-(4-fluorophenyl)-benzamide (250 mg, 1 mmol) in
anhydrous tetrahydrofuran (6 mL) was added sodium hydride (60% oil dispersion,
0.241 mg, 6 mmol). The reaction was stirred for 15 minutes or until gas
evolution
ceased. To the reaction was added 1-(4-chloromethyl-thiazol-2-yl)-piperidine
(239
mg, 1.1 mmol) and tetra-n-butylammonium iodide (74 mg, 0.2 mmol), and the
reaction was heated to 80 C. After stirring for 2 hours, the reaction was
cooled to
room temperature and slowly quenched with saturated sodium bicarbonate (10
mL).
The aqueous phase was extracted with ethyl acetate (3 x 20 mL). The organic
phases were combined, dried over anhydrous sodium sulfate, filtered and the
solvent
removed under reduced pressure to provide a dark yellow oil. Purification by
chromatography (silica gel; 20-30% ethyl acetate in hexane) provided 4-chloro-
N-(4-
fluorophenyl)-N-(2-piperidin-1-yl-thiazol-4-yl-methyl)-benzamide (249 mg, 0.58
mmol). MS (base): m/z 430 [M+H]; HPLC (base): tr = 3.4 min.
Treatment of the free base with ethereal hydrochloric acid provided 4-chloro-N-
(4-
fluorophenyl)-N-(2-piperidin-1-yl-thiazol-4-yl-methyl)-benzamide hydrochloride
(250
mg, 0.58 mmol) as a white foam.
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EXAMPLE 21: PREPARATION OF 2-(4-CHLOROPHENYL)-N-(4-
FLUOROPH ENYL)-N-[6-(4-METHYL-PI PERAZI N-1-YL)-PYRI DI N-3-YLMETHYL]-
ISOBUTYRAMIDE HYDROCHLORIDE (COMPOUND NO. 34)
O CI F / \NH / \ ~NO OH ~N-
CI ~ \ SOC12 CI / \ N
(iPr)2NH, CH2CI2
F
CI
-N /-\ N N
N-
To a suspension of 2-(4-chlorophenyl)-2-methyl propanoic acid (199 mg, 1 mmol)
in
chloroform (5 mL) was added thionyl chloride (220 pL, 3 mmol) and the reaction
heated to reflux for 1 hour. The reaction was cooled and concentrated under
reduced pressure to provide 2-(4-chlorophenyl)-2-methyl-propionyl chloride.
To a solution of 2-(4-chlorophenyl)-2-methyl-propionyl chloride in
dichloromethane (5
mL) and diisopropyl amine (700 pL, 5 mmol) was added (4-fluorophenyl)-[6-(4-
methyl-piperazin-l-yl)-pyridin-3-ylmethyl]-amine (180 mg, 0.6 mmol). After
stirring for
30 minutes, the reaction was quenched with saturated sodium bicarbonate (10
mL)
and extracted with ethyl acetate (2 x 10 mL). The organic phases were
combined,
dried over anhydrous sodium sulfate, filtered, and concentrated under reduced
pressure. Purification by reverse phase chromatography and isolation of the
free
base provided 2-(4-chlorophenyl)-N-(4-fluorophenyl)-N-[6-(4-methyl-piperazin-1-
yl)-
pyridin-3-ylmethyl]-isobutyramide. MS (base): m/z 481 [M+H]; HPLC (base): tr =
2.7
min.
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Treatment of the free base with ethereal hydrochloric acid provided 2-(4-
chlorophenyl)-N-(4-fluorophenyl)-N-[6-(4-methyl-pi perazi n-1-yl)-pyrid in-3-
yl methyl]-
isobutyramide hydrochloride (300 mg, 0.58 mmol) as a white solid.
EXAMPLE 22: PREPARATION OF 1-(4-CHLOROPHENYL)-
CYCLOBUTANECARBOXYLIC ACID (4-FLUOROPHENYL)-[6-(4-METHYL-
PIPERAZIN-I-YL)-PYRIDIN-3-YLMETHYL]-AMIDE HYDROCHLORIDE
(COMPOUND NO. 35)
F ~ \ NH
HO O O CI ~ \ N~N-
SOCI2 - N
CI
(iPr)2NH, CH2CI2
F
N- N
-N\,_j N \ / 0 / CI
To a suspension of 1-(4-chlorophenyl)-1-cyclobutane carboxylic acid (211 mg, 1
mmol) in chloroform (5 mL) was added thionyl chloride (220 pL, 3 mmol) and the
reaction heated to reflux for 1 hour. The reaction was cooled and concentrated
under reduced pressure to provide 1-(4-chlorophenyl)-cyclobutanecarbonyl
chloride.
To a solution of 1-(4-chlorophenyl)-cyclobutanecarbonyl chloride in
dichloromethane
(5 mL) and diisopropyl amine (700 pL, 5 mmol) was added (4-fluorophenyl)-[6-(4-
methyl-piperazin-l-yl)-pyridin-3-ylmethyl]-amine (150 mg, 0.5 mmol). After
stirring for
30 minutes, the reaction was quenched with saturated sodium bicarbonate (10
mL)
and extracted with ethyl acetate (2 x 10 mL). The organic phases were
combined,
dried over anhydrous sodium sulfate, filtered, and concentrated under reduced
pressure. Purification by reverse phase chromatography and isolation of the
free
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base provided 1-(4-chlorophenyl)-N-(4-fluorophenyl)-N-((6-(4-methylpiperazin-1-
yl)pyridin-3-yl)methyl)cyclobutanecarboxamide.
Treatment of the free base with ethereal hydrochloric acid provided 1-(4-
chlorophenyl)-cyclobutanecarboxylic acid (4-fluorophenyl)-[6-(4-methyl-
piperazin-l-
yl)-pyridin-3-ylmethyl]-amide hydrochloride (238mg, 0.45 mmol ) as a white
solid.
EXAMPLE 23. 4-CHLORO-N-{[6-(DIPHENYLAMINO)PYRIDIN-3-YL]METHYL}-N-(4-
FLUOROPHENYL)BENZAMIDE (COMPOUND NO. 273)
ci
O N
I \ I \
N N
F
Preparation of 4-chloro-N-{[6-(diphenylamino)pyridin-3-yl]methyl}-N-(4-
fluorophenyl)benzamide
To a stirred solution of 4-chloro-N-[(6-chloropyridin-3-yl)methyl]-N-(4-
fluorophenyl)benzamide (0.10 g, 0.26 mmol) and diphenylamine (0.05 g, 0.26
mmol)
in toluene (5 mL) was added Pd2(dba)3 (0.01 g, 0.015 mmol) and BINAP (0.03 g,
0.04
mmol) and cesium carbonate (0.13 g, 0.40 mmol) and the resulting solution was
heated to 100 C for 2 days. The mixture was partitioned between 1.0 N NaOH
solution and ethyl acetate. The organic phase was concentrated. Flash column
separation using 0-30% ethyl acetate/hexane gave 4-chloro-N-{[6-
(diphenylamino)pyridin-3-yl]methyl}-N-(4-fluorophenyl)benzamide as a white
solid.
(0.03 g, 22%).
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TABLE 2A
HPLC
No. Chemical Name Salt Retention lonlecular
SchemeMethod ime
min
100N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4- 1 B 4.6 378.1
luorophen I benzamide
101 N-{[6-(diethylamino)pyridin-3-yl]methyl}-2-fluoro- 1 B 4.6 396.1
N- 4-fluorophen I benzamide
102N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4- 1 B 4.5 408.1
luorophen I -2-methox benzamide
103N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4- 1 B 4.7 392.1
luorophen I -2-meth Ibenzamide
104N-{[6-(diethylamino)pyridin-3-yl]methyl}-3-fluoro- 1 B 4.6 396
N- 4-fluorophen I benzamide
105N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4- 1 B 4.6 408.1
luorophen I -3-methox benzamide
106N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4- 1 B 4.8 392.1
luorophen I -3-meth Ibenzamide
107N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4- 1 B 4.6 408.1
luorophen I -4-methox benzamide
1084-tert-butyl-N-{[6-(diethylamino)pyridin-3- 1 B 5.1 434.1
I]meth I-N- 4- fluorophen I benzamide
109N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4- 1 B 4.9 392.1
luorophen I -4-meth Ibenzamide
1104-cyano-N-{[6-(diethylamino)pyridin-3- 1 B 4.6 403.1
I]meth I-N- 4-fluorophen I benzamide
111 N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4- 1 B 2.8 428.1
luorophen I -2-naphthamide
112N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4- 1 B 4.9 480.1
luorophen I -9-oxo-9H-fluorene-4- carboxamide
113 luorophenyl)carbamoyl]benzoate methyl 4-[{[6- 1 B 4.7 436.1
dieth lamino p ridin-3- I]meth I 4-
114N-(2-isopropylphenyl)-N-[(2-piperidin-l-yl-1,3- 3 B 5.2 420.1
thiazol-4- I meth I]benzamide
1152-fluoro-N-(2-isopropylphenyl)-N-[(2-piperidin-l- 3 B 5.2 438.1
I-1,3-thiazol-4- I meth I]benzamide
116N. (2-isopropylphenyl)-2-methoxy-N-[(2- 3 B 5.1 450.1
piperidin-l- I-1,3-thiazol-4- I meth I]benzamide
117N-(2-isopropylphenyl)-2-methyl-N-[(2-piperidin- 3 B 5.4 434.1
1- I-1,3-thiazol-4- I meth I]benzamide
1183-fluoro-N-(2-isopropylphenyl)-N-[(2-piperidin-l- 3 B 5.3 438.1
I-1,3-thiazol-4- I meth I]benzamide
119N-(2-isopropylphenyl)-3-methyl-N-[(2-piperidin- 3 B 5.5 434.1
1- I-1,3-thiazol-4- I meth I]benzamide
1204-chloro-N-(2-isopropylphenyl)-N-[(2-piperidin-l- 3 B 5.6 454
I-1,3-thiazol-4- I meth I]benzamide
121 N-(2-isopropylphenyl)-4-methoxy-N-[(2-
3 B 5.2 450.1
piperidin-l- I-1,3-thiazol-4- I meth I]benzamide
122 N-4-meth Iphen I-N-[ 2-p rrolidin-l- I-1,3- HCI 3 B 378.1
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thiazol-5- I meth I]benzamide
1232-fluoro-N-(4-methylphenyl)-N-[(2-pyrrolidin-1-yl-HCI3 B 4 396.1
1,3-thiazol-5- I meth I]benzamide
1242-methoxy-N-(4-methylphenyl)-N-[(2-pyrrolidin- HCI3 B 3.9 08.1
1- I-1,3-thiazol-5- I meth I]benzamide
1252-methyl-N-(4-methylphenyl)-N-[(2-pyrrolidin-l- HCI 3 B 4 392.1
I-1,3-thiazol-5- I meth I]benzamide
1263-fluoro-N-(4-methylphenyl)-N-[(2-pyrrolidin-1-yl-HCI3 B 4 396.1
1,3-thiazol-5- I meth I]benzamide
1273-methoxy-N-(4-methylphenyl)-N-[(2-pyrrolidin- HCI3 B 4 08.1
1- I-1,3-thiazol-5- I meth I]benzamide
1283-methyl-N-(4-methylphenyl)-N-[(2-pyrrolidin-l- HCI 3 B 4 392.1
I-1,3-thiazol-5- I meth I]benzamide
1294-fluoro-N-(4-methylphenyl)-N-[(2-pyrrolidin-1-yl-HCI3 B 4 396.1
1,3-thiazol-5- I meth I]benzamide
1304-chloro-N-(4-methylphenyl)-N-[(2-pyrrolidin-1- HCI3 B 4.1 412
I-1,3-thiazol-5- I meth I]benzamide
1314-methoxy-N-(4-methylphenyl)-N-[(2-pyrrolidin- HCI3 B 4 08.1
1- I-1,3-thiazol-5- I meth I]benzamide
132N-(4-methylphenyl)-N-[(2-pyrrolidin-1 -yl-1,3- HCI3 B .2 54.1
thiazol-5- I meth I]biphen I-4- carboxamide
1334-tert-butyl-N-(4-methylphenyl)-N-[(2-pyrrolidin- HCI 3 B .3 34.1
1- I-1,3-thiazol-5- I meth I]benzamide
1344-methyl-N-(4-methylphenyl)-N-[(2-pyrrolidin-1 - HCI 3 B 4 392.1
I-1,3-thiazol-5- I meth I]benzamide
1354-cyano-N-(4-methylphenyl)-N-[(2-pyrrolidin-1- HCI3 B 3.9 03.1
I-1,3-thiazol-5- I meth I]benzamide
136N-(4-fluoro-2-methylphenyl)-N-[(2-piperidin-1- HCI B .2 05.1
Ip rimidin-5- I meth I]benzamide
1372-fluoro-N-(4-fluoro-2-methylphenyl)-N-[(2- HCI B .2 23.1
piperidin-l- Ip rimidin-5- I meth I]benzamide
138N. (4-fluoro-2-methylphenyl)-2-methyl-N-[(2- HCI B .2 19.1
piperidin-l- Ip rimidin-5- I meth I]benzamide
1393-fluoro-N-(4-fluoro-2-methylphenyl)-N-[(2- HCI B .2 23.1
piperidin-l- Ip rimidin-5- I meth I]benzamide
140 N-(4-fluoro-2-methylphenyl)-3-methoxy-N-[(2- HCI B 2 35
piperidin-l- Ip rimidin-5- I meth I]benzamide .1
1414-fluoro-N-(4-fluoro-2-methylphenyl)-N-[(2- HCI B .2 23.1
piperidin-l- Ip rimidin-5- I meth I]benzamide
1424-chloro-N-(4-fluoro-2-methylphenyl)-N-[(2- HCI B .3 39.1
piperidin-l- Ip rimidin-5- I meth I]benzamide
N-(4-fluoro-2-methylphenyl)-4-methoxy-N-[(2-
143piperidin-1- Ip rimidin-5- I meth I]benzamide HCI B .2 35.1
1444-tert-butyl-N-(4-fluoro-2-methylphenyl)-N-[(2- HCI B .6 61.2
piperidin-l- Ip rimidin-5- I meth I]benzamide
145N. (4-fluoro-2-methylphenyl)-4-methyl-N-[(2- HCI B .3 19.1
piperidin-l- Ip rimidin-5- I meth I]benzamide
1464-cyano-N-(4-fluoro-2-methylphenyl)-N-[(2- HCI B .1 30.1
piperidin-l- Ip rimidin-5- I meth I]benzamide
147N-(4-fluoro-2-methylphenyl)-N-[(2-piperidin-1- HCI B .4 55.1
Ip rimidin-5- I meth I]-2- naphthamide
148N-(4-fluoro-2-methylphenyl)-9-oxo-N-[(2- HCI B .3 507.1
piperidin-l- Ip rimidin-5- I meth I]-9H- fluorene-
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4-carboxamide
149methyl 4-{(4-fluoro-2-methylphenyl)[(2-piperidin- HCI B .2 63.1
1 - Ip rimidin-5- I meth I]carbamo I benzoate
150N. (2-isopropylphenyl)-3-methoxy-N-[(2- HCI B .4 50.1
piperidin-1- 1-1,3-thiazol-4- I meth I]benzamide
1514-fluoro-N-(2-isopropylphenyl)-N-[(2-piperidin-1- HCI B .4 38.1
I-1,3-thiazol-4- I meth I]benzamide
152N-(2-isopropylphenyl)-N-[(2-piperidin-1-yl-1,3- HCI B .8 96.1
thiazol-4- I meth I]biphen I-4- carboxamide
1534-tert-butyl-N-(2-isopropylphenyl)-N-[(2- HCI B .8 76.2
piperidin-l- I-1,3-thiazol-4- I meth I]benzamide
154N-(2-isopropylphenyl)-4-methyl-N-[(2-piperidin- HCI B .5 34.1
1- I-1,3-thiazol-4- I meth I]benzamide
1554-cyano-N-(2-isopropylphenyl)-N-[(2-piperidin-1-HCI B .3 45.1
I-1,3-thiazol-4- I meth I]benzamide
156N-(2-isopropylphenyl)-N-[(2-piperidin-l-yl-1,3- HCI B .6 70.1
thiazol-4- I meth I]-2- naphthamide
N-(2-isopropylphenyl)-9-oxo-N-[(2-piperidin-l-yl-
1571,3-thiazol-4-yl)methyl]-9H-fluorene-4- HCI B .6 522.1
carboxamide
1583-cyano-N-(2-isopropylphenyl)-N-[(2-piperidin-1-HCI B .3 45.1
I-1,3-thiazol-4- I meth I]benzamide
159methyl4-{(2-isopropylphenyl)[(2-piperidin-1-yl- HCI B .4 78.1
1,3-thiazol-4- I meth I]carbamo I benzoate
160N-(4-methylphenyl)-N-[(2-pyrrolidin-1 -yl-1,3- HCI3 B .1 28.1
thiazol-5- I meth I]-2-naphthamide
161 N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin- HCI 5 B 4.2 394
2- I]meth I benzamide
162N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin- HCI5 B 3.8 12.1
2- I]meth I -2-fluorobenzamide
163N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin- HCI5 B 3.8 424
2- I]meth I -2-methox benzamide
164N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin- HCI5 B 3.8 08.1
2- I]meth I -2-meth Ibenzamide
165N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin- HCI 5 B 3.8 412
2- I]meth I -3-fluorobenzamide
166N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin- HCI5 B 3.8 424
2- I]meth I -3-methox benzamide
167N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin- HCI5 B 3.8 08.1
2- I]meth I -3-meth Ibenzamide
168N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin- HCI5 B 3.8 412
2- I]meth I -4-fluorobenzamide
1694-chloro-N-(4-chlorophenyl)-N-{[6- HCI5 B 3.9 428
dieth lamino p ridin-2- I]meth I benzamide
170N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin- HCI5 B 3.8 24.1
2- I]meth I -4-methox benzamide
171 N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin- HCI 5 B 4 70.1
2- I]meth I biphen I-4- carboxamide
1724-tert-butyl-N-(4-chlorophenyl)-N-{[6- HCI5 B 4 50.1
dieth lamino p ridin-2- I]meth I benzamide
173N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin- HCI5 B 3.8 08.1
2- I]meth I -4-meth Ibenzamide
174N- 4-chlorophen I-4-c ano-N- [6- HCI 5 B 3.8 419
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dieth lamino p ridin-2- I]meth I benzamide
175N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin- HCI5 B 3.9 144.1
2- I]meth I -2-naphthamide
N-(4-chlorophenyl)-N-{[6-(diethylamino)pyridin- HCI 5 B 3.9 96
1762_ I]meth I-9-oxo-9H-fluorene-4- carboxamide .1
177N-(4-chlorophenyl)-3-cyano-N-{[6- HCI 5 B 3.7 19.1
dieth lamino p ridin-2- I]meth I benzamide
methyl 4-[(4-chlorophenyl){[6-
178(diethylamino)pyridin-2- HCI 5 B 3.8 452
I]meth I carbamo I]benzoate
179 N-(4-fluoro-2-methylphenyl)-2-methoxy-N-[(2- HCI B 3.6 35
piperidin-1- Ip rimidin-5- I meth I]benzamide .1
180N. (4-fluoro-2-methylphenyl)-3-methyl-N-[(2- HCI B 3.7 19.1
piperidin-1- Ip rimidin-5- I meth I]benzamide
1814-carboxamide N-(4-fluoro-2-methylphenyl)-N- HCI B .3 81.1
[ 2-piperidin-1- Ip rimidin-5- I meth I]biphen I-
182N-{[6-(diethylamino)pyridin-3-yl]methyl}-4-fluoro-HCI 1 B 3.6 396.1
N- 4-fluorophen I benzamide
183N-{3-[cyclopropyl(ethyl)amino]benzyl}-2-fluoro- HCI 6 B 3.7 07.1
N- 4-fluorophen I benzamide
4-chloro-N-(4-fluorophenyl)-N-{[6-(4-
185methylpiperazin-1-yl)pyridin-3- HCI 7
I]meth I benzamide
N-cyclopentyl-3,4,5-trimethoxy-N-{[6-(4-
186methylpiperazin-1-yl)pyridin-3- HCIB 6.7 69.2
I]meth I benzamide
5-fluoro-N-(4-fluorophenyl)-2-methyl-N-{[6-(4-
187methylpiperazin-1-yl)pyridin-3- HCI
I]meth I benzamide
188N'-(4-chlorophenyl)-N-(4-fluorophenyl)-N-{[6-(4- HCI
meth Ipiperazin-1- I p ridin-3- I]meth I urea
N-(4-fl uorophenyl )-4-methyl-N-{[6-(4-
189methylpiperazin-1-yl)pyridin-3- HCI
I]meth I benzamide
4-chloro-N-(4-fluorophenyl)-2-methoxy-N-{[6-(4-
190methylpiperazin-1-yl)pyridin-3- HCI
I]meth I benzamide
N-(4-fluorophenyl)-4-methoxy-N-{[6-(4-
191 methylpiperazin-1-yl)pyridin-3- HCI
I]meth I benzamide
N-(4-fl uorophenyl )-3-methyl-N-{[6-(4-
192methylpiperazin-1-yl)pyridin-3- HCI
I]meth I benzamide
4-(acetylamino)-N-(4-fluorophenyl)-N-{[6-(4-
193methylpiperazin-1-yl)pyridin-3- TFA
I]meth I benzamide
1944-chloro-N-(4-fluorophenyl)-N-{[6-(4-methyl-114- HCI
diazepan-1- I p ridin-3- I]meth I benzamide
1954-chloro-N-{[6-(diethylamino)pyridin-3- HCI
I]meth I-N- 4-fluorophen I benzamide TFA
4-chloro-N-({6-[[2-
196(dimethylamino)ethyl](methyl)amino]pyridin-3- HCI
I meth I-N- 4- fluorophen I benzamide
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4-chloro-N-{[6-(1,1-d ioxidothiomorpholin-4-
197y1)pyridin-3-yl]methyl}-N-(4-
luorophen I benzamide
4-chloro-N-(2,6-dimethylphenyl)-N-{[6-(4-
198methylpiperazin-1-yl)pyridin-3- HCI
I]meth I benzamide
4-(5-{[(4-chlorobenzoyl)(4-
1991uorophenyl)amino]methyl}pyridin-2-yl)-N- HCI
eth Ipiperazine-1-carboxamide
4-chloro-N-(4-fluorophenyl)-N-({6-[4-(2-
200morpholin-4-ylethyl)piperazin-l- yl]pyridin-3- HCI
I meth I benzamide
201 N-(4-methylphenyl)-N-[(6-piperazin-1-ylpyridin- HCI
3- I meth I]benzamide
(4-fluorophenyl)benzamide N-({6-[4-(1H-
202benzimidazol-2-yl)piperidin-1-yl]pyridin-3- HCI
I meth I -4-chloro-N-
2034-chloro-N-(4-fluorophenyl)-N-[(6-pyrrolidin-l- HCI
Ip ridin-3- I meth I]benzamide
4-chloro-N-(4-fluorophenyl)-N-({6-[4-
204(methylsulfonyl)piperazin-1-yl]pyridin-3- HCI
I meth I benzamide
4-chloro-N-(4-fluorophenyl)-N-({6-[3-
205(methylamino)pyrrolidin-1-yl]pyridin-3- HCI
I meth I benzamide
2064-chloro-N-(4-fluorophenyl)-N-[(2-piperidin-1-yl- HCI
1,3-thiazol-4- I meth I]benzamide
207N-benzyl-N-({2-[cyclopropyl(ethyl)amino]-1,3- HCI 9 11.1 410
thiazol-4- I meth I-4- fluorobenzamide
208N-benzyl-N-({2-[cyclopropyl(ethyl)amino]-1,3- HCI 9 11 02.2
thiazol-4- I meth I-2- phen lacetamide
209N-cyclohexyl-4-fluoro-N-[(2-morpholin-4-y1-1,3- HCI 9 10 04.1
thiazol-4- I meth I]benzamide
210N-benzyl-4-fluoro-N-[(2-morpholin-4-y1-1,3- HCI 9 9.9 411.6
thiazol-4- I meth I]benzamide
2114-chloro-N-[(2-cyclohexyl-1,3-thiazol-4- HCI 10 11.5 428.8
I meth I]-N- 4-fluorophen I benzamide
212N-(4-fluorophenyl)-N-[(2-morpholin-4-y1-1,3- HCI 11 10.5 142.6
thiazol-4- I meth I]-2- nitrobenzamide
N-(4-fluorophenyl)-N-[(2-morpholin-4-y1-1,3-
213thiazol-4-yl)methyl]-3,5- HCI 11 10.7 533.9
bis trifluorometh I benzamide
N-(4-fl uorophenyl)-3,5-d imethoxy-N-[(2-
214morpholin-4-y1-1,3-thiazol-4- HCI 11 9.4 457.9
I meth I]benzamide
tert-butyl 4-(4-{[(4-chlorobenzoyl)(4-
2151uorophenyl)amino]methyl}-1,3-thiazol-2- 12 11 529.8
I piperidine-l-carbox late
4-ch loro-N-cyclohexyl-N-({2-
216[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 9 11.5 417.8
I meth I benzamide
2174-chloro-N-(4-fluorophenyl)-N-[(2-piperidin-4-yl- HCI 12 7.6 430
1,3-thiazol-4- I meth I]benzamide
218N- 4-fluorophen I-N-[ 2-morpholin-4- I-1,3- HCI
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thiazol-4- I meth I]-4- nitrobenzamide
219N-(4-fluorophenyl)-4-methoxy-N-[(2-morpholin- HCI 9.3 428
4- I-1,3-thiazol-4- I meth I]benzamide
220N-(4-fluorophenyl)-3-methoxy-N-[(2-morpholin- HCI 9.3
4- I-1,3-thiazol-4- I meth I]benzamide
N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-
221 yl}methyl)-4-fluoro-N-(4- HCI 10.6 413.9
luorophen I benzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
222thiazol-4-yl}methyl)-N-(4- HCI 11 29.7
luorophen I benzamide
2-ch loro-N-cyclohexyl-N-({2-
223[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 9 11.2 417.8
I meth I benzamide
3-ch loro-N-cyclohexyl-N-({2-
224[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 9 11.4 417.8
I meth I benzamide
225N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]- HCI 9 10.7 413.7
1,3-thiazol-4- I meth I-2- methox benzamide
226N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]- HCI 9 10.9 413.8
1,3-thiazol-4- I meth I-3- methox benzamide
3,5-dichloro-N-cyclohexyl-N-({2-
227[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 9 12 51.7
I meth I benzamide
N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-
2281,3-thiazol-4-yl}methyl)-3,5- HCI 9 11 143.9
dimethoxybenzamide
3-cyano-N-cyclo hexyl-N-({2-
229[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 9 10.7 408.9
I meth I benzamide
230N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]- HCI 9 11.5 433.9
1,3-thiazol-4- I meth I-1- naphthamide
231 4-chloro-N-(4-fluorophenyl)-N-[2-(2-morpholin-4- HCI 13 10 145.7
I-1,3-thiazol-4- I eth I]benzamide
232 4-chloro-N-(4-fluorophenyl)-N-[3-(2-morpholin-4- HCI 13 10.3 59.6
I-1,3-thiazol-4- I prop I]benzamide
4-chloro-N-(3-cyanophenyl)-N-({2-
233[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 10.7 436.6
I meth I benzamide
N-(2-carbamoylphenyl)-4-chloro-N-({2-
234[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 10.2 455
I meth I benzamide
N-(3-carbamoylphenyl)-4-chloro-N-({2-
235[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 9.4 54.6
I meth I benzamide
N-(4-carbamoylphenyl)-4-chloro-N-({2-
236[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 9.4 54.6
I meth I benzamide
N-biphenyl-2-yl-4-chloro-N-({2-
237[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 11.8 487.7
I meth I benzamide
N-biphenyl-4-yl-4-chloro-N-({2-
238[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 11.8 487.7
I meth I benzamide
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2394-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3- HCI 11.4 461.7
thiazol-4- I meth I-N-1- naphthylbenzamide
2404-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3- HCI 10.5 450.7
thiazol-4- I meth I-N-1 H-indol-5- Ibenzamide
N-[4-(benzyloxy)phenyl]-4-chloro-N-({2-
241 [cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 11.7 517.7
I meth I benzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
242thiazol-4-yl}methyl)-N-(4- HCI 10 27.7
h drox phen I benzamide
N-(3-acetamidophenyl)-4-chloro-N-({2-
243[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 9.9 68.7
I meth I benzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
244thiazol-4-yl}methyl)-N-(2,6- HCI 11.4 439.7
dimeth Iphen I benzamide
N-(3-tert-butylphenyl)-4-chloro-N-({2-
245[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 11.8 467.7
I meth I benzamide
4-chloro-N-(3-chloro-2-methoxyphenyl)-N-({2-
246[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 11.4 475.6
I meth I benzamide
4-chloro-N-(5-chloro-2-methylphenyl)-N-({2-
247[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 11.5 459.6
I meth I benzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
248thiazol-4-yl}methyl)-N-(2,3- HCI 11.6 479.6
dichlorophen I benzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
249thiazol-4-yl}methyl)-N-(3,5- HCI 11.9 479.6
dichlorophen I benzamide
tert-butyl 3-[(4-chlorobenzoyl)({2-
250[cyclopropyl(ethyl)amino]-1,3-thiazol-4- 11.6 511.8
I meth I amino]benzoate
tert-butyl 4-[(4-chlorobenzoyl)({2-
251 [cyclopropyl(ethyl)amino]-1,3-thiazol-4- 11.8 511.8
I meth I amino]benzoate
2524-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3- HCI 10.2 412.7
thiazol-4- I meth I-N-p ridin-2- Ibenzamide
2534-chloro-N-({2-[cyclopropyl(ethyl)amino]-113- HCI 9.8 12.7
thiazol-4- I meth I-N-p ridin-3- Ibenzamide
4-chloro-N-(6-chloropyridin-3-yl)-N-({2-
254[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 10.8 446.7
I meth I benzamide
4-chloro-N-(2-chloropyridin-4-yl)-N-({2-
255[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 10.9 446.7
I meth I benzamide
2564-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3- HCI 10.3 462.7
thiazol-4- I meth I-N-quinolin-6- Ibenzamide
2574-chloro-N-({2-[cyclopropyl(ethyl)amino]-113- HCI 10.7 462.7
thiazol-4- I meth I-N-quinolin-3- ylbenzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-
258thiazol-4-yl}methyl)-N-(5- methylisoxazol-3- HCI 10.6 416.7
I benzamide
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3-[(4-chlorobenzoyl)({2-
259[cyclopropyl(ethyl)amino]-1,3-thiazol-4- HCI 10.1 455.9
I meth I amino]benzoic acid
260N-[(6-chloropyridin-3-yl)methyl]-N-cyclopentyl- 14 9 405
3,4,5-trimethoxybenzamide
261 N-[(6-chloropyridin-3-yl)methyl]-N-cyclohexyl- 14 9.4 419
3,4,5-trimethoxybenzamide
N-cyclohexyl-3,4,5-trimethoxy-N-{[6-(4-
262methylpiperazin-1-yl)pyridin-3- HCI 17 7.1 483.3
I]meth I benzamide
N-cyclohexyl-N-({6-[4-(hyd roxymethyl)piperid in-
2631-y1]pyridin-3-yl}methyl)-3,4,5- HCI 17 7.7 498.2
trimethoxybenzamide
2644-chloro-N-[(6-chloropyridin-3-yl)methyl]-N-(4- 7 10 374.9
luorophen I benzamide
265N-[(6-chloropyridin-3-yl)methyl]-3-cyano-N-(4- 7 9 365.9
luorophen I benzamide
266N-(4-fluorophenyl)-N-[(2-morpholin-4-y1-1,3- 11 10.1 448.1
thiazol-4- I meth I]-1-naphthamide
2673-cyano-N-(4-fluorophenyl)-N-{[6- 15 9.3 399.7
trifluorometh I p ridin-3- I]meth I benzamide
2684-chloro-N-(4-fluorophenyl)-N-{[6- 15 10.2 408.7
trifluorometh I p ridin-3- I]meth I benzamide
3-cyano-N-(4-fluorophenyl)-N-({6-[4-(4-
2691uorophenyl)piperazin-1-yl]pyridin-3- 16 10.4 509.9
I meth I benzamide
2703-cyano-N-(4-fluorophenyl)-N-{[6-(4-pyridin-2- HCI 16 8.7 492.9
Ipiperazin-1- I p ridin-3- I]meth I benzamide
3-cyano-N-(4-fluorophenyl)-N-({6-[4-(2-
271 phenylethyl)piperazin-1-yl]pyridin-3- HCI 16 8.2 520
I meth I benzamide
N-(4-fluorophenyl)benzamide N-[(6-{4-[bis(4-
2721uorophenyl)methyl]piperazin-1-yl}pyridin-3- HCI 16 11.4
I meth I]-3-c ano-
2734-chloro-N-{[6-(diphenylamino)pyridin-3- HCI 11.4 508
I]meth I-N- 4-fluorophen I benzamide
274N-[(6-chloropyridin-3-yl)methyl]-3-cyano-N-[3- 8 9.5 415.9
trifluorometh I phen I]benzamide
275N-[(6-chloropyridin-3-yl)methyl]-3-cyano-N-[4- 8 9.7 415.9
trifluorometh I phen I]benzamide
2763-cyano-N-(4-fluorophenyl)-N-{[6-(2,2,2- 18 10 429.9
trifluoroethox p ridin-3- I]meth I benzamide
3-cyano-N-{[6-(4-methylpiperazi n-1-yl )pyrid in-3-
277y1]methyl}-N-[3- HCI 7 7.4 480
trifluorometh I phen I]benzamide
3-cyano-N-{[6-(4-methylpiperazi n-1-yl )pyrid in-3-
278y1]methyl}-N-[4- HCI 7 7.6 480
trifluorometh I phen I]benzamide
4-chloro-N-(4-fluorophenyl)-N-({6-[methyl(2-
279pyridin-2-ylethyl)amino]pyridin-3- HCI
I meth I benzamide
4-chloro-N-(4-fluoro-2-methylphenyl)-N-{[6-(4-
280methylpiperazin-1 -yl)pyridin-3- HCI
I]meth I benzamide
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2-(4-chlorophenoxy)-N-(4-fluorophenyl)-N-{[6-(4-
281 methylpiperazin-1-yl)pyridin-3- TFA 469
I]meth I acetamide
1-(4-chlorophenyl)-N-(4-fluorophenyl)-N-{[6-(4-
282methylpiperazin-1-yl)pyridin-3- HCI 442
I]meth I c clobutanecarboxamide
2-(4-chlorophenyl)-N-(4-fluorophenyl)-N-{[6-(4-
283methylpiperazin-1-yl)pyridin-3- HCI 467
I]meth I propanamide
2-(4-chlorophenyl)-2-methyl-N-{[6-(4-
284methylpiperazin-1-yl)pyridin-3-yl]methyl}- N- TFA 463
phen Ipropanamide
285N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]- HCI 18 11.2 398.1
1,3-thiazol-4- I meth I-2- phen lacetamide
N-(4-fluorophenyl)-2-(3-methoxyphenyl)-N-[(2-
286morpholin-4-y1-1,3-thiazol-4- HCI 9.7 141.9
I meth I]acetamide
N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-
287y1}methyl)-N-(4-fluorophenyl)-2- HCI 10.8 409.9
phenylacetamide
288N-(4-fluorophenyl)-N-[(2-morpholin-4-y1-1,3- HCI 10 10.2 128.1
thiazol-4- I meth I]-4- phenoxybutanamide 9.6 156.2
N-(4-fluorophenyl)-N-[(2-morpholin-4-y1-1,3-
289thiazol-4-yl)methyl]-2- HCI 10 9.6 428.1
phenox acetamide
N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-
290y1}methyl)-N-(4-fluorophenyl)-2- HCI 9.1 111.1
p ridin-3- lacetamide
N-(4-fluorophenyl)-N-{[2-(4-methylpiperazin-1-
291 yl)-1,3-thiazol-4-yl]methyl}-2- HCI 2 r .7 126.1
p ridin-3- lacetamide
TABLE 2B.
Cpd Chemical Name HPLC Observed Ion
No. m/e
Method retention [M+H]
time (min.)
6 4-Chloro-N-cyclopentyl-N-[6-(4-methyl-piperazin-1-yl)- C 2.5 413
p ridin-3- Imeth I]-benzamide
8 N-Cyclopentyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- C 3.4 379
ylmethyl]-benzamide
9 N-Cyclopentyl-3,4,5-trimethoxy-N-{[6-(4- C 3.7 469
meth Ipiperazin-1- I p ridin-3- I]meth I benzamide
18 5-Fluoro-N-(4-fluorophenyl)-2-methoxy-N-[6-(4- C 3.5 453
meth I-piperazin-1- I-p ridin-3- Imeth I]-benzamide
20 4-Chloro-N-(4-fluorophenyl)-2-methoxy-N-[6-(4- C 4.0 469
meth I-piperazin-1- I-p ridin-3- Imeth I]-benzamide
21 N- 4-Fluorophen I-2,5-dimethox -N-[6- 4-meth I- C 3.6 465
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Cpd Chemical Name HPLC Observed Ion
No. m/e
Method retention [M+H]
time (min.)
piperazin-1- I-p ridin-3- Imeth I]-benzamide
22 4-Chloro-N-(4-fluorophenyl)-N-{6-[4-(2-hydroxy-ethyl)- C 3.3 469
piperazin-1- I]-p ridin-3- Imeth I-benzamide
26 4-Chloro-N-(4-fluorophenyl)-N-{6-[(2-hydroxy-ethyl)- C 3.0 414
meth I-amino]-p ridin-3- Imeth I-benzamide
29 N-(4-Fluorophenyl)-N-[6-(4-methyl-piperazin-1-yl)- C 4.0 473
p ridin-3- Imeth I]-4-trifluorometh I-benzamide
32 4-Chloro-N-(4-fluorophenyl)-N-(6-morpholin-4-yl- C 3.0 426
p ridin-3- Imeth I -benzamide
33 4-Chloro-N-{6-[(2-methoxylethyl)-methyl-amino]- C 3.2 428
p ridin-3- Imeth I-N- 4-fluorophen I-benzamide
34 N-(4-Fluorophenyl)-N-[6-(4-methyl-piperazin-1-yl)- C 2.9 484
p ridin-3- Imeth I]-4-sulfamo I-benzamide
35 4-Chloro-N-(4-fluorophenyl)-N-[6-(4-methyl- C 2.4 453
[1,4]diazepan-1- I -p ridin-3- Imeth I]-benzamide
36 4-Chloro-N-(4-fluorophenyl)-N-[6-(4-chlorobenzoyl- C 3.2 508
meth I-amino -p ridin-3- Imeth I]-benzamide
41 4-Chloro-N-(4-fluorophenyl)-N-[6-(4-pyridin-2-yl- C 3.3 502
piperazin-1- I-p ridin-3- Imeth I]-benzamide
44 N-(4-Fluorophenyl)-2-hydroxy-N-[6-(4-methyl- C 3.2 421
piperazin-1- I-p ridin-3- Imeth I]-benzamide
45 4-Chloro-N-(4-fluorophenyl)-N-{6-[4-(2-methoxy-ethyl)- C 3.5 483
piperazin-1- I]-p ridin-3- Imeth I-benzamide
46 4-Chloro-N-[6-(4-dimethylcarbamoylmethyl-piperazin- C 3.3 510
1 - I-p ridin-3- Imeth I]-N- 4-fluorophen I-benzamide
47 4-Chloro-N-{6-[(2-dimethylamino-ethyl)-methyl-amino]- C 2.3 441
p ridin-3- Imeth I-N- 4-fluorophen I-benzamide
48 4-Chloro-N-[6-(1,1-dioxo-1A -thiomorpholin-4-yl)- C 2.9 474
p ridin-3- Imeth I]-N- 4-fluorophen I-benzamide
49 4-Chloro-N-(4-chlorophenyl)-N-[6-(4-methyl-piperazin- C 2.6 455
1 - I-p ridin-3- Imeth I]-benzamide
51 N-(4-chlorophenyl)-4-methyl-N-[6-(4-methyl-piperazin- C 2.6 435
1 - I-p ridin-3- Imeth I]-benzamide
52 N-[6-(4-Acetyl-piperazin-1 -yl)-pyridin-3-ylmethyl]-4- C 3.0 467
chloro-N- 4-fluorophen I -benzamide
53 4-Chloro-N-(4-fluorophenyl)-N-{6-[methyl-(2-pyridin-3- C 3.3 475
I-eth I-amino]-p ridin-3- Imeth I-benzamide
56 4-Chloro-N-{6-[4-(2-dimethylamino-ethyl)-piperazin-1- C 2.4 496
I]-p ridin-3- Imeth I-N- 4-fluorophen I-benzamide
59 4-Chloro-N-(4-fluorophenyl)-N-[6-(4-isopropyl- C 3.8 467
piperazin-1 -I-p ridin-3- Imeth I]-benzamide
60 4-Chloro-N-(4-fluorophenyl)-N-{6-[4-(2-morpholin-4-yl- C 2.4 538
eth I-piperazin-1- I]-p ridin-3- Imeth I-benzamide
65 4-Chloro-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- C 2.5 421
Imeth I]-N-phen I-benzamide
66 4-Chloro-N-(4-fluorophenyl)-N-(6-pyrrolidin-1 -yl- C 3.3 410
p ridin-3- Imeth I -benzamide
68 4-Chloro-N-(4-fluorophenyl)-N-(6-imidazol-1 -yl-pyridin- C 3.1 407
3- Imeth I -benzamide
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Cpd Chemical Name HPLC Observed Ion
No. m/e
Method retention [M+H]
time (min.)
69 4-Chloro-N-(4-fluorophenyl)-N-[6-(3-methylamino- C 3.8 439
p rrolidin-l- I-p ridin-3- Imeth I]-benzamide
71 4-Chloro-N-(6-dimethylamino-pyridin-3-ylmethyl)-N-(4- C 3.2 384
fluorophen I -benzamide
74 4-Chloro-N-(6-cyclopropylamino-pyridin-3-ylmethyl)-N- C 3.1 396
4-fluorophen I -benzamide
75 4-Chloro-N-[6-(cyclopropyl-methyl-amino)-pyridin-3- C 3.3 410
Imeth I]-N- 4-fluorophen I -benzamide
76 4-Chloro-N-(4-fluorophenyl)-N-(2-morpholin-4-yl- C 3.1 432
thiazol-4- Imeth I -benzamide
77 N-(4-Fluorophenyl)-N-(2-morpholin-4-yl-thiazol-4- C 3.0 398
Imeth I -benzamide
78 N-(4-Fluorophenyl)-4-methyl-N-(2-morpholin-4-yl- C 3.0 412
thiazol-4- Imeth I -benzamide
82 3-(4-chlorophenyl)-1-(4-fluorophenyl)-1-[6-(4-methyl- C 4.0 454
piperazin-l- I-p ridin-3- Imeth I]-urea
85 (4-Fluorophenyl)-[6-(4-methyl-piperazin-1-yl)-pyridin- C 4.1 455
3- Imeth I]-carbamic acid 4-chlorophenyl ester
86 N-Cyclopentyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- C 2.5 407
Imeth I]-3-phen I-propionamide
87 N-Cyclopropyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin- C 2.5 385
3- Imeth I]-3-phen I-propionamide
88 N-Cyclopentyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- C 2.4 393
Imeth I]-2-phen I-acetamide
90 3-(2-Chloro-phenyl)-N-(4-fluorophenyl)-N-[6-(4-methyl- C 4.9 465
piperazin-l- I-p ridin-3- Imeth I]-acr lamide
93 2-(4-Chloro-phenoxy)-N-(4-fluorophenyl)-N-[6-(4- C 4.2 469
meth I-piperazin-l- I-p ridin-3- Imeth I]-acetamide
96 2-(4-chlorophenyl)-N-(4-fluorophenyl)-N-[6-(4-methyl- C 2.7 467
piperazin-l- I-p ridin-3- Imeth I]-propionamide
97 N-(4-Fluorophenyl)-N-[6-(4-methyl-piperazin-1-yl)- C 2.6 447
p ridin-3- Imeth I]-3-phen I-but ramide
98 2-(4-chlorophenyl)-N-[6-(4-methyl-piperazin-1-yl)- C 2.7 463
pyridin-3-ylmethyl]-N-phenyl-isobutyramide
EXAMPLE 24: PHARMACOLOGICAL TESTING
Representative compounds of formula (I) are screened for activity against
calcium
channel targets in several standard pharmacological test procedures. Based on
the
activity shown in the standard pharmacological test procedures, the compounds
of
the present teachings can be useful as ion channel modulators.
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Oocyte Assay
This assay was essentially performed as described in Lin et al. (1997), Neuron
18(11): 153-166; Pan J. and Lipsombe D. (2000), J. Neurosci.,20(13): 4768-75;
and
Xu W. and Lipscombe D. (2001), J. Neurosci., 21(16): 5944-5951, the entire
disclosures of which are herein incorporated by reference, using Xenopus
oocyte
heterologeous expression system. The assay was performed on various calcium
channels (e.g., Cav2.2 subfamily) whereby the modulation of the calcium
channel
was measured for each tested compound. For measuring compound potency on
Cav2.2, a train of five depolarizing pulses of 20-30 ms to about +10 mV was
applied
at a frequency of 5 Hz from a holding potential of -100 mV every 30 seconds.
The
50% inhibitory concentration (IC50) of the test compounds was calculated by
measuring the current obtained at the fifth pulse (P5).
HEK Assay
HEK-293T/17 cells were transiently transfected in a similar manner as
described in
FuGENE 6 Package Insert Version 7, April 2002, Roche Applied Science,
Indianapolis, IN. The cells were plated at 2.5 x 105 cells in 2 mL in a 6-well
plate,
incubated for one night, and achieved a -30-40% confluence. In a small sterile
tube,
sufficient serum-free medium was added as diluent for FuGENE Transfection
Reagent (Roche Applied Science, Indianapolis, IN) to a total volume of 100 pL.
To
this medium was added 3 pL of FuGENE 6 Reagent. The mixture was tapped gently
to mix. To the prediluted FuGENE 6 Reagent was added 2 pg of DNA solution (0.8-
2.0 pg/pL). The DNA/Fugene 6 mixture was gently pipeted to mix the contents
and
incubated for about 15 minutes at room temperature. The complex mixture was
then
added to the HEK-293T/17 cells, distributed around the well, and swirled to
ensure
even dispersal. The cells were returned to the incubator for 24 hours. The
transfected cells were then replated at density 2.5 x 105 in a 35 mm dish with
5 glass
coverslips and grew in low serum (1%) media for 24 hours. Coverslips with
isolated
cells were then transferred into a chamber, and calcium channel (e.g., L-type,
N-type,
etc.) current or other currents for counter screening were recorded from the
transiently transfected HEK-293T/17 cells.
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The whole-cell voltage clamp configuration of the patch clamp technique was
employed to evaluate voltage-dependent calcium currents essentially as
described
by Thompson and Wong (1991), J. Physiol., 439: 671-689, the entire disclosure
of
which is herein incorporated by reference. To record calcium channel (e.g., L-
type,
N-type, etc.) currents for evaluation of inhibitory potency of compounds
(steady-state
concentration-response analysis), five pulses of 20-30 ms voltage steps to
about +10
mV (the peak of the current voltage relationship) were delivered at five Hz
every 30
second from a holding potential at -100mV. In order to obtain an estimate of
the
degree of use-dependent block of the test compounds, IC50 values were
determined
at the first and fifth pulse of the train (P, and P5, respectively, in Table
2). Compound
evaluations were carried out essentially as described by Sah D.W. and Bean
B.P.
(1994), Mol. Pharmacol., 45:84-92, the entire disclosure of which is herein
incorporated by reference.
FLIPR Assay
TSA201 cells stably transfected with human Cav2.2 (composed of the subunits
al,
03 and a26) and human Kir2.3 to enhance the FLIPR Ca2+ signal were used. These
cells were plated on 384-well collagen-coated plates (BD Bioscience, Franklin
Lakes,
NJ) at a density of 2x104 cells/well one day prior to the FLIPR assay. For
each assay
plate, FLUO-4 dye (Invitrogen, Carlsbad, CA) was diluted in 12 mL of
Dulbecco's
Modified Eagle's Medium (Invitrogen, Carlsbad, CA) to a final concentration of
4 M in
the presence of Pluronic F-127 (Invitrogen, Carlsbad, CA). Culture media is
removed
and replaced with 25 l of the FLUO-4 dye solution and incubated for one hour
at
room temperature. The cell plate is then placed on the FLIPR where the dye is
aspirated off and replaced with 25 l of HBSS (Invitrogen, Carlsbad, CA). The
HBSS
is then aspirated and replaced with 25 l of compound which is diluted in HBSS
with
1% DMSO. Compounds are incubated on the cells for 15 minutes. The cells are
then depolarized with 25 l of 140mM KCI solution (also containing 2mM CaCl2
and
10mM HEPES). The final concentration of KCI on the cells is 70mM.
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The results for selected compounds are summarized in Tables 3 and 4 below.
Data
presented represent the average value when one or more samples were tested.
TABLE 3
Cp Oocyte HEK HEK
d Cav2.2 P5 Cav2.2 P, Cav2.2 P5
IC50 PM IC50 PM ICSO I~M
4-Chloro-N-(4-fluorophenyl)-N-[6-(4-methyl-
1 piperazin-1-yl)-pyridin-3-ylmethyll-benzamide 12.6 4.0 0.80
4-Chloro-N-(6-diethylamino-pyridin-3-ylmethyl)-
2 N- 4-fluorophen I-benzamide 10.4 2.9 1.1
4-Chloro-N-(4-fluorophenyl)-N-(2-pyrrolidin-1-yl-
3 thiazol-5- Imeth I-benzamide 4.3 3.4
5-Fluoro-N-(4-fluorophenyl)-2-methyl-N-[6-(4-
methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
benzamide 15.5 22.3 3.7
4-Chloro-N-(4-fluorophenyl)-N-{6-[methyl-(2-
pyridin-2-yl-ethyl)-amino]-pyridin-3-ylmethyl}-
11 benzamide 7.5 3.2 0.7
N-(4-Fluorophenyl )-2-methoxy-N-[6-(4-methyl-
12 piperazin-1-yl)-pyridin-3-ylmethyll-benzamide 51.1
N-(4-Fluorophenyl)-N-[6-(4-methyl-piperazin-l-
13 I-p ridin-3- Imeth I]-benzamide 19.1 40.9 8.3
N-(4-Fluorophenyl )-3-methoxy-N-[6-(4-methyl-
14 i erazin-1- I- ridin-3- Imeth I-benzamide 42.2
N-(4-Fluorophenyl)-2-methyl-N-[6-(4-methyl-
piperazin-1- I-p ridin-3- Imeth I]-benzamide 25.6
2-Fluoro-N-(4-fluorophenyl)-N-[6-(4-methyl-
16 piperazin-1- I-p ridin-3- Imeth I]-benzamide 13.6 20.3 6.6
N-(4-Fluorophenyl)-4-methyl-N-[6-(4-methyl-
17 i erazin-1- I- ridin-3- Imeth I-benzamide 23.1 17.0 2.0
5-Fluoro-N-(4-fluorophenyl)-2-methoxy-N-[6-(4-
methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
18 benzamide 19.4
N-(4-Fluorophenyl)-2,4-dimethyl-N-[6-(4-methyl-
19 piperazin-1- I-p ridin-3- Imeth I]-benzamide 8.3 8.1 2.5
4-Ch loro-N-(4-fl uorophenyl )-2-methoxy-N-[6-(4-
methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
benzamide 19.7 5.6 2.0
N-(4-Fluorophenyl)-2,5-dimethoxy-N-[6-(4-
methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
21 benzamide 75.1
4-Ch loro-N-(4-fl uorophenyl )-N-{6-[4-(2-hyd roxy-
ethyl)-piperazin-1-yl]-pyridin-3-ylmethyl}-
22 benzamide 41.2 5.9 2.4
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N-(4-Fluorophenyl )-4-methoxy-N-[6-(4-methyl-
23 piperazin-1- I-p ridin-3- Imeth I]-benzamide 47.0
N-(4-Fluorophenyl)-3-methyl-N-[6-(4-methyl-
24 i erazin-1- I- ridin-3- Imeth I-benzamide 18.0 22.2 5.3
3-Chloro-N-(4-fluorophenyl)-N-[6-(4-methyl-
25 piperazin-1- I-p ridin-3- Imeth I]-benzamide 11.0 11.8 3.2
4-Ch loro-N-(4-fl uorophenyl )-N-{6-[(2-hyd roxy-
ethyl)-methyl-amino]-pyridin-3-ylmethyl}-
26 benzamide 26.2 16.1 3.3
4-Chloro-N-(4-fluoro-2-methylphenyl)-N-[6-(4-
methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
27 benzamide 20.9 3.7 0.8
4-Chloro-N-(4-fluorophenyl)-N-{6-[methyl-(2-
morpholin-4-yl-ethyl)-amino]-pyridin-3-ylmethyl}-
28 benzamide 13.7 6.2 1.8
N-(4-Fluorophenyl)-N-[6-(4-methyl-piperazin-l-
yl)-pyridin-3-ylmethyl]-4-trifluoromethyl-
29 benzamide 24.2 6.6 1.5
4-Cyano-N-(4-fluorophenyl)-N-[6-(4-methyl-
30 piperazin-1-yl)-pyridin-3-ylmethyll-benzamide 32.7
4-Acetylamino-N-(4-fluorophenyl)-N-[6-(4-
methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
31 benzamide 145.0
4-Chloro-N-(4-fluorophenyl)-N-(6-morpholin-4-
32 I- ridin-3- Imeth I-benzamide 20.8 14.9 3.0
4-Chloro-N-{6-[(2-methoxylethyl)-methyl-amino]-
pyridin-3-ylmethyl}-N-(4-fluorophenyl)-
33 benzamide 4.4 10.7 1.9
N-(4-Fluorophenyl)-N-[6-(4-methyl-piperazin-l-
34 I-p ridin-3- Imeth I]-4-sulfamo I-benzamide 50.8
4-Chloro-N-(4-fluorophenyl)-N-[6-(4-methyl-
[1,4]diazepan-1-yl)-pyridin-3-ylmethyl]-
35 benzamide 21.9 3.4 1.3
4-Chloro-N-(4-fluorophenyl)-N-[6-(4-
chlorobenzoyl-methyl-amino)-pyridin-3-
36 ylmethyll-benzamide 4.2 2.4 0.7
4-Chloro-N-[6-(4-methyl-piperazin-1-yl)-pyridin-
37 3- Imeth I]-N-m-tol I-benzamide 12.3 7.5 1.6
4-Chloro-N-[6-(4-methyl-piperazin-1-yl)-pyridin-
38 3- Imeth I-N-o-tol I-benzamide 33.7
4-Chloro-N-(3,5-dimethylphenyl)-N-[6-(4-methyl-
39 piperazin-1- I-p ridin-3- Imeth I]-benzamide 18.9 5.1 1.1
4-Chloro-N-(2-isopropyl-phenyl)-N-[6-(4-methyl-
40 piperazin-1- I-p ridin-3- Imeth I]-benzamide 23.1 1.9 0.4
41 4-Chloro-N- 4-fluorophen I-N-[6- 4-p ridin-2- I- 2.3 0.3 0.1
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IC50 M IC50 M ICSO M
piperazin-1- I-p ridin-3- Imeth I]-benzamide
4-Chloro-N-(4-fluorophenyl)-N-(6-piperazin-l-yl-
42 ridin-3- Imeth I-benzamide 9.2 1.8 1.2
4-Chloro-N-(4-fluorophenyl)-N-(6-thiomorpholin-
43 4- I-p ridin-3- Imeth I-benzamide 15.3 2.6 0.6
4-Ch loro-N-(4-fl uorophenyl )-N-{6-[4-(2-m ethoxy-
ethyl)-piperazin-1-yl]-pyridin-3-ylmethyl}-
45 benzamide 15.5 1.6 1.0
4-Chloro-N-[6-(4-dimethylcarbamoylmethyl-
piperazin-1-yl)-pyridin-3-ylmethyl]-N-(4-
46 fluoro hen I-benzamide 24.6 9.8 3.4
4-Chloro-N-[6-(1,1-dioxo-1 /\6-thiomorpholin-4-
yl)-pyridin-3-ylmethyl]-N-(4-fluorophenyl)-
48 benzamide 14.8 12.4 3.4
4-Chloro-N-(4-chlorophenyl)-N-[6-(4-methyl-
49 piperazin-1 -I-p ridin-3- Imeth I]-benzamide 15.8 3.3 0.9
4-Chloro-N-[6-(4-methyl-piperazin-1-yl)-pyridin-
50 3- Imeth I-N- -tol I-benzamide 17.7 7.9 1.5
N-(4-chlorophenyl)-4-methyl-N-[6-(4-methyl-
51 piperazin-1 -I-p ridin-3- Imeth I]-benzamide 30.8 13.3 2.2
N-[6-(4-Acetyl-piperazin-1-yl)-pyridin-3-
ylmethyl]-4-chloro-N-(4-fluorophenyl)-
52 benzamide 13.6 13.2 2.3
4-Chloro-N-(4-fluorophenyl)-N-{6-[methyl-(2-
pyridin-3-yl-ethyl)-amino]-pyridin-3-ylmethyl}-
53 benzamide 5.7 1.7 0.4
4-Chloro-N-(3-isopropyl-phenyl)-N-[6-(4-methyl-
54 piperazin-1 -I-p ridin-3- Imeth I]-benzamide 5.3 1.4 0.4
4-Chloro-N-(2,6-dimethylphenyl)-N-[6-(4-methyl-
55 piperazin-1 - I- ridin-3- Imeth I-benzamide 46.8
4-Chloro-N-{6-[4-(2-dimethylamino-ethyl)-
piperazin-1-yl]-pyridin-3-ylmethyl}-N-(4-
56 fluorophen I -benzamide 34.0
5'-{[(4-Chloro-benzoyl)-(4-fluorophenyl)-amino]-
m ethyl}-3, 4, 5, 6-tetra h yd ro-2 H-[ 1, 2'] bi pyri d i nyl-4-
57 carboxylic acid amide 19.0 29.3 6.7
4-(5-{[(4-Ch loro-benzoyl)-(4-fluorophenyl)-
amino]-methyl}-pyridin-2-yl)-piperazine-1-
58 carboxylic acid ethylamide 12.0 3.9 1.9
4-Chloro-N-(4-fluorophenyl)-N-[6-(4-isopropyl-
59 piperazin-1 -I-p ridin-3- Imeth I]-benzamide 11.3 4.4 1.1
4-Chloro-N-(4-fluorophenyl)-N-{6-[4-(2-
morpholin-4-yl-ethyl)-piperazin-l-yl]-pyridin-3-
60 Imeth I -benzamide 30.8
61 N- 6-Piperazin-l- I-p ridin-3- Imeth I-N-p-tol I- 49.3
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IC50 M IC50 M ICSO M
benzamide
N-[6-(4-Methanesulfonyl-piperazin-1-yl)-pyridin-
62 3- Imeth I-N- -tol I-benzamide 24.5 24.8 4.6
N-[6-(4-Acetyl-piperazin-1 -yl)-pyridin-3-
64 Imeth I]-N-p-tol I-benzamide 77.7 10.3
4-Chloro-N-[6-(4-methyl-piperazin-1-yl)-pyridin-
65 3- Imeth I-N- hen I-benzamide 7.1 1.3
4-Chloro-N-(4-fluorophenyl)-N-(6-pyrrolidin-1 -yl-
66 p ridin-3- Imeth I-benzamide 2.0 1.3
4-Chloro-N-(4-fluorophenyl)-N-[6-(4-
methanesulfonyl-piperazin-1-yl)-pyridin-3-
67 ylmethyl]-benzamide 5.6 1.9
4-Chloro-N-(4-fluorophenyl)-N-(6-imidazol-1 -yl-
68 ridin-3- Imeth I -benzamide
4-Chloro-N-(4-fluorophenyl)-N-[6-(3-
methylamino-pyrrolidin-1 -yl)-pyridin-3-ylmethyl]-
69 benzamide 2.1 1.3
4-Chloro-N-(4-fluorophenyl)-N-(2-methyl-thiazol-
72 4- Imeth I-benzamide 18.2 6.4
4-Chloro-N-(4-fluorophenyl)-N-(6-methylamino-
73 p ridin-3- Imeth I-benzamide 4.1 1.4
4-Ch loro-N-(6-cyclopropylam i no-pyrid i n-3-
74 Imeth I-N- 4-fluoro hen I-benzamide 3.1 1.9
4-Chloro-N-[6-(cyclopropyl-methyl-amino)-
pyridin-3-ylmethyl]-N-(4-fluorophenyl)-
75 benzamide 1.2 0.4
4-Chloro-N-(4-fluorophenyl)-N-(2-morpholin-4-
76 I-thiazol-4- Imeth I-benzamide 3.3 1.8
4-Chloro-N-(4-fluorophenyl)-N-[2-(4-methyl-
79 piperazin-l -I-thiazol-5- Imeth I]-benzamide 10.1 3.2
4-Chloro-N-(4-fluorophenyl)-N-(2-pyridin-4-yl-
80 thiazol-4- Imeth I-benzamide 14.9 2.6
94 2-(4-chlorophenyl)-N-(4-fluorophenyl)-N-[6-(4- 17.2 1.9 0.6
methyl-piperazin-1 -yl)-pyridin-3-ylmethyl]-
isobut ramide
95 1-(4-chlorophenyl)-cyclobutanecarboxylic acid 32.8 0.5 0.2
(4-fluorophenyl)-[6-(4-methyl-piperazin-1-yl)-
p ridin-3- Imeth I]-amide
96 2-(4-chlorophenyl)-N-(4-fluorophenyl)-N-[6-(4- 13.4 2.5 1.0
methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-
propionamide
97 N-(4-Fluorophenyl)-N-[6-(4-methyl-piperazin-1- 4.8 0.9
I- ridin-3- Imeth I-3- hen I-but ramide
98 2-(4-chlorophenyl)-N-[6-(4-methyl-piperazin-1- 1.5 0.5
I-p ridin-3- Imeth I]-N-phen I-isobut ramide
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99 1-(4-Methoxy-phenyl)-cyclopentanecarboxylic
acid (4-fluorophenyl)-[6-(4-methyl-piperazin-l-
I-p ridin-3- Imeth I]-amide 15.4 3.8 1.4
TABLE 4
FLIPR
Ca,2.2 I C50
Chemical Name M
100 N- [6- dieth lamino p ridin-3- I]meth I-N- 4-fluorophen I benzamide 5.3
N-{[6-(diethylamino)pyridin-3-yl]methyl}-2-fluoro-N-(4- 3.7
101 luorophen I benzamide
N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-fluorophenyl)-2- 1 9
102 methoxybenzamide
N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-fluorophenyl)-2- 3.8
103 methylbenzamide
N-{[6-(diethylamino)pyridin-3-yl]methyl}-3-fluoro-N-(4- 4.2
104 luorophen I benzamide
N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-fluorophenyl)-3- 3.2
105 methoxybenzamide
N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-fluorophenyl)-3- 5.1
106 methylbenzamide
N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-fluorophenyl)-4- 14.8
107 methoxybenzamide
4-tert-butyl-N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4- 10.7
108 luorophen I benzamide
N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-fluorophenyl)-4- 2.3
109 methylbenzamide
4-cyano-N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4- 3.4
110 luorophen I benzamide
111 N- 6- dieth lamino ridin-3- I meth I-N- 4-fluoro hen I-2-na hthamide 10.2
N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4-fluorophenyl)-9-oxo-9H- 8.3
112 luorene-4- carboxamide
luorophenyl)carbamoyl]benzoate methyl 4-[{[6-(diethylamino)pyridin-3- 11.4
113 I meth I 4-
N-(2-isopropylphenyl)-N-[(2-piperidin-1-y1-1,3-thiazol-4- 8.3
114 I meth I]benzamide
2-fluoro-N-(2-isopropylphenyl)-N-[(2-piperidin-1 -yl-1,3-thiazol-4- 11.6
115 yl)methyllbenzamide
N-(2-isopropylphenyl)-2-methoxy-N-[(2-piperidin-1-y1-1,3-thiazol-4- 8.9
116 I meth I]benzamide
N-(2-isopropylphenyl)-2-methyl-N-[(2-piperidin-1 -yl-1,3-thiazol-4- 10.4
117 I meth I benzamide
3-fluoro-N-(2-isopropylphenyl)-N-[(2-piperidin-1 -yl-1,3-thiazol-4- 5.8
118 yl)methyl]benzamide
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N-(2-isopropylphenyl)-3-methyl-N-[(2-piperidin-1-y1-1,3-thiazol-4- 8.7
119 I meth I]benzamide
4-chloro-N-(2-isopropylphenyl)-N-[(2-piperidin-1-y1-1,3-thiazol-4- 14.2
120 I meth I]benzamide
N-(2-isopropylphenyl)-4-methoxy-N-[(2-piperidin-1-y1-1,3-thiazol-4- 9.2
121 I meth I]benzamide
122 N- 4-meth I hen I-N- 2- rrolidin-1- I-1,3-thiazol-5- I meth I benzamide
13.7
2-fluoro-N-(4-methylphenyl)-N-[(2-pyrrolidin-1-y1-1,3-thiazol-5- 13.3
123 yl)methyl]benzamide
2-methoxy-N-(4-methylphenyl)-N-[(2-pyrrolidin-1-y1-1,3-thiazol-5- 6.1
124 I meth I]benzamide
2-methyl-N-(4-methylphenyl)-N-[(2-pyrrolidin-1 -yl-1,3-thiazol-5- 8.8
125 yl)methyl]benzamide
3-fluoro-N-(4-methylphenyl)-N-[(2-pyrrolidin-1 -yl-1,3-thiazol-5- 8.7
126 I meth I]benzamide
3-methoxy-N-(4-methylphenyl)-N-[(2-pyrrolidin-1 -yl-1,3-thiazol-5- 9.2
127 I meth I]benzamide
3-methyl-N-(4-methylphenyl)-N-[(2-pyrrolidin-1 -yl-1,3-thiazol-5- 12.6
128 yl)methyl]benzamide
4-fluoro-N-(4-methylphenyl)-N-[(2-pyrrolidin-1 -yl-1,3-thiazol-5- 5.2
129 I meth I]benzamide
4-chloro-N-(4-methylphenyl)-N-[(2-pyrrolidin-1 -yl-1,3-thiazol-5- 11.6
130 yl)methyl]benzamide
4-methoxy-N-(4-methylphenyl)-N-[(2-pyrrolidin-1 -yl-1,3-thiazol-5- 11.6
131 yl)methyl]benzamide
N-(4-methylphenyl)-N-[(2-pyrrolidin-1 -yl-1,3-thiazol-5-yl)methyl]biphenyl-4-
41.8
132 carboxamide
4-tert-butyl-N-(4-methylphenyl)-N-[(2-pyrrolidin-1 -yl-1,3-thiazol-5- 12.3
133 I meth I]benzamide
4-methyl-N-(4-methylphenyl)-N-[(2-pyrrolidin-1 -yl-1,3-thiazol-5- 9.2
134 yl)methyl]benzamide
4-cyano-N-(4-methylphenyl)-N-[(2-pyrrolidin-1 -yl-1,3-thiazol-5- 6
135 I meth I]benzamide
N-(4-fluoro-2-methylphenyl)-N-[(2-piperidin-1 -ylpyrimidin-5- 5.9
136 I meth I]benzamide
2-fluoro-N-(4-fluoro-2-methylphenyl)-N-[(2-piperidin-1 -ylpyrimidin-5- 7.5
137 yl)methyl]benzamide
N-(4-fluoro-2-methylphenyl)-2-methyl-N-[(2-piperidin-1 -ylpyrimidin-5- 8.7
138 I meth I]benzamide
3-fluoro-N-(4-fluoro-2-methylphenyl)-N-[(2-piperidin-1 -ylpyrimidin-5- 6.7
139 I meth I]benzamide
N-(4-fluoro-2-methylphenyl)-3-methoxy-N-[(2-piperidin-1 -ylpyrimidin-5- 6.1
140 yl)methyl]benzamide
4-fluoro-N-(4-fluoro-2-methylphenyl)-N-[(2-piperidin-1 -ylpyrimidin-5- 6.3
141 I meth I]benzamide
4-chloro-N-(4-fluoro-2-methylphenyl)-N-[(2-piperidin-1 -ylpyrimidin-5- 10.5
142 I meth I]benzamide
N-(4-fluoro-2-methylphenyl)-4-methoxy-N-[(2-piperidin-1 -ylpyrimidin-5- 8.1
143 I meth I]benzamide
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4-tert-butyl-N-(4-fluoro-2-methylphenyl)-N-[(2-piperidin-1-ylpyrimidin-5- 10.2
144 I meth I]benzamide
N-(4-fluoro-2-methylphenyl)-4-methyl-N-[(2-piperidin-1-ylpyrimidin-5- 10.3
145 I meth I]benzamide
4-cyano-N-(4-fluoro-2-methylphenyl)-N-[(2-piperidin-1-ylpyrimidin-5- 7.4
146 I meth I]benzamide
N-(4-fluoro-2-methylphenyl)-N-[(2-piperidin-1 -ylpyrimidin-5-yl)methyl]-2- 23
2
147 naphthamide
N-(4-fluoro-2-methylphenyl)-9-oxo-N-[(2-piperidin-1 -ylpyrimidin-5- 9.5
148 I meth I-9H- fluorene-4-carboxamide
methyl 4-{(4-fluoro-2-methylphenyl)[(2-piperidin-1-ylpyrimidin-5- 5.4
149 I meth I]carbamo I benzoate
N-(2-isopropylphenyl)-3-methoxy-N-[(2-piperidin-1-yl-1,3-thiazol-4- 7.4
150 yl)methyllbenzamide
4-fluoro-N-(2-isopropylphenyl)-N-[(2-piperidin-l-yl-1,3-thiazol-4- 8.6
151 I meth I]benzamide
N-(2-isopropylphenyl)-N-[(2-piperidin-1 -yl-1,3-thiazol-4-yl)methyl]biphenyl-
27.1
152 4- carboxamide
4-tert-butyl-N-(2-isopropylphenyl)-N-[(2-piperidin-1-yl-1,3-thiazol-4- 29
153 yl)methyl]benzamide
N-(2-isopropylphenyl)-4-methyl-N-[(2-piperidin-l-yl-1,3-thiazol-4- 11.2
154 I meth I benzamide
4-cyano-N-(2-isopropylphenyl)-N-[(2-piperidin-1 -yl-1,3-thiazol-4- 10.9
155 I meth I]benzamide
N-(2-isopropylphenyl)-N-[(2-piperidin-1 -yl-1,3-thiazol-4-yl)methyl]-2- 27.3
156 naphthamide
N-(2-isopropylphenyl)-9-oxo-N-[(2-piperidin-1 -yl-1,3-thiazol-4-yl)methyl]-
29.9
157 9H- fluorene-4-carboxamide
3-cyano-N-(2-isopropylphenyl)-N-[(2-piperidin-1 -yl-1,3-thiazol-4- 10
158 I meth I benzamide
methyl 4-{(2-isopropylphenyl)[(2-piperidin-1-yl-1,3-thiazol-4- 20.9
159 yl)methyl]carbamoyllbenzoate
N-(4-methylphenyl)-N-[(2-pyrrolidin-l-yl-l,3-thiazol-5-yl)methyl]-2- 23.8
160 naphthamide
4-chloro-N-(4-fluorophenyl)-N-{[6-(4-methylpiperazin-l-yl)pyridin-3- 4.2
185 I]meth I benzamide
N-cyclopentyl-3,4,5-trimethoxy-N-{[6-(4-methylpiperazin-l-yl)pyridin-3- 48.5
186 I meth I benzamide
5-fluoro-N-(4-fluorophenyl)-2-methyl-N-{[6-(4-methylpiperazin-l-yl)pyridin- 22
6
187 3- I]meth I benzamide
N'-(4-chlorophenyl)-N-(4-fluorophenyl)-N-{[6-(4-methylpiperazin-1- 6.7
188 yl)pyridin-3- I meth I urea
N-(4-fluorophenyl)-4-methyl-N-{[6-(4-methylpiperazin-l-yl)pyridin-3- 8.4
189 I]meth I benzamide
4-chloro-N-(4-fluorophenyl)-2-methoxy-N-{[6-(4-methylpiperazin-1- 8.9
190 I ridin-3- I meth I benzamide
N-(4-fluorophenyl)-4-methoxy-N-{[6-(4-methylpiperazin-1 -yl)pyridin-3- 10.3
191 I]meth I benzamide
192 N- 4-fluorophen I-3-meth I-N- [6- 4-meth Ipiperazin-1- I p ridin-3- 4.6
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I]meth I benzamide
4-(acetylamino)-N-(4-fluorophenyl)-N-{[6-(4-methylpiperazin-1-yl)pyridin-3-
7.9
193 I meth I benzamide
4-chloro-N-(4-fluorophenyl)-N-{[6-(4-methyl-1,4-diazepan-1-yl)pyridin-3- 3.85
194 I]meth I benzamide
4-chloro-N-{[6-(diethylamino)pyridin-3-yl]methyl}-N-(4- 15.6
195 luoro hen I benzamide
4-chloro-N-({6-[[2-(dimethylamino)ethyl](methyl)amino]pyridin-3-yl}methyl)-
11.9
196 N- 4- fluorophen I benzamide
4-chloro-N-{[6-(1,1-dioxidothiomorpholin-4-yl)pyridin-3-yl]methyl}-N-(4- 2
197 luorophen I benzamide
4-chloro-N-(2,6-dimethylphenyl)-N-{[6-(4-methylpiperazin-1-yl)pyridin-3- 15
198 yl]methyllbenzamide
4-(5-{[(4-chlorobenzoyl)(4-fluorophenyl)amino]methyl}pyridin-2-yl)-N- 6.6
199 eth Ipiperazine-1-carboxamide
4-chloro-N-(4-fluorophenyl)-N-({6-[4-(2-morpholin-4-ylethyl)piperazin-1- 11.8
200 I]p ridin-3- I meth I benzamide
201 N- 4-meth Iphen I-N-[ 6-piperazin-1- Ip ridin-3- I meth I]benzamide 11.3
(4-fluorophenyl)benzamide N-({6-[4-(1 H-benzimidazol-2-yl)piperidin-1- 2.2
202 yl]pyridin-3-yllmethyl)-4-chloro-N-
4-chloro-N-(4-fluorophenyl)-N-[(6-pyrrolidin-1 -ylpyridin-3- 4.1
203 I meth I]benzamide
4-chloro-N-(4-fluorophenyl)-N-({6-[4-(methylsulfonyl)piperazin-1-yl]pyridin-
9.6
204 3- I meth I benzamide
4-chloro-N-(4-fluorophenyl)-N-({6-[3-(methylamino)pyrrolidin-l-yl]pyridin-3-
6.4
205 I meth I benzamide
4-chloro-N-(4-fluorophenyl)-N-[(2-piperidin-1-yl-1,3-thiazol-4- 16.2
206 I meth I]benzamide
N-benzyl-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-4- 4
207 luorobenzamide
N-benzyl-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-2- 6.1
208 phenylacetamide
N-cyclohexyl-4-fluoro-N-[(2-morpholin-4-y1-1,3-thiazol-4- 13.8
209 I meth I benzamide
210 N-benz I-4-fluoro-N-[ 2-morpholin-4- I-1,3-thiazol-4- I meth I]benzamide
7.9
4-chloro-N-[(2-cyclohexyl-1,3-thiazol-4-yl)methyl]-N-(4- 6.3
211 luorophen I benzamide
N-(4-fluorophenyl)-N-[(2-morpholin-4-y1-1,3-thiazol-4-yI)methyl]-2- 7.6
212 nitrobenzamide
N-(4-fluorophenyl)-N-[(2-morpholin-4-y1-1,3-thiazol-4-yl)methyl]-3,5- 6.2
213 bis trifluorometh I benzamide
N-(4-fluorophenyl)-3,5-dimethoxy-N-[(2-morpholin-4-y1-1,3-thiazol-4- 5.5
214 yl)methyl]benzamide
tert-butyl 4-(4-{[(4-chlorobenzoyl)(4-fluorophenyl)amino]methyl}-1,3- 6.8
215 thiazol-2- I piperidine-1-carbox late
4-chloro-N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4- 7.5
216 I meth I benzamide
4-chloro-N-(4-fluorophenyl)-N-[(2-piperidin-4-y1-1,3-thiazol-4- 3.5
217 yl)methyl]benzamide
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N-(4-fluorophenyl)-N-[(2-morpholin-4-y1-1,3-thiazol-4-yl)methyl]-4- 3.4
218 nitrobenzamide
N-(4-fluorophenyl)-4-methoxy-N-[(2-morpholin-4-y1-1,3-thiazol-4- 6.3
219 I meth I]benzamide
N-(4-fluorophenyl)-3-methoxy-N-[(2-morpholin-4-y1-1,3-thiazol-4- 4.9
220 I meth I]benzamide
N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-4-fluoro-N-(4- 5.1
221 luorophen I benzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-N-(4- 4
222 luoro hen I benzamide
2-chloro-N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4- 4.6
223 I meth I benzamide
3-chloro-N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4- 5.9
224 I meth I benzamide
N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-2- 3.1
225 methoxybenzamide
N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-3- 3.4
226 methoxybenzamide
3,5-dichloro-N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4- 11.3
227 I meth I benzamide
N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-3,5- 4.1
228 dimethoxybenzamide
3-cyano-N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4- 1 7
229 I meth I benzamide
4-chloro-N-(4-fluorophenyl)-N-[2-(2-morpholin-4-y1-1,3-thiazol-4- 1.6
231 yl)ethyllbenzamide
4-chloro-N-(4-fluorophenyl)-N-[3-(2-morpholin-4-y1-1,3-thiazol-4- 3.8
232 yl)propyl]benzamide
4-chloro-N-(3-cyanophenyl)-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4- 7.4
233 I meth I benzamide
N-(2-carbamoylphenyl)-4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3- 11
234 thiazol-4- I meth I benzamide
N-(3-carbamoylphenyl)-4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3- 5.6
235 thiazol-4- I meth I benzamide
N-(4-carbamoylphenyl)-4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3- 6.3
236 thiazol-4- I meth I benzamide
N-biphenyl-2-yl-4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4- 17
237 I meth I benzamide
N-biphenyl-4-yl-4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4- 73
238 I meth I benzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-N-1- 16.7
239 na hth Ibenzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-N-1 H- 7.2
240 indol-5- ylbenzamide
N-[4-(benzyloxy)phenyl]-4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3- 17.9
241 thiazol-4- I meth I benzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-N-(4- 4.4
242 h drox phen I benzamide
243 N- 3-acetamidophen I-4-chloro-N- 2-[c cloprop l eth I amino]-1,3- 5.2
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thiazol-4- I meth I benzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-N-(2,6- 5.2
244 dimeth I hen I benzamide
N-(3-tert-butylphenyl)-4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol- 3
245 4- I meth I benzamide
4-chloro-N-(3-chloro-2-methoxyphenyl)-N-({2-[cyclopropyl(ethyl)amino]- 4.3
246 1,3- thiazol-4- I meth I benzamide
4-chloro-N-(5-chloro-2-methylphenyl)-N-({2-[cyclopropyl(ethyl)amino]-1,3- 6.7
247 thiazol-4- I meth I benzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-N-(2,3- 9.1
248 dichlorophen I benzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-N-(3,5- 20.8
249 dichlorophen I benzamide
tert-butyl 3-[(4-chlorobenzoyl)({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4- 22
3
250 I meth I amino]benzoate
tert-butyl 4-[(4-chlorobenzoyl)({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-
34.2
251 I meth I amino]benzoate
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-N-pyridin-
3.5
252 2- ylbenzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-N-pyridin- 1
9
253 3- ylbenzamide
4-chloro-N-(6-chloropyridin-3-yl)-N-({2-[cyclopropyl(ethyl)amino]-1,3- 6.3
254 thiazol-4- I meth I benzamide
4-chloro-N-(2-chloropyridin-4-yl)-N-({2-[cyclopropyl(ethyl)amino]-1,3- 6.8
255 thiazol-4- I meth I benzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-N- 5.1
256 quinolin-6- ylbenzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-N- 10.3
257 quinolin-3- ylbenzamide
4-chloro-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-N-(5- 6.3
258 meth lisoxazol-3- I benzamide
3-[(4-chlorobenzoyl)({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4- 64.9
259 I meth I amino]benzoic acid
260 N- 6-chloro ridin-3- I meth I-N-c clo ent I-3,4,5-trimethox benzamide 20.2
261 N-[ 6-chlorop ridin-3- I meth I]-N-c clohex I-3,4,5-trimethox benzamide
9.5
N-cyclohexyl-3,4,5-trimethoxy-N-{[6-(4-methylpiperazin-1-yl)pyridin-3- 20
262 yl]methyllbenzamide
N-cyclohexyl-N-({6-[4-(hydroxymethyl)piperidin-1-yl]pyridin-3-yl}methyl)- 16.8
263 3,4,5- trimethoxybenzamide
264 4-chloro-N-[ 6-chlorop ridin-3- I meth I]-N- 4-fluorophen I benzamide 4
265 N-[ 6-chlorop ridin-3- I meth I]-3-c ano-N- 4-fluorophen I benzamide 6.1
N-(4-fluorophenyl)-N-[(2-morpholin-4-yl-1,3-thiazol-4-yl)methyl]-1- 7.9
266 naphthamide
3-cyano-N-(4-fluorophenyl)-N-{[6-(trifluoromethyl)pyridin-3- 3.6
267 I]meth I benzamide
4-chloro-N-(4-fluorophenyl)-N-{[6-(trifluoromethyl)pyridin-3- 4.3
268 I meth I benzamide
269 3-c ano-N- 4-fluorophen I-N- 6-[4- 4-fluorophen I piperazin-1- I]p ridin-
4.5
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3- I meth I benzamide
3-cyano-N-(4-fluorophenyl)-N-{[6-(4-pyridin-2-ylpiperazin-l-yl)pyridin-3- 3.7
270 I meth I benzamide
3-cyano-N-(4-fluorophenyl)-N-({6-[4-(2-phenylethyl)piperazin-l-yl]pyridin-3-3
9
271 I meth I benzamide
N-(4-fluorophenyl)benzamide N-[(6-{4-[bis(4- 13.7
272 luoro hen I meth I i perazi I ridin-3- I meth I-3-c ano-
4-chloro-N-{[6-(diphenylamino)pyridin-3-yl]methyl}-N-(4- 13.1
273 luorophen I benzamide
N-[(6-chloropyridin-3-yl)methyl]-3-cyano-N-[3- 5.4
274 trifluorometh I phen I]benzamide
N-[(6-chloropyridin-3-yl)methyl]-3-cyano-N-[4- 7
275 trifluorometh I phen I]benzamide
3-cyano-N-(4-fluorophenyl)-N-{[6-(2,2,2-trifluoroethoxy)pyridin-3- 3.4
276 I]meth I benzamide
3-cyano-N-{[6-(4-methylpiperazin-l-yl)pyridin-3-yl]methyl}-N-[3- 10.4
277 trifluorometh I phen I]benzamide
3-cyano-N-{[6-(4-methylpiperazin-l-yl)pyridin-3-yl]methyl}-N-[4- 13.4
278 trifluorometh I phen I]benzamide
4-chloro-N-(4-fluorophenyl)-N-({6-[methyl(2-pyridin-2-ylethyl)amino]pyridin-
6.9
279 3- I meth I benzamide
4-chloro-N-(4-fluoro-2-methylphenyl)-N-{[6-(4-methylpiperazin-1 -yl)pyridin-
4.3
280 3- I]meth I benzamide
2-(4-chlorophenoxy)-N-(4-fluorophenyl)-N-{[6-(4-methylpiperazin-1- 12.6
281 yl)pyridin-3- I]meth I acetamide
1-(4-chlorophenyl)-N-(4-fluorophenyl)-N-{[6-(4-methylpiperazin-1- 17.6
282 I p ridin-3- I]meth I c clobutanecarboxamide
2-(4-chlorophenyl)-N-(4-fluorophenyl)-N-{[6-(4-methylpiperazin-1- 5.8
283 I p ridin-3- I]meth I propanamide
2-(4-chlorophenyl)-2-methyl-N-{[6-(4-methylpiperazin-l-yI)pyridin-3- 8.6
284 yl]methyll- N-phen Ipropanamide
N-cyclohexyl-N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-2- 5.5
285 phenylacetamide
N-(4-fluorophenyl)-2-(3-methoxyphenyl)-N-[(2-morpholin-4-y1-1,3-thiazol-4- 5.5
286 I meth I]acetamide
N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-N-(4-fluorophenyl)-
4.1
287 2- phenylacetamide
N-(4-fluorophenyl)-N-[(2-morpholin-4-y1-1,3-thiazol-4-yl)methyl]-4- 3.3
288 phenoxybutanamide
N-(4-fluorophenyl)-N-[(2-morpholin-4-y1-1,3-thiazol-4-yl)methyl]-2- 4.1
289 phenoxyacetamide
N-({2-[cyclopropyl(ethyl)amino]-1,3-thiazol-4-yl}methyl)-N-(4-fluorophenyl)-
2- 5.6
290 p ridin-3- lacetamide
N-(4-fluorophenyl)-N-{[2-(4-methylpiperazin-l-yl)-1,3-thiazol-4-yl]methyl}-2-
27 7
291 pyridin-3-ylacetamide
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Variations, modifications, and other implementations of what is described
herein will
occur to those of ordinary skill in the art without departing from the spirit
and the
essential characteristics of the present teachings. It is not intended that
the present
invention be limited to the illustrated embodiments but rather by the
following claims,
and all changes that come within the meaning and range of equivalency of the
claims
are intended to be embraced therein.
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