U.S. patent application number 14/753936 was filed with the patent office on 2016-06-23 for n-piperidinyl acetamide derivatives as calcium channel blockers.
The applicant listed for this patent is Zalicus Pharmaceuticals, Ltd.. Invention is credited to Nagasree CHAKKA, Yanbing DING, Michael Edward GRIMWOOD, Ramesh KAUL, Hassan PAJOUHESH, Jason TAN, Lingyun ZHANG, Yuanxi ZHOU, Yongbao ZHU.
Application Number | 20160175315 14/753936 |
Document ID | / |
Family ID | 41380590 |
Filed Date | 2016-06-23 |
United States Patent
Application |
20160175315 |
Kind Code |
A1 |
PAJOUHESH; Hassan ; et
al. |
June 23, 2016 |
N-PIPERIDINYL ACETAMIDE DERIVATIVES AS CALCIUM CHANNEL BLOCKERS
Abstract
Methods and compounds effective in ameliorating conditions
characterized by unwanted calcium channel activity, particularly
unwanted T-type calcium channel activity are disclosed.
Specifically, a series of compounds containing N-piperidinyl
acetamide derivatives as shown in formula (1). ##STR00001##
Inventors: |
PAJOUHESH; Hassan; (West
Vancouver, CA) ; KAUL; Ramesh; (Burnaby, CA) ;
DING; Yanbing; (Richmond, CA) ; ZHU; Yongbao;
(Langley, CA) ; ZHANG; Lingyun; (Vancouver,
CA) ; CHAKKA; Nagasree; (Cambridge, MA) ;
GRIMWOOD; Michael Edward; (North Vancouver, CA) ;
TAN; Jason; (Vancouver, CA) ; ZHOU; Yuanxi;
(Richmond, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Zalicus Pharmaceuticals, Ltd. |
Boston |
MA |
US |
|
|
Family ID: |
41380590 |
Appl. No.: |
14/753936 |
Filed: |
June 29, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14013934 |
Aug 29, 2013 |
9096522 |
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14753936 |
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13601357 |
Aug 31, 2012 |
8569344 |
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14013934 |
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12420793 |
Apr 8, 2009 |
8377968 |
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13601357 |
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61058179 |
Jun 2, 2008 |
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Current U.S.
Class: |
514/210.18 ;
514/210.2; 514/235.5; 514/316; 514/318; 514/321; 514/322; 514/326;
514/331 |
Current CPC
Class: |
C07D 413/12 20130101;
A61P 15/16 20180101; C07D 417/12 20130101; C07D 409/12 20130101;
C07D 211/38 20130101; A61K 31/4525 20130101; A61P 43/00 20180101;
C07D 405/06 20130101; A61P 29/00 20180101; C07D 211/66 20130101;
A61P 3/10 20180101; C07D 211/62 20130101; C07D 211/28 20130101;
A61P 25/18 20180101; A61P 25/20 20180101; A61K 31/454 20130101;
A61K 31/453 20130101; A61P 3/04 20180101; A61P 25/30 20180101; A61P
13/10 20180101; A61P 25/04 20180101; C07D 211/46 20130101; A61P
25/16 20180101; C07D 211/26 20130101; C07D 405/14 20130101; A61K
31/4535 20130101; A61K 31/4545 20130101; A61P 35/00 20180101; A61P
25/08 20180101; C07D 401/06 20130101; C07D 401/12 20130101; A61K
31/445 20130101; A61K 31/5377 20130101; A61P 15/00 20180101; C07D
405/12 20130101; A61P 9/00 20180101; A61P 13/12 20180101; A61P
25/00 20180101 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/4525 20060101 A61K031/4525; A61K 31/453
20060101 A61K031/453; A61K 31/454 20060101 A61K031/454; A61K
31/4535 20060101 A61K031/4535; A61K 31/445 20060101 A61K031/445;
A61K 31/4545 20060101 A61K031/4545 |
Claims
1. A pharmaceutical composition comprising a compound of formula
(1): ##STR00658## or a pharmaceutically acceptable salt or
conjugate thereof in admixture with a pharmaceutically acceptable
excipient, wherein A is C(O)NR' or NR'C(O) wherein R' is H or
methyl; X is an optionally substituted C1-C4 alkylene, C2-C4
heteroalkylene, C2-C4 alkenylene, or C2-C4 heteroakenylene; n is 0
or 1; Ar is substituted phenyl or optionally substituted pyrazolyl,
imidazolyl, pyridinyl, isoxazolyl, thiazolyl, thiophenyl,
benzothiazolyl, or indolyl; B is OH or NY.sub.2, wherein each Y is
independently H, SR'', SOR'', SO.sub.2R'', or each Y is an
optionally substituted group selected from C1-C10 alkyl, C2-C10
alkenyl, 2-C10 alkynyl, C2-C10 heteroalkyl, C2-C10 heteroalkenyl,
C2-C10 heteroalkynyl; or two Y may together form an optionally
substituted heterocyclic ring having 4-6 ring members; each R is
independently H, halo, CN, NO.sub.2, CF.sub.3, OCF.sub.3, COOR'',
CONR''.sub.2, OR'', SR'', SOR'', SO.sub.2R'', NR''.sub.2,
NR''(CO)R'', and NR''SO.sub.2R''; or each R is independently
optionally substituted groups selected from C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C2-C6 heteroalkyl, C2-C6 heteroalkenyl,
C2-C6 heteroalkynyl; or two R on the same carbon atom taken
together .dbd.O, .dbd.NOR'' or .dbd.NCN; or two R together form an
optionally substituted cyclic or heterocyclic ring having 3-6 ring
members; or if B is NY.sub.2, one R and one Y together form an
optionally substituted heterocyclic ring having 4-6 ring members,
or two Y together form an optionally substituted heterocyclic ring
having 4-6 ring members; each R'' is independently H or an
optionally substituted group selected from C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C2-C6 heteroalkyl, C2-C6 heteroalkenyl, or
C2-C6 heteroalkynyl, wherein the optional substituents on Y, R and
R'' may be one or more halo, .dbd.O, .dbd.NOR'', CN, NO.sub.2,
CF.sub.3, OCF.sub.3, COOR'', CONR''.sub.2, OR'', SR'', SOR'',
SO.sub.2R'', NR''.sub.2, NR''(CO)R'', and NR''SO.sub.2R'', C1-C6
alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 heteroalkyl, C2-C6
heteroalkenyl, or C2-C6 heteroalkynyl; wherein the optional
substituents on X and Ar may be one or more halo, CN, CF.sub.3,
OCF.sub.3, COOR'', CONR''.sub.2, OR'', SR'', SOR'', SO.sub.2R'',
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 heteroalkyl, C2-C6
heteroalkenyl, C2-C6 heteroalkynyl, C6-C10 aryl, heteroaryl having
5-12 ring members, C6-C10 D-aryl, O-heteroaryl having 5-12 ring
members, C6-C12 aryl-C1-C6-alkyl; and wherein optional substituents
on X may be additionally selected from .dbd.O, .dbd.NOR'',
NO.sub.2, NR''.sub.2, NR''(CO)R'', and NR'' SO.sub.21=1''; and
wherein two substituents on Ar may form a cyclic or heterocyclic
ring having 4-7 ring members.
2. The pharmaceutical composition of claim 1 wherein Ar is
substituted phenyl.
3. The pharmaceutical composition of claim 1 wherein n is 0.
4. The pharmaceutical composition of claim 1 wherein the
substituents on Ar are independently selected from fluoro, bromo,
chloro, trifluoromethyl, methyl, difluoromethoxy, trifluoromethoxy,
methylsulfonyl, t-butyl, t-butyloxy, methoxy, phenoxy,
pyrrolidinyl, pyridinyloxy morpholinomethyl, hydroxy,
(CH.sub.3).sub.3COC(O) or wherein two optional substituents
together form a five membered heterocyclic ring with Ar wherein the
two substituents together form --O--CH.sub.2--O--,
--O--CF.sub.2--O-- or --O--CH.sub.2CH.sub.2--.
5. The pharmaceutical composition of claim 1 wherein B is
NY.sub.2.
6. The pharmaceutical composition of claim 5 wherein at least one Y
is H or methyl.
7. The pharmaceutical composition of claim 5 wherein at least one Y
is an alkyl or heteroalkyl.
8. The pharmaceutical composition of claim 5 wherein a carbonyl is
immediately adjacent to the N in B.
9. The pharmaceutical composition of claim 1 wherein each R is H,
or two R on the same carbon atom together form .dbd.O.
10. The pharmaceutical composition of claim 1 wherein the compound
is of formula (2): ##STR00659## or a pharmaceutically acceptable
salt or conjugate thereof, wherein Y is as defined in claim 19, L
is C(O)CH.sub.2 or CH.sub.2CH.sub.2, one R.sup.3 is H, halo,
CF.sub.3, CH.sub.3, OCH.sub.3 or OCF.sub.3, and one R.sup.3 is
halo, CF.sub.3, CH.sub.3, OCH.sub.3 or OCF.sub.3.
11. The pharmaceutical composition of claim 10 wherein one Y is H
or methyl and one Y is an optionally substituted alkyl (1-6C) or
SO.sub.2R.sup.4 wherein R.sup.4 is an optionally substituted C1-C5
alkyl.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/601,357, filed Aug. 31, 2012, which is a
continuation of U.S. patent application Ser. No. 12/420,793, filed
Apr. 8, 2009, which claims benefit to U.S. Provisional Application
No. 61/058,179, filed Jun. 2, 2008, each of which is hereby
incorporated by reference in its entirety.
TECHNICAL FIELD
[0002] The invention relates to compounds useful in treating
conditions associated with calcium channel function, and
particuarly conditions associated with T-type calcium channel
activity. More specifically, the invention concerns compounds
containing substituted amino N-piperidinyl acetamide derivatives
that are useful in treatment of conditions such as cardiovascular
disease, epilepsy, cancer and pain.
BACKGROUND ART
[0003] The entry of calcium into cells through voltage-gated
calcium channels mediates a wide variety of cellular and
physiological responses, including excitation-contraction coupling,
hormone secretion and gene expression (Miller, R. J., Science
(1987) 235:46-52; Augustine, G. J. et al., Annu Rev Neurosci (1987)
10: 633-693). In neurons, calcium channels directly affect membrane
potential and contribute to electrical properties such as
excitability, repetitive firing patterns and pacemaker activity.
Calcium entry further affects neuronal functions by directly
regulating calcium-dependent ion channels and modulating the
activity of calcium-dependent enzymes such as protein kinase C and
calmodulin-dependent protein kinase II. An increase in calcium
concentration at the presynaptic nerve terminal triggers the
release of neurotransmitter, which also affects neurite outgrowth
and growth cone migration in developing neurons.
[0004] Calcium channels mediate a variety of normal physiological
functions, and are also implicated in a number of human disorders.
Examples of calcium-mediated human disorders include but are not
limited to congenital migraine, cerebellar ataxia, angina,
epilepsy, hypertension, ischemia, and some arrhythmias. The
clinical treatment of some of these disorders has been aided by the
development of therapeutic calcium channel antagonists (e.g.,
dihydropyridines, phenylalkyl amines, and benzothiazapines all
target L-type calcium channels) (Janis, R. J. & Triggle, D. J.,
Ion Calcium Channels: Their Properties, Functions, Regulation and
Clinical Relevance (1991) CRC Press, London).
[0005] Native calcium channels have been classified by their
electrophysiological and pharmacological properties into T-, L-,
N-, P/Q- and R-types (reviewed in Catterall, W., Annu Rev Cell Dev
Biol (2000) 16: 521-555; Huguenard, J. R., Annu Rev Physiol (1996)
58: 329-348). T-type (or low voltage-activated) channels describe a
broad class of molecules that transiently activate at negative
potentials and are highly sensitive to changes in resting
potential.
[0006] The L-, N- and P/Q-type channels activate at more positive
potentials (high voltage-activated) and display diverse kinetics
and voltage-dependent properties (Catterall (2000); Huguenard
(1996)). T-type channels can be distinguished by having a more
negative range of activation and inactivation, rapid inactivation,
slow deactivation, and smaller single-channel conductances. There
are three subtypes of T-type calcium channels that have been
molecularly, pharmacologically, and elecrophysiologically
identified: these subtypes have been termed .alpha..sub.1G,
.alpha..sub.1H, and .alpha..sub.1I (alternately called Cav 3.1, Cav
3.2 and Cav 3.3 respectively).
[0007] T-type calcium channels are involved in various medical
conditions. In mice lacking the gene expressing the .alpha..sub.1G
subunit, resistance to absence seizures was observed (Kim, C. et
al., Mol Cell Neurosci (2001) 18(2): 235-245). Other studies have
also implicated the .alpha..sub.1H subunit in the development of
epilepsy (Su, H. et al., J Neurosci (2002) 22: 3645-3655). There is
strong evidence that some existing anticonvulsant drugs, such as
ethosuximide, function through the blockade of T-type channels
(Gomora, J. C., et al., Mol Pharmacol (2001) 60: 1121-1132).
[0008] Low voltage-activated calcium channels are highly expressed
in tissues of the cardiovascular system. Mibefradil, a calcium
channel blocker 10-30 fold selective for T-type over L-type
channels, was approved for use in hypertension and angina. It was
withdrawn from the market shortly after launch due to interactions
with other drugs (Heady, T. N., et al., Jpn J Pharmacol. (2001)
85:339-350).
[0009] There is also a growing body of evidence that suggests that
T-type calcium channels are abnormally expressed in cancerous cells
and that blockade of these channels may reduce cell proliferation
in addition to inducing apoptosis. Recent studies also show that
the expression of T-type calcium channels in breast cancer cells is
proliferation state dependent, i.e. the channels are expressed at
higher levels during the fast-replication period, and once the
cells are in a non-proliferation state, expression of this channel
is minimal. Therefore, selectively blocking calcium channel entry
into cancerous cells may be a valuable approach for preventing
tumor growth (PCT Patent Application Nos. WO 05/086971 and WO
05/77082; Taylor, J. T., et al., World J. Gastroenterol (2008)
14(32): 4984-4991; Heo, J. H., et al., Biorganic & Medicinal
Chemistry Letters (2008) 18:3899-3901).
[0010] Growing evidence suggests T-type calcium channels are also
involved in pain (see for example: US Patent Application No.
2003/086980; PCT Patent Application Nos. WO 03/007953 and WO
04/000311). Both mibefradil and ethosuximide have shown
anti-hyperalgesic activity in the spinal nerve ligation model of
neuropathic pain in rats (Dogrul, A., et al., Pain (2003)
105:159-168). In addition to cardiovascular disease, epilepsy (see
also US Patent Application No. 2006/025397), cancer and chronic and
acute pain, T-type calcium channels have been implicated in
diabetes (US Patent Application No. 2003/125269), sleep disorders
(US Patent Application No. 2006/003985), Parkinson's disease (US
Patent Application No. 2003/087799); psychosis such as
schizophrenia (US Patent Application No. 2003/087799), overactive
bladder (Sui, G.-P., et al., British Journal of Urology
International (2007) 99(2): 436-441; see also US 2004/197825),
renal disease (Hayashi, K., et al., Journal of Pharmacological
Sciences (2005) 99: 221-227), neuroprotection and male birth
control.
[0011] All patents, patent applications and publications are herein
incorporated by reference in their entirety.
DISCLOSURE OF THE INVENTION
[0012] The invention relates to compounds useful in treating
conditions modulated by calcium channel activity and in particular
conditions mediated by T-type channel activity. The compounds of
the invention are N-piperidinyl acetamide derivatives with
structural features that enhance the calcium channel blocking
activity of the compounds. Thus, in one aspect, the invention is
directed to a method of treating conditions mediated by calcium
channel activity by administering to patients in need of such
treatment at least one compound of formula (1):
##STR00002##
[0013] or a pharmaceutically acceptable salt or conjugate thereof,
wherein
[0014] A is C(O)NR' or NR'C(O) wherein R' is H or methyl;
[0015] X is an optionally substituted alkylene (1-4C),
heteroalkylene (2-4C), alkenylene (2-4C), or heteroalkenylene
(2-4C);
[0016] n is 0 or 1;
[0017] Ar is an optionally substituted aryl (6-10C) or heteroaryl
(5-12C); B is OH or NY.sub.2, wherein each Y is independently H,
SR'', SOR'', SO.sub.2R'', or each Y is an optionally substituted
group selected from alkyl (1-10C), alkenyl (2-10C), alkynyl
(2-10C), heteroalkyl (2-10C), heteroalkenyl (2-10C), heteroalkynyl
(2-10C); or two Y may together form an optionally substituted
heterocyclic ring (4-6 ring members);
[0018] each R is independently H, halo, CN, NO.sub.2, CF.sub.3,
OCF.sub.3, COOR'', CONR''.sub.2, OR'', SR'', SOR'', SO.sub.2R'',
NR''.sub.2, NR''(CO)R'', and NR''SO.sub.2R''; or each R is
independently optionally substituted groups selected from alkyl
(1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C),
heteroalkenyl (2-6C), heteroalkynyl (2-6C); or two R on the same
carbon atom taken together are .dbd.O, .dbd.NOR'' or .dbd.NCN; or
two R together form an optionally substituted cyclic or
heterocyclic ring (3-6 ring members); or if B is NY.sub.2, one R
and one Y together form an optionally substituted heterocyclic ring
(4-6 ring members);
[0019] each R'' is independently H or an optionally substituted
group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C),
heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2-6C),
wherein the optional substituents on Y, R and R'' may be one or
more halo, .dbd.O, .dbd.NOR', CN, NO.sub.2, CF.sub.3, OCF.sub.3,
COOR', CONR'.sub.2, OR', SR', SOR', SO.sub.2R', NR'.sub.2,
NR'(CO)R', and NR'SO.sub.2R', alkyl (1-6C), alkenyl (2-6C), alkynyl
(2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl
(2-6C); wherein the optional substituents on X and Ar may be one or
more halo, CN, CF.sub.3, OCF.sub.3, COOR'', CONR''.sub.2, OR'',
SR'', SOR'', SO.sub.2R'', alkyl (1-6C), alkenyl (2-6C), alkynyl
(2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl
(2-6C); aryl (6-10C), heteroaryl (5-12 ring members), O-aryl
(6-10C), O-heteroaryl (5-12 ring members), aryl (6-12C)-alkyl
(1-6C) or heteroaryl (5-12 ring members)-alkyl (1-6C); and wherein
optional substituents on X may be additionally selected from
.dbd.O, .dbd.NOR'', NO.sub.2, NR''.sub.2, NR''(CO)R'', and
NR''SO.sub.2R''; and wherein two substituents on Ar or X may
together form a cyclic or heterocyclic ring (4-7 ring members).
[0020] The invention is also directed to the use of compounds of
formula (1) for the preparation of medicaments for the treatment of
conditions requiring modulation of calcium channel activity, and in
particular T-type calcium channel activity. In another aspect, the
invention is directed to pharmaceutical compositions containing
compounds of formula (1) in admixture with a pharmaceutically
acceptable excipient with the additional proviso that Ar is not a
benzimidazolyl and to the use of these compositions for treating
conditions requiring modulation of calcium channel activity, and
particularly T-type calcium channel activity. The invention is also
directed to compounds of formula (1) useful to modulate calcium
channel activity, particularly T-type channel activity.
BRIEF DESCRIPTION OF THE FIGURES
[0021] FIG. 1 is an image that illustrates in the non-inactivating
protocol, the holding potential is set at -110 mV and with a
pre-pulse at -100 mV for 1 second prior to the test pulse at -40 mV
for 50 ms. In the inactivation protocol, the pre-pulse is at
approximately -85 mV for 1 second, which inactivates about 15% of
the T-type channels.
DETAILED DESCRIPTION
[0022] As used herein, the term "alkyl," "alkenyl" and "alkynyl"
include straight-chain, branched-chain and cyclic monovalent
substituents, as well as combinations of these, containing only C
and H when unsubstituted. Examples include methyl, ethyl, isobutyl,
cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl, and the like.
Typically, the alkyl, alkenyl and alkynyl groups contain 1-10C
(alkyl) or 2-10C (alkenyl or alkynyl). In some embodiments, they
contain 1-8C, 1-6C, 1-4C, 1-3C or 1-2C (alkyl); or 2-8C, 2-6C, 2-4C
or 2-3C (alkenyl or alkynyl). Further, any hydrogen atom on one of
these groups can be replaced with a halogen atom, and in particular
a fluoro or chloro, and still be within the scope of the definition
of alkyl, alkenyl and alkynyl. For example, CF.sub.3 is a 1C alkyl.
These groups may be also be substituted by other substituents.
[0023] Heteroalkyl, heteroalkenyl and heteroalkynyl are similarly
defined and contain at least one carbon atom but also contain one
or more O, S or N heteroatoms or combinations thereof within the
backbone residue whereby each heteroatom in the heteroalkyl,
heteroalkenyl or heteroalkynyl group replaces one carbon atom of
the alkyl, alkenyl or alkynyl group to which the heteroform
corresponds. In some embodiments, the heteroalkyl, heteroalkenyl
and heteroalkynyl groups have C at each terminus to which the group
is attached to other groups, and the heteroatom(s) present are not
located at a terminal position. As is understood in the art, these
heteroforms do not contain more than three contiguous heteroatoms.
In some embodiments, the heteroatom is O or N.
[0024] The designated number of carbons in heteroforms of alkyl,
alkenyl and alkynyl includes the heteroatom count. For example, if
heteroalkyl is defined as 1-6C, it will contain 1-6 C, N, O, or S
atoms such that the heteroalkyl contains at least one C atom and at
least one heteroatom, for example 1-5C and 1N or 1-4C and 2N.
Similarly, when heteroalkyl is defined as 1-6C or 1-4C, it would
contain 1-5C or 1-3C respectively, i.e., at least one C is replaced
by 0, N or S. Accordingly, when heteroalkenyl or heteroalkynyl is
defined as 2-6C (or 2-4C), it would contain 2-6 or 2-4 C, N, O, or
S atoms, since the heteroalkenyl or heteroalkynyl contains at least
one carbon atom and at least one heteroatom, e.g. 2-5C and 1N or
2-4C and 20. Further, heteroalkyl, heteroalkenyl or heteroalkynyl
substituents may also contain one or more carbonyl groups. Examples
of heteroalkyl, heteroalkenyl and heteroalkynyl groups include
CH.sub.2OCH.sub.3, CH.sub.2N(CH.sub.3).sub.2, CH.sub.2OH,
(CH.sub.2).sub.nNR.sub.2, OR, COOR, CONR.sub.2, (CH.sub.2).sub.n
OR, (CH.sub.2).sub.n COR, (CH.sub.2).sub.nCOOR, (CH.sub.2).sub.nSR,
(CH.sub.2).sub.nSOR, (CH.sub.2).sub.nSO.sub.2R, (CH.sub.2).sub.n
CONR.sub.2, NRCOR, NRCOOR, OCONR.sub.2, OCOR and the like wherein
the group contains at least one C and the size of the substituent
is consistent with the definition of alkyl, alkenyl and
alkynyl.
[0025] "Aromatic" moiety or "aryl" moiety refers to any monocyclic
or fused ring bicyclic system which has the characteristics of
aromaticity in terms of electron distribution throughout the ring
system and includes a monocyclic or fused bicyclic moiety such as
phenyl or naphthyl; "heteroaromatic" or "heteroaryl" also refers to
such monocyclic or fused bicyclic ring systems containing one or
more heteroatoms selected from O, S and N. The inclusion of a
heteroatom permits inclusion of 5-membered rings to be considered
aromatic as well as 6-membered rings. Thus, typical
aromatic/heteroaromatic systems include pyridyl, pyrimidyl,
indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl,
benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl,
oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl, imidazolyl and
the like. Because tautomers are theoretically possible, phthalimido
is also considered aromatic. Typically, the ring systems contain
5-12 ring member atoms or 6-10 ring member atoms. In some
embodiments, the aromatic or heteroaromatic moiety is a 6-membered
aromatic rings system optionally containing 1-2 nitrogen atoms.
More particularly, the moiety is an optionally substituted phenyl,
pyridyl, indolyl, pyrimidyl, pyridazinyl, benzothiazolyl or
benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl,
benzothiazolyl, indolyl. Even more particularly, such moiety is
phenyl, pyridyl, or pyrimidyl and even more particularly, it is
phenyl.
[0026] "O-aryl" or "O-heteroaryl" refers to aromatic or
heteroaromatic systems which are coupled to another residue through
an oxygen atom. A typical example of an O-aryl is phenoxy.
Similarly, "arylalkyl" refers to aromatic and heteroaromatic
systems which are coupled to another residue through a carbon
chain, saturated or unsaturated, typically of 1-8C, 1-6C or more
particularly 1-4C or 1-3C when saturated or 2-8C, 2-6C, 2-4C or
2-3C when unsaturated, including the heteroforms thereof. For
greater certainty, arylalkyl thus includes an aryl or heteroaryl
group as defined above connected to an alkyl, heteroalkyl, alkenyl,
heteroalkenyl, alkynyl or heteroalkynyl moiety also as defined
above. Typical arylalkyls would be an aryl(6-12C)alkyl(1-8C),
aryl(6-12C)alkenyl(2-8C), or aryl(6-12C)alkynyl(2-8C), plus the
heteroforms. A typical example is phenylmethyl, commonly referred
to as benzyl.
[0027] Typical optional substituents on aromatic or heteroaromatic
groups include independently halo, CN, NO.sub.2, CF.sub.3,
OCF.sub.3, COOR', CONR'.sub.2, OR', SR', SOR', SO.sub.2R',
NR'.sub.2, NR'(CO)R',NR'C(O)OR', NR'C(O)NR'.sub.2,
NR'SO.sub.2NR'.sub.2, or NR'SO.sub.2R', wherein each R' is
independently H or an optionally substituted group selected from
alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,
heteroaryl, and aryl (all as defined above); or the substituent may
be an optionally substituted group selected from alkyl, alkenyl,
alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl,
heteroaryl, O-aryl, O-heteroaryl and arylalkyl.
[0028] Optional substituents on a non-aromatic group, are typically
selected from the same list of substituents suitable for aromatic
or heteroaromatic groups and may further be selected from .dbd.O
and .dbd.NOR' where R' is H or an optionally substituted group
selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteralkynyl, heteroaryl, and aryl (all as defined above).
[0029] Halo may be any halogen atom, especially F, Cl, Br, or I,
and more particularly it is fluoro, chloro or bromo and even more
particularly it is fluoro or chloro.
[0030] In general, any alkyl, alkenyl, alkynyl, or aryl (including
all heteroforms defined above) group contained in a substituent may
itself optionally be substituted by additional substituents. The
nature of these substituents is similar to those recited with
regard to the substituents on the basic structures above. Thus,
where an embodiment of a substituent is alkyl, this alkyl may
optionally be substituted by the remaining substituents listed as
substituents where this makes chemical sense, and where this does
not undermine the size limit of alkyl per se; e.g., alkyl
substituted by alkyl or by alkenyl would simply extend the upper
limit of carbon atoms for these embodiments, and is not included.
However, alkyl substituted by aryl, amino, halo and the like would
be included.
[0031] A is C(O)NH or NHC(O). "n" is 0 or 1 indicating that X is
present when n is 1 and X is absent when n is O. X is an optionally
substituted alkylene (1-4C), heteroalkylene (2-4C), alkenylene
(2-4C), or heteralkenylene (2-4C). In more particular embodiments X
is absent (i.e. n=0) or X is an optionally substituted alkylene
(1-2C) or X is an optionally substituted alkenylene(2C). When X is
present, the substituents on X are as defined above, however, in
particular embodiments X may be unsubstituted or be substituted
with an optionally substituted phenyl. When X is an unsubstituted
alkenylene, in particular embodiments, X is in the trans
configuration.
[0032] Ar is an optionally substituted aryl (6-10C) or heteroaryl
(5-12C). In particular embodiments, Ar is an optionally substituted
phenyl, pyrazolyl, imidazolyl, pyridinyl, isoxazolyl,
benzimidazolyl, thiazolyl, benzothiazolyl or indolyl. In more
particular embodiments, Ar is an optionally substituted phenyl.
Optional substituents on Ar are as defined above, however, in more
particular embodiments such optional substituents may independently
be selected from fluoro, bromo, chloro, trifluoromethyl, methyl,
difluoromethoxy, trifluoromethoxy, methylsulfonyl, t-butyl,
t-butyloxy, methoxy, phenoxy, pyrrolidinyl, pyridinyloxy,
morpholinomethyl, hydroxyl, (CH.sub.3).sub.3COC(O). In addition,
two optional substituents on Ar may together form a cyclic or
heterocyclic ring with Ar. For example, in some embodiments, the
two substituents on Ar together form --O--CH.sub.2--O--,
--O--CF.sub.2--O, or --O--CH.sub.2CH.sub.2--. In even more
particular embodiments, Ar is a phenyl and as such, the Ar group,
including substituents that together form a 5 membered heterocyclic
ring, is a benzodioxole, 2,2-difluorobenzodioxole, or
dihydrobenzofuran.
[0033] Each R is independently is independently H, halo, CN,
NO.sub.2, CF.sub.3, OCF.sub.3, COOR'', CONR''.sub.2, OR'', SR'',
SOR'', SO.sub.2R'', NR''.sub.2, NR''(CO)R'', and NR''SO.sub.2R'';
or each R is independently optionally substituted groups selected
from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl; or two R on the same carbon atom taken together are
.dbd.O, .dbd.NOR'' or .dbd.NCN; or two R together form an
optionally substituted cyclic or heterocyclic ring (3-6 ring
members). In many embodiments, each R is H. In other embodiments,
one or more R may be an optionally substituted alkyl or
heteroalkyl. In some embodiments, two R together form .dbd.O or a
4-6 membered optionally substituted cyclic or heterocylic ring. R''
is independently H or an optionally substituted group selected from
alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl.
[0034] In compounds of formula (1), there are two carbon atoms
between the piperidine nitrogen and B. The alpha carbon is
immediately adjacent to the piperidine nitrogen and the beta carbon
is immediately adjacent to B. In many embodiments, the two R on the
beta carbon together form .dbd.O or a 4-6 membered optionally
substituted cyclic or heterocyclic ring. In many alternate or
concurrent embodiments, the two R on the alpha carbon are H or
together form .dbd.O.
[0035] B may be a hydroxyl or NY.sub.2 where Y is H, SR'', SOR'',
SO.sub.2R'', or each Y is an optionally substituted group selected
from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl; or two Y may together form an optionally substituted
heterocyclic ring (4-6 ring members). In some embodiments, at least
one Y is a hydrogen whereas in other embodiments both Y are
hydrogen. In many embodiments, at least one Y is an alkyl or a
heteroalkyl. In many embodiments, a carbonyl or a sulfonyl in Y is
adjacent to the N in B. In some embodiments, a ureido functionality
(NO(O)N) is created with Y and the N in B. In some embodiments, one
Y and one R together form an optionally substituted heterocyclic
ring, and even more particularly, the R is on the beta carbon as
defined above. In other embodiments, two Y together form an
optionally substituted heterocyclic ring. In yet other embodiments,
one Y is H or methyl and one Y is an optionally substituted alkyl
(1-6C) or SO.sub.2R.sup.4 wherein R.sup.4 is an optionally
substituted alkyl (1-5C).
[0036] In some embodiments, the compound is of formula (2):
##STR00003##
[0037] Wherein Y is as defined above, L is C(O)CH.sub.2 or
CH.sub.2CH.sub.2 and R.sup.3 is H, halo, CF.sub.3, CH.sub.3,
OCH.sub.3 or OCF.sub.3.
[0038] In some preferred embodiments, two or more of the
particularly described groups are combined into one compound: it is
often suitable to combine one of the specified embodiments of one
feature as described above with a specified embodiment or
embodiments of one or more other features as described above. For
example, a specified embodiment includes a compound of formula (1)
with Ar equal to phenyl, and another specified embodiment has n
equal to 0. Thus one preferred embodiment combines both of these
features together, i.e., Ar is phenyl in combination with n=0. In
some specific embodiments, B is OH and in others A is NHC(O). Thus
additional preferred embodiments include B as OH in combination
with any of the preferred combinations set forth above; other
preferred combinations include A as NHC(O) in combination with any
of the preferred combinations set forth above.
[0039] The compounds of the invention may be in the form of
pharmaceutically acceptable salts. These salts may be acid addition
salts involving inorganic or organic acids or the salts may, in the
case of acidic forms of the compounds of the invention be prepared
from inorganic or organic bases. Frequently, the compounds are
prepared or used as pharmaceutically acceptable salts prepared as
addition products of pharmaceutically acceptable acids or bases.
Suitable pharmaceutically acceptable acids and bases are well-known
in the art, such as hydrochloric, sulphuric, hydrobromic, acetic,
lactic, citric, or tartaric acids for forming acid addition salts,
and potassium hydroxide, sodium hydroxide, ammonium hydroxide,
caffeine, various amines, and the like for forming basic salts.
Methods for preparation of the appropriate salts are
well-established in the art.
[0040] In some cases, the compounds of the invention contain one or
more chiral centers. The invention includes each of the isolated
stereoisomeric forms as well as mixtures of stereoisomers in
varying degrees of chiral purity, including racemic mixtures. It
also encompasses the various diastereomers and tautomers that can
be formed.
[0041] Compounds of formula (1) are also useful for the manufacture
of a medicament useful to treat conditions characterized by
undesired T-type calcium channel activities.
[0042] In addition, the compounds of the invention may be coupled
through conjugation to substances designed to alter the
pharmacokinetics, for targeting, or for other reasons. Thus, the
invention further includes conjugates of these compounds. For
example, polyethylene glycol is often coupled to substances to
enhance half-life; the compounds may be coupled to liposomes
covalently or noncovalently or to other particulate carriers. They
may also be coupled to targeting agents such as antibodies or
peptidomimetics, often through linker moieties. Thus, the invention
is also directed to the compounds of formula (1) when modified so
as to be included in a conjugate of this type.
[0043] Merck & Co., Inc. has filed two patent applications
directed towards T-type calcium channel blockers with a similar
piperidinyl acetamide core to that disclosed in the present
invention, namely Patent Cooperation Treaty applications WO
2007/002361 and WO 2007/002884 (the '361 and '884 patent
applications). However, in the '361 patent it is essential that the
piperidinyl group be substituted by a fluoro at the 3 position
while in the '884 application, it is essential that the piperidinyl
group be substituted by a fluoro at the 4 position. Not only does
Merck view the presence of fluorine on the piperidinyl ring as
required but also that the position on the ring gives rise to two
separate inventions. No experimental data is provided for any of
the compounds in either patent, no explanation is given for the
role of the fluorine in either patent application, nor is it even
clear what subtype of the T-type calcium channel is affected by
their compounds (i.e. .alpha..sub.1G, .alpha..sub.1H or
.alpha..sub.1I). Surprisingly, we have found that the central
piperidinyl core does not need to be fluorinated in order to obtain
activity against the T-type calcium channel. Of more importance is
the presence of a nitrogen or hydroxy on the beta carbon spaced
from the piperidinyl nitrogen which, unexpectantly, also provides
selectivity against the hERG K.sup.+ channel. Activity against the
.alpha..sub.1G and .alpha..sub.1H T-type calcium channel subtypes
as well as against the hERG K.sup.+ channel are shown for selected
compounds below in tables 4 and 5.
MODES OF CARRYING OUT THE INVENTION
[0044] The compounds of formula (1) are useful in the methods of
the invention and, while not bound by theory, are believed to exert
their desirable effects through their ability to modulate the
activity of calcium channels, particularly the activity of T-type
calcium channels. This makes them useful for treatment of certain
conditions where modulation of T-type calcium channels is desired,
including:
[0045] cardiovascular disease; epilepsy; diabetes; cancer; pain,
including both chronic and acute pain; sleep disorders; Parkinson's
disease; psychosis such as schizophrenia; overactive bladder; renal
disease, neuroprotection, addiction and male birth control.
[0046] Cardiovascular disease as used herein includes but is not
limited to hypertension, pulmonary hypertension, arrhythmia (such
as atrial fibrillation and ventricular fibrillation), congestive
heart failure, angina pectoris, arteriosclerosis, atherosclerosis,
and stroke.
[0047] Epilepsy as used herein includes but is not limited to
partial seizures such as temporal lobe epilepsy, absence seizures,
generalized seizures, and tonic/clonic seizures.
[0048] Cancer as used herein includes but is not limited to breast
carcinoma, neuroblastoma, retinoblastoma, glioma, prostate
carcinoma, esophageal carcinoma, fibrosarcoma, colorectal
carcinoma, pheochromocytoma, adrenocarcinoma, insulinoma, lung
carcinoma, melanoma, and ovarian cancer.
[0049] Acute pain as used herein includes but is not limited to
nociceptive pain and post-operative pain. Chronic pain includes but
is not limited by: peripheral neuropathic pain such as
post-herpetic neuralgia, diabetic neuropathic pain, neuropathic
cancer pain, failed back-surgery syndrome, trigeminal neuralgia,
and phantom limb pain; central neuropathic pain such as multiple
sclerosis related pain,
[0050] Parkinson disease related pain, post-stroke pain,
post-traumatic spinal cord injury pain, and pain in dementia;
musculoskeletal pain such as osteoarthritic pain and fibromyalgia
syndrome; inflammatory pain such as rheumatoid arthritis and
endometriosis; headache such as migraine, cluster headache, tension
headache syndrome, facial pain, headache caused by other diseases;
visceral pain such as interstitial cystitis, irritable bowel
syndrome and chronic pelvic pain syndrome; and mixed pain such as
lower back pain, neck and shoulder pain, burning mouth syndrome and
complex regional pain syndrome.
[0051] For greater certainty, in treating osteoarthritic pain,
joint mobility will also improve as the underlying chronic pain is
reduced. Thus, use of compounds of the present invention to treat
osteoarthritic pain inherently includes use of such compounds to
improve joint mobility in patients suffering from
osteoarthritis.
[0052] Addiction includes but is not limited to dependence,
withdrawal and/or relapse of cocaine, opioid, alcohol and
nicotine
[0053] It is known that calcium channel activity is involved in a
multiplicity of disorders, and particular types of channels are
associated with particular conditions. The association of T-type
channels in conditions associated with neural transmission would
indicate that compounds of the invention which target T-type
receptors are most useful in these conditions. Many of the members
of the genus of compounds of formula (1) exhibit high affinity for
T-type channels. Thus, as described below, they are screened for
their ability to interact with T-type channels as an initial
indication of desirable function. It is particularly desirable that
the compounds exhibit IC.sub.50 values of <1 .mu.M. The
IC.sub.50 is the concentration which inhibits 50% of the calcium,
barium or other permeant divalent cation flux at a particular
applied potential.
[0054] In order to be maximally useful in treatment, it is also
helpful to assess the side reactions which might occur. Thus, in
addition to being able to modulate a particular calcium channel, it
is desirable that the compound has very low activity with respect
to the hERG K.sup.+ channel which is expressed in the heart.
Compounds that block this channel with high potency may cause
reactions which are fatal. Thus, for a compound that modulates the
calcium channel, it is preferred that the hERG channel is not
inhibited. Some inhibition of the hERG K.sup.+ channel may be
tolerated in a drug as long as the compound is sufficiently
selective for the target of interest over the hERG K.sup.+ channel.
For example, 10 fold selectivity of a T-type calcium channel over
the hERG K.sup.+ channel would be beneficial and more preferably 30
fold selectivity or 100 fold selectivity.
[0055] Similarly, it would be undesirable for the compound to
inhibit cytochrome p450 since this enzyme is required for drug
detoxification. Finally, the compound will be evaluated for calcium
ion channel type specificity by comparing its activity among the
various types of calcium channels, and specificity for one
particular channel type is preferred. The compounds which progress
through these tests successfully are then examined in animal models
as actual drug candidates.
[0056] The compounds of the invention modulate the activity of
calcium channels; in general, said modulation is the inhibition of
the ability of the channel to transport calcium. As described
below, the effect of a particular compound on calcium channel
activity can readily be ascertained in a routine assay whereby the
conditions are arranged so that the channel is activated, and the
effect of the compound on this activation (either positive or
negative) is assessed. Furthermore, the compounds of the invention
are selective against the hERG K.sup.+ channel. Typical assays are
described hereinbelow in Example 17.
[0057] Libraries and Screening
[0058] The compounds of the invention can be synthesized
individually using methods known in the art per se, or as members
of a combinatorial library.
[0059] Synthesis of combinatorial libraries is now commonplace in
the art. Suitable descriptions of such syntheses are found, for
example, in Wentworth, Jr., P., et al., Current Opinion in Biol.
(1993) 9:109-115; Salemme, F. R., et al., Structure (1997)
5:319-324. The libraries contain compounds with various
substituents and various degrees of unsaturation, as well as
different chain lengths. The libraries, which contain, as few as
10, but typically several hundred members to several thousand
members, may then be screened for compounds which are particularly
effective against a specific subtype of calcium channel, e.g., the
N-type channel. In addition, using standard screening protocols,
the libraries may be screened for compounds that block additional
channels or receptors such as sodium channels, potassium channels
and the like.
[0060] Methods of performing these screening functions are well
known in the art. These methods can also be used for individually
ascertaining the ability of a compound to agonize or antagonize the
channel. Typically, the channel to be targeted is expressed at the
surface of a recombinant host cell such as human embryonic kidney
cells. The ability of the members of the library to bind the
channel to be tested is measured, for example, by the ability of
the compound in the library to displace a labeled binding ligand
such as the ligand normally associated with the channel or an
antibody to the channel.
[0061] More typically, ability to antagonize the channel is
measured in the presence of calcium, barium or other permeant
divalent cation and the ability of the compound to interfere with
the signal generated is measured using standard techniques. In more
detail, one method involves the binding of radiolabeled agents that
interact with the calcium channel and subsequent analysis of
equilibrium binding measurements including, but not limited to, on
rates, off rates, K.sub.d values and competitive binding by other
molecules.
[0062] Another method involves the screening for the effects of
compounds by electrophysiological assay whereby individual cells
are impaled with a microelectrode and currents through the calcium
channel are recorded before and after application of the compound
of interest.
[0063] Another method, high-throughput spectrophotometric assay,
utilizes loading of the cell lines with a fluorescent dye sensitive
to intracellular calcium concentration and subsequent examination
of the effects of compounds on the ability of depolarization by
potassium chloride or other means to alter intracellular calcium
levels.
[0064] As described above, a more definitive assay can be used to
distinguish inhibitors of calcium flow which operate as open
channel blockers, as opposed to those that operate by promoting
inactivation of the channel or as resting channel blockers. The
methods to distinguish these types of inhibition are more
particularly described in the examples below. In general,
open-channel blockers are assessed by measuring the level of peak
current when depolarization is imposed on a background resting
potential of about -100 mV in the presence and absence of the
candidate compound. Successful open-channel blockers will reduce
the peak current observed and may accelerate the decay of this
current.
[0065] Compounds that are inactivated channel blockers are
generally determined by their ability to shift the voltage
dependence of inactivation towards more negative potentials. This
is also reflected in their ability to reduce peak currents at more
depolarized holding potentials (e.g., -70 mV) and at higher
frequencies of stimulation, e.g., 0.2 Hz vs. 0.03 Hz. Finally,
resting channel blockers would diminish the peak current amplitude
during the very first depolarization after drug application without
additional inhibition during the depolarization.
[0066] Accordingly, a library of compounds of formula (1) can be
used to identify a compound having a desired combination of
activities that includes activity against at least one type of
calcium channel. For example, the library can be used to identify a
compound having a suitable level of activity on T-type calcium
channels while having minimal activity on HERG K+ channels.
[0067] Utility and Administration
[0068] For use as treatment of human and animal subjects, the
compounds of the invention can be formulated as pharmaceutical or
veterinary compositions. Depending on the subject to be treated,
the mode of administration, and the type of treatment
desired--e.g., prevention, prophylaxis, therapy; the compounds are
formulated in ways consonant with these parameters. A summary of
such techniques is found in Remington's Pharmaceutical Sciences,
latest edition, Mack Publishing Co., Easton, Pa., incorporated
herein by reference.
[0069] In general, for use in treatment, the compounds of formula
(1) may be used alone, as mixtures of two or more compounds of
formula (1) or in combination with other pharmaceuticals. An
example of other potential pharmaceuticals to combine with the
compounds of formula (1) would include pharmaceuticals for the
treatment of the same indication but having a different mechanism
of action from T-type calcium channel blocking. For example, in the
treatment of pain, a compound of formula (1) may be combined with
another pain relief treatment such as an NSAID, or a compound which
selectively inhibits COX-2, or an opioid, or an adjuvant analgesic
such as an antidepressant. Another example of a potential
pharmaceutical to combine with the compounds of formula (1) would
include pharmaceuticals for the treatment of different yet
associated or related symptoms or indications. Depending on the
mode of administration, the compounds will be formulated into
suitable compositions to permit facile delivery.
[0070] The compounds of the invention may be prepared and used as
pharmaceutical compositions comprising an effective amount of at
least one compound of formula (1) admixed with a pharmaceutically
acceptable carrier or excipient, as is well known in the art.
Formulations may be prepared in a manner suitable for systemic
administration or topical or local administration. Systemic
formulations include those designed for injection (e.g.,
intramuscular, intravenous or subcutaneous injection) or may be
prepared for transdermal, transmucosal, or oral administration. The
formulation will generally include a diluent as well as, in some
cases, adjuvants, buffers, preservatives and the like. The
compounds can be administered also in liposomal compositions or as
microemulsions.
[0071] For injection, formulations can be prepared in conventional
forms as liquid solutions or suspensions or as solid forms suitable
for solution or suspension in liquid prior to injection or as
emulsions. Suitable excipients include, for example, water, saline,
dextrose, glycerol and the like. Such compositions may also contain
amounts of nontoxic auxiliary substances such as wetting or
emulsifying agents, pH buffering agents and the like, such as, for
example, sodium acetate, sorbitan monolaurate, and so forth.
[0072] Various sustained release systems for drugs have also been
devised. See, for example, U.S. Pat. No. 5,624,677.
[0073] Systemic administration may also include relatively
noninvasive methods such as the use of suppositories, transdermal
patches, transmucosal delivery and intranasal administration. Oral
administration is also suitable for compounds of the invention.
Suitable forms include syrups, capsules, tablets, as is understood
in the art.
[0074] For administration to animal or human subjects, the dosage
of the compounds of the invention is typically 0.01-15 mg/kg,
preferably 0.1-10 mg/kg. However, dosage levels are highly
dependent on the nature of the condition, drug efficacy, the
condition of the patient, the judgment of the practitioner, and the
frequency and mode of administration. Optimization of the dosage
for a particular subject is within the ordinary level of skill in
the art.
[0075] Synthesis of the Invention Compounds
[0076] The following reaction schemes and examples are intended to
illustrate the synthesis of a representative number of compounds.
Accordingly, the following examples are intended to illustrate but
not to limit the invention. Additional compounds not specifically
exemplified may be synthesized using conventional methods in
combination with the methods described hereinbelow.
Example 1
Synthesis of
N-((1-((1-(ethylsulfonamido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-
-bis(trifluoromethyl)benzamide (Compound 3)
##STR00004##
[0077] A. Synthesis of
N-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide
##STR00005##
[0079] To a solution of 1-Boc-4-(aminomethyl)piperidine (18.0 g,
84.1 mmol) and DIPEA (12.9 g, 100 mmol) in anhydrous
CH.sub.2Cl.sub.2 (200 mL) at 15.degree. C. was added
3,5-bis-(trifluoromethyl)benzoyl chloride (23.4 g, 85.0 mmol)
slowly. After the reaction mixture was stirred at room temperature
for 30 min, water (50 mL) was added followed by adding aqueous HCl
(0.5 N, 100 mL). The organic fraction was collected. The aqueous
fraction was extracted with CH.sub.2Cl.sub.2 (100 mL). The combined
organic solution was dried over anhydrous N.alpha..sub.2SO.sub.4
and passed through a silica gel plug. The desired compound was
eluted off with EtOAc/petroleum ether (1:3 in v/v). Solvents were
removed and the product was dissolved in EtOAc (200 mL). To the
solution HCl (g) bubbled for 5 min to form a white suspension. The
suspension was stirred at room temperature for 30 min, and then
concentrated to around 100 mL. Diethyl ether (150 mL) was added and
the suspension was cooled at 7.degree. C. for 1 h. A white HCl salt
was collected by filtration. The salt was dissolved in a mixture of
methanol/water (30/300 mL), and aqueous NaOH (2 N) was added until
pH=.about.11. The mixture was extracted with CH.sub.2Cl.sub.2
(5.times.200 ML) and the combined organic solution was dried over
anhydrous N.alpha..sub.2SO.sub.4. After filtration the filtrate was
concentrated in vacuo to give pale yellow sticky foam (28.8 g,
97%).).
B. Synthesis of
N-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluor-
omethyl)benzamide
##STR00006##
[0081] To a solution of
N-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide (546 mg,
1.54 mmol) and N-BOC-cycloleucinal (329 mg, 1.54 mmol) in
CH.sub.2Cl.sub.2 (15 mL) was added NaBH(OAC).sub.3 (481 mg, 2.16
mmol). The resulting mixture was allowed to stir at room
temperature for 18 hours and then diluted with ethyl acetate. The
organic fraction was washed with sat. NaHCO.sub.3 (30 mL), brine
(30 mL) and dried over N.alpha..sub.2SO.sub.4. The solvent was
removed in vacuo to provide crude tert-butyl
1-((4-((3,5-bis(trifluoromethyl)benzamido)
methyl)piperidin-1-yl)methyl) cyclopentyl carbamate as an oil.
[0082] The above crude tert-butyl
1-((4-((3,5-bis(trifluoromethyl)benzamido)
methyl)piperidin-1-yl)methyl) cyclopentyl carbamate dissolved in
CH.sub.2Cl.sub.2 (3 mL) and TFA (2 mL) was added at room
temperature. The reaction was allowed to stir at room temperature
for 2 hours and then diluted with CH.sub.2Cl.sub.2 (15 mL). The
organic mixture was washed with the mixture of sat. NaHCO.sub.3 (10
mL) and 2 N NaOH (5 mL), dried over N.alpha..sub.2SO.sub.4. Removal
of solvent in vacuo provided oil. The crude oil was purified by
Biotage (10% MeOH in CH.sub.2Cl.sub.2) to yield
N-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluor-
omethyl)benzamide (379 mg, 56% over two steps).
C. Synthesis of
N-((1-((1-(ethylsulfonamido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-
-bis(trifluoromethyl)benzamide (Compound 3)
##STR00007##
[0084] To a solution of
N-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluor-
omethyl) benzamide (100 mg, 0.28 mmol) and i-Pr.sub.2NEt (0.2 mL,
1.1 mmol) in CH.sub.2Cl.sub.2 (5 mL) was added ethanesulfonyl
chloride (0.05 mL, 0.53 mmol). The reaction mixture was allowed to
stir at room temperature for 18 hours and then diluted with ethyl
acetate. The organic fraction was washed with sat. NaHCO.sub.3, and
then brine and dried over N.alpha..sub.2SO.sub.4. The solvent was
removed and the crude was purified by High Throughput Purification
System (HiTOPs) to provide
N-((1-((1-(ethylsulfonamido)cyclopentyl)methyl)
piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide.
Example 2
Synthesis of
N-((1-((1-(3-ethylureido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bi-
s(trifluoromethyl)benzamide (Compound 11)
##STR00008##
[0086] To a solution of
N-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluor-
omethyl) benzamide (100 mg, 0.28 mmol) in CH.sub.2Cl.sub.2 (5 mL)
was added ethyl isocyanate (0.05 mL, 0.63 mmol). The reaction
mixture was allowed to stir at room temperature for 18 hours and
then diluted with ethyl acetate. The organic fraction was washed
with sat. NaHCO.sub.3, and then brine and dried over
N.alpha..sub.2SO.sub.4. The solvent was removed and the crude was
purified by HiTOPs to provide N-((1-((1-(3-ethylureido)
cyclopentyl)
methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide.
Example 3
Synthesis of ethyl
1-((4-((3,5-bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)methyl)cy-
clopentylcarbamate (Compound 17)
##STR00009##
[0088] To a solution of
N-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluor-
omethyl) benzamide (100 mg, 0.28 mmol) and i-Pr.sub.2NEt (0.2 mL,
1.1 mmol) in CH.sub.2Cl.sub.2 (5 mL) was added ethyl chloroformate
(0.05 mL, 0.53 mmol). The reaction mixture was allowed to stir at
room temperature for 18 hours and then diluted with ethyl acetate.
The organic fraction was washed with sat. NaHCO.sub.3, and then
brine and dried over N.alpha..sub.2SO.sub.4. The solvent was
removed and the crude was purified by HiTOPs to provide ethyl
1-((4-((3,5-bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)methyl)cy-
clopentylcarbamate.
Example 4
Synthesis of synthesis of
N-((1-(2-(1-methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-3,5-bis(t-
rifluoromethyl)benzamide (Compound 20)
##STR00010##
[0089] A. Synthesis of
N-((1-(cyanomethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzami-
de
##STR00011##
[0091] N-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide
(3.54 g, 10.0 mmol) was dissolved in CH.sub.3CN (100 mL). DIPEA
(1.94 g, 15.0 mmol) and bromoacetonitrile (1.32 g, 11.0 mmol) were
added. The reaction mixture was heated at 50.degree. C. overnight.
The solvent was removed in vacuo. Saturated NaHCO.sub.3 (40 mL) was
added and the mixture was extracted with CH.sub.2Cl.sub.2
(4.times.30 mL). The combined organic solution was dried over
anhydrous N.alpha..sub.2SO.sub.4 and passed through a silica gel
plug. The desired compound was eluted off with EtOAc. The product
was further purified by crystallization from EtOAc/petroleum ether
as a white solid (3.62 g, 92%).
B. Synthesis of
N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzam-
ide
##STR00012##
[0093] Hydrogenation flask charged with a solution of
N-((1-(cyanomethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzami-
de (2.80 g, 7.13 mmol) in methanol (20 mL) and Raney nickel
(.about.1 g, rinsed with methanol). The flask was shaken at room
temperature under hydrogen (40 psi) overnight. The reaction mixture
was then filtered through a celite cake, and the filtrate was
concentrated to give sticky foam which was used in the next step
without further purification.
C. Synthesis of
N-((1-(2-(1-methylethylsulfonamido)ethyl)piperidin-4-yl)methyl)-3,5-bis(t-
rifluoromethyl)benzamide (Compound 20)
##STR00013##
[0095] A solution of
N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzam-
ide (70 mg, 0.18 mmol) and 2,6-lutidine (123 .mu.L, 0.882 mmol) in
CH.sub.2Cl.sub.2 (2 mL) was treated with isopropylsulfonyl chloride
(49.9 mg, 0.35 mmol). The reaction was stirred overnight and then
transferred to a test tube containing saturated aqueous NaHCO.sub.3
(4 mL) and EtOAc (4 mL). The biphasic mixture was mixed vigourously
and allowed to separate for 15 min. After separation, the mixture
was cooled to -20.degree. C. until the aqueous layer was frozen.
The organic layer was then poured off and the solvent was removed
under reduced pressure at 50.degree. C. The resulting residue was
purified by HiTOPs
Example 5
Synthesis of ethyl
2-(4-((3,5-bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethylcarba-
mate (Compound 36)
##STR00014##
[0097] A solution of
N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzam-
ide (66 mg, 0.17 mmol) in a 2:1 mixture of CH.sub.2Cl.sub.2:DMF (3
mL) and TEA (69 .mu.L, 0.50 mmol) was treated with ethyl
chloroformate (27 mg, 0.25 mmol). The reaction mixture was allowed
to stir overnight, then the solvent was removed in vacuo and the
residue was purified by HiTOPs.
Example 6
Synthesis of tert-butyl
2-(4-((3-fluoro-5-(trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethylc-
arbamate (Compound 38)
##STR00015##
[0098] A. Synthesis of tert-butyl
2-(4-cyanopiperidin-1-yl)ethylcarbamate
##STR00016##
[0100] A mixture of piperidine-4-carbonitrile (1.10 g, 10 mmol),
tert-butyl 2-oxoethylcarbamate (1.59 g, 10 mmol) and sodium
triacetoxy borohydride (2.5 g, 12 mmol) in 25 ml of
CH.sub.2Cl.sub.2 was stirred at room temperature overnight. Solvent
was evaporated and ethyl acetate was added and washed with water.
The solvent was removed in vacuo to provide oil. The crude oil was
purified by column chromatography (100% ethyl acetate) to yield
colorless oil (2.3 g, 91%).
B. Synthesis of tert-butyl 2-(4-aminomethyl)
piperidin-1-yl)ethylcarbamate
##STR00017##
[0102] To a mixture of tert-butyl
2-(4-cyanopiperidin-1-yl)ethylcarbamate (2.3 g, 9.05 mmol) and
Raney Nickel (1.1 g) in CH.sub.3OH (50 mL) was bubbled ammonia gas
for 5 min. The reaction mixture was shaken at room temperature
under hydrogen (40 psi) overnight. The catalyst was filtered
through celite. The solvent was removed in vacuo to provide oil
(2.3 g, 98.5%).
C. Synthesis of tert-butyl
2-(4-((3-fluoro-5-(trifluoromethyl)benzamido)methyl)piperidin-1-yl)ethylc-
arbamate (Compound 38)
##STR00018##
[0104] A solution of tert-butyl
2-(4-(aminomethyl)piperidin-1-yl)ethylcarbamate (50 mg, 0.19 mmol),
TEA (135 .mu.L, 0.972 mmol), and
3-fluoro-5-(trifluoromethyl)benzoic acid (48 mg, 0.23 mmol) in a
mixture of 1:1 CH.sub.2Cl.sub.2:THF (2 mL) was treated with a
solution of HATU (111 mg, 0.292 mmol) in DMF (1 mL). The resulting
solution was stirred overnight, then transferred to a test tube
containing saturated aqueous NaHCO.sub.3 (4 mL) and EtOAc (4 mL).
The biphasic mixture was mixed vigorously and allowed to separate
for 15 minutes. After separation, the mixture was cooled to
-20.degree. C. until the aqueous layer was frozen. The organic
layer was then poured off and the solvent was removed under reduced
pressure at 50.degree. C. The resulting residue was purified by
HiTOPs.
Example 7
Synthesis of tert-butyl
2-(4-((2,2-difluorobenzo[d][1,3]dioxole-5-carboxamido)methyl)piperidin-1--
yl)ethylcarbamate (Compound 54)
##STR00019##
[0106] A solution of tert-butyl
2-(4-(aminomethyl)piperidin-1-yl)ethylcarbamate (50 mg, 0.19 mmol)
and TEA (135 .mu.L, 0.972 mmol) in a mixture of 1:1
CH.sub.2Cl.sub.2:THF (2.5 mL) was treated with
2,2-difluorobenzo[d][1,3]dioxole-5-carbonyl chloride (51 mg, 0.23
mmol). The resulting solution was stirred overnight, then
transferred to a test tube containing saturated aqueous NaHCO.sub.3
(4 mL) and EtOAc (4 mL). The biphasic mixture was mixed vigorously
and allowed to separate for 15 minutes. After separation, the
mixture was cooled to -20.degree. C. until the aqueous layer was
frozen. The organic layer was then poured off and the solvent was
removed under reduced pressure at 50.degree. C. The resulting
residue was purified by HiTOPs.
Example 8
Synthesis of
N-((1-(2-pivalamidoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)b-
enzamide (Compound 60)
##STR00020##
[0108] A solution of
N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzam-
ide (70 mg, 0.18 mmol) and TEA (123 .mu.L, 0.881 mmol) in a 1:1
mixture of CH.sub.2Cl.sub.2:DMF (2 mL) was treated with pivaloyl
chloride (42 mg, 0.35 mmol). The reaction mixture was stirred
overnight then transferred to a test tube containing saturated
aqueous NaHCO.sub.3 (4 mL) and EtOAc (4 mL). The biphasic mixture
was mixed vigorously and allowed to separate for 15 min. After
separation, the mixture was cooled to -20.degree. C. until the
aqueous layer was frozen. The organic layer was then poured off and
the solvent was removed under reduced pressure at 50.degree. C. The
resulting residue was purified by HiTOPs.
Example 9
Synthesis of
N-((1-(2-(2-cyclopropylacetamido)ethyl)piperidin-4-yl)methyl)-3,5-bis(tri-
fluoromethyl)benzamide (Compound 63)
##STR00021##
[0110] A solution of
N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzam-
ide (70 mg, 0.18 mmol), TEA (123 .mu.L, 0.881 mmol), and
2-cyclopropylacetic acid (35 mg, 0.35 mmol) in a 1:1 mixture of
CH.sub.2Cl.sub.2:DMF (2 mL) was treated with a solution of HATU
(100 mg, 0.264 mmol) in DMF (1 mL). The reaction was stirred over
night then transferred to a test tube containing saturated aqueous
NaHCO.sub.3 (4 mL) and EtOAc (4 mL). The biphasic mixture was mixed
vigorously and allowed to separate for 15 min. After separation,
the mixture was cooled to -20.degree. C. until the aqueous layer
was frozen. The organic layer was then poured off and the solvent
was removed under reduced pressure at 50.degree. C. The resulting
residue was purified by HiTOPs.
Example 10
Synthesis of
N-((1-(2-(3-tert-butylureido)ethyl)piperidin-4-yl)methyl)-3,5-bis(trifluo-
romethyl)benzamide (Compound 72)
##STR00022##
[0112] A solution of
N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzam-
ide (25 mg, 0.063 mmol) in CH.sub.2Cl.sub.2 (1.5 mL) was treated
with t-butyl isocyanate (30 mg, 0.13 mmol). The mixture was stirred
overnight, treated with MeOH (1 mL). The solvent was removed in
vacuo. The residue was purified by HiTOPs.
Example 11
Synthesis of
(R)--N-((1-(5-oxopyrrolidine-2-carbonyl)piperidin-4-yl)methyl)-3,5-bis(tr-
ifluoromethyl)benzamide (Compound 83)
##STR00023##
[0114] A solution of
N-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide (48 mg,
0.14 mmol), TEA (95 .mu.L, 0.68 mmol), and
(R)-5-oxopyrrolidine-2-carboxylic acid (20.66 mg, 0.16 mmol) in DMF
(1.5 mL) was treated with a solution of HATU (77 mg, 0.20 mmol) in
DMF (1 mL). The reaction mixture was stirred overnight then
transferred to a test tube containing saturated aqueous NaHCO.sub.3
(4 mL) and EtOAc (4 mL). The biphasic mixture was mixed vigorously
and allowed to separate for 15 min. After separation, the mixture
was cooled to -20.degree. C. until the aqueous layer was frozen.
The organic layer was then poured off and the solvent was removed
in vacuo at 50.degree. C. The resulting residue was dissolved in
CH.sub.2Cl.sub.2 (1 mL) and treated with 2M HCl in Et.sub.2O (3 mL)
and allowed to stir overnight at room temperature. The solvent was
removed under reduced pressure and the crude solid was purified by
HiTOPs.
Example 12
Synthesis of
N-((1-(2-(cyclopentylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3,5-bis(tri-
fluoromethyl)benzamide (Compound 93)
##STR00024##
[0116] A solution of
2-(4-((3,5-bis(trifluoromethyl)benzamido)methyl)piperidin-1-yl)acetic
acid (73 mg, 0.18 mmol), TEA (123 .mu.L, 0.88 mmol), and
cyclopentylamine (30 mg, 0.35 mmol) in DMF (1 mL) was treated with
a solution of HATU (100 mg, 0.26 mmol) in DMF (1 mL). The reaction
mixture was stirred overnight then transferred to a test tube
containing saturated aqueous NaHCO.sub.3 (4 mL) and EtOAc (4 mL).
The biphasic mixture was mixed vigourously and allowed to separate
for 15 min. After separation, the mixture was cooled to -20.degree.
C. until the aqueous layer was frozen. The organic layer was then
poured off and the solvent was removed under reduced pressure at
50.degree. C. The resulting residue was purified by HiTOPs.
Example 13
Synthesis of
3-bromo-5-(trifluoromethyl)-N-((1-(2-(trifluoromethylsulfonamido)ethyl)pi-
peridin-4-yl)methyl)benzamide (Compound 116)
##STR00025##
[0117] A. Synthesis of tert-butyl
(1-(2-(trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methylcarbamate
##STR00026##
[0119] To a solution of 2-aminoethanol (0.84 g, 13.8 mmol) and
triethylamine (3.85 mL, 27.7 mmol) in CH.sub.2Cl.sub.2 (100 mL) at
-78.degree. C. was added slowly trifluoromethanesulfonic anhydride
(8.4 g, 29.8 mmol). The reaction mixture was stirred at -78.degree.
C. for 2 hrs, warmed to -40.degree. C. and stirred at -40.degree.
C. overnight. The reaction mixture was then diluted with
CH.sub.2Cl.sub.2 (50 mL), washed with cold 0.1 N aqueous HCl
(2.times.150 mL) and cold saturated aqueous NaHCO.sub.3 (150 mL),
and dried over anhydrous N.alpha..sub.2SO.sub.4. After filtration
to the filtrate was added tert-butyl piperidin-4-ylmethylcarbamate
(3.00 g, 14.0 mmol). The reaction mixture was concentrated at
0.degree. C. to 50 mL and stirred at room temperature for 3 hrs.
The solvent was then removed, and the residue was purified by flash
chromatography (3-8% MeOH in CH.sub.2Cl.sub.2) to provide
tert-butyl (1-(2-(trifluoromethyl sulfonamido)
ethyl)piperidin-4-yl)methylcarbamate (1.40 g, 26%).
B. Synthesis of
N-(2-(4-(aminomethyl)piperidin-1-yl)ethyl)-1,1,1-trifluoromethanesulfonam-
ide di-HCl salt
##STR00027##
[0121] tert-Butyl
(1-(2-(trifluoromethylsulfonamido)ethyl)piperidin-4-yl)methylcarbamate
(1.25 g, 3.21 mmol) was dissolved in CH.sub.3OH (15 mL) and bubbled
with HCl(g) for 30 sec. After the reaction mixture was stirred at
room temperature for 15 min the solvent was removed in vacuo to
provide N-(2-(4-(aminomethyl)
piperidin-1-yl)ethyl)-1,1,1-trifluoromethanesulfonamide di-HCl salt
as a white solid (1.01 g, 87%).
C. Synthesis of
3-bromo-5-(trifluoromethyl)-N-((1-(2-(trifluoromethylsulfonamido)ethyl)pi-
peridin-4-yl)methyl)benzamide (Compound 116)
##STR00028##
[0123] To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid
(0.1 g, 0.37 mmol) in CH.sub.2Cl.sub.2 (4 mL) was added DIPEA (0.3
mL, 1.8 mmol), N-(2-(4-(aminomethyl)
piperidin-1-yl)ethyl)-1,1,1-trifluoromethanesulfonamide
dihydrochloride salt (0.1 g, 0.3 mmol) and HATU (0.17 g, 0.4 mmol).
The reaction mixture was stirred at room temperature for 2 h. The
organic layer was washed with sat. NaHCO.sub.3 aq. (8 mL), dried
over N.alpha..sub.2SO.sub.4, and concentrated to give crude product
as gummy solid. Purification of the crude material was done using
High Throughput Purification System (HiTOPs).
Example 14
Synthesis of
3,5-dichloro-N-((1-(2-(cyclopropanesulfonamido)ethyl)piperidin-4-yl)methy-
l)benzamide (Compound 131)
##STR00029##
[0124] A. Synthesis of tert-butyl
(1-(cyanomethyl)piperidin-4-yl)methylcarbamate
##STR00030##
[0126] tert-Butyl piperidin-4-ylmethylcarbamate (5 g, 23.2 mmol)
was dissolved in CH.sub.3CN (40 mL). Potassium carbonate (3.5 g, 25
mmol), DI PEA (4.4 mL, 25 mmol) and bromoacetonitrile (2.77 g, 23.2
mmol) were added, and the mixture was stirred at room temperature
overnight. The solution was then concentrated and saturated
NaHCO.sub.3 (40 mL) was added. The mixture was extracted with
CH.sub.2Cl.sub.2 (4.times.30 mL). The extract was dried over
anhydrous Na2SO4. The dried extract was passed through a silica gel
plug, and the desired compound was eluted off with EtOAc. The
product was further purified by crystallization from
EtOAc/petroleum ether as a white solid (5.4 g, 92%).
B. Synthesis of tert-butyl
(1-(2-aminoethyl)piperidin-4-yl)methylcarbamate
##STR00031##
[0128] To a hydrogenation flask charged with a solution of
tert-butyl (1-(cyanomethyl)piperidin-4-yl)methylcarbamate (5.4 g,
21.3 mmol) in CH.sub.3OH (20 mL) was added Raney nickel (.about.1
g, rinsed with CH.sub.3OH). The flask was shaken at room
temperature under hydrogen (40 psi) overnight. The reaction mixture
was then filtered through a celite cake, and the filtrate was
concentrated to give sticky foam which was used in the next step
without further purification.
C. Synthesis of tert-butyl
(1-(2-(cyclopropanesulfonamido)ethyl)piperidin-4-yl)methylcarbamate
##STR00032##
[0130] At 15.degree. C., to a solution of tert-butyl
(1-(2-aminoethyl)piperidin-4-yl)methylcarbamate (2.00 g, 7.78 mmol)
and DIPEA (3.00 g, 23.3 mmol) in CH.sub.2Cl.sub.2 (40 mL) was added
slowly cyclopropylsulfonyl chloride (3.40 g, 25.0 mmol) under Ar.
The reaction mixture was stirred at room temperature for 2 hrs.
Water (30 mL) was added, and the mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.30 mL). The combined extract was washed
with saturated NaHCO.sub.3 (40 mL) and dried over anhydrous
N.alpha..sub.2SO.sub.4. After filtration the solvent was removed in
vacuo, and the residue was applied to flash column chromatography
(3-7% CH.sub.3OH in CH.sub.2Cl.sub.2) to provide tert-butyl
(1-(2-(cyclopropanesulfonamido)ethyl)piperidin-4-yl)methylcarbamate
as pale yellow oil (2.2 g, 78%).
D. Synthesis of
N-(2-(4-(aminomethyl)piperidin-1-yl)ethyl)cyclopropanesulfonamide
di-HCl salt
##STR00033##
[0132] tert-Butyl
(1-(2-(cyclopropanesulfonamido)ethyl)piperidin-4-yl)methylcarbamate
(2.20 g, 6.09 mmol) was dissolved in CH.sub.3OH (15 mL) and bubbled
with HCl(g) for 30 sec. After the reaction mixture was stirred at
room temperature for 30 min the solvent was removed in vacuo to
provide N-(2-(4-(aminomethyl)
piperidin-1-yl)ethyl)cyclopropanesulfonamide di-HCl salt as a white
solid (1.8 g, 89%).
E. Synthesis of
3,5-dichloro-N-((1-(2-(cyclopropanesulfonamido)ethyl)piperidin-4-yl)methy-
l)benzamide (Compound 131)
##STR00034##
[0134] To a solution of 3,5-dichlorobenzoic acid (23 mg, 0.12 mmol)
in DMF (2 mL) was added DIPEA (0.1 mL, 0.6 mmol),
N-(2-(4-(aminomethyl)
piperidin-1-yl)ethyl)-1,1,1-trifluoromethanesulfonamide
dihydrochloride salt (40 mg, 0.12 mmol) and HATU (60 mg, 0.15
mmol). The reaction mixture was stirred at room temperature
overnight. The organic layer was washed with sat. NaHCO.sub.3 aq.
(8 mL), dried over N.alpha..sub.2SO.sub.4, and concentrated to give
crude product which was subsequently purified by High Throughput
Purification System (HiTOPs).
Example 15
Synthesis of
N-((1-(2-(tert-butylamino)acetyl)piperidin-4-yl)methyl)-3,5-bis(trifluoro-
methyl)benzamide (Compound 242)
##STR00035##
[0135] A. Synthesis of
N-((1-(2-chloroacetyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benz-
amide
##STR00036##
[0137] A solution of
N-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide (2.0 g,
5.66 mmol) and DIPEA (1.2 mL) in CH.sub.2Cl.sub.2 (10 mL) was added
2-chloroacetyl chloride (0.64, 5.66 mmol) dropwise, the mixture was
stirred overnight. The mixture was washed with water, dried with
N.alpha..sub.2SO.sub.4, filtered, and the solvent was removed in
vacuo. The residue was purified by automated flash chromatography
to yield the product (2.0 g, 82%).
B. Synthesis of
N-((1-(2-(tert-butylamino)acetyl)piperidin-4-yl)methyl)-3,5-bis(trifluoro-
methyl)benzamide (Compound 242)
##STR00037##
[0139] A solution of
N-((1-(2-chloroacetyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benz-
amide (50 mg, 0.12 mmol) and TEA (65 .mu.L, 0.46 mmol) in
CH.sub.3CN (1 mL) was stirred at room temperature overnight. The
reaction mixture was then diluted with EtOAc (4 mL) and washed with
saturated aqueous NaHCO.sub.3 (4 mL). The layers were allowed to
separate and the mixture was cooled to -20.degree. C. in the
freezer. After the aqueous layer had frozen, the organic layer was
poured off, and the solvent was removed in vacuo. The crude residue
was purified by reverse phase HPLC
Example 16
[0140] Following the general procedures set forth in Examples 1-15,
the following compounds listed in Table 1 below were prepared. Mass
spectrometry was employed with the final compound and at various
stages throughout the synthesis as a confirmation of the identity
of the product obtained (M+1). For the mass spectrometric analysis,
samples were prepared at an approximate concentration of 1 .mu.g/mL
in acetonitrile with 0.1% formic acid. Samples were then manually
infused into an Applied Biosystems API3000 triple quadrupole mass
spectrometer and scanned in Q1 in the range of 50 to 700 m/z.
TABLE-US-00001 TABLE 1 Mass Cmpd Spec No. Name Structure (m/z) 1
N-((1-((1- (methylsulfonamido)- cyclopentyl)methyl)-
piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide
##STR00038## 530.18 2 N-((1-((1- (cyclopropanesulfonamido)-
cyclopentyl)meth- yl)piperidin-4-yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00039## 556.19 3 N-((1-((1-
(ethylsulfonamido)cyclopentyl)- methyl)piperidin- 4-yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00040## 544.19 4 N-((1-((1-(1-
methylethylsulfonamido)- cyclopentyl)methyl)-
piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide
##STR00041## 558.21 5 3,5-bis(trifluoromethyl)- N-((1-((1-
(trifluoromethylsulfonamido)- cyclopentyl)meth- yl)piperidin-4-
yl)methyl)benzamide ##STR00042## 584.16 6
3-fluoro-N-((1-(2-methyl-2- (trifluoromethylsulfonamido)-
propyl)piperidin- 4-yl)methyl)-5- (trifluoromethyl)benzamide
##STR00043## 508.14 7 N-((1-(2-(ethylsulfonamido)-2-
methylpropyl)piperidin-4- yl)methyl)-3-fluoro-
5-(trifluoromethyl)benzamide ##STR00044## 468.19 8 N-((1-(2-
(cyclopropanesulfonamido)-2- methylpropyl)piperidin-4-
yl)methyl)-3-fluoro- 5-(trifluoromethyl)benzamide ##STR00045##
480.19 9 3-fluoro-N-((1-(2-methyl-2-(1- methylethylsulfonamido)-
propyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00046## 482.20 10 3-fluoro-N-((1-(2- methyl-2-(2,2,2-
trifluoroethylsulfonamido)- propyl)piperidin-4- yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00047## 522.16 11 N-((1-((1-(3-
ethylureido)cyclopentyl)- methyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)- benzamide ##STR00048## 523.24 12
N-((1-((1-(3-tert- butylureido)cyclopentyl)methyl)- piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)- benzamide ##STR00049## 551.27
13 N-((1-((1-(3- propylureido)cyclopentyl)- methyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)- benzamide ##STR00050## 537.25
14 N-((1-((1-(3- cyclohexylureido)cyclopentyl)- methyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00051## 577.28
15 N-((1-((1-(3- isopropylureido)cyclopentyl)- methyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00052## 537.25
16 methyl 1-((4-((3,5- bis(trifluoromethyl)benzamido)-
methyl)piperidin- 1-yl)methyl)- cyclopentylcarbamate ##STR00053##
510.21 17 ethyl 1-((4-((3,5- bis(trifluoromethyl)benzamido)-
methyl)piperidin- 1-yl)methyl)- cyclopentylcarbamate ##STR00054##
524.22 18 isobutyl 1-((4-((3,5- bis(trifluoromethyl)benzamido)-
methyl)piperidin- 1-yl)methyl)- cyclopentylcarbamate ##STR00055##
552.25 19 N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)- benzamide ##STR00056## 502.15
20 N-((1-(2-(1- methylethylsulfonamido)- ethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)- benzamide ##STR00057## 504.16
21 3,5-bis(trifluoromethyl)- N-((1-(2-
(trifluoromethylsulfonamido)- ethyl)piperidin-
4-yl)methyl)benzamide ##STR00058## 530.10 22 N-((1-(2-
(cyclopropylmethylsulfonamido)- ethyl)piperidin- 4-yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00059## 516.17 23 3-fluoro-5-
(trifluoromethyl)-N- ((1-(2-(3,3,3- trifluoropropyl-
sulfonamido)ethyl)- piperidin-4- yl)methyl)benzamide ##STR00060##
508.14 24 N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00061##
452.16 25 3,5-bis(trifluoromethyl)-N- ((1-(2-(3,3,3-
trifluoropropylsulfonamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00062## 558.14 26 3-fluoro-N-((1-(2-(2-
methylpropylsulfonamido)- ethyl)piperidin-4-
yl)methyl)-5-(trifluoromethyl)- benzamide ##STR00063## 468.19 27
N-((1-(2-(2- methylpropylsulfonamido)- ethyl)piperidin-4-
yl)methyl)-3,5-bis- (trifluoromethyl)benzamide ##STR00064## 518.18
28 N-((1-(2- (cyclopropylmethylsulfonamido)- ethyl)piperidin-
4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00065##
466.17 29 N-((1-(2-(methylsulfonamido)- ethyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00066## 476.14
30 N-((1-(2-(ethylsulfonamido)- ethyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00067## 490.15 31
N-((1-(2-(2,2,2- trifluoroethylsulfonamido)- ethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00068## 544.12
32 3-fluoro-N-((1-(2-(2,2,2- trifluoroethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)-5-(trifluoromethyl)- benzamide
##STR00069## 494.13 33 3-fluoro-5-(trifluoromethyl)- N-((1-(2-
(trifluoromethylsulfonamido)- ethyl)piperidin-
4-yl)methyl)benzamide ##STR00070## 480.11 34 3-fluoro-N-((1-(2-(1-
methylethylsulfonamido)- ethyl)piperidin-4- yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00071## 454.17 35 tert-butyl
2-(4-((3,5- bis(trifluoromethyl)- benzamido)methyl)piperidin-
1-yl)ethylcarbamate ##STR00072## 498.21 36 ethyl 2-(4-((3,5-
bis(trifluoromethyl)- benzamido)methyl)piperidin-
1-yl)ethylcarbamate ##STR00073## 470.18 37 isobutyl 2-(4-((3,5-
bis(trifluoromethyl)benzamido)- methyl)piperidin-
1-yl)ethylcarbamate ##STR00074## 498.21 38 tert-butyl
2-(4-((3-fluoro-5- (trifluoromethyl)benzamido)- methyl)piperidin-
1-yl)ethylcarbamate ##STR00075## 448.21 39 tert-butyl 2-(4-((3-
(trifluoromethyl)benzamido)- methyl)piperidin- 1-yl)ethylcarbamate
##STR00076## 430.22 40 tert-butyl 2-(4-((3-chloro-5-
(trifluoromethyl)benzamido)- methyl)piperidin- 1-yl)ethylcarbamate
##STR00077## 464.18 41 tert-butyl 2-(4-((3-bromo-5-
(trifluoromethyl)benzamido)- methyl)piperidin- 1-yl)ethylcarbamate
##STR00078## 508.13 42 tert-butyl 2-(4-((3,5-
dimethylbenzamido)methyl)- piperidin-1- yl)ethylcarbamate
##STR00079## 390.26 43 tert-butyl 2-(4-((3,5-
dichlorobenzamido)methyl)- piperidin-1- yl)ethylcarbamate
##STR00080## 430.15 44 tert-butyl 2-(4-((3-
(trifluoromethoxy)benzamido)- methyl)piperidin- 1-yl)ethylcarbamate
##STR00081## 446.21 45 tert-butyl 2-(4-((3-
(methylsulfonyl)benzamido)- methyl)piperidin- 1-yl)ethylcarbamate
##STR00082## 440.21 46 tert-butyl 2-(4-((4-
(methylsulfonyl)benzamido)- methyl)piperidin- 1-yl)ethylcarbamate
##STR00083## 440.21 47 tert-butyl 2-(4-((3,5- difluorobenzamido)-
methyl)piperidin-1- yl)ethylcarbamate ##STR00084## 398.21 48
tert-butyl 2-(4-((3- chlorobenzamido)- methyl)piperidin-1-
yl)ethylcarbamate ##STR00085## 396.19 49 tert-butyl
2-(4-((3,5-di-tert- butylbenzamido)- methyl)piperidin-1-
yl)ethylcarbamate ##STR00086## 474.36 50 tert-butyl 2-(4-((3-tert-
butoxybenzamido)- methyl)piperidin-1- yl)ethylcarbamate
##STR00087## 434.29 51 tert-butyl 2-(4-((2,4- difluorobenzamido)-
methyl)piperidin-1- yl)ethylcarbamate ##STR00088## 398.21 52
tert-butyl 2-(4-((3,4- dimethoxybenzamido)methyl)- piperidin-1-
yl)ethylcarbamate ##STR00089## 422.25 53 tert-butyl 2-(4-((2-
(trifluoromethyl)benzamido)- methyl)piperidin- 1-yl)ethylcarbamate
##STR00090## 430.22 54 tert-butyl 2-(4-((2,2-
difluorobenzo[d][1,3]dioxole-5- carboxamido)methyl)piperidin-1-
yl)ethylcarbamate ##STR00091## 442.20 55 tert-butyl 2-(4-((2-
(trifluoromethoxy)benzamido)- methyl)piperidin- 1-yl)ethylcarbamate
##STR00092## 446.21 56 tert-butyl 2-(4-((3,4,5-
trimethoxybenzamido)methyl)- piperidin-1- yl)ethylcarbamate
##STR00093## 452.26 57 tert-butyl 2-(4-((4-
phenoxybenzamido)methyl)- piperidin-1- yl)ethylcarbamate
##STR00094## 454.26 58 N-((1-(2-propionamidoethyl)- piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00095## 454.18
59 N-((1-(2- (cyclopropanecarboxamido)- ethyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00096## 466.18
60 N-((1-(2-pivalamidoethyl)- piperidin-4- yl)methyl)-3,5-bis-
(trifluoromethyl)benzamide ##STR00097## 482.21 61 N-(2-(4-((3,5-
bis(trifluoromethyl)benzamido)- methyl)piperidin- 1-yl)ethyl)-1-
methylpiperidine-4- carboxamide ##STR00098## 523.24 62 N-((1-(2-
(cyclopentanecarboxamido)- ethyl)piperidin-4- yl)methyl)-3,5-bis-
(trifluoromethyl)benzamide ##STR00099## 494.21 63 N-((1-(2-(2-
cyclopropylacetamido)- ethyl)piperidin-4- yl)methyl)-3,5-bis-
(trifluoromethyl)benzamide ##STR00100## 480.20 64
N-((1-(2-((1r,4r)-4- methylcyclohexanecarboxamido)-
ethyl)piperidin- 4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide
##STR00101## 522.24 65 N-((1-(2-(2-hydroxy-2-
methylpropanamido)ethyl)- piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00102## 484.19 66
N-((1-(2-(4,4,4- trifluorobutanamido)- ethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00103## 522.17
67 (R)-N-(2-(4-((3,5- bis(trifluoromethyl)benzamido)-
methyl)piperidin- 1-yl)ethyl)-5-oxopyrrolidine-2- carboxamide
##STR00104## 509.19 68 N-((1-(2-(3- methoxypropanamido)-
ethyl)piperidin-4- yl)methyl)-3,5- bis(trifluoromethyl)benzamide
##STR00105## 484.19 69 N-(2-(4-((3,5-
bis(trifluoromethyl)benzamido)- methyl)piperidin- 1-yl)ethyl)-1-
methylpiperidine-3- carboxamide ##STR00106## 523.24 70
N-((1-(2-(3-cyclohexylureido)- ethyl)piperidin- 4-yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00107## 523.24 71
N-((1-(2-(3-propylureido)- ethyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00108## 483.21 72
N-((1-(2-(3-tert- butylureido)ethyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00109## 410.72 73 N-((1-(2-(3-
isopropylureido)- ethyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00110## 483.21 74 N-((1-(2-(3-
ethylureido)ethyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00111## 461.02 75 N-((1-(2-(3-
(tetrahydrosulfonylphen-3- yl)ureido)ethyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00112## 551.01
76 (S)-N-((1-(2-hydroxy-3,3- dimethylbutanoyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00113## 469.18
77 N-((1-(4-hydroxypiperidine-4- carbonyl)pipendin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00114## 482.18
78 N-((1-(4-aminotetrahydro- 2H-pyran-4- carbonyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00115##
482.18
79 N-((1-(1- aminocyclopropanecarbonyl)- piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00116## 438.15
80 N-((1-((2R,4R)-4- hydroxypyrrolidine-2- carbonyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00117## 468.16
81 (R)-N-((1-(pyrrolidine-2- carbonyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00118## 452.17 82
(S)-N-((1-(pyrrolidine-2- carbonyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00119## 452.17 83
(R)-N-((1-(5-oxopyrrolidine-2- carbonyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00120## 466.15
84 N-((1-(4-hydroxypiperidine-4- carbonyl)piperidin-4-
yl)methyl)benzo[d]- [1,3]dioxole-5- carboxamide ##STR00121## 390.20
85 N-((1-(1- aminocyclopentanecarbonyl)- piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00122## 466.19
86 N-((1-(1- aminocyclohexanecarbonyl)- piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00123## 480.20
87 (R)-N-((1-(pyrrolidine- 2-carbonyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00124## 452.17 88
(S)-N-((1-(piperidine-2- carbonyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00125## 466.19 89
N-((1-(2-hydroxy-2,3,3- trimethylbutanoyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00126## 483.20
90 N-((1-(2-ethyl-2-hydroxy-3,3- dimethylbutanoyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00127## 497.22
91 N-((1-(2-hydroxy-3,3- dimethylbutanoyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00128## 469.18
92 N-((1-(2-(cyclopentylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00129## 480.20
93 N-((1-(2-(2- methylcyclohexylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00130## 508.23
94 N-((1-(2-(cyclohexylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00131## 494.22
95 N-((1-(2- (cyclopropylamino)-2- oxoethyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00132## 452.17
96 N-((1-(2-((1r,4r)-4- hydroxycyclohexylamino)-
2-oxoethyl)piperidin- 4-yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00133## 510.21 97
N-((1-(2-((1r,4r)-4- methylcyclohexylamino)- 2-oxoethyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00134## 508.23
98 N-((1-(2-(3- hydroxypiperidin-1-yl)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00135## 496.20
99 N-((1-(2-(3- methylpiperidin-1-yl)-2- oxoethyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00136## 494.22
100 N-((1-(2-(2- ethylpiperidin-1-yl)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00137## 508.23
101 N-((1-(2- (cyclohexyl(methyl)amino)-2- oxoethyl)piperidin-4-
methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00138## 508.23 102
N-((1-(2-(4- hydroxypiperidin-1-yl)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00139## 496.20
103 N-((1-(2-(4- methoxypiperidin-1-yl)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00140## 510.21
104 (R)-N-((1-(2-(2- methylpiperidin-1-yl)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00141## 494.22
105 N-((1-(2-(2- ethylpyrrolidin-1-yl)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00142## 494.22
106 N-((1-(2-(4- (hydroxymethyl)piperidin- 1-yl)-2-
oxoethyl)piperidin-4- yl)methyl)-3,5- bis(trifluoromethyl)benzamide
##STR00143## 510.21 107 N-((1-(2-oxo-2-(2-
(trifluoromethyl)pyrrolidin- 1-yl)ethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00144## 534.17
108 N-((1-(2-oxo-2-(4- (trifluoromethyl)piperidin-
1-yl)ethyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00145## 548.19 109
N-((1-(2-(3,3- difluoropiperidin-1-yl)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00146## 516.18
110 N-((1-(2-(4,4- difluoropiperidin-1-yl)-2- oxoethyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00147## 516.18
111 N-((1-(2-(4-tert- butylpiperidin-1-yl)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00148## 536.26
112 N-((1-(2-(4- cyanopiperidin-1-yl)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00149## 505.20
113 N-((1-(2-(4- morpholinopiperidin-1-yl)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00150## 565.25
114 N-((1-(2-(2- hydroxybutylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00151## 484.20
115 3-bromo-5-(trifluoromethyl)- N-((1-(2- (trifluoromethyl-
sulfonamido)ethyl)piperidin- 4-yl)methyl)benzamide ##STR00152##
540.03 116 3,5-dimethyl-N-((1-(2- (trifluoromethylsulfonamido)-
ethyl)piperidin- 4-yl)methyl)benzamide ##STR00153## 422.16 117
3-(trifluoromethyl)-N-((1-(2- (trifluoromethylsulfonamido)-
ethyl)piperidin- 4-yl)methyl)benzamide ##STR00154## 462.12 118
3-chloro-5- (trifluoromethyl)-N-((1-(2-
(trifluoromethylsulfonamido)- ethyl)piperidin-
4-yl)methyl)benzamide ##STR00155## 496.08 119
3,5-dichloro-N-((1-(2- (trifluoromethylsulfon-
amido)ethyl)piperidin- 4-yl)methyl)benzamide ##STR00156## 462.06
120 3-(trifluoromethoxy)-N-((1-(2- (trifluoromethylsulfon-
amido)ethyl)piperidin- 4-yl)methyl)benzamide ##STR00157## 478.12
121 3,5-difluoro-N-((1-(2- (trifluoromethylsulfon-
amido)ethyl)piperidin- 4-yl)methyl)benzamide ##STR00158## 430.11
122 3-chloro-N-((1-(2- (trifluoromethylsulfonamido)-
ethyl)piperidin- 4-yl)methyl)benzamide ##STR00159## 428.09 123
3,5-dimethoxy-N-((1-(2- (trifluoromethylsulfonamido)-
ethyl)piperidin- 4-yl)methyl)benzamide ##STR00160## 454.15 124
N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-3- (trifluoromethyl)benzamide ##STR00161## 434.16 125
3-chloro-N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-5- (trifluoromethyl)benzamide ##STR00162## 468.13 126
3-bromo-N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-5- (trifluoromethyl)benzamide ##STR00163## 512.08 127
N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-4-fluoro-3- (trifluoromethyl)benzamide ##STR00164##
452.16 128 N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-3,5- dimethylbenzamide ##STR00165## 394.21 129 N-((1-(2-
(cyclopropanesulfonamido)- ethyl)piperazin-4- yl)methyl)-3,5-
dimethoxybenzamide ##STR00166## 426.20 130 3,5-dichloro-N-((1-(2-
(cyclopropanesulfonamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00167## 434.10 131 N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)-3- (trifluoromethoxy)benzamide
##STR00168## 450.16 132 N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)-3- (methylsulfonyl)benzamide
##STR00169## 444.15 133 N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)-4- (methylsulfonyl)benzamide
##STR00170## 444.15 134 N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)-3,5- difluorobenzamide ##STR00171##
402.16 135 3-chloro-N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00172## 400.14 136
3-tert-butoxy-N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00173## 438.23 137
4-tert-butyl-N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00174## 422.24 138
N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-3-methoxy-5- (trifluoromethyl)benzamide ##STR00175##
464.18 139 N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-4- (trifluoromethoxy)benzamide ##STR00176## 450.16 140
3,5-dimethyl-N-((1-(2-(1- methylethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00177## 396.22 141
3-chloro-N-((1-(2-(1- methylethylsulfonamido)- ethyl)piperidin-4-
yl)methyl)benzamide ##STR00178## 402.15 142
3,5-difluoro-N-((1-(2-(1- methylethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00179## 404.17 143
4-tert-butyl-N-((1-(2-(1- methylethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00180## 424.26 144
3,5-dimethoxy-N-((1-(2-(1- methylethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00181## 428.21 145
3,5-dichloro-N-((1-(2-(1- methylethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00182## 436.11 146
N-((1-(2-(1- methylethylsulfonamido)- ethyl)piperidin-4-
yl)methyl)-3- (trifluoromethyl)benzamide ##STR00183## 436.18 147
3-tert-butoxy-N-((1-(2-(1- methylethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00184## 440.25 148
N-((1-(2-(1- methylethylsulfonamido)- ethyl)piperidin-4-
yl)methyl)-3- (trifluoromethoxy)benzamide ##STR00185## 452.18 149
3-methoxy-N-((1-(2-(1- methylethylsulfonamido)- ethyl)piperidin-4-
yl)methyl)-5- (trifluoromethyl)benzamide ##STR00186## 466.19 150
3-chloro-N-((1-(2-(1- methylethylsulfonamido)- ethyl)piperidin-4-
yl)methyl)-5- (trifluoromethyl)benzamide ##STR00187## 470.14 151
3-bromo-N-((1-(2-(1- methylethylsulfonamido)- ethyl)piperidin-4-
yl)methyl)-5- (trifluoromethyl)benzamide ##STR00188## 514.09 152
N-((1-(2-(1- methylethylsulfonamido)- ethyl)piperidin-4-
yl)methyl)-4- (trifluoromethoxy)benzamide ##STR00189## 452.18 153
N-(3,5-bis(trifluoromethyl)- phenyl)-2-(1-(2- hydroxy-3,3-
dimethylbutyl)piperidin-4- yl)acetamide ##STR00190## 455.21 154
N-(3,5-bis(trifluoromethyl)- phenyl)-2-(1-(2- hydroxy-2-
methylpropanoyl)piperidin-4- yl)acetamide ##STR00191## 441.15 155
(R)-N-(3,5- bis(trifluoromethyl)phenyl)- 2-(1- (2-hydroxy-3,3-
dimethylbutanoyl)piperidin-4- yl)acetamide ##STR00192## 469.18 156
N-(3,5-bis(trifluoromethyl)- phenyl)-2-(1-((4- hydroxypiperidin-4-
yl)methyl)piperidin-4- yl)acetamide ##STR00193## 468.20 157
N-(3,5-bis(trifluoromethyl)- phenyl)-2-(1-(4- hydroxypiperidine-4-
carbonyl)piperidin-4- yl)acetamide ##STR00194## 482.18 158
2-(1-(2-amino-2- methylpropanoyl)piperidin- 4-yl)-N-(3,5-
bis(trifluoromethyl)- phenyl)acetamide ##STR00195## 440.17 159
2-(1-((1-aminocyclopentyl)- methyl)piperidin- 4-yl)-N-(3,5-
bis(trifluoromethyl)- phenyl)acetamide ##STR00196## 452.21 160
N-(3,5-bis(trifluoromethyl)- phenyl)-2-(1-((1- (methylsulfonamido)-
cyclopentyl)methyl)- piperidin-4-yl)acetamide ##STR00197## 530.18
161 N-((1,5-dimethyl-1H- pyrazol-3-yl)methyl)-2- (1-(2-hydroxy-3,3-
dimethylbutyl)piperidin-4- yl)acetamide ##STR00198## 351.27
162 2-(1-(2-hydroxy-3,3- dimethylbutyl)piperidin-
4-yl)-N-((1-methyl-1H- imidazol-4- yl)methyl)acetamide ##STR00199##
337.25 163 N-(5-fluoropyridin-3-yl)- 2-(1-(2-hydroxy-3,3-
dimethylbutyl)piperidin- 4-yl)acetamide ##STR00200## 338.22 164
2-(1-(2-hydroxy-3,3- dimethylbutyl)piperidin- 4-yl)-N-(4-
(morpholinomethyl)- benzyl)acetamide ##STR00201## 432.31 165
2-(1-(2-hydroxy-3,3- dimethylbutyl)piperidin-
4-yl)-N-((5-methylisoxazol-3- yl)methypacetamide ##STR00202##
338.24 166 N-(1H-benzo[d]imidazol- 2-yl)-2-(1-(2- hydroxy-3,3-
dimethylbutyl)piperidin-4- yl)acetamide ##STR00203## 359.24 167
2-(1-(2-hydroxy-3,3- dimethylbutyl)piperidin- 4-yl)-N-(thiazol-2-
ylmethyl)acetamide ##STR00204## 340.20 168 2-(1-(2-hydroxy-3,3-
dimethylbutyl)piperidin- 4-yl)-N-(4- (trifluoromethyl)pyridin-2-
yl)acetamide ##STR00205## 388.21 169 N-(3-fluoro-5-
(trifluoromethyl)phenyl)-2-(1- (2-hydroxy-3,3-
dimethylbutyl)piperidin-4- yl)acetamide ##STR00206## 405.21 170
2-(1-(2-hydroxy-3,3- dimethylbutyl)piperidin-
4-yl)-N-(2-hydroxypyridin- 3-yl)acetamide ##STR00207## 336.22 171
2-(1-(2-hydroxy-3,3- dimethylbutyl)piperidin-
4-yl)-N-(4-(pyridin-2- yloxy)benzyl)acetamide ##STR00208## 426.27
172 2-(1-(2-hydroxy-3,3- dimethylbutyl)piperidin-
4-yl)-N-(4-p-tolylthiazol- 2-yl)acetamide ##STR00209## 416.23 173
N-(benzo[d]thiazol-2-yl)- 2-(1-(2-hydroxy-3,3-
dimethylbutyl)piperidin- 4-yl)acetamide ##STR00210## 376.20 174
2-(1-(2-hydroxy-3,3- dimethylbutyl)piperidin- 4-yl)-N-(4-
phenoxybenzyl)acetamide ##STR00211## 425.27 175
N-(3-(difluoromethoxy)- benzyl)-2-(1-(2- hydroxy-3,3-
dimethylbutyl)piperidin-4- yl)acetamide ##STR00212## 399.24 176
N-((2,3-dihydrobenzofuran- 5-yl)methyl)-2-(1- (2-hydroxy-3,3-
dimethylbutyl)piperidin-4- yl)acetamide ##STR00213## 375.26 177
N-(4-fluorophenethyl)- 2-(1-(2-hydroxy-3,3-
dimethylbutyl)piperidin- 4-yl)acetamide ##STR00214## 365.25 178
N-(3,5-bis(trifluoromethyl)- phenyl)-2-(1- (3,3,3-trifluoro-2-
hydroxypropyl)piperidin-4- yl)acetamide ##STR00215## 467.13 179
N-(3,5-bis(trifluoromethyl)- phenyl)-2-(1-((1-
(cyclopropanesulfonamido)- cyclopentyl)meth-
yl)piperidin-4-yl)acetamide ##STR00216## 556.20 180
(2S,4R)-tert-butyl 2-(4-(2-(3,5- bis(trifluoromethyl)-
phenylamino)-2- oxoethyl)piperidine-1- carbonyl)-4-
hydroxypyrrolidine-1- carboxylate ##STR00217## 568.22 181
tert-butyl 1-(4-(2-(3,5- bis(trifluoromethyl)- phenylamino)-2-
oxoethyl)piperidine-1- carbonyl)cyclohexylcarbamate ##STR00218##
580.25 182 tert-butyl 1-(4-(2-(3,5- bis(trifluoromethyl)-
phenylamino)-2- oxoethyl)piperidine-1-
carbonyl)cyclopropylcarbamate ##STR00219## 538.21 183
(R)-tert-butyl 2-(4-(2-(3,5- bis(trifluoromethyl)- phenylamino)-2-
oxoethyl)piperidine-1- carbonyl)pyrrolidine-1- carboxylate
##STR00220## 552.22 184 (S)-tert-butyl 2-(4-(2-(3,5-
bis(trifluoromethyl)- phenylamino)-2- oxoethyl)piperidine-1-
carbonyl)pyrrolidine-1- carboxylate ##STR00221## 552.22 185
tert-butyl 1-(4-(2-(3,5- bis(trifluoromethyl)- phenylamino)-2-
oxoethyl)piperidin-1- yl)-2-methyl-1- oxopropan-2-
yl(methyl)carbamate ##STR00222## 554.24 186 tert-butyl
4-(4-(2-(3,5- bis(trifluoromethyl)- phenylamino)-2-
oxoethyl)piperidine-1- carbonyl)tetrahydro- 2H-pyran-4-ylcarbamate
##STR00223## 582.23 187 tert-butyl 2-(4-(2-(3,5-
bis(trifluoromethyl)- phenylamino)-2- oxoethyl)piperidine-1-
carbonyl)piperidine-1- carboxylate ##STR00224## 566.24 188
N-(3,5-bis(trifluoromethyl)- phenyl)-2-(1- ((2S,4R)-4-
hydroxypyrrolidine-2- carbonyl)piperidin-4- yl)acetamide
##STR00225## 468.16 189 2-(1-(1- aminocyclohexanecarbonyl)-
piperidin-4-yl)- N-(3,5-bis(trifluoromethyl)- phenyl)acetamide
##STR00226## 480.20 190 2-(1-(1- aminocyclopropane-
carbonyl)piperidin-4-yl)- N-(3,5-bis(trifluoromethyl)-
phenyl)acetamide ##STR00227## 438.15 191 (R)-N-(3,5-
bis(trifluoromethyl)phenyl)- 2-(1- (pyrrolidine-2-
carbonyl)piperidin-4- yl)acetamide ##STR00228## 452.17 192
(S)-N-(3,5- bis(trifluoromethyl)phenyl)- 2-(1- (pyrrolidine-2-
carbonyl)piperidin-4- yl)acetamide ##STR00229## 452.17 193
N-(3,5-bis(trifluoromethyl)- phenyl)-2-(1-(2- methyl-2-
(methylamino)propanoyl)- piperidin- 4-yl)acetamide ##STR00230##
454.19 194 2-(1-(4-aminotetrahydro- 2H-pyran-4-
carbonyl)piperidin-4- yl)-N-(3,5- bis(trifluoromethyl)phenyl)-
acetamide ##STR00231## 482.18 195 (S)-N-(3,5-
bis(trifluoromethyl)phenyl)- 2-(1- (piperidine-2-
carbonyl)piperidin-4- yl)acetamide ##STR00232## 466.19 196
tert-butyl 1-(4-(2-(2- (5-fluoro-1H-indol-3- yl)ethylamino)-2-
oxoethyl)piperidin-1-yl)-3,3- dimethylbutan-2-ylcarbamate
##STR00233## 503.33 197 tert-butyl 1-(4-(2-(2- (1H-indol-3-
yl)ethylamino)-2- oxoethyl)piperidin-1-yl)-3,3-
dimethylbutan-2-ylcarbamate ##STR00234## 485.34 198 tert-butyl
1-(4-(2-(3,5- dichlorobenzylamino)- 2-oxoethyl)piperidin-1-
yl)-3,3-dimethylbutan- 2-ylcarbamate ##STR00235## 500.24 199
2-(1-(2-amino-3,3- dimethylbutyl)piperidin-4-
yl)-N-(2-(5-fluoro-1H-indol-3- yl)ethyl)acetamide ##STR00236##
403.28 200 N-(2-(1H-indol-3-yl)ethyl)- 2-(1-(2-amino-3,3-
dimethylbutyl)piperidin-4- yl)acetamide ##STR00237## 385.29 201
2-(1-(2-amino-3,3- dimethylbutyl)piperidin-4- yl)-N-(3,5-
dichlorobenzyl)acetamide ##STR00238## 400.18 202
2-(1-(3,3-dimethyl-2- (methylsulfonamido)butyl)- piperidin-4-yl)-N-
(2-(5-fluoro-1H-indol- 3-yl)ethyl)acetamide ##STR00239## 481.26 203
2-(1-(2-(ethylsulfonamido)-3,3- dimethylbutyl)piperidin-
4-yl)-N-(2-(5-fluoro- 1H-indol-3-yl)ethyl)acetamide ##STR00240##
495.27 204 2-(1-(2- (cyclopropanesulfonamido)-3,3-
dimethylbutyl)piperidin- 4-yl)-N-(2-(5-fluoro-
1H-indol-3-yl)ethyl)acetamide ##STR00241## 507.27 205
2-(1-(3,3-dimethyl-2- (trifluoromethylsulfonamido)-
butyl)piperidin- 4-yl)-N-(2-(5-fluoro-1H-indol-3-
yl)ethyl)acetamide ##STR00242## 535.23 206 2-(1-(3,3-dimethyl-2-(1-
methylethylsulfonamido)- butyl)piperidin-4-yl)- N-(2-(5-fluoro-1H-
indol-3-yl)ethyl)acetamide ##STR00243## 509.29 207
N-(3,5-dichlorobenzyl)-2- (1-(3,3-dimethyl-2-
(methylsulfonamido)butyl)- piperidin-4- yl)acetamide ##STR00244##
478.16 208 N-(3,5-dichlorobenzyl)-2-(1-(2- (ethylsulfonamido)-3,3-
dimethylbutyl)piperidin- 4-yl)acetamide ##STR00245## 492.18 209
2-(1-(2- (cyclopropanesulfonamido)-3,3- dimethylbutyl)piperidin-
4-yl)-N-(3,5- dichlorobenzyl)acetamide ##STR00246## 504.18 210
N-(3,5-dichlorobenzyl)-2- (1-(3,3-dimethyl-2-
(trifluoromethylsulfonamido)- butyl)piperidin- 4-yl)acetamide
##STR00247## 532.13 211 N-(3,5-dichlorobenzyl)-2-
(1-(3,3-dimethyl-2- (1-methylethylsulfonamido)- butyl)piperidin-4-
yl)acetamide ##STR00248## 506.19 212 N-(2-(1H-indol-3-
yl)ethyl)-2-(1-(2- (cyclopropanesulfonamido)- 3,3-
dimethylbutyl)piperidin- 4-yl)acetamide ##STR00249## 489.28 213
N-(2-(1H-indol-3-yl)ethyl)- 2-(1-(3,3-dimethyl-
2-(methylsulfonamido)- butyl)piperidin-4- yl)acetamide ##STR00250##
463.27 214 N-(2-(1H-indol-3- yl)ethyl)-2-(1-(3,3-dimethyl- 2-
(trifluoromethylsulfonamido)- butyl)piperidin- 4-yl)acetamide
##STR00251## 517.24 215 N-(2-(1H-indol-3-yl)ethyl)-
2-(1-(3,3-dimethyl- 2-(1-methylethylsulfonamido)- butyl)piperidin-
4-yl)acetamide ##STR00252## 491.30 216 tert-butyl 1-(4-(2-(bis(3-
fluorophenyl)methylamino)-2- oxoethyl)piperidin-1-yl)-
3,3-dimethylbutan-2- ylcarbamate ##STR00253## 544.33 217
2-(1-(2-amino-3,3- dimethylbutyl)piperidin-4- yl)-N-(bis(3-
fluorophenyl)methyl)acetamide ##STR00254## 444.27 218 2-(1-(1-
aminocyclopentanecarbonyl)- piperidin-4-yl)-
N-(3,5-bis(trifluoromethyl)- phenyl)acetamide ##STR00255## 466.19
219 N-(bis(3-fluorophenyl)- methyl)-2-(1-(3,3- dimethyl-2-
(methylsulfonamido)- butyl)piperidin-4- yl)acetamide ##STR00256##
522.25 220 N-(bis(3-fluorophenyl)- methyl)-2-(1-(2-
(ethylsulfonamido)-3,3- dimethylbutyl)piperidin- 4-yl)acetamide
##STR00257## 536.27 221 N-(bis(3- fluorophenyl)methyl)-2-(1-(2-
(cyclopropanesulfonamido)- 3,3- dimethylbutyl)piperidin-4-
yl)acetamide ##STR00258## 548.27 222 N-(bis(3-fluorophenyl)methyl)-
2-(1-(3,3- dimethyl-2-(1- methylethylsulfonamido)butyl)-
piperidin-4- yl)acetamide ##STR00259## 550.28 223 methyl
1-(4-(2-(3,5- dichlorobenzylamino)-2- oxoethyl)piperidin-1-
yl)-3,3-dimethylbutan-2- ylcarbamate ##STR00260## 458.19 224 ethyl
1-(4-(2-(3,5- dichlorobenzylamino)-2- oxoethyl)piperidin-1-
yl)-3,3-dimethylbutan-2- ylcarbamate ##STR00261## 472.21 225
isobutyl 1-(4-(2-(3,5- dichlorobenzylamino)-2-
oxoethyl)piperidin-1- yl)-3,3-dimethylbutan-2- ylcarbamate
##STR00262## 500.24 226 N-((1-(2-(3,3- difluoropyrrolidin-1-
yl)acetyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00263## 502.42 227
N-((1-(2-(3,3- difluoropyrrolidin-1- yl)acetyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00264##
452.41 228 N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-3- (trifluoromethyl)benzamide ##STR00265## 434.49 229
3-tert-butoxy-N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00266## 438.60 230
N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00267##
452.48 231 (E)-N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)-3-(3,5- difluorophenyl)acrylamide
##STR00268## 428.51 232 N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)-4- (trifluoromethoxy)benzamide
##STR00269## 450.49 233 N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)-3,5- dimethylbenzamide ##STR00270##
394.55 234 N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-3- (trifluoromethoxy)benzamide ##STR00271## 450.49 235
N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-3-methoxy-5- (trifluoromethyl)benzamide ##STR00272##
464.52 236 3-chloro-N-((1-(2-(1- methylethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00273## 402.96 237
N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-2-(3- fluorophenyl)acetamide ##STR00274## 398.51
238 4-tert-butyl-N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00275## 422.60 239
N-((1-(2-(tert- butylamino)acetyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00276## 468.45 240
N-((1-(2-(3-hydroxypiperidin-1- yl)acetyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00277## 496.46
241 N-((1-(2-(pentylamino)- acetyl)piperidin-4- yl)methyl)-3,5-bis-
(trifluoromethyl)benzamide ##STR00278## 482.48 242
N-((1-(2-(3-methylpiperidin-1- yl)acetyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00279## 494.49
243 N-((1-(2-(2-ethylpiperidin-1- yl)acetyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00280## 508.52
244 N-((1-(2-(3- morpholinopropylamino)- acetyl)piperidin-4-
yl)methyl)-3,5-bis- (trifluoromethyl)benzamide ##STR00281## 539.53
245 N-((1-(2-(3- (dimethylamino)propylamino)- acetyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00282## 497.50
246 N-((1-(2- (cyclohexyl(methyl)amino)- acetyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00283## 508.52
247 N-((1-(2- (cyclopentylamino)- acetyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00284## 480.46
248 N-((1-(2-(2- methylcyclohexylamino)- acetyl)piperidin-4-
yl)methyl)-3,5-bis- (trifluoromethyl)benzamide ##STR00285## 508.52
249 N-((1-(2-(cyclohexylamino)- acetyl)piperidin- 4-yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00286## 494.49 250 N-((1-(2-(4-
hydroxypiperidin-1- yl)acetyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00287## 496.46 251
N-((1-(2-(4-methoxypiperidin-1- yl)acetyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00288## 510.49
252 (R)-N-((1-(2-(2- methylpiperidin-1- yl)acetyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00289## 494.49
253 N-((1-(2-(2-ethylpyrrolidin-1- yl)acetyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00290## 494.49
254 N-((1-(2-(4- (hydroxymethyl)piperidin-1- yl)acetyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00291## 510.49
255 3,5-bis(trifluoromethyl)- N-((1-(2-(3-
(trifluoromethyl)piperidin-1- yl)acetyl)piperidin-4-
yl)methyl)benzamide ##STR00292## 548.46 256 N-((1-(2-(3,3-
difluoropiperidin-1- yl)acetyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00293## 516.44 257 N-((1-(2-
(cyclopropylamino)acetyl)- piperidin- 4-yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00294## 452.41 258
N-((1-(2-(4-tert- butylpiperidin-1- yl)acetyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00295## 536.57
259 N-((1-(2-(4-cyanopiperidin-1- yl)acetyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00296## 505.47
260 N-((1-(2-(4- morpholinopiperidin-1- yl)acetyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00297## 565.57
261 N-((1-(2-(2,6- dimethylmorpholino)- acetyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00298## 510.49
262 N-((1-(2- morpholinoacetyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00299## 482.44 263
(R)-N-((1-(2-(3- hydroxypyrrolidin-1- yl)acetyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00300## 482.44
264 N-((1-(2-((1r,4r)-4- methylcyclohexylamino)-
acetyl)piperidin-4- yl)methyl)-3,5-bis- (trifluoromethyl)benzamide
##STR00301## 508.52 265 N-((1-(2-(tert-
butylamino)acetyl)piperidin-4- yl)methyl)-3-fluoro-5-
(trifluoromethyl)benzamide ##STR00302## 418.45 266
3-fluoro-N-((1-(2-(3- hydroxypiperidin-1- yl)acetyl)piperidin-4-
yl)methyl)-5- (trifluoromethyl)benzamide ##STR00303## 446.46 267
3-fluoro-N-((1-(2- (pentylamino)acetyl)pipendin- 4-yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00304## 432.47 268
3-fluoro-N-((1-(2-(3- methylpiperidin-1- yl)acetyl)piperidin-4-
yl)methyl)-5- (trifluoromethyl)benzamide ##STR00305## 444.48 269
N-((1-(2-(2-ethylpiperidin-1- yl)acetyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00306##
458.51 270 3-fluoro-N-((1-(2-(3- morpholinopropylamino)-
acetyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00307## 489.53 271 N-((1-(2-(3- (dimethylamino)propylamino)-
acetyl)piperidin- 4-yl)methyl)-3-fluoro-5-
(trifluoromethyl)benzamide ##STR00308## 447.49 272 N-((1-(2-
(cyclohexyl(methyl)- amino)acetyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00309##
458.51 273 N-((1-(2-(cyclopentylamino)- acetyl)piperidin-
4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00310##
430.46 274 3-fluoro-N-((1-(2-(2- methylcyclohexylamino)-
acetyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00311## 458.51 275 3-fluoro-N-((1-(2-(2-
hydroxycyclohexylamino)- acetyl)piperidin-4- yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00312## 460.48 276
N-((1-(2-(cyclohexylamino)- acetyl)piperidin-
4-yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00313##
444.48 277 3-fluoro-N-((1-(2-(4- hydroxypiperidin-1-
yl)acetyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00314## 446.46 278 3-fluoro-N-((1-(2-(4- methoxypiperidin-1-
yl)acetyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00315## 460.48 279 (R)-3-fluoro-N-((1-(2-
(2-methylpiperidin-1- yl)acetyl)piperidin-4- yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00316## 444.48 280
N-((1-(2-(2-ethylpyrrolidin-1- yl)acetyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00317##
444.48 281 3-fluoro-N-((1-(2-(4- (hydroxymethyl)piperidin-1-
yl)acetyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00318## 460.48 282 3-fluoro-5-(trifluoromethyl)- N-((1-(2-(3-
(trifluoromethyl)piperidin-1- yl)acetyl)piperidin-4-
yl)methyl)benzamide ##STR00319## 498.45 283 N-((1-(2-(3,3-
difluoropiperidin-1- yl)acetyl)piperidin-4- yl)methyl)-3-fluoro-5-
(trifluoromethyl)benzamide ##STR00320## 466.44 284 N-((1-(2-
(cyclopropylamino)- acetyl)piperidin- 4-yl)methyl)-3-fluoro-5-
(trifluoromethyl)benzamide ##STR00321## 402.40 285
N-((1-(2-(4-tert- butylpiperidin-1- yl)acetyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00322##
486.57 286 N-((1-(2-(4-cyanopiperidin-1- yl)acetyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00323##
455.47 287 3-fluoro-N-((1-(2-(4- morpholinopiperidin-1-
yl)acetyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00324## 515.56 288 N-((1-(2-(2,6- dimethylmorpholino)-
acetyl)piperidin-4- yl)methyl)-3-fluoro-5-
(trifluoromethyl)benzamide ##STR00325## 460.48 289
3-fluoro-N-((1-(2- morpholinoacetyl)piperidin- 4-yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00326## 432.43 290
(R)-3-fluoro-N-((1- (2-(3-hydroxypyrrolidin-1-
yl)acetyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00327## 432.43 291 3-fluoro-N-((1-(2-((1r,4r)-4-
methylcyclohexylamino)- acetyl)piperidin-4- yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00328## 458.51 292
N-((1-(2-pivalamidoethyl)- piperidin-4- yl)methyl)-3-
(trifluoromethoxy)benzamide ##STR00329## 430.48 293
3,5-difluoro-N-((1-(2- pivalamidoethyl)piperidin-4-
yl)methyl)benzamide ##STR00330## 382.47 294 3-fluoro-N-((1-(2-
pivalamidoethyl)piperidin- 4-yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00331## 432.47 295
3,5-dimethyl-N-((1-(2- pivalamidoethyl)piperidin-4-
yl)methyl)benzamide ##STR00332## 374.54 296 N-((1-(2-
pivalamidoethyl)piperidin-4- yl)methyl)-3-
(trifluoeomethyl)benzamide ##STR00333## 414.48 297 (E)-3-(3,5-
difluorophenyl)-N-((1-(2- pivalamidoethyl)piperidin-4-
yl)methyl)acrylamide ##STR00334## 408.50 298 3,5-dichloro-N-((1-(2-
pivalamidoethyl)piperidin-4- yl)methyl)benzamide ##STR00335##
415.38 299 3-chloro-N-((1-(2- pivalamidoethyl)piperidin-
4-yl)methyl)benzamide ##STR00336## 380.93 300 (E)-3-(3,5-
dichlorophenyl)-N-((1-(2- pivalamidoethyl)piperidin-4-
yl)methyl)acrylamide ##STR00337## 441.41 301 3-chloro-N-((1-(2-
pivalamidoethyl)piperidin- 4-yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00338## 448.93 302
3-bromo-N-((1-(2- pivalamidoethyl)piperidin- 4-yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00339## 493.38 303
3-methoxy-N-((1-(2- pivalamidoethyl)piperidin- 4-yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00340## 444.51 304 N-((1-(2-(2-
cyanopropan-2-ylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00341## 479.44 305 N-((1-(2-(4-
ethoxypiperidin-1-yl)-2- oxoethyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00342## 524.52 306 N-((1-(2-
(cyclobutanesulfonamido)- ethyl)piperidin-4- yl)methyl)-3-fluoro-5-
(trifluoromethyl)benzamide ##STR00343## 466.51 307 N-((1-(2-
(cyclopentanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00344##
480.54 308 3-fluoro-N-((1-(2-(3- fluoropropylsulfonamido)-
ethyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00345## 472.49 309 3-chloro-5-fluoro-N-((1-(2-
pivalamidoethyl)piperidin-4- yl)methyl)benzamide ##STR00346##
398.92 310 N-((1-(2- pivalamidoethyl)piperidin-4- yl)methyl)-4-
(trifluoromethyl)picolinamide ##STR00347## 415.47 311
N-((1-(2-(4,4,4- trifluorobutanamido)- ethyl)piperidin-4-
yl)methyl)-3- (trifluoromethoxy)benzamide ##STR00348## 470.43 312
3,5-dimethyl-N-((1-(2-(4,4,4- trifluorobutanamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00349## 414.48 313
N-((1-(2-(4,4,4- trifluorobutanamido)- ethyl)piperidin-4-
yl)methyl)-3- (trifluoromethyl)benzamide ##STR00350## 454.43 314
(E)-N-(2-(4-((3-(3,5- difluorophenyl)- acrylamido)methyl)piperidin-
1-yl)ethyl)-4,4,4- trifluorobutanamide ##STR00351## 448.45 315
3-chloro-N-((1-(2-(4,4,4- trifluorobutanamido)- ethyl)piperidin-4-
yl)methyl)benzamide ##STR00352## 420.87 316 (E)-N-(2-(4-((3-(3,5-
dichlorophenyl)- acrylamido)methyl)piperidin- 1-yl)ethyl)-4,4,4-
trifluorobutanamide ##STR00353## 481.36 317
3-methoxy-N-((1-(2-(4,4,4- trifluorobutanamido)- ethyl)piperidin-4-
yl)methyl)-5- (trifluoromethyl)benzamide ##STR00354## 484.45 318
3-fluoro-5-methoxy-N-((1-(2-(1- methylethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00355## 416.53 319
3,5-dibromo-N-((1-(2-(1- methylethylsulfonamido)-
ethyl)piperidin-4-
yl)methyl)benzamide ##STR00356## 526.31 320
3-chloro-5-methoxy-N-((1-(2-(1- methylethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00357## 432.98 321
N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-3-fluoro-5- methoxybenzamide ##STR00358## 414.51 322
3-chloro-N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-5-methoxybenzamide ##STR00359## 430.97 323
3-bromo-N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)benzamide ##STR00360## 445.40 324 N-((1-(2-
(cyclopropanesulfonamido)- ethyl)piperidin-4- yl)methyl)-3,4-
dimethoxybenzamide ##STR00361## 426.55 325
3-fluoro-5-methoxy-N-((1-(2- (trifluoromethylsulfonamido)-
ethyl)piperidin- 4-yl)methyl)benzamide ##STR00362## 442.44 326
3-chloro-5-methoxy-N-((1-(2- (trifluoromethylsulfonamido)-
ethyl)piperidin- 4-yl)methyl)benzamide ##STR00363## 458.90 327
3-methoxy-5-(trifluoromethyl)- N-((1-(2-
(trifluoromethylsulfonamido)- ethyl)piperidin-
4-yl)methyl)benzamide ##STR00364## 492.45 328
3-fluoro-4-(trifluoromethyl)- N-((1-(2-
(trifluoromethylsulfonamido)- ethyl)piperidin-
4-yl)methyl)benzamide ##STR00365## 480.41 329
3-chloro-5-fluoro-N-((1-(2- (trifluoromethylsulfonamido)-
ethyl)piperidin- 4-yl)methyl)benzamide ##STR00366## 446.86 330
3-bromo-N-((1-(2- (trifluoromethylsulfonamido)- ethyl)piperidin-
4-yl)methyl)benzamide ##STR00367## 473.33 331
3-fluoro-5-methyl-N-((1-(2- (trifluoromethylsulfonamido)-
ethyl)piperidin- 4-yl)methyl)benzamide ##STR00368## 426.44 332
3,4-dimethoxy-N-((1-(2- (trifluoromethylsulfonamido)-
ethyl)piperidin- 4-yl)methyl)benzamide ##STR00369## 454.48 333
2,5-dichloro-N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)thiophene-3- carboxamide ##STR00370##
441.41 334 N-(2-(4-(2-(3,5- bis(trifluoromethyl)- phenylamino)-2-
oxoethyl)piperidin-1- yl)ethyl)pivalamide ##STR00371## 482.48 335
N-((1-(2-(2-fluoro-2- methylpropanamido)- ethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00372## 486.44
336 3-fluoro-N-((1-(2-(2-fluoro-2- methylpropanamido)-
ethyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00373## 436.44 337 N-((1-(2-(1- methylcyclopropane-
carboxamido)- ethyl)- piperidin-4-yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00374## 480.46 338
N-((1-(2-(3,3,3-trifluoro-2,2- dimethylpropanamido)ethyl)-
piperidin-4- yl)methyl)-3,5- bis(trifluoromethyl)benzamide
##STR00375## 536.45 339 3-fluoro-N-((1-(2-(3,3,3- trifluoro-2,2-
dimethylpropanamido)- ethyl)piperidin-4- yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00376## 486.44 340
3,5-bis(trifluoromethyl)- N-((1-(2-(1- (trifluoromethyl)-
cyclopentanecarboxamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00377## 562.49 341 3-fluoro-5-(trifluoromethyl)- N-((1-(2-(1-
(trifluoromethyl)- cyclopentanecarboxamido)- ethyl)piperidin-4-
yl)methyl)benzamide ##STR00378## 512.48 342
3,5-bis(trifluoromethyl)- N-((1-(2-(1- (trifluoromethyl)-
cyclopropanecarboxamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00379## 534.43 343 3-fluoro-5-(trifluoromethyl)- N-((1-(2-(1-
(trifluoromethyl)- cyclopropanecarboxamido)- ethyl)piperidin-4-
yl)methyl)benzamide ##STR00380## 484.43 344
N-((1-(2-(isopropylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00381## 454.43 345
N-((1-(2-oxo-2- (propylamino)ethyl)piperidin- 4-yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00382## 454.43 346
N-((1-(2-oxo-2-(tert- pentylamino)ethyl)piperidin-
4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00383## 482.48
347 N-((1-(2-(1,3-dimethoxypropan- 2-ylamino)-
2-oxoethyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00384## 514.48 348
(S)-N-((1-(2-oxo-2-(3- (trifluoromethyl)pyrrolidin-1-
yl)ethyl)piperidin-4- yl)methyl)-3,5- bis(trifluoromethyl)benzamide
##STR00385## 534.43 349 N-((1-(2-(4- fluoropiperidin-1-yl)-2-
oxoethyl)piperidin-4- yl)methyl)-3,5- bis(trifluoromethyl)benzamide
##STR00386## 498.45 350 3-fluoro-N-((1-(2- (isopropylamino)-2-
oxoethyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00387## 404.42 351 3-fluoro-N-((1-(2-oxo-2-
(propylamino)ethyl)piperidin- 4-yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00388## 404.42 352
3-fluoro-N-((1-(2-(1- methylcyclobutylamino)-
2-oxoethyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00389## 430.46 353 3-fluoro-N-((1-(2-oxo-2-(tert-
pentylamino)ethyl)piperidin- 4-yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00390## 432.47 354
N-((1-(2-(1,3-dimethoxypropan- 2-ylamino)- 2-oxoethyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00391##
464.47 355 (S)-3-fluoro-N-((1-(2-oxo-2-(3-
(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4- yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00392## 484.43 356
3-fluoro-N-((1-(2-(4- fluoropiperidin-1-yl)-2-
oxoethyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00393## 448.45 357 N-((1-((1- (methylsulfonamido)-
cyclopropyl)methyl)- piperidin-4-yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00394## 502.49 358 N-((1-((1-
(ethylsulfonamido)- cyclopropyl)methyl)-
piperidin-4-yl)methyl)-3,5- bis(trifluoromethyl)benzamide
##STR00395## 516.52 359 N-((1-((1- (cyclopropanesulfonamido)-
cyclopropyl)methyl)- piperidin-4-yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00396## 528.53 360
3,5-bis(trifluoromethyl)-N- ((1-((1-(3,3,3-
trifluoropropylsulfonamido)- cyclopropyl)- methyl)piperidin-4-
yl)methyl)benzamide ##STR00397## 584.51 361 N-((1-((1-
pivalamidocyclopropyl)- methyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00398## 508.52 362
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3,5-
dimethylbenzamide ##STR00399## 360.51 363
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3-fluoro-5- methylbenzamide ##STR00400## 364.48 364
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3-
chlorobenzamide ##STR00401## 366.90 365
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3,5-
difluorobenzamide ##STR00402## 368.44 366
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3-fluoro-5- methoxybenzamide ##STR00403## 380.48 367
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3-chloro-5- fluorobenzamide ##STR00404## 384.89 368
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3,5-
dimethoxybenzamide ##STR00405## 392.51 369 (E)-N-((1-(2-(tert-
butylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3-(3,5-
difluorophenyl)acrylamide ##STR00406## 394.48 370
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3,5-
dichlorobenzamide ##STR00407## 401.35 371
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3-
(trifluoromethyl)benzamide ##STR00408## 400.46 372
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4- yl)methyl)-4-
(trifluoromethyl)picolinamide ##STR00409## 401.44 373
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-2-(pyrrolidin- 1-yl)isonicotinamide ##STR00410## 402.55
374 3-bromo-N-((1-(2- (tert-butylamino)-2- oxoethyl)piperidin-4-
yl)methyl)benzamide ##STR00411## 411.36 375
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3-
(trifluoromethoxy)benzamide ##STR00412## 416.46 376
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00413##
418.45 377 N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- diethoxybenzamide ##STR00414## 420.57 378
(E)-N-((1-(2-(tert- butylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3-(3,5- dichlorophenyl)acrylamide ##STR00415## 427.39
379 N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3-methoxy-5- (trifluoromethyl)benzamide ##STR00416##
430.48 380 N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3-chloro-5- (trifluoromethyl)benzamide ##STR00417##
434.90 381 3-bromo-N-((1-(2- (tert-butylamino)-2-
oxoethyl)piperidin-4- yl)methyl)-5- chlorobenzamide ##STR00418##
445.81 382 3-bromo-N-((1-(2- (tert-butylamino)-2-
oxoethyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00419## 479.36 383 2-(3,5- bis(trifluoromethyl)phenyl)-
N-((1-(2- (tert-butylamino)-2- oxoethyl)piperidin-4-
yl)methyl)acetamide ##STR00420## 482.48 384 3,5-dibromo-N-((1-
(2-(tert-butylamino)-2- oxoethyl)piperidin-4- yl)methyl)benzamide
##STR00421## 490.26 385 3-chloro-5-fluoro-N-((1-(2-(1-
methylethylsulfonamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00422## 420.95 386 3-bromo-N-((1-(2-(1-
methylethylsulfonamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00423## 447.41 387 N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)-3-fluoro-4-
(trifluoromethyl)benzamide ##STR00424## 452.48 388
3,5-dibromo-N-((1-(2- (trifluoromethylsulfonamido)-
ethyl)piperidin- 4-yl)methyl)benzamide ##STR00425## 552.23 389
4-(trifluoromethoxy)-N-((1-(2- (trifluoromethylsulfonamido)-
ethyl)piperidin- 4-yl)methyl)benzamide ##STR00426## 478.42 390
3-chloro-N-((1-(2- (cyclopropanesulfonamido)- ethyl)piperidin-4-
yl)methyl)-5-fluorobenzamide ##STR00427## 418.93 391 N-(3-bromo-5-
(trifluoromethyl)phenyl)-2-(1- (2-(1- methylethylsulfonamido)-
ethyl)piperidin-4- yl)acetamide ##STR00428## 515.41 392 N-((1-(2-
(cyclopentanecarboxamido)- ethyl)piperidin-4- yl)methyl)-3,5-
dimethylbenzamide ##STR00429## 386.55 393 N-((1-(2-
(cyclopentanecarboxamido)- ethyl)piperidin-4-
yl)methyl)-3-fluoro-5- methylbenzamide ##STR00430## 390.51 394
3-chloro-N-((1-(2- (cyclopentanecarboxamido)- ethyl)piperidin-4-
yl)methyl)benzamide ##STR00431## 392.94 395 N-((1-(2-
(cyclopentanecarboxamido)- ethyl)piperidin-4- yl)methyl)-3,5-
difluorobenzamide ##STR00432## 394.48 396 N-((1-(2-
(cyclopentanecarboxamido)- ethyl)piperidin-4-
yl)methyl)-3-fluoro-5- methoxybenzamide ##STR00433## 406.51 397
3-chloro-N-((1-(2- (cyclopentanecarboxamido)- ethyl)piperidin-4-
yl)methyl)-5-fluorobenzamide ##STR00434## 410.93 398 N-((1-(2-
(cyclopentanecarboxamido)- ethyl)piperidin-4- yl)methyl)-3-
(trifluoromethyl)benzamide ##STR00435## 426.49 399 N-((1-(2-
(cyclopentanecarboxamido)- ethyl)piperidin-4-
yl)methyl)-2-(pyrrolidin-1- yl)isonicotinamide ##STR00436## 428.59
400 3-bromo-N-((1-(2- (cyclopentanecarboxamido)- ethyl)piperidin-4-
yl)methyl)benzamide ##STR00437## 437.40 401 N-((1-(2-
(cyclopentanecarboxamido)- ethyl)piperidin-4- yl)methyl)-3-
(trifluoromethoxy)benzamide ##STR00438## 442.49 402 N-((1-(2-
(cyclopentanecarboxamido)- ethyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00439##
444.48 403 N-((1-(2- (cyclopentanecarboxamido)- ethyl)piperidin-4-
yl)methyl)-3,5- diethoxybenzamide ##STR00440## 446.60 404 N-((1-(2-
(cyclopentanecarboxamido)- ethyl)piperidin-4-
yl)methyl)-3-methoxy-5- (trifluoromethyl)benzamide ##STR00441##
456.52 405 3-chloro-N-((1-(2- (cyclopentanecarboxamido)-
ethyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00442## 460.94 406 3-bromo-5-chloro-N-((1-(2-
(cyclopentanecarboxamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00443## 471.84 407 3-bromo-N-((1-(2-
(cyclopentanecarboxamido)- ethyl)piperidin-4- yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00444## 505.40 408
N-(2-(4-((2-(3,5- bis(trifluoromethyl)phenyl)- acetamido)methyl)-
piperidin-1- yl)ethyl)cyclo- pentanecarboxamide ##STR00445## 508.52
409 3,5-dibromo-N-((1-(2- (cyclopentanecarboxamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00446## 516.30 410
(S)-N-tert-butyl-2-((4- ((3-fluoro-5- (trifluoromethyl)benzamido)-
methyl)piperidin- 1-yl)methyl)pyrrolidine- 1-carboxamide
##STR00447## 487.55 411 N-((1-(2-(3-tert-
butylureido)ethyl)piperidin-4- yl)methyl)-3-fluoro-N- methyl-5-
(trifluoromethyl)benzamide ##STR00448## 461.52 412
3-fluoro-N-methyl-N-((1-(2- pivalamidoethyl)piperidin-4-
yl)methyl)-5- (trifluoromethyl)benzamide ##STR00449## 446.50 413
N-((1-(2-(3,3- dimethylbutanamido)ethyl)- piperidin-4-
yl)methyl)-3-fluoro-N- methyl-5- (trifluoromethyl)benzamide
##STR00450## 460.53 414 N-((1-(2- (cyclopentanecarboxamido)-
ethyl)piperidin-4- yl)methyl)-3-fluoro- N-methyl-5-
(trifluoromethyl)benzamide ##STR00451## 458.51 415
3-fluoro-N-methyl-N- ((1-(2-(4,4,4- trifluorobutanamido)-
ethyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00452## 486.44 416 (S)-3-fluoro-N-((1-((1-
(methylsulfonyl)pyrrolidin-2- yl)methyl)piperidin-4- yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00453## 466.51 417 (S)-N-((1-((1-
(ethylsulfonyl)pyrrolidin-2- yl)methyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00454##
480.54 418 (S)-N-((1-((1- (cyclopropylsulfonyl)pyrrolidin-
2-yl)methyl)piperidin-4- yl)methyl)-3-fluoro-5-
(trifluoromethyl)benzamide ##STR00455## 492.55 419 (S)-N-((1-((1-
(cyclobutylsulfonyl)pyrrolidin-2- yl)methyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00456##
506.57 420 (S)-N-((1-((1- (cyclopentylsulfonyl)pyrrolidin-
2-yl)methyl)piperidin-4- yl)methyl)-3-fluoro-5-
(trifluoromethyl)benzamide ##STR00457## 520.60 421 (S)-N-((1-((1-
(cyclopropylmethylsulfonyl)- pyrrolidin-2- yl)methyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00458##
506.57 422 (S)-3-fluoro-5- (trifluoromethyl)-N-((1-((1-
(3,3,3-trifluoropropyl- sulfonyl)pyrrolidin-2-
yl)methyl)piperidin-4- yl)methyl)benzamide ##STR00459## 548.53 423
(S)-3-fluoro-N-((1- ((1-pivaloylpyrrolidin-2- yl)methyl)piperidin-
4-yl)methyl)-5- (trifluoromethyl)benzamide ##STR00460## 472.54 424
(S)-N-((1-((1-(3,3- dimethylbutanoyl)pyrrolidin-2-
yl)methyl)piperidin-4- yl)methyl)-3-fluoro-5-
(trifluoromethyl)benzamide ##STR00461## 486.57 425 (S)-N-((1-((1-
(cyclopentanecarbonyl)- pyrrolidin-2- yl)methyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00462##
484.55 426 (S)-3-fluoro-N-((1-((1-(4,4,4-
trifluorobutanoyl)pyrrolidin-2- yl)methyl)piperidin-4-
yl)methyl)-5- (trifluoromethyl)benzamide ##STR00463## 512.48 427
N-(3-fluoro-5- (trifluoromethyl)phenyl)-2-(1- (2-(2-
methylpropylsulfonamido)- ethyl)piperidin-4- yl)acetamide
##STR00464## 468.53 428 N-((1-(2-(tert-butylamino)-2-
oxoethyl)piperidin-4- yl)methyl)-1-(4- chlorophenyl)-
cyclopentanecarboxamide ##STR00465## 435.02 429 3-bromo-N-((1-(2-
(tert-butylamino)-2- oxoethyl)piperidin-4- yl)methyl)-5-
(trifluoromethoxy)benzamide ##STR00466## 495.36 430
N-((1-(2-(1-hydroxy-2- methylpropan-2- ylamino)-2-oxoethyl)-
piperidin-4-yl)methyl)- 3,5- bis(trifluoromethyl)benzamide
##STR00467## 484.45 431 N-((1-(2-(1- methylcyclohexylamino)-2-
oxoethyl)piperidin-4- yl)methyl)-3,5- bis(trifluoromethyl)benzamide
##STR00468## 508.52 432 N-((1-(2-(tert-butylamino)-2-
oxoethyl)piperidin-4- yl)methyl)-1- phenylcyclopentanecarboxamide
##STR00469## 400.58 433 N-(2,6-dimethylphenyl)- 2-(1-(2-(1-
methylethylsulfonamido)- ethyl)piperidin-4- yl)acetamide
##STR00470## 396.57 434 3,5-bis(trifluoromethyl)- N-((1-(2-(1-
(trifluoromethyl)- cyclobutanecarboxamido)ethyl)-
piperidin-4-yl)methyl)benzamide ##STR00471## 548.19 435
3-fluoro-5-(trifluoromethyl)- N-((1-(2-(1- (trifluoromethyl)-
cyclobutanecarboxamido)ethyl)- piperidin-4-yl)methyl)benzamide
##STR00472## 498.19 436 N-((1-(2-(isopropylamino)-2-
oxoethyl)piperidin-4- yl)methyl)-3,5- dimethylbenzamide
##STR00473## 346.24 437 3-fluoro-N-((1-(2- (isopropylamino)-2-
oxoethyl)piperidin-4- yl)methyl)-5- methylbenzamide ##STR00474##
350.22 438 3-fluoro-N-((1-(2- (isopropylamino)-2-
oxoethyl)piperidin-4- yl)methyl)-5- methoxybenzamide ##STR00475##
366.21 439 N-((1-(2-(isopropylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- dimethoxybenzamide ##STR00476## 378.23 440
N-((1-(2-(isopropylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3-
(trifluoromethyl)benzamide ##STR00477## 386.20 441
3-bromo-N-((1-(2- (isopropylamino)-2- oxoethyl)piperidin-4-
yl)methyl)benzamide ##STR00478## 396.12 442 3-chloro-N-((1-(2-
(isopropylamino)-2- oxoethyl)piperidin-4- yl)methyl)benzamide
##STR00479## 352.17 443 3-chloro-5-fluoro-N-
((1-(2-(isopropylamino)- 2-oxoethyl)piperidin-
4-yl)methyl)benzamide ##STR00480## 370.16 444
N-((1-(2-(isopropylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3-
(trifluoromethoxy)benzamide ##STR00481## 402.19 445
3,5-dimethyl-N-((1-(2-oxo-2- (propylamino)ethyl)piperidin-4-
yl)methyl)benzamide ##STR00482## 346.24 446 3-fluoro-5-methyl-N-
((1-(2-oxo-2- (propylamino)ethyl)piperidin- 4- yl)methyl)benzamide
##STR00483## 350.22 447 3-fluoro-5-methoxy-N- ((1-(2-oxo-2-
(propylamino)ethyl)piperidin-4- yl)methyl)benzamide ##STR00484##
366.21 448 3,5-dimethoxy-N-((1-(2-oxo-2-
(propylamino)ethyl)piperidin-4- yl)methyl)benzamide ##STR00485##
378.23 449 N-((1-(2-oxo-2- (propylamino)ethyl)piperidin-
4-yl)methyl)-3- (trifluoromethyl)benzamide ##STR00486## 386.20 450
3-bromo-N-((1-(2-oxo-2- (propylamino)ethyl)piperidin-4-
yl)methyl)benzamide ##STR00487## 396.12 451
3-chloro-N-((1-(2-oxo-2- (propylamino)ethyl)piperidin-4-
yl)methyl)benzamide ##STR00488## 352.17 452 3-chloro-5-fluoro-N-
((1-(2-oxo-2- (propylamino)ethyl)piperidin-4- yl)methyl)benzamide
##STR00489## 370.16 453 N-((1-(2-oxo-2-
(propylamino)ethyl)piperidin- 4-yl)methyl)-3-
(trifluoromethoxy)benzamide ##STR00490## 402.19 454
3,5-dimethyl-N-((1-(2- oxo-2-(1,1,1-trifluoro- 2-methylpropan-2-
ylamino)ethyl)piperidin-4- yl)methyl)benzamide ##STR00491## 414.23
455 3-fluoro-5-methyl-N-((1- (2-oxo-2-(1,1,1-
trifluoro-2-methylpropan-2- ylamino)ethyl)piperidin-4-
yl)methyl)benzamide ##STR00492## 418.20 456 3-fluoro-5-methoxy-N-
((1-(2-oxo-2-(1,1,1- trifluoro-2-methylpropan-2-
ylamino)ethyl)piperidin-4- yl)methyl)benzamide ##STR00493## 434.20
457 3,5-dimethoxy-N-((1- (2-oxo-2-(1,1,1-
trifluoro-2-methylpropan-2- ylamino)ethyl)piperidin-4-
yl)methyl)benzamide ##STR00494## 446.22 458 N-((1-(2-oxo-2-(1,1,1-
trifluoro-2- methylpropan-2- ylamino)ethyl)piperidin-4-
yl)methyl)-3- (trifluoromethyl)benzamide ##STR00495## 454.19 459
3-bromo-N-((1-(2- oxo-2-(1,1,1-trifluoro-2- methylpropan-2-
ylamino)ethyl)piperidin-4- yl)methyl)benzamide ##STR00496## 464.11
460 3-chloro-N-((1-(2-oxo- 2-(1,1,1-trifluoro-2- methylpropan-2-
ylamino)ethyl)piperidin-4- yl)methyl)benzamide ##STR00497## 420.16
461 3-chloro-5-fluoro-N- ((1-(2-oxo-2-(1,1,1-
trifluoro-2-methylpropan-2- ylamino)ethyl)piperidin-4-
yl)methyl)benzamide ##STR00498## 438.15 462 N-((1-(2-oxo-2-(1,1,1-
trifluoro-2- methylpropan-2- ylamino)ethyl)piperidin-4-
yl)methyl)-3- (trifluoromethoxy)benzamide ##STR00499## 470.18 463
(S)-3,5-dimethyl-N- ((1-(2-oxo-2-(2- (trifluoromethyl)pyrrolidin-1-
yl)ethyl)piperidin-4- yl)methyl)benzamide ##STR00500## 426.23 464
(S)-3-fluoro-5-methyl- N-((1-(2-oxo-2-(2- (trifluoromethyl)-
pyrrolidin-1- yl)ethyl)piperidin-4- yl)methyl)benzamide
##STR00501## 430.20 465 (S)-3-fluoro-5-methoxy- N-((1-(2-oxo-2-(2-
(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-
yl)methyl)benzamide ##STR00502## 446.20 466 (S)-3,5-dimethoxy-N-
((1-(2-oxo-2-(2- (trifluoromethyl)- pyrrolidin-1-
yl)ethyl)piperidin-4- yl)methyl)benzamide ##STR00503## 458.22 467
(S)-N-((1-(2-oxo-2-(2- (trifluoromethyl)pyrrolidin-1-
yl)ethyl)piperidin-4- yl)methyl)-3- (trifluoromethyl)benzamide
##STR00504## 466.19 468 (S)-3-bromo-N-((1-(2-oxo-2-(2-
(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-
yl)methyl)benzamide ##STR00505## 476.11 469
(S)-3-chloro-N-((1-(2-oxo-2-(2- (trifluoromethyl)pyrrolidin-1-
yl)ethyl)piperidin-4- yl)methyl)benzamide ##STR00506## 432.16 470
(S)-3-chloro-5-fluoro- N-((1-(2-oxo-2-(2-
(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-
yl)methyl)benzamide ##STR00507## 450.15 471 (S)-N-((1-(2-oxo-2-(2-
(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4- yl)methyl)-3-
(trifluoromethoxy)benzamide ##STR00508## 482.18 472
3-chloro-5-fluoro-N-((1-(2-(1- (trifluoromethyl)cyclo-
propanecarboxamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00509## 450.15 473 3-(trifluoromethyl)-N-((1-(2-(1-
(trifluoromethyl)-
cyclopropanecarboxamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00510## 466.19 474 3-(trifluoromethoxy)- N-((1-(2-(1-
(trifluoromethyl)- cyclopropanecarboxamido)- ethyl)piperidin-4-
yl)methyl)benzamide ##STR00511## 482.18 475
3,5-dimethyl-N-((1-(2-(1- methylcyclobutylamino)-2-
oxoethyl)piperidin-4- yl)methyl)benzamide ##STR00512## 372.26 476
3-fluoro-5-methyl-N-((1-(2-(1- methylcyclobutylamino)-2-
oxoethyl)piperidin-4- yl)methyl)benzamide ##STR00513## 376.23 477
3-fluoro-5-methoxy-N-((1-(2-(1- methylcyclobutylamino)-2-
oxoethyl)piperidin-4- yl)methyl)benzamide ##STR00514## 392.23 478
3,5-dimethoxy-N-((1-(2-(1- methylcyclobutylamino)-2-
oxoethyl)piperidin-4- yl)methyl)benzamide ##STR00515## 404.25 479
N-((1-(2-(1- methylcyclobutylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3- (trifluoromethyl)benzamide ##STR00516## 412.21 480
3-bromo-N-((1-(2-(1- methylcyclobutylamino)-2-
oxoethyl)piperidin-4- yl)methyl)benzamide ##STR00517## 422.14 481
3-chloro-N-((1-(2- (1-methylcyclobutylamino)-
2-oxoethyl)piperidin-4- yl)methyl)benzamide ##STR00518## 378.19 482
3-chloro-5-fluoro-N-((1-(2-(1- methylcyclobutylamino)-2-
oxoethyl)piperidin-4- yl)methyl)benzamide ##STR00519## 396.18 483
N-((1-(2-(1- methylcyclobutylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3- (trifluoromethoxy)benzamide ##STR00520## 428.21 484
N-((1-(2-(2,5-dioxopyrrolidin-1- yl)ethyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00521##
430.17 485 N-((1-(2-(methoxyamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00522## 442.15
486 N-((1-(2-(ethoxyamino)-2- oxoethyl)piperidin- 4-yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00523## 456.16 487
3-fluoro-N-((1-(2-(2- oxopyrrolidin-1- yl)ethyl)piperidin-4-
yl)methyl)-5- (trifluoromethyl)benzamide ##STR00524## 416.19 488
3,5-dimethyl-N-((1- (2-(3,3,3-trifluoro-2,2- dimethylpropanamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00525## 428.24 489
3-fluoro-5-methyl-N- ((1-(2-(3,3,3-trifluoro-
2,2-dimethylpropanamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00526## 432.22 490 3-fluoro-5-methoxy-N-
((1-(2-(3,3,3-trifluoro- 2,2-dimethylpropanamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00527## 448.21 491
3,5-dimethoxy-N-((1-(2- (3,3,3-trifluoro-2,2- dimethylpropanamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00528## 460.23 492
N-((1-(2-(3,3,3-trifluoro-2,2- dimethylpropanamido)-
ethyl)piperidin-4- yl)methyl)-3- (trifluoromethyl)benzamide
##STR00529## 468.20 493 3-bromo-N-((1-(2- (3,3,3-trifluoro-2,2-
dimethylpropanamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00530## 478.12 494 3-chloro-N-((1-(2- (3,3,3-trifluoro-2,2-
dimethylpropanamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00531## 434.17 495 3-chloro-5-fluoro-N-
((1-(2-(3,3,3-trifluoro- 2,2-dimethylpropanamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00532## 452.16 496
N-((1-(2-(3,3,3-trifluoro-2,2- dimethylpropanamido)-
ethyl)piperidin-4- yl)methyl)-3- (trifluoromethoxy)benzamide
##STR00533## 484.20 497 3,5-dimethyl-N-((1- (2-(1-
(trifluoromethyl)- cyclopropanecarboxamido)- ethyl)piperidin-4-
yl)methyl)benzamide ##STR00534## 426.23 498
3-fluoro-5-methyl-N-((1-(2-(1- (trifluoromethyl)-
cyclopropanecarboxamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00535## 430.20 499 3-fluoro-5-methoxy- N-((1-(2-(1-
(trifluoromethyl)- cyclopropanecarboxamido)- ethyl)piperidin-
4-yl)methyl)benzamide ##STR00536## 446.20 500
3,5-dimethoxy-N-((1-(2-(1- (trifluoromethyl)-
cyclopropanecarboxamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00537## 458.22 501 3-bromo-N-((1-(2-(1- (trifluoromethyl)-
cyclopropanecarboxamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00538## 476.11 502 3-chloro-N-((1-(2-(1- (trifluoromethyl)-
cyclopropanecarboxamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00539## 432.16 503 (Z)-N-((1-(2-(tert- butylamino)-2-
(cyanoimino)ethyl)piperidin- 4-yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00540## 492.21 504
(R)-3-chloro-5-fluoro- N-((1-(2-oxo-2-(2-
(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-
yl)methyl)benzamide ##STR00541## 450.15 505 (R)-3-fluoro-5-methoxy-
N-((1-(2-oxo-2-(2- (trifluoromethyl)- pyrrolidin-1-
yl)ethyl)piperidin-4- yl)methyl)benzamide ##STR00542## 446.20 506
(R)-3-fluoro-5-methyl- N-((1-(2-oxo-2-(2-
(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4-
yl)methyl)benzamide ##STR00543## 430.20 507
(R)-3-chloro-N-((1-(2-oxo-2-(2- (trifluoromethyl)pyrrolidin-1-
yl)ethyl)piperidin-4- yl)methyl)benzamide ##STR00544## 432.16 508
(R)-3-fluoro-N-((1-(2-oxo-2-(2- (trifluoromethyl)pyrrolidin-1-
yl)ethyl)piperidin-4- yl)methyl)benzamide ##STR00545## 416.19 509
3-fluoro-N-((1-((1R,2R)-2- pivalamidocyclohexyl)-
piperidin-4-yl)methyl)- 5-(trifluoromethyl)benzamide ##STR00546##
486.27 510 (Z)-N-((1-(2-(tert-butylamino)-2- (cyanoimino)ethyl)-
piperidin-4-yl)methyl)-3- fluoro-5- (trifluoromethyl)benzamide
##STR00547## 442.22 511 3-chloro-5-fluoro-N-((1-(2-(1-
(trifluoromethyl)- cyclobutanecarboxamido)- ethyl)piperidin-4-
yl)methyl)benzamide ##STR00548## 464.16 512 3-chloro-N-((1-(2-(1-
(trifluoromethyl)- cyclobutanecarboxamido)- ethyl)piperidin-4-
yl)methyl)benzamide ##STR00549## 446.17 513 3-fluoro-5-methoxy-N-
((1-(2-(1- (trifluoromethyl)- cyclobutanecarboxamido)-
ethyl)piperidin-4- yl)methyl)benzamide ##STR00550## 460.21 514
N-((1-(2-(N-tert- butylsulfamoyl)ethyl)- piperidin-4-yl)methyl)-3-
fluoro-5- (trifluoromethyl)benzamide ##STR00551## 468.19 515
3-fluoro-N-((1-(2-(N- methylpivalamido)- ethyl)piperidin-4-
yl)methyl)-5- (trifluoromethyl)benzamide ##STR00552## 446.24 516
3-fluoro-N-((1-(2-(N- methylcyclopentane- carboxamido)- ethyl)-
piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide ##STR00553##
458.24 517 3-fluoro-N-((1-(2- (4,4,4-trifluoro-N-
methylbutanamido)- ethyl)piperidin-4- yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00554## 486.19 518 N-((1-(2-(N,1-
dimethylcyclopropane- carboxamido)ethyl)- piperidin-4-yl)methyl)-
3-fluoro-5- (trifluoromethyl)benzamide ##STR00555## 444.22 519
N-((1-(2-(N,4- dimethylcyclohexane- carboxamido)ethyl)-
piperidin-4-yl)methyl)- 3-fluoro-5- (trifluoromethyl)benzamide
##STR00556## 486.27 520 3-fluoro-N-((1-(2-(N-methyl-1-
(trifluoromethyl)cyclo- propanecarboxamido)-
ethyl)piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide
##STR00557## 498.19 521 3-fluoro-N-((1-(2-(3,3,3- trifluoro-N,2,2-
trimethylpropanamido)- ethyl)piperidin-4- yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00558## 500.21 522
3-fluoro-N-((1-(2-(N-methyl-1- (trifluoromethyl)cyclo-
pentanecarboxamido)- ethyl)piperidin-4-yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00559## 526.22 523
N-((1-(2-(3-tert-butyl-1- methylureido)ethyl)piperidin-
4-yl)methyl)-3- fluoro-5- (trifluoromethyl)benzamide ##STR00560##
461.25 524 N-((1-(2-(3-ethyl-1- methylureido)ethyl)-
piperidin-4-yl)methyl)-3- fluoro-5- (trifluoromethyl)benzamide
##STR00561## 433.21 525 N-((1-(2-(3-cyclohexyl-1-
methylureido)ethyl)- piperidin-4-yl)methyl)-3- fluoro-5-
(trifluoromethyl)benzamide ##STR00562## 487.26 526
3-fluoro-N-((1-(2-(1-methyl-3- propylureido)ethyl)-
piperidin-4-yl)methyl)-5- (trifluoromethyl)benzamide ##STR00563##
447.23 527 3-chloro-N-((1-(2-oxo- 2-(piperidin-1-
ylamino)ethyl)piperidin-4- yl)methyl)benzamide ##STR00564## 393.20
528 N-((1-(2-(1- methylcyclobutylamino)-2- oxoethyl)piperidin-
4-yl)methyl)benzamide ##STR00565## 344.23 529 4-fluoro-N-((1-(2-(1-
methylcyclobutylamino)- 2-oxoethyl)piperidin-4- yl)methyl)benzamide
##STR00566## 362.22 530 2-(4-((3-fluoro-5-
(trifluoromethyl)benzamido)- methyl)piperidin- 1-yl)ethyl
cyclohexylcarbamate ##STR00567## 474.23 531 3-chloro-N-((1-(2-
(cyclopentylamino)-2- oxoethyl)piperidin- 4-yl)methyl)-5-
fluorobenzamide ##STR00568## 396.18 532
N-((1-(2-(cyclopentylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3-fluoro-5- methoxybenzamide ##STR00569## 392.23 533
N-((1-(2-(cyclopentylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3-fluoro-5- methylbenzamide ##STR00570## 376.23 534
3-chloro-N-((1-(2- (cyclopentylamino)-2- oxoethyl)piperidin-4-
yl)methyl)benzamide ##STR00571## 378.19 535
N-((1-(2-(cyclopentylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3-
fluorobenzamide ##STR00572## 362.22 536
N-((1-(2-(cyclopentylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3-
(trifluoromethoxy)benzamide ##STR00573## 428.21 537 N-((1-(2-(1,1-
dimethylethylsulfinamido)- ethyl)piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00574##
452.19 538 3-chloro-5-fluoro-N- ((1-(2-(1-methoxy-2-
methylpropan-2-ylamino)-2- oxoethyl)piperidin-4-
yl)methyl)benzamide ##STR00575## 414.19 539 N-((1-(2-(tert-butyl-
(methyl)amino)-2- oxoethyl)piperidin-4- yl)methyl)-3,5-
dimethylbenzamide ##STR00576## 374.27 540 N-((1-(2-(tert-butyl-
(methyl)amino)-2- oxoethyl)piperidin-4- yl)methyl)-3-fluoro-5-
methylbenzamide ##STR00577## 378.25 541 N-((1-(2-(tert-
butyl(methyl)amino)-2- oxoethyl)piperidin-4- yl)methyl)-3-fluoro-5-
methoxybenzamide ##STR00578## 394.24 542 N-((1-(2-(tert-
butyl(methyl)amino)-2- oxoethyl)piperidin-4- yl)methyl)-3-
(trifluoromethyl)benzamide ##STR00579## 414.23 543 N-((1-(2-(tert-
butyl(methyl)amino)-2- oxoethyl)piperidin-4- yl)methyl)-3-
chlorobenzamide ##STR00580## 380.20 544 N-((1-(2-(tert-
butyl(methyl)amino)-2- oxoethyl)piperidin-4- yl)methyl)-3-chloro-5-
fluorobenzamide ##STR00581## 398.19 545 N-((1-(2-(tert-
butyl(methyl)amino)-2- oxoethyl)piperidin- 4-yl)methyl)-3-
(trifluoromethoxy)benzamide ##STR00582## 430.22 546 N-((1-(1-(tert-
butylamino)-1-oxopropan-2- yl)piperidin-4- yl)methyl)-3-chloro-5-
fluorobenzamide ##STR00583## 398.19 547 3-chloro-5-fluoro-N-
((1-(1-oxo-1-(1,1,1- trifluoro-2-methylpropan- 2-ylamino)propan-
2-yl)piperidin-4- yl)methyl)benzamide ##STR00584##
452.16 548 3-chloro-5-fluoro-N- ((1-(1-oxo-1-((S)-2-
(trifluoromethyl)pyrrolidin- 1-yl)propan-2- yl)piperidin-4-
yl)methyl)benzamide ##STR00585## 464.16 549 3-chloro-N-((1-(1-
(cyclopentylamino)-1- oxopropan-2- yl)piperidin-4-yl)methyl)-5-
fluorobenzamide ##STR00586## 410.19 550 3-chloro-5-fluoro-
N-((1-(1-(1- methylcyclohexylamino)- 1-oxopropan-2- yl)piperidin-4-
yl)methyl)benzamide ##STR00587## 438.22 551 3-chloro-5-fluoro-N-
((1-(1-(1-methoxy-2- methylpropan-2- ylamino)-1-oxopropan-2-
yl)piperidin-4- yl)methyl)benzamide ##STR00588## 428.20 552
N-((1-(2-(tert- butyl(methyl)amino)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- dichlorobenzamide ##STR00589## 414.16 553
3-chloro-5-fluoro-N- ((1-(2-(2- fluoropropylamino)-2-
oxoethyl)piperidin-4- yl)methyl)benzamide compound with ethane
(1:1) ##STR00590## 388.15 554 3-chloro-N-((1-(2- (2-fluoro-2-
methylpropylamino)- 2-oxoethyl)piperidin-4- yl)methyl)benzamide
##STR00591## 384.18 555 N-((1-(2-(2-fluoro-2- methylpropylamino)-2-
oxoethyl)piperidin-4- yl)methyl)-3,5- bis(trifluoromethyl)benzamide
##STR00592## 486.19 556 3-fluoro-N-((1-(2- (2-fluoro-2-
methylpropylamino)-2- oxoethyl)piperidin-4- yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00593## 436.19 557
3-fluoro-N-((1-(2-(2-fluoro-2- methylpropylamino)-2-
oxoethyl)piperidin-4- yl)methyl)-5-methoxybenzamide ##STR00594##
398.22 558 3-chloro-5-fluoro-N- ((1-(1-oxo-1-((R)-2-
(trifluoromethyl)pyrrolidin- 1-yl)propan-2- yl)piperidin-4-
yl)methyl)benzamide ##STR00595## 464.16 559 3-chloro-5-fluoro-N-
((1-(1-oxo-1-(thiazolidin- 3-yl)propan-2-yl)piperidin-4-
yl)methyl)benzamide ##STR00596## 414.13 560
N-((1-(2-(tert-butoxyamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3,5- bis(trifluoromethyl)benzamide ##STR00597## 484.20
561 3-fluoro-N-((1-(2-oxo- 2-(1-(tetrahydro-2H- pyran-4-
yl)cyclopropylamino)- ethyl)piperidin- 4-yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00598## 486.23 562
3-fluoro-5-methoxy- N-((1-(2-oxo-2-(1- (tetrahydro-2H-pyran-4-
yl)cyclopropylamino)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00599## 448.25 563 3-chloro-5-fluoro-N- ((1-(2-oxo-2-(1-
(tetrahydro-2H-pyran-4- yl)cyclopropylamino)- ethyl)piperidin-4-
yl)methyl)benzamide ##STR00600## 452.20 564 3-fluoro-N-((1-(2-
(1-methoxy-2- methylpropan-2-ylamino)-2- oxoethyl)piperidin-
4-yl)methyl)-5- (trifluoromethyl)benzamide ##STR00601## 448.21 565
3-chloro-N-((1-(2-(1,1- dimethylethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)-5-fluorobenzamide ##STR00602## 434.16
566 3-chloro-N-((1- (2-(1-methoxy-2- methylpropan-2-ylamino)-2-
oxoethyl)piperidin-4- yl)methyl)benzamide ##STR00603## 396.20 567
3-fluoro-5-methoxy-N- ((1-(2-(1-methoxy-2-
methylpropan-2-ylamino)-2- oxoethyl)piperidin-4-
yl)methyl)benzamide ##STR00604## 410.24 568
N-((1-(2-(2,4-dioxo-1,3- diazaspiro[4.5]decan-
3-yl)ethyl)piperidin-4- yl)methyl)-3-fluoro-5-
(trifluoromethyl)benzamide ##STR00605## 499.23 569
N-((1-(2-(6,8-dioxo-5,7- diazaspiro[3.4]octan-
7-yl)ethyl)piperidin-4- yl)methyl)-3-fluoro-5-
(trifluoromethyl)benzamide ##STR00606## 471.19 570 N-((1-(2-(1-
aminocyclohexane- carboxamido)ethyl)- piperidin-4-yl)methyl)-
3-fluoro-5- (trifluoromethyl)benzamide ##STR00607## 473.25 571
N-((1-(2-(1- aminocyclobutane- carboxamido)ethyl)- piperidin-4-
yl)methyl)-3-fluoro-5- (trifluoromethyl)benzamide ##STR00608##
445.21 572 tert-butyl 1-(2-(4-((3-fluoro-5- (trifluoromethyl)-
benzamido)methyl)piperidin- 1-yl)ethylcarbamoyl)-
cyclobutylcarbamate ##STR00609## 545.27 573 3-chloro-N-((1-(2-(1,1-
dimethylethylsulfonamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00610## 416.17 574 N-((1-(2-(1,1- dimethylethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)-3- (trifluoromethoxy)benzamide
##STR00611## 466.19 575 N-((1-(2-(1,1- dimethylethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)-3-fluoro-5- methylbenzamide
##STR00612## 414.21 576 N-((1-(2-(1,1- dimethylethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)-3,5- dimethoxybenzamide ##STR00613##
442.23 577 N-((1-(2-(1,1- dimethylethylsulfonamido)-
ethyl)piperidin-4- yl)methyl)-3-fluoro-5- methoxybenzamide
##STR00614## 430.21 578 N-((1-(2-(3,3- dimethylmorpholino)-2-
oxoethyl)piperidin-4- yl)methyl)-3,5- bis(trifluoromethyl)benzamide
##STR00615## 510.21 579 3-chloro-5-fluoro-N- ((1-(2-(methyl(1,1,1-
trifluoro-2-methylpropan- 2-yl)amino)-2- oxoethyl)piperidin-4-
yl)methyl)benzamide ##STR00616## 452.16 580 3-chloro-N-((1-(2-
(methyl(1,1,1-trifluoro-2- methylpropan-2-yl)amino)-2-
oxoethyl)piperidin-4- yl)methyl)benzamide ##STR00617## 434.17 581
3-fluoro-5-methoxy-N- ((1-(2-(methyl(1,1,1-
trifluoro-2-methylpropan- 2-yl)amino)-2- oxoethyl)piperidin-4-
yl)methyl)benzamide ##STR00618## 448.21 582 N-((1-(2-(2,2-
dimethylpyrrolidin-1-yl)-2- oxoethyl)piperidin-4- yl)methyl)-3,5-
bis(trifluoromethyl)benzamide ##STR00619## 494.22 583
3-chloro-5-fluoro-N- ((1-(2-(methyl(1- methylcyclobutyl)amino)-2-
oxoethyl)piperidin-4- yl)methyl)benzamide ##STR00620## 410.19 584
3-fluoro-5-methoxy-N- ((1-(2-(methyl(1- methylcyclobutyl)amino)-2-
oxoethyl)piperidin-4- yl)methyl)benzamide ##STR00621## 406.24 585
N-((1-(2-(cyclopentylamino)-2- oxoethyl)piperidin-4- yl)methyl)-3-
(methylsulfonyl)-5- (trifluoromethyl)benzamide ##STR00622## 490.19
586 3-(methylsulfonyl)-5- (trifluoromethyl)-N-((1- (2-(1-
(trifluoromethyl)- cyclobutanecarboxamido)- ethyl)piperidin-4-
yl)methyl)benzamide ##STR00623## 558.18 587 3-(methylsulfonyl)-N-
((1-(2-(3,3,3-trifluoro- 2,2-dimethylpropanamido)-
ethyl)piperidin-4- yl)methyl)-5- (trifluoromethyl)benzamide
##STR00624## 546.18 588 N-((1-(2- (cyclopropanesulfonamido)-
ethyl)piperidin-4- yl)methyl)-3-(methylsulfonyl)-5-
(trifluoromethyl)benzamide ##STR00625## 512.14 589
(R)-3-(methylsulfonyl)- N-((1-(2-oxo-2-(2-
(trifluoromethyl)pyrrolidin-1- yl)ethyl)piperidin-4- yl)methyl)-5-
(trifluoromethyl)benzamide ##STR00626## 544.16 590
3-chloro-5-methoxy-N- ((1-(2-(1- (trifluoromethyl)-
cyclopropanecarboxamido)- ethyl)piperidin-4- yl)methyl)benzamide
##STR00627## 462.17 591 3-chloro-5-methoxy-N- ((1-(2-(methyl(1-
methylcyclobutyl)amino)-2- oxoethyl)piperidin-4-
yl)methyl)benzamide ##STR00628## 422.21 592 3,5-dichloro-N-((1-
(2-(methyl(1- methylcyclobutyl)amino)-2- oxoethyl)piperidin-4-
yl)methyl)benzamide ##STR00629## 426.16 593
3-bromo-N-((1-(2-(methyl(1- methylcyclobutyl)amino)-2-
oxoethyl)piperidin-4- yl)methyl)benzamide ##STR00630## 436.15 594
3-fluoro-N-((1-(2-(methyl(1- methylcyclobutyl)amino)-2-
oxoethyl)piperidin- 4-yl)methyl)-5- (trifluoromethyl)benzamide
##STR00631## 444.22 595 3-bromo-5-chloro-N- ((1-(2-(methyl(1-
methylcyclobutyl)amino)-2- oxoethyl)piperidin-4-
yl)methyl)benzamide ##STR00632## 470.11 596 N-((1-(2-(tert-
butyl(methyl)amino)-2- oxoethyl)piperidin-4- yl)methyl)-3-chloro-5-
methoxybenzamide ##STR00633## 410.21 597 tert-butyl
3-(4-((3-chloro-5- fluorobenzamido)- methyl)piperidin-1-
yl)azetidine-1-carboxylate ##STR00634## 426.19 598 tert-butyl
4-((4-((3-chloro-5- fluorobenzamido)- methyl)piperidin-1-
yl)methyl)-4- hydroxypiperidine-1-carboxylate ##STR00635## 484.23
599 tert-butyl 4-((4-((3-fluoro-5- (trifluoromethyl)-
benzamido)methyl)piperidin- 1-yl)methyl)-4- hydroxypiperidine-1-
carboxylate ##STR00636## 518.26 600 3-chloro-N-((1-(1-(3-chloro-5-
methoxybenzoyl)azetidin- 3-yl)piperidin-4-
yl)methyl)-5-fluorobenzamide ##STR00637## 494.13 601
3-chloro-N-((1-(1-(3,5- dichlorobenzoyl)azetidin- 3-yl)piperidin-4-
yl)methyl)-5-fluorobenzamide ##STR00638## 498.08 602 N-((1-(1-(3-
bromobenzoyl)azetidin-3- yl)piperidin-4- yl)methyl)-3-chloro-5-
fluorobenzamide ##STR00639## 508.07 603
3-chloro-5-fluoro-N-((1-(1-(3- (trifluoromethoxy)-
benzoyl)azetidin-3- yl)piperidin-4- yl)methyl)benzamide
##STR00640## 514.14 604 3-chloro-5-fluoro-N- ((1-(1-(3-fluoro-5-
(trifluoromethyl)- benzoyl)azetidin-3- yl)piperidin-4-
yl)methyl)benzamide ##STR00641## 516.14 605 3-chloro-N-((1-(1-
(3-chloro-5- fluorobenzoyl)azetidin- 3-yl)piperidin-4-
yl)methyl)-5-fluorobenzamide ##STR00642## 482.11 606
3-chloro-N-((1-(1-(3- chlorobenzoyl)azetidin-
3-yl)piperidin-4-yl)methyl)-5- fluorobenzamide ##STR00643## 464.12
607 3-chloro-5-fluoro-N- ((1-(1-pivaloylazetidin-3- yl)piperidin-4-
yl)methyl)benzamide ##STR00644## 410.19 608
3-chloro-5-fluoro-N-((1-(1-(1- methylcyclopropanecarbonyl)-
azetidin-3- yl)piperidin-4- yl)methyl)benzamide ##STR00645## 408.18
609 3-chloro-5-fluoro-N- ((1-(1-(1- (trifluoromethyl)-
cyclopropanecarbonyl)- azetidin-3-yl)piperidin-4-
yl)methyl)benzamide ##STR00646## 462.15 610 3-chloro-5-fluoro-N-
((1-(1-(1- (trifluoromethyl)- cyclobutanecarbonyl)azetidin-
3-yl)piperidin-4- yl)methyl)benzamide ##STR00647## 476.16 611
3-chloro-N-((1-(1-(4,4- difluoro-1- methylcyclohexane-
carbonyl)azetidin-3- yl)piperidin-4- yl)methyl)-5-fluorobenzamide
##STR00648## 486.21 612 N-tert-butyl-3-(4-((3-chloro-5-
fluorobenzamido)methyl)- piperidin-1- yl)azetidine-1-carboxamide
##STR00649## 425.20 613 N-((1-(2-(tert-butylamino)-2-
oxoethyl)piperidin-4- yl)methyl)-2'- chlorobiphenyl-3-carboxamide
##STR00650## 442.22 614 N-((1-(2-(tert-butylamino)-2-
oxoethyl)piperidin-4- yl)methyl)-2',3'-
dichlorobiphenyl-3-carboxamide ##STR00651## 476.18 615
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin- 4-yl)methyl)-3'-
chlorobiphenyl-3-carboxamide ##STR00652## 442.22 616
N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-
4-yl)methyl)-2',4'- dichlorobiphenyl-3-carboxamide ##STR00653##
476.18 617 N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-
4-yl)methyl)-4'- chlorobiphenyl-3-carboxamide ##STR00654## 442.22
618 N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3',4'- dichlorobiphenyl-3-carboxamide ##STR00655##
476.18 619 N-((1-(2-(tert-butylamino)-2- oxoethyl)piperidin-4-
yl)methyl)-3'- (trifluoromethyl)biphenyl- 3-carboxamide
##STR00656## 476.24 620 N-((1-(2-(tert-butylamino)-2-
oxoethyl)piperidin-4- yl)methyl)-3',5'- dichlorobiphenyl-3-
carboxamide ##STR00657## 476.18
Example 17
T-type Channel Blocking Activities of Various Invention
Compounds
[0141] A. Transformation of HEK Cells:
[0142] T-type calcium channel blocking activity was assayed in
human embryonic kidney cells, HEK 293, stably transfected with the
T-type calcium channel subunits. Briefly, cells were cultured in
Dulbecco's modified eagle medium (DMEM) supplemented with 10% fetal
bovine serum, 200 U/ml penicillin and 0.2 mg/ml streptomycin at
37.degree. C. with 5% CO.sub.2. At 85% confluency cells were split
with 0.25% trypsin/1 mM EDTA and plated at 10% confluency on glass
coverslips. At 12 hours the medium was replaced and the cells
stably transfected using a standard calcium phosphate protocol and
the appropriate calcium channel cDNA's. Fresh DMEM was supplied and
the cells transferred to 28.degree. C./5% CO.sub.2. Cells were
incubated for 1 to 2 days prior to whole cell recording.
[0143] Standard patch-clamp techniques were employed to identify
blockers of T-type currents. Briefly, previously described HEK cell
lines stably expressing human .alpha..sub.1G, .alpha..sub.1H and
.alpha..sub.1I T-type channels were used for all the recordings
(passage #: 4-20, 37.degree. C., 5% CO.sub.2). Whole cell patch
clamp experiments were performed using an Axopatch 200B amplifier
(Axon Instruments, Burlingame, Calif.) linked to a personal
computer equipped with pCLAMP software. Data were analyzed using
Clampfit (Axon Instruments) and SigmaPlot 4.0 (Jandel Scientific).
To obtain T-type currents, plastic dishes containing semi-confluent
cells were positioned on the stage of a ZEISS AXIOVERT S100
microscope after replacing the culture medium with external
solution (see below). Whole-cell patches were obtained using
pipettes (borosilicate glass with filament, O.D.: 1.5 mm, I.D.:
0.86 mm, 10 cm length), fabricated on a SUTTER P-97 puller with
resistance values of -5 MO (see below for internal solution).
TABLE-US-00002 TABLE 2 External Solution 500 ml - pH 7.4, 265.5
mOsm Salt Final mM Stock M Final ml CsCl 142 1 71 CaCl.sub.2 2 1 1
MgCl.sub.2 1 1 0.5 HEPES 10 0.5 10 glucose 10 -- 0.9 grams
TABLE-US-00003 TABLE 3 Internal Solution 50 ml - pH 7.3 with CsOH,
270 mOsm Salt Final mM Stock M Final ml Cs-Methanesulfonate 126.5
-- 1.442 gr/50 ml MgCl2 2 1 0.1 HEPES 10 0.5 1 EGTA-Cs 11 0.25 2.2
ATP 2 0.2 0.025 (1 aliquot/2.5 ml)
[0144] T-type currents were reliably obtained by using two voltage
protocols: [0145] (1) "non-inactivating", and [0146] (2)
"inactivation"
[0147] In the non-inactivating protocol, the holding potential is
set at -110 mV and with a pre-pulse at -100 mV for 1 second prior
to the test pulse at -40 mV for 50 ms. In the inactivation
protocol, the pre-pulse is at approximately -85 mV for 1 second,
which inactivates about 15% of the T-type channels (FIG. 1).
[0148] Test compounds were dissolved in external solution,
0.1-0.01% DMSO. After .about.10 min rest, they were applied by
gravity close to the cell using a WPI microfil tubing. The
"non-inactivated" pre-pulse was used to examine the resting block
of a compound. The "inactivated" protocol was employed to study
voltage-dependent block. However, the initial data shown below were
mainly obtained using the non-inactivated protocol only. IC.sub.50
values are shown for various compounds of the invention in Table 4
for the drug of interest. Values are shown in .quadrature.M and
values above 10.quadrature.M are simply represented as
10.quadrature.M. Similarly, IC.sub.51 values for
.quadrature..sub.1G below 0.30.quadrature.M are simply represented
as 0.30.quadrature.M
TABLE-US-00004 TABLE 4 T-type Calcium Channel Block Compound
.quadrature..sub.1G (.quadrature.M) .quadrature..sub.1H
(.quadrature.M) 1 1.01 0.37 2 0.30 0.54 3 0.30 0.55 6 1.32 7 4.33 8
2.42 11 1.89 3.80 12 0.48 1.66 13 0.63 1.87 14 0.30 1.17 15 1.03
3.04 16 0.30 0.19 17 0.30 0.12 18 0.30 0.08 19 1.74 0.74 20 0.30
0.40 21 3.66 0.59 26 0.20 27 0.19 35 0.41 0.16 36 4.30 1.70 37 0.30
0.17 39 1.31 1.17 40 0.30 0.16 41 0.30 0.15 42 1.64 0.76 43 0.30
0.15 44 0.62 0.32 45 10.00 47 3.11 0.88 48 1.57 0.79 49 0.34 7.30
50 8.97 51 10.00 53 10.00 55 10.00 57 1.05 10.00 58 4.01 59 1.66 60
0.22 61 10.00 62 0.23 63 0.43 64 0.20 65 6.37 66 0.37 68 7.56 76
7.62 85 10.00 86 10.00 88 10.00 10.00 89 4.10 10.00 90 4.27 91
10.00 92 0.06 93 0.09 94 0.06 95 10.00 96 10.00 97 0.10 98 3.60 99
0.21 100 0.10 101 0.14 102 10.00 103 1.21 104 0.14 105 0.28 106
5.56 107 0.16 108 0.25 115 0.23 116 10.00 153 0.30 0.07 154 6.71
157 10.00 159 0.31 3.36 160 0.02 0.50 166 10.00 169 0.30 0.23 172
1.62 10.00 174 2.48 10.00 175 10.00 176 10.00 177 10.00 178 0.72
5.10 179 0.002 0.08 190 10.00 191 10.00 194 10.00 195 4.78 1.97 196
10.00 10.00 197 10.00 198 0.40 1.30 201 10.00 206 10.00 207 10.00
208 10.00 209 8.60 217 5.82 219 10.00 220 6.91 221 4.08 10.00 222
2.03 10.00 223 8.15 224 3.76 6.19 225 0.52 0.77 226 10.00 10.00 228
1.67 2.35 229 10.00 10.00 230 4.76 0.85 231 10.00 10.00 232 5.01
2.87 233 2.04 1.38 234 1.45 0.97 235 0.30 0.44 236 0.86 1.72 238
10.00 10.00 239 0.30 1.73 240 10.00 10.00 241 0.30 0.52 242 2.48
1.19 243 0.53 0.81 244 7.19 10.00 246 1.31 1.13 247 0.30 0.50 248
0.30 0.48 249 0.30 0.58 251 10.00 10.00 252 2.43 2.34 253 0.48 1.31
255 0.57 2.34 256 5.57 10.00 257 3.21 2.42 258 1.18 3.24 259 10.00
263 10.00 264 0.30 0.53 265 2.06 3.76 267 0.39 0.87 268 10.00 10.00
269 1.40 3.14 270 10.00 272 2.84 10.00 273 0.36 1.42 274 0.30 0.66
275 1.99 10.00 276 0.31 1.09 279 10.00 10.00 280 9.70 5.59 282 2.50
7.16 284 10.00 285 4.94 10.00 291 0.30 0.51 292 0.36 0.74 293 5.18
4.07 294 0.57 0.81 295 1.34 1.26 296 0.61 1.10 297 10.00 10.00 298
0.30 0.28 299 1.21 1.98 300 2.81 3.25 301 0.30 0.45 302 0.30 0.30
303 0.30 0.60 304 0.30 0.37 305 7.42 4.45 306 0.34 0.39 307 0.30
0.34 308 1.23 0.88 309 0.85 0.35 310 10.00 10.00 311 2.65 0.33 312
4.26 0.75 313 6.31 0.62 314 10.00 9.24 315 9.90 1.47 316 10.00 5.83
317 0.66 0.56 318 0.50 0.87 319 0.30 0.15 320 0.76 1.62 321 1.33
1.92 322 4.05 2.14 323 1.87 2.66 324 10.00 10.00 325 6.58 3.39 326
10.00 6.99 327 0.30 0.74 328 1.03 1.55 329 3.24 4.05 330 10.00
10.00 331 10.00 10.00 332 10.00 333 0.80 2.42 334 0.30 0.22 335
0.33 0.31 336 1.75 1.16 337 0.27 0.37 338 0.30 0.16 339 0.30 0.13
340 0.30 0.12 341 0.30 0.12 342 0.30 0.07 343 0.33 0.13 344 0.30
0.12 345 0.30 0.11 346 0.30 0.05 347 0.30 0.24 348 0.30 0.11 349
0.30 0.30 350 0.91 0.75 351 1.72 1.30 352 0.30 0.08 353 0.30 0.06
354 1.84 2.14 355 0.30 0.16 356 0.55 0.83 357 2.15 1.27 358 0.52
0.53 359 0.38 0.49 360 0.30 0.25 361 0.70 0.60 362 0.30 0.17 363
0.30 0.20 364 0.30 0.23 365 0.80 0.56 366 0.30 0.12 367 0.30 0.05
368 0.30 0.17 369 6.91 7.01 370 0.30 0.04 371 0.30 0.14 372 10.00
10.00 373 10.00 10.00 374 0.30 0.09 375 0.30 0.07 376 0.30 0.16 377
0.30 0.45 378 1.60 1.44 379 0.30 0.13 380 0.30 0.11 381 0.30
0.08
382 0.30 0.09 383 1.22 1.35 384 0.30 0.09 385 0.58 0.80 386 0.87
0.49 387 0.99 0.72 388 0.30 0.16 389 10.00 10.00 390 0.30 391 0.30
392 2.01 393 6.04 394 4.61 395 10.00 396 2.91 397 1.78 398 3.53 400
1.50 401 0.91 402 0.54 403 1.11 404 0.38 405 0.30 406 0.30 407 0.30
408 3.36 409 0.30 410 1.15 411 10.00 412 10.00 413 10.00 416 10.00
417 9.49 418 2.17 419 1.63 420 0.70 421 4.04 422 1.93 423 2.08 424
0.44 425 0.30 426 0.30 427 0.30 428 0.30 429 0.30 430 0.30 431 0.30
432 0.30 433 10.00 434 0.300 0.06 435 0.300 0.09 436 10.00 10.00
437 10.00 10.00 438 3.91 1.71 439 3.28 2.17 440 10.00 10.00 441
9.48 10.00 442 10.00 10.00 443 3.31 2.81 444 7.40 10.00 445 10.00
10.00 446 10.00 10.00 447 9.15 3.08 448 9.73 4.64 449 10.00 10.00
450 8.88 10.00 451 10.00 10.00 452 4.24 7.92 453 8.24 10.00 454
0.30 0.04 455 0.30 0.03 456 0.30 0.02 457 0.30 0.05 458 0.30 0.04
459 0.30 0.02 460 0.30 0.03 461 0.30 0.02 462 0.30 0.03 463 0.30
0.21 464 0.30 0.14 465 0.30 0.17 466 0.30 0.27 467 0.30 0.17 468
0.30 0.09 469 0.30 0.12 470 0.30 0.07 471 0.30 0.06 472 0.30 0.04
473 0.68 0.13 474 0.30 0.04 475 0.30 0.17 476 0.30 0.14 477 0.30
0.06 478 0.30 0.11 479 0.30 0.15 480 0.30 0.18 481 0.30 0.25 482
0.30 0.08 483 0.30 0.11 486 10.00 10.00 487 10.00 488 0.42 0.13 489
0.37 0.12 490 0.30 0.15 491 0.30 0.19 492 0.30 0.09 493 0.30 0.06
494 0.30 0.16 495 0.30 0.09 496 0.30 0.09 497 0.77 0.16 498 0.77
0.22 499 0.30 0.14 500 0.30 0.18 501 0.30 0.12 502 0.59 0.23 503
1.55 7.20 504 0.42 0.42 505 0.77 0.58 506 5.36 1.48 507 2.98 1.48
508 10.00 9.22 510 3.97 10.00 511 0.30 0.09 512 0.30 0.19 513 0.30
0.09 514 0.30 0.31 515 0.31 0.31 516 0.46 0.22 517 1.10 0.42 518
1.31 0.81 519 0.30 0.24 520 0.30 0.19 522 0.30 0.14 523 5.74 0.91
524 10.00 10.00 525 2.36 0.77 526 10.00 3.24 527 2.65 2.84 528
10.00 8.54 529 5.44 2.51 530 0.59 0.86 531 0.30 0.08 532 0.30 0.13
533 0.43 0.40 534 0.38 0.42 535 3.62 2.14 536 0.30 0.12 537 2.47
0.36 538 0.30 0.06 539 1.68 0.51 540 1.40 0.55 541 0.31 0.41 542
0.98 0.45 543 0.58 0.41 544 0.30 0.17 545 0.47 0.21 546 0.30 0.13
547 0.30 0.03 548 0.30 0.16 549 0.30 0.11 550 0.30 0.02 551 0.37
0.14 552 0.30 0.06 553 2.52 1.73 554 10.00 10.00 555 0.53 0.89 556
1.37 1.77 557 3.58 1.31 558 0.30 0.46 559 9.06 10.00 560 0.47 0.59
561 0.30 0.27 562 0.40 0.66 563 0.30 0.31 564 0.30 0.10 565 0.31
0.22 566 0.76 0.82 567 0.30 0.35 568 1.36 0.89 579 3.79 4.35 570
2.06 2.36 571 10.00 10.00 572 0.49 1.56 573 1.27 1.01 574 0.30 0.20
575 1.25 1.04 576 0.43 0.93 577 0.30 0.45 578 0.30 0.16 579 0.30
0.05 580 0.30 0.22 581 0.30 0.21 583 0.30 0.15 584 0.30 0.28 585
10.00 10.00 586 10.00 4.80 587 10.00 3.59 589 10.00 590 0.30 0.07
591 0.17 592 0.08 593 0.26 594 0.16 595 0.08 596 0.16 597 6.52 598
1.65 599 1.47 600 2.05 601 1.87 602 2.41 603 0.81 604 1.90 605 3.58
606 3.30 607 3.17 608 10.00 609 3.05 610 0.77 611 0.29 612
10.00
TABLE-US-00005 TABLE 5 hERG K.sup.+ Channel Block Compound hERG
(.quadrature.M) 26 2.60 59 2.80 115 8.30 153 2.80 159 1.30 160 0.19
178 1.60 179 0.33 334 0.92 343 6.20 344 9.10 362 8.30 363 8.30 364
8.30 366 8.30 367 8.30 368 8.30 371 14.70 374 7.80 375 8.80 376
11.00 391 0.63 427 0.45 457 16.60 460 6.90 461 7.40 462 4.10 468
4.20 469 9.50 470 2.60 471 2.30 472 2.80 473 2.20 476 16.60 477
16.60 478 16.60 482 7.90 489 8.80 490 10.90 492 4.70 493 2.50 495
4.10 499 11.10 500 5.50 501 5.60 511 2.90 513 16.60 531 2.40 537
17.00 538 13.00 541 17.00 542 6.40 543 5.20 544 6.00 545 6.60 552
1.80 567 17.00 574 4.10 577 17.00 578 5.40 580 8.30 581 11.00 583
1.70 594 17.00 590 2.20
Example 18
L5/L6 Spinal Nerve Ligation (SNL)--Chung Pain Model
[0149] The Spinal Nerve Ligation is an animal model representing
peripheral nerve injury generating a neuropathic pain syndrome. In
this model experimental animals develop the clinical symptoms of
tactile allodynia and hyperalgesia. L5/L6 Spinal nerve ligation
(SNL) injury may be induced using the procedure of Kim and Chung
(Kim, S. H., et al., Pain (1992) 50:355-363) in male Sprague-Dawley
rats (Harlan; Indianapolis, Ind.) weighing 200 to 250 grams.
[0150] Anaesthesia may be induced with 2% isofluorane in O.sub.2 at
2 L/min and maintained with 0.5% isofluorane in O.sub.2. Rats can
then be shaved and aseptically prepared for surgeries. A 2 cm
paraspinal incision can be made at the level of L4-52. L4/L5 can be
exposed by removing the transverse process above the nerves with a
small rongeur. The L5 spinal nerve is the larger of the two visible
nerves below the transverse process and lies closest to the spine.
The L6 spinal nerve is located beneath the corner of the slope
bone. A home-made glass Chung rod can be used to hook L5 or L6 and
a pre-made slip knot of 4.0 silk suture can be placed on the tip of
the rod just above the nerve and pulled underneath to allow for the
tight ligation. The L5 and L6 spinal nerves can be tightly ligated
distal to the dorsal root ganglion. The incision may be closed, and
the animals allowed to recover for 5 days. Rats that exhibited
motor deficiency (such as paw-dragging) or failure to exhibit
subsequent tactile allodynia should be excluded from further
testing.
[0151] Sham control rats may undergo the same operation and
handling as the experimental animals, but without SNL.
[0152] Prior to initiating drug delivery, baseline behavioural
testing data should be obtained. At selected times after infusion
of the Test or Control Article behavioural data can then be
collected again.
A. Assessment of Tactile Allodynia--Von Frey
[0153] The assessment of tactile allodynia consists of measuring
the withdrawal threshold of the paw ipsilateral to the site of
nerve injury in response to probing with a series of calibrated von
Frey filaments (innocuous stimuli). Animals should be acclimated to
the suspended wire-mesh cages for 30 min before testing. Each von
Frey filament may be applied perpendicularly to the plantar surface
of the ligated paw of rats for 5 sec. A positive response is
indicated by a sharp withdrawal of the paw. For rats, the first
testing filament is 4.31. Measurements can be taken before and
after administration of test articles. The paw withdrawal threshold
is determined by the non-parametric method of Dixon (Dixon, W.,
Ann. Rev. Pharmacol. Toxicol. (1980) 20:441-462.), in which the
stimulus is incrementally increased until a positive response was
obtained, and then decreased until a negative result is observed.
The protocol can be repeated until three changes in behaviour were
determined ("up and down" method) (Chaplan, S. R., et al., J.
Neuroscience Methods (1994) 53:55-63.). The 50% paw withdrawal
threshold can be determined as (10.sup.[Xf+k.delta.])/10,000, where
X.sub.f=the value of the last von Frey filament employed, k=Dixon
value for the positive/negative pattern, and .delta.=the
logarithmic difference between stimuli. The cut-off values for rats
may be no less than 0.2 g and no higher than 15 g (5.18 filament);
for mice no less than 0.03 g and no higher than 2.34 g (4.56
filament). A significant drop of the paw withdrawal threshold
compared to the pre-treatment baseline is considered tactile
allodynia.
B. Assessment of Thermal Hypersensitivity--Hargreaves
[0154] The method of Hargreaves and colleagues (Hargreaves, K., et
al., Pain (1988) 32:77-8) can be employed to assess paw-withdrawal
latency to a noxious thermal stimulus.
[0155] Rats may be allowed to acclimate within a Plexiglas
enclosure on a clear glass plate for 30 minutes. A radiant heat
source (i.e., halogen bulb coupled to an infrared filter) can then
be activated with a timer and focused onto the plantar surface of
the affected paw of treated rats. Paw-withdrawal latency can be
determined by a photocell that halted both lamp and timer when the
paw is withdrawn. The latency to withdrawal of the paw from the
radiant heat source can be determined prior to L5/L6 SNL, 7-14 days
after L5/L6 SNL but before drug, as well as after drug
administration. A maximal cut-off of 33 seconds is employed to
prevent tissue damage. Paw withdrawal latency can thus be
determined to the nearest 0.1 second. A significant drop of the paw
withdrawal latency from the baseline indicates the status of
thermal hyperalgesia. Antinociception is indicated by a reversal of
thermal hyperalgesia to the pre-treatment baseline or a significant
(p<0.05) increase in paw withdrawal latency above this baseline.
Data is converted to % anti hyperalgesia or % anti nociception by
the formula: (100.times.(test latency-baseline
latency)/(cut-off-baseline latency) where cut-off is 21 seconds for
determining anti hyperalgesia and 40 seconds for determining anti
nociception.
Example 19
Electroconvulsive Shock (ECS) Threshold Test Epilepsy Model
[0156] The proconvulsant or anticonvulsant activity of compounds
can be evaluated using the electroconvulsive shock threshold test
following the method described by Swinyard et al., (J. Pharmacol.
Exp. Ther., 106, 319-330, 1952).
[0157] To elicit tonic convulsions, a rectangular electroconvulsive
shock is administered to OF1 mice for 0.4 s at 50 Hz, via corneal
electrodes connected to a constant current shock generator (Ugo
Basile: Type 7801). The threshold for tonic convulsions is
determined as follows: The first animal is exposed to 30 mA. If the
first animal does not exhibit tonic convulsions within 5 seconds,
the second animal is exposed to 40 mA, and so on (increments of 10
mA) until the first tonic convulsion is observed. Once the first
tonic convulsion is observed, the intensity of ECS is decreased by
5 mA for the next animal and then the intensity is decreased or
increased by 5 mA from animal to animal depending on whether the
previous animal convulsed or not. The minimum intensity given is 5
mA and the maximum intensity given is 95 mA.
[0158] Each treatment group consists of a number mice that are all
exposed to ECS, but only the first 3 animals are used to estimate
the threshold current and are not included in the analysis.
[0159] For optimal results, each test substance is evaluated at
multiple doses, administered i.p. or p.o., prior to ECS to coincide
with times of peak optimal effect (Tmax), and compared with a
vehicle control group. Diazepam administered under the same
experimental conditions can be used as reference substance and the
vehicle alone can be administered as a vehicle control.
[0160] The results are reported as the mean intensity administered,
number of deaths and percent change from control for each treatment
group for approximately 30 minutes after the animal receives the
ECS. A positive percent change indicates an anticonvulsant effect
whereas a negative percent change indicates a proconvulsant effect.
For the test substances, data (intensity) can be analyzed using a
one-way ANOVA followed by Dunnett's t test in case of a significant
group effect. The effects of the reference substance (diazepam) can
be analyzed using a Student's t test.
Example 20
GAERS (Genetic Absence Epilepsy Rats from Strasbourg) Epilepsy
Model
[0161] The GAERS (Genetic Absence Epilepsy Rats from Strasbourg) is
noted for its long and frequently recurring absence seizure
episodes. Investigators have determined, using electrophysiological
recordings from neurons within the thalamus, that the activity and
expression of the low-voltage calcium channels is significantly
increased in GAERS. Eight female GAERS rats, bred in the Ludwig
Institute for Cancer Research, were used for this study. Rats
weighed between 180 and 250 g and aged between 18 and 26 weeks at
the start of the experiment.
[0162] Electrodes were made in our laboratory by soldering together
gold-plated sockets (220-S02 Ginder Scientific, VA, Canada),
stainless steel teflon coated wire (SDR clinical technology, NSW,
Australia) and a small stainless steel screw (1.4.times.3 mm, Mr.
Specks, Australia). Animals were anaethetised with inhalation of
Isoflurane in equal parts of medical air and oxygen (5% induction,
2.5-1.5% maintenance) or alternatively by intraperitoneal injection
with xylazine (10 mg/kg) and ketamine (75 mg/kg). The animals were
fixated in a stereotaxic frame by means of ear bars. A midline
incision on the scalp was made, skin and connective tissue was
scraped and pushed laterally to expose underlying skull. 6 holes
were drilled bilaterally, 2 in the frontal bone and 4 in the
parietal bone, approximately 2 mm anterior to bregma, and 4 and 10
mm posterior to bregma. 6 electrodes were implanted in the holes,
and gold-plated sockets were clipped into 9-pin ABS plug
(GS09PLG-220, Ginder Scientific, Canada). 2 two side-anchoring
screws were placed laterally into skull to improve strength of cap
fixation, then caps were held in place with dental cement.
[0163] Post-operatively, animals were given the analgesic Rimadyl
(4 mg/kg), placed in their cages on a heat mat, and observed until
recovery. Rats were caged separately throughout the study, weighed
and health-checked daily, and were allowed 7 days to recover prior
to commencement of the experimental procedures. Rats were allowed
free access to rodent chow (brand, WA stock feeders) and water
under 12:12 light dark conditions in the Biological Research
Facility of the Department of Medicine (RMH).
[0164] Prior to first drug treatment, rats were tested for
absence-type seizures, which are accompanied by generalised spike
and wave discharges (SWD) on an EEG recording. Testing, and all
further experiments were performed in a quiet, well lit room with
rats in their home cages. Rats were connected via 6-channel wire
cables, which were cut and soldered to 6 gold-plated pins inserted
into a 9 pin socket. Cables were connected to a computer running
Compumedics.TM. EEG acquisition software (Melbourne, Australia). 3
rats which did not have adequate baseline seizures at the start of
the study were commenced in week 2 and their treatments were made
up for at the end according to the schedule (see table 2). On week
1, day 1 after the acclimation period following surgical
implantation of subdural electrodes, 4 animals (#1-4) were
habituated with the cable connected for 15 minutes, then had their
SWDs recorded for 60 minutes as baseline. Immediately following
baseline, rats were given one of the test, reference or control
articles according to the treatment schedule, and target period was
recorded from 15 after injection for 120 minutes. Animals were
monitored throughout the experiment, and were kept quietly wakeful
during baseline and target periods
[0165] The seizure expression for the 60 minutes pre-injection and
120 minutes post-injection EEG recording (starting 15 minutes
post-drug administration) was quantified by marking the start and
finish of the burst of SW Ds. This was done with the assistance of
SWCFinder.RTM. software which has been custom designed to
quantitate GAERS seizures, and researchers were blinded to the
nature of the drug administered, whereby the analysis was performed
blinded. Standard criteria for GAERS seizures is an SWD burst of
amplitude of more than three times baseline, a frequency of 7 to 12
Hz, and a duration of longer than 0.5 s. From this, the total
percent time spent in seizure over the 120 minutes post-injection
EEG recording was determined (percentage time in seizure) as the
primary outcome variable.
[0166] Table 6 shows the average percentage time in seizure of
vehicle, compounds 365 and 368 administered IP with a 30 mg/kg dose
compared to baseline. Both compounds 365 and 368 demonstrated a
significant decrease in the percentage of time in seizure activity
compared to both baseline and vehicle.
TABLE-US-00006 TABLE 6 Percent Recording Time in Seizure Activity
Cmpd No. Baseline Post-injection Vehicle 13.85 .+-. 2.89 9.67 .+-.
1.92 364 12.12 .+-. 1.82 0.45 .+-. 0.20 367 9.99 .+-. 2.07 0.87
.+-. 0.44
* * * * *