U.S. patent application number 16/390957 was filed with the patent office on 2020-04-09 for substituted benzamides and methods of use thereof.
This patent application is currently assigned to GENENTECH, INC.. The applicant listed for this patent is GENENTECH, INC. XENON PHARMACEUTICALS INC.. Invention is credited to Jean-Christophe ANDREZ, Paul Robert BICHLER, Chien-An CHEN, Sultan CHOWDHURY, Shannon Marie DECKER, Christoph Martin DEHNHARDT, Thilo FOCKEN, Michael Edward GRIMWOOD, Ivan William HEMEON, Qi JIA, Jun LI, Zhiguo LIU, Daniel F. ORTWINE, Brian Salvatore SAFINA, Tao SHENG, Shaoyi SUN, Daniel SUTHERLIN, Andrew D. WHITE, Michael Scott WILSON, Alla Yurevna ZENOVA, Jiuxiang ZHU.
Application Number | 20200108054 16/390957 |
Document ID | / |
Family ID | 53198372 |
Filed Date | 2020-04-09 |
View All Diagrams
United States Patent
Application |
20200108054 |
Kind Code |
A1 |
ANDREZ; Jean-Christophe ; et
al. |
April 9, 2020 |
SUBSTITUTED BENZAMIDES AND METHODS OF USE THEREOF
Abstract
The invention provides compounds having the general formula I:
##STR00001## and pharmaceutically acceptable salts thereof, wherein
the variables R.sup.A, R.sup.AA, subscript n, ring A, X.sup.2, L,
subscript m, X.sup.1, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
and R.sup.N have the meaning as described herein, and compositions
containing such compounds and methods for using such compounds and
compositions.
Inventors: |
ANDREZ; Jean-Christophe;
(Burnaby, CA) ; BICHLER; Paul Robert; (Burnaby,
CA) ; CHEN; Chien-An; (Shanghai, CN) ;
CHOWDHURY; Sultan; (Burnaby, CA) ; DECKER; Shannon
Marie; (Burnaby, CA) ; DEHNHARDT; Christoph
Martin; (Burnaby, CA) ; FOCKEN; Thilo;
(Burnaby, CA) ; GRIMWOOD; Michael Edward;
(Burnaby, CA) ; HEMEON; Ivan William; (Burnaby,
CA) ; JIA; Qi; (Burnaby, CA) ; LI; Jun;
(South San Francisco, CA) ; LIU; Zhiguo;
(Shanghai, CN) ; ORTWINE; Daniel F.; (South San
Francisco, CA) ; SAFINA; Brian Salvatore; (South San
Francisco, CA) ; SUTHERLIN; Daniel; (South San
Francisco, CA) ; SHENG; Tao; (Burnaby, CA) ;
SUN; Shaoyi; (Burnaby, CA) ; WHITE; Andrew D.;
(Shanghai, CN) ; WILSON; Michael Scott; (Burnaby,
CA) ; ZENOVA; Alla Yurevna; (Burnaby, CA) ;
ZHU; Jiuxiang; (Shanghai, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GENENTECH, INC.
XENON PHARMACEUTICALS INC. |
South San Francisco
Bumaby |
CA |
US
CA |
|
|
Assignee: |
GENENTECH, INC.
South San Francisco
CA
XENON PHARMACEUTICALS INC.
Burnaby
|
Family ID: |
53198372 |
Appl. No.: |
16/390957 |
Filed: |
April 22, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16130703 |
Sep 13, 2018 |
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16390957 |
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15875992 |
Jan 19, 2018 |
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16130703 |
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15620597 |
Jun 12, 2017 |
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15875992 |
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15275131 |
Sep 23, 2016 |
9694002 |
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15620597 |
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14603273 |
Jan 22, 2015 |
9546164 |
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15275131 |
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PCT/CN2014/092269 |
Nov 26, 2014 |
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14603273 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 19/02 20180101;
C07D 211/32 20130101; C07D 417/06 20130101; C07F 7/0812 20130101;
C07D 211/96 20130101; C07D 295/155 20130101; A61P 25/24 20180101;
C07D 265/30 20130101; C07D 305/08 20130101; C07D 413/12 20130101;
A61P 11/00 20180101; A61P 35/00 20180101; C07D 207/12 20130101;
C07D 237/08 20130101; C07D 233/68 20130101; A61P 25/00 20180101;
A61P 29/00 20180101; C07D 211/60 20130101; A61K 31/4412 20130101;
A61P 9/10 20180101; A61P 25/18 20180101; A61P 25/22 20180101; A61K
31/397 20130101; C07D 205/12 20130101; A61P 25/06 20180101; A61K
31/4545 20130101; C07D 403/04 20130101; A61K 31/4015 20130101; C07D
205/04 20130101; C07D 413/06 20130101; C07D 451/02 20130101; A61P
17/02 20180101; C07D 405/12 20130101; C07D 487/08 20130101; A61K
31/337 20130101; C07D 451/06 20130101; C07D 211/42 20130101; C07D
211/54 20130101; C07D 295/26 20130101; A61P 9/00 20180101; A61P
13/10 20180101; A61P 31/18 20180101; C07D 453/02 20130101; C07D
241/04 20130101; C07D 401/04 20130101; C07D 401/12 20130101; A61K
31/415 20130101; A61K 31/445 20130101; A61K 31/495 20130101; A61P
1/02 20180101; A61P 1/04 20180101; A61P 25/04 20180101; C07D 211/22
20130101; C07D 401/06 20130101; C07D 403/12 20130101; A61P 17/00
20180101; C07D 405/04 20130101; A61K 31/4523 20130101; A61P 1/00
20180101; A61P 25/08 20180101 |
International
Class: |
A61K 31/445 20060101
A61K031/445; C07D 205/12 20060101 C07D205/12; C07D 417/06 20060101
C07D417/06; C07D 405/12 20060101 C07D405/12; C07D 413/12 20060101
C07D413/12; C07D 413/06 20060101 C07D413/06; C07D 211/22 20060101
C07D211/22; C07D 295/155 20060101 C07D295/155; C07D 451/06 20060101
C07D451/06; C07D 401/04 20060101 C07D401/04; C07D 451/02 20060101
C07D451/02; C07D 405/04 20060101 C07D405/04; C07D 295/26 20060101
C07D295/26; C07F 7/08 20060101 C07F007/08; C07D 211/96 20060101
C07D211/96; A61K 31/4545 20060101 A61K031/4545; A61K 31/4523
20060101 A61K031/4523; C07D 211/60 20060101 C07D211/60; C07D 211/54
20060101 C07D211/54; C07D 211/32 20060101 C07D211/32; C07D 487/08
20060101 C07D487/08; C07D 403/04 20060101 C07D403/04; C07D 453/02
20060101 C07D453/02; C07D 403/12 20060101 C07D403/12; C07D 401/12
20060101 C07D401/12; C07D 401/06 20060101 C07D401/06; C07D 305/08
20060101 C07D305/08; C07D 207/12 20060101 C07D207/12; C07D 241/04
20060101 C07D241/04; C07D 237/08 20060101 C07D237/08; C07D 233/68
20060101 C07D233/68; A61K 31/495 20060101 A61K031/495; A61K 31/4412
20060101 A61K031/4412; A61K 31/415 20060101 A61K031/415; A61K
31/4015 20060101 A61K031/4015; A61K 31/397 20060101 A61K031/397;
A61K 31/337 20060101 A61K031/337; C07D 265/30 20060101 C07D265/30;
C07D 211/42 20060101 C07D211/42; C07D 205/04 20060101
C07D205/04 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 27, 2013 |
CN |
PCT/CN2013/001452 |
Nov 28, 2013 |
CN |
PCT/CN2013/088062 |
Nov 3, 2014 |
CN |
PCT/CN2014/090171 |
Claims
1. A compound of formula I: ##STR02185## or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 is C.sub.1-8 alkyl,
C.sub.2-8 alkenyl, C.sub.1-8 haloalkyl, C.sub.1-8 alkoxy, C.sub.3-8
carbocycle, C-linked C.sub.2-7 heterocycle, or --NR.sup.1AR.sup.1B,
wherein R.sup.1A and R.sup.1B are each independently selected from
the group consisting of hydrogen, C.sub.1-8 alkyl, C.sub.1-8
alkoxy, and wherein R.sup.1A and R.sup.1B are optionally combined
to form a 3 to 8 membered heterocyclic ring optionally comprising 1
additional heteroatom selected from N, O and S; and wherein R.sup.1
is optionally substituted with from 1 to 5 substituents selected
from the group consisting of C.sub.1-4 alkyl, C.sub.1-4 haloalkyl,
F, Cl, Br, I, --OH, --CN, --NO.sub.2, --NR.sup.R1aR.sup.R1b,
--OR.sup.R1a, --SR.sup.R1a, --Si(R.sup.R1a).sub.3 and C.sub.3-6
carbocycle; wherein R.sup.R1a and R.sup.R1b are independently
selected from the group consisting of hydrogen, C.sub.1-8 alkyl,
C.sub.1-8 haloalkyl; R.sup.N is hydrogen, C.sub.1-4alkyl or
C.sub.1-4haloalkyl; R.sup.2 is selected from the group consisting
of H, F, Cl, Br, I, --CN, C.sub.1-8 alkyl, C.sub.1-8 haloalkyl and
C.sub.1-8 alkoxy; R.sup.3 is selected from the group consisting of
H, F, Cl, Br, I, --CN, C.sub.1-8 alkyl, C.sub.1-8 haloalkyl and
C.sub.1-8 alkoxy; R.sup.4 is selected from the group consisting of
H, F, Cl, Br, I, --CN, C.sub.1-8 alkyl, C .sub.1-8 haloalkyl and
C.sub.1-8 alkoxy; R.sup.5 is selected from the group consisting of
H, F, Cl, Br, I, --CN, C.sub.1-8 alkyl, C.sub.1-8 haloalkyl,
C.sub.1-8 alkoxy, C.sub.3-8 cycloalkyl and C.sub.2-7 heterocycle,
wherein said C.sub.3-8 cycloalkyl and C.sub.2-7 heterocycle is
optionally substituted with 1-3 substituents selected from F, Cl,
Br and I; L is a linker selected from the group consisting of
C.sub.1-4 alkylene, C.sub.2-4 alkenylene and C.sub.2-4 alkynylene,
wherein L is optionally substituted with from 1 to 3 substituents
selected from the group consisting of .dbd.O, C.sub.1-4 alkyl,
halo, and C.sub.1-4 haloalkyl; the subscript m represents the
integer 0 or 1; X.sup.1 and X.sup.2 are each independently selected
from the group consisting of absent, --O--, --S(O)--,
--S(O).sub.2-- and --N(R.sup.X)-- wherein R.sup.X is H, C.sub.1-8
alkyl, C.sub.1-8 alkanoyl, or --S(O).sub.2(C.sub.1-8 alkyl), and
wherein if the subscript m is 0 then one of X.sup.1 or X.sup.2 is
absent; the subscript in is an integer from 0 to 5; the ring A is a
C.sub.2-11 heterocycle comprising a nitrogen atom and further
optionally comprising 1-2 heteroatoms selected from N, O and S;
each R.sup.AA is independently selected from the group consisting
of C.sub.1-6 alkyl, C.sub.1- 6 haloalkyl, C.sub.1-6 heteroalkyl,
CN, F, Cl, Br and I; and R.sup.A is selected from the group
consisting of --(X.sup.RB).sub.0-1OR.sup.A1, C.sub.6-10
aryl-(X.sup.RA)--, C.sub.1-20 heteroaryl-(X.sup.RA)--, C.sub.3-12
carbocycle-(X.sup.RA)--, --R.sup.A2, --S(O).sub.2--R.sup.A2, and
C.sub.2-11 heterocycle-(X.sup.RA)--, wherein said C.sub.6-10 aryl,
C.sub.5-9 heteroaryl, C.sub.3-12 carbocycle and C.sub.2-11
heterocycle of R.sup.A is optionally substituted with from 1 to 5
substitutents selected from F, Cl, Br, I, --NH.sub.2, --OH, --CN,
--NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy,
C.sub.1-4(halo)alkoxy, C.sub.1-4 alkylamino, C.sub.1-4
dialkylamino, C.sub.1-4 alkanoyl, C.sub.1-4 alkyl-OC(.dbd.O)--,
C.sub.1-4 alkyl-S(O).sub.2--, C.sub.3-6carbocycle, and phenyl that
is optionally substituted with one or more substituents selected
from fluoro, chloro, and bromo; R.sup.A1 is selected from the group
consisting of hydrogen, C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.1-8 haloalkyl, C.sub.3-8 cycloalkyl, phenyl and benzyl;
R.sup.A2 is selected from the group consisting of C.sub.1-8 alkyl
that is optionally substituted with one or more substituents
selected from oxo (.dbd.O), fluoro, amino, C.sub.1-4 alkylamino and
C.sub.1-4 dialkylamino; X.sup.RA is selected from the group
consisting of absent, --O--, --S--, --N(H)--, --N(C.sub.1-4
alkyl)-, --S(O)--, --S(O).sub.2--, --C(.dbd.O)--, C.sub.1-4
alkylene, C.sub.1-4 heteroalkylene, C.sub.2-4 alkenylene and
C.sub.2-4 alkynylene; X.sup.RB is selected from the group
consisting of absent, C.sub.1-4 alkylene, C.sub.1-4 heteroalkylene,
C.sub.2-4 alkenylene and C.sub.2-4 alkynylene; wherein any
C.sub.1-4 alkylene, C.sub.1-4 heteroalkylene, C.sub.2-4 alkenylene
and C.sub.2-4 alkynylene of X.sup.RA or X.sup.RB is optionally
substituted with 1 to 3 substituents selected from the group
consisting of C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
heteroalkyl, oxo (.dbd.O), hydroxy, and phenyl that is optionally
substituted with 1 to 5 substitutents selected from F, Cl, Br, I,
--NH.sub.2, --OH, --CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, C.sub.1-4 alkoxy, C.sub.1-4(halo)alkoxy, C.sub.1-4
alkylamino and C.sub.1-4 dialkylamino; or wherein X.sup.RA or
X.sup.RB is optionally substituted with 2 substituents that combine
to form a 3 to 5 membered carbocycle or a 3-5 membered heterocycle;
provided the compound of formula I is not: ##STR02186##
##STR02187## ##STR02188## ##STR02189##
2-64. (canceled)
Description
[0001] The present invention relates to organic compounds useful
for therapy and/or prophylaxis in a mammal, and in particular to
inhibitors of sodium channel (e.g., NAV1.7) that are useful for
treating sodium channel-mediated diseases or conditions, such as
pain, as well as other diseases and conditions associated with the
mediation of sodium channels.
[0002] Voltage-gated sodium channels, transmembrane proteins that
initiate action potentials in nerve, muscle and other electrically
excitable cells, are a necessary component of normal sensation,
emotions, thoughts and movements (Catterall, W. A., Nature (2001),
Vol. 409, pp. 988-990). These channels consist of a highly
processed alpha subunit that is associated with auxiliary beta
subunits. The pore-forming alpha subunit is sufficient for channel
function, but the kinetics and voltage dependence of channel gating
are in part modified by the beta subunits (Goldin et al., Neuron
(2000), Vol. 28, pp. 365-368).
Electrophysiological recording, biochemical purification, and
molecular cloning have identified ten different sodium channel
alpha subunits and four beta subunits (Yu, F. H., et al., Sci. STKE
(2004), 253; and Yu, F. H., et al., Neurosci. (2003),
20:7577-85).
[0003] The hallmarks of sodium channels include rapid activation
and inactivation when the voltage across the plasma membrane of an
excitable cell is depolarized (voltage-dependent gating), and
efficient and selective conduction of sodium ions through
conducting pores intrinsic to the structure of the protein (Sato,
C., et al., Nature (2001), 409:1047-1051). At negative or
hyperpolarized membrane potentials, sodium channels are closed.
Following membrane depolarization, sodium channels open rapidly and
then inactivate. Channels only conduct currents in the open state
and, once inactivated, have to return to the resting state,
favoured by membrane hyperpolarization, before they can reopen.
Different sodium channel subtypes vary in the voltage range over
which they activate and inactivate as well as their activation and
inactivation kinetics.
[0004] The sodium channel family of proteins has been extensively
studied and shown to be involved in a number of vital body
functions. Research in this area has identified variants of the
alpha subunits that result in major changes in channel function and
activities, which can ultimately lead to major pathophysiological
conditions. The members of this family of proteins are denoted
NaV1.x, where x=1 to 9. NaV1.1 and NaV1.2 are highly expressed in
the brain (Raymond, C. K., et al., J. Biol. Chem. (2004),
279(44):46234-41) and are vital to normal brain function. Some loss
of function mutations in NaV1.1 in humans result in epilepsy,
apparently because many of these channels are expressed in
inhibitory neurons (Yu, F. H., et al., Nat Neurosci (2006), 9 (9),
1142-9). Thus, block of NaV1.1 in the CNS may be counter-productive
because it can produce hyperexcitability. However, NaV1.1 is also
expressed in the peripheral nervous system and block may afford
analgesic activity.
[0005] NaV1.3 is expressed primarily in the fetal central nervous
system. It is expressed at very low levels or not at all in the
peripheral nervous system, but expression is upregulated in the
dorsal horn sensory neurons of rats after nervous system injury
(Hains, B. D., et al., J. Neurosci. (2003), 23(26):8881-92). Thus,
it is an inducible target for treatment of pain following nerve
injury.
[0006] NaV1.4 is expressed primarily in skeletal muscle (Raymond,
C. K., et al., op. cit.). Mutations in this gene have been shown to
have profound effects on muscle function including paralysis,
(Tamaoka A., Intern. Med. (2003), (9):769-70).
[0007] NaV1.5, is expressed mainly in cardiac myocytes (Raymond, C.
K., et al., op. cit.), including atria, ventricles, the sino-atrial
node, atrio-ventricular node and cardiac Purkinje fibers. The rapid
upstroke of the cardiac action potential and the rapid impulse
conduction through cardiac tissue is due to the opening of NaV1.5.
Abnormalities in the function of NaV1.5 can result in the genesis
of a variety of cardiac arrhythmias. Mutations in human NaV1.5
result in multiple arrhythmic syndromes, including, for example,
long QT3 (LQT3), Brugada syndrome (BS), an inherited cardiac
conduction defect, sudden unexpected nocturnal death syndrome
(SUNDS) and sudden infant death syndrome (SIDS) (Liu, H., et al.,
Am. J. Pharmacogenomics (2003), 3(3):173-9). Sodium channel blocker
therapy has been used extensively in treating cardiac
arrhythmias.
[0008] NaV1.6 is a widely distributed voltage-gated sodium channel
found throughout the central and peripheral nervous systems. It is
expressed at high density in the nodes of Ranvier of myelinated
neurons (Caldwell, J. H., et al., Proc. Natl. Acad. Sci. USA
(2000), 97(10): 5616-20).
[0009] NaV1.7 is a tetrodotoxin-sensitive voltage-gated sodium
channel encoded by the gene SCN9A. Human NaV1.7 was first cloned
from neuroendocrine cells (Klugbauer, N., et al., 1995 EMBO J., 14
(6): 1084-90.) and rat NaV1.7 was cloned from a pheochromocytoma
PC12 cell line (Toledo-Aral, J. J., et al., Proc. Natl. Acad. Sci.
USA (1997), 94:1527-1532) and from rat dorsal root ganglia
(Sangameswaran, L., et al., (1997), J. Biol. Chem., 272 (23):
14805-9). NaV1.7 is expressed primarily in the peripheral nervous
system, especially nocieptors and olfactory neurons and sympathetic
neurons. The inhibition, or blocking, of NaV1.7 has been shown to
result in analgesic activity. Knockout of NaV1.7 expression in a
subset of sensory neurons that are predominantly nociceptive
results in resistance to inflammatory pain (Nassar, et al., op.
cit.). Likewise, loss of function mutations in humans results in
congenital indifference to pain (CIP), in which the individuals are
resistant to both inflammatory and neuropathic pain (Cox, J. J., et
al., Nature (2006); 444:894-898; Goldberg, Y. P., et al., Clin.
Genet. (2007); 71:311-319). Conversely, gain of function mutations
in NaV1.7 have been established in two human heritable pain
conditions, primary erythromelalgia and familial rectal pain,
(Yang, Y., et al., J. Med. Genet. (2004), 41 (3):171-4). In
addition, a single nucleotide polymorphism (R1150W) that has very
subtle effects on the time- and voltage-dependence of channel
gating has large effects on pain perception (Estacion, M., et al.,
2009. Ann Neurol 66: 862-6; Reimann, F., et al., Proc Natl Acad Sci
USA (2010), 107: 5148-53). About 10% of the patients with a variety
of pain conditions have the allele conferring greater sensitivity
to pain and thus might be more likely to respond to block of
NaV1.7. Because NaV1.7 is expressed in both sensory and sympathetic
neurons, one might expect that enhanced pain perception would be
accompanied by cardiovascular abnormalities such as hypertension,
but no correlation has been reported. Thus, both the CIP mutations
and SNP analysis suggest that human pain responses are more
sensitive to changes in NaV1.7 currents than are perturbations of
autonomic function.
[0010] NaV1.8 is expressed primarily in sensory ganglia of the
peripheral nervous system, such as the dorsal root ganglia
(Raymond, C. K., et al., op. cit.). There are no identified human
mutations for NaV1.8 that produce altered pain responses. NaV1.8
differs from most neuronal NaV's in that it is insensitive to block
by tetrodotoxin. Thus, one can isolate the current carried by this
channel with tetrodotoxin. These studies have shown that a
substantial portion of total sodium current is NaV1.8 in some
dorsal root ganglion neurons (Blair, N. T., et al., J Neurosci
(2002), 22: 10277-90). Knock-down of NaV1.8 in rats has been
achieved by using antisense DNA or small interfering RNAs and
virtually complete reversal of neuropathic pain was achieved in the
spinal nerve ligation and chronic constriction injury models (Dong,
X. W., et al., Neuroscience (2007), 146: 812-21; Lai J., et al.
Pain (2002), 95: 143-52). Thus, NaV1.8 is considered a promising
target for analgesic agents based upon the limited tissue
distribution of this NaV isoform and the analgesic activity
produced by knock-down of channel expression.
[0011] NaV1.9 is also a tetrodotoxin insensitive, sodium channel
expressed primarily in dorsal root ganglia neurons (Dib-Hajj, S.
D., et al. (see Dib-Hajj, S. D., et al., Proc. Natl. Acad. Sci. USA
(1998), 95(15):8963-8). It is also expressed in enteric neurons,
especially the myenteric plexus (Rugiero, F., et al., J Neurosci
(2003), 23: 2715-25). The limited tissue distribution of this NaV
isoform suggests that it may be a useful target for analgesic
agents (Lai, J., et al., op. cit.; Wood, J. N., et al., op. cit.;
Chung, J. M., et al., op. cit.). Knock-out of NaV1.9 results in
resistance to some forms of inflammatory pain (Amaya, F., et al., J
Neurosci (2006), 26: 12852-60; Priest, B. T., et al., Proc Natl
Acad Sci USA (2005), 102: 9382-7).
[0012] This closely related family of proteins has long been
recognized as targets for therapeutic intervention. Sodium channels
are targeted by a diverse array of pharmacological agents. These
include neurotoxins, antiarrhythmics, anticonvulsants and local
anesthetics (England, S., et al., Future Med Chem (2010), 2:
775-90; Termin, A., et al., Annual Reports in Medicinal Chemistry
(2008), 43: 43-60). All of the current pharmacological agents that
act on sodium channels have receptor sites on the alpha subunits.
At least six distinct receptor sites for neurotoxins and one
receptor site for local anesthetics and related drugs have been
identified (Cestele, S., et al., Biochimie (2000), Vol. 82, pp.
883-892).
[0013] The small molecule sodium channel blockers or the local
anesthetics and related antiepileptic and antiarrhythmic drugs
interact with overlapping receptor sites located in the inner
cavity of the pore of the sodium channel (Catterall, W. A., Neuron
(2000), 26:13-25). Amino acid residues in the S6 segments from at
least three of the four domains contribute to this complex drug
receptor site, with the IVS6 segment playing the dominant role.
These regions are highly conserved and as such most sodium channel
blockers known to date interact with similar potency with all
channel subtypes. Nevertheless, it has been possible to produce
sodium channel blockers with therapeutic selectivity and a
sufficient therapeutic window for the treatment of epilepsy (e.g.,
lamotrignine, phenytoin and carbamazepine) and certain cardiac
arrhythmias (e.g., lignocaine, tocainide and mexiletine). However,
the potency and therapeutic index of these blockers is not optimal
and have limited the usefulness of these compounds in a variety of
therapeutic areas where a sodium channel blocker would be ideally
suited.
[0014] Sodium channel blockers have been shown to be useful in the
treatment of pain, including acute, chronic, inflammatory and/or
neuropathic pain (see, e.g., Wood, J. N., et al., J. Neurobiol.
(2004), 61(1), 55-71. Preclinical evidence demonstrates that sodium
channel blockers can suppress neuronal firing in peripheral and
central sensory neurons, and it is via this mechanism that they are
considered to be useful for relieving pain. In some instances,
abnormal or ectopic firing can original from injured or otherwise
sensitized neurons. For example, it has been shown that sodium
channels can accumulate in peripheral nerves at sites of axonal
injury and may function as generators of ectopic firing (Devor et
al., J. Neurosci. (1993), 132: 1976). Changes in sodium channel
expression and excitability have also been shown in animal models
of inflammatory pain where treatment with proinflammatory materials
(CFA, Carrageenan) promoted pain-related behaviors and correlated
with increased expression of sodium channel subunits (Gould et al.,
Brain Res., (1999), 824(2): 296-99; Black et al., Pain (2004),
108(3): 237-47). Alterations in either the level of expression or
distribution of sodium channels, therefore, may have a major
influence on neuronal excitability and pain-related behaviors.
[0015] Controlled infusions of lidocaine, a known sodium channel
blocker, indicate that the drug is efficacious against neuropathic
pain, but has a narrow therapeutic index. Likewise, the orally
available local anesthetic, mexiletine, has dose-limiting side
effects (Wallace, M. S., et al., Reg. Anesth. Pain Med. (2000), 25:
459-67). A major focus of drug discovery targeting voltage-gated
sodium channels has been on strategies for improving the
therapeutic index. One of the leading strategies is to identify
selective sodium channel blockers designed to preferentially block
NaV1.7, NaV1.8, NaV1.9 and/or NaV1.3. These are the sodium channel
isoforms preferentially expressed in sensory neurons and unlikely
to be involved in generating any dose-limiting side effects. For
example, there is concern that blocking of NaV1.5 would be
arrhythmogenic, so that selectivity of a sodium channel blocker
against NaV1.5 is viewed as highly desirable. Furthermore, nearly
700 mutations of the SCN1A gene that codes for NaV1.1 have been
identified in patients with Severe Myoclonic Epilepsy of Infancy
(SMEI), making this the most commonly mutated gene in human
epilepsy. Half of these mutations result in protein truncation
(Meisler, M. H., et al., The Journal of Physiology (2010), 588:
1841-8). Thus, selectivity of a sodium channel blocker against
NaV1.1 is also desirable.
[0016] In addition to the strategies of identifying selective
sodium channel blockers, there is the continuing strategy of
identifying therapeutic agents for the treatment of neuropathic
pain. There has been some degree of success in treating neuropathic
pain symptoms by using medications originally approved as
anticonvulsants, such as gabapentin, and more recently pregabalin.
However, pharmacotherapy for neuropathic pain has generally had
limited success for a variety of reasons: sedation, especially by
drugs first developed as anticonvulsants or anti-depressants,
addiction or tachyphylaxis, especially by opiates, or lack of
efficacy, especially by NSAIDs and anti-inflammatory agents.
Consequently, there is still a considerable need to explore novel
treatment modalities for neuropathic pain, which includes, but is
not limited to, post-herpetic neuralgia, trigeminal neuralgia,
diabetic neuropathy, chronic lower back pain, phantom limb pain,
and pain resulting from cancer and chemotherapy, chronic pelvic
pain, complex regional pain syndrome and related neuralgias.
[0017] There are a limited number of effective sodium channel
blockers for the treatment of pain with a minimum of adverse side
effects which are currently in the clinic. There is also an unmet
medical need to treat neuropathic pain and other sodium channel
associated pathological states effectively and without adverse side
effects due to the blocking of sodium channels not involved in
nociception. The present invention provides methods to meet these
critical needs.
SUMMARY OF THE INVENTION
[0018] In one aspect the present invention provides for novel
compounds. In a first embodiment of such compounds (Embodiment 1;
abbreviated as "E1") the invention provides for a compound of
formula I:
##STR00002##
[0019] or a pharmaceutically acceptable salt thereof, wherein:
[0020] R.sup.1 is C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.1-8haloalkyl, C.sub.1-8alkoxy, C.sub.3-8carbocycle, C-linked
C.sub.2-7heterocycle, or --NR.sup.1AR.sup.1B, wherein R.sup.1A and
R.sup.1B are each independently selected from the group consisting
of hydrogen, C.sub.1-8alkyl, C.sub.1-8alkoxy, and wherein R.sup.1A
and R.sup.1B are optionally combined to form a 3 to 8 membered
heterocyclic ring optionally comprising 1 additional heteroatom
selected from N, O and S; and wherein R.sup.1 is optionally
substituted with from 1 to 5 substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4haloalkyl, F, Cl, Br, I,
--OH, --CN, --NO.sub.2, --NR.sup.R1aR.sup.R1b, --OR.sup.R1a,
--SR.sup.R1a, --Si(R.sup.R1a).sub.3 and C.sub.3-6carbocycle;
wherein R.sup.R1a and R.sup.R1b are independently selected from the
group consisting of hydrogen, C.sub.1-8alkyl,
C.sub.1-8haloalkyl;
[0021] R.sup.N is hydrogen, C.sub.1-4alkyl or
C.sub.1-4haloalkyl;
[0022] R.sup.2 is selected from the group consisting of H, F, Cl,
Br, I, --CN, C.sub.1-8alkyl, C.sub.1-8haloalkyl and
C.sub.1-8alkoxy;
[0023] R.sup.3 is selected from the group consisting of H, F, Cl,
Br, I, --CN, C.sub.1-8alkyl, C.sub.1-8haloalkyl and
C.sub.1-8alkoxy;
[0024] R.sup.4 is selected from the group consisting of H, F, Cl,
Br, I, --CN, C.sub.1-8alkyl, C.sub.1-8haloalkyl and
C.sub.1-8alkoxy;
[0025] R.sup.5 is selected from the group consisting of H, F, Cl,
Br, I, --CN, C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.1-8alkoxy,
C.sub.3-8cycloalkyl and C.sub.2-7heterocycle, wherein said
C.sub.3-8cycloalkyl and C.sub.2-7heterocycle is optionally
substituted with 1-3 substituents selected from F, Cl, Br and
I;
[0026] L is a linker selected from the group consisting of
C.sub.1-4alkylene, C.sub.2-4alkenylene and C.sub.2-4alkynylene,
wherein L is optionally substituted with from 1 to 3 substituents
selected from the group consisting of .dbd.O, C.sub.1-4alkyl, halo,
and C.sub.1-4haloalkyl;
[0027] the subscript m represents the integer 0 or 1;
[0028] X.sup.1 and X.sup.2 are each independently selected from the
group consisting of absent, --O--, --S(O)--, --S(O).sub.2-- and
--N(R.sup.X)-- wherein R.sup.X is H, C.sub.1-8alkyl,
C.sub.1-8alkanoyl, or --S(O).sub.2(C.sub.1-8alkyl), and wherein if
the subscript m is 0 then one of X.sup.1 or X.sup.2 is absent;
[0029] the subscript n is an integer from 0 to 5;
[0030] the ring A is a C.sub.2-11heterocycle comprising a nitrogen
atom and further optionally comprising 1-2 heteroatoms selected
from N, O and S;
[0031] each R.sup.AA is independently selected from the group
consisting of C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.1-6heteroalkyl, CN, F, Cl, Br and I; and
[0032] R.sup.A is selected from the group consisting of
--(X.sup.RB).sub.0-1OR.sup.A1, C.sub.6-10aryl-(X.sup.RA)--,
C.sub.1-20heteroaryl-(X.sup.RA)--,
C.sub.3-12carbocycle-(X.sup.RA)--, --R.sup.A2,
--S(O).sub.2--R.sup.A2 and C.sub.2-11heterocycle-(X.sup.RA)--,
wherein said C.sub.6-10aryl, C.sub.5-9heteroaryl,
C.sub.3-12carbocycle and C.sub.2-11heterocycle of R.sup.A is
optionally substituted with from 1 to 5 substitutents selected
from, F, Cl, Br, I, --NH.sub.2, --OH, --CN, --NO.sub.2,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy,
C.sub.1-4(halo)alkoxy, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
C.sub.1-4alkanoyl, C.sub.1-4alkyl-OC(.dbd.O)--,
C.sub.1-4alkyl-S(O).sub.2--, C.sub.3-6carbocycle, and phenyl that
is optionally substituted with one or more substituents selected
from fluoro, chloro, and bromo; R.sup.A1 is selected from the group
consisting of hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.2-8haloalkyl, C.sub.3-8cycloalkyl, phenyl and benzyl;
R.sup.A2 is selected from the group consisting of C.sub.1-8alkyl
that is optionally substituted with one or more substituents
selected from oxo (.dbd.O), fluoro, amino, C.sub.1-4alkylamino and
C.sub.1-4dialkylamino; X.sup.RA is selected from the group
consisting of absent, --O--, --S--, --N(H)--, --N(C.sub.1-4alkyl)-,
--S(O)--, --S(O).sub.2--, --C(.dbd.O)--, C.sub.1-4alkylene,
C.sub.1-4heteroalkylene, C.sub.2-4alkenylene and
C.sub.2-4alkynylene; X.sup.RB is selected from the group consisting
of absent, C.sub.1-4alkylene, C.sub.1-4heteroalkylene,
C.sub.2-4alkenylene and C.sub.2-4alkynylene; wherein any
C.sub.1-4alkylene, C.sub.1-4heteroalkylene, C.sub.2-4alkenylene and
C.sub.2-4alkynylene of X.sup.RA or X.sup.RB is optionally
substituted with 1 to 3 substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4haloalkyl,
C.sub.1-4heteroalkyl, oxo (.dbd.O), hydroxy, and phenyl that is
optionally substituted with 1 to 5 substitutents selected from, F,
Cl, Br, I, --NH.sub.2, --OH, --CN, --NO.sub.2, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, C.sub.1-4(halo)alkoxy,
C.sub.1-3alkylamino and C.sub.1-4dialkylamino; or wherein X.sup.RA
or X.sup.RB is optionally substituted with 2 substituents that
combine to form a 3 to 5 membered carbocycle or a 3-5 membered
heterocycle;
[0033] provided the compound of formula I is not:
##STR00003## ##STR00004## ##STR00005## ##STR00006##
E2 The compound or salt of E1 wherein:
[0034] R.sup.1 is C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.1-8haloalkyl, C.sub.1-8alkoxy, C.sub.3-8carbocycle, C-linked
C.sub.2-7heterocycle, or --NR.sup.1AR.sup.1B, wherein R.sup.1A and
R.sup.1B are each independently selected from the group consisting
of hydrogen, C.sub.1-8alkyl, C.sub.1-8alkoxy, and wherein R.sup.1A
and R.sup.1B are optionally combined to form a 3 to 8 membered
heterocyclic ring optionally comprising 1 additional heteroatom
selected from N, O and S; and wherein R.sup.1 is optionally
substituted with from 1 to 5 substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4haloalkyl, F, Cl, Br, I,
--OH, --CN, --NO.sub.2, --NR.sup.R1aR.sup.R1b, --OR.sup.R1a,
--SR.sup.R1a, --Si(R.sup.R1a).sub.3 and C.sub.3-6carbocycle;
wherein R.sup.R1a and R.sup.R1b are independently selected from the
group consisting of hydrogen, C.sub.1-8alkyl,
C.sub.1-8haloalkyl;
[0035] R.sup.N is hydrogen, C.sub.1-4alkyl or
C.sub.1-4haloalkyl;
[0036] R.sup.2 is selected from the group consisting of H, F, Cl,
Br, I, --CN, C.sub.1-8alkyl, C.sub.1-8haloalkyl and
C.sub.1-8alkoxy;
[0037] R.sup.3 is selected from the group consisting of H, F, Cl,
Br, I, --CN, C.sub.1-8alkyl, C.sub.1-8haloalkyl and
C.sub.1-8alkoxy;
[0038] R.sup.4 is selected from the group consisting of H, F, Cl,
Br, I, --CN, C.sub.1-8alkyl, C.sub.1-8haloalkyl and
C.sub.1-8alkoxy;
[0039] R.sup.5 is selected from the group consisting of H, F, Cl,
Br, I, --CN, C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.1-8alkoxy,
C.sub.3-8cycloalkyl and C.sub.2-7heterocycle, wherein said
C.sub.3-8cycloalkyl and C.sub.2-7heterocycle is optionally
substituted with 1-3 substituents selected from F, Cl, Br and
I;
[0040] L is a linker selected from the group consisting of
C.sub.1-4alkylene, C.sub.2-4alkenylene and C.sub.2-4alkynylene,
wherein L is optionally substituted with from 1 to 3 substituents
selected from the group consisting of .dbd.O, C.sub.1-4alkyl, halo,
and C.sub.1-4haloalkyl;
[0041] the subscript m represents the integer 0 or 1;
[0042] X.sup.1 and X.sup.2 are each independently selected from the
group consisting of absent, --O--, --S(O)--, --S(O).sub.213 and
--N(R.sup.X)-- wherein R.sup.X is H, C.sub.1-8alkyl,
C.sub.1-8alkanoyl, or --S(O).sub.2(C.sub.1-8alkyl), and wherein if
the subscript m is 0 then one of X.sup.1 or X.sup.2 is absent:
[0043] the subscript n is an integer from 0 to 5;
[0044] the ring A is a C.sub.2-11heterocycle comprising a nitrogen
atom and further optionally comprising 1-2 heteroatoms selected
from N, O and S;
[0045] each R.sup.AA is independently selected from the group
consisting of C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.1-6heteroalkyl, F, Cl, Br and I; and
[0046] R.sup.A is selected from the group consisting of
--(X.sup.RB).sub.0-1OR.sup.A1, C.sub.6-10aryl-(X.sup.RA)--,
C.sub.5-9heteroaryl-(X.sup.RA)--,
C.sub.3-12carbocycle-(X.sup.RA)--, --R.sup.A2,
--S(O).sub.2R.sup.A2, and C.sub.2-11heterocycle-(X.sup.RA)--,
wherein said C.sub.6-10aryl, C.sub.5-9heteroaryl,
C.sub.3-12carbocycle and C.sub.2-11heterocycle of R.sup.A is
optionally substituted with from 1 to 5 substitutents selected
from, F, Cl, Br, I, --NH.sub.2, --OH, --CN, --NO.sub.2,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy,
C.sub.1-4(halo)alkoxy, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
C.sub.1-4alkanoyl, C.sub.1-4alkyl-OC(.dbd.O)--,
C.sub.1-4alkyl-S(O).sub.2, C.sub.3-6carbocycle, and phenyl that is
optionally substituted with one or more substituents selected from
fluoro, chloro, and bromo; R.sup.A1 is selected from the group
consisting of hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl, phenyl and benzyl;
R.sup.A2 is selected from the group consisting of C.sub.1-8alkyl
that is optionally substituted with one or more substituents
selected from oxo (.dbd.O), fluoro, amino, C.sub.1-4alkylamino and
C.sub.1-4dialkylamino; X.sup.RA is selected from the group
consisting of absent, --O--, --S--, --N(C.sub.1-8alkyl)-, --S(O)--,
--S(O).sub.2--, --C(.dbd.O)--, C.sub.1-4alkylene,
C.sub.1-4heteroalkylene, C.sub.2-4alkenylene and
C.sub.2-4alkynylene: X.sup.RB is selected from the group consisting
of absent, C.sub.1-4alkylene, C.sub.1-4heteroalkylene,
C.sub.2-4alkenylene and C.sub.2-4alkynylene; wherein any
C.sub.1-4alkylene, C.sub.1-4heteroalkylene, C.sub.2-4alkenylene and
C.sub.2-4alkynylene of X.sup.RA or X.sup.RB is optionally
substituted with 1 to 3 substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4haloalkyl,
C.sub.2-4heteroalkyl, oxo (.dbd.O), and phenyl that is optionally
substituted with 1 to 5 substitutents selected from, F, Cl, Br, I,
--NH.sub.2, --OH, --CN, --NO.sub.2, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, C.sub.1-4(halo)alkoxy,
C.sub.1-4alkylamino and C.sub.1-4dialkylamino; or wherein X.sup.RA
or X.sup.RB is optionally substituted with 2 substituents that
combine to form a 3 to 5 membered carbocycle or a 3-5 membered
heterocycle;
E3 The compound or salt of E1 or E2 wherein:
[0047] R.sup.1 is C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.1-8haloalkyl, C.sub.1-8alkoxy, C.sub.3-8carbocycle, C-linked
C.sub.2-7heterocycle, or --NR.sup.1AR.sup.1B, wherein R.sup.1A and
R.sup.1B are each independently selected from the group consisting
of hydrogen, C.sub.1-8alkyl, C.sub.1-8alkoxy, and wherein R.sup.1A
and R.sup.1B are optionally combined to form a 3 to 8 membered
heterocyclic ring optionally comprising 1 additional heteroatom
selected from N, O and S; and wherein R.sup.1 is optionally
substituted with from 1 to 5 substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4haloalkyl, F, Cl, Br, I,
--OH, --CN, --NO.sub.2, --NR.sup.R1aR.sup.R1b, --OR.sup.R1a,
--SR.sup.R1a, --Si(R.sup.R1a).sub.2 and C.sub.3-6carbocycle;
wherein R.sup.R1a and R.sup.R1b are independently selected from the
group consisting of hydrogen, C.sub.1-8alkyl,
C.sub.1-8haloalkyl;
[0048] R.sup.N is hydrogen, C.sub.1-4alkyl or
C.sub.1-4haloalkyl;
[0049] R.sup.2 is selected from the group consisting of H, F, Cl,
Br, I, --CN, C.sub.1-8alkyl, C.sub.1-8haloalkyl and
C.sub.1-8alkoxy;
[0050] R.sup.3 is selected from the group consisting of H, F, Cl,
Br, I, --CN, C.sub.1-8alkyl, C.sub.1-8haloalkyl and
C.sub.1-8alkoxy;
[0051] R.sup.4 is selected from the group consisting of H, F, Cl,
Br, I, --CN, C.sub.1-8alkyl, C.sub.1-8haloalkyl and
C.sub.1-8alkoxy;
[0052] R.sup.5 is selected from the group consisting of H, F, Cl,
Br, I, --CN, C.sub.1-8alkyl, C.sub.1-8haloalkyl, C.sub.1-8alkoxy,
C.sub.3-8cycloalkyl and C.sub.2-7heterocycle, wherein said
C.sub.3-8cycloalkyl and C.sub.2-7heterocycle is optionally
substituted with 1-3 substituents selected from F, Cl, Br and
I;
[0053] L is a linker selected from the group consisting of
C.sub.1-4alkylene, C.sub.2-4alkenylene and C.sub.2-4alkynylene,
wherein L is optionally substituted with from 1 to 3 substituents
selected from the group consisting of .dbd.O, C.sub.1-4alkyl, halo,
and C.sub.1-4haloalkyl;
[0054] the subscript m represents the integer 0 or 1;
[0055] X.sup.1 and X.sup.2 are each independently selected from the
group consisting of absent, --O--, --S(O)--, --S(O).sub.2-- and
--N(R.sup.X)-- wherein R.sup.X is H, C.sub.1-8alkyl,
C.sub.1-8alkanoyl, or --S(O).sub.2(C.sub.1-8alkyl), and wherein if
the subscript m is 0 then one of X.sup.1 or X.sup.2 is absent;
[0056] the subscript n is an integer from 0 to 5;
[0057] the ring A is a C.sub.2-11heterocycle comprising a nitrogen
atom and further optionally comprising 1-2 heteroatoms selected
from N, O and S;
[0058] each R.sup.AA is independently selected from the group
consisting of C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.1-6heteroalkyl, F, Cl, Br and I; and
[0059] R.sup.A is selected from the group consisting of
--(X.sup.RB).sub.0-1OR.sup.A1, C.sub.6-10aryl-(X.sup.RA)--,
C.sub.5-9heteroaryl-(X.sup.RA)--,
C.sub.3-12carbocycle-(X.sup.RA)--, and
C.sub.2-11heterocycle-(X.sup.RA)--, wherein said C.sub.6-10aryl,
C.sub.5-9heteroaryl, C.sub.3-12carbocycle and C.sub.2-11heterocycle
of R.sup.A is optionally substituted with from 1 to 5 substitutents
selected from, F, Cl, Br, I, --NH.sub.2, --OH, --CN, --NO.sub.2,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy,
C.sub.1-4(halo)alkoxy, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
phenyl, C.sub.1-4alkanoyl, C.sub.1-4alkyl-OC(.dbd.O)--,
C.sub.1-4alkyl-S(O).sub.2--, and C.sub.3-6carbocycle; R.sup.A1 is
is selected from the group consisting of hydrogen, C.sub.1-8alkyl,
C.sub.2-8alkenyl, C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl, phenyl
and benzyl; R.sup.RA is selected from the group consisting of
absent, --O--, --S--, --N(H)--, --N(C.sub.1-4alkyl)-,
--S(O).sub.2--, --C(.dbd.O)--, C.sub.1-4alkylene,
C.sub.1-4heteroalkylene, C.sub.2-4alkenylene and
C.sub.2-4alkynylene; X.sup.RB is selected from the group consisting
of absent, C.sub.1-4alkylene, C.sub.1-4heteroalkylene,
C.sub.2-4alkenylene and C.sub.2-4alkynylene; wherein any
C.sub.1-4alkylene, C.sub.1-4heteroalkylene, C.sub.2-4alkenylene and
C.sub.2-4alkynylene of X.sup.RA or X.sup.RB is optionally
substituted with 1 to 3 substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4haloalkyl,
C.sub.1-4heteroalkyl, oxo (.dbd.O), and phenyl that is optionally
substituted with 1 to 5 substitutents selected from, F, Cl, Br, I,
--NH.sub.2, --OH, --CN, --NO.sub.2, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, C.sub.1-4(halo)alkoxy,
C.sub.1-4alkylamino and C.sub.1-4dialkylamino; or wherein X.sup.RA
or X.sup.RB is optionally substituted with 2 substituents that
combine to form a 3 to 5 membered carbocycle or a 3-5 membered
heterocycle.
E4 The compound of E1, E2, or E3 wherein the compound has the
formula Ia:
##STR00007##
E5 The compound of E1, E2, or E3, wherein the compound has the
formula Ib:
##STR00008##
E6 The compound of E1, E2, or E3, wherein the compound has the
formula Ic:
##STR00009##
E7 The compound of E1, E2, E3, E4, E5, or E6 wherein R.sup.1 is
selected from the group consisting of C.sub.1-8alkyl,
C.sub.1-8haloalkyl, C.sub.3-8carbocycle, C.sub.2-7heterocycle, and
--NR.sup.1AR.sup.1B, wherein R.sup.1A and R.sup.1B are each
independently selected from the group consisting of C.sub.1-8alkyl
and C.sub.1-8alkoxy, and wherein and R.sup.1A and R.sup.1B are
optionally combined to form a 3 to 6 membered heterocyclic ring;
and wherein R.sup.1 is optionally substituted with from 1 to 5
substituents selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4haloalkyl, F, Cl, Br, I, --OH, --OR.sup.R1a, --SR.sup.R1a,
--Si(R.sup.R1a).sub.3 and C.sub.3-8carbocycle; wherein R.sup.R1a
and R.sup.R1b are independently selected from the group consisting
of hydrogen, C.sub.1-8alkyl, C.sub.1-8haloalkyl E8 The compound of
E1, E2, E3, E4, E5, or E6 wherein R.sup.1 is methyl, cyclopropyl,
cyclopropylmethyl, 1-azetidinyl, 1-methylcycloprop-1-yl,
difluoromethyl, N-methylamino, ethyl, 2-methoxyeth-1-yl,
2-trimethylsilyleth-1-yl, propyl, 1,1,1 -trifluoroprop-3-yl, butyl,
morpholino, pyrrolidino, or 3-fluoroazetidin-1-yl. E9 The compound
of E1, E2, E3, E4, E5, or E6 wherein R.sup.1 is methyl,
cyclopropyl, 1-azetidinyl or 2-methoxyethyl. E10 The compound of
E1, E2, E3, E7, E8, or E9 wherein R.sup.2 is H. E11 The compound of
E1, E2, E3, E4, E5, E6, E7, E8, E9, or E10 wherein R.sup.3 is F,
Cl, or Br. E12 The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
or E10 wherein R.sup.3 is F. E13 The compound of E1, E2, E3, E4,
E5, E6, E7, E8, E9, E10, E11, or E12 wherein R.sup.4 is H. E14 The
compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, or
E13 wherein R.sup.5 is C.sub.3-5cycloalkyl. E15 The compound of E1,
E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, or E13 wherein
R.sup.5 is cyclopropyl. E16 The compound of E1, E2, E3, E4, E5, E6,
E7, E8, E9, E10, E11, E12, E13, E14, or E15 wherein X.sup.1 is
--O-- or --N(H)--; X.sup.2 is absent; the subscript m is 1; and
--(L)-- is an optionally substituted group selected from the group
consisting of C.sub.1-4alkylene, C.sub.2-4alkenylene or
C.sub.2-4alkynylene. E17 The compound of E1, E2, E3, E4, E5, E6,
E7, E8, E9, E10, E11, E12, E13, E14, or E15 wherein X.sup.1 is
--O-- or --N(H)--; X.sup.2 is absent; the subscript m is 1; and
--(L)-- is selected from the group consisting of --CH.sub.2--,
--C(.dbd.O)--, --C(H)(CH.sub.3)--, --CH.sub.2CH.sub.2--,
--CH.sub.2--C(H)(CH.sub.3)--, --C(H)(CH.sub.3)--C(H.sub.2)--,
--CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2--C(H)(CH.sub.3)--CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--. E18 The compound of E1, E2,
E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, or E15 wherein
X.sup.1 is --O--; the subscript m is 1 and --(L)-- is --CH.sub.2--
or --CH.sub.2--CH.sub.2--. E19 The compound of E1, E2, E3, E4, E5,
E6, E7, E8, E9, E10, E11, E12, E13, E14, or E15 wherein X.sup.1 is
absent; X.sup.2 is --O-- or --N(H)--; the subscript m is 1; and
--(L)-- is selected from the group consisting of --C(H).sub.2--,
--C(.dbd.O)--, --C(H)(CH.sub.3)--, --CH.sub.2CH.sub.2--,
--CH.sub.2--C(H)(CH.sub.3)--, --C(H)(CH.sub.3)--C(H.sub.2)--,
--CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2--C(H)(CH.sub.3)--CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--. E20 The compound of E1, E2,
E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, or E15 wherein
X.sup.1 is X.sup.2 is absent; the subscript m is 1; and --(L)-- is
selected from the group consisting of --C(H).sub.2--,
--C(.dbd.O)--, --C(H)(CH.sub.3)--, --CH.sub.2CH.sub.2--,
--CH.sub.2--C(H)(CH.sub.3)--, --C(H)(CH.sub.3)--C(H.sub.2)--,
--CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2--C(H)(CH.sub.3)--CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--. E21 The compound of E1, E2,
E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, or E15 wherein
m is 0; X.sup.1 is selected from --O--, and --N(H)--; and X.sup.2
is absent. E22 The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, or E21
wherein A is optionally substituted and is selected from azetidine,
pyrrolidine, piperidine, morpholine, homopiperazine, and
piperazine. E23 The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, or E21
wherein:
##STR00010##
is selected from the group consisting of:
##STR00011##
E24 The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,
E12, E13, E14, E15, E16, E17, E18, E19, E20, or E21 wherein:
##STR00012##
is selected from the group consisting of:
##STR00013##
E25 The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,
E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, or E24
wherein R.sup.AA is selected from the group consisting of methyl,
trifluoromethyl, ethyl, CN, F, Cl, Br, and I. E26 The compound of
E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15,
E16, E17, E18, E19, E20, E21, E22, E23, or E24 wherein R.sup.AA is
selected from the group consisting of methyl, trifluoromethyl,
ethyl, F, Cl, Br, and I. E27 The compound of E1, E2, E3, E4, E5,
E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19,
E20, E21, E22, E23, E24, E25, or E26 wherein R.sup.A is selected
from the group consisting of phenyl-(X.sup.RA)--, wherein said
phenyl is optionally substituted with from 1 to 5 substitutents
selected from, F, Cl, Br, --NH.sub.2, --OH, --CN, --NO.sub.2,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, phenyl,
C.sub.1-4alkanoyl, C.sub.1-4alkyl-OC(.dbd.O)-- and
C.sub.3-6carbocycle; and wherein X.sup.RA is selected from the
group consisting of absent, --O--, --S--, --N(H)--,
--N(C.sub.1-4alkyl)-, C.sub.1-4alkylene, C.sub.1-4heteroalkylene,
C.sub.2-4alkenylene and C.sub.2-4alkynylene; and wherein X.sup.RA
is optionally substituted with 1 to 3 substituents selected from
the group consisting of C.sub.1-4alkyl, C.sub.1-4haloalkyl,
C.sub.1-4heteroalkyl, and phenyl that is optionally substituted
with 1 to 5 substitutents selected from, F, Cl, Br, I, --NH.sub.2,
--OH, --CN, --NO.sub.2, C.sub.1-4alkyl, C.sub.1-4haloalkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylamino and C.sub.1-4dialkylamino. E28
The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,
E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, or
E26 wherein R.sup.A is phenyl-(X.sup.RA)--, wherein said phenyl is
optionally substituted with from 1 to 5 substitutents selected
from, F, Cl, C.sub.1-4alkyl, --CN, C.sub.3-6carbocycle and
C.sub.1-4haloalkyl; wherein X.sup.RA is selected from the group
consisting of absent and C.sub.1-4alkylene; and wherein X.sup.RA is
optionally substituted with 1 to 3 substituents selected from the
group consisting of C.sub.1-4alkyl and phenyl that is optionally
substituted with 1 to 5 substitutents selected from, F, Cl,
C.sub.1-4alkyl, and C.sub.1-4haloalkyl. E29 The compound of E1, E2,
E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17,
E18, E19, E20, E21, E22, E23, E24, E25, or E26 wherein R.sup.A is
--(X.sup.RB).sub.0-1OR.sup.A1; R.sup.A1 is selected from the group
consisting of hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl,
C.sub.1-8haloalkyl, C.sub.3-8cycloalkyl, phenyl and benzyl; and
X.sup.RB is selected from the group consisting of absent and
C.sub.1-4alkylene that is optionally substituted with 1 to 3
substituents selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4haloalkyl, C.sub.1-4heteroalkyl, oxo (.dbd.O), and phenyl
that is optionally substituted with 1 to 5 substitutents selected
from, F, Cl, Br, I, --NH.sub.2, --OH, --CN, --NO.sub.2,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy,
C.sub.1-4(halo)alkoxy, C.sub.1-4alkylamino and
C.sub.1-4dialkylamino. E30 The compound of E1, E2, E3, E4, E5, E6,
E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20,
E21, E22, E23, E24, E25, or E26 wherein R.sup.A is selected from
the group consisting of
##STR00014## ##STR00015##
E31 The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,
E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24,
E25, or E26 wherein R.sup.A is selected from the group consisting
of
##STR00016##
E32 The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,
E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24,
E25, or E26 wherein R.sup.A is selected from the group consisting
of phenyl, phenylmethyl, pyrazolyl, pyrazolylmethyl, cyclobutyl,
cyclohexylmethyl, cyclopentyl, cyclopentylmethyl, cyclobutyl,
cyclobutylmethyl, pyrimidinyl, pyrimidinylmethyl, pyrazinyl,
pyrazinylmethyl, pyridazinyl, pyridazinylmethyl, indolinyl,
indolinylmethyl, isoindolinyl, and isoindolinylmethyl, and wherein
R.sup.A is optionally substituted with from 1 to 5 substitutents
selected from F, Cl, Br, I, --NH.sub.2, --OH, --CN, --NO.sub.2,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy,
C.sub.1-4(halo)alkoxy, C.sub.1-4dialkylamino, C.sub.1-4alkanoyl,
C.sub.1-4alkyl-OC(.dbd.O)--, C.sub.1-4alkyl-S(O).sub.2--,
C.sub.3-6carbocycle, and phenyl that is optionally substituted with
one or more substituents selected from fluoro, chloro, and bromo.
E33 The compound of claim E1, E2, E3, E4, E5, E6, E7, E8, E9, E10,
E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23,
E24, E25, or E26 wherein R.sup.A is selected from the group
consisting of --(X.sup.RB).sub.0-1OR.sup.A1,
C.sub.6-10aryl-(X.sup.RA)--, C.sub.1-20heteroaryl-(X.sup.RA)--,
C.sub.3-12carbocycle-(X.sup.RA)--, and
C.sub.2-11heterocycle-(X.sup.RA)--, wherein said of R.sup.A
C.sub.6-10aryl, C.sub.5-9heteroaryl, C.sub.3-12carbocycle and
C.sub.2-11heterocycle of R.sup.A is optionally substituted with
from 1 to 5 substitutents selected from, F, Cl, Br, I, --NH.sub.2,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, phenyl,
C.sub.1-4alkanoyl, C.sub.1-4alkyl-OC(.dbd.O)--,
C.sub.3-6carbocycle; R.sup.A1 is selected from the group consisting
of hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.1-8haloalkyl,
C.sub.3-8cycloalkyl, phenyl, and benzyl; X.sup.RA is selected from
the group consisting of absent, --O--, --S--, --N(H)--,
--N(C.sub.1-4alkyl)-, C.sub.1-4alkylene, C.sub.1-4heteroalkylene,
C.sub.2-4alkenylene and C.sub.2-4alkynylene; and X.sup.RB selected
from the group consisting of absent, C.sub.1-4alkylene,
C.sub.1-4heteroalkylene, C.sub.2-4alkenylene and
C.sub.2-4alkynylene; wherein any C.sub.1-4alkylene,
C.sub.1-4heteroalkylene, C.sub.2-4alkenylene and
C.sub.2-4alkynylene of X.sup.RA or X.sup.RB is optionally
substituted with 1 to 3 substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4haloalkyl, and
C.sub.1-4heteroalkyl. E34 The compound of E1, E2, E3, E4, E5, E6,
E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20,
E21, E22, E23, E24, E25, or E26 wherein R.sup.A is selected from
the group consisting of --(X.sup.RB).sub.0-1OR.sup.A1,
C.sub.6-10aryl-(X.sup.RA)--, C.sub.5-9heteroaryl-(X.sup.RA)--,
C.sub.3-12carbocycle-(X.sup.RA)--, and
C.sub.2-11heterocycle-(X.sup.RA)--, wherein said C.sub.6-10aryl,
C.sub.5-9heteroaryl, C.sub.3-12carbocycle and C.sub.2-11heterocycle
of R.sup.A is optionally substituted with from 1 to 5 substitutents
selected from, F, Cl, Br, I, --NH.sub.2, --OH, --CN, --NO.sub.2,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy,
C.sub.1-4alkylamino, C.sub.1-4dialkylamino, phenyl,
C.sub.1-4alkanoyl, C.sub.1-4alkyl-OC(.dbd.O)-- and
C.sub.3-6carbocycle; R.sup.A1 is selected from the group consisting
of hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.1-8haloalkyl,
C.sub.3-8cycloalkyl, phenyl, and benzyl; X.sup.RA is selected from
the group consisting of absent, --O--, --S--, --N(H)--,
--N(C.sub.1-4alkyl)-, C.sub.1-4alkylene, C.sub.1-4heteroalkylene,
C.sub.2-4alkenylene and C.sub.2-4alkynylene; and X.sup.RB selected
from the group consisting of absent, C.sub.1-4alkylene,
C.sub.1-4heteroalkylene, C.sub.2-4alkenylene and
C.sub.2-4alkynylene; wherein any C.sub.1-4alkylene,
C.sub.1-4heteroalkylene, C.sub.2-4alkenylene and
C.sub.2-4alkynylene of X.sup.RA or X.sup.RB is optionally
substituted with 1 to 3 substituents selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4haloalkyl, and
C.sub.1-4heteroalkyl. E35 The compound of E1, E2, E3, E4, E5, E6,
E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20,
E21, E22, E23, E24, E25, or E26 wherein R.sup.A is selected from
the group consisting of optionally substituted with from 1 to 5
substitutents selected from, F, Cl, Br, --NH.sub.2, --OH, --CN,
--NO.sub.2, C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy,
C.sub.1-4(halo)alkoxy, C.sub.1-4alkylamino, C.sub.1-4dialkylamino,
phenyl, C.sub.1-4alkanoyl, C.sub.1-4alkyl-OC(.dbd.O)--,
C.sub.1-4alkyl-S(O).sub.2--, and C.sub.3-6carbocycle; and X.sup.RA
is selected from the group consisting of --C(.dbd.O)--,
C.sub.1-4alkylene, C.sub.1-4heteroalkylene, C.sub.2-4alkenylene and
C.sub.2-4alkynylene; wherein any C.sub.1-4alkylene,
C.sub.1-4heteroalkylene, C.sub.2-4alkenylene and
C.sub.2-4alkynylene of X.sup.RA is optionally substituted with 1 to
3 substituents selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4heteroalkyl, oxo
(.dbd.O), and phenyl that is optionally substituted with 1 to 5
substitutents selected from, F, Cl, Br, I, --NH.sub.2, --OH, --CN,
--NO.sub.2, C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy,
C.sub.1-4(halo)alkoxy, C.sub.1-4alkylamino and
C.sub.1-4dialkylamino. E36 The compound of E1, E2, E3, E4, E5, E6,
E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20,
E21, E22, E23, E24, E25, or E26wherein R.sup.A is phenyl
--(X.sup.RA)--, wherein said phenyl is optionally substituted with
from 1 to 5 substitutents selected from, F, Cl, --CN,
C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, and
C.sub.1-4(halo)alkoxy; and X.sup.RA is C.sub.1-4alkylene that is
optionally substituted with 1 to 3 substituents selected from the
group consisting of C.sub.1-4alkyl, C.sub.1-4haloalkyl,
C.sub.1-4heteroalkyl, oxo (.dbd.O), and phenyl that is optionally
substituted with 1 to 5 substitutents selected from, F, Cl, Br, I,
--NH.sub.2, --OH, --CN, --NO.sub.2, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, C.sub.1-4(halo)alkoxy,
C.sub.1-4alkylamino and C.sub.1-4dialkylamino. E37 The compound of
E1, E2, E3, E7, E8, E9, E16, E17, E18, E19, E20, E20, E21, E22,
E23, E24, E25, E26, E27, E28, E29, E30, E31, E32, E33, E34, E35, or
E36 wherein the compound has the formula Id:
##STR00017##
E38 The compound of E37 wherein R.sup.1 is methyl, ethyl,
cyclopropyl, or 1-azetidinyl. E39 The compound of E37 or E38
wherein --X.sup.2--(L).sub.m--X.sup.1-- is --O--, --CH.sub.2--, or
--CH.sub.2CH.sub.2--O--. E40 The compound of E37, E38, or E39
wherein:
##STR00018##
E41 The compound of E37, E38, or E39 wherein:
##STR00019##
E42 The compound of E37, E38, or E39 wherein A is optionally
substituted azetidine, pyrrolidine, piperidine, morpholine,
homopiperazine, and piperazine. E43 The compound of E37, E38, or
E39 wherein:
##STR00020##
is selected from the group consisting of:
##STR00021##
E44 The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,
E12, E13, E14, E15, E16, E17, E18, E19, E20, E37, E38, or E39
wherein:
##STR00022##
is selected from the group consisting of:
##STR00023##
E45 The compound of E1, E2, E3, E4, E7, E8, E9, E10, E11, E12, E13,
E14, E15, E25, E26, E27, E28, E29, E30, E31, E32, E33, E34, E35,
E36, E37, or E38 wherein: has the formula:
##STR00024##
E46 The compound of E41, wherein
##STR00025##
E47 The compound of claim E46, wherein R.sup.AA is selected from
the group consisting of hydrogen, F, Cl and C.sub.1-4haloalkyl. E48
The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12,
E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25,
E26, E37, E38, E39, E40, E41, E42, E43, E44, E45, E46, or E47
wherein R.sup.A is
##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030##
##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035##
##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040##
##STR00041## ##STR00042## ##STR00043## ##STR00044##
E49 The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,
E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24,
E25, E26, E37, E38, E39, E40, E41, E42, E43, E44, E45, E46, or E47
wherein R.sup.A is
##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049##
##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054##
##STR00055## ##STR00056##
E50 The compound of E1 which is selected from:
##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061##
##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066##
##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071##
##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076##
##STR00077## ##STR00078## ##STR00079##
##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084##
##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089##
##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094##
##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099##
##STR00100## ##STR00101## ##STR00102##
##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107##
##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112##
##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117##
##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122##
##STR00123## ##STR00124## ##STR00125## ##STR00126##
##STR00127##
##STR00128## ##STR00129## ##STR00130## ##STR00131## ##STR00132##
##STR00133## ##STR00134## ##STR00135## ##STR00136## ##STR00137##
##STR00138## ##STR00139## ##STR00140## ##STR00141## ##STR00142##
##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147##
##STR00148##
##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153##
##STR00154##
and salts thereof. E51 The compound of E1, which is selected
from:
##STR00155## ##STR00156## ##STR00157## ##STR00158## ##STR00159##
##STR00160## ##STR00161## ##STR00162## ##STR00163## ##STR00164##
##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169##
##STR00170## ##STR00171## ##STR00172## ##STR00173## ##STR00174##
##STR00175## ##STR00176## ##STR00177## ##STR00178##
##STR00179##
and salts thereof. E52 The compound of E1, which is selected from
the compounds of Examples 162-593 and the free bases and salts
thereof. E53 The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22,
E23, E24, E25, or E26 wherein R.sup.A is selected from the group
consisting of benzyl, 3,5-dichlorobenzyl, N-acetylpiperidin-3-yl,
2-chloro-4-fluorobenzyl, 2,4-difluorobenzyl, 2,6-dichlorobenzyl,
N-(cyclohexylmethyl)piperidin-3-yl,
1-methyl-3-phenyl-1H-pyrazol-5-ylmethyl, pyridazin-4- ylmethyl,
isoindolin-4-ylmethyl, alpha-phenylbenzyl, 3,4-dichlorobenzyl,
4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl,
4-methylbenzyl, 2-(trifluoromethyl)-4-fluorobenzyl, 4-fluorophenyl,
phenyl, 3,5-dichlorophenyl, benzyl,
alpha-methyl-3,5-dichlorobenzyl, 3,5-dichlorophenoxy,
tert-butoxycarbonyl, 3-fluorobenzyl, 3-chloro-5-fluorobenzyl, and
4-(trifluoromethyl)-3-fluorobenzyl. E54 The compound of E1, E2, E3,
E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17,
E18, E19, E20, E21, E22, E23, E24, E25, or E26 wherein R.sup.A is
selected from the group consisting of:
##STR00180## ##STR00181## ##STR00182## ##STR00183## ##STR00184##
##STR00185##
E55 The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,
E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24,
E25, or E26 wherein R.sup.A is C.sub.6-10aryl-(X.sup.RA)--, wherein
said C.sub.6-10aryl, of R.sup.A is optionally substituted with from
1 to 5 substitutents selected from, F, Cl, Br, I, --NH.sub.2, --OH,
--CN, --NO.sub.2, C.sub.1-4alkyl, C.sub.1-4haloalkyl,
C.sub.1-4alkoxy, C.sub.1-4(halo)alkoxy, C.sub.1-4alkylamino,
C.sub.1-4dialkylamino, phenyl, C.sub.1-4alkanoyl,
C.sub.1-4alkyl-OC(.dbd.O)--, C.sub.1-4alkyl-S(O).sub.2--, and
C.sub.3-6carbocycle; and X.sup.RA is C.sub.1-4alkylene that is
optionally substituted with 1 to 3 substituents selected from the
group consisting of C.sub.1-4alkyl, C.sub.1-4haloalkyl,
C.sub.1-4heteroalkyl, oxo (.dbd.O), and phenyl that is optionally
substituted with 1 to 5 substitutents selected from, F, Cl, Br, I,
--NH.sub.2, --OH, --CN, --NO.sub.2, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, C.sub.1-4alkoxy, C.sub.1-4(halo)alkoxy,
C.sub.1-4alkylamino and C.sub.1-4dialkylamino. E56 The compound of
E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15,
E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, or E26 wherein
R.sup.A is
##STR00186##
E57 The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,
E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24,
E25, or E26 wherein R.sup.A is
##STR00187##
E58 The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11,
E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24,
E25, E26, E37, E38, E39, E40, E41, E42, E43, E44, E45, E46, or E47
wherein R.sup.A is
##STR00188##
E59 The compound of E1, which is selected from:
##STR00189##
and salts thereof.
[0060] In another aspect the present invention provides for a
pharmaceutical composition comprising a compound of formula I or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable excipient.
[0061] In another aspect the present invention provides for a
method a treating disease or condition in a mammal selected from
the group consisting of pain, depression, cardiovascular diseases,
respiratory diseases, and psychiatric diseases, and combinations
thereof, wherein the method comprises administering to the mammal
in need thereof a therapeutically effective amount of a compound of
formula I, or a pharmaceutically acceptable salt thereof. In
another aspect of the present invention said disease or condition
is selected from the group consisting neuropathic pain,
inflammatory pain, visceral pain, cancer pain, chemotherapy pain,
trauma pain, surgical pain, post-surgical pain, childbirth pain,
labor pain, neurogenic bladder, ulcerative colitis, chronic pain,
persistent pain, peripherally mediated pain, centrally mediated
pain, chronic headache, migraine headache, sinus headache, tension
headache, phantom limb pain, dental pain, peripheral nerve injury
or a combination thereof. In another aspect of the present
invention said disease or condition is selected from the group
consisting of pain associated with HIV, HIV treatment induced
neuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia,
heat sensitivity, tosarcoidosis, irritable bowel syndrome, Crohns
disease, pain associated with multiple sclerosis (MS), amyotrophic
lateral sclerosis (ALS), diabetic neuropathy, peripheral
neuropathy, arthritis, rheumatoid arthritis, osteoarthritis,
atherosclerosis, paroxysmal dystonia, myasthenia syndromes,
myotonia, malignant hyperthermia, cystic fibrosis,
pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar
depression, anxiety, schizophrenia, sodium channel toxi related
illnesses, familial erythromelalgia, primary erythromelalgia,
familial rectal pain, cancer, epilepsy, partial and general tonic
seizures, restless leg syndrome, arrhythmias, fibromyalgia,
neuroprotection under ischaemic conditions cause by stroke or
neural trauma, tach-arrhythmias, atria fibrillation and ventricular
fibrillation.
[0062] In another aspect the present invention provides for a
method of treating pain in a mammal by the inhibition of ion flux
through a voltage-dependent sodium channel in the mammal, wherein
the method comprises administering to the mammal in need thereof a
therapeutically effective amount of a compound of formula I, or a
pharmaceutically acceptable salt thereof.
[0063] In another aspect the present invention provides for a
method of decreasing ion flux through a voltage-dependent sodium
channel in a cell in a mammal, wherein the method comprises
contacting the cell with a compound of formula I, or a
pharmaceutically acceptable salt thereof.
[0064] In another aspect the present invention provides for a
method of treating pruritus in a mammal, wherein the method
comprises administering to the mammal in need thereof a
therapeutically effective amount of a compound of formula I, or a
pharmaceutically acceptable salt thereof.
[0065] In another aspect the present invention provides for a
method of treating cancer in mammal, wherein the method comprises
administering to the mammal in need thereof a therapeutically
effective amount a compound of formula I, or a pharmaceutically
acceptable salt thereof.
[0066] In another aspect the present invention provides for a
method of treating, but not preventing, pain in a mammal, wherein
the method comprises administering to the mammal in need thereof a
therapeutically effective amount of a compound of formula I, or a
pharmaceutically acceptable salt thereof. In another aspect of the
present invention the pain as selected from the group consisting of
neuropathic pain, inflammatory pain, visceral pain, cancer pain,
chemotherapy pain, trauma pain, surgical pain, post-surgical pain,
childbirth pain, labor pain, neurogenic bladder, ulcerative
colitis, chronic pain, persistent pain, peripherally mediated pain,
centrally mediated pain, chronic headache, migraine headache, sinus
headache, tension headache, phantom limb pain, dental pain,
peripheral nerve injury or a combination thereof. In another aspect
the present invention the pain is associated with a disease or
condition selected from the group consisting of HIV, HIV treatment
induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia,
eudynia, heat sensitivity, tosarcoidosis, irritable bowel syndrome,
Crohns disease, pain associated with multiple sclerosis (MS),
amyotrophic lateral sclerosis (ALS), diabetic neuropathy,
peripheral neuropathy, arthritis, rheumatoid arthritis,
osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia
syndromes, myotonia, malignant hyperthermia, cystic fibrosis,
pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar
depression, anxiety, schizophrenia, sodium channel toxi related
illnesses, familial erythromelalgia, primary erythromelalgia,
familial rectal pain, cancer, epilepsy, partial and general tonic
seizures, restless leg syndrome, arrhythmias, fibromyalgia,
neuroprotection under ischaemic conditions cause by stroke or
neural trauma, tach-arrhythmias, atrial fibrillation and
ventricular fibrillation.
[0067] In another aspect the present invention provides for a
method of treating, but not preventing, acute pain or chronic pain
in a mammal, wherein the method comprises administering to the
mammal in need thereof a therapeutically effective amount of a
compound of formula I, or a pharmaceutically acceptable salt
thereof.
[0068] In another aspect the present invention provides for a
method of treating, but not preventing, neuropathic pain or
inflammatory pain in a mammal, wherein the method comprises
administering to the mammal in need thereof a therapeutically
effective amount of a compound of formula I, or a pharmaceutically
acceptable salt thereof.
[0069] In another aspect the present invention provides for a
method for the treatment or prophylaxis of pain, depression,
cardiovascular disease, respiratory disease, or psychiatric
disease, or a combinations thereof, in an animal which method
comprises administering an effective amount of a compound of
formula I, or a pharmaceutically acceptable salt thereof.
[0070] In another aspect the present invention provides for a
compound of formula I, or a pharmaceutically acceptable salt
thereof for the use as a medicament for the treatment of diseases
and disorders selected from the group consisting of pain,
depression, cardiovascular diseases, respiratory diseases, and
psychiatric diseases, or a combination thereof.
[0071] In another aspect the present invention provides for the use
of a compound of formula I, or a pharmaceutically acceptable salt
thereof for the manufacture of a medicament for the treatment of
diseases and disorders selected from the group consisting of pain,
depression, cardiovascular diseases, respiratory diseases, and
psychiatric diseases, or a combination thereof.
[0072] In another aspect the present invention provides for the
invention as described herein.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0073] As used herein, the term "alkyl", by itself or as part of
another substituent, means, unless otherwise stated, a straight or
branched chain hydrocarbon radical, having the number of carbon
atoms designated (i.e., C.sub.1-8 means one to eight carbons).
Examples of alkyl groups include methyl, ethyl, n-propyl,
iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-hexyl,
n-heptyl, n-octyl, and the like. The term "alkenyl" refers to an
unsaturated alkyl radical having one or more double bonds.
Similarly, the term "alkynyl" refers to an unsaturated alkyl
radical having one or more triple bonds. Examples of such
unsaturated alkyl groups include vinyl, 2-propenyl, crotyl,
2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,
3-(1,4-pentadienyl), ethynyl, 1- and 3 -propynyl, 3-butynyl, and
the higher homologs and isomers.
[0074] The term "heteroalkyl," by itself or in combination with
another term, means, unless otherwise stated, a stable straight or
branched chain hydrocarbon radical, consisting of the stated number
of carbon atoms and from one to three heteroatoms selected from the
group consisting of O, N, Si and S, and wherein the nitrogen and
sulfur atoms can optionally be oxidized and the nitrogen heteroatom
can optionally be quaternized. The heteroatom(s) O, N and S can be
placed at any interior position of the heteroalkyl group. The
heteroatom Si can be placed at any position of the heteroalkyl
group, including the position at which the alkyl group is attached
to the remainder of the molecule. A "heteroalkyl" can contain up to
three units of unsaturation, and also include mono- and
poly-halogenated variants, or combinations thereof. Examples
include --CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--O--CF.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--C H.sub.3, --S(O)--CH.sub.3,
--CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --Si(CH.sub.3).sub.3,
--CH.sub.2--CH.dbd.N--OCH.sub.3, and
--CH.dbd.CH.dbd.N(CH.sub.3)--CH.sub.3. Up to two heteroatoms can be
consecutive, such as, for example, --CH.sub.2NH--OCH.sub.3 and
--CH.sub.2--O--Si(CH.sub.3).sub.3.
[0075] The term "alkylene" by itself or as part of another
substituent means a divalent radical derived from an alkane
(including branched alkane), as exemplified by
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2-- and
--CH(CH.sub.2)CH.sub.2CH.sub.2--. Typically, an alkyl (or alkylene)
group will have from 1 to 24 carbon atoms, with those groups having
10 or fewer carbon atoms being preferred in the present invention.
"Alkenylene" and "alkynylene" refer to the unsaturated forms of
"alkylene" having double or triple bonds, respectively. "Alkylene",
"alkenylene" and "alkynylene" are also meant to include mono and
poly-halogenated variants.
[0076] The term "heteroalkylene" by itself or as part of another
substituent means a divalent radical, saturated or unsaturated or
polyunsaturated, derived from heteroalkyl, as exemplified by and
--CH.sub.2--CH.sub.2--S--CH.sub.2--CH.sub.2-- and
--CH.sub.2--S--CH.sub.2--NH--CH.sub.2--,
--O--CH.sub.2--CH.dbd.CH--,
--CH.sub.2--CH.dbd.CH(H)CH.sub.2--O--CH.sub.2-- and
--S--CH.sub.2--C.dbd.C--. For heteroalkylene groups, heteroatoms
can also occupy either or both of the chain termini (e.g.,
alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the
like). The term "heteroalkylene" is also meant to include mono and
poly-halogenated variants.
[0077] The terms "alkoxy," "alkylamino" and "alkylthio", are used
in their conventional sense, and refer to those alkyl groups
attached to the remainder of the molecule via an oxygen atom
("oxy"), an amino group ("amino") or thio group, and further
include mono- and poly-halogenated variants thereof. Additionally,
for dialkylamino groups, the alkyl portions can be the same or
different.
[0078] The terms "halo" or "halogen," by themselves or as part of
another substituent, mean, unless otherwise stated, a fluorine,
chlorine, bromine, or iodine atom. The term "(halo)alkyl" is meant
to include both a "alkyl" and "haloalkyl" substituent.
Additionally, the term "haloalkyl," is meant to include
monohaloalkyl and polyhaloalkyl. For example, the term
"C.sub.1-4haloalkyl" is mean to include trifluoromethyl,
2,2,2,-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl,
difluoromethyl, and the like.
[0079] The term "aryl" as used herein refers to a single all carbon
aromatic ring or a multiple condensed all carbon ring system
wherein at least one of the rings is aromatic. For example, in
certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to
14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl
radical. Aryl also includes multiple condensed ring systems (e.g.,
ring systems comprising 2, 3 or 4 rings) having about 9 to 20
carbon atoms in which at least one ring is aromatic and wherein the
other rings may be aromatic or not aromatic (i.e., carbocycle).
Such multiple condensed ring systems are optionally substituted
with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle
portion of the multiple condensed ring system. The rings of the
multiple condensed ring system can be connected to each other via
fused, spiro and bridged bonds when allowed by valency
requirements. It is to be understood that the point of attachment
of a multiple condensed ring system, as defined above, can be at
any position of the ring system including an aromatic or a
carbocycle portion of the ring. Non-limiting examples of aryl
groups include, but are not limited to, phenyl, indenyl, naphthyl,
1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.
[0080] The term "carbocycle" or "carbocyclyl" refers to a single
saturated (i.e., cycloalkyl) or a single partially unsaturated
(e.g., cycloalkenyl, cycloalkadienyl, etc.) all carbon ring having
3 to 7 carbon atoms (i.e., (C.sub.3-C.sub.7)carbocycle). The term
"carbocycle" or "carbocyclyl" also includes multiple condensed,
saturated and partially unsaturated all carbon ring systems (e.g.,
ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly,
carbocycle includes multicyclic carbocyles such as a bicyclic
carbocycles (e.g., bicyclic carbocycles having about 6 to 12 carbon
atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and
polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycles
with up to about 20 carbon atoms). The rings of the multiple
condensed ring system can be connected to each other via fused,
spiro and bridged bonds when allowed by valency requirements. For
example, multicyclic carbocyles can be connected to each other via
a single carbon atom to form a spiro connection (e.g.,
spiropentane, spiro[4,5]decane, etc), via two adjacent carbon atoms
to form a fused connection (e.g., carbocycles such as
decahydronaphthalene, norsabinane, norcarane) or via two
non-adjacent carbon atoms to form a bridged connection (e.g.,
norbornane, bicyclo[2.2.2]octane, etc). The "carbocycle" or
"carbocyclyl" can also be optionally substituted with one or more
(e.g., 1, 2 or 3) oxo groups. In one embodiment the term carbocycle
includes a C.sub.3-12carbocycle. In one embodiment the term
carbocycle includes a C.sub.3-8carbocycle. In one embodiment the
term carbocycle includes a C.sub.3-6carbocycle. In one embodiment
the term carbocycle includes a C.sub.3-5carbocycle. Non-limiting
examples of carbocycles include cyclopropyl, cyclobutyl,
cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,
1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1 -enyl,
1-cyclohex-2-enyl, bicyclo[2.2.1]heptane, pinane, adamantane,
norborene, spirocyclic C.sub.3-12alkane, and 1-cyclohex-3-enyl.
[0081] The term "heteroaryl" as used herein refers to a single
aromatic ring that has at least one atom other than carbon in the
ring, wherein the atom is selected from the group consisting of
oxygen, nitrogen and sulfur; "heteroaryl" also includes multiple
condensed ring systems that have at least one such aromatic ring,
which multiple condensed ring systems are further described below.
Thus, "heteroaryl" includes single aromatic rings of from about 1
to 6 carbon atoms and about 1-4 heteroatoms selected from the group
consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen
atoms may also be present in an oxidized form provided the ring is
aromatic. Exemplary heteroaryl ring systems include but are not
limited to pyridyl, pyrimidinyl, oxazolyl or furyl. "heteroaryl"
also includes multiple condensed ring systems (e.g., ring systems
comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined
above, is condensed with one or more rings selected from
heteroaryls (to form for example a naphthyridinyl such as
1,8-naphthyridinyl), heterocycles, (to form for example a
1,2,3,4-tetrahydronaphthyridinyl such as
1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for
example 5,6,7,8 -tetrahydroquinolyl) and aryls (to form for example
indazolyl) to form the multiple condensed ring system. Thus, a
heteroaryl (a single aromatic ring or multiple condensed ring
system) has about 1-20 carbon atoms and about 1-6 heteroatoms
within the heteroaryl ring. Such multiple condensed ring systems
may be optionally substituted with one or more (e.g., 1, 2, 3 or 4)
oxo groups on the carbocycle or heterocycle portions of the
condensed ring. The rings of the multiple condensed ring system can
be connected to each other via fused, spiro and bridged bonds when
allowed by valency requirements. It is to be understood that the
individual rings of the multiple condensed ring system may be
connected in any order relative to one another. It is also to be
understood that the point of attachment of a multiple condensed
ring system (as defined above for a heteroaryl) can be at any
position of the multiple condensed ring system including a
heteroaryl, heterocycle, aryl or carbocycle portion of the multiple
condensed ring system. It is also to be understood that the point
of attachment for a heteroaryl or heteroaryl multiple condensed
ring system can be at any suitable atom of the heteroaryl or
heteroaryl multiple condensed ring system including a carbon atom
and a heteroatom (e.g., a nitrogen). Exemplary heteroaryls include
but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl,
pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl,
isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl,
quinazolyl, 5,6,7,8 tetrahydroisoquinolinyl benzofuranyl,
benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl,
quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole
and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclo-
penta[1,2-c]pyrazole.
[0082] The term "heterocyclyl" or "heterocycle" as used herein
refers to a single saturated or partially unsaturated ring that has
at least one atom other than carbon in the ring, wherein the atom
is selected from the group consisting of oxygen, nitrogen and
sulfur; the term also includes multiple condensed ring systems that
have at least one such saturated or partially unsaturated ring,
which multiple condensed ring systems are further described below.
Thus, the term includes single saturated or partially unsaturated
rings (e.g., 3, 4, 5, 6 or 7 -membered rings) from about 1 to 6
carbon atoms and from about 1 to 3 heteroatoms selected from the
group consisting of oxygen, nitrogen and sulfur in the ring. The
ring may be substituted with one or more (e.g., 1, 2 or 3) oxo
groups and the sulfur and nitrogen atoms may also be present in
their oxidized forms. Exemplary heterocycles include but are not
limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The term
"heterocycle" also includes multiple condensed ring systems (e.g.,
ring systems comprising 2, 3 or 4 rings) wherein a single
heterocycle ring (as defined above) can be condensed with one or
more groups selected from heterocycles (to form for example a
1,8-decahydronapthyridinyl), carbocycles (to form for example a
decahydroquinolyl) and aryls to form the multiple condensed ring
system. Thus, a heterocycle (a single saturated or single partially
unsaturated ring or multiple condensed ring system) has about 2-20
carbon atoms and 1-6 heteroatoms within the heterocycle ring. Such
multiple condensed ring systems may be optionally substituted with
one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or
heterocycle portions of the multiple condensed ring. The rings of
the multiple condensed ring system can be connected to each other
via fused, spiro and bridged bonds when allowed by valency
requirements. It is to be understood that the individual rings of
the multiple condensed ring system may be connected in any order
relative to one another. It is also to be understood that the point
of attachment of a multiple condensed ring system (as defined above
for a heterocycle) can be at any position of the multiple condensed
ring system including a heterocycle, aryl and carbocycle portion of
the ring. It is also to be understood that the point of attachment
for a heterocycle or heterocycle multiple condensed ring system can
be at any suitable atom of the heterocycle or heterocycle multiple
condensed ring system including a carbon atom and a heteroatom
(e.g., a nitrogen). In one embodiment the term heterocycle includes
a C.sub.2-20heterocycle. In one embodiment the term heterocycle
includes a C.sub.2-7 heterocycle. In one embodiment the term
heterocycle includes a C.sub.2-5heterocycle. In one embodiment the
term heterocycle includes a C.sub.2-4heterocycle. Exemplary
heterocycles include, but are not limited to aziridinyl,
azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl,
morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl,
dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl,
1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl,
chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl,
1,3-benzodioxolyl, 1,4-benzodioxanyl,
spiro[cyclopropane-1,1'-isoindolinyl]-3'-one, isoindolinyl-1-one,
2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one
N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam,
valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide,
1,4-dioxane, thiomorpholine, thiomorpholine-S-oxide,
thiomorpholine-S,S-oxide, pyran, 3-pyrroline, thiopyran, pyrone,
tetrhydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane,
(1R,5S)-3-azabicyclo[3.2.1]octane,
(1s,4s)-2-azabicyclo[2.2.2]octane,
(1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and pyrrolidin-2-one.
[0083] the above terms (e.g., "alkyl," "aryl" and "heteroaryl"), in
some embodiments, will include both substituted and unsubstituted
forms of the indicated radical. Preferred substituents for each
type of radical are provided below.
[0084] Substituents for the alkyl radicals (including those groups
often referred to as alkylene, alkenyl, alkynyl, heteroalkyl,
carbocycle, and heterocyclyl) can be a variety of groups including,
but not limited to, -halogen, --OR', --NR'R'', --SR',
--SiR'R''R''', --OC(O)R', --C(O)R', --CONR'R'', --OC(O)NR'R'',
--NR''C( O)R', --NR'''C(O)NR'R'', --NR''C(O).sub.2R',
--NHC(NH.sub.2).dbd.NH, --NRC(NH.sub.2).dbd.NH,
--NHC(NH.sub.2).dbd.NR', --NR'''C(NR'R'').dbd.N--CN,
--NR'''C(NR'R'').dbd.NOR', --NHC(NH.sub.2).dbd.NR',--S(O)R',
--S(O).sub.2R', --S(O).sub.2NR'R'', --NR'S(O).sub.2R'',
--NR'''S(O).sub.1NR'R'', --CN, --NO.sub.2,
--(CH.sub.2).sub.1-4--OR', --(CH.sub.2).sub.1-4--SR',
--(CH.sub.2).sub.1-4--SiR'R''R''', --(CH.sub.2).sub.1-4--OC( O)R',
--(CH.sub.2).sub.1-4--C(O)R', --(CH.sub.2).sub.1-4--CO.sub.2R',
--(CH.sub.2).sub.1-4CONR'R'', in a number ranging from zero to (2
m'+1), where m' is the total number of carbon atoms in such
radical. R', R'' and R''' each independently refer groups
including, for example, hydrogen, unsubstituted C.sub.1-6alkyl,
unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted
with 1-3 halogens, unsubstituted C.sub.1-6alkyl, C.sub.1-6alkoxy or
thioalkoxy groups, or unsubstituted aryl-C.sub.1-4alkyl groups,
unsubstituted heteroaryl, substituted heteroaryl, among others.
When R' and R'' are attached to the same nitrogen atom, they can be
combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or
7-membered ring. For example, --NR'R'' is meant to include
1-pyrrolidinyl and 4-morpholinyl. Other substitutents for alkyl
radicals, including heteroalkyl, alkylene, include for example,
.dbd.O, .dbd.NR', .dbd.N--OR', .dbd.N--CN, .dbd.NH, wherein R'
include substituents as described above.
[0085] Similarly, substituents for the aryl and heteroaryl groups
are varied and are generally selected from the group including, but
not limited to halogen, --OR', --OC(O)R', --NR'R'', --SR',
--R',--CN, --NO.sub.2, --CONR'R'', --C(O)R', --OC(O)NR'R'',
--NR''C(O)R', --NR''C(O).sub.2R', --NR'C(O)NR''R''',
--NHC(NH.sub.2).dbd.NH, --NR'C(NH.sub.1).dbd.NH,
--NHC(NH.sub.2).dbd.NR', --S(O)R', --S(O).sub.2R',
--S(O).sub.2NR'R'', --NJ'S(O).sub.2R'', --N.sub.3,
perfluoro-C.sub.1-4alkoxy, and perfluoro-C.sub.1-4alkyl,
--(CH.sub.2).sub.1-4--OR', --(CH.sub.1).sub.1-4--NR'R'',
--(CH.sub.2).sub.1-4--SR', --(CH.sub.2).sub.1-4SiR'R''R''',
--C(CH.sub.2).sub.1-4-OC(O)R', --(CH.sub.2).sub.1-4--CO.sub.2R',
--(CH.sub.2).sub.1-4CONR'R'', in a number ranging from zero to the
total number of open valences on the aromatic ring system; and
where and R', R'' and R''' are independently selected from
hydrogen, C.sub.1-6alkyl, C.sub.3-6carbocycle, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted
aryl)-C.sub.1-4alkyl, and unsubstituted aryloxy-C.sub.1-4alkyl.
Other suitable substituents include each of the above aryl
substituents attached to a ring atom by an alkylene tether of from
1-4 carbon atoms. When a substituent for the aryl heteroaryl group
contains an alkylene linker (e.g., --(CH.sub.2).sub.1-4--NR'R''),
the alkylene linker includes halo variants as well. For example,
the linker "--(CH.sub.2).sub.1-4--" when used as part of a
substituent is meant to include difluoromethylene,
1,2-difluoroethylene, etc.
[0086] As used herein, the term "heteroatom" is meant to include
oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
[0087] As used herein, the term "chiral" refers to molecules which
have the property of non-superimposability of the mirror image
partner, while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0088] As used herein, the term "stereoisomers" refers to compounds
which have identical chemical constitution, but differ with regard
to the arrangement of the atoms or groups in space.
[0089] As used herein a wavy line "" that intersects a bond in a
chemical structure indicates the point of attachment of the bond
that the wavy bond intersects in the chemical structure to the
remainder of a molecule.
[0090] As used herein, the term "C-linked" means that the group
that the term describes is attached the remainder of the molecule
through a ring carbon atom.
[0091] As used herein, the term "N-linked" means that the group
that the term describes is attached to the remainder of the
molecule through a ring nitrogen atom.
[0092] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties, e.g.
melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers can separate under high
resolution analytical procedures such as electrophoresis and
chromatography.
[0093] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0094] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds",
John Wiley & Sons, Inc., New York, 1994. The compounds of the
invention can contain asymmetric or chiral centers, and therefore
exist in different stereoisomeric forms. It is intended that all
stereoisomeric forms of the compounds of the invention, including
but not limited to, diastereomers, enantiomers and atropisomers, as
well as mixtures thereof such as racemic mixtures, form part of the
present invention. Many organic compounds exist in optically active
forms, i.e., they have the ability to rotate the plane of
plane-polarized light. In describing an optically active compound,
the prefixes D and L, or R and S, are used to denote the absolute
configuration of the molecule about its chiral center(s). The
prefixes d and l or (+) and (-) are employed to designate the sign
of rotation of plane-polarized light by the compound, with (-) or l
meaning that the compound is levorotatory. A compound prefixed with
(+) or d is dextrorotatory. For a given chemical structure, these
stereoisomers are identical except that they are mirror images of
one another. A specific stereoisomer can also be referred to as an
enantiomer, and a mixture of such isomers is often called an
enantiomeric mixture. A 50:50 mixture of enantiomers is referred to
as a racemic mixture or a racemate, which can occur where there has
been no stereoselection or stereospecificity in a chemical reaction
or process. The terms "racemic mixture" and "racemate" refer to an
equimolar mixture of two enantiomeric species, devoid of optical
activity.
[0095] As used herein, the term "tautomer" or "tautomeric form"
refers to structural isomers of different energies which are
interconvertible via a low energy barrier. For example, proton
tautomers (also known as prototropic tautomers) include
interconversions via migration of a proton, such as keto-enol and
imine-enamine isomerizations. Valence tautomers include
interconversions by reorganization of some of the bonding
electrons.
[0096] As used herein, the term "solvate" refers to an association
or complex of one or more solvent molecules and a compound of the
invention. Examples of solvents that form solvates include, but are
not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl
acetate, acetic acid, and ethanolamine. The term "hydrate" refers
to the complex where the solvent molecule is water.
[0097] As used herein, the term "protecting group" refers to a
substituent that is commonly employed to block or protect a
particular functional group on a compound. For example, an
"amino-protecting group" is a substituent attached to an amino
group that blocks or protects the amino functionality in the
compound. Suitable amino-protecting groups include acetyl,
trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ)
and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a
"hydroxy-protecting group" refers to a substituent of a hydroxy
group that blocks or protects the hydroxy functionality. Suitable
protecting groups include acetyl and silyl. A "carboxy-protecting
group" refers to a substituent of the carboxy group that blocks or
protects the carboxy functionality. Common carboxy-protecting
groups include phenylsulfonylethyl, cyanoethyl,
2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,
2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,
2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general
description of protecting groups and their use, see P. G. M. Wuts
and T. W. Greene, Greene's Protective Groups in Organic Synthesis
4.sup.th edition, Wiley-Interscience, New York, 2006.
[0098] As used herein, the term "mammal" includes, but is not
limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats,
horses, cows, pigs, and sheep
[0099] As used herein, the term "pharmaceutically acceptable salts"
is meant to include salts of the active compounds which are
prepared with relatively nontoxic acids or bases, depending on the
particular substituents found on the compounds described herein.
When compounds of the present invention contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of salts derived from pharmaceutically-acceptable inorganic bases
include aluminum, ammonium, calcium, copper, ferric, ferrous,
lithium, magnesium, manganic, manganous, potassium, sodium, zinc
and the like. Salts derived from pharmaceutically-acceptable
organic bases include salts of primary, secondary and tertiary
amines, including substituted amines, cyclic amines,
naturally-occurring amines and the like such as arginine, betaine,
caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine and the like. When
compounds of the present in invention contain relatively basic
functionalities, acid addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired acid, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable acid addition salts include those
derived from inorganic acids like hydrochloric, hydrobromic,
nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, malonic, benzoic, succinic,
suberic, fumaric, mandelic, phthalic, benzenesulfonic,
p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
Also included are salts of amino acids such as arginate and the
like, and salts of organic acids like glucuronic or galactunoric
acids and the like (see, for example, Berge, S. M., et al.,
"Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977,
66, 1-19). Certain specific compounds of the present invention
contain both basic and acidic functionalities that allow the
compounds to be converted into either base or acid addition
salts.
[0100] The neutral forms of the compounds can be generated by
contacting the salt with a base or acid and isolating the parent
compound in the conventional manner. The parent form of the
compound differs from the various salt forms in certain physical
properties, such as solubility in polar solvents, but otherwise the
salts are equivalent to the parent form of the compound for the
purposes of the present invention.
[0101] In addition to salt forms, the present invention provides
compounds which are in a prodrug form. As used herein the term
"prodrug" refers to those compounds that readily undergo chemical
changes under physiological conditions to provide the compounds of
the present invention. Additionally, prodrugs can be converted to
the compounds of the present invention by chemical or biochemical
methods in an ex vivo environment. For example, prodrugs can be
slowly converted to the compounds of the present invention when
placed in a transdermal patch reservoir with a suitable enzyme or
chemical reagent.
[0102] Prodrugs of the invention include compounds wherein an amino
acid residue, or a polypeptide chain of two or more (e.g., two,
three or four) amino acid residues, is covalently joined through an
amide or ester bond to a free amino, hydroxy or carboxylic acid
group of a compound of the present invention. The amino acid
residues include but are not limited to the 20 naturally occurring
amino acids commonly designated by three letter symbols and also
includes phosphoserine, phosphothreonine, phosphotyrosine,
4-hydroxyproline, hydroxylysine, demosine, isodemosine,
gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic
acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,
penicillamine, ornithine, 3-methylhistidine, norvaline,
beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine,
homoserine, methyl-alanine, para-benzoylphenylalanine,
phenylglycine, propargylglycine, sarcosine, methionine sulfone and
tert-butylglycine.
[0103] Additional types of prodrugs are also encompassed. For
instance, a free carboxyl group of a compound of the invention can
be derivatized as an amide or alkyl ester. As another example,
compounds of this invention comprising free hydroxy groups can be
derivatized as prodrugs by converting the hydroxy group into a
group such as, but not limited to, a phosphate ester,
hemisuccinate, dimethylaminoacetate, or
phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D.
et al., (1996) Improved oral drug delivery; solubility limitations
overcome by the use of prodrugs Advanced Drug Delivery Reviews,
19:115. Carbamate prodrugs of hydroxy and amino groups are also
included, as are carbonate prodrugs, sulfonate esters and sulfate
esters of hydroxy groups. Derivatization of hydroxy groups as
(acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group
can be an alkyl ester optionally substituted with groups including,
but not limited to, ether, amine and carboxylic acid
functionalities, or where the acyl group is an amino acid ester as
described above, are also encompassed. Prodrugs of this type are
described in J. Med. Chem., (1996), 39:10. More specific examples
include replacement of the hydrogen atom of the alcohol group with
a group such as (C.sub.1-6)alkanoyloxymethyl,
1-((C.sub.1-6)alkanoyloxy)ethyl,
1-methyl-1-((C.sub.1-6)alkanoyloxy)ethyl,
(C.sub.1-6)alkoxycarbonyloxymethyl,
N--(C.sub.1-6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-6)alkanoyl, alpha-amino(C.sub.1-4)alkanoyl, arylacyl and
alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where each
alpha-aminoacyl group is independently selected from the naturally
occurring L-amino acids, P(O)(OH).sub.2,
--P(O)(O(C.sub.1-6)alkyl).sub.2 or glycosyl (the radical resulting
from the removal of a hydroxyl group of the hemiacetal form of a
carbohydrate).
[0104] For additional examples of prodrug derivatives, see, for
example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier,
1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K.
Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design
and Development, edited by Krogsgaard-Larsen and H. Bundgaard,
Chapter 5 "Design and Application of Prodrugs," by H. Bundgaard p.
113-191 (1991); c) H. Bungaard, Advanced Drug Delivery Reviews,
8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical
Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Pharm.
Bull., 32:692 (1984), each of which is specifically incorporated
herein by reference.
[0105] Additionally, the present invention provides for metabolites
of compounds of the invention. As used herein, a "metabolite"
refers to a product produced through metabolism in the body of a
specified compound or salt thereof. Such products can result for
example from the oxidation, reduction, hydrolysis, amidation,
deamidation, esterification, deesterification, enzymatic cleavage,
and the like, of the administered compound.
[0106] Metabolite products typically are identified by preparing a
radiolabelled (e.g., .sup.14C or .sup.3H) isotope of a compound of
the invention, administering it parenterally in a detectable dose
(e.g., greater than about 0.5 mg/kg) to an animal such as rat,
mouse, guinea pig, monkey, or to man, allowing sufficient time for
metabolism to occur (typically about 30 seconds to 30 hours) and
isolating its conversion products from the urine, blood or other
biological samples. These products are easily isolated since they
are labeled (others are isolated by the use of antibodies capable
of binding epitopes surviving in the metabolite). The metabolite
structures are determined in conventional fashion, e.g., by MS,
LC/MS or NMR analysis. In general, analysis of metabolites is done
in the same way as conventional drug metabolism studies well known
to those skilled in the art. The metabolite products, so long as
they are not otherwise found in vivo, are useful in diagnostic
assays for therapeutic dosing of the compounds of the
invention.
[0107] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms are equivalent to unsolvated
forms and are intended to be encompassed within the scope of the
present invention. Certain compounds of the present invention can
exist in multiple crystalline or amorphous forms. In general, all
physical forms are equivalent for the uses contemplated by the
present invention and are intended to be within the scope of the
present invention.
[0108] Certain compounds of the present invention possess
asymmetric carbon atoms (optical centers) or double bonds; the
racemates, diastereomers, geometric isomers, regioisomers and
individual isomers (e.g., separate enantiomers) are all intended to
be encompassed within the scope of the present invention.
[0109] The compounds of the present invention can also contain
unnatural proportions of atomic isotopes at one or more of the
atoms that constitute such compounds. For example, the present
invention also embraces isotopically-labeled variants of the
present invention which are identical to those recited herein, bur
the for the fact that one or more atoms are replace by an atom
haying the atomic mass or mass number different from the
predominant atomic mass or mass number usually found in nature for
the atom. All isotopes of any particular atom or element as
specified are contemplated within the scope of the compounds of the
invention, and their uses. Exemplary isotopes that can be
incorporated in to compounds of the invention include istopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine,
chlorine and iodine, such as .sup.2H ("D"), .sup.3H, .sup.11C,
.sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O, .sup.17O,
.sup.18O, .sup.32P, .sup.33P, .sup.35S, .sup.18F, .sup.36Cl,
.sup.123I and .sup.125I. Certain isotopically labeled compounds of
the present invention (e.g., those labeled with .sup.3H or
.sup.14C) are useful in compound and/or substrate tissue
distribution assays. Tritiated (.sup.3H) and carbon-14 (.sup.14C)
isotopes are useful for their ease of preparation and
detectability. Further substitution with heavier isotopes such as
deuterium (i.e., .sup.2H) may afford certain therapeutic advantages
resulting from greater metabolic stability (e.g., increased in vivo
half-life or reduced dosage requirements) and hence may be
preferred in some circumstances. Positron emitting isotopes such as
.sup.15O, .sup.13N, .sup.11C, and .sup.18F are useful for positron
emission tomography (PET) studies to examine substrate receptor
occupancy. Isotopically labeled compounds of the present inventions
can generally be prepared by following procedures analogous to
those disclosed in the Schemes and/or in the Examples herein below,
by substituting an isotopically labeled reagent for a
non-isotopically labeled reagent.
[0110] The terms "treat" and "treatment" refer to both therapeutic
treatment and/or prophylactic treatment or preventative measures,
wherein the object is to prevent or slow down (lessen) an undesired
physiological change or disorder, such as, for example, the
development or spread of cancer. For purposes of this invention,
beneficial or desired clinical results include, but are not limited
to, alleviation of symptoms, diminishment of extent of disease or
disorder, stabilized (i.e., not worsening) state of disease or
disorder, delay or slowing of disease progression, amelioration or
palliation of the disease state or disorder, and remission (whether
partial or total), whether detectable or undetectable. "Treatment"
can also mean prolonging survival as compared to expected survival
if not receiving treatment. Those in need of treatment include
those already with the disease or disorder as well as those prone
to have the disease or disorder or those in which the disease or
disorder is to be prevented.
[0111] The phrase "therapeutically effective amount" or "effective
amount" of a compound of the present invention that (i) treats or
prevents the particular disease, condition, or disorder, (ii)
attenuates, ameliorates, or eliminates one or more symptoms of the
particular disease, condition, or disorder, or (iii) prevents or
delays the onset of one or more symptoms of the particular disease,
condition, or disorder described herein. For cancer therapy,
efficacy can, for example, be measured by assessing the time to
disease progression (TTP) and/or determining the response rate
(RR).
[0112] The term "bioavailability" refers to the systemic
availability (i.e., blood/plasma levels) of a given amount of drug
administered to a patient. Bioavailability is an absolute term that
indicates measurement of both the time (rate) and total amount
(extent) of drug that reaches the general circulation from an
administered dosage form.
[0113] In another embodiment, the compound is selected from
compounds of formula I as described in the Examples herein and
salts thereof.
Synthesis of Compounds
[0114] Compounds of formula (I) may be prepared by the process
illustrated in Schemes 1 and 2. Compounds of formula (I), wherein
X.sup.1 is O, S, or NH, may be prepared by the processes
illustrated in Scheme 1.
##STR00190##
[0115] Compounds of formula (I) can be made from compounds of
formula (II) by displacement with formula (III) and a base
(reaction step ii in Scheme 1). Suitable conditions include
potassium tert-butoxide or cesium carbonate in DMSO, NaH in DMF, or
K.sub.2CO.sub.3 in DMF. Formula (II) can be made according to step
(i) by activation of the acid group of formula (IV) with reagents
such as oxalyl chloride, carbonyl di-imidazole (CDI),
propylphosphonic anhydride, a uronium based amide coupling agent or
a carbodiimide reagent followed by displacement with a sulfonamide
of formula (VII) in the presence of a nucleophilic base such as
4-dimethylaminopyridine. Illustrative conditions comprise N,
N-dimethylaminopropyl-N'-ethylcarbodiimide and 4-dimethylamino-
pyridine with N, N-diisopropylethylamine.
[0116] Alternatively, compounds of formula (I) can be made from
compounds of formula (IV) by reversing steps (i) and (ii) as
described in Scheme 1. Illustrative conditions for steps vi and vii
are as previously described in steps (ii) and (i),
respectively.
[0117] Compounds of formula (I) can also be made from compounds of
formula (V) according to step (v) by displacement of the ester with
compounds of formula (VII) and a suitable base such as potassium
tert-butoxide, NaH or DBU. Compounds of formula (I) can also be
made from compounds of formula (v) by a two steps sequence (see
steps viii and vii in Scheme 1). Compounds of formula (V) can be
made from compounds of formula (VIII) according to step (iv) via a
nucleophilic substitution reaction using compounds of formula (III)
and a base as described in step ii. Compounds of formula (VIII) can
be made from compounds of formula (IV) according to step (iii)
using protecting group methodology as described in references such
as `Greene's Protective Groups in Organic Synthesis`. When Pg is
tolyl, illustrative conditions comprise thionyl chloride or
carbonyldiimidazole with para-cresol. When Pg is tert-butyl,
illustrative conditions comprise di-tert-butyl dicarbonate and
4-dimethylaminopyridine in tert-butanol. Compounds of formula (I),
wherein R.sup.5 is C.sub.1-8alkyl, C.sub.1-8haloalkyl,
C.sub.1-8alkoxy, C.sub.3-8cycloalkyl or C.sub.2-7heterocycloalkyl
can be prepared by the process illustrated in Scheme 2. In certain
embodiment, W groups in compounds of formula (IX, X and XI) are an
ester or cyano group.
##STR00191##
[0118] Compounds of formula (I) can be prepared from compounds of
formula (XII) (--V.dbd.OH) according to reaction step (iv) by
activation of the acid group with reagents such as oxalyl chloride,
carbonyl di-imidazole (CDI), as uronium based amide coupling agent,
propylphosphonic anhydride or a carbodiimide reagent followed by
displacement with a suitable sulfonamide of formula (VII) in the
presence of a nucleophilic base such as
4-dimethylaminopyridine.
[0119] Alternatively, compounds of formula (I) can be prepared from
compounds of formula (XII) (--V.dbd.NH.sub.2) according to reaction
step (v) by displacement of a sulfonyl chloride of formula (XIII)
under basic reaction conditions.
[0120] Compounds of formula (XII) can be prepared by hydrolysis of
the nitrile functional group in compounds of formula (XI, W.dbd.CN)
or by hydrosis of the ester functional group in compounds of
formula (XI, W.dbd.CO.sub.2Pg) by either acidic or basic methods
according to step (iii) as required.
[0121] Compounds of formula (XI) can be prepared from compounds of
formula (X) by palladium-catalyzed coupling of a compound of
formula (R.sub.5M) according to step (ii). Conveniently the
coupling is effective with a boronic acid or ester of formula
(R.sub.5M). The coupling reaction can be carried out with a variety
of palladium catalysis such as palladium acetate or
tetrakistriphenylphosphine palladium (0) in various solvents and in
the presence of bases such as sodium and potassium carbonate,
cesium fluoride or potassium phosphate. Compounds of formula (X)
can be prepared under similar conditions as described for the
preparation of compounds of formula (V), (VI) and (I) in Scheme
1.
Pharmaceutical Composition and Administration
[0122] In addition to one or more of the compounds provided above
(or stereoisomers, geometric isomers, tautomers, solvates,
metabolites, isotopes, pharmaceutically acceptable salts, or
prodrugs thereof), the invention also provides for compositions and
medicaments comprising a compound of formula I or and embodiment
thereof and at least one pharmaceutically acceptable carrier,
diluent or excipient. The compositions of the invention can be used
to selectively inhibit NaV1.7 in patients (e.g, humans).
[0123] The term "composition," as used herein, is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts. By "pharmaceutically acceptable" it is meant the
carrier, diluent or excipient must be compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof.
[0124] In one embodiment, the invention provides for pharmaceutical
compositions (or medicaments) comprising a compound of formula I or
an embodiment thereof, and its stereoisomers, geometric isomers,
tautomers, solvates, metabolites, isotopes, pharmaceutically
acceptable salts, or prodrugs thereof) and a pharmaceutically
acceptable carrier, diluent or excipient. In another embodiment,
the invention provides for preparing compositions (or medicaments)
comprising compounds of the invention. In another embodiment, the
invention provides for administering compounds of formula I or its
embodiments and compositions comprising compounds of formula I or
an embodiment thereof to a patient (e.g., a human patient) in need
thereof.
[0125] Compositions are formulated, dosed, and administered in a
fashion consistent with good medical practice. Factors for
consideration in this context include the particular disorder being
treated, the particular mammal being treated, the clinical
condition of the individual patient, the cause of the disorder, the
site of delivery of the agent, the method of administration, the
scheduling of administration, and other factors known to medical
practitioners. The effective amount of the compound to be
administered will be governed by such considerations, and is the
minimum amount necessary to inhibit NaV1.7 activity as required to
prevent or treat the undesired disease or disorder, such as for
example, pain. For example, such amount may be below the amount
that is toxic to normal cells, or the mammal as a whole.
[0126] In one example, the therapeutically effective amount of the
compound of the invention administered parenterally per dose will
be in the range of about 0.01-100 mg/kg, alternatively about e.g.,
0.1 to 20 mg/kg of patient body weight per day, with the typical
initial range of compound used being 0.3 to 15 mg/kg/day. The daily
does is, in certain embodiments, given as a single daily dose or in
divided doses two to six times a day, or in sustained release form.
In the case of a 70 kg adult human, the total daily dose will
generally be from about 7 mg to about 1,400 mg. This dosage regimen
may be adjusted to provide the optimal therapeutic response. The
compounds may be administered on a regimen of 1 to 4 times per day,
preferably once or twice per day.
[0127] The compounds of the present invention may be administered
in any convenient administrative form, e.g., tablets, powders,
capsules, solutions, dispersions, suspensions, syrups, sprays,
suppositories, gels, emulsions, patches, etc. Such compositions may
contain components conventional in pharmaceutical preparations,
e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents,
and further active agents.
[0128] The compounds of the invention may be administered by any
suitable means, including oral, topical (including buccal and
sublingual), rectal, vaginal, transdermal, parenteral,
subcutaneous, intraperitoneal, intrapulmonary, intradermal,
intrathecal and epidural and intranasal, and, if desired for local
treatment, intralesional administration. Parenteral infusions
include intramuscular, intravenous, intraarterial, intraperitoneal,
intracerebral, intraocular, intralesional or subcutaneous
administration.
[0129] The compositions comprising compounds of formula I or an
embodiment thereof are normally formulated in accordance with
standard pharmaceutical practice as a pharmaceutical composition. A
typical formulation is prepared by mixing a compound of the present
invention and a diluent, carrier or excipient. Suitable, diluents,
carriers and excipients are well known to those skilled in the art
and are described in detail in, e.g., Ansel, Howard C., et al.,
Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.
Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro,
Alfonso R., et al. Remington: The Science and Practice of Pharmacy.
Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,
Raymond C. Handbook of Pharmaceutical Excipients, Chicago,
Pharmaceutical Press, 2005. The formulations may also include one
or more buffers, stabilizing agents, surfactants, wetting agents,
lubricating agents, emulsifiers, suspending agents, preservatives,
antioxidants, opaquing agents, glidants, processing aids,
colorants, sweeteners, perfuming agents, flavoring agents, diluents
and other known additives to provide an elegant presentation of the
drug (i.e., a compound of the present invention or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
[0130] Suitable carriers, diluents and excipients are well known to
those skilled in the art and include materials such as
carbohydrates, waxes, water soluble and/or swellable polymers,
hydrophilic or hydrophobic materials, gelatin, oils, solvents,
water and the like. The particular carrier, diluent or excipient
used will depend upon the means and purpose for which a compound of
the present invention is being applied. Solvents are generally
selected based on solvents recognized by persons skilled in the art
as safe (GRAS) to be administered to a mammal. In general, safe
solvents are non-toxic aqueous solvents such as water and other
non-toxic solvents that are soluble or miscible in water. Suitable
aqueous solvents include water, ethanol, propylene glycol,
polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures
thereof. The formulations can also include one or more buffers,
stabilizing agents, surfactants, wetting agents, lubricating
agents, emulsifiers, suspending agents, preservatives,
antioxidants, opaquing agents, glidants, processing aids,
colorants, sweeteners, perfuming agents, flavoring agents and other
known additives to provide an elegant presentation of the drug
(i.e., a compound of the present invention or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
[0131] Acceptable diluents, carriers, excipients and stabilizers
are nontoxic to recipients at the dosages and concentrations
employed, and include buffers such as phosphate, citrate and other
organic acids; antioxidants including ascorbic acid and methionine;
preservatives (such as octadecyldimethylbenzyl ammonium chloride;
hexamethonium chloride; benzalkonium chloride, benzethonium
chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as
methyl or propyl paraben; catechol; resorcinol; cyclohexanol;
3-pentanol; and m-cresol); low molecular weight (less than about 10
residues) polypeptides; proteins, such as serum albumin, gelatin,
or immunoglobulins; hydrophilic polymers such as
polyvinylpyrrolidone: amino acids such as glycine, glutamine,
asparagine, histidine, arginine, or lysine; monosaccharides,
disaccharides and other carbohydrates including glucose, mannose,
or dextrins; chelating agents such as EDTA; sugars such as sucrose,
mannitol, trehalose or sorbitol; salt-forming counter-ions such as
sodium; metal complexes (e.g., Zn-protein complexes); and/or
non-ionic surfactants such as TWEEN.TM., PLURONICS.TM. or
polyethylene glycol (PEG). A active pharmaceutical ingredient of
the invention (e.g., compound of formula I or an embodiment
thereof) can also be entrapped in microcapsules prepared, for
example, by coacervation techniques or by interfacial
polymerization, for example, hydroxymethylcellulose or
gelatin-microcapsules and poly-(methylmethacylate) microcapsules,
respectively, in colloidal drug delivery systems (for example,
liposomes, albumin microspheres, microemulsions, nano-particles and
nanocapsules) or in macroemulsions. Such techniques are disclosed
in Remington: The Science and Practice of Pharmacy: Remington the
Science and Practice of Pharmacy (2005) 21.sup.st Edition,
Lippincott Williams & Wilkins, Philadelphia, Pa.
[0132] Sustained-release preparations of a compound of the
invention (e.g., compound of formula I or an embodiment thereof)
can be prepared. Suitable examples of sustained-release
preparations include semipermeable matrices of solid hydrophobic
polymers containing a compound of formula I or an embodiment
thereof, which matrices are in the form of shaped articles, e.g.,
films, or microcapsules. Examples of sustained-release matrices
include polyesters, hydrogels (for example,
poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)),
polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic
acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers
22:547, 1983), non-degradable ethylene-vinyl acetate (Langer et
al., J. Biomed. Mater. Res. 15:167, 1981), degradable lactic
acid-glycolic acid copolymers such as the LUPRON DEPOT.TM.
(injectable microspheres composed of lactic acid glycolic acid
copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric
acid (EP 133,988A). Sustained release compositions also include
liposomally entrapped compounds, which can be prepared by methods
known per se (Epstein et al., Proc. Natl. Acad. Sci. U.S.A.
82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A. 77:4030,
1980; U.S. Pat. Nos. 4,485,045 and 4,544,345; and EP 102,324A).
Ordinarily, the liposomes are of the small (about 200-800
Angstroms) unilamelar type in which the lipid content is greater
than about 30 mol % cholesterol, the selected proportion being
adjusted for the optimal therapy.
[0133] The formulations include those suitable for the
administration routes detailed herein. The formulations can
conveniently be presented in unit dosage form and can be prepared
by any of the methods well known in the art of pharmacy. Techniques
and formulations generally are found in Remington: The Science and
Practice of Pharmacy: Remington the Science and Practice of
Pharmacy (2005) 21.sup.st Edition, Lippincott Williams &
Wilkins, Philadelphia, Pa. Such methods include the step of
bringing into association the active ingredient with the carrier
which constitutes one or more accessory ingredients.
[0134] In general the formulations are prepared uniformly and
intimately bringing into association the active ingredient with
liquid carriers, diluents or excipients or finely divided solid
carriers, diluents or excipients, or both, and then, if necessary,
shaping the product. A typical formulation is prepared by a
compound of the present invention and a carrier, diluent or
excipient. The formulations can be prepared using conventional
dissolution and mixing procedures. For example, the bulk drug
substance (i.e., compound of the present invention or stabilized
form of the compound (e.g., complex with a cyclodextrin derivative
or other known complexation agent) is dissolved in a suitable
solvent in the presence of one or more of the excipients described
above. A compound of the present invention is typically formulated
into pharmaceutical dosage forms to provide an easily controllable
dosage of the drug and to enable patient compliance with the
prescribed regimen.
[0135] In one example, compounds of formula I or an embodiment
thereof may be formulated by mixing at ambient temperature at the
appropriate pH, and at the desired degree of purity, with
physiologically acceptable carriers, i.e., carriers that are
non-toxic to recipients at the dosages and concentrations employed
into a galenical administration form. The pH of the formulation
depends mainly on the particular use and the concentration of
compound, but preferably ranges anywhere from about 3 to about 8.
In one example, a compound of formula I (or an embodiment thereof)
is formulated in an acetate buffer, at pH 5. In another embodiment,
the compounds of formula I or an embodiment thereof are sterile.
The compound may be stored, for example, as a solid or amorphous
composition, as a lyophilized formulation or as an aqueous
solution.
[0136] Formulations of a compound of the invention (e.g., compound
of formula I or an embodiment thereof) suitable for oral
administration can be prepared as discrete units such as pills,
capsules, cachets or tablets each containing a predetermined amount
of a compound of the invention.
[0137] Compressed tablets can be prepared by compressing in a
suitable machine the active ingredient in a free-flowing form such
as a powder or granules, optionally mixed with a binder, lubricant,
inert diluent, preservative, surface active or dispersing agent.
Molded tablets can be made by molding in a suitable machine a
mixture of the powdered active ingredient moistened with an inert
liquid diluent. The tablets can optionally be coated or scored and
optionally are formulated so as to provide slow or controlled
release of the active ingredient therefrom.
[0138] Tablets, troches, lozenges, aqueous or oil suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
e.g., gelatin capsules, syrups or elixirs can be prepared for oral
use. Formulations of a compound of the invention (e.g., compound of
formula I or an embodiment thereof) intended for oral use can be
prepared according to any method known to the art for the
manufacture of pharmaceutical compositions and such compositions
can contain one or more agents including sweetening agents,
flavoring agents, coloring agents and preserving agents, in order
to provide a palatable preparation. Tablets containing the active
ingredient in admixture with non-toxic pharmaceutically acceptable
excipient which are suitable for manufacture of tablets are
acceptable. These excipients can be, for example, inert diluents,
such as calcium or sodium carbonate, lactose, calcium or sodium
phosphate; granulating and disintegrating agents, such as maize
starch, or alginic acid; binding agents, such as starch, gelatin or
acacia; and lubricating agents, such as magnesium stearate, stearic
acid or talc. Tablets can be uncoated or can be coated by known
techniques including microencapsulation to delay disintegration and
adsorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate alone
or with a wax can be employed.
[0139] An example of a suitable oral administration form is a
tablet containing about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80
mg, 100 mg, 150 mg, 250 mg, 300 mg and 500 mg of the compound of
the invention compounded with about 90-30 mg anhydrous lactose,
about 5-40 mg sodium croscarmellose, about 5-30 mg
polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium
stearate. The powdered ingredients are first mixed together and
then mixed with a solution of the PVP. The resulting composition
can be dried, granulated, mixed with the magnesium stearate and
compressed to tablet form using conventional equipment. An example
of an aerosol formulation can be prepared by dissolving the
compound, for example 5-400 mg, of the invention in a suitable
buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g.
a salt such sodium chloride, if desired. The solution may be
filtered, e.g., using a 0.2 micron filter, to remove impurities and
contaminants.
[0140] For treatment of the eye or other external tissues, e.g.,
mouth and skin, the formulations are preferably applied as a
topical ointment or cream containing the active ingredient(s) in an
amount of, for example, 0.075 to 20% w/w. When formulated in an
ointment, the active ingredient can be employed with either a
paraffinic or a water-miscible ointment base. Alternatively, the
active ingredients can be formulated in a cream with an
oil-in-water cream base. If desired, the aqueous phase of the cream
base can include a polyhydric alcohol, i.e., an alcohol having two
or more hydroxyl groups such as propylene glycol, butane 1,3-diol,
mannitol, sorbitol, glycerol and polyethylene glycol (including PEG
400) and mixtures thereof. The topical formulations can desirably
include a compound which enhances absorption or penetration of the
active ingredient through the skin or other affected areas.
Examples of such dermal penetration enhancers include dimethyl
sulfoxide and related analogs.
[0141] The oily phase of the emulsions invention can be constituted
from known ingredients in a known manner. While the phase can
comprise merely an emulsifier, it desirably comprises a mixture of
at least one emulsifier with a fat or an oil or with both a fat and
an oil. Preferably, a hydrophilic emulsifier is included together
with a lipophilic emulsifier which acts as a stabilizer. It is also
preferred to include both oil and a fat. Together, the
emulsifier(s) with or without stabilizer(s) make up the so-called
emulsifying wax, and the wax together with the oil and fat make up
the so-called emulsifying ointment base which forms the dispersed
phase of the cream formulations. Emulsifiers and emulsion
stabilizers suitable for use in the formulation of the invention
include Tween.RTM. 60, Span.RTM. 80, cetostearyl alcohol, benzyl
alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl
sulfate.
[0142] In one aspect of topical applications, it is desired to
administer an effective amount of a pharmaceutical composition
according to the invention to target area, e.g., skin surfaces,
mucous membranes, and the like, which are adjacent to peripheral
neurons which are to be treated. This amount will generally range
from about 0.0001 mg to about 1 g of a compound of the invention
per application, depending upon the area to be treated, whether the
use is diagnostic, prophylactic or therapeutic, the severity of the
symptoms, and the nature of the topical vehicle employed. A
preferred topical preparation is an ointment, wherein about 0.001
to about 50 mg of active ingredient is used per cc of ointment
base. The pharmaceutical composition can be formulated as
transdermal compositions or transdermal delivery devices
("patches"). Such compositions include, for example, a backing,
active compound reservoir, a control membrane, liner and contact
adhesive. Such transdermal patches may be used to provide
continuous pulsatile, or on demand delivery of the compounds of the
present invention as desired.
[0143] Aqueous suspensions of a compound of the invention (e.g.,
compound of formula I or an embodiment thereof) contain the active
materials in admixture with excipients suitable for the manufacture
of aqueous suspensions. Such excipients include a suspending agent,
such as sodium carboxymethylcellulose, croscarmellose, povidone,
methylcellulose, hydroxypropyl methylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous
suspension can also contain one or more preservatives such as ethyl
or n-propyl p-hydroxybenzoate, one or more coloring agents, one or
more flavoring agents and one or more sweetening agents, such as
sucrose or saccharin.
[0144] Formulations of a compound of the invention (e.g., compound
of formula I or an embodiment thereof) can be in the form of a
sterile injectable preparation, such as a sterile injectable
aqueous or oleaginous suspension. This suspension can be formulated
according to the known art using those suitable dispersing or
wetting agents and suspending agents which have been mentioned
above. The sterile injectable preparation can also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, such as a solution in 1,3-butanediol
or prepared as a lyophilized powder. Among the acceptable vehicles
and solvents that can be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile fixed oils
can conventionally be employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid can likewise be used in the preparation of
injectables.
[0145] The amount of active ingredient that can be combined with
the carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans can contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which can vary from about 5
to about 95% of the total compositions (weight:weight). The
pharmaceutical composition can be prepared to provide easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion can contain from about 3
to 500 .mu.g of the active ingredient per milliliter of solution in
order that infusion of a suitable volume at a rate of about 30
mL/hr can occur.
[0146] Formulations suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which can
contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
can include suspending agents and thickening agents.
[0147] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredient is dissolved
or suspended in a suitable carrier, especially an aqueous solvent
for the active ingredient. The active ingredient is preferably
present in such formulations in a concentration of about 0.5 to 20%
w/w, for example about 0.5 to 10% w/w, for example about 1.5%
w/w.
[0148] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredient in a
flavored basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0149] Formulations for rectal administration can be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0150] Formulations suitable for intrapulmonary or nasal
administration have a particle size for example in the range of 0.1
to 500 microns (including particle sizes in a range between 0.1 and
500 microns in increments microns such as 0.5, 1, 30 microns, 35
microns, etc.), which is administered by rapid inhalation through
the nasal passage or by inhalation through the mouth so as to reach
the alveolar sacs. Suitable formulations include aqueous or oily
solutions of the active ingredient. Formulations suitable for
aerosol or dry powder administration can be prepared according to
conventional methods and can be delivered with other therapeutic
agents such as compounds heretofore used in the treatment of
disorders as described below.
[0151] The formulations can be packaged in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and can be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example water, for
injection immediately prior to use. Extemporaneous injection
solutions and suspensions are prepared from sterile powders,
granules and tablets of the kind previously described. Preferred
unit dosage formulations are those containing a daily dose or unit
daily sub-dose, as herein above recited, or an appropriate fraction
thereof, of the active ingredient.
[0152] When the binding target is located in the brain, certain
embodiments of the invention provide for a compound of formula I
(or an embodiment thereof) to traverse the blood-brain barrier.
Certain neurodegenerative diseases are associated with an increase
in permeability of the blood-brain barrier, such that a compound of
formula I (or an embodiment thereof) can be readily introduced to
the brain. When the blood-brain barrier remains intact, several
art-known approaches exist for transporting molecules across it,
including, but not limited to, physical methods, lipid-based
methods, and receptor and channel-based methods.
[0153] Physical methods of transporting a compound of formula I (or
an embodiment thereof) across the blood-brain barrier include, but
are not limited to, circumventing the blood-brain barrier entirely,
or by creating openings in the blood-brain barrier.
[0154] Circumvention methods include, but are not limited to,
direct injection into the brain (see, e.g., Papanastassiou et al.,
Gene Therapy 9:308-406, 2000, interstitial
infusion/convection-enhanced delivery (see, e.g., Bobo et al.,
Proc. Natl. Acad. Sci. U.S.A. 91 :2076-2080, 1994), and implanting
a delivery device in the brain (see, e.g., Gill et al., Nature Med,
9:589-595, 2003; and Gliadel Wafers.TM., Guildford.
[0155] Pharmaceutical). Methods of creating openings in the barrier
include, but are not limited to, ultrasound (see, e.g., U.S. Patent
Publication No. 2002/0038086), osmotic pressure (e.g., by
administration of hypertonic mannitol (Neuwelt, E. A., Implication
of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2,
Plenum Press, N.Y., 1989)), and permeabilization by, e.g.,
bradykinin or permeabilizer A-7 (see, e.g., U.S. Pat. Nos.
5,112,596, 5,268,164, 5,506,206, and 5,686,416).
[0156] Lipid-based methods of transporting a compound of formula I
(or an embodiment thereof) across the blood-brain barrier include,
but are not limited to, encapsulating the a compound of formula I
(or an embodiment thereof) in liposomes that are coupled to
antibody binding fragments that bind to receptors on the vascular
endothelium of the blood-brain barrier (see, e.g., U.S. Patent
Application Publication No. 2002/0025313), and coating a compound
of formula I (or an embodiment thereof) in low-density lipoprotein
particles (see, e.g., U.S. Patent Application Publication No.
2004/0204354) or apolipoprotein E (see, e.g., U.S. Patent
Application Publication No. 2004/0131692).
[0157] Receptor and channel-based methods of transporting a
compound of formula I (or an embodiment thereof) across the
blood-brain barrier include, but are not limited to, using
glucocorticoid blockers to increase permeability of the blood-brain
barrier (see, e.g., U.S. Patent Application Publication Nos.
2002/0065259, 2003/0162695, and 2005/0124533); activating potassium
channels (see, e.g., U.S. Patent Application Publication No.
2005/0089473), inhibiting ABC drug transporters (see, U.S. Patent
Application Publication No. 2003/0073713); coating compound of
formula I (or an embodiment thereof) with a transferrin and
modulating activity of the one or more transferrin receptors (see,
e.g., U.S. Patent Application Publication No. 2003/0129186), and
cationizing the antibodies (see, e.g., U.S. Pat. No.
5,004,697).
[0158] For intracerebral use, in certain embodiments, the compounds
can be administered continuously by infusion into the fluid
reservoirs of the CNS, although bolus injection may be acceptable.
The inhibitors can be administered into the ventricles of the brain
or otherwise introduced into the CNS or spinal fluid.
Administration can be performed by use of an indwelling catheter
and a continuous administration means such as a pump, or it can be
administered by implantation, e.g., intracerebral implantation of a
sustained release vehicle. More specifically, the inhibitors can be
injected through chronically implanted cannulas or chronically
infused with the help of osmotic minipumps. Subcutaneous pumps are
available that deliver proteins through a small tubing to the
cerebral ventricles. Highly sophisticated pumps can be refilled
through the skin and their delivery rate can be set without
surgical intervention. Examples of suitable administration
protocols and delivery systems involving a subcutaneous pump device
or continuous intracerebroventricular infusion through a totally
implanted drug delivery system are those used for the
administration of dopamine, dopamine agonists, and cholinergic
agonists to Alzheimer's disease patients and animal models for
Parkinson's disease, as described by Harbaugh, J. Neural Transm.
Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2: 143,
1987.
[0159] A compound of formula I (or an embodiment thereof) used in
the invention are formulated, dosed, and administered in a fashion
consistent with good medical practice. Factors for consideration in
this context include the particular disorder being treated, the
particular mammal being treated, the clinical condition of the
individual patient, the cause of the disorder, the site of delivery
of the agent, the method of administration, the scheduling of
administration, and other factors known to medical practitioners. A
compound of formula I (or an embodiment thereof) need not be, but
is optionally formulated with one or more agent currently used to
prevent or treat the disorder in question. The effective amount of
such other agents depends on the amount of a compound of the
invention present in the formulation, the type of disorder or
treatment, and other factors discussed above.
[0160] These are generally used in the same dosages and with
administration routes as described herein, or about from 1 to 99%
of the dosages described herein, or in any dosage and by any route
that is empirically/clinically determined to be appropriate.
[0161] For the prevention or treatment of disease, the appropriate
dosage of a compound of formula I (or an embodiment thereof) (when
used alone or in combination with other agents) will depend on the
type of disease to be treated, the properties of the compound, the
severity and course of the disease, whether the compound is
administered for preventative or therapeutic purposes, previous
therapy, the patient's clinical history and response to the
compound, and the discretion of the attending physician. The
compound is suitably administered to the patient at one time or
over a series of treatments. Depending on the type and severity of
the disease, about 1 .mu.g/kg to 15 mg/kg (e.g., 0.1 mg/kg-10
mg/kg) of compound can be an initial candidate dosage for
administration to the patient, whether, for example, by one or more
separate administrations, or by continuous infusion. One typical
daily dosage might range from about 1 .mu.g kg to 100 mg/kg or
more, depending on the factors mentioned above. For repeated
administrations over several days or longer, depending on the
condition, the treatment would generally be sustained until a
desired suppression of disease symptoms occurs. One exemplary
dosage of a compound of formula I (or an embodiment thereof) would
be in the range from about 0.05 mg/kg to about 10 mg/kg. Thus, one
or more doses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg, or 10 mg/kg
(or any combination thereof) may be administered to the patient.
Such doses may be administered intermittently, e.g., every week or
every three weeks (e.g., such that the patient receives from about
two to about twenty, or, e.g., about six doses of the antibody). An
initial higher loading dose, followed by one or more lower doses
may be administered. An exemplary dosing regimen comprises
administering an initial loading dose of about 4 mg/kg, followed by
a weekly maintenance dose of about 2 mg kg of the compound.
However, other dosage regimens ma be useful. The progress of this
therapy is easily monitored by conventional techniques and
assays.
[0162] Other typical daily dosages might range from, for example,
about 1 g/kg to up to 100 mg/kg or more (e.g., about 1 .mu.g kg to
1 mg/kg, about 1 .mu.g/kg to about 5 mg/kg, about 1 mg kg to 10
mg/kg, about 5 mg/kg to about 200 mg/kg, about 50 mg/kg to about
150 mg/mg, about 100 mg/kg to about 500 mg/kg, about 100 mg/kg to
about 400 mg/kg, and about 200 mg/kg to about 400 mg/kg), depending
on the factors mentioned above. Typically, the clinician will
administer a compound until a dosage is reached that results in
improvement in or, optimally, elimination of, one or more symptoms
of the treated disease or condition. The progress of this therapy
is easily monitored by conventional assays. One or more agent
provided herein may be administered together or at different times
(e.g., one agent is administered prior to the administration of a
second agent). One or more agent may be administered to a subject
using different techniques (e.g., one agent may be administered
orally, while a second agent is administered via intramuscular
injection or intranasally). One or more agent may be administered
such that the one or more agent as a pharmacologic effect in a
subject at the same time. Alternatively, one or more agent may be
administered, such that the pharmacological activity of the first
administered agent is expired prior the administration of one or
more secondarily administered agents (e.g., 1, 2, 3, or 4
secondarily administered agents).
Indications and Methods of Treatment
[0163] The compounds of the invention modulate, preferably inhibit,
ion flux through a voltage-dependent sodium channel in a mammal,
(e.g. a human). Any such modulation, whether it be partial or
complete inhibition or prevention of ion flux, is sometimes
referred to herein as "blocking" and corresponding compounds as
"blockers" or "inhibitors". In general, the compounds of the
invention modulate the activity of a sodium channel downwards by
inhibiting the voltage-dependent activity of the sodium channel,
and/or reduce or prevent sodium ion flux across a cell membrane by
preventing sodium channel activity such as ion flux.
[0164] The compounds of the invention inhibit the ion flux through
a voltage-dependent sodium channel. In one aspect, the compounds
are state or frequency dependent modifers of the sodium channels,
having a low affinity for the rested/closed state and a high
affinity for the inactivated state. Without being bound by any
particular theory, it is thought that these compounds are likely to
interact with overlapping sites located in the inner cavity of the
sodium conducting pore of the channel similar to that described for
other state-dependent sodium channel blockers (Cestele, S., et al.,
op. cit.). These compounds may also be likely to interact with
sites outside of the inner cavity and have allosteric effects on
sodium ion conduction through the channel pore.
[0165] Any of these consequences may ultimately be responsible for
the overall therapeutic benefit provided by these compounds.
[0166] Accordingly, the compounds of the invention are sodium
channel blockers and are therefore useful for treating diseases and
conditions in mammals, for example humans, and other organisms,
including all those diseases and conditions which are the result of
aberrant voltage-dependent sodium channel biological activity or
which may be ameliorated by modulation of voltage-dependent sodium
channel biological activity. In particular, the compounds of the
invention, i.e., the compounds of formula (I) and embodiments and
(or stereoisomers, geometric isomers, tautomers, solvates,
metabolites, isotopes, pharmaceutically acceptable salts, or
prodrugs thereof), are useful for treating diseases and conditions
in mammals, for example humans, which are the result of aberrant
voltage-dependent NaV1.7 biological activity or which may be
ameliorated by the modulation, preferably the inhibition, of NaV1.7
biological activity. In certain aspects, the compounds of the
invention selectively NaV1.7 over NaV1.5.
[0167] As defined herein, a sodium channel-mediated disease or
condition refers to a disease or condition in a mammal, preferably
a human, which is ameliorated upon modulation of the sodium channel
and includes, but is not limited to, pain, central nervous
conditions such as epilepsy, anxiety, depression and bipolar
disease; cardiovascular conditions such as arrhythmias, atrial
fibrillation and ventricular fibrillation; neuromuscular conditions
such as restless leg syndrome and muscle paralysis or tetanus;
neuroprotection against stroke, neural trauma and multiple
sclerosis; and channelopathies such as erythromyalgia and familial
rectal pain syndrome.
[0168] In one aspect, the present invention relates to compounds,
pharmaceutical compositions and methods of using the compounds and
pharmaceutical compositions for the treatment of sodium
channel-mediated diseases in mammals, preferably humans and
preferably diseases and conditions related to pain, central nervous
conditions such as epilepsy, anxiety, depression and bipolar
disease; cardiovascular conditions such as arrhythmias, atrial
fibrillation and ventricular fibrillation; neuromuscular conditions
such as restless leg syndrome and muscle paralysis or tetanus;
neuroprotection against stroke, neural trauma and multiple
sclerosis; and channelopathies such as erythromyalgia and familial
rectal pain syndrome, by administering to a mammal, for example a
human, in need of such treatment an effective amount of a sodium
channel blocker modulating, especially inhibiting, agent.
[0169] A sodium channel-mediated disease or condition also includes
pain associated with HIV, HIV treatment induced neuropathy,
trigeminal neuralgia, glossopharyngeal neuralgia, neuropathy
secondary to metastatic infiltration, adiposis dolorosa, thalamic
lesions, hypertension, antoimmune disease, asthma, drug addiction
(e.g., opiate, benzodiazepine, amphetamine, cocaine, alcohol,
butane inhalation), Alzheimer, dementia, age-related memory
impairment, Korsakoff syndrome, restenosis, urinary dysfunction,
incontinence, Parkinson's disease, cerebrovascular ischemia,
neurosis, gastrointestinal disease, sickle cell anemia, transplant
rejection, heart failure, myocardial infarction, reperfusion
injury, intermittant claudication, angina, convulsion, respiratory
disorders, cerebral or myocardial ischemias, long-QT syndrome,
Catecholeminergic polymorphic ventricular tachycardia, ophthalmic
diseases, spasticity, spastic paraplegia, myopathies, myasthenia
gravis, paramyotonia congentia, hyperkalemic periodic paralysis,
hypokalemic periodic paralysis, alopecia, anxiety disorders,
psychotic disorders, mania, paranoia, seasonal affective disorder,
panic disorder, obsessive compulsive disorder (OCD), phobias,
autism, Aspergers Syndrome, Retts syndrome, disintegrative
disorder, attention deficit disorder, aggressivity, impulse control
disorders, thrombosis, pre clampsia, congestive cardiac failure,
cardiac arrest, Freidrich's ataxia, Spinocerebellear ataxia,
myelopathy, radiculopathy, systemic lupus erythamatosis,
granulomatous disease, olivo-ponto-cerebellar atrophy,
spinocerebellar ataxia, episodic ataxia, myokymia, progressive
pallidal atrophy, progressive supranuclear palsy and spasticity,
traumatic brain injury, cerebral oedema, hydrocephalus injury,
spinal cord injury, anorexia nervosa, bulimia, Prader-Willi
syndrome, obesity, optic neuritis, cataract, retinal haemorrhage,
ischaemic retinopathy, retinitis pigmentosa, acute and chronic
glaucoma, macular degeneration, retinal artery occlusion, Chorea,
Huntington's chorea, cerebral edema, proctitis, post-herpetic
neuralgia, eudynia, heat sensitivity, sarcoidosis irritable bowel
syndrome, Tourette syndrome, Lesch-Nyhan Syndrome, Brugado
syndrome, Liddle syndrome, Crohns disease, multiple sclerosis and
the pain associated with multiple sclerosis (MS), amyotrophic
lateral sclerosis (ALS), disseminated sclerosis, diabetic
neuropathy, peripheral neuropathy, charcot marie tooth syndrome,
arthritic, rheumatoid arthritis, osteoarthritis, chondrocalcinosis,
atherosclerosis, paroxysmal dystonia, myasthenia syndromes,
myotonia, myotonic dystrophy, muscular dystrophy, malignant
hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis,
mental handicap, hypothyroidism, bipolar depression, anxiety,
schizophrenia, sodium channel toxin related illnesses, familial
erythromelalgia, primary erythromelalgia, rectal pain, cancer,
epilepsy, partial and general tonic seizures, febrile seizures,
absence seizures (petit mal), myoclonic seizures, atonic seizures,
clonic seizures, Lennox Gastaut, West Syndome (infantile spasms),
multiresistant seizures, seizure prophylaxis (anti-epileptogenic),
familial Mediterranean fever syndrome, gout, restless leg syndrome,
arrhythmias, fibromyalgia, neuroprotection under ischaemic
conditions caused by stroke or neural trauma, tachy-arrhythmias,
atrial fibrillation and ventricular fibrillation and as a general
or local anaesthetic.
[0170] As used herein, the term "pain" refers to all categories of
pain and is recognized to include, but is not limited to,
neuropathic pain, inflammatory pain, nociceptive pain, idiopathic
pain, neuralgic pain, orafacial pain, burn pain, burning mouth
syndrome, somatic pain, visceral pain, myofacial pain, dental pain,
cancer pain, chemotherapy pain, trauma pain, surgical pain,
post-surgical pain, childbirth pain, labor pain, chronic regional
pain syndrome (CRPS), reflex sympathetic dystrophy, brachial plexus
avulsion, neurogenic bladder, acute pain (e.g., musculoskeletal and
post-operative pain), chronic pain, persistent pain, peripherally
mediated pain, centrally mediated pain, chronic headache, migraine
headache, familial hemiplegic migraine, conditions associated with
cephalic pain, sinus headache, tension headache, phantom limb pain,
peripheral nerve injury, pain following stroke, thalamic lesions,
radiculopathy, HIV pain, post-herpetic pain, non-cardiac chest
pain, irritable bowel syndrome and pain associated with bowel
disorders and dyspepsia, and combinations thereof.
[0171] Furthermore, sodium channel blockers have clinical uses in
addition to pain. The present invention therefore also relates to
compounds, pharmaceutical compositions and methods of using the
compounds and pharmaceutical compositions for the treatment of
diseases or conditions such as cancer and pruritus (itch).
[0172] Pruritus, commonly known as itch, is a common dermatological
condition. While the exact causes of pruritus are complex and
incompletely understood, there has long been evidence that itch
involves sensory neurons, especially C fibers, similar to those
that mediate pain (Schmelz, M., et al., Neurosci. (1997), 17:
8003-8). In particular, it is believed that sodium influx through
voltage-gated sodium channels is essential for the propagation of
itch sensation from the skin. Transmission of the itch impulses
results in the unpleasant sensation that elicits the desire or
reflex to scratch.
[0173] Multiple causes and electrical pathways for eliciting itch
are known. In humans, pruritis can be elicited by histamine or
PAR-2 agonists such as mucunain that activate distinct populations
of C fibers (Namer, B., et al., J. Neurophysiol. (2008),100:
2062-9). A variety of neurotrophic peptides are known to mediate
itch in animal models (Wang, H., and Yosipovitch, G., International
Journal of Dermatology (2010), 49: 1-11). Itch can also be elicited
by opioids, evidence of distinct pharmacology from that of pain
responses.
[0174] There exists a complex interaction between itch and pain
responses that arises in part from the overlapping sensory input
from the skin (Ikoma, A., et al., Arch. Dermatol. (2003),139:
1475-8) and also from the diverse etiology of both pain and
pruritis. Pain responses can exacerbate itching by enhancing
central sensitization or lead to inhibition of painful scratching.
Particularly severe forms of chronic itch occur when pain responses
are absent, as in the case of post-herpetic itch (Oaklander, A. L.,
et al., Pain (2002), 96: 9-12).
[0175] The compounds of the invention can also be useful the
treating pruritus. The rationale for treating itch with inhibitors
of voltage-gated sodium channels, especially NaV1.7, is as
follows:
[0176] The propagation of electrical activity in the C fibers that
sense pruritinergic stimulants requires sodium entry through
voltage-gated sodium channels.
[0177] NaV1.7 is expressed in the C fibers and kerotinocytes in
human skin (Zhao, P., et al., Pain (2008), 139: 90-105).
[0178] A gain of function mutation of NaV1.7 (L858F) that causes
erythromelalgia also causes chronic itch (Li, Y., et al., Clinical
and Experimental Dermatology (2009), 34: e313-e4).
[0179] Chronic itch can be alleviated with treatment by sodium
channel blockers, such as the local anesthetic lidocaine
(Oaklander, A. L., et al., Pain (2002), 96: 9-12; Villamil, A. G.,
et al. The American Journal of Medicine (2005), 118: 1160-3). In
these reports, lidocaine was effective when administered either
intravenously or topically (a Lidoderm patch). Lidocaine can have
multiple activities at the plasma concentrations achieved when
administered systemically, but when administered topically, the
plasma concentrations are only about 1 .mu.M (Center for Drug
Evaluation and Research NDA 20-612). At these concentrations,
lidocaine is selective for sodium channel block and inhibits
spontaneous electrical activity in C fibers and pain responses in
animal models (Xiao, W. H., and Bennett, G. J., Pain (2008), 137:
218-28). The types of itch or skin irritation, include, but are not
limited to:
[0180] psoriatic pruritus, itch due to hemodyalisis, aguagenic
pruritus, and itching caused by skin disorders (e.g., contact
dermatitis), systemic disorders, neuropathy, psychogenic factors or
a mixture thereof:
[0181] itch caused by allergic reactions, insect bites,
hypersensitivity (e.g., dry skin, acne, eczema, psoriasis),
inflammatory conditions or injury;
[0182] itch associated with vulvar vestibulitis; and
[0183] skin irritation or inflammatory effect from administration
of another therapeutic such as, for example, antibiotics,
antivirals and antihistamines.
[0184] The compounds of the invention are also useful in treating
certain cancers, such as hormone sensitive cancers, such as
prostate cancer (adenocarcinoma), breast cancer, ovarian cancer,
testicular cancer and thyroid neoplasia, in a mammal, preferably a
human. The voltage gated sodium channels have been demonstrated to
be expressed in prostate and breast cancer cells. Up-regulation of
neonatal NaV1.5 occurs as an integral part of the metastatic
process in human breast cancer and could serve both as a novel
marker of the metastatic phenotype and a therapeutic target (Clin.
Cancer Res. (2005), August 1; 11(15): 5381-9). Functional
expression of voltage-gated sodium channel alpha-subunits,
specifically NaV1.7, is associated with strong metastatic potential
in prostate cancer (CaP) in vitro. Voltage-gated sodium channel
alpha-subunits immunostaining, using antibodies specific to the
sodium channel alpha subunit was evident in prostatic tissues and
markedly stronger in CaP vs non-CaP patients (Prostate Cancer
Prostatic Dis., 2005; 8(3): 266-73). See also Diss, J. K. J., et
al., Mol. Cell. Neurosci. (2008), 37:537-547 and Kis-Toth, K., et
al., The Journal of Immunology (2011), 187:1273-1280.
[0185] In consideration of the above, in one embodiment, the
present invention provides a method for treating a mammal for, or
protecting a mammal from developing, a sodium channel-mediated
disease, especially pain, comprising administering to the mammal,
especially a human, in need thereof, a therapeutically effective
amount of a compound of the invention or a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of the invention wherein the compound modulates the
activity of one or more voltage-dependent sodium channels.
[0186] In another embodiment of the invention is a method of
treating a disease or a condition in a mammal, preferably a human,
wherein the disease or condition is selected from the group
consisting of pain, depression, cardiovascular diseases,
respiratory diseases, and psychiatric diseases, and combinations
thereof, and wherein the method comprises administering to the
mammal in need thereof a therapeutically effective amount of an
embodiment of a compound of the invention, as set forth above, as a
stereoisomer, enantiomer or tautomer thereof or mixtures thereof,
or a pharmaceutically acceptable salt, solvate or prodrug thereof,
or a pharmaceutical composition comprising a therapeutically
effective amount of a compound of the invention, as set forth
above, as a stereoisomer, enantiomer or tautomer thereof or
mixtures thereof, or a pharmaceutically acceptable salt, solvate or
prodrug thereof, and a pharmaceutically acceptable excipient.
[0187] One embodiment of this embodiment is wherein the disease or
condition is selected from the group consisting of neuropathic
pain, inflammatory pain, visceral pain, cancer pain, chemotherapy
pain, trauma pain, surgical pain, post surgical pain, childbirth
pain, labor pain, neurogenic bladder, ulcerative colitis, chronic
pain, persistent pan, peripherally mediated pain, centrally
mediated pain, chronic headache, migraine headache, sinus headache,
tension headache, phantom limb pain, peripheral nerve injury, and
combinations thereof.
[0188] Another embodiment of this embodiment is wherein the disease
or condition is selected from the group consisting of pain
associated with HIV, HIV treatment induced neuropathy, trigeminal
neuralgia, post herpetic neuralgia, eudynia, heat sensitivity,
tosarcoidosis, irritable bowel syndrome, Crohns disease, pain
associated with multiple sclerosis (MS), amyotrophic lateral
sclerosis (ALS), diabetic neuropathy, peripheral neuropathy,
arthritic, rheumatoid arthritis, osteoarthritis, atherosclerosis,
paroxysmal dystonia, myasthenia syndromes, myotonia, malignant
hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis,
hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium
channel toxin related illnesses, familial erythromelalgia, primary
erythromelalgia, familial rectal pain, cancer, epilepsy, partial
and general tonic seizures, restless leg syndrome, arrhythmias,
fibromyalgia, neuroprotection under ischaemic conditions caused by
stroke or neural trauma, tachy arrhythmias, atrial fibrillation and
ventricular fibrillation.
[0189] Another embodiment of the invention is a method of treating,
but not preventing, pain in a mammal, wherein the method comprises
administering to the mammal in need thereof therapeutically
effective amount of a compound of the invention, as set forth
above, as a stereoisomer, enantiomer or tautomer thereof or
mixtures thereof, or a pharmaceutically acceptable salt, solvate or
prodrug thereof, or a pharmaceutical composition comprising a
therapeutically effective amount of a compound of the invention, as
set forth above, as a stereoisomer, enantiomer or tautomer thereof
or mixtures thereof, or a pharmaceutically acceptable salt, solvate
or prodrug thereof, and a pharmaceutically acceptable
excipient.
[0190] One embodiment of this embodiment is a method wherein the
pain is selected from the group consisting of neuropathic pain,
inflammatory pain, visceral pain, cancer pain, chemotherapy pain,
trauma pain, surgical pain, post surgical pain, childbirth pain,
labor pain, dental pain, chronic pain, persistent pain,
peripherally mediated pain, centrally mediated pain, chronic
headache, migraine headache, sinus headache, tension headache,
phantom limb pain, peripheral nerve injury, trigeminal neuralgia,
post herpetic neuralgia, eudynia, familial erythromelalgia, primary
erythromelalgia, familial rectal pain or fibromyalgia, and
combinations thereof.
[0191] Another embodiment of this embodiment is a method wherein
the pain is associated with a disease or condition selected from
HIV, HIV treatment induced neuropathy, heat sensitivity,
tosarcoidosis, irritable bowel syndrome, Crohns disease, multiple
sclerosis, amyotrophic lateral sclerosis, diabetic neuropathy,
peripheral neuropathy, rheumatoid arthritis, osteoarthritis,
atherosclerosis, paroxysmal dystonia, myasthenia syndromes,
myotonia, malignant hyperthermia, cystic fibrosis,
pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar
depression, anxiety, schizophrenia, sodium channel toxin related
illnesses, neurogenic bladder, ulcerative colitis, cancer,
epilepsy, partial and general tonic seizures, restless leg
syndrome, arrhythmias, ischaemic conditions caused by stroke or
neural trauma, tachy arrhythmias, atrial fibrillation and
ventricular fibrillation.
[0192] Another embodiment of the invention is the method of
treating pain in a mammal, preferably a human, by the inhibition of
flux through a voltage dependent sodium channel in the mammal,
wherein the method comprises administering to the mammal in need
thereof a therapeutically effective amount of an embodiment of a
compound of the invention, as set forth above, as a stereoisomer,
enantiomer or tautomer thereof or mixtures thereof, or a
pharmaceutically acceptable salt, solvate or prodrug thereof, or a
pharmaceutical composition comprising a therapeutically effective
amount of a compound of the invention, as set forth above, as a
stereoisomer, enantiomer or tautomer thereof or mixtures thereof,
or a pharmaceutically acceptable salt, solvate or prodrug thereof,
and a pharmaceutically acceptable excipient.
[0193] Another embodiment of the invention is the method of
treating pruritus in a mammal, preferably a human, wherein the
method comprises administering to the mammal in need thereof a
therapeutically effective amount of an embodiment of a compound of
the invention, as set forth above, as a stereoisomer, enantiomer or
tautomer thereof or mixtures thereof, or a pharmaceutically
acceptable salt, solvate or prodrug thereof, or a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of the invention, as set forth above, as a stereoisomer,
enantiomer or tautomer thereof or mixtures thereof, or a
pharmaceutically acceptable salt, solvate or prodrug thereof, and a
pharmaceutically acceptable excipient.
[0194] Another embodiment of the invention is the method of
treating cancer in a mammal, preferably a human, wherein the method
comprises administering to the mammal in need thereof a
therapeutically effective amount of an embodiment of a compound of
the invention, as set forth above, as a stereoisomer, enantiomer or
tautomer thereof or mixtures thereof, or a pharmaceutically
acceptable salt, solvate or prodrug thereof, or a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of the invention, as set forth above, as a stereoisomer,
enantiomer or tautomer thereof or mixtures thereof, or a
pharmaceutically acceptable salt, solvate or prodrug thereof, and a
pharmaceutically acceptable excipient.
[0195] Another embodiment of the invention is the method of
decreasing ion flux through a voltage dependent sodium channel in a
cell in a mammal, wherein the method comprises contacting the cell
with an embodiment of a compound of the invention, as set forth
above, as a stereoisomer, enantiomer or tautomer thereof or
mixtures thereof, or a pharmaceutically acceptable salt, solvate or
prodrug thereof.
[0196] Another embodiment of the invention is the method of
selectively inhibiting a first voltage-gated sodium channel over a
second voltage-gated sodium channel in a mammal, wherein the method
comprises administering to the mammal an inhibitory amount of a
compound of formula (I), or an embodiment of a compound of formula
(I).
[0197] Another embodiment of the invention is the method of
selectively inhibiting NaV1.7 in a mammal or a mammalian cell as
compared to NaV1.5, wherein the method comprises administering to
the mammal in need thereof an inhibitory amount of a compound of
formula (I) or an embodiment of an embodiment thereof.
[0198] For each of the above embodiments described related to
treating diseases and conditions in a mammal, the present invention
also contemplates relatedly a compound of formula I or an
embodiment thereof for the use as a medicament in the treatment of
such diseases and conditions.
[0199] For each of the above embodiments described related to
treating diseases and conditions in a mammal, the present invention
also contemplates relatedly the use of a compound of formula I or
an embodiment thereof for the manufacture of a medicament for the
treatment of such diseases and conditions.
[0200] Another embodiment of the invention is a method of using the
compounds of formula (I) as standards or controls in in vitro or in
vivo assays in determining the efficacy of test compounds in
modulating voltage-dependent sodium channels.
[0201] In another embodiment of the invention, the compounds of
formula (I) are isotopically-labeled by having one or more atoms
therein replaced by an atom having a different atomic mass or mass
number. Such isotopically-labeled (i.e., radiolabelled) compounds
of formula (I) are considered to be within the scope of this
invention. Examples of isotopes that can be incorporated into the
compounds of formula (I) include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and
iodine, such as, but not limited to, .sup.2H, .sup.3H, .sup.11C,
.sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O, .sup.17O,
.sup.18O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, .sup.36Cl,
.sup.123I, and .sup.125I, respectively. These isotopically-labeled
compounds would be useful to help determine or measure the
effectiveness of the compounds, by characterizing, for example, the
site or mode of action on the sodium channels, or binding affinity
to pharmacologically important site of action on the sodium
channels, particularly NaV1.7. Certain isotopically-labeled
compounds of formula (I), for example, those incorporating a
radioactive isotope, are useful in drug and/or substrate tissue
distribution studies. The radioactive isotopes tritium, i.e.
.sup.3H, and carbon-14, i.e., .sup.14C, are particularly useful for
this purpose in view of their ease of incorporation and ready means
of detection.
[0202] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
[0203] Substitution with positron emitting isotopes, such as
.sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy. Isotopically-labeled compounds of formula (I)
can generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the Examples as set out below using an appropriate
isotopically-labeled reagent in place of the non-labeled reagent
previously employed.
Testing Compounds
[0204] The assessment of the compounds of the invention in
mediating, especially inhibiting, the sodium channel ion flux can
be determined using the assays described hereinbelow.
Alternatively, the assessment of the compounds in treating
conditions and diseases in humans may be established in industry
standard animal models for demonstrating the efficacy of compounds
in treating pain. Animal models of human neuropathic pain
conditions have been developed that result in reproducible sensory
deficits (allodynia, hyperalgesia, and spontaneous pain) over a
sustained period of time that can be evaluated by sensory testing.
By establishing the degree of mechanical, chemical, and temperature
induced allodynia and hyperalgesia present, several
physiopathological conditions observed in humans can be modeled
allowing the evaluation of pharmacotherapies.
[0205] In rat models of peripheral nerve injury, ectopic activity
in the injured nerve corresponds to the behavioural signs of pain.
In these models, intravenous application of the sodium channel
blocker and local anesthetic lidocaine can suppress the ectopic
activity and reverse the tactile allodynia at concentrations that
do not affect general behaviour and motor function (Mao, J. and
Chen, L. L., Pain (2000), 87:7-17). Allometric scaling of the doses
effective in these rat models, translates into doses similar to
those shown to be efficacious in humans (Tanelian, D. L. and Brose,
W. G., Anesthesiology (1991), 74(5):949-951). Furthermore,
Lidoderm.RTM., lidocaine applied in the form of a dermal patch, is
currently an FDA approved treatment for post-herpetic neuralgia
(Devers, A. and Glaler, B. S., Clin. J. Pain (2000),
16(3):205-8).
[0206] The present invention readily affords many different means
for identification of sodium channel modulating agents that are
useful as therapeutic agents. Identification of modulators of
sodium channel can be assessed using a variety of in vitro and in
vivo assays, e.g., measuring current, measuring membrane potential,
measuring ion flux, (e.g., sodium or guanidinium), measuring sodium
concentration, measuring second messengers and transcription
levels, and using e.g., voltage-sensitive dyes, radioactive
tracers, and patch-clamp electrophysiology.
[0207] One such protocol involves the screening of chemical agents
for ability to modulate the activity of a sodium channel thereby
identifying it as a modulating agent.
[0208] A typical assay described in Bean et al., J. General
Physiology (1983), 83:613-642, and Leuwer, M., et al., Br. J.
Pharmacol (2004), 141(1):47-54, uses patch-clamp techniques to
study the behaviour of channels. Such techniques are known to those
skilled in the art, and may be developed, using current
technologies, into low or medium throughput assays for evaluating
compounds for their ability to modulate sodium channel
behaviour.
[0209] Throughput of test compounds is an important consideration
in the choice of screening assay to be used. In some strategies,
where hundreds of thousands of compounds are to be tested, it is
not desirable to use low throughput means. In other cases, however,
low throughput is satisfactory to identify important differences
between a limited number of compounds. Often it will be necessary
to combine assay types to identify specific sodium channel
modulating compounds.
[0210] Electrophysiological assays using patch clamp techniques is
accepted as a gold standard for detailed characterization of sodium
channel compound interactions, and as described in Bean et al., op.
cit. and Leuwer, M., et al., op. cit. There is a manual
low-throughput screening (LTS) method which can compare 2-10
compounds per day; a recently developed system for automated
medium-throughput screening (MTS) at 20-50 patches (i.e. compounds)
per day; and a technology from Molecular Devices Corporation
(Sunnyvale, Calif.) which permits automated high-throughput
screening (HTS) at 1000-3000 patches (i.e. compounds) per day.
[0211] One automated patch-clamp system utilizes planar electrode
technology to accelerate the rate of drug discovery. Planar
electrodes are capable of achieving high-resistance, cells-attached
seals followed by stable, low-noise whole-cell recordings that are
comparable to conventional recordings. A suitable instrument is the
PatchXpress 7000A (Axon Instruments Inc, Union City, Calif.). A
variety of cell lines and culture techniques, which include
adherent cells as well as cells growing spontaneously in suspension
are ranked for seal success rate and stability. Immortalized cells
(e.g. HEK and CHO) stably expressing high levels of the relevant
sodium ion channel can be adapted into high-density suspension
cultures.
[0212] Other assays can be selected which allow the investigator to
identify compounds which block specific states of the channel, such
as the open state, closed state or the resting state, or which
block transition from open to closed, closed to resting or resting
to open. Those skilled in the art are generally familiar with such
assays.
[0213] Binding assays are also available. Designs include
traditional radioactive filter based binding assays or the confocal
based fluorescent system available from Evotec OAI group of
companies (Hamburg, Germany), both of which are HTS.
[0214] Radioactive flux assays can also be used. In this assay,
channels are stimulated to open with veratridine or aconitine and
held in a stabilized open state with a toxin, and channel blockers
are identified by their ability to prevent ion influx. The assay
can use radioactive 22[Na] and 14[C] guanidinium ions as tracers.
FlashPlate & Cytostar-T plates in living cells avoids
separation steps and are suitable for HTS. Scintillation plate
technology has also advanced this method to HTS suitability.
Because of the functional aspects of the assay, the information
content is reasonably good.
[0215] Yet another format measures the redistribution of membrane
potential using the FLIPR system membrane potential kit (HTS)
available from Molecular Dynamics (a division of Amersham
Biosciences, Piscataway, N.J.). This method is limited to slow
membrane potential changes. Some problems may result from the
fluorescent background of compounds. Test compounds may also
directly influence the fluidity of the cell membrane and lead to an
increase in intracellular dye concentrations. Still, because of the
functional aspects of the assay, the information content is
reasonably good.
[0216] Sodium dyes can be used to measure the rate or amount of
sodium ion influx through a channel. This type of assay provides a
very high information content regarding potential channel blockers.
The assay is functional and would measure Na+ influx directly.
CoroNa Red, SBFI and/or sodium green (Molecular Probes, Inc. Eugene
Oreg.) can be used to measure Na influx; all are Na responsive
dyes. They can be used in combination with the FLIPR instrument.
The use of these dyes in a screen has not been previously described
in the literature. Calcium dyes may also have potential in this
format.
[0217] In a another assay, FRET based voltage sensors are used to
measure the ability of a test compound to directly block Na influx.
Commercially available HTS systems include the VIPR.TM. II FRET
system (Life Technologies, or Aurora Biosciences Corporation, San
Diego, Calif., a division of Vertex Pharmaceuticals, Inc.) which
may be used in conjunction with FRET dyes, also available from
Aurora Biosciences. This assay measures sub-second responses to
voltage changes. There is no requirement for a modifier of channel
function. The assay measures depolarization and hyperpolarizations,
and provides ratiometric outputs for quantification. A somewhat
less expensive MTS version of this assay employs the
FLEXstation.TM. (Molecular Devices Corporation) in conjunction with
FRET dyes from Aurora Biosciences. Other methods of testing the
compounds disclosed herein are also readily known and available to
those skilled in the art.
[0218] Modulating agents so identified are then tested in a variety
of in vivo models so as to determine if they alleviate pain,
especially chronic pain or other conditions such as cancer and
pruritus (itch) with minimal adverse events. The assays described
below in the Biological Assays Section are useful in assessing the
biological activity of the instant compounds.
[0219] Typically, the efficacy of a compound of the invention is
expressed by its IC50 value ("Inhibitory Concentration--50%"),
which is the measure of the amount of compound required to achieve
50% inhibition of the activity of the target sodium channel over a
specific time period. For example, representative compounds of the
present invention have demonstrated IC50's ranging from less than
100 nanomolar to less than 10 micromolar in the patch voltage clamp
NaV1.7 electrophysiology assay described herein.
[0220] In another aspect of the invention, the compounds of the
invention can be used in in vitro or in vivo studies as exemplary
agents for comparative purposes to find other compounds also useful
in treatment of, or protection from, the various diseases disclosed
herein.
[0221] Another aspect of the invention relates to inhibiting
NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or
NaV1.9 activity, preferably NaV1.7 activity, in a biological sample
or a mammal, preferably a human, which method comprises
administering to the mammal, preferably a human, or contacting said
biological sample with a compound of formula (I) or a
pharmaceutical composition comprising a compound of formula (I).
The term "biological sample", as used herein, includes, without
limitation, cell cultures or extracts thereof; biopsied material
obtained from a mammal or extracts thereof; and blood, saliva,
urine, feces, semen, tears, or other body fluids or extracts
thereof.
[0222] Inhibition of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,
NaV1.6, NaV1.7, NaV1.8, or NaV1.9 activity in a biological sample
is useful for a variety of purposes that are known to one of skill
in the art. Examples of such purposes include, but are not limited
to, the study of sodium ion channels in biological and pathological
phenomena; and the comparative evaluation of new sodium ion channel
inhibitors.
[0223] The compounds of the invention (or stereoisomers, geometric
isomers, tautomers, solvates, metabolites, isotopes,
pharmaceutically acceptable salts, or prodrugs thereof) and/or the
pharmaceutical compositions described herein which comprise a
pharmaceutically acceptable excipient and one or more compounds of
the invention, can be, used in the preparation of a medicament for
the treatment of sodium channel-mediated disease or condition in a
mammal.
Combination Therapy
[0224] The compounds of the invention may be usefully combined with
one or more other compounds of the invention or one or more other
therapeutic agent or as any combination thereof, in the treatment
of sodium channel-mediated diseases and conditions. For example, a
compound of the invention may be administered simultaneously,
sequentially or separately in combination with other therapeutic
agents, including, but not limited to:
[0225] opiates analgesics, e.g., morphine, heroin, cocaine,
oxymorphine, levorphanol, levallorphan, oxycodone, codeine,
dihydrocodeine, propoxyphene, nalmefene, fentanyl, hydrocodone,
hydromorphone, meripidine, methadone, nalorphine, naloxone,
naltrexone, buprenorphine, butorphanol, nalbuphine and
pentazocine;
[0226] non-opiate analgesics, e.g., acetomeniphen, salicylates
(e.g., aspirin); nonsteroidal antiinflammatory drugs (NSAIDs),
e.g., ibuprofen, naproxen, fenoprofen, ketoprofen, celecoxib,
diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal
flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,
meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen,
nimesulide, nitroflurbiprofen, olsalazine, oxaprozin,
phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin and
zomepirac;
[0227] anticonvulsants, e.g., carbamazepine, oxcarbazepine,
lamotrigine, valproate, topiramate, gabapentin and pregabalin;
[0228] antidepressants such as tricyclic antidepressants, e.g.,
amitriptyline, clomipramine, despramine, imipramine and
nortriptyline;
[0229] COX-2 selective inhibitors, e.g., celecoxib, rofecoxib,
parecoxib, valdecoxib, deracoxib, etoricoxib, and lumiracoxib;
[0230] alpha-adrenergics, e.g., doxazosin, tamsulosin, clonidine,
guanfacine, dexmetatomidine, modafinil, and
4-amino-6,7-dimethoxy-2-(5-methane
sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)
quinazoline;
[0231] barbiturate sedatives, e.g., amobarbital, aprobarbital,
butabarbital, butabital, mephobarbital, metharbital, methohexital,
pentobarbital, phenobartital, secobarbital, talbutal, theamylal and
thiopental;
[0232] tachykinin (NK) antagonist, particularly NK-3, NK-2 or NK-1
antagonist, e.g., (oR,
9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9-methyl-5-(-
4-methylphenyl)-7H-[1,4]diazoc
ino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637),
5-[[2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl]ethoxy-3-(4-fluorophe-
nyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one
(MK-869), aprepitant, lanepitant, dapitant or
3-[[2-methoxy5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine
(2S,3S);
[0233] coal-tar analgesics, in particular paracetamol;
[0234] serotonin reuptake inhibitors, e.g., paroxetine, sertraline,
norfluoxetine (fluoxetine desmethyl metabolite), metabolite
demethylsertraline, '3 fluvoxamine, paroxetine, citalopram,
citalopram metabolite desmethylcitalopram, escitalopram,
d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin,
litoxetine, dapoxetine, nefazodone, cericlamine, trazodone and
fluoxetine;
[0235] noradrenaline (norepinephrine) reuptake inhibitors, e.g.,
maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,
tomoxetine, mianserin, buproprion, buproprion metabolite
hydroxybuproprion, nomifensine and viloxazine (Vivalan.RTM.)),
especially a selective noradrenaline reuptake inhibitor such as
reboxetine, in particular (S,S)-reboxetine, and venlafaxine
duloxetine neuroleptics sedative/anxiolytics;
[0236] dual serotonin-noradrenaline reuptake inhibitors, such as
venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,
clomipramine, clomipramine metabolite desmethylclomipramine,
duloxetine, milnacipran and imipramine;
[0237] acetylcholinesterase inhibitors such as donepezil;
[0238] 5-HT3 antagonists such as ondansetron;
[0239] metabotropic glutamate receptor (mGluR) antagonists;
[0240] local anaesthetic such as mexiletine and lidocaine;
[0241] corticosteroid such as dexamethasone;
[0242] antiarrhythimics, e.g., mexiletine and phenytoin;
[0243] muscarinic antagonists, e.g., tolterodine, propiverine,
tropsium t chloride, darifenacin, solifenacin, temiverine and
ipratropium;
[0244] cannabinoids;
[0245] vanilloid receptor agonists (e.g., resinferatoxin) or
antagonists (e.g., capsazepine);
[0246] sedatives, e.g., glutethimide, meprobamate, methaqualone,
and dichloralphenazone;
[0247] analytics such as benzodiazepines,
[0248] antidepressants such as mirtazapine,
[0249] topical agents (e.g., lidocaine, capsacin and
resiniferotoxin);
[0250] muscle relaxants such as benzodiazepines, baclofen,
carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol and
orphrenadine;
[0251] anti-histamines or H1 antagonists;
[0252] NMDA receptor antagonists;
[0253] 5-HT receptor agonists/antagonists;
[0254] PDEV inhibitors;
[0255] Tramadol.RTM.;
[0256] cholinergic (nicotine) analgesics;
[0257] alpha-2-delta ligands;
[0258] prostaglandin E2 subtype antagonists;
[0259] leukotriene B4 antagonists;
[0260] 5-lipoxygenase inhibitors; and
[0261] 5-HT3 antagonists.
[0262] Sodium channel-mediated diseases and conditions that may be
treated and/or prevented using such combinations include but not
limited to, pain, central and peripherally mediated, acute,
chronic, neuropathic as well as other diseases with associated pain
and other central nervous disorders such as epilepsy, anxiety,
depression and bipolar disease; or cardiovascular disorders such as
arrhythmias, atrial fibrillation and ventricular fibrillation;
neuromuscular disorders such as restless leg syndrome and muscle
paralysis or tetanus; neuroprotection against stroke, neural trauma
and multiple sclerosis; and channelopathies such as erythromyalgia
and familial rectal pain syndrome.
[0263] As used herein "combination" refers to any mixture or
permutation of one or more compounds of the invention and one or
more other compounds of the invention or one or more additional
therapeutic agent. Unless the context makes clear otherwise,
"combination" may include simultaneous or sequentially delivery of
a compound of the invention with one or more therapeutic agents.
Unless the context makes clear otherwise, "combination" may include
dosage forms of a compound of the invention with another
therapeutic agent. Unless the context makes clear otherwise,
"combination" may include routes of administration of a compound of
the invention with another therapeutic agent. Unless the context
makes clear otherwise, "combination" may include formulations of a
compound of the invention with another therapeutic agent. Dosage
forms, routes of administration and pharmaceutical compositions
include, but are not limited to, those described herein.
[0264] The invention will be more fully understood by reference the
following examples. They should not, however, be construed limiting
the scope of the invention.
EXAMPLES
[0265] These examples serve to provide guidance to a skilled
artisan to prepare and use the compounds, compositions and methods
of the invention. While particular embodiments of the present
invention are described, the skilled artisan will appreciate that
various changes and modifications can be made without departing
from the spirit and scope of the inventions.
[0266] The chemical reactions in the examples described can be
readily adapted to prepare a number of other compounds of the
invention, and alternative methods for preparing the compounds of
this invention are deemed to be within the scope of this invention.
For example, the synthesis of non-examplified compounds according
to the invention can be successfully performed by modifications
apparent to those skilled in the art, for example, by appropriately
protecting interferring group, by utilizing other suitable reagents
known in the art, for example, by appropriately protecting
interferring groups by utilizing other suitable reagents known in
the art other than those described, and/or by making routine
modifications of reaction conditions.
[0267] In the examples below, unless otherwise indicated all
temperatures are set forth in degrees Celsius. Commercially aviable
reagents were purchased from suppliers such as Aldrich Chemical
Company, Lancaster, TCI or Maybridge and were used without further
purification unless otherwise indicated. The reactions set forth
below were done generally under a positive pressure of nitrogen or
argon or with a drying tube (unless otherwise stated) in anhydrous
solvents, and the reaction flasks were typically fitted with rubber
septa for the introduction of substrates and reagents via syringe.
Glassware was oven dried and/or heat dried. .sup.1H NMR spectra
were obtained in deuterated CDCl.sub.3, d.sub.6-DMSO, CH.sub.3OD or
d.sub.6-acetone solvent solutions (reported in ppm) using or
trimethylsilane (TMS) or residual non-deuterated solvent peaks as
the reference standard. When peak multiplicities are reported, the
following abbreviates are used: s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet, br (broadened), dd (doublet
of doublets), dt (doublet of triplets). Coupling constants, when
given, ar reported in Hz, (Hertz).
[0268] All abbreviations used to describe reagents, reaction
conditions or equipment are intended to be consistent with the
definitions set forth in the "List of standard abbreviates and
acronyms". The chemical names of discrete compounds of the
invention were obtained using the structure naming feature of
ChemDraw naming program.
LCMS Analytical Methods
[0269] Final compounds were analyzed using three different LC/MS
conditions, with UV detector monitoring at 214 nm and 254 nm, and
mass spectrometry scanning 110-800 amu in ESI+ ionization mode.
[0270] LC/MS Method A (8.0 min LC-MS Run): XBridge C18 column
(4.6.times.50 mm, 3.5 .mu.m, 40.degree. C.); mobile phase: A=10 mM
ammonium hydrogen carbonate in water, B-=acetonitrile; gradient:
0.0-8.0 min, 5%-95% B; flow rate=1.2 mL/min.
[0271] LC/MS Method B (8.0 min LC-MS Run): XBridge, C18 column
(4.6.times.50 mm, 3.5 .mu.m, 40.degree. C.); mobile phase: A=0.1%
ammonia in water, B=acetonitrile; gradient: 0.0-8.0 min, 5%-95% B;
flow rate=1.2 mL/min.
[0272] LC/MS Method C (8.0 min LC-MS Run): XBridge C18 column
(4.6.times.50 mm, 3.5 .mu.m, 40.degree. C.); mobile phase: A=0.1%
TFA in water, B=acetonitrile; gradient: 0.0-8.0 min, 5%-95% B; flow
rate=1.2 mL/min.
[0273] LC/MS Method D: Agilent SB C18, 2.1.times.30 min, 1.8 .mu.m;
mobile phase: A water (0.05TFA), B CH.sub.3CN (0.05% TFA);
gradient: 3% B (0.3 min), followed by 3-95% B (6.5 min), 95% B (1.5
min); flow rate: 0.4 ml/min; oven temperature 25.degree. C.
[0274] LC/MS Method E: Acquity BEH C18, 2.1.times.50 mm, 1.8 .mu.m;
mobile phase: A water (0.1% FA), B CH.sub.3CN (0.1% FA); gradient:
3% B (0.4 min), followed by 3-95% B (7.5 min), 95% B (0.5 min);
flow rate: 0.5 mL/min; oven temperature 25.degree. C.
[0275] LC/MS Method F: Agilent SB C18, 2.1.times.30 mm, 1.8 .mu.m;
mobile phase: A water (0.05% TFA), B CH.sub.3CN (05% TFA);
gradient: 3% B (0.3 min), followed by 3-95% B (6.5 min), 95% B (1.5
min); flow rate: 0.4 mL/min; oven temperature 25.degree. C.
[0276] LC/MS Method G: Acquity BEH C18, 2.1.times.50 mm, 1.8 .mu.m;
mobile phase: A water (0.1% FA), B CH.sub.3CN (0.1% FA); gradient:
3% B (0.4 min), followed by 3-95% B (7.5 min), 95% B (0.5 min);
flow rate: 0.5 mL/min; oven temperature 25.degree. C.
Abbreviations
[0277] MeCN Acetonitrile [0278] EtOAc Ethyl acetate [0279] DCE
Dichloroethane [0280] DCM Dichloromethane [0281] DIPEA
Diisopropylethylamine [0282] DEA Diethylamine [0283] DMAP
4-dimethylaminopyridine [0284] DMF N,N-Dimethylformamide [0285]
DMSO Dimethyl sulfoxide [0286] FA Formic acid [0287] IPA Isopropyl
alcohol [0288] TFA Trifluoroacetic acid [0289] EDCl
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride [0290]
HCl Hydrochloric acid [0291] HPLC High Pressure Liquid
Chromatography [0292] LCMS Liquid Chromatography Mass Spectrometry
[0293] MeOH Methanol [0294] NMP N-methyl-2-pyrrolidone [0295]
RPHPLC Reverse phase high pressure chromatography [0296] RT
Retention time [0297] THF Tetrahydrofuran
EXAMPLES
Example 1
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-4-((1-benzylpiperidin-3-yl)oxy)-
5-cyclopropyl-2-fluorobenzamide
##STR00192##
[0298] Step 1. Preparation of (R)-tert-butyl
4-((1-benzylpiperidin-3-yl)oxy)-5-chloro-fluorobenzoate
##STR00193##
[0300] To a solution of (R)-1-benzylpiperidin-3-ol(0.38 g, 2.00
mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (0.50 g, 2.00
mmol) in anhydrous dimethyl sulfoxide (6 mL) was added cesium
carbonate (2.16 g, 4.00 mmol). The reaction mixture was stirred at
70.degree. C. for 2 hours under an atmosphere of nitrogen and then
cooled to ambient temperature and quenched by addition of 10 mL of
water. The mixture was extracted with ethyl acetate (3.times.15
mL); the organic layers were combined and washed with brine (15
mL), dried over anhydrous magnesium sulfate, filtered and
concentrated. The residue was purified by column chromatography
eluting with a gradient of ethyl acetate in hexanes to (0 to 25%)
to give the title compound (0.66 g, 78%) as a white solid: .sup.1H
NMR (300 MHz, CDCl.sub.3) d 7.85 (d, J=7.74 Hz, 1H), 7.36-7.18 (m,
5H), 6.63 (d, J=12.2 Hz, 1H), 4.49-4.31 (m, 1H), 3.57 (s, 2H),
3.10-2.96 (m, 1H), 2.82-2.66 (m, 1H), 2.27 (m, 1H), 2.20-2.02 (m,
2H), 1.92-1.75 (m, 1H), 1.73-1.59 (m, 1H), 1.60-1.50 (m, 10H).
Step 2. Preparation of (R)-tert-butyl
4-((1-benzylpiperidin-3-yl)oxy-5-cyclopropyl- 2-fluorobenzoate
##STR00194##
[0302] To a solution of (R)-tert-butyl
4-((1-benzylpiperidin-3-yl)oxy)-5-chloro-2-fluorobenzoate (0.38 g,
0.90 mmol) and cyclopropylboronic acid (0.12 g, 1.35 mmol) in
toluene (3 mL) and water (0.3 mL) was added potassium phosphate
tribasic (0.64 g, 1.80 mmol), palladium (II) acetate (0.02 g, 0.09
mmol), and tricyclohexyl phosphonium tetrafluoroborate (0.07 g,
0.18 mmol) and the mixture was degassed thoroughly and the reaction
vessel filled up with nitrogen before heating at 115.degree. C. for
40 min under microwave irradiation. The reaction mixture was then
cooled to ambient temperature and quenched by addition of 10 mL of
water. The mixture was then extracted with diethyl ether
(2.times.15 mL). The organic layers were combined, concentrated and
The residue was purified by column chromatography (10 to 30%
gradient of ethyl acetate in hexanes) to give the title compound
(0.37 g, 98%) as a colorless oil: .sup.1H NMR (300 MHz, CDCl.sub.3)
d7.36 (d, J=8.4 Hz, 1H), 7.33-7.13 (m, 5H), 6.53 (d, J=12.8 Hz,
1H), 4.44-4.30 (m, 1H), 3.61-3.49 (m, 2H), 3.09-2.94 (m, 1H),
2.76-2.63 (m, 1H), 2.31-1.96 (m, 4H), 1.90-1.60 (m, 3H), 1.59-1.54
(m, 9H), 0.92-0.83 (m, 2H), 0.67-0.60 (m, 2H); MS(ES+) m/z 426.2 (M
+1).
Step 3. Preparation of
(R)-N-(azetidin-1-ylsulfonyl)-4-((1-benzylpiperidin-3-yl)oxy)-5-
cyclopropyl-2-fluorobenzamide
##STR00195##
[0304] T a solution of (R)-tert-butyl
4-((1-benzylpiperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate
(0.127 g, 0.30 mmol) in dichloromethane (1 mL) was added
trifluoroacetic acid (1 mL). After stirring at ambient temperature
for 1 hour, reaction mixture was concentrated, diluted with
dichloromethane (10 mL) and washed with aqueous hydrochloric acid
(1.0 N, 10 mL). The aqueous layers was extracted with
dichloromethane (10 mL), the organic layers were combined, dried
over anhydrous sodium sulfate, filtered and concentrated to give
the corresponding carboxylic acid which was used directly for the
next step. To a solution of the carboxylic acid (0.11 g, 0.30 mmol)
in dichloromethane (2 mL) was added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.124 g, 0.48 mmol)
and 4-dimethylaminopyridine (0.091 g, 0.75 mmol) and azetidine
sulfonamide (0.052 g, 0.39 mmol). The reaction mixture was stirred
at ambient temperature for 16 hours and then diluted with
dichloromethane (10 mL) and washed with aqueous hydrochloric acid
(1.0 N, 10 mL). The aqueous layer was extracted with
dichloromethane (10 mL); the organic layers were combined, dried
over anhydrous sodium sulfate, filtered and concentrated. The
residue was first purified by column chromatography eluting with a
gradient of methanol in dichlorometharte (0% to 15%) and further
purified by preparative HPLC (gradient of acetonitrile in water) to
give the title compound as a white solid (0.021 g, 14%): .sup.1H
NMR (300 MHz, CDCl.sub.3) d 7.54 (d, J=9.1 Hz, 1H), 7.33-7.22 (m,
5H), 6.56 (d, J=14.5 Hz, 1H), 4.48-4.34 (m, 1H), 4.22 (t, J=7.7 Hz,
4H), 3.57 (s, 2H), 3.07-2.93 (m, 1H), 2.78-2.67 (m, 1H), 2.35-2.13
(m, 4H), 2.13-1.99 (m, 2H), 1.91-1.78 (m, 1H), 1.76-1.46 (m, 2H),
0.95-0.85 (m, 2H), 0.69-0.61 (m, 2H). MS(ES+) m/z: 488.1 (M+1);
MS(ES-) m/z 486.2 (M-1).
Example 2
Synthesis of (S)-N-(azetidin-1-sulfonyl)-4-((1-benzylpiperidin-3-
yl)oxy)-5-cyclopropyl-2-fluorobenzamide
##STR00196##
[0306] Following the procedure as described in Example 1 step 1 to
step 3, and making variation as required to replace
(R)-1-benzylpiperdin-3-ol with (S)-1-benzylpiperidin-3-ol, the
title compound was obtained as a white solid (0.012 g, 45%):
.sup.1H NMR (300 MHz, CDCl.sub.3)d 7.54 (d, J=9.15 Hz, 1H),
7.33-7,22 (m, 5H), 6.56 (d, J=14.5 Hz, 1H), 4.48-4.34 (m, 1H), 4.22
(t, J=7.7 Hz, 4H), 3.57 (s, 2H), 3.07-2.93 (m, 1H), 2.78-2.67 (m,
1H), 2.35-2.13 (m, 4H), 2.13-1.99 (m, 2H), 1.9-1.78 (m, 1H),
1.76-1.46 (m, 2H), 0.95-.085 (m, 2H), 0.69-0.61 (m, 2H); MS(E+) m/z
488.1 (M+1); MS(ES-) m/z 486.2 (M-1).
Example 3
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(3,5-dichlorobenzyl)piper-
idin- 3-yl)oxy)-2-fluorobenzamide
##STR00197##
[0307] Step 1. Preparation of (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-chloro-5-
fluorophenoxy)piperidine-1-carboxylate
##STR00198##
[0309] To a solution of (R)-tert-butyl
3-hydroxypiperidine-1-carboxylate (10.05 g, 50.00 mmol) and
tert-butyl 5-chloro-2,4-difluorobenzoate (13.02 g, 52.50 mmol) in
anhydrous DMSO (200 mL) was added cesium carbonate (40.62 g, 75.00
mmol). The reaction mixture was stirred at 70.degree. C. for 1 hour
under an atmosphere of nitrogen and then cooled to ambient
temperature and quenched by addition of 50 mL of water. The mixture
was extracted with ethyl acetate (3.times.100 mL); the organic
layers were combined and washed with brine (150 mL), dried over
anhydrous magnesium sulfate, filtered and concentrated. The crude
material (22.50 g, 99%) was used directly for the next step without
further purification; MS(ES+) m/z 430.2, 431.2 (M+1).
Step 2. Preparation of (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)piperidine-1-car-
boxylate
##STR00199##
[0311] To a solution of (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)piperidine-
1-carboxylate (22.50 g, 50.00 mmol) and cyclopropylboronic acid
(7.22 g, 83.90 mmol) in toluene (150 mL) and water (15 mL) was
added potassium phosphate tribasic (39.53 g, 111.90 mmol),
palladium (II) acetate (1.25 g, 5.60 mmol), and tricyclohexyl
phosphonium tetrafluoroborate (4.10 g, 11.20 mmol). The mixture was
degassed thoroughly and the reaction vessel filled up with nitrogen
before heating at 115.degree. C. for 16 hours. The reaction mixture
was then cooled to ambient temperature and quenched by addition of
100 mL of water. The mixture was extracted with diethyl ether
(2.times.100 mL). The organic layers were combined, concentrated.
The residue was purified by column chromatography (10 to 30%
gradient of ethyl acetate in hexanes) to give the title compound as
an colorless oil (16.50 g, 75%). .sup.1H NMR (300 MHz, CDCl.sub.3)d
7.36 (d, J=8.4 Hz, 1H), 6.55 (d, J=12.6 Hz, 1H), 4.37-4.21 (m,
3.81-3.32 (m, 4H), 2.03-1.76 (m, 5H), 1.55 (s, 9H), 0.92-0.79 (m,
2H), 0.73-0.50 (m, 2H).
Step 3. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoic acid,
trifluoroacetic acid salt
##STR00200##
[0313] To a solution of (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)-
piperidine-1-carboxylate (9.5 g, 21.8 mmol) in dichloromethane (200
mL), was added trifluoroacetic acid (40 ml). The reaction mixture
was stirred at ambient temperature for 3 hours and then
concentrated in vacuo. The residue was purified by column
chromatography (5% to 100% methanol in water on C18 column)
afforded the title compound as colorless solid (5.3 g, 64%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.83 (brs, 2H), 7.27
(d, J=8.5 Hz, 1H), 7.02 (d, J=13.1 Hz, 1H), 4.76 (brs, 1H),
3.36-3.32 (m, 1H), 3.22-3.16 (m, 1H), 3.04 (brs, 2H), 2.27-2.18 (m,
1H), 1.96-1.66 (m, 4H), 0.92-0.87 (m, 2H), 0.66-0.52 (m, 2H);
MS(ES+) m/z 280.3 (M+1); MS(ES-) m/z 278.4 (M-1).
Step 4. Preparation of
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-
yl)oxy)-2-fluorobenzoic acid hydrochloride
##STR00201##
[0315] To a stirred solution of
(R)-5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoic acid
trifluoroacetate (0.20 g, 0.53 mmol) in tetrahydrofuran (1 mL)
under an atmosphere of nitrogen were introduced
3,5-dichlorobenzaldehyde (0.11 g, 0.64 mmol) and sodium
triacetoxyborohydride (0.31 g, 0.96 mmol) and the mixture was
stirred for 16 hours. Aqueous hydrochloric acid (1M, 5 mL) was
added and the mixture was extracted with ethyl acetate (3.times.10
mL) and concentrated. The residue was purified by column
chromatography eluting with 5% methanol in dichloromethane to give
the title compound as an oil (0.16 g, 63%): MS(ES+) m/z 438.1,
440.1 (M+1); MS(ES-) m/z 436.1, 438.1 (M-1).
Step 5. Preparation of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(3,5-dichlorobenzyl)piper-
idin-3-yl)oxy)-2-fluorobenzamide
##STR00202##
[0317] To a solution of
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid hydrochloride (0.07 g, 0.17 mmol) in dichloromethane (1
mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.04
g, 0.25 mmol) and 4-dimethylaminopyridine (0.05 g, 0.42 mmol) and
cyclopropylsulfonamide (0.02 g, 0.17 mmol). The reaction mixture
was stirred at ambient temperature for 16 hours and then diluted
with dichloromethane (10 mL) and washed with aqueous hydrochloric
acid (1M, mL). The aqueous layer was extracted with dichloromethane
(10 mL), the organic layers were combined, dried over anhydrous
sodium sulfate, filtered and concentrated to give an oil which was
purified over silica gel chromatography (0 to 15% gradient of
methanol containing 1% ammonia solution in dichloromethane) to give
the title compound (0.02 g, 20%): .sup.1H NMR (300 MHz, CDCl.sub.3)
d 7.41 (d, J=12.6 Hz, 1H), 7.23-7.18 (m, 3H), 6.54 (d, J=12.6 Hz,
1H), 4.49-4.33 (m, 1H), 3.56-3.39 (m, 2H), 2.94-2.81 (m, 1H),
2.68-2.53 (m, 1H), 2.46-2.31 (m, 1H), 2.31-2.16 (m, 1H), 2.11-1.97
(m, 2H), 1.92-1.78 (m, 1H), 1.73-1.52 (m, 3H), 0.98-0.79 (m, 6H),
0.72-0.57 (m, 2H); MS(ES+) m/z 541.1, 543.1 (M+1); MS(ES-) m/z
539.2, 541.2 (M-1).
Example 4
Synthesis of
(R)-4-((1-acetylpiperidin-3-yl)oxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-
- 2-fluorobenzamide
##STR00203##
[0319] This compound was isolated as a side product during the
synthesis of Example 3 in step 5 (0.02 g, 24%) as a colorless
solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) d 7.21-7.00 (m, 2H),
4.83-4.52 (m, 1H), 4.06-3.93 (m, 1H), 3.86-3.69 (m, 1H), 3.63-3.38
(m, 2H), 3.13-2.93 (m, 2H), 1.99-1.76 (m, 5H), 172-1.36 (m, 2H),
1.29-1.03 (m, 4H), 0.90-0.79 (m, 2H), 0.69-0.60 (m, 2H); MS(ES+)
m/z 425.2 (M+1); MS(ES-) m/z 423.3 (M-1).
Example 5
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)pip-
eridin- 3-yl)oxy)-2-fluorobenzamide
##STR00204##
[0321] Following the procedure as described in Example 3 step 5,
and making variation as required to replace cyclopropylsulfonamide
with azetidine-1-sulfonamide, the title compound was obtained (0.02
g, 25%) as a colorless solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.63-11.45 (m, 1H), 7.46-7.40 (m, 1H), 7.38-7.29 (m, 2H),
7.11 (d, J=8.36 Hz, 1H), 6.97 (d, J=13.0 Hz, 1H), 4.68-4.53 (m,
1H), 4.05-3.92 (m, 4H), 3.63-3.43 (m, 2H), 2.74-2.63 (m, 1H),
2.44-2.25 (m, 2H), 2.20-1.99 (m, 3H), 1.93-1.67 (m, 2H), 1.63-1.48
(m, 3H), 0.96-0.79 (m, 2H), 0.77-0.60 (m, 2H); MS(ES+) m/z 556.1,
558.1 (M+1); MS(ES-) m/z 554.2, 556.2 (M-1).
Example 6
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3--
yl)oxy-5-cyclopropyl-2-fluorobenzamide
##STR00205##
[0323] Following the procedure as described in Example 3 steps 4
and 5, and making variations as required to replace
3,5-dichlorobenzaldehyde with 2-chloro-4-fluorobenzaldehyde and
cyclopropylsulfonamide with azetidine-1-sulfonamide, the title
compound was obtained (0.035 g, 50%) as a colorless solid: .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.62-11.47 (m, 1H), 7.45-7.40
(m, 1H), 7.38-7.28 (m, 2H), 7.11 (d, J=8.3 Hz, 1H), 4.68-4.53 (m,
1H), 4.05-3.92 (m, 4H), 3.62-3.42 (m, 2H), 2.75-2.63 (m, 1H),
2.44-2.26 (m, 2H), 2.20-2.00 (m, 3H), 1.90-1.67 (m, 2H), 1.63-1.48
(m, 3H), 0.94-0.81 (m, 2H), 0.76-0.62 (m, 2H); MS(ES+) m/z 540.1,
542.1 (M+1); MS(ES-) m/z 538.2, 540.2 (M-1).
Example 7
Synthesis of
(R)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-
N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR00206##
[0325] Following the procedures as described in Example 3 steps 4
and 5, and making variation as required to replace
3,5-dichlorobenzaldehyde with 2-chloro-4-fluorobenzaldehyde, the
title compound was obtained (0.038 g, 37%) as a colorless solid:
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.89-11.60 (m, 1H),
7.49 (dd, J=8.5, 6.5 Hz, 1H), 7.37 (dd, J=8.8, 2.6 Hz, 1H),
7.17-7.05 (m, 2H), 6.98 (d, J=13.2 Hz, 1H), 4.68-4.50 (m, 1H),
3.63-3.52 (m, 2H), 3.11-2.97 (m, 1H), 2.84-2.70 (m, 1H), 2.61-2.49
(m, 2H), 2.43-2.29 (m, 1H), 2.12-1.98 (m, 1H), 1.98-1.65 (m, 2H),
1.64-1.45 (m, 2H), 1.13-1.02 (m, 4H), 0.91-0.81 (m, 2H), 0.72-0.62
(m, 2H); MS(ES+) m/z 525.1, 527.1 (M+1); MS(ES-) m/z 523.2, 525.2
(M-1).
Example 8
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(2,4-difluorobenzyl)-
piperidin-3-yl)oxy)-2-fluorobenzamide
##STR00207##
[0327] Following the procedures as described in Example 3 steps 4
and 5, and making variations as required to replace
3,5-dichlorobenzaldehyde with 2,4-difluorobenzaldehyde and
cyclopropylsulfonamide with azetidine-1-sulfonamide, the title
compound was obtained (0.048 g, 57%) as a colorless solid: .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.95-11.21 (m, 1H), 7.44 (dd,
J=15.4, 8.53 Hz, 1H), 7.26-6.81 (m, 4H), 4.67-4.52 (m, 1H),
4.08-3.97 (m, 4H), 3.62-3.54 (m, 2H), 2.90-2.77 (m, 1H), 2.64-2.53
(m, 1H), 2.46-2.22 (m, 2H), 2.22-2.05 (m, 3H), 2.01-1.87 (m, 1H),
1.85-1.69 (m, 1H), 1.68-1.39 (m, 2H), 0.95-0.82 (m, 2H), 0.76-0.64
(m, 2H); MS(ES+) m/z 524.1 (M+1); MS(ES-) m/z 522.2 (M-1).
Example 9
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(2,4-difluorobenzyl)-
piperidin-3-yl)oxy)-2-fluorobenzamide
##STR00208##
[0329] Following the procedures as described in Example 3 steps 4
and 5, and making variation as required to replace
3,5-dichlorobenzaldehyde with 2,4-difluorobenzaldehyde, the title
compound was obtained (0.035 g, 39%) as a colorless solid: .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.87-11.57 (m, 1H), 7.51-7.38
(m, 1H), 7.26-6.95 (m, 4H), 4.67-4.51 (m, 1H), 3.62-3.55 (m, 2H),
3.13-3.00 (m, 1H), 2.90-2.77 (m, 1H), 2.65-2.52 (m, 1H),
2.45-2.16(m, 2H), 2.11-2.01 (m, 1H), 1.99-1.87 (m, 1H), 1.83-1.68
(m, 1H), 1.67-1.38 (m, 2H), 1.14-1.01 (m, 4H), 0.93-0.83 (m, 2H),
0.75-0.61 (m, 2H); MS(ES+) m/z 509.2 (M+1); MS(ES-) m/z 507.3
(m-1).
Example 10
Synthesis of
(R)-5-cyclopropyl-4-((1-(2.6-dichlorobenzyl)piperidin-3-yl)oxy)-
2-fluoro-N-(methylsulfonyl)benzamide
##STR00209##
[0331] Following the procedures as described in Example 3 steps 4
and 5, and making variations as required to replace
3,5-dichlorobenzaldehyde with 2,6-dichlorobenzaldehyde and
cyclopropylsulfonamide with methylsulfonamide, the title compound
was obtained (0.018 g, 13%) as a colorless solid: .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 7.46-7.34 (m, 2H), 7.28 (dd, J=8.8, 7.18
Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 4.39-4.24 (m, 1H), 3.67 (m, 2H),
2.94-2.80 (m, 1H), 2.80-2.72 (m, 3H), 2.61-2.53 (m, 1H), 2.44-2.37
(m, 1H), 2.37-2.23 (m, 1H), 2.05-1.83 (m, 2H), 1.78-1.60 (m, 1H),
1.54-1.36 (m, 2H), 0.86-0.73 (m, 2H), 0.56-0.42 (m, 2H); MS(ES+)
m/z 515.2, 517.2 (M+1); MS(ES-) m/z 513.3, 515.3 (M+1).
Example 11
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-4-((1-(cyclohexylmethyl)piperidin-3-
yl)oxy)-5-cyclopropyl-2-fluorobenzamide
##STR00210##
[0333] Following the procedures as described in Example 3 steps 4
and 5, and making variations as required to replace
3,5-dichlorobenzaldehyde with cyclohexanecarbaldehyde and
cyclopropylsulfonamide with azetidine-1-sulfonamide, the title
compound was obtained (0.041 g, 51%) as a colorless solid: .sup.1H
NMR (300 MHz, acetonitrile-d.sub.3) .delta. 736-7.26 (m, 1H),
7.07-6.95 (m, 1H), 5.01-4.88 g (m, 1H), 4.18-4.08 (m, 4H),
2.98-2.83 (m, 2H), 2.31-2.15 (m, 7H), 1.84-1.57 (m, 9H), 1.36-1.11
(m, 4H), 1.08-0.87 (m, 4H), 0.70-0.62 (m, 2H); MS(ES+) m/z 494.3
(M+1); MS(ES-) m/z 492.4 (M-1).
Example 12
Synthesis of
(R)-5-cyclopropyl-2-fluoro-4-((1-(1-methyl-3-phenyl-1H-pyrazol-
5-yl)methyl)piperidin-3-yl)oxy)-N-(methylsulfonyl)benzamide
##STR00211##
[0335] Following the procedures as described in Example 3 steps 4
and 5, and making variations as required to replace
3,5-dichlorobenzaldehyde with
1-methyl-3-phenyl-1H-pyrazole-5-carbaldehyde and
cyclopropylsulfonamide with methylsulfonamide, the title compound
was obtained (0.023 g, 39%) as a colorless solid: .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 7.75-7.61 (m, 2H), 7.33 (t, J=7.5 Hz,
2H), 7.25-7.13 (m, 2H), 6.81-6.67 (m, 1H), 6.52 (d, J.ltoreq.3.3
Hz, 1H), 4.53-4.41 (m, 1H), 3.79 (s, 3H), 3.61-3.50 (m, 2H),
2.88-2.74 (m, 4H), 2.31-2.19 (m, 1H), 2.07-1.83 (m, 3H), 1.79-1.68
(m, 1H), 1.57-1.38 (m, 3H), 0.86-0.78 (m, 2H), 0.58-0.48 (m, 2H);
MS(ES+) m/z 527.3 (M+1); MS(ES-) m/z 525.3 (M-1).
Example 13
Synthesis of
(R)-5-cyclopropyl-2-fluoro-N-methylsulfonyl)-4-((1-(pyridazin-4-
ylmethyl)piperidin-3-yl)oxy)benzamide
##STR00212##
[0337] Following the procedures as described in Example 3 steps 4
and 5, and making variations as required to replace
3,5-dichlorobenzaldehyde with 1-methyl-3-phenyl-1H-
pyrazole-5-carbaldehyde and cyclopropylsulfonamide with
methylsulfonamide, the title compound was obtained (0.035 g, 40%)
as a colorless solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.87-8.82 (m, 1H), 8.75 (dd, J=5.2, 0.8 Hz, 1H), 7.23-7.18 (m, 1H),
7.08 (d, J=8.8 Hz, 1H), 6.36 (d, J=13.5 Hz, 1H), 4.28-4.16 (m, 1H),
3.35 (d, J=15.0 Hz, 1H), 3.26 (d, J=15.0 Hz, 1H), 2.88 (s, 3H),
2.59-2.48 (m, 1H), 2.38-2.02 (m, 4H), 1.85-1.76 (m, 2H), 1.46-1.29
(m, 3H), 0.68-0.59 (m, 2H), 0.46-0.34 (m, 2H); MS(ES+) m/z 449.1
(M+1).
Example 14
Synthesis of
(R)-5-cyclopropyl-2-fluoro-4-((1-(isoindolin-4-ylmethyl)piperidin-
3-yl)oxy)-N-(methylsulfonyl)benzamide
##STR00213##
[0338] Step 1. Preparation of (R)-tert-butyl
4-((3-(2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)-phenoxy)piper-
idin-1-yl)methyl)isoindoline-2-carboxylate
##STR00214##
[0340] Following the procedures as described in Example 3 steps 4
and 5, and making variations as required to replace
3,5-dichlorobenzaldehyde with tert-butyl
4-formylisoindoline-2-carboxylate and cyclopropylsulfonamide with
methylsulfonamide, the title compound was obtained (0.030 g, 16%):
MS(ES+) m/z 588.2 (M+1).
Step 2. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-((1-(isoindolin-4-ylmethyl)-
piperidin-3-yl)oxy)-N-(methylsulfonyl)benzamide
##STR00215##
[0342] To a stirred solution of (R)-tert-butyl
4-((3-(2-cyclopropyl-5-fluoro-4-((methylsulfonyl)-carabamoyl)phenoxy)pipe-
ridin-1-yl)methyl)isoindoline-2-carboxylate (0.030 g, 0.051 mmol)
in dichloromethane (1 mL) was added trifluoroacetic acid (0.3 mL)
and the mixture was stirred at ambient temperature for 1 hour and
then concentrated. The residue was purified by silica gel
chromatography (0 to 15% gradient of methanol plus 1% ammonia
solution in dichloromethane) to give the title compound (0.01 g,
38%): .sup.1H NMR (300 MHz, MeOD-d.sub.4) d 7.41-7.18 (m, 4H), 6.69
(d, J=13.1 Hz, 1H), 4.77-4.54 (m, 2H), 4.53-4.43 (m, 1H), 3.61-3.55
(m, 2H), 3.54-3.40 (m, 1H), 3.37-3.03 (m, 4H), 2.88-2.79 (m, 1H),
2.61-2.52 (m, 1H), 2.51-2.41 (m, 1H), 2.38-2.26 (m, 1H), 2.10-1.99
(m, 2H), 1.94-1.82 (m, 1H), 1.78-1.70 (m, 1H), 1.69-1.56 (m, 1H),
0.94-0.85 (m, 2H), 0.70-0.57 (m, 2H); MS(ES+) m/z 488.3 (M+1);
MS(ES-) m/z 486.4 (M-1).
Example 15
Synthesis
of(R)-N-(azetidin-1-ylsulfonyl)-4-((1-benzhydrylpiperidin-3-yl)o-
xy)- 5-cyclopropyl-2-fluorobenzamide
##STR00216##
[0343] Step 1. Preparation of
(R)-4-((1-benzhydrylpiperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoic
acid.
##STR00217##
[0345] To a stirred solution of
(R)-5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoic acid
trifluoroacetate (0.20 g, 0.53 mmol) in acetonitrile (2 mL) under
an atmosphere of nitrogen were added (bromomethylene)dibenzene
(0.16 g, 0.64 mmol), potassium carbonate (0.17 g, 1.28 mmol) and
sodium iodide (0.09 g, 0.64 mmol) and the mixture was stirred at
reflux for 16 hours. After cooled to ambient temperature, 1M
aqueous hydrochloric acid (5 mL) was added slowly and the mixture
was extracted with ethyl acetate (3.times.10 mL) and concentrated.
The residue was purified over silica gel chromatography eluting
with 30% ethyl acetate (containing 1% Formic acid) in hexanes to
give compound the title compound as an oil (0.16 g, 70%): MS(ES+)
m/z 446.1 (M+1).
Step 2. Preparation of
(R)-N-(azetidin-1-ylsulfonyl)-4-((1-benzhydrylpiperidin-3-yl)oxy)-5-cyclo-
propyl-2-fluorobenzamide
##STR00218##
[0347] Following the procedure as described in Example 3 step 5,
and making variations as required to replace cyclopropylsulfonamide
with azetidine-1-sulfonamide, the title compound was obtained
(0.035 g, 34%) as a colorless solid: .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.65-11.53 (m, 1H), 7.43-7.35 (m, 2H),
7.31-7.19 (m, 4H), 7.19-7.05 (m, 5H), 6.86 (d, J=13.0 Hz, 1H),
4.71-4.57 (m, 1H), 4.39-4.33 (m, 1H), 4.08-3.95 (m, 4H), 2.62-2.49
(m, 1H), 2.44-2.21 (m, 3H), 2.20-2.05 (m, 3H), 1.94-1.70 (m, 2H),
1.67-1.48 (m, 0,96-0.87 (m, 2H), 0.79-0.69 (m, 2H); MS(ES+) m/z
564.3 (M+1); MS(ES-) m/z 562.4 (M-1).
Example 16
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-4-((1-benzhydrylpiperidin-3-yl)oxy)-5-cyclo-
propyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR00219##
[0349] Following the procedure as described in Example 15 step 2,
and making variations as required to replace
azetidine-1-sulfonamide with cyclopropylsulfonamide, the title
compound was obtained (0.048 g, 52%) as a colorless solid: .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.90-11.73 (m, 1H), 7.43-7.34
(m, 2H), 7.31-7.20 (m, 4H), 7.19-7.04 (m, 5H), 6.86 (d, J=13.2 Hz,
1H), 4.73-4.55 (m, 1H), 4.40-4.32 (m, 1H), 3.12-2.99 (m, 1H),
2.62-2.49 (m, 1H), 2.44-2.21 (m, 3H), 2.20-2.05 (m, 1H), 1.94-1.71
(m, 2H), 1.68-1.46 (m, 2H), 1.15-1.02 (m, 4H), 0.96-0.87 (m, 2H),
0.79-0.68 (m, 2H); MS(ES+) m/z 549.3 (M+1); MS(ES-) m/z 547.4
(M-1).
Example 17
Synthesis of
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-
2-fluoro-N-(methylsulfonyl)benzamide
##STR00220##
[0350] Step 1. Preparation of
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-
yl)oxy)-2-fluorobenzoic acid
##STR00221##
[0352] To a solution of
(R)-5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoic acid (0.40
g, 1.43 mmol) and 3,4-dichlorobenzaldehyde (0.3 g, 1.72 mmol) in
tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride (0.55
g, 2.58 mmol). The reaction mixture was stirred at ambient
temperature for 2 hours, and concentrated in vacuo. The residue was
diluted with ethyl acetate (50 mL), washed with aqueous ammonium
chloride (25% solution, 2.times.25 mL); dried over anhydrous sodium
sulfate and concentrated invacuo. The crude product was purified by
column chromatography (5% to 100% methanol in water on C18 column)
afforded the title compound as colorless solid (0.42 g, 56%):
MS(ES+) m/z 438.2, 440.2 (M+1); MS(ES-) m/z 436.3, 438.3 (M-1).
Step 2. Preparation of
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-
2-fluoro-N-(methylsulfonyl)benzamide
##STR00222##
[0354] To a mixture of
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid (0.10 g, 0.23 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.10 g, 0.52 mmol)
and 4-dimethylaminopyridine (0.06 g, 0.52 mmol) in anhydrous
dichloromethane (2 mL) was added methanesulfonamide (0.03 g, 0.34
mmol) at ambient temperature. The resulting mixture was stirred at
ambient temperature for 16 hours. The mixture was diluted with
ethyl acetate (50 mL), washed with aqueous ammonium chloride (25%
solution, 2.times.25 mL), dried over anhydrous sodium sulfate, and
filtered.
[0355] The filtrate was concentrated in vacuo, the crude product
was purified by silica gel column chromatography using 10-100%
ethyl acetate in hexanes as an eluent to afford the title compound
as colorless solid (0.07 g, 58%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.74 (brs, 1H), 7.57-7.53 (m, 2H), 7.29 (dd,
J=1.8, 8.3 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.99 (d, J=13.2 Hz,
1H), 4.63-4.61 (m, 3.61 (d, J =14.0 Hz, 1H), 3.53 (d, j=14.0 Hz,
1H), 3.29 (s, 3H), 2.79-2.75 (m, 1H), 2.55-2.32 (m, 3H), 2.12-2.03
(m, 1H), 1.92-1.89 (m, 1H), 1.83-1.77 (m, 1H), 1.63-1.53 (m, 2H),
0.93-0.85 (m, 2H), 0.76-0.65 (m, 2H); MS(ES+) m/z 515.2, 517.2
(M+1); MS(ES-) m/z 513.1, 515.1 (M-1).
Example 18
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(3,4-dichlorobenzyl)-
piperidin-3-yl)oxy-2-fluorobenzamide
##STR00223##
[0357] Following the procedure as described in Example 17 step 2,
and making variations as required to replace methanesulfonamide
with cyclopropanesulfonamide, the title compound was obtained as
colorless solid (06 g, 51%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.72 (brs, 1H), 7.56-7.53 (m, 2H), 7.28 (dd, J=1.8, 8.3
Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.00 (d, J=13.2 Hz, 1H), 4.63-4.61
(m, 1H), 3.60 (d, J=14.0 Hz, 1H), 3.51 (d, J=14.0 Hz, 1H),
3.11-3.02 (m, 1H), 2.77-2.74 (m, 1H), 2.54-2.34 (m, 3H), 2.13-2.03
(m, 1H), 1.92-1.77 (m, 2H), 1.60-1.56 (m, 2H), 0.12-1.07 (m, 4H),
0.92-0.88 (m, 2H), 0.74-0.69 (m, 2H); MS(ES+) m/z 541.2, 543.2
(M+1); MS(ES-) m/z 539.1, 541.1 (M-1).
Example 19
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)-
piperidin-3-yl)oxy-2-fluorobenzamide
##STR00224##
[0359] Following the procedure as described in Example 17 step 2,
and making variations as required to replace methanesulfonamide
with azetidine-1-sulfonamide, the title compound was obtained as
colorless solid (0.01 g, 11%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.65 (brs, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.44-7.35 (m, 2H),
7.16-7.14 (m, 1H), 6.58 (d, J=14.1 Hz, 1H), 4.44 (brs, 1H),
4.27-4.22 (m, 4H), 3.56-3.45 (m, 2H), 2.92-2.88 (m, 1H), 2.67-2.63
(m, 1H), 2.41-2.22 (m, 4H), 2.12-2.03 (m, 2H), 1.91-1.87 (m, 1H),
1.68-1.63 (m, 2H), 0.97-0.91 (m, 2), 0.71-0.67 (m, 2H); m/z 556.2,
558.2 (M+1); MS(ES-) m/z 554.2, 556.2 (M-1).
Example 20
Synthesis of
(R)-5-cyclopropyl-2-fluoro-4-((1-(4-fluorobenzyl)piperidin-3-yl)oxy-N-(me-
thylsulfonyl)benzamide
##STR00225##
[0360] Step 1. Preparation of
(5)-5-cyclopropyl-2-fluoro-4-((1-(4-fluorobenzyl)piperidin-
3-yl)oxy)benzoic acid
##STR00226##
[0362] Following the procedure as described in Example 17 step 1,
and making variations as required to replace
3,4-dichlorobenzaldehyde with 4-fluorobenzaldehyde, the title
compound was obtained as is colorless solid (0.22 g, 41%): MS(ES+)
m/z 388.2(M+1); MS(ES-) m/z 386.2 (M-1).
Step 2. Preparation of ((R
)-5-cyclopropyl-2-fluoro-4-((1-(4-fluorobenzyl)piperidin-3-
yl)oxy)-N-(methylsulfonyl)benzamide
##STR00227##
[0364] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with (R)-5
-cyclopropyl-2-fluoro-4-((1-(4-fluorobenzyl)piperidin-3-yl)oxy)benzoic
acid, the title compound was obtained as colorless solid (0.01 g,
14%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.68 (brs, 1H),
7.36-7.31 (m, 2H), 7.15-7.09 (m, 3H), 6.93 (d, J=13.1 Hz, 1H),
4.59-4.55 (m, 1H), 3.62-3.50 (m, 2H), 3.21 (m, 3H), 2.84-2.81 (m,
1H), 2.60-2.56 (m, 1H), 2.44-2.26 (m, 2H), 2.10-2.01 (m, 1H),
1.98-1.92 (m, 1H), 1.82-1.76 (m, 1H), 1.64-1.46 (m, 2H), 0.90-0.87
(m, 2H), 0.69-0.65 (m, 2H); MS(ES+) m/z 465.3 (M+1); MS(ES-) m/z
463.2 (M-1).
Example 21
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(4-
fluorobenzyl)piperidin-3-yl)oxy)benzamide
##STR00228##
[0366] Following the procedure as described in Example 17 step 2,
and making variations required to replace (R)-5-cyclopropyl-4-((1
-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorobenzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(4-fluorobenzyl)piperidin-3-yl)oxy)benzo-
ic acid and methanesulfonamide with cyclopropanesulfonamide, the
title compound was obtained as colorless solid (0.05 g, 51%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.62 (brs, 1H),
7.36-7.31 (m, 2H), 7.15-7.09 (m, 3H), 6.97 (d, J=13.2 Hz, 1H),
4.62-4.57 (m, 1H), 3.63-3.52 (m, 2H), 3.09-3.01 (m, 1H), 2.83-2.80
(m, 1H), 2.60-2.56 (m, 1H), 2.42-2.27 (m, 2H), 2.11-2.02 (m, 1H),
1.98-1.92 (m, 1H), 1.82-1.76 (m, 1H), 1.61-1.50 (m, 2H), 1.10-1.06
(m, 4H), 0.91-0.87 (m, 2H), 0.71-0.67 (m, 2H); MS(ES+) m/z 491.3
(M+1); MS(ES-) m/z 489.3 (M-1).
Example 22
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-(4-
fluorobenzyl)piperidin-3-yl)oxy)benzamide
##STR00229##
[0368] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(4-fluorobenzyl)piperidin-3-yl)oxy)benzo-
ic acid and methanesulfonamide with azetidine-1-sulfonamide, the
title compound was obtained as colorless solid (0.04 g, 44%):
.sup.1HNMR (300 MHz, DMSO-d.sub.6) .delta. 11.48 (brs, 1H),
7.35-7.31 (m, 2H), 7.14-7.09 (m, 3H), 6.98 (d, J=13.0 Hz, 1H),
4.60-4.58 (m, 1H), 4.01 (t, J=7.7 Hz, 4H), 3.62-3.50 (m, 2H),
2.82-2.79 (m, 1H), 2.60-2.56 (m, 1H), 2.41-2.26 (m, 2H), 2.20-2.04
(m, 3H), 1.98-1.92 (m, 1H), 1.82-1.76 (m, 1H), 1.64-1.46 (m, 2H),
0.91-0.85 (m, 2H), 0.72-0.68 (m, 2H); MS(ES+) m/z 506.3 (M+1);
MS(ES-) m/z 504.3 (M-1).
Example 23
Synthesis of
(R)-4-((1-(2-chlorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-N-
(cyclopropylsulfonyl)-2-fluorobenzamide
##STR00230##
[0369] Step 1. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-((1-(2-chlorobenzyl)piperidin-3-
yl)oxy)benzoic acid
##STR00231##
[0371] Following the procedure as described in Example 17 step 1,
and making variations as required to replace
3,4-dichlorobenzaldehyde with 2-chlorobenzaldehyde, the title
compound was obtained as colorless solid (0.28 g, 41%): MS(ES+) m/z
404.2, 406.2 (M+1); MS(ES-) m/z 402.2, 404.2 (M-1).
Step 2. Preparation of
(R)-4-((1-(2-chlorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-N-(cyclopropy-
lsulfonyl)-2-fluorobenzamide
##STR00232##
[0373] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(2-chlorobenzyl)piperidin-3-yl)oxy)benzo-
ic acid and methanesulfonamide with cyclopropanesulfonamide, the
title compound was obtained as colorless solid (0.09 g, 98%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.71 (brs, 1H),
7.48-7.45 (m, 1H), 7.39-7.36 (m, 1H), 7.24-7.21 (m, 2H), 7.08 (d,
J=8.4 Hz, 1H), 6.97 (d, J=13.2 Hz, 1H), 4.60-4.58 (m, 1H), 3.59 (s,
2H), 3.07-2.99 (m, 1H), 2.79-2.76 (m, 1H), 2.58-2.51 (m, 1H),
2.50-2.36 (m, 2H), 2.10-2.00 (m, 1H), 1.91-1.88 (m, 1H), 1.81-1.75
(m, 1H), 1.58-1.51 (m, 2H), 1.08-1.04 (m, 4H), 0.87-0.83 (m, 2H),
0.68-0.65 (m, 2H); MS(ES+) m/z 507.3, 509.3 (M+1); MS(ES-) m/z
505.3, 507.3 (M-1).
Example 24
Synthesis of
(R)-4-((1-(2-chlorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-
fluoro-N-(methylsulfonyl)benzamide
##STR00233##
[0375] Following the procedure as described in Example 17 step 3,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(2chlorobenzyl)piperidin-3-yl)oxy)benzoi-
c acid the title compound was obtained as colorless solid (0.05 g,
58%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.79 (brs, 1H),
7.52-7.49 (m, 1H), 7.43-739 (m, 1H), 7.28-7.24 (m, 2H), 7.13 (d,
J=8.4 Hz, 1H), 7.00 (d, J=13.2 Hz, 1H), 4.64-4.561 (m, 1H), 3.64
(s, 2H), 3.31 (s, 3H), 2.83-2.80 (m, 1H), 2.63-2.57 (m, 1H),
2.53-2.38 (m, 2H), 2.33-2.04 (m, 1H), 1.95-1.92 (m, 1H), 1.84-1.77
(m, 1H), 1.62-1.57 (m, 2H), 0.92-0.85 (m, 2H), 0.72-0.68 (m, 2H);
MS(ES+) m/z 481.2, 483.2 (M+1); MS(ES-) m/z 479.3, 481.3 (M-1).
Example 25
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-4-((1-(2-chlorobenzyl)piperidin-3-
yl)oxy)-5-cyclopropyl-2-fluorobenzamide
##STR00234##
[0377] Following the procedure as described to Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(2-chlorobenzyl)piperidin-3-yl)oxy)benzo-
ic acid and methanesulfonamide with azetidine-1-sulfonamide, the
title compound was obtained as colorless solid (0.07 g, 74%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.56 (brs, 1H),
7.53-7.49 (m, 1H), 7.43-7.38 (m, 110, 7.29-7.23 (m, 2H), 7.13 (d,
J=8.3 Hz, 1H), 7.02 (d, J=13.0 Hz, 1H), 4.64-4.62 (m, 1H), 4.03 (t
J=7.7 Hz, 4H), 3.63 (s, 2H), 2.84-2.80 (m, 1H), 2.62-2.57 (m, 1H),
2.49-2.39 (m, 2H), 2.21-2.05 (m, 3H), 1.95-1.92 (m, 1H), 1.84-1.79
(m, 1H), 1.62-1.54 (m, 2H), 0.92-0.87 (m, 2H), 0.73-0.69 (m, 2H);
MS(ES+) m/z 522.3, 524.2 (M+1); MS(ES-) m/z 520.3, 522.3 (M-1).
Example 26
Synthesis of
(R)-4-((1-(3-chlorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-
fluoro-N-(methylsulfonyl)benzamide
##STR00235##
[0378] Step 1. Preparation of
(R)-4-((1-(3-chlorobenzyl)piperidin-3-yl)oxy)-5-
cyclopropyl-2-fluorobenzoic acid
##STR00236##
[0380] Following the procedure as described to Example 17 step 1,
and making variations as required to replace
3,4-dichlorobenzaldehyde with 3-chlorobenzaldehyde, the title
compound was obtained as colorless solid (0.23 g, 41%): MS(ES+) m/z
404.2, 406.2 (M+1); MS(ES-) m/z 402.2, 404.2 (M-1).
Step 2. Preparation of
(R)-4-((1-(3-chlorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-N-(cyclopropy-
lsulfonyl)-2-fluorobenzamide
##STR00237##
[0382] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(3-chlorobenzyl)piperidin-3-yl)oxy)benzo-
ic acid, the title compound was obtained as colorless solid (0.04
g, 51%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.71 (brs,
1H), 7.39-7.25 (m, 4H), 7.13 (d, J=8.4 Hz, 1H), 6.99 (d, J=13.1 Hz,
1H), 4.63-4.61 (m, 1H), 3.66-3.54 (m, 2H), 3.29 (s, 3H), 2.81-2.78
(m, 1H), 2.56-2.36 (m, 3H), 2.11-2.03 (m, 1H), 1.93-1.89 (m, 1H),
1.83-1.77 (m, 1H), 1.63-1.53 (m, 2H), 0.92-0.88 (m, 2H), 0.72-0.68
(m, 2H); MS(ES+) m/z 481.2, 483.2 (M+1); MS(ES-) m/z 479.3, 481.3
(M-1).
Example 27
Synthesis of
(R)-4-((1-(3-chlorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-N-(cyclopropy-
lsulfonyl)-2-fluorobenzamide
##STR00238##
[0384] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy-2-fluorobe-
nzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(3-chlorobenzyl)piperidin-3-yl)oxy)benzo-
ic acid and methanesulfonamide with cyclopropanesulfonamide, the
title compound was obtained as colorless solid (0.06 g, 65%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.71 (brs, 1H),
7.38-7.24 (m, 4H), 7.12 (d, J=8.4 Hz, 1H), 6.99 (d, J=13.2 Hz, 1H),
4.3-4.61 (m, 1H), 3.63-3.51 (m, 2H), 3.10-3.01 (m, 2H), 2.79-2.75
(m, 1H), 2.57-2.33 (m, 3H), 2.13-2.04 (m, 1H), 1.93-1.77 (m, 2H),
1.61-1.52 (m, 2H), 1.11-1.06 (m, 4H), 0.92-0.89 (m, 2H), 0.72-0.68
(m, 2H); MS(ES+) m/z 507.2, 509.2 (M+1); MS(ES-) m/z 505.3, 507.3
(M-1).
Example 28
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-4-((1-(3-chlorobenzyl)piperidin-3-yl)oxy)-
5-cyclopropyl-2-fluorobenzamide
##STR00239##
[0386] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(3-chlorobenzyl)piperidin-3-yl)oxy)benzo-
ic acid and methanesulfonamide with azetidine-1-sulfonamide, the
title compound was obtained as colorless solid (0.02 g, 22%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.55 (brs, 1H),
7.37-7.24 (m, 4H), 7.14 (d, J=8.4 Hz, 1H), 6.98 (d, J=13.0 Hz, 1H),
4.61-4.59 (m, 1H), 3.99 (t, J=7.6 Hz, 4H), 3.61-3.49 (m, 2H),
2.78-2.74 (m, 1H), 2.54-2.27 (m, 3H), 2.18-2.04 (m, 3H), 1.95-1.90
(m, 1H), 1.82-1.76 (m, 1), 1.60-1.52 (m, 2H), 0.93-0.85 (m, 2H),
0.72-0.68 (m, 2H); MS(ES+) m/z 522.2, 524.2 (M+1); MS(ES-) m/z
520.3, 522.3 (M-1).
Example 29
Synthesis of
(R)-5-cyclopropyl-4-((1-(2,4-dichlorobenzyl)piperidin-3-yl)oxy)-
2-fluoro-N-(methylsulfonyl)benzamide
##STR00240##
[0387] Step 1. Preparation of
(R)-5-cyclopropyl-4-((1-(2,4-dichlorobenzyl)piperidin-3-
yl)oxy-2-fluorobenzoic acid
##STR00241##
[0389] Following the procedure as described in Example 17 step 1,
and making variations as required to replace
3,4-dichlorobenzaldehyde with 2,4-dichlorobenzaldehyde, the title
compound was obtained as colorless solid (0.35 g, 56%): MS(ES+) m/z
438.2, 440.2 (M+1); MS(ES-) m/z 436.2, 438.2 (M-1).
Step 2. Preparation of
(R)-5-cyclopropyl-4-((1-(2,4-dichlorobenzyl)piperidin-3-yl)oxy-2-
fluoro-N-(methylsulfonyl)benzamide
##STR00242##
[0391] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(2,4-dichlorobenzyl)piperidin-3-yl)oxy)b-
enzoic acid, the title compound was obtained as colorless solid
(0.02 g, 25%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.84
(brs, 1H), 7.57 (d, J=2.1 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.33
(dd, J=2.1 Hz, 8.3 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.99 (d, J
=13.2 Hz, 1H), 4.63-4.61 (m, 1H), 3.59 (m, 2H), 3.30 (s, 3H),
2.81-2.76 (m, 1H), 2.58-2.39 (m, 3H), 2.12-2.04 (m, 1H), 1.94-1.77
(m, 2H), 1.61-1.53 (m, 2H), 0.91-0.88 (m, 2H), 0.72-0.69 (m, 2H);
MS(ES+) m/z 515.1, 517.1 (M+1); MS(ES-) m/z 513.2, 515.2 (M-1).
Example 30
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(2,4-dichlorobenzyl)pip-
eridin- 3-yl)oxy)-2fluorobenzamide
##STR00243##
[0393] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(2,4-dichlorobenzyl)piperidin-3-yl)oxy)b-
enzoic acid and methanesulfonamide with azetidine-1-sulfonamide,
the title compound was obtained as colorless solid (0.06 g, 64%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.58 (brs, 1H), 7.56
(d, J=2.1 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.33 (dd, J=2.1 Hz, 8.3
Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.01 (d, J=13.1 Hz, 1H), 4.63-4.61
(m, 1H), 4.03 (t, J=7.7 Hz, 4H), 3.59 (s, 2H), 2.79-2.76 (m, 1H),
2.58-2.39 (m, 3H), 2.21-2.04 (m, 3H), 1.94-1.79 (m, 2H), 1.59-1.56
(m, 2H), 0.92-0.88 (m, 2H), 0.73-0.69 (m, 2H); MS(ES-) m/z 556.2,
558.2 (M+1); MS(ES-) m/z 554.3, 556.3 (M-1).
Example 31
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(2,4-dichlorobenzyl)piper-
idin- 3-yl)oxy)-2-fluorobenzamide
##STR00244##
[0395] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(2,4-dichlorobenzyl)piperidin-3-yl)oxy)b-
enzoic acid and methanesulfonamide with cyclopropanesulfonamide,
the title compound was obtained as colorless solid (0.05 g, 48%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.79 (brs, 1H), 7.57
(d, J=2.1 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.33 (dd, J=2.1 Hz, 8.3
Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.01 (d, J=13.2 Hz, 1H), 4.63-4.61
(m, 1H), 3.59 (s, 2H), 3.11-3.03 (m, 1H), 2.80-2.76 (m, 1H),
2.58-2.39 (m, 3H), 2.12-2.04 (m, 1H), 1.94-1.77 (m, 2H), 1.60-1.55
(m, 2H), 1.12-1.07 (m, 4H), 0.91-0.88 (m, 2H), 0.72-0.69 (m, 2H);
MS(ES+) m/z 541.2, 543.1 (M+1); MS(ES-) m/z 539.3, 542,2 (M-1).
Example 32
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(4-
methylbenzyl)piperidin- 3-yl)oxy)benzamide
##STR00245##
[0396] Step 1. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-((1-(4-methylbenzyl)piperidin-
3-yl)oxy)benzoic acid
##STR00246##
[0398] Following the procedure as described in Example 17 step 1,
and making variations as required to replace
3,4-dichlorobenzaldehyde with 4-methylbenzaldehyde, the title
compound was obtained as colorless solid (0.24 g, 44%): MS(ES+) m/z
384.3 (M+1); MS(ES-) m/z 382.3 (M-1).
Step 2. Preparation of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(4-methylbenzyl)-
piperidin-3-yl)oxy)benzamide
##STR00247##
[0400] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid and methanesulfonamide with cyclopropanesulfonamide,
the title compound was obtained as colorless solid (0.01 g, 18%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.46 (brs, 1H),
7.20-7.09 (m, 5H), 6.96 (d, J=13.1 Hz, 1H), 4.59-4.57 (m, 1H),
3.63-3.52 (m, 2H), 3.08-3.00 (m, 1H), 2.86-2.82 (m, 1H), 2.63-2.59
(m, 1H), 2.43-2.33 (m, 2H), 2.26 (s, 3H), 2.11-2.02 (m, 1H),
1.98-1.92 (m, 1H), 1.82-1.77 (m, 1H), 1.64-1.49 (m, 2H), 1.08-1.03
(m, 4H), 0.90-0.87 (m, 2H), 0.70-0.66 (m, 2H); MS(ES+) m/z 487.2
(M+1); MS(ES-) m/z 485.3 (M-1).
Example 33
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-(4-methylbenzy-
l)piperidin- 3-yl)oxy)benzamide
##STR00248##
[0402] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(4-methylbenzyl)piperidin-3-yl)oxy)benzo-
ic acid and methanesulfonamide with azetidine-1-sulfonamide, the
title compound was obtained as off-white solid (0.05 g, 54%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.28 (brs, 1H),
7.25-7.12 (m, 5H), 7.00 (d, J=13.0 Hz, 1H), 4.66-4.64 (m, 1H), 4.01
(t, J=7.7 Hz, 4H), 3.75-3.63 (m, 2H), 2.96-2.92 (m, 1H), 2.71-2.67
(m, 1H), 2.56-2.42 (m, 2H), 2.27 (s, 3H), 2.19-2.05 (m, 3H),
1.99-1.80 (m, 2H), 1.69-1.50 (m, 2H), 0.92-0.86 (m, 2H), 0.71-0.68
(m, 2H); MS(ES+) m/z 502.2 (M+1); MS(ES-) m/z 500.3 (M-1).
Example 34
Synthesis of (R)-5-cyclopropyl-2-fluoro-4-((1
-(4-fluoro-2-(trifluoromethyl)benzyl)piperidin-
3-yl)oxy)-N-(methylsulfonyl)benzamide
##STR00249##
[0403] Step 1. Preparation of (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate
##STR00250##
[0405] To a solution of (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-
fluorophenoxy)piperidine-1-carboxylate (22.50 g 51.80 mmol) in
anhydrous methanol (400 mL), was added sulfuric acid (10.0 mL). The
reaction mixture was refluxed for 16 hours and then concentrated in
vacuo. The pH of the residue was adjusted to 8.about.9 with 1M
aqueous sodium hydroxide solution, and extracted with ethyl acetate
(2.times.300 mL). Organic layers were combined, washed with
saturated sodium bicarbonate (50 mL), brine solution (50 mL), dried
over anhydrous sodium sulfate and concentrated invacuo. The crude
product was purified by column chromatography (5% to 20% methanol
in dichloromethane) afforded the title compound as an oil (10.00 g,
66%): MS(ES+) m/z 294.3 (M+1).
Step 2. Preparation of (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-(4-fluoro-2-(trifluoromethyl)-benzyl)piperid-
in-3-yl)oxy)benzoate
##STR00251##
[0407] To a solution of (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate (0.225 g,
0.768 mmol) in anhydrous dimethylformamide (10 mL) was added
potassium carbonate (0.269 g, 1.95 mmol) and
1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (0.13 mL, 0.84
mmol). The mixture was stirred at ambient temperature for 1 hour,
then poured into water (50 mL) and extracted with ethyl acetate
(3.times.30 mL). The combined organic layer was washed with water
(2.times.30 mL), brine (30 mL), dried over anhydrous sodium
sulfate, filtered and concentrated invacuo. The residue was
purified by column chromatography (0 to 30% ethyl acetate in
hexanes) to give the title compound (0.286 g, 79%): MS(ES+) m/z
470.2 (M+1).
Step 3. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-((1-(4-fluoro-2-
(trifluoromethyl)benzyl)piperidin-3-yl)oxy)-N-(methylsulfonyl)benzamide
##STR00252##
[0409] To a solution of (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-(4-fluoro-2-(trifluoromethyl)-
benzyl)piperidin-3-yl)oxy)benzoate (0.525 g, 1.12 mmol) in water
and tetrahydrofuran (1:1, 20 mL) was added lithium hydroxide (0.265
g, 11.10 mmol). The mixture was heated to reflux for 2 hours and
then stirred for an additional 16 hours at ambient temperature
before neutralized with a 1 M aqueous hydrochloric acid solution.
The aqueous layer was then extracted with ethyl acetate (3.times.10
mL). The combined organic layers were washed with brine (30 mL),
dried over anhydrous sodium sulfate, filtered and concentrated in
vacuo. The crude product was used directly for the next step
without further purification. To a solution of crude
(R)-5-cyclopropyl-2-fluoro-4- ((1
-(4-fluoro-2-(trifluoromethyl)benzyl)piperidin-3-yl)oxy)benzoic
acid (0.161 g, 0.354 mmol) in anhydrous dichloromethane (5 mL) was
added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(0.212 g, 1.11 mmol), 4-dimethylaminopyridine (0.199 g, 1.63 mmol)
and methanesulfonamide (0.105 g, mmol). The mixture was stirred at
ambient temperature for 32 hours, then diluted with ethyl acetate
(50 mL) and washed with a 5% aqueous hydrochloric acid solution
(2.times.25 mL). The combined aqueous layers were extracted with
ethyl acetate (3.times.50 mL). The combined organic layers were
then washed with water (50 mL) and brine (50 mL); dried over
anhydrous sodium sulfate; filtered and concentrated in vacuo. The
residue was purified by column chromatography (0 to 100% ethyl
acetate (containing 0.2% acetic acid) in hexanes) to afford the
title compound (0.033 g, 17%). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.87 (brs, 1H), 7.84-7.79 (m, 1H), 7.58-7.54 (m, 1H),
7.46-7.40 (m, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.99 (d, J=13.2 Hz, 1H),
4.63 (brs, 1H), 3.63 (m, 2H), 3.32 (s, 3H), 2.74-2.70 (m, 1H),
2.44-2.32 (m, 2H), 2.14-2.05 (m, 1H), 1.98-1.74 (m, 3H), 1.66-1.53
(m, 2H), 0.97-0.87 (m, 2H), 0.76-0.67 (m, 3H); .sup.19F NMR (282
MHz, DMSO -d.sub.6) .delta.-114.1, -113.1, -58.4; MS(ES+) m/z 533.2
(M+H).
Example 35
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(4-fluoro-2-(tri-
fluoromethyl)-benzyl)piperidin-3-yl)oxy)benzamide
##STR00253##
[0411] Following the procedure as described in example 34 step 3
and making variations as required to replace methanesulfonamide
with cyclopropylsulfonamide, the title compound was obtained (0.04
g, 20%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.81 (brs,
1H), 7.83-7.79 (m, 1H), 7.58-7.54 (m, 1H), 7.46-7.40 (m, 1H), 7.12
(d, J=8.4 Hz, 1H), 6.99 (d, J=13.2 Hz, 1H), 4.63 (brs, 1H), 3.62
(m, 2H), 3.11-3.03 (m, 1H), 2.73-2.69 (m, 1H), 2.44-2.32 (m, 1H),
2.16-2.03 (m, 1H), 1.99-1.73 (m, 2H), 1.67-1.53 (m, 2H), 1.23 (s,
2H), 1.13-1.08 (m, 4H), 0.93-0.86 (m, 2H), 0.77-0.65 (m, 2H);
.sup.19F NMR (282 MHz, DMSO-d.sub.6) .delta. -114.1, -112.8, -58.4;
MS(ES+) m/z 559.2 (M+H).
Example 36
Synthesis of (R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-
4-((1-(4-fluoro-2-(trifluoromethyl)benzyl)piperidin-3-yl)oxy)benzamide
##STR00254##
[0413] Following the procedure as described in example 34 step 3
and making variations as required to replace methanesulfonamide
with azetidine-1-sulfonamide, the title compound was obtained
(0.053 g, 26%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.60
(br s, 1H), 7.83-7.78 (m, 1H), 7.58-7.54 (m, 1H), 7.46-7.40 (m,
1H), 7.14 (d, J=8.3 Hz, 1H), 6.99 (d, J=13.1 Hz, 1H), 4.63 (br s,
1H), 4.04 (t, J=7.7 Hz, 4H), 3.63 (m, 2H), 2.73-2.69 (m, 1H),
2.45-2.33 (m, 2H), 2.21-2.06 (m, 3H), 1.96-1.74 (m, 2H), 1.67-1.52
(m, 2H), 1.23 (s, 1H), 0.93-0.89 (m, 2H), 0.79-0.67 (m, 2H),
.sup.1F NMR (282 MHz, DMSO-d.sub.6) .delta. -114.1, -113.1, -58.4;
MS (ES+) m/z 574.2 (M+H).
Example 37
Synthesis of (R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-
4-((1-(4-fluorophenyl)piperidin-3-yl)oxy)benzamide, trifluoroacetic
acid salt
##STR00255##
[0414] Step 1. Preparation of (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-(4-fluorophenyl)piperidin-
3-yl)oxy)benzoate
##STR00256##
[0416] To a mixture (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yl)oxy)benzoate (0.587 g, 2.0
mmol), 4-fluorophenylboronic acid (0.56 g, 4.0 mmol), and
copper(II) acetate (0.363 g, 2.0 mmol in anhydrous dichloromethane
(8 mL) was added triethylamine (0.56 mL, 4.0 mmol) and the reaction
mixture was stirred for 72 hours at ambient temperature under an
atmosphere of dry air. The mixture was filtered through a plug of
celite, the filter cake was washed with a mixture of
dichloromethane and methanol (1:1, 20 mL), and the combined
filtrate was concentrated in vacuo. Purification of the residue by
column chromatography (0 to 50% ethyl acetate in hexanes) afforded
the title compound as a light yellow oil (0.448 g 58%): .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.42 (d, J=8.4 Hz, 1H), 6.97-6.81 (m,
4H), 6.62 (d, J=12.8 Hz, 1H), 4.54-4.45 (m, 1H), 3.86 (s, 3H),
3.63-3.55 (m, 1H), 3.36-3.26 (m, 1H), 3.01 (dd, J=11.9, 8.0 Hz,
1H), 2.89 (ddd, J=12.0, 9.3, 2.9 Hz, 1H), 2.21-2.09 (m, 1H),
2.04-1.91 (m, 2H), 1.84-1.64 (m, 1H), 1.60-1.53 (m, 1H), 0.90-0.81
(m, 2H), 0.65-0.59 (m, 2H); MS(ES+) m/z 388.3 (M+1).
Step 2. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-((1-(4-fluorophenyl)piperidin-
3-yl)oxy)benzoic acid
##STR00257##
[0418] To a mixture of (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-(4-fluorophenyl)piperidin-3-
yl)oxy)benzoate (0.448 g, 1:16 mmol) in tetrahydrofuran (10 mL) was
added a solution of lithium hydroxide (0.139 g, 5.8 mmol) in water
(3 mL). The reaction mixture was stirred for 16 hours at ambient
temperature and subsequently for 1 hour at 60.degree. C. After
cooling to ambient temperature, the reaction mixture was adjusted
to pH 1 with 1 N hydrochloric acid solution and extracted with
dichloromethane (3.times.20 mL). The combined organic phase was
washed with brine (5 mL), dried over anhydrous sodium sulfate, and
filtered. Concentration of the filtrate in vacuo gave the title
compound as a yellowish oil (0.43 g, 99%), which was used without
further purification; MS(ES+) m/z 374.3 (M+1).
Step 3. Preparation of
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-(4-fluoropheny-
l)piperidin-3-yl)oxy)benzamide, trifluoroacetic acid salt
##STR00258##
[0420] To a mixture of
(R)-5-cyclopropyl-2-fluoro-4-((1-(4-fluorophenyl)piperidin-3-yl)oxy)benzo-
ic acid (0.215 g, 0.58 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.167
g, 0.87 mmol), and 4-(dimethylamino)pyridine (0.213 g, 1.74 mmol)
in anhydrous dichloromethane was added azetidine-1-sulfonamide
(0.119 g, 0.87 mmol). The reaction mixture was stirred for 48 hours
at ambient temperature. The mixture was diluted with ethyl acetate
(100 mL) and then quenched by addition of 1 N hydrochloric acid
solution (10 mL). The organic phase was washed with 1 N
hydrochloric acid solution (5 mL), water (5 mL) and brine (5 mL);
dried over anhydrous sodium sulfate and filtered. Concentration of
the filtrate gave a residue which was purified first by column
chromatography (0 to 50% ethyl acetate in hexanes) and then by
reverse-phase preparative HPLC to afford the title compound as an
off-white solid (0.168 g, 48%): .sup.1H NMR (300 MHz:,
DMSO-d.sub.6) .delta. 11.61 (s, 1H), 7.30 (brs, 1H), 7.18-6.93 ((m,
6H), 4.78-4.68 (m, 1H), 4.04 (t, J=7.7, 7.7 Hz, 4H), 3.52 (dd,
J=12.2, 2.7 Hz, 1H), 3.31-3.18 (m, 2H), 3.13-3.03 (m, 1H),
2.23-2.10 (m, 2H), 2.10-1.99 (m, 1H), 1.99-1.84 (m, 2H), 1.76-1.61
(m, 2H), 0.86-0.77 (m, 2H), 0.70-0.62 (m, 2H); .sup.19F NMR (282
MHz, DMSO-d.sub.6) .delta. -75.0, -112.9, -125.2; MS(ES-) m/z 490.3
(M-1).
Example 38
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-
(4-fluorophenyl)piperidin-3-yl)oxy)benzamide
##STR00259##
[0422] Following the procedure as described in Example 37 Step 3
and making variations as required to replace
azetidine-1-sulfonamide with cyclopropanesulfonamide and
purification by column chromatography (0 to 50% ethyl acetate in
hexanes), the title compound was obtained as a colorless solid
(0.177 g, 64%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.82
(s, 1H), 7.18-6.89 (m, 6H), 4.77-4.66 (m, 1H), 3.50 (dd, J=12.3,
2,9 Hz, 1H), 3.29-3.15 (m, 2H), 3.13-3.01 (m, 2H), 2.09-1.99 (m,
1H), 1.97-1.81 (m, 2H), 1.75-1.60 (m, 2H), 1.16-1.06 (m, 4H),
0.86-0.77 (m, 2H), 0.69-0.61 (m, 2H); .sup.19F NMR (282 MHz,
DMSO-d.sub.6) .delta. -112.63, -125.87; MS(ES-) m/z 475.3
(M-1).
Example 39
Synthesis of
(R)-5-chloro-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-
yl)oxy)-N-(cyclopropylsulfonyl)-2-fluorobenzamide, trifluoroacetic
acid salt
##STR00260##
[0423] Step 1. Preparation of
(R)-5-chloro-4-((1-(2-chloro-4-fluorobenzyl)piperidin-
3-yl)oxy)-2-fluorobenzoic acid
##STR00261##
[0425] To a mixture of (R)-methyl
5-chloro-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-
2-fluorobenzoate (0.15 g, 0.35 mmol) in tetrahydrofuran (20 mL) and
water (20 mL) was added lithium hydroxide monohydrate (0.15 g, 3.5
mmol). The reaction mixture was heated to reflux for 4 hours. The
reaction mixture was diluted with ethyl acetate (80 mL), washed
with 1 M hydrochloric acid solution (50 mL) and brine (2.times.50
mL); dried over anhydrous sodium sulfate, filtered and concentrated
in vacuo to provide the title compound as a solid (0.15 g, quant.);
MS(ES+) m/z 414.2, 416.2 (M+1).
Step 2. Preparation of
(R)-5-chloro-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-N-(cyclop-
ropylsulfonyl)-2-fluorobenzamide, trifluoroacetic acid salt
##STR00262##
[0427] A mixture of
(R)-5-chloro-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid (0.15 g, 0.35 mmol), cyclopropanesulfonamide (0.064 g,
0.53 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (0.10 g, 0.53 mmol), and 4-dimethylaminopyridine
(0.13 g, 1.05 mmol) in dichloromethane (20 mL) was stirred at
ambient temperature for 18 hours. The reaction was concentrated in
vacuo and the residue was first purified by flash chromatography (0
to 4% methanol in dichloromethane), then by reverse phase HPLC
(acetonitrile in water+0.1% TFA) to provide the title compound
(0.03 g, 17%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.03
(brs, 1H), 9.45 (brs 1H), 7.77 (d, J=7.6 Hz, 1H), 7.74-7.64 (m,
1H), 7.60-7.49 (m, 1H), 7.41-7.26 (m, 2H), 4.85-4.67 (m, 1H),
4.53-3.99 (m, 5H), 3.43-3.29 (m, 1H), 3.18-2.99 (m, 2H), 2.01-1.88
(m, 1H), 1.81-1.56 (m, 2H), 1.15-1.04 (m, 4H); MS (ES+) m/z 519.1,
521.1 (M+H).
Example 40
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-phenylpiperidin-
3-yl)oxy)benzamide
##STR00263##
[0428] Step 1. Preparation of (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-phenylpiperidin-3-yl)oxy)benzoate
##STR00264##
[0430] To a degassed mixture of (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate (0.76 g, 2.68
mmol), iodobenzene (1.49 mL, 13.4 mmol), L-proline (0.62 g, 5.36
mmol), and potassium carbonate (1.88 g, 13.4 mmol) in anhydrous
dimethylsulfoxide (30 mL) was added copper (1) iodide (0.51 g, 2.68
mmol). The resulting mixture was heated to 15.degree. C. under
nitrogen for 2 hours. And then iodobenzene (1.0 mL, 9.0 mmol) was
added to the reaction mixture stirring was continued at 75.degree.
C. under nitrogen for 24 hours. The reaction mixture was diluted
with ethyl acetate (100 mL), washed with water (50 mL), saturated
ammonium chloride (3.times.50 mL) and brine (50 mL); dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo. The
residue was purified by flash chromatography (R.sub.f=0.2 in 9:1
hexanes:ethyl acetate) to provide the title compound as an oil
(0.74 g, 75%): .sup.1H NMR (300 MHz, CDCl.sub.6) .delta. 7.46-7.39
(m, 1H), 7.31-7.17 (m, 3H), 6.95-6.88 (m, 1H), 6.86-6.79 (m, 1H),
6.63 (d, J=12.8 Hz, 1H), 4.55-4.44 (m, 1H), 3.87 (s, 3H), 3.76-3.68
(m, 1H), 3.48-3.39 (m, 1H), 3.10 (dd, J=13.1, 8.0 Hz, 1H),
3.03-2.93 (m, 1H), 2.21-2.12 (m, 1H), 2.03-1.91 (m, 2H), 1.56-1.66
(m, 2H), 0.89-0.82 (m, 2H), 0.65-0.57 (m, 2H); MS(ES+) m/z 370.2
(M+H).
Step 2. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-((1-phenylpiperidin-3-yl)oxy)benzoic
acid
##STR00265##
[0432] Following the procedure as described in Example 39 step 1
and making variation as required to replace (R)-methyl
5-chloro-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-2-fluorobenzo-
ate with (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-phenylpiperidin-3-yl)oxy)benzoate, the
title compound was obtained as a colorless solid (0.61 g, 86%):
MS(ES+) m/z 356.2 (M+H).
Step 3. Preparation of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-phenylpiperidin--
3-yl)oxy)benzamide
##STR00266##
[0434] Following the procedure as described in Example 39 step 2
and making variation as required to replace
(R)-5-chloro-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-phenylpiperidin-3-yl)oxy)benzoic
acid and purification by flash chromatography [(R.sub.f=0.2 in 2.1
hexanes:ethyl acetate (containing 0.2% acetic acid)], the title
compound was obtained as a colorless solid (0.075 g, 18%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.78 (brs, 1H), 7.17-7.02 (m,
4H), 6.90-6.84 (m, 2H), 6.72-6.65 (m, 1H), 4.72-4.64 (m, 1H),
3.56-3.48 (m, 1H), 3.29-3.20 (m, 2H), 3.15-3.07 (m, 1H), 3.07-2.98
(m, 1H), 2.05-1.96 (m, 1H), 1.91-1.79 (m, 2H), 1.73-1.58 (m, 2H),
1.11-1.03 (m, 4H), 0.79-0.72 (m, 2H), 0.63-0.56 (m, 2H); MS(ES+)
m/z 459.2 (M+H).
Example 41
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-phenylpiperidi-
n- 3-yl)oxy)benzamide
##STR00267##
[0436] Following the procedure as described in Example 39 step 2
and making variations as required to replace
(R)-5-chloro-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-phenylpiperidin-3-yl)oxy)benzoic
acid and cyclopropanesulfonamide with 1-azetidinesulfonamide and
purification by flash chromatography [(R.sub.f=0.2 in 2:1
hexanes:ethyl acetate (containing 0.2% acetic acid)], the title
compound was obtained as a colorless solid (0.08 g, 20%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.57 (brs, 1H), 7.18-7.03 (m,
4H), 6.91-6.49 (m, 2H), 6.72-6.65 (m, 1H), 4.72-4.63 (m, 1H), 4.00
(t, J=7.6 Hz, 4H), 3.56-3.48 (m, 1H), 3.28-3.19 (m, 2H), 3.15-3.05
(m, 1H), 2.12 (quintet, J=7.6 Hz, 2H), 2.05-1.95 (m, 1H), 1.91-1.78
(m, 2H), 1.73-1.58 (m, 2H), 0.80-0.71 (m, 2H), 0.65-0.57 (m, 2H);
MS(ES+) m/z 474.25 (M+H).
Example 42
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(3,5-dichlorophenyl)piper-
idin- 3-yl)oxy)-2-fluorobenzamide
##STR00268##
[0437] Step 1. Preparation of (R)-methyl
5-cyclopropyl-4-((1-(3,5-dichlorophenyl)piperidin-3-yl)oxy)-2-fluorobenzo-
ate
##STR00269##
[0439] Following the procedure as described in Example 40 step 1
and making variation as required to replace iodobenzene with
1,3-dichloro-5-iodobenzene, the title compound was obtained as a
colorless oil (1.08 g, 47%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.39 (d, J=8.3 Hz, 1H), 6.74-6.69 (m, 3H), 6.57 (d, J=12.7
Hz, 1H), 4.52-4.43 (m, 1H), 3.86 (s, 3H), 3.59 (dd, J=12.8, 3.07
Hz, 1H), 3.39-3.29 (m, 2H), 3.24-3.12 (m, 1H), 2.15-2.04 (m, 1H),
2.00-1.91 (m, 1H), 1.90-1.78 (m, 2H), 1.75-1.62 (m, 1H), 0.86-0.77
(m, 2H), 0.60-0.53 (m, 2H); MS(ES+) m/z 438.2, 440.2 (M+H).
Step 2. Preparation of
(R)-5-cyclopropyl-4-((1-(3,5-dichlorophenyl)piperidin-3-
yl)oxy)-2-fluorobenzoic acid
##STR00270##
[0441] Following the procedure as described in Example 39 step 1
and making variation as required to replace (R)-methyl
5-chloro-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-2-fluorobenzo-
ate with (R)-methyl
5-cyclopropyl-4-((1-(3,5-dichlorophenyl)piperidin-3-yl)oxy)-2-fluorobenzo-
ate, the title compound was obtained as a colorless solid (1.04 g,
quant.); MS(ES+) m/z 424.2, 426.2 (M+H).
Step 3. Preparation of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-
(3,5-dichlorophenyl)piperidin-3-yl)oxy)-2-fluorobenzamide
##STR00271##
[0443] Following the procedure as described in Example 39 step 2
and making variation as required to replace (R)-5-chloro-4-((1
-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-2-fluorobenzoic acid
with
(R)-5-cyclopropyl-4-((1-(3,5-dichlorophenyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid and purification by flash chromatography [R.sub.f=0.25
in 2:1 hexanes:ethyl acetate (containing 0.2% acetic acid)), the
title compound was obtained as a colorless solid (0.175 g, 47%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.77 (brs, 1H), 7.06
(d, J=13.2 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 6.85 (d, J=1.8 Hz, 2H),
6.69 (dd, J=1.7, 1.7 Hz, 1H), 4.73-4.65 (m, 1H), 3.73-3.63 (m, 1H),
3.57-3.49 (m, 1H), 3.48-3.39 (m, 2H), 3.27-3.21 (m, 1H), 3.08-2.97
(m, 1H), 2.00-1.88 (m, 1H), 1.84-1.71 (m, 1H), 1.67-1.59 (m, 1H),
1.57-1.46 (m, 1H), 1.13-1.03 (m, 4H), 0.70-0.60 (m, 2H), 0.57-0.48
(m, 2H); MS(ES+) m/z 527.1, 529.1 (M+H).
Example 43
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(3,5-dichlorophenyl)pip-
eridin-3-yl)oxy-2-fluorobenzamide
##STR00272##
[0445] Following the procedure as described in Example 39 step 2
and making variation as required to replace
(R)-5-chloro-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-4-((1-(3,5-dichlorophenyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid and cyclopropanesulfonamide with 1-azetidinesulfamide
and purification by flash chromatography (R.sub.f=0.25 in 2:1
hexanes:ethyl acetate (+0.2% acetic acid)), the title compound was
obtained as a colorless solid (0.16 g, 42%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.55 (brs, 1H), 7.09-7.00(m, 2H), 6.86 (d,
J=1.7 Hz, 2H), 6.71-6.68 (m, 1H), 4.72-4.65 (m, 1H), 3.99 (t, J=7.7
Hz, 4H), 3.67 (dd, J=13.7, 5.5 Hz, 1H), 3.52 (dd, J=13.7, 2.3 Hz,
1H), 3.48-3.39 (m, 1H), 3.27-3.21 (m, 1H), 2.11 (p, J=7.7 Hz, 2H),
1.99-1.88 (m, 1H), 1.84-1.71 (m, 2H), 1.68-1.59 (m, 1H), 1.59-1.46
(m, 1H), 0.69-0.61 (m, 2H), 0.57-0.50 (m, 2H); MS (ES+) m/z 542.2,
544.1 (M+H).
Example 44
Synthesis of
(R)-5-cyclopropyl-4-((1-(3,5-dichlorophenyl)piperidin-3-yl)oxy)-
2-fluoro-N-(methylsulfonyl)benzamide
##STR00273##
[0447] Following the procedure as described in Example 3 step 2 and
making variations as required to replace (R)-5-chloro-4-((1
-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-2-fluorobenzoic acid
with
(R)-5-cyclopropyl-4-((1-(3,5-dichlorophenyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid and cyclopropanesulfonamide with methanesulfonamide and
purification by flash chromatography (R.sub.f=0.5 in 2:1
hexanes:ethyl acetate (+0.2% acetic acid)), the title compound was
obtained as a colorless solid (0.15 g 42%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.83 (brs 1H), 7.08-6.99 (m, 2H), 6.85 (d,
J=1.7 Hz, 2H), 6.70-6.68 (m, 1H), 4.72-4.65 (m, 1H), 3.68 (dd,
J=13.7, 5.4 Hz, 1H), 3.53 (dd, J=13.7, 2.4 Hz, 1H), 3.48-3.38 (m,
1H), 3.30 (s, 3H), 3.26-3.21 (m, 1H), 1.99-1.88 (m, 1H), 1.83-1.70
(m, 2H), 1.69-1.59 (m, 1H), 1.57-1.45 (m, 1H), 0.69-0.61 (m, 2H),
0.57-0.49 (m, 2H); MS(ES+) m/z 501.1, 503.1 (M+H)
Example 45
Synthesis of
(S)-N-(azetidin-1-ylsulfonyl)-4-((1-benzylpyrrolidin-3-yl)oxy)-5-cyclopro-
pyl-2-fluorobenzamide
##STR00274##
[0449] Following the procedure as described in Example 3 steps 1 to
5, and making variations as required to replace (R)-tert-butyl
3-hydroxypiperidine-1-carboxylate with (S)-tert-butyl
3-hydroxypyrrolidine-1-carboxylate, 3,5-dichlorobenzaldehyde with
benzaldehyde and cyclopropylsulfonamide with
azetidine-1-sulfonamide, the title compound was obtained (0.027 g,
5%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) d 7.40-7.17 (m, 5H), 7.13
(d, J=8.8 Hz, 1H), 6.69 (d, J=12.61 Hz, 1H), 5.00-4.87 (m, 1H),
3.86-3.71 (m, 4H), 3.65-3.59 (m, 2H), 2.98-2.84 (m, 1H), 2.78-2.56
(m, 3H), 2.37-1.77 (m, 5H), 0.92-0.78 (m, 2H), 0.62-0.52 (m, 2H);
MS(ES+) m/z 474.2 (M+1); MS(ES-) m/z 472.3 (M-1).
Example 46
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-4-((1-benzylpyrrolidin-3-yl)oxy)-5-cyclopro-
pyl-2-fluorobenzamide
##STR00275##
[0451] Following the procedures as described in Example 3 steps 1
to 5, and making variations as required to replace (R)-tert-butyl
3-hydroxypiperidine-1-carboxylate with (R)-tert-butyl
3-hydroxypyrrolidine-1-carboxylate, 3,5-dichlorobenzaldehyde with
benzaldehyde and cyclopropylsulfonamide with
azetidine-1-sulfonamide, the title compound was obtained (0.095 g,
27% ): .sup.1H NMR (300 MHz, DMSO-d.sub.6) d 7.45-7.18 (m, 5H),
7.10 (d, J=8.3 Hz, 1H), 6.82 (d, J=12.7 Hz, 1H), 5.07-4.94 (m, 1H),
3.98-3.87 (m, 4H), 3.76 (s, 2H), 3.06 (dd, J=11.0, 5.8 Hz, 1H),
2.91-2.74 (m, 2H), 2.72-2.57 (m, 1H), 2.34 (dt, J=13.9, 7.1 Hz,
1H), 2.17-1.94 (m, 3H), 1.93-1.79 (m, 1H), 0.90-0.77 (m, 2H),
0.67-0.56 (m, 2H); MS(ES+) m/z 474.2 (M+1); MS(ES-) m/z 472.3
(M-1)
Example 47
Synthesis of
N-(azetidin-1-ylsulfonyl)-4-((8-(2-chlorobenzyl)-8-azabicyclo[3.2.1]octan-
-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzamide
##STR00276##
[0452] Step 1. Preparation of benzyl
3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR00277##
[0454] To a solution of 8-Azabicyclo[3.2.1]octan-3-ylmethanol (1.00
g, 7.09 mmol) in dichloromethane (15 mL) and a saturated aqueous
sodium bicarbonate solution (10 mL) at 0.degree. C. was added
benzyl chloroformate (1.26 g, 7.45 mmol) and the reaction mixture
was stirred at 0.degree. C. for 30 min. The reaction mixture was
then extracted with dichloromethane (3.times.100 mL). The organic
layers were combined and washed with brine (150 mL); dried over
anhydrous sodium sulfate, filtered and concentrated to give the
title compound, which was used directly for the next step. (1.50 g,
73%). .sup.1H NMR (300 MHz, CDCl.sub.3) d 7.43-7.24 (m, 5H),
5.15-5.09 (m, 2H), 4.59-4.57 (m, 1H), 4.40-4.27 (m, 2H), 3.41 (m,
2H), 2.14-1.90 (m, 3H), 1.88-1.80 (m, 1H), 1.73-1.48 (m, 4H).
Step 2. Preparation of benzyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)-
8-azabicyclo[3.2.1]octane-8-carboxylate
##STR00278##
[0456] To a solution of benzyl
3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.92 g,
7.00 mmol) in anhydrous dimethylsulfoxide (15 mL) was added cesium
carbonate (5.69 g, 10.50 mmol) and tert-butyl
5-chloro-2,4-difluorobenzoate (1.82 g, 7.35 mmol). The reaction
mixture was stirred at 70.degree. C. for 16 hours; cooled to
ambient temperature and acidified to pH=1 with 5% aqueous
hydrochloric acid solution and extracted with ethyl acetate
(2.times.15 mL), the combined organics were washed with brine (15
mL); dried over anhydrous sodium sulfate; filtered and concentrated
in vacuo. Purification of the residue by column chromatography (0
to 10% gradient of ethyl acetate in hexanes) afforded the title
compound (2.00 g, 54%): .sup.1H NMR (300 MHz, CDCl.sub.3) d 7.85
(d, J=7.6 Hz, 1H), 7.39-7.26 (m, 5H), 6.56 (d, J=12.1 Hz, 1H),
5.13(s, 2H), 4.46-4.28 (m, 2H), 3.81-3.73 (m, 2H), 2.54-2.32 (m,
1H), 2.03-1.96 (m, 4H), 1.79-1.65 (m, 4H), 1.60-1.51 (m, 9H);
MS(ES+) m/z 504.2, 506.2 (m+1).
Step 3. Preparation of benzyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)-
8-azabicyclo[3.2.1]octane-8-carboxylate.
##STR00279##
[0458] To a solution of benzyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)-
methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.50 g, 2.98
mmol), cyclopropylboronic acid (0.38 g, 4.46 mmol), potassium
phosphate (2.10 g, 5.95 mmol) and tricyclohexylphosphine
tetrafluoroborate (0.22 g, 0.60 mmol) in toluene (15 mL) and water
(1.5 mL) under a nitrogen atmosphere was added palladium acetate
(0.06 g, 0.31 mmol). The reaction mixture was heated at reflux for
16 hours, and then cooled to ambient temperature. Water (50 mL) was
added and the mixture was extracted with diethyl ether (2.times.100
mL), the combined organics were washed with brine (30 mL); dried
over anhydrous sodium sulfate and concentrated in vacuo.
Purification of the residue by column chromatography (10 to 30%
gradient of ethyl acetate in hexanes) afforded the title compound
(1.05 g, 66%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.48 (d,
J=8.4 Hz, 1H), 6.58 (d, J=12.9 Hz, 1H), 3.87 (dd, J=6.9, 2.3 Hz,
2H), 2.17-1.91 (m, 3H), 1.76-1.31 (m, 8H), 0.98-0.84 (m, 5H),
0.67-0.58 (m, 2H).
Step 4. Preparation of benzyl
3-((4-((azetidin-1-ylsulfonyl)carbamoyl)-2-cyclopropyl-
5-fluorophenoxy)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate.
##STR00280##
[0460] To a stirred solution of benzyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-
fluorophenoxy)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.56
g, 1.10 mmol) in dichloromethane (5 mL) at 0.degree. C. was added
trifluoroacetic acid (1 mL) and the mixture was stirred for 1.5
hours at ambient temperature and then concentrated. The residue was
further concentrated 2 times with toluene (5 mL) and then diluted
with dichloromethane (5 mL). To this solution was added
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.426
g, 1.65 mmol) and 4-(dimethylamino)pyridine (0.335 g, 2.75 mmol)
and azetidine-1-sulfonamide (0.165 g, 1.21 mmol). The reaction
mixture was stirred at room temperature for 16 hours and then
diluted with dichloromethane (10 mL) and washed with aqueous
hydrochloric acid (1M, 10 mL). The aqueous layer was extracted with
dichloromethane (10 mL); the organic layers were combined, dried
over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by column chromatography (0 to 15% gradient of
methanol, containing 1% NH.sub.3 in dichloromethane) to give the
title compound (460 mg, 73%): MS(ES+) m/z 572.2 (M+1 ); MS(ES-) m/z
570.2 (M-1).
Step 5. Preparation of
4-(8-azabicyclo[3.2.1]octan-3-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-cycl-
opropyl-2-fluorobenzamideate.
##STR00281##
[0462] To a stirred solution of benzyl
3-((4-((azetidin-1-ylsulfonyl)carbamoyl)-2-cyclopropyl-
5-fluorophenoxy)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
(0.46 g, 0.81 mmol) in degassed ethyl acetate was added palladium
20% on carbon (0.050 g). The reaction mixture was stirred for 2
hours under an atmosphere of hydrogen. The reaction mixture was
then filtered over a plug of silica gel and rinsed (2.times.15 mL)
with a solution of 20% methanol and 2% acetic acid in
dichloromethane. The filtrate was concentrated to give the title
compound (0.2 g, 56%). .sup.1H NMR (300 MHz, MeO-d.sub.4) .delta.
7.37-7.13 (m, 1H), 6.87-6.61 (m, 1H), 4.33-3.73 (m, 1H), 3.38-3.23
(m, 1H), 2.68-1.64 (m, 2H), 1.03-0.75 (m, 2H), 0.69-0.51 (m,
2H).
Step 6. Preparation of
N-(azetidin-1-ylsulfonyl)-4-((8-(2-chlorobenzyl)-8-
azabicyclo[3.2.1]octan-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzamide
##STR00282##
[0464] To a stirred solution of
4-(8-azabicyclo[3.2.1]octan-3-ylmethoxy)-N-(azetidin-1-
ylsulfonyl)-5-cyclopropyl-2-fluorobenzamideate (50 mg, 0.11 mmol)
in tetrahydrofuran (1 mL) under an atmosphere of nitrogen were
introduced 2-chlorobenzaldehyde (19 mg, 0.14 mmol) and sodium
triacetoxyborohydride (66 mg, 0.21 mmol) and the mixture was
stirred for 16 hours. 1N aqueous hydrochloric acid (5 mL) was added
and the mixture was extracted with ethyl acetate (3.times.10 mL)
and concentrated. The residue was purified by chromatography
eluting with 5% methanol in dichloromethane to give the title
compound, which was lyophilized to give a white solid (0.035 g,
29%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) d 7.71 (d, J=6.5 Hz, 1H),
7.44 (d, J=7.3 Hz, 1H), 7.40-7.28 (m, 2H), 7.12 (d, J=8.3 Hz, 1H),
6.86 (d, J=12.7 Hz, 1H), 4.00-3.79 (m, 8H), 3.55-3.42 (m, 2H),
2.33-1.94 (m, 6H), 1.83-1.60 (m, 6H), 0.90-0.80 (m, 2H), 0.68-0.56
(m, 2H). MS(ES+) m/z 562.2, 564.2 (M+1); MS(ES-) m/z 560.3, 562.3
(M-1).
Example 48
Synthesis of
N-(azetidin-1-ylsulfonyl)-4-((8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)meth-
oxy)-5-cyclopropyl-2-fluorobenzamide
##STR00283##
[0466] Following the procedure as described in Example 47 step 6,
and making variation as required to replace 2-chlorobenzaldehyde
with benzyaldehyde, the title compound was obtained as a white
solid (0.025 g, 41%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) d
7.66-7.52 (m, 2H), 7.47-7.36 (m, 3H), 7.22-7.12 (m, 1H), 6.82-6.71
(m, 1H), 4.18-4.01 (m, 2H), 3.97-3.62 (m, 8H), 2.42-2.16 (m, 3H),
2.14-1.71 (m, 9H), 0.91 -0.76 (m, 2H), 0.63-0.52 (m, 2H); MS(ES+)
m/z 528.2 (M+1).
Example 49
Synthesis of
N-(azetidin-1-ylsulfonyl)-4-((8-benzhydryl-8-azabicyclo[3.2.1]-octan-3-yl-
)methoxy)-5-cyclopropyl-2-fluorobenzamide
##STR00284##
[0468] To a stirred solution of
4-(8-azabicyclo[3.2.1]octan-3-ylmethoxy)-N-(azetidin-1-
ylsulfonyl)-5-cyclopropyl-2-fluorobenzamideate (0.05 g, 011 mmol)
in acetonitrile (2 mL) under an atmosphere of nitrogen was added
(bromomethylene)dibenzene (0.034 g, 0.14 mmol), potassium carbonate
(0.038 g, 0.27 mmol) and sodium iodide (0.021 g, 0.14 mmol). The
reaction mixture was stirred at reflux for 16 hours and then cooled
to ambient temperature. 1N aqueous hydrochloric acid (5 mL) was
added and the mixture was extracted with ethyl acetate (3.times.10
mL) and concentrated. The residue was first purified by column
chromatography eluting with 30% ethyl acetate (containing 1% formic
acid) in hexanes and then purified by reverse phase chromatography
eluting with a gradient of acetonitrile in water (containing 0.1%
trifluoroacetic acid) and finally crystallized in isopropyl alcohol
to give the title compound (0.03 g, 43%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) d 12.18-11.67 (m, 1H), 8.75-8.53 (m, 1H), 7.98-7.76
(m, 4H), 7.61-7.49 (m, 1H), 7.47-7.30 (m, 6H), 6.59 (d, J=14.1 1H),
4.77-4.65 (m, 1H), 4.28-4.17 (m, 4H), 4.07-3.98 (m, 2H), 3.97-3.87
(m, 2H), 2.90-2.56 (m, 3H), 2.51-2.34 (m, 3H), 2.24 (m, 2H),
2.12-2.01 (m, 2H), 1.95-1.81 (m, 2H), 0.90-0.76 (m, 2H), 0.67-0.55
(m, 2H); MS(ES+) m/z 564.3 (M+1); MS(ES-) m/z 562.3.
Example 50
Synthesis of
(5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-3-
yl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00285##
[0469] Step 1. Preparation of methyl
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)-
piperidin-3-yl)oxy)-2-fluorobenzoate and methyl
5-cyclopropyl-4-(((R)-1-((R)-1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)o-
xy)-2-fluorobenzoate
##STR00286##
[0471] To a mixture of (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate (0.52 g, 1.77
mmol), potassium carbonate (0.73 g, 5.30 mmol) and sodium iodide
(0.26 g, 1.77 mmol) in acetonitrile (50 mL) was added
1,3-dichloro-5-(1-chloroethyl)benzene (0.37 g, 1.77 mmol). The
reaction mixture was heated at reflux for 16 hours, and
concentrated in vacuo. To the he residue was added 25% aqueous
ammonium chloride solution (40 mL) and extracted with ethyl acetate
(2.times.70 mL). The combined organic layer was washed with brine
(40 mL), dried over anhydrous sodium sulfate and concentrated in
vacuo. The residue was purified by column chromatography (0-20%
ethyl acetate in hexanes) afforded the title compound. The first
eluting fraction was arbitrarily assigned as methyl
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-
3-yl)oxy)-2-fluorobenzoate (0.18 g, 22%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.42 (d, J=8.4 Hz, 1H), 7.22-7.21 (m, 3H), 6.54
(d, J=12.9 Hz, 1H), 4.39-4.37 (m, 1H), 3.87 (s, 3H), 3.47 (q, J=1
6.6 Hz, 1H), 2.97-2.94 (m, 1H), 2.57-2.54 (m, 1H), 2.35-2.23 (m,
2H), 2.11-1.98 (m, 2H), 1.85-1.77 (m, 1H), 1.65-1.51 (m, 2H), 1.31
(d, J=6.7 Hz, 3H), 0.94-0.90 (m, 2H), 0.68-0.63 (m, 2H); MS(ES+)m/z
466.1, 468.1 (M+1). The second eluting fraction was arbitrarily
assigned methyl
5-cyclopropyl-4-(((R)-1-((R)-1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)o-
xy)-2-fluorobenzoate (0.18 g, 22%): .sup.1H NMR (300 Hz,
CDCl.sub.3) .delta. 7.42 (d, J=8.4 Hz, 1H), 7.22-7.21 (m, 3H), 6.54
(d, J=12.9 Hz, 1H), 4.39-4.37 (m, 1H), 3.87 (s, 3H), 3.47 (q, J=1
6.6 Hz, 1H), 2.97-2.94 (m, 1H), 2.57-2.54 (m, 1H), 2.35-2.23 (m,
2H), 2.11-1.98 (m, 2H), 1.85-1.77 (m, 1H), 1.65-1.51 (m, 2H), 1.31
(d, J=6.7 Hz, 3H), 0.94-0.90 (m, 2H), 0.68-0.63 (m, 2H); MS(ES+)
m/z 466.1, 468.1 (M+1).
Step 2. Preparation of
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)-piperidin-3-yl)-
oxy)-2-fluorobenzoic acid
##STR00287##
[0473] To a mixture of
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)-piperidin-3-yl)-
oxy-2-fluorobenzoate (0.20 g, 0.43 mmol) in tetrahydrafurane (30
mL) and water (5 mL) was added lithium hydroxide (0.10 g, 4.3
mmol). The reaction mixture was heated to reflux for 16 hours and
adjusted pH to 7 with 1N aqueous hydrochloric acid solution,
extracted with ethyl acetate (2.times.50) mL), the combined
organics were washed with 25% aqueous ammonium chloride solution
(2.times.30 mL), dried over anhydrous sodium sulfate and
concentrated in vacuo. Purification of the residue by column
chromatography (20%-100% ethyl acetate in hexanes) afforded the
title compound (0.15 g, 77%): MS(ES+) m/z 452.1, 454.1 (M +1);
MS(ES-) m/z 450.2, 452.2(M-1).
Step 3. Preparation of
(5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)-piperidin-3-yl-
)oxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00288##
[0475] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)-ethyl)piperidin-3-
yl)oxy)-2-fluorobenzoic acid, the title compound was obtained as
colorless solid (0.05 g, 33%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.87 (brs, 1H), 7.46-7.37 (m, 3H), 7.13 (d, J=8.4 Hz, 1H),
6.95 (d, J=13.2 Hz, 1H), 4.59-4.57 (m, 1H), 3.63-3.62 (m, 1H), 3.28
(s, 3H), 2.77-2.73 (m, 1H), 2.43-2.33 (m, 3H), 2.13-2.03 (m, 1H),
2.18-1.73 (m, 2H), 1.55-1.53 (m, 2H), 1.27 (d, J=6.7 Hz, 3H),
0.91-0.88 (m, 2H), 0.73-0.66 (m, 2H); MS(ES+) m/z 529.1, 531.1
(M+1); MS(ES-) m/z 527.2, 529.2 (M-1).
Example 51
Synthesis of
(5-cyclopropyl-4-(((R)-1-((R)-1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)-
oxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00289##
[0476] Step 1. Preparation of 5-cyclopropyl-4-(((R)-1-((R)-1-(3,5
-dichlorophenyl)ethyl)-piperidin-3-yl)oxy)-2-fluorobenzoic acid
##STR00290##
[0478] Following the procedure as described in Example 50 step 2
and making variations as required to replace
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-
3-yl)oxy)-2-fluorobenzoate with
5-cyclopropyl-4-(((R)-1-((R)-1-(3,5-dichlorophenyl)ethyl)-
piperidin-3-yl)oxy)-2-fluorobenzoate, the title compound was
obtained as beige color solid (0.18 g, 2%): MS(ES+) m/z 452.2,
454.2 (M+1); MS(ES-) m/z 450.2, 452.2 (M-1).
Step 2. Preparation of
(5-cyclopropyl-4-(((R)-1-((R)-1-(3,5-dichlorophenyl)ethyl)-piperidin-3-yl-
)oxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00291##
[0480] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
5-cyclopropyl-4-(((R)-1-((R)-1-(3,5-dichlorophenyl)ethyl)-piperidin-3-
yl)oxy)-2-fluorobenzoic acid, the title compound was obtained as
colorless solid (0.06 g, 30%): .sup.1H NMR (300 MHz, DMSO.sub.6)
.delta. 11.87 (brs, 1H), 7.47-7.40 (m, 3H), 7.12 (d, J=8.4 Hz, 1H),
6.96 (d, J=13.2 Hz, 1H), 4.58-4.56 (m, 1H), 3.68 (q, J=6.3 Hz, 1H),
3.29 (s, 3H), 2.80-2.77 (m, 1H), 2.60-2.56 (m, 1H), 2.37-2.20 (m,
2H), 2.08-2.03 (m, 1H), 1.91-1.74 (m, 2H), 1.57-1.46 (m, 2H), 1.27
(d, J=6.7 Hz, 3H), 0.90-0.87 (m, 2H), 0.75-0.63 (m, 2H); MS(ES+)
m/z 529.1, 531.1 (M+1); MS(ES-) m/z 527.2, 529.2 (M-1).
Example 52
Synthesis of
5-((3R,6R)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)oxy)-5-cycl-
opropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00292##
[0481] Step 1. Preparation of (2R,5R)-benzyl
5-hydroxy-2-methylpiperidine-1-carboxylate
##STR00293##
[0483] To a cooled (0.degree. C.) solution of
(3R,6R)-6-methylpiperidin-3-ol (1.06 g, 9.19 mmol) (Ian A. O'Neil
et al., Synlett, 2000, 5, 695) and triethylamine (1.35 mL, 9.65
mmol) dichloromethane (60 mL) was added benzyl chloroformate (1.38
mL, 9.65 mmol) dropwise. The reaction mixture was stirred at
ambient temperature for 16 h, diluted with aqueous saturated
ammonium chloride solution (35 mL), and extracted with ethyl
acetate (3.times.70 mL). The combined organic layers were washed
with brine (100 mL), dried over anhydrous magnesium sulfate,
filtered and concentrated in vacuo. The residue was purified by
column chromatography eluting with a gradient of ethyl acetate in
hexanes (0 to 60%) to give the title compound (1.30 g, 57%) as a
colorless oil: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.40-7.29
(m, 5H), 5.14 (s, 2H), 4.57-4.45 (m, 1H), 4.13-4.02 (m, 1H), 3.94
(s, 1H), 3.18-3.03 (m, 1H), 2.19-2.03 (m, 1H), 1.88-1.62 (m, 3H),
1.39-1.26 (m, 1H), 1.19-1.13 (m, 3H); MS(ES+) m/z 250.2 (M+1).
Step 2. Preparation of (2R,5R)-benzyl
5-(4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)-
2-methylpiperidine-1-carboxylate
##STR00294##
[0485] Following the procedure as described in Example 1 step 1,
and making variation as required to replace
(R)-1-benzylpiperidin-3-ol with
(2R,5R)-benzyl-5-hydroxy-2-methylpiperidine-1-carboxylate, the
title compound was obtained (1.80 g, 72%) as a colorless oil:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.84-7.77 (m, 1H),
7.32-7.08 (m, 5H), 6.64-6.53 (m, 1H), 5.09-4.92 (m, 2H), 4.69-4.56
(m, 1H), 4.46 (s, 1H), 4.39-4.29 (m, 1H), 3.19-3.07 (m, 1H),
2.32-2.16 (m, 1H), 2.01-1.89 (m, 2H), 1.56 (s, 9H), 1.41-1.31 (m,
1H), 1.24-1.18 (m, 3H); MS(ES+) m/z 478.2 (M+1).
Step 3. Preparation of (2R,5R)-benzyl
5-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)-2-methylpiperid-
ine-1-carboxylate
##STR00295##
[0487] Following the procedure as described in Example 1 step 2,
and making variation as required to replace (R)-tert-butyl
4-((1-benzylpiperidin-3-yl)oxy)-5-chloro-2-fluorobenzoate with
(2R,5R)-benzyl 5(4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)-
2-methylpiperidine-1-carboxylate, the title compound was obtained
(1.62 g, 89%) as a colorless oil: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.39-7.32 (m, 1H), 7.30-7.03 (m, 5H), 6.52-6.41 (m, 1H),
5.06-4.92 (m, 2H), 4.68-4.55 (m, 1H), 4.46 (s, 1H), 4.42-4.29 (m,
1H), 3.20-3.07 (m, 1H), 2.27-2.08(m, 1H), 2.04-1.82 (m, 3H), 1.56
(s, 9H), 1.42-1.31 (m, 1H), 1.24-1.19 (m, 3H), 0.83-0.73 (m, 2H),
0.58-0.47 (m) 2H); MS(ES+) m/z 484.3 (M+1).
Step 4. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-(((3R,6R)-6-methylpiperidin-
3-yl)oxy)benzoate
##STR00296##
[0489] To a solution of (2R,5R)-benzyl
5-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)-2-methylpiperid-
ine-1-carboxylate (1.62 g, 3.35 mmol) in ethyl acetate (15 mL) and
methanol (30 mL) was added 10% palladium on carbon (0.5 g). The
reaction mixture was stirred at ambient temperature under hydrogen
atmosphere using a balloon for 1 h and filtered through a pad of
Celite. The filtrate was concentrated in vacuo to give the title
compound (0.94 g, 80%) as colorless oil: MS(ES+) m/z 350.3
(M+1).
Step 5. Preparation of
tert-butyl-4-(((3R,6R)-1-(2-chloro-4-fluorobenzyl)piperidin-3-
yl)oxy)-5-cyclopropyl-2-fluorobenzoate
##STR00297##
[0491] Following the procedure as described in Example 34 step 2,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yl)oxy)benzoate with
tert-butyl
5-cyclopropyl-2-fluoro-4-(((3R,6R)-6-methylpiperidin-3-yl)oxy)benzoate,
and to replace 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene
with 1-(bromomethyl)-2- chloro-4-fluorobenzene, the title compound
was obtained (1.29 g, 98%) as a colorless oil: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.58-7.48 (m, 1H), 7.36-7.29 (m, 1H),
7.11-7.03 (m, 1H), 7.00-6.90 (m, 1H), 6.50-6.39 (m, 1H), 4.36-4.23
(m, 1H), 4.05-3.92 (m, 1H), 3.43-3.32 (m, 1H), 3.10-2.99 (m, 1H),
2.58-2.41 (m, 1H), 2.29-2.11 (m, 2H), 2.04-1.83 (m, 2H), 1.64-1.39
(m, 11H), 1.21-1.10 (m, 3H), 0.94-0.80 (m, 2H), 0.65-0.55 (m, 2H);
MS(ES+) m/z 492.2, 494.4 (M+1).
Step 6. Preparation of
4-(((3R,6R)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)oxy)-
5-cyclopropyl-2-fluorobenzoic acid
##STR00298##
[0493] Following the procedure as described in Example 3 step 3,
and making variation as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)piperidine-
1-carboxylate with of tert-butyl
4-(((3R,6R)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-
yl)oxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained (1.10 g, 97%) as a colorless solid; MS(ES+) m/z 436.2,
438.2 (M+1).
Step 7. Preparation of
4-(((3R,6R)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)oxy)-5-cyc-
lopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00299##
[0495] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
4-(((3R,6R)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)oxy)-5-cyc-
lopropyl- 2-fluorobenzoic acid, the title compound was obtained
(0.065 g, 22%) as a colorless solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.80-8.56 (m, 1H), 7.59-7.46 (m, 2H), 7.13-7.05
(m, 1H), 7.01-6.89 (m, 1H), 6.54-6.40 (.English Pound.(m, 1H),
4.38-4.26 (m, 1H), 4.06-3.95 (m, 1H), 3.46-3.33 (m, 4H), 3.09-3.00
(m, 1H), 2.59-2.45 (m, 1H), 2.32-2.11 (m, 2H), 2.09-1.86 (m, 2H),
1.70-1.41 (m, 2H), 1.22-1.16 (m, 3H), 0.96-0.85 (m, 2H), 0.67-0.59
(m, 2H); MS(ES+) m/z 513.1, 515.1 (M+1).
Example 53
Synthesis of
(S)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((3-(3,5-dichlorophenoxy)-pip-
eridin-1-yl)methyl)-2-fluorobenzamide.
##STR00300##
[0496] Step 1. Preparation of (S)-tert-butyl
3-(3,5-dichlorophenoxy)piperidine-1-carboxylate
##STR00301##
[0498] A mixture of (S)-tert-butyl
3-hydroxypiperidine-1-carboxylate (1.00 g, 4.97 mmol),
3,5-dichloroiodobenzene (1.36 g, 4.97 mmol), copper(I) iodide
(0.142 g, 0.75 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline
(0.352 g, 1.49 mmol), molecular sieves 4 .ANG. (1.00 g), and cesium
carbonate (4.86 g, 14.9 mmol) in toluene (6 mL) was degassed and
then heated to 90.degree. C. for 16 hours. After cooling to ambient
temperature, the mixture was filtered through a plug of celite. The
filter cake was washed with dichloromethane (100 mL), and the
combined filtrate concentrated in vacuo. Purification of the
residue by column chromatography (0 to 30% ethyl acetate in
hexanes) afforded the title compound as a colorless oil: (1.20 g,
70%): MS(ES+) m/z 346.1, 348.1 (M+1).
Step 2. Preparation of (S)-3-(3,5-dichlorophenoxy)piperidine,
trifluoroacetic acid salt
##STR00302##
[0500] A solution of (S)-tert-butyl
3-(3,5-dichlorophenoxy)piperidine-1-carboxylate (1.17 g, 3.38 mmol)
in dichloromethane (30 mL) was treated with trifluoroacetic acid
(10 mL). The mixture was stirred at ambient temperature for 1 hour
and then concentrated in vacuo to provide the title compound as an
oil (1.22 g, quant.); MS(ES+) m/z 246.2, 248.1 (M+1)
Step 3. Preparation of (S)-tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-
yl)methyl)-2-fluorobenzoate
##STR00303##
[0502] A mixture of tert-butyl
5-cyclopropyl-2-fluoro-4-(((methylsulfonyl)oxy)methyl)benzoate
(0.64 g, 1.86 mmol), (S)-3-(3,5-dichlorophenoxy)piperidine,
trifluoroacetic acid salt (0.74 g, 2.05 mmol), and potassium
carbonate (0.64 g, 4.65 mmol) in anhydrous dimethylformamide (15
mL) was stirred at ambient temperature for 18 hours. The reaction
mixture was diluted with ethyl acetate (100 mL), washed with water
(80 mL), saturated ammonium chloride (2.times.80 mL), brine (80
mL), dried over anhydrous sodium sulfate, filtered the solid, and
concentrated in vacuo. The residue was purified by flash
chromatography (0 to 25% ethyl acetate in hexanes) to provide the
title compound as an oil (0.70 g, 76%): .sup.1H NMR (300 MHz,
CDCl.sub.3) d 7.48 (d, J=7.3 Hz, 1H), 7.15 (d, J=11.8 Hz, 1H),
6.90-6.87 (m, 1H), 6.76-6.73 (m, 2H), 4.35-4.23 (m, 1H), 3.72-3.58
(m, 2H), 2.97-2.88 (m, 1H), 2.71-2.61 (m, 1H), 2.31-2.12 (m, 2H),
2.06-1.88 (m, 2H), 1.85-1.74 (m, 1H), 1.70-1.38 (m, 11H), 0.94-0.82
(m, 2H), 0.64-0.54 (m, 2H); MS(ES+) m/z 494.3, 496.3 (M+1).
Step 4. Preparation of
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid
##STR00304##
[0504] A solution of (S)-tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-
1-yl)methyl)-2-fluorobenzoate (1.04 g, 2.10 mmol) in
dichloromethane (30 mL) was treated with trifluoroacetic acid (10
mL). The resulting solution was stirred at ambient temperature for
1 hour and then concentrated in vacuo to provide the title compound
as a colorless solid (0.92 g, quant.); MS(ES+) m/z 438.1, 440.1
(M+1).
Step 5. Preparation of
(S)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((3-(3,5-dichlorophenoxy)pipe-
ridin-1-yl)methyl)-2-fluorobenzamide
##STR00305##
[0506] A mixture of
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid (0.30 g, 0.68 mmol), cyclopropanesulfonamide (0.12
g, 1.02 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0.20
g, 1.02 mmol), and 4-dimethylaminopyridine (0.25 g, 2.04 mmol) in
dichloromethane (12 mL) was stirred at ambient temperature for 24
hours. The reaction mixture was treated with acetic acid (1.0 mL)
and purified by flash chromatography (0 to 30% ethyl acetate
(containing 0.2% acetic acid) in hexanes) to provide the title
compound as a colorless solid (0.175 g, 48%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.93 (br s, 1H), 7.24 (d, J=11.7 Hz, 1H),
7.18 (d, J=7.0 Hz, 1H), 7.09-7.07 (m, 1H), 7.01 (d, J=1.9 Hz, 2H),
4.61-4.51 (m, 1H), 3.69 (s, 2H), 3.08-2.99 (m, 1H), 2.85-2.77 (m,
1H), 2.63-2.52 (m, 1H), 2.41-2.21 (m, 2H), 2.05-1.97 (m, 1H),
1.96-1.84 (m, 1H), 1.78-1.67 (m, 1H), 1.63-1.51 (m, 1H), 1.49-1.34
(m, 1H), 1.11-1.03 (m, 4H), 0.91-0.79 (m, 2H), 0.68-0.56 (m, 2H);
MS(ES+) m/z 541.2, 543.2 (M+1).
Example 54
Synthesis of
(S)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)pi-
peridin- 1-yl)methyl)-2-fluorobenzamide, acetic acid salt
##STR00306##
[0508] Following the procedure as described in Example 53, step 5,
and making variation as required to replace cyclopropanesulfonamide
with azetidine-1-sulfonamide, the title compound was obtained as a
colorless solid (0.16 g, 42%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.74 (br s, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.35-7.26 (m, 1H),
6.91 (s, 1H), 6.77 (s, 2H), 4.39-4.28 (m, 1H), 4.24 (t, J=7.7 Hz,
4H), 3.37-3.65 (m, 2H), 2.96-2.86 (m, 1H), 2.74-2.62 (m, 1H),
2.39-2.19 (m, 4H), 2.08 (s, 3H), 1.98-1.79 (m, 3H), 1.72-1.44 (m,
3H), 1.00-0.88 (m, 2H), 0.71-0.59 (m, 2H); MS(ES+) m/z 556.2, 558.2
(M+1).
Example 55
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((3-(3,5-dichlorophenoxy)pipe-
ridin- 1-yl)methyl)-2-fluorobenzamide
##STR00307##
[0509] Step 1. Preparation of (R)-tert-butyl
3-(3,5-dichlorophenoxy)piperidine-1-carboxylate
##STR00308##
[0511] Following the procedure as described in Example 53 step 1
and making variation as required to replace (S)-tert-butyl
3-hydroxypiperidine-1-carboxylate with (R)-tert-butyl
3-hydroxypiperidine-1-carboxylate, the title compound was obtained
as a colorless oil (0.461 g, 83%): .sup.1H NMR (300 MHz,
CDCl.sub.3) d 6.91-6.87 (m, 1H), 6.76-6.74 (m, 2H), 4.23-4.12 (m,
1H), 3.92-3.03 (m, 4H), 2.01-1.88 (m, 1H), 1.85-1.63 (m, 2H),
1.55-1.27 (m, 10H).
Step 2. Preparation of (R)-3-(3,5-dichlorophenoxy)piperidine,
trifluoroacetic acid salt
##STR00309##
[0513] Following the procedure as described in Example 53 step 2,
and making variation as required to replace (S)-tert-butyl
3-(3,5-dichlorophenoxy)piperidine-1-carboxylate with (R)-tert-butyl
3-(3,5-dichlorophenoxy)piperidine-1-carboxylate, the title compound
was obtained as an oil (0.43 g, quant.); MS (ES+) m/z 246.2, 248.2
(M+1).
Step 3. Preparation of (R)-tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoate
##STR00310##
[0515] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with (R)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid
salt, the title compound was obtained as an oil (0.38 g, 72%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.48 (d, J=7.3 Hz, 1H),
7.15 (d, J=11.7 Hz, 1H), 6.90-6.87 (m, 1H), 6.76-6.73 (m, 2H),
4.35-4.24 (m, 1H), 3.72-3.58 (m, 2H), 2.97-2.88 (m, 1H), 2.71-2.61
(m, 1H), 2.31-2.12 (m, 2H), 2.08-1.98 (m, 1H), 1.97-1.88 (m, 1H),
1.85-1.75 (m, 1H), 1.68-1.39 (m, 11H), 11), 0.93-0.84 (m, 2H),
0.64-0.56 (m, 2H); MS (ES+) m/z 494.3, 496.3 (M+1).
Step 4. Preparation of
(R)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid
##STR00311##
[0517] Following the procedure as described in Example 53 step 4,
and making variation as required to replace (S)-tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoate with (R)-tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoate, the title compound was obtained as an colorless solid
(0.34 g, quant.): MS(ES+) m/z 438.1, 440.1 (M+1).
Step 5. Preparation of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((3-(3,5-dichlorophenoxy)-
piperidin-1-yl)methyl)-1-fluorobenzamide
##STR00312##
[0519] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
(R)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid, the title compound was obtained as a colorless
solid (0.12 g, 57%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.85-8.67 (m, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.29 (d, J=14.0 Hz, 1H),
6.91 (s, 1H), 6.75 (s, 2H), 4.37-4.26 (m, 1H), 3.78-3.61 (m, 2H),
3.13-3.03 (m, 1H), 2.94-2.85 (m, 1H), 2.72-2.61 (m, 1H), 2.37-2.18
(m, 2H), 2.09-1.98 (m, 1H), 1.97-1.79 (m, 2H), 1.71-1.49 (m, 2H),
1.48-1.41 (m, 2H), 1.18-1.09 (m, 2H), 0.99-0.88 (m, 2H), 0.70-0.59
(m, 2H); MS(ES+) m/z 541.2, 543.2 (M+1).
Example 56
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)pi-
peridin-1-yl)methyl)-2-fluorobenzamide
##STR00313##
[0521] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
(R)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid and cyclopropanesulfonamide with
azetidine-1-sulfonamide, the title compound was obtained as a
colorless solid (0.30 g, 58%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.80-8.62 (m, 1H), 7.73 (d, J=7.3 Hz, 1H), 7.35-7.26 (m,
1H), 6.91 (s, 1H), 6.76 (s, 2H), 4.38-4.28 (m, 1 H), 4.23 (t, J=7.7
Hz, 4H), 3.77-3.62 (m, 2H), 2.95-2.86 (m, 1H), 2.72-2.62 (m, 1H),
2.37-2.18 (m, 3H), 2.06-1.99 (m, 1H), 1.97-1.88 (m, 1H), 1.86-1.79
(m, 1H), 1.72-1.45 (m, 3H), 1.01-0.89 (m, 2H), 0.71-0.59 (m, 2H);
MS(ES+) m/z 556.2, 558.2 (M+1).
Example 57
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4-(3,5-dichlorophenoxy)piperidi-
n-1-yl)methyl)-2-fluorobenzamide, trifluoroacetic acid
##STR00314##
[0522] Step 1. Preparation of tert-butyl
4-(3,5-dichlorophenoxy)piperidine-1-carboxylate
##STR00315##
[0524] Following the procedure as described in Example 53 step 1,
and making variations as required to replace (S)-tert-butyl
3-hydroxypiperidine-1-carboxylate with tert-butyl
4-hydroxypiperidine-1-carboxylate, the title compound was obtained
as an oil (0.84 g, 41%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
6.92-6.89 (m, 1H), 6.77-6.74 (m, 2H), 4.44-4.34 (m, 1H), 3.69-3.58
(m, 2H), 3.37-3.25 (m, 2H), 1.93-1.80 (m, 2H), 1.75-1.63 (m, 2H),
1.43 (s, 9H).
Step 2. Preparation of 4-(3,5dichlorophenoxy)piperidine,
trifluoroacetic acid salt
##STR00316##
[0526] Following the procedure as described in Example 53 step 2,
and making variation as required to replace (S)-tert-butyl
3-(3,5-dichlorophenoxy)piperidine-1-carboxylate with tert-butyl
4-(3,5-dichlorophenoxy)piperidine-1-carboxylate, the title compound
was obtained as an oil (0.88 g, quant.); MS (ES+) m/z 246.2, 248.2
(M+1).
Step 3. Preparation of tert-butyl
5-cyclopropyl-4-((4-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoate
##STR00317##
[0528] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt,
the title compound was obtained as an oil (0.74 g, 62%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.48 (d, J=7.3 Hz, 1H), 7.17 (d,
J=11.8 Hz, 1H), 6.92-6.88 (m, 1H), 6.79-6.74 (m, 2H), 4.35-4.25 (m,
1H), 3.65 (s, 2H), 2.75-164 (m, 2H), 2.42-2.30 (m, 2H), 1.77-1.90
(m, 3H), 1.86-1.73 (m, 2H), 1.55 (s, 9H), 0.96-0.87 (m, 2H),
0.65-0.57 (m, 2H); MS(ES+) m/z 494.3, 496.3 (M+1).
Step 4. Preparation of
5-cyclopropyl-4-((4-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoic acid
##STR00318##
[0530] Following the procedure as described in Example 53 step 4,
and making variation as required to replace (S)-tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-
1-yl)methyl)-2-fluorobenzoate with tert-butyl
5-cyclopropyl-4-((4-(3,5-dichlorophenoxy)-
piperidin-1-yl)methyl)-2-fluorobenzoate, the title compound was
obtained as an colorless solid (0.66 g, quant.); MS(ES+) m/z 438.2,
440.2 (M+1).
Step 5. Preparation of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4-(3,5-dichlorophenoxy)-
piperidin-1-yl)methyl)-2-fluorobenzamide, trifluoroacetic acid
salt
##STR00319##
[0532] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoic acid and purification by reverse phase HPLC, the title
compound was obtained as a colorless solid (0.20 g, 49%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 12.25 (brs, 1H), 9.76 (brs,
1H), 7.52 (d, J=10.9 Hz, 1H), 7.24 (d, J=6.7 Hz, 1H), 7.20-7.06 (m,
3H), 4.90-4.77 (m, 1H), 4.56 (s, 2H), 3.55-3.41 (m, 1H), 3.34-3.18
(m, 3H), 3.11-3.01 (m, 1H), 2.30-1.92 (m, 4H), 1.86-1.72 (m, 1H),
1.15-1.06 (m, 4H), 1.03-0.95 (m, 2H), 0.80-0.72 (m, 2H); MS (ES+)
m/z 541.2, 543.2 (M+1).
Example 58
Synthesis of
N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((4-(3,5-dichlorophenoxy)piperi-
din-1-yl)- methyl)-2-fluorobenzamide, trifluoroacetic acid salt
##STR00320##
[0534] Following the procedure as described in Example 53 step 5,
and making variations as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoic acid and cyclopropanesulfonamide with
azetidine-1-sulfonamide and purification by reverse phase HPLC, the
title compound was obtained as a colorless solid (0.19 g, 46%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.00 (brs, 1H), 9.69
(brs, 1H), 7.52 (d, J=10.8 Hz, 1H), 7.26 (d, J=6.5 Hz, 1H),
7.20-7.07 (m, 3H), 4.89-4.79 (m, 1H), 4.56 (s, 2H), 4.03 (t, J=7.6
Hz, 4H), 3.54-3.42 (m, 1H), 3.39-3.18 (m, 3H), 2.24-2.09 (m, 4H),
2.08-1.98 (m, 2H), 1.87-1.70 (m, 1H), 1.04-0.96 (m, 2H), 0.82-0.74
(m, 2H); MS(ES+) m/z 556.2, 558.2 (M+1).
Example 59
Synthesis of
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-chloro-2-fluoro-
N-(methylsulfonyl)benzamide
##STR00321##
[0536] To a solution of (1-benzhydrylazetidin-3-yl)methanol (40.4
mg, 0.159 mmol) and
5-chloro-2,4-difluoro-N-methylsulfonyl-benzamide (43.0 mg, 0.159
mmol) in DMSO (0.80 mL) at rt was added potassium tert-butoxide in
1:10 THF-DMSO (0.38 mL, 0.93 M). The mixture was stirred at rt for
1 hr. LCMS showed major product. Diluted with EtOAc, the contents
were washed with 1:4 mixture of 1M HCl and 1M NaH.sub.2PO.sub.4
(2.times.) and brine (1.times.), dried (Na.sub.2SO.sub.4). After
filtration and concentration, the crude was purified with HPLC
(55.7 mg). LCMS (Method D): RT=5.37 min, m/z: 503.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.79 (d, J=7.5 Hz, 1H),
7.47-7.40 (m, 4H), 7.32 (t, J=7.5 Hz, 4H), 7.27-7.15 (m, 3H), 4.78
(s, 1H), 4.29 (d, J=6.1 Hz, 2H), 3.45 (s, 2H), 3.20 (m, 3H), 2.96
(s, 1H).
Example 60
Synthesis of
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-((2-(trim-
ethylsilyl)ethyl)sulfonyl)benzamide
##STR00322##
[0537] Step 1: Preparation of tert-butyl
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-fluoro-2-fluorobenzoate
[0538] To solution of (1-benzhydrylazetidin-3-yl)methanol (1.14 g)
and tert-butyl 5-chloro-2,4-difluoro-benzoate (1.244 g, .about.90%
pure) in DMSO (13.5 mL) at 14.degree. C. (bath) was added potassium
tert-butoxide (0.606 g). The mixture was stirred at rt for 1 hr.
Diluted with EtOAc, the contents were washed with dilute
NaHCO.sub.3 (2.times.) and brine (1.times.), and dried
(Na.sub.2SO.sub.4). After filtration and concentration, the crude
was purified with silica gel flash chromatography (0-40%
EtOAc/heptane) to give the product (1.359 g, 63%).
Step 2: Preparation of tert-butyl
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate
[0539] A mixture of tert-butyl
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-chloro-2-fluorobenzoate
(1.35 g), cyclopropylboronic acid (506 mg), potassium phosphate
(1.52 g), and potassium fluoride (163 mg) in toluene (16.8 mL) and
water (0.56 mL) was purge with nitrogen. Tricyclohexylphosphine
tetrafluoroborate (213 mg) and palladium acetate (64 mg) were
added. The mixture was heated at 90.degree. C. for 7 hours. The
mixture was diluted with EtOAc and filtered. The filtrate was
concentrated. The residue was purified with silica gel flash
chromatography (0-20% EtOAc/heptane with 0.5% Et.sub.3N) to give
the product (1.092 g, 80%.
Step 3: Preparation of
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid
[0540] A to of tert-butyl
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate
(248 mg) and potassium hydroxide (228 mg) in DMSO (2.0 mL) was
slimed at rt for 16 hr. The contents were acidified with 1M
NaH.sub.2PO.sub.4. Solid was collected with filtration, washed with
water, and dried under vacuum (171 rug, 78%).
Step 4: Preparation of
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-((2-(trim-
ethylsilyl)ethyl)sulfonyl)benzamide
[0541] A mixture of
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid (26.2 mg), 2-(trimethylsilyl)ethanesulfonamide (44.0 mg), HBTU
(30.9 mg), and DIPEA (0.053 mL) DCE (0.83 mL) was heated at
40.degree. C. for 16 hr. Acidified with 0.5 M NaH.sub.2PO.sub.4,
the contents were extracted with DCM (2.times.). The combined
extracts were dried (Na.sub.2SO.sub.4). The crude was purified with
HPLC (18.0 mg, 50%). LCMS (Method D): RT=5.47 min, m/z: 595.2
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.66 (s, 1H),
7.45-7.36 (m, 4H), 7.25 (t, J=7.5 Hz, 4H), 7.19-7.07 (m, 3H), 6.93
(d, J=12.7 Hz, 1H), 4.45 (s, 1H), 4.19 (d, J=6.2 Hz, 2H), 3.38-3.29
(m, 2H), 2.99 (s, 2H), 2.84 (s, 1H), 2.07-1.97 (m, 1H), 0.93-0.81
(m, 4H), 0.66-0.59 (m, 2H), -0.00 (s, 7H), -0.03 (s, 4H).
Example 61
Synthesis of
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-((2-metho-
xyethyl)sulfonyl)benzamide
##STR00323##
[0543] The compound was prepared in a similar manner to Example 60
from
4-((1-benzhydrylazetidin-3-yl)-methoxy)-5-cyclopropyl-2-fluorobenzoic
acid and 2-methoxyethanesulfonamide. LCMS (Method D): RT=4.53 min,
m/z: 553.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
7.46-7.37 (m, 4H), 7.33-7.23 (m, 4H), 7.21-7.12 (m, 3H), 6.84 (d,
J=12.6 Hz, 1H), 4.48 (s, 1H), 4.18 (d, J=6.1 Hz, 2H), 3.64 (t,
J=6.6 Hz, 3H), 3.51 (s, 2H), 3.26 (s, 2H), 3.21 (s, 3H), 3.14 (s,
1H), 3.02 (d, J=6.5 Hz, 2H), 2.92-2.79 (m, 1H), 2.10-1.98 (m, 1H),
1.25 (q, J=7.6, 6.4 Hz, 6H), 0.94-0.83 (m, 2H), 0.66-0.55 (m,
2H).
Example 62
Synthesis of
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-N-((difluoromethyl)-
sulfonyl)-2-fluorobenzamide
##STR00324##
[0545] The compound was prepared in a similar manner to Example 60
from
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid and difluoromethanesulfonamide, LCMS (Method E): RT=3.95 min,
m/z: 545.2 [M+H].sup.+.
Example 63
Synthesis of
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-
((3,3,3-trifluoropropyl)sulfonyl)benzamide
##STR00325##
[0547] The compound was prepared in a similar manner to Example 60
from
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid and 3,3,3-trifluoropropane-1-sulfonamide. LCMS (Method E):
RT=5.14 min, m/z: 591.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 7.44 (d, J=7.2 Hz, 4H), 7.40-7.30 (m, 4H), 7.26 (s, 2H),
7.21 (d, J=8.4 Hz, 1H), 6.88 (d, J=12.7 Hz, 1H), 4.22 (d, J=6.2 Hz,
2H), 3.53 (s, 3H), 2.76-2.60 (m, 2H), 2.09-1.98 (m, 1H), 0.93-0.82
(m, 2H), 0.66-0.57 (m, 2H).
Example 64
Synthesis of 4-((1
-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-N-((cyclopropylmethyl)-
sulfonyl)-2-fluorobenzamide
##STR00326##
[0549] The compound was prepared in a similar manner to Example 60
from
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid and cyclopropylmethanesulfonamide. LCMS (Method E): RT=4.89
min, m/z: 549.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
11.84 (s, 1H), 7.46-7.37 (m, 4H), 7.28 (t, J=7.6 Hz, 4H), 7.23-7.10
(m, 3H), 6.95 (d, J=12.8 Hz, 1H), 4.49 (s, 1H), 4.22 (d, J=6.2 Hz,
2H), 3.37 (d, J=7.1 Hz, 2H), 3.02 (s, 2H), 2.94-2.80 (m, 1H),
2.10-1.99 (m, 1H), 1.11-0.97 (m, 1H), 0.94-0.84 (m, 2H), 0.71-0.63
(m, 2H), 0.60-0.52 (m, 2H), 0.37 0.28 (m, 2H), 0.37-0.28 (m, 2).2H
hidden under water
Example 65
Synthesis of
4-((1-benzhydrylazetidin-3-yl)methoxy)-N-(butylsulfonyl)-5-cyclopropyl-
2-fluorobenzamide
##STR00327##
[0551] The compound was prepared in a similar manner to Example 60
from
4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid and butane-1-sulfonamide. LCMS (Method E): RT=5.08 min, m/z:
551.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.75 (s,
1H), 7.42 (dd, J=8.2, 1.4 Hz, 4H), 7.27 (dd, J=8.3, 6.9, Hz, 4H),
7.21-7.11 (m, 3H), 6.92 (d, J=12.7 Hz, 1H), 4.47 (s, 1H), 4.20 (d,
J=6.2 Hz, 2H), 3.37 (t, J=7.9 Hz, 2H), 3.01 (t, J=6.6 Hz, 2H),
2.93-2.81(m, 1H), 2.09-1.99 (m, 1H), 1.71-1.59 (m, 2H), 1.45-1.34
(m, 2H), 0.94-0.83 (m, 5H), 0.69-0.59 (m, 2H). 2H hidden under
water
Example 66
Synthesis of
4-((1-benzyl-3-fluoroazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(met-
hylsulfonyl)benzamide
##STR00328##
[0552] Step 1: Preparation of
4-((1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methoxy)-5-
chloro-2-fluorobenzoic acid
[0553] To a solution of tert-butyl
3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (0.16 g, 0.784
mmol) and 5-chloro-2,4-difluoro-benzoic acid (151 mg, 0.784 mmol)
in dimethyl sulfoxide (4.00 mL/mmol, 44.1 mmol, 99.8 mass %) at
14.degree. C. (bath) was added potassium tert-butoxide (194 mg,
1.73 mmol). The mixture was stirred at that temp for 5 min then at
rt for 30 min. Diluted with EtOAc, the contents were washed with
1:4 mixture of 0.3M HCl and 0.3M NaH.sub.2PO.sub.4 (3.times.) and
brine, and dried (Na.sub.2SO.sub.4). After filtration and
concentration, the white solid crude (327 mg) was used as-is.
Step 2: Preparation of tert-butyl
3-((2-chloro-4-(ethoxycarbonyl)-5-fluorophenoxy)methyl)-3-fluoroazetidine-
-1-carboxylate
[0554] To a suspension of product from step 1 (278 mg) and
potassium carbonate (185 mg, 1,32 mmol) in N,N-dimethylformamide
(2.65 mL) was added iodoethane (156 mg, 0.99 mmol). The mixture was
heated at 50.degree. C. for 2 hr. LCMS showed completion. Diluted
with EtOAc (50 mL), the contents were washed with diluted
NaHCO.sub.3 (2.times.) and brine, and dried (Na.sub.2SO.sub.4).
After filtration and concentration, the residue was purified with
silica gel flash chromatography (0-40% EtOAc/heptane) to give the
product (141 mg).
Step 3: Preparation of ethyl
4-((1-benzyl-3-fluoroazetidin-3-yl)methoxy)-5-cyclopropyl-
2-fluorobenzoate
[0555] A mixture of product from step 2 (57 mg, 0.14 mmol) and
trifluoroacetic acid (0.28 mL, 3.6 mmol) in dichloromethane (0.83
mL) was stirred at 0.degree. C. for 30 min then at rt for 2 h. The
contents were concentrated and used as-is.
Step 4: Preparation of ethyl
4-((1-benzyl-3-fluoroazetidin-3-yl)methoxy)-5-cyclopropyl-
2-fluorobenzoate
[0556] To the residue from step 3 was added dichloromethane (0.83
mL), followed by N,N-diisopropylethylamine (0.19 mL, 1.1 mmol) and
benzyl bromide (26 mg, 0.15 mmol). The mixture The mixture was
stirred at rt for 16 hr. Dilute aq Na.sub.2CO.sub.3 was added. The
contents were extracted with DCM (2.times.). The combined extracts
were dried (Na.sub.2SO.sub.4). The crude was purified with silica
gel flash chromatography (0-25% EtOAc/heptane) to give the product
as viscous oil (43.8 mg).
Step 5: Preparation of
4-((1-benzyl-3-fluoroazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid
[0557] A mixture of product from previous step (41.7 mg, 0.104
mmol) and potassium hydroxide (11.7 mg, 0.208 mmol) in methanol
(0.62 mL) and water (0.16 mL) was stirred at rt for 3 hr then
heated at 50.degree. C. for 1.5 hr. Diluted with water and
acidified with 1M NaH.sub.2PO.sub.4, the contents were extracted
with DCM (3x). The combined extracts were dried (Na.sub.2SO.sub.4)
and concentrated. The crude (37.6 mg) was used as-is.
Step 6: Preparation of
4-((1-benzyl-3-fluoroazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-
N-(methylsulfonyl)benzamide
[0558] A Mixture of product from previous step (37.6 mg, 0.101
mmol), methanesulfonamide (28.7 mg, 0.302 mmol),
N,N-diisopropylethylamine (0.089 mL, 0.503 mmol), and HBTU ((51.2
mg, 0.131 mmol) in 1,2-dichloroethane (1 mL) was stirred at
50.degree. C. for 2 hr then at 65.degree. C. for 1 hr. To the
mixture was added 1M NaH.sub.2PO.sub.4. The contents were extracted
with DCM (2.times.). The combined extracts were dried
(Na.sub.2SO.sub.4). The crude was purified with HPLC (23.0 mg,
50.7%). LCMS (Method D): RT=4.24 min, m/z: 451.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.39-7.22 (m, 5H), 7.17 (d,
J=8.3 J 8.3 Hz, 1H), 7.01 (d, J=12.7 Hz, 1H), 4.43 (d, J=23.8 Hz,
2H), 3.74 (s, 2H), 3.59 (dd, J=13.3, 9.1 Hz, 2H), 3.25 (s, 3H),
2.06-1.95 (m, 1H), 0.92-0.82 (m, 2H), 0.71-0.62 (m, 2H).
Example 67
Synthesis of
4-((1-benzyl-3-fluoroazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-
N-(methylsulfonyl)benzamide
##STR00329##
[0560] The compound was prepared in a similar manner to Example 66
while in step 3 benzyl bromide being replaced by
bromodiphenylmethane and DCM being replaced by DMF. LCMS (Method
D): RT=4.67 min, m/z: 427.2 [M+H].sup.+. .sup.1H NMR (400 DMSO-d6)
.delta. 11.90 (s, 1H), 7.49-7.40 (m, 4H), 7.29 (dd, J=8.4, 6.8 Hz,
4H), 7.23-7.13 (m, 3H), 7.02 (d, J=12.7 Hz, 1H), 4.60 (s, 1H), 4.48
(d, J=23.1 Hz, 2H), 3.49-3.38 (m, 2H), 3.27-3.15 (m, 5H), 2.06-1.91
(m, 1H), 0.90-0.79 (m, 2H), 0.70-0.60 (m, 2H).
Example 68
Synthesis of
4-((1-benzhydryl-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-
fluoro-N-(methylsulfonyl)benzamide
##STR00330##
[0561] Step 1: Preparation of tert-butyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)-
3-methylazetidine-1-carboxylate
[0562] The compound was prepared from to tert-butyl
3-(hydroxymethyl)-3-methylazetidine-1-carboxylate and tert-butyl
5-chloro-2,4-difluorobenzoate in a similar manner to step 1 of
Example 60.
Step 2: Preparation of tert-butyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl- 5-fluorophenoxy)methyl)-
3-methylazetidine-1-carboxylate
[0563] The compound was prepared from tert-butyl
3-((4-(tert-butoxycarbonyl)-2 -chloro-5
-fluorophenoxy)methyl)-3-methylazetidine-1-carboxylate in a similar
manner to step 2 of Example 60.
Step 3: Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-((3-methylazetidin-3-
yl)methoxy)benzoate
[0564] To a solution of tert-butyl
3-[(4-tert-butoxycarbonyl-2-cyclopropyl-5-fluorophenoxy)methyl]-
3-methyl-azetidine-1-carboxylate (73.3 mg, 0.168 mmol) in
acetonitrile (1.35 mL) at 7.degree. C. (bath) was added
p-toluenesulfonic acid hydrate (38.4 mg, 0.202 mmol). After 10 min,
the mixture was stirred at rt for 20 hr. Tert-butyl acetate (0.23
mL) and p-toluenesulfonic acid hydrate (16.0 mg, 0.842 mmol) were
added. After 1 hr, acetonitrile (3 mL) and K.sub.2CO.sub.3 was
added (500 mg). After well mixing, the contents were diluted with
EtOAc and filtered. The filtrated was concentrated. The residue was
used as-is.
Step 4: Preparation of tert-butyl
4-((1-benzhydryl-3-methylazetidin-3-yl)methoxy)-5-
cyclopropyl-2-fluorobenzoate
[0565] A mixture of tert-butyl
5-cyclopropyl-2-fluoro-4-[(3-methylazetidin-3-yl)methoxy]benzoate
(56.3 mg, 0.168 mmol), bromodiphenylmethane (62.3 mg, 0.252 mmol),
and cesium carbonate (164 mg, 0.504 mmol) in acetonitrile (1.68 mL)
was heated at 50.degree. C. for 16 hr. The contents were
concentrated. The residue was suspended in water and extracted with
DCM (2.times.). The combined extracts were dried
(Na.sub.2SO.sub.4). The crude was purified with silica gel flash
chromatography (0-30% EtOAc/heptane) to give the product (96.9
mg).
Step 5: Preparation of
4-((1-benzhydryl-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-
2-fluorobenzoic acid
[0566] A mixture of product from previous step (96.9 mg) and
potassium hydroxide (86.7 mg, 1.55 mmol) in DMSO (1.93 mL) was
stirred at rt for 40 hr. Acidified with 0.5M NaH.sub.2PO.sub.4, the
contents were extracted with DCM (3.times.). The combined extracts
were dried (Na.sub.2SO.sub.4) and concentrated. The crude was used
as-is (103 mg).
Step 6: Preparation of
4-((1-benzhydryl-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-
2-fluorobenzoic acid
[0567] The compound was prepared in a similar manner to step 4 of
Example 60 from
4-((1-benzhydryl-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-f-
luorobenzoic acid and methanesulfonamide. LCMS (Method D): RT=4.49
min, m/z: 523.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
11.83 (s, 1H), 7.48-7.38 (m, 4H), 7.28 (t, J=7.6 Hz, 4H), 7.23-7.13
(m, 3H), 6.98 (d, J=12.8 Hz, 1H), 4.53 (s, 1H), 4.11 (s, 2H), 3.17
(s, 2H), 2.88 (d, J=11.8 Hz, 2H), 2.12-2.00 (m, 1H), 1.35 (s, 3H),
0.94-0.85 (m, 2H), 0.72-0.62 (m, 2H).
Example 69
Synthesis of
4-((1-benzhydryl-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-N-
(ethylsulfonyl)-2-fluorobenzamide
##STR00331##
[0569] The compound was prepared in a similar manner to step 4 of
Example 60 from
4-((1-benzhydryl-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-f-
luorobenzoic acid and ethanesulfonamide. LCMS (Method D): RT=4.63
min, m/z: 537.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
11.75 (s, 1H), 7.47-7.37 (m, 4H), 7.28 (t, J=7.5 Hz, 4H), 7.18 (t,
J=7.3 Hz, 3H), 6.99 (d, J=12.8 Hz, 1H), 4.50 (s, 1H), 4.10 (s, 2H),
3.50-3.38 (m, 2H), 3.15 (s, 2H), 2.95-2.81 (m, 2H), 2.12-1.99 (m,
1H), 1.35 (s, 3H), 1.24 (t, J =7.4 Hz, 3H), 0.94-0.83 (m, 2H),
0.71-0.60 (m, 2H).
Example 70
Synthesis of
4-((1-benzhydryl-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-N-
(cyclopropylsulfonyl)-2-fluorobenzamide
##STR00332##
[0571] The compound was prepared in a similar manner to step 4 of
Example 60 from 4-((1
-benzhydryl-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid and cyclopropanesulfonamide. LCMS (Method E): RT=4.69 min,
m/z: 549.2 [M+H].sup.+. .sup.1H NMR (400 MHZ, DMSO-d6) .delta.
11.79 (s, 1H), 7.46-7.38 (m, 4H), 7.32-7.23 (m, 4H), 7.22-7.13 (m,
3H), 6.94 (d, J=12.8 Hz, 1H), 4.50 (s, 1H), 4.09 (s, 2H), 3.14 (d,
J=7.1 Hz, 2H), 3.07-2.96 (m, 1H), 2.92-2.80 (m, 2H), 2.13-2.00 (m,
1H), 1.30-1.20 (m, 3H), 1.03 (d, J=17.8 Hz, 4H), 0.94-0.83 (m, 2H),
0.69-0.60 (m, 2H).
Example 71
Synthesis of
N-(azetidin-1-ylsulfonyl)-4-((1-benzhydryl-3-methylazetidin-3-yl)methoxy)-
- 5-cyclopropyl-2-fluorobenzamide
##STR00333##
[0573] The compound was prepared is a similar manner to step 4 of
Example 60 from
4-((1-benzhydryl-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-f-
luorobenzoic acid and azetidine-1-sulfonamide. LCMS (Method D):
RT=4.74 min, m/z: 564.2 [M+H].sup.+.
Example 72
Synthesis of tert-butyl
3-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)phenoxy)-methyl)a-
zetidine-1-carboxylate
##STR00334##
[0574] Steps 1-2: Preparation of tert-butyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)-azetidi-
ne-1-carboxylate
[0575] The compound was prepared from tert-butyl
3-(hydroxymethyl)azetidine-1-carboxylate and tert-butyl
5-chloro-2,4-difluorobenzoate in a similar manner to steps 1-2 of
Example 60.
Step 3: Preparation of
4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)-5-
cyclopropyl-2-fluorobenzoic acid
[0576] To a mixture of tert-butyl
3-[(4-tert-butoxycarbonyl-2-cyclopropyl-5-fluorophenoxy)-
methyl]azetidine-1-carboxylate (0.711 g, 1.69 mmol) and potassium
hydroxide (1.14 g, 20.2 mmol) in methanol (8.43 mL) was slowly
added water (0.84 mL). The resulting mixture was heated at
60.degree. C. for 16 hr. LCMS showed completion. The contents were
diluted with water and acidified with 1:4 mixture of 1M HCl and 1M
NaH.sub.2PO.sub.4, and extracted with DCM (2.times.). The combined
DCM solutions were dried (Na.sub.2SO.sub.4). After filtration, and
concentration, the crude was used as-is.
Step 4: Preparation of tert-butyl
3-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)-phenoxy)methyl)a-
zetidine-1-carboxylate
[0577] The compound was prepared at a similar manner to step 4 of
Example 60 from
4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)-5-cyclopropyl-2-
-fluorobenzoic acid and methanesulfonamide. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 11.88 (s, 1H), 7.17 (d, J=8.3 Hz, 1H), 6.97 (d,
J=12.8 Hz, 1H), 4.29-4.15 (m, 2H), 3.96 (s, 2H), 3.85-3.71 (m, 2H),
3.31 (s, 3H), 3.06-2.93 (m, 1H), 2.04-1.89 (m, 1H), 1.36 (s, 9H),
0.93-0.80 (m, 2H), 0.74-0.59 (m, 2H).
Example 73
Synthesis of
5-cyclopropyl-2-fluoro-4-((1-(3-fluorobenzyl)azetidin-3-yl)methoxy)-
N-(methylsulfonyl)benzamide
##STR00335##
[0579] A mixture of tert-butyl
3-[[2-cyclopropyl-5-fluoro-4-(methylsulfonylcarbamoyl)phenoxy]-methyl]aze-
tidine-1-carboxylate (39.2 mg, 0.0753 mmol, Example 77) and
trifluoroacetic acid (0.15 mL, 1.9 mmol) in dichloromethane (0.45
mL) was stirred at 0.degree. C. for 10 min then at rt for 1 h. The
contents were concentrated. To the residue was added 1,
2-dichloroethane (1.5 mL). The mixture was cooled at 0.degree. C.
N, N-diisopropylethylamine (0.158 mL, 0.904 mmol) was added,
followed by 3-fluorobenzaldehyde (28.0 mg, 0.226 mmol) and sodium
triacetoxyborohydride (63.8 mg, 0.301 mmol). The mixture was
stirred at rt for 20 hr. Diluted with 0.5M NaH.sub.2PO.sub.4, the
contents were extracted with 1:5 mixture of IPA-DCM (3.times.x).
The combined org solutions were dried (Na.sub.2SO.sub.4). The crude
purified with HPLC (10.9 mg). LCMS (Method E): RT=3.29 min, m/z:
451.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.43 (q,
J=7.4 Hz, 1H), 7.27-7.12 (m, 4H), 6.85 (d, J=12.7 Hz, 1H), 4.19 (d,
J=6.1 Hz, 2H), 3.98 (s, 2H), 3.74 (s, 2H), 3.56 (s, 2H), 3.06 (s,
4H), 2.11-1.97 (m, 1H), 0.94-0.82 (m, 2H), 0.66-0.57 (m, 2H).
Example 74
Synthesis of
-((1-benzylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-
(methylsulfonyl)benzamide
##STR00336##
[0581] The compound was prepared in a similar manner to Example 73
from tert-butyl
3-[[2-cyclopropyl-5-fluoro-4-(methylsulfonylcarbamoyl)phenoxy]methyl]azet-
idine-1-carboxylate and benzaldehyde. LCMS (Method D): RT=3.88 min,
m/z: 433.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
7.49-7.31 (m, 5H), 7.23 (d, J=8.5 Hz, 1H), 6.80 (d, J=12.7 Hz, 1H),
4.18 (d, J=6.1 Hz, 2H), 4.08 (s, 2H), 3.92-3.78 (m, 2H), 3.68 (d,
J=8.1 Hz, 2H), 3.18-3.05 (m, 1H), 2.99 (s, 3H), 2.11-1.94 (m, 1H),
0.94-0.81 (m, 2H), 0.65-0.53 (m, 2H).
Example 75
Synthesis of
4-((1-(3-chloro-5-fluorobenzyl)azetidin-3-yl)methoxy)-5-cyclopropyl-2-flu-
oro- N-(methylsulfonyl)benzamide
##STR00337##
[0583] The compound was prepared in a similar manner to Example 73
from tert-butyl
3-[[2-cyclopropyl-5-fluoro-4-(methylsulfonylcarbamoyl)phenoxy]methyl]azet-
idine-1-carboxylate and 3-chloro-5-fluorobenzaldehyde. LCMS (Method
D): RT=4115 min, m/z: 485.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 7.41-7.34 (m, 1H), 7.29 (s, 1H), 7.24-7.15 (m,
2H), 6.90 (d, J=12.8 Hz, 1H), 4.20 (d, J=6.2 Hz, 2H), 3.88 (s, 2H),
3.65 (t, J=8.1 Hz, 2H), 3.44 (t, J=7.4 Hz, 2H), 3.17 (s, 3H),
3.08-2.95 (m, 1H), 2.04 (tt, J=8.6, 5.3 Hz, 1H), 0.94-0.83 (m, 2H),
0.69-0.60 (m, 2H).
Example 76
Synthesis of 5-cyclopropyl-2
-fluoro-4-((1-(3-fluoro-4-(trifluoromethyl)piperidin)azetidin-
3-yl)methoxy)-N-(methylsulfonyl)benzamide
##STR00338##
[0585] The compound was prepared in a similar manner to Example 73
from tert-butyl
3-[[2-cyclopropyl-5-fluoro-4-(methylsulfonylcarbamoyl)phenoxy]methyl]azet-
idine-1-carboxylate and 3-fluoro-4-(trifluoromethyl)benzaldehyde.
LCMS (Method D): RT=4.33 min, m/z: 519.2 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 7.76 (t, J=7.8 Hz, 1H), 7.45 (d, J=11.9
Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.19 (d, J =8.4 Hz, 1H), 6.91 (d,
J=12.8 Hz, 1H), 4.21 (d, J=6.2 Hz, 2H), 3.87 (s, 2H), 3.58 (t,
J=7.9 Hz, 2H), 3.18 (s, 3H), 3.05-2.93 (m, 1H), 2.06-1.98 (m, 1H),
0.94-0.85 (m, 2H), 0.68-0.61 (m, 2H).
Example 77
Synthesis of
5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)-3-methylazetidin-3-yl)methoxy)-
2-fluoro-N-(methylsulfonyl)benzamide
##STR00339##
[0586] Steps 1-4: Preparation of tert-butyl
3-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)-phenoxy)methyl)--
3-methylazetidine-1-carboxylate
[0587] The compound was prepared in a similar manner to Example 72
while in step 1 tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate
was replaced by tert-butyl
3-(hydroxymethyl)-3-methylazetidine-1-carboxylate.
Step 5: Preparation of
5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)-3-methylazetidin-3-yl)methoxy)-2-
-fluoro-N-(methylsulfonyl)benzamide
[0588] The compound was prepared in a similar manner to Example 73
from tert-butyl
3-(2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)phenoxy)-3-methyla-
zetidine-1-carboxylate and 3,5-dichlorobenzaldehyde. LCMS (Method
D): RT=4.42 min, m/z: 515.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 7.54 (t, J=2.0 Hz, 1H), 7.39 (d, J=1.9 Hz, 2H),
7.22 (d, J=8.4 Hz, 1H), 6.91 (d, J=12.8 Hz, 1H), 4.08 (s, 2H), 3.84
(s, 2H), 3.49 (s, 2H), 3.17 (s, 3H), 2.09-1.98 (m, 1H), 1.37 (s,
3H), 0.94-0.83 (m, 2H), 0.70-0.59 (m, 2H).
Example 78
Synthesis of tert-butyl
4-((2-chloro-5-fluoro-4-((methylsulfonyl)carbamoyl)phenoxy)-
methyl)piperidine-1-carboxylate
##STR00340##
[0590] The compound was prepared in a similar manner to Example 59
from tert-butyl 4-(hydroxymethyl)-piperidine-1-carboxylate and
5-difluoro-N- methylsulfonylbenzamide. LCMS (Method D): RT=6.77
min, m/z: 409.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
7.77 (d, J=7.7 Hz, 1H), 7.13 (d, J=12.3 Hz, 1h), 4.08-3.88 (m, 4H),
3.13 (s, 3H), 2.74 (d, J=9.9 Hz, 2H), 1.97 (q, J=7.2, 5.8 Hz, 1H),
1.81-1.68 (m, 2H), 1.40 (s, 9H), 1.19 (qd, J=12.4, 4.1 Hz, 2H).
Example 79
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-phenylpiperidin-
4-yl)methoxy)benzamide
##STR00341##
[0592] The compound was prepared in a similar manner to Example 60
from (1-phenylpiperidin-4-yl)methanol and
5-chloro-2,4-difluoro-N-methylsulfonyl-benzamide.
[0593] LCMS (Method E): RT=4.68 min, m/z: 447.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.82 (s, 1H), 7.26-7.11 (m,
3H), 7.00-6.89 (m, 3H), 6.74 (t, J=7.2 Hz, 1H), 4.00 (d, J=6.2 Hz,
3H), 3.79-3.67 (m, 2H), 3.29 (s, 3H), 2.78-2.56 (m, 2H), 2.07-1.92
(m, 2H), 1.87 (d, J=11.9 Hz, 2H), 1.55-1.41 (m, 2H), 0.94-0.83 (m,
2H), 0.72-0.61 (m, 2H).
Example 80
##STR00342##
[0594]
5-Cyclopropyl-4-((1-(3,4-dichlorophenyl)(phenyl)methyl)azetidin-3-y-
l)methoxy-2-fluoro-N-(methylsulfonyl)benzamide
##STR00343##
[0595] Step 1
##STR00344##
[0596] (3,4-Dichlorophenyl)(phenyl)methanol
[0597] A mixture of (3,4-dichlorophenyl)(phenyl)methanone (2.0 g,
8.0 mmol) and sodium borohydride (456 mg, 12 mmol), in EtOH (10 mL)
was stirred at 25.degree. C. for 2 h. After removal of the solvent,
the residue was diluted with water (20 mL) and extracted with EtOAc
(20 mL.times.3). The combined organic layers were washed with brine
(20 mL), dried over anhydrous sodium sulfate, filtered and
concentrated to give the desired product (2.0 g, 100%) as yellow
oil. LCMS(ESI) m/z: 251.1 [M-H].sup.-.
Step 2
##STR00345##
[0598] 1,2-Dichloro-4-(chloro(phenyl)methyl)benezene
[0599] A solution of (3,4-dichlorophenyl)(phenyl)methanol (2.0 g,
7.9 mmol) in thionyl chloride (10 mL) was stirred at 60.degree. C.
for 3 h. After cooling to room temperature, the reaction mixture
was concentrated and purified by silica gel column (eluting with
petroleum ether/ethyl acetate=100/1) to give the desired product
(1.6 g, 76%) as yellow oil.
Step 3
##STR00346##
[0600] tert-Butyl
5-cyclopropyl-4-((1-((3,4-dichlorophenyl)(phenyl)methyl)-azetidin-3-yl)me-
thoxy)-2-fluorobenzoate
[0601] A mixture of methyl tert-butyl
4-(azetidin-3-ylmethoxy)-5-cyclopropyl-2- fluorobenzoate (100 mg,
0.31 mmol), 1,2-dichloro-4-(chloro(phenyl)methyl)benzene (126 mg,
0.47 mmo), sodium iodide (93 mg, 0.62 mmol) and potassium carbonate
(128 mg, 0.93 mmol) in MeCN (10 mL) was stirred at 80.degree. C.
for 16 h. After cooling to room temperature, the reaction mixture
was diluted with EtOAc (100 mL) and brine (50 mL). The organic
layer was separated and washed with brine (50 mL), dried over
anhydrous sodium sulfate, filtered and concentrated. The residue
was purified by silica gel chromatography (eluting with petroleum
ether/ethyl acetate=4/1) to give the target compound (100 mg, 58%)
as a pale yellow oil. LCMS(ESI) m/z: 556.0 [M+H].sup.+.
Step 4
##STR00347##
[0602]
5-Cyclopropyl-4-((1-(3,4-dichlorophenyl)(phenyl)methyl)azetidin-3-y-
l)methoxy)-2-fluorobenzoic acid
[0603] Trifluoroacetic acid (1 mL) was added to a solution of
tert-butyl 5-cyclopropyl-4-((1-
((3,4-dichlorophenyl)(phenyl)methyl)azetidin-3-yl)methoxy)-2-fluorobenzoa-
te (100 mg, 0.18 mmol) in DCM (2 mL) and the reaction stirred at
room temperature for 1 h. The mixture was then concentrated to give
the desired product (80 mg, crude) as a pale yellow solid.
LCMS(ESI): 500.0 [M-H].sup.-.
Step 5
##STR00348##
[0604]
5-Cyclopropyl-4-((1-((3,4-dichlorophenyl)(phenyl)methyl)azetidin-3--
yl)methoxy-2- fluoro-N-(methylsulfonyl)benzamide
[0605] 1. A mixture of
5-cyclopropyl-4-((1-((3,4-dichlorophenyl)(phenyl)methyl)-
azetidin-3-yl)methoxy)-2-fluorobenzoic acid (80 mg, 0.16 mmol),
methanesulfonamide (23 mg, 0.24 mmol), EDCI (61 mg, 0.32 mmol) and
DMAP (39 mg, 0.32 mmol) in DCM (4 mL) was stirred at 25.degree. C.
for 16 h. The reaction mixture was diluted with EtOAc (100 mL),
washed with HCl (2.0 M, 20 mL) and brine (50 mL), dried over
anhydrous sodium sulfate, filtered and concentrated. The residue
was purified by reverse phase combiflash (30-40% MeCN in 0.1%
NH.sub.4HCO.sub.3) to give the target product (35 mg, 38%) as an
off-white solid. LCMS(ESI) Method A: RT=6.24 min, m/z: 577.2.
[M+H].sup.+. .sup.1H NMR (500 MHz, MeOD-d.sub.4) .delta.7.60 (d,
J=2.0 Hz, 1H), 7.48-7.24 (m, 8H), 6.85 (d, J=13.0 Hz, 1H), 4.58 (s,
1H), 4.23 (d, J=6.0 Hz, 2H), 3.48-3.42 (m, 2H), 3.32 (s, 3H),
3.27-3.21 (m, 2H), 3.06-3.00 (m, 1H), 2.13-2.09 (m, 1H), 0.97-0.94
(m, 2H), 0.70-0.67 (m, 2H).
##STR00349##
Example 81
(R)-5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenyl(pyridin-3-yl)m-
ethyl)azetidin-3-yl)methoxy)benzamide
##STR00350##
[0606] Step 1
##STR00351##
[0607] Phenyl(pyridin-3-yl)methanol
[0608] A mixture of phenyl(pyridin-3-yl)methanone (2.0 g, 11 mmol)
and sodium borohydride (623 mg, 16 mmol) in EtOH (30 mL) was
stirred at 25.degree. C. for 2 h. The mixture was then
concentrated, diluted with water (20 mL) and extracted with EtOAc
(20 mL.times.3). The combined organic layers were washed with brine
(20 mL), dried over anhydrous sodium sulfate, filtered and
concentrated to give the desired product (2.0 g, 100%) as yellow
oil. LCMS(ESI): m/z 184.3 [M+H].sup.+.
Step 2
##STR00352##
[0609] 3-(Chloro(phenyl)methyl)pyridine
[0610] A solution of phenyl(pyridin-3-yl)methanol (1.5 g, 8.1 mmol)
in thionyl chloride (10 mL) was stirred at 80.degree. C. for 16 h.
The mixture was then cooled to room temperature, concentrated and
purified silica gel chromatography (eluting with DCM/MeOH from
100/1 to 20/1) to give the desired product (1.5 g, 94%) as a brown
solid. LCMS(ESI): m/z 204.3 [M+H].sup.+.
Step 3
##STR00353##
[0611]
tert-butyl-5-Cyclopropyl-2-fluoro-4-((1-(phenyl(pyridin-3-yl)methyl-
)azetidin- 3-yl)methoxy)benzoate
[0612] The compound was synthesized as described in step 3, Example
80. LCMS(ESI) m/z: 489.1 [M+H].sup.+.
Step 4
##STR00354##
[0613]
5-Cyclopropyl-2-fluoro-4-((1-(phenyl(pyridin-3-yl)methyl)azetidin-3-
-yl)methoxy)benzoic acid
[0614] The compound was synthesized as described in step 4, Example
80. LCMS(ESI) m/z: 433.1 [M+H].sup.+.
Step 5
##STR00355##
[0615]
(R)-5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenyl(pyridin-
-3-yl)methyl)azetidin-3-yl)methoxy)benzamide
[0616] The compound was synthesized as described in step 5, Example
80. The enantionmer was separated by chiral SFC from the racemate.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH, A:B=75:25; flow: 3 mL/min;
column temperature: 40.degree. C.; RT=4.83 min). LCMS(ESI) Method
B: RT=4.56 min, m/z: 510.2 [M+H].sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.90 (s, 1H), 8.66 (s, 1H), 8.43 (s, 1H),
7.80 (d, J=8.0 1H), 7.45-7.44 (m, 2H), 7.32-7.29 (m, 3H), 7.22-7.16
(m, 2H), 6.92 (d, J=13.0 Hz, 1H), 4.55 (s, 1H), 4.21 (d, J=6.5 Hz,
2H), 3.29-3.24 (m, 2H), 3.22 (s, 3H), 3.04-3.00 (m, 2H), 2.90-2.84
(m, 1H), 2.08-2.02 (m, 1H), 0.91-0.87 (m, 2H), 0.66-0.63 (m,
2H).
##STR00356##
Example 82
(S)-5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenyl(pyridin-3-yl)m-
ethyl)azetidin-3-yl)methoxy)benzamide
[0617] The compound was synthesized as described in Example 81.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m, mobile Phase:
A: supercritical CO.sub.2, B: MeOH, A:B=75:25; flow: 3 mL/min;
column temperature: 40.degree. C.; RT=4.08 mm). LCMS(ESI) Method B:
RT=4.56 min, m/z: 510.2 [M+H].sup.+.sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.90 (s, 1H), 8.64 (s, 1H), 8.41 (s, 1H),
7.79 (d, J=8.0 Hz, 1H), 7.45-7.44 (m, 2H), 7.32-7.29 (m, 3H),
7.22-7.16 (m, 2H), 6.92 (d, J=13.0 Hz, 1H), 4.55 (s, 1H), 4.21 (d,
J=6.5 Hz, 2H), 3.29-3.24 (m, 2H), 3.20 (s, 3H), 3.04-3.00 (m, 2H),
2.90-2.84 (m, 1H), 2.07-2.02 (m, 1H), 0.91-0.87 (m, 2H), 0.66-0.63
(m, 2H).
##STR00357##
Example 83
4-((1-((5-Chloro-6-isopropoxypyridin-3-yl)methyl)azetidin-3-yl)methoxy)-5--
cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00358##
[0618] Step 1
##STR00359##
[0619] 5-Bromo-3-chloro-2-isopropoxypyridine
[0620] A mixture of potassium tert-butoxide (10 g, 88.8 mmol) in
isopropanol (15 mL) was stirred at 95.degree. C. for 3 h,
5-bromo-2,3-dichloropyridine (5 g, 22.2 mmol) was then added. The
reaction mixture was refluxed overnight then partitioned between
ethyl acetate and water. The organic layer was washed with water,
brine, dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by silica column
chromatography (eluting with petroleum ether/ethyl acetate=100/1)
to give 5-bromo-3-chloro-2-isopropoxypyridine (3.2 g, 58% yield) as
colorless oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta.
8.25-8.20 (m, 2H), 5.27-5.23 (m, 1H), 1.32 (d, J=5.5 Hz, 6H).
Step 2
##STR00360##
[0621] 5-Chloro-6-isopropoxynicotinaldehyde
[0622] n-BuLi (2.5 M, 9.6 mL, 24 mmol) was added dropwise to a
solution of 5-bromo-2,3-dichloropyridine (3.0 g, 12 mmol) in
anhydrous THF (20 mL) at -78.degree. C. The resulting mixture was
stirred at this temperature for 10 min then DMF (2.6 g, 36 mmol)
was added at -50.degree. C. The mixture was warmed to room
temperature and partitioned with EtOAc (100 mL) and 1N HCl (10 mL).
The organic layer was washed with saturated brine (50 mL), dried
over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by silica gel chromatography (eluting with
petroleum ether/ethyl acetate=50/1) to give
5-chloro-6-isopropoxynicotinaldehyde (700 mg, 29% yield) as
colorless oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 9.94
(s, 1H), 8.70 (d, J=1.5 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 5.40-5.31
(m, 1H), 1.37 (d, J=6.0 Hz, 6H).
Step 3
##STR00361##
[0623] (5-Chloro-6-isopropoxypyridin-3-yl)methanol
[0624] The compound was synthesized as described in step 1, Example
80. LCMS(ESI) m/z: 200.1 [M-H].sup.-.
Step 4
##STR00362##
[0625] 3-Chloro-5-(chloromethyl)-2-isopropoxypyridine
[0626] The compound was synthesized as described in step 2, Example
80.
Step 5
##STR00363##
[0627] 2tert-butyl
4-((1-((5-Chloro-6-isopropoxypyridin-3-yl)methyl)azetidin-3-yl)methoxy)-5-
-cyclopropyl-2-fluorobenzoate
[0628] The compound was synthesized as described in step 3, Example
80. LCMS(ESI) m/z: 505.1 [M+H].sup.+.
Step 6
##STR00364##
[0629]
4-((1-((5-Chloro-6-isopropoxypyridin-3-yl)methyl)azetidin-3-yl)meth-
oxy)-5-cyclopropyl-2-fluorobenzoic acid
[0630] The compound was synthesized as described in step 4 Example
80. LCMS(ESI) m/z: 449.1 [M+H].sup.+.
##STR00365##
Step 7
4-((1-((5-Chloro-6-isopropoxypyridin-3-yl)methyl)azetidin-3-yl)methoxy-5-c-
yclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[0631] The compound was synthesized as described in step 5, Example
80. LCMS(ESI) Method A: RT=5.06 min, m/z: 526.2 [M+H].sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 7.99 (d, J=2.0 Hz,
1H), 7.55 (d, J=2.0 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 6.71 (d,
J=13.0 Hz, 1H), 5.28-5.26 (m, 1H), 4.11 (d, J=6.0 Hz, 2H), 3.55 (s,
2H), 3.39-3.33 (m, 2H), 3.13-3.11 (m, 2H), 2.86-2.83 (m, 4H), 2.00
(m, 1H), 1.31 (d, J=6.0 Hz, 6H), 0.88-0.85 (m, 2H), 0.56-0.53 (m,
2H).
##STR00366##
Example 84
(S)-5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(1-phenylethyl)azetidi-
n-3 -yl)methoxy)benzamide
##STR00367##
[0632] Step 1
##STR00368##
[0633] tert-Butyl
5-chloro-4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-2-fluorobenzoate
[0634] Potassium tert-butoxide (7.8 g, 70 mmol) was added to a
solution of (2,2-dimethyl-1,3-dioxan-5-yl)methanol (9.3 g, 63.7
mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (16.6 g, 66.9
mmol) in DMSO (200 mL) at 14.degree. C. After stirring at room
temperature for 1 h, the reaction mixture was diluted with water
(500 mL) and extracted with EtOAc (200 mL.times.3). The combined
organics was washed with brine, dried over anhydrous sodium sulfate
and concentrated. The residue was purified by silica gel
chromatography (eluting with petroleum ether/ethylacetate, 5/1) to
afford the target compound (16.4 g, yield: 69%) as a white
solid.
Step 2
##STR00369##
[0635] tert-Butyl
5-cyclopropyl-4-(2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-2-fluorobenzoate
[0636] Palladium acetate (23 mg 0.1 mmol) was added to a mixture of
tert-butyl
5-chloro-4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-2-fluorobenzoate
(375 mg, 1 mmol), cyclopropylboronic acid (176 mg, 2 mmol),
potassium phosphate (1.06 g, 5 mmol) and tricyclohexylphosphine
tetrafluoroborate (74 mg, 0.2 mmol) in toluene (5 mL) and water
(0.25 mL) under a nitrogen atmosphere. The reaction mixture was
heated at 100.degree. C. for 16 hours then cooled to room
temperature. The mixture was then diluted with water (200 mL) and
extracted with ethyl acetate (100 mL.times.3). The combined
organics were washed with brine, dried over anhydrous sodium
sulfate and concentrated in vacuo. The residue was purified by
silica gel chromatography (eluting with petroleum ether/ethyl
acetate=5/1) to afford tert-butyl
5-cyclopropyl-4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-2-fluorobenzoate
(350 mg, yield: 92%) as a white solid.
Step 3
##STR00370##
[0637] tert-Butyl
5-cyclopropyl-2-fluoro-4-(3-hydroxy-2-(hydroxymethyl)-propoxy)benzoate
[0638] A solution of tert-butyl
5-cyclopropyl-4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-
2-fluorobenzoate (350 mg, 0.92 mmol) in a mixture of THF (10 mL)
and HCl (1 M, 10 mL) was stirred at room temperature for 2 h. The
reaction mixture was diluted with DCM (20 mL.times.2) and washed
with saturated aqueous NaHCO.sub.3 (10 mL). The combined organic
layers were dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by silica gel column
chromatography (eluting with hexanes/ethyl acetate=2/1) to give
tert-butyl
5-cyclopropyl-2-fluoro-4-(3-hydroxy-2-(hydroxymethyl)propoxy)benzoate
(300 mg, yield: 96%) as a yellow solid. LCMS(ESI) m/z: 339.1
[M-H].sup.-.
Step 4
##STR00371##
[0639] (S)-tert-Butyl
5-cyclopropyl-2-fluoro-4-((1-(1-phenylethyl)azetidin-3-
yl)methoxy)benzoate
[0640] Trifluoromethanesulfonic anhydride (200 mg, 0.71 mmol) was
added dropwise to a 0.degree. C. mixture of tert-butyl
5-cyclopropyl-2-fluoro-4-(3-hydroxy-2-(hydroxymethyl)-
propoxy)benzoate (60 mg, 0.18 mmol) and N,N-diisopropylethylamine
(91 mg, 0.71 mmol) in acetonitrile (5 mL). The mixture was stirred
at 0.degree. C. for 1 h, then (S)-1-phenylethanamine (21 mg, 0.18
mmol) added, and the solution stirred for a further 1 h at room
temperature. The reaction was quenched with water (10 mL) and
extracted with ethyl acetate (10 mL.times.3). The combined organic
layers were washed with brine (10 mL), dried over anhydrous sodium
sulfate, filtered and concentrated. The crude product was purified
by silica column chromatography (eluting with petroleum ether/ethyl
acetate=10/1) to give (S)-tert-butyl 5-cyclopropyl-2-
fluoro-4-((1-(1-phenylethyl)azetidin-3-yl)methoxy)benzoate (32 mg,
43%) as an oil. LCMS(ESI): m/z: 426.8 [M+H].sup.+.
Step 5
##STR00372##
[0641]
(S)-5-Cyclopropyl-2-fluoro-4-((1-(1-phenylethyl)azetidin-3-yl)metho-
xy)benzoic acid
[0642] The compound was synthesized as described in step 4, Example
80. LCMS(ESI) m/f: 370.1 [M+H].sup.+.
Step 6
##STR00373##
[0643]
(S)-5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(1-phenylethyl)-
azetidin-3-yl)methoxy)benzamide
[0644] The compound was synthesized as described in step 5, Example
80. LCMS(ESI) Method A: RT=4.31 min, m/z: 447.0 [M+H].sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 7.37-7.32 (m, 5H),
7.20 (d, J=8.5 Hz, 1H), 6.83 (d, J=12.5 Hz, 1H), 4.17 (d, J=6.5 Hz,
2H), 3.75-3.46 (m, 5H), 3.04 (s, 3H), 3.00-2.98 (m, 1H), 2.03-2.00
(m, 1H), 1.29 (d, J=5.0 Hz, 3H), 0.88-0.87 (m, 2H), 0.62-0.59 (m,
2H).
Example 85
##STR00374##
[0645]
(R)-5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(1-phenylethyl)-
azetidin- 3 -yl)methoxy)benzamide
[0646] The compound was synthesized as described in Example 5.
LCMS(ESI) Method A: RT=4.32 min, m/z: 447.0 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6): .delta. 7.39-7.33 (m, 5H), 7.20 (d,
J=8.5 Hz, 1H), 6.82 (d, J=12.5 Hz, 1H), 4.17 (d, J=5.5 Hz, 2H),
3.93-3.49 (m, 5H), 3.04 (s, 3H), 3.02-2.98 (m, 1H), 2.04-2.00 (m,
1H), 1.29 (d, J=6.0 Hz, 3H), 0.88-0.85 (m, 2H), 0.62-0.59(m,
2H).
Example 86
##STR00375##
[0647]
5-Cyclopropyl-4-((1-(1-(3,5-difluorophenyl)ethyl)azetidin-3-yl)meth-
oxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00376##
[0649] The compound was synthesized as described in Example 80.
LCMS(ESI) Method A: RT=4.79 min, m/z: 483.0 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6): .delta. 7.18-7.07 (m, 4H), 6.91 (d,
J=13.0 Hz, 1H), 4.19 (d, J=6.0 Hz, 2H), 3.64-3.63 (m, 1H),
3.52-3.49 (m, 1H), 3.40-3.33 (m, 1H), 3.22-3.17 (m, 5H), 2.90-2.88
(m, 1H), 2.04-2.01 (m, 1H), 1.18 (d, J=6.0 Hz, 3H), 0.89-0.86 (m,
2H), 0.66-0.64 (m, 2H).
Example 87
##STR00377##
[0650]
4-((1-Benzylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methy-
lsulfonyl)benzamide
##STR00378##
[0651] Step 1
##STR00379##
[0652] tert-Butyl
4-((1-benzylpiperidin-4-yl)methoxy)-5-chloro-2-fluorobenzoate
[0653] Potassium tert-butoxide (135 mg, 1.12 mmol) was added to a
mixture of tert-butyl 5-chloro-2,4-difluorobenzoate (300 mg, 0.93
mmol) and (1-benzylpiperidin-4- yl)methanol (230 g, 1.12 mmol) in
DMSO (5 mL) at 15.degree. C. After stirring at room temperature for
1 h, the mixture was diluted with EtOAc, washed with brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated. The resulting
residue was purified by silica gel column chromatography (eluting
with petroleum ether/ethyl acetate=10/1) to give the desired
product (105 mg, 26% yield) as an oil. LCMS(ESI): m/z 434.0
[M+H].sup.+.
Step 2.
##STR00380##
[0654] tert-Butyl
4-((1-benzylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate
[0655] Palladium acetate (8 mg, 0.037 mmol) was added to a solution
of tert-butyl
4-((1-benzylpiperidin-4-yl)methoxy)-5-chloro-2-fluorobenzoate (160
mg, 0.37 mmol), cyclopropylboronic acid (47 mg, 0.55 mmol),
potassium phosphate (157 mg, 0.74 mmol) and tricyclohexylphosphine
tetrafluoroborate (27 mg, 0.074 mmol) in toluene (2mL) and water
(0.1 mL) under a nitrogen atmosphere. The reaction mixture was
heated at 100.degree. C. for 18 hours then cooled to room
temperature. The mixture was diluted with water (10 mL) and
extracted with ethyl acetate (10 mL.times.3). The combined organic
layers were washed with brine (10 mL), dried over anhydrous sodium
sulfate, filtered and concentrated. The residue was purified by
silica gel chromatography (eluting with petroleum ether/ethyl
acetate=10/1) to give the desired product (110 mg, 68% yield) as an
oil. LCMS(ESI): m/z 440.0 [M+H].sup.+.
Step 3
##STR00381##
[0656]
4-((1-Benzylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid
[0657] The synthetic procedure was same as the step 4 of Example
80. LCMS(ESI) m/z: 384.0 [M+H].sup.+.
Step 4
##STR00382##
[0658]
4-((1-benzylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-
(methylsulfonyl)benzamide
[0659] The compound was synthesized as described in step 5 of
Example 80. LCMS(ESI) Method A: RT=4.76 min, m/z: 461.1
[M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 7.41-7.35
(m, 5H), 7.19 (d, J=8.5 Hz, 1H), 6.78 (d, J=12.5 Hz, 1H), 3.91 (d,
J=6.0 Hz, 2H), 3.89 (s, 2H), 3.13-3.11 (m, 2H), 3.02 (s, 3H),
2.52-2.50 (m, 2H), 2.02-1.97 (m, 1H), 1.93-1.86 (m, 3H), 1.51-1.45
(m, 2H), 0.89-0.85 (m, 2H), 0.60-0.57 (m, 2H).
Example 88
##STR00383##
[0660]
4-((1-(3-Fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluor-
o-N-(methylsulfonyl)benzamide
##STR00384##
[0661] Step 1
##STR00385##
[0662] tert-butyl
4-((4-(tert-Butoxycarbonyl)-2-chloro-5-fluorophenoxy)-
methyl)piperidine-1-carboxylate
[0663] Potassium tert-butoxide (6.2 g, 55.6 mmol) was added to a
solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate
(10.0 g, 6.3 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate
(12.6 g, 50.9 mmol) in DMSO (200 mL). After stirring at room
temperature for 1 h, the reaction mixture was diluted with water
(500 mL) and extracted with EtOAc (200 mL.times.3). The combined
organic layers were washed with brine, dried over anhydrous sodium
sulfate, filtered and concentrated. The residue was purified by
silica gel column chromatography (eluting with petroleum
ether/ethyl acetate, from 20/1 to 5/1) to afford the target
compound (12.3 g, yield: 60%) as a pale yellow liquid. LCMS(ESI)
m/z: 331.9. [M-111].sup.+.
##STR00386##
Step 2
tert-Butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)-
methyl)piperidine-1-carboxylate
[0664] Palladium acetate (672 mg, 3 mmol) was added to a solution
of tert-butyl
4-((4-(tert-butoxycarbonyl)cyclohexyl)methoxy)-5-chloro-2-fluorobenzoate
(13.3 g, 30 mmol), cyclopropylboronic acid (5.16 g, 60 mmol),
potassium phosphate (25.5 g, 120 mmol) and tricyclohexylphosphine
tetrafluoroborate (2.2 g, 6 mmol) in toluene (200 mL) and water (10
mL) under a nitrogen atmosphere. The reaction mixture was heated at
100.degree. C. for 16 hours then cooled to room temperature. The
mixture was diluted with water (200 mL) was and extracted with
ethyl acetate (100 mL.times.3). The combined organic layers were
washed with brine, dried over anhydrous sodium sulfate, filtered
and concentrated. The residue was purified by silica gel column
chromatography (eluting with petroleum ether/ethyl acetate, from
10/1 to 2/) to afford the target compound (10.8 g, yield 80%) as a
pale yellow liquid. LCMS(ESI) m/z: 338.0 [M-111].sup.+.
Step 3
##STR00387##
[0665] 5-Cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoic
acid
[0666] A solution of tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-
fluorophenoxy)methyl)piperidine-1-carboxylate (11.0 g, 24.5 mmol)
in DCM (20 mL) and TFA (20 mL) was stirred at room temperature for
1 h. The reaction was quenched with saturated aqueous sodium
bicarbonate and extracted with DCM (50 mL.times.3). The combined
organic layers were dried over anhydrous sodium sulfate, filtered
and concentrated to give target compound (6.5 g, yield: 90%) as a
white solid which was used in the next step without further
purification. LCMS(ESI) m/z: 294.1 [M+H].sup.+.
Step 4
##STR00388##
[0667] Methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
[0668] Thionyl chloride (8 mL) was added dropwise to a solution of
5-cyclopropyl-2-fluoro-4- (piperidin-4-ylmethoxy)benzoic acid (5.0
g, 17 mmol) in MeOH (80 ml). After stirring at 70.degree. C. for 1
h, the solution was concentrated to give a brown solid, which was
recrystallized (petroleum ether/ethyl acetate=5/1) to give the
target compound as a gray solid (yield: 80%). LCMS(ESI) m/z: 308.1
[M+H].sup.+.
Step 5
##STR00389##
[0669] Methyl 4-((1-(3-fluorobenzyl)piperidin-4-yl)methoxy)-5-
cyclopropyl-2-fluorobenzoate
[0670] A mixture of methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate (100 mg,
0.33 mmol), 1-(chloromethyl)-3-fluorobenzene (48 mg, 0.33 mmo),
sodium iodide (149 mg, 0.99 mmol) and potassium carbonate (137 mg,
0.99 mol) in MeCN (10 mL) was stirred at 80.degree. C. for 1 h. The
reaction mixture was diluted with EtOAc (100 mL) and brine (50 mL).
The organic layer was separated, washed with brine (50 mL), dried
over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by silica gel chromatography (eluting with
petroleum ether/EtOAc=5/1) to give the target compound (110 mg,
81%) as a pale yellow oil. LCMS(ESI) m/z: 416.0 [M+H].sup.+.
Step 6
##STR00390##
[0671]
4-((1-(3-Fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluor-
obenzoic acid
[0672] A mixture of methyl
4-((1-(3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-
2-fluorobenzoate (110 mg, 0.27 mmol) and lithium hydroxide (64 mg,
2.7 mmol) in THF (5 mL) and water 15 mL) was stirred at 50.degree.
C. for 3 h. After cooling to room temperature, the mixture was
adjusted to a pH of 2-3 with HCl (2M) then extracted with EtOAc
(10.times.2 mL). The combined organic layers were washed with brine
(10 mL), dried over anhydrous sodium sulfate, filtered and
concentrated to give the product (68 mg, 64%) as a pale yellow
solid. LCMS(ESI) m/z: 402.1 [M+H].sup.+.
Step 7
##STR00391##
[0673]
4-((1-(3-Fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluor-
o-N- (methylsulfonyl)benzamide
[0674] The compound was synthesized as described in step 5 of
Example 80. LCMS(ESI) Method A: RT=5.02 min, m/z: 479.0
[M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 7.43-7.42
(m, 1H), 7.41-7.13 (m, 4H), 6.81 (d, J=12.5 Hz, 1H), 3.92 (d, J=6.0
Hz, 2H), 3.74 (s, 2H), 3.18 (s, 3H), 3.07-2.99 (m, 2H), 2.30-2.28
(m, 2H), 2.04-1.98 (m, 1H), 1.87-1.82 (m, 3H), 1.47-1.24 (m, 2H),
0.89-0.85 (m, 2H), 0.62-0.59 (m, 2H).
Example 89
##STR00392##
[0675]
5-Cyclopropyl-4-((1-(1-(3,5-difluorophenyl)ethyl)piperidin-4-yl)met-
hoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0676] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.39 min, m/z: 511.0 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6): .delta. 7.17-7.10 (m, 4H), 6.85 (d,
J=13.0 Hz, 1H), 3.91 (d, J=6.0 Hz, 2H). 3.81-3.74 (m, 1H), 3.16 (s,
3H), 3.11-3.08(m, 1H), 2.92-2.90 (m, 1H), 2.20-2.10 (m, 2H),
2.03-1.97 (m, 1H), 1.85-1.78 (m, 3H), 1.45-1.36 (m, 5H), 0.89-0.85
(m, 2H), 0.64-0.61 (m, 2H).
Example 90
##STR00393##
[0677]
5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidi-
n-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00394##
[0678] Step 1
##STR00395##
[0679] 2-(3,5-Dichlorophenyl)oxirane
[0680] Sodium hydride (280 mg, 6.9 mmol) was added to an ice-cooled
solution of trimethylsulfonium iodide (1.4 g, 6.9 mmol) in DMSO (40
mL). After stirring at room temperature for 30 min,
3,5-dichlorobenzaldehyde (1 g, 5.7 mmol) was added and mixture
stirred further at room temperature for 1 h. The mixture was then
quenched with water (40 mL) and extracted with EtOAc (20
mL.times.3). The combined organic layers were washed with brine (40
mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The crude product was used in the next step without
further purification.
Step 2
##STR00396##
[0681] 1-(3,5-Dichlorophenyl)-2-methoxyethanol
[0682] 2-(3,5-Dichlorophenyl)oxirane (1 g, crude) was added to a
solution of sodium (1.2 g, 53 mmol) in methanol (50 mL) and the
mixture heated at 60.degree. C. for 1 h. After cooling to room
temperature, the mixture was diluted with water (50 mL) and
extracted with EtOAc (20 mL.times.3). The combined organic layers
were washed with brine (40 mL), dried over anhydrous sodium
sulfate, filtered and concentrated. The residue was purified by
silica gel chromatography (eluting with petroleum ether/EtOAc=50/1)
to give the target compound (160 mg, 14%) as a pale yellow oil.
LCMS(ESI) m/z: 219.0 [M+H].sup.+.
Step 3
##STR00397##
[0683] 1,3-dichloro-5-(1-chloro-2-methoxyethyl)benzene
[0684] The compound was synthesized as described in step 2 of
Example 80.
Step 4
##STR00398##
[0685] Methyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidin-
4-yl)methoxy)-2-fluorobenzoate
[0686] The compound was synthesized as described in step 5 of
Example 88. LCMS(ESI) m/z: 510.1 [M+H].sup.+.
Step 5
##STR00399##
[0687]
5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidi-
n-4-yl)methoxy)-2-fluorobenzoic acid
[0688] The compound was synthesized as described in step 6 of
Example 88. LCMS(ESI) m/z: 496.1 [M+H].sup.+.
Step 6
##STR00400##
[0689]
5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidi-
n-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0690] The compound synthesized as described in step 5 of Example
80. LCMS(ESI) Method A: RT=5.78 min, m/z: 572.9 [M+H].sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 11.73 (brs, 1H),
7.50-7.49 (m, 1H), 7.39-7.38 (m, 2H), 7.16 (d, J=8.0 Hz, 1H), 6.82
(d, J=13.0 Hz, 1H), 3.88 (d, J=5.5 Hz, 2H), 3.73-3.65 (m, 3H), 3.22
(s, 3H), 3.14 (s, 3H), 2.99-2.97 (m, 1H), 2.81-2.79 (m, 1H),
2.11-2.07 (m, 1H), 2.02-1.95 (m, 2H), 1.79-1.71 (m, 3H), 1.38-1.28
(m, 2H), 0.89-0.85 (m, 2H), 0.63-0.60 (m, 2H).
Example 91
##STR00401##
[0691]
5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)azetidin-
-3-yl)methoxy)- 2-fluoro-N-(methylsulfonyl)benzamide
##STR00402##
[0692] Step 1
##STR00403##
[0693] tert-Butyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)-3-
azetidin-3-yl)methoxy)-2-fluorobenzoate
[0694] The compound was synthesized as described in step 3 of
Example 80. LCMS(ESI) m/z: 524.0 [M+H].sup.+.
Step 2
##STR00404##
[0695]
5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)azetidin-
-3-yl)methoxy)- 2-fluorobenzoic acid
[0696] The compound was synthesized as described in step 4 of
Example 80. LCMS(ESI) m/z: 467.9 [M+H].sup.+.
Step 3
##STR00405##
[0697]
5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)azetidin-
-3- yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0698] The compound was synthesized as described in step 5 of
Example 80. LCMS(ESI) Method A: RT=5.26 min, m/z: 544.8
[M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 7.50 (m,
1H), 7.35 (m, 2H), 7.17 (d, J=8.0 Hz, 1H), 6.89 (d, J=13.0 Hz, 1H),
4.16 (d, J=6.0 Hz, 2H), 3.60 (m, 1H), 3.48-3.45 (m, 1H), 3.42-3.32
(m, 3H), 3.20 (s, 3H), 3.18 (s, 3H), 3.15-3.12 (m, 1H), 3.09-3.07
(m, 1H), 2.87-2.85 (m, 1H), 2.04-2.00 (m, 1H), 0.89-0.87 (m, 2H),
0.64-0.63 (m, 2H).
Example 92
##STR00406##
[0699]
4-((1-(3-Chlorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluor-
o- N-(methylsulfonyl)benzamide
[0700] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.35 min, m/z 494.9 [M+H].sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6): .delta. 7.42-7.31 (m, 4H), 7.19-7.17 (d,
J=8.5 Hz, 1H), 6.81-6.79 (d, J=13.0 Hz, 1H), 3.92-3.91 (m, 2H),
3.68 (br s, 2H), 3.04-2.96 (m, 5H), 2.24-2.22 (m, 2H), 2.02-1.99
(m, 1H), 1.84-1.81 (d, J=12.5 Hz, 3H), 1.43-1.40 (m, 2H), 0.89-0.86
(m, 2H), 0.61-0.58 (m, 2H).
Example 93
##STR00407##
[0701]
5-Cyclopropyl-2-fluoro-4-((1-(4-methylbenzyl)piperidin-4-yl)methoxy-
)-N- (methylsulfonyl)benzamide
[0702] The compound was synthesized as described n Example 88.
LCMS(ESI) Method A: RT=4.88 min, m/z 475.0 [M+H].sup.+. .sup.1H
NMR, (500 MHz, DMSO-.sub.6): .delta. 7.31-7.29 (d, J=7.5 Hz, 2H),
7.23-7.18 (m, 3H), 6.79-6.77 (d, J=12.5 Hz, 1H), 3.92 (m, 4H),
3.16-3.14 (m, 2H), 3.00 (s, 3H), 2.50 (s, 2H), 2.31 (s, 3H),
2.01-1.87 (m, 4H), 1.50-1.48 (m, 2H), 0.88-0.86 (m, 2H), 0.59-0.58
(m, 2H).
Example 94
##STR00408##
[0703]
5-Cyclopropyl-2-fluoro-4-((1-(3-fluoro-4-methoxybenzyl)piperidin-4-
yl)methoxy)-N-(methylsulfonyl)benzamide
[0704] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=4.70 min, m/z 509.0 [M+H].sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6): .delta. 7.29-7.27 (d, J=12.5 Hz, 1H),
7.19-7.18 (d, J=6.0 Hz, 3H), 6.81-6.78 (d, J=13.0 Hz, 1H), 3.92 (m,
2H), 3.88 (m, 5H), 3.14-3.12 (m, 2H), 3.04 (s, 3H), 2.50 (s, 2H),
2.00-1.86 (m, 4H), 1.50-1.48 (m, 2H), 0.88-0.86 (m, 2H), 0.60-0.59
(m, 2H).
Example 95
##STR00409##
[0705]
(S)-5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((4-(methylsulf-
onyl)-phenyl)(phenyl)methyl)azetidin-3-yl)methoxy)benzamide
[0706] The compound was synthesized as described in Example 81.
LCMS(ESI) Method A: RT=4.99 min, m/z 587.3 [M+H].sup.+. .sup.1H NMR
(500 MHz, MeOD-.sub.4): .delta. 7.90 (d, J=8.0 Hz, 2H), 7.73 (d,
J=8.5 Hz, 2H), 7.45 (d, J =7.0 Hz, 2H), 7.37-7.25 (m, 3H), 7.23 (d,
J=7.0 Hz, 1H), 6.76 (d, J=12.5 Hz, 1H), 4.66 (s, 1H), 4.20 (d,
J=6.0 Hz, 2H), 3.47-3.33 (m, 2H), 3.24-3.16 (m, 5H), 3.09 (s, 3H),
3.03-3.00 (m, 1H), 2.10 (t, J=10.5 Hz, 1H), 0.94-0.90 (m, 2H),
0.70-0.67 (m, 2H).
Example 96
##STR00410##
[0707]
(R)-5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((4-(methylsulf-
onyl)-phenyl)(phenyl)methyl)azetidin-3-yl)methoxy)benzamide
[0708] The compound was synthesized as described in Example 81.
LCMS(ESI) Method A: RT=4.99 min, m/z 587.2 [M+H].sup.+. .sup.1H NMR
(500 MHz, MeOD-d.sub.4): .delta. 7.91 (d, J=8.5 Hz, 2H), 7.74 (d,
J=8.0 Hz, 2H), 7.45 (d, J =7.0 Hz, 2H), 7.34-7.31 (m, 3H), 7.26 (d,
J=7.0 Hz, 1H), 6.85 (d, J=13.0 Hz, 1H), 4.71 (s, 1H), 4.25 (d,
J=6.0 Hz, 2H), 3.50-3.43 (m, 2H), 3.34-3.21 (m, 5H), 3.09 (s, 3H),
3.06-3.04 (m, 1H), 2.10 (t, J=10.5 Hz, 1H), 0.97-0.93 (m, 2H),
0.70-0.67 (m, 2H).
Example 97
##STR00411##
[0709]
5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)met-
hoxy)- 2-fluoro-N-(methylsulfonyl)benzamide
[0710] The compound was synthesized as described in Example 88.
LCMS(ESI): Method A: RT=6.17 min, m/z 543.0 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d.sub.4): .delta. 7.51 (s, 3H), 7.35 (d, J=8.5
Hz, 1H), 6.63 (d, J=12.5 Hz, 1H), 4.14 (s, 1H), 3.82 (s, 2H), 3.54
(d, J=10.0 Hz, 1H), 3.21 (d, J=12.5 Hz, 4H), 2.66-2.62 (m, 2H),
2.09-2.00 (m, 4H), 1.69-1.59 (m, 5H), 0.88 (m, 2H), 0.63 (m,
2H).
Example 98
##STR00412##
[0711]
5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)azetidin-3-yl)meth-
oxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0712] The compound was synthesized as described in Example 80.
LCMS(ESI) Method A: RT=5.51 min, m/z 515.0 [M+H].sup.+. .sup.1H NMR
(500 MHz, MeOD-d.sub.4): .delta. 7.43 (s, 1H), 7.38-7.35 (m, 3H),
6.77 (d, J=13.0 Hz, 1H), 4.20-4.17 (m, 2H), 3.79 (s, 2H), 3.58 (d,
J=7.0 Hz, 1H), 3.49 (d, J=4.0 Hz, 2H), 3.25 (s, 3H), 3.11 (t,
J=13.0 Hz, 1H), 2.09-2.06 (m, 1H), 1.36 (d, J=6.5 Hz, 3H), 0.94 (m,
2H), 0.68 (m, 2H).
Example 99
##STR00413##
[0713]
(R)-5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin)-4-y-
l)methoxy)-2-fluoro-N-(methylsulfonyl)-benzamide
[0714] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate. Chiral
HPLC (column: AD-3, 4.6.times.150 mm, 3 .mu.m; mobile Phase:
n-hexane (0.1% DEA)/ EtOH 0.1% DEA)=90/10; flow: 1 mL/min; column
temperature: 40.degree. C.; RT=6.59 min). LCMS(ESI) Method A:
RT=6.13 min. m/z 543.0 [M+H].sup.+. .sup.1H NMR (500 MHz,
MeOD-d.sub.4): .delta. 7.51 (s, 1H), 7.40 (d, J=1.5 Hz, 2H), 7.17
(d, J=3 8.5 Hz, 1H), 6.82 (d, J=12.5 Hz, 1H), 3.91 (d, J=5.5 Hz,
2H), 3.70 (t, J=4.0 Hz, 1H), 3.32 (s, 3H), 3.03 (d, J=8.5 Hz, 1H),
2.86 (t, J=12.0 Hz, 1H), 2.05-1.99 (m, 3H), 1.83-1.76 (m, 3H),
1.40-1.33 (m, 5H), 0.89-0.86 (m, 2H), 0.63-0.59 (m, 2).
Example 100
##STR00414##
[0715]
(S)-5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl-
)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0716] The compound was synthesized as described in Example 99.
Chiral HPLC (column: AD-3, 4.6.times.150 mm, 3 .mu.m; mobile Phase:
n -hexane (0.1% DEA)/EtOH 0.1% DEA)=90/10; flow: 1 mL/min; column
temperature: 40.degree. C.; RT=9.38 min). LCMS(ESI) Method A:
RT=6.06 min, m/z 542.9 [M+H].sup.+. .sup.1H NMR (500 MHz,
MeOD-d.sub.4): .delta. 7.50 (s, 1H), 7.39 (s, 2H), 7.19 (d, J=8.5
Hz, 1H), 6.78 (d, J=12.5 Hz, 1H), 3.89 (d, J=5.5 Hz, 2H), 3.65 (s,
1H), 3.03-2.99 (m, 4H), 2.84 (d, J=11.0 Hz, 1H), 2.04-1.98 (m, 3H),
1.82-1.75 (m, 3H), 1.38-1.31 (m, 5H), 0.88-0.85 (m, 2H), 0.61-0.57
(m, 2H).
Example 101
##STR00415##
[0717] 5-Cycloproyl-4-((1-(1-(3
,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluor-
obenzamide
[0718] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=6.22 min, m/z 557.0 [M+H].sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6): .delta. 7.52 (s, 1H), 7.42 (s, 2H), 7.14
(d, J=9.0 Hz, 1H), 6.89 (d, J=12.5 Hz, 1H), 3.92 (d, J=6.0 Hz, 2H),
3.75 (s, 1H), 3.38 (d, J=7.0 Hz, 2H), 3.06 (d, J=10.0 Hz, 1H), 2.89
(d, J=9.5 Hz, 1H), 2.12-1.99 (m, 3H), 1.84-1.77 (m, 3H), 1.40-1.35
(m, 5H), 1.21 (t, J=14.5 Hz, 3H), 0.89-0.85 (m, 2H), 0.65-0.62 (m,
2H).
Example 102
##STR00416##
[0719]
5-Cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(1-(3,5-dichlorophenyl)-
-ethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide
[0720] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=6.26 min, m/z 569.0 [M+H].sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.52 (s, 1H), 7.41 (s, 2H), 7.14
(d, J=8.0 Hz, 1H), 6.90 (d, J=13.0 Hz, 1H), 3.93 (d, J=5.5 Hz, 2H),
3.73 (s, 1H), 3.06-3.02 (m, 2H), 2.89 (d, J=8.5 Hz, 1H), 2.11-1.99
(m, 3H), 1.84-1.77 (m, 3H), 1.41-1.34 (m, 5H), 1.06-1.01 (m, 4H),
0.90-0.86 (m, 2H), 0.65-0.62 (m, 2H).
Example 103
##STR00417##
[0721]
N-(Azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(1-(3,5-dichloropheny-
l)-ethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide
[0722] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=6.34 min, m/z 583.9 [M+H].sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6): .delta. 7.48 (s, 1H), 7.38 (d, J=1.5 Hz,
2H), 7.19 (d, J=7.5 Hz, 1H), 6.81 (d, J=12.5 Hz, 1H), 3.88 (d,
J=22.5 Hz, 6H), 3.61 (d, J=6.5 Hz, 1H), 2.97 (d, J=10.5 Hz, 1H),
2.81 (d, J=10.0 Hz, 1H), 2.08-1.96 (m, 5H), 1.82-1.74 (m, 3H),
1.37-1.30 (m, 5H), 0.88 (m, 2H), 0.61 (m, 2H).
Example 104
##STR00418##
[0723]
4-((1-(4-Chlorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluor-
o- N-(methylsulfonyl)benzamide
[0724] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.29 min, m/z 494.9 [M+H].sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6): .delta. 7.41 (d, J=8.0 Hz, 2H), 7.36 (d,
J=8.5 Hz, 2H), 7.20 (t, J =8.5 Hz, 1H), 6.74 (d, J=13.0 Hz, 1H),
3.90 (d, J=5.5 Hz, 2H), 3.61 (s, 2H), 2.93 (d, J=9.0 Hz, 5H), 2.16
(s, 2H), 1.99 (d, J=5.5 Hz, 1H), 1.80 (d, J=11.0 Hz, 3H), 1.40 (d,
J=11.0 Hz, 2H), 0.87-0.86 (m, 2H), 0.56 (m, 2H).
Example 105
##STR00419##
[0725]
4-((1-(2-Chloro-4-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropy-
l-2-fluoro-N-(methylsulfonyl)benzamide
[0726] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.69 min, m/z 513.0 [M+H].sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6): .delta. 7.57 (t, J=15.0 Hz, 1H), 7.45 (t,
J=9.0 Hz, 1H), 7.27-7.24 (m, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.89 (d,
J=12.5 Hz, 1H), 3.95 (d, J=5.5 Hz, 2H), 3.70 (s, 2H), 3.21 (s, 3H),
2.97 (d, J=10.5 Hz, 2H), 2.28 (t, J=22 Hz, 2H), 2.02 (t, J=10.0 Hz,
1H), 1.87-1.81 (m, 3H), 1.41 (d, J =11.5 Hz, 2H), 0.89 (m, 2H),
0.64 (m, 2H).
Example 106
##STR00420##
[0727]
5-Cyclopropyl-4-((1-(2,4-dichlorobenzyl)piperidin-4-yl)methoxy)-2-
fluoro-N-(methylsulfonyl)benzamide
[0728] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=6.03 min, m/z 528.8 [M+H].sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6): .delta. 7.61 (s, 1H), 7.54 (d, J=8.0 Hz,
1H), 7.45 (t, J=9.0 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.90 (d,
J=13.0 Hz, 1H), 3.95 0), (d, J=6.0 Hz, 2H), 3.67 (s, 2H), 3.23 (s,
3H), 2.94 (d, J=10.5 Hz, 2H), 2.24 (t, J=22 Hz, 2H), 2.03-1.99 (m,
1H), 1.86-1.80 (m, 3H), 1.13-1.37 (m, 2H), 0.89 (m, 2H), 0.65 (m,
2H).
Example 107
##STR00421##
[0729]
4-((1-(2,5-bis(trifluoromethyl)piperidin)-4-methylpiperidin-4-yl)me-
thoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[0730] The compound was prepared in a similar manner to Example 73
starting from tert-butyl
4-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)phenoxy)methyl)-4-
-methylpiperidine-1-carboxylate (Example 73 step 1-2) and
2,5-bis(trifluoromethyl)benzaldehyde. LCMS (Method F): RT=4.76 min,
m/z: 577.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
11.76 (s, 1H), 8.15 (d, J=1.7 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.85
(dd, J=8.3, 1.5 1H), 7.18 (d, J=8.3 Hz, 1H), 6.96 (d, J=12.9 Hz,
1H), 3.86 (s, 2H), 3.77 (s, 2H), 2.64-2.53 (m, 2H), 2.47-2.36 (m,
2H), 2.08-1.98 (m, 1H), 1.81-1.68 (m, 2H), 1.52-1.39 (m, 2), 1.09
(s, 3H), 0.94-0.83 (m, 2H), 0.71-0.62 (m, 2H).
Example 108
##STR00422##
[0731]
(S)-4-((1-((3-Cyanophenyl)(phenyl)methyl)azetidin-3-yl)methoxy)-5-c-
yclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[0732] The compound was synthesized as described in Example 81.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH, A:B=75.25; flow: 2.25 mL/min;
column temperature: 36.degree. C.; RT=6.85 min). LCMS(ESI) Method
A: RT=5.66, m/z: 534.2 [M+H].sup.+. .sup.1H NMR (500 MHz, MeOD-d4):
.delta. 7.82 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.60 (d, J=7.5 Hz,
1H), 7.52-7.49 (m, 1H), 7.45-7.43 (m, 2H), 7.35-7.32 (m, 3H),
7.27-7.24 (m, 1H), 6.85 (d, J=13.0 Hz, 1H), 4.63 (s, 1H), 4.24 (d,
J=6.5 Hz, 2H), 3.47-3.43 (m, 2H), 3.33 (s, 3H), 3.23-3.20 (m, 2H),
3.04-3.02 (m, 1H), 2.13-2.10 (m, 1H), 0.97-0.94 (m, 2H), 0.70-0.67
(m, 2H).
Example 109
##STR00423##
[0733]
(R)-4-((1-((3-Cyanophenyl)(phenyl)methyl)azetidin-3-yl)methoxy)-5-c-
yclopropyl-2-fluoro-N-(methylsulfonyl)benazmide
[0734] The compound was synthesized as described in Example 81.
Chiral HPLC (column: OJ_H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH, A:B=75:25; flow: 2.25 mL/min;
column temperature: 36.degree. C.; RT=8.24 min). LCMS(ESI) Method
A: RT=5.34 min, m/z: 534.3 [M+H].sup.+. .sup.1H NMR (500 MHz,
MeOD-d4): .delta. 7.82 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.60 (d,
J=7.5 Hz, 1H), 7.52-7.49 (m, 1H), 7.45-7.43 (m, 2H), 7.35-7.32 (m,
3H), 7.27-7.24 (m, 1H), 6.85 (d, J=12.5 Hz, 1H), 4.63 (s, 1H), 4.24
(d, J=6.0 Hz, 2H), 3.47-3.41 (m, 2H), 3.33 (s, 3H), 3.23-3.20 (m,
2H), 3.04-3.02 (m, 1H), 2.12-2.09 (m, 1H), 0.96-0.94 (m, 2H),
0.69-0.68 (m, 2H).
##STR00424##
Example 110
(S)-4-((1-((4-Cyanophenyl)(phenyl)methyl)azetidin-3-yl)methoxy)-5-cyclopro-
pyl-2-fluoro-N-(methylsulfonyl)benazmide
[0735] The compound was synthesized as described in Example 81.
Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOD (0.1% DEA), A:B=65:35; flow:
1.95 mL/min; column temperature: 40.degree. C.; RT=4.13 min).
LCMS(ESI) Method A: RT=5.64 min, m/z: 534.2 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d4): .delta. 7.69 -7.64 (m, 4H), 7.43 (d, J=7.0
Hz, 2H), 7.34-7.31 (m, 3H), 7.26-7.23 (m, 1H), 6.84 (d, J=13.0 Hz,
1H), 4.65 (s, 1H), 4.23 (d, J=6.0 Hz, 2H), 3.48-3.40 (m, 2H), 3.31
(s, 3H), 3.25-3.18 (m, 2H), 3.05-3.01 (m, 1H), 2.12-2.08 (m, 1H),
0.97-0.93 (m, 2H), 0.70-0.67 (m, 2H).
Example 111
##STR00425##
[0736]
(R)-4-((1-((4-Cyanophenyl)(phenyl)methyl)azetidin-3-yl)methoxy)-5-c-
yclopropyl-2-fluoro-N-(methylsulfonyl)benazmide
[0737] The compound was synthesized as described in Example 81.
Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=65:35; flow:
1.95 mL/min; column temperature: 40.degree. C.; RT=6.36 min).
LCMS(ESI) Method A: RT=5.64 min, m/z: 534.2 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d4): .delta. 7.69-7.64 (m, 4H), 7.43 (d, J=7.5
Hz, 2H), 7.34-7.30 (m, 3H), 7.26-7.23 (m, 1H), 6.82 (d, J=13.0 Hz,
1H), 4.63 (s, 1H), 4.22 (d, J=5.5 Hz, 2H), 3.47-3.39 (m, 2H), 3.29
(s, 3H), 3.24-3.16 (m, 2H), 3.05-3.00 (m, 1H), 2.13-2.07 (m, 1H),
0.96-0.92 (m, 2H), 0.70-0.66 (m, 2H).
Example 112
##STR00426##
[0738]
(S)-5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenyl(4-(trif-
luoromethoxy)phenyl)-methyl)azetidin-3-yl)methoxy)benazmide
[0739] The compound was synthesized as described in Example 81.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=80:20; flow: 2.4
mL/min; column temperature: 40.degree. C.; RT=3.62 min). LCMS(ESI)
Method A: RT=6.36 min, m/z: 593.2 [M+H].sup.+. .sup.1H NMR (500
MHz, MeOD-d4): .delta. 7.55-7.53 (m, 2H), 7.44-7.42 (m, 2H),
7.34-7.31 (m, 3H), 7.26-7.22 (m, 3H), 6.80 (d, J=12.0 Hz, 1H), 4.63
(s, 1H), 4.21 (d, J=6.0 Hz, 2H), 3.47-3.45 (m, 2H), 3.33-3.31 (m,
5H), 3.10-3.00 (m, 1H), 2.10-2.09 (m, 1H), 0.95-0.92 (m, 2H),
0.68-0.67 (m, 2H).
Example 113
##STR00427##
[0740]
(R)-5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenyl(4-(trif-
luoromethoxy)phenyl)methyl)-azetidin-3-yl)methoxy)benzamide
[0741] The compound was synthesized as described in Example 81.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=80:20; flow: 2.4
mL/min; column temperature: 4.degree. C.; RT=4.11 min). LCMS(ESI)
Method B: RT=6.38 min, m/z: 593.2 [M+H].sup.+. .sup.1H NMR (500
MHz, MeOD-d4): .delta. 7.55-7.53 (m, 2H), 7.44-7.42 (m, 2H),
7.36-7.32 (m, 3H), 7.27-7.23 (m, 3H), 6.84 (d, J=12.5 Hz, 1H), 4.71
(s, 1H), 4.23 (d, J=6.0 Hz, 2H), 3.53-3.51 (m, 2H), 3.40-3.20 (m,
5H), 3.08-3.07 (m, 1H), 2.12-2.09 (m, 1H), 0.97-0.93 (m, 2H),
0.70-0.67 (m, 2H).
Example 114
##STR00428##
[0742]
(S)-4-((1-((5-Chloro-6-isopropoxypyridin-3-yl)(phenyl)methyl)azetid-
in-
3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[0743] The compound was synthesized as described in Example 81.
Chiral HPLC (column: OH-J, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=75:25; flow:
2.25 mL/min; column temperature: 40.degree. C.; RT=4.49 min).
LCMS(ESI) Method A: RT=5.88 min, m/z: 602.1 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d4): .delta. 8.04 (d, J=5.0 Hz, 1H), 7.46 (m,
2H), 7.36-7.25 (m, 5H), 6.84 (d, J=13.0 Hz, 1H), 5.34-5.29 (m, 1H),
5.01 (s, 1H), 4.19 (d, J=5.5 Hz, 2H), 3.53-3.50 (m, 1H), 3.30-3.28
(m, 5H), 3.15-3.12 (m, 1H), 3.04-3.01 (m, 1H), 2.19-2.15 (m, 1H),
1.36 (d, J=6.5 Hz, 3H), 1.32 (d, J=6.5 Hz, 3H), 1.01-0.97 (m, 2H),
0.71-0.70 (m, 2H).
Example 115
##STR00429##
[0744]
(R)-4-((1-((5-Chloro-6-isopropoxypyridin-3-yl)(phenyl)methyl)azetid-
in-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[0745] The compound was synthesized as described in Example 81.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=75:25; flow:
2.25 mL/min; column temperature: 40.degree. C.; RT=4.49 min).
LCMS(ESI) Method A: RT=5.56 min, m/z: 602.2 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d4): .delta. 8.04 (d, J=5.0 Hz, 1H), 7.46 (m,
2H), 7.36-7.25 (m, 5H), 6.85 (d, J=13.0 Hz, 1H), 5.34-5.30 (m, 1H),
5.01 (s, 1H), 4.19 (d, J=5.0 Hz, 2H), 3.53-3.50 (m, 1H), 3.32-3.30
(m, 5H), 3.15-3.12 (m, 1H), 3.04-3.01 (m, 1H), 2.19-2.15 (m, 1H),
1.36 (d, J=6.5 Hz, 3H), 1.32 (d, J=6.5 Hz, 3H), 1.01-0.97 (m, 2H),
0.71-0.70 (m, 2H).
Example 116
##STR00430##
[0746]
5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(2,2,2-trifluoroeth-
yl)-piperidin-4-yl)methoxy)-benzamide
##STR00431##
[0747] Step 1
##STR00432##
[0748] Methyl
5-cyclopropyl-2-fluoro-4-((1-(2,2,2-trifluoroethyl)piperidin-
4-yl)methoxy)benzoate
[0749] A Mixture of methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate (180 mg,
0.59 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (151 mg,
0.65 mmol) and DIPEA (152 mg, 1.18 mmol) in THF (15 mL) was stirred
at 60.degree. C. for 2 h. The reaction mixture was diluted with
ethyl acetate (30 mL), washed with brine (50.times.2 mL), dried
over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by silica gel chromatography (eluting with
petroleum ether/ethyl acetate=5/1) to give the target compound (160
mg, 69%) as a yellow solid. LCMS(ESI) m/z: 390.2 [M+H].sup.+.
Step 2
##STR00433##
[0750]
5-Cyclopropyl-2-fluoro-4-((1-(2,2,2-trifluoroethyl)piperidin-4-
yl)methoxy)benzoic acid
[0751] A mixture of methyl
5-cyclopropyl-2-fluoro-4-((1-(2,2,2-triflouroethyl)piperidin-
4-yl)methoxy)benzoate (160 mg, 0.4 mmol) and lithium hydroxide (250
mg, 10.0 mmol) in THF (10 mL) and H.sub.2O (10 mL) was stirred at
room temperature for 2 h. The mixture was diluted with EtOAc (50
mL), washed with HCl (2.0 M, 10 mL), brine (50.times.2 mL), dried
over anhydrous sodium sulfate, filtered and concentrated to give
the target compound (120 mg) as yellow solid which was used in the
next step without further purification. LCMS(ESI) m/z: 376.0
[M+H].sup.+.
Step 3
##STR00434##
[0752]
5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(2,2,2-trifluoroeth-
yl)-piperidin-4-yl)methoxy)-benzamide
[0753] A mixture of
5-cyclopropyl-2-fluoro-4-((1-(2,2,2-trifluoroethyl)piperidin-
4-yl)methoxy)benzoic acid (120 mg, 0.32 mmol), methanesulfonamide
(45.6 mg, 0.48 mmol), EDCI (92 mg, 0.48 mmol) and DMAP (59 mg, 0.48
mmol) in DCM (20 mL) was stirred at 25.degree. C. for 1 h. The
reaction mixture was diluted with EtOAc (100 mL), washed with HCl
(2.0 M, 20 mL), brine (50.times.2 mL), dried over anhydrous sodium
sulfide, filtered and concentrated. The residue was purified by
reverse phase combiflash (25%-30% MeCN in 0.5% NH.sub.4HCO.sub.3)
to give the target product (65.0 mg, 45%) as a white solid.
LCMS(ESI) Method A: RT=5.97 min, m/z: 453.1 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOH-d.sub.4): .delta. 7.36 (d, J=8.5 Hz, 1H), 6.65
(d, J =12.5 Hz, 1H), 3.90 (d, J=5.5 Hz, 2H), 3.11-3.05 (m, 7H),
2.46-2.42 (m, 2H), 2.08-2.06 (m, 1H), 1.89-1.86 (m, 3H), 1.55-1.52
(m, 2H), 0.91-0.87 (m, 2H), 0.67-0.05 (m, 2H).
Example 117
##STR00435##
[0754]
5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(3,3,3-trifluoropro-
pyl) piperidin-4-yl)methoxy)-benzamide
[0755] The compound was synthesized as described in Example 37.
LCMS(ESI) Method A: RT=4.66 min, m/z: 467.0 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d.sub.4): .delta. 7.24 (d, J=8.5 Hz, 1H), 6.56
(d, J=12.5 Hz, 1H), 3.81 (d, J=5.5 Hz, 2H), 3.01 (s, 3H), 2.96-2.94
(m, 2H), 2.60 (m, 2H), 2.39-2.33 (m, 2H), 2.11-2.07 (m, 2H),
1.97-1.93 (m, 1H), 1.84-1.81 (m, 2H), 1.47-1.42 (m, 2H), 1.22-1.20
(m, 1H), 0.79-0.76 (m, 2H), 0.54-0.53 (m, 2H).
Example 118
##STR00436##
[0756]
(S)-5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenyl(pyridin-
-2-yl)methyl)azetidin-3-yl)methoxy)benzamide
[0757] The compound was synthesized as described in Example 81.
Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=75:25; flow:
2.25 mL/min; column temperature: 40.degree. C.; RT=4.55 min).
LCMS(ESI) Method A: RT=4.86 min, m/z 510.3 [M+H].sup.+. .sup.1H NMR
(500 MHz, CDCl.sub.3): .delta. 8.51 (d, J=3.0 Hz, 1H), 7.62-7.57
(m, 2H), 7.50-7.47 (m, 3H), 7.29-7.22 (m, 4H), 7.11 (s, 1H), 6.61
(d, J=14.5 Hz, 1H), 4.61 (s, 1H), 4.20 (d, J=6.0 Hz, 2H), 3.41 (d,
J=5H), 3.14 (s, 1H), 3.01 (s, 1H), 2.04 (m, 1H), 0.94 (m, 2H), 0.65
(m, 2H).
Example 119
##STR00437##
[0758]
(S)-5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenyl(pyridin-
-2-yl)methyl)azetidin-3-yl)methoxy)benzamide
[0759] The compound was synthesized as described in Example 81.
Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=75:25; flow:
2.25 mL/min; column temperature: 40.degree. C.; RT=5.70 min).
LCMS(ESI) Method A: RT=4.86 min m/z: 510.3 [M+H].sup.+. .sup.1H NMR
(500 MHz, CDCl.sub.3): 8.50 (d, J=4.5 Hz, 1H), 7.64-7.57 (m, 2H),
7.50-7.47 (m, 3H), 7.31-7.21 (m, 4H), 7.12-7.10 (m, 1H), 6.60 (d,
J=14.5 Hz, 1H), 4.60 (s, 1H), 4.20 (d, J=6.0 Hz, 2H), 3.41 (s, 5H),
3.15 (s, 1H), 3.01 (s, 1H), 2.06-2.01 (m, 1H), 0.93 (m, 2H), 0.65
(m, 2H).
Example 120
##STR00438##
[0760]
(S)-5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)azetidin-3-
yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00439##
[0761] Step 1
##STR00440##
[0762]
(S,E)-N-(1-(3,5-Dichlorophenyl)ethylidene)-2-methylpropane-2-sulfin-
amide
[0763] Tetraisopropoxytitanium (6.14 g, 21.2 mmol) was added to a
solution of 3,5-dichlorophenyl ethanone (1.0 g, 5.3 mmol) and
(S)-2-methylpropane-2- sulfinamide (128 g, 10.6 mmol) in dry THF
(20 mL). After stirring at 80.degree. C. for 16 h, ethyl acetate
(15 mL) and brine was added to quench the reaction. The white
precipitate was filtered and the filtrate was concentrated and
purified by silica gel chromatography (eluting with ethyl
acetate/petroleum ether=1/10) to give the target compound as a
yellow solid (1.24 g, 80%). LCMS(ESI): m/z 292.0 [M+H].sup.+.
Step 2
##STR00441##
[0764]
(S)-N-(S)-1-(3,5-Dichlorophenyl)ethyl-2-methylpropane-2-sulfinamide
[0765] Sodium borohydride (0.49 g, 12.9 mmol) was added to a
solution (S,
E)-N-(1-(3,5-dichlorophenyl)ethylidene)-2-methylpropane-2-sulfinamide
(1.24 g, 4.3 mmol) in THF (20 mL, with 2% H.sub.2O) at -60.degree.
C. After stirring at room temperature for 3 h, the solvent was
removed under reduced pressure and the crude product was purified
by silica gel chromatography (eluting with ethyl acetate/petroleum
ether=1/12) to afford target compound (1.07 g, 85%) as white solid.
LCMS(ESI): m/z 294.0 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3, 500
MHz): .delta. 7.28 (t, J=2.0 Hz, 1H), 7.23 (d, J=2.0 Hz, 2H), 4.48
(m, 1 H), 3.41 (d, J=2.5 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H), 1.24 (s,
9H).
Step 3
##STR00442##
[0766] (S)-1-(3,5-Dichlorophenyl)ethanamine hydrochloride
[0767] HCl (1M in MeOH, 10 mL) was added to a solution of
(S)-N-(S)-1-(3,5-dichlorophenyl)ethyl)-2-methylpropane-2-sulfinamide
(1.07 g, 3.66 mmol) in MeOH (5 ml). After stirring at room
temperature for 2 h, the mixture was diluted with ethyl acetate (30
mL). The resultant white precipitate was filtered and washed with
ethyl acetate (10 mL) to provide the target compound (820 mg, 99%)
as a white solid. LCMS (ESI): m/z 190.0 [M+H].sup.+.
Step 4
##STR00443##
[0768] (S)-tert-Butyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)azetidin-3-
yl)methoxy)-2-fluorobenzoate
[0769] The compound was synthesized as described in step 4 of
Example 5 LCMS(ESI): m/z 494.1 [M+H].sup.+.
Step 5
##STR00444##
[0770]
(S)-5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)azetidin-3-yl)-
methoxy)- 2-fluorobenzoic acid
[0771] The compound was synthesized as described in step 5 of
Example 5. LCMS(ESI): m/z 438.1 [M+H].sup.+.
Step 6
##STR00445##
[0772]
(S)-5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)azetidin-3-yl)-
methoxy)- 2-fluoro-N-(methylsulfonyl)benzamide
[0773] The compound was synthesized as described in step 6 of
Example 5. Chiral HPLC (column: OZ-H, 4.6.times.250 mm, 5 .mu.m;
mobile Phase: A: supercritical CO.sub.2, B: MeOH (0.1% DEA),
A:B=65:35; flow: 1.95 mL/min; column temperature: 40.degree. C.;
RT=7.28 min). LCMS(ESI) Method A: RT=5.55 min m/z 514.9
[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 500 MHz: .delta. 7.58 (d,
J=9.0 Hz, 1H), 7.23 (m, 1H), 7.19 (d, J=2.0 Hz, 2H), 6.59 (d,
J=14.5 Hz, 1H), 4.17 (m, 2H), 3.38 (m, 4H), 3.30 (m, 2H). 3.07 (m,
2H), 2.92 (m, 1H), 2.02 (m, 1H), 1.18 (d, 3H), 0.94 (m, 2H), 0.66
(m, 2H).
Example 121
##STR00446##
[0774]
(R)-5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)azetidin-3-yl)-
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0775] The compound was synthesized as described in Example 41.
Chiral HPLC (column: OZ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=65:35; flow:
1.95 mL/min; column temperature: 40.degree. C,; RT=5.37 min).
LCMS(ESI) Method A: RT=5.41 min m/z 514.8 [M+H].sup.+. .sup.1H-NMR
CDCl.sub.3, 500 MHz): .delta. 7.58 (d, J=9.0 Hz, 1H), 7.23 (m, 1H),
7.19 (d, J=2.0 Hz, 2H), 6.59 (d, J=14.5 Hz, 1H), 4.17 (m, 2H), 3.38
(m, 4H), 3.30 (m, 2H), 3.07 (m, 2H), 2.92 (m, 1H), 2.02 (m, 1H),
1.18 (d, 3H), 0.94 (m, 2H), 0.66 (m, 2H).
Example 122
##STR00447##
[0776]
4-((1-(5-chloro-2-(trifluoromethyl)piperidin)-4-methylpiperidin-4-y-
l)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[0777] The compound was prepared in a similar manner to Example 73
starting from tert-butyl
4-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)phenoxy)methyl)-4-
-methylpiperidine-1-carboxylate (Example 73 step 1-2) and
5-chloro-2-(trifluoromethyl)benzaldehyde. LCMS (Method F): RT=4.76
min, m/z: 577.2 [M+H].sup.+.
Example 123
##STR00448##
[0778]
5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)-4-methylpiperidin-4-yl)met-
hoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0779] The compound was prepared in a similar manner to Example 73
starting from tert-butyl
4-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)phenoxy)methyl)-4-
-methylpiperidine-1-carboxylate (Example 73 step 1-2) and
3,5-dichlorobenzaldehyde. LCMS (Method F): RT=4.64 min, m/z: 543.2
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.54 (t, J=1.9
Hz, 1H), 7.41 (d, J=1 -2.0 Hz, 2H), 7.20 (d, J=8.4 Hz, 1H), 6.90
(d, J=12.9 Hz, 1H), 3.84 (s, 2H), 3.72 (s, 2H), 3.19 (s, 3H),
2.76-2.61 (m, 2H), 2.06-1.96 (m, 1H), 1.76-1.64 (m, 2H), 1.50 (d,
J=14.0 Hz, 2H), 1.09 (s, 3H), 0.94-0.83 (m, 2H), 0.69-0.59 (m,
2H).
Example 124
##STR00449##
[0780]
(S)-5-Cyclopropyl-2-fluoro-4-((1-((2-fluorophenyl)(phenyl)methyl)az-
etidin-3-yl)methoxy)-N-(methylsulfonyl)benzamide
[0781] The compound was synthesized as described in Example 81.
Chiral HPLC (column: OH-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=85:15; flow:
2.25 mL/min; column temperature: 40.degree. C.; RT=14.2 min).
LCMS(ESI) Method A: RT=5.48 min, m/z: 527.2 [M+H].sup.+.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6,): .delta.7.64-7.62 (m, 1H),
7.43-7.03 (m, 9H), 6.81 (d, J=12.5 Hz, 1H), 5.00 (s, 1H), 4.18 (d,
J=5.0 Hz, 2H), 3.55-3.46 (m, 3H), 3.28 (m, 4H), 3.07-3.05 (m, 1H),
2.16-2.13 (m, 1H), 0.98-0.96 (m, 2H), 0.69-0.68 (m, 2H).
Example 125
##STR00450##
[0782]
(R)-5-Cyclopropyl-2-fluoro-4-((1-((2-fluorophenyl)(phenyl)methyl)az-
etidin-3-yl)methoxy)-N-(methylsulfonyl)benzamide
[0783] The compound was synthesized as described in Example 81.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=85:15; flow:
2.25 mL/min; column temperature: 40.degree. C.; RT=16.3 min).
LCMS(ESI) Method A: RT=5.69 min, m/z: 527.2 [M+H].sup.+.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6): (m, 1H), 7.43-7.03 (m, 9H),
6.83 (d, J=13.0 Hz, 1H), 5.05 (s, 1H), 4.19 (d, J=5.5 Hz, 2H),
3.59-3.40 (m, 4H), 3.28 (s, 3H), 3.10-3.08 (m, 1H), 2.17-2.13 (m,
1H), 0.98-0.96 (m, 2H), 0.71-0.68 (m, 2H).
Example 126
##STR00451##
[0784]
5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(4-(trifluoromethyl-
)piperidin)piperidin-4-yl)methoxy)benzamide
[0785] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.54 min, m/z: 528.9 [M+H].sup.+.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6,): .delta.7.74-7.58 (m, 4H),
7.16 (d, J=8.5 Hz, 1H), 6.86 (d, J =12.5 Hz, 1H), 3.94 (d, J=6.0
Hz, 2H), 3.79 (s, 2H), 3.16 (s, 3H), 2.99-2.98 (m, 2H), 2.29-2.26
(m, 2H), 2.02-1.99 (m, 1H), 1.88-1.82 (m, 3H), 1.44-1.42 (m, 2H),
0.89-0.86 (m, 2H), 0.64-0.61 (m, 2H).
Example 127
##STR00452##
[0786]
5-Cyclopropyl-2-fluoro-4-((1-(2-fluorobenzyl)piperidin-4-yl)methoxy-
)- N-(methylsulfonyl)benzamide
[0787] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=4.89 min, m/z: 479.0 [M+H].sup.+.
.sup.1H-NMR (500 MHz, MeOH-d.sub.4,): .delta.7.46-7.36 (m, 2H),
7.23-7.16 (m, 3H), 6.83 (d, J=12.5 Hz, 1H), 3.92-3.91 (m, 2H), 3.76
(s, 2H), 3.11 (s, 3H), 3.03-3.01 (m, 2H), 2.33-2.30 (m, 2H),
2.02-1.82 (m, 4H), 1.46-1.42 (m, 2H), 0.89-0.86 (m, 2H), 0.62-0.60
(m, 2H).
Example 128
##STR00453##
[0788]
4-((1-((5-Chloro-6-isopropoxypyridin-3-yl)methyl)piperidin-4-yl)met-
hoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[0789] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.86 min, m/z: 553.8 [M+H].sup.+.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6,): .delta.8.06 (d, J=5.0 Hz,
1H), 7.16-6.88 (m, 3H), 5.30-5.28 (m, 1H), 3.94 (d, J=3 6.0 Hz,
2H), 3.60 (s, 2H), 3.21 (s, 3H), 2.89-2.87 (m, 2H), 2.16-2.12 (m,
2H), 2.03-2.01 (m, 1H), 1.80-1.78 (m, 3H), 1.41-1.39 (m, 2H), 1.31
(d, J=6.5 Hz, 6H), 0.90-0.87 (m, 2H), 0.66-0.63 (m, 2H).
Example 129
##STR00454##
[0790]
5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenylsulfonyl)-
azetidin-3-yl)methoxy)benzamide
##STR00455##
[0791] Step 1
##STR00456##
[0792] tert-Butyl
5-cyclopropyl-2-fluoro-4-((1-(phenylsulfonyl)azetidin-3-
yl)methoxy)benzoate
[0793] Benzenesulfonyl chloride (54 mg, 0.31 mol) was added to a
mixture of tert-butyl
4-(azetidin-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate (100 mg,
0.31 mmol) and triethylamine (94 mg, 0.93 mmol) in DCM (10 ml).
After stirring at room temperature for 2 h, the mixture was
quenched with water (10 ml), extracted with DCM (10 ml.times.3),
dried over sodium sulfate, filtered and concentrated to give target
compound as a yellow solid. (112 mg, 78%). LCMS(ESI) m/z: 462.1
[M+H].sup.+.
Step 2
##STR00457##
[0794]
5-Cyclopropyl-2-fluoro-4-((1-(phenylsulfonyl)azetidin-3-yl)methoxy)-
benzoic acid
[0795] The compound was synthetized as described in step 3 of
Example 88.
Step 3
##STR00458##
[0796]
5-Cyclopropyl-2-fluoro-4-((1-(phenylsulfonyl)azetidin-3-yl)methoxy)-
benzamide
[0797] The compound was synthesized as described in step 5 of
Example 80. LCMS(ESI) Method A: RT=4.66 min, m/z: 483.2
[M+H].sup.+. .sup.1H-NMR (500 MHz, DMSO-d.sub.6,): .delta.7.89-7.66
(m, 5H), 7.26 (d, J=8.0 Hz, 1H), 6.76 (d, J=12.5 Hz, 1H), 4.02 (d,
J=5.5 Hz, 2H), 3.97-3.94 (m, 2H), 3.83-3.81 (m, 2H), 3.36 (s, 3H),
2.99-2.96 (m, 1H), 1.91-1.88 (m, 1H), 0.91-0.88 (m, 2H), 0.63-0.60
(m, 2H).
Example 130
##STR00459##
[0798]
5-cyclopropyl-2-fluoro-4-((1-(4-fluoro-2-(trifluoromethyl)piperidin-
)-4-methylpiperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[0799] The compound was prepared in a similar manner to Example 73
starting from tert-butyl
4-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)phenoxy)methyl)-4-
-methylpiperidin-1-carboxylate (Example 73 step 1-2) and
4-fluoro-2-trifluoromethylbenzaldehyde. LCMS (Method F): RT=4.62
min, m/z: 561.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
11.68 (s, 1H), 7.87-7.78 (m, 1H), 7.62-7.49 (m, 2H), 7.18 (d, J=8.3
Hz, 1H), 6.95 (d, J=13.0 Hz, 1H), 3.85 (s, 2H), 3.66 (s, 2H), 3.28
(s, 3H), 2.61-2.52 (m, 2H), 2.46-2.36 (m, 2H), 2.06-1.95 (m, 1H),
1.74-1.61 (m, 2H), 1.47 (d, J=13.3 Hz, 2H), 1.09 (s, 3H), 0.93-0.84
(m, 2H), 0.70-0.61 (m, 2H).
Example 131
##STR00460##
[0800]
5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenyl(4-(trifluor-
omethyl)phenyl)methyl)- azetidin-3-yl)methoxy)benzamide
[0801] The compound was synthesized as described in Example 80.
LCMS(ESI) Method A: RT=6.00 min, m/z: 577.3 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d.sub.4): .delta. 7.65-7.60 (m, 4H), 7.44-7.43
(m, 2H), 7.34-7.31 (m, 3H), 7.25-7.23 (m, 1H), 6.81-6.78 (m, 1H),
4.65 (s, 1H), 4.21 (d, J=6.0 Hz, 2H), 3.48-3.41 (m, 2H), 3.29-3.19
(m, 5H), 3.04-3.01 (m, 1H), 2.12-2.08 (m, 1H), 0.96-0.68 (m, 2H),
0.67 (s, 2H).
Example 132
##STR00461##
[0802]
5-Cyclopropyl-4-((1-(3,5-dichlorobenzyl)azetidin-3-yl)methoxy)-2-fl-
uoro-N-(methylsulfonyl)benzamide
[0803] The compound was synthesized as described in Example 80.
LCMS(ESI) Method A: RT=5.26 min, m/z: 501.1 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6): .delta. 7.56 (s, 1H), 7.41-7.41 (m,
2H), 7.20-7.18 (m, 1H), 6.90-6.88 (m, 1H), 4.20-4.18(d, J=6.5 Hz,
2H), 3.85 (s, 2H), 3.63 (s, 2H), 3.42 (s, 2H), 3.14 (s, 3H),
3.02-3.00 (m, 1H), 2.06-2.02 (m, 1H), 0.91-0.87 (m, 2H), 0.65-0.62
(m, 2H).
Example 133
##STR00462##
[0804]
4-((1-(4-Chloro-3-fluorobenzyl)azetidin-3-yl)methoxy)-5cyclopropyl--
2-fluoro-N-(methylsulfonyl)benzamide
[0805] The compound was synthesized as described in Example 80.
LCMS(ESI) Method A: RT=4.81 min, m/z: 485.0 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6): .delta. 7.58 (t, J=8.0 Hz, 1H), 7.38
(d, J=9.5, 1H), 7.22-7.19 (m, 2H), 6.86 (d, J=12.5 Hz, 1H), 4.19
(d, J=6.0 Hz, 2H), 3.87 (s, 2H), 3.63 (s, 2H), 3.49 (s, 2H), 3.10
(s, 3H), 3.02-3.00 (m, 1H), 2.04-2.00 (m, 1H), 0.90-0.86 (m, 2H),
0.64-0.61 (m, 2H).
Example 134
##STR00463##
[0806]
5-Cyclopropyl-4-((1-(3,5-dichlorobenzoyl)azetidin-3-yl)methoxy)-2-
fluoro-N-(methylsulfonyl)benzamide
##STR00464##
[0807] Step 1
##STR00465##
[0808] tert-Butyl
5-cyclopropyl-4-((1-(3,5-dichlorobenzoyl)azetidin-3-yl)methoxy)-2-
fluorobenzoate
[0809] A mixture of 3,5-dichlorobenzoic acid (100 mg 0.52 mmol),
tert-butyl 4-(azetidin-3-ylmethoxy)- 5-cyclopropyl-2-fluorobenzoate
(140 mg, 0.44 mmol), EDCI (140 mg, 0.72 mmol) and DMAP (27 mg, 0.22
mmol) in DCM (5 mL) was stirred at room temperature for 18 h. The
mixture was diluted with DCM (10 mL) and washed with HCl (2 N, 15
mL.times.2). The organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated. The residue was purified by
silica gel chromatography (eluting with petroleum ether/EtOAc=4/1)
to give the target compound (200 mg, 92%) as a white solid.
LCMS(ESI) m/z: 437.9 [M+H].sup.+. .sup.1H NMR
Step 2
##STR00466##
[0810]
5-Cyclopropyl-4-((1-(3,5-dichlorobenzoyl)azetidin-3-yl)methoxy)-2-f-
luorobenzoic acid
[0811] The compound was synthesized as described in step 3 of
Example 88. LCMS(ESI) m/z: 438.0 [M+H].sup.+. .sup.1H NMR
Step 3
##STR00467##
[0812]
5-Cyclopropyl-4-((1-(3,5-dichlorobenzoyl)azetidin-3-yl)methoxy)-2-f-
luoro- N-(methylsulfonyl)benzamide
[0813] The compound was synthesized as described in step 5 of
Example 80. LCMS(ESI) Method A: RT=4.65 min, m/z: 515.0
[M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 11.90 (s,
1H), 7.80 (t, J=1.5 Hz, 1H), 7.8 (d, J=2.0 Hz, 2H), 7.15 (d, J=8.0
Hz, 1H), 6.96 (d, J=12.5 Hz, 1H), 4.52 (t, J=8.5 Hz, 1H), 4.27-4.16
(m, 1H), 3.99-3.97 (m, 1H), 3.28 (s, 3H), 3.12-3.09 (m, 1.95-1.89
(m, 1H), 0.89-0.84 (m, 1H), 0.76-0.60 (m, 3H).
Example 135
##STR00468##
[0814]
5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(4-(trifluoromethox-
y) benzyl)piperidin-4-yl)methoxy)benzamide
[0815] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.55 min, m/z: 544.8 [M+H].sup.+. .sup.1H
NMR R (500 MHz, DMSO-d.sub.6): .delta. 7.51 (d, J=8.5 Hz, 2H), 7.38
(d, J=8.0 Hz, 2H), 7.17 (d, J=8.5 Hz, 1H), 6.83 (d, J=12.5 Hz, 1
H), 3.92 (d, J=6.5 Hz, 2H), 3.827 (s, 2H), 3.11 (s, 3H), 3.05 (d,
J=11.0 Hz, 2H), 2.41-2.37 (m, 2H), 2.03-1.98 (m, 1H), 1.90-1.85 (m,
3H), 1.48-1.42 (m, 2H), 0.89-0.85 (m, 2H), 0.63-0.60 (m, 2H).
Example 136
##STR00469##
[0816]
4-((1-(3-Chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)methoxy)--
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[0817] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=6.15 min, m/z: 578.8 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6): .delta. 7.48 (s, 2H), 7.35 (s, 1H),
7.15 (d, J=8.0 Hz, 1 H), 6.87 (d, J=13.5 Hz, 1H), 3.93 (d, J=5.5
Hz, 2H), 3.67 (s, 2H), 3.18 (s, 3H), 2.90 (d, J=10 Hz, 2H),
2.20-2.15 (m, 2H), 2.07-1.98 (m, 1H), 1.88-1.80 (m, 3H), 1.44-1.36
(m, 2H), 0.89-0.86 (m, 2H), 0.65-0.62 (m, 2H).
Example 137
##STR00470##
[0818]
4-((1-(3-Chloro-5-(trifluoromethyl)piperidin)piperidin-4-yl)methoxy-
)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[0819] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=6.06 min, m/z: 562.8 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6): .delta. 7.76 (s, 2H), 7.73 (s, 1H),
7.67 (s, 1H), 7.18 (d, J=8.5 Hz, 1 H), 6.82 (d, J=11.5 1 H), 3.93
(d, J=5.5 2H), 3.67 (s, 2H), 3.10 (s, 3H), 2.89 (d, J=10.5 Hz,
Example 138
##STR00471##
[0820]
4-((1-(4-Chloro-3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropy-
l-2-fluoro-N-(methylsulfonyl)benzamide
[0821] The compound synthesized as described in Example 88.
LCMS(ESI) Method A: RT=4.72 min, m/z: 513.2 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6): .delta. 7.56-7.23 (m, 1H), 7.60-7.58
(m, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1 H), 6.97 (d,
J=12.5 Hz, 1 H), 4.32 (s, 2H), 3.98 (s, 2H), 3.42-3.34 (m, 2H),
3.33 (s, 3H), 2.97 (s, 2H), 2.06-1.97 (m, 4), 1.58-1.56 (m, 2H),
0.90-0.86 (m, 2H), 0.70-0.67(m, 2H).
Example 139
##STR00472##
[0822]
5-Cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-4-yl)methoxy)-
2-fluoro-N-(methylsulfonyl)benzamide
[0823] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.75 min, m/z: 528.8 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6): .delta. 7.53 (s, 1H), 7.40 (s, 2H),
7.16 (d, J=8.5 Hz, 1H), 6.84 (d, J=12.0 Hz, 1H), 3.93 (d, J=5.5 Hz,
2H), 3.64-3.61 (m, 2H), 3.14 (s, 3H), 2.93-2.91 (m, 2H), 2.17-2.16
(m, 2H), 2.03-2.00 (m, 1H), 1.82-1.80 (m, 3H), 1.41-1.39 (m, 2H),
0.90-0.86 (m, 2H), 0.63-0.62 (d, 2H).
Example 140
##STR00473##
[0824]
4-((1-(3-chloro-5-(trifluoromethyl)piperidin)-4-methylpiperidin-4-y-
l)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[0825] The compound was prepared in a similar manner to Example 73
starting from tert-butyl
4-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)phenoxy)methyl)-4-
-methylpiperidine-1-carboxylate (Example 73 step 1-2) and
3-chloro-5-(trifluoromethyl)benzaldehyde. LCMS (Method G): RT=5.81
min, m/z: 577.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
7.81-7.65 (m, 3H), 7.20 (d, J=8.4 Hz, 1H), 6.90 (d, J=12.9 Hz, 1H),
3.84 (s, 2H), 3.76 (s, 2H), 3.20 (s, 3H), 2.72-2.58 (m, 2H),
2.07-1.96 (m, 1H), 1.78-1.65 (m, 2H), 1.56-1.43 (m, 2H), 1.09 (s,
3H), 0.92-0.83 (m, 2H), 0.68-0.59 (m, 2H).
Example 141
##STR00474##
[0826]
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-methylpipe-
ridin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[0827] The compound was prepared in a similar manner to Example 73
starting from tert-butyl
4-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)phenoxy)methyl)-4-
-methylpiperidine-1-carboxylate (Example 73 step 1-2) and
3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde. LCMS (Method G):
RT=6.67 min, m/z: 595.14 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 11.58 (s, 1H), 8.02 (dd, J=6.4, 2.3 Hz, 1H), 7.80
(dd, J=5.9, 2.3 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 6.91 (d, J=12.9
Hz, 1H), 3.84 (s, 2H), 3.75 (s, 2H), 3.24 (s, 3H), 2.72-2.57 (m,
2H), 2.08-1.96 (m, 1H), 1.77-1.62 (m, 2H), 1.53-1.40 (m, 2H), 1.07
(s, 3H), 0.93-0.82 (m, 2H), 0.69-0.59 (m, 2H).
Example 142
##STR00475##
[0828]
(S)-5-Cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)methyl)azetidi-
n-3-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0829] The compound was synthesized as described in Example 81.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH, A:B=65:35; flow: 195 mL/min;
column temperature: 40.degree. C.; RT=4.15 min). LCMS(ESI) Method
A: RT=6.20 mm, m/z: 577.2 [M+H].sup.+. .sup.1H-NMR (500 MHz,
MeOD-d.sub.4): .delta.7.30-7.28 (m, 4H), 7.23-7.20 (m, 3H),
7.17-7.12 (m, 2H), 6.70 (d, J=12.5 Hz, 1H), 4.42 (s, 1H), 4.10 (d,
J=7.0 Hz, 2H), 3.33-3.26 (m, 2H), 3.16 (s, 3H), 3.10-3.05 (m, 2H),
2.90-2.87 (m, 1H), 2.00-1.96 (m, 1H), 0.86-0.80 (m, 2H), 0.56-0.54
(m, 2H).
Example 143
##STR00476##
[0830]
(R)-5-Cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)methyl)azetidi-
n-3-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0831] The compound was synthesized as described in Example 81.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH, A:B=65:35; flow: 1.95 mL/min;
column temperature: 40.degree. C.; RT=5.47 min). LCMS(ESI) Method
A: RT=6.19 min, m/z: 577.2 [M+H].sup.+. .sup.1H-NMR (500 MHz,
MeOD-d.sub.4): .delta.7.30-7.28 (m, 4H), 7.23-7.20 (m, 3H),
7.17-7.12 (m, 2H), 6.70 (d, J=12.5 Hz, 1H), 4.42 (s, 1H), 4.10 (d,
J=7.0 Hz, 2H), 3.33-3.26 (m, 2H), 3.16 (s, 3H), 3.10-3.05 (m, 2H),
2.90-2.87 (m, 1H), 2.00-1.96 (m, 1H), 0.86-0.80 (m, 2H), 0.56-0.54
(m, 2H).
Example 144
##STR00477##
[0832]
(S)-5-Cyclopropyl-2-fluoro-4-((1-((4-fluorophenyl)(phenyl)methyl)az-
etidin-3-yl)methoxy)-N-(methylsulfonyl)benzamide
[0833] The compound was synthesized as described in Example 81.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=75:25; flow:
2.25 mL/min; column temperature: 40.degree. C.; RT=5.77 min).
LCMS(ESI) Method A: RT=4.83 min, m/z: 527.2 [M+H].sup.+.
.sup.1H-NMR (500 MHz, MeOH-d.sub.4): .delta. 7.35-7.29 (m, 4H),
7.24-7.20 (m, 3H), 7.16-7.12 (m, 1H), 6.97-6.93 (m, 2H), 6.67 (d,
J=13.0 Hz, 1H), 4.63 (s, 1H), 4.08 (d, J=6.0 Hz, 2H), 3.45-3.43 (m,
2H), 3.25-3.22 (m, 2H), 3.15 (s, 3H), 2.98-2.95 (m, 1H), 1.99-1.95
(m, 1H), 0.84-0.79 (m, 2H), 0.56-0.54 (m, 2H).
Example 145
##STR00478##
[0834]
(R)-5-Cyclopropyl-2-fluoro-4-((1-((4-fluorophenyl)(phenyl)methyl)-a-
zetidin-3-yl)methoxy)-N-(methylsulfonyl)benzamide
[0835] The compound was synthesized as described in Example 88.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B:75:25; flow:
2.25 mL/min; column temperature: 40.degree. C.; RT=6.50 min).
LCMS(ESI) Method A: RT=4.79 min, m/z: 527.2 [M+H].sup.+.
.sup.1H-NMR (500 MHz, MeOH-d.sub.4): .delta. 7.35-7.29 (m, 3H),
7.24-7.20 (m, 3H), 7.16-7.12 (m, 1H), 6.97-6.93 (m, 2H), 6.67 (d,
J=13.0 Hz, 1H), 4.63 (s, 1H), 4.08 (d, J=6.0 Hz, 2H), 3.45-3.43 (m,
2H), 3.25-3.22 (m, 2H), 3.15 (s, 3H), 2.98-2.95 (m, 1H), 1.99-1.95
(m, 1H), 0.84-0.79 (m, 2H), 0.56-0.54 (m, 2H).
Example 146
##STR00479##
[0836]
5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(1-phenylethyl)-
piperidin-4-yl)methoxy)benzamide
[0837] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=4.70 min, m/z: 476.2 [M+H].sup.+. 1H-NMR
(500 MHz, DMSO-d.sub.6): .delta. 7.42-7.36 (m, 5H), 7.18 (d, J=8.0
Hz, 1H), 6.78 (d, J=13.0 Hz, 1H), 4.04 (brs, 1H), 3.90 (d, J=5.0
Hz, 2H), 3.32 (s, 3H), 3.02 (m, 4H), 2.02-1.97 (m, 1H), 1.90-1.84
(m, 3H), 1.50-1.49 (m, 5), 0.88-0.83 (m, 2H), 0.60-0.57 (m,
2H).
Example 147
##STR00480##
[0838]
5-Cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-4-yl)methoxy)-2-f-
luoro-N-(methylsulfonyl)benzamide
[0839] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.75 min, m/z: 528.9 [M+H].sup.+.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. 7.64-7.63 (m, 2H),
7.37-7.36 (m, 1H), 7.17-7.16 (m, 1H), 6.85 (d, J=13.0 Hz, 1H), 3.94
(s, 2H), 3.72 (s, 2H), 3.15 (s, 3H), 3.00-298 (m, 2H), 2.29 (s,
2H), 2.02-2.01 (m, 1H), 1.85-1.82 (m, 3H), 1.44-1.42 (m, 2H),
0.88-0.87 (m, 2H), 0.63 (s, 2H).
Example 148
##STR00481##
[0840]
4-((1-(1-(3-Chlorophenyl)ethyl)piperidin-4-yl)methoxy)-5-cyclopropy-
l-2-fluoro-N-(methylsulfonyl)benzamide
[0841] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.52 min, m/z: 508.9 [M+H].sup.+.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. 7.40-7.31 (m, 4H),
7.17 (d, J=8.5 Hz, 1H), 6.83 (d, J =12.5 Hz, 1H), 3.92-3.91 (m,
3H), 3.31-3.27 (m, 4H), 3.17-3.16 (m, 1H), 2.98-2.96 (m, 1H),
2.27-2.26 (m, 1H), 2.02-1.98 (m, 1H), 1.88-1.80 (m, 3H), 1.46-1.41
(m, 5H), 0.89-0.85 (m, 2H), 0.63-0.60 (m, 2H).
Example 149
##STR00482##
[0842]
4-((1-(2-Cyanobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-
- N-(methylsulfonyl)benzamide
[0843] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=4.86 min, m/z: 486.0 [M+H].sup.+.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. 7.83-7.81 (m, 1H),
7.71-7.67 (m, 1H), 7.60-7.59 (m, 1H), 7.50-7.47 (m, 1H), 7.15 (d,
J=8.0 Hz, 1H), 6.91 (d, J=12.5 Hz, 1H), 3.94 (d, J=6.0 Hz, 2H),
3.70 (s, 2H), 3.25 (s, 3H), 2.90-2.88 (m, 2H), 2.19-2.15 (m, 2H),
2.03-2.00 (m, 1H), 1.84-1.78 (m, 3H), 1.42-1.34 (m, 2H), 0.90-0.86
(m, 2H), 0.66-0.63 (m, 2H).
Example 150
##STR00483##
[0844]
(S)-4-((1-((2-Chlorophenyl)(phenyl)methyl)azetidin-3-yl)methoxy)-5--
cyclopropyl-2-fluoro- N-(methylsulfonyl)benzamide
[0845] The compound was synthesized as described in Example 81.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=65:35; flow:
1.95 mL/min; column temperature: 40.degree. C.; RT=4.38 min).
LCMS(ESI) Method A: RT=6.04 min, m/z: 543.2 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 11.89 (s, 1H), 7.81 (d, J=6.6
Hz, 1H), 7.39 (dd, J=19.1, 7.6 Hz, 4H), 7.29 (t, J=7.6 Hz, 2H),
7.23 (dd, J=13.4, 7.6 Hz, 2H), 7.16 (d, J=8.3 Hz, 1H), 6.95 (d,
J=12.6 Hz, 1H), 4.88 (s, 1H), 4.18 (d, J=5.7 Hz, 2H), 3.30-3.29 (m,
1H), 3.29-3.23 (m, 3H), 3.15 (s, 2H), 2.93 (s, 2H), 2.10 (s, 1H),
0.91 (t, J=8.9 Hz, 2H), 0.69 (s, 2H).
Example 151
##STR00484##
[0846] (R)-4-((1
-((2-Chlorophenyl)(phenyl)methyl)azetidin-3-yl)methoxy)-5-cyclopropyl-2-f-
luoro-N-(methylsulfonyl)benzamide
[0847] The compound was synthesized as described in Example 81.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=65:35; flow:
1.95 mL/min; column temperature: 40.degree. C.; RT=5.23 min).
LCMS(ESI) Method A: RT=6.11 min, m/z: 543.2 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 11.89 (s, 1H), 7.81 (d, J=6.6
Hz, 1H), 7.39 (dd, J=19.1, 7.6 Hz, 4H), 7.29 (t, J=7.6 Hz, 2H),
7.23 (dd, J=13.4, 7.6 Hz, 2H), 7.16 (d, J=8.3 Hz, 1H), 6.95 (d,
J=12.6 Hz, 1H), 4.88 (s, 1H), 4.18 (d, J=5.7 Hz, 2H), 3.30-3.29 (m,
1H), 3.29-3.23 (m, 3H), 3.15 (s, 2H), 2.93 (s, 2H), 2.10 (s, 1H),
0.91 (t, J=8.9 Hz, 2H), 0.69 (s, 2H).
Example 152
##STR00485##
[0848]
(S)-5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenyl(pyridin-
-4-yl)methyl)azetidin-3-yl)methoxy)benzamide
[0849] The compound was synthesized as described in Example 81.
Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=65:35; flow:
1.95 mL/min; column temperature: 40.degree. C.; RT=4.20 min).
LCMS(ESI) Method A: RT=4.72 min, m/z: 510.3 [M+H].sup.+. (500 MHz,
MeOD-d.sub.4) .delta. 8.46 (d, J=5.1 Hz, 2H), 7.54 (d, J=5.9 Hz,
2H), 7.44 (d, 7.3 Hz, 2H), 7.33 (t, J=7.5 Hz, 3H), 7.26 (t, J=7.3
Hz, 1H), 6.83 (d, J=12.8 Hz, 1H), 4.59 (s, 1H), 4.23 (d, J=1H),
4.23 (d, J=6.0 Hz, 2H), 3.49 (t, J=7.7 Hz, 1H), 3.39 (t, J=7.6 Hz,
1H), 3.30 (s, 3H), 3.26-3.22 (m, 1H), 3.17 (t, J=6.9 Hz, 1H),
3.06-3.00 (m, 1H), 2.13-2.05 (m, 1H), 0.97-0.92 (m, 2H), 0.68 (d,
J=4.3 Hz, 2H).
Example 153
##STR00486##
[0850]
(R)-5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(phenyl(pyridin-
-4-yl)methyl)azetidin-3-yl)methoxy)benzamide
[0851] The compound was synthesized as described in Example 81.
Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=65:35; flow:
1.95 mL/min; column temperature: 40.degree. C.; RT=7.60 min).
LCMS(ESI) Method B: RT=4.70 min, m/z: 510.3 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d.sub.4) .delta. 8.34 (t, J=4.6 Hz, 2H), 7.41
(d, J=5.8 Hz, 2H), 7.32 (d, J=7.3 Hz, 2H), 7.21 (t, J=7.5 Hz, 3H),
7.13 (t, J=7.3 Hz, 1H), 6.70 (d, J=12.8 Hz, 1H), 4.47 (s, 1H), 4.11
(d, J=6.1 Hz, 2H), 3.37 (t, J=7.7 Hz, 1H), 3.27 (t, J=7.7 Hz, 1H),
3.17 (s, 3H), 3.14-3.10 (m, 2H), 3.07-3.03 (m, 1H), 2.02-1.92 (m,
1H), 0.86-0.78 (m, 2H), 0.55 (d, J=4.3 Hz, 2H).
Example 154
##STR00487##
[0852]
5-Cyclopropyl-2-fluoro-4-((1-((3-fluorophenyl)(phenyl)methyl)azetid-
in-3-yl)methoxy)-N-(methylsulfonyl)benzamide
[0853] The compound was synthesized as described in Example 80.
LCMS(ESI) Method B: RT=b 5.84 min, m/z: 527.2 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d.sub.4) .delta. 7.43 (d, J=7.3 Hz, 2H), 7.34
(dd, J=7.9, 5.0 Hz, 4H), 7.26 (dd, J=7.4, 4.4 Hz, 2H), 7.19 (d,
J=9.9 Hz, 1H), 6.98 (t, J=8.5 Hz, 1H), 6.83 (d, J=12.9 Hz, 1H),
4.66 (s, 1H), 4.22 (d, J=5.9 Hz, 2H), 3.56-3.45 (m, 2H), 3.32-3.32
(m, 2H), 3.30 (s, 3H), 3.06 (s, 1H), 2.11 (t, J=Hz, 1H), 0.98-0.91
(m, 2H), 0.69 (q, J=5.9 Hz, 2H).
Example 155
##STR00488##
[0854]
5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)propyl)piperidin-4-yl)me-
thoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0855] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=6.40 min, m/z: 556.8 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 7.52 (s, 1H), 7.34 (s, 2H),
7.16 (d, J=8.4 Hz, 1H), 6.80 (d, J=12.8 Hz, 1H), 3.87 (d, J=5.9 Hz,
2H), 3.51 (s, 1H), 3.10 (s, 3H), 3.03 (s, 1H), 2.91 (s, 1H), 1.99
(s, 2H), 1.88 (s, 2H), 1.76 (d, J=14.0 Hz, 4H), 1.35 (m, 2H),
0.89-0.81 (m, 2H), 0.72 (t, J=7.2 Hz, 3H), 0.60 (d, J=4.1 Hz,
2H).
##STR00489##
Example 156
5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(1-(trifluoromethoxy)-phen-
yl)ethyl)piperidin-4-yl)methoxy)benzamide
[0856] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.68 min, m/z: 558.9 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d.sub.4) .delta. 7.63 (s, 2H), 7.37 (m, 3H),
6.58 (s, 1H), 4.33 (s, 1H), 3.79 (m, 3H), 3.16 (s, 3H), 2.76 (s,
2H), 2.00 (m, 4H), 1.85-1.47 (m, 6H), 0.86 (s, 2H), 0.63 (s,
2H).
##STR00490##
Example 157
5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(1-(4-(trifluoromethoxy)-p-
henyl)ethyl)azetidin-3-yl)methoxy)benzamide
[0857] The compound was synthesized as described in Example 80.
LCMS(ESI) Method A: RT=5.24 min, m/z: 516.9 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d.sub.4) .delta. 7.50 (d, J=8.6 Hz, 2H), 7.28
(m, 3H), 6.49 (d, J=12.3 Hz, 1H), 4.92 (m, 2H), 4.05 (m, 1H), 3.77
(m, 2H), 3.44-3.35 (m, 2H), 3.26 (m, 1H), 3.22 (s, 3H), 2.12 (m,
1H), 1.35 (d, J=6.5 Hz, 3H), 0.98-0.88 (m, 2H), 0.68 (m, 2H).
Example 158
##STR00491##
[0858]
5-Cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)propyl)azetidin-3-yl)met-
hoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0859] The compound was synthesized as described in Example 80.
LCMS(ESI) Method A: RT=5.74 min, m/z: 529.0 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d.sub.4) .delta. 7.50-7.41 (m, 1H), 7.40-7.30
(m, 3H), 6.83-6.69 (m, 1H), 4.18 (s, 2H), 3.76 (m, 1H), 3.47 (m,
4H), 3.24 (s, 3H), 3.09 (m, 1H), 2.08 (m, 1H), 1.88 (m, 1H), 1.56
(m, 1H), 0.93 (m, 2H), 0.76 (m, 3H), 0.68 (s, 2H).
##STR00492##
Example 159
5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(2-(trifluoromethyl)-benzy-
l)piperidin-4-yl)methoxy)benzamide
[0860] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.94 min, m/z: 529.0 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d.sub.4) .delta. 7.88 (d, J=7.8 Hz, 1H), 7.73
(d, J=7.9 Hz, 1H), 7.66 (t, J =7.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H),
7.35 (s, 1H), 6.72 (d, J=12.9 Hz, 1H), 3.93 (m, 4H), 3.22 (m, 3H),
3.12 (m, 2H), 2.43 (m, 2H), 2.07 (m, 1H), 2.01 (m, 1H), 1.95 (m,
2H), 1.68-1.55 (m, 2H), 0.91 (m, 2H), 0.65 (m, 2H).
Example 160
##STR00493##
[0861]
5-Cyclopropyl-4-((1-(3,4-difluorobenzyl)piperidin-4-yl)methoxy)-2-
fluoro-N-(methylsulfonyl)benzamide
[0862] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=4.46 min, m/z: 497.2 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 7.43 (m, 2H), 7.25-7.13 (m,
2H), 6.83 (d, J=12.8 Hz, 1H), 3.93 (d, J=5.9 Hz, 2H), 3.70 (s, 2H),
3.11 (s, 3H), 2.99 (m, 2H), 2.28 (m, 2H), 2.05-1.90 (m, 1H), 1.83
(m, 3H), 1.42 (m, 2H), 0.87 (m, 2H), 0.61 (m, 2H).
##STR00494##
Example 161
5-Cyclopropyl-2-fluoro-4-((1-(4-fluorobenzyl)piperidin-4-yl)methoxy)-
N-(methylsulfonyl)benzamide
[0863] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=4.90 min, m/z: 479.0 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 7.46-7.39 (m, 2H), 7.20 (m,
3H), 6.80 (d, J=12.8 Hz, 1H), 3.92 (d, J=6.0 Hz, 2H), 3.80 (m, 2H),
3.04 (m, 5H), 2.40 (m, 2H), 2.00 (m, 1H), 1.86 (m, 3H), 1.45 (m,
2H), 0.87 (m, 2H), 0.59 (m, 2H).
##STR00495##
Example 162
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidin-4-
-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00496##
[0864] Step 1
##STR00497##
[0865] 2-(3,5-Dichlorophenyl)oxirane
[0866] The compound was synthesized as described in step 1 of
Example 90.
Step 2
##STR00498##
[0867] 1-(3,5-Dichlorophenyl)-2-methoxyethanol
[0868] The compound was synthesized as described in step 2 of
Example 90.
Step 3
##STR00499##
[0869] 1,3-Dichloro-5-(1-chloro-2-methoxyethyl)benzene
[0870] The compound was synthesized as described in step 2 of
Example 80.
Step 4
##STR00500##
[0871] (R)-methyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidin-4-yl-
)methoxy)-2-fluorobenzoate
[0872] The compound was synthesized as described in step 5 of
Example 88. The enantiomer was separated by chiral SFC from the
racemate, the first eluting fraction was arbitrarily assigned as
(R)-methyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidin-4-yl-
)methoxy)-2-fluorobenzoate. Chiral HPLC (column: AD-H,
4.6.times.250 mm, 5 .mu.m; mobile Phase: A: supercritical CO.sub.2,
B: EtOH, A:B=85:15; flow: mL/min; column temperature: 40.degree.
C.; RT=3.89 min). LCMS(ESI) m/z: 510.1 [M+H].sup.+.
##STR00501##
Step 5
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidin-4-
-yl)methoxy)-2-fluorobenzoic acid
[0873] The compound was synthesized as described in step 6 of
Example 88. LCMS(ESI) m/z: 496.1 [M+H].sup.+.
##STR00502##
Step 6
(R)-5-cyclopropyl-4-((1-((1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidin--
4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0874] The compound was synthesized as described in step 5 of
Example 80. Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m;
mobile Phase: A: supercritical CO.sub.2, B: MeOH, A:B=85:15; flow:
2.55 mL/min; column temperature: 39.8.degree. C.; RT=6.09 min).
LCMS(ESI) Method A: RT=5.79 min, m/z: 572.8 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6): .delta. 11.65 (brs, 1H), 7.51-7.50 (m,
1H), 7.41-7.40 (m, 2H), 7.14 (d, J=9.0 Hz, 1H), 6.88 (d, J=13.0 Hz,
1H), 3.91 (d, J=5.5 Hz, 2H), 3.78-3.67 (m, 3H), 3.25 (s, 3H), 3.23
(s, 3H), 3.03-3.01 (m, 1H), 2.84-2.82(m, 1H), 2.16-2.12 (m, 1H),
2.06-1.97 (m, 2H), 1.80-1.73 (m, 3H), 1.41-1.31 (m, 2H), 0.89-0.86
(m, 2H), 0.66-0.63 (m, 2H).
##STR00503##
Example 163
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidin-4-
-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0875] The compound was synthesized as described in Example 162.
The enantiomer was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidin--
4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC
(column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH, A:B=85:15; flow: 2.55 mL/min;
column temperature: 40.6.degree. C.; RT=6.48 min). LCMS(ESI) Method
A: RT=5.79 min, m/z: 572.8 [M+H].sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 11.63 (brs, 1H), 7.52-7.51 (m, 1H),
7.41-7.40 (m, 2H), 7.14 (d, J=8.5 Hz, 1H), 6.89 (d, J=12.5 Hz, 1H),
3.91 (d, J=6.0 Hz, 2H), 3.79-3.68 (m, 3H), 3.25 (s, 3H), 3.23 (s,
3H), 3.03-3.02 (m, 1H), 2.85-2.82 (m, 1H), 2.17-2.13 (m, 1H),
2.05-1.97 (m, 2H), 1.80-1.73 (m, 3H), 1.41-1.31 (m, 2H), 0.89-0.86
(m, 2H), 0.66-0.63 (m, 2H).
##STR00504##
Example 164
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(1-(3,5-dichlorophenyl)-2--
methoxyethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide
[0876] The compound was synthesized as described in Example 162.
The enantiomer was arbitrarily assigned as
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(1-(3,5-dichlorophenyl)-2-
-methoxyethyl) piperidin-4-yl)methoxy)-2-fluorobenzamide. Chiral
HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH, A:B=80:20; flow: 2.4 mL/min;
column temperature: 38.0.degree. C.; RT=13.16 min). LCMS(ESI)
Method A: RT=6.27 min, m/z: 598.8 [M+H].sup.+. .sup.1H NMR (500
MHz, DMSO-d.sub.6): .delta.11.67 (brs, 1H), 7.50 (s, 1H), 7.39 (s,
2H), 7.13 (d, J=8.0 Hz, 1H), 6.89 (d, J=12.5 Hz, 1H), 3.91 (d,
J=5.5 Hz, 2H), 3.74-3.67 (m, 3H), 3.23 (s, 3H), 3.06-2.98 (m,
2.82-2.80 (m, 1H), 2.12-2.08 (m, 1H), 2.03-1.97 (m, 2H), 1.79-1.72
(m, 3H), 1.39-1.23 (m, 2H), 1.08-1.03 (m, 4H), 0.89-0.86 (m, 2H),
0.65-0.64 (m, 2H).
##STR00505##
Example 165
(S)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(1-(3,5-dichlorophenyl)-2--
methoxyethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide
[0877] The compound was synthesized as described in Example 163.
The enantiomer was arbitrarily assigned as
(S)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(1-(3,5-dichlorophenyl)-2-
-methoxyethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide, Chiral
HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH, A:B=80:20; flow: 2.4 mL/min;
column temperature: 39.7.degree. C.; RT=11.96 min). LCMS(ESI)
Method A: RT=6.19 min, m/z: 598.9 [M+H].sup.+. .sup.1H NMR (500
MHz, DMSO-d.sub.6): .delta. 11.69 (brs, 1H), 7.50 (s, 1H), 7.39 (s,
2H), 7.13 (d, J=8.0 Hz, 1H), 6.89 (d, J=13.0 Hz, 1H), 3.90 (d,
J=6.0 Hz, 2H), 3.73-3.67 (m, 3H), 3.22 (s, 3H), 3.06-2.98 (m, 2H),
2.82-2.80 (m, 1H), 2.11-2.07 (m, 1H), 2.03-1.96 (m, 2H), 1.79-1.72
(m, 3H), 1.37-1.23 (m, 2H), 1.07-1.02 (m, 4H), 0.89-0.85 (m, 2H),
0.65-0.62 (m, 2H).
Example 166
##STR00506##
[0878]
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(1-(3,5-dichlorop-
henyl)-2-methoxyethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide
[0879] The compound was synthesized as described in Example 162.
The enantiomer was arbitrarily assigned as
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-
-2-methoxyethyl) piperidin-4-yl)methoxy)-2-fluorobenzamide. Chiral
HPLC (column: (s,s-whelk-ol, 4.6.times.250 mm, 5 .mu.m; mobile
Phase: A: n-hexane, B: MeOH, B:=80:20, flow: 1 mL/min; column
temperature: 40.degree. C.; RT=11.97 min). LCMS(ESI) Method A:
RT=6.34 min, m/z: 614.0 [M+H].sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 11.52 (brs, 1H), 7.50-7.49 (m, 1H),
7.39-7.38 (m, 2H), 7.15 (d, J=8.5 Hz, 1H), 6.87 (d, J=12.5 Hz, 1H),
3.97-3.94 (m, 4H), 3.90 (d, J=6.5 Hz, 2H), 3.74-3.66 (m, 3H), 3.22
(s, 3H), 2.99-2.97 (m, 1H), 2.81-2.79 (m, 1H), 2.15-2.06 (m, 3H),
2.02-1.94 (m, 2H), 1.79-1.69 (m, 3H), 1.37-1.28 (m, 2H), 0.89-0.86
(m, 2H), 0.66-0.63 (m, 2H).
##STR00507##
Example 167
(S)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)--
2-methoxyethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide
[0880] The compound was synthesized as described in Example 163.
The enantiomer was arbitrarily assigned as
(S)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-
-2-methoxyethyl) piperidin-4-yl)methoxy)-2-fluorobenzamide. Chiral
HPLC (column: (s,s-whelk-ol, 4.6.times.250 mm, 5 .mu.m; mobile
Phase: A: n-hexane, B: MeOH, B:=80:20, flow: 1 mL/min; column
temperature: 40.degree. C.; RT=12.14 min). LCMS(ESI) Method A:
RT=6.36 min, m/z: 614.0 [M+H].sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 7.49-7.48 (m, 1H), 7.38-7.37 (m, 2H), 7.18
(d, J=9.0 Hz, 1H), 6.87 (d, J=12.5 Hz, 1H), 3.88-3.85 (m, 6H),
3.72-3.65 (m, 3H), 3.21 (s, 3H), 2.98-2.96 (m, 1H), 2.80-2.78 (m,
1H), 2.09-1.92 (m, 5H), 1.79-1.71 (m, 3H), 1.37-1.28 (m, 2H),
0.89-0.86 (m, 2H), 0.62-0.59 (m, 2H).
Example 168
##STR00508##
[0881]
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)pipe-
ridin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[0882] The compound was synthesized as described in Example 162.
The enantiomer was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidin--
4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide LCMS(ESI) Method
A: RT=5.99 :min, m/z: 587.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.49-7.48 (m, 1H), 7.38-7.37 (m, 2H), 7.16
(d, J=8.8 Hz, 1H), 6.77 (d, J=12.8 Hz, 1H), 3.87 (d, J=6.0 Hz, 2H),
3.73-3.65 (m, 3H), 3.21-3.19 (m, 5H), 2.98-2.95 (m, 1H), 2.80-2.77
(m, 1H), 2.06-1.94 (m, 3H), 1.79-1.70 (m, 3H), 1.36-1.26 (m, 2H),
1.15 (t, J=7.4 Hz, 3H), 0.89-0.84 (m, 2H), 0.61-0.57 (m, 2H).
Example 169
##STR00509##
[0883]
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)pipe-
ridin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[0884] The compound was synthesized as described in Example 163.
The enantiomer was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidin--
4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide. LCMS(ESI) Method
A: RT=5.99 min, m/z: 587.2 [M+H].sup.+. .sup.1H NMR (400
DMSO-d.sub.6): .delta. 7.49-7.48 (m, 1H), 7.38-7.37 (m, 2H), 7.16
(d, J=8.4 Hz, 1H), 6.77 (d, J=12.8 Hz, 1H), 3.87 (d, J=6.0 Hz, 2H),
3.73-3.65 (m, 3H), 3.24-3.19 (m, 5H), 2.98-2.95 (m, 1H), 2.80-2.77
(m, 1H), 2.09-1.91 (m, 3H), 1.79-1.67 (m, 3H), 1.36-1.26 (m, 2H),
1.16 (t, J=7.4 Hz, 3H), 0.89-0.84 (m, 2H), 0.61-0.57 (m, 2H).
##STR00510##
Example 170
(R)-5-cyclopropyl-2-fluoro-4-((1-(1-(3-fluoro-5-(trifluoromethyl)phenyl)et-
hyl)-4-methylpiperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[0885] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the first
eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-2-fluoro-4-((1-(1-(3-fluoro-5-(trifluoromethyl)phenyl)e-
thyl)-4-methylpiperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: IC-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH, A:B=75:25; flow: 2.25 mL/min;
column temperature: 40.degree. C.; RT=4.46 min). LCMS(ESI) Method
A: RT=6.13 min, m/z: 575.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 11.45 (brs, 1H), 7.58-7.54 (m, 3H), 7.20 (d,
J=8.4 Hz, 1H), 6.87 (d, J=13.2 Hz, 1H), 3.80 (m, 3H), 3.18 (s, 3H),
2.68-2.66 (m, 1H), 2.56-2.54 (m, 2H), 2.39-2.33 (m, 1H), 2.04-1.97
(m, 1H), 1.71-1.66 (m, 2H), 1.50-1.44 (m, 2H), 1.37 (d, J=6.8 Hz,
3H), 1.04 (s, 3H), 0.89-0.85 (m, 2H), 0.65-0.61 (m, 2H).
Example 171
##STR00511##
[0886]
(S)-5-cyclopropyl-2-fluoro-4-((1-(1-(3-fluoro-5-(trifluoromethyl)ph-
enyl)ethyl)-4-methylpiperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[0887] The compound was synthesized as described in Example 170.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-2-fluoro-4-((1-(1-(3-fluoro-5-(trifluoromethyl)phenyl)e-
thyl)-4-methylpiperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: IC-H, 4.6.times.250 mm, mobile Phase: A:
supercritical CO.sub.2, B: MeOH, A:B=75:25; flow: 2.25 mL/min;
column temperature: 39.9.degree. C.; RT=4.96 min). LCMS(ESI) Method
A: RT=6.11 min, m/z: 575.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta.7.58-7.54 (m, 3H), 7.19 (d, J=8.4 Hz, 1H),
6.87 (d, J=12.8 Hz, 1H), 3.80 (m, 3H), 3.17 (s, 3H), 2.71-2.67 (m,
1H), 2.56-2.54 (m, 2H), 2.38-2.32 (m, 1H), 2.04-1.97 (m, 1H),
1.71-1.66 (m, 2H), 1.49-1.44 (m, 2H), 1.37 (d, J=6.8 Hz, 3H), 1.04
(s, 3H), 0.89-0.85 (m, 2H), 0.64-0.61 (m, 2H).
##STR00512##
Example 172
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)-4-methylpi-
peridin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00513##
[0888] Step 1
##STR00514##
[0889]
2-(4-((2-Cyclopropyl-5-fluoro-4-(methoxycarbonyl)phenxoy)methyl)-4--
methylpiperidin-1-yl)-2-(3,5-dichlorophenyl)acetic acid
[0890] A mixture of methyl
5-cyclopropyl-2-fluoro-4-((4-methylpiperidin-4-yl)methoxy)benzoate
(1.8 g, 5.6 mmol), 3,5-dichlorophenylboronic acid (1.6 g, 8.4
mmol), 2-oxoacetic acid (638 mg, 8.4 mmol) and 1.8 g of 4 A
molecular sieve in toluene (30 mL) was stirred at 100.degree. C.
for 2 h. The mixture was then filtered, washed with DCM (20 mL) and
concentrated. The residue was purified by silica gel chromatography
(eluting with DCM/MeOH from 100/1 to 10/1) to afford the target
compound (2.8 g, 96%) as a white solid. LCMS(ESI) m/z: 524.0
[M+H].sup.+.
##STR00515##
Step 2
(R)-methyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)-4-m-
ethylpiperidin-4-yl)methoxy)-2-fluorobenzoate
[0891] A mixture of
2-(4-((2-cyclopropyl-5-fluoro-4-(methoxycarbonyl)phenoxy)methyl)-4-methyl-
piperidin-1-yl)-2-(3,5-dichlorophenyl)acetic acid (2.0 g, 8 mmol)
in borane-THF (20 mL) was stirred at room temperature for 2 h,
quenched with MeOH (20 mL) and concentrated. The residue was
purified by silica gel chromatography (eluting with DCM/MeOH from
300/1 to 100/1) to afford the racemate (2.8 g, 96%) as an oil. The
enantiomer was separated by chiral SFC from the racemate. The
enantiomer was arbitrarily assigned as (R)-methyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)-4-methylpiper-
idin-4-yl)methoxy)-2-fluorobenzoate. Chiral HPLC (column: OZ-H
4.6.times.250 mm, 5 .mu.m; mobile Phase: A: n-Hexane, B: EtOH, A:
B=85:15; flow: 1 mL/min: column temperature: 40.degree. C.; RT=6.83
min). LCMS(ESI) m/z: 510.1 [M+H].sup.+.
Step 3
##STR00516##
[0892]
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)-4-m-
ethylpiperidin-4-yl)methoxy)-2-fluorobenzoic acid
[0893] To a solution of (R)-methyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)-4-methylpiper-
idin-4-yl)methoxy)-2-fluorobenzoate (100 mg, 0.2 mmol) in THF (5
mL) was added sodium hydride (39 mg, 0.98 mmol) at 0.degree. C. The
mixture was stirred at room temperature for 30 min, then methyl
iodide (56 mg, 0.39 mmol) was added. The mixture was stirred for
another 16 h, quenched with water (15 mL), acidified with HCl (1 M)
to pH 2-3, and extracted with EtOAc (20 mL.times.3). The combined
organic layers were washed with brine (20 mL) and dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduce pressure to afford a yellow solid. LCMS(ESI) m/z: 510.1
[M+H].sup.+.
##STR00517##
Step 4
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)-4-methylpi-
peridin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0894] The compound was synthesized as described in step 5 of
Example 80. Chiral HPLC (column: OZ-H, 4.6.times.250 mm, 5 .mu.m;
mobile Phase: A: supercritical CO.sub.2, B: MeOH, A:B=65:35; flow:
1.95 mL/min; column temperature: 40.degree. C.; RT=5.13 min).
LCMS(ESI) Method A: RT=6.28 min, m/z: 587.2 [M+H].sup.+. .sup.1H
NMR (400 Hz, DMSO-d.sub.6): .delta. 11.69 (brs, 1H), 7.50 (s, 1H),
7.41 (s, 2H), 7.18 (d, J=8.4 Hz, 1H), 6.90 (d, J=12.8 Hz, 1H),
3.79-3.69 (m, 5H), 3.23 (s, 3H), 3.22 (s, 3H), 2.67-2.66 (m, 1H),
2.58-2.50 (m, 1H), 2.50-2.35 (m, 2H), 2.03-1.97 (m, 1H), 1.68-1.62
(m, 2H), 1.49-1.37 (m, 2H), 1.01 (s, 3H), 0.90-0.86 (m, 2H),
0.65-0.62 (m, 2H).
Example 173
##STR00518##
[0895]
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)-4-m-
ethylpiperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0896] The compound was synthesized as described in Example 172.
The enantiomer was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)-4-methylp-
iperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide Chiral
HPLC (column: OZ-H, 4.6.times.250 mm, 5 .mu.m, mobile Phase: A:
supercritical CO.sub.2, B: MeOH, A:B=65:35; flow: 1.95 mL/min;
column temperature: 40.1.degree. C.; RT=4.52 min). LCMS(ESI) Method
A: RT=6.28 min, m/z: 587.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 11.64 (brs, 1H), 7.50 (s, 1H), 7.41 (s, 2H),
7.18 (d, J=8.4 Hz, 1H), 6.89 (d, J=12.8 Hz, 1H), 3.78-3.66 (m, 5H),
3.22 (s, 6H), 2.67-2.66 (m, 1H), 2.58-2.50 (m, 1H), 2.45-2.33 (m,
2H), 2.03-1.97 (m, 1H), 1.68-1.62 (m, 2H), 1.49-1.37(m, 2H), 1.01
(s, 3H), 0.90-0.86 (m, 2H), 0.65-0.62 (m, 2H).
##STR00519##
Example 174
5-Cyclopropyl-4-((1-(3-(3,5-dichlorophenyl)oxetan-3-yl)piperidin-4-yl)meth-
oxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00520##
[0897] Step 1
##STR00521##
[0898] 3-(3,5-Dichlorophenyl)oxetan-3-ol
[0899] To a solution of 1-bromo-3,5-dichlorobenzene (1.0 g, 4.5
mmol) in dry THF (20 mL) was added n-BuLi (2.2 mL, 5.4 mmol)
dropwise and the mixture stirred 30 min at -78.degree. C.
Oxetan-3-one (386 mg, 5.4 mmol) was then added and the mixture was
left to warm to room temperature. The mixture was then quenched
with aqueous ammonium chloride (20 mL) and extracted with EtOAc (20
mL.times.3). The combined organic layers were washed with brine (20
mL), dried over anhydrous sodium sulfate and concentrated. The
residue was purified by silica gel chromatography (eluting with
ethyl acetate/petroleum ether=1/10) to afford the target compound
(0.7 g, 71%) as an oil. LCMS(ESI) m/z: 217.1 [M-H].sup.-.
##STR00522##
Step 2
Methyl
5-cyclopropyl-4-((1-(3-(3,5-dichlorophenyl)oxetan-3-yl)piperidin-4--
yl)methoxy)-2fluorobenzoate
[0900] To solution of 3-(3,5-dichlorophenyl)oxetan-3-ol (400 mg,
1.8 mmol) and DIPEA (1.4 g, mmol) in DCM (10 mL),
trifluoromethanesulfonic anhydride (0.9 mL, 5.5 mmol) was added
dropwise at -20.degree. C. The mixture was then stirred at room
temperature for 3 h, and methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate (280 mg,
0.92 mmol) in acetonitrile (10 mL) was added. Then the reaction
mixture was stirred at room temperature for another 16 h. The
mixture was then concentrated in vacuo and the residue purified by
silica gel chromatography (eluting with ethyl acetate/petroleum
ether=1/3) to afford the target compound (320 mg, 69%) as an oil.
LCMS(ESI) m/z: 508.1 [M+H].sup.+.
##STR00523##
Step 3
5-Cyclopropyl-4-((1-(3-(3,5-dichlorophenyl)oxetan-3-yl)piperidin-4-yl)meth-
oxy)-2-fluorobenzoic acid
[0901] The compound was synthesized as described in step 6 of
Example 88. LCMS(ESI) m/z: 494.1 [M+H].sup.+.
Step 4
##STR00524##
[0902]
5-Cyclopropyl-4-((1-(3-(3,5-dichlorophenyl)oxetan-3-yl)piperidin-4--
yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0903] The compound was synthesized as described step 5 of Example
80. LCMS(ESI) Method A: RT=5.76 min, m/z: 571.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 11.82 (brs, 1H),
7.47-7.44 (m, 2H), 7.39-7.37 (m, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.88
(d, J=13.2 Hz, 1H), 3.90 (d, J=6.0 Hz, 2H), 3.24 (m, 1H), 3.23 (s,
3H), 3.02-2.94 (m, 2H), 2.87-2.79 (m, 3H), 2.15-2.08 (m, 2H),
2.02-1.98 (m, 1H), 1.75-1.69 (m, 3H), 1.33-1.30 (m, 2H), 0.90-0.85
(m, 2H), 0.66-0.62 (m, 2H).
##STR00525##
Example 175
5-Cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(3-(3,5-dichlorophenyl)oxetan--
3-yl)piperidin-4-yl)methoxy)-2-fluorobenzamide
[0904] The compound was synthesized as described in Example 174.
LCMS(ESI) Method A: RT=5.91 min, m/z: 597.2 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 11.79 (brs, 1H), 7.47-7.44 (m,
2H), 7.39-7.35 (m, 1H), 7.15 (d, J=8.4 1Hz, 1H), 6.85 (d, J=12.8
Hz, 1H), 3.89 (d, J=5.6 Hz, 2H), 3.23-3.22 (m, 3H), 3.01-2.93 (m,
3H), 2.87-2.79 (m, 3H), 2.12-2.07 (m, 2H), 2.01-1.97 (m, 1H),
1.72-1.69 (m, 3H), 1.33-1.30 (m, 2H), 1.03-0.97 (m, 4H), 0.90-0.85
(m, 2H), 0.65-0.61 (m, 2H).
Example 176
##STR00526##
[0905]
N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(3-(3,5-dichloropheny-
l)oxetan-3-yl)piperidin-4-yl)methoxy)-2-fluorobenzamide
[0906] The compound was synthesized as described in Example 174.
LCMS(ESI) Method A: RT=6.06 min, m/z: 612.5 [M+H].sup.+. .sup.1H
NMR (400 MHz, MeOD-d.sub.4): .delta.7.41-7.38 (m, 2H), 7.34-7.30
(m, 2H), 6.75 (d, J=13.2 Hz, 1H), 4.12-3.91 (m, 4H), 3.91 (d, J=6.0
Hz, 2H), 3.31 (m, 1H), 3.16-3.07 (m, 2H), 2.93-2.91 (m, 3H),
2.28-2.20 (m, 4H), 2.09-2.05 (m, 1H), 1.86-1.80 (m, 3H), 1.52-1.49
(m, 2H), 0.95-0.90 (m, 2H), 0.68-0.64 (m, 2H).
Example 177
##STR00527##
[0907]
5-Cyclopropyl-4-((1-(3-(3,5-dichlorophenyl)oxetan-3-yl)piperidin-4--
yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[0908] The compound was synthesized as described in Example 174.
LCMS(ESI) Method A: RT=6.86 min, m/z: 585.2 [M+H].sup.+. .sup.1H
NMR (400 MHz, MeOD-d.sub.4): .delta.7.42-7.39 (m, 2H), 7.34-7.28
(m, 2H), 6.87 (d, J=13.2 Hz, 1H), 3.92 (d, J=6.0 Hz, 2H), 3.51-3.45
(m, 2H), 3.35 (s, 1H), 3.21-3.13 (m, 2H), 2.98-2.92 (m, 3H),
2.34-2.67 (m, 2H), 2.09-2.05 (m, 1H), 1.90-1.82 (m, 3H), 1.57-1.51
(m, 2H), 1.37 (d, J=7.4 Hz, 3H), 0.95-0.90 (m, 2H), 0.68-0.64 (m,
2H).
##STR00528##
Example 178
5-Cyclopropyl-4-((1-(3-(3,5-dichlorophenyl)oxetan-3-yl)-4-methylpiperidin--
4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0909] The compound was synthesized in a similar manner to Example
174 from methyl
5-cyclopropyl-2-fluoro-4-((4-methylpiperidin-4-yl)methoxy)benzoate
and 3-(3,5-Dichlorophenyl)oxetan-3-ol. LCMS(ESI) Method A: RT=5.91
min, m/z: 585.3 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta.7.47-7.44 (m, 2H), 7.39-7.35 (m, 1H), 7.23-7.19 (m, 1H),
6.84 (d, J=10.8 Hz, 1H), 3.76 (s, 2H), 3.23-3.22 (m, 1H), 3.12 (s,
3H), 2.87-2.76 (m, 3H), 2.69-2.61 (m, 2H), 2.45-2.39 (m, 2H),
2.03-1.95 (m, 1H), 1.66-1.61 (m, 2H), 1.38-1.33 (m, 2H), 1.03 (s,
3H), 0.88-0.85 (m, 2H), 0.61-0.60 (m, 2H).
##STR00529##
Example 179
(R)-5-cyclopropyl-4-(1-(2-(diisopropylamino)-2-oxoethyl)piperidin-3-yloxy)-
-2-fluoro-N-(methylsulfonyl)benzamide
##STR00530##
[0910] Step 1
##STR00531##
[0911] (R)-tert-butyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate
[0912] To a solution of (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)piperidine-1-car-
boxylate (1.0 g, 2.3 mmol) in tert-butylacetate (4 mL) was added
sulfuric acid (0.6 mL, 11.5 mmol) at room temperature. The reaction
mixture was stirred for 2 h, quenched with aqueous ammonium
bicarbonate (10 mL) and extracted with ethyl acetate (20
mL.times.3). The combined organic layers were distilled off under
reduced pressure to afford the target compound (500 mg, 65%) as a
pale yellow oil. LCMS(ESI) m/z: 336.0 [M+H].sup.+.
Step 2
##STR00532##
[0913] 2-Bromo-N,N-diisopropylacetamide
[0914] Diisopropylamine (1.0 g, 5.0 mmol) was added to a solution
of 2-bromoacetyl bromide (1.0 g, 10.0 mmol) in DCM (30 mL) at
0.degree. C. The reaction mixture was left to warm to room
temperature and stirred for 1 h, then quenched with saturated
ammonium chloride, extracted with DCM (2.0 mL.times.3), washed with
brine (20 mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by silica gel chromatography
(eluting with petroleum ether/ethyl acetate=10/1) to afford the
target compound (810 mg, 81%) as a pale yellow oil. LCMS(ESI) m/z:
222.0 [M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3-d)
.delta.3.98-3.95 (m, 1H), 3.81 (s, 2H), 3.45-3.42 (m, 1H),
1.40-1.88 (m, 6H), 1.28-1.25 (m, 6H).
Step 3
##STR00533##
[0915] (R)-tert-butyl
5-cyclopropyl-4-(1-(2-(diisopropylamino)--oxoethyl)piperidin-3-yloxy)-2-f-
luorobenzoate
[0916] A mixture of (R)-tert-butyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate (56 mg, 0.17
mmol), 2-bromo-N,N-diisopropylacetamide (44 mg, 0.20 mmol) and
potassium carbonate (69 mg, 0.50 mmol) in acetonitrile (2 mL) was
heated at 80.degree. C. for 16 h. The reaction mixture was
filtered, washed with ethyl acetate (10 mL) and concentrated. The
residue was purified by silica gel chromatography (eluting with
petroleum ether/ethyl acetate=5/1) to afford the target compound
(61 mg, 75%) as a pale yellow oil. LCMS(ESI) m/z: 477.0
[M+H].sup.+.
Step 4
##STR00534##
[0917]
(R)-5-cyclopropyl-4-(1-(2-(diiospropylamino)-2-oxoethyl)piperidin-3-
-yloxy)-2-fluorobenzoic acid
[0918] The compound was synthesized as described in step 4, Example
80. LCMS(ESI) m/z: 421.1 [M+H].sup.+.
Step 5
##STR00535##
[0919]
(R)-5-cyclopropyl-4-(1-(2-(diisopropylamino)-2-oxoethyl)piperidin-3-
-yloxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0920] The compound was synthesized as described in step 5, Example
80. LCMS(ESI) Method A: RT=4.61 min, m/z: 498.0 [M+H].sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.14 (d, J=8.5 Hz, 1H),
6.92 (d, J=13.0 Hz, 1H), 4.58 (m, 1H), 4.09 (m, 1H), 3.41-3.38 (m,
3H), 3.15 (s, 3H), 2.97 (m, 1H), 2.70-2.63 (m, 2H), 2.49-2.46 (m,
1H), 2.07 (m, 1H), 1.95 (m, 1H), 1.83 (m, 1H), 1.64-1.57 (m, 2H),
1.28-1.24 (m, 6H), 1.14-1.10 (m, 6H), 0.89-0.85 (m, 2H), 0.68-0.61
(m, 2H).
##STR00536##
Example 180
5-Cyclopropyl-4-((1-(2-(diisopropylamino)-2-oxoethyl)piperidin-4-yl)methox-
y)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00537##
[0921] Step 1
##STR00538##
[0922] Methyl
5-cyclopropyl-4-((1-(2-(diisopropylamino)-2-oxoethyl)piperidin-4-yl)metho-
xy)-2-fluorobenzoate
[0923] The compound was synthesized as described in step 3 of
Example 179. LCMS(ESI) m/z: 449.1 [M+H].sup.+.
Step 2
##STR00539##
[0924]
5-Cyclopropyl-4-((1-(2-(diisopropylamino)-2-oxoethyl)piperidin-4-yl-
)methoxy)-2-fluorobenzoic acid
[0925] The compound was synthesized as described in step 6 of
Example 88. LCMS(ESI) m/z: 435.1 [M+H].sup.+.
Step 3
##STR00540##
[0926]
5-Cyclopropyl-4-((1-(2-(diiospropylamino)-2-oxoethyl)piperidin-4-yl-
)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0927] The compound was synthesized as described in step 5 of
Example 80. LCMS(ESI) Method A: RT=4.52 min, m/z: 512.0
[M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.21 (d,
J=8.5 Hz, 1H), 6.77 (d, J=12.0 Hz, 1H), 3.93-3.77 (m, 5H),
3.51-3.49 (m, 1H), 3.23 (m, 2H), 2.96 (s, 3H), 2.75-2.57 (m, 2H),
2.04-1.88 (m, 4H), 1.69-1.56 1 (m, 2H), 1.33-1.32 (m, 6H),
1.16-1.15 (m, 6H), 0.89-0.85 (m, 2H), 0.60-0.57 (m, 2H).
##STR00541##
Example 181
(R)-4-((1-(1-(3-chloro-4-fluorophenyl)-2-methoxyethyl)piperidin-4-yl)metho-
xy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[0928] The compound was synthesized as described in Example 172.
The enantiomer was arbitrarily assigned as
(R)-4-((1-(1-(3-chloro-4-fluorophenyl)-2-methoxyethyl)piperidin-4-yl)meth-
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide Chiral HPLC
(column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH, A:B=75:25; flow: 2.25 mL/min;
column temperature: 41.7.degree. C.; RT=2.97 min). LCMS(ESI) Method
A: RT=5.51 mm, m/z: 557.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 11.58 (brs, 1H), 7.55 (d, J=6.0 Hz, 1H),
7.41-7.36 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 6.85 (d, 12.8 Hz, 1H),
3.89 (d, J=6.0 Hz, 2H), 3.78-3.70 (m, 3H), 3.23 (s, 3H), 3.17 (s,
3H), 3.05-3.03 (m, 1H), 2.85-2.82 1H), 2.15-2.12 (m, 1H), 2.03-1.97
(m, 2H), 1.80-1.72 (m, 3H), 1.41-1.31 (m, 2H), 0.89-0.85 (m, 2H),
0.64-0.60 (m, 2H).
Example 182
##STR00542##
[0929]
(S)-4-((1-(1-(3-chloro-4-fluorophenyl)-2-methoxyethyl)piperidin-4-y-
l)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[0930] The compound was synthesized as described in Example 172.
The enantiomer was arbitrarily assigned as
(S)-4-((1-(1-(3-chloro-4-fluorophenyl)-2-methoxyethyl)piperidin-4-yl)meth-
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide. Chiral
HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH, A:B=75:25; flow: 2.25 mL/min;
column temperature: 39.5.degree. C.; RT=3.58 min). LCMS(ESI) Method
A: RT=5.50 min, m/z: 557.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 11.60 (brs, 1H), 7.55 (d, J=6.8 Hz, 1H),
7.41-7.36 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 6.85 (d, J=12.8 Hz, 1H),
3.89 (d, J=5.6 Hz, 2H), 3.78-3.70 (m, 3H), 3.23 (s, 3H), 3.17 (s,
3H), 3.05-3.03 (m, 1H), 2.85-2.82. (m, 1H), 2.20-2.12 (m, 1H),
2.03-1.97 (m, 2H), 1.80-1.72 (m, 3H), 1.41-1.31 (m, 2H), 0.89-0.85
(m, 2H), 0.64-0.60 (m, 2H).
Example 183
##STR00543##
[0931]
4-((1-(3-Chloro-4-methoxybenzyl)piperidin-4-yl)methoxy)-5-cycloprop-
yl-2-fluoro-N-(methylsulfonyl)benzamide
[0932] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.08 min, m/z: 525.2 [M+H].sup.+. .sup.1H
NMR (400 MHz, MeOD-d.sub.4) .delta.10.51 (brs, 1H), 7.48 (s, 1H),
7.35-7.33 (m, 1H), 7.20-7.16 (m, 2H), 6.89 (d, J=12.8 Hz, 1H), 3.92
(d, J=5.6 Hz, 2H), 3.86 (s, 3H), 3.82 (s, 2H), 3.11-3.08 (m, 2H),
3.01 (s, 3H), 2.50-2.39 (m, 2H), 2.03-1.97 (m, 1H), 1.91-1.85 (m,
3H), 1.48-1.45 (m, 2H), 0.89-0.85 (m, 2H), 0.61-0.57 (m, 2H).
##STR00544##
Example 184
5-Cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-4-yl)methoxy)-N-(ethylsu-
lfonyl)-2-fluorobenzamide
[0933] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=6.34 min, m/z: 543.2 [M+H].sup.+. .sup.1H
NMR (400 MHz, MeOD-d.sub.4) .delta.11.47 (brs, 1H), 7.54-7.52 (m,
1H), 7.40-7.39 (m, 2H), 7.15-7.13(m, 1H), 6.90-6.87 (m, 1H), 3.93
(d, J=6.0 Hz, 2H), 3.62 (m, 2H), 3.35-3.32 (m, 2H), 2.93-2.90 (m,
2H), 2.19-1.99 (m, 3H), 1.82-1.79 (m, 3H), 1.44-1.38 (m, 2H),
1.22-1.18 (m, 3H), 0.90-0.85 (m, 2H), 0.61-0.57 (m, 2H).
Example 185
##STR00545##
[0934]
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-3-methylazeti-
din-3-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0935] The compound was synthesized as described in Example 81. The
enantiomer was separated by chiral SFC from the racemate, the first
eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-3-methylazetidin-3--
yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC
(column: OZ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH (0.5% DEA), A:B=70:30; flow: 3
mL/min; column temperature: 38.5.degree. C.; RT=5.7 min). LCMS(ESI)
Method C: RT =5.48 min, m/z: 528.8 [M+H].sup.+. .sup.1H NMR (400
MHz, MeOD-.sub.4) .delta.7.44 (s, 1H), 7.39-7.35 (m, 3H), 6.81 (d,
J =12.4 Hz, 1H), 4.10-4.04 (m, 2), 3.83-3.81 (m, 1H), 3.65-3.59 (m,
2H), 3.40-3.38 (m, 1H), 3.27-3.25 (m, 4H), 2.10-2.07 (m, 1H), 1.48
(s, 3H), 1.37-1.35 (m, 3H), 0.95-0.93 (m, 2H), 0.69-0.68 (m,
2H).
Example 186
##STR00546##
[0936]
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-3-methylazeti-
din-3-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[0937] The compound was synthesized as described in Example 81. The
enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-3-methylazetidin-3--
yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC
(column: OZ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH (0.5% DEA), A:B=70:30; flow: 3
mL/min; column temperature: 38.5.degree. C.; RT=8.13 min).
LCMS(ESI) Method C: RT =5.42 min, m/z: 528.7 [M+H].sup.+. .sup.1H
NMR (400 MHz, MeOD-d.sub.4).delta. 7.42 (s, 1H), 7.38-7.36 (m, 3H),
6.81 (d, J =12.8 Hz, 1H), 4.10-4.03 (m, 2H), 3.79-3.77 (m, 1H),
3.60-3.50 (m, 2H), 3.34-3.32 (m, 1H), 3.25-3.23 (m, 4H),
2.09-2.01(m, 1H), 1.47 (s, 3H), 1.35-1.30 (m, 3H), 0.97-0.91 (m,
2H), 0.68-0.66 (m, 2H).
Example 187
##STR00547##
[0938]
(R)-5-cyclopropyl-2-fluoro-4-((1-(1-(4-fluoro-3-(trifluoromethyl)ph-
enyl)-2-methoxyethyl)piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[0939] The compound was synthesized as described in Example 172.
The enantiomer was separated by chiral SFC from the racemate, the
first eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-2-fluoro-4-((1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)--
2-methoxyethyl)piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=80:20; flow: 3
mL/min; column temperature: 39.5.degree. C.; RT =3.55 min).
LCMS(ESI) Method C: RT=4.82 min, m/z: 591.0 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.72-7.70) (m, 2H), 7.51-7.46
(m, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.87 (d, J=12.8 Hz, 1H), 3.91-3.84
(m, 5H), 3.28-3.27 (m, 1H), 3.22-3.21 (m, 5H), 3.06-3.03 (m, 1H),
2.83-2.81 (m, 1H), 2.16-1.96 (m, 3H), 1.77-1.72 (m, 3H), 1.40-1.30
(m, 2H), 0.89-0.84 (m, 2H), 0.65-0.61 (m, 2H).
Example 188
##STR00548##
[0940]
(S)-5-cyclopropyl-2-fluoro-4-((1-(1-(4-fluoro-3-(trifluoromethyl)ph-
enyl)-2-methoxyethyl)piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[0941] The compound was synthesized as described in Example 172.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-2-fluoro-4-((1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)--
2-methoxyethyl)piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: AD-H, 4.6.times.250 min, 5 .mu.m; mobile
Phase: A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=80:20;
flow: 3 mL/min; column temperature: 39.5.degree. C.; RT =6.51 min).
LCMS(ESI) Method C: RT=4.83 min, m/z 591.1 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.72-7.70 (m, 2H), 7.51-7.46 (m,
1H), 7.15 (d, J=8.4 Hz, 1H), 6.87 (d, J=13.2 Hz, 1H), 3.91-3.72 (m,
4H), 3.29-3.28 (m, 1H), 3.23-3.21 (m, 5H), 3.05-3.02 (m, 1H),
2.83-2.81 (m, 2H), 2.02-1.96 (m, 3H), 1.83-1.72 (m, 3H), 1.40-1.30
(m, 2H), 0.89-0.84 (m, 2H), 0.66-0.62 (m, 2H).
##STR00549##
Example 189
5-Cyclopropyl-2-fluoro-4-((1-(4-fluoro-3-(trifluoromethyl)piperidin)piperi-
din-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[0942] The compound was synthesized as described in Example 88.
LCMS(ESI) Method C: RT=3.95 min, m/z: 547.0 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.33-7.72 (m, 2H), 7.52-7.47
(m, 1H), 7.18 (d, J=8.8 Hz, 1H), 6.80 (d, J=12.8 Hz, 1H), 3.92 (d,
J=5.6 Hz, 2H), 3.68 (s, 2H), 3.04 (s, 3H), 2.94-2.91 (m, 2H),
2.03-1.99 (m, 3H), 1.83-1.80 (m, 3H), 1.44-1.38 (m, 2H), 0.89-0.86
(m, 2H), 0.60-0.59 (m, 2H).
##STR00550##
Example 190
4-((1-((5-Chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)piperidin-4--
yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00551##
##STR00552##
[0943] Step 1
5-Chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid
[0944] A mixture of 2,2,2-trifluoroethanol (1.0 g, 5.2 mmol) and
potassium hydroxide (874 mg, 15.6 mmol) in DMSO (15 mL) was stirred
at 120.degree. C. for 24 h. The reaction mixture was acidified with
HCl (1M), extracted with DCM (30 mL.times.3), dried over anhydrous
sodium sulfate and concentrated. The crude compound (960 mg) was
used in next step without further purification. LCMS(ESI) m/z:
255.8 [M+H].sup.+.
Step 2
##STR00553##
[0945] (5-Chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol
[0946] The compound was synthesized as described to step 2 of
Example 172. LCMS(ESI) m/z: 241.9 [M+H].sup.+.
##STR00554##
Step 3
3-Chloro-5-(chloromethyl)-2-(2,2,2-trifluoroethoxy)pyridine
[0947] The compound was synthesized as described in step 2 of
Example 80.
Step 4
##STR00555##
[0948] Methyl
4-((1-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)piperidin-4-
-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate
[0949] The compound was synthesized as described in step 3 of
Example 80. LCMS(ESI) m/z: 531.0 [M+H].sup.+.
##STR00556##
Step 5
4-((1-((5-Chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)piperidin-4--
yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid
[0950] The compound was synthesized as described in step 6 of
Example 88. LCMS(ESI) m/z: 517.0 [M+H].sup.+.
##STR00557##
Step 6
4-((1-((5-Chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)piperidin-4--
yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[0951] The compound was synthesized as described in step 5 of
Example 80. LCMS(ESI) Method A: RT=5.70 min, m/z 594.0 [M+H].sup.+.
.sup.1H NMR (500 MHz, MeOD-d.sub.4) .delta. 8.14-8.11 (m, 1H),
7.97-7.94 (m, 1H), 7.35-7.34 (m, 1H), 6.70-6.66 (m, 1H), 5.0-4.94
(m, 2H), 3.90-3.71 (m, 4H), 3.30-3.15 (m, 5H), 2.50-2.49 (m, 2H),
2.07-1.93 (m, 4H), 1.61-1.55 (m, 2H), 0.90-0.89 (m, 2H), 0.65-0.63
(m, 2H).
Example 191
##STR00558##
[0952]
4-((1-(2-Chlorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluor-
o-N-(methylsulfonyl)benzamide
[0953] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.67 min, m/z: 495.0 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d.sub.4): .delta. 7.58-7.57 (m, 1H), 7.47-7.46
(m, 1H), 7.36-7.33 (m, 3H), 6.68 (d, J=12.0 Hz, 1H), 3.94-3.90 (m,
4H), 3.27-3.12 (m, 5H), 2.54-2.47 (m, 1H), 2.08-1.95 (m, 4H),
1.63-1.60 (m, 2H), 1.28-1.25 (m, 1H), 0.91-0.87 (m, 2H), 0.67-0.64
(m, 2H).
Example 192
##STR00559##
[0954]
5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(2,2,3,3-tetrafluor-
opropyl)piperidin-4-yl)methoxy)benzamide
[0955] The compound was synthesized as described in Example 116.
LCMS(ESI) Method A: RT=5.34 min, m/z: 485.1 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6): .delta. 11.87 (s, 1H), 7.15 (d, J=9.0
Hz, 1H), 6.90 (d, J=13.0 Hz, 1H), 6.58-6.37 (m, 1H), 3.92 (d, J=6.0
Hz, 2H), 3.23 (s, 3H), 3.0-2.89 (m, 4H), 2.32-2.27 (m, 2H),
2.03-2.0 (m, 1H), 1.78-1.74 (m, 3H), 1.40-1.32 (m, 2H), 0.91-0.87
(m, 2H), 0.66-0.63 (m, 2H).
Example 193
##STR00560##
[0956]
5-Cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(3,3,3-trifluo-
ropropyl)piperidin-4-yl)methoxy)benzamide
[0957] The compound was synthesized as described in Example 116.
LCMS(ESI) Method A: RT=4.98 min, m/z: 493.0 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta.7.15 (d, J=8.0 Hz, 1H), 6.88 (d,
J=12.5 Hz, 1H), 3.94 (d, J=5.5 Hz, 2H), 3.04-3.00 (m, 3H),
2.65-2.63 (m, 2H), 2.56-2.50 (m, 2H), 2.17-2.12 (m, 2H), 2.04-1.99
(m, 1H), 1.82-1.79 (m, 3H), 1.42-1.35 (m, 2H), 1.06-0.97 (m, 4H),
0.90-0.87 (m, 2H), 0.65-0.62 m, 2H).
Example 194
##STR00561##
[0958]
N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-(3,3,3-trifl-
uoropropyl)piperidin-4-yl)methoxy)benzamide
[0959] The compound was synthesized as described in Example 116.
LCMS(ESI) Method A: RT=5.13 min, m/z: 508.0 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 7.17 (d, J=8.5 Hz, 1H), 6.87
(d, J=13.0 Hz, 1H), 3.94-3.93 (m, 6H), 2.98-2.96 (m, 2H), 2.61-2.58
(m, 2-H), 2.52-2.50 (m, 1H), 2.49-2.48 (m, 1H), 2.12-2.01 (m, 5H),
1.38-1.35 (m, 3H), 0.90-0.87 (m, 2H), 0.90-0.87 (m, 2H), 0.65-0.62
(m, 2H).
Example 195
##STR00562##
[0960]
4-((1-(3-Chlorobenzoyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluo-
ro-N-(methylsulfonyl)benzamide
[0961] The compound was synthesized as described in step Example
134. LCMS(ESI) Method A: RT 4.61 min, m/z: 509.0 [M+H].sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.87 (s, 1H),
7.53-7.43 (m, 3H), 7.34 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H),
6.96 (d, J=10.4 Hz, 1H), 4.51-4.49 (m, 1H), 3.99 (d, J=4.4 Hz, 2H),
3.57-3.51 (m, 1H), 3.28 (s, 3H), 3.12-3.04 (m, 1H), 2.89-2.81(m,
1H), 2.13-1.72 (m, 4H), 1.32-1.23 (m, 2H), 0.91-0.84 (m, 2H),
0.68-0.64 (m, 2H).
Example 196
##STR00563##
[0962]
4-((1-(3-Chlorobenzoyl)piperidin-4-yl)methoxy)-5-cyclopropyl-N-(cyc-
lopropylsulfonyl)-2-fluorobenzamide
[0963] The compound was synthesized as described in step Example
134. LCMS(ESI) Method A: RT=4.74 min, m/z: 535.0 [M+H].sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.87 (s, 1H),
7.53-7.43 (m, 3H), 7.34 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H),
6.96 (d, J=12.5 Hz, 1H), 4.52-4.50 (m, 1H), 4.00 (d, J=5.0 Hz, 2H),
3.58-3.32 (m, 1H), 3.13-3.00 (m, 2H), 2.85-2.83 (m, 1H), 2.14-1.90
(m, 4H), 1.34-1.33 (m, 2H), 1.24-1.22 (m, 4H), 0.91-0.87 (m, 2H),
0.69-0.66 (m, 2H).
##STR00564##
Example 197
4-((1-Benzoylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfo-
nyl)benzamide
[0964] The compound was synthesized as described in step Example
134. LCMS(ESI) Method A: RT=4.17 min, m/z: 475.0 [M+H].sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.11.87 (s, 1H), 7.45-7.44
(m, 3H), 7.38-7.36 (m, 2H), 7.15 (d, J=8.5 Hz, 1H), 6.96 (d, J=13.0
Hz, 1H), 4.0-3.99 (m, 1H), 3.99 (d, J=4.4 Hz, 2H), 3.62-3.60 (m,
1H), 3.32 (s, 3H), 3.17-3.09 (m, 1H), 3.02-3.01 (m, 1H), 2.13-1.76
(m, 4H), 1.32-1.24 (m, 2H), 0.91-0.84 (m, 2H), 0.69-0.63 (m,
2H).
Example 198
##STR00565##
[0965]
4-((1-Benzoylpiperidin-4-yl)methoxy)-5-cyclopropyl-N-(cyclopropylsu-
lfonyl)-2-fluorobenzamide
[0966] The compound was synthesized as described in step Example
134. LCMS(ESI) Method A: RT=4.38 min, m/z: 501.0 [M+H].sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.11.81 (s, 1H),
7.45.sub.7-7.44 (m, 3H), 7.38-7.36 (m, 2H), 7.15 (d, J=8.0 Hz, 1H),
6.93 (d, J=13.0 Hz, 1H), 4.52-4.51 (m, 1H), 3.98 (d, J=4.8 Hz, 2H),
3.62-3.60 (m, 1H), 3.09-3.01 (m, 2H), 2.83-2.81 (m, 1H), 2.14-1.71
(m, 4H), 1.32-1.31 (m, 2H), 1.07-1.03 (m, 4H), 0.90-0.84 (m, 2H),
0.66-0.61 (m, 2H).
Example 199
##STR00566##
[0967]
5-Cyclopropyl-2-fluoro-4-((1-((1R,2S)-2-hydroxy-2,3dihydro-1H-inden-
-1-yl)piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
##STR00567## ##STR00568##
[0968] Step 1
##STR00569##
[0969] tert-Butyl
5-chloro-4-(cyclopent-3-en-1-ylmethoxy)-2-fluorobenzoate
[0970] A mixture of cyclopent-3-enylmethanol (0.9 g, 9.2 mmol),
tert-butyl 5-chloro-2,4-difluorobenzoate (2.3 g, 9.3 mmol) and
cesium carbonate. (6.0 g, 18.4 mmol) in DMSO (20 mL) was stirred at
80.degree. C. for 10 h. The reaction mixture was diluted with EtOAc
(50 mL) and brine (100 mL). The organic layer was washed by brine
(30 mL.times.3), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by flash column (petroleum
ether) to afford the title compound as a white solid (2.1 g,
70%).
Step 2
##STR00570##
[0971] tert-Butyl
5-chloro-2-fluoro-4-(4-hydroxy-2-(2-hydroxyethyl)butoxy)benzoate
[0972] Ozone was bubbled into a solution of tert-butyl
5-chloro-4-(cyclopent-3-enylmethoxy)-2-fluorobenzoate (1.63 g, 5
mmol) in dry DCM (50 mL) at -78.degree. C. until the solution
turned blue. Then the reaction was purged with nitrogen gas until
the reaction mixture turned colorless. Sodium borohydride (0.76 g,
20 mmol) and methanol (50 mL) was then added and the resultant
mixture allowed to warm to room temperature and stirred for 5 h.
The mixture was then concentrated in vacuo and the residue purified
by silica gel chromatography (eluting with 50% ethyl acetate in
petroleum ether) to afford the title compound as a colorless oil
(1.63 g, 90%).
##STR00571##
Step 3
tert-Butyl
5-cyclopropyl-2-fluoro-4-(4-hydroxy-2-(2-hydroxyethyl)butoxy)be-
nzoate
[0973] A mixture a tert-butyl
5-chloro-2-fluoro-4-(4-hydroxy-2-(2-hydroxyethyl)butoxy)benzoate
(1.09 g, 3 mmol), cyclopropylboronic acid (0.515 g, 6 mmol),
diacetoxypalladium (0.067 g, 0.3 mmol) and potassium phosphate (1.3
g, 6 mmol) in toluene (30 mL) and H.sub.2O (1.5 mL) was stirred at
90.degree. C. for 16 h. The reaction mixture was filtered,
concentrated in vacuo and the residue purified by silica gel
chromatography (eluting with 40% ethyl acetate in petroleum ether)
to afford the target compound as a colorless oil (0.77 g, 70%).
##STR00572##
Step 4
tert-Butyl
4-(4-bromo-2-(2-bromoethyl)butoxy)-5-cyclopropyl-2-fluorobenzoa-
te
[0974] A mixture of tert-butyl
5-cyclopropyl-2-fluoro-4-(4-hydroxy-2-(2-hydroxyethyl)butoxy)benzoate
(0.73 g, 2 mmol), triphenylphosphine (2.1 g, 8 mmol), carbon
tetrabromide (2.65 g, 8 mmol) in DCM (30 mL) was stirred at room
temperature for 20 h. The mixture was concentrated in vacuo and the
residue purified by silica gel chromatography (eluting with 10%
ethyl acetate in petroleum ether) to afford the target compound as
a pale yellow oil (0.84 g, 85%).
Step 5
##STR00573##
[0975] tert-butyl
5-cyclopropyl-2-fluoro-4-((1-(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-
piperidin-4-yl)methoxy)benzoate
[0976] A mixture of tert-butyl
4-(4-bromo-2-(2-bromoethyl)butoxy)-5-cyclopropyl-2-fluorobenzoate
(0.84 g, 1.7 mmol), (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol
(0.253 g, 1.7 mmol), potassium carbonate (0.47 g, 3.4 mmol) and
sodium iodide (0.020 g, 0.17 mmol) in acetonitrile (10 mL) was
stirred at 80.degree. C. for 8 h. The reaction mixture was quenched
with brine (40 mL), extracted with ethyl acetate (10 mL.times.3),
dried over anhydrous sodium sulfate, and concentrated. The residue
was purified by silica gel chromatography (eluting with 15% ethyl
acetate in petroleum ether) to afford the target compound as a
white solid (0.712 g, 87%). MS(ESI): m/z: 482.3 [M+1].sup.+.
Step 6
##STR00574##
[0977]
5-Cyclopropyl-2-fluoro-4-((1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inde-
n-1-yl)piperidin-4-yl)methoxy)benzoic acid
[0978] The compound was synthesized as described in step 3 of
Example 88. LCMS(ESI) m/z: 426.2 [M+1].sup.+.
Step 7
##STR00575##
[0979]
5-Cyclopropyl-2-fluoro-4-((1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inde-
n-1-yl)piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[0980] The compound was synthesized as described in step 5 of
Example 80. LCMS(ESI): Method A: RT=4.71 min, m/z: 503.2
[M+1].sup.+. .sup.1HNMR (500 MHz, DMSO-d.sub.6) .delta. 7.43 (d,
J=7.6 Hz, 1H), 7.33-7.21 (m, 3H), 7.21 (d, J=8.4 Hz, 1H), 6.72 (d,
J=2.8 Hz, 1H), 4.65-4.60 (m, 1H), 4.32 (s, 1H), 3.88 (d, J=5.6 Hz,
2H), 3.27-3.25 (m, 2H), 3.13-3.04 (m, 3H), 2.91-2.83 (m, 4H),
2.03-1.96 (m, 1H), 1.88-1.80 (m, 3H), 1.57-1.48 (m, 2H), 0.88-0.83
(m, 2H), 0.58-0.54 (m, 2H).
##STR00576##
Example 200
5-Cyclopropyl-2-fluoro-4-((1-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-
piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[0981] The compound was synthesized as described in Example 199.
LCMS(ESI) Method A: RT=4.30 min, m/z: 503.2 [M+1].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.7.35-7.33 (m, 1H), 7.25-7.24 (m,
3H), 7.17 (d, J=8.4 Hz, 1H), 6.85 (d, J=12.8 Hz, 1H), 5.18-5.16 (m,
1H), 4.60-4.58 (m, 1H), 4.19-4.17 (m, 1H), 3.93 (d, J =6.0 Hz, 1H),
3.31-3.29 (m, 1H), 3.26-3.12 (m, 5H), 2.77-2.66 (m, 3H), 2.05-2.00
(m, 1H), 1.89-1.79 (m, 3H), 1.48-1.36 (m, 2H), 0.90-0.82 (m, 2H),
0.64-0.60 (m, 2H).
##STR00577##
Example 201
(R)-5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)-1-methoxypropan-2-yl)piper-
idin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00578## ##STR00579##
[0982] Step 1
##STR00580##
[0983] Methyl 2-bromo-2-(3,5-dichlorophenyl)acetate
[0984] To a solution of methyl 2-(3,5-dichlorophenyl)acetate (0.43
g, 90 mmol) and N-bromo- succinimide (0.72 g, 4 mmol) in carbon
tetrachloride (10 mL) was added benzoyl peroxide (0.048 g, 0.2
mmol). The mixture was stirred at 80.degree. C. for 8 h, cooled to
ambient temperature, filtered and concentrated. The residue was
purified by silica gel chromatography (eluting with 15% ethyl
acetate in petroleum ether) to give the title compound as a yellow
oil (0.46 g, 80%). MS(EI) m/z: 295.9 [M].sup.+.
Step 2
##STR00581##
[0985] Methyl
2-(3,5-dichlorophenyl)-2-(4-(hydroxymethyl)piperidin-1-yl)acetate
[0986] To a solution of methyl
2-bromo-2-(3,5-dichlorophenyl)acetate (0.46 g, 1.57 mmol)
acetonitrile (10 mL) was added potassium carbonate (0.65 g, 4.7
mmol) and piperidin-4-yl-methanol (0.37 g, 3.2 mmol). The reaction
mixture was stirred at 80.degree. C. for 4 h, diluted with
dichloromethane (30 mL) and washed with brine (20 mL.times.3). The
combined organic layers were dried over anhydrous sodium sulfate,
filtered and concentrated to give the crude product as colorless
oil (0.5 g) which was used directly without further purification.
LCMS(ESI) m/z: 332.1 [M+1].sup.+.
Step 3
##STR00582##
[0987] Methyl
2-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-2-(3,5-dichlor-
ophenyl)acetate
[0988] To a solution of methyl
2-(3,5-dichlorophenyl)-2-(4-(hydroxymethyl)piperidin-1-yl)acetate
(0.51 g, 1.54 mmol, crude) dichloromethane (20 mL) was added
imidazole (0.35 g, 5.14 mmol) and tert-butylchlorodimethylsilane
(0.47 g, 3.1 mmol). The mixture was stirred at room temperature for
2 h, then filtered, concentrated and purified by silica gel
chromatography (eluting with 5% ethyl acetate in petroleum ether)
to give the title compound (0.6 g, 86%) as a colorless oil.
LCMS(ESI) m/z: 446.1 [M+1].sup.+.
Step 4
##STR00583##
[0989] Methyl
2-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-2-(3,5-dichlor-
ophenyl)propanoate
[0990] To a solution of methyl
2-(4-(((tert-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-2-(3,5-dichlor-
ophenyl)acetate (0.58 g, 1.3 mmol) in dry THF (10 mL) at
-78.degree. C., was added sodium bis(trimethylsilyl) amide (1 M in
THF, 2.6 mL). The resultant mixture was maintained at -78.degree.
C. and stirred for 1 hour. Methyl iodide (0.55 g, 3.9 mmol) was
then added and the mixture allowed to warm to room temperature
overnight. The mixture was diluted with EtOAc (15 mL) and brine (30
mL), extracted with EtOAc (10 mL.times.3), dried over anhydrous
sodium sulfate, filtered and concentrated. The residue was purified
by silica gel chromatography (eluting with 5% EtOAc in petroleum
ether) to afford the title compound as a colorless oil (0.49 g,
82%). LCMS(ESI) m/z: 460.1 [M+1].sup.+.
Step 5
##STR00584##
[0991]
2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-2-(3,5-d-
ichlorophenyl)propan-1-ol
[0992] To a solution of methyl
2-(4-((tert-butyldimethylsilyloxy)methyl)piperidin-1-yl)-2-(3,5-dichlorop-
henyl)propanoate (0.49 g , 1.06 mmol) in THF (20 mL) at -78.degree.
C., diisobutyl aluminium hydride (1M in THF, 4.3 mL) was added
dropwise. The resultant mixture was allowed to warm to room
temperature and stirred for 16 h. The mixture was quenched with
brine and the white precipitate filtered and washed with EtOAc (30
mL). The combined organic layers were dried over anhydrous sodium
sulfate and concentrated to give the title compound which was used
in next step without further purification. LCMS(ESI) m/z: 432.1
[M+1].sup.+.
Step 6
##STR00585##
[0993]
4-(((tert-Butyldimethylsilyl)oxy)methyl)-1-(2-(3,5-dichlorophenyl)--
1-methoxypropan-2-yl)piperidine
[0994] To a solution of
2-(4-((tert-butyldimethylsilyloxy)methyl)piperidin-1-yl)-2-(3,5-dichlorop-
henyl)propan-1-ol (0.46 g, 106 mmol, crude) in dry THF (20 mL) was
added sodium hydride (60% in mineral oil, 0.4 g, 10 mmol) under
N.sub.2 atmosphere at room temperature. Methyl iodide (1.41 g, 10
mmol) was added after 2 h and the resultant mixture was stirred
overnight. The mixture was quenched with water (20 mL), extracted
with EtOAc (10 mL.times.3), dried over sodium sulfate and
concentrated. The residue was purified by silica gel chromatography
(eluting vial 8% EtOAc in petroleum ether) to afford the title
compound as a viscous oil (0.4 g, 85%). LCMS(ESI) m/z: 446.1
[M+1].sup.+.
Step 7
##STR00586##
[0995]
(1-(2-(3,5-dichlorophenyl)-1-methoxypropan-2-yl)piperidin-4-yl)meth-
anol
[0996] To a solution of
4-((tert-butyldimethylsilyloxy)methyl)-1-(2-(3,5-dichlorophenyl)-1-methox-
ypropan-2-yl)piperidine (0.4 g, 0.9 mmol) in DCM (20 mL), HCl in
methanol (4M, 2mL) was added dropwise. The mixture was stirred at
room temperature for 2 h and concentrated in vauo to give the title
compound as a pale yellow oil. LCMS(ESI) m/z: 332.1
[M+1].sup.+.
Step 8
##STR00587##
[0997] (R)-methyl
5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)-1-methoxypropan-2-yl)piperidi-
n-4-yl)methoxy)-2-fluorobenzoate
[0998] A mixture of
(1-(2-(3,5-dichlorophenyl)-1-methoxypropan-2-yl)piperidin-4-yl)methanol
(0.298 g, 0.9 mmol), methyl
5-cyclopropyl-2-fluoro-4-hydroxybenzoate (0.19 g, 0.9 mmol),
triphenylphosphine (0.472 g, 1.8 mmol) and diisopropyl azodiformate
(0.365 g, 1.8 mmol) in dry THF (10 mL) was stirred under an N.sub.2
atmosphere for 24 h. The reaction mixture was filtered,
concentrated in vacuo, and the residue was purified by silica gel
chromatography (eluting with 10% EtOAc in petroleum ether) to give
the racemate (0.33 g, 70%). The enantiomer was separated by chiral
SFC from the racemate. The enantiomer was arbitrarily assigned as
(R)methyl
5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)-1-methoxypropan-2-yl)piperidi-
n-4-yl)methoxy)-2-fluorobenzoate. Chiral HPLC (column: AD-H,
4.6.times.250 mm, 5 .mu.m; mobile Phase: A: supercritical CO.sub.2,
MeOH, A:B=90:10; flow: 3 mL/min; column temperature: 38.9.degree.
C., RT=4.36 min). LCMS(ESI) m/z: 524.1 [M+1].sup.+.
Step 9
##STR00588##
[0999]
(R)-5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)-1-methoxypropan-2-y-
l)piperidin-4-yl)methoxy)-2-fluorobenzoic acid
[1000] The compound was synthesized as described in step 6 of
Example 88. LCMS(ESI) m/z: 510.1 [M+1].sup.+.
Step 10
##STR00589##
[1001]
(R)-5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)-1-methoxypropan-2-y-
l)piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1002] The compound was synthesized as described in step 5 of
Example 80. The enantiomer was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)-1-methoxypropan-2-yl)pipe-
ridin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
LCMS(ESI): Method A: RT=6.39 min, m/z: 587.31 [M+1].sup.+.
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 7.49 (d, J=1.6 Hz, 2H),
7.44 (m, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.82 (d, J=12.4 Hz, 1H), 3.91
(d, J=5.6 Hz, 2H), 3.53-3.40 (m, 2H), 3.18 (s, 3H), 3.10 (s, 3H),
2.88 (d, J=9.6 Hz, 1H), 2.57 (m, 1H), 2.28-2.13 (m, 2H), 2.01-2.02
(m, 1H), 1.80-1.70 (m, 3H), 1.37-1.24 (m, 5H), 0.89-0.85 (m, 2H),
0.63-0.60 (m, 2H).
##STR00590##
Example 202
(S)-5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)-1-methoxypropan-2-yl)piper-
idin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1003] The compound was synthesized as described n Example 201. The
enantiomer was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)-1-methoxypropan-2-yl)pipe-
ridin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
LCMS(ESI): Method A: RT=6.52 min, m/z: 587.2 [M+1].sup.+.
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 7.49 (d, J=2.0 Hz, 2H),
7.44 (m, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.82 (d, J=12.8 Hz, 1H), 3.91
(d, J=6.0 Hz, 2H), 3.53-3.40 (m, 2H), 3.18 (s, 3H), 3.10 (s, 3H),
2.88 (d, J=9.6 Hz, 1H), 2.57 (m, 1H), 2.28-2.13 (m, 2H), 2.02-2.00
(m, 1H), 1.80-1.70 (m, 3H), 1.37-1.24 (m, 5H), 0.89-0.85 (m, 2H),
0.63-0.60 (m, 2H).
Example 203
##STR00591##
[1004]
(S)-5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)-1-methoxypropan-2-y-
l)piperidin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[1005] The compound was synthesized as described in Example 201.
The enantiomer was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)-1-methoxypropan-2-yl)pipe-
ridin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide. LCMS(ESI):
Method A: RT=6.19 min, m/z: 601.31 [M+1].sup.+. .sup.1HNMR (400
MHz, , DMSO-d.sub.6) .delta. 7.49 (d, J=2.0 Hz, 2H), 7.44 (m, 1H),
7.19 (d, J=8.8 Hz, 1H), 6.82 (d, J=12.8 Hz, 1H), 3.91 (d, J=6.0 Hz,
2H), 3.53-3.40 (m, 2H), 3.18 (s, 3H), 3.10 (s, 3H), 3.08-3.06 (m,
2H), 2.88 (d, J=9.6 Hz, 1H), 2.58-2.56 (m, 1H), 2.28-2.13 (m, 2H),
2.02-2.00 (m, 1H), 1.80-1.70 (m, 3H), 1.37-1.24 (m, 5H), 0.89-0.85
(m, 2H), 0.63-0.60 (m, 2H).
##STR00592##
Example 204
(S)-5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)-1-methoxypropan-2-yl)piper-
idin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[1006] The compound was synthesized as described in Example 201.
The enantiomer was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)-1-methoxypropan-2-yl)pipe-
ridin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide. LCMS(ESI):
Method A: RT=6.21 min, m/z: 601.2 [M+1].sup.+. .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 7.49 (d, J=2.0 Hz, 2H), 7.44 (m, 1H), 7.19
(d, J=8.8 Hz, 1H), 6.82 (d, J=12.8 Hz, 1H), 3.91 (d, J=6.0 Hz, 2H),
3.53-3.40 (m, 2H), 3.18 (s, 3H), 3.10 (s, 3H), 3.08-3.06 (m, 2H),
2.88 (d, J=9.6 Hz, 1H), 2.58-2.56 (m, 1H), 2.28-2.13 (m, 2H),
2.02-2.00 (m, 1H), 1.80-1.70 (m, 3H), 1.37-1.24 (m, 5H), 0.89-0.85
(m, 2H), 0.63-0.60 (m, 2H).
Example 205
##STR00593##
[1007]
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxy-2-methylp-
ropyl)piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00594##
[1008] Step 1
##STR00595##
[1009]
1-(4-(((tert-Butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-1-(3,5-d-
ichlorophenyl)-2-methylpropan-2-ol
[1010] To a solution of methyl
2-(4-((tert-butyldimethylsilyloxy)methyl)piperidin-1-yl)-2-(3,5-dichlorop-
henyl)acetate (0.58 g, 1.3 mmol) in dry THF (10 mL) at -78.degree.
C. was added methylmagnesium bromide (3M in THF, 2.6 mL). The
resultant mixture was allowed to warm to room temperature and
stirred overnight, quenched with water (20 mL), extracted with
EtOAc (10 mL.times.3), dried over sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by silica gel
chromatography (eluting with 5% EtOAc in petroleum ether) to afford
title compound as a colorless oil (0.47 g, 81%). LCMS(ESI) m/z:
445.1 [M+1].sup.+.
Step 2
##STR00596##
[1011]
4-(((tert-Butyldimethylsilyl)oxy)methyl)-1-(1-(3,5-dichlorophenyl)--
2-methoxy-2-methylpropyl)piperidine
[1012] The compound was synthesized as described in step 6 of
Example 201. LCMS(ESI) m/z: 460.2 [M+1].sup.+.
Step 3
##STR00597##
[1013]
(1-(1-(3,5-Dichlorophenyl)-2-methoxy-2-methylpropyl)piperidin-4-yl)-
methanol
[1014] The compound was synthesized as described in step 7 of
Example 201. LCMS(ESI) m/z: 346.1 [M+1].sup.+.
Step 4
##STR00598##
[1015] (R)-methyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl)pipe-
ridin-4-yl)methoxy)-2-fluorobenzoate
[1016] The compound was synthesized as described in step 8 of
Example 201. The enantiomer was separated by chiral SFC from the
racemate, the enantiomer was arbitrarily assigned as (R)-methyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl)pipe-
ridin-4-yl)methoxy)-2-fluorobenzoate. Chiral HPLC (column: AD-H,
4.6.times.250 mm, 5 .mu.m; mobile Phase: A: supercritical CO.sub.2,
B: MeOH, A:B=85:15; flow: 3 mL/min; column temperature:
40.4.degree. C., RT=2.85 min). LCMS(ESI) m/z: 538.1
[M+1].sup.+.
Step 5
##STR00599##
[1017]
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl-2-methoxy-2-methylpr-
opyl)piperidin-4-yl)methoxy)-2-fluorobenzoic acid
[1018] The compound was synthesized as described in step 9 of
Example 201. LCMS(ESI) m/z: 524.1 [M+1].sup.+.
Step 6
##STR00600##
[1019]
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxy-2-methylp-
ropyl)piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1020] The compound synthesized as described in step 9 of Example
201. The enantiomer was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl)-
piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
LCMS(ESI): Method A: RT=6.95 min, m/z: 601.31 [M+1].sup.+.
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.83 (brs, 1H),
7.50-7.44 (m, 3H), 7.15-7.13 (m, 1H), 6.86 (d, J=12.8 Hz, 1H),
3.86-3.85 (m, 2H), 3.46-3.44 (m, 2H), 3.29 (s, 1H), 3.24 (s, 3H),
3.16 (s, 3H), 2.82 (d, J=10.8 Hz, 1H), 2.00-1.95 (m, 2H), 1.72-1.71
(m, 3H), 1.55-1.54 (m, 1H), 1.40-1.23 (m, 4H), 0.93 (s, 3H),
0.88-0.83 (m, 2H), 0.65-0.61 (m, 2H).
##STR00601##
Example 206
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl)p-
iperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1021] The compound was synthesized as described in Example 205.
The enantiomer was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl)-
piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
LCMS(ESI): Method A: RT=6.95 min, m/z: 601.3 [M+1].sup.+.
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.83 (brs, 1H),
7.50-7.44 (m, 3H), 7.15-7.13 (m, 1H), 6.86 (d, J=12.8 Hz, 1H),
3.86-3.85 (m, 2H), 3.46-3.44 (m, 2H), 3.29 (s, 1H), 3.24 (s, 3H),
3.16 (s, 3H), 2.82 (d, J=10.8 Hz, 1H), 2.00-1.95 (m, 2H), 1.72-1.71
(m, 3H), 1.55-1.54 (m, 1H), 1.40-1.23 (m, 4H), 0.93 (s, 3H),
0.88-0.83 (m, 2H), 0.65-0.61 (m, 2H).
##STR00602##
Example 207
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl)p-
iperidin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[1022] The compound was synthesized as described in Example 205.
The enantiomer was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl)-
piperidin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide.
LCMS(ESI): Method A: RT=7.04 min, m/z: 615.3 [M+1].sup.+.
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 7.49 (d, J=2.0 Hz, 2H),
7.44 (m, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.82 (d, J=12.8 Hz, 1H), 3.91
(d, J=6.0 Hz, 2H), 3.53-3.40 (m, 2H), 3.42-3.37 (m, 2H), 3.18 (s,
3H), 3.10 (s, 3H), 3.07 (m, 2H), 2.88 (d, J=9.6 Hz, 1H), 2.57-2.56
(m, 1H), 2.28-2.13 (m, 2H), 2.01-2.00 (m, 1H), 1.80-1.70 (m, 3H),
1.37-1.24 (m, 5H), 0.89-0.85 (m, 2H), 0.63-0.60 (m, 2H).
Example 208
##STR00603##
[1023]
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-methoxy-2-methylp-
ropyl)piperidin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[1024] The compound was synthesized as described in Example 205.
The enantiomer was arbitrarily assigned as (S)-5-cyclopropyl-4-((1
-(1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl)piperidin-4-yl)methoxy)-
-N-(ethylsulfonyl)-2-fluorobenzamide. LCMS(ESI): Method A: RT=7.12
min, m/z: 615.2 [M+1].sup.+. .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 7.49 (d, J=2.0 Hz, 2H), 7.44 (m, 1H), 7.19 (d, J=8.8 Hz,
1H), 6.82 (d, J=12.8 Hz, 1H), 3.91 (d, J=6.0 Hz, 2H), 3.53-3.40 (m,
2H), 3.42-3.37 (m, 2H), 3.18 (s, 3H), 3.10 (s, 3H), 3.07-3.06 (m,
2H), 2.88 (d, J=9.6 Hz, 1H), 2.58-2.56 (m, 1H), 2.28-2.13 (m, 2H),
2.01-2.00 (m, 1H), 1.80-1.70 (m, 3H), 1.37-1.24 (m, 5H), 0.89-0.85
(m, 2H), 0.63-0.60 (m, 2H).
##STR00604##
Example 209
5-Cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)propan-2-yl)piperidin-4-yl)meth-
oxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00605##
[1025] Step 1
##STR00606##
[1026] Methyl
5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)propan-2-yl)piperidin-4-yl)met-
hoxy)-2-fluorobenzoate
[1027] To a solution of methyl
5-cyclopropyl-4-((1-(3,5-dichlorobenzoyl)piperidin-4-yl)methoxy)-2-fluoro-
benzoate (0.81 g, 1.7 mmol) and 2,6-di-tert-butyl-4-methylpyridine
(1.4 g, 6.8 mmol) in dry THF (15 mL) under N.sub.2 atmosphere, was
added trifluoromethanesulfonic anhydride dropwise at -78.degree. C.
The mixture was stirred at -40.degree. C. for 3 h followed by the
addition of MeLi (3M in THF, 2.3 mL). The reaction mixture was
allowed to warm to room temperature and stirred overnight, quenched
with water (10 mL), extracted with EtOAc (10 mL.times.3), dried
over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by silica gel chromatography (eluting with
1.5% ethyl acetate in petroleum ether) to afford the target
compound as a white solid (0.17 g, 20%). LCMS(ESI): m/z: 494.2
[M+1].sup.+.
Step 2
##STR00607##
[1028]
5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)propan-2-yl)piperidin-4--
yl)methoxy)-2-fluorobenzoic acid
[1029] The compound was synthesized as described in step 6 of
Example 88. LCMS(ESI) m/z: 480.2 [M+1].sup.+.
Step 3
##STR00608##
[1030]
5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)propan-2-yl)piperidin-4--
yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1031] The compound was synthesized as described in step 5 of
Example 80. LCMS(ESI): Method A: RT=7.01 min, m/z: 557.0
[M+1].sup.+. .sup.1HNMR (500 MHZ, DMSO-d.sub.6) .delta. 7.51 (s,
2H), 7.44 (s, 1H), 7.21 (d, J=8.5 Hz, 1H), 6.76 (d, J=13.0 Hz, 1H),
3.90 (d, J=5.5 Hz, 2H), 3.00 (s, 3H), 2.75-2.73 (m, 2H), 2.12-2.10
(m, 2H), 2.01-1.98 (m, 1H), 1.78-1.76 (m, 3H), 1.35-1.23 (m, 8H),
0.89-0.85 (m, 2H), 0.60-0.57 (m, 2H).
Example 210
##STR00609##
[1032]
5-Cyclopropyl-4-((1-(2-((3,5-dichlorophenyl)propan-2-yl)piperidin-4-
-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[1033] The compound was synthesized as described in Example 209.
LCMS(ESI): Method A: RT=6.81 min, m/z: 571.2 [M+1].sup.+.
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 7.51 (s, 2H), 7.44 (s,
1H), 7.17 (d, J=8.8 Hz, 1H), 6.81 (d, J=12.8 Hz, 1H), 3.92 (d,
J=5.2 Hz, 2H), 3.29-3.24 (m, 2H), 2.76-2.67 (m, 2H), 2.14-2.09 (m,
2H), 2.03-1.96 (m, 1H), 1.77-1.76 (m, 3H), 1.37-1.24 (m, 8H), 1.17
(t, J=7.6 Hz, 3H), 0.89-0.85 (m, 2H), 0.63-0.59 (m, 2H).
##STR00610##
Example 211
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-4-methylpiperidin-4--
yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1034] The compound was synthesized as described in Example 170.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-4-methylpiperidin-4-
-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC
(column: IC 4.6.times.150 mm 5.mu.m; mobile Phase: A: supercritical
CO.sub.2, B: MeOH, A:B=70:30; flow: 3.0 mL/min; column temperature:
39.9.degree. C.; RT=6.78min). LCMS(ESI) Method A: RT=5.50 min, m/z:
556.7 [M+1].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta.7.53-7.43 (m, 3H), 7.20 (d, J=, 8.4 Hz, 1H), 6.89 (d, J=12.4
Hz, 1H), 3.80 (s, 3H), 3.14 (s, 3H), 3.21-3.16 (m, 2H), 2.42-2.40
(m, 1H), 2.01-1.99 (m, 1H), 1.69-1.68 (m, 2H), 1.47-1.35 (m, 3H),
0.89-0.86 (m, 2H), 0.62-0.61 (m, 2H).
##STR00611##
Example 212
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-4-methylpiperidin-4--
yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1035] The compound was synthesized as described in Example 170.
The enantiomer was separated by chiral SFC from the racemate, the
first eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-4-methylpiperidin-4-
-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC
(column: IC 4.6.times.150 mm 5 .mu.m, mobile Phase: A:
supercritical CO.sub.2, B: Method A:B=70:30; flow: 3.0 as mL/min;
column temperature: 39.9.degree. C.; RT=5.75 min). LCMS(ESI) Method
A: RT=5.46 min, mm/z: 556.7 [M+1].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta.7.53-7.43 (m, 3H), 7.20 (d, J=8.4 Hz, 1H),
6.89 (d, J=12.4 Hz, 1H), 3.80 (s, 3H), 3.14 (s, 3H), 3.21-3.16 (m,
2H), 2.44-2.40 (m, 1H), 2.01-1.99 (m, 1H), 1.69-1.68 (m, 2H),
1.47-1.35 (m, 6H), 1.04 (s, 3H), 0.90-0.85 (m, 2H), 0.64-0.60 (m,
2H).
##STR00612##
Example 213
5-Cyclopropyl-4-((1-(2,4-dichlorobenzyl)piperidin-4-yl)methoxy)-N-(ethylsu-
lfonyl)-2-fluorobenzamide
[1036] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=6.25 min, m/z: 542.8 [M+1].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta.7.60-7.51 (m, 3H), 7.13 (d,
J=8.4 Hz, 1H), 6.91 (d, J=12.8 Hz, 1H), 3.94 (d, J=6.0 Hz, 2H),
3.62 (s, 2H), 3.40-3.37 (m, 2H), 2.92-2.90 (m, 2H), 2.20-1.79 (m,
6H), 1.42-1.37 (m, 2H), 1.23-1.19 (m, J=7.4 Hz, 3H), 0.89-0.86 (m,
2H), 0.66-0.63 (m, 2H).
##STR00613##
Example 214
(R)-5-cyclopropyl-4-((1-(1-(3,4-dichlorophenyl)ethyl)piperidin-4-yl)methox-
y)-2-fluoro-N-(methylsulfonyl)benzamide
[1037] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the first
eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,4-dichlorophenyl)ethyl)piperidin-4-yl)metho-
xy)-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC (column:
AD-H, 4.6.times.250 mm, 5 .mu.m: mobile Phase: A: supercritical
CO.sub.2, B: MeOH, A:B=70:30; flow: 3.0 mL/min; column temperature:
37.7.degree. C.; RT=6.44 min). LCMS(ESI) Method A: RT=6.11 min,
m/z: 542.9 [M+1].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta.7.63-7.62 (m, 2H), 7.39-7.38 (m, 1H), 7.17 (d, J=6.4 Hz,
1H), 6.80 (d, J=10.4 Hz, 1H), 3.90 (d, J=4.4 Hz, 3H), 3.08 (s, 3H),
2.86-2.84 (m, 2H), 2.01-1.98 (m, 3H), 1.85-1.78 (m, 3H), 1.39-1.35
(m, 5H), 0.88-0.86 (m, 2H), 0.62-0.59 (m, 2H).
##STR00614##
Example 215
(S)-5-cyclopropyl-4-((1-(1-(3,4-dichlorophenyl)ethyl)piperidin-4-yl)methox-
y)-2-fluoro-N-(methylsulfonyl)benzamide
[1038] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(3,4-dichlorophenyl)ethyl)piperidin-4-yl)metho-
xy)-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC (column:
AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A: supercritical
CO.sub.2, B: MeOH, A:B=70:30; flow: 3.0 mL/min; column temperature:
37.7.degree. C.; RT=10.00 min). LCMS(ESI) Method A: RT=6.11 min,
m/z: 542.9 [M+1].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta.7.64-7.62 (m, 2H), 7.38-7.36 (m, 1H), 7.17 (d, J=6.8 Hz,
1H), 6.80(d, J=10.4 Hz, 1H), 3.91 (d, J=4.4 Hz, 3H), 3.10 (s, 3H),
2.92-2.91 (m, 2H), 2.19-1.17 (m, 2H), 2.01-1.78 (m, 4H), 1.42-1.35
(m, 5)H, 0.88-0.86) (m, 2H), 0.64-0.61 (m, 2H).
Example 216
##STR00615##
[1039]
4-((1-(3-Chloro-5-(trifluoromethyl)piperidin)piperidin-4-yl)methoxy-
)-5-cyclopropyl-N-(ethylsulfonyl)-2-fluorobenzamide
[1040] The compound was synthesized as described as Example 88.
LCMS(ESI) Method A: RT=6.31 min, m/z: 576.8 [M+1].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta.7.77-7.67 (m, 3H), 7.14 (d,
J=8.4 Hz, 1H), 6.88 (d, J=12.8 Hz, 1H), 3.94 (d, J=5.6 Hz, 2H),
3.68 (s, 2H), 3.35-3.33 (m, 2H), 2.91-2.88 (m, 2H), 2.14-1.79 (m,
6H), 1.40-1.38 (m, 2H), 1.20 (t, J=7.4 Hz, 3H), 0.89-0.86 (m, 2H),
0.66-0.63 (m, 2H).
##STR00616##
Example 217
4-((1-((5-Chloro-6-isopropoxypyridin-3-yl)methyl)piperidin-4-yl)methoxy)-5-
-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[1041] The compound was synthesized as described in Example 190.
LCMS(ESI) Method A: RT=5.88 min, m/z: 553.8 [M+1].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta.8.06 (d, J=4.0 Hz, 1H), 7.15
(d, J=9.6 Hz, 1H), 7.10 (d, J=4.4 Hz, 1H), 6.89 (d, J=10.4 Hz, 1H),
5.30-5.28 (m, 1H), 3.95-3.94 (m, 2H), 3.60 (s, 2H), 3.21 (s, 3H),
2.89-2.87 (m, 2H), 2.16-2.11 (m, 2H), 2.03-2.01 (m, 1H), 1.80-1.78
(m, 3H), 1.41-1.39 (m, 2H), 1.31 (d, J=5.2 Hz, 6H), 0.91-0.87 (m,
2H), 0.66-0.63 (m, 2H).
##STR00617##
Example 218
(R)-5-cyclopropyl-4-((1-(1-(3,4-dichlorophenyl)ethyl)-4-methylpiperidin-4--
yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1042] The compound was synthesized as described in Example 170.
The enantiomer was separated by chiral SFC from the racemate, the
first eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,4-dichlorophenyl)ethyl)-4-methylpiperidin-4-
-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC
(column: OJ-H (4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH, A: B=75:25; flow: 3.0 mL/min;
column temperature: 40.0.degree. C.; RT=4.18 min). LCMS(ESI) Method
A: RT=6.25 min, m/z: 556.8 [M+1].sup.+. .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta.7.65-7.63 (m, 2H), 7.40-7.38 (m, 1H), 7.20(d,
J=8.1 Hz, 1H), 6.84 (d, J=12.9 Hz, 1H), 3.79-3.78 (m, 2H), 3.11 (s,
3H), 2.57-2.56 (m, 1H), 2.45-2.42 (m, 3H), 2.01-1.99 (m, 1H),
1.69-1.37 (m, 8H), 1.04 (s, 3H), 0.89-0.85 (m, 2H), 0.62-0.60 (m,
2H).
Example 219
##STR00618##
[1043]
(S)-5-cyclopropyl-4-((1-(1-(3,4-dichlorophenyl)ethyl)-4-methylpiper-
idin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1044] The compound was synthesized as described in Example 170.
The enantiomer was separated by chiral SFC from the racemate,
second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(3,4-dichlorophenyl)ethyl)-4-methylpiperidin-4-
-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC
(column: OJ-H (4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH, A: B=75:25; flow: 3.0 mL/min;
column temperature: 40.0.degree. C.; RT=6.43 min). LCMS(ESI) Method
A: RT=6.26 min, m/z: 556.8 [M+1].sup.+. .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta.7.65-7.63 (m, 2H), 7.40-7.38 (m, 1H), 7.20
(d, J=8.1 Hz, 1H), 6.83 (d, J=12.9 Hz, 1H), 3.79-3.78 (m, 2H), 3.11
(s, 3H), 2.57-2.56 (m, 1H), 2.45-2.42 (m, 3H), 2.01-1.99 (m, 1H),
1.69-1.37 (m, 8H), 1.04 (s, 3H), 0.88-0.86 (m, 2H), 0.62-0.60 (m,
2H).
##STR00619##
Example 220
4-(((1-(3-Chloro-4-(trifluoromethyl)piperidin)piperidin-4-yl)methoxy)-5-cy-
clopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[1045] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=6.25 min, m/z: 562.8 [M+1].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 7.86-7.84 (m, 1H), 7.69-7.52
(m, 2H), 7.15 (d, J=8.4 Hz, 1H), 6.88 (d, J=12.8 Hz, 1H), 3.94 (d,
J=6.0 Hz, 2H), 3.72 (s, 2H), 3.20 (s, 3H), 2.95-2.92 (m, 2H),
2.20-1.80 (m, 6H), 1.43-1.40 (m, 2H), 0.90-0.86 (m, 2H), 0.66-0.63
(m, 2H).
##STR00620##
Example 221
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzoyl)piperidin-3-yl)oxy)-2-fluoro--
N-(methylsulfonyl)benzamide
[1046] The compound was synthesized as described in step Example
134. LCMS(ESI) Method A: RT=4.69 min, m/z: 528.8 [M+1].sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 7.74-7.28 (m, 3H),
7.17 (d, J=8.0 Hz, 1H), 6.78 (d, J=12.5 Hz, 1H), 4.68-4.67 (m, 1H),
4.19-4.16 (m, 1H), 3.68-3.50 (m, 2H), 3.28-3.14 (m, 4H), 2.02-1.60
(m, 5H), 0.93-0.92 (m, 2H), 0.71-0.68 (m, 2H).
Example 222
##STR00621##
[1047]
(R)-5-cyclopropyl-2-fluoro-4-((1-(2-methoxy-1-phenylethyl)piperidin-
-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[1048] The compound was synthesized as described in Example 172.
The enantiomer was separated by chiral SFC from the racemate, the
first eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-2-fluoro-4-((1-(2-methoxy-1-phenylethyl)piperidin-4-yl)-
methoxy)-N-(methylsulfonyl)benzamide. Chiral HPLC (column: OJ-H,
4.6.times.250mm, 5 .mu.m; mobile Phase: A :supercritical CO.sub.2,
B: MeOH, A:B=75:25; flow: 3.0 mL/min; column temperature:
40.2.degree. C.; RT=3.18 min). LCMS(ESI) Method A: RT=4.83 min,
m/z: 505.0 [M+1].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6):
.delta.7.36-7.32 (m, 5H), 7.16 (d, J=8.0 Hz, 1H), 6.82 (d, J=13.5
Hz, 1H), 3.90-3.71 (m, 5H), 3.29-3.25 (m, 4H), 3.11-2.90 (m, 4H),
2.35-1.75 (m, 6H), 1.49-1.38 (m, 2H), 0.88-0.85 (m, 2H), 0.61-0.60
(m, 2H).
##STR00622##
Example 223
(S)-5-cyclopropyl-2-fluoro-4-((1-(2-methoxy-1-phenylethyl)piperidin-4-yl)m-
ethoxy)-N-(methylsulfonyl)benzamide
[1049] The compound was synthesized as described in Example 172.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-2-fluoro-4-((1-(2-methoxy-1-phenylethyl)piperidin-4-yl)-
methoxy)-N-(methylsulfonyl)benzamide. Chiral HPLC (column: OJ-H,
4.6.times.250mm, 5 .mu.m, mobile Phase: A: supercritical CO.sub.2,
MeOH, A:B=75:25; flow: 3.0 mL/min; column temperature: 40.2.degree.
C.; RT=5.20 min). LCMS(ESI) Method A: RT=4.83 min, m/z: 504.9
[M+1].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta.7.36-7.32
(m, 5H), 7.16 (d, J=9.0 Hz, 1H), 6.82 (d, J=13.0 Hz, 1H), 3.90-3.69
(m, 5H), 3.31 (s, 3H), 3.11-2.90 (m, 5H), 2.01-1.75 (m, 6H),
1.49-1.38 (m, 2H), 0.88-0.85 (m, 2H), 0.61-0.59 (m, 2H).
##STR00623##
Example 224
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2-difluoroethyl)piperidi-
n-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00624##
[1050] Step 1
##STR00625##
[1051] 1-(3,5 -Dichlorophenyl)-2,2-difluoroethanol
[1052] A mixture of 3,5-dichlorobenzaldehyde (800 mg, 4.6 mmol),
(difluoromethyl)trimethylsilane (850 mg, 6.8 mmol) and CsF (441 mg,
2.3 mmol) in DMF (20 mL) was stirred for 36 h at room temperature.
The reaction mixture was diluted with ethyl acetate (50 mL), washed
with brine (30 mL.times.3), dried over anhydrous sodium sulfate and
concentrated. The residue was purified by silica gel chromatography
(eluting with petroleum ether/ethyl acetate=10/1) to afford the
title compound as a pale yellow oil. (500 mg, 48%). LCMS(ESI) m/z:
225.0 [M-1].sup.-.
Step 2
##STR00626##
[1053] Methyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2-difluoroethyl)piperidin-4-
-yl)methoxy)-2-fluorobenzoate
[1054] To a mixture of 1-(3,5-dichlorophenyl)-2,2-difluoroethanol
(200 mg, 0.9 mmol) and DIPEA (270 mg, 2.7 mmol) in DCM (20 mL) was
added trifluoromethanesulfonic anhydride (507 mg, 1.8 mmol) at
0.degree. C., and the mixtures stirred for 2 h. Methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate (277 mg,
0.9 mmol) was then added at 0.degree. C. and the mixture left to
warm to room temperature and stirred for 16 h. The reaction was
quenched with ethyl acetate (40 mL) and water (40 mL), extracted
with ethyl acetate (20 mL.times.3), dried over anhydrous sodium
sulfate and concentrated. The residue was purified by silica gel
chromatography (eluting with petroleum ether/ethyl acetate=5/1) to
afford the title compound as a pale yellow oil. (230 mg, 20%).
Step 3
##STR00627##
[1055]
5-Cyclopropyl-4-((1-(1-(3,5dichlorophenyl)-2,2-difluoroethyl)piperi-
din-4-yl)methoxy)-2-fluorobenzoic acid
[1056] The compound was synthesized as described in step 6 of
Example 88. LCMS(ESI) m/z: 502.1 [M+1].sup.+.
Step 4
##STR00628##
[1057]
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2-difluoroethyl)p-
iperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1058] The compound was synthesized as described in step 5 of
Example 80. The enantiomer was separated by chiral SFC from the
racemate, the second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2-difluoroethyl)piperid-
in-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC
(column: AD-H, 4.6.times.250mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH, A:B=85:15; flow: 3.0 mL/min;
column temperature: 40.1.degree. C.; RT=15.85 min). LCMS(ESI)
Method A: RT=6.16 min, m/z: 579.0 [M+1].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta.7.62-7.47 (m, 3H), 7.14 (d, J=8.4 Hz,
1H), 6.89-6.65 (m, 2H), 4.04-3.89 (m, 3H), 3.29-3.24 (m, 3H),
2.98-2.92 (m, 2H), 2.17-2.15 (m, 1H), 2.00-1.73 (m, 5H), 1.35-1.32
(m, 2H), 0.89-0.84 (m, 2H), 0.66-0.62 (m, 2H).
Example 225
##STR00629##
[1059]
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2-difluoroethyl)p-
iperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1060] The compound was synthesized as described in Example 224.
The enantiomer was separated by chiral SFC from the racemate, the
first eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2-difluoroethyl)piperid-
in-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC
(column: AD-H, 4.6.times.250mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH, A:B=85:15; flow: 3.0 mL/min;
column temperature: 40.1.degree. C.; RT=13.82 min). LCMS(ESI)
Method A: RT=6.16 min, m/z: 579.0 [M+1].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta.7.62-7.42 (m, 3H), 7.14 (d, J=8.4 Hz,
1H), 6.77-6.65 (m, 2H), 4.04-3.85 (m, 3H), 3.29-3.27 (m, 1H),
3.02-2.92 (m, 4H), 2.16-2.14 (m, 1H), 2.00-1.68 (m, 5H), 1.39-1.29
(m, 2H), 0.88-0.83 (m, 2H), 0.60-0.58 (m, 2H).
Example 226
##STR00630##
[1061]
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2-difluoroethyl)p-
iperidin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[1062] The compound was synthesized as described in Example 224.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2-difluoroethyl)piperid-
in-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide. Chiral HPLC
(column: AD-H, 4.6.times.250 mm, 5.mu.m: mobile Phase: A:
supercritical CO.sub.2, B: MeOH, A:B=85:15; flow: 3.0 mL/min;
column temperature: 42.0.degree. C.; RT=13.5 min). LCMS(ESI) Method
A: RT=6.15 min, m/z: 593.2 [M+1].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta.7.62-7.61 (m, 1H), 7.47-7.46 (m, 2H), 7.12
(d, J=8.4 Hz, 1H), 6.90-6.58 (m, 2H), 4.08-3.89 (m, 3H), 3.39-3.37
(m, 2H), 3.01-2.92 (m, 2H), 2.15-2.13 (m, 1H), 1.98-1.72 (m, 4H),
1.35-1.19 (m, 6H), 0.87-0.84 (m, 2H), 0.62-0.60 (m, 2H).
##STR00631##
Example 227
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2-difluoroethyl)piperidi-
n-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[1063] The compound was synthesized as described in Example 224.
The enantiomer was separated by chiral SFC from the racemate, the
first eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2-difluoroethyl)piperid-
in-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide. Chiral HPLC
(column: AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH, A:B=85:15; flow: 3.0 mL/min;
column temperature: 42.0.degree. C.; RT=12.33 min). LCMS(ESI)
Method A: RT=6.15 min, m/z: 593.2 [M+1].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta.7.62-7.61 (m, 1H), 7.47-7.46 (m, 2H),
7.12 (d, J=8.4 Hz, 1H), 6.90-6.58 (m, 2H), 4.08-3.89 (m, 3H),
3.39-3.37 (m, 2H), 3.01-2.94 (m, 2H), 2.15-1.91 (m, 3H), 1.76-1.68
(m, 3H), 1.35-1.32 (m, 2H), 1.21 (t, J=7.4 Hz, 3H), 0.89-0.84 (m,
2H), 0.66-0.63 (m, 2H).
Example 228
##STR00632##
[1064]
5-Cyclopropyl-2-fluoro-4-((1-(3-fluoro-5-(trifluoromethyl)piperidin-
)piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[1065] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.71 min, m/z 546.9 [M+1].sup.+. .sup.1H-NMR
(500 MHz, DMSO-d.sub.6): .delta.11.34 (s, 1H), 7.62-7.53 (m, 3H),
7.16 (d, J=9.0 Hz, 1H), 6.89 (d, J=13.0 Hz, 1H), 3.95 (d, J=6.0 Hz,
2H), 3.77 (s, 2H), 3.21 (s, 3H), 2.97-2.95 (m, 2H), 2.27-2.23 (m,
2H), 2.04-2.00 (m, 1H), 1.87-1.82 (m, 3H), 1.46-1.40 (m, 2H),
0.90-0.86 (m, 2H), 0.66-0.63 (m, 2H).
##STR00633##
Example 229
4-((1-(4-Chloro-3-(trifluoromethyl)piperidin)piperidin-4-yl)methoxy)-5-cyc-
lopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[1066] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.88 min, m/z 563.0 [M+1].sup.+. .sup.1H-NMR
(500 MHz, DMSO-d.sub.6): .delta.11.24 (brs, 1H), 7.83 (s, 1H), 7.75
(d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H),
6.85 (d, J=12.5 Hz, 1H), 3.93 (d, J=6.0 Hz, 2H), 3.74 (s, 2H), 3.14
(s, 3H), 2.97-2.95 (m, 2H), 2.24 (s, 2H), 2.04-1.98 (m, 1H),
1.86-1.77 (m, 3H), 1.45-1.38 (m, 2H), 0.89-0.86 (m, 2H), 0.64-0.61
(m, 2H).
Example 230
##STR00634##
[1067]
(R)-4-((1-(1-(3-chloro-5-fluorophenyl)ethyl)piperidin-4-yl)methoxy)-
-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[1068] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the first
eluting fraction was arbitrarily assigned as
(R)-4-((1-(1-(3-chloro-5-fluorophenyl)ethyl)piperidin-4-yl)methoxy)-5-cyc-
lopropyl-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC (column:
AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A: supercritical
CO.sub.2, B: MeOH (0.1% DEA), A:B=70:30; flow: 2.1 mL/min; column
temperature: 40.degree. C.; RT=4.01 min). LCMS(ESI) Method A: RT
=5.99 min, m/z 527.2 [M+1].sup.+. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta.7.35 (d, J=8.8 Hz, 1H), 7.30 (s, 1H), 7.21
(d, J=9.2 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.83 (d, J=12.4 Hz, 1H),
3.91 (d, J=5.6Hz, 2H), 3.74 (brs, 1H), 3.11 (s, 3H), 3.07-3.03 (m,
1H), 2.91-2.87 (m, 1H), 2.12-2.09 (m, 2H), 2.03-1.98 (m, 1H),
1.84-1.77 (m, 3H), 1.41-1.34 (m, 5H), 0.89-0.85 (m, 2H), 0.63-0.59
(m, 2H).
##STR00635##
Example 231
(S)-4-((1-(1-(3-chloro-5-fluorophenyl)ethyl)piperidin-4-yl)methoxy)-5-cycl-
opropyl-2-fluoro-N-(methylsulfonyl)benzamide
[1069] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(R)-4-((1-(1-(3-chloro-5-fluorophenyl)ethyl)piperidin-4-yl)methoxy)-5-cyc-
lopropyl-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC (column:
AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A: supercritical
CO.sub.2, B: MeOH (0.1% DEA), A:B=70:30; flow: 2.1 mL/min; column
temperature: 40.degree. C.; RT=4.83 min). LCMS(ESI) Method A: RT
=5.99 min, m/z 527.2 [M+1].sup.+. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta.7.35 (d, J=8.8 Hz, 1H), 7.30 (s, 1H), 7.21
(d, J=9.2 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.83 (d, J=12.4 Hz, 1H),
3.91 (d, J=5.6 Hz, 2H), 3.74 (brs, 1H), 3.11 (s, 3H), 3.07-3.03 (m,
1H), 2.91-2.87 (m, 1H), 2.12-2.09 (m, 2H), 2.03-1.98 (m, 1H),
1.84-1.77 (m, 3H), 1.41-1.34 (m, 5H), 0.89-0.85 (m, 2H), 0.63-0.59
(m, 2H).
##STR00636##
Example 232
5-Cyclopropyl-4-((1-(3,4-dichlorobenzoyl)piperidin-4-yl)methoxy)-2-fluoro--
N-(methylsulfonyl)benzamide
[1070] The compound was synthesized as described in Example 134.
LCMS(ESI) Method A: RT=5.03 min, m/z 542.8 [M+1].sup.+. .sup.1H-NMR
(500 MHz, DMSO-d.sub.6): .delta.11.89 (s, 1H), 7.72 (d, J=8.0 Hz,
1H), 7.66 (d, J=2.0 Hz, 1H), 7.39-7.37 (m, 1H), 7.15 (d, J=9.0 Hz,
1H), 6.95 (d, J=12.5 Hz, 1H), 4.48 (brs, 1H), 3.98 (d, J=6.0 Hz,
2H), 3.56 (brs, 1H), 3.29 (s, 3H), 3.18-3.12 (m, 1H), 2.84-2.76 (m,
1H), 2.13-2.10 (m, 1H), 2.05-1.99 (m, 1H), 1.89-1.76(m, 2H), 1.33
(brs, 2H), 0.91-0.87 (m, 2H), 0.68-0.65 (m, 2H).
Example 233
##STR00637##
[1071]
5-Cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(3,4-dichlorobenzoyl)pi-
peridin-4-yl)methoxy)-2-fluorobenzamide
[1072] The compound was synthesized as described in Example 134.
LCMS(ESI) Method A: RT=5.18 min, m/z 568.8 [M+1].sup.+. .sup.1H-NMR
(500 MHz, DMSO-d.sub.6): .delta.11.81 (s, 1H), 7.72 (d, J=8.5 Hz,
1H), 7.66 (d, J=2.0 Hz, 1H), 7.39-7.37 (m, 1H), 7.14 (d, J=8.0 Hz,
1H), 6.97 (d, J=12.3 Hz, 1H), 4.48 (brs, 1H), 3.99 (d, J=5.0 Hz,
2H), 3.56 (brs, 1H), 3.12-3.04 (m, 2H), 2.84 (s, 1H), 2.13-2.12 (m,
1H), 2.04-1.99 (m, 1H), 1.89 (s, 1H), 1.77 (s, 1H), 1.33 (s, 2H),
1.12-1.07 (m, 4H), 0.91-0.87 (m, 2H), 0.68-0.65 (m, 2H).
##STR00638##
Example 234
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)-2-oxopiperidin-4-yl)methoxy)--
2-fluoro-N-(methylsulfonyl)benzamide
##STR00639##
[1073] Step 1
##STR00640##
[1074] 1-(3,5-Dichlorobenzyl)-2-oxopiperidine-4-carboxylic acid
[1075] A mixture of methyl 2-oxopiperidine-4-carboxylate (1.00 g,
6.36 mmol), 1,3-dichloro-5-(chloromethyl)benzene (1.49 g, 7.63
mmol) and potassium hydroxide (1.79 g, 31.8 mmol) in DMSO (30 was
stirred at room temperature for 4 h. The reaction was quenched with
HCl (3.0 M, 50 mL) and ethyl acetate (150 mL). The organic layer
was separated and washed with brine (50 mL.times.3), dried over
anhydrous sodium sulfate, filtered and concentrated. The residue
was purified by silica gel chromatography (eluting with 2% ethyl
acetate in petroleum ether) to afford target compound as white
solid (1.65 g, 85%). LCMS(ESI) m/z: 302.0 [M+1].sup.+.
Step 2
##STR00641##
[1076] Methyl
1-(3,5-dichlorobenzyl)-2-oxopiperidine-4-carboxylate
[1077] A solution of
1-(3,5-dichlorobenzyl)-2-oxopiperidine-4-carboxylic acid (1.65 g,
5.46 mmol) in thionyl chloride (30 mL) was refluxed for 2 h. Then
the solution was added dropwise to methanol (100 mL) at 0.degree.
C. and the mixture stirred at room temperature For 2 h. The mixture
was concentrated in vacuo to afford the target compound as brown
oil which was used without further purification. LCMS(ESI) m/z:
316.0 [M+1].sup.+.
Step 3
##STR00642##
[1078] 1-(3,5-Dichlorobenzyl)-4-(hydroxymethyl)piperidin-2-one
[1079] A mixture of methyl
1-(3,5-dichlorobenzyl)-2-oxopiperidine-4-carboxylate (1.80 g, 5.69
mmol) and sodium borohydride (1.08 g, 28.5 mmol) in THF (20 mL) and
MeOH (10 mL) was stirred at room temperature for 16 h. The solvent
was removed and the residue was purified by reverse phase
chromatography (eluting with 25-30% CH.sub.3CN in 0.5%
NH.sub.4HCO.sub.3) to give target compound as brown oil (630 mg,
38%). LCMS(ESI) m/z: 288.0 [M+1].sup.+.
Step 4
##STR00643##
[1080] (1-(3,5-Dichlorobenzyl)-2-oxopiperidin-4-yl)methyl
4-methylbenzenesulfonate
[1081] A mixture of
1-(3,5-dichlorobenzyl)-4-(hydroxymethyl)piperidin-2-one (630 mg,
2.19 mmol) and sodium hydride (437 mg, 10.9 mmol) in THF (30 mL)
was stirred at room temperature for 30 min. Tosyl chloride (500 mg,
2.62 mmol) in THF (10 mL) was then added and the resulting mixture
was stirred at room temperature for 16 h. The react was quenched
with ice water, extracted with ethyl acetate (100 mL), washed with
brine (50 mL.times.2), dried over anhydrous sodium sulfate,
filtered and concentrated. The residue was purified by reverse
phase chromatography (eluting with 50-60% CH.sub.3CN in 0.5%
NH.sub.4HCO.sub.3) to afford the target compound as brown oil (380
mg, 39%). LCMS(ESI) m/z: 442.0 [M+1].sup.+.
Step 5
##STR00644##
[1082]
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)-2-oxopiperidin-4-yl)me-
thoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1083] A mixture of
(1-(3,5-dichlorobenzyl)-2-oxopiperidin-4-yl)methyl
4-methylbenzenesulfonate (380 mg, 0.859 mmol), potassium carbonate
(1.19 g, 8.61 mmol) and
5-cyclopropyl-2-fluoro-4-hydroxy-N-(methylsulfonyl)benzamide (352
mg, 1.29 mmol), in DMF (20 mL) was stirred at 85.degree. C. for 16
h. The reaction was quenched with ethyl acetate (100 mL) and HCl
(2.0 M, 40 mL), washed with brine (50 mL.times.2), dried over
anhydrous sodium sulfate, filtered and concentrated. The residue
was purified by reverse phase chromatography (eluting with 25-40%
CH.sub.3CN in 0.5% NH.sub.4HCO.sub.3) to afford the racemate as a
white solid. The enantiomer was separated by chiral SFC from the
racemate, the first eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)-2-oxopiperidin-4-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC (column:
AS-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A: supercritical
CO.sub.2, B: MeOH (0.1% DEA), A:B=75:25; flow: 2.25 mL/min; column
temperature: 40.degree. C.; RT=5.59 min). LCMS(ESI) Method A:
RT=5.14 min, m/z: 542.80 [M+1].sup.+. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta.11.92 (s, 1H), 7.53-7.52 (m, 1H), 7.31-7.29
(m, 2H), 7.15 (d, J=8.4 Hz, 1H), 6.95 (d, J=12.8 Hz, 1H), 4.56-4.47
(m, 2H), 4.00 (d, J=6.4 Hz, 2H), 3.32-3.30 (m, 2H), 3.28 (s, 3H),
2.57-2.51 (m, 1H), 2.44-2.39 (m, 1H), 2.30-2.24 (m, 1H), 2.07-1.98
(m, 2H), 1.69-1.63 (m, 1H), 0.92-0.87 (m, 2H), 0.69-0.65 (m,
2H).
##STR00645##
Example 235
(S)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)-2-oxopiperidin-4-yl)methoxy)--
2-fluoro-N-(methylsulfonyl)benzamide
[1084] The compound was synthesized as described in Example 234.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)-2-oxopiperidin-4-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC (column:
AS-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A: supercritical
CO.sub.2, (0.1% DEA), A: B=75:25; flow: 2.25 mL/min: column
temperature: 40.degree. C.; RT=7.28 min). LCMS(ESI) Method A:
RT=5.12 min, m/z: 542.80 [M+1].sup.+. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta.11.92 (s, 1H), 7.53-7.52 (m, 1H), 7.31-7.29
(m, 2H), 7.15 (d, J=8.4 Hz, 1H), 6.95 (d, J=12.8 Hz, 1H), 4.56-4.47
(m, 2H), 4.00 (d, J=6.4 Hz, 2H), 3.32-3.30 (m, 2H), 3.28 (s, 3H),
2.57-2.51 (m, 1H), 2.44-2.39 (m, 1H), 2.30-2.24 (m, 1H), 2.07-1.98
(m, 2H), 1.69-1.63 (m, 1H), 0.92-0.87 (m, 2H), 0.69-0.65 (m,
2H).
##STR00646##
Example 236
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichloro-2-fluorophenyl)ethyl)piperidin-4--
yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1085] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichloro-2-fluorophenyl)
ethyl)piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1 DEA), A:B=65:35; flow: 1.95
mL/min; column temperature: 40.8.degree. C.; RT=3.74 min).
LCMS(ESI) Method A: RT=6.22 min, m/z: 561.2 [M+1].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) 7.69 (dd, J=6.1, 2.6 Hz, 1H), 7.47 (dd,
J=5.3, 2.6 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.83 (d, J=12.8 Hz,
1H), 3.90-3.89 (m, 3H), 3.14 (s, 3H), 3.03-3.02 (m, 1H), 2.87-2.85
(m, 1H), 2.01-2.00 (m, 2H), 1.94-1.68 (m, 4H), 1.42-1.26 (m, 5H),
0.91-0.82 (m, 2H), 0.61 (d, J=5.1 Hz, 2H).
##STR00647##
Example 237
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichloro-2-fluorophenyl)ethyl)piperidin-4--
yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1086] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the first
eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichloro-2-fluorophenyl)
ethyl)piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1 DEA), A:B=65:35; flow: 1.95
mL/min; column temperature: 40.8.degree. C.; RT=3.11 min).
LCMS(ESI) Method A: RT=5.83 min, m/z: 561.0 [M+1].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.69 (dd, J=1.2.6 Hz, 1H), 7.47
(dd, J=5.3, 2.5 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.82 (d, J=12.7
Hz, 1H), 3.88-3.91 (m, 3H), 3.12 (s, 3H), 3.03 (d, J=9.7 Hz, 1H),
2.86-2.85 (m, 1H), 1.99-1.97 (m, 2H), 1.93-1.69 (m, 4H), 1.40-1.25
(m, 5H), 0.86-0.84 (m, 2H), 0.61-0.60 (m, 2H).
##STR00648##
Example 238
(S)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)ethyl)piperidin-4-yl)methox-
y)-2-fluoro-N-(methylsulfonyl)benzamide
[1087] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)
ethyl)piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: AS-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1 DEA), A:B=75:25; flow: 2.25
mL/min; column temperature: 38.1.degree. C.; RT=4.08 min).
LCMS(ESI) Method A: RT=6.43 min, m/z: 542.9 [M+1].sup.+. .sup.1H
NMR (500 MHz, MeOD-d.sub.4) .delta. 7.56 (d, J=8.5 Hz, 1H), 7.44
(d, J=2.1 Hz, 1H), 7.33 (dd, J=8.4, 2.1 Hz, 1H), 7.22 (d, J=8.3 Hz,
1H), 6.52 (d, J=12.8 Hz, 1H), 4.34 (brs, 1H), 3.74 (s, 2H), 3.45
(s, 1H), 3.06-3.04 (m, 3H), 2.97-2.96 (m, 1H), 2.52-2.29 (m, 2H),
1.91-1.90 (m, 3H), 1.80-1.79 (m, 1H), 1.56-1.55 (m, 1H), 1.42-1.40
(m, 4H), 0.80-0.73 (m, 2H), 0.51-0.50 (m, 2H).
##STR00649##
Example 239
(R)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)ethyl)piperidin-4-yl)methox-
y)-2-fluoro-N-(methylsulfonyl)benzamide
[1088] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the first
eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)
ethyl)piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: AS-H, 4.6=250 mm, 5 .mu.m, mobile Phase: A:
supercritical CO.sub.2, B: MeOH (0.1% DEA), A: B=75:25; flow: 2.25
mL/min; column temperature: 41.5.degree. C.; RT=2.87 min).
LCMS(ESI) Method A: RT =6.48 min, m/z: 542.9 [M+1].sup.+. .sup.1H
NMR (500 MHz, MeOD-d.sub.4) .delta. 7.56 (d, J=8.5 Hz, 1H), 7.44
(d, J=2.1 Hz, 1H), 7.33 (dd, J=8.4, 2.1 Hz, 1H), 7.22 (d, J=8.3 Hz,
1H), 6.52 (d, J=12.8 Hz, 1H), 4.34-4.33 (m, 1H), 3.74 (brs, 2H),
3.43-3.44 (m, 1H), 3.06 (s, 3H), 2.97-2.96 (m, 1H), 2.52-2.29 (m,
2H), 1.91-1.90 (m, 3H), 1.80 (m, 1H), 1.56 (m, 1H), 1.42 (m, 4H),
0.75 (m, 2H), 0.51 (m, 2H).
Example 240
##STR00650##
[1089]
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)propyl)piperidin-4-y-
l)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1090] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)
propyl)piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: OZ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.5% DEA), A: B=70:30; flow:
2.1 mL/min; column temperature: 41.0.degree. C.; RT=10.67 min).
LCMS(ESI) Method A: RT =6.42 min, m/z: 557.3 [M+1].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.52 (m, 1H), 7.34 (d, J=1.8
Hz, 2H), 7.16 (d, 8.5 Hz, 1H), 6.81 (d, J=12.9 Hz, 1H), 3.88 (d,
J=6.0 Hz, 2H), 3.53 (m, 1H), 3.13 (s, 3H), 3.05 (m, 1H), 2.93 (m,
1H), 2.01 (m, 4H), 1.76 (m, 4H), 1.34 (m, 2H), 0.86 (m, 2H), 0.72
(m, 3H), 0.60 (m, 2H).
##STR00651##
Example 241
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)propyl)piperidin-4-yl)metho-
xy)-2-fluoro-N-(methylsulfonyl)benzamide
[1091] The compound was synthesized as described in Example 88. The
enantiomer was separated by Chiral SFC from the racemate, the first
eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl
propyl)piperidin-4-yl)methoxy)-2-fluoro-N-
(methylsulfonyl)benzamide. Chiral HPLC (column: OZ-H, 4.6.times.250
mm, 5 .mu.m, mobile Phase: A: supercritical CO.sub.2, B: MeOH (0.5%
DEA), A:B=70:30; flow: 2.1 mL/min; column temperature: 39.3.degree.
C.; RT=9.34 min). LCMS(ESI) Method A: RT=6.35 min, m/z: 557.2
[M+1].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.52 (m,
1H), 7.34 (d, J=1.8 Hz, 2H), 7.16 (d, J=8.5 Hz, 1H), 6.81 (d,
J=12.9 Hz, 1H), 3.88 (d, J=6.0 Hz, 2H), 3.53 (m, 1H), 3.13 (s, 3H),
3.05 (m, 1H), 2.93 (m, 1H), 2.01 (m, 4H), 1.76 (m, 4H), 1.34 (m,
2H), 0.85 (m, 2H), 0.72 (m, 3H), 0.61 (m, 2H).
##STR00652##
Example 242
5-Cyclopropyl-4-((1-(3,5-dichloro-2-fluorobenzyl)piperidin-4-yl)methoxy)-2-
-fluoro-N-(methylsulfonyl)benzamide
[1092] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.98 min, m/z: 547.0 [M+1].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.72 (dd, J=6.1, 2.6 Hz, 1H),
7.47 (d, J=5.5, 2.6 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.85 (d,
J=12.9 Hz, 1H), 3.92 (d, J=5.8 Hz, 2H), 3.63 (s, 2H), 3.16 (s, 3H),
2.89 (m, 2H), 2.12 (m, 2H), 2.01 (m, 1H), 1.79 (m, 3H), 1.38 (m,
2H), 0.85 (m, 2H), 0.63 (m, 2H).
Example 243
##STR00653##
[1093]
(S)-4-((1-(1-(2-chloro-4-fluorophenyl)ethyl)piperidin-4-yl)methoxy)-
-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[1094] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the
second fraction was arbitrarily assigned as
(S)-4-((1-(1-(2-chloro-4-fluorophenyl)
ethyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)be-
nzamide. Chiral HPLC (column: AD-H, 4.times.250 mm, 5 .mu.m; mobile
Phase: A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=70:30;
flow: 2.1 mL/min; column temperature: 41.6.degree. C.; RT=5.88
min). LCMS(ESI) Method A: RT=5.88 min, m/z: 526.9 [M+1].sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.61 (dd, J=8.6, 6.6
Hz, 1H), 7.41 (dd, J=8.8, 2.5 Hz, 1H), 7.24 (m, 1H), 7.16 (d, J=8.5
Hz, 1H), 6.84 (d, J=12.8 Hz, 1H), 3.91 (m, 3H), 3.15 (m, 4H), 2.75
(m, 1H), 2.12 (m, 1H), 2.01 (m, 2H), 1.75(m, 3H), 1.39 (m, 1H),
1.28 (m, 4H), 0.87 (m, 2H), 0.62 (m, 2H).
Example 244
##STR00654##
[1095]
(R)-4-((1-(1-(2-chloro-4-fluorophenyl)ethyl)piperidin-4-yl)methoxy)-
-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[1096] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the first
eluting fraction was arbitrarily assigned as
(R)-4-((1-(1-(2-chloro-4-fluorophenyl)
piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamid-
e. Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m, mobile
Phase: A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=70:30;
flow: 2.1 mL/min; column temperature: 38.1.degree. C.; RT=3.41
min). LCMS(ESI) Method A: RT=5.88 min, m/z: 526.9 [M+1].sup.+.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.65 (dd, J=8.6, 6.6
Hz, 1H), 7.43 (dd, J=8.8, 2.5 Hz, 1H), 7.27 (m, 1H), 7.15 (d, J=8.4
Hz, 1H), 6.88 (d, J=12.9 Hz, 1H), 4.03 (m, 3H), 3.21 (m, 4H), 2.81
(m, 1H), 2.17 (m, 2H), 2.01 (m, 1H), 1.81 (m, 1H), 1.44 (m, 1H),
1.33. (m, 4H), 0.88 (m, 2H), 0.64 (m, 2H).
Example 245
##STR00655##
[1097]
(S)-4-((1-(1-(2-chloro-4-fluorophenyl)ethyl)piperidin-4-yl)methoxy)-
-5-cyclopropyl-N-(ethylsulfonyl)-2-fluorobenzamide
[1098] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-4-((1-(1-(2-chloro-4-fluorophenyl)
ethyl)piperidin-4-yl)methoxy)-5-cyclopropyl-N-(ethylsulfonyl)-2-fluoroben-
zamide. Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m;
mobile Phase: A: supercritical CO.sub.2, B: MeOH (0.1% DEA),
A:B=65:35; flow: 1.95 mL/min; column temperature: 39.6.degree. C.;
RT=3.31 min). LCMS(ESI) Method A: RT=5.85 min, m/z: 541.3
[M+1].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.46 (s,
1H), 7.61 (dd, J=8.7, 6.5 Hz, 1H), 7.41 (dd, J=8.9, 2.6 Hz, 1H),
7.25 (m, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.90 (d, J=12.9 Hz, 1H), 3.92
(d, J=6.1 Hz, 3H), 3.40 (m, 2H), 3.18 (m, 1H), 2.77 (m, 1H), 2.15
(s, 1H), 2.01 (m, 2H), 1.84 (m, 2H), 1.72 (m, 1H), 1.40 (m, 1H),
1.29 (m, 4H), 1.21 (t, J=7.4 Hz, 3H), 0.85 (m, 2H), 0.64 (m,
2H).
Example 246
##STR00656##
[1099]
(R)-4-((1-(1-(2-chloro-4-fluorophenyl)ethyl)piperidin-4-yl)methoxy)-
-5-cyclopropyl-N-(ethylsulfonyl)-2-fluorobenzamide
[1100] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the first
eluting fraction was arbitrarily assigned as
(R)-4-((1-(1-(2-chloro-4-fluorophenyl)
ethyl)piperidin-4-yl)methoxy)-5-cyclopropyl-N-(ethylsulfonyl)-2-fluoroben-
zamide. Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m;
mobile Phase: A: supercritical MeOH (0.1% DEA), A:B=65:35; flow:
1.95 mL/min; column temperature: 40.degree. C.; RT=2.62. min).
LCMS(ESI) Method A: RT=5.86 min, m/z: 541.3 [M+1].sup.+. .sup.1H
NMR (400 DMSO-d.sub.6) .delta. 11.46 (s, 1H), 7.61 (dd, J=8.7, 6.5
Hz, 1H), 7.41 (dd, J=8.9, 2.6 Hz, 1H), 7.25 (m, 1H), 7.14 (d, J=8.4
Hz, 1H), 6.90 (d, J=2.9 Hz, 1H), 3.92 (d, J=6.1 Hz, 3H), 3.40 (m,
2H), 3.18 (m, 1H), 2.77 (m, 1H), 2.15 (m, 1H), 2.01 (m, 2H), 1.84
(m, 2H), 1.72 (m, 1H), 1.40 (m, 1H), 1.29 (m, 4H), 1.21 (t, J=7.4
Hz, 3H), 0.85 (m, 2H), 0.64 (m, 2H).
Example 247
##STR00657##
[1101]
5-cyclopropyl-2-fluoro-4-((1-(3-fluoro-4-(trifluoromethyl)piperidin-
)piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[1102] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.77 min, m/z: 547.2 [M+1].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.78 (m, 1H), 7.45 (m, 2H),
7.17 (d, J=8.4 Hz, 1H), 6.88 (d, J=12.9 Hz, 1H), 3.94 (d, J=5.9 Hz,
2H), 3.74 (s, 2H), 3.19 (s, 3H), 2.95 (m, 2H), 2.23 (m, 2H), 2.02
(m, 1H), 1.84 (m, 3H), 1.43 (m, 2H), 0.88 (m, 2H), 0.65 (m,
2H).
Example 248
##STR00658##
[1103]
(S)-5-cyclopropyl-2-fluoro-4-((4-1-(1-(4-(trifluoromethoxy)phenyl)e-
thyl)piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[1104] The compound was synthesized as described in Example 170.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-2-fluoro-4-((4-methyl-1-(1-(4-(trifluoromethoxy)phenyl)-
ethyl)piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide. Chiral
HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=80:20; flow: 2.4
mL/min; column temperature: 40.1.degree. C.; RT=4.93 min).
LCMS(ESI) Method A: RT=5.98 min, m/z: 573.3 [M+1].sup.+. .sup.1H
NMR (b 400 MHz, DMSO-d.sub.6) .delta. 7.52 (d, J=8.1 Hz, 2H), 7.37
(d, J=8.1 Hz, 2H), 7.21 (d, J=5 Hz, 1H), 6.80 (d, J=12.8 Hz, 1H),
3.79 (brs, 2H), 3.30 (m, 1H), 3.04 (s, 3H), 2.61 (m, 1H), 2.49 (S,
3H), 1.99 (m, 1H), 1.70 (m, 2H), 1.46 (m, 5H), 1.04 (s, 3H), 0.87
(m, 2H), 0.59 (m, 2H).
Example 249
##STR00659##
[1105]
(R)-5-cyclopropyl-2-fluoro-4-((4-methyl-1-(1-(4-(trifluoromethoxy)p-
henyl)ethyl)piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[1106] The compound was synthesized as described in Example 170.
The enantiomer was separated by chiral SFC from the racemate, the
first eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-2-fluoro-4-((4-methyl-1-(1-(4-(trifluoromethoxy)
phenyl)ethyl)piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=80:20; flow: 2.4
mL/min; column temperature; 39.9.degree. C.; RT=2.52 min).
LCMS(ESI) Method A: RT=5.95 min, m/z: 573.3 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.52 (m, 2H), 7.37 (m, 2H),
7.21 (d, J=8.5 Hz, 1H), 6.80 (d, J=12.8 Hz, 1H), 3.79 (brs, 2H),
3.31 (m, 1H), 3.04 (s, 3H), 2.61 (m, 1H), 2.49 (s, 3H), 1.99 (m,
1H), 1.70 (m, 2H), 1.46 (m, 5H), 1.04 (s, 3H), 0.87 (m, 2H), 0.59
(m, 2H).
##STR00660##
Example 250
(R)-5-cyclopropyl-2-fluoro-4-((1-(1-(3-fluorophenyl)ethyl-4-methylpiperidi-
n-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[1107] The compound was synthesized as described in Example 170.
The enantiomer was separated by chiral SFC from the racemate, the
first eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-2-fluoro-4-((1-(1-(3-fluorophenyl)
ethyl-4-methylpiperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: OJ-H, 4.6.times.250 min, 5 .mu.m; Phase: A:
supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=80:20; flow: 2.4
mL/min; column temperature: 38.8.degree. C.; RT=4.89 min).
LCMS(ESI) Method A: RT =5.42 min, m/z: 507.3 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.43 (m, 1H), 7.29 (m, 2H),
7.23 (d, J =8.6 Hz, 1H), 7.16 (m, 1H), 6.80 (d, J=12.8 Hz, 1H),
3.95 (m, 1H), 3.79 (s, 2H), 3.03 (s, 3H), 2.91 (m, 1H), 2.70 (m,
2H), 2.59 (m, 1H), 2.03 (m, 1H), 1.76 (m, 2H), 1.50 (m, 5H), 1.05
(s, 3H), 0.88 (m, 2H), 0.60 (m, 2H).
Example 251
##STR00661##
[1108]
(S)-5-cyclopropyl-2-fluoro-4-((1-(1-(3-fluorophenyl)ethyl-4-methylp-
iperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
[1109] The compound was synthesized as described in Example 170.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-2-fluoro-4-((1-(1-(3-fluorophenyl)
ethyl-4-methylpiperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=80:20; flow: 2.4
mL/min; column temperature: 40.6.degree. C.; RT=6.92 min).
LCMS(ESI) Method A: RT =5.42 min, m/z: 507.3 [M+H].sup.+. .sup.1H
NMR (400 DMSO-d.sub.6), .delta. 7.43 (m, 1H), 7.29 (m, 2H), 7.23
(d, J =8.6 Hz, 1H), 7.16 (m, 1H), 6.80 (d, J=12.8 Hz, 1H), 3.95 (m,
1H), 3.79 (s, 2H), 3.03 (s, 3H), 2.91 (m, 1H), 2.70 (m, 2H), 2.59
(m, 1H), 2.03 (m, 1H), 1.76 (m, 2H), 1.50 (m, 5H), 1.05 (s, 3H),
0.85 (m, 2H), 0.60 (m, 2H).
##STR00662##
Example 252
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((1-(trifluoromethyl)cyclo-
propyl)methyl)piperidin-4-yl)methoxy)benzamide
[1110] The compound was synthesized as described in Example 88.
LCMS(ESI) Method B: RT=5.42 min, m/z: 492.9 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6), .delta. 7.16 (d, J=8.4 Hz, 1H), 6.90
(d, J=12.9 Hz, 1H), 3.94 (d, J=5.8 Hz, 2H), 3.24 (s, 3H), 3.01 (m,
2H), 2.59 (s, 2H), 2.03 (m, 3H), 1.79 (m, 3H), 1.37 (m, 2H), 0.99
(m, 2H), 0.88 (m, 2H), 0.76 (m, 2H), 0.66 (m, 2H).
Example 253
##STR00663##
[1111]
5-Cyclopropyl-4-((1-((3,5-dichlorobenzoyl)piperidin-4-yl)methoxy)-2-
-fluoro-N-(methylsulfonyl)benzamide
[1112] The compound was synthesized as described in Example 134.
LCMS(ESI) Method A: RT=4.92 min, m/z 542.8 [M+H].sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.71 (s, 1H), 7.45 (s, 2H), 7.15
(d, J=8.5 Hz, 1H), 6.92 (d, J=13.0 Hz, 1H), 4.49-4.47 (m, 1H), 3.97
(d, J=4.5 Hz, 2H), 3.53-3.50 (m, 1H), 3.26 (s, 3H), 3.15-3.12 (m,
1H), 2.85-2.84 (m, 1H), 2.14-2.10 (m, 1H), 2.05-1.99 (m, 1H),
1.89-1.88 (m, 1H), 1.78-1.75 (m, 1H), 1.35-1.32 (m, 2H), 0.89-0.88
(m, 2H), 0.66-0.65 (m, 2H).
##STR00664##
Example 254
5-Cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(3,5-dichlorobenzoyl)piperidin-
-4-yl)methoxy)-2-fluorobenzamide
[1113] The compound was synthesized as described in Example 134.
LCMS(ESI) Method A: RT=5.28 min, m/z: 569.0 [M+H].sup.+. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 11.80 (s, 1H), 7.71 (s, 1H),
7.40 (m, 2H), 7.16 (d, J =8.0 Hz, 1H), 6.92 (d, J=12.1 Hz, 1H),
4.47 (m, 1H), 3.97 (s, 2H), 3.51 (m, 1H), 3.08 (m, 2H), 2.84 (m,
1H), 2.07 (m, 2H), 1.82 (m, 2H), 1.34 (m, 2H), 1.01 (m, 4H), 0.89
(m, 2H), 0.62 (m, 2H).
Example 255
##STR00665##
[1114]
5-Cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(2-(trifluoromethyl-
)benzoyl)piperidin-4-yl)methoxy)benzamide
[1115] The compound was synthesized as described in Example 134.
LCMS(ESI) Method A: RT=4.54 min, m/z: 542.9 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d.sub.4) .delta. 7.82 (d, J=7.9 Hz, 1H), 7.75
(m, 1H), 7.67 (d, J=7.4 Hz, 1H), 7.46 (m, 1H), 7.31 (m, 1H), 6.82
(m, 1H), 4.77 1(m, 1H), 4.01 (d, J=5.2 Hz, 2H), 3.43 (m, 1H), 3.33
(s, 3H), 3.17 (m, 1H), 2.96 (m, 1H), 2.20 (m, 1H), 2.07 (m, 2H),
1.81 (m, 1H), 1.42 (m, 2H), 0.94 (m, 2H), 0.66 (m, 2H).
Example 256
##STR00666##
[1116]
5-Cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(2-(trifluorom-
ethyl)benzoyl)piperidin-4-yl)methoxy)benzamide
[1117] The compound was synthesized as described in Example 134.
LCMS(ESI) Method A: RT=4.69 min, m/z: 568.9 [M+H].sup.+. .sup.1H
NMR (500 MHz, MeOD-d.sub.4) .delta. 7.82 (m, 1H), 7.76 (m, 1H),
7.67 (m, 1H), 7.46 (m, 1H), 7.30 (m, 1H), 6.82 (dd, J=12.8, 4.8 Hz,
1H), 4.77 (m, 1H), 4.01 (m, 2H), 3.43 (m, 1H), 3.17 (m, 2H), 2.96
(m, 1H), 2.20 (m, 1H), 2.02 (m, 2H), 1.81 (m, 1H), 1.47 (m, 2H),
1.29 (m, 2H), 1.13 (m, 2H), 0.92 (m, 2H), 0.66 (m, 2H).
Example 257
##STR00667##
[1118]
5-Cyclopropyl-4-((1-(2,4-dichlorobenzoyl)piperidin-4-yl)methoxy)-2--
fluoro-N-(methylsulfonyl)benzamide
[1119] The compound was synthesized as described in Example 134.
LCMS(ESI) Method A: RT=4.82 min, m/z 542.8 [M+H].sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.73-7.72 (m, 1H), 7.53-7.49 (m,
1H), 7.43-7.37 (m, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.91 (d, J=13.0 Hz,
1H), 4.57-4.52 (m, 1H), 3.99-3.95 (m, 2H), 3.30-3.28 (m, 1H), 2.25
(s, 3H), 3.13-3.03 (m, 1H), 2.85-2.82 (m, 1H), 2.13-1.97 (m, 2H),
1.92-1.89 (m, 1H), 1.75-1.72 (m, 1H), 1.43-1.25 (m, 2H), 0.89-0.85
(m, 2H), 0.67-0.63 (m, 2H).
Example 258
##STR00668##
[1120]
5-Cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(2,4-dichlorobenzoyl)pi-
peridin-4-yl)methoxy)-2-fluorobenzamide
[1121] The compound was synthesized as described in Example 134.
LCMS(ESI) Method A: RT=5.00 min, m/z 568.1 [M+H].sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.73 (s, 1H), 7.53-7.49 (m, 1H),
7.43-7.37 (m, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.94 (d, J=13.0 Hz, 1H),
4.57-4.52 (m, 1H), 3.99-3.96 (m, 2H), 3.13-3.04 (m, 2H), 2.87-2.83
(m, 1H), 2.12-1.89 (m, 3H), 1.75-1.72 (m, 1H), 1.42-1.23 (m, 3H),
1.10-1.06 (m, 4H), 0.89-0.86 (m, 2H), 0.69-0.63 (m, 2H).
##STR00669##
Example 259
5-Cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(3,5-dichlorobenzoyl)piperidin-
-4-yl)methoxy)-2-fluorobenzamide
[1122] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=6.21 min, m/z 555.0 [M+H].sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.52 (s, 1H), 7.39 (s, 2H), 7.14
(d, J=8.0 Hz, 1H), 6.89 (d, J=13.0 Hz, 1H), 3.94 (d, J=5.5 Hz, 2H),
3.62 (s, 2H), 3.05-2.90 (m, 1H), 2.91 (d, J=11.51 Hz, 2H), 2.16 (t,
J=11.3 Hz, 2H), 2.03-1.99 (m, 1H), 1.82-1.79 (m, 3H), 1.43-1.37(m,
2H), 1.05-0.99 (m, 4H), 0.90-0.86 (m, 2H), 0.65-0.52 (m, 2H).
##STR00670##
Example 260
N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidi-
n-4-yl)methoxy)-2-fluorobenzamide
[1123] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=6.47 min, m/z 570.0 [M+H].sup.+. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.52 (s, 1H), 7.39 (s, 2H), 7.15
(d, J=8.0 Hz, 1H), 6.90 (d, J =12.5 Hz, 1H), 3.98-3.94 (m, 6H),
3.60 (s, 2H), 2.90 (d, J=11.0 Hz, 2H), 2.15-2.11 (m, 4H), 2.03-2.01
(m, 1H), 1.82-1.79 (m, 3H), 1.43-1.37 (m, 2H), 0.90-0.87 (m, 2H),
0.66-0.64 (m, 2H).
Example 261
##STR00671##
[1124]
4-((1-(3-Chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)methoxy)--
5-cyclopropyl-N-(ethylsulfonyl)-2-fluorobenzamide
[1125] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=6.34 min, m/z 593.3 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.48 (s, 2H), 7.35 (s, 1H), 7.14
(d, J=8.4 Hz, 1H), 6.90 (d, J=12.8 Hz, 1H), 3.95 (d, J=6.0 Hz, 2H),
3.67 (s, 2H), 3.40-3.32 (m, 1H), 2.92 (d, J=10.4 Hz, 2H), 2.20-2.15
(m, 2H), 2.03-1.98 (m, 1H), 1.82-1.79 (m, 3H), 1.45-1.37 (m, 2H),
1.21 (t, J=74 Hz, 3H), 0.90-0.86 (m, 2H), 0.65-0.62 (m, 2H).
Example 262
##STR00672##
[1126]
(R)-4-((1-(1-(3-chlorophenyl)-2-methoxyethyl)piperidin-4-yl)methoxy-
)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[1127] The compound was synthesized as described in Example 172.
The enantiomer was separated by chiral SFC from the racemate, the
first eluting fraction was arbitrarily assigned as
(R)-4-((1-(1-(3-chlorophenyl)-2-methoxyethyl)
piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamid-
e. Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile
Phase: A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=75: 25;
flow: 3 mL/min; column temperature: 40.degree. C.; RT=3.05 min).
LCMS(ESI) Method A: RT=5.47 min, m/z 538.9 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 7.41-7.30 (m, 4H), 7.15 (d, J=8.4
Hz, 1H), 6.86 (d, J=12.8 Hz, 1H), 3.89 (d, J=5.6 Hz, 2H), 3.81-3.78
(m, 1H), 3.73-3.71 (m, 2H), 3.23 (s, 3H), 3.18 (s, 3H), 3.09-3.06
(m, 1H), 2.87-2.84 (m, 1H), 2.22-2.16 (m, 1H), 2.10-2.06 (m, 1H),
2.03-2.96 (m, 1H), 1.81-1.73 (m, 3H), 1.45-1.26 (m, 2), 0.89-0.84
(m, 2H), 0.65-0.61 (m, 2H).
Example 263
##STR00673##
[1128]
(S)-4-((1-(1-(3-chlorophenyl)-2-methoxyethyl)piperidin-4-yl)methoxy-
)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[1129] The compound was synthesized as described in Example 172.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-4-((1-(1-(3-chlorophenyl)-2-methoxyethyl)
piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamid-
e. Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile
Phase: A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=75: 25;
flow: 3 mL/min; column temperature: 40.degree. C.; RT=4.35 min).
LCMS(ESI) Method A: RT=5.46 min, m/z 539.0 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 7.41-7.30 (m, 4H), 7.15 (d, J=8.4
Hz, 1H), 6.86 (d, J =12.8 Hz, 1H), 3.89 (d, J=5.6 Hz, 2H),
3.81-3.78 (m, 1H), 3.73-3.71 (m, 2H), 3.23 (s, 3H), 3.18 (s, 3H),
3.09-3.06 1(m, 1H), 2.87-2.84 (m, 1H), 2.22-2.16 (m, 1H), 2.10-2.06
(m, 1H), 2.03-2.96 (m, 1H), 1.81-1.73 (m, 3H), 1.45-1.26 (m, 2H),
0.89-0.84 (m, 2H), 0.65-0.61 (m, 2
Example 264
##STR00674##
[1130]
(R)-5-cyclopropyl-4-((1-(1-(3,4-dichlorophenyl)-2-methoxyethyl)pipe-
ridin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1131] The compound was synthesized as described in Example 172.
The enantiomer was separated by chiral SFC from the racemate, the
first eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,4-dichlorophenyl)-2-methoxyethyl)
piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A: B=75: 25; flow: 3
mL/min; column temperature: 40.degree. C.; RT=3.71 min). LCMS(ESI)
Method A: RT=5.74 min, m/z 573.0 [M+H].sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): .delta. 7.60-7.58 (m, 2H), 7.32 (d, J=8.5 Hz, 1H),
7.15 (d, J=8.0 Hz, 1H), 6.83 (d, J=13.0 Hz, 1H), 3.89 (d, J=6 Hz,
2H), 3.74-3.68 (m, 3H), 3.22 (s, 3H), 3.15 (s, 3H), 3.01-3.00 (m,
1H), 2.82-2.78 (m, 1H), 2.14-2.09 (m, 1H), 2.02-1.96 (m, 2H),
1.79-1.71 (m, 3H), 1.38-1.28 (m, 1H), 0.88-0.85 (m, 2H), 0.63-0.60
(m, 2H).
##STR00675##
Example 265
(S)-5-cyclopropyl-4-((1-(1-(3,4-dichlorophenyl)-2-methoxyethyl)piperidin-4-
-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1132] The compound was synthesized as described in Example 172.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(3,4-dichlorophenyl)-2-methoxyethyl)
piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A: B=75: 25; flow: 3
mL/min; column temperature: 40.degree. C.; RT=5.12 min). LCMS(ESI)
Method A: RT=5.71 min, m/z 573.0 [M+H].sup.+. .sup.1H NMR (500
DMSO-d.sub.6): .delta. 7.60-7.58 (m, 2H), 7.32 (d, J=8.5 Hz, 1H),
7.15 (d, J=8.0 Hz, 1H), 6.83 (d, J=13.0 Hz, 4H), 3.89 (d, J=6 Hz,
2H), 3.74-3.68 (m, 3H), 3.22 (s, 3H), 3.15 (s, 3H), 3.01-3.00 (m,
1H), 2.82-2.78 (m, 1H), 2.14-2.09 (m, 1H), 2.02-1.96 (m, 2H),
1.79-1.71 (m, 3H), 1.38-1.28 (m, 2H), 0.88-0.85 (m, 2H), 0.63-0.60
(m, 2H).
Example 266
##STR00676##
[1133]
((R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)pip-
eridin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00677##
##STR00678##
[1134] Step 1
Methyl 2-bromo-2-(3,5-dichlorophenyl)acetate
[1135] A mixture of methyl 2-(3,5-dichlorophenyl)acetate (2.0 g,
9.11 mol), N-bromosuccinimide (6.5 g, 36.51 mmol) and
2,2'-azobis(2-methylpropionitrile) (600 mg, 3.64 mmol) in carbon
tetrachloride (50 mL) was stirred at 80.degree. C. for 16 h. The
reaction mixture was diluted with dichloromethane (200 mL) and
brine (50 mL). The organic layer was separated, washed with brine
(50 mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by silica gel chromatography
(eluting with 10% ethylacetate in petroleum ether) to afford the
target compound (2.5 g, 92%) as a pale yellow oil.
##STR00679##
Step 2
Methyl
2-(4-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)phenoxy)-
methyl)piperidin-1-yl)-2-(3,5-dichlorophenyl)acetate
[1136] The compound was synthesized as described in step 5 of
Example 88. LCMS(ESI) m/z: 587.2 [M+H].sup.+.
Step 3
##STR00680##
[1137]
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)pipe-
ridin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1138] A mixture of methyl
2-(4-((2-cyclopropyl-5-fluoro-4-(methysulfonylcarbamoyl)phenoxy)methyl)pi-
peridin-1-yl)-2-(3,5-dichlorophenyl) acetate (200 mg, 0.37 mmol)
and sodium borohydride (142 mg, 3.7 mmol) in MeOH (5 mL) was
stirred at 25.degree. C. for 2 h. The mixture was then
concentrated, diluted with water (20 mL) and extracted with DCM (20
mL.times.3). The combined organic layers were washed with brine (20
mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by reverse phase
chromatography (eluting with 30-40% MeCN in 0.1% NH.sub.4HCO.sub.3)
to afford the racemate (100 mg, 48.3%) as an white solid. The
enantiomer was separated by chiral SFC from the racemate, the first
eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)piperidin--
4-yl) methoxy)-2-fluoro-N-(methylsulfonyl)benzamide. Chiral HPLC
(column: OJ-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=80: 20; flow: 3
mL/min; column temperature: 40.degree. C.; RT=5.25 min). LCMS(ESI)
Method A: RT=5.28 min, m/z 559.0 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.52 (s, 1H), 7.42 (s, 2H), 7.15 (d, J=8.4
Hz, 1H), 6.85 (d, J=12.8 Hz, 1H), 4.77 (brs, 1H), 3.90 (d, J=5.6
Hz, 2H), 3.78 (s, 2H), 3.65-3.61 (m, 1H), 3.17-3.11 (m, 4H),
2.86-2.85 (m, 1H), 2.20-1.97 (m, 3H), 1.82-1.74 (m, 3H), 1.44-1.16
(m, 2H), 0.89-85 (m, 2H), 0.65-0.61 (m, 2H).
Example 267
##STR00681##
[1139]
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)pipe-
ridin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1140] The compound was synthesized as described in Example 266.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)
piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: OH-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOH (0.1% DEA), A: B=80:20; flow: 3
mL/min; column temperature: 40.degree. C.; RT=6.45 min). LCMS(ESI)
Method A: RT=5.35 min, m/z 559.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.52 (s, 1H), 7.42 (s, 2H), 7.15 (d, J=8.4
Hz, 1H), 6.85 (d, J=12.8 Hz, 1H), 4.77 (br, 1H), 3.90 (d, J=5.6 Hz,
2H), 3.78 (s, 2H), 3.65-3.61 (m, 1H), 3.17-3.11 (m, 4H), 2.86-2.85
(m, 1H), 2.20-1.97 (m, 3H), 1.82-1.74 (m, 3H), 1.44-1.16 (m, 2H),
0.89-85 (m, 2H), 0.65-0.61 (m, 2H).
Example 268
##STR00682##
[1141]
4-((1-(3-Chloro-5-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropy-
l-2-fluoro-N-(methylsulfonyl)benzamide
[1142] The compound was synthesized as described in Example 88.
LCMS(ESI) Method A: RT=5.75 min, m/z: 513.0 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 7.35-7.34 (m, 1H), 7.28-7.27
(m, 1H), 7.20-7.16 (m, 2H), 6.86-6.83 (m, 1H), 3.94-3.92 (d, J=5.0
Hz, 2H), 3.63 (s, 2H), 3.13 (s, 3H), 2.94-2.91 (m, 2H), 2.19-2.15
(m, 2H), 2.01 (m, 1H), 1.82-1.80 (m, 3H), 1.42-1.40 (m, 2H),
0.89-0.86(m, 2H), 0.64-0.62 (m, 2H).
##STR00683##
Example 269
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(1-(3,5-dichlorophenyl)eth-
yl)piperidin-4-yl)methoxy)-2-fluorobenzamide
##STR00684##
[1143] Step 1
##STR00685##
[1144] (R)-methyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)--
2-fluorobenzoate
[1145] The compound was synthesized as described in step 5 of
Example 88. The enantiomer was separated by chiral SFC from the
racemate, the enantiomer was arbitrarily assigned as (R)-methyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)
ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoate. Chiral HPLC
(column: AD-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOH (0.1% DEA), A:B=80:20; flow: 2.4
mL/min; column temperature: 39.9.degree. C.; RT=4.49 min).
LCMS(ESI) m/z: 480.1 [M+H].sup.+.
Step 2
##STR00686##
[1146]
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl-
)methoxy)-2-fluorobenzoic acid
[1147] The compound was synthesized as described in step 6 of
Example 88. LCMS(ESI) m/z: 460.0 [M+H].sup.+.
##STR00687##
Step 3
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(1-(3,5-dichlorophenyl)eth-
yl)piperidin-4-yl)methoxy)-2-fluorobenzamide
[1148] The compound was synthesized as described in step 5 of
Example 80. The enantiomer was arbitrarily assigned as
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(1-(3,5-dichlorophenyl)
ethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide. LCMS(ESI) Method
A: RT=6.52 min, m/z: 569.0 [M+H].sup.+. .sup.1H-NMR (500 MHz,
DMSO-d.sub.6): .delta. 7.52 (m, 1H), 7.41 (m, 2H), 7.15-7.13 (d,
J=5.0 Hz, 1H), 6.91-6.88 (d, J=13.0 Hz, 1H), 3.93-3.73 (m, 2H),
3.72-3.70 (m, 1H), 3.05-3.03 (m, 2H), 2.89-2.87 (m, 1H), 2.36-2.00
(m, 3H), 1.84-1.77 (m, 3H), 1.42-1.30 (m, 5H), 1.06-1.02 (m, 4H),
0.91-0.83 (m, 2H), 0.71-0.62 (m, 2H).
##STR00688##
Example 270
(S)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(1-(3,5-dichlorophenyl)eth-
yl)piperidin-4-yl)methoxy)-2-fluorobenzamide
[1149] The compound was synthesized as described in Example 269.
The enantiomer was arbitrarily assigned as
(S)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(1-(3,5-dichlorophenyl)
ethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide. LCMS(ESI) Method
A: RT=6.51 min, m/z: 569.0 [M+H].sup.+. .sup.1H-NMR (500 MHz,
DMSO-d.sub.6): .delta. 7.52 (m, 1H), 7.41 (m, 2H), 7.15-7.13 (d,
J=5.0 Hz, 1H), 6.90-6.88 (d, J=13.0 Hz, 1H), 3.93-3.73 (m, 2H),
3.72-371 (m, 1H), 3.05-3.03 (m, 2H), 2.89-2.87 (m, 1H), 2.21-1.98
(m, 3H), 1.84-1.77 (m, 3H), 1.42-1.30 (m, 5H), 1.29-0.98 (m, 4H),
0.91-0.83 (m, 2H), 0.71-0.62 (m, 2H).
Example 271
##STR00689##
[1150]
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(1-(3,5-dichlorop-
henyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide
[1151] The compound was synthesized as described in Example 269.
The enantiomer was arbitrarily assigned as
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)
ethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide. LCMS(ESI) Method
A: RT=6.66 min, m/z: 584.0 [M+H].sup.+. .sup.1H-NMR (500 MHz,
DMSO-d.sub.6): .delta. 7.49 (s, 1H), 7.39-7.38 (d, J=1.0 Hz, 2H),
7.19-7.17 (d, J=7.5 Hz, 1H), 6.86-6.83 (d, J=13.0 Hz, 1H),
3.91-3.90 (m, 6H), 3.64-3.63 (m, 1H), 2.98 (m, 1H), 2.84-2.82 (m,
1H), 2.11-1.98 (m, 5H), 1.82-1.75 (m, 3H), 1.36-1.31 (m, 5H),
0.88-0.86 (m, 2H), 0.63-0.62 (m, 2H).
##STR00690##
Example 272
(S)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)
ethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide
[1152] The compound was synthesized as described in Example 269.
The enantiomer was arbitrarily assigned as
(S)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)
ethyl)piperidin-4-yl)methoxy)-2-fluorobenzamide. LCMS(ESI) Method
A: RT=6.67 min, m/z: 584.0 [M+H].sup.+. .sup.1H-NMR (500 MHz,
DMSO-d.sub.6): .delta. 7.49 (s, 1H), 7.39-7.38 (d, J=1.0 Hz, 2H),
7.19-7.17 (d, J=7.5 Hz, 1H), 6.83-6.80 (d, J=13.0 Hz, 1H),
3.91-3.86 (m, 6H), 3.64-3.63 (m, 1H), 2.98 (m, 1H), 2.82-2.80 (m,
1H), 2.11-1.98 (m, 5H), 1.82-1.75 (m, 3H), 1.36-1.31 (m, 5H),
0.88-0.86 (m, 2H), 0.63-0.62 (m, 2H).
Example 273
##STR00691##
[1153]
5-Cyclopropyl-4-((1-((3,5-dichlorophenyl)sulfonyl)piperidin-4-yl)me-
thoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1154] The compound was synthesized as described in Example 129.
LCMS(ESI) Method A: RT=5.54 min, m/z: 579.0 [M+H].sup.+.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta.11.87 (brs, 1H), 8.13
(s, 1H), 8.04 (d, J=5.0 Hz, 2H), 7.14 (d, J=8.5 Hz, 1H), 6.90 (d,
J=10.0 Hz, 1H), 3.94 (d, J=5 Hz, 2H), 3.75-3.74 (m, 2H), 3.26-3.22
(m, 3H), 3.46-3.36 (m, 2H), 1.99-1.85 (m, 4H), 1.42-1.35 (m, 2H),
0.89-0.83 (m, 2H), 0.67-0.62 (m, 2H).
##STR00692##
Example 274
5-Cyclopropyl-4-((1-((3,5-dichlorophenyl)sulfonyl)azetidin-3-yl)methoxy)-2-
-fluoro-N-(methylsulfonyl)benzamide
[1155] The compound was synthesized as described in Example 129.
LCMS(ESI) Method A: RT=5.01 min, m/z: 551.0 [M+H].sup.+.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta.11.90 (brs, 1H), 8.09
(s, 1H), 7.84-7.83 (d, J=1.5 Hz, 2H), 7.15-7.13 (d, J=8.5 Hz, 1H),
6.89-6.87 (d, J=13.0 Hz, 1H), 4.08-4.06 (m, 2H), 3.96-3.92 (m, 2H),
3.78-3.75 (m, 2H), 3.24 (s, 3H), 3.02-2.96 (m, 1H), 1.81-1.76 (m,
1H), 0.83-0.79 (m, 2H), 0.63-0.61 (m, 2H).
##STR00693##
Example 275
5-Cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-((3,5-dichlorophenyl)sulfonyl)-
piperidin-4-yl)methoxy)-2-fluorobenzamide
[1156] The compound was synthesized as described in Example 129.
LCMS(ESI) Method A: RT=5.68 min, m/z: 604.8 [M+H].sup.+.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta.8.05 (s, 1H), 7.76 (d,
J=2.5 Hz, 2H), 7.14-7.12 (d, J=8.5 Hz, 1H), 6.91-6.88 (d, J=13.0
Hz, 1H), 3.94-3.93 (d, J=5.0 Hz, 2H), 3.75-3.73 (m, 2H), 3.05-3.02
(m, 1H), 2.50-2.42 (m, 2H), 1.98-1.85 (m, 4H), 1.42-1.37 (m, 2H),
0.87-0.85 (m, 4H), 0.66-0.64 (m, 2H), 0.62-0.56 (m, 2H).
Example 276
##STR00694##
[1157]
(R)-4-((1-(1-(3-chloro-5-(trifluoromethyl)phenyl)etnyl)piperidin-4--
yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[1158] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the first
eluting fraction was arbitrarily assigned as
(R)-4-((1-(1-(3-chloro-5-(trifluoromethyl)
phenyl)ethyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulf-
onyl)benzamide. Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5
.mu.m; mobile Phase: A: supercritical CO.sub.2, B: MeOD (0.1% DEA),
A:B=80:20; flow: 2.4 mL/min; column temperature: 40.1.degree. C.;
RT=5.80 min). LCMS(ESI) Method A: RT=6.43 min, m/z: 577.0
[M+H].sup.+. .sup.1H-NMR (400 MHz, MeOD-d.sub.4): .delta. 7.80 (s,
1H), 7.73 (s, 2H), 7.34-7.32 (m, 1H), 6.67-6.64 (d, J=12.8 Hz, 1H),
4.05-4.03 (m, 1H), 3.86-3.85 (m, 2H), 3.44-3.42 (m, 1H), 3.21 (s,
3H), 3.11-3.08 (m, 1H), 2.49-2.44 (m, 2H), 2.05-1.93 (m, 4H),
1.66-1.54 (m, 5H), 0.91-0.87 (m, 2H), 0.83-0.80 (m, 2H).
##STR00695##
Example 277
(S)-4-((1-(1-(3-chloro-5-(trifluoromethyl)phenyl)ethyl)piperidin-4-yl)meth-
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[1159] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-4-((1-(1-(3-chloro-5-(trifluoromethyl)
phenyl)ethyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulf-
onyl)benzamide. Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5
.mu.m; mobile Phase: A: supercritical CO.sub.2, B: MeOD (0.1% DEA),
A:B=80:20; flow: 2.4 mL/min; column temperature: 40.1.degree. C.;
RT=7.02 min). LCMS(ESI) Method A: RT=6.42 min, m/z: 577.0
[M+H].sup.+. .sup.1H-NMR (400 MHz, MeOD-d.sub.4): .delta. 7.79 (s,
1H), 7.74 (s, 2H), 7.34-7.32 (m, 1H), 6.71-6.65 (m, 1H), 4.11-4.05
(m, 1H), 3.88-3.83 (m, 2H), 3.46-3.45 (m, 1H), 3.23 (s, 3H),
3.15-3.11 (m, 1H), 2.51-2.48 (m, 2H), 2.04-1.93 (m, 4H), 1.69-1.51
(m, 5H), 0.91-0.86 (m, 2H), 0.73-0.68 (m, 2H).
##STR00696##
Example 278
(R)-4-((1-(1-(3-chloro-5-(trifluoromethyl)phenyl)ethyl)-4-methylpiperidin--
4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[1160] The compound was synthesized as described in Example 170.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-4-((1-(1-(3-chloro-5-(trifluoromethyl)phenyl)
ethyl)-4-methylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsu-
lfonyl)benzamide. Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5
.mu.m; mobile Phase: A: supercritical MeOD (0.1% DEA), A:B=80:20;
flow: 2.4 mL/min; column temperature: 40.0.degree. C.; RT=5.35
min). LCMS(ESI) Method A: RT=6.42 min, m/z: 591.2 [M+H].sup.+.
.sup.1H-NMR (400 MHz, MeOD-d.sub.4): .delta. 7.77-7.72 (m, 3H),
7.36-7.34 (d, J=8.8 Hz, 1H), 6.76-6.68 (m, 1H), 4.00-3.95 (m, 1H),
3.81-3.78 (s, 2H), 3.23-3.22 (s, 3H), 3.10-3.02 (m, 1H), 2.78-2.67
(m, 3H), 2.08-2.02 (m, 1H), 1.94-1.84 (m, 2H), 1.68-1.55 (m, 5H),
1.16 (s, 3H), 0.92-0.88 (m, 2H), 0.67-0.63 (m, 2H).
##STR00697##
Example 279
(S)-4-((1-(1-(3-chloro-5-(trifluoromethyl)phenyl)ethyl)-4-methylpiperidin--
4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[1161] The compound was synthesized as described in Example 170.
The enantiomer was separated by chiral SFC from the racemate, the
first eluting fraction was arbitrarily assigned as
(S)-4-((1-(1-(3-chloro-5-(trifluoromethyl)phenyl)ethyl)-4-methylpiperidin-
-4-yl) methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: AD-H, 4.6.times.250 min, 5 .mu.m; mobile
Phase: A: supercritical CO.sub.2, B: MeOD (0.1% DEA), A:B=80:20;
flow: 2.4 mL/min; column temperature: 40.0.degree. C.; RT=4.69
min). LCMS(ESI) Method A: RT=6.42 min, m/z: 591.3 [M+H].sup.+.
.sup.1H-NMR (400 MHz, MeOD-d.sub.4): .delta. 7.79-7.72 (m, 3H),
7.36-7.34 (d, J=8.8 Hz, 1H), 6.76-6.68 (m, 1H), 4.00-3.95 (m, 1H),
3.81-3.78 (s, 2H), 3.23-3.22 (s, 3H), 3.07-3.05 (m, 1H), 2.78-2.67
(m, 3H), 2.08-2.02 (m, 1H), 1.94-1.84 (m, 2H), 1.69-1.53 (m, 5H),
1.16 (s, 3H), 0.92-0.88 (m, 2H), 0.67-0.63 (m, 2H)
Example 280
##STR00698##
[1162]
(S)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)ethyl)-4-methylpiper-
idin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1163] The compound was synthesized as described in Example 170.
The enantiomer was separated by chiral SFC from the racemate, the
first eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)
ethyl)-4-methylpiperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzami-
de. Chiral HPLC (column: AD-H, 4.6.times.250 mm, 5 .mu.m; mobile
Phase: A: supercritical CO.sub.2, B: MeOD (0.1% DEA), A:B=70:30;
flow: 2.4 mL/min; column temperature: 39.9.degree. C.; RT=3.89
min). LCMS(ESI) Method A: RT=6.46 min, m/z: 557.2 [M+H].sup.+.
.sup.1H-NMR (400 MHz, MeOD-d.sub.4): .delta. 7.68-7.66 (d, J=11.5
Hz, 1H), 7.57-7.56 (d, J=2.5 Hz, 1H), 7.46-7.42 (m, 1H), 7.38-7.36
(d, J=8.5 Hz, 1H), 6.75-6.72 (d, H=13.0 Hz, 1H), 4.47-4.46 (m, 1H),
3.82 (s, 2H), 3.20-3.17 (m, 4H), 2.90-2.79 (m, 3H), 2.06-2.04 (m,
1H), 1.94-1.88 (m, 2H), 1.66 (s, 2H), 1.54-1.53 (d, J=7.0 Hz, 3H),
1.18 (s, 3H), 0.93-0.89 (m, 2H), 0.67-0.63 (m, 2H).
##STR00699##
Example 281
(R)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)ethyl)-4-methylpiperidin-4--
yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1164] The compound was synthesized as described in Example 170.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)
ethyl)-4-methylpiperidin-4-yl)methoxy)-2-fluoro-N-(methyl)sulfonyl)benzam-
ide. Chiral HPLC (column: AD-H, 4.6.times.250 min, 5 .mu.m; mobile
Phase: A: supercritical CO.sub.2, B: MeOD (0.1% DEA), A:B=70:30;
flow: 2.4 mL/min; column temperature: 39.9.degree. C.; RT=5.67
min). LCMS(ESI) Method A: RT=6.40 min, m/z: 557.2 [M+H].sup.+.
.sup.1H-NMR (400 MHz, MeOD-d.sub.4): .delta. 7.70-7.68 (d, J=11.5
Hz, 1H), 7.57-7.56 (d, J=2.5 Hz, 1H), 7.47-7.45 (m, 1H), 7.36-7.34
(d, J=8.5 Hz, 1H), 6.72-6.69 (d, J=13.0 Hz, 1H), 4.47-4.46 (m, 1H),
3.82 (s, 2H), 3.20-3.17 (m, 4H), 2.88-2.82 (m, 3H), 2.06-2.04 (m,
1H), 1.96-1.85 (m, 2H), 1.66 (s, 2H), 1.54-1.53 (d, J=7.0 Hz, 3H),
1.18 (s, 3H), 0.93-0.89 (m, 2H), 0.67-0.63 (m, 2H).
Example 282
##STR00700##
[1165]
(S)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)-2-methoxyethyl)pipe-
ridin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1166] The compound was synthesized as described in Example 172.
The enantiomer was separated by chiral SFC from the racemate, the
first eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)-2-methoxyethyl)
piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: AS-H, 4.0.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical B: MeOD (0.1% DEA), A:B=75:25; flow: 2.25 mL/min;
column temperature: 40.3.degree. C.; RT=2.95 min). LCMS(ESI) Method
A: RT=6.00 min, m/z: 573.1 [M+H].sup.+. .sup.1H-NMR (400 MHz,
MeOD-d.sub.4): .delta.7.69-7.66 (m, 1H), 7.55-7.54 (d, J=2.0 Hz,
1H), 7.41-7.39 (m, 1H), 7.33-7.31 (d, J=8.4 Hz, 1H), 6.75-6.71 (m,
1H), 4.41 (m, 1H), 3.94-3.92 (m, 2H), 3.77 (s, 2H), 3.43-3.32 (m,
4H), 3.24 (s, 3H), 2.98 (m, 1H), 2.55-2.41 (m, 2H), 2.08-1.80 (m,
4H), 1.67-1.51 (m, 2H), 0.93-0.89 (m, 2H), 0.66-0.64 (d, J=4.8 Hz,
2H).
##STR00701##
Example 283
(R)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)-2-methoxyethyl)piperidin-4-
-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
[1167] The compound was synthesized as described in Example 172.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)-2-methoxyethyl)
piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: AS-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOD (0.1% DEA), A:B=75:25; flow:
2.25 mL/min; column temperature: 40.3.degree. C.; RT=3.85 min).
LCMS(ESI) Method A: RT=6.01 min, m/z: 573.1 [M+H].sup.+.
.sup.1H-NMR (400 MHz, MeOD-d.sub.4): .delta.7.69-7.66 (m, 1H),
7.55-7.54 (d, J=2.0 Hz, 1H), 7.41-7.39 (m, 1H), 7.33-7.31 (d, J=8.4
Hz, 1H), 6.75-6.71 (m, 1H), 4.21 (m, 1H), 3.81-3.78(m, 2H), 3.77
(s, 2H), 3.43-3.32 (m, 4H), (s, 3H), 2.98 (m, 1H), 2.55-2.41 (m,
2H), 2.08-1.86 (m, 4H), 1.67-1.51 (m, 2H), 0.93-0.89 (m, 2H),
0.66-0.64 (m, 2H).
Example 284
##STR00702##
[1168]
(R)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)ethyl)piperidin-4-yl-
)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[1169] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)-2-methoxyethyl)
piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide.
Chiral HPLC (column: AS-H, 4.6.times.250 mm, 5 .mu.m, mobile Phase:
A: supercritical CO.sub.2, B: MeOD (0.1% DEA), A:B=75:25; flow:
2.25 mL/min; column temperature: 37.7.degree. C.; RT=4.46 min).
LCMS(ESI) Method A: RT=6.28 min, m/z: 557.1 [M+H].sup.+.
.sup.1H-NMR (400 MHz, MeOD-d.sub.4): .delta.7.69-7.64 (m, 1H),
7.55-7.54 (m, 1H), 7.44-7.42 (d, J=8.4 Hz, 1H), 7.31-7.29 (d, J=8.4
Hz, 1H), 6.73-6.70 (d, J=12.8 Hz, 1H), 4.36-4.35 (m, 1H), 3.92-3.86
(m, 2H), 3.53-3.50 (m, 1H), 3.34-3.32 (m, 2H), 3.06-3.03 (m, 1H),
2.49-2.41 (m, 2H), 2.08-1.89 (m, 4H), 1.68-1.65 (m, 1H), 1.54-1.49
(m, 4H), 1.38-1.33 (s, 3H), 0.93-0.82 (m, 2H), 0.61-0.59 (m,
2H).
##STR00703##
Example 285
(S)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)ethyl)piperidin-4-yl)methox-
y)-N-(ethylsulfonyl)-2-fluorobenzamide
[1170] The compound was synthesized as described in Example 88. The
enantiomer was separated by chiral SFC from the racemate, the first
eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)
ethyl)piperidin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide.
Chiral HPLC (column: AS-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase:
A: supercritical CO.sub.2, B: MeOD (0.1% DEA), A:B=75:25; flow:
2.25 mL/min; column temperature: 37.7.degree. C.; RT=2.99 min).
LCMS(ESI) Method A: RT=6.29 min, m/z: 557.2 [M+H].sup.+.
.sup.1H-NMR (400 MHz, MeOD-d.sub.4): .delta.7.71-7.65 (m, 1H),
7.56-7.55 (m, 1H), 7.46-7.42 (d, J=8.4 Hz, 1H), 7.31-7.30 (d, J=8.4
Hz, 1H), 6.73-6.70 (d, J=12.8 Hz, 1H), 4.49 (m, 1H), 3.89-3.86 (m,
2H), 3.58-3.55 (m, 1H), 3.34-3.32 (m, 2H), 3.06-3.03 (m, 1H),
2.49-2.41 (m, 2H), 2.08-1.89 (m, 4H), 1.68-165 (m, 1H), 1.54-1.49
(m, 4H), 1.38-1.33 (s, 3H), 0.93-0.82 (m, 2H), 0.61-0.59 (m,
2H).
Example 286
##STR00704##
[1171]
(S)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)-2-methoxyethyl)pipe-
ridin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[1172] The compound was synthesized as described in Example 172.
The enantiomer was separated by chiral SFC from the racemate, the
first eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)-2-methoxyethyl)
piperidin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide. Chiral
HPLC (column: AS-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOD (0.1% DEA), A:B=75:25; flow: 2.25
mL/min; column temperature: 40..degree. C.; RT=2.87 min). LCMS(ESI)
Method A: RT=6.10 min, m/z: 587.0 [M+H].sup.+. .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta.7.58-7.54 (m, 2H), 7.43-7.40 (m, 1H),
7.16-7.13 (d, J=10.5 Hz, 1H), 6.86-6.83 (d, J=12.8 Hz, 1H),
4.05-4.02 (m, 1H), 3.90-3.88 (m, 2H), 3.68-3.58 (m, 2H), 3.29-3.28
(m, 2H), 3.19 (s, 3H), 3.10-3.08 (m, 1H), 2.73-2.69 (m, 1H),
2.19-2.13 (m, 1H), 2.03-1.97 (m, 2H), 1.81-1.67 (m, 3H), 1.35-1.18
(m, 5H), 0.95-0.82 (m, 2H), 0.72-0.61 (m, 2H).
Example 287
##STR00705##
[1173]
(R)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)-2-methoxyethyl)pipe-
ridin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[1174] The compound was synthesized as described in Example 172.
The enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(2,4-dichlorophenyl)-2-methoxyethyl)
piperidin-4-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide. Chiral
HPLC (column: AS-H, 4.6.times.250 mm, 5 .mu.m; mobile Phase: A:
supercritical CO.sub.2, B: MeOD (0.1% DEA), A:B=75:25; flow: 2.25
mL/min; column temperature: 40.5.degree. C.; RT=3.66 min).
LCMS(ESI) Method A: RT=6.10 min, m/z: 587.0 [M+H].sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.7.58-7.54 (m, 2H),
7.43-7.40 (m, 1H), 7.16-7.14(d, J=10.5 Hz, 1H), 6.86-6.82 (d,
J=12.8 Hz, 1H), 4.05-4.02 (m, 1H), 3.90-3.88 (m, 2H), 3.67-3.58 (m,
2H), 3.30-3.28 (m, 2H), 3.19 (s, 3H), 3.10-3.08 (m, 1H), 2.71-2.69
(m, 1H), 2.18-2.13 (m, 1H), 2.03-1.97 (m, 2H), 1.81-1.67 (m, 3H),
1.35-1.18 (m, 5H), 0.89-0.81 (m, 2H), 0.61-0.59 (m, 2H).
##STR00706##
Example 288
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-3-methylazetidin-3-y-
l)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[1175] The compound was synthesized as described in Example 68. The
enantiomer was separated by chiral SFC from the racemate, the first
eluting fraction was arbitrarily assigned as
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)
ethyl)-3-methylazetidin-3-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide-
. Chiral HPLC (column: IC, 4.6.times.150 mm, 4.6.times.250 mm, 5
.mu.m; mobile Phase: A: supercritical CO.sub.2, B: MeOD (0.1% DEA),
A:B=65:35; flow: 1.95 mL/min; column temperature: 39.9.degree. C.;
RT=2.73 min). LCMS(ESI) Method A: RT=6.04 min, m/z: 543.1
[M+H].sup.+. .sup.1H-NMR (400 MHz, MeOD-d.sub.4): .delta.7.42-7.33
(m, 4H), 6.83-6.76 (m, 1H), 4.10-4.04 (m, 2H), 3.81 (m, 1H),
3.64-3.45 (m, 2H), 3.43-3.36 (m, 2H), 3.36-3.35 (m, 1H), 3.12-3.22
(m, 1H), 2.09-2.06 (m, 1H), 1.47 (s, 3H), 1.39-1.30 (m, 6H),
0.94-0.92 (m, 2H), 0.70-0.65 (m, 2H).
##STR00707##
Example 289
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-3-methylazetidin-3-y-
l)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
[1176] The compound was synthesized as described in Example 68. The
enantiomer was separated by chiral SFC from the racemate, the
second eluting fraction was arbitrarily assigned as
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)
ethyl)-3-methylazetidin-3-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide-
. Chiral HPLC (column: IC, 4.6.times.150 mm, 4.6.times.250 mm, 5
.mu.m; mobile Phase: A: supercritical CO.sub.2, B: MeOD (0.1% DEA),
A:B=65:35; flow: 1.95 mL/min; column temperature: 39.9.degree. C.;
3.22 min). LCMS(ESI) Method A: RT=6.04 min, m/z: 543.1 [M+H].sup.+.
.sup.1H-NMR (400 MHz, MeOD-d.sub.4): .delta.57.40-7.33 (m, 4H),
6.84-6.76 (m, 1H), 4.10-4.04 (m, 2H), 3.72 (m, 1H), 3.55-3.43 (m,
2H), 3.45-3.33 (m, 2H), 3.36-3.35 (m, 1H), 3.12-3.22 (m, 1H),
2.09-2.06 (m, 1H), 1.47 (s, 3H), 1.39-1.30 (m, 6H), 0.94-0.92 (m,
2H), 0.71-0.65 (m, 2H).
##STR00708##
Example 290
5-Cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-phenylpiperidin-4-yl)-
methoxy)benzamide
[1177] The compound was synthesized as described in Example 79.
LCMS(ESI) Method A: RT=5.51 min, m/z: 473.1 [M+H].sup.+.
.sup.1H-NMR (500 DMSO-d.sub.6): .delta.7.27-7.23 (m, 1H), 7.25-7.23
(d, J=7 Hz, 2H), 7.04-7.03 (d, J=8.0 Hz, 2H), 6.87-6.84 (m, 1H),
6.78-6.75 (d, J=12.5 Hz, 1H), 4.00-3.99 (d, J=6.0 Hz, 2H),
3.77-3.75 (m, 2H), 3.26 (s, 1H), 2.82-1.72 (m, 2H), 2.09-1.99 (m,
4H), 1.71-1.65 (m, 2H), 1.06-1.05 (m, 2H), 0.93-0.66 (m, 2H), 0.65
(m, 1H).
##STR00709##
Example 291
N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-phenylpiperidin-4-y-
l)methoxy)benzamide
[1178] The compound was synthesized as described in Example 79.
LCMS(ESI) Method A: RT=5.40 min, m/z: 488.0 [M+H].sup.+.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta.7.23-7.18 (m, 3H),
6.95-6.94 (m, 2H), 6.75-6.69 (m, 2H), 3.93-3.92 (d, J=6.0 Hz, 2H),
3.75-3.73 (m, 2H), 3.68-3.65 (m, 2.72-2.68 (m, 2H), 2.01-1.89 (m,
6H), 1.49-1.46 (m, 2H), 0.87-0.84 (m, 2H), 0.54-0.52 (m, 2H).
##STR00710##
Example 292
5-Cyclopropyl-4-((1-(3,5-dichlorophenyl)piperidin-4-yl)methoxy)-2-fluoro-N-
-(methylsulfonyl)benzamide
[1179] The compound was synthesized as described in Example 79.
LCMS(ESI) Method A: RT=6.07 min, m/z: 514.8 [M+H].sup.+.
.sup.1H-NMR (500 MHz, CDCl.sub.3-d.sub.4): .delta.7.20-7.19 (d,
J=8.5 Hz, , 1H), 6.93 (d, J=1.5 2H), 6.82-6.79 (m, 2H), 3.95-3.94
(d, J=6.5 Hz, 2H), 3.86-3.83 (m, 2H), 3.04 (s, 3H), 2.82 (m, 2H),
1.98 (m, 2H), 1.84-1.82 (m, 2H), 1.43 (m, 2H), 0.86-0.84 (m, 2H),
0.60-0.59 (m, 2H).
##STR00711##
Example 293
4-((1-(2-Chlorophenyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(me-
thylsulfonyl)benzamide
[1180] The compound was synthesized as described in Example 79.
LCMS(ESI) Method A: RT=5.53 min, m/z: 480.9 [M+H].sup.+.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta.7.41-7.39 (m, 1H),
7.39-7.27 (m, 1H), 7.21-7.16 (m, 2H), 7.04-7.01 (m, 1H), 6.85-6.82
(m, 1H), 4.00-3.99 (d, J=5.5 Hz, 2H), 3.32 (m, 2H), 3.05-3.01 (m,
3H), 2.71-2.54 (m, 2H), 2.05-1.90 (m, 4H), 1.58-1.50 (m, 2H),
0.91-0.89 (m, 2H), 0.62-0.61 (m, 2H).
##STR00712##
Example 294
4-((1-(3-Chlorophenyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(me-
thylsulfonyl)benzamide
[1181] The compound was synthesized as described in Example 79.
LCMS(ESI) Method A: RT=5.55 min, m/z: 480.9 [M+H].sup.+.
.sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta.7.20-7.17 (m, 2H),
6.94-6.90 (m, 3H), 6,74-6.72 (d, J=7.5 Hz 1H), 3.97-3.95 (d, J=6.5
Hz, 2H), 3.80-3.78 (m, 2H), 3.12-3.11 (s, 3H), 2.78-2.74 (m, 2H),
2.00-1.98 (m, 2H), 1.87-1.84 (m, 2H), 1.45-1.43 (m, 2H), 0.87-0.85
(m, 2H), 0.62-0.61 (m, 2H).
Example 295
Synthesis of
4-(((R)-1-((S)-1-(2-chloro-4-fluorophenyl)ethyl)piperidin-3-yl)oxy)-5-cyc-
lopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00713##
[1182] Step 1. Preparation of methyl
4-(((R)-1-((R)-1-(2-chloro-4-fluorophenyl)ethyl)
piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate and methyl
4-(((R)-1-(2-chloro-4-fluorophenyl)ethyl)piperidin-3-yl)oxy-5-cyclopropyl-
-2-fluorobenzoate
##STR00714##
[1184] Following the procedure as described in Example 50 step 1,
and making variations as required to replace
1,3-dichloro-5-(1-chloroethyl)benzene with
2-chloro-1-(1-chloroethyl)-4-fluorobenzene. The first eluting
fraction was arbitrarily assigned as methyl
4-(((R)-1-((S)-1-(2-chloro-4-fluorophenyl)ethyl)
piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate was obtained as
a colorless solid (0.17 g, 15%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.7.50-7.42 (m, 2H), 7.06 (dd, J=2.6 Hz, 8.6 Hz, 1H), 6.87
(dt, J=1.5 Hz, 8.4 Hz, 1H), 6.52 (d, J=12.9 Hz, 1H), 4.38-4.36 (m,
1H), 3.92 (q, J=6.6 Hz, 1H), 3.88 (s, 3H), 3.07-3.04 (m, 1H),
2.55-2.51 (m, 1H), 2.39-2.28 (m, 2H), 2.13-2.01 (m, 2H), 1.84-1.77
(m, 1H), 1.67-1.56 (m, 3H), 1.27 (d, J=6.5 Hz, 3H), 0.96-0.89 (m,
2H), 0.69-0.65 (m, 2H); MS(ES+) m/z 450, 452 (M+1).
[1185] The second eluting fraction was arbitrarily assigned as
methyl 4-(((R)-1-((R)-1-(2-chloro-4-fluorophenyl)
ethyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate as a
colorless solid (0.26 g, 22%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.7.56-7.51 (m, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.06-6.95 (m,
2H), 6.46(d, J=13.0 Hz, 1H), 4.32-4.26 (m, 1H), 3.94 (q, J=6.6 Hz,
1H), 3.86 (s, 3H), 2.96-2.89 (m, 2H), 2.39-1.83 (m, 6H), 1.68-1.45
(m, 2H), 1.27 (d, J=6.6 Hz, 3H), 0.90-0.84 (m, 2H), 0.64-0.59 (m,
2H); MS(ES+) m/z 450.2, 452.2 (M+1).
Step 2. Preparation of
4-(((R)-1-((S)-1-(2-chloro-4-fluorophenyl)ethyl)piperidin-3-yl)oxy)-5-cyc-
lopropyl-2-fluorobenzoic acid
##STR00715##
[1187] Following the procedure as described in Example 50 step 2,
and making variations as required to replace methyl
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)-
piperidin-3-yl)oxy)-2-fluorobenzoate with methyl
4-(((R)-1-((S)-1-(2-chloro-4-fluorophenyl)ethyl)piperidin-3-yl)oxy)-5-cyc-
lopropyl-2-fluorobenzoate, the title compound was obtained as a
colorless solid (0.04 g, 24%): MS(ES+) m/z 436.2, 438.2 (M+1);
MS(ES-) m/z 434.3, 436.3 (M-1).
Step 3. Preparation of 4-(((R)-1-((S)-1-(2-chloro-4-fluorophenyl)
ethyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzam-
ide
##STR00716##
[1189] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
4-(((R)-1-((S)-1-(2-chloro-4-fluorophenyl)ethyl)piperidin-3-yl)oxy)-5-cyc-
lopropyl-2-fluorobenzoic acid, the title compound was obtained as a
colorless solid (0.01. g, 32%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.85 (br s, 1H), 7.51 (dd, J=6.6 Hz, 8.6 Hz, 1H), 7.37
(dd, J=2.6 Hz, 8.9 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.05 (dt, J=2.6
Hz, 8.6 Hz, 1H), 6.92 (d, J=13.1 Hz, 1H), 4.56-4.55 (m, 1H),
3.91-3.89 (m, 1H), 3.32 (s, 3H), 2.78-2.74 (m, 2H), 2.47-2.42 (m,
2H), 2.15-2.06 (m, 1H), 1.87-1.77 (m, 2H), 1.59-1.46 (m, 2H), 1.23
(d, J=6.4 Hz, 3H), 0.93-0.90 (m, 2H), 0.70-0.67 (m, 2H); MS(ES+)
m/z: 513.2, 515.1 (M+1); MS(ES-) m/z 511.2, 513.2 (M-1).
Example 296
Synthesis of
4-(((R)-1-((R)-1-(2-chloro-4-fluorophenyl)ethyl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00717##
[1190] Step 1. Preparation of
4-(((R)-1-((R)-1-(2-chloro-4-fluorophenyl)ethyl)
piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00718##
[1192] Following the procedure as described in Example 50 step 2
and making variations as required to replace methyl
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-
3-yl)oxy)-2-fluorobenzoate with methyl
4-(((R)-1-((R)-1-(2-chloro-4-fluorophenyl)ethyl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained as a beige color solid (0.23 g, 99%): MS(ES+) m/z 436.2,
438.1 (M+1); MS(ES-) m/z 434.2, 436.2 (M-1).
Step 2. Preparation of
4-(((R)-1-((R)-1-(2-chloro-4-fluorophenyl)ethyl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00719##
[1194] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
4-(((R)-1-(R)-1-(2-chloro-4-fluorophenyl)ethyl)piperidin-3-yl)oxy)-5-cycl-
opropyl-2-fluorobenzoic acid, the title compound was obtained as a
colorless solid (0.17 g, 48%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.82 (br s, 1H), 7.61 (dd, J=6.5 Hz, 8.7 Hz, 1H), 7.38
(dd, J=2.4 Hz, 8.8 Hz, 1H), 7.22 (dt, J=2.6 Hz, 8.5 Hz, 1H), 7.09
(d, J=8.4 Hz, 1H), 6.91 (d, J=13.1 Hz, 1H), 4.55-4.50 (m, 1H), 3.92
(q, J=6.3 Hz, 1H), 3.32 (s, 3H), 2.77-2.74 (m, 2H), 2.36-2.19 (m,
2H), 2.08-1.94 (m, 2H), 1.81-1.75 (m, 1H), 1.59-1.46 (m, 2H), 1.23
(d, J=6.6 Hz, 3H), 0.89-0.85 (m, 2H), 0.70-0.65 (m, 2H); MS(ES+)
m/z 513.2, 515.1 (M+1); MS(ES-) m/z 511.2, 513.2 (M-1).
Example 297 and Example 298
Synthesis of
4-(((R)-1-((R)-1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)piperidin-
-3-yl) oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00720##
[1195] And
4-(((R)-1-((S)-1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl-
)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00721##
[1196] Step 1. Preparation of
1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl
trifluoromethanesulfonate
##STR00722##
[1198] To a solution of
1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethanol (1.14 g, 5.00
mmol) and 2,6-dimethylpyridine (0.86 g, 8.00 mmol) in cyclohexane
(10 mL) was added dropwise trifluoromethanesulfonic anhydride (2.12
g, 7.50 mmol) at 10.degree. C. The reaction mixture was stirred at
ambient temperature for 5 hours, and diluted with hexanes (200 mL).
The organic layer was washed with 1N aqueous hydrochloric acid
solution (30 mL), 25% aqueous ammonium chloride solution
(2.times.40 mL); dried over anhydrous sodium sulfate and
concentrated in vacuo to afford the title compound as a colorless
oil (1.30 g, 72%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.7.66-7.61 (m, 1H), 7.26-7.22 (m, 1H), 7.19-7.12 (m, 1H),
6.46 (q, J=5.6 Hz, 1H).
Step 2. Preparation of methyl 4-(((3R)-1-(1-(2
-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)
piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate
##STR00723##
[1200] To a mixture of (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate (1.07 g, 3.66
mmol) and potassium carbonate (0.69 g, 4.99 mmol) in cyclohexane
(10 mL) was added 1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl
trifluoromethanesulfonate (1.20 g, 3.33 mmol). The reaction mixture
was heated a 70.degree. C. for 72 hours, cooled to ambient
temperature and diluted with ethyl acetate (250 mL). The organic
layer was washed with 1N aqueous hydrochloric acid solution (30 mL)
and 25% aqueous ammonium chloride solution (2.times.40 mL); dried
over anhydrous sodium sulfate and concentrated in vacuo. The
residue was purified by column chromatography (0-25% ethyl acetate
in hexanes) afforded the title compound as a colorless oil (1.20 g,
71%): MS(ES+) m/z 504.1, 506.1 (M+1);
Step 3. Preparation of
4-(((3R)-1-(1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)
piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00724##
[1202] Following the procedure as described in Example 50 step 2
and making variations as required to replace methyl
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl-
piperidin-3-yl) oxy)-2-fluorobenzoate and methyl with methyl
4-(((3R)-1-(1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)
piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate, the title
compound was obtained as a colorless oil (0.98 g, 92%), .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta.7.53-7.43 (m, 2H), 7.25-7.21 (m,
0.5H), 7.17-7.13 (m, 0.5H), 7.03-6.95 (m, 1H), 6.47 (d, J=12.9 Hz,
0.5H) 6.37 (d, J=12.9 Hz, 0.5H), 4.76-4.66 (m, 1H), 4.38-4.31 (m,
0.5H), 4.27-4.20 (m, 0.5H), 3.14-3.10 (m, 1H), 2.94-2.84 (m, 1H),
2.75-2.60 (m, 2H), 2.05-1.96 (m, 2H), 1.91-1.80 (m, 1H), 1.70-1.52
(m, 2H), 0.91-0.85 (m, 2H), 0.70-0.57 (m, 2H); MS(ES+) m/z 490.2,
492.2 (M+1); MS(ES-) m/z 488.2, 490.2 (M-1).
Step 4. Preparation of
4-(((R)-1-((R)-1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)
piperidin-3-yl)oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00725##
[1203] And
4-(((R)-1-((S)-1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl- )
piperidin-3-yl)oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00726##
[1205] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
4-(((3R)-1-(1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)piperidin-3--
yl) oxy)-5-cyclopropyl-2-fluorobenzoic acid. The residue was
purified by preparative-HPLC, the first eluting fraction was
arbitrarily assigned as
4-(((R)-1-((R)-1-(2-chloro-4-fluorophenyl)-2,2,2trifluoroethyl)
piperidin-3-yl)oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
as a colorless solid (0.02 g, 4%): .sup.1H NMR (300 MHz, CDC3)
.delta.8.69 (d, J=16.0 Hz, 1H), 7.52-7.46 (m, 2H), 7.12 (dd, J=2.6
Hz, 8.4 Hz, 1H), 7.02-6.95 (m, 1H), 6.44 (d, J=14.6 Hz, 1H), 4.70
(q, J=8.8 Hz, 1H), 4.37-4.32 (m, 1H), 3.42 (s, 3H), 3.13-3.08 (m,
1H), 2.93-2.89 (m, 1H), 2.75-2.69 (m, 2H), 2.10-1.85 (m, 3H),
1.72-1.53 (m, 2H), 0.95-0.87 (m, 2H), 0.72-0.66 (m, 1H), 0.62-0.56
(m, 1H); MS(ES+) m/z 567.1,569.1 (M+1); MS(ES-) m/z 565.1, 567.1
(M-1).
[1206] The second eluting fraction was arbitrarily assigned as
4-(((R)-1-((S)-1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)
piperidin-3-yl)oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
as a colorless solid (0.01 g, 2%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.8.68 (d, J=16.0 Hz, 1H), 7.57-7.51 (m, 2H),
7.26-7.22 (m, 1H), 7.04-6.97 (m, 1H), 6.38 (d, J=14.6 Hz, 1H), 4.73
(q, J=8.8 Hz, 1H), 4.31-4.23 (m, 1H), 3.41 (s, 3H), 3.16-3.12 (m,
1H), 2.91-2.85 (m, 1H), 2.78-2.60 (m, 2H), 2.09-1.99 (m, 2H),
1.70-1.54 (m, 3H), 0.94-0.91 (m, 2H), 0.67-0.63 (m, 2H); MS(ES+)
m/z 567.1,569.1 (M+1); MS(ES-) m/z 565.1, 567.1 (M-1)
Example 299
Synthesis of
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)
piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00727##
[1207] Step 1. Preparation of
1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl
trifluoromethanesulfonate
##STR00728##
[1209] Following the procedure as described in Example 297 step 1,
and making variation as required to replace
1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethanol with
1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanol, the title compound
was obtained as a colorless oil (1.30 g, 72%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta.7.66-7.61 (m, 1H), 7.19-7.12 (m, 2H), 6.46
(q, J=5.6 Hz, 1H).
Step 2. Preparation of tert-butyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)
piperidin-4-yl)methoxy)-2-fluorobenzoate
##STR00729##
[1211] Following the procedure as described in Example 297 step 2,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
tert-butyl 5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
and to replace 1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl
trifluoromethanesulfonate with
1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl
trifluoromethanesulfonate, the title compound was obtained as a
colorless oil (1.20 g, 90%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.7.37-7.29 (m, 4H), 6.47 (d, J=12.6 Hz, 1H), 4.49-4.01 (m,
1H), 3.80 (d, J=5.9 Hz, 2H), 2.99-2.93 (m, 2H), 2.47-2.29 (m, 2H),
2.01-1.92 (m, 1H), 1.84-1.81 (m. 3H), 1.55 (s, 9H), 1.50-1.33 (m,
2H), 0.89-0.83 (m, 2H), 0.63-0.57 (m, 2H).
Step 3. Preparation of
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)
piperidin-4-yl)methoxy)-2-fluorobenzoic acid
##STR00730##
[1213] To a solution of tert-butyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)
piperidin-4-yl)methoxy)-2-fluorobenzoate (1.10 g, 1.91 mmol) in
dichloromethane (30 mL) was added trifluoroacetic acid (10 mL). The
resulting solution was stirred at ambient temperature for 1 hour
and then concentrated in vacuo to provide the title compound as a
gummy solid (1.0 g, 99%): MS(ES+) m/z 520.1, 522.1 (M+1); MS(ES-)
m/z 518.1, 520.1 (M-1).
Step 4. Preparation of
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)
piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00731##
[1215] Following the procedure as described in Example 3 step 5,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidi-
n-4-yl) methoxy)-2-fluorobenzoic acid, and to replace
cyclopropylsulfonamide with methanesulfonamide, the title compound
was obtained as a colorless solid (0.35 g, 50%), .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta.11.88 (br s, 1H), 7.72 (s, 1H), 7.45-7.44
(m, 2H), 7.12 (d, J=8.3 Hz, 1H), 6.93 (d, J=13.0 Hz, 1H), 4.77 (q,
J=9.3 Hz, 1H), 3.91 (d, J=5.7 Hz, 2H), 3.33 (s, 3H), 3.00-2.99 (m,
2H), 2.33-2.25 (m, 1H), 2.04-1.95 (m, 2H), 1.79-1.70 (m, 3H),
1.41-1.30 (m, 2H), 0.90-0.84 (m, 2H), 0.69-0.64 (m, 2H); MS(ES+)
m/z 597.1, 599.0 (M+1).
Example 300
Synthesis of
4-((1-(1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00732##
[1216] Step 1. Preparation of methyl
4-((1-(1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)
piperidin-4-yl)methoxy)-5-cyclopropyl-fluorobenzoate
##STR00733##
[1218] Following the procedure as described in Example 297 step 2,
and making variation as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
tert-butyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate, the title
compound was obtained as a colorless solid (0.80 g, 47%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta.7.59-7.54 (m, 1H), 7.43 (d, J=8.3
Hz, 1H), 7.20 (dd, 2.6 Hz, 8.4 Hz, 1H), 7.03 (d, J=2.6 Hz, 8.3 Hz,
1H), 6.51 (d, J=12.7 Hz, 1H), 4.69 (q, J=8.7 Hz, 1H), 3.87 (s, 3H),
3.81 (d, J=6.0 Hz, 2H), 3.13-3.09 (m, 1H), 3.00-2.96 (m, 1H), 2.52
(t, J=11.2 Hz, 1H), 2.30 (t, J=11.1 Hz, 1H), 2.03-1.94 (m, 1H),
1.83-1.77 (m, 3H), 1.48-1.31 (m, 2H), 0.90-1.85 (m, 2H), 0.65-0.59
(m, 2H); MS(ES+) m/z 518.1, 520.1 (M+1).
Step 2. Preparation of
4-((1-(1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)
piperidin-4-yl)methoxy-5-cyclopropyl-2-fluorobenzoic acid
##STR00734##
[1220] Following the procedure as described in Example 50 step 2
and making variations as required to replace methyl
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)o-
xy)-2-fluorobenzoate with methyl
4-((1-(1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained as a colorless solid (0.75 g, 96%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta.12.82 (s, 1H), 7.65-7.59 (m, 2H), 7.36-7.28
(m, 2H), 6.87 (d, J=13.1 Hz, 1H), 4.84 (q, J=9.1 Hz, 1H), 3.90 (d,
J=5.7 Hz, 2H), 3.07-2.95 (m, 2H), 2.49-2.40 (m, 1H), 2.20-2.13 (m,
1H), 2.02-1.93 (m, 1H), 1.77-1.74 (m, 3H), 1.33-1.27 (m, 2H),
0.93-0.83 (m, 2H), 0.59-0.54 (m, 2H); MS(ES+) m/z 504.1, 506.1
(M+1);
Step 3. Preparation of
4-((1-(1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)
piperidin-4-yl)methoxy-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00735##
[1222] Following the procedure as described in Example 3 step 5,
and making variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
4-((1-(1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace
cyclopropylsulfonamide with methanesulfonamide, the title compound
was obtained as a colorless solid (0.32 g, 56%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.88 (br s, 1H), 7.65-7.59 (m, 2H),
7.33 (dt, J=2.7 Hz, 8.5 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.93 (d,
J=13.0 Hz, 1H), 4.84 (q, J=9.0 Hz, 1H), 3.91 (d, J=5.6 Hz, 2H),
3.33 (s, 3H), 3.01 (dd, J=11.1 Hz, 27.2 Hz, 2H), 2.49-2.40 (m, 1H),
2.16 (t, J=10.9 Hz, 1H), 2.03-1.94 (m, 1H), 1.77-1.74 (m, 3H),
1.38-1.27 (m, 2H), 0.90-0.83 (m, 2H), 0.68-0.63 (m, 2H); MS(ES+)
m/z 581.2, 583.2 (M+1); MS(ES-) m/z 579.2, 581.2 (M-1).
Example 301
Synthesis of
4-((1-(1-(3-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00736##
[1223] Step 1. Preparation of
1-(3-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl
trifluoromethanesulfonate
##STR00737##
[1225] Following the procedure as described in Example 297 step 1,
and making variation as required to replace
1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethanol with
1-(3-chloro-4-fluorophenyl)-2,2,2-trifluoroethanol, the title
compound was obtained as a brown oil (4.60 g, 76%): .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta.7.58-7.55 (m, 1H), 7.42-7.37 (m, 1H),
7.29-7.24 (m, 1H), 5.78 (q, J=5.7 Hz, 1H).
Step 2. Preparation of tert-butyl
4-((1-(1-(3-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)
piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR00738##
[1227] Following the procedure as described in Example 297 step 2,
and making variation as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
tert-butyl 5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
and to replace 1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl
trifluoromethanesulfonate with
1-(3-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl
trifluoromethanesulfonate, the title compound was obtained as a
pale yellow oil (0.70 g, 54%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.7.47-7.44 (m, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.29-7.24 (m,
1H), 7.13 (t, J=8.6 Hz, 1H), 6.46 (d, J=12.6 Hz, 1H), 4.05 (q,
J=8.7 Hz, 1H), 3.79 (d, J=5.9 Hz, 2H), 2.98-2.95 (m, 2H), 2.41 (t,
J=11.2 Hz, 1H), 2.27 (t, J=11.4 Hz, 1H), 2.01-1.91 (m, 1H),
1.83-1.79 (m, 3H), 1.54 (m, 9H), 1.48-1.33 (m, 2H), 0.88-0.82 (m,
2H), 0.62-0.57 (m, 2H); MS(ES+) m/z 506.0, 508.0 (M+1).
Step 3. Preparation of
4-((1-(1-(3-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)
piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00739##
[1229] Following the procedure as described in Example 299 step 3,
and making variation as required to replace tert-butyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidi-
n-4-yl) methoxy)-2-fluorobenzoate with tert-butyl
4-((1-(1-(3-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)
piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate, the title
compound was obtained as a colorless solid (0.55 g, 87%): MS(ES+)
m/z 504.1, 506.0 (M+1); MS(ES-) m/z 502.1, 504.1 (M-1).
Step 4. Preparation of
4-((1-(1-(3,5-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00740##
[1231] Following the procedure as described in Example 3 step 5,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
4-((1-(1-(3-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace
cyclopropylsulfonamide with methanesulfonamide, the title compound
was obtained as a colorless solid (0.23 g, 39%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.88 (br s, 1H), 7.63-7.60 (m, 1H),
7.53-7.41 (m, 2H), 7.12 (d, J=8.3 Hz, 1H), 6.93 (d, J=13.0 Hz, 1H),
4.72 (q, J=9.4 Hz, 1H), 3.91 (d, J=5.9 Hz, 2H), 3.33 (s, 3H),
3.01-2.98 (m, 2H), 2.31-2.24 (m, 1H), 2.05-1.94 (m, 2H), 1.78-1.66
(m, 3H), 1.42-1.29 (m, 2H), 0.90-0.84 (m, 2H), 0.69-0.63 (m, 2H);
MS(ES+) m/z 581.1, 583.1 (M+1); MS(ES-) m/z 579.1, 581.0 (M-1).
Example 302
Synthesis of
5-cyclopropyl-4-(2-(1-(3,5-dichlorobenzyl)piperidin-4-yl)
ethoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR00741##
[1232] Step 1. Preparation of tert-butyl
4-(2-(4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)
ethyl)piperidine-1-carboxylate
##STR00742##
[1234] Following the procedure as described in Example 3 step 1,
and making variation as required to replace
(R)-tert-butyl-3-hydroxypiperidine-1-carboxylate with tert-butyl
4-(2-hydroxyethyl)piperidine-1-carboxylate, the title compound was
obtained as a colorless oil. (3.80 g, 95%): MS(ES+) m/z 458.2,
460.2 (M+1).
Step 2. Preparation of tert-butyl
4-(2-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenyl)ethyl)piperidi-
ne-1-carboxylate
##STR00743##
[1236] Following the procedure as described in Example 3 step 2,
and making variation as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)piperidine-
1-carboxylate with tert-butyl
4-(2-(4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)ethyl)piperidine-1-
-carboxylate, the title compound was obtained as a light yellow oil
(1.90 g, 95%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.34 (d,
J=8.4 Hz, 1H), 6.48 (d, J=12.7 Hz, 1H), 4.10-3.99 (m, 4H), 2.67 (d,
J=12.4 Hz, 2H), 2.01-1.92 (m, 1H), 1.80-1.63 (m, 5H), 1.53 (s, 9H),
1.42 (s, 9H), 1.22-1.11 (m, 2H), 0.89-0.82 (m, 2H), 0.62-0.57 (m,
2H); MS(ES+) m/z 464.3 (M=1).
Step 3. Preparation of
5-cyclopropyl-2-fluoro-4-(2-(piperidin-4-yl)ethoxy)benzoic acid
##STR00744##
[1238] Following the procedure as described in Example 3 step 3,
and making variation as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)-
piperidine-1-carboxylate with tert-butyl
4-(2-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)ethyl)piperid-
ine-1-carboxylate, the title compound was obtained as
trifluoroacetic acid salt (1.72 g, 99%): MS(ES+) m/z 308.1
(M+1).
Step 4. Preparation of
5-cyclopropyl-4-(2-(1-(3,5-dichlorobenzyl)piperidin-4-yl)
ethoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt
##STR00745##
[1240] Following the procedure as described in Example 3 step 4,
and making variation as required to replace
(R)-5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoic acid with
5-cyclopropyl-2-fluoro-4-(2-(piperidin-4-yl) ethoxy)benzoic acid,
the title compound was obtained (1.37 g, 56%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 12.87 (brs, 1H), 9.62 (br, 1H), 7.76 (s,
1H), 7.61-7.60 (m, 2H), 7.31 (d, J=8.5 Hz, 1H), 6.92 (d, J=13.1 Hz,
1H), 4.29-4.12 (m, 4H), 3.40-3.36 (m, 2H), 2.95-2.88 (m, 2H),
2.02-1.74 (m, 6H), 1.48-1.37 (m, 2H), 0.92-0.86 (m, 2H), 0.62-0.57
(m, 2H); MS(ES+) m/z 466.1, 468.0 (M+1).
Step 5. Preparation of
5-cyclopropyl-4-(2-(1-(3,5-dichlorobenzyl)piperidin-4-yl)
ethoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR00746##
[1242] Following the procedure as described in 3 step 5, and making
variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
5-cyclopropyl-4-(2-(1-(3,5-dichlorobenzyl)piperidin-4-yl)ethoxy)-2-fluoro-
benzoic acid and cyclopropylsulfonamide with methanesulfonamide,
the title compound was obtained as a colorless solid (0.02 g, 10%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.87 (br s, 1H), 9.55
(br s, 1H), 7.74-7.72 (m, 1H), 7.58-7.57 (m, 2H), 7.09 (d, J=8.3
Hz, 1H), 6.95 (d, J=13.0 Hz, 1H), 4.26 (s, 2H), 4.10-4.08 (m, 2H),
3.37-3.33 (m, 2H), 3.30 (s, 3H), 2.94-2.86 (m, 2H), 2.01-1.89 (m,
3H), 1.72-1.68 (m, 3H), 1.45-1.37 (m, 2H), 0.88-0.82 (m, 2H),
0.67-0.62 (m, 2H); MS(ES+) m/z 543.0, 545.0 (M+1).
Example 303
Synthesis of
5-cyclopropyl-4-(2-(1-(3,5-dichlorobenzyl)piperidin-4-yl)
ethoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR00747##
[1244] Following the procedure as described in Example 3 step 5,
and making variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
5-cyclopropyl-4-(2-(1-(3,5-dichlorobenzyl)piperidin-4-yl)ethoxy)-2-fluoro-
benzoic acid and to replace cyclopropylsulfonamide with
ethanesulfonamide, the title compound was obtained as a colorless
solid (0.06 g, 34%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
11.78 (br s, 1H), 9.73 (br s, 1H), 7.73-7.72 (m, 1H), 7.58-7.57 (m,
2H), 7.09 (d, J=8.3 Hz, 1H), 6.94 (d, J=13.0 Hz, 1H), 4.26 (s, 2H),
4.10-4.08 (m, 2H), 3.44 (q, J=7.3 Hz, 2H), 3.37-3.33 (m, 2H),
2.94-2.86 (m, 2H), 2.01-1.88 (m, 3H), 1.72-1.68 (m, 3H), 1.45-1.37
(m, 2H), 1.21 (t, J=7.3 Hz, 3H), 0.88-0.82 (m, 2H), 0.67-0.62 (m,
2H); MS(ES+) m/z 557.0, 559.0 (M+1).
Example 304
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-(2-(1-(3,5-dichlorobenzyl)piperid-
in-4-yl) ethoxy)-2-fluorobenzamide, trifluoroacetic acid salt
##STR00748##
[1246] Following the procedure as described in Example 3 step 5,
and making variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
5-cyclopropyl-4-(2-(1-(3,5-dichlorobenzyl)piperidin-4-yl)ethoxy)-2-fluoro-
benzoic acid, the title compound was obtained as a colorless solid
(0.10 g, 56%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.81
(br s, 1H), 9.75 (br s, 1H), 7.73-7.72 (m, 1H), 7.58-7.57 (m, 2H),
7.09 (d, J=8.3 Hz, 1H), 6.95 (d, J=3.0 Hz, 1H), 4.26 (s, 2H),
4.10-4.08 (m, 2H), 3.37-3.33 (m, 2H), 3.08-3.00 (m, 1H) (m, 2H),
2.01-1.89(m, 3H), 1.72-1.68 (m, 3H), 1.45-1.37 (m, 2H), 1.10-1.05
(m, 4H), 0.88-0.82 (m, 2H), 0.67-0.62 (m, 2H); MS(ES+) m/z 568.9,
570.9 (M+1).
Example 305
Synthesis of
(R)-5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)pyridin-2-yl)
methyl)piperidin-3-yl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00749##
[1248] Following the procedure as described in Example 50 step 1,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(piperidin-3-yloxy)benzam-
ide and to replace 1,3-dichloro-5-(1-chloroethyl)benzene with
2-(chloromethyl)-6-cyclopropyl-4-(trifluoromethyl)pyridine, the
title compound was obtained as a colorless solid (0.17 g, 28%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.71 (br s, 1H), 7.54
(s, 1H), 7.47 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.99 (d, J=13.2 Hz,
1H), 4.66 (br s, 1H), 3.79-3.67 (m, 2H), 3.29 (s, 3H), 2.87-2.84
(m, 1H), 2.59-2.55 (m, 2H), 2.46-2.43 (m, 1H), 2.28-2.19 (m, 1H),
2.12-2.03 (m, 1H), 1.91-1.80 (m, 2H), 1.63-1.58 (m, 2H), 1.03-0.82
(m, 1H), 0.74-0.65 (m, 2H); MS(ES+) m/z 556.1 (M+1); MS(ES-) m/z
554.1 (M-1).
Example 306
Synthesis of
5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)pyridin-2-yl)methy-
l) piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00750##
[1249] Step 1. Preparation of tert-butyl
5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)pyridin-2-yl)
methyl)piperidin-4-yl)methoxy)-2-fluorobenzoate
##STR00751##
[1251] Following the procedure as described in Example 50 step 1,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
tert-butyl 5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
and to replace 1,3-dichloro-5-(1-chloroethyl) benzene with
2-(chloromethyl)-6-cyclopropyl-4-(trifluoromethyl)pyridine, the
title compound was obtained as a colorless solid (1.00 g, 64%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.40-7.35 (m, 2H), 7.19
(s, 1H), 6.49 (d, J=12.7 Hz, 1H), 3.85 (d, J=5.9 Hz, 2H), 3.76 (s,
2H), 3.08-3.04 (m, 2H), 2.29-2.21 (m, 2H), 2.13-1.97 (m, 1H),
1.88-1.84 (m, 3H), 1.63-1.50 (m, 11H), 1.05-1.02 (m, 4H), 0.91-0.85
(m, 2H), 0.64-0.59 (m, 2H); MS(ES+) m/z 549.2 (M+1).
Step 2. Preparation of
5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)pyridin-2-yl)
methyl)piperidin-4-yl)methoxy)-2-fluorobenzoic acid,
trifluoroacetic acid salt
##STR00752##
[1253] Following the procedure as described in Example 3 step 3,
and making variation as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)-
piperidine-1-carboxylate with tert-butyl
5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)pyridin-2-yl)methy-
l) piperidin-4-yl)methoxy)-2-fluorobenzoate, the title compound was
obtained as a colorless oil (1.31 g, 99%): MS(ES+) m/z 493.0
(M+1).
Step 3. Preparation of
5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)
pyridin-2-yl)methyl)piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)be-
nzamide
##STR00753##
[1255] Following the procedure as described in Example 3 step 5,
and making variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)pyridin-2-yl)methy-
l)piperidin-4-yl) methoxy)-2-fluorobenzoic acid and to replace
cyclopropylsulfonamide with methanesulfonamide, the title compound
was obtained as a colorless solid (0.10 g, 28%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.00 (br s, 1H), 7.60 (s, 1H), 7.48 (s,
1H), 7.13 (d, J=8.4 Hz, 1H), 6.83 (d, J=12.9 Hz, 1H), 3.92-3.87 (m,
4H), 3.11 (s, 3H), 3.05-3.01 (m, 2H), 2.45-2.37 (m, 2H), 2.28-2.23
(m, 1H), 2.01-1.96 (m, 1H), 1.83-1.80 (m, 3H), 1.51-1.39 (m, 2H),
1.02-0.96 (m, 4H), 0.88-0.81 (m, 2H), 0.62-0.57 (m, 2H); MS(ES+)
m/z 570.0 (M+1); MS(ES-) m/z 568.0 (M-1).
Example 307
Synthesis of
5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)pyridin-2-yl)methy-
l)piperidin-4-yl) methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
##STR00754##
[1257] Following the procedure as described in Example 3 step 5,
and making variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)pyridin-2-yl)methy-
l)piperidin-4-yl) methoxy)-2-fluorobenzoic acid and to replace
cyclopropylsulfonamide with ethanesulfonamide, the title compound
was obtained as a colorless solid (0.14 g, 39%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.15 (br s, 1H), 7.62 (s, 1H), 7.50 (s,
1H), 7.15 (d, J=8.4 Hz, 1H), 6.88 (d, J=12.9 Hz, 1H), 3.96-3.94 (m,
2H), 3.85 (s, 2H), 3.37-3.30 (m, 2H), 3.05-3.01 (m, 2H), 2.41-2.24
(m, 3H), 2.06-1.97 (m, 1H), 1.85-1.82 (m, 3H), 1.52-1.41 (m, 2H),
1.20 (t, J=7.3 Hz, 3H), 1.04-0.99 (m, 4H), 0.91-0.85 (m, 2H),
0.66-0.61 (m, 2H); MS(ES+) m/z 584.0 (M+1); MS(ES-) m/z 582.1
(M-1).
Example 308
Synthesis of
5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)pyridin-2-yl)methy-
l)piperidin-4-yl) methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide
##STR00755##
[1259] Following the procedure as described in Example 3 step 5,
and making variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)pyridin-2-yl)methy-
l)piperidin-4-yl)methoxy)-2-fluorobenzoic acid, the title compound
was obtained as a colorless solid (0.13 g, 36%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.22 (br s, 1H), 7.61 (s, 1H), 7.49 (s,
1H), 7.15 (d, J=8.4 Hz, 1H), 6.89 (d, J=12.9 Hz, 1H), 3.95 (d,
J=5.8 Hz, 2H), 3.83 (s, 2H), 3.04-2.99 (m, 3H), 2.38-2.24 (m, 3H),
2.07-1.97 (m, 1H), 1.85-1.81 (m, 3H), 1.52-1.41 (m, 2H), 1.04-0.99
(m, 8H), 0.91-0.85 (m, 2H), 0.66-0.61 (m, 2H); MS(ES+) m/z 596.1
(M+1); MS(ES-) m/z 594.2 (M-1).
Example 309
Synthesis of
4-(((R)-1-((R)-1-(5-chloro-6-cyclopropylpyridin-2-yl)ethyl)piperidin-3-yl-
) oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
(arbitrarily assigned)
##STR00756##
[1260] Step 1. Preparation of methyl
4-(((R)-1-((R)-1-(5-chloro-6-cyclopropylpyridin-2-yl)ethyl)piperidin-3-yl-
) oxy)-5-cyclopropyl-2-fluorobenzoate and methyl
4-(((R)-1-((S)-1-(5-chloro-6-cyclopropylpyridin-2-yl)
ethyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate
##STR00757##
[1262] Following the procedure as described in Example 50 step 1
and making variations as required to replace
1,3-dichloro-5-(1-chloroethyl)benzene with
3-chloro-6-(1-chloroethyl)-2-cyclopropylpyridine. The residue was
purified by preparative-HPLC, the first eluting fraction was
arbitrarily assigned as methyl
4-(((R)-1-((R)-1-(5-chloro-6-cyclopropylpyridin-2-yl)ethyl)piperidin-3-yl-
)oxy)-5-cyclopropyl-2-fluorobenzoate (0.36 g, 50%): .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta.7.44 (d, J=8.2 Hz, 1H), 7.38 (d, J=8.4
Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 6.52 (d, J=12.9 Hz, 1H), 4.36-4.28
(m, 1H), 3.84 (s, 3H), 3.63 (q, J=6.8 Hz, 1H), 2.99-2.95 (m, 1H),
2.66-2.62 (m, 1H), 2.45-2.40 (m, 1H), 2.29-2.15 (m, 2H), 2.05-1.96
(m, 2H), 1.80-1.74 (m, 1H), 1.60-1.42 (m, 2H), 1.29 (d, J=6.8 Hz,
3H), 1.07-0.84 (m, 6H), 0.63-0.58 (m, 2H); MS(ES+) m/z 473.1, 475.1
(M+1).
[1263] The second eluting fraction was arbitrarily assigned as
methyl 4-(((R)-1-((S)-1-(5-chloro-6-cyclopropylpyridin-2-yl)ethyl)
piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate (0.36 g, 50%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.45 (d, J=8.2 Hz, 1H),
7.41 (d, J=8.4 Hz, 1H), 7.04 (d, J=7.5 Hz, 1H), 6.53 (d, J=12.8 Hz,
1H), 4.35-4.29 (m, 1H), 3.85 (s, 3H), 3.67 (q, J=6.8 Hz, 1H),
3.039-3.00 (m, 1H), 2.72-2.68 (m, 1H), 2.49-2.41 (m, 1H), 2.28-2.13
(m, 2H), 2.05-1.96 (m, 2H), 1.82-1.77 (m, 1H), 1.64-1.38 (m, 2H),
1.31 (d, J=6.8 Hz, 3H), 1.06-0.86 (m, 6H), 0.65-0.60 (m, 2H);
MS(ES+) m/z 473.1, 475.1 (M+1).
Step 2. Preparation of
4-(((R)-1-((R)-1-(5-chloro-6-cyclopropylpyridin-2-yl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00758##
[1265] Following the procedure as described in Example 50 step 2
and making variations as required to replace methyl
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-
3-yl) oxy)-2-fluorobenzoate with methyl
4-(((R)-1-((R)-1-(5-chloro-6-cyclopropylpyridin-2-yl)ethyl)
piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate, the title
compound was obtained as a pale yellow oil (0.06 g, 17%): MS(ES+)
m/z 459.1, 461.1 (M+1); MS(ES-) m/z 457.1, 459.1 (M-1).
Step 3. Preparation of
4-(((R)-1-((R)-1-(5-chloro-6-cyclopropylpyridin-2-yl)ethyl)piperidin-3-yl-
) oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00759##
[1267] Following the procedure as described in Example 3 step 5,
and making variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
4-(((R)-1-((R)-1-(5-chloro-6-cyclopropylpyridin-2-yl)ethyl)piperidin-3-yl-
)oxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace
cyclopropylsulfonamide with methanesulfonamide, the title compound
was obtained as a colorless solid (0.01 g, 50%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.77 (br s, 1H), 7.67 (d, J=7.9 Hz, 1H),
7.53 (d, J=8.8 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 6.87 (d, J=13.5 Hz,
1H), 4.86-4.82 (m, 1H), 4.66-4.64 (m, 1H), 3.95-3.92 (m, 1H),
3.68-3.64 (m, 1H), 3.38 (s, 3H), 2.95-2.86 (m, 1H), 2.60-2.55 (m,
2H), 2.36-2.31 (m, 1H), 2.13-2.07 (m, 2H), 1.92-1.87 (m, 1H), 1.69
(d, J=6.4 Hz, 3H), 1.62-161 (m, 1H), 1.10-0.86 (m, 6H), 0.62-0.60
(m, 2H); MS(ES+) m/z 536.1, 538.1 (M+1).
Example 310
Synthesis of
4-(((R)-1-((S)-1-(5-chloro-6-cyclopropylpyridin-2-yl)ethyl)piperidin-3-yl-
) oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00760##
[1268] Step 1. Preparation of
4-(((R)-1-((S)-1-(5-chloro-6-cyclopropylpyridin-2-yl)ethyl)piperidin-3-yl-
) oxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00761##
[1270] Following the procedure as described in Example 50 step 2
and making variations as required to replace methyl
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)o-
xy)-2-fluorobenzoate with methyl
4-(((R)-1-((S)-1-(5-chloro-6-cyclopropylpyridin-2-yl)ethyl)piperidin-3-yl-
) oxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained as a colorless solid (0.17 g, 49%): MS(ES+) m/z 459.1,
461.0 (M+1); MS(ES-) m/z 457.1, 459.1 (M-1).
Step 2. Preparation of
4-(((R)-1-((S)-1-(5-chloro-6-cyclopropylpyridin-2-yl)ethyl)piperidin-3-yl-
) oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00762##
[1272] Following the procedure as described in Example 3 step 5,
and making variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
4-(((R)-1-((S)-1-(5-chloro-6-cyclopropylpyridin-2-yl)ethyl)piperidin-3-yl-
)oxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace
cyclopropylsulfonamide with methanesulfonamide, the title compound
was obtained as a colorless solid (0.05 g, 44%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta.8.77 (br s, 1H), 7.67 (d, J=7.7 Hz, 1H),
7.57 (d, J=8.0 Hz, 1H), 7.08 (d, J=7.4 Hz, 1H), 6.89 (d, J=13.6 Hz,
1H), 4.95-4.89 (m, 1H), 4.67-4.66 (m, 1H), 3.92-3.89 (m, 1H),
3.62-3.59 (m, 1H), 3.39 (s, 3H), 3.05-2.97 (m, 1H), 2.62-2.50 (m,
2H), 2.38-2.34 (m, 1H), 2.05-1.93 (m, 3H), 1.67 (d, J=4.4 Hz, 3H),
1.51-1.45 (m, 1H), 1.10-0.90 (m, 6H), 0.65-0.63 (m, 2H); MS(ES+)
m/z 536.1, 538.1 (M+1).
Example 311
Synthesis of
(R)-4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00763##
[1274] Following the procedure as described in Example 3 step 4,
and making variation as required to replace
(R)-5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoic acid
trifluoroacetate with
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(piperidin-3-yloxy)benzam-
ide and to replace 3,5-dichlorobenzaldehyde with
3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde, the title
compound was obtained as a colorless solid (0.18 g, 35%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.80 (br s, 1H), 7.98 (dd,
J=1.9 Hz, 6.3 Hz, 1H), 7.79 (dd, J=1.9 Hz, 5.6 Hz, 1H), 7.12 (d,
J=8.4 Hz, 1H), 7.02 (d, J=13.2 Hz, 1H), 4.65-4.63 (m, 1H), 3.71 (d,
J=2.0 Hz, 2H), 3.32 (s, 3H), 2.83-2.79 (m, 1H), 2.56-2.54 (m, 2H),
2.41-2.36 (m, 1H), 2.10-2.00 (m, 1H), 1.90-1.77 (m, 2H), 1.60-1.55
(m, 2H), 0.89-0.84 (m, 2H), 0.73-0.67 (m, 2H); MS(ES+) m/z 567.2,
569.0 (M+1); MS(ES-) m/z 565.1, 567.1 (M-1).
Example 312
Synthesis of
(R)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fl-
uoro-N-(methylsulfonyl)benzamide
##STR00764##
[1276] Following the procedure as described in Example 3 step 5,
and making variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy-5-cyclopropyl-2-flu-
orobenzoic acid and to replace cyclopropylsulfonamide with
methanesulfonamide, the title compound was obtained as a colorless
solid (0.05 g, 60%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
11.79 (br s, 1H), 7.55-7.50 (m, 1H), 7.42-7.38 (m, 1H), 7.17-7.11
(m, 2H), 7.00 (d, J=13.2 Hz, 1H), 4.62-4.60 (m, 1H), 3.60 (s, 2H),
3.31 (s, 3H), 2.82-2.79 (m, 1H), 2.60-2.55 (m, 1H), 2.49-2.39 (m,
2H), 2.12-2.03 (m, 1H), 1.94-1.91 (m, 1H), 1.83-1.79 (m, 1H),
1.61-1.57 (m, 2H), 0.91-0.85 (m, 2H), 0.72-0.68 (m, 2H); MS(ES+)
m/z 499.2, 501.2 (M+1); MS(ES-) m/z 497.3, 499.3 (m-1).
Example 313
Synthesis of
(R)-5-cyclopropyl)-N-(cyclpropylsulfonyl)-2-fluoro-4-((1-(3-fluoro-4-((1--
(3-fluoro-4-methoxybenzyl) piperidin-3-yl)oxy)benzamide
##STR00765##
[1278] Following the procedure as described in Example 3 step 5,
and making variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(3-fluoro-4-methoxybenzyl)piperidin-3-yl-
)oxy)benzoic acid, the title compound was obtained as a colorless
solid (0.03 g, 23%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.55
(d, J=9.1 Hz, 1H), 7.11-6.86 (m, 3H), 6.60 (d, J=18.1 Hz, 1H), 4.50
(s, 1H), 3.88 (s, 3H), 3.53 (s, 2H), 3.12-3.05 (m, 1H), 3.02-2.91
(m, 1H), 2.83-2.66 (m, 1H), 2.44-2.20 (m, 2H), 2.15-1.98 (m, 2H),
1.95-1.82 (m, 2H), 1.66-1.53 (m, 2H), 1.48-1.42 (m, 2H), 1.17-1.13
(m, 2H), 0.96-0.88 (m, 2H), 0.69-0.64 (m, 2H); MS(ES+) m/z 521.2
(M+1), MS(ES-+) m/z 519.3 (M-1).
Example 314
Synthesis of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(methylsulfonyl)piper-
idin-3-yl)oxy)benzamide
##STR00766##
[1280] Following the procedure as described in Example 3 step 5,
and making variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(methylsulfonyl)piperidin-3-yl)oxy)benzo-
ic acid and to replace cyclopropylsulfonamide with
methanesulfonamide, the title compound was obtained as a colorless
solid (0.07 g, 40%) .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.72
(d, J=15.9 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 6.65 (d, J=14.2 Hz,
1H), 4.49 (brs, 1H), 3.74 (d, J=14.2 Hz, 1H), 3.51-3.45 (m, 1H),
3.41 (s, 3H), 3.25-3.12 (m, 2H), 2.83 (s, 3H), 2.11-2.01 (m, 3H),
1.85-1.79 (m, 2H), 0.94 (d, J=8.4 Hz, 2H), 0.66 (d, J=5.2 Hz, 2H);
MS(ES+) m/z 435.1 (M+1); MS(ES-) m/z 433.2 (M-1).
Example 315
Synthesis of
5-cyclopropyl-2-fluoro-4-(((R)-1-((S)-1-(4-fluorophenyl)ethyl)piperidin-3-
-yl)oxy)-N-(methylsulfonyl)benzamide
##STR00767##
[1281] Step 1. Preparation of methyl
5-cyclopropyl-2-fluoro-4-(((R)-1-((S)-1-(4-fluorophenyl)ethyl)piperidin-3-
-yl)oxy)benzoate and methyl
5-cyclopropyl-2-fluoro-4-(((R)-1-((R)-1-(4-fluorophenyl)ethyl)piperidin-3-
-yl)oxy)benzoate
##STR00768##
[1283] Following the procedure as described in Example 50 step 1,
and making variations as required to replace
1,3-dichloro-5-(1-chloroethyl)benzene with
1-(1-chloroethyl)-4-fluorobenzene, the first eluting fraction was
arbitrarily assigned as methyl 5-cyclopropyl
-2-fluoro-4-(((R)-1-((S)-1-(4-fluorophenyl)
ethyl)piperidin-3-yl)oxy)benzoate (0.50 g, 38%): .sup.1H NMR (300
MHz, CDCl3) .delta.7.41 (d, J=8.4 Hz, 1H), 7.27-7.22 (m, 2H), 6.95
(t, J=8.7 Hz, 2H), 6.53 (d, J=13 Hz, 1H), 4.39-4.32 (m, 1H), 3.86
(s, 3H), 3.54-3.46 (m, 1H), 3.02-3.00 (m, 1H), 2.62-2.59 (m, 1H),
2.25-1.96 (m, 4H), 1.83-1.76 (m, 1H), 1.63-1.43 (m, 2H), 1.32 (d,
J=6.8 Hz, 3H), 0.91-0.88 (m, 2H), 0.66-0.62 (m, 2H); MS(ES+) m/z
416.2 (M+1).
[1284] The second eluting fraction was arbitrarily assigned as
methyl 5-cyclopropyl-2-fluoro-4-(((R)-1-((R)-1-(4-fluorophenyl)
ethyl)piperidin-3-yl)oxy)benzoate (0.5 g, 38%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.36 (d, J=8.4 Hz, 1H), 7.23-7.21 (m, 2H),
6.94 (t, J=8.9 Hz, 2H), 6.46 (d, J=12.9 Hz, 1H), 4.32-4.24 (m, 1),
3.82 (s, 3H), 3.50 (q, J=6.7 Hz, 1H), 2.94-2.91 (m, 1H), 2.77-2.73
(m, 1H), 2.15-1.93 (m, 4H), 1.88-1.76 (m, 1H), 1.65-1.37 (m, 2H),
1.30 (d, J=6.8 Hz, 3H), 0.85-0.81 (m, 2H), 0.61-0.57 (m, 2H);
MS(ES+) m/z 416.2 (M+1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-4-(((R)-1-((S)-1-(4-fluorophenyl)ethyl)
piperidin-3-yl)oxy)benzoic acid
##STR00769##
[1286] Following the procedure as described 1, ample 50 step 2, and
making variations as required to replace methyl
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)-piperidin-3-yl)-
oxy)-2-fluorobenzoate with methyl
5-cyclopropyl-2-fluoro-4-(((R)-1-((S)-1-(4-fluorophenyl)ethyl)piperidin-3-
-yl) oxy)benzoate, the title compound was obtained as a colorless
solid (0.16 g, 33%): MS(ES+) m/z 402.2 (M+1); MS(ES-) m/z 400.2
(M-1).
Step 3. Preparation of
5-cyclopropyl-2-fluoro-4-(((R)-1-((S)-1-(4-fluorophenyl)ethyl)
piperidin-3-yl)oxy)-N-(methylsulfonyl)benzamide
##STR00770##
[1288] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
5-cyclopropyl-2-fluoro-4-(((R)-1-((S)-1-(4-fluorophenyl)ethyl)piperidin-3-
-yl)oxy)benzoic acid, the title compound was obtained as a
colorless solid (0.12 g, 62%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.99-8.66 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.45-7.42 (m,
2H), 7.19 (t, J=8.0 Hz, 2H), 6.96 (d, J=12.9 Hz, 1H), 5.01-4.86 (m,
1H), 4.61-4.47 (m, 1H), 4.06-3.92 (m, 1H), 3.59-3.46 (m, 1H), 3.41
(s, 3H), 2.59-2.42 (m, 2H), 2.39-2.28 (m, 1H), 2.23-2.00 (m, 2H),
1.97-1.87 (m, 1H), 1.81 (d, J=5.3 Hz, 3H), 1.64-1.46 (m, 1H),
0.93-0.88 (m, 2H), 0.64-0.60 (m, 2H); MS(ES+) m/z 479.1 (M+1);
MS(ES-) m/z 477.2 (M-1).
Example 316
Synthesis of
5-cyclopropyl-2-fluoro-4-(((R)-1-(4-fluorophenyl)ethyl)piperidin-3-yl)oxy-
)-N-(methylsulfonyl)benzamide
##STR00771##
[1289] Step 1. Preparation of
5-cyclopropyl-2-fluoro-4-(((R)-1-((R)-1-(4-fluorophenyl)ethyl)
piperidin-3-yl)oxy benzoic acid
##STR00772##
[1291] Following the procedure as described in Example 50 step 2
and making variations as required to replace methyl
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-
3-yl)oxy)-2-fluorobenzoate with methyl
5-cyclopropyl-2-fluoro-4-(((R)-1-((R)-1-(4-fluorophenyl)ethyl)piperidin-3-
-yl)oxy) benzoate, the title compound was obtained as a beige color
solid (0.23 g, 99%): MS(ES-) m/z 400.2 (M-1); MS(ES+) m/z 402.2
(M+1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-4-(((R)-((R)-1-(4-fluorophenyl)
ethyl)piperidin-3-yl)oxy)-N-(methylsulfonyl)benzamide
##STR00773##
[1293] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
5-cyclopropyl-2-fluoro-4-(((R)-1-((R)-1-(4-fluorophenyl)ethyl)piperidin-3-
-yl)oxy)benzoic acid, the title compound was obtained as a
colorless solid (0.04 g, 15%) .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.9.07-8.61 (m, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.45-7.41 (m,
2H), 7.18 (t, J=8.26 Hz, 2H), 7.02-6.89 (m, 1H), 5.10-4.91 (m, 1H),
4.63-4.46 (m, 1H), 3.82-3.56 (m, 2H), 3.40 (s, 3H), 2.63-2.41 (m,
2H), 2.40-2.28 (m, 1H), 2.25-1.87 (m, 3H), 1.80 (d, J=6.3 Hz, 3H),
1.63-1.43 (m, 1H), 0.95-0.87 (m, 2H), 0.67-0.59 (m, 2H); MS(ES+)
m/z 479.1 (M+1); MS(ES-) m/z 477.2 (M-1).
Example 317
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-(((R)-1-((R)-1-(4-fluoro-
phenyl) ethyl)piperidin-3-yl)oxy)benzamide
##STR00774##
[1295] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
5-cyclopropyl-2-fluoro-4-(((R)-1-((R)-1-(4-fluorophenyl)ethyl)piperidin-3-
-yl)oxy)benzoic acid and to replace methanesulfonamide with
cyclopropylsulfonamide, the title compound was obtained as a
colorless solid (0.01 g, 6%) .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.91-8.63 (m, 1H), 7.61-7.51 (m, 1H), 7.49-7.38 (m, 2H),
7.19-7.12 (m, 2H), 7.04-6.89 (m, 1H), 5.12-4.88 (m, 1H), 4.63-4.46
(m, 1H), 3.86-3.52 (m, 2H), 3.17-3.02 (m, 1H), 2.69-2.28 (m, 3H),
2.23-1.89 (m, 3H), 1.89-1.85 (m, 3H), 1.50-1.41 (m, 3H), 1.21-1.10
(m, 2H), 0.96-0.85 (m, 2H), 0.69-0.58 (m, 2H); MS(ES+) m/z 505.2
(M+1); MS(ES-) m/z 503.2 (M-1).
Example 318
Synthesis of
(R)-5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(trifluoromethyl)benzyl)
piperidin-3-yl)oxy)-N-(methylsulfonyl)benzamide
##STR00775##
[1296] Step 1. Preparation of (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(trifluoromethyl)
benzyl)piperidin-3-yl)oxy)benzoate
##STR00776##
[1298] Following the procedure as described in Example 50 step 1,
and making variations as required to replace
1,3-dichloro-5-(1-chloroethyl)benzene with
2-(bromomethyl)-4-fluoro-1-(trifluoromethyl) benzene, the title
compound was obtained as a colorless oil (0.20 g, 99%): MS(ES+) m/z
470.2 (M+1).
Step 2. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(trifluoromethyl)benzyl)
piperidin-3-yl)oxy)benzoic acid
##STR00777##
[1300] Following the procedure as described in Example 50 step 2
and making variations as required to replace methyl
5-cyclopropyl-4-(((R)-1-((S)-(1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)
oxy)-2-fluorobenzoate with (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(trifluoromethyl)
benzyl)piperidin-3-yl)oxy)benzoate, the title compound was obtained
as a colorless oil (0.12 g, 59%): MS(ES+) m/z 456.1 (M+1); MS(ES-)
m/z 454.2 (M-1).
Step 3. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(trifluoromethyl)benzyl)
piperidin-3-yl)oxy)-N-(methylsulfonyl)benzamide
##STR00778##
[1302] Following the procedure is described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(trifluoromethyl)piperidin)p-
iperidin-3-yl)oxy)benzoic acid, the title compound was obtained as
a colorless solid (0.03 g, 18%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.99-8.55 (m, 1H), 7.78-7.74 (m, 2H), 7.56-7.53 (d, J=8.6
Hz, 1H), 7.27-7.22 (m, 1H), 4.97-4.83 (m, 1H), 4.61-4.56 (m, 1H),
4.37-4.33 (m, 1H), 3.81-3.57 (m, 1H), 3.38 (s, 3H), 3.35-3.25 (m,
1H), 3.03-2.78 (m, 2H), 2.37-2.22 (m, 1H), 2.17-1.98 (m, 3H),
1.87-1.69 (m, 1H), 0.92 (d, J=8.1 Hz, 2H), 0.68-0.56 (m, 2H);
MS(ES+) m/z 533.2 (M+1); MS(ES-) m/z 531.2 (M-1).
Example 319
Synthesis of
((R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(3-(trifluoromethyl)-
benzyl) piperidin-3-yl)oxy)benzamide
##STR00779##
[1303] Step 1. Preparation of (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-(3-(trifluoromethyl)benzyl)
piperidin-3-yl)oxy)benzoate
##STR00780##
[1305] Following the procedure as described in Example 50 step 1,
and making variations as required to replace
1,3-dichloro-5-(1-chloroethyl)benzene with
1-(chloromethyl)-3-(trifluoromethyl)benzene, the title compound was
obtained as a colorless oil (0.24 g, 28%): MS(ES+) m/z 452.2
(M+1).
Step 2. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-((1-(3-(trifluoromethyl)benzyl)
piperidin-3-yl)oxy)benzoic acid
##STR00781##
[1307] Following the procedure as described in Example 50 step 2
and making variations as required to replace methyl
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-
3-yl)oxy)-2-fluorobenzoate with (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-(3-(trifluoromethyl)piperidin)piperidin-3-yl-
)oxy) benzoate, the title compound was obtained as colorless oil
(0.25 g, 99%): MS(ES+) m/z 438.2 (M+1); MS(ES-) m/z 436.2
(M-1).
Step 3. Preparation of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(3-(trifluoromethyl)
benzyl)piperidin-3-yl)oxy)benzamide
##STR00782##
[1309] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-(3-(trifluoromethyl)piperidin)piperidin--
3-yl)oxy)benzoic acid, the title compound was obtained as a
colorless solid (0.04 g, 16%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.9.03-8.68 (m, 1H), 7.76-7.67 (m, 4H), 7.56-7.54 (m, 1H),
6.95-6.71 (m, 1H), 4.96-4.78 (m,1H), 4.47-4.23 (m, 2H), 4.02-3.72
(m, 1H), 3.40 (s, 3H), 2.96-2.58 (m, 2H), 2.43-2.26 (m, 1H),
2.21-1.91 (m, 3H), 1.83-1.56 (m, 2H), 0.98-0.80 (m, 2H), 0.68-0.51
(m, 2H); MS(ES+) m/z 515.1 (M+1).
Example 320
Synthesis of
4-((2-(2-chloro-4-fluorobenzyl)-2-azaspiro[3.3]heptan-6-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR00783##
[1310] Step 1. Preparation of tert-butyl
6-(4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)-2-azaspiro[3.3]hepta-
ne-2-carboxylate
##STR00784##
[1312] Following the procedure as described in Example 3 step 1,
and making variation as required to replace (R)-tert-butyl
3-hydroxypiperidine-1-carboxylate with tert-butyl
6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate, the title compound
was obtained as a colorless solid (2.36 g, 53%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta.7.85 (d, J=7.6 Hz, 1H), 6.42 (d, J=11.9 Hz,
1H), 4.64-4.55 (m, 1H), 3.95 (d, J=11.2 Hz, 4H), 2.78-2.71 (m, 2H),
2.44-2.37 (m, 2H), 1.55 (s, 9H), 1.42 (s, 9H); MS(ES+) m/z 442.1,
444.0 (M +1).
Step 2. Preparation of tert-butyl
6-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)-2-azaspiro[3.3]-
heptane-2-carboxylate
##STR00785##
[1314] Following the procedure as described in Example 3 step 2,
and making variation as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)piperidine-
1-carboxylate with tert-butyl
6-(4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)-2-azaspiro[3.3]hepta-
ne-2-carboxylate, the title compound was obtained as a colorless
oil (0.96 g, 95%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.3.1
(d, J=8.3 Hz, 1H), 6.28 (d, J=12.4 Hz, 1H), 4.61-4.52 (m, 1H), 3.94
(d, J=12.2 Hz, 4H), 2.75-2.68 (m, 2H), 2.37-2.30 (m, 2H), 2.01-1.93
(m, 1H), 1.54 (s, 9H), 1.41 (s, 9H), 0.90-0.82 (m, 2H), 0.63-0.57
(m, 2H); MS(ES+) m/z 448.2 (M+1).
Step 3. Preparation of
4-(2-azaspiro[3.3]heptan-6-yloxy)-5-cyclopropyl-2-fluorobenzoic
acid, trifluoroacetic acid salt
##STR00786##
[1316] Following the procedure as described in Example 3step 3, and
making variation as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)-
piperidine-1-carboxylate with tert-butyl
6-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)-2-azaspiro[3.3]-
heptane-2-carboxylate, the title compound was obtained (0.86 g,
99%): MS(ES+) m/z 292.2 (M+1); MS(ES-) m/z 290.3 (M-1)
Step 4. Preparation of
4-((2-(2-chloro-4-fluorobenzyl)-2-azaspiro[3.3]heptan-6-yl)
oxy)-5-cyclopropyl-2-fluorobenzoic acid, trifluoroacetic acid
salt
##STR00787##
[1318] Following the procedure as described in Example 3 step 4,
and making variation as required to replace
(R)-5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoic acid with
4-(2-azaspiro[3.3]heptan-6-yloxy)-5-cyclopropyl-2-fluorobenzoic
acid and to replace 3,5-dichlorobenzaldehyde with
2-chloro-4-fluorobenzaldehyde, the title compound was obtained as
colorless solid (0.30 g, 37%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 12.87 (br s, 1H), 10.35 (br s, 1H), 7.70-7.62 (m, 2H),
7.42-7.36 (m, 1H), 7.27 (d, J=8.4 Hz, 1H), 6.72 (d, J=12.9 Hz, 1H),
4.79-4.71(m, 1H), 4.51-4.49 (m, 2H), 4.32-4.10 (m, 4H), 2.92-2.80
(m, 2H), 2.39-2.30 (m, 2H), 2.04-1.95 (m, 1H), 0.93-0.86 (m, 2H),
0.62-0.57 (m, 2H); MS(ES+) m/z 434.1, 436.1 (M+1); MS(ES-) m/z
432.2, 434.1 (M-1).
Step 5. Preparation of
4-((2-(2-chloro-4-fluorobenzyl)-2-azaspiro[3.3]heptan-6-yl)
oxy-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR00788##
[1320] Following the procedure as described in Example 3 step 5,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy-2-fluorobe-
nzoic acid with
4-((2-chloro-4-fluorobenzyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-5-cyclopropy-
l-2-fluorobenzoic acid and to replace cyclopropylsulfonamide with
methanesulfonamide, the title compound was obtained as colorless
solid (0.04 g, 22%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.8.73
(br s, 1H), 7.59-7.52 (m, 2H), 7.25-7.21 (m, 1H), 7.14-7.08 (m,
1H), 6.31 (d, J=13.8 Hz, 1H), 4.66-4.62 (m, 1H), 4.52-4.40 (m, 4H),
3.95-3.93 (m, 2H), 3.40 (s, 3H), 3.06-3.00 (m, 1H), 2.86-2.80 (m,
1H), 2.60-2.45 (m, 2H), 2.02-1.93 (m, 1H), 0.96-0.90 (m, 2H),
0.66-0.61 (m, 2H); MS(ES+) m/z 511.8, 513.1 (M+1); MS(ES-) m/z
509.2, 511.2 (M-1).
Example 321
Synthesis of
4-((2-(2-chloro-4-fluorobenzyl)-2-azaspiro[3.3]heptan-6-yl)
oxy-5-cyclopropyl-2-fluoro-N-((3-fluoroazetidin-1-yl)sulfonyl)benzamide
##STR00789##
[1322] Following the procedure as described in Example 3 step 5,
and making variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
4-((2-(2-chloro-4-fluorobenzyl)-2-azaspiro[3.3]heptan-6-yl)oxy)-5-cyclopr-
opyl-2-fluorobenzoic acid and to replace cyclopropylsulfonamide
with 3-fluoroazetidine-1-sulfonamide, the title compound was
obtained as colorless solid (0.08 g, 39%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.48 (br s, 1H), 7.69-7.62 (m, 2H), 7.39
(dt, J=2.6 Hz, 8.4 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 6.79 (d, J=12.7
Hz, 1H), 5.48-5.42 (m, 0.5H), 5.29-5.23 (m, 0.5H), 4.80-4.71 (m,
1H), 4.50 (s, 2H), 4.43-4.12 (m, 8H), 2.86 (br s, 2H), 2.37-2.30
(m, 2H), 2.06-1.97 (m, 1H), 0.93-0.86 (m, 2H), 0.71-0.66 (m, 1H);
MS(ES+) m/z 570.1, 572.1 (M+1); MS(ES-) m/z 568.1, 570.1 (M-1).
Example 322
Synthesis of
N-(azetidin-1-ylsulfonyl)-4-(((3R,6R)-1-(2-chloro-4-fluorobenzyl)-6-methy-
lpiperidin-3-yl) oxy)-5-cyclopropyl-2-fluorobenzamide
##STR00790##
[1324] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
4-(((3R,6R)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)oxy)-5-cyc-
lopropyl- 2-fluorobenzoic acid, and to replace methanesulfonamide
with azetidine-1-sulfonamide, the title compound was obtained as a
colorless solid (0.07 g, 23%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.70-8.55 (m, 1H), 7.59-7.48 (m, 2H), 7.13-7.04 (m, 1H),
6.99-6.89 (m, 1H), 6.52-6.43 (m, 1 H), 4.40-4.14 (m, 5H), 4.06-3.94
(m, 1H), 3.45-3.32 (m, 1H), 3.09-3.00 (m, 1H), 2.60-2.46 (m, 1H),
2.33-2.13 (m, 4H), 2.09-1.87 (m, (m, 2H), 1.69-1.42 (m, 2H),
1.22-1.14 (m, 3H), 0.97-0.86 (m, 2H), 0.69-0.60 (m, 2H); MS(ES+)
m/z 554.2, 556.2 (M+1).
Example 323
Synthesis of
4-(((3R,6R)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)
oxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR00791##
[1326] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)oxy)-2-fluorob-
enzoic acid with
4-(((3R,6R)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)oxy)-5-cyc-
lopropyl- 2-fluorobenzoic acid, and to replace methanesulfonamide
with cyclopropanesulfonamide, the title compound was obtained as a
colorless solid (0.14 g, 44%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.75-8.57 (m, 1H), 7.58-7.47 (m, 2H), 7.13-7.03 (m, 1H),
7.00-6.88 (m, 1H), 6.53-6.41 (m, 1H), 4.39-4.25 (m, 1H), 4.07-3.93
(m, 1H), 3.44-3.33 (m, 1H), 3.14-2.99 (m, 2H), 2.57-2.46 (m, 1H),
2.31-2.11 (m, 2H), 2.08-1.85 (m, 2H), 1.69-1.37 (m, 5H), 1.22-1.08
(m, 4H), 0.96-0.84 (m, 2H), 0.69-0.56 (m, 2H); MS(ES+) m/z 539.2,
541.2, (M+1).
Example 324
Synthesis of
4-(((3R,6S)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00792##
[1327] Step 1. Preparation of (2S,5R)-benzyl
5-hydroxy-2-methylpiperidine-1-carboxylate
##STR00793##
[1329] Following the procedure as described in Example 52 step 1,
and making variations as required to replace
(3R,6R)-6-methylpiperidin-3-ol with (3R,6S)-6-methylpiperidin-3-ol
(Ian A. O'Neil et al., Synlett, 2000, 5, 695), the title compound
was obtained (1.45 g, 27%) as a colorless oil: MS(ES+) m/z 250.2
(M+1).
Step 2. Preparation of (2S,5R)-benzyl
5-(4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)-2-methylpiperidine-1-
-carboxylate
##STR00794##
[1331] Following the procedure as described in Example 1 step 1,
and making variation as required to replace
(R)-1-benzylpiperidin-3-ol with (2S,5R)-benzyl
5-hydroxy-2-methylpiperidine-1-carboxylate, the title compound was
obtained as a colorless oil (1.63 g, 59%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.7.91-7.84 (m, 1H), 7.43-7.28 (m, 5H), 6.78-6.61
(m, 1H), 5.23-5.06 (m, 2H), 4.61-4.09 (m, 3H), 3.07-2.88 (m, 1H),
2.17-1.99 (m, 1H), 1.96-1.50 (m, 12H), 1.31-1.17 (m, 3H); MS(ES+)
m/z 478.2, 480.2 (M+1).
Step 3. Preparation of (2S,5R)-benzyl
5-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)-2-methylpiperid-
ine-1-carboxylate
##STR00795##
[1333] Following the procedure as described in Example 1 step 2,
and making variation as required to replace (R)-tert-butyl
4-((1-benzylpiperidin-3-yl)oxy)-5-chloro-2-fluorobenzoate with
(2S,5R)-benzyl
5-(4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)-2-methylpiperidine-1-
-carboxylate, the title compound was obtained as a colorless oil
(1.35 g, 82%): .sup.1H NMR (300 MHz, CDCl.sub.3) 67 7.43-7.28 (m,
6H), 6.64-6.53 (m, 1H), 5.23-5.07 (m, 2H), 4.63-4.10 (m, 3H),
3.01-2.82 (m, 1H), 2.14-1.94 (m, 2H), 1.89-1.75 (m, 2H), 1.73-1.62
(m, 1H), 1.57 (s, 9H), 1.28-1.19 (m, 3H), 0.94-0.84 (m, 2H),
0.67-0.58 (m, 2H); MS(ES+) m/z 484.3 (M+1).
Step 4. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-(((3R,6S)-6-methylpiperidin-3-yl)oxy)benzoate
##STR00796##
[1335] Following the procedure as described in Example 52 step 4,
and making variation as required to replace (2R,5R)-benzyl
5-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)-2-methylpiperid-
ine-1-carboxylate with (2S,5R)-benzyl
5-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)-2-methylpiperid-
ine-1-carboxylate, the title compound was obtained as a colorless
oil (0.97 g, 99%): MS(ES+) m/z 350.3 (M+1).
Step 5. Preparation of tert-butyl
4-(((3R,6S)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)
oxy)-5-cyclopropyl-2-fluorobenzoate
##STR00797##
[1337] Following the procedure as described in Example 34 step 2,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yl)oxy)benzoate with
tert-butyl
5-cyclopropyl-2-fluoro-4-(((3R,6S)-6-methylpiperidin-3-yl)oxy)benzoate,
and to replace 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene
with 1-(bromomethyl)-2-chloro-4-fluorobenzene, the title compound
was obtained as a colorless oil (1.10 g, 82%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta.7.53-7.43 (m, 1H), 7.41-7.34 (m, 1H),
7.08-6.99 (m, 1H), 6.86-6.73 (m, 1H), 6.48-6.36 (m, 1H), 4.48-4.34
(m, 1H), 3.93-3.76 (m, 1H), 3.50-3.36 (m, 1H), 2.97-2.81 (m, 1H),
2.79-2.65 (m, 1H), 2.58-2.42 (m, 1H), 2.22-2.04 (m, 1H), 2.01-1.66
(m, 4H), 1.57 (s, 9H), 1.19-1.09 (m, 3H), 0.97-0.87 (m, 2H),
0.75-0.62 (m, 2H); MS(ES+) m/z 492.3, 494.3 (M+1).
Step 6. Preparation of
4-(((3R,6S)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)
oxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00798##
[1339] Following the procedure as described in Example 3 step 3,
and making variation as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)piperidine-
1-carboxylate with tert-butyl
4-(((3R,6S)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)oxy)-5-cyc-
lopropyl-2-fluorobenzoate the title compound was obtained as a
colorless solid (0.94 g, 96%): MS(ES+) m/z 436.2, 438.2 (M+1).
Step 7. Preparation of
4-(((3R,6S)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00799##
[1341] Following the procedure as described in Example 17 step 2,
and making variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
4-(((3R,6S)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)oxy)-5-cyc-
lopropyl-2-fluorobenzoic acid, the title compound was obtained as a
colorless solid (0.03 g, 9%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.77-8.58 (m, 1H), 7.62-7.53 (m, 1H), 7.48-7.40 (m, 1H),
7.08-6.99 (m, 1H), 6.82-6.72 (m, 1H), 6.49-6.38 (m, 1H), 4.47-4.37
(m, 1H), 3.92-3.79 (m, 1H), 3.49-3.35 (m, 4H), 2.96-2.81 (m, 1H),
2.80-2.67 (m, 1H), 2.56-2.43 (m, 1H), 2.20-2.05 (m, 1H), 2.03-1.66
(m, 4H), 1.19-1.07 (m, 3H), 1.02-0.87 (m, 2H), 0.78-0.60 (m, 2H);
MS(ES+) m/z 513.2, 515.2 (M+1).
Example 325
Synthesis of
N-(azetidin-1-ylsulfonyl)-4-(((3R,6S)-1-(2-chloro-4-fluorobenzyl)-6-methy-
lpiperidin-3-yl) oxy)-5-cyclopropyl-2-fluorobenzamide
##STR00800##
[1343] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
4-(((3R,6S)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)oxy)-2-flu-
orobenzoic acid, and to replace methanesulfonamide with
azetidine-1-sulfonamide, the title compound was obtained as a
colorless solid (0.08 g, 27%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.69-8.55 (m, 1H), 7.63-7.57 (m, 1H), 7.50-7.41 (m, 1),
7.08-6.99 (m, 1H), 6.83-6.73 (m, 1H), 6.50-6.39 (m, 1H), 4.48-4.38
(m, 1H), 4.34-4.15 (m, 4H), 3.92-3.81 (m, 1H), 3.48-3.36 (m, 1H),
2.94-2.83 (m, 1H), 2.78-2.67 (m, 1H), 2.54-2.45 (m, 1H), 2.34-2.20
(m, 2H), 2.19-2.08 (m, 1H), 2.04-1.67 (m, 4H), 1.20-1.10 (m, 3H),
1.01-0.89 (m, 2H), 0.80-0.64 (m, 2H); MS(ES+) m/z 554.0, 556.0
(M+1).
Example 326
Synthesis of
4-(((3R,6S)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)
oxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR00801##
[1345] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
4-(((3R,6S)-1-(2-chloro-4-fluorobenzyl)-6-methylpiperidin-3-yl)oxy)-5-cyc-
lopropyl-2-fluorobenzoic acid, and to replace methanesulfonamide
with cyclopropanesulfonamide, the title compound was obtained as a
colorless solid (0.11 g, 35%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.72-8.60 (m, 1H), 7.62-7.54 (m, 1H), 7.50-7.41 (m, 1H),
7.07-6.99 (m, 1H), 6.84-6.72 (m, 1H), 6.50-6.38 (m, 1H), 4.49-4.37
(m, 1H), 3.93-3.80 (m, 1H), 3.49-3.36 (m, 1H), 3.17-3.03 (m, 1H),
2.95-2.84 (m, 1H), 2.79-2.67 (m, 1H), 2.55-2.45 (m, 1H), 2.21-2.06
(m, 1H), 2.02-1.67 (m, 4H), 1.49-1.39 (m, 2H), 1.19-1.11 (m, 5H),
0.99-0.92 (m, 2H), 0.77-0.64 (m, 2H); MS(ES+) m/z 539.1, 541.1
(M+1).
Example 327
Synthesis of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((1-(trifluoromethyl)
cyclopentyl)methyl)piperidin-3-yl)oxy)benzamide
##STR00802##
[1346] Step 1. Preparation of (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-((1-(trifluoromethyl)
cyclopentyl)methyl)piperidin-3-yl)oxy)benzoate
##STR00803##
[1348] To a stirred solution of (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate (1.84 g, 6.26
mmol) in acetone (31 mL) was added triethylamine (4.36 mL, 31.30
mmol), followed by addition of
(1-(trifluoromethyl)cyclopentyl)methyl trifluoromethanesulfonate
(1.84 g, 6.26 mmol) (A. Wolniewicz et al., Journal of Fluorine
Chemistry, 2001, 109, 95-102). The reaction mixture was stirred at
reflux for 48 hours, cooled to ambient temperature, and
concentrated in i vacuo. The residue was diluted with ethyl acetate
(70 mL), and washed with saturated aqueous sodium bicarbonate
solution (30 mL). The layers were separated and the aqueous layer
was extracted with ethyl acetate (2.times.70 mL). The combined
organic layers were washed with brine (80 mL), dried over anhydrous
magnesium sulfate, filtered and concentrated. The residue was
purified by column chromatography eluting with a gradient of ethyl
acetate in hexanes to (0 to 25%) to give the title compound as a
colorless oil (0.84 g, 30%): MS(ES+) m/z 444.4 (M+1).
Step 2. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-((1-(1-(trifluoromethyl)
cyclopentyl)methyl)piperidin-3-yl)oxy)benzoic acid
##STR00804##
[1350] Following the procedure as described in Example 50 step 2,
and making variations as required to replace methyl
4-((1-(3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-
2-fluorobenzoate with (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-((1-(trifluoromethyl)cyclopentyl)methyl)pipe-
ridin-3-yl) oxy)benzoate, the title compound was obtained as a
colorless solid (0.78 g, 90%): MS(ES+) m/z 430.2 (M+1).
Step 3. Preparation of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((1-(trifluoromethyl)
cyclopentyl)methyl)piperidin-3-yl)oxy)benzamide
##STR00805##
[1352] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
(R)-5-cyclopropyl-2-fluoro-4-((1-((1-(trifluoromethyl)cyclopentyl)methyl)-
piperidin-3-yl)oxy)benzoic acid, the title compound was obtained as
a colorless solid (0.11 g, 17%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.71 (s, 1H), 7.60-7.52 (m, 1H), 6.66-6.54 (m, 1H),
4.45-4.29 (m, 1H), 3.41 (s, 3H), 3.08-2.98 (m, 1H), 2.76-2.63 (m,
1H), 2.60-2.38 (m, 4H), 2.12-1.94 (m, 2H), 1.91-1.55 (m, 11H),
0.98-0.86 (m, 2H), 0.72-0.60 (m, 2H); MS(ES+) m/z 507.2 (M+1).
Example 328
Synthesis of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((1-(trifluoromethyl)
cyclobutyl)methyl)piperidin-3-yl)oxy)benzamide
##STR00806##
[1353] Step 1. Preparation of (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-((1-(trifluoromethyl)
cyclobutyl)methyl)piperidin-3-yl)oxy)benzoate
##STR00807##
[1355] To a mixture of (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate (1.51 g, 5.15
mmol), (1-(trifluoromethyl)cyclobutyl)methyl
trifluoromethanesulfonate (1.34 g, 4.68 mmol) (A. Wolniewicz, et
al., Journal of Fluorine Chemistry, 2001, 109, 95-102), and
potassium carbonate (0.97 g, 7.02 mmol) in cyclohexane (35 mL) was
stirred as reflux for 96 hours. The mixture was cooled to ambient
temperature, diluted with hexanes (100 mL), washed with saturated
aqueous sodium bicarbonate solution (30 mL), brine (40 mL), dried
over anhydrous magnesium sulfate, filtered and concentrated. The
residue was purified by column chromatography eluting with a
gradient of ethyl acetate in hexanes (0 to 25%) to give the title
compound as a colorless oil (0.90 g, 39%): MS(ES+) m/z 430.2
(M+1).
Step 2. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-((1-((1-(trifluoromethyl)
cyclobutyl)methyl)piperidin-3-yl)oxy)benzoic acid
##STR00808##
[1357] Following the procedure as described in Example 50 step 2,
and making variations as required to replace methyl
4-((1-(3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-
2-fluorobenzoate with (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-((1-(trifluoromethyl)cyclobutyl)methyl)piper-
idin-3-yl) oxy)benzoate, the title compound was obtained as a
colorless solid (0.58 g, 67%): MS(ES+) m/z 416.2 (M+1).
Step 3. Preparation of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((1-(trifluoromethyl)
cyclobutyl)methyl)piperidin-3-yl)oxy)benzamide
##STR00809##
[1359] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid With
(R)-5-cyclopropyl-2-fluoro-4-((1-((1-(trifluoromethyl)cyclobutyl)methyl)p-
iperidin-3-yl)oxy)benzoic acid, the title compound was obtained as
a colorless solid (0.24 g, 35%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.70 (s, 1H), 7.61-7.50 (m, 1H), 6.67-6.52 (m, 1H),
4.49-4.31 (m, 1H), 3.41 (s, 3H), 3.05-2.96 (m, 1H), 2.75-2.64 (m, 1
H), 2.59 (s, 2H), 2.53-2.32 (m, 2H), 2.29-2.15 (m, 2H), 2.11-1.93
(m, 5H), 1.92-1.80 (m, 2H), 1.73-1.58 (m, 2H), 0.99-0.85 (m, 2H),
0.71-0.60 (m, 2H); MS(ES+) m/z 493.2 (M+1).
Example 329
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((1-(trifluoromethyl)
cyclopentyl)methyl)piperidin-4-yl)methoxy)benzamide trifluoroacetic
acid salt
##STR00810##
[1360] Step 1. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-((1-((1-(trifluoromethyl)
cyclopentyl)methyl)piperidin-4-yl)methoxy)benzoate
##STR00811##
[1362] Following the procedure as described in Example 328 step 1,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
tert-butyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzonate, and to
replace (1-(trifluoromethyl)cyclobutyl)methyl
trifluoromethanesulfonate with
(1-(trifluoromethyl)cyclopentyl)methyl trifluoromethanesulfonate,
the title compound was obtained as a colorless oil (0.42 g, 54%):
MS(ES+) m/z 500.3 (M+1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-4-((1-((1-(trifluoromethyl)
cyclopentyl)methyl)piperidin-4-yl)methoxy)benzoic acid
##STR00812##
[1364] Following the procedure as described in Example 3 step 3,
and making variations as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)piperidine-1-car-
boxylate tert-butyl
5-cyclopropyl-2-fluoro-4-((1-((1-(trifluoromethyl)
cyclopentyl)methyl)piperidin-4-yl)methoxy)benzoate, the title
compound was obtained as a colorless solid (0.36 g, 97%): MS(ES+)
m/z 444.3 (M+1).
Step 3. Preparation of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((1-(trifluoromethyl)
cyclopentyl)methyl)piperidin-4-yl)methoxy)benzamide trifluoroacetic
acid salt
##STR00813##
[1366] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((1-(trifluoromethyl)cyclopentyl)methyl)pipe-
ridin-4-yl) methoxy)benzoic acid, the title compound was obtained
as a colorless solid (0.04 g, 17%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.8.82-8.64 (m, 1H), 7.64-7.53 (m, 1H), 6.63-6.49
(m, 1H), 4.00-3.68 (m, 4H), 3.42 (s, 3H), 3.28 (s, 2H), 3.06-2.70
(m, 2H), 2.28-1.69 (m, 14H), 1.01-0.88 (m, 2H), 0.71-0.59 (m, 2H);
MS(ES+) m/z 521.2 (M+1).
Example 330
Synthesis of
5-cyclopropyl-4-(((2S,3S)-1-(3,5-dichlorobenzyl)-2-methylpiperidin-3-yl)
oxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR00814##
[1367] Step 1. Preparation of tert-butyl
4-(((2S,3S)-1-benzyl-2-methylpiperidin-3-yl)
oxy)-5-chloro-2-fluorobenzoate
##STR00815##
[1369] Following the procedure as described in Example 1 step 1,
and making variation as required to replace
(R)-1-benzylpiperidin-3-ol with
(2S,3S)-1-benzyl-2-methylpiperidin-3-ol (Peter H. Huy et al., Org.
Lett., 2013, 15, 5178), the title compound was obtained as a pale
yellow oil (0.15 g, 11%): MS(ES+) m/z 434.2, 436.2 (M+1).
Step 2. tert-butyl
4-(((2S,3S)-1-benzyl-2-methylpiperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobe-
nzoate
##STR00816##
[1371] Following the procedure as described in Example 1 step 2,
and making variation as required to replace (R)-tert-butyl
4-((1-benzylpiperidin-3-yl)oxy)-5-chloro-2-fluorobenzoate with
tert-butyl
4-(((2S,3S)-1-benzyl-2-methylpiperidin-3-yl)oxy)-5-chloro-2-fluorobenzoat-
e, the title compound was obtained (0.343 g, 96%) as a colorless
oil:.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.39-7.18 (m, 6H),
6.57-6.48 (m, 1H), 4.51-4.38 (m, 1H), 3.74-3.52 (m, 2H), 3.32-3.18
(m, 1H), 2.59-2.32 (m, 2H), 2.04-1.93 (m, 1H), 1.91-1.58 (m, 4H),
1.54 (s, 9H), 1.07 (d, J=6.6 Hz, 3H), 0.91-0.79 (m, 2H), 0.67-0.52
(m, 2H).
Step 3. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-(((2S,3S)-2-methylpiperidin-3-yl)oxy)benzoate
##STR00817##
[1373] To a mixture of tert-butyl
4-((2S,3S)-1benzyl-2-methylpiperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenz-
oate (0.34 g, 0.78 mmol) and ammonium formate (0.49 g, 7.74 mmol)
in methanol (16 mL) was added 10% palladium on carbon (0.04 g). The
reaction mixture was stirred at reflux for 1 hour, cooled to
ambient temperature, and filtered through a pad of diatomaceous
earth. The filtrate was concentrated. The residue was diluted with
ethyl acetate (100 mL), washed with aqueous saturated sodium
bicarbonate solution (25 mL), water (25 mL), and brine (40 mL);
dried over anhydrous magnesium sulfate; filtered and concentrated
in vacuo to give the title compound as a colorless solid (0.22 g,
81%): MS(ES+) m/z 349.9 (M+1).
Step 4. Preparation of tert-butyl
5-cyclopropyl-4-(((2S,3S)-1-(3,5-dichlorobenzyl)-2-methylpiperidin-3-yl)o-
xy)-2-fluorobenzoate
##STR00818##
[1375] Following the procedure as described in Example 50 step 1,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
tert-butyl
4-(((2S,3S)-1-benzyl-2-methylpiperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobe-
nzoate, and to replace 1,3-dichloro-5-(1-chloroethyl)benzene with
1,3-dichloro-5-(chloromethyl)benzene, the title compound was
obtained as a colorless oil (0.27 g, 84%): MS(ES+) m/z 508.1, 510.1
(M+1).
Step 5. Preparation of
5-cyclopropyl-4-(((2S,3S)-1-(3,5-dichlorobenzyl)-2-methylpiperidin-3-yl)
oxy)-2-fluorobenzoic acid
##STR00819##
[1377] Following the procedure as described in Example 3 step 3,
and making variation as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)piperidine-
1-carboxylate with tert-butyl
5-cyclopropyl-4-(((2S,3S)-1-(3,5-dichlorobenzyl)-2-methylpiperidin-3-yl)
oxy)-2-fluorobenzoate, the title compound was obtained as a
colorless solid (0.24 g, 99%): MS(ES+) m/z 452.1, 454.0 (M+1).
Step 6. Preparation of
5-cyclopropyl-4-(((2S,3S)-1-(3,5-dichlorobenzyl)-2-methylpiperidin-3-yl)
oxy)-2-fluoro-N-(methylsulfonyl)benzamide trifluoroacetic acid
salt
##STR00820##
[1379] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
5-cyclopropyl-4-(((2S,3S)-1-(3,5-dichlorobenzyl)-2-methylpiperidin-3-yl)o-
xy)-2-fluorobenzoic acid, the title compound was obtained as a
colorless solid (0.06 g, 36%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.93-8.61 (m, 1H), 7.70-7.53 (m, 1H), 7.50-7.35 (m, 3H),
6.89-6.67 (m, 1H), 5.02-4.82 (m, 1H), 4.46-4.12 (m, 2H), 4.09-3.85
(m, 1H), 3.47-3.33 (m, 3H), 3.31-2.87 (m, 2H), 2.18-1.86 (m, 5H),
1.62-1.39 (m, 3H), 1.03-0.83 (m, 2H), 0.73-0.54 (m, 2H); MS(ES+)
m/z 529.1, 531.1 (M+1).
Example 331
Synthesis of
5-cyclopropyl-4-(((2S,3R)-1-(3,5-dichlorobenzyl)-2-methylpiperidin-3-yl)
oxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR00821##
[1380] Step 1. Preparation of tert-butyl
4-(((2S,3R)-1-benzyl-2-methylpiperidin-3-yl)
oxy)-5-chloro-2-fluorobenzoate
##STR00822##
[1382] Following the procedure as described in Example 1 step 1,
and making variation as required to replace
(R)-1-benzylpiperidin-3-ol with
(2S,3R)-1-benzyl-2-methylpiperidin-3-ol (Peter H. Huy et al., Org.
Lett., 2013, 15, 5178), the title compound was obtained as a
colorless oil (0.26 g, 37%): MS(ES+) m/z 434.1, 436.1 (M+1).
Step 2. Preparation of tert-butyl
4-(((2S,3R)-1-benzyl-2-methylpiperidin-3-yl)
oxy)-5-cyclopropyl-2-fluorobenzoate
##STR00823##
[1384] Following the procedure as described in Example 1 step 2,
and making variation as required to replace (R)-tert-butyl
4-((1-benzylpiperidin-3-yl)oxy)-5-chloro-2-fluorobenzoate with
tert-butyl
4-(((2S,3R)-1-benzyl-2-methylpiperidin-3-yl)oxy)-5-chloro-2-fluorobenzoat-
e, the title compound was obtained as a pale yellow oil (0.21 g,
80%): MS(ES+) m/z 440.4 (M+1).
Step 3. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-(((2S,3R)-2-methylpiperidin-3-yl)oxy)benzoate
##STR00824##
[1386] Following the procedure as described in Example 330 step 3,
and making variations as required to replace tert-butyl
4-(((2S,3R)-1-benzyl-2-methylpiperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobe-
nzoate with tert-butyl
4-(((2S,3R)-1-benzyl-2-methylpiperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobe-
nzoate, the title compound was obtained as a colorless oil (0.16 g,
95%): MS(ES+) m/z 350.3 (M+1).
Step 4. Preparation of tert-butyl
5-cyclopropyl-4-(((2S,3R)-1-(3,5-dichlorobenzyl)-2-methylpiperidin-3-yl)o-
xy)-2-fluorobenzoate
##STR00825##
[1388] Following the procedure as described in Example 50 step 1,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
tert-butyl
5-cyclopropyl-2-fluoro-4-(((2S,3R)-2-methylpiperidin-3-yl)oxy)benzoate,
and to replace 1,3-dichloro-5-(1-chloroethyl)benzene with
1,3-dichloro-5-(chloromethyl)benzene, the title compound was
obtained as a colorless oil (0.15 g, 68%): MS(ES+) m/z 508.1, 510.1
(M+1).
Step 5. Preparation of
5-cyclopropyl-4-(((2S,3R)-1-(3,5-dichlorobenzyl)-2-methylpiperidin-3-yl)
oxy)-2-fluorobenzoic acid
##STR00826##
[1390] Following the procedure as described in Example 3 step 3,
and making variation as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)piperidine-
1-carboxylate with tert-butyl
5-cyclopropyl-4-(((2S,3R)-1-(3,5-dichlorobenzyl)-2-methylpiperidin-3-yl)
oxy)-2-fluorobenzoate, the title compound was obtained as a
colorless solid (0.08 g, 64%): MS(ES+) m/z 452.1, 454.0 (M+1).
Step 6. Preparation of
5-cyclopropyl-4-(((2S,3R)-1-(3,5-dichlorobenzyl)-2-methylpiperidin-3-yl)
oxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR00827##
[1392] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
5-cyclopropyl-4-(((2S,3R)-1-(3,5-dichlorobenzyl)-2-methylpiperidin-3-yl)o-
xy)-2-fluorobenzoic acid, the title compound was obtained as a
colorless solid (0.03 g, 27%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.88-8.66 (m, 1H), 7.67-7.58 (m, 1H), 7.52-7.36 (m, 3H),
6.79-6.64 (m, 1H), 4.89-4.58 (m, 2H), 4.12-3.90 (m, 1H), 3.54-3.21
(m, 5H), 3.00-2.75 (m, 1H), 2.44-1.93 (m, 5H), 1.84-1.64 (m, 3H),
1.06-0.90 (m, 2H), 0.80-0.54 (m, 2H); MS(ES+) m/z 529.1, 531.1
(M+1).
Example 332
Synthesis of (R)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00828##
[1393] Step 1. Preparation of (R)-tert-butyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)
methyl)piperidine-1-carboxylate
##STR00829##
[1395] Following the procedure as described in Example 1 step 1,
and making variation as required to replace
(R)-1-benzylpiperidin-3-ol with (R)-tert-butyl
3-(hydroxymethyl)piperidine-1-carboxylate, the title compound was
obtained (13.11 g, 79%) as a colorless oil: MS(ES+) m/z 444.2,
446.2 (M+1).
Step 2. Preparation of (R)-tert-butyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)piperidine-1-carboxylate
##STR00830##
[1397] Following the procedure as described in Example 1 step 2,
and making variation as required to replace (R)-tert-butyl
4-((1-benzylpiperidin-3-yl)oxy)-5-chloro-2-fluorobenzoate with
(R)-tert-butyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)piperidine-1--
carboxylate, the title compound was obtained as a colorless solid
(8.61 g, 65%): MS(ES+) m/z 450.3 (M+1).
Step 3. Preparation (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-ylmethoxy)benzoate
##STR00831##
[1399] Following the procedure as described in Example 34 step 1,
and making variations as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-
fluorophenoxy)piperidine-1-carboxylate with (R)-tert-butyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)piperidine-1-carboxylate, the title compound was obtained as
a colorless oil (5.89 g, 99%): MS(ES+) m/z 308.2 (M+1).
Step 4. Preparation of (R)-methyl
4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR00832##
[1401] Following the procedure as described in Example 34 step 2,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
(R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-ylmethoxy)benzoate, and to
replace 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene with
1-(bromomethyl)-2-chloro-4-fluorobenzene, the title compound was
obtained as a colorless oil (4.06 g, 94%): MS(ES+) m/z 450.1, 452.1
(M+1).
Step 5. Preparation of
(R)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00833##
[1403] Following the procedure as described in Example 50 step 2,
and making variations as required to replace methyl
4-((1-(3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-
2-fluorobenzoate with (R)-methyl
4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)methoxy)-5-cyclopropyl-2-fl-
uorobenzoate, the title compound was obtained as a colorless solid
(3.80 g, 97%): MS(ES+) m/z 436.1, 438.1 (M+1).
Step 6. Preparation of
(R)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00834##
[1405] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
(R)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)methoxy)-5-cyclopropyl--
2-fluorobenzoic acid, the title compound was obtained as a
colorless solid (0.25 g, 35%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.11.53 (br s, 1H), 7.59-7.48 (m, 1H), 7.47-7.39 (m, 1H),
7.25-7.09 (m, 2H), 6.96-6.85 (m, 1H), 4.09-3.85 (m, 2H), 3.78-3.54
(m, 2H), 3.26 (s, 3H), 3.01-2.78 (m, 2H), 2.36-2.02 (m, 3H),
1.91-1.47 (m, 4H), 1.29-1.12 (m, 1H), 0.86-0.68 (m, 2H), 0.64-0.52
(m, 2H); MS(ES+) m/z 513.2, 515.1 (M+1).
Example 333
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3--
yl) methoxy)-5-cyclopropyl-2-fluorobenzamide
##STR00835##
[1407] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
(R)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)methoxy)-5-cyclopropyl--
2-fluorobenzoic acid, and to replace methanesulfonamide with
azetidine-1-sulfonamide, the title compound was obtained as a
colorless solid (0.14 g, 19%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.65 (s, 1H), 7.62-7.55 (m, 1H), 7.47-7.38 (m, 1H),
7.12-7.04 (m, 1H), 6.96-6.86 (m, 1H), 6.61-6.51 (m, 1H), 4.33-4.14
(m, 4H), 4.01-3.82 (m, 2H), 3.64-3.49 (m, 2H), 3.00-2.86 (m, 1H),
2.83-2.69 (m, 1H), 2.37-2.03 (m, 5H), 1.99-1.61 (m, 4H), 1.37-1.17
(m, 1H), 0.97-0.75 (m, 2H), 0.71-0.53 (m, 2H); MS(ES+) m/z 554.2,
556.2 (M+1).
Example 334
Synthesis of
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)methoxy)-2-flu-
oro-N-(methylsulfonyl)benzamide
##STR00836##
[1408] Step 1. Preparation of (R)-methyl
5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)methoxy)-2-fluorob-
enzoate
##STR00837##
[1410] Following the procedure as described in Example 50 step 1,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
(R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-ylmethoxy)benzoate, and to
replace 1,3-dichloro-5-(1-chloroethyl) benzene with
1,3-dichloro-5-(chloromethyl)benzene, the title compound was
obtained as a colorless oil (0.68 g, 89%): MS(ES+) m/z 466.2, 468.1
(M+1).
Step 2. Preparation of
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)
methoxy)-2-fluorobenzoic acid
##STR00838##
[1412] Following the procedure as described in Example 50 step 2,
and making variations as required to replace methyl
4-((1-(3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-
2-fluorobenzoate with (R)-methyl
5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)methoxy)-2-fluorob-
enzoate, the title compound was obtained as a colorless solid (0.60
g, 91%): MS(ES+) m/z 452.1, 454.1 (M+1).
Step 3. Preparation of
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00839##
[1414] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)methoxy)-2-flu-
orobenzoic acid, the title compound was obtained as a colorless
solid (0.14 g, 39%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.8.68
(s, 1H), 7.59-7.53 (m, 3H), 7.25-7.18 (m, 3H), 6.59-6.52 (m, 1H),
3.96-3.82 (m, 2H), 3.53-3.35 (m, 5H), 2.96-2.84 (m, 1H), 2.81-2.67
(m, 1H), 2.33-2.06 (m, 2H), 2.05-1.63 (m, 5H), 1.36-1.16 (m, 1H),
0.95-0.75 (m, 2H), 0.69-0.51 (m, 2H); MS(ES+) m/z 529.1, 531.1
(M+1).
Example 335
Synthesis of (S)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00840##
[1415] Step 1. Preparation of (S)-tert-butyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)
methyl)piperidine-1-carboxylate
##STR00841##
[1417] Following the procedure as described in Example 1 step 1,
and making variation as required to replace
(R)-1-benzylpiperidin-3-ol with (S)-tert-butyl
3-(hydroxymethyl)piperidine-1-carboxylate, the title compound was
obtained as a colorless oil (12.94 g, 78%): MS(ES+) m/z 444.2,
446.2 (M+1).
Step 2. Preparation of (S)-tert-butyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)piperidine-1-carboxylate
##STR00842##
[1419] Following the procedure as described in Example 1 step 2,
and making variation as required to replace (R)-tert-butyl
4-((1-benzylpiperidin-3-yl)oxy)-5-chloro-2-fluorobenzoate with
(S)-tert-butyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)piperidine-1--
carboxylate, the title compound was obtained as a colorless solid
(10.22 g, 78%): MS(ES+) m/z 450.3 (M+1).
Step 3. Preparation of (S)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3ylmethoxy)benzoate
##STR00843##
[1421] Following the procedure as described in Example 34 step 1,
making variations as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-
fluorophenoxy)piperidine-1-carboxylate with (R)-tert-butyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)piperidine-1-carboxylate, the title compound was obtained as
a pale yellow oil (6.99 g, 99%): MS(ES+) m/z 308.2 (M+1).
Step 4. Preparation of (S)-methyl
4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR00844##
[1423] Following the procedure as described in Example 34 step 2,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
(S)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yl)methoxy)benzoate, and to
replace 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl) benzene with
1-(bromomethyl)-2- chloro-4-fluorobenzene, the title compound was
obtained as a colorless oil (1.85 g, 42%): MS(ES+) m/z 450.2, 452.2
(M+1).
Step 5. Preparation of
(S)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00845##
[1425] Following the procedure as described in Example 50 step 2,
an making variations as required to replace
4-((1-(3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-
2-fluorobenzoate with (S)-methyl
4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)methoxy)-5-cyclopropyl-2-fl-
uorobenzoate, the title compound was obtained as a colorless solid
(1.78 g, 99%): MS(ES+) m/z 436.2, 438.1 (M+1).
Step 6. Preparation of
(S)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00846##
[1427] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
(S)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)methoxy)-5-cyclopropyl--
2-fluorobenzoic acid, the title compound was obtained as a
colorless solid (0.19 g, 37%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta.11.53 (br s, 1H), 7.58-7.48 (m, 1H), 7.47-7.38 (m, 1H),
7.24-7.09 (m, 2H), 6.96-6.86 (m, 1H), 4.08-3.85 (m, 2H), 3.79-3.56
(m, 2H), 3.26 (s, 3H), 3.01-2.78 (m, 2H), 2.34-2.21 (m, 1H),
2.20-2.02 (m, 2H), 1.92-1.50 (m, 4H), 1.31-1.12 (m, 1H), 0.85-0.69
(m, 2H), 0.65-0.53 (m, 2H); MS(ES+) m/z 513.2, 515.2 (M+1).
Example 336
Synthesis of
(S)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00847##
[1428] Step 1. Preparation of (S)-methyl
5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)
methoxy)-2-fluorobenzoate
##STR00848##
[1430] Following the procedure as described in Example 50 step 1,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
(S)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yl)methoxy)benzoate, and to
replace 1,3-dichloro-5-(1-chloroethyl)benzene with
1,3-dichloro-5-(chloromethyl)benzene, the title compound was
obtained as a colorless oil (0.65 g, 86%): MS(ES+) m/z 466.2, 468.2
(M+1).
Step 2. Preparation of
(S)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)
methoxy)-2-fluorobenzoic acid
##STR00849##
[1432] Following the procedure as described in Example 50 step 2,
and making variations as required to replace methyl
4-((1-(3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-
2-fluorobenzoate with (S)-methyl
5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)methoxy)-2-fluorob-
enzoate, the title compound was obtained as a colorless solid (0.52
g, 83%): MS(ES+) m/z 452.1, 454.2 (M+1).
Step 3. Preparation of
(S)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR00850##
[1434] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
(S)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)methoxy)-2-flu-
orobenzoic acid, the title compound was obtained as a colorless
solid (0.07 g, 20%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.8.78
(s, 1H), 7.60-7.50 (m, 1H), 7.24-7.20 (m, 3H), 6.61-6.50 (m, 1H),
3.99-3.82 (m, 2H), 3.55-3.32 (m, 5H), 2.97-2.83 (m, 1H), 2.82-2.67
(m, 1H), 2.32-2.05 (m, 2H), 2.05-1.60 (m, 5H), 1.33-1.15 (m, 1H),
0.95-0.75 (m, 2H), 0.68-0.48 (m, 2H); MS(ES+) m/z 529.1, 531.1
(M+1).
Example 337 and Example 338
Synthesis of
5-cyclopropyl-4-(((S)-1-((R)-1-(3,5-dichlorophenyl)ethyl)
piperidin-3-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR00851##
[1435] And
5-cyclopropyl-4-(((S)-1-((S)-1-(3,5-dichlorophenyl)ethyl)
piperidin-3-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR00852##
[1436] Step 1. Preparation of methyl
5-cyclopropyl-4-(((3S)-1-(1-(3,5-dichlorophenyl)ethyl)
piperidin-3-yl)methoxy)-2-fluorobenzoate
##STR00853##
[1438] Following the procedure as described in Example 50 step 1,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
(S)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-ylmethoxy)benzoate, the title
compound was obtained as a pale yellow oil (1.92 g, 75%): MS(ES+)
m/z 480.2, 482.2 (M+1).
Step 2. Preparation of
5-cyclopropyl-4-(((3S)-1-(1-(3,5-dichlorophenyl)ethyl)
piperidin-3-yl)methoxy)-2-fluorobenzoic acid
##STR00854##
[1440] Following the procedure as described in Example 50 step 2,
and making variations as required to replace methyl
4-((1-(3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-
2-fluorobenzoate with methyl
5-cyclopropyl-4-(((3S)-1-(1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)meth-
oxy)-2-fluorobenzoate, the title compound was obtained as a
colorless solid (1.72 g, 92%): MS(ES+) m/z 452.1, 454.2 (M+1).
Step 3. Preparation of
5-cyclopropyl-4-(((S)-1-((R)-1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR00855##
[1441] And 5-cyclopropyl-4-(((S)-1-((S)-1-(3,5
-dichlorophenyl)ethyl)piperidin-3-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR00856##
[1443] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
5-cyclopropyl-4-(((3S)-1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)methoxy-
)-2-fluorobenzoic acid, a mixture of diastereomers was obtained.
The mixture of diastereomers was then purified by preparative HPLC.
The first eluting fraction was arbitrarily assigned as
5-cyclopropyl-4-(((S)-1-((R)-1-(3,5-dichlorophenyl)
ethyl)piperidin-3-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt (0.03 g, 4%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6, 1 drop of D.sub.2O) .delta.7.80-7.75 (m, 1H),
7.68-7.63 (m, 2H), 7.19-7.12 (m, 1H), 6.98-6.90 (m, 1H), 4.62-4.51
(m, 1H), 4.11-4.04 (m, 1H), 3.94-3.84 (m, 1H), 3.79-3.67 (m, 1H),
3.36-3.28 (m, 4H), 2.85-2.63 (m, 2H), 2.36-2.20 (m, 1H), 2.04-1.91
(m, 1H), 1.88-1.73 (m, 2H), 1.73-1.58 (m, 4H), 1.39-1.26 (m, 1H),
0.80-0.51 (m, 4H); MS(ES+) m/z 543.2, 545.1 (M+1).
[1444] The second eluting fraction was arbitrarily assigned as
5-cyclopropyl-4-(((S)-1-((S)-1-(3,5-dichlorophenyl)
ethyl)piperidin-3-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt (0.03 g, 4%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.13.00 (br s, 1H), 8.81-8.64 (m, 1H), 7.66-7.57
(m, 1H), 7.50-7.43 (m, 1H), 7.37-7.30 (m, 2H), 6.58-6.49 (m, 1H),
4.51-4.36 (m, 1H), 4.07-3.77 (m, 3H), 3.64-3.52 (m, 1H), 3.41 (s,
3H), 2.83-2.65 (m, 1H), 2.58-2.39 (m, 2H), 2.26-2.09 (m, 1H),
2.08-1.91 (m, 2H), 1.91-1.71 (m, 4H), 1.50-1.32 (m, 1H), 0.92-0.76
(m, 2H), 0.71-0.50 (m, 2H); MS(ES+) m/z 543.2, 545.1 (M+1).
Example 339
Synthesis of
(S)-N-(azetidin-1-ylsulfonyl)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3--
yl) methoxy)-5-cyclopropyl-2-fluorobenzamide, trifluoroacetic acid
salt
##STR00857##
[1446] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
(S)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)methoxy)-5-cyclopropyl--
2-fluorobenzoic acid, and to replace methanesulfonamide with
azetidine-1-sulfonamide, the title compound was obtained as a
colorless solid (0.05 g, 7%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.12.89 (br s, 1H), 8.79-8.49 (m, 1H), 7.79-7.69 (m, 1H),
7.67-7.58 (m, 1H), 7.24-7.17 (m, 1H), 7.17-7.06 (m, 1H), 6.60-6.45
(m, 1H), 4.43 (s, 2H), 4.32-4.16 (m, 4H), 4.08-3.84 (m, 2H),
3.81-3.57 (m, 2H), 2.83-2.63 (m, 2H), 2.34-1.82 (m, 7H), 1.66-1.39
(m, 1H), 0.98-0.81 (m, 2H), 0.73-0.55 (m, 2H); MS(ES+) m/z 554.1,
556.1 (M+1).
Example 340
Synthesis of (S)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR00858##
[1448] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
(S)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)methoxy)-5-cyclopropyl--
2-fluorobenzoic acid, and to replace methanesulfonamide with
cyclopropanesulfonamide, the title compound was obtained as a
colorless solid (0.17 g, 33%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.13.17 (br s, 1H), 8.78-8.58 (m, 1H), 7.80-7.70 (m, 1H),
7.64-7.56 (m, 1H), 7.22-7.16 (m, 1H), 7.14-7.05 (m, 1H), 6.58-6.44
(m, 1H), 4.41 (s, 2H), 4.05-3.81 (m, 2H), 3.77-3.55 (m, 2H),
3.14-3.01 (m, 1H), 2.82-2.60 (m, 3H), 2.22-1.79 (m, 4H), 1.58-1.36
(m, 3H), 1.20-1.05 (m, 2H), 0.96-0.79 (m, 2H), 0.72-0.50 (m, 2H);
MS(ES+) m/z 539.2, 541.2 (M+1).
Example 341
Synthesis
5-cyclopropyl-4-(((3R,6R)-1-(3,5-dichlorobenzyl)-6-methylpiperid-
in-3-yl) methoxy)-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR00859##
[1449] Step 1. Preparation of (2R,5R)-benzyl
5-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)
methyl)-2-methylpiperidin-1-carboxylate
##STR00860##
[1451] Following the procedure as described in Example 1 step 1,
and making variations as required to replace
(R)-1-benzylpiperidin-3-ol with (2R,5R)-benzyl
5-(hydroxymethyl)-2-methylpiperidine-1-carboxylate (WO 2010/048010
A1), the title compound was obtained as a colorless oil (1.61 g,
66%): MS(ES+) m/z 492.2, 494.1 (M+1).
Step 2. Preparation of (2R,5R)-benzyl
5-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-2-methylpiperidine-1-carboxylate
##STR00861##
[1453] Following the procedure as described in Example 1 step 2,
and making variations as required to replace (R)-tert-butyl
4-((1-benzylpiperidin-3-yl)oxy)-5-chloro-2-fluorobenzoate with
(2R,5R)-benzyl
5-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)-2-methylpipe-
ridine-1-carboxylate, the title compound was obtained as a
colorless solid (1.46 g, 90%): MS(ES+) m/z 498.3 (M+1).
Step 3. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-(((3R,6R)-6-methylpiperidin-3-yl)methoxy)benzoat-
e
##STR00862##
[1455] Following the procedure as described in Example 52 step 4,
and making variation as required to replace (2R,5R)-benzyl
5-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-
fluorophenoxy)-2-methylpiperidine-1-carboxylate with (2R,5R)-benzyl
5-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-2-methylpiperidine-1-carboxylate, the title compound was
obtained as a colorless oil (1.00 g, 94%): MS(ES+) m/z 364.3
(M+1).
Step 4. Preparation of tert-butyl
5cyclopropyl-4-(((3R,6R)-1-(3,5-dichlorobenzyl)-6-methylpiperidin-3-yl)me-
thoxy)-2-fluorobenzoate
##STR00863##
[1457] Following the procedure as described in Example 50 step 1,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
tert-butyl
5-cyclopropyl-2-fluoro-4-(((3R,6R)-6-methylpiperidin-3-yl)methoxy)benzoat-
e, and to replace 1,3-dichloro-5-(1-chloroethyl)benzene with
1,3-dichloro-5-(chloromethyl)benzene, the title compound was
obtained a colorless oil (0.71 g, 98%): MS(ES+) m/z 522.2, 524.2
(M+1).
Step 5. Preparation of
5-cyclopropyl-4-(((3R,6R)-1-(3,5-dichlorobenzyl)-6-methylpiperidin-3-yl)
methoxy)-2-fluorobenzoic acid
##STR00864##
[1459] Following the procedure as described in Example 3 step 3,
and making variations as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)piperidine-
1-carboxylate with tert-butyl
5-cyclopropyl-4-(((3R,6R)-1-(3,5-dichlorobenzyl)-6-methylpiperidin-3-yl)
methoxy)-2-fluorobenzoate, the title compound was obtained as a
colorless solid (0.56 g, 88%): MS(ES+) m/z 466.1, 468.1 (M+1).
Step 6. Preparation of
5-cyclopropyl-4-(((3R,6R)-1-(3,5-dichlorobenzyl)-6-methylpiperidin-3-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR00865##
[1461] Following the procedure as described in Example 17 step 2,
and making variations required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
5-cyclopropyl-4-(((3R,6R)-1-(3,5-dichlorobenzyl)-6-methylpiperidin-3-yl)m-
ethoxy)-2-fluorobenzoic acid, the title compound was obtained as a
colorless solid (0.09 g, 40%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta.8.82-8.62 (m, 1H), 7.67-7.52 (m, 1H), 7.51-7.42 (m, 1H),
7.42-7.34 (m, 2H), 6.57-6.42 (m, 1H), 4.76-4.57 (m, 1H), 4.03-3.76
(m, 3H), 3.53-3.44 (m, 1H), 3.41 (s, 3H), 3.04-2.71 (m, 2H),
2.55-2.37 (m, 1H), 2.28-2.10 (m, 1H), 2.09-1.95 (m, 2H), 1.80-1.61
(m, 4H), 1.56-1.42 (m, 1H), 0.87-0.75 (m, 2H), 0.66-0.49 (m, 2H)
MS(ES+) m/z 543.2, 545.2 (M+1).
Example 342
Synthesis of
5-cyclopropyl-4-(((3R,6R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)-6-methylpip-
eridin-3-yl) methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
trifluoroacetic acid salt (arbitrarily assigned)
##STR00866##
[1462] Step 1. Preparation of tert-butyl
5-cyclopropyl-4-(((3R,6R)-1-((S)-1-(3,5-dichlorophenyl)
ethyl-6-methylpiperidin-3-yl)methoxy)-2-fluorobenzoate
##STR00867##
[1463] And tert-butyl
5-cyclopropyl-4-(((3R,6R)-1-(3,5-dichlorophenyl)ethyl)-6-methylpiperidin--
3-yl) methoxy)-2-fluorobenzoate
##STR00868##
[1465] Following the procedure as described in Example 50 step 1,
and making variations as required to replace (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate with
tert-butyl
5-cyclopropyl-2-fluoro-4-(((3R,6R)-6-methylpiperidin-3-yl)methoxy)benzoat-
e. The mixture of diastereomers was separated by column
chromatography eluting with a gradient of methanol in
dichloromethane (0 to 5%). The first eluting fraction was
arbitrarily assigned as tert-butyl 5-cyclopropyl-4-(((3
R,6R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)-6-methylpiperidin-3-yl)
methoxy)-2-fluorobenzoate (0.23 g, 32%) as a pale yellow oil:
MS(ES+) m/z 536.0, 538.2 (M+1).
[1466] The second eluting fraction was arbitrarily assigned as
tert-butyl 5-cyclopropyl-4-(((3R,6R)-1-((R)-1-(3,5-dichlorophenyl)
ethyl)-6-methylpiperidin-3-yl)methoxy)-2-fluorobenzoate (0.23 g,
32%) as a pale yellow oil: MS(ES+) m/z 536.1, 538.1 (M+1).
Step 2. Preparation of
5-cyclopropyl-4-(((3R,6R)-1-((S)-1-(3,5-dichlorophenyl)
ethyl)-6-methylpiperidin-3-yl)methoxy)-2-fluorobenzoic acid
##STR00869##
[1468] Following the procedure as described in Example 3 step 3,
and making variations as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)piperidine-
1-carboxylate with tert-butyl
5-cyclopropyl-4-(((3R,6R)-1-((S)-1-(3,5-dichlorophenyl)
ethyl)-6-methylpiperidin-3-yl)methoxy)-2-fluorobenzoate, the title
compound was obtained as a colorless solid (0.20 g, 99%): MS(ES+)
m/z 480.1, 482.1 (M+1).
Step 3. Preparation of
5-cyclopropyl-4-(((3R,6R)-1-((S)-1-(3,5-dichlorophenyl)
ethyl)-6-methylpiperidin-3-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzami-
de, trifluoroacetic acid salt
##STR00870##
[1470] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
5-cyclopropyl-4-(((3R,6R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)-6-methylpip-
eridin-3-yl) methoxy)-2-fluorobenzoic acid, the title compound was
obtained as a colorless solid (0.05 g, 38%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.12.12 (br s, 1H), 8.91-8.53 (m, 1H), 7.65-7.57
(m, 1H), 7.53-7.48 (m, 2H), 7.45-7.39 (m, 1H), 6.56-6.44 (m, 1H),
5.05-4.92 (m, 1H), 4.02-3.76 (m, 2H), 3.41 (s, 3H), 3.27-3.08 (m,
2H), 2.88-2.71 (m, 1H), 2.72-2.56 (m, 2H), 2.36-2.20 (m, 1H),
2.09-1.92 (m, 2H), 1.83-1.49 (m, 7H), 0.94-0.75 (m, 2H), 0.71-0.50
(m, 2H); MS(ES+) m/z 557.0, 559.0 (M+1).
Example 343
Synthesis of
5-cyclopropyl-4-(((3R,6R)-1-((R)-1-(3,5-dichlorophenyl)
ethyl)-6-methylpiperidin-3-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzami-
de, trifluoroacetic acid salt
##STR00871##
[1471] Step 1. Preparation of
5-cyclopropyl-4-(((3R,6R)-1-((R)-1-(3,5-dichlorophenyl)
ethyl)-6-methylpiperidin-3-yl)methoxy)-2-fluorobenzoic acid
##STR00872##
[1473] Following the procedure as described in Example 3 step 3,
and making variations as required to replace (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)piperidine-1-car-
boxylate with tert-butyl
5-cyclopropyl-4-(((3R,6R)-1-((R)-1-(3,5-dichlorophenyl)
ethyl)-6-methylpiperidin-3-yl)methoxy)-2-fluorobenzoate, the title
compound was obtained as a colorless solid (0.21 g, 99%): MS(ES+)
m/z 480.1, 482.1 (M+1).
Step 3. Preparation of
5-cyclopropyl-4-(((3R,6R)-1-((R)-1-(3,5-dichlorophenyl)
ethyl)-6-methylpiperidin-3-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzami-
de, trifluoroacetic acid salt
##STR00873##
[1475] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoroben-
zoic acid with
5-cyclopropyl-4-(((3R,6R)-1-((R)-1-(3,5-dichlorophenyl)ethyl)-6-methylpip-
eridin-3-yl) methoxy)-2-fluorobenzoic acid, the title compound was
obtained as a colorless solid (0.05 g, 28%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.13.00 (br s, 1H), 8.91-8.59 (m, 1H), 7.72-7.59
(m, 1H), 7.54-7.45 (m, 1H), 7.31-7.27 (m, 2H), 6.61-6.51 (m, 1H),
5.04-4.91 (m, 1H), 4.14-3.90 (m, 2H), 3.85-3.73 (m, 1H), 3.42 (s,
3H), 2.96-2.64 (m, 2H), 2.60-2.42 (m, 1H), 2.26-2.06 (m, 1H),
2.04-1.65 (m, 9H), 1.56-1.36 (m, 1H), 0.87-0.73 (m, 2H), 0.67-0.54
(m, 2H); MS(ES+) m/z 557.0, 559.0 (M+1).
Example 344
Synthesis of
5-cyclopropyl-4-(((3R,6R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)-6-methylpip-
eridin-3-yl) methoxy)-N-(ethylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR00874##
[1477] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
5-cyclopropyl-4-(((3R,6R)-1-((S)-1-(3,5-dichlorophenyl)ethyl)-6-methylpip-
eridin-3-yl) methoxy)-2-fluorobenzoic acid, and to replace
methanesulfonamide with ethanesulfonamide, the title compound was
obtained as a colorless solid (0.05 g, 31%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta.11.80 (br s, 1H), 9.19-9.02 (m, 1H), 7.84-7.64
(m, 3H), 7.21-7.10 (m, 1H), 6.98-6.84 (m, 1H), 5.16-4.95 (m, 1H),
4.16-3.95 (m, 1H), 3.87-3.68 (m, 1H), 3.50-3.37 (m, 2H), 3.11-2.85
(m, 2H), 2.30-1.89 (m, 3H), 1.83-1.29 (m, 10H), 1.25-1.14 (m, 3H),
0.79-0.35 (m, 4H); MS(ES+) m/z 571.1, 573.1 (M+1).
Example 345
Synthesis of
5-cyclopropyl-4-(((3R,6R)-1-((R)-1-(3,5-dichlorophenyl)
ethyl)-6-methylpiperidin-3-yl)methoxy)-N-(ethylsulfonyl)-2-fluorobenzamid-
e, trifluoroacetic acid salt
##STR00875##
[1479] Following the procedure as described in Example 17 step 2,
and making variations as required to replace
(R)-5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-3-yl)-oxy)-2-fluoro-
benzoic acid with
5-cyclopropyl-4-(((3R,6R)-1-((R)-1-(3,5-dichlorophenyl)ethyl)-6-methylpip-
eridin-3-yl) methoxy)-2-fluorobenzoic acid, and to replace to
methanesulfonamide with ethanesulfonamide, the title compound was
obtained as a colorless solid (0.02 g, 17%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta.11.84 (br s, 1H), 9.71-9.51 (m, 1H), 7.86-7.60
(m, 3H), 7.24-7.14 (m, 1H), 7.03-6.90 (m, 1H), 5.21-4.98 (m, 1H),
4.15-3.99 (m, 1H), 3.94-3.81 (m, 1H), 3.52-3.39 (m, 2H), 2.97-2.80
(m, 1H), 2.47-2.22 (m, 2H), 2.04-1.35 (m, 11H), 1.29-1.18 (m, 3H),
0.82-0.55 (m, 4H); MS(ES+) m/z 571.1, 573.1 (M+1).
Example 346
Synthesis of
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-y-
l) methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
trifluoroacetic acid salt
##STR00876##
[1480] Step 1. Preparation of tert-Butyl
4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate
##STR00877##
[1482] To a solution of
1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid (5.00
g, 20.20 mmol) in tetrahydrofuran (100 mL) was added a solution of
borane tetrahydrofuran complex (30.3 mL, 30.30 mmol, 1.0 M solution
in tetrahydrofuran). The reaction mixture was refluxed for 16
hours, and then another 24 mL of borane tetrahydrofuran complex was
added and continued to reflux for another 16 hours. After cooling
to ambient temperature the reaction mixture poured onto ice-cold
water (50 mL) and saturated ammonium chloride (100 mL), and
extracted with ethyl acetate (3.times.100 mL), dried over anhydrous
sodium sulfate and filtered. The filtrate was concentrated to
afford the title compound (4.60 g, 98%). Which was used in the next
step without further purification; MS(ES+) m/z 234.1 (M +1).
Step 2. Preparation of tert-butyl
4-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)
methyl)-4-fluoropiperidine-1-carboxylate
##STR00878##
[1484] To a mixture of tert-butyl
4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (4.60 g, 19.70
mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (4.89 g, 19.70
mmol) in dimethyl sulfoxide (50 mL) was added cesium carbonate
(9.65 g, 29.60 mmol) and the reaction mixture was heated at
80.degree. C. for 4 hours. After cooling to an ambient temperature,
water (50 mL) was added, and then extracted with ethyl acetate
(3.times.100 mL). The organic layer was washed with brine
(2.times.50 mL), dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated in vacuo and the residue was purified
by silica gel column chromatography eluting with gradient of 0-30%
ethyl acetate in hexanes to afford the title compound as a
colorless gum (6.60 g, 73%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.82 (d, J=7.6 Hz, 1H), 6.58 (d, J=11.8 Hz, 1H), 3.90-4.10
(m, 3H), 3.07 (t, J=12.4 Hz, 2H), 1.98-1.89 (m, 3H), 1.84-1.56 (m,
2H), 1.51 (s, (H), 1.40 (s, 9H); MS(ES+) m/z 464.1, 462.1
(M+1).
Step 3. Preparation of tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-4-fluoropiperidine-1-carboxylate
##STR00879##
[1486] To a mixture of tert-butyl
4-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)-4-fluoropipe-
ridin-1-carboxylate (6.60 g, 14.30 mmol), cyclopropylboronic acid
(3.07 g, 35.80 mmol), potassium phosphate (12.2 g, 57.3 mmol) and
tricyclohexylphosphine tetrafluoroborate (0.79 g, 2.15 mmol) in
toluene (120 mL) and water (12 mL) under a nitrogen atmosphere was
added palladium acetate (0.32 g, 1.43 mmol). The reaction mixture
was heated at 100.degree. C. for 16 hours and cooled to ambient
temperature. To the reaction mixture was added water (20 mL) and
extracted with ethyl acetate (3.times.100 mL). The combined organic
extracts was washed with brine, dried over anhydrous sodium sulfate
and filtered. The filtrate was concentrated in vacuo and the
residue was purified by column chromatography eluting with 5% ethyl
acetate in hexanes to afford the title compound as a colorless gum
(4.00 g, 60%): MS(ES+) m/z 468.6 (M+1).
Step 4. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl) methoxy)benzoate
hydrochloride
##STR00880##
[1488] To a solution of tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-4-fluoropiperidine-1-carboxylate (4.00 g, 8.50 mmol) in
dioxane (12 mL) was added a solution of hydrogen chloride in
dioxane (4M, 4.0 mL, 16.00 mmol). The reaction solution was stirred
at an ambient temperature for 3 hours. The title compound
precipitated out from solution was collected by filtration. The
filtrate was concentrated to afford another portion of product
(1.90 g in total, 61%) as a pale yellow solid: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.97 (br s, 1H), 7.26 (d, J=8.4 Hz, 1H),
6.93 (d, J =12.9 Hz, 1H), 4.23 (d, J=19.9 Hz, 2H), 3.31-3.20 (m,
2H), 3.11-2.92 (m, 2H), 2.15-2.06 (m, 2H), 2.04-1.92 (m, 2H), 1.47
(s, 9H), 0.91-0.85 (m, 2H), 0.60-0.54 (m, 2H); MS(ES+) m/z 368.2
(M+1).
Step 5. Preparation of tert-butyl
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)
benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR00881##
[1490] A mixture of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl)methoxy)benzoate
hydrochloride (0.29 g, 0.70 mmol),
1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)benzene (0.18
g, 0.70 mmol) and potassium carbonate (0.24 g, 2.10 mmol) in
N,N-dimethylformamide (2 mL) was heated at 90.degree. C. for 16
hours. The solid was filtered off and the filtrate was subjected to
column chromatography eluting with 40% ethyl acetate in hexanes to
afford the title compound as a gum (0.29 g, 71%): MS(ES+) m/z
578.2, 580.2 (M+1).
Step 6. Preparation of 4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)
benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid
##STR00882##
[1492] To a solution of tert-butyl
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoate (0.29 g, 0.50 mmol)
in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL).
The reaction mixture was stirred for 3 hours and concentrated
invacuo to afford the title compound as a colorless solid (0.20 g,
76%): MS(ES-) m/z 520.2, 518.2 (M-1).
Step 7. Preparation of
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR00883##
[1494] To a mixture of
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid (0.10 g, 0.19
mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.068 g, 0.44
mmol), 4-dimethylaminopyridine (0.054 g, 0.44 mmol) was added
methanesulfonamide (0.027 g, 0.29 mmol) in dichloromethane (3 mL).
After stirring at ambient temperature for 16 hours, the reaction
mixture was diluted with ethyl acetate (5 mL), washed with brine
(10 mL), dried over anhydrous sodium sulfate and filtered. The
filtrate was concentrated in vacuo and the residue was purified by
preparative-HPLC to afford the title compound as a colorless solid
(0.05 g, 44%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.91
(br s, 1H), 10.24 (br s, 1H), 8.22 (d, J=3 Hz, 1H), 8.00 (d, J=3
Hz, 1H), 7.13 (d, J=9 Hz, 1H), 6.98 (d, J=12 Hz, 1H), 4.65-4.10 (m,
5H), 3.53-3.01 (m, 6H), 2.32-1.81 (m, 5H), 0.94-0.78 (m, 2H),
0.72-0.56 (m, 2H); MS (ES+) m/z 599.1, 601.3 (M+1).
Example 347
Synthesis of
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR00884##
[1496] Following the procedure as described in Example 346 step 7
and making non-critical variation as required to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.04 g, 35%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.89 (br s, 1H), 10.10 (br s, 1H), 8.28
(d, J=6 Hz, 1H), 8.05 (d, J=6 Hz, 1H), 7.15 (d, J=9 Hz, 1H), 7.02
(d, J=15 Hz, 1H), 4.60-4.20 (m, 5H), 3.59-3.16 (m, 4H), 3.14-2.99
(m, 1H), 2.37-1.88 (m, 5H), 1.18-1.04 (m, 3H), 0.96-0.83 (m, 2H),
0.74-0.64 (m, 2H); MS(ES+) m/z 625.1, 627.3 (M+1).
Example 348
Synthesis of
4-((1-(3-chloro-4-(trifluoromethoxy)benzyl)-4-fluoropiperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR00885##
[1497] Step 1. Preparation of tert-butyl
4-((1-(3-chloro-4-(trifluoromethoxy)benzyl)-4-fluoropiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR00886##
[1499] To a solution of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl)methoxy)benzoate
(0.250 g, 0.62 mmol) and 3-chloro-4-(trifluoromethoxy)benzaldehyde
(0.17 g, 0.74 mmol) in tetrahydrofuran (5 mL) was added sodium
triacetoxyborohydride (0.30 g, 1.40 mmol). The reaction mixture was
stirred at ambient temperature for 16 hours and concentrated
invacuo. The residue was subjected to column chromatography to
afford the title compound as a colorless gum (0.10 g, 23%): MS(ES+)
m/z 576.2, 578.2 (M+1).
Step 2. Preparation of
4-((1-(3-chloro-4-(trifluoromethoxy)benzyl)-4-fluoropiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00887##
[1501] Following the procedure as described in Example 346 step 6,
and making non-critical variation as required to replace tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)-4-fluor-
opiperidine-1-carboxylate with tert-butyl
4-((1-(3-chloro-4-(trifluoromethoxy)benzyl)-4-fluoropiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained as a colorless solid (0.12 g, quant. yield): MS(ES+) m/z
522.2, 520.2 (M+1)
Step 3. Preparation of
4-((1-(3-chloro-4-(trifluoromethoxy)benzyl-4-fluoropiperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
trifluoroacetic acid salt
##STR00888##
[1503] Following the procedure as described in Example 346 step 7
and making non-critical variation as respired to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.02 g, 14%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta..alpha.11.89 (br s, 1H), 10.00 (br s,
1H), 7.90 (s, 1H), 7.75-7.56 (m, 2H), 7.15 (d, J=9 Hz, 1H), 7.03
(d, J=12 Hz, 1H), 4.54-4.2 (m, 4H), 3.25-2.97 (m, 2H), 2.34-1.88
(m, 3H), 2.32-1.85 (m, 5H), 1.21-1.03 (m, 4H), 0.95-0.83 (m, 2H),
0.75-0.61 (m, 2H); MS(ES+) m/z 625.0, 623.1 (M+1).
Example 348
Synthesis of
4-((1-(5-chloro-2-(trifluoromethyl)piperidin)-4-fluoropiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR00889##
[1505] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin-4-fluoropiperidin-4-
-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-(5-chloro-2-(trifluoromethyl)piperidin-4-fluoropiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was
obtained as a colorless solid (0.02 g, 23%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.95 (br, s, 1H), 8.13 (br, s, 1H),
7.96-7.79 (m, 2H), 7.16 (d, J=6 Hz, 1H), 7.02 (d, J=15 Hz, 1H),
4.68-4.41 (m, 2H), 4.39-4.18 (m, 3H), 3.46-3.23 (m, 2H), 3.34 (s,
3H), 2.33-1.93 (m, 6H), 0.95-0.85 (m, 2H), 0.74-0.65 (m, 2H);
MS(ES+) m/z 583.1, 581.2 (M+1).
Example 349
Synthesis of
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-
-yl) methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic
acid salt
##STR00890##
[1506] Step 1. Preparation of (S)-tert-butyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)
ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoate
##STR00891##
[1508] Following the procedure as described in Example 346 step 5
and making non-critical variations as required to replace
1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)benzene with
(R)-1-(3,5-dichlorophenyl)ethyl 4-methylbenzenesulfonate, the title
compound was obtained as a colorless solid (0.40 g, 60%): MS(ES+)
m/z 542.2, 540.2 (M+1).
Step 2. Preparation of
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-
-yl) methoxy)-2-fluorobenzoic acid
##STR00892##
[1510] Following the procedure as described in Example 346 step 6,
and making non-critical variations as required to replace
tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)-4-fluor-
opiperidine-1-carboxylate with (R)-tert-butyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-yl)
methoxy)-2-fluorobenzoate, the title compound was obtained as a
colorless solid (0.20 g, 41%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 12.9 (br s, 1H), 7.73 (s, 1H), 7.61 (s, 2H), 7.30 (d, J=8.4
Hz, 1H), 6.93 (d, J=12.9 Hz, 1H), 4.73-4.53 (m, 1H), 4.23 (d,
J=20.3 Hz, 2H), 3.81-3.3.63 (m, 1H), 3.26-3.14 (m, 1H), 3.09-2.90
(m, 2H), 2.15-2.06 (m, 2H), 2.04-1.92 (m, 2H), 1.64 (brs, 3H),
0.89-0.83 (m, 2H), 0.60-0.55 (m, 2H); MS(ES+) m/z 486.3, 484.1
(M+1).
Step 3. Preparation of
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-
-yl) methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic
acid salt
##STR00893##
[1512] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin-4-fluoropiperidin-4-
-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)
ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoic acid, the
title compound (0.05 g, 42% yield) was obtained as a colorless
solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.95 (br s,
1H), 7.87-7.54 (m, 3H), 7.16 (d, J=9 Hz, 1H), 7.02 (d, J=12 Hz,
1H), 4.57 (br, s, 1H), 4.39-4.18 (m, 2H), 3.52 (br, s, 6H),
2.36-1.85 (m, 8H), 1.33-1.14 (m, 1H), 0.89-0.80 (m, 2H), 0.74-0.61
(m, 2H); MS (ES+) m/z 563.3, 561.1 (M+1).
Example 350
Synthesis of
(S)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(1-(3,5-dichlorophenyl)
ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzamide
##STR00894##
[1514] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)
ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoic acid and to
replace methanesulfonamide with cyclopropylsulfonamide, the title
compound was obtained as a colorless solid (0.07 g, 57%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.85 (br s, 1H), 10.01 (br s,
1H), 7.73 (s, 1H), 7.615 (d, J=3.0 Hz, 2H), 7.12 (d, J=6.0 Hz, 1H),
6.99 (d, J=15.0 Hz, 1H), 4.6 (brs, 1H), 4.24 (d, J=18.0 Hz, 2H),
3.81-3.62 (m, 1H), 3.27-3.11 (m, 1H), 3.09-2.89 (m, 2H), 2.36-1.83
(m, 5H), 1.73-1.51 (m, 3H), 1.16-1.01 (m, 3H), 0.91-0.78 (m, 2H),
0.71-0.60 (m, 2H); MS(ES+) m/z 589.3, 587.1 (M+1).
Example 351
Synthesis of
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-
-yl) methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic
acid
##STR00895##
[1515] Step 1. Preparation of (R)-tert-butyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)
ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoate
##STR00896##
[1517] Following the procedure as described in Example 346 step 5
and making non-critical variations as required to replace
1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)benzene with
(S)-1-(3,5-dichlorophenyl)ethyl 4-methylbenzenesulfonate, the title
compound was obtained (0.04 g, 60%): MS(ES+) m/z 542.2, 540.2
(M+1).
Step 2. Preparation of
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-
-yl) methoxy)-2-fluorobenzoic acid
##STR00897##
[1519] Following the procedure as described in Example 346 step 6
and making non-critical variations as required to replace
tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-4-fluoropiperidine-1-carboxylate with (S)-tert-butyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)
ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoate, the title
compound was obtained as a colorless solid (0.12 g, quant. yield):
MS(ES+) m/z 484.1, 486.3 (M+1).
Step 3. Preparation of
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-
-yl) methoxy-2-fluoro-N-(methylsulfonyl)benzamide
##STR00898##
[1521] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
(R)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)
ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoic acid, the
compound was obtained as a colorless solid (0.01 g, 7%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.94 (br s, 1H), 7.87-7.54 (m,
3H), 7.16 (d, J=9.0 Hz, 1H), 7.02 (d, J=12.0 Hz, 1H), 4.57 (brs,
1H), 4.39-4.18 (m, 2H), 3.52 (brs, 6H), 2.36-1.85 (m, 8H),
1.33-1.14 (m, 1H), 0.89-0.80 (m, 2H), 0.74-0.61 (m, 2H); MS(ES+)
m/z 563.3, 561.1 (M+1).
Example 352
Synthesis of 4-((1-(bis(3-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR00899##
[1522] Step 1. Preparation of tert-butyl
4-((1-(bis(3-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR00900##
[1524] Following the procedure as described in Example 346 step 5
and making non-critical variations as required to replace of
tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl)methoxy)benzoate
with tert-butyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate and
1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)benzene with
3,3'(bromomethylene)bis(chlorobenzene), the title compound was
obtained as a colorless solid (0.58 g, 35%): MS(ES+) m/z 586.1,
584.1 (M+1).
Step 2. Preparation of
4-((1-(bis(3-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00901##
[1526] Following the procedure as described in Example 346 step 6,
and making non-critical variations as required to replace
tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-4-fluoropiperidine-1-carboxylate with tert-butyl
4-((1-(bis(3-chlorophenyl)methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2--
fluorobenzoate, the title compound was obtained as a colorless
solid (0.31 g, 54%): MS(ES+) m/z 530.1, 528.1 (M+1).
Step 3. Preparation of
4-((1-(bis(3-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR00902##
[1528] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-(bis(3-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was
obtained as a colorless solid (0.01 g, 38%): .sup.1H NMR (300 MHz,
DMSO-d.sub.61% D.sub.2O) .delta.7.72 (s, 2H), 7.63-7.61 (m, 2H),
7.54-7.46 (m, 4H), 7.10 (d, J=8.3 Hz, 1H), 6.93 (d, J=12.9 Hz, 1H),
5.67 (s, 1H), 3.98 (d, J=4.6 Hz, 2H), 3.30 (s, 3H), 3.25-3.21 (m,
2H), 3.09-2.98 (m, 2H), 2.21-2.08 (m, 1H), 2.04-1.97 (m, 3H),
1.72-1.64 (m, 2H), 0.89-0.83 (m, 2H), 0.65-0.60 (m, 2H); MS(ES+)
m/z 605.1, 607.1 (M+1).
Example 353
Synthesis of
5-cyclopropyl-4-(((1R,3S,5S)-8-((R)-1-(3,5-dichlorophenyl)ethyl)-8-azabic-
yclo[3.2.1]octan-3-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR00903##
[1530] Following the procedure as described in Example 346 step 5
and making non-critical variations as required to replace of
tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl)methoxy)benzoate
with 4-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide and to
replace 1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)
benzene with (S)-1,3-dichloro-5-(1-chloroethyl)benzene, the title
compound was obtained as a colorless solid (0.03 g, 54%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta.11.89 (br s, 11H), 9.58 (br s,
1H), 7.84-7.74 (m, 2H), 7.73-7.68 (m, 1H), 7.09 (d, J=8.2 Hz, 1H),
6.98 (d, J=12.9 Hz, 1H), 4.54-4.36 (m, 1H), 4.31-4.17 (m, 1H),
4.16-4.06 (m, 1H), 3.96-3.80 (m, 2H), 3.73-3.42 (m, 3H), 3.43-3.34
(m, 1H), 2.39-2.22 (m, 1H), 2.17-1.73 (m, 7H), 1.72-1.52 (m, 4H),
0.91-0.79 (m, 2H), 0.70-0.59 (m, 2H); MS(ES+) m/z 570.1, 571.1
(M+1).
Example 354
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-((2-methylthiazol-4--
yl) methyl)piperidin-4-yl)methoxy)benzamide, trifluoroacetic acid
salt
##STR00904##
[1531] Step 1. Preparation of methyl
5-cyclopropyl-2-fluoro-4-((1-((2-methylthiazol-4-yl)
methyl)piperidin-4-yl)methoxy)benzoate
##STR00905##
[1533] Following the procedure as described in Example 346 step 5
and making non-critical variations as required to replace
tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl)methoxy)benzoate
with methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
hydrochloride and to replace
1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)benzene with
4-(chloromethyl)-2-methylthiazole, the title compound was obtained
as a colorless solid (0.20 g, 66%): MS(ES+) m/z 419.2 (M+1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-4-((1-((2-methylthiazol-4-yl)
methyl)piperidin-4-yl)methoxy)benzoic acid
##STR00906##
[1535] To a solution of methyl
5-cyclopropyl-2-fluoro-4-((1-((2-methylthiazol-4-yl)methyl)
piperidin-4-yl)methoxy)benzoate (0.20 g, 0.48 mmol) in
tetrahydrofuran (10 mL) was a added a solution of lithium hydroxide
(0.11 g, 4.80 mmol) in water (5 mL). The reaction mixture was
refluxed for 5 hours, cooled to ambient temperature, and acidified
with 1N hydrochloric acid solution. The reaction mixture was
extracted with ethyl acetate (3.times.10 mL), dried over anhydrous
sodium sulfate, filtered.
[1536] The filtrate was concentrated invacuo to afford the title
compound as a colorless gum (0.14 g, 72% yield): MS(ES+) m/z 405.2
(M+1).
Step 3. Preparation of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-((2-methylthiazol-4--
yl) methyl)piperidin-4-yl)methoxy)benzamide
##STR00907##
[1538] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((2-methylthiazol-4-yl)
methyl)piperidin-4-yl)methoxy)benzoic acid and to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.03 g, 20%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.86 (br s, 1H), 9.85 (br s, 1H), 7.72
(s, 1H), 7.12 (d, J=9.0 Hz, 1H), 6.98 (d, J=12.8 Hz, 1H), 4.36 (s,
2H), 4.01-3.91 (m, 2H), 3.56-3.39 (m, 2H), 3.13-2.92 (m, 3H), 2.70
(s, 3H), 2.16-1.82 (m, 4H), 1.77-1.52 (m, 2H), 1.18-1.03 (m, 4H),
0.95-0.82 (m, 2H), 0.74-0.60 (m, 2H); MS(ES+) m/z 508.2 (M+1).
Example 355
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-((2-isopropylthiazol-
-4-yl) methyl)piperidin-4-yl)methoxy)benzamide trifluoroacetic acid
salt
##STR00908##
[1539] Step 1. Preparation of methyl
5-cyclopropyl-2-fluoro-4-((1-((2-isopropylthiazol-4-yl)methyl)
piperidin-4-yl)methoxy)benzoate
##STR00909##
[1541] Following the procedure as described in Example 346 step 5
and making non-critical variations as required to replace
tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl)methoxy)benzoate
with methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
hydrochloride and to replace
1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)benzene with
4-(chloromethyl)-2-isopropylthiazole, the title compound was
obtained as a colorless gum (0.23 g, 70%): MS(ES+) m/z 447.2
(M+1).
Step 2. Preparation of
5-cyclopropyl-fluoro-4-((1-((2-isopropylthiazol-4-yl)piperidin-4-yl)
methoxy)benzoic acid
##STR00910##
[1543] Following the procedure as described in Example 354 step 2
and making non-critical variations as required to replace methyl
5-cyclopropyl-2-fluoro-4-((1-((2-methylthiazol-4-yl)methyl)piperidin-4-yl-
) methoxy)benzoate with methyl
5-cyclopropyl-2-fluoro-4-((1-((2-isopropylthiazol-4-yl)
methyl)piperidin-4-yl)methoxy)benzoate, the title compound was
obtained as a colorless solid (0.15 g, 77%): MS(ES+) m/z 432.2
(M+1).
Step 3. Preparation of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-((2-isopropylthiazol-
-4-yl) methyl)piperidin-4-yl)methoxy)benzamide
2,2,2-trifluoroacetate
##STR00911##
[1545] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace a
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((2-isopropylthiazol-4-yl)
methyl)piperidin-4-yl)methoxy)benzoic acid and to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.08 g, 47%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.82 (br s, 1H), 9.81 (s, 1H), 7.76 (s,
1H), 7.12 (d, J=8.2 Hz, 1H), 6.93 (d, J=12.9 Hz, 1H), 4.38 (s, 2H),
4.07-3.86 (m, 2H), 3.41-3.19 (m, 3H), 3.16-2.90 (m, 3H), 2.16-1.84
(m, 4H), 1.75-1.47 (m, 2H), 1.42-1.26 (m, 6H), 1.19-1.00 (m, 4H),
0.95-0.79 (m, 2H), 0.73-0.59 (m, 2H); MS(ES+) m/z 536.2 (M+1).
Example 356
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(5-fluoro-2-(isoprop-
ylamino) benzyl)piperidin-4-yl)methoxy)benzamide, trifluoroacetic
acid salt
##STR00912##
[1546] Step 1. Preparation of methyl
4-((1-(2-amino-5-fluorobenzoyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fl-
uorobenzoate
##STR00913##
[1548] To a mixture of 2-amino-5-fluorobenzoic acid (0.16 g, 1.00
mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium
hexafluorophosphate (PyBOP) (0.70 g, 1.50 mmol) and
N,N-diisopropylethylamine (0.71 g, 4.00 mmol) in dichloromethane (2
mL) was added methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate (0.52 g,
1.50 mmol). After stirring at an ambient temperature for 16 hours,
the reaction mixture was diluted with dichloromethane (10 mL),
washed with saturated solution of ammonium chloride (3.times.5 mL),
dried over anhydrous sodium sulfate and filtered. The filtrate was
concentrated and the residue was purified by column chromatography
eluting with ethyl acetate in hexane to afford the title compound
as a colorless solid (0.05 g, 11%): MS(ES+) m/z 445.2 (M+1).
Step 2. Preparation of methyl
4-((1-(2-amino-5-fluorobenzoyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR00914##
[1550] To a solution of methyl
4-((1-(2-amino-5-fluorobenzoyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fl-
uorobenzoate (0.18 g, 0.40 mmol) in anhydrous tetrahydrofuran (4
ml), was added borane dimethyl sulfide complex (1.5 mL, 150 mmol).
After stirring at ambient temperature for 1 hour, the reaction
mixture was added slowly to methanol (50 mL), followed by addition
of hydrogen chloride (4.0M in dioxane solution, 5 mL), and then
concentrated invacuo to afford the title compound as a colorless
solid (0.10 g, 58%): MS(ES+) m/z 431.2 (M+1).
Step 3. Preparation of methyl
5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(isopropylamino)
benzyl)piperidin-4-yl)methoxy)benzoate
##STR00915##
[1552] To 20 mL microwave vial was added methyl
4-((1-(2-amino-5-fluorobenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate (0.20 g, 0.50 mmol),
methanol (5 mL), sodium cyanoborohydride (0.20 g, 3.00 mmol),
acetone (1 mL) and acetic acid (1 mL). The reaction mixture was
heated at 130.degree. C. for 15 minutes. After cooling to ambient
temperature, the reaction mixture was concentrated and basified
with sodium bicarbonate solution, extracted with ethyl acetate
(2.times.20 mL), dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated in vacuo to afford the title compound
as a gum (0.12 g, 51%). Which was used in next step without further
purification: MS(ES+) m/z 473.2 (M+1).
Step 4. Preparation of
5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(isopropylamino)
benzyl)piperidin-4-yl)methoxy)benzoic acid
##STR00916##
[1554] Following the procedure as described in Example 354 step 2
and making non-critical variations as required to replace methyl
5-cyclopropyl-2-fluoro-4-((1-((2-methylthiazol-4-yl)methyl)piperidin-4-yl-
) methoxy)benzoate with methyl
5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(isopropylamino)
benzyl)piperidin-4-yl)methoxy)benzoate, the title compound was
obtained as a gum (0.04 g, 34%). Which was used in next step
without further purification; MS(ES+) m/z 459.6 (M+1).
Step 4. Preparation of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(5-fluoro-2-(isoprop-
ylamino) benzyl)piperidin-4-yl)methoxy)benzamide
##STR00917##
[1556] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(isopropylamino)
benzyl)piperidin-4-yl)methoxy)benzoic acid and to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.01 g, 23%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.86 (br s, 1H), 7.33 (s, 1H),
7.23-7.06 (m, 3H), 7.04-6.94 (m, 1H), 6.76-6.68 (m, 1H), 4.30 (s,
2H), 3.98 (s, 2H), 3.70-3.54 (m, 1H), 3.50-3.34 (m, 2H), 3.19-2.97
(m, 3H), 2.54 (s, 4H), 2.18-1.92 (m, 3H), 1.75-1.57 (m, 2H),
1.22-1.07 (m, 8H), 0.05-0.85 (m, 2H), 0.73-0.63 (m, 2H); MS(ES+)
m/z 562.2 (M+1).
Example 357
Synthesis of
4-((1-((5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)pipe-
ridin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR00918##
[1557] Step 1. Preparation of methyl
4-((1-((5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)pipe-
ridin-4-yl)
methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR00919##
[1559] To a mixture or methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate (0.12 g,
0.40 mmol),
5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde
(0.08 g, 0.40 mmol) in dichloroethane (2 mL) was added sodium
triacetoxyborohydride (0.25 g, 1.20 mmol) and acetic acid (0.07 g,
1.20 mmol). After stirring at ambient temperature for 16 hours, the
reaction mixture was quenched by addition aqueous ammonium
hydroxide solution (28%, 3 mL) and extracted with dichloromethane,
dried over anhydrous sodium sulfate and filtered. The filtrate was
concentrated in vacuo to afford the title compound as a colorless
gum (0.01 g, 50%). Which was used in next step without further
purification; MS(ES+) m/z 506.2, 504.2 (M+1).
Step 2. Preparation of
4-((1-((5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)
methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid
##STR00920##
[1561] Following the procedure as described in Example 354 step 2
and making non-critical variations as required to replace methyl
5-cyclopropyl-2-fluoro-4-((1-((2-methylthiazol-4-yl)methyl)piperidin-4-yl-
) methoxy)benzoate with methyl
4-((1-((5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)
methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate, the
title compound was obtained as a colorless solid (0.10 g, quant.
yield): MS(ES+) m/z 492.3, 490.1 (M+1).
Step 3. Preparation of
4-((1-((5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)
methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fl-
uorobenazmide 2,2,2,-trifluoroacetate
##STR00921##
[1563] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-((5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)
methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid
and to replace methanesulfonamide with cyclopropylsulfonamide, the
title compound was obtained as a colorless solid (0.01 g, 10%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.85 (br s, 1H), 7.3
(s, 1H), 7.12 (s, 1H), 6.98 (s, 1H), 4.21-4.03 (m, 1H), 3.95 (s,
3H), 3.80-3.20 (m, 6H), 3.1-2.8 (m, 2H), 2.1-1.8 (m, 4H), 1.61-1.42
(m, 2H), 1.21-1.01 (m, 4H), 0.95-0.85 (m, 2H), 0.72-0.55 (m, 2H);
MS(ES+) m/z 595.1, 593.2 (M+1).
Example 358
Synthesis of
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-fluoroethyl)piperidin-4-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR00922##
[1564] Step 1. Preparation of tert-butyl,
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)
piperidin-4-yl)methoxy)-2-fluorobenzoate
##STR00923##
[1566] To a mixture of tert-butyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate(1.31 g,
3.75 mmol), glyoxylic acid monohydrate (0.55 g, 5.99 mmol) and 4
.ANG. molecular sieves (1.0 g) in anhydrous toluene (15 mL) was
added 3,5-dichlorophenyl)boronic acid (0.79 g, 4.12 mmol). The
reaction mixture was refluxed for 16 hours, cooled to ambient
temperature and filtered off the solid. The filtrated was
concentrated and the residue was redissolved in anhydrous
tetrahydrofuran (10 mL). A boron tetrahydrofuran complex (1.0 M
tetrahydrofuran, 25 mL, 25.00 mmol) was added to the solution and
stirred at ambient temperature for 16 hours. The reaction mixture
was quenched with 1N hydrochloric acid solution (15 mL) and
extracted with ethyl acetate (3.times.25 mL). The combined organic
layer was dried over anhydrous sodium sulfate and filtered. The
filtrate was concentrated and the residue was purified by column
chromatography eluting with ethyl acetate in hexanes to afford the
title compound as a gum (0.95 g, 48%). Which was used in the next
step without further purification: MS(ES+) m/z 540.2, 538.2
(M+1).
Step 2. Preparation of
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-fluoroethyl)piperidin-4-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR00924##
[1568] To a solution of tert-butyl
5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)piperidin-4-yl-
) methoxy)-2-fluorobenzoate (0.95 g, 1.77 mmol) in dichloromethane
(15 mL) was added methoxyethyl)aminosulfur trifluoride (BAST) (0.57
g, 3.54 mmol). The reaction mixture was stirred at ambient
temperature for 16 hours and washed with aqueous sodium bicarbonate
solution (3.times.5 mL), dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated invacuo and the residue was
redissolved in dichloromethane (15 mL). To this solution was added
trifluoroacetic acid (5 mL), after stirring at ambient temperature
for 3 hours, the reaction mixture was concentrated invacuo. The
residue was redissolved in anhydrous tetrahydrofuran (15 mL). To
this solution was added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.43 g, 3.54 mmol),
4-dimethylaminopyridine (1.08 g, 8.85 mmol) and methanesulfonamide
(0.34 g, 3.54 mmol). After stirring at a ambient temperature for 16
hours. The reaction mixture was diluted with ethyl acetate (15 mL),
washed with brine (10 mL), dried over anhydrous sodium sulfate and
filtered. The filtrate was concentrated in vacuo and the residue
was purified by preparative HPLC afford the title compound as a
colorless solid (0.06 g, 6% in 3 steps): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 11.84 (br s, 1H), 10.06 (br s, 1H), 7.72 (dd,
J=1.79, 1.79 Hz, 1H), 7.54 (s, 2H), 7.11 (d, J=8.31 Hz, 1H), 6.96
(d, J=12.93 Hz, 1H), 6.33-6.03 (m, 1H), 4.11-3.37 (m, 8H),
3.22-2.95 (m, 2H), 2.50 (s, 3H), 2.17-1.87 (m, 2H), 1.83-1.58 (m,
2H), 0.94-0.78 (m, 2H), 0.71-0.61 (m, 2H); MS(ES+) m/z (M+1)
563.1
Example 359
Synthesis of
(S)-N-(cyclopropylsulfonyl)-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin--
4-yl) methoxy)-2-fluoro-5-methylbenzamide, trifluoroacetic acid
salt
##STR00925##
[1569] Step 1. Preparation of tert-butyl
4-((1-benzylpiperidin-4-yl)methoxy)-2-fluoro-5-methylbenzoate
##STR00926##
[1571] Following the procedure as described in Example 346 step 2
and making non-critical variations as required to replace
tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-carboxylate with
(1-benzylpiperidin-4-yl)methanol and to replace tert-butyl
5-chloro-2,4-difluorobenzoate with tert-butyl
2,4-difluoro-5-methylbenzoate, the title compound was obtained as a
colorless foam (0.85 g, 43%): MS(ES+) m/z 416.1, 414.2 (M+1).
Step 2. Preparation of tert-butyl
2-fluoro-5-methyl-4-(piperidin-4-yl)methoxy)benzoate
##STR00927##
[1573] To a mixture of tert-butyl
4-((1-benzylpiperidin-4-yl)methoxy)-2-fluoro-5-methylbenzoate (0.63
g, 1.52 mmol), ammonium formate (0.12 g, 1.82 mmol) was added 10%
Pd/C (0.21 g) in methanol (15 mL). The reaction mixture was
refluxed for 1 hour cooled to ambient temperature, filtered through
a pad of diatomaceous earth, and washed with methanol. The filtrate
was concentrated in vacuo and the residue was directly used in the
next step; MS(ES+) m/z 324.2 (M+1).
Step 3. Preparation of (S)-tert-butyl
4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluoro-5-methylbenzoate
##STR00928##
[1575] Following the procedure as described as Example 345 step 5
and making non-critical variations as required to replace
tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl)methoxy)benzoate
hydrochloride with tert-butyl
2-fluoro-5-methyl-4-(piperidin-4-ylmethoxy)benzoate, and to replace
1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)benzene with
(R)-1-(3,5-dichlorophenyl)ethyl 4-methylbenzenesulfonate, the title
compound was obtained as a colorless foam (0.30 g, 82%): MS (ES+)
m/z 498.1, 496.2 (M+1).
Step 4. Preparation of
(S)-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluoro-5-methylbenzoic acid
##STR00929##
[1577] Following the procedure as described in Example 346 step 6,
and making non-critical variations as required to replace
tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-4-fluoropiperidine-1-carboxylate with (S)-tert-butyl
4-((1-(1-(3,5-dichlorophenyl)ethyl)
piperidin-4-yl)methoxy)-2-fluoro-5-methylbenzoate, the title
compound was obtained as a gum (0.25 g, 95%). Which was used in the
next step without further purification; MS(ES-) m/z 438.1, 437.0
(M-1).
Step 5. Preparation of
(S)-N-(cyclopropylsulfonyl)-4-((1-(1-(3,5-dichlorophenyl)ethyl)
piperidin-4-yl)methoxy)-2-fluoro-5-methylbenzamide trifluoroacetic
acid salt
##STR00930##
[1579] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
(S)-4-((1-(1-(3,5-dichlorophenyl)
ethyl)piperidin-4-yl)methoxy)-2-fluoro-5-methylbenzoic acid, and to
replace methanesulfonamide with cyclopropylsulfonamide, the title
compound was obtained as a colorless solid (0.01 g, 6%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.83 (br s, 1H), 9.49 (br s,
1H), 7.76 (brs, 1H), 7.65 (br s, 2H), 7.49 (d, J=9.0 Hz, 1H), 6.97
(d, J=12.0 Hz, 1H), 4.55 (br s, 1H), 4.00-3.19 (m, 2H), 3.17-3.01
(m, 2H), 2.94-2.75 (m, 2H), 2.31-2.24 (m, 1H), 2.13 (s, 3H),
2.08-1.89 (m, 3H), 1.72-1.48 (m, 5H), 1.19-1.05 (m, 4H); MS(ES+)
m/z 545.1, 543.1 (M+1).
Example 360
Synthesis of (S)-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluoro-5-methyl-N-(methylsulfonyl)benzamide,
trifluoroacetic acid
##STR00931##
[1581] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
(S)-4-((1-(1-(3,5-dichlorophenyl)
ethyl)piperidin-4-yl)methoxy-2-fluoro-5-methylbenzoic acid, the
title compound was obtained as a colorless solid (0.04 g, 63%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.89 (br s, 1H), 9.60
(br s, 1H), 7.76 (s, 1H), 7.65 (d, J=3.0 Hz, 2H), 7.50 (d, J=9.0
Hz, 1H), 6.97 (d, J=12.0 Hz, 1H), 4.62-4.49 (m, 1H), 4.01-3.89 (m,
2H), 3.73-3.63 (m, 1H), 3.41-3.33 (m, 1H), 3.34 (s, 3H), 2.92-2.75
(m, 2H), 2.13 (s, 3H), 2.08-1.89 (m, 3H), 1.73-1.53 (m, 5H);
MS(ES+) m/z 519.1, 517.1 (M+1).
Example 361
Synthesis of 4-((1-(bis(2-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid
##STR00932##
[1583] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-(bis(2-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was
obtained as a colorless solid (0.07 g, 39%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6+1% D2O) .delta. 7.76-7.73 (m, 2H), 7.57-7.40 (m, 6H),
7.09 (d, J=1 8.3 Hz, 1H), 6.91 (d, J=12.9 Hz, 1H), 6.05 (s, 1H),
3.99-3.92 (m, 2H), 3.29 (s, 3H), 3.27-3.18 (m, 2H), 3.17-3.08 (m,
2H), 2.22-2.09 (m, 1H), 2.05-1.94 (m, 3H), 1.69-1.54 (m, 2H),
0.90-0.84 (m, 2H), 0.64-0.59 (m, 2H); MS(ES+) m/z 605.2, 607.1
(M+1).
Example 362
Synthesis of 4-((1-(bis(4-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR00933##
[1584] Step 1. Preparation of tert-butyl
4-((1-(bis(4-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR00934##
[1586] Following the procedure as described in Example 346 step 5
and making non-critical variations as required to replace
tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl)methoxy)benzoate
with tert-butyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-yl)methoxy)benzoate, and to
replace
1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)benzene with
4,4'-(bromomethylene)bis(chlorobenzene), the title compound was
obtained as a colorless foam (0.59 g, 95%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.37-7.21 (m, 9H), 6.48 (d, J=12.7 Hz, 1H),
4.23(s, 1H), 3.8 1(d, J=6.3 Hz, 2H), 2.87 (d, J=12.7 Hz, 2H),
1.99-1.74 (m, 6H), 1.54 (s, 9H), 1.54-1.38 (m, 2H), 0.88-0.81 (m,
2H), 0.62-0.57 (m, 2H); MS(ES+) m/z 554.2, 552.2 (M+1).
Step 2. Preparation of
4-((1-(bis(4-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00935##
[1588] Following the procedure as described in Example 346 step 6,
and making non-critical variations as required to replace
tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-4-fluoropiperidine-1-carboxylate with tert-butyl
4-((1-(bis(4-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained as a gum (0.25 g, 95%). Which was used directly in the
next step without further purification; MS(ES-) m/z 438.1, 437.0
(M-1).
Step 3. Preparation of
4-((1-(bis(4-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00936##
[1590] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-(bis(4-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was
obtained as a colorless solid (0.06 g, 36%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6+1% D.sub.2O) .delta. 7.64-7.61 (m, 4H), 7.55-7.52 (m,
4H), 7.09 (d, J=8.3 Hz, 1H), 6.92 (d, J=12.9 Hz, 1H), 5.53 (s, 1H),
3.97-3.96 (m, 2H), 3.30 (s, 3H), 3.25-3.18 (m, 2H), 3.08-2.96 (m,
2H), 2.18-2.06 (m, 1H), 2.04-1.90 (m, 3H), 1.71-1.55 (m, 2H),
0.89-0.83 (m, 2H), 0.64-0.59 (m, 2H) (acidic protons were not
observed): MS(ES+) m/z 604.9, 606.9 (M+1).
Example 363
Synthesis of 4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR00937##
[1591] Step 1. Preparation of tert-butyl
4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR00938##
[1593] Following the procedure as described in Example 346 step 5
and making non-critical variations as required to replace
tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl)methoxy)benzoate
with tert-butyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate, and to
replace
1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)benzene with
4,4'-(bromomethylene)bis(fluorobenzene), the title compound was
obtained as a colorless foam (0.59 g, 95%): MS(ES+) m/z 554.2,
552.2 (M+1).
Step 2. Preparation of
4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00939##
[1595] Following the procedure as described in Example 346 step 6,
and making non-critical variations as required to replace
tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-4-fluoropiperidine-1-carboxylate with tert-butyl
4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained as a gum (0.57 g, quant. yield). Which was used directly
in the next step without further purification; MS(ES+) m/z 493.1,
492.1 (M-1).
Step 3. Preparation of
4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR00940##
[1597] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, and to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.02 g, 5%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.82 (br s, 1H), 9.99 (br s, 1H),
7.76-7.62 (m, 2H), 7.38-7.27 (m, 2H), 7.12-6.94 (m, 4H), 6.84-6.72
(m, 2H), 4.02-3.99 (m, 4H), 3.30-3.18 (m, 2H), 3.08-3.00 (m, 1H),
2.07-1.93 (m, 3H), 1.87-1.78 (m, 2H), 1.17-1.04 (m, 4H), 0.87-0.77
(m, 2H), 0.06-0.61 (m, 2H); MS(ES+) m/z 600.1, 599.2 (M+1).
Example 364
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-((3-(trifluoromethyl-
)pyridin-2-yl) methyl)piperidin-4-yl)methoxy)benzamide,
trifluoroacetic acid salt
##STR00941##
[1598] Step 1. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-((1-((3-(trifluoromethyl)pyridin-2-yl)
methyl)piperidin-4-yl)methoxy)benzoate
##STR00942##
[1600] Following the procedure as described in Example 346 step 5
and making non-critical variations as required to replace
tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl)methoxy)benzoate
with tert-butyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate, and to
replace
1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)benzene with
2-(chloromethyl)-3-(trifluoromethyl)pyridine, the title compound
was obtained as a colorless foam (0.55 g, 95%): MS(ES+) m/z 510.1,
509.0 (M+1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-4-((1-((3-(trifluoromethyl)pyridin-2-yl)
methyl)piperidin-4-yl)methoxy)benzoic acid
##STR00943##
[1602] Following the procedure as described in Example 346 step 6,
and making non-critical variations as required to replace
tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-4-fluoropiperidine-1-carboxylate with tert-butyl
5-cyclopropyl-2-fluoro-4-((1-((3-(trifluoromethyl)
pyridin-2-yl)methyl)piperidin-4-yl)methoxy)benzoate, the title
compound was obtained as a gum (0.49 g, quant. yield). Which was
used directly in the next step without further purification;
MS(ES-) m/z 493.1, 492.1 (M-1).
Step 3. Preparation of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-((3-(trifluoromethyl-
) pyridin-2-yl)methyl)piperidin-4-yl)methoxy)benzamide,
trifluoroacetic acid salt
##STR00944##
[1604] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((3-(trifluoromethyl)
pyridin-2-yl)methyl)piperidin-4-yl)methoxy)benzoic acid, and to
replace methanesulfonamide with cyclopropylsulfonamide, the title
compound was obtained as a colorless solid (0.07 g, 24%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.83 (br s, 1H), 9.49 (br s,
1H), 8.95 (d, J=4.7 Hz, 1H), 8.32 (d, J=8.2 Hz, 1H), 7.71 (d,
J=7.9, 4.9 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.97 (d, J=12.9 Hz,
1H), 4.69 (s, 2H), 3.97 (d, J=5.2 Hz, 2H) 1H), 3.64-3.39 (m, 2H),
3.30-3.18 (m, 2H), 3.08-3.00 (m, 1H), 2.07-1.93 (m, 3H), 1.87-1.78
(m, 2H), 1.19-1.05 (m, 4H), 0.92-0.82 (m, 2H), 0.68-0.63 (m, 2H);
MS(ES+) m/z 557.1, 556.1 (M+1).
Example 365
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((3-(trifluoromethyl)pyri-
din-2-yl) methyl)piperidin-4-yl)methoxy)benzamide, trifluoroacetic
acid salt
##STR00945##
[1606] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((3-(trifluoromethyl)
pyridin-2-yl)methyl)piperidin-4-yl)methoxy)benzoic acid, and to
replace methanesulfonamide with cyclopropylsulfonamide, the title
compound was obtained as a colorless solid (0.06 g, 23%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.89 (br s, 1H), 9.98 (br s,
1H), 8.95 (d, J=4.8 Hz, 1H), 8.32 (d, J=7.7 Hz, 1H), 7.71 (dd,
J=8.0, 4.9 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.97 (d, J=12.9 Hz,
1H), 4.69 (s, 2H), 3.97 (d, J=5.1 Hz, 2H) 1H), 3.60-3.48 (m, 2H),
3.30-3.18 (m, 2H), 3.08-3.00 (m, 1H), 2.07-1.93 (m, 3H), 1.87-1.78
(m, 2H), 1.19-1.05 (m, 4H), 0.92-0.82 (m, 2H), 0.68-0.63 (2H);
MS(ES+) m/z 531.0, 530.0 (M+1).
Example 366
Synthesis of
4-((1-((4-bromo-5-chloro-2-fluorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00946##
[1607] Step 1. Preparation of
4-((1-((4-bromo-5-chloro-2-fluorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00947##
[1609] To a mixture of tert-butyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-yl)methoxy)benzoate (0.50 g,
1.43 mmol) and triethylamine (0.4 mL) in anhydrous tetrahydrofuran
(5 mL) was added 4-bromo-5-chloro-2-fluorobenzene-1-sulfonyl
chloride (0.66 g, 2.15 mmol). After stirring at ambient temperature
for 16 hours, the reaction mixture was diluted with ethyl acetate
(5 mL), washed with 1M aqueous hydrochloric acid solution
(3.times.2 mL), dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated invacuo and the residue was
redissolved in dichloromethane (5 mL) and trifluoroacetic acid (2
mL). The reaction mixture was stirred at ambient temperature for 3
hours and concentrated invacuo. The residue was triturated with
ether to afford the title compound as a colorless solid (0.30 g,
37%). Which was used directly in the next step without any further
purification: MS(ES+) m/z 567.1, 565.1 (M+1).
Step 2. Preparation of
4-((1-((4-bromo-5-chloro-2-fluorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)
##STR00948##
[1611] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin-4-fluoropiperidin-4-
-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-((4-bromo-5-chloro-2-fluorophenyl)
sulfonyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid, the title compound was obtained as a colorless solid (0.06 g,
36%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.70 (d, J=15.0 Hz,
1H), 7.93 (d, J=6.0 Hz, 1H), 7.62-7.49 (m, 2H), 6.56 (d, J=15.0 Hz,
1H), 4.03-3.93 (m, 2H), 3.93-3.86 (m, 2H), 3.41 (s, 3H), 2.73-2.60
(m, 2H), 2.03-1.79 (m, 4H), 1.48-1.27 (m, 2H), 0.95-0.81 (m, 2H),
0.71-0.59 (m, 2H); MS(ES+) m/z 645.0, 643.0 (M+1).
Example 367
Synthesis of
4-((1-((4-bromo-5-chloro-2-fluorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR00949##
[1613] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-((4-bromo-5-chloro-2-fluorophenyl)
sulfonyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid, and to replace methanesulfonamide with
cyclopropylsulfonamide, the title compound was obtained as a
colorless solid (0.01 g, 6%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.82 (br s, 1H), 8.16 (d, J=12.0 Hz, 1H), 7.91 (d, J=12.0
Hz, 1H), 7.12 (d, J=6.0 Hz, 1H), 6.94 (d, J=6.0 Hz, 1H), 4.02-3.91
(m, 2H), 3.80-3.68 (m, 2H), 3.13-2.99 (m, 1H), 2.75-2.60 (m, 2H),
2.05-1.79 (m, 2H), 1.44-1.18 (m, 4H), 1.17-1.03 (m, 4H), 0.93-0.79
(m, 2H), 0.71-0.6 (m, 2H); MS(ES+) m/z 671.0, 669.0 (M+1).
Example 368
Synthesis of
4-((1-((4-bromo-3-fluorophenyl)sulfonyl)piperidin-4-yl)methoxy)-5-cyclopr-
opyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00950##
[1614] Step 1. Preparation of
4-((1-((4-bromo-3-fluorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00951##
[1616] Following the procedure as described in Example 366 step 1
and making non-critical variations as required to replace
4-bromo-5-chloro-2-fluorobenzene-1-sulfonyl chloride with
4-bromo-3-fluorobenzene-1-sulfonyl chloride, the title compound was
obtained as a colorless solid (0.30 g, 75%): MS(ES-) m/z 528.1,
526.1 (M-1).
Step 2. Preparation of
4-((1-((4-bromo-3-fluorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00952##
[1618] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-((4-bromo-3-fluorophenyl)
sulfonyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid, the title compound was obtained as a colorless solid (0.05 g,
30%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.85 (s, 1H),
7.98 (dd, J=8.3, 6.8 Hz, 1H), 7.72 (dd, J=8.2, 1.9 Hz, 1H), 7.49
(d, J=8.3, 1.8 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.88 (d, J=12.9 Hz,
1H), 3.93 (d, J=5.9 Hz, 2H), 3.74 (d, J=12.2 Hz, 2H), 3.29 (s, 3H),
2.40-2.32 (m, 2H), 1.99-1.89 (m, 2H), 1.89-1.76 (m, 2H), 1.42-1.30
(m, 2H), 0.89-0.80 (m, 2H), 0.64-0.59 (m, 2H); MS(ES+) m/z 609.1,
607.0 (M+1).
Example 369
Synthesis of
4-((1-((4-bromo-3-fluorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR00953##
[1620] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-((4-bromo-3-fluorophenyl)
sulfonyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid, and to replace methanesulfonamide with
cyclopropylsulfonamide, the title compound was obtained as a
colorless solid (0.08 g, 46%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.79 (br s, 1H), 7.98 (dd, J=8.3, 6.4 Hz, 1H), 7.72 (dd,
J=8.2, 1.9 Hz, 1H), 7.49 (d, J=8.3, 1.8 Hz, 1H), 7.08 (d, J=8.3 Hz,
1H), 6.89 (d, J=12.9 Hz, 1H), 3.90 (d, J=5.4 Hz, 2H), 3.70 (d,
J=11.4 Hz, 2H), 3.07-2.98 (m, 1H), 2.36 (t, J=10.9, 10.9, 2H),
1.98-1.87 (m, 1H), 1.43-1.27 (m, 2H), 1.11-1.04 (m, 3H), 0.88-0.78
(m, 4H), 0.64-0.59 (m, 2H); MS(ES+) m/z 635.1, 633.1 (M+1).
Example 370
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((2-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00954##
[1621] Step 1. Preparation of
5-cyclopropyl-2-fluoro-4-((1-((2-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzoic acid
##STR00955##
[1623] Following the procedure as described in Example 366 step 1
and making non-critical variations as required to replace
4-bromo-5-chloro-2-fluorobenzene-1-sulfonyl chloride with
2-(trifluoromethyl)benzene-1-sulfonyl chloride, the title compound
(0.24 g, 59% yield) was obtained as a colorless solid; MS(ES-) m/z
500.1 (M-1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((2-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)
##STR00956##
[1625] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((2-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzoic acid, the title
compound was obtained as a colorless solid (0.06 g, 36%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.88 (br s, 1H), 8.05-7.98 (m,
2H), 7.98-7.84 (m, 2H), 7.09 (d, J=8.3 Hz, 1H), 6.91 (d, J=13.0 Hz,
1H), 3.93 (d, J=5.9 Hz, 2H), 3.74 (d, J=12.2 Hz, 2H), 3.28 (s, 3H),
2.81-2.69 (m, 2H), 1.98-1.89 (m, 2H), 1.85-1.76 (m, 2H), 1.42-1.27
(m, 2H), 0.87-0.80 (m, 2H), 0.65-0.60 (m, 2H); MS(ES+) m/z 579.1
(M+1).
Example 371
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-((2-(trifluoromethyl-
) phenyl)sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00957##
[1627] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((2-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzoic acid, and to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.10 g, 65%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.80 (br s, 1H), 8.05-7.98 (m, 2H),
7.90-7.87 (m, 2H), 7.09 (d, J=8.3 Hz, 1H), 6.91 (d, J=13.0 Hz, 1H),
6.75 (brs, 1H), 3.94 (d, J=5.9 Hz, 2H), 3.70 (d, J=11.1 Hz, 2H),
3.74 (d, J=12.4 Hz, 2H), 3.07-2.91 (m, 1H), 2.82-2.71 (m, 2H),
2.35-1.89 (m, 2H), 1.89-1.77 (m, 2H), 1.42-1.26 (m, 2H), 1.11-1.02
(m, 3H), 0.89-0.78 (m, 4H), 0.86-0.58 (m, 2H); MS(ES+) m/z 605.2,
607.1 (M+1).
Example 372
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((4-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00958##
[1628] Step 1. Preparation of
5-cyclopropyl-2-fluoro-4-((1-((4-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzoic acid
##STR00959##
[1630] Following the procedure as described in Example 366 step 1
and making non-critical variations as required to replace
4-bromo-5-chloro-2-fluorobenzene-1-sulfonyl chloride with
4-(trifluoromethyl)benzene-1-sulfonyl chloride, the title compound
was obtained as a colorless solid (0.27 g, 66%): MS(ES+) m/z 502.1
(M+1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((4-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00960##
[1632] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((4-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzoic acid, the title
compound was obtained as a colorless solid (0.05 g, 29%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.85 (br s, 1H), 8.01 (d,
J=8.5 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.3 Hz, 1H), 6.89
(d, J=13.0 Hz, 1H), 3.89 (d, J=5.4 Hz, 2H), 3.69 (d, J=11.4 Hz,
2H), 3.29 (s, 3H), 2.38-2.27 (m, 2H), 1.98-1.88 (m, 1H), 1.87-1.74
(m, 3H), 1.44-1.26 (m, 2H), 0.86-0.78 (m, 2H), 0.64-0.59 (m, 2H);
MS(ES+) m/z 579.1 (M+1).
Example 373
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-((4-(trifluoromethyl-
) phenyl)sulfonyl)piperidin-4-yl)methoxy)benzamide (
##STR00961##
[1634] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((4-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzoic acid, and to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.09 g, 58%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.78 (br s, 1H), 8.00 (d, J=8.6 Hz,
2H), 7.94 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.3 Hz, 1H), 6.89 (d,
J=12.9 Hz, 1H), 6.75 (s, 1H), 3.89 (d, J=5.4 Hz, 2H), 3.70 (d,
J=11.1 Hz, 2H), 3.07-2.98 (m, 1H), 2.42-2.26 (m, 2H), 1.98-1.89 (m,
1H), 1.88-1.72 (m, 2H), 1.44-1.28 (m, 2H), 1.11-1.02 (m, 3H),
0.89-0.78 (m, 4H), 0.67-0.58 (m, 2H); MS(ES+) m/z 605.2, 607.1
(M+1).
Example 374
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((3-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00962##
[1635] Step 1. Preparation of
5-cyclopropyl-2-fluoro-4-((1-((3-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzoic acid
##STR00963##
[1637] Following the procedure as described in Example 366 step 1
and making non-critical variations as required to replace
4-bromo-5-chloro-2-fluorobenzene-1-sulfonyl chloride with
3-(trifluoromethyl)benzene-1-sulfonyl chloride, the title compound
was obtained as a colorless solid (0.21 g, 52%): MS(ES-) m/z 500.1
(M-1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((3-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00964##
[1639] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((4-((3-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzoic acid, the title
compound was obtained as a colorless solid (0.08 g, 50%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 11.89 (br s, 1H), 8.18-8.06 (m,
2H), 8.00-7.88 (m, 2H), 7.11 (d, J=9.0 Hz, 1H), 6.92 (d, J=15.0 Hz,
1H), 3.97-3.88 (m, 2H), 3.82-3.70 (m, 2H), 3.33 (s, 3H), 2.41-2.28
(m, 2H), 2.02-1.91 (m, 1H), 1.88-1.75 (m, 3H), 1.49-1.30 (m, 2H),
0.9-0.8 (m, 2H), 0.7-0.6 (m, 2H); MS(ES-) m/z 577.2 (M-1).
Example 375
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-((3-(trifluoromethyl-
) phenyl)sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00965##
[1641] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin-4-fluoropiperidin-4-
-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((3-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzoic acid, and to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.04 g, 70%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.82 (br s, 1H), 8.18-8.04 (m, 3H),
8.00-7.88 (m, 2H), 7.10 (d, J=9.0 Hz, 1H), 6.91 (d, J=15.0 Hz, 1H),
3.98-3.87 (m, 2H), 3.82-3.70 (m, 2H), 3.12-3.00 (m, 1H), 2.42-2.29
(m, 2H), 2.01-1.91 (m, 1H), 1.91-1.76 (m, 2H), 1.48-1.30 (m, 2H),
1.28-1.04 (m, 4H), 0.93-0.81 (m, 2H), 0.70-0.60 (m, 2H); MS(ES+)
m/z 605.2 (M+1).
Example 376
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((tetrahydro-2H-pyran-4-y-
l) sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00966##
[1642] Step 1. Preparation of
5-cyclopropyl-2-fluoro-4-((1-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperidi-
n-4-yl) methoxy)benzoic acid
##STR00967##
[1644] Following the procedure as described in Example 366 step 1
and making non-critical variations as required to replace
4-bromo-5-chloro-2-fluorobenzene-1-sulfonyl chloride with
tetrahydro-2H-pyran-4-yl) sulfonyl chloride, the title compound
(0.10 g, 26% yield) was obtained as a colorless gum; MS(ES-) m/z
400.2 (M+1).
Step 2. Preparation of 5
-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((tetrahydro-2H-pyran-4-yl-
) sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00968##
[1646] Following the procedure as described as Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((tetrahydro-2H-pyran-4-yl)
sulfonyl)piperidin-4-yl)methoxy)benzoic acid, the title compound
was obtained as a colorless solid (0.05 g, 76%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.87 (br s, 1H), 7.10 (d, J=8.3 Hz,
1H), 6.93 (d, J=13.0 Hz, 1H), 3.96 (d, J=6.1 Hz, 2H ), 3.90-3.85
(m, 2H), 3.67-3.63 (m, 2H), 3.43-3.25 (m, 6H), 2.97-2.89 (m, 2H),
2.02-1.93 (m, 2H), 1.83-1.79 (m, 4H), 1.57 (ddd, J=12.4, 12.4, 4.7
Hz, 2H), 1.37-1.23 (m, 2H), 0.89-0.82 (m, 2H), 0.67-0.61 (m, 2H);
MS(ES+) m/z 519.1 (M+1).
Example 377
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-((tetrahydro-2H-pyra-
n-4-yl) sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00969##
[1648] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((tetrahydro-2H-pyran-4-yl)
sulfonyl)piperidin-4-yl)methoxy)benzoic acid, and to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.04 g, 68%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.80 (br s, 1H), 7.10 (d, J=8.3 Hz,
1H), 6.93 (d, J=13.0 Hz, 1H), 3.94 (d, J=6.1 Hz, 2H), 3.90-3.85 (m,
2H), 3.67-3.63 (m, 2H), 3.43-3.25 (m, 3H), 3.08-2.89 (m, 3H),
2.02-1.93 (m, 2H), 1.83-1.79 (m, 4H), 1.57 (ddd, J=4.6, 12.4, 12.4
Hz, 2H), 1.37-1.23 (m, 2H), 1.09-1.05 (m, 4H), 0.89-0.82 (m, 2H),
0.66-0.61 (m, 2H); MS(ES+) m/z 545.1 (M+1).
Example 378
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((4-(trifluoromethoxy)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00970##
[1649] Step 1. Preparation of
5-cyclopropyl-2-fluoro-4-((1-((4-(trifluoromethoxy)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzoic acid
##STR00971##
[1651] Following the procedure as described in Example 366 step 1
and making non-critical variations as required to replace
4-bromo-5-chloro-2-fluorobenzene-1-sulfonyl chloride with
4-(trifluoromethoxy)benzene-1-sulfonyl chloride, the title compound
was obtained as a colorless gum (0.25 g, 60%): MS(ES-) m/z 516.2
(M-1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((4-(trifluoromethoxy)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00972##
[1653] Following the procedure described in Example 346 step 7 and
making non-critical variations as required to replace
-4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-((1-((4-(triflu-
oromethoxy) phenyl)sulfonyl)piperidin-4-yl)methoxy)benzoic acid,
the title compound was obtained as a colorless solid (0.06 g, 36%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.85 (br s, 1H), 7.86
(d, J=8.5 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.3 Hz, 1H),
6.88 (d, J=12.9 Hz, 1H), 3.89 (d, J=5.1 Hz, 2H), 3.70-3.66 (m, 2H),
3.27 (m, 3H), 2.34-2.26 (m, 2H), 1.98-1.89 (m, 1H), 1.84-1.80 (m,
3H), 1.41-1.29 (m, 2H), 0.86-0.80 (m, 2H), 0.64-0.59 (m, 2H);
MS(ES+) m/z 595.0 (M+1).
Example 379
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-((4-(trifluoromethox-
y) phenyl)sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00973##
[1655] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((4-(trifluoromethoxy)
phenyl)sulfonyl)piperidin-4-yl)methoxy)benzoic acid, and to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.01 g, 6%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta.11.79 (br s, 1H), 7.88-7.84 (m, 2H),
7.62-7.59 (m, 2H), 7.08 (d, J=8.3 Hz, 1H), 6.89 (d, J=13.0 Hz, 1H),
3.90 (d, J=5.4 Hz, 2H), 3.70-3.66 (m, 2H), 3.07-2.98 (m, 1H),
2.33-2.26 (m, 2H), 1.98-1.89 (m, 1H), 1.84-1.80 (m, 3H), 1.41-1.28
(m, 2H), 1.08-1.04 (m, 4H), 0.86-0.80 (m, 2H), 0.64-0.59 (m, 2H);
MS(ES+) m/z 621.0 (M+1).
Example 380
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((3,4,5-trifluorophenyl)
sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00974##
[1656] Step 1. Preparation of
5-cyclopropyl-2-fluoro-4-((1-((3,4,5-trifluorophenyl)
sulfonyl)piperidin-4-yl)methoxy)benzoic acid
##STR00975##
[1658] Following the procedure as described in Example 366 step 1
and making non-critical variations as required to replace
4-bromo-5-chloro-2-fluorobenzene-1-sulfonyl chloride with
3,4,5-trifluorobenzene-1-sulfonyl chloride, the title compound was
obtained as a colorless gum (0.23 g, 59%): MS(ES+) m/z 488.1
(M+1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-((3,4,5-trifluorophenyl)
sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00976##
[1660] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((3,4,5-trifluorophenyl)
sulfonyl)piperidin-4-yl)methoxy)benzoic acid, the title compound
was obtained as a colorless solid (0.08 g, 49%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.89 (br s, 1H), 7.86-7.71 (m, 2H),
7.13 (d, J=9.0 Hz, 1H), (d, J=12.0 Hz, 1H), 4.00-3.89 (m, 2H),
3.77-3.64 (m, 2H), 2.47-2.36 (m, 2H), 2.03-1.91 (m, 2H), 1.90-1.74
(m, 3H), 1.48-1.20 (m, 4H), 0.92-0.81 (m, 2H), 0.70-0.62 (m,
2H).
Example 381
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-((3,4,5-trifluorophe-
nyl) sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00977##
[1662] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-(3,4,5-trifluorophenyl)
sulfonyl)piperidin-4-yl)methoxy)benzoic acid, and to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.05 g, 31%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.82 (br s, 1H), 7.88-7.75 (m, 2H),
7.11 (d, J=9.0 Hz, 1H), 6.94 (d, J=15.0 Hz, 1H), 3.98-3.89 (m, 2H),
3.77-3.66 (m, 2H), 3.11-3.00 (m, 1H), 2.47-2.37 (m, 3H), 2.04-1.92
(m, 1H), 1.90-1.76 (m, 3H), 1.47-1.31 (m, 2H), 1.16-1.04 (m, 3H),
0.90-0.80 (m, 2H), 0.71-0.61 (m, 2H); MS(ES+) m/z 591.2 (M+1).
Example 382
Synthesis of
4-((1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00978##
[1663] Step 1. Preparation of
4-((1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00979##
[1665] Following the procedure as described in Example 366 step 1
and making non-critical variations as required to replace
4-bromo-5-chloro-2-fluorobenzene-1-sulfonyl chloride with
3-chloro-4-fluorobenzene-1-sulfonyl chloride, the title compound
was obtained as a colorless gum (0.23 g, 59%): MS(ES-) m/z 488.1,
486.1 (M-1).
Step 2. Preparation of
4-((1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00980##
[1667] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-((3-chloro-4-fluorophenyl)
sulfonyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid, the title compound was obtained as a colorless solid (0.03 g,
17%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.88 (br s, 1H),
7.93 (dd, J=2.0, 6.8 Hz, 1H), 7.78-7.64 (m, 2H), 7.09 (d, J=8.3
1H), 6.87 (d, J=12.9 Hz, 1H), 3.90 (d, J=5.1 Hz, 2H), 3.70-3.66 (m,
2H), 3.25 (s, 3H), 2.38-2.30 (m, 2H), 1.96-1.80 (m, 4H), 1.41-1.27
(m, 2H), 0.86-0.80 (m, 2H), 0.64-0.59 (m, 2H); MS(ES-) m/z 561.1
(M-1).
Example 383
Synthesis of
4-((1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR00981##
[1669] Following the procedure as described as Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-((3-chloro-4-fluorophenyl)
sulfonyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid, and to replace methanesulfonamide with
cyclopropylsulfonamide, the title compound was obtained as a
colorless solid (0.04 g, 25%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.78 (br s, 1H), 7.93 (dd, J=2.1, 6.8 Hz, 1H), 7.78-7.64
(m, 2H), 7.08 (d, J=8.3 Hz, 1H), 6.90 (d, J=13.0 Hz, 1H), 3.90 (d,
J=5.3 Hz, 2H), 3.70-3.66 (m, 2H), 3.07-2.99 (m, 1H), 2.37-2.30 (m,
2H), 1.98-1.80 (m, 4H), 1.41-1.29 (m, 2H), 1.09-1.05 (m, 4H),
0.86-0.80 (m, 2H), 0.64-0.59 (m, 2H); MS(ES+) m/z 589.0. 591.0
(M+1).
Example 384
Synthesis of
4-((1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00982##
[1670] Step 1. Preparation of
4-((1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00983##
[1672] Following the procedure as described in Example 366 step 1
and making non-critical variations as required to replace
4-bromo-5-chloro-2-fluorobenzene-1-sulfonyl chloride with
2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride, the title
compound was obtained as a colorless gum: (0.26 g, 61%) MS(ES-) m/z
534.0, 532.1 (M-1).
Step 2. Preparation of
4-((1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00984##
[1674] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-((3-chloro-2-(trifluoromethyl)piperidin)-4-fluoropiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-((2-chloro-4-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid, the title compound was obtained as a colorless solid (0.08 g,
49%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.86 (br s, 1H),
8.16-8.15 (m, 1H), 8.07-8.04 (m, 1H), 7.94 (d, J=8.3 Hz, 1H), 7.09
(d, J=8.3 Hz, 1H), 6.91 (d, J=13.0 Hz, 1H), 3.93 (d, J=5.8 Hz, 2H),
3.80-3.76 (m, 2H), 3.30 (s, 3H), 2.86-2.79 (m, 2H), 1.98-1.80 (m,
4H), 1.39-1.26 (m, 2H), 0.86-0.80 (m, 2H), 0.65-0.60 (m, 2H);
MS(ES+) m/z 613.0, 615.0 (M+1).
Example 385
Synthesis of
4-((1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR00985##
[1676] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-((2-chloro-4-(trifluoromethyl)
phenyl)sulfonyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid, and to replace methanesulfonamide with
cyclopropylsulfonamide, the title compound was obtained as a
colorless solid (0.03 g, 14%): .sup.1H NMR (300 MHZ, DMSO-d.sub.6)
.delta. 11.79 (br s, 1H), 8.16-8.15 (m, 1H), 8.07-8.04 (m, 1H),
7.94 (d, J=8.3 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.91 (d, J=13.0 Hz,
1H), 3.93 (d, J=5.8 Hz, 2H), 3.80-3.76 (m, 2H), 3.07-2.99 (m, 1H),
2.86-2.79 (m, 2H), 1.98-1.80 (m, 4H). 1.39-1.26 (m, 2H), 1.09-1.056
(m, 4H), 0.86-0.80 (m, 2H), 0.64-0.59 (m, 2H); MS(ES+) m/z 639.0,
641.0 (M+1).
Example 386
Synthesis of
5-cyclopropyl-2-fluoro-4-((1-((4-fluoro-2-methylphenyl)sulfonyl)
piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
##STR00986##
[1677] Step 1. Preparation of
5-cyclopropyl-2-fluoro-4-((1-((4-fluoro-2-methylphenyl)sulfonyl)
piperidin-4-yl)methoxy)benzoic acid
##STR00987##
[1679] Following the procedure as described in Example 366 step 1
and making non-critical variations as required to replace
4-bromo-5-chloro-2-fluorobenzene-1-sulfonyl chloride with
4-fluoro-2-methylbenzene-1-sulfonyl chloride, the title compound
was obtained as a colorless gum (0.28 g, 75%): MS(ES-) m/z 464.1
(M-1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-4-((1-((4-fluoro-2-methylphenyl)sulfonyl)
piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
##STR00988##
[1681] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((4-fluoro-2-methylphenyl)
sulfonyl)piperidin-4-yl)methoxy)benzoic acid, the title compound
was obtained as a colorless solid (0.06 g, 36%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.86 (br s, 1H), 7.84 (dd, J=8.8, 5.9
Hz, 1H), 7.33 (dd, J=10.0, 2.6 Hz, 1H), 7.23 (ddd, J=8.6, 2.8. Hz,
1H), 7.09 (d, J=8.3 Hz, 1H), 6.91 (d, J=13.0 Hz, 1H), 3.92 (d,
J=5.8, 2H), 3.62 (d, J=12.0, 2H), 3.30 (s, 3H), 2.68-1.54 (m, 2H),
2.53 (s, 3H), 1.99-1.75 (m, 4H), 1.40-1.26 (m, 2H), 0.87-0.81 (m,
2H), 0.65-0.60 (m, 2H); MS(ES-) m/z 542.0, 541.0 (M-1).
Example 387
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-((4-fluoro-2-methylp-
henyl) sulfonyl)piperidin-4-yl)methoxy)benzamide
##STR00989##
[1683] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-((4-fluoro-2-methylphenyl)
sulfonyl)piperidin-4-yl)methoxy)benzoic acid, and to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.01 g, 6%), .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.79 (br s, 1H), 7.84 (dd, J=8.8, 5.9
Hz, 1H), 7.33 (dd, J=10.0, 2.6 Hz, 1H), 7.23 (ddd, J=8.5, 8.5, 2.7
Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.92 (d, J=12.9 Hz, 1H), 3.92 (d,
J =5.8, 2H), 3.63 (d, J=12.1, 2H), 3.30 (s, 3H), 3.08-2.99 (m, 1H),
2.68-1.54 (m, 2H), 2.53 (s, 3H), 1.99-1.75 (m, 4H), 1.41-1.22 (m,
2H), 1.11-1.01 (m, 4H), 0.87-0.81 (m, 2H), 0.65-0.60 (m, 2H);
MS(ES+) m/z 570.0, 569.0 (M+1).
Example 388
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(naphthalen-2-ylsulfonyl)
piperidin-4-yl)methoxy)benzamide
##STR00990##
[1684] Step 1. Preparation of
5-cyclopropyl-2-fluoro-4-((1-(naphthalen-2-ylsulfonyl)
piperidin-4-yl)methoxy)benzoic acid
##STR00991##
[1686] Following the procedure as described in Example 366 step 1
and making non-critical variations as required to replace
4-bromo-5-chloro-2-fluorobenzene-1-sulfonyl chloride with
4-fluoro-2-methylbenzene-1-sulfonyl chloride, the title compound
was obtained as a colorless gum (0.28 g, 72%): MS(ES-) m/z 482.1
(M-1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(naphthalen-2-ylsulfonyl)
piperidin-4-yl)methoxy)benzamide
##STR00992##
[1688] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-(naphthalen-2-ylsulfonyl)
piperidin-4-yl)methoxy)benzoic acid, the title compound was
obtained as a colorless solid (0.06 g, 36%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.84 (br s, 1H), 8.41 (s, 1H), 8.19-8.12 (m,
2H), 8.06-8.04 (m, 1H), 7.75-7.63 (m, 3H), 7.07 (d, J=8.3 Hz, 1H),
6.87 (d, J=13.0 Hz, 1H), 3.87 (d, J=5.6 Hz, 2H), 3.77-3.73 (m, 2H),
3.28 (s, 3H), 2.34-2.27 (m, 2H), 1.93-1.78 (m, 4H), 1.44-1.30 (m,
2H), 0.83-0.76 (m, 2H), 0.62-0.57 (m, 2H); MS(ES+) m/z 561.1
(M+1).
Example 389
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(naphthalen-2-ylsulf-
onyl) piperidin-4-yl)methoxy)benzamide
##STR00993##
[1690] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-(naphthalen-2-ylsulfonyl)
piperidin-4-yl)methoxy)benzoic acid, and to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.01 g, 6%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.77 (br s, 1H), 8.41 (s, 1H),
8.19-8.12 (m, 2H), 8.06-8.03 (m, 1H), 7.75-7.63 (m, 3H), 7.06 (d,
J=8.3 Hz, 1H), 6.87 (d, J=13.0 Hz, 1H), 3.87 (d, J=5.5 Hz, 2H),
3.77-3.74 (m, 2H), 3.07-2.98 (m, 1H), 2.34-2.27 (m, 2H), 1.93-1.73
(m, 4H), 1.43-1.32 (m, 2H), 1.09-1.05 (m, 4H), 0.82-0.76 (m, 2H),
0.62-0.56 (m, 2H); MS(ES+) m/z 585.1 (M+1).
Example 390
Synthesis of
4-((1-((4-bromo-3-chlorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00994##
[1691] Step 1. Preparation of
4-((1-((4-bromo-3-chlorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR00995##
[1693] Following the procedure as described in Example 366 step 1
and making non-critical variations as required to replace
4-bromo-5-chloro-2-fluorobenzene-1-sulfonyl chloride with
4-bromo-3-chlorobenzene-1-sulfonyl chloride, the title compound was
obtained as a colorless gum (0.34 g, 78%): MS(ES-) m/z 544.0, 542.1
(M-1).
Step 2. Preparation of
4-((1-((4-bromo-3-chlorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR00996##
[1695] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-((4-bromo-3-chlorophenyl)sulfonyl)
piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid, the
title compound was obtained as a colorless solid (0.06 g, 36%):
.sup.1H NMR (300 MHz, d6-DMSO) .delta. 11.89 (br s, 1H), 8.07 (d,
J=9.0 Hz, 1H), 7.95-7.89 (d, J=3.0 Hz, 1H), 7.62 (dd, J=12.0, 3.0
Hz, 1H), 7.13 (d, J=9.0, 1H), 6.93 (d, J=12.0 Hz, 1H), 3.98-3.87
(m, 2H), 3.77-3.64 (m, 2H), 3.31 (s, 3H), 2.46-2.32 (m, 2H),
2.03-1.92 (m, 1H), 1.91-1.76 (m, 3H), 1.49-1.30 (m, 2H), 0.94-0.81
(m, 2H), 0.71-0.61 (m, 2H); MS(ES+) m/z 625.0, 627.0 (M+1)
Example 391
Synthesis of
4-((1-((4-bromo-3-chlorophenyl)sulfonyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR00997##
[1697] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-((4-bromo-3-chlorophenyl)
sulfonyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid, and to replace methanesulfonamide with
cyclopropylsulfonamide, the title compound was obtained as a
colorless solid (0.01 g, 6%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.82 (br s, 1H), 8.06 (d, J=9.0 Hz, 1H), 7.92 (d, J=3 Hz,
1H), 7.62 (dd, J=12 Hz, 3 Hz, 1H), 7.11 (d, J=9 Hz, 1H), 6.93 (d,
J=12 Hz, 1H), 3.99-3.89 (m, 2H), 3.76-3.63 (m, 2H), 3.12-2.99 (m,
1H), 2.43-2.32 (m, 3H), 2.01-1.91 (m, 1H), 1.91-1.74 (m, 4H),
1.48-1.29 (m, 2H), 1.16-1.05 (m, 2H), 0.93-0.82 (m, 2H), 0.70-0.61
(m, 2H); MS(ES+) m/z 653.0, 651.0 (M+1).
Example 392
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(oxetan-3-ylsulfonyl)
piperidin-4-yl)methoxy)benzamide (
##STR00998##
[1698] Step 1. Preparation of 5-cyclopropyl-2-fluoro-4-((
1-(oxetan-3-ylsulfonyl) piperidin-4-yl)methoxy)benzoic acid
##STR00999##
[1700] Following the procedure as described in Example 366 step 1
and making non-critical variations as required to replace
4-bromo-5-chloro-2-fluorobenzene-1-sulfonyl chloride with
oxetane-3-sulfonyl chloride, the title compound was obtained as a
colorless gum (0.14 g, 39%): MS(ES-) m/z 512.1 (M-1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(oxetan-3-ylsulfonyl)
piperidin-4-yl)methoxy)benzamide
##STR01000##
[1702] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-(oxetan-3-ylsulfonyl)
piperidin-4-yl)methoxy)benzoic acid, the title compound was
obtained as a colorless solid (0.03 g, 35%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.86 (br s, 1H), 7.10 (d, J=8.3 Hz, 1H),
6.92 (d, J=13.0 Hz, 1H), 4.80-4.66 (m, 5H), 3.94 (d, J=6.0 Hz, 2H),
3.62-3.58 (m, 2H), 3.29 (s, 3H), 2.80-2.72 (m, 2H), 2.02-1.80 (m,
4H), 1.34-1.20 (m, 2H), 0.89-0.82 (m, 2H), 0.66-0.61 (m, 2H);
MS(ES-) m/z 489.1 (M-1).
Example 393
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(oxetan-3-ylsulfonyl-
) piperidin-4-yl)methoxy)benzamide
##STR01001##
[1704] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-(oxetan-3-ylsulfonyl)
piperidin-4-yl)methoxy)benzoic acid, and to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.07 g, 76%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.79 (br s, 1H), 7.09 (d, J=8.3 Hz,
1H), 6.93 (d, J=13.0 Hz, 1H), 4.80-4.66 (m, 5H), 3.95 (d, J=6.0 Hz,
2H), 3.62-3.58 (m, 2H), 3.08-3.00 (m, 1H), 2.80-2.73 (m, 2H),
2.02-1.80 (m, 4H), 1.35-1.20 (m, 2H), 1.10-1.06 (m, 4H), 0.89-0.83
(m, 2H), 0.66-0.61 (m, 2H); MS(ES-) m/z 515.2 (M-1).
Example 394
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(methylsulfonyl)
piperidin-4-yl)methoxy)benzamide
##STR01002##
[1705] Step 1. Preparation of methyl
5-cyclopropyl-2-fluoro-4-((1-(methylsulfonyl)
piperidin-4-yl)methoxy)benzoate
##STR01003##
[1707] To a cooled (0.degree. C.) solution of
4-bromo-2-chlorobenzyl alcohol (0.75 g, 3.40 mmol) in anhydrous
tetrahydrofuran (20 mL) was added methanesulfonyl chloride (0.66
mL, 8.50 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.50 mmol).
After stirring at 0.degree. C. under a nitrogen atmosphere for 40
minutes, the reaction mixture was diluted with ethyl acetate (100
mL), washed with 1 M hydrochloric acid solution (100 mL) and brine
(100 mL), dried over anhydrous magnesium sulfate, filtered and
concentrated invacuo. The residue was dissolved in anhydrous
N,N-dimethylformamide (15 mL), and methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
hydrochloride (0.98 g, 3.2 mmol) and potassium carbonate (1.52 g,
11.0 mmol) were added to this solution. The reaction mixture was
heated at 90.degree. C. under a nitrogen atmosphere for 17 hours,
cooled to ambient temperature, diluted with brine (200 mL) and
extracted with ethyl acetate (2.times.150 mL). The combined organic
layers were dried over anhydrous magnesium sulfate, filtered, and
concentrated to in vacuo. The residue was purified by column
chromatography, eluting with a 0-50% gradient of ethyl acetate with
10% isopropanol, 10% triethylamine in hexanes to afford the title
compound as a colorless solid (0.30 g, 25%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.43 (d, J=8.2 Hz, 1H), 6.52 (d, J=12.6 Hz,
1H), 3.89-3.83 (m, 7H), 2.78 (s, 3H), 2.75-2.67 (m, 2H), 2.02-1.94
(m, 4H), 1.63-1.50 (m, 2H), 0.92-0.87 (m, 2H), 0.65-0.60 (m, 2H);
MS(ES+) m/z 386.1 (M+1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-4-((1-(methylsulfonyl)piperidin-4-yl)
methoxy)benzoic acid
##STR01004##
[1709] To a solution of methyl
5-cyclopropyl-2-fluoro-4-((1-(methylsulfonyl)piperidin-4-yl)
methoxy)benzoate (0.30 g, 0.77 mmol) in tetrahydrofuran (10 mL),
water (5 mL) was added lithium hydroxide (0.40 g, 17.00 mmol). The
mixture was refluxed for 4.5 hours, cooled to ambient temperature.
The reaction mixture was acidified with 1 M hydrochloric acid
solution (100 mL), extracted with ethyl acetate (100 mL) and
dichloromethane (2.times.100 mL). The combined organic layers were
dried over anhydrous magnesium sulfate, filtered and concentrated
in vacuo to afford the title compound as a colorless solid (0.16 g,
57%). The aqueous layer contained solid that was filtered, washed
with water (50 mL) and diethyl ether (30 mL) to afford additional
amount of the title compound as a colorless solid (0.05 g, 18%):
MS(ES-) m/z 370.1 (M-1).
Step 3. Preparation of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(methylsulfonyl)
piperidin-4-yl)methoxy)benzamide
##STR01005##
[1711] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-(methylsulfonyl)
piperidin-4-yl)methoxy)benzoic acid and to replace
methanesulfonamide with cyclopropylsulfonamide, the title compound
was obtained as a colorless solid (0.06 g, 45%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.80 (br s, 1H), 7.09 (d, J=8.3 Hz,
1H), 6.94 (d, J=13.0 Hz, 1H), 3.97 (d, J=5.8 Hz, 2H), 3.58-3.54 (m,
2H), 3.08-3.00 (m, 1H), 2.82 (s, 3H), 2.75-2.67 (m, 2H), 2.02-1.84
(m, 4H), 1.43-1.30 (m, 2H), 1.09-1.05 (m, 4H), 0.90-0.83 (m, 2H),
0.67-0.62 (m, 2H); MS(ES+) m/z 475.1 (M+1).
Example 395
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(methylsulfonyl)
piperidin-4-yl)methoxy)benzamide
##STR01006##
[1713] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((1-(methylsulfonyl)
piperidin-4-yl)methoxy)benzoic acid, the title compound was
obtained as a colorless solid (0.03 g, 25%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.87 (br s, 1H), 7.10 (d, J=8.3 Hz, 1H),
6.94 (d, J=13.0 Hz, 1H), 3.96 (d, J=5.8 Hz, 2H), 3.58-3.54 (m, 2H),
3.30 (s, 3H), 2.82 (s, 3H), 2.75-2.67 (m, 2H), 2.04-1.84 (m, 4H),
1.42-1.30 (m, 2H), 0.90-0.83 (m, 2H), 0.67-0.62 (m, 2H); MS(ES+)
m/z 449.0 (M+1).
Example 396
Synthesis of
4-((1R,3S,5S)-8-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-8-azabic-
yclo[3.2.1]octan-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01007##
[1714] Step 1. Preparation of (1R, 3S, 5S)-benzyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)
methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR01008##
[1716] Following the procedure as described in Example 346 step 2
and making non-critical variations as required to replace of
tert-butyl-4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (4.60
g, 19.70 mmol) with (1R, 3S, 5S)-benzyl
3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate, the
title compound was obtained as a colorless gum (7.10 g, 98%):
MS(ES+) m/z 506.2, 504.2 (M+1).
Step 2. Preparation of (1R,3S,5S)-benzyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR01009##
[1718] Following the procedure as described in Example 346 step 3
and making non-critical variations as required to replace of
tert-butyl 4-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)
methyl)-4-fluoropiperidine-1-carboxylate with (1R,3S,5S)-benzyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)
methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate, the title compound
was obtained as a colorless solid (5.7 g, 80%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 7.34-7.27 (m, 6H), 6.44 (d, J=12.6 Hz,
1H), 5.12 (s, 2H), 4.05 (br s, 2H), 3.75 (d, J=4.8 Hz, 2H),
2.49-2.34 (m, 1H), 2.03-1.88 (m, 3H), 1.76-1.64 (m, 5H), 1.55 (s,
9H), 0.91-0.80 (m, 2H), 0.66-0.61 (m, 2H).
Step 3. Preparation of
4-(((1R,3S,5S)-8-((benzyloxy)carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR01010##
[1720] Following the procedure as described in Example 346 step 6,
and making non-critical variations as required to replace
tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-4-fluoropiperidine-1-carboxylate with (1R,3S,5S)-benzyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate, the title compound
was obtained as a colorless solid (1.30 g, 27%): MS(ES+) m/z 455.1,
454.1 (M+1).
Step 4. Preparation of (1R,3S,5S)-benzyl
3-((2-cyclopropyl-4-((cyclopropylsulfonyl)carbamoyl)-5-fluorophenoxy)
methyl)-8-azabicyclo[3.2.1]-octane-8-carboxylate
##STR01011##
[1722] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-(((1R,3S,5S)-8-((benzyloxy)
carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)methoxy)-5-cyclopropyl-2-fluorobe-
nzoic acid, the title compound was obtained as a colorless solid
(1.19 g, quant. yield): MS(ES+) m/z 556.2, 555.2 (M+1).
Step 5. Preparation of
4-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-ylmethoxy)-5-cyclopropyl-N-(cycl-
opropylsulfonyl)-2-fluorobenzamide
##STR01012##
[1724] A mixture of (1R,3S,5S)-benzyl
3-((2-cyclopropyl-4-((cyclopropylsulfonyl)carbamoyl)-5-fluorophenoxy)
methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.70 g, 3.01
mmol), Pd/C (0.080 g) and acetic acid (0.10 g) in ethanol (60 mL)
was stirred at ambient temperature under hydrogen balloon for 2
hours. The solid was filtered and the solvent was concentrated
invacuo to afford the title compound as a beige solid (1.19 g,
94%): MS(ES+) m/z 423.1 (M+1).
Step 6. Preparation of
4-(((1R,3S,5S)-8-(3-chloro-2-fluoro-5-(trifluoromethyl)
benzyl)-8-azabicyclo[3.2.1]octan-3-yl)methoxy)-5-cyclopropyl-N-(cycloprop-
ylsulfonyl)-2-fluorobenzamide, trifluoroacetic acid salt
##STR01013##
[1726] Following the procedure as described in Example 346 step 5
and making non-critical variations as required to replace of
tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl)methoxy)benzoate
with
4-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-ylmethoxy)-5-cyclopropyl-N-(cycl-
opropylsulfonyl)-2-fluorobenzamide, the title compound was combined
as a colorless solid (0.09 g, 5%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.81 (br s, 1H), 9.88 (br s, 1H), 8.25 (d,
J=4.9 Hz, 1H), 8.06 (d, J=5.5 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 6.98
(d, J=12.9 Hz, 1H), 4.33 (s, 2H), 4.05 (brs, 2H), 3.86 (d, J=6.2
Hz, 2H), 3.08-2.99 (m, 2H), 2.41-2.27 (m, 2H), 2.06-1.96 (m, 3H),
1.83-1.67 (m, 2H), 1.11-1.03 (m, 4H), 0.88-0.80 (m, 2H), 0.66-0.61
(m, 2H); MS(ES+) m/z 634.0, 633.0 (M+1).
Example 397
Synthesis of
4-(((1R,3S,5S)-8-(2-fluoro-5-(trifluoromethyl)piperidin)-8-azabicyclo[3.2-
.1]octan-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01014##
[1728] Following the procedure as described in Example 346 step 5
and making non-critical variations as required to replace of
tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl)methoxy)benzoate
with
4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-ylmethoxy)-5-cyclopropyl-N-(cycl-
opropylsulfonyl)-2-fluorobenzamide, and to replace
1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)benzene with
1-chloro-2-(chloromethyl)-4-(trifluoromethyl)benzene, the title
compound was obtained as a colorless solid (0.01 g, 6%) .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 11.80 (br s, 1H), 9.36 (br s, 1H),
8.19 (s, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.91 (d, J=12.9 Hz, 1H), 6.05
(s, 1H), 3.99-3.92 (m, 2H), 3.29 (s, 3H), 3.27-3.18 (m, 2H),
3.17-3.08 (m, 2H), 2.22-2.09 (m, 1H), 2.05-1.94 (m, 3H), 1.69-1.54
(m, 2H), 0.90-0.84 (m, 2H), 0.64-0.59 (m, 2H); MS(ES+) m/z 617.1,
615.1 (M+1).
Example 398
Synthesis of
4-(((1R,3S,5S)-8-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-8-azabi-
cyclo[3.2.1]octan-3-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01015##
[1729] Step 1. Preparation of (1R,3S,5S)-benzyl
3-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)
carbamoyl)phenoxy)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR01016##
[1731] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-(((1R,3S,5S)-8-((benzyloxy)
carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)methoxy)-5-cyclopropyl-2-fluorobe-
nzoic acid and to replace methanesulfonamide with
cyclopropylsulfonamide, the title compound was obtained as a
colorless solid (0.45 g, 14%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 11.86 (br s, 1H), 7.39-7.25 (m, 5H), 7.10 (d, J=8.3 Hz,
1H), 6.89 (d, J=12.9 Hz, 1H), 5.03 (s, 2H), 4.22-4.14 (m, 2H), 3.85
(d, J=5.1 Hz, 2H), 3.29 (s, 3H), 2.41-2.31 (m, 1H), 1.94-1.84 (m
3H), 1.72-1.44 (m, 6H), 0.85-0.76 (m, 2H), 0.65-0.59 (m, 2H);
MS(ES+) m/z 532.1, 531.1 (M+1).
Step 2. Preparation of
4-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-ylmethoxy)-5-cyclopropyl-2-fluor-
o-N-(methylsulfonyl)benzamide
##STR01017##
[1733] Following the procedure as described in Example 396 step 5
and making non-critical variations as required to replace
(1R,3S,5S)-benzyl
3-((2-cyclopropyl-4-((cyclopropylsulfonyl)carbamoyl)-5-fluorophenoxy)
methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate with
(1R,3S,5S)-benzyl
3-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)phenoxy)methyl)-8-
-azabicyclo[3.2.1]octane-8-carboxylate, title compound was obtained
as a beige solid (1.10 g, 88%): MS(ES+) m/z 398.1, 397.1 (M+1).
Step 3. Preparation of
4-(((1R,3S,5S)-8-(3-chloro-2-fluoro-5-(trifluoromethyl)
benzyl)-8-azabicyclo[3.2.1]octan-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(-
methylsulfonyl)benzamide, trifluoroacetic acid salt
##STR01018##
[1735] Following the procedure as described in Example 346 step 5
and making non-critical variations as required to replace of
tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl)methoxy)benzoate
with
4-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-ylmethoxy)-5-cyclopropyl-2fluoro-
-N-(methylsulfonyl) benzamide, the title compound was obtained as a
colorless solid (0.02 g, 14%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6+1% D.sub.2) .delta. 8.21-8.18 (m, 1), 8.03-8.01 (m,
1H), 7.08 (d, J=8.2 Hz, 1H), 6.92 (d, J=12.9 Hz, 1H), 4.31 (br s,
2H), 4.04-3.96 (m, 2H), 3.91-3.82 (m, 2H), 3.29 (s, 3H), 2.42-2.27
(m, 3H), 2.04-1.84 (m, 3H), 1.95-1.88 (m, 2H), 1.78-1.67 (m, 2H),
0.90-0.84 (m, 2H), 0.64-0.59 (m, 2H); MS(ES+) m/z 609.0, 607.0
(M+1).
Example 399
Synthesis of 4-(((1R,3S,5S)-8-(2-chloro-5-(trifluoromethyl)
benzyl)-8-azabicyclo[3.2.1]octan-3-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(-
methylsulfonyl)benzamide, trifluoroacetic acid salt
##STR01019##
[1737] Following the procedure as described in Example 346 step 5
and making non-critical variations as required to replace of
tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoropiperidin-4-yl)methoxy)benzoate
with
4-((1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-ylmethoxy)-5-cyclopropyl-2-fluor-
o-N-(methylsulfonyl) benzamide and to replace
1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)benzene with
1-chloro-2-(chloromethyl)-4-(trifluoromethyl)benzene, the title
compound was obtained as a colorless solid (0.04 g, 29%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6+1% D.sub.2O) .delta. 8.10 (s, 1H),
7.97-7.76 (m, 2H), 7.04 (d, J=8.1 Hz, 1H), 6.87 (d, J=12.9 Hz, 1H),
4.31 (s, 2H), 4.04-3.94 (m, 2H), 3.92-3.82 (m, 2H), 3.25 (s, 3H),
2.46-2.29 (m, 3H), 2.07-1.95 (m, 3H), 1.94-1.84 (m, 2H), 1.78-1.64
(m, 2H), 0.87-0.81 (m, 2H), 0.59-53 (m, 2H); MS(ES+) m/z 591.0,
589.1 (M +1).
Example 400
Synthesis of 4-((1-(bis(4-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01020##
[1739] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-y-
l) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-(bis(4-chlorophenyl)methyl)
piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid, and to
replace methanesulfonamide with cyclopropylsulfonamide, the title
compound was obtained as a colorless solid (0.07 g, 55%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6+1% D.sub.2O) .delta.7.63-7.60 (m, 4H),
7.54-7.51 (m, 4H), 7.07 (d, J=8.3 Hz, 1H), 6.91 (d, J=12.9 Hz, 1H),
5.51 (s, 1H), 4.02-3.96 (m, 2H), 3.27-3.19 (m, 2H), 3.06-2.98 (m,
3H), 2.18-2.06 (m, 1H), 2.03-1.94 (m, 3H), 1.71-1.56 (m, 2H),
1.11-1.08 (m, 4H), 0.89-0.83 (m, 2H), 0.62-1.57 (m, 2H); MS(ES+)
m/z 631.1, 633.1 (M+1).
Example 401
Synthesis of 4-((1-(bis(3-chlorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01021##
[1741] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-y-
l) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-(bis(4-chlorophenyl)methyl)
piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid, and to
replace methanesulfonamide with cyclopropylsulfonamide, the title
compound was obtained as a colorless solid (0.06 g, 34%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6+1% D.sub.2O) .delta.7.70 (br s, 2H),
7.61-7.59 (m, 2H), 7.54-7.45 (m, 4H), 7.08 (d, J=8.3 Hz, 1H), 6.92
(d, J=12.9 Hz, 1H), 5.51 (s, 1H), 3.98-3.96 (m, 2H), 3.24-3.21 (m,
2H), 3.07-2.98 (m, 3H), 2.19-2.07 (m, 1H), 2.04-1.95 (m, 3H),
1.73-1.57 (m, 2H), 1.11-1.06 (m, 4H), 0.90-0.83 (m, 2H), 0.63-0.58
(m, 2H); MS(ES+) m/z 631.0, 633.0 (M+1).
Example 402
Synthesis of
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01022##
[1742] Step 1. Preparation of (S)-tert-butyl
5-chloro-4-((1-(1-(3,5-dichlorophenyl)
ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoate
##STR01023##
[1744] To a solution of tert-butyl
5-chloro-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate hydrochloride
(0.13 g, 0.33 mmol) in anhydrous N,N-dimethylformamide (5 mL) was
added (R)-1-(3,5-dichlorophenyl)ethyl 4-methylbenzenesulfonate
(0.14 g, 0.39 mmol) and potassium carbonate (0.16 g, 1.1 mmol). The
reaction mixture was heated to 90.degree. C. under a nitrogen
atmosphere for 15 hours, then cooled and diluted with water (100
mL). The mixture was extracted with ethyl acetate (2.times.100 mL)
and the combined organic layers were dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo. The residue was
purified by column chromatography eluting with a gradient of 0-50%
ethyl acetate containing 10% isopropanol and 10% triethylamine in
hexanes to afford the title compound as a colorless syrup (0.13 g,
73%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.84 (d, J=7.7 Hz,
1H), 7.20-7.19 (m, 3H), 6.59 (d, J=12.2 Hz, 1H), 4.84 (q, J=6.5 Hz,
1H), 3.83 (d, J=6.1 Hz, 2H), 3.40-3.33 (m, 1H), 3.03-3.00 (m, 1H),
2.81-2.77 (m, 1H), 2.04-1.76 (m, 6H), 1.55 (s, 9H), 1.31 (d, J=6.5
Hz, 3H); MS(ES+) m/z 516.0, 518.0, 520.0 (M+1).
Step 2. Preparation of
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt
##STR01024##
[1746] To a solution of (S)-tert-butyl
5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoate (0.13 g, 0.24 mmol) in dichloromethane (6
mL) was added trifluoroacetic acid (3 mL). The reaction mixture was
stirred at ambient temperature for 40 minutes and concentrated in
vacuo to afford the title compound as a colorless syrup that was
used directly in the next step; MS(ES+) m/z 460.0, 462.0 (M+1).
Step 3. Preparation of
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide trifluoroacetic acid
salt
##STR01025##
[1748] To a solution of
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt in
anhydrous dichloromethane (10 mL) was added
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.09
g, 0.48 mmol), 4-(dimethylamino)pyridine (0.07 g, 0.54 mmol), and
methanesulfonamide (0.04 g, 0.41 mmol). The reaction mixture was
stirred at ambient temperature for 16 hours, and then diluted with
ethyl acetate (100 mL). The mixture was washed with saturated
aqueous ammonium chloride (100 mL), brine (2.times.100 mL), dried
over anhydrous magnesium sulfate, filtered and concentrated
invacuo. The residue was purified by reverse-phase HPLC, eluting
with a gradient of 20-80% acetonitrile in water with 0.1%
trifluoroacetic acid to afford the title compound as a colorless
solid (0.01 g, 15% in 2 steps): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 12.11 (br s, 1H), 9.42 (br s, 1H), 7.76-7.72 (m, 2H), 7.60
(s, 2H), 7.22 (d, J=12.4 Hz, 1H), 4.50 (br s, 1H), 4.02-4.00 (m,
2H), 3.66-3.59 (m, 1H), 3.34 (brs, 1H), 3.29 (s, 3H), 2.86-2.69 (m,
2H), 2.05-1.89 (m, 3H), 1.61-1.47 (m, 5H); MS(ES+) m/z 537.0,
539.0, 541.0 (M+1).
Example 403
Synthesis of
(S)-5-chloro-N-(cyclopropylsulfonyl)-4-((1-(1-(3,5-dichlorophenyl)ethyl)
piperidin-4-yl)methoxy)-2-fluorobenzamide, trifluoroacetic acid
salt
##STR01026##
[1750] Following the procedure as described in Example 402 Step 3
and making non-critical variations as required to replace
methanesulfonamide with cyclopropanesulfonamide, the title compound
was obtained as a colorless solid (0.01 g, 13% in 2 steps): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 12.03 (br s, 1H), 9.42 (br s,
1H), 7.75-7.72 (m, 2H), 7.60 (s, 2H), 7.23 (d, J=12.4 Hz, 1H), 4.51
(brs, 1H), 4.02-4.00 (m, 2H), 3.67-3.60 (m, 1H), 3.45 (br s, 1H),
3.08-2.99 (m, 1H), 2.86-2.76 (m, 2H), 2.05-1.89 (m, 3H), 1.62-1.47
(m, 5H), 1.10-1.07 (m, 4H); MS(ES+) m/z 563.1, 565.1, 567.0
(M+1).
Example 404
Synthesis of
(R)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic
acid
##STR01027##
[1751] Step 1. Preparation of (R)-tert-butyl
5-chloro-4-((1-(1-(3,5dichlorophenyl)ethyl)
piperidin-4-yl)methoxy)-2-fluorobenzoate
##STR01028##
[1753] Following the procedure as described in Example 402 step 1
and making non-critical variations to replace
(R)-1-(3,5-dichlorophenyl)ethyl 4-methylbenzenesulfonate with
(S)-1-(3,5-dichlorophenyl) ethyl 4-methylbenzenesulfonate, the
title compound was obtained as a colorless syrup (0.10 g, 62%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.84 (d, J=7.6 Hz, 1H),
7.20-7.19 (m, 3H), 6.59 (d, J=12.1 Hz, 1H), 4.83 (q, J=6.5, 6.5,
6.4 Hz, 1H), 3.83 (d, J=5.9 Hz, 2H), 3.40-3.34 (m, 1H), 3.03-3.00
(m, 1H), 2.81-2.77 (m, 1H), 2.04-1.76 (m, 6H), 1.55 (s, 9H), 1.31
(d, J=6.2 Hz, 3H); MS(ES+) m/z 516.0, 518.0, 520.0 (M+1).
Step 2. Preparation of
(R)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)
piperidin-4-yl)methoxy)-2-fluorobenzoic acid, trifluoroacetic acid
salt
##STR01029##
[1755] Following the procedure as described in Example 402 step 2
and making non-critical variations as required to replace
(S)-tert-butyl 5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)
piperidin-4-yl)methoxy)-2-fluorobenzoate with (R)-tert-butyl
5-chloro-4-((1-(1-(3,5-dichlorophenyl)
ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoate, the title compound
was obtained as a colorless syrup (0.11 g, quant. yield) that was
used directly in the next step; MS(ES+) m/z 460.0, 462.0 (M+1).
Step 3. Preparation of
(R)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)
piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01030##
[1757] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-
-fluorobenzoic acid, trifluoroacetic acid salt with
(R)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt, the title
compound was obtained as a colorless solid (0.01 g, 20% in 2
steps): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.08 (br s,
1H), 9.46 (br s, 1H), 7.76-7.72 (m, 2H), 7.60 (s, 2H), 7.21 (d,
J=12.4 Hz, 1H), 4.48 (br s, 1H), 4.02-4.00 (m, 2H), 3.64-3.57 (m,
1H), 3.32 (br s, 1H), 3.27 (s, 3H), 2.83-2.73 (m, 2H), 2.04-1.88
(m, 3H), 1.60-1.46 (m, 5H); MS(ES+) m/z 537.0, 539.0, 541.0
(M+1).
Example 405
Synthesis of
(R)-5-fluoro-N-(cyclopropylsulfonyl)-4-((1-((1-(3,5-dichlorophenyl)ethyl)
piperidin-4-yl)methoxy)-2-fluorobenzamide, trifluoroacetic acid
salt
##STR01031##
[1759] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt with
(R)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)
ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoic acid, trifluoroacetic
acid salt and to replace methanesulfonamide with
cyclopropanesulfonamide, the title compound was obtained as a
colorless solid (0.01 g, 13% over 2 steps): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 12.01 (br s, 1H), 9.48 (br s, 1H), 7.75-7.70
(m, 2H), 7.58 (s, 2H), 7.21 (d, J=12.4 Hz, 1H), 4.44 (br s, 1H),
4.02-4.00 (m, 2H), 3.62-3.53 (m, 1H), 3.44 (br s, 1H), 3.06-2.97
(m, 1H), 2.77-2.69 (m, 2H), 2.01-1.87 (m, 3H), 1.58-1.45 (m, 5H),
1.08-1.04 (m, 4H); MS(ES+) m/z 563.2, 565.3 (M+1).
Example 406
Synthesis of
5-chloro-4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01032##
[1760] Step 1. Preparation of 3-chloro-5-(trifluoromethoxy)benzyl
4-methylbenzenesulfonate
##STR01033##
[1762] To a cooled (0.degree. C.) solution of
3-chloro-5-(trifluoromethoxy)benzaldehyde (0.45 g, 2.00 mmol) in
anhydrous methanol (10 mL) was added sodium borohydride (0.15 g,
4.00 mmol). After stirring at 0.degree. C. under a nitrogen
atmosphere for 1 hour, the reaction mixture was quenched with
saturated aqueous ammonium chloride (3 mL), diluted with ethyl
acetate (100 mL), washed with 1 M hydrochloric acid solution
(2.times.75 mL), dried over anhydrous magnesium sulfate, filtered,
and concentrated in vacuo. The residue was dissolved in anhydrous
dichloromethane (20 mL) and to this solution was added
4-methylbenzene-1-sulfonyl chloride (0.47 g, 2.5 mmol),
triethylamine (1.4 mL, 9.9 mmol), and 4-dimethylaminopyridine
(0.031 g, 0.25 mmol). The reaction mixture was stirred at ambient
temperature for 2.5 hours, then diluted with dichloromethane (100
mL), washed with water (100 mL) and brine (100 mL), dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
The residue was purified by column chromatography, eluting with a
gradient of 0-10% ethyl acetate in hexanes to afford the title
compound as a colorless syrup (0.25 g, 33%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.75 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H),
7.14 (br s, 2H), 6.96 (br s, 1H), 5.01 (s, 2H), 2.42 (s, 3H).
Step 2. Preparation of tert-butyl
5-chloro-4-((1-(3-chloro-5-(trifluoromethoxy)
benzyl)piperidin-4-yl)methoxy)-2-fluorobenzoate
##STR01034##
[1764] Following the procedure as described in Example 402 step 1
and making non-critical variations to replace
(R)-1-(3,5-dichlorophenyl)ethyl 4-methylbenzenesulfonate with
3-chloro-5-(trifluoromethoxy) benzyl 4-methylbenzenesulfonate, the
title compound was obtained as a colorless syrup (0.27 g, 83%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.58 (d, J=7.7 Hz, 1H),
7.26 (br s, 1H), 7.10 (brs, 2H), 6.60 (d, J=12.1 Hz, 1H), 3.85 (d,
J=6.3 Hz, 2H), 3.47 (s, 2H), 2.89-2.85 (m, 2H), 2.07-2.00 (m, 2H),
1.90-1.82 (m, 3H), 1.56 (s, 9H), 1.48-1.39 (m, 2H); MS(ES+) m/z
552.0, 554.0 (M+1).
Step 3. Preparation of
5-chloro-4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)
piperidin-4-yl)methoxy)-2-fluorobenzoic acid, trifluoroacetic acid
salt
##STR01035##
[1766] Following the procedure as described in Example 402 Step 2
and making non-critical variations as required to replace
(S)-tert-butyl 5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)
piperidin-4-yl)methoxy)-2-fluorobenzoate with tert-butyl
5-chloro-4-((1-(3-chloro-5-(trifluoromethoxy)
benzyl)piperidin-4-yl)methoxy)-2-fluorobenzoate, the title compound
was obtained as a light yellow syrup (0.29 g, 98%) that was used
directly in the next reaction; MS(ES+) m/z 498.0, 496.0 (M+1).
Step 4. Preparation of
5-chloro-4-((1-(3-Chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01036##
[1768] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt with
5-chloro-4-((1-(3-chloro-5-(trifluoromethoxy)
benzyl)piperidin-4-yl)methoxy)-2-fluorobenzoic acid,
trifluoroacetic acid salt, the title compound (0.05. g, 41% in 2
steps) as obtained as a colorless solid: .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.90 (br s, 1H), 9.81) (br s, 1H), 7.75 (d,
J=7.5 Hz, 1H), 7.67-7.64 (m, 2H), 7.52 (s, 1H), 7.21 (d, J=12.4 Hz,
1H), 4.27 (brs, 2H), 4.04-4.02 (m, 2H), 3.32 (brs, 2H), 3.27 (s,
3H), 2.97-2.85 (m, 2H), 2.06-1.90 (m, 3H), 1.59-1.46 (m, 2H);
MS(ES+) m/z 573.0, 575.0 (M+1).
Example 407
Synthesis of
5-chloro-4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)
methoxy)-N-(cyclopropylsulfonyl)-2-fluorobenzamide, trifluoroacetic
acid salt
##STR01037##
[1770] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt with
5-chloro-4-((1-(3-chloro-5-(trifluoromethoxy)
benzyl)piperidin-4-yl)methoxy)-2-fluorobenzoic acid,
trifluoroacetic acid salt and to replace methanesulfonamide with
cyclopropanesulfonamide, the title compound was obtained as a
colorless solid (0.05 g, 46% over 2 steps): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 12.04 (br s, 1H), 9.75 (br s, 1H), 7.74 (d,
J=7.5 Hz, 1H), 7.69-7.66 (m, 2H), 7.54 (s, 1H), 7.24 (d, J=12.4 Hz,
1H), 4.33 (brs, 2H), 4.04-4.02 (m, 2H), 3.43-3.40 (m, 2H),
3.08-2.93 (m, 3H), 2.07-1.92 (m, 3H), 1.60-1.47 (m, 2H), 1.11-1.08
(m, 4H); MS(ES+) m/z 599.3, 601.0 (M+1).
Example 408
Synthesis of
N-(azetidin-1-ylsulfonyl)-5-chloro-4-((1-(3-chloro-5-(trifluoromethoxy)
benzyl)piperidin-4-yl)methoxy)-2-fluorobenzamide, trifluoroacetic
acid salt
##STR01038##
[1772] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt with
5-chloro-4-((1-(3-chloro-5-(trifluoromethoxy)
benzyl)piperidin-4-yl)methoxy)-2-fluorobenzoic acid,
trifluoroacetic acid salt and to replace methanesulfonamide with
azetidine-1-sulfonamide, the title compound was obtained as a
colorless solid (0.06 g, 53% in 2 steps): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.82 (br s, 1H), 9.57 (br s, 1H), 7.77 (d,
J=7.4 Hz, 1H), 7.70-7.66 (m, 2H), 7.54 (s, 1H), 7.24 (d, J=12.2 Hz,
1H), 4.32 (br s, 2H), 4.04-3.99 (m, 6H), 3.43-3.39 (m, 2H),
3.01-2.92 (m, 2H), 2.19-1.93 (m, 5H), 1.58-1.45 (m, 2H); MS(ES+)
m/z 613.9, 615.9 (M+1).
Example 409
Synthesis of
4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)
methoxy)-5-cyano-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01039##
[1773] Step 1. Preparation of tert-butyl
4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)
methoxy)-5-cyano-2-fluorobenzoate
##STR01040##
[1775] Following the procedure as described in Example 402 step 1
and making non-critical variations as required to replace
tert-butyl 5-chloro-2-fluoro-4-(piperidin-4-yl)methoxy)benzoate
hydrochloride with tert-butyl
5-cyano-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate, trifluoroacetic
acid salt and to replace (R)-1-(3,5-dichlorophenyl)ethyl
4-methylbenzenesulfonate with 3-chloro-5-(trifluoromethoxy) benzyl
4-methylbenzenesulfonate, the title compound was obtained as a
colorless syrup (0.03 g, 7%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.12 (d, J=8.0 Hz, 1H), 7.26 (br s, 1H), 7.09 (br s, 2H),
6.65 (d, J=12.1 Hz, 1H), 3.90 (d, J=6.6 Hz, 2H), 3.47 (s, 2H),
2.89-2.85 (m, 2H), 2.07-1.84 (m, 5H), 1.56 (s, 9H), 1.45-1.32 (m,
2H); MS(ES+) m/z 543.3, 545.1 (M+1).
Step 2. Preparation of
4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)
methoxy)-5-cyano-2-fluorobenzoic acid, trifluoroacetic acid
salt
##STR01041##
[1777] Following the procedure as described in Example 402 step 2
and making non-critical variations as required to replace
(S)-tert-butyl
5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoate with tert-butyl
4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)
methoxy)-5-cyano-2-fluorobenzoate, the title compound was obtained
as a colorless solid (0.03 g, quant. yield) that was used directly
in the next step; MS(ES+) m/z 487.0 (M+1).
Step 3. Preparation of
4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)
methoxy)-5-cyano-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01042##
[1779] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt with
4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)
piperidin-4-yl)methoxy)-5-cyano-2-fluorobenzoic acid,
trifluoroacetic acid salt and to replace methanesulfonamide with
cyclopropanesulfonamide, the title compound (0.02 g, 43% in 2
steps) was obtained as a colorless solid: .sup.1H NMR (300 MHz,
DMSO-d.sub.6+5% D.sub.2O) .delta. 8.12 (d, J=7.8 Hz, 1H), 7.67-7.64
(m, 2H), 7.52 (s, 1H), 7.31 (d, J=12.6 Hz, 1H), 4.31 (s, 2H),
4.09-4.07 (m, 2H), 3.43-3.39 (m,2H), 3.06-2.93 (m, 3H), 2.11-1.03
(m, 1H), 1.96-1.92 (m, 2H), 1.57-1.44 (m, 2H), 1.10-1.07 (m, 4H);
MS(ES+) m/z 592.0, 590.0 (M+1).
Example 410
Synthesis of
4-((1-((3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01043##
[1780] Step 1. Preparation of methyl
4-((1-((3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)
methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR01044##
[1782] Following the procedure as described in Example 402 step 1
and making non-critical variations as required to replace
tert-butyl 5-chloro-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
hydrochloride with methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
hydrochloride and to replace (R)-(1-(3,5-dichlorophenyl)ethyl
4-methylbenzenesulfonate with
5-(chloromethyl)-3-(2-chlorophenyl)-1,2,4-oxadiazole and adding
tetra-n-butylammonium iodide to the reaction mixture, the title
compound was obtained as a colorless syrup (1.13 g, 85%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta.7.92 (dd, J =2.0, 7.4 Hz, 1H),
7.52 (dd, J=1.3, 7.8 Hz, 1H), 7.46-7.34 (m, 3H), 6.52 (d, J=12.7
Hz, 1H), 3.97 (s, 2H), 3.86-3.83 (m, 5H), 3.09-3.05 (m, 2H),
2.37-2.29 (m, 2H), 2.05-1.96 (m, 1H), 1.89-1.86 (m, 3H), 1.61-1.47
(m, 2H), 0.92-0.85 (m, 2H), 0.64-0.59 (m, 2H); MS(ES+) m/z 500.0,
502.0 (M+1).
Step 2. Preparation of
4-((1-((3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR01045##
[1784] Following the procedure as described in Example 354 step 2
and making non-critical variations as required to replace
5-cyclopropyl-2-fluoro-4-((1-((2-methylthiazol-4-yl)methyl)piperidin-4-yl-
) methoxy)benzoate with methyl
4-((1-((3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)
piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate, the title
compound was obtained following trituration in diethyl ether (10
mL) as a colorless solid (0.43 g, 39%): MS(ES+) m/z 488.0, 486.0
(M+1).
Step 3. Preparation of
4-((1-((3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01046##
[1786] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5
-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoic acid,
trifluoroacetic acid salt with
4-((1-((3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)
methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid,
the title compound was obtained as a colorless solid (0.08 g, 39%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.76 (br s, 2H), 7.93
(dd, J=1.8, 7.6 Hz, 1H), 7.70-7.52 (m, 3H), 7.10 (d, J=8.3 Hz, 1H),
6.94 (d, J=13.0 Hz, 1H), 4.68 (br s, 2H), 3.97 (d, J=5.1 Hz, 2H),
3.53-3.48 (m, 2H), 3.30 (s, 3H), 3.03-2.92 (m, 2H), 2.05-1.92 (m,
4H), 1.66-1.54 (m, 2H), 0.89-0.83 (m, 2H), 0.67-0.62 (m, 2H);
MS(ES+) m/z 562.9, 564.9 (M+1).
Example 411
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-((3,5-dichlorophenyl)
(phenyl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01047##
[1787] Step 1. Preparation of methyl
5-cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)methyl)piperidin-4-yl)
methoxy)-2-fluorobenzoate
##STR01048##
[1789] Following the procedure as described in Example 402 step 1
and making non-critical variations as required to replace
tert-butyl 5-chloro-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
hydrochloride with methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
hydrochloride and to replace (R)-1-(3,5-dichlorophenyl)ethyl
4-methylbenzensulfonate with
1-(bromo(phenyl)methyl)-3,5-dichlorobenzene and adding
tetra-n-butylammonium iodide to the reaction mixture, the title
compound was obtained as a colorless syrup (0.66 g, 70%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.42 (d, J =8.3 Hz, 1H),
7.33-7.21 (m, 7H), 7.16-7.15 (m, 1H), 6.52(d, J=12.8 Hz, 1H), 4.21
(s, 1H), 3.86-3.82 (m, 5H), 2.92-2.84 (m, 2H), 2.02-1.76 (m, 6H),
1.54-1.37 (m, 2H), 0.90-0.84 (m, 2H), 0.64-0.58 (m, 2H); MS(ES+)
m/z 544.0, 542.0 (M+1).
Step 2. Preparation of
5-cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)methyl)
piperidin-4-yl)methoxy)-2-fluorobenzoic acid
##STR01049##
[1791] To a solution of methyl
5-cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)methyl)piperidin-4-yl)
methoxy)-2-fluorobenzoate (0.66 g, 1.20 mmol) in tetrahydrofuran
(20 mL) and water (5 mL) was added lithium hydroxide (0.30 g, 12.00
mmol). The reaction mixture was refluxed for 16 hours, then cooled
to ambient temperature, diluted with 1 M hydrochloric acid solution
(100 mL) and extracted with dichloromethane (100 mL). The solid
present in the organic layer was filtered and washed with diethyl
ether (20 mL) to afford the title compound as a colorless solid
(0.25 g, 39%). The aqueous layer was further extracted with
dichloromethane (2.times.75 mL). The organic layers were combined
with the filtrate from the previous filtration, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo to
afford additional amount of the title compound as a colorless solid
(0.32 g, 50%): MS(ES+) m/z 528.1, 530.0 (M+1).
Step 3. Preparation of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-((3,5-dichlorophenyl)
(phenyl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzamide
trifluoroacetic acid salt
##STR01050##
[1793] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-((1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt with
5-cyclopropyl-4-((1-(3,5-dichlorophenyl)
(phenyl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzoic acid, and to
replace methanesulfonamide with cyclopropanesulfonamide, the title
compound was obtained as a colorless solid (0.09 g, 30%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6+5% D.sub.2O) .delta. 7.69 (s, 2H),
7.61-7.56 (m, 3H), 7.47-7.35 (m, 3H), 7.06 (d, J=8.3 Hz, 1H), 6.91
(d, J=12.9 Hz, 1H), 5.44 (br s, 1H), 3.96-3.94 (m, 2H), 3.29-3.11
(m, 2H), 3.05-2.86 (m, 3H), 2.10-1.92 (m, 4H), 1.66-1.54 (m, 2H),
1.08-1.02 (m, 4H), 0.86-0.80 (m, 2H), 0.61-0.56 (m, 2H); MS(ES+)
m/z 631.1, 633.0 (M+1).
Example 412
Synthesis of
5-cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)methyl)piperidin-4-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01051##
[1795] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt with
5-cyclopropyl-4-((1-((3,5-dichlorophenyl)
(phenyl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzoic acid, the
title compound was obtained as a colorless solid (0.03 g, 11%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6+5% D.sub.2O) .delta. 7.69 (s,
2H), 7.62-7.57 (m, 3H), 7.48-7.35 (m, 3H), 7.07 (d, J=8.3 Hz, 1H),
6.92 (d, J=12.9 Hz, 1H), 5.44 (brs, 1H), 3.96-3.95 (m, 2H), 3.28
(s, 3H), 3.19-2.28 (m, 4H), 2.07-1.92 (m, 4H), 1.65-1.55 (m, 2H),
0.86-0.80 (m, 2H), 0.63-0.58 (m, 2H); MS(ES+) m/z 605.1, 607.1
(M+1).
Example 413
Synthesis of
4-((1-(4-bromo-2-chlorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-flu-
oro-N-(methylsulfonyl) benzamide, trifluoroacetic acid salt
##STR01052##
[1796] Step 1. Preparation of methyl
4-((1-(4-bromo-2-chlorobenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR01053##
[1798] Following the procedure described in Example 402 step 1 and
making non-critical variations as required to replace tert-butyl
5-chloro-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate hydrochloride
with methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
hydrochloride and to replace (R)-1-(3,5-dichlorophenyl)ethyl
4-methylbenzenesulfonate with
4-bromo-2-chloro-1-(chloromethyl)benzene and adding
tetra-n-butylammonium iodide to the reaction mixture, the title
compound was obtained as a light yellow solid (1.55 g, 86%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.49 (br s, 1H),
7.44-7.35 (m, 3H), 6.52 (dd, J=2.5, 12.8 Hz, 1H), 3.87-3.82 (m,
5H), 3.55 (d, J=2.5 Hz, 2H), 2.93-2.89 (m, 2H), 2.16-1.81 (m, 6H),
1.50-1.38 (m, 2H), 0.92-0.85 (m, 2H), 0.65-0.61 (m, 2H); MS(ES+)
m/z 514.0, 512.0, 510,0 (M+1).
Step 2. Preparation of
4-((1-(4-bromo-2-chlorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-flu-
orobenzoic acid
##STR01054##
[1800] Following the procedure as described in Example 411 step 2
and making non-critical variations as required to replace methyl
4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2--
fluorobenzoate with methyl
4-((1-(4-bromo-2-chlorobenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained was obtained following trituration in diethyl ether (1mL)
as a light pink solid (0.10 g, 22%): MS(ES+) m/z 500.0, 498.2,
496.0 (M+1).
Step 3. Preparation of
4-((1-(4-bromo-2-chlorobenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01055##
[1802] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-
-fluorobenzoic acid, trifluoroacetic acid salt with
4-((1-(4-bromo-2-chlorobenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was
obtained as a colorless solid (0.02 g, 21%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.86 (br s, 1H), 9.48 (br s, 1H), 7.89 (d,
J=1.7 Hz, 1H), 7.70 (dd, J=1.7, 8.3 Hz, 1H), 7.60 (d, J=8.3 Hz,
1H), 7.10 (d, J=8.3 Hz, 1H), 6.94 (d, J=12.9 Hz, 1H), 4.35 (s, 2H),
3.94 (brs, 2H), 3.40 (br s, 2H), 3.30 (s, 3H), 3.14-3.04 (m, 2H),
2.08-1.92 (m, 4H), 1.62-1.47 (m, 2H), 0.88-0.82 (m, 2H), 0.68-0.62
(m, 2H); MS(ES+) m/z 577.0, 575.0, 573.0 (M+1).
Example 414
Synthesis of 4-((1-(4-bromo-2-chlorobenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01056##
[1804] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt with
4-((1-(4-bromo-2-chlorobenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, and to replace
methanesulfonamide with cyclopropanesulfonamide, the title compound
was obtained as a colorless solid (0.02 g, 26%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.80 (br s, 1H), 9.46 (br s, 1H), 7.89
(d, J=1.6 Hz, 1H), 7.70 (dd, J=1.6, 8.3 Hz, 1H), 7.60 (d, J=8.3 Hz,
1H), 7.09 (d, J=8.3 Hz, 1H), 6.95 (d, J=12.9 Hz, 1H), 4.35 (s, 2H),
3.95-3.94 (m, 2H), 3.39 (br s, 2H), 3.13-2.99 (m, 3H), 2.04-1.93
(m, 4H), 1.61-1.46 (m, 2H), 1.09-1.06 (m, 4H), 0.89-0.82 (m, 2H),
0.67-0.62 (m, 2H); MS(ES+) m/z 603.0, 601.0, 599.0 (M=1).
Example 415
Synthesis of 4-((1-(2-chloro-4-cyclopropylbenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01057##
[1805] Step 1. Preparation of methyl
4-((1-(2-chloro-4-cyclopropylbenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR01058##
[1807] To a solution of methyl
4-((1-(4-bromo-2-chlorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-flu-
orobenzoate (1.03 g, 2.02 mmol) in anhydrous 1,4-dioxane (15 mL)
was added cyclopropylboronic acid (1.06 g, 12.30 mmol), tribasic
potassium phosphate (1.74 g, 8.22 mmol), and
tetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.42 mmol). The
suspension was degassed used with argon and heated at 100.degree.
C. for 30 minutes in a microwave reactor. After cooling to ambient
temperature, the reaction mixture was diluted with ethyl acetate
(100 mL), washed with saturated aqueous ammonium chloride
(2.times.100 mL), dried over anhydrous magnesium sulfate, filtered
and concentrated in vacuo. The residue was purified by column
chromatography eluting with a 0-20% gradient of ethyl acetate with
10% isopropanol, 10% triethylamine in hexanes to afford the title
compound as a yellow syrup (0.94 g, 99%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.42 (d, J=8.3 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H),
7.02 (d, J=1.6 Hz, 1H), 6.92 (dd, J=1.6, 7.9 Hz, 1H), 6.52 (d,
J=12.8 Hz, 1H), 3.86-3.81 (m, 5H), 3.57 (s, 2H), 2.96-2.92 (m, 2H),
2.13-1.96 (m, 3), 1.87-1.80 (m, 4H), 1.49-1.37 (m, 2H), 0.98-0.85
(m, 4H), 0.55-0.50 (m, 4H); MS(ES+) m/z 474.1, 472.1 (M=1).
Step 2. Preparation of
4-((1-(2-chloro-4-cyclopropylbenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR01059##
[1809] To a solution of methyl
4-((1-(2-chloro-4-cyclopropylbenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-
-2-fluorobenzoate (0.93 g, 2.00 mmol) in tetrahydrofuran (25 mL)
and water (7 mL) was added lithium hydroxide (0.48 g, 20.00 mmol).
The mixture was refluxed for 15 hours and cooled to ambient
temperature. The reaction mixture was acidified with 1 M aqueous
hydrochloric acid solution (10 mL), diluted with saturated aqueous
ammonium chloride (150 mL) and extracted with ethyl acetate
(2.times.150 mL). The combined organic layers were dried over
anhydrous magnesium sulfate, filtered and concentrated in vacuo.
The residue was triturated in diethyl ether (15 mL) to afford the
title compound as a colorless solid (0.16 g, 18%). The aqueous
layer contained white solid that was filtered, washed with water
(100 mL) and diethyl ether (40 mL) to afford additional amount of
the title compound as a colorless solid (0.24 g, 27%): .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 10.25 (br s, 1H), 7.70 (d, J=7.9
Hz, 1H), 7.27-7.25 (m, 2H), 7.11 (d, J=7.9 Hz, 1H), 6.88 (d, J=13.0
Hz, 1H), 4.31 (d, J=3.7 Hz, 2H), 3.92 (d, J=5.4 Hz, 2H), 3.40-3.31
(m, 5H), 3.11-3.00 (m, 2H), 2.06-1.90 (m, 5H), 1.76-1.68 (m, 2H),
1.01-0.95 (m, 2H), 0.89-0.83 (m, 2H), 0.75-0.70 (m, 2H), 0.57-0.52
(m, 2H); MS(ES+) m/z 460.0, 558.2. (M=1).
Step 3. Preparation of
4-((1-(2-chloro-4-cyclopropylbenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01060##
[1811] Following the procedure as described in Example 402 Step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt with
4-((1-(2-chloro-4-cyclopropylbenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was
obtained as a colorless solid (0.06 g, 36%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.84 (br s, 1H), 9.57 (s, 1H), 7.51 (d,
J=8.0 Hz, 1H), 7.28-7.27 (m, 1H), 7.14-7.08 (m, 2H), 6.94 (d,
J=12.9 Hz, 1H), 4.33 (s, 2H), 3.94 (s, 2H), 3.39 (br s, 2H), 3.30
(s, 3H), 3.12-3.04 (m, 2H), 2.10-1.92 (m, 5H), 1.64-1.55 (m, 2H),
1.02-0.96 (m, 2H), 0.88-0.82 (m, 2H), 0.75-0.70 (m, 2H), 0.67-0.62
(m, 2H); MS(ES+) m/z 537.1, 535.1 (M=1).
Example 416
Synthesis of 4-((1-(2-chloro-4-cyclopropylbenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01061##
[1813] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-
-fluorobenzoic acid, trifluoroacetic acid salt with
4-((1-(2-chloro-4-cyclopropylbenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace
methanesulfonamide with cyclopropanesulfonamide, the title compound
was obtained as a colorless solid (0.05 g, 26%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.81 (br s, 1H), 9.47 (br s, 1H), 7.51
(d, J=8.0 Hz, 1H), 7.29-7.28 (m, 1H), 7.14-7.07 (m, 2H), 6.95 (d,
J=13.0 Hz, 1H), 4.33 (s, 2H), 3.94-3.93 (m, 2H), 3.43-3.40 (m, 2H),
3.13-2.99 (m, 3H), 2.07-1.92 (m, 5H), 1.62-1.50 (m, 2H), 1.09-1.06
(m, 4H), 1.02-0.96 (m, 2H), 0.88-0.82 (m, 2H), 0.75-0.70 (m, 2H),
0.67-0.62 (m, 2H); MS(ES+) m/z 563.1, 561.2 (M=1).
Example 417
Synthesis of
N-(azetidin-1-ylsulfonyl)-4-((1-(2-chloro-4-cyclopropylbenzyl)piperidin-4-
-yl) methoxy)-5-cyclopropyl-2-fluorobenzamide, trifluoroacetic acid
salt
##STR01062##
[1815] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt with
4-((1-(2-chloro-4-cyclopropylbenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace
methanesulfonamide with azetidine-1-sulfonamide, the title compound
was obtained as a colorless solid (0.06 g, 23%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.59 (br s, 1H), 9.38 (br s, 1H), 7.51
(d, J=8.0 Hz, 1H), 7.29-7.28 (m, 1H), 7.15-7.07 (m, 2H), 6.95 (d,
J=12.8 Hz, 1H), 4.33 (s, 2H), 4.01 (t, J=7.7 Hz, 4H), 3.94-3.93 (m,
2H), 3.44-3.40 (m, 2H), 3.12-3.04 (m, 2H), 2.18-1.91 (m, 7H),
1.62-1.50 (m, 2H), 1.02-0.96 (m, 2H), 0.89-0.82 (m, 2H), 0.75-0.70
(m, 2H), 0.68-0.63 (m, 2H); MS(ES+) m.z 578.0, 576.0 (M=1).
Example 418
Synthesis of 4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01063##
[1816] Step 1. Preparation of methyl
4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR01064##
[1818] Following the procedure as described in Example 402 step 1
and making non-critical variations as required to replace
tert-butyl 5-chloro-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
hydrochloride with methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
hydrochloride and to replace (R)-1-(3,5-dichlorophenyl)ethyl
4-methylbenzenesulfonamide with
4,4'-(bromomethylene)bis(fluorobenzene) and adding
tetra-N-butylammonium iodide to the reaction mixture, the title
compound was obtained as a light yellow syrup (0.19 g, 18%):
.sup.1H NMR (300 MHz, CDCl.sub.3), .delta. 7.42 (d, J=8.3 Hz, 1H),
7.36-7.29 (m, 4H), 6.98-6.92 (m, 4H), 6.52 (d, J=12.8 Hz, 1H), 4.26
(s, 1H), 3.86 (s, 3H), 3.83 (d, J=6.1 Hz, 2H), 2.90-2.86 (m, 2H),
2.01-1.96 (m, 1H), 1.91-1.77 (m, 5H), 1.49-1.38 (m, 2H), 0.90-0.83
(m, 2H), 0.64-0.58 (m, 2H); MS(ES+) m/z 510.2 (M=1).
Step 2. Preparation of
4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR01065##
[1820] To a solution of methyl
4-(bis(4-fluorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate (0.19 g, 0.38 mmol) in
tetrahydrofuran (10 mL) and water (3 mL) was added lithium
hydroxide (0.10 g, 4.10 mmol). The mixture was refluxed for 6
hours, and then cooled to ambient temperature. The mixture was
diluted with 1 M hydrochloric acid solution (100 mL) and extracted
with ethyl acetate (2.times.100 mL). The combined organic layers
were dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo to afford the title compound as a colorless
syrup (0.19 g, quant. yield) that was used directly in the next
reaction: MS(ES+) m/z 496.0 (M=1).
Step 3. Preparation of
4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01066##
[1822] Following the procedure as described in Example 402 Step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt with
4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was
obtained as a colorless solid (0.04 g, 27% in 2 steps): .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta.0 11.88 (br s, 1H), 9.98 (br s, 1H),
7.67 (br s, 4H), 7.31 (brs, 4H), 7.09 (d, J=8.2 Hz, 1H), 6.95 (d,
J=13.0 Hz, 1H), 5.62-5.59 (m, 1H), 3.95 (d, J =5.0 Hz, 2H), 3.30
(s, 3H), 3.26-3.22 (m, 2H), 3.04-2.95 (m, 2H), 2.05-1.96 (m, 3H),
1.84-1.81 (m, 1H), 1.60-1.55 (m, 2H), 0.87-0.82 (m, 2H), 0.66-0.61
(m, 2H); MS(ES+) m/z 573.1 (M=1).
Example 419
Synthesis of
N-azetidin-1-ylsulfonyl)-4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoorobenzamide, trifluoroacetic acid
salt
##STR01067##
[1824] Following the procedure as described in Example 402 Step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt with
4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, and to replace
methanesulfonamide with azetidine-1-sulfonamide, the title compound
was obtained as a colorless solid (0.04 g, 28%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 11.59 (br s, 1H), 10.24 (br s, 1H), 7.72
(br s, 4H), 7.31 (br s, 4H), 7.09 (d, J=8.2 Hz, 1H), 6.96 (d,
J=12.5 Hz, 1H), 4.01 (t, J=7.7, 7.7 Hz, 4H), 3.95 (d, J=4.4 Hz,
2H), 3.26-3.22 (m, 2H), 2.15-1.97 (m, 4H), 1.85-1.65 (m, 2H), 1.14
(t, J=7.3, 7.3 Hz, 2H), 0.87-0.82 (m, 2), 0.66-0.61 (m, 2H);
MS(ES+) m/z 614.1 (M=1).
Example 420
Synthesis of
5-cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-
-3-yl) methoxy)-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01068##
[1825] Step 1. Preparation of methyl
5-cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)
methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoate
##STR01069##
[1827] Following the procedure as described in Example 402 step 1
and making non-critical variations as required to replace
tert-butyl 5-chloro-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
hydrochloride with methyl
5-cyclopropyl-2-fluoro-4-((3-methylazetidin-3-yl)methoxy)benzoate
hydrochloride, and to replace (R)-1-(3,5-dichlorophenyl)ethyl
4-methylbenzenesulfonate with
1-(bromo(phenyl)methyl)-3,5-dichlorobenzene and adding
tetra-n-butylammonium iodide to the reaction mixture, the title
compound was obtained as a light yellow syrup (0.56 g, 62%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.47 (d, J=8.3 Hz, 1H),
7.37-7.20 (m, 2H), 7.16-7.15 (m, 1H), 6.61 (d, J=12.6 Hz, 1H), 4.32
(s, 1H), 4.02 (s, 2H), 3.88 (s, 3H), 3.21 (dd, J=7.4, 12.0 Hz, 2H),
2.89 (dd, J=7.4, 9.8 Hz, 2H), 2.06-1.97 (m, 1H), 1.38 (s, 3H),
0.92-0.86 (m, 2H), 0.67-0.62 (m, 2H); MS(ES+) m/z 530.0, 528.0
(M=1).
Step 2. Preparation of
5-cyclopropyl-4-((1-(3,5-dichlorophenyl)(phenyl)
methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoic acid
##STR01070##
[1829] Following the procedure as described in Example 402 step 2
and making non-critical variations as required to replace methyl
4-((1-(bis(4-fluorophenyl)methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2--
fluorobenzoate with methyl
5-cyclopropyl-4-((1-(3,5-dichlorophenyl)(phenyl)
methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoate, the title
compound was obtained following trituration in diethyl ether (15
mL) (0.44 g, 80%) as a colorless solid: MS(ES+) m/z 516.1, 514.1
(M=1).
Step 3. Preparation of
5-cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)
methyl)-3-methylazetidin-3-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzami-
de, trifluoroacetic acid salt
##STR01071##
[1831] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzinc acid, trifluoroacetic acid salt with
5-cyclopropyl-4-((1-((3,5-dichlorophenyl)
(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoic
acid, the title compound was obtained as a colorless solid (0.11 g,
37%): .sup.1H NMR (300 MHz, DMSO-d.sub.6+5% D.sub.2O) .delta. 7.60
(s, 1H), 7.52-7.51 (m, 2H), 7.45-7.35 (m, 5H), 7.13 (d, J=8.3 Hz,
1H), 6.91 (d, J=12.8 Hz, 1H), 5.50 (br s, 1H), 4.13 (br s, 2H),
3.89-3.57 (m, 4H), 3.29 (s, 3H), 2.04-1.95 (m, 1H), 1.40 (s, 3H),
0.85-0.78 (m, 2H), 0.65-0.56 (m, 2H); MS(ES+) m/z 592.9, 590.9
(M+1).
Example 421
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-((3,5-dichlorophenyl)(phenyl)
methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01072##
[1833] Following the procedure as described in Example 402 step 3
and making non-critical variations as required to replace
(S)-5-chloro-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)
methoxy)-2-fluorobenzoic acid, trifluoroacetic acid salt with
5-cyclopropyl-4-((1-((3,5-dichlorophenyl)
(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoic acid
and to replace methanesulfonamide with cyclopropanesulfonamide, the
title compound was obtained as a colorless solid (0.14 g, 47%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6+5% D.sub.2O) .delta. 7.61 (s,
1H), 7.54-7.53 (m, 2H), 7.47-7.35 (m, 5H), 7.12 (d, J=8.3 Hz, 1H),
6.91 (d, J=12.8 Hz, 1H), 5.60 (br s, 1H), 4.14 (br s, 2H),
3.98-3.91 (m, 2H), 3.82-3.76 (m, 2H), 3.06-2.98 (m, 1H), 2.04-1.94
(m, 1H), 1.42 (s, 3H), 1.09-1.06 (m, 4H), 0.84-0.78 (m, 2H),
0.62-0.57 (m, 2H); MS(ES+) m/z 616.9, 618.9 (M+1).
Example 422
Synthesis of
(R)-4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluuoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01073##
[1834] Step 1. Preparation of
(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR01074##
[1836] To a solution of (R)-tert-butyl
3-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)piperidine-1-car-
boxylate (3.50 g, 8.05 mmol) in dichloromethane (20 mL)
trifluoroacetic acid (5 mL) was added. The mixture was stirred for
1.5 hours and then a saturated aqueous solution of sodium
bicarbonate (25 mL) was added followed by di-tert-butyl dicarbonate
(1.93 g, 8.85 mmol). The reaction mixture was stirred for 1 hour,
acidified with 1M aqueous hydrochloric acid solution to pH=1 and
then extracted with dichloromethane (2.times.20 mL). The organic
layers were combined, dried over anhydrous sodium sulfate, filtered
and concentrated to give the title compound as a colorless solid
(3.05 g, quant. yield): MS(ES+) m/z 380.2 (M+1).
Step 2. Preparation of (R)-tert-butyl
3-(2-cyclopropyl-5-fluoro-4-((methylsulfonyl)
carbamoyl)phenoxy)piperidine-1-carboxylate
##STR01075##
[1838] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
(R)-4-((1-(tert-butoxycarbonyl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluorobenzoic acid and the residue was
purified by column chromatography eluting with gradient of 0% to
10% methanol containing 1% ammonia in dichloromethane, the title
compound was obtained as a colorless solid (2.76 g, 75%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.89-8.45 (brs, 1H), 7.56 (d,
J=9.0 Hz, 1H), 6.61 (d, J=14.5 Hz, 1H), 4.41-4.25 (m, 1H),
3.81-3.25 (m, 7H), 2.10-1.75 (m, 4H), 1.66-1.17 (m, 10H), 0.96-0.81
(m, 2H), 0.75-0.52 (m, 2H).
Step 3. Preparation of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(piperidin-3-yloxy)benzam-
ide, trifluoroacetic acid salt
##STR01076##
[1840] Following the procedure as described in Example 346 step6,
and making non-critical variations as required to replace
tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-4-fluoropiperidine-1-carboxylate with (R)-tert-butyl
3-(2-cyclopropyl-5-fluoro-4-((methylsulfonyl)
carbamoyl)phenoxy)piperidine-1-carboxylate, the title compound was
obtained as a colorless solid (2.75 g, quant. yield): MS(ES+) m/z
357.1 (M+1).
Step 4.
(R)-4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01077##
[1842] To a stirred solution of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(piperidin-3-yloxy)
benzamide trifluoroacetic (0.05 g, 0.10 mmol) and
3-chloro-5-(trifluoromethoxy)benzaldehyde (0.033 g, 0.15 mmol) in
tetrahydrofuran (1 mL) was added sodium triacetoxyborohydride
(0.073 g, 0.23 mmol). After stirring at ambient temperature for 16
hours, the reaction was quenched by adding 1 n aqueous hydrochloric
acid solution (0.4 mL) and the mixture was purified by column
chromatography eluting with 5% methanol in dichloromethane to give
an oil, which was further purified by preparative HPLC to afford
the title compound as a colorless solid (0.03 g, 45%): .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 12.19-11.69 (m, 1H), 10.04-9.66 (m,
1H), 7.76-7.62 (m, 2H), 7.61-7.49 (m, 1H), 7.14-7.01 (m, 2H),
5.01-4.58 (m, 1H), 4.57-4.18 (m, 2H), 3.67-2.77 (m, 7H), 2.42-1.49
(m, 5H), 0.96-0.76 (m, 2H), 0.73-0.60 (m, 2H); MS(ES+) m/z 567.0,
565.0 (M+1).
Example 423
Synthesis of
(R)-5-cyclopropyl-4-((1-(2,4-dimethylbenzyl)piperidin-3-yl)
oxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
##STR01078##
[1844] Following the procedure as described in Example 422 step 4,
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
2,4-dimethylbenzaldehyde, the title compound was obtained as a
colorless solid (0.02 g, 50%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. b 12.21-11.69 (m, 1H), 9.97-8.99 (m, 1H),
7.45-7.28 (m, 1H), 7.20-6.98 (m, 4H), 4.98-4.62 (m, 1H), 4.45-4.22
(m, 2H), 3.74-2.86 (m, 7H), 2.42-2.28 (m, 3H), 2.25 (s, 3H),
2.21-1.42 (m, 5H), 0.94-0.79 (m, 2H), 0.75-0.59 (m, 2H); MS(ES+)
m/z 475.2 (M+1).
Example 424
Synthesis of (R)-4-((1-(2-chloro-4-methylbenzyl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01079##
[1846] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
2-choro-4-methylbenzaldehyde, the title compound was obtained as a
colorless solid (0.03 g, 61%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.24-11.69 (m, 1H), 9.78-9.46 (m, 1H), 7.57
(d, J=7.41 Hz, 1H), 7.41 (s, 1H), 7.25 (d, J=8.00 Hz, 1H),
7.18-7.01 (m, 2H), 5.03-4.65 (m, 1H), 4.54-4.37 (m, 2H), 3.75-3.35
(m, 2H), 3.31 (s, 3H), 3.28-2.89 (m, 2H), 2.30 (s, 3H), 2.25-1.51
(m, 5H), 0.94-0.79 (m, 2H), 0.74-0.60 (m, 2H); MS(ES+) m/z 497.0,
495.0 (M+1).
Example 425
Synthesis of (R)-4-((1-(4-(tert-butyl)piperidin)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01080##
[1848] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
4-(tert-butyl)benzaldehyde, the title compound was obtained as a
colorless solid (0.03 g, 61%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.14-11.80 (m, 1H), 9.96-9.16 (m, 1H),
7.52-7.33 (m, 4H), 7.17-6.98 (m, 2H), 4.99-4.58 (m, 1H), 4.46-4.17
(m, 2H), 3.72-3.37 (m, 2H), 3.36-2.78 (m, 5H), 2.42-1.49 (m, 5H),
1.25 (s, 9H), 0.94-0.80 (m, 2H), 0.74-0.59 (m, 2H); MS(ES+) m/z
503.2 (M+1).
Example 426
Synthesis of (R)-4-((1-([1,1'-biphenyl]-4-ylmethyl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01081##
[1850] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
[1,1'-biphenyl]-4-carbaldehyde, the title compound was obtained as
a colorless solid (0.02 g, 36%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.14-11.77 (m, 1H), 10.15-9.40 (m, 1H), 7.76
(d, J=8.1 Hz, 2H), 7.67 (d, J=7.3 Hz, 2H), 7.64-7.54 (m, 2H), 7.46
(t, J=7.5 Hz, 2H), 7.41-7.33 (m, 1H), 7.19-7.01 (m, 2H), 5.02-4.61
(m, 1H), 4.55-4.29 (m, 2H), 3.76-3.44 (m, 2H), 3.40-2.86 (m, 5H),
2.42-1.53 (m, 5H), 0.95-0.79 (m, 2H), 0.72-0.61 (m, 2H); MS(ES+)
m/z 523.2 (M+1).
Example 427
Synthesis of (R)-4-((1-(5-chloro-2-hydroxybenzyl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-4-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01082##
[1852] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
5-chloro-2-hydroxybenzaldehyde, the title compound was obtained as
a colorless solid (0.04 g, 59%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.10-11.77 (m, 1H), 10.72-10.50 (m, 1H),
10.16-9.18 (m, 1H), 7.58-7.47 (m, 1H), 7.30 (dd, J=8.6, 2.1 Hz,
1H), 7.17-7.03 (m, 2H), 6.93 (d, J=8.4 Hz, 1H), 5.01-4.68 (m, 1H),
4.35-4.21 (m, 2H), 3.70-2.85 (m, (m, 7H), 2.41-1.56 (m, 5H),
0.95-0.79 (m, 2H), 0.72-0.61 (m, 2H); MS(ES+) m/z 499.1, 497.1
(M+1).
Example 428
Synthesis of
(R)-5-cyclopropyl-4-((1-(2,4-diethoxybenzyl)piperidin-3-yl)
oxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01083##
[1854] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
2,4-diethoxybenzaldehyde, the title compound was obtained as a
colorless solid (0.04 g, 77%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta.12.13-11.74 (m, 1H), 9.87-9.15 (m, 1H), 7.34
(dd, J=8.7, 8.7 Hz, 1H), 7.18-7.02 (m, 2H), 6.62-6.52 (m, 2H),
5.02-4.65 (m, 1H), 4.38-4.16 (m, 2H), 4.11-3.96 (m, 4H), 3.69-2.82
(m, 7H), 2.43-2.09 (m, 1H), 2.08-1.56 (m, 4H), 1.38-1.22 (m, 6H),
0.93-0.78 (m, 2H), 0.76-0.57 (m, 2H); MS(ES+) m/z 535.1. (M+1).
Example 429
Synthesis of
(R)-5-cyclopropyl-4-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)piper-
idin-3-yl) oxy)-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01084##
[1856] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde, the title compound
was obtained as a colorless solid (0.03 g, 64%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 12.09-11.82 (m, 1H), 9.90-9.22 (m, 1H),
7.18-6.99 (m, 3H), 6.98-6.87 (m, 2H), 4.98-4.60 (m, 1H), 4.39-4.09
(m, 6H), 3.69-2.75 (m, 7H), 2.38-1.49 (m, 5H), 0.95-0.79 (m, 2H),
0.75-0.60 (m, 2H); MS(ES+) m/z 505.1 (M+1).
Example 430
Synthesis of
(R)-5-cyclopropyl-4-((1-(3,4-dimethoxybenzyl)piperidin-3-yl)
oxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01085##
[1858] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluorormethoxy)benzaldehyde with
3,4-dimethoxybenzaldehyde, the title compound was obtained as a
colorless solid (0.03 g, 71%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.09-11.81 (m, 1H), 9.95-9.19 (m, 1H),
7.18-6.94 (m, 5H), 4.97-4.62 (m, 1H), 4.43-4.13 (m, 2H), 3.80-3.68
(m, 6H), 3.67-3.36 (m, 2H), 3.31 (s, 3H), 3.25-2.82 (m, 2H),
2.39-2.10 (m, 1H), 2.09-1.52 (m, 4H), 0.97-0.76 (m, 2H), 0.74-0.61
(m, 2H); MS(ES+) m/z 507.1 (M+1).
Example 431
Synthesis of
(R)-5-cyclopropyl-2-fluoro-4-((1-(4-fluoro-2-methylbenzyl)piperidin-3-yl)
oxy)-N-(methylsulfonyl)benzamide, trifluoroacetic acid salt
##STR01086##
[1860] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
4-fluoro-2-methylbenzaldehyde, the title compound was obtained as a
colorless solid (0.03 g, 82%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.13-11.78 (m, 1H), 9.82-9.03 (m, 1H),
7.63-7.43 (m, 1H), 7.23-7.00 (m, 4H), 4.96-4.62 (m, 1H), 4.44-4.27
(m, 2H), 3.71-2.91 (m, 7H), 2.43-2.13 (m, 4H), 2.13-1.47 (m, 4H),
0.94-0.79 (m, 2H), 0.75-0.60 (m, 2H); MS(ES+) m/z 479.0 (M+1).
Example 432
Synthesis of (R)-4-((1-(2-chloro-4-methoxybenzyl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01087##
[1862] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
2-chloro-4-methoxybenzaldehyde, the title compound was obtained as
a colorless solid (0.03 g, 67%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.17-11.73 (m, 1H), 9.99-9.27 (m, 1H),
7.67-7.52 (m, 1H), 7.20-6.97 (m, 4H), 5.03-4.60 (m, 1H), 4.48-4.34
(m, 2H), 3.78 (s, 3H), 3.67-2.88 (m, 7H), 2.42-1.51 (m, 5H),
0.95-0.78 (m, 2H), 0.76-0.61 (m, 2H); MS(ES+) m/z 513.1, 511.1
(M+1).
Example 433
Synthesis of
(R)-4-((1-(3-chloro-4-(trifluoromethyl)piperidin)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01088##
[1864] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
3-chloro-4-(trifluoromethyl)benzaldehyde, the title compound was
obtained as a colorless solid (0.03 g, 69%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.19-11.63 (m, 1H), 9.79-9.50 (m, 1H),
8.12-7.95 (m, 1H), 7.91-7.69 (m, 2H), 7.16-6.98 (m, 2H), 5.00-4.58
(m, 1H), 4.56-4.27 (m, 2H), 3.70-2.77 (m, 7H), 2.42-1.48 (m, 5H),
0.97-0.76 (m, 2H), 0.75-0.59 (m, 2H); MS(ES+) m/z 551.0, 549.0
(M+1).
Example 434
Synthesis of
(R)-5-cyclopropyl-2-fluoro-4-((1-(4-methoxy-2-methylbenzyl)piperidin-3-yl-
) oxy)-N-(methylsulfonyl)benzamide, trifluoroacetic acid salt
##STR01089##
[1866] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
4-methoxy-2-methylbenzaldehyde, the title compound was obtained as
a colorless solid (0.03 g, 71%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.09-11.80 (m, 1H), 9.72-8.85 (m, 1H), 7.41
(dd, J=16.1, 8.6 Hz, 1H), 7.17-7.00 (m, 2H), 6.89-6.78 (m, 2H),
4.96-4.63 (m, 1H), 4.39-4.20 (m, 2H), 3.72 (s, 3H), 3.68-3.36 (m,
2H), 3.31 (s, 3H), 3.24-2.91 (m, 2H), 2.34 (s, 3H), 2.27-1.51 (m,
5H), 0.94-0.79 (m, 2H), 0.74-0.58 (m, 2H); MS(ES+) m/z 491.2
(M+1).
Example 435
Synthesis of (R)-4-((1-(3-chloro-4-methylbenzyl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01090##
[1868] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzylaldehyde with
3-chloro-4-methylbenzaldehyde, the title compound was obtained as a
colorless solid (0.04 g, 91%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.16-11.76 (m, 1H), 9.74-9.43 (m, 1H),
7.58-7.43 (m, 2H), 7.41-7.28 (m, 1H), 7.19-7.01 (m, 2H), 4.97-4.64
(m, 1H), 4.44-4.20 (m, 2H), 3.70-3.39 (m, 2H), 3.31 (s, 3H),
3.26-2.85 (m, 2H), 2.31 (s, 3H), 2.26-1.46 (m, 5H), 0.95-0.77 (m,
2H), 0.73-0.61 (m, 2H); MS(ES+) m/z 497.1, 495.1 (M+1).
Example 436
Synthesis of
(R)-5-cyclopropyl-4-((1-(3,5-dimethylbenzyl)piperidin-3-yl)
oxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01091##
[1870] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
3,5-dimethylbenzaldehyde, the title compound was obtained as a
colorless solid (0.02 g, 51%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.21-11.75 (m, 1H), 10.27-9.47 (m, 1H),
7.20-6.96 (m, 5H), 5.00-4.62 (m, 1H), 4.43-4.12 (m, 2H), 3.70-3.37
(m, 2H), 3.31 (s, 3H), 3.27-2.85 (m, 2H), 2.42-2.11 (m, 7H),
2.07-1.54 (m, 4H), 0.94-0.77 (m, 2H), 0.75-0.57 (m, 2H); MS(ES+)
m/z 475.2 (M+1).
Example 437
Synthesis of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(3-(trifluoromethoxy)
benzyl)piperidin-3-yl)oxy)benzamide, trifluoroacetic acid salt
##STR01092##
[1872] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
3-(trifluoromethoxy)benzaldehyde, the title compound was obtained
as a colorless solid (0.02 g, 33%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.23-11.62 (m, 1H), 9.77-9.45 (m, 1H),
7.68-7.39 (m, 3H), 7.20-6.98 (m, 2H), 5.03-4.59 (m, 1H), 4.59-4.26
(m, 2H), 3.67-2.77 (m, 7H), 2.42-1.48 (m, 5H), 1.20-0.57 (m, 4H);
MS(ES+) m/z 531.1 (M+1).
Example 438
Synthesis of
(R)-5-cyclopropyl-2-fluoro-4-((1-(2-methoxy-4-(trifluoromethoxy)
benzyl)piperidin-3-yl)oxy)-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01093##
[1874] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
2-methoxy-4-(trifluoromethoxy)benzaldehyde, the title compound was
obtained as a colorless solid (0.04 g, 60%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.18-11.73 (m, 1H), 9.25-9.01 (m, 1H),
7.63-7.49 (m, 1H), 7.19-6.98 (m, 4H), 5.00-4.61 (m, 1H), 4.41-4.24
(m, 2H), 3.90-3.77 (m, 3H), 3.74-2.83 (m, 7H), 2.42-1.53 (m, 5H),
0.95-0.79 (m, 2H), 0.74-0.61 (m, 2H); MS(ES+) m/z 561.1 (M+1).
Example 439
Synthesis of
(R)-5-cyclopropyl-4-((1-(3,4-dimethylbenzyl)piperidin-3-yl)
oxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01094##
[1876] Following the procedure as described in Example 426 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
3,4-dimethylbenzaldehyde, the title compound was obtained as a
colorless solid (0.03 g, 60%): .sup.1H NMR (300 MHz,
DMSO-.sub.6).delta. 12.09-11.80 (m, 1H), 10.35-9.35 (m, 1H),
7.34-7.16 (m, 3H), 7.16-6.98 (m, 3H), 4.98-4.67 (m, 1H), 4.42-4.12
(m, 2H), 3.69-3.36 (m, 2H), 3.31 (s, 3H), 3.27-2.79 (m, 2H),
2.42-2.12 (m, 7H), 2.06-1.51 (m, 4H), 0.95-0.78 (m, 2H), 0.73-0.59
(m, 2H); MS(ES+) m/z 475.2 (M+1).
Example 440
Synthesis of
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)
oxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR01095##
[1878] Following the procedure as described in Example 422 step 4
and making variation as required to replace
3-chloro-5-(trifluoromethoxy)benzaldehyde with
3,5-dichlorobenzaldehyde and to purify the residue using column
chromatography eluting with 5% methanol containing 0.5% ammonia in
dichloromethane, the title compound was obtained as a colorless
solid (0.12 g, 72%): .sup.1H NMR (300 MHz, CDCl.sub.3).delta. 7.53
(d, J=9.1 Hz, 1H), 7.27-7.16 (m, 3H), 6.55 (d, J=14.5 Hz, 1H),
4.50-4.36 (m, 1H), 3.56-3.41 (m, 2H), 3.39 (s, 3H), 2.86 (d, J=10.4
Hz, 1H), 2.67-2.56 (m, 1H), 2.45-2.33 (m, 1H), 2.32-2.21 (m, 1H),
2.13-1.97 (m, 2H), 1.94-1.78 (m, 1H), 1.74-1.54 (m, 2H), 1.00-0.87
(m, 2H), 0.73-0.59 (m, 2H); MS(ES+) m/z: 515.0, 517.1 (M+1).
Example 441
Synthesis of
(R)-4-((1-(2-chloro-4-(methylsulfonyl)piperidin)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01096##
[1880] To a stirred solution of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(piperidin-3-yloxy)
benzamide trifluoroacetate (0.05 g, 0.14 mmol) and
1-(bromomethyl)-2-chloro-4-(methylsulfonyl)benzene (0.06 g, 0.21
mmol) in acetonitrile (2 mL) was added potassium carbonate (0.05 g,
0.34 mmol) and potassium iodide (0.03 g, 0.17 mmol). The reaction
mixture was stirred at reflux for 16 hours, cooled to ambient
temperature, and then 1N aqueous hydrochloric acid solution (5 mL)
was added; extracted with ethyl acetate (3.times.10 mL) and
concentrated invacuo. The residue was purified by column
chromatography eluting with gradient of 0% to 30% ethyl acetate
containing 1% formic acid in hexanes to obtained an oil, which was
further purified by preparative HPLC (gradient of acetonitrile in
water) to afford the title compound (0.04 g, 44%) as a colorless
solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6).delta. 7.90 (s, 1H),
7.78-7.71 (m, 2H), 7.16 (d, J=8.70 Hz, 1H), 6.85-6.67 (m, 1H),
4.57-4.45 (m, 1H), 3.66 (m, 2H), 3.22 (s, 3H), 2.85-2.72 (m, 2H),
2.62-2.50 (m, 1H), 2.40-2.29 (m, 1H), 2.10-1.97 (m, 1), 1.97-1.85
(m, 1H), 1.84-1.72 (m, 1H), 1.63-1.44 (m, 2H), 0.90-0.79 (m, 2H),
0.63-0.51 (m, 2H); MS(ES+) m/z: 559.0, 561.0 (M+1).
Example 442
Synthesis of (R)-4-((1-([1,1'-biphenyl]-2-yl)methyl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01097##
[1882] Following the procedure as described in Example 441 and
making variation as required to replace
1-(bromomethyl)-2-chloro-4-(methylsulfonyl)benzene with
2-(bromomethyl)-1,1'-biphenyl, the title compound was obtained as a
colorless solid (0.02 g, 28%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.22-11.69 (m, 1H), 9.66-8.78 (m, 1H),
7.80-7.62 (m, 1H), 7.57-7.21 (m, 8H), 7.17-7.04 (m, 1H), 6.96 (d, J
=12.9 Hz, 1H), 4.89-4.11 (m, 5H), 3.41-2.87 (m, 5H), 2.42-1.38 (m,
5H), 0.96-0.77 (m, 2H), 0.76-0.59 (m, 2H); MS(ES+) m/z 523.2
(M+1).
Example 443
Synthesis of (R)-4-((1-([1,1'-biphenyl]-3-ylmethyl)piperidin-3-yl)
oxy-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01098##
[1884] Following the procedure as described in Example 441, and
making variation as required to replace
1-(bromomethyl)-2-chloro-4-(methylsulfonyl)benzene with
3-(bromomethyl)-1,1'-biphenyl, the title compound was obtained as a
colorless solid (0.01 g, 8%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 12.06-11.82 (m, 1H), 10.20-9.29 (m, 1H), 7.92-7.60 (m, 2H),
7.60-7.42 (m, 6H), 7.42-7.34 (m, 1H), 7.17-6.98 (m, 2H), 4.99-4.62
(m, 1H), 4.60-4.27 (m, 2H), 3.75-3.43 (m, 2H), 3.39-2.89 (m, 5H),
2.41-1.50 (m, 5H), 0.93-0.54 (m, 4H); MS(ES+) m/z 523.2 (M+1).
Example 444
Synthesis of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(spiro[3.5]nonan-7-yl-
methyl) piperidin-3-yl)oxy)benzamide, trifluoroacetic acid salt
##STR01099##
[1885] Step 1. Preparation of spiro[3.5]nonan-7-ylmethyl
methanesulfonate
##STR01100##
[1887] To a solution of spiro[3.5]nonan-7-ylmethanol (0.77 g, 5.00
mmol) and triethylamine (1.05 mL, 7.50 mmol) in dichloromethane (20
mL) was added dropwise methanesulfonyl chloride (0.42 mL, 5.5 mmol)
at 0.degree. C. The mixture was stirred for 1.5 hours, and then
saturated aqueous solution of ammonium chloride (10 mL) was added
and the mixture was extracted with dichloromethane (2.times.20 mL).
The combined organic layers were washed with brine (15 mL), dried
over anhydrous sodium sulfate, filtered and concentrated invacuo to
afford the title compound (1.16 g, quant. yield), which was used
next step without further purification.
Step 2. Preparation of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(spiro[3.5]nonan-7-yl-
methyl) piperidin-3-yl)oxy)benzamide, trifluoroacetic acid salt
##STR01101##
[1889] Following the procedure as described in Example 441, and
making variation as required to replace
1-(bromomethyl)-2-chloro-4-(methylsulfonyl)benzene with
spiro[3.5]nonan-7-ylmethyl methanesulfonate, the title compound was
obtained as a colorless solid (0.02 g, 31%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6).delta. 12.09-11.80 (m, 1H), 9.28-8.58 (m, 1H),
7.18-7.01 (m, 2H), 5.03-4.62 (m, 1H), 3.74-3.59 (m, 2H), 3.31 (s,
3H), 3.14-2.81 (m, 4H), 2.43-2.11 (m, 2H), 2.06-1.85 (m, 2H),
1.85-1.44 (m, 12H), 1.30-1.12 (m, 2H), 1.07-0.79 (m, 4H), 0.78-0.56
(m, 2H); MS(ES+) m/z 493.2 (M+1).
Example 445
Synthesis of
(R)-4-((1-(2-chloro-4-fluorobenzyl)-5,5-difluoropiperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide (
##STR01102##
[1890] Step 1. Preparation of
(R)-3-((tert-butyldimethylsilyl)oxy)-1-(4-methoxy)piperidine-2,6-dione
##STR01103##
[1892] To a solution of
(R)-3-hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione (prepared
accordingly to Yuan-Ping et al., Chirality, 2005, 17, 595-599)
(3.50 g, 14.00 mmol) in dichloromethane (20 mL) was added
tert-butylchlorodimethylsilane (2.30 g, 15.50 mmol) and imidazole
(1.30 g, 19.70 mmol). After stirring at ambient temperature for 1
hour, the reaction mixture was quenched with saturated aqueous
ammonium chloride solution (25 mL and extracted with
dichloromethane (2.times.40 mL), washed with brine (30 mL), dried
over anhydrous sodium sulfate, filtered and concentrated invacuo.
The residue was purified by column chromatography (0% to 15% ethyl
acetate in hexanes) to give the title compound (2.80 g, 55% 0);
MS(ES+) m/z 364.1 (M+1).
Step 2. Preparation of (5R)-5-((tert-butyldimethylsilyl)
oxy)-6-hydroxy-1-(4-methoxybenzyl)piperidin-2-one
##STR01104##
[1894] To a solution of
(R)-3-((tert-butyldimethylsilyl)oxy)-1-(4-methoxybenzyl)piperidine-2,6-di-
one (2.80 g. 7.70 mmol) in methanol (10 mL) and dichloromethane (10
mL) under nitrogen atmosphere at -30.degree. C. was added sodium
borohydride (1.40 g, 38.50 mmol). After stirring for 30 minutes at
-30.degree. C., the reaction mixture was warmed to 0.degree. C.
over 30 minutes and quenched with saturated aqueous ammonium
chloride solution (20 mL) and extracted with dichloromethane
(2.times.15 mL). The combined extracts were dried over anhydrous
sodium sulfate, filtered and concentrated invacuo to give an oil
(2.70 g, 76%) which was used in the next step without further
purification: MS(ES+) m/z 366.2 (M+1).
Step 3. Preparation of
(R)-5-((tert-butyldimethylsilyl)oxy)-1-(4-methoxybenzyl)piperidin-2-one
##STR01105##
[1896] To a solution of (5R)-5-((tert-butyldimethylsilyl)oxy)
6-hydroxy-1-(4-methoxybenzyl)piperidin-2-one (2.70 g, 7.60 mmol)
and triethylsilane (11.50 g, 77.10 mmol) in dry dichloromethane (20
mL) was added boron trifluoride diethyl ether complex (2.9 mL,
23.00 mmol) at -78.degree. C. under nitrogen atmosphere. After
stirring for 30 minutes at -78.degree. C., the reaction mixture was
warmed up slowly to 0.degree. C. and stirred at this temperature
for 2 hours before it was quenched with saturated aqueous solution
of sodium bicarbonate solation (5 mL) and extracted with
dichloromethane (2.times.10 mL). The combined organic layers were
dried over anhydrous sodium sulfate, filtered, an concentrated
invacuo to afford the title compound as an oil (1.26 g, 47%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.16 (d, J=8.5 Hz, 2H),
6.82 (d, J=8.6 Hz, 2H), 4.71 (d, J=14.6 Hz, 1H), 4.27 (d, J=14.6
Hz, 1H), 4.08-3.98 (m, 1H), 3.77 (s, 3H), 3.24 (dd, J=12.4, 3.7 Hz,
1H), 3.05 (dd, J=12.3, 4.5 Hz, 1H), 2.68 (m, 1H), 2.39 (td, J=17.6,
5.7 Hz, 1H), 1.91-1.78 (m, 2H), 0.81 (s, 9H), 0.00 (s, 3H), -0.06
(s, 3H).
Step 4. Preparation of
(R)-5-hydroxy-1-(4-methoxybenzyl)piperidin-2-one
##STR01106##
[1898] To a solution of
(R)-5-((tert-butyldimethylsilyl)oxy)-1-(4-methoxybenzyl)piperidin-2-one
(1.25 g, 3.58 mmol) in tetrahydrofuran (10 mL) was added
tetra-butylammonium fluoride (1.0M in THF, 5.3 mL, 5.3 mmol) under
nitrogen atmosphere. After stirring a ambient temperature for
30minutes, the reaction mixture was quenched with saturated aqueous
ammonium chloride solution (2.5 mL) and extracted with
dichloromethane (2.times.10 mL). The combined extracts were
concentrated invacuo and filtered over a plug of silica gel eluting
with 10% hexanes in ethyl acetate followed by ethyl acetate to
afford the title compound as oil (0.84 g, quant. yield): MS(ES+)
m/z 236.2 (M+1).
Step 5. Preparation of (R)-tert-butyl
5-chloro-2-fluoro-4-((1-(4-methoxybenzyl)-6-oxopiperidin-3-yl)oxy)benzoat-
e
##STR01107##
[1900] To a solution of
(R)-5-hydroxy-1-(4-methoxybenzyl)piperidin-2-one (0.84 g, 3.58
mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (0.98 g, 3.95
mmol) in dimethylsulfoxide (10 mL) was added cesium carbonate (1.52
g, 10.7 mmol). After stirring for 48 hours at 80.degree. C., the
reaction mixture was quenched with saturated aqueous solution of
ammonium chloride solution (20 mL) and extracted with
dichloromethane (2.times.10 mL). The organic layers were
concentrated under reduced pressure and the residue was purified by
chromatography eluting with a gradient of ethyl acetate in hexanes
(50% to 100%) to afford the title compound as a gum (1.38 g, 83%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.80 (d, J =7.7 Hz, 1H),
7.08 (d, J=8.6 Hz, 2H), 6.71 (d, J=8.6 Hz, 2H), 6.46 (d, J=11.9 Hz,
1H), 4.79 (d, J =14.6 Hz, 1H), 4.71-4.62 (m, 1H), 4.17 (d, J=14.6
Hz, 1H), 3.69 (s, 3H), 3.43-3.37 (m, 2H), 2.71 (ddd, J=17.6, 11.1,
6.6 Hz, 1H), 2.46 (ddd, J=17.7, 6.2, 3.7 Hz, 1H), 2.26-2.13 (m,
1H), 2.12-2.00 (m, 1H), 1.52 (s, 9H); MS(ES+) m/z 466.1, 464.1
(M+1).
Step 6. Preparation of (R)-tert-butyl
5-cyclopropyl-2-fluoro-4-((1-(4-methoxybenzyl)-6-oxopiperidin-3-yl)oxy)be-
nzoate
##STR01108##
[1902] Following the procedure as described in Example 346 step 3
and making variation as required to replace tert-butyl
4-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)-4-fluoropipe-
ridine-1-carboxylate with (R)-tert-butyl
5-chloro-2-fluoro-4-((1-(4-methoxybenzyl)-6-oxopiperidin-3-yl)
oxy)benzoate and the reaction mixture was heated at 150.degree. C.
for 1 hour under microwave irradiation, the title compound was
obtained as a colorless oil (0.90 g, 64%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.32 (d, J=8.4 Hz, 1H), 7.15-7.09 (m, 2H),
6.77-6.70 (m, 2H), 6.39 (d, J=12.4 Hz, 1H), 4.73-4.64 (m, 2H),
4.35-4.28 (m, 1H), 3.72 (s, 3H), 3.47-3.42 (m, 2H), 2.75-2.59 (m,
1H), 2.55-2.42 (m, 1H), 2.30-2.17 (m, 1H), 2.12-2.01 (m, 1H),
1.89-1.76 (m, 1H), 1.53 (s, 9H), 0.89-0.78 (m, 2H), 0.60-0.49 (m,
2H).
Step 7. Preparation of (R)-tert-butyl
5-cyclopropyl-4-((5,5-difluoro-1-(4-methoxybenzyl)-6-oxopiperidin-3-yl)
oxy)-2-fluorobenzoate
##STR01109##
[1904] To a solution of diisopropyl amine (0.10 mL, 0.75 mmol) in
anhydrous tetrahydrofuran (1 mL) under nitrogen was added butyl
lithium solution (1.5M solution in hexanes, 0.46 mL, 0.69 mmol) at
-78.degree. C. After stirring at -78.degree. C. for 1 hour, a
solution of (R)-tert-butyl
5-cyclopropyl-2-fluoro-4-((1-(4-methoxybenzyl)-6-oxopiperidin-3-yl)
oxy)benzoate (0.25 g, 0.53 mmol) in tetrahydrofuran (1.5 mL) was
added, stirring was continued at -78.degree. C. for another 1 hour.
To this reaction mixture, was added a solution of
N-fluorobenzenesulfonimide (0.39 g, 0.75 mmol) in tetrahydrofuran
(2 mL) slowly over 10 minutes. The reaction mixture was stirred for
30 minutes at -78.degree. C. and then slowly warmed up to
-30.degree. C. over 1 hour. The reaction mixture was cooled to
-78.degree. C. again and lithium bis(trimethylsilyl)amide (1.0 M
solution in toluene, 0.8 mL, 0.8 mmol) was added. The reaction
mixture was stirred for 30 min at -78.degree. C., a solution of
N-fluorobenzenesulfonimide (0.39 g, 0.75 mmol) in tetrahydrofuran
(2 mL) was added and the reaction mixture was slowly warmed up to
-30.degree. C. over 1 hour and then quenched with a saturated
aqueous solution of ammonium chloride solution (10 mL), extracted
with ethyl acetate (2.times.15 mL) and concentrated. The residue
was purified by column chromatography eluting with a gradient of
30% to 80% ethyl acetate in hexanes to afford the title compound
(0.05 g, 20%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.92 (d,
J=7.0 Hz, 1H), 7.62-7.45 (m, 2H), 7.22-7.12 (m, 2H), 6.77 (d, J=8.6
Hz, 2H), 6.40-6.16 (m, 1H), 4.94-4.82 (m, 1H), 4.76-4.64 (m, 1H),
4.47-4.28 (m, 1H), 3.75 (s, 3H), 3.70-3.54 (m, 2H), 2.72 (dt,
J=14.6, 4.8 Hz, 1H), 1.88-1.59 (m, 2H), 1.54 (s, 9H), 0.90-0.72 (m,
2H), 0.61-0.47 (m, 2H); MS(ES+) m/z 450.1 (M-t-Bu+1).
Step 8. Preparation of (R)-tert-butyl
5-cyclopropyl-4-((5,5-difluoro-1-(4-methoxybenzyl)piperidin-3-yl)
oxy)-2-fluorobenzoate
##STR01110##
[1906] To a solution of (R)-tert-butyl
5-cyclopropyl-4-((5,5-difluoro-1-(4-methoxybenzyl)
-6-oxopiperidin-3-yl)oxy)-2-fluorobenzoate (0.05 g, 0.10 mmol) in
tetrahydrofuran (1 mL), borane (1.0M in tetrahydrofuran, 0.3 mL,
0.3 mmol,) was added. The reaction mixture was stirred for 2 hours
at ambient temperature and then quenched with methanol (1 mL). The
reaction mixture was concentrated and the residue was purified by
column chromatography eluting with a gradient of 0% to 20% ethyl
acetate in hexanes to afford the title compound as an oil (0.03 g,
61%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.35 (d, J=8.3 Hz,
1H), 7.21 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 6.52 (d,
J=12.4 Hz, 1H), 4.64-4.49 (m, 1H), 3.78 (s, 3H), 3.68 (d, J=13.1
Hz, 1H), 3.61 (d, J=13.1 Hz, 1H), 3.20-3.09 (m, 1H), 3.08-2.92 (m,
1H), 2.68-2.22 (m, 3H), 2.01-1.89 (m, 2H), 1.55 (s, 9H), 0.85-0.78
(m, 2H), 0.65-0.55 (m, 2H); MS(ES+) m/z 492.1 (M+1).
Step 9. Preparation of (R)-tert-butyl
5-cyclopropyl-4-((5,5-difluoropiperidin-3-yl) oxy)-2-fluorobenzoate
trifluoroacetate
##STR01111##
[1908] To a stirred solution of 4(R)-tert-butyl
5-cyclopropyl-4-((5,5-difluoro-1-(4-methoxybenzyl)piperidin-3-yl)
oxy)-2-fluorobenzoate (0.23 g, 0.47 mmol)) in degassed ethyl
acetate (5 mL), and trifluoroacetic acid (0.2 mL) was added 10%
palladium on carbon (20 mg) and the flask was put under 1 atm of
hydrogen gas. The reaction mixture was stirred for 4 hours at
ambient tendperature, and then filtered over diatomaceous earth and
rinsed with ethyl acetate (2.times.20 mL). The filtrate was
concentrated to afford the title compound (0.23 g, quant. yield):
MS(ES+) m/z 372.2 (M+1).
Step 10. Preparation of
(R)-4-((1-(2-chloro-4-fluorobenzyl)-5,5-difluoropiperidin-3-yl)
oxy)-5-cyclopropyl-2-fluorobenzoic acid hydrochioric acid
##STR01112##
[1910] To a stirred solution of (R)-tert-butyl
5-cyclopropyl-4-(5,5-difluoropiperidin-3-yl) oxy)-2-fluorobenzoate
trifluoroacetate (0.23 g, 0.47 mmol) in dichloromethane (1 mL) was
added trifluoroacetic acid (1 mL). After stirring at ambient
temperature for 2 hours, the reaction mixture was concentrated in
vacuo. The residue was dissolved in tetrahydrofuran (1 mL), and to
the solution was added 2-chloro-4-fluorobenzaldehyde (0.07 g, 0.50
mL) and sodium triacetoxyborohydride (0.24 g, 0.74 mmol). The
reaction mixture was stirred for 16 hours at ambient temperature,
quenched with 1N aqueous hydrochloric acid solution (5 mL) and
extracted with ethyl acetate (3.times.10 mL), and concentrated in
vacuo. The residue was purified by column chromatography eluting
with 40% ethyl acetate (plus 0.5% trifluoroacetic acid) in hexanes
to afford the title compound as a colorless solid (0.16 g, 81%):
.sup.1H NMR (300 MHz, CDDl.sub.3) .delta. 7.55-7.41 (m, 2H), 7.10
(dd, J=8.4, 2.6 Hz, 1H), 6.96 (dt, J=8.4, 2.6 Hz, 1H), 6.57 (d,
J=12.5 Hz, 1H), 6.47-6.12 (brs, 2H), 4.63 (m, 1H), 3.77 (s, 2H),
3.13 (dd, J=11.4, 3.1 Hz, 1H), 3.02 (dd, J=20.3, 9.1 Hz, 1H),
2.72-2.48 (m, 3H), 2.15-2.05 (m, 1H), 2.01-1.96 (m, 1H), 0.88-0.79
(m, 2H), 0.66-0.58 (m, 2H).
Step 11. Preparation of
(R)-4-((1-(2-chloro-4-fluorobenzyl)-5,5-difluoropiperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01113##
[1912] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
(R)-4-((1-(2-chloro-4-fluorobenzyl)-5,5-difluoropiperidin-3-yl)
oxy-5-cyclopropyl-2-fluorobenzoic acid hydrochloric acid, the title
compound was obtained as a colorless solid (0.02 g, 41%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 8.68 (d, J=15.8 Hz, 1H), 7.56
(d, J=9.0 Hz, 1H), 7.46 (dd, J=8.5, 6.2 Hz, 1H), 7.11 (dd, J=8.4,
2.5 Hz, 1H), 6.96 (dt, J=8.3, 2.5 Hz, 1H), 6.57 (d, J=14.1 Hz, 1H),
4.71-4.57 (m, 1H), 3.77 (s, 2H), 3.39 (s, 3H), 3.18-2.94 (m, 2H),
2.75-2.49 (m, 3H), 2.19-1.98 (m, 2H), 0.98-0.83 (m, 2H), 0.68-0.59
(m, 2H); MS(ES+) m/z 537.2, 535.2 (M+1).
Example 446
Synthesis of
(R)-4-((1-(2-chloro-4-fluorobenzyl)-5,5-difluoropiperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01114##
[1913] Step 1. Preparation of
N-(2-chloro-4-fluorobenzyl)-5-oxotetrahydrofuran-2-carboxamide
##STR01115##
[1915] A mixture of (R)-5-oxotetrahydrofuran-2-carboxylic acid
(10.0 g, 76.9 mmol) and thionyl chloride (20.0 g, 307.0 mmol) was
refluxed for 10 hours, and then the excess thionyl chloride was
removed under reduced pressure. The residue was redissolved in
anhydrous dichloromethiane (150 mL) and cooled to 0.degree. C. To
this solution was added triethylamine (10.1 g, 100.0 mmol) and
(2-chloro-4-fluorophenyl)methanamine (12.2 g, 76.9 mmol)
successively. After stirring at 0.degree. C. for 3 hours, the
reaction mixture was directly poured on a silica column and eluted
with 20% to 70% ethyl acetate in hexanes to afford the title
compound as a colorless solid (20.80 g, quant. yield): .sup.1H NMR
(300MHz, CDCl.sub.3) .delta. 7.34 (dd, J=8.5, 6.0 Hz, 1H), 7.13
(dd, J=8.4, 2.6 Hz, 1H), 6.95 (dt, J=8.3, 2.6 Hz, 1H), 6.82-6.68
(m, 1H), 4.86 (t, J=7.4 Hz, 1H), 4.51 (d, J=6.0 Hz, 2H), 2.72-2.50
(m, 3H), 2.41-2.28 (m, 1H).
Step 2. Preparation of
(R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-4-fluorobenzyl)piperidin-
e-2,6-dione
##STR01116##
[1917] To a Solution of
N-(2-chloro-4-fluorobenzyl)-5-oxotetrahydrofuran-2-carboxamide
(20.8 g, 77.0 mmol) in anhydrous tetrahydrofuran (200 mL) was added
a cooled 1.0 M solution of potassium tert-butoxide in anhydrous
tetrahydrofuran (46.0 mL, 46.0 mmol) at -78.degree. C. under
nitrogen atmosphere. After 10 minutes of stirring at -78.degree.
C., the temperature was allowed to arise to -60.degree. C. over 10
min, and then the reaction mixture was stirred at -60.degree. C.
for 1.5 hours. Another portion of potassium tert-butoxide (46.0 mL,
46.0 mmol) was added and the reaction mixture was stirred for
another 1.5 hours at -45.degree. C. and then a solution of
tert-butyldimethylsilyl chloride (12.80 g, 85.70 mmol) in
tetrahydrofuran (20 mL) was added dropwise and stirring was
continued for 30 minutes at -45.degree. C. The reaction mixture was
quenched with saturated aqueous ammonium chloride solution (25 mL)
at -45.degree. C., and extracted with ethyl acetate (2.times.100
mL). The combined extracts were washed with brine (50 mL), dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by flash chromatography
eluting with a gradient of 0 to 15% ethyl acetate in hexanes to
give the title compound (28.1 g, 93%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.03 (dd, J=8.4, 2.4 Hz, 1H), 6.89 (d, J=8.5,
6.1 Hz, 1H), 6.79 (dt, J=8.5, 2.4 Hz, 1H), 4.94 (d, J=15.7 Hz, 1H),
4.88 (d, J=15.7 Hz, 1H), 4.35 (dd, J=6.3, 3.7 Hz, 1H), 2.94 (ddd,
J=17.8, 8.9, 5.7 Hz, 1H), 2.62 (td, J =17.8, 5.7 Hz, 1H), 2.13-1.97
(m, 2H), 0.85 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H).
Step 3. Preparation of
(5R)-5-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-4-fluorobenzyl)-6-hydro-
xypiperidin-2-one
##STR01117##
[1919] Following the procedure as described in Example 445 step 2
and step 3, and making variation as required to replace
(R)-3-((tert-butyldimethylsilyl)oxy)-1-(4-methoxybenzyl)piperidine-2,6-di-
one with
(R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-4-fluorobenzyl)p-
iperidine-2,6-dione, the title compound was obtained (0.68 g, 79%
in 2 steps) and used without further purification: MS(ES+) m/z
390.1, 388.1 (M+1).
Step 4. Preparation of
(R)-5-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-4-fluorobenzyl)piperidin-
-2-one
##STR01118##
[1921] To a cooled solution (-78.degree. C.) of
(5R)-5-((tert-butyldimethylsilyl)oxy)-6-hydroxy-1-(4-methoxybenzyl)piperi-
din-2-one (2.70 g, 7.60 mmol) and triethylsilane (11.50 g, 77.10
mmol) in anhydrous dichloromethane (20 mL) under nitrogen
atmosphere was added boron trifluoride diethyl ether complex (2.9
mL, 23 mmol). The reaction mixture was stirred for 30 minutes at
-78.degree. C., and then warmed up slowly to 0.degree. C. and
stirred at this temperature for 2 hours. The reaction mixture was
quenched with a saturated aqueous solution of sodium bicarbonate (5
mL) and extracted with dichloromethane (2.times.10 mL). The
combined organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure to give the title
compound as an oil (1.26 g, 47%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.16 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.6 Hz, 2H), 4.71 (d,
J=14.6 Hz, 1H), 4.27 (d, J=14.6 Hz, 1H), 4.08-3.98 (m, 1H), 3.77
(s, 3H), 3.24 (dd, J=12.4, 3.7 Hz, 1H), 3.05 (dd, J=12.3, 4.5 Hz,
1H), 2.68 (m, 1H), 2.39 (td, J=17.6, 5.7 Hz, 1H), 1.91-1.78 (m,
2H), 0.81 (s, 9H), 0.00 (s, 3H), -0.06 (s, 3H).
Step 4. Preparation of
(5R)-5-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-4-fluorobenzyl)-3-fluor-
opiperidin-2-one
##STR01119##
[1923] To a stirred solution of diisopropylamine (0.068 g, 0.67
mmol) in tetrahydrofuran (2 mL) at -78.degree. C. was added
n-butyllithium (1.5 M solution in hexanes, 0.41 mL, 0.62 mmol).
After stirring for 45 minutes at -78.degree. C., a solution of
(R)-5-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-4-fluorobenzyl)piperidin-
-2-one (0.18 g, 0.48 mmol) tetrahydrofuran (2 mL) was added
dropwise and the reaction mixture was stirred for 40 minutes at
-78.degree. C. A solution of N-fluorobenzenesulfonimide (0.21 g,
0.67 mmol) in tetrahydrofuran (1.5 mL) was added via syringe pump
over a 10 minutes period and the reaction mixture was stirred at
-78.degree. C. for 5 hours and then slowly warmed up to -40.degree.
C., The reaction mixture was quenched by addition of saturated
aqueous solution of ammonium chloride (10 mL), and extracted with
ethyl acetate (2.times.10 mL). The combined organic phases were
washed with water (10 mL) and brine (10 mL), dried over sodium
sulfate, filtered and concentrated invacuo. To the residue was
added dichloromethane and methyl tert-butylether (10 mL, 1/1, v/v)
the resulting precipitate was removed by filtration. The filtrate
was concentrated to give a light yellow residue which was purified
by silica gel chromatography using a gradient (0 to 30%) of ethyl
acetate in hexanes to give the title compound as a gum (0.08 g,
39%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.29 (dd, J =8.6,
6.1 Hz, 1H), 7.10 (dd, J=8.4, 2.6 Hz, 1H), 6.92 (dt, J=8.4, 2.6 Hz,
1H), 5.18 (ddd, J=47.6, 10.1, 6.1 Hz, 1H), 4.99 (d, J=15.5 Hz, 1H),
4.37 (d, J=15.5 Hz, 1H), 4.29-4.20 (m, 1H), 3.44 (dd, J =12.6, 3.3
Hz, 1H), 3.18-3.09 (m, 1H), 2.51-2.35 (m, 1H), 2.23-2.07 (m, 1H),
0.83 (s, 9H), 0.06 (s, 3H), -0.03 (s, 3H).
Step 5. Preparation of (R)-5-((tert-butyldimethylsilyl)
oxy)-1-(2-chloro-4-fluorobenzyl)-3,3-difluoropiperidin-2-one
##STR01120##
[1925] Following the procedure as described in Example 445 step 4,
and making variation as required to replace
(R)-5-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-4-fluorobenzyl)piperidin-
-2-one with
(5R)-5-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-4-fluorobenzyl)-3-fluor-
opiperidin-2-one, the title compound was obtained as a colorless
solid (0.075 g, 99%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.35 (dd, J =8.6, 6.1 Hz, 1H), 7.12 (dd, J=8.4, 2.6 Hz, 1H), 6.96
(dt, J=8.4, 8.3, 2.6 Hz, 1H), 4.83 (d, J=15.3 Hz, 1H), 4.56 (d,
J=15.2 Hz, 1H), 4.23-4.13 (m, 1H), 3.44 (dd, J=12.4, 4.0 Hz, 1H),
3.21 (dd, J=12.5, 6.3 Hz, 1H), 2.62-2.27 (m, 2H), 0.82 (s, 9H),
0.05 (s, 3H), -0.01 (s, 3H); MS(ES+) m/z 410.2, 408.2 (M+1).
Step 6. Preparation of
(R)-1-(2-chloro-4-fluorobenzyl)-5,5-difluoropiperidin-3-ol
##STR01121##
[1927] To a solution of
(R)-5-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-4-fluorobenzyl)-3,3-difl-
uorpiperidin-2-one (0.015 g, 0.04 mmol) in tetrahydrofuran (1 mL)
was added borane (1.0 M solution in tetrahydrofuran 0.9 mL, 0.9
mmol) under nitrogen atmosphere. After 30 minutes stirring, the
reaction mixture was quenched by addition of 6 N hydrochloric acid
solution (2.5 mL) and stirring was continued for 2.5 hours. The
solution was neutralized by addition of a saturated aqueous
solution of sodium bicarbonate and extracted with dichloromethane
(2.times.10 mL). The combined organic extracts were concentrated
under reduced pressure and filtered over a plug of silica gel
eluting with 10% ethyl acetate in hexanes followed by 100% ethyl
acetate to give the title compound as a colorless oil (0.01 g,
85%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.38 (dd, J=8.5,
6.2 Hz, 1H), 7.11 (dd, J=8.5, 2.6 Hz, 1H), 6.97 (dt, J=8.3, 2.6 Hz,
1H), 4.05-3.96 (m, 1H), 3.72-3.67 (m, 2H), 2.98-2.83 (m, 1H),
2.82-2.71 (m, 1H), 2.60-2.45 (m, 2H), 2.24-1.90 (m, 2H); MS(ES+)
m/z 282.1, 280.1 (M+1).
Step 7. Preparation of (R)-tert-butyl
5-chloro-4-((1-(2-chloro-4-fluorobenzyl)-5,5-difluoropiperidin-3-yl)oxy)--
2-fluorobenzoate
##STR01122##
[1929] Following the procedure as described in Example 445 step 4
and making variation as required to replace
(R)-5-hydrozyl-1-(4-methoxybenzyl)piperidin-2-one with
(R)-1-(2-chloro-4-fluorobenzyl)-5,5-difluoropiperidin-3-ol, the
title compound was obtained as a colorless solid (0.01 g, 67%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.87 (d, J=7.7 Hz, 1H),
7.47 (dd, J=8.6, 6.3 Hz, 1), 7.10 (dd, J=8.5, 2.6 Hz, 1H), 6.97
(dt, J=8.3, 8.3, 2.6 Hz, 1H), 6.64 (d, J=11.8 Hz, 1H), 4.65-4.51
(m, 1H), 3.75 (s, 2H), 3.19-2.96 (m, 2H), 2.69-2.42 (m, 3H),
2.12-2.03 (m, 1H), 1.56 (s, 9H); MS(ES+) m/z 510.0, 508.0 (M
+1).
Step 8. Preparation of
(R)-4-((1-(2-chloro-4-fluorobenzyl)-5,5-difluoropiperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01123##
[1931] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with with
(R)-tert-butyl
5-chloro-4-((1-(2-chloro-4-fluorobenzyl)-5,5-difluoropiperidin-3-yl)
oxy)-2-fluorobenzoate, the title compound was obtained as a solid
(0.004 g, 32%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.77 (d,
J=7.4 Hz, 1H), 7.63 (dd, J=8.6, 6.3 Hz, 1H), 7.19 (dd, J=8.7, 2.6
Hz, 1H), 7.09-6.97 (m, 2H), 4.84-4.75 (m, 1H), 3.86-3.79 (m, 2H),
3.33 (s, 3H), 3.09-2.79 (m, 3H), 2.77-2.64 (m, 1H), 2.59-2.41 (m,
1H), 2.33-2.14 (m, 1H); MS(ES+) m/z 531.1, 529.1 (M+1).
Example 447
Synthesis of
5-cyclopropyl-4-(((R)-1-((R)-1-(3,5-dichlorophenyl)-2-methoxyethyl)piperi-
din-3-yl) oxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR01124##
[1932] Step 1. Preparation of
2-((R)-3-(2-cyclopropyl-5-fluoro-4-(methoxycarbonyl)
phenoxy)piperidin-1-yl)-2-(3,5-dichlorophenyl)acetic acid
##STR01125##
[1934] To a stirred solution of (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate (0.59 g, 2.00
mmol) in toluene (8 mL) under an atmosphere of nitrogen were added
50% glyoxylic acid in water (0.24 g, 3.20 mmol), molecular sieve 4
.ANG. (0.5 g) and (3,5-dichlorophenyl)boronic acid (0.420 g, 2.20
mmol). The reaction mixture was stirred at 100.degree. C. for 2
hours, cooled to ambient temperature and filtered to remove the
molecular sieve. The filtrate was concentrated. The residue (0.15
g, 15%) was used directly in the next step without further
purification.
Step 2. Preparation of methyl
5-cyclopropyl-4-(((R)-1-((R)-1-(3,5-dichlorophenyl)-2-hydroxyethyl)
piperidin-3-yl)(oxy)-2-fluorobenzoate
##STR01126##
[1936] To a stirred solution of
2-((R)-3-(2-cyclopropyl-5-fluoro-4-(methoxycarbonyl)
phenoxy)piperidin-1-yl)-2-(3,5-dichlorophenyl)acetic acid (0.15 g,
0.30 mmol) in tetrahydrofuran (3 mL) under an atmosphere of
nitrogen was added borate in tetrahydrofuran (1.0 M solution in
tetrahydrofuran, 1 mL, 1.00 mmol). After stirring at ambient
temperature for 16 hours, the reaction mixture was quenched by
addition of methanol (2 mL), and concentrated. The residue was
purified by chromatography eluting with a gradient (0 to 30%) of
ethyl acetate in hexanes to give the title compound (0.09 g, 55%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.43 (d, J=8.4 Hz, 1H),
7.29 (t, J=1.8 Hz, 1H), 7.06 (d, J=1.9 Hz, 2H), 6.54 (d, J=12.8 Hz,
1H), 4.50-4.39 (m, 1H), 3.93-3.82 (m, 4H), 3.69-3.58 (m, 2H),
2.72-2.57 (m, 3H), 2.40-2.27 (m, 1H), 2.01-1.49 (m, 5H), 0.87-0.78
(m, 2H), 0.68-0.57 (m, 2H). The other diastereoisomer methyl
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)-2-hydroxyethyl)
piperidin-3-yl)oxy)-2-fluorobenzoate was also isolated (0.07 g,
45%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.42 (d, J=8.4 Hz,
1H), 7.33-7.29 (m, 1H), 7.10-7.07 (m, 2H), 6.52 (d, J=12.7 Hz, 1H),
4.48-4.35 (m, 1H), 3.96-3.82 (m, 4H), 3.73-3.58 (m, 2H), 2.97-2.88
(m, 1H), 2.61-2.39 (m, 3H), 1.94-1.53 (m, 5H), 0.85-0.79 (m, 2H),
0.67-0.56 (m, 2H).
Step 3. Preparation of methyl
5-cyclopropyl-4-(((R)-1-((R)-1-(3,5-dichlorophenyl)-2-methoxyethyl)
piperidin-3-yl)oxy)-2-fluorobenzoate
##STR01127##
[1938] To a stirred solution of methyl
5-cyclopropyl-4-(((R)-1-((R)-1-(3,5-dichlorophenyl)-2-hydroxyethyl)
piperidin-3-yl)oxy)-2-fluorobenzoate (0.08 g, 0.14 mmol) in
dimethoxyethane (1 mL) under an atmosphere of nitrogen was added
sodium hydride (60% in mineral oil, 0.03 g, 0.69 mmol) and the
reaction mixture was stirred for 30 minutes. Methyl iodide (0.030
g, 0.21 mmol) was added to the reaction mixture. After stirring for
16 hours, water (10 mL) was added and the reaction mixture was
extracted with dichloromethane (2.times.10 mL), the combined
organic layers were concentrated. The residue was purified by
chromatography eluting with a gradient of methanol in
dichloromethane (0 to 5%) to give the title compound (0.04g, 58%):
MS(ES+) m/z 498.1, 496.1 (M+1).
Step 4. Preparation of
5-cyclopropyl-4-(((R)-1-((R)-1-(3,5-dichlorophenyl)-2-methoxyethyl)
piperidin-3-yl)oxy)-2-fluorobenzoic acid hydrochloride
##STR01128##
[1940] To a stirred solution of methyl
5-cyclopropyl-4-(((3R)-1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)
piperidin-3-yl)oxy)-2-fluorobenzoate (0.075 g, 0.15 mmol) in DMSO
(1 mL) under an atmosphere of nitrogen were added lithium hydroxide
(0.036 g, 1.52 mmol) and the mixture was stirred for 1 hour at
70.degree. C. and then quenched with 1N aqueous hydrochloric acid
solution (5 mL) and extracted with dichloromethane (3.times.10 mL),
dried over anhydrous sodium sulfate, filtered and concentrated to
give the title compound (0.06 g, 76%) as a colorless solid: MS(ES+)
m/z 484.2, 482.2 (M+1).
Step 5. Preparation of
5-cyclopropyl-4-(((R)-1-((R)-1-(3,5-dichlorophenyl)-2-methoxyethyl)
piperidin-3-yl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR01129##
[1942] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-fluoropiperidin--
4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
5-cyclopropyl-4-(((3R)-1-(1-(3,5-dichlorophenyl)-2-methoxyethyl)
piperidin-3-yl)oxy)-2-fluorobenzoic acid hydrochloride (0.06 g,
0.12 mmol), the title compound was obtained as a colorless solid
(0.006 g, 9%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.86-8.62
(m, 1H), 7.56 (d, J=8.9 Hz, 1H), 7.52-7.42 (m, 2H), 6.94-6.83 (m,
1H), 5.06-4.92 (m, 1H), 4.48-4.36 (m, 1H), 4.48-4.36 (m, 1H),
4.20-4.08 (m, 1H), 4.06-3.34 (m, 1H), 2.94-2.73 (m, 1H), 2.33-1.94
(m, 3H), 1.77-1.58 (m, 1H), 0.96-0.86 (m, 2H), 0.69-0.59 (m, 2H);
MS(ES+) m/z 561.1, 559.1 (M+1).
Example 448
Synthesis of
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)-2-methoxyethyl)
piperidin-3-yl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01130##
[1943] Step 1. Preparation of
2-((R)-3-(2-cyclopropyl-5-fluoro-4-((methylsulfonyl)
carbamoyl)phenoxy)piperidin-1-yl)-2-(3,5-dichlorophenyl)acetic
acid
##STR01131##
[1945] To a stirred solution of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(piperidin-3-yloxy)benzam-
ide (1.50 g, 3.31 mmol) in toluene (10 mL) under an atmosphene of
nitrogen was introduced 50% glyoxylic acid in water (0.39 g, 5.30
mmol), molecular sieve 4 .ANG. (0.5 g) and
(3,5-dichlorophenyl)boronic acid (0.69 g, 3.64 mmol). The reaction
mixture was stirred at 100.degree. C. for 2 hours, cooled to
ambient temperature and filtered to remove the molecular sieve. The
filtrate was concentrated to give the title compound as a colorless
solid (2.16 g, 99%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
11.90-11.82 (m, 1H), 7.70-7.58 (m, 1H), 7.52-7.42 (m, 2H), 7.10 (t,
J=7.9 Hz, 1H), 6.98 (dd, J=13.0, 6.0 Hz, 1H), 4.78-4.56 (m, 2H),
3.30 (s, 3H), 3.04-2.92 (m, 1H), 2.90-2.77 (m, 1H), 2.76-2.63 (m,
1H), 2.62-2.51 (m, 1H), 2.19-1.97 (m, 1H), 1.98-1.77 (m, 2H),
1.74-1.47 (m, 2H), 0.95-0.78 (m, 2H), 0.76-0.58 (m, 2H); MS(ES+)
m/z 561.0, 559.0 (M+1).
Step 2. Preparation of
5-cyclopropyl-4-(((3R)-1-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)
piperidin-3-yl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR01132##
[1947] To a stirred solution of
2-((R)-3-(2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)
phenoxy)piperidin-1-yl)-2-(3,5-dichlorophenyl)acetic acid (0.80 g,
1.43 mmol) in tetrahydrofuran (8 mL) was added carbonyl diimidazole
(0.26 g, 1.57 mmol) under nitrogen. The reaction mixture was reflux
for 1 hour and cooled to ambient temperature. To the reaction
mixture was added sodium borohydride (0.064 g, 2.0 mmol). After
stirring for 2 hours, the reaction mixture was quenched by addition
of 1N aqueous hydrochloric acid solution (10 mL) and extracted with
dichloromethane (3.times.20 mL). The combined organics was
concentrated, the residue was purified by chromatography eluting
with a gradient of 5 to 10% dichloromethane in methanol containing
2% ammonia to afford the title compound as a colorless solid (0.13
g, 14%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.47-7.40 (m,
1H), 7.38-7.83 (m, 2H), 7.18-7.09 (m, 1H), 6.86-6.67 (m, 1H),
4.64-4.53 (m, 1H), 4.51-4.37 (m, 1H), 3.80-3.59 (m, 2H), 3.58-3.48
(m, 1H), 3.06-2.57 (m, 5H), 2.38-2.11 (m, 2H), 2.07-1.93 (m, 1H),
1.93-1.77 (m, 1H), 1.76-1.61 (m, 1H), 1.59-1.29 (m, 2H), 0.90-0.76
(m, 2H), 0.65-0.48 (m, 2H); MS(ES+) m/z 547.1, 545.1 (M+1).
Step 3. Preparation of
5-cyclopropyl-4-(((R)-1-((S)-1-(3,5-dichlorophenyl)-2-methoxyethyl)
piperidin-3-yl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01133##
[1949] To a solution of
5-cyclopropyl-4-(((3R)-1-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)piperidin-
-3-yl) oxy)-2-fluoro-N-(methylsulfonyl)benzamide (0.08 g, 0.12
mmol) in dimethoxyethane (1 mL) was added sodium hydride (60% in
mineral oil, 0.025 g, 0.62 mmol). The reaction mixture was stirred
for 30 minutes and methyl iodide (0.026 g, 0.19 mmol) was added.
After stirring for 16 hours, the reaction mixture was quenched by
addition of water (10 mL) and extracted with dichloromethane
(2.times.10 mL). The combined organic layers was concentrated and
the residue purified by preparative HPLC eluting with a gradient of
acetonitrile in water containing 0.1% trifluoroacetic acid to
afford the title compound as a colorless solid (0.011 g, 14%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.82-8.64 (m, 1H), 7.55
(d, J=8.8 Hz, 1H), 7.47-7.38 (m, 3H), 6.88 (d, J=14.4 Hz, 1H),
4.92-4.81 (m, 1H), 4.26-4.19 (m, 1H), 4.12-4.02 (m, 1H), 3.92-3.79
(m, 2H), 3.39 (s, 3H), 3.36 (s, 3H), 3.35-3.28 (m, 1H), 2.79-2.65
(m, 2H), 2.28-2.18 (m, 1), 2.09-1.96 (m, 2H), 1.71-1.56 (m, 2H),
0.96-0.87 (m, 2H), 0.67-0.59 (m, 2H); MS(ES+) m/z 561.1, 559.1
(M+1).
Example 449
Synthesis of
5-cyclopropyl-4-(((1R,3R,5S)-8-(3,5-dichlorobenzyl)-8-azabicyclo[3.2.1]oc-
tan-3-yl) methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR01134##
[1950] Step 1. Preparation of benzyl
3-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)
carbamoyl)phenoxy)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR01135##
[1952] Following the procedure as described in Example 346 Step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-y-
l) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((8-((benzyloxy)carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was
obtained as a colorless solid (0.75 g, 72%): MS(ES+) m/z 531.1
(M+1).
Step 2. Preparation of
4-(8-azabicyclo[3.2.1]octan-3-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(methyl-
sulfonyl)benzamide
##STR01136##
[1954] Following the procedure as described in Example 396 step 5
and making non-critical variations as required to replace (1R,
3S,5S)-benzyl-3-((2-cyclopropyl-4-((cyclopropylsulfonyl)carbamoyl)-5-fluo-
rophenoxy) methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate with (1
R,3,5S)-benzyl 3-((2-cyclopropyl-5-fluoro-4-(methylsulfonyl)
carbamoyl)phenoxy)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
the title compound was obtained (0.55 g, 98%): MS(ES+) m/z 367.1
(M+1).
Step 3. Preparation of
5-cyclopropyl-4-(((1B,3r,5S)-8-(3,5-dichlorobenzyl)-8-azabicyclo[3.2.1]oc-
tan-3-yl) methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR01137##
[1956] Following the procedure as described in Example 441, and
making variation as required to replace
4-(8-azabicyclo[3.2.1]octan-3-ylmethoxy)-N-(azetidin-1-
ylsulfonyl)-5-cyclopropyl-2-fluorobenzamideate with
4-(8-azabicyclo[3.2.1]octan-3-ylmethoxy)-5-cyclopropyl-2-fluoro-N-(methyl-
sulfonyl)benzamide and to replace (bromomethylene)dibenzene with
1,3-dichloro-5-(chloromethyl)benzene, the title compound was
obtained (0.04 g, 41%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
7.67-7.44 (m, 3H), 7.14 (d, J=8.4 Hz, 1H), 6.79 (d, J=12.9 Hz, 1H),
3.92-3.73 (m, 4H) 3.54-3.36 (m, 2H), 3.05 (s, 3H), 2.33-1.55 (m,
10H), 0.91-0.77 (m, 2H), 0.63-0.53 (m, 2H); MS(ES+) m/z 557.1,
555.1 (M+1).
Example 450
Synthesis of
4-(((1R,4S,6R)-2-((S)-1-(2-chloro-4-fluorophenly)ethyl)-2-azabicyclo[2.2.-
1]heptan-6-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01138##
[1957] Step 1. Preparation of tert-butyl
5-chloro-2-fluoro-4-(((1R,4S,6R)-2-((S)-1-phenlyethyl)-2-azabicyclo[2.2.1-
]heptan-6-yl)oxy)benzoate
##STR01139##
[1959] Following the procedure as described in Example 445 step 4
and making variation as required to replace
(R)-5-hydroxy-1-(4-methoxybenzyl)piperidin-2-one with
(1R,4S,6R)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptan-6-ol,
and purifying the compound by column chromatognaphy eluting with a
gradient of ethyl acetate in hexanes (50% to 100%), the title
compound was obtained (2.76 g, 49%). MS(ES+) m/z: 448.1, 446.1
(M+1).
Step 2. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-(((1R,4S,6R)-2-((S)-1-phenylethyl)-2-azabicyclo[-
2.2.1]heptan-6-yl)oxy)benzoate
##STR01140##
[1961] Following the procedure as described in Example 445 step 5,
and making variation as required to replace (R)-tert-butyl
5-chloro-2-fluoro-4-((1-(4-methoxybenzyl)-6-oxopiperidin-3-yl)oxy)benzoat-
e with tert-butyl
5-chloro-2-fluoro-4-(((1R,4S,6R)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1-
]heptan-6-yl) oxy)benzoate, the title compound was obtained as a
colorless gum (1.82 g, 66%): MS(ES+) m/z 452.2 (M+1).
Step 3. Preparation of tert-butyl
4-((1R,4S,6R)-2-azabicyclo[2.2.1]heptan-6-yloxy)-5-cyclopropyl-2-fluorobe-
nzoate
##STR01141##
[1963] To a stirred solution of tert-butyl
5-cyclopropyl-2-fluoro-4-((1R,4S,6R)-2-((S)-1-phenylethyl)-2-azabicyclo[2-
.2.1]heptan-6-yl) oxy)benzoate (1.75 g, 3.88 mmol) and ammonium
formate (7.3 g, 116 mmol) in methanol (50 mL) and water (5 mL) was
added 10% palladium on carbon (0.05 g). After stirring for 2 hours
at reflux, the reaction mixture was filtered over diatomaceous
earth and rinsed with methanol (2.times.30 mL). The filtrate was
concentrated, basified with saturated sodium bicarbonate solution
and extracted with dichloromethane (2.times.40 mL). The combined
organic layers were dried over anhydrous sodium sulfate, filtered
and concentrated to afford the title compound (1.22 g, 80%):
MS(ES+) m/z 348.2 (M+1).
Step 4. Preparation of tert-butyl
4-(((1R,4S,6R)-2-((S)-1-(2-chloro-4-fluorophenyl)
ethyl)-2-azabicyclo[2.2.1]heptan-6-yl)oxy-5-cyclopropyl-2-fluorobenzoate
##STR01142##
[1964] And tert-butyl
4-(((1R,4S,6R)-2-((R)-1-(2-chloro-4-fluorophenyl)
ethyl)-2-azabicyclo[2.2.1]heptan-6-yl)oxy-5-cyclopropyl-2-fluorobenzoate
##STR01143##
[1966] To a stirred solution of tert-butyl
4-((1R,4S,6R)-2-azabicyclo[2.2.1]heptan-6-yloxy)-5-cyclopropyl-2-fluorobe-
nzoate (1.22 g, 3.51 mmol) in acetonitrile (15 mL) under a nitrogen
atmosphere was added 2-chloro-1-(1-chloroethyl)-4-fluorobenzene
(0.87 g, 4.55 mmol), potassium carbonate (1.38 g, 10 mmol) and
potassium iodide (0.165 g, 1 mmol). After stirring at reflux for 16
hours, the reaction mixture was was cooled to ambient temperature,
quenched with water (15 mL) and extracted with ethyl acetate
(3.times.20 mL). The combined organic layers was concentrated and
the residue was purified by column chromatography (0% to 30% ethyl
acetate in hexanes) to give the title compound (0.28 g, 16%).
MS(ES+) m/z 504.1 (M+1); its diastereoisomer tert-butyl
4-(((1R,4S,6R)-4-fluorophenyl)ethyl)-2-azabicyclo[2.2.1]heptan-6-yl)oxy)--
5-cyclopropyl-2-fluorobenzoate was also isolated (0.25 g, 14%):
MS(ES+) m/z 504.1 (M+1).
Step 5. Preparation of
4-(((1R,4S,6R)-2-((S)-1-(2-Chloro-4-fluorophenyl)
ethyl)-2-azabicyclo[2.2.1]heptan-6-yl)oxy-5-cyclopropyl-2-fluoro-N-(methy-
lsulfonyl)benzamide, trifluoroacetic acid salt
##STR01144##
[1968] To a stirred solution of tert-butyl
4-(((1R,4S,6R)-2-((S)-1-(2-chloro-4-fluorophenyl)
ethyl)-2-azabicyclo[2.2.1]heptan-6-yl)oxy)-5-cyclopropyl-2-fluorobenzoate
(0.13 g, 0.26 mmol) in dichloromethane (2 ml) was added
trifluoroacetic acid (1 mL). After stirring at ambient temperature
for 30 minutes, the reaction mixture was concentrated and
co-concentrated with toluene (2.times.10 mL). The residue was
dissolved in dichloromethane (0.5 mL), and to this solution was
added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.11 g, 0.44
mmol) 4-dimethylaminopyridine (0.09 g, 0.78 mmol) and
methanesulfonamide (0.03 g, 0.34 mmol). After stirring at at
ambient temperature for 16 hours, the reaction mixture was quenched
with aqueous hydrochloric acid solution (6N, 0.2 mL), diluted with
acetonitrile (0.5 mL) and purified by preparative HPLC (gradient of
acetonitrile in water +0.1% trifluoroacetic acid) to afford the
title compound as a colorless solid (0.06 g, 71%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 12.30-11.64 (br s, 1H), 11.36-10.08 (br
s, 1H), 7.99-7.84 (m, 1H), 7.67-7.51 (m, 1H), 7.49-7.38 (m, 1H),
7.23-6.98 (m, 1H), 6.91-6.00 (m, 1H), 5.25-4.47 (m, 2H), 3.86-2.51
(m, 7H), 2.29-2.06 (m, 1H), 2.06-1.79 (m, 3H), 1.78-1.41 (m, 4H),
0.95-0.48 (m, 4H); MS(ES+) m/z 527.1, 525.1 (M+1).
Example 451
Synthesis of 4-(((1R,4S,6R)-2-((R)-1-(2-chloro-4-fluorophenyl)
ethyl)-2-azabicyclo[2.2.1]heptan-6-yl)oxy-5-cyclopropyl-2-fluoro-N-(methy-
lsulfonyl)benzamide, trifluoroacetic acid salt
##STR01145##
[1970] Following the procedure as described in Example 450 step 5
and making variation as required to replace tert-butyl
4-(((1R,4S,6R)-2-((S)-1-(2-chloro-4-fluorophenyl)
ethyl)-2-azabicyclo[2.2.1]heptan-6-yl)oxy-5-cyclopropyl-2-fluorobenzoate
with its diastereoisomer tert-butyl
4-(((1R,4S,6R)-2-((R)-1-(2-chloro-4-fluorophenyl)
ethyl)-2-azabicyclo[2.2.1]heptan-6-yl)oxy-5-cyclopropyl-2-fluorobenzoate,
the title compound was obtained as a colorless solid (0.04 g, 51%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.12.14-11.78 (br s, 1H),
10.49-10.27 (br s, 1H), 8.15-8.00 (m, 1H), 7.64-7.53 (m, 1H),
7.52-7.39 (m, 1H), 7.11-7.03 (m, 1H), 6.36-6.22 (m, 1H), 5.01-4.80
(m, 2H), 3.64-2.64 (m, 7H), 2.30-1.99 (m, 2H), 1.96-1.78 (m, 2H),
1.75-1.46 (m, 4H), 0.87-0.72 (m, 2H), 0.65-0.53 (m, 2H); MS(ES+)
m/z 527.1, 525.1. (M+1).
Example 452
Synthesis of
4-(((R)-1-(R)-1-(2-chloro-4-fluorophenyl)ethyl)-5,5-dimethylpiperidin-3-y-
l) oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01146##
[1971] Step 1. Preparation of (R)-tert-butyl
4-((1-benzyl-5,5-dimethylpiperidin-3-yl)
oxy)-5-chloro-2-fluorobenzoate
##STR01147##
[1973] Following the procedure as described in Example 422 step 1
and making variation as required to replace
(R)-1-benzylpiperidin-3-ol with
(R)-1-benzyl)-5,5-dimethylpiperidin-3-ol (prepared accordingly to
Ma Y., Lahue B. R. et al.; U.S. patent 2008/0004287 A1), the title
compound waa obtained as a colorless solid (0.73 g, 68%): MS(ES+)
m/z 450.2, 448.2 (M+1).
Step 2. Preparation of (R)-tert-butyl
4-((1-benzyl-5,5dimethylpiperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoat-
e
##STR01148##
[1975] Following the procedure as described in Example 422 step 2
and making variation as required to replace (R)-tert-butyl
4-((1-benzylpiperidin-3-yl)oxy)-5-chloro-2-fluorobenzoate with
(R)-tert-butyl
4-((1-benzyl-5,5-dimethylpiperidin-3-yl)oxy)-5-chloro-2-fluorobenzoate,
the title compound was obtained as oil (0.47 g, 63%): MS(ES+) m/z
454.1 (M+1).
Step 3. Preparation of (R)-tert-butyl
5-cyclopropyl-4-((5,5-dimethylpiperidin-3-yl)oxy)-2-fluorobenzoate
##STR01149##
[1977] Following the procedure as described in Example 450
.sub.step 3, and making variation as required to replace tert-butyl
5-cyclopropyl-2-fluoro-4-(((1R,4S,6R)-2-((S)-1-phenylethyl)-2-azabicyclo[-
2.2.1]heptan-6-yl) oxy)benzoate with (R)-tert-butyl
4-((1-benzyl-5,5-dimethylpiperidin-3-yl)
oxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained as an oil (0.38 g, 96%): MS(ES+) m/z 364.2 (M+1).
Step 4. Preparation of tert-butyl
4-(((3R)-1-(1-(2-fluorophenyl)ethyl)-5,5-dimethylpiperidin-3-yl)
oxy-5-cyclopropyl-2-fluorobenzoate
##STR01150##
[1979] Following the procedUre as described in Example 450 step 4,
and making variation as required to replace tert-butyl
4-((1R,4S,6R)-2-azabicyclo[2.2.1]heptan-6-yloxy)-5-cyclopropyl-2-fluorobe-
nzoate with tert-butyl
5-cyclopropyl-4-((5,5-dimethylpiperidin-3-yl)oxy)-2-fluorobenzoate,
the title compound was obtained as an oil (0.22 g, 43%): MS(ES+)
m/z 522.1, 520.1 (M+1).
Step 5. Preparation of
4-(((R)-1-((R)-1-(2-Chloro-4-fluorophenyl)ethyl)-5,5-dimethylpiperidin-3--
yl) oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01151##
[1981] Following the procedure as described in Example 450 step 5,
and making variation as required to replace tert-butyl
4-(((1R,4S,6R)-2-((S)-1-(2-chloro-4-fluorophenyl)ethyl)-2-azabicyclo[2.2.-
1]heptan-6-yl) oxy)-5-cyclopropyl-2-fluorobenzoate with tert-butyl
4-(((3R)-1-(1-(2-chloro-4-fluorophenyl)
ethyl)-5,5-dimethylpiperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate,
the title compound was obtained as a colorless solid (0.02 g, 15%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.7.61 (dd, J=8.7, 6.5 Hz,
1H), 7.35 (dd, J=8.9, 2.6 Hz, 1H), 7.25-7.02 (m, 3H), 6.65-6.50 (m,
2H), 4.56-4.39 (m, 1H), 3.87 (q, J=6.3 Hz, 1H), 3.06-2.74 (m, 4H),
2.39 (d, J=10.7 Hz, 1H), 2.19-2.01 (m, 1H), 2.00-1.85 (m, 2H),
1.80-1.67 (m, 1H), 1.32-1.17 (m, 4H), 0.97 (s, 3), 0.93 (s, 3H),
0.86-0.73 (m, 2H), 0.60-0.44 (m, 2H); MS(ES+) m/z 543.1, 541.1
(M+1).
Example 453
Synthesis of
5-cyclopropyl-4-((1-(2,4-dichloro-5-fluorobenzyl)piperidin-4-yl)methoxy)--
2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid salt
##STR01152##
[1982] Step 1. Preparation of
4-((1-benzylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfo-
nyl)benzamide
##STR01153##
[1984] To a solution of tert-butyl
4-((1-benzylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate
(1.55 g, 3.54 mmol) in dichlormethane (10 mL) was added
trifluoroacetic acid (5 mL). The reaction mixture was stirred for
1.5 h and the solvent was concentration invacuo. The residue was
redissolved in anhydrous dichloromethane (10 mL). To this solution,
was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.37 g,
5.30 mmol), 4-dimethylaminopyridine (1.08 g, 8.84 mmol) and
methanesulfonamide (0.37 g, 3.89 mmol). The reaction mixture was
stirred at ambient tenperature for 16 hours, and then diluted with
dichloromethane (20 mL), washed with 1N aqueous hydrochloric acid
solution (10 mL), the aqueous layer was extracted with
dichloromethane (20 mL). The combined organic layer dried over
anhydrous sodium sulfate, filtered and concentrated. The residue
was purified by column chromatography (0% to 10% methanol (1%
ammonia) in dichloromethane) to afford the title compound as a gum
(1.32 g, 81%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.55 (d,
J=9.04 Hz, 1H), 7.44-7.36 (m, 5H), 6.52 (d, J=14.25 Hz, 1H),
4.16-4.02 (m, 2H), 3.94-3.86 (m, 2H), 3.64-3.43 (m, 2H), 3.39 (s,
3H), 2.68-2.43 (m, 2H), 2.09-1.87 (m, 6H), 0.97-0.85 (m, 2H),
0.65-0.55 (m, 2H).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(piperidin-4-ylmethoxy)
benzamide hydrochloride
##STR01154##
[1986] To a stirred solution of
4-((1-benzylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfo-
nyl)benzamide (1.25 g, 2.72 mmol)) in degassed ethyl acetate (5mL)
was added 10% palladium on carbon (0.02 g) and the flask was put
under 1 atm of hydrogen. The reaction mixture was stirred for 24
hours at ambient temperature, then filtered over diatomaceous earth
and rinsed with a 1:1 mixture of methanol and 1 M aqueous
hydrochloric acid solution (2.times.20 mL). The filtrate was
concentrated to give the title compound (0.55 g, 55%). MS(ES+) m/z
371.1 (M-1).
Step 3. Preparation of
5-cyclopropyl-4-((1-(2,4-dihloro-5-fluorobenzyl)piperidin-4-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetate
##STR01155##
[1988] To a stirred solution of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-(piperidin-4-ylmethoxy)benzam-
ide hydrochloride (0.05 g, 0.12. mmol) in acetonitrile (2 mL) under
a nitrogen atmosphere was added
1,5-dichloro-2-(chloromethyl)-4-fluorobenzene (0.04 g, 0.18 mmol),
potassium carbonate (0.04 g, 0.30 mmol) and potassium iodide (0.024
g, 0.15 mmol). The reaction mixture was stirred at reflux for 16
hours, cooled to ambient temperature, 1N aqueous hydrochloric acid
solution (5 mL) was added and the mixture was extracted with ethyl
acetate (3.times.10 mL), concentrated and purified by column
chromatography (0% to 30% ethyl acetate (+1% formic acid) in
hexanes) to give an oil which was further purified by preparative
HPLC (gradient of acetonitrile in water +0.1% trifluoroacetic acid)
to give the title compound as a colorless solid (0.04, 43%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6).delta. 12.15-11.63 (m, 1H),
9.91-9.31 (m, 1H), 7.99 (d, J=6.88 Hz, 1H), 7.77 (d, J=9.55 Hz,
1H), 7.10 (d, J=8.24 Hz, 1H), 6.95 (d, J=13.00 Hz, 1H), 4.44-4.31
(m, 2H), 4.01-3.90 (m, 2H), 3.53-3.40 (m, 2H), 3.30 (s, 3H),
3.21-3.00 (m, 2H), 2.17-1.88 (m, 4H), 1.68-1.46 (m, 2H), 0.93-0.79
(m, 2H), 0.72-0.60 (m, 2H); MS(ES+) m/z: 547.1, 549.1 (M+1).
Example 454
Synthesis of
5-cyclopropyl-4-((3,5-dichloro-4-fluorobenzyl)piperidin-4-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01156##
[1990] Following the procedure as described in Example 453 step 3
and making variation as required to replace
1,5-dichloro-2-(chloromethyl)-4-fluorobenzene with
1,3-dichloro-5-(chloromethyl)-2-fluorobenzene, the title compound
was obtained as a colorless solid (0.03 g, 33%): .sup.1H NMR (300
MHz, DMSO-d.sub.6).delta. 12.12-11.60 (m, 1H), 9.87-9.63 (m, 1H),
7.83-7.62 (m, 2H), 7.14-7.06 (m, 1H), 6.98-6.90 (m, 1H), 4.35-4.21
(m, 2H), 4.00-3.91 (m, 2H), 3.52-3.36 (m, 2H), 3.30 (s, 3H),
3.04-2.85 (m, 2H), 2.15-1.80 (m, 4H), 1.67-1.45 (m, 2H), 0.92-0.79
(m, 2H), 0.71-0.60 (m, 2H); MS(ES+) m/z 547.0, 549.0 (M+1).
Example 455
Synthesis of 4-((1-(5-chloro-2,4-difluorobenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01157##
[1992] Following the procedure as described in Example 453 step 3,
and making variation as require to replace
1,5-dichloro-2-(chloromethyl)-4-fluorobenzene with
1-chloro-5-(chloromethyl)-2,4-difluorobenzene, the title compound
was obtained as a colorless solid (0.02 g, 23%): .sup.1H NMR (300
MHz, DMSO-d.sub.6).delta. 12.06-11.74 (m, 1H), 9.65-9.36 (m, 1H),
7.87 (dd, J=7.9, 7.9 Hz, 1H), 7.71 (dd, J =9.6, 9.6 Hz, 1H), 7.10
(d, J=8.2 Hz, 1H), 6.94 (d, J=12.9 Hz, 1H), 4.35-4.22 (m, 2H),
3.99-3.91 (m, 2H), 3.50-3.42 (m, 2H), 3.30 (s, 3H), 3.11-2.93 (m,
2H), 2.13-1.88 (m, 4H), 1.62-1.43 (m, 2H), 0.92-0.80 (m, 2H),
0.70-0.61 (m, 2H); MS(ES+) m/z 533.1, 531.1 (M+1).
Example 456
Synthesis of
4-((1-(3-chloro-4,5-difluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl--
2-fluoro-N-(methysulfonnyl)benzamide, trifluoroacetic acid salt
##STR01158##
[1994] Following the procedure as described in Example 453 step 3,
and making variation as required to replace
1,5-dichloro-2-(chloromethyl)-4-fluorobenzene with
1-chloro-5-(chloromethyl)-2,3-difluorobenzene, the title compound
was obtained as a colorless solid (0.03 g, 31%): .sup.1H NMR (300
MHz, DMSO-d.sub.6).delta. 11.40-11.06 (m, 1H), 7.50-7.35 (m, 2H),
7.12 (d, J=8.4 Hz, 1H), 6.85 (d, J=12.9 Hz, 1H), 3.91 (d, J=6.0 Hz,
2H), 3.67-3.59 (m, 2H), 3.16 (s, 3H), 2.99-2.82 (m, 2H), 2.23-2.06
(m, 2H), 2.04-1.91 (m, 1H), 1.86-1.72 (m, 3H), 1.46-1.27 (m, 2H),
0.90-0.80 (m, 2H), 0.66-0.55 (m, 2H); MS(ES+) m/z 533.2, 531.2
(M+1).
Example 457
Synthesis of
4-((1-(5-chloro-2-trifluoromethyl)piperidin)-4-fluoropiperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01159##
[1995] Step 1. Preparation of tert-butyl
4-((1-(5-chloro-2-(trifluoromethyl)piperidin)-4-fluoropiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR01160##
[1997] Following the procedure as described in Example 346 step 5
and making non-critical variations as required to replace
1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)benzene with
5-chloro-2-(trifluoromethyl)piperidin methanesulfonate, the title
compound was obtained as a colorless gum (0.45 g, 69%): MS(ES+) m/z
562.1, 560.1 (M+1).
Step 2. Preparation of
4-((1-(5-chloro-2-(trifluoromethyl)piperidin)-4-fluoropiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR01161##
[1999] Following the procedure as described in Example 346 step 6,
and making non-critical variations as required to replace
terr-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)-4-fluor-
opiperidine-1-carboxylate with tert-butyl
4-((1-(5-chloro-2-(trifluoromethyl)piperidin)-4-fluoropiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate to afford the title
compound as a colorless solid (0.36 g, 88%): MS(ES+) m/z 506.2,
504.0 (M+1).
Step 3. Preparation of
4-((1-(5-chloro-2-(trifluoromethyl)piperidin)-4-fluoropiperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01162##
[2001] Following the procedure as described in Example 346 step 7
and making non-critical variations as required to replace
4-((1-(3-chloro-2-fluoro-5-(4trifluoromethyl)piperidin)-4-fluoropiperidin-
-4-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid with
4-((1-(5-chloro-2-(trifluoromethyl)
benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid and to replace methanesulfonamide with cyclopropanesulfonamide
the title compound was obtained as a colorless solid (0.03 g, 28%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.87 (br s, 1H), 9.99
(br s, 1H), 8.13 (br s, 1H), 7.61 (br s, 2H), 7.15 (d, J=8.3 Hz,
1H), 7.03 (d, J=12.8 Hz, 1H), 4.80-4.42 (m, 2H), 4.28 (d, J =20.6
Hz, 2H), 3.60-3.17 (m, 4H), 3.12-3.03 (m, 1H), 2.31-2.17 (m, 2H),
2.08-1.99 (m, 3H), 1.14-1.09 (m, 4H), 0.94-0.87 (m, 2H), 0.73-0.67
(m, 2H); MS(ES+) m/z 506.2, 504.0 (M+1).
Example 458
Synthesis of
(R)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluoro-N-
-(methylsulfonyl)benzamide
##STR01163##
[2002] Step 1. Preparation of
(R)-1-chloro-3-(3,4-dichlorophenyl)propan-2-ol
##STR01164##
[2004] A 50 mL flask charged magnesium turnings (0.32 g, 13.33
mmol) was heated via heat gun under hi-vac. The flask was cooled to
ambient temperature and flushed with argon before freshly distilled
diethyl ether (1 mL) and 1,2-dibromoethane (2 drops) were added.
The flask was equipped with a condenser before a solution of
4-bromo-1,2-dichlorobenzene (1.68 mL, 13.00 mmol) in diethyl ether
(14 mL) was added dropwise so as to maintain a gentle reflux. The
cloudy solution was stirred for 1 hour at ambient temperature.
After cooling to 0.degree. C., copper iodide (0.21 g, 1.08 mmol)
was added. After 10 minutes stiring, a solution of
(R)-epichlorohydrin (0.85 mL, 10.80 mmol) in diethyl ether (14 mL)
was added dropwise. The reaction mixture was slowly warmed to
ambient temperature and stirred overnight, quenched with saturated
aqueous ammonium chloride solution (10 mL) at 0.degree. C., and
then poured into water (40 mL). The biphasic mixture was stirred
until all solids dissolved. The blue aqueous layer was isolated and
extracted with ethyl acetate (3.times.30 mL). The combined organic
Layers were washed with brine (150 mL); dried over anhydrous sodium
sulfate, filtered and concentrated. The residue was purified using
flash chromatography [0% to 5% to 10% ethyl acetate in hexanes] to
yield the title compound as a colourless oil (2.50 g, 80%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta.7.38 (d, J=8.2 Hz, 1H), 7.35 (d,
J=2.0 Hz, 1H), 7.09 (dd, J=2.0, 8.2 Hz, 1H), 4.06-3.99 (m, 1H),
3.62 (dd, J=3.9, 11.2 Hz, 1H), 3.49 (dd, J=6.3, 11.2 Hz, 1H), 2.84
(d, J=5.8 Hz, 1H), 2.83 (d, J=7.1 Hz, 1H), 2.22 (br s, 1H).
Step 2. Preparation of (R)-2-(3,4-dichlorobenzyl)morpholine
##STR01165##
[2006] To a solution of sodium hydroxide (2.50 g, 62.40 mmol) in
water (5 mL) was added a solution of
(R)-1-chloro-3-(3,4-dichlorophenyl)propan-2-ol (2.50 g, 10.40 mmol)
in methanol (11 mL). After 5 minutes, 2-aminoethyl hydrogen sulfate
(5.86 g, 41.60 mmol) was added in portions (4.times.1.47 g). The
resulting suspension was heated at 40.degree. C. for 5 hours.
Toluene (25 mL) and powdered sodium hydroxide (2.50 g, 62.40 mmol)
were added. The reaction mixture was stirred overnight at 6.degree.
C. After cooling to ambient temperature, the reaction mixture was
quenched with water (300 mL). The aqueous layer was isolated and
extracted with toluene (2.times.150 mL). The combined organics were
washed with water (50 mL) and brine (50 mL), and concentrated. The
residue was purified using flash chromatography [0% to 100%
(80:10:10 ethyl acetate/isopropanol/triethylamine) in hexanes] to
yield the title compound as a colourless oil (0.83 g, 32%): MS(ES+)
m/z 246.1, 248.1 (M+1).
Step 3. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-(iodomethyl)benzoate
##STR01166##
[2008] To a suspension of polymer bound triphenylphosphine (2.60 g,
7.80 mmol) in dichloromehane (60 mL) was added imidazole (0.53 g,
7.80 mmol) and iodine (2.00 g, 7.80 mmol). After 5 minutes,
tert-butyl 5-cyclopropyl-2-fluoro-4-(hydroxymethyl)benzoate (1.60
g, 6.0 mmol) was added and the reaction mixture was stirred at
ambient temperature overnight. The reaction mixture was filtered
and the filtrate was washed with saturated aqueous sodium bisulfate
solution (50 mL) and water (50 mL). The organic layer was dried
over sodium sulfate, decanted and concentrated. The residue was
dissolved in ethyl acetate (100 mL) and washed with saturated
aqueous sodium bisulfate solution (20 mL), 1N hydrochloric acid
solution (20 mL) and brine (20 mL). The organic layer was dried
over sodium sulfate, decanted and concentrated to yield the title
compound as a yellow solid (2.14 g, 94%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.50 (d, J=7.3 Hz, 1H), 7.05 (d, J=10.9 Hz,
1H), 4.58 (m, 2H), 1.97-1.84 (m, 1H), 1.58 (s, 9H), 1.08-0.99 (m,
2H), 0.78-0.70 (m, 2H).
Step 4. Preparation of (R)-tert-butyl
5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)
metoxy)-2-fluorobenzoate
##STR01167##
[2010] A suspension of tert-butyl 5-cyclopropyl
-2-fluoro-4-(iodomethyl)benzoate (0.46 g, 1.22 mmol),
(R)-2-(3,4-dichlorobenzyl)morpholine (0.60 g, 2.44 mmol), potassium
phosphate (0.52 g, 2.44 mmol) in N,N-dimethyl formamide (22 mL) was
heated as 80.degree. C. for 2 hours. The reaction mixture was
cooled to ambient temperature, and diluted with water (400 mL) and
ethyl acetate (200 mL). The aqueous layer was isolated and
extracted with ethyl acetate (3.times.100 mL). The combined
organics were concentrated and the residue was purified by flash
chromatography (0% to 10% ethyl acetate in hexanes) to yield the
title compound (0.59 g, 97%): .sup.1NMR (300 MHz, CDCl.sub.3)
.delta.7.49 (d, J=7.2 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.32 (d,
J=2.0 Hz, 1H), 7.15 (d, J=11.7 Hz, 1H), 7.05 (dd, J=2.0, 8.2 Hz,
1H), 3.84 (d, J=10.6 Hz, 1H), 3.77-3.67 (m, 1H), 3.67-3.54 (m, 3H),
2.80-2.58 (m, 4H), 2.30-2.16 (m, 1H), 2.07-1.90 (m, 2H), 1.58 (s,
9H), 1.00-0.87 (m, 2H), 0.70-0.58 (m, 2H); MS(ES+) m/z 494.2, 496.1
(M+1).
Step 5. Preparation of
(R)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)
methyl)-2-fluorobenzoic acid hydrochloride
##STR01168##
[2012] A solution of (R)-tert-butyl
5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluorobenzoa-
te (0.17 g, 0.34 mmol) and hydrogenchloride (4.0 N solution in
1,4-dioxane, 1.72 mL, 6.88 mmol) in 1,4-dioxane (5 mL) was stirred
overnight at ambient temperature, and then heated at 60.degree. C.
for 2 hours. The reaction mixture was cooled to ambient temperature
and diluted with toluene (10 mL) and concentrated to yield the
title compound (0.17 g, quant. yield), which was used without
purification: MS(ES+) m/z 438.1, 440.0 (M+1); MS(ES-) m/z 436.1,
438.1 (M-1).
Step 6. Preparation of
(R)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluoro-N-
-(methylsulfonyl)benzamide
##STR01169##
[2014] To a solution of
(R)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluorobe-
nzoic acid hydrochloride (0.17 g, 0.36 mmol) in dichloromethane (10
mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (0.10 g, 0.54 mmol), and 4-dimethylaminopyridine
(0.10 g, 0.82 mmol). The reaction was stirred at ambient
temperature for 10 minutes, methanesulfonamide (0.06 g, 0.58 mmol)
was added and stirring was continued at ambient temperature
overnight. The reaction mixture was concentrated, diluted with
ethyl acetate (20 mL) and washed with 5% aqueous hydrochloric acid
solution (10 mL). The organic layer was separated, washed with
water and brine, dried over anhydrous sodium sulfate and
concentrated. The residue was purified by flash chromatography (0%
to 50% ethyl acetate in hexanes) to yield the title compound as a
colorless solid (0.09 g, 50%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.94-8.69 (m, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.36-7.31 (m,
3H), 7.05 (d, J=8.1 Hz, 1H), 3.87 (d, J=11.2 Hz, 1H), 3.81-3.57 (m,
4H), 3.42 (s, 3H), 2.83-2.58 (m, 4H), 2.34-2.19 (m, 1H), 2.12-1.99
(m, 1H), 1.99-1.88 (m, 1H), 1.02-0.92 (m, 2H), 0.70-0.59 (m, 2H);
MS(ES+) m/z 515.1, 517.1 (M+1), MS(ES-) m/z 513.2, 515.1 (M-1).
Example 459
Preparation of
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)
morpholino)methyl)-2-fluorobenzamide
##STR01170##
[2016] Following the procedure as described in Example 458 step 6
and making non-critical variations as required to replace
methanesulfonamide with azetidine-1-sulfonamide, the title compound
was obtained as a colorless solid (0.08 g, 41): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.73 (d, J=15.7 Hz, 1H), 7.74 (d, J=7.8
Hz, 1H), 7.36-7.31 (m, 3H), 7.06 (dd, J=2.0, 8.2 Hz, 1H), 4.26 (t,
J=7.7 Hz, 4H), 3.89-3.85 (m, 1H), 3.79-3.58 (m, 4H), 2.81-2.58 (m,
4H), 2.33-2.20 (m, 3H), 2.11-1.91 (m, 2H), 1.00-0.92 (m, 2H),
0.71-0.63 (m, 2H); MS(ES+) m/z 556.1, 558.1 (M+1), MS(ES-) m/z
554.2, 556.1 (M -1).
Example 460
Preparation or
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((2-(3,4-dichlorobenzyl)
morpholino)methyl)-2-fluorobenzamide
##STR01171##
[2018] Following the procedure as described in Example 458 step 6
and making non-critical variations as required to replace
methanesulfonamide with cyclopropanesulfonamide, the title compound
was obtained as a colorless solid (0.07g, 35%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.78 (d, J=15.0 Hz, 1H), 7.74 (d, J=7.8
Hz, 1H), 7.36-7.31 (m, 3H), 7.05 (dd, J=1.9, 8.2 Hz, 1H), 3.91-3.85
(m, 1H), 3.81-3.57 (m, 4H), 3.16-3.02 (m, 1H), 2.83-2.52 (m, 4H),
2.32-2.19 (m, 1H), 2.08-1.85 (m, 2H), 1.51-1.38 (m, 2H), 1.20-1.06
(m, 2H), 1.00-0.87 (m, 2H), 0.70-0.56 (m, 2H); MS(ES+) m/z 541.1,
543.1 (M+1), MS(ES-) m/z 539.1, 541.1 (M-1).
Example 461
Synthesis of
(S)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluoro-N-
-(methylsulfonyl)benzamide
##STR01172##
[2019] Step 1. Preparation of
(S)-1-chloro-3-(3,4-dichlorophenyl)propan-2-ol
##STR01173##
[2021] Following the procedure as described in Example 458 step 1
and making no variations as required to replace (R)-epichlorohydrin
with (S)-epichlorohydrin, the title compound was obtained as a
colorless oil (2.70 g, 87%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.7.39 (d, J=8.3 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.09 (dd,
J=2.0, 8.2 Hz, 1H), 4.10-3.98 (m, 1H), 3.62 (dd, J=3.9, 11.2 Hz,
1H), 3.49 (dd, J=6.3 Hz, 1H), 2.85-2.82 (m, 2H), 2.20 (br s,
1H).
Step 2. Preparation of (S)-2-(3,4-dichlorobenzyl)morpholine
##STR01174##
[2023] Following the procedure as described in Example 458 step 2
and making non-critical variations as required to replace
(R)-1-chloro-3-(3,4-dichlorophenyl)propan-2-ol with
(S)-1-chloro-3-(3,4-dichlorophenyl) propan-2-ol, the title compound
was obtained as a colorless oil (1.04 g, 37%): MS(ES+) m/z 246.1,
248.1 (M+1).
Step 3. Preparation of (S)-tert-butyl
5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)
methyl)-2-fluorobenzoate
##STR01175##
[2025] Following the procedure as described in Example 458 step 4
and making non-critical variations as required to replace
(R)-2-(3,4-dichlorobenzyl)morpholine with
(S)-2-(3,4-dichlorobenzyl)morpholine, the title compound was
obtained (0.46 g, 98%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.7.50 (d, J=7.3 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.32 (d,
J=2.0 Hz, 1H), 7.14 (d, J=11.7 Hz, 1H), 7.05 (dd, J=2.0, 8.2 Hz,
1H), 3.85 (d, J=10.6 Hz, 1H), 3.78-3.66 (m, 1H), 3.66-3.55 (m, 3H),
2.80-2.57 (m, 4H), 2.22 (dt, J=3.0,11.2 Hz, 1H), 2.05-1.92 (m, 2H),
1.58 (s, 9H), 0.97-0.89 (m, 2H), 0.67-0.59 (m, 2H); MS(ES+) m/z
494.0, 496.0 (M+1).
Step 4. Preparation of
(S)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluorobe-
nzoic acid hydrochloride
##STR01176##
[2027] Following the procedure as described in Example 458 step 5
and making non-critical variations as required to replace
(R)-tert-butyl 5-cyclopropyl -4-((2-(3,4-dichlorobenzyl)morpholino)
methyl)-2-fluorobenzoate with (S)-tert-butyl
5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)
methyl)-2-fluorobenzoate, the title compound was obtained as a
cotoriess solid (0.43 g, 98%): MS(ES+) m/z 438.1, 440.0 (M+1);
MS(ES-) 436.1, 438.1 (M-1).
Step 5. Preparation of
(S)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluoro-N-
-(methylsulfonyl)benzamide
##STR01177##
[2029] Following the procedure as described in Example 458 step 6
and making non-critical variations as required to replace
(R)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluorobe-
nzoic acid hydrochloride with
(S)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluorobe-
nzoic acid hydrochloride, the title compound was obtained as a
colorless solid (0.04 g, 20%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.94-8.69 (m, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.36-7.31 (m,
3H), 7.05 (d, J=8.1 Hz, 1H), 3.87 (d, J=11.2 Hz, 1H), 3.81-3.57 (m,
4H), 3.42 (s, 3H), 2.83-2.58 (m, 4H), 2.34-2.19 (m, 1H), 2.12-1.99
(m, 1H), 1.99-1.88 (m, 1H), 1.02-0.92 (m, 2H), 0.70-0.59 (m, 2H);
MS(ES+) m/z 515.1, 517.1 (M+1), MS(ES-) m/z 513.2, 515.2 (M-1).
Example 462
Preparation of
(S)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((2-(3,4-dichlorobenzyl)
morpholino)methyl)-2-fluorobenzamide
##STR01178##
[2031] Following the procedure as described in Example 458 step 6
and making non-critical variations as required to replace
(R)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluorobe-
nzoic acid hydrochloride with
(S)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)
methyl)-2-fluorobenzoic acid hydrochloride, and to replace
methanesulfonamide with cyclopropanesulfonamide, the title compound
was obtained as a colorless solid (0.02 g, 11%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.78 (d, J=13.5 Hz, 1H), 7.74 (d, J=7.8
Hz, 1H), 7.38-7.23 (m, 3H), 7.07-7.04 (m, 1H), 3.94-3.82 (m, 1H),
3.82-3.57 (m, 4H), 3.16-3.04 (m, 1H), 2.83-2.55 (m, 4H), 237-2.21
(m, 1H), 2.12-1.88 (m, 2H), 1.53-1.42 (m, 2H), 1.22-1.10 (m, 2H),
1.03-0.92 (m, 2H), 0.72-0.61 (m, 2H); MS(ES+) m/z 541.1, 543.1
(M+1), MS(ES-) m/z 539.2, 541.2 (M-1).
Example 463
Synthesis of
(R)-5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)morpholino)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide
##STR01179##
[2032] Step 1. Preparation of
(R)-1-chloro-3-(3,5-dichlorophenyl)propan-2-ol
##STR01180##
[2034] Following the procedure as described in Example 458 step 1
and making non-critical variations as required to replace
4-bromo-1,2-dichlorobenzene with 1-bromo-3,5-dichlorobenzene, the
title compound was obtained as a colorless oil (12.93 g, 83%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.27-7.24 (m, 1H),
7.18-7.12 (m, 2H), 4.09-3.98 (m, 1H), 3.62 (dd, J=3.9, 11.2 Hz,
1H), 3.49 (dd, J=6.3, 11.2 Hz, 1H), 2.87-2.79 (m, 2H), 2.22 (br s,
1H).
Step 2. Preparation of (R)-2-(3,5-dichlorobenzyl)morpholine
##STR01181##
[2036] Following the procedure as described in Example 458 step 2
and making non-critical variations as required to replace
(R)-1-chloro-3-(3,4-dichlorophenyl)propan-2-ol with
(R)-1-chloro-3-(3,5-dichlorophenyl)propan-2-ol, the title compound
was obtaind as a colorless oil (6.98 g, 53%): MS(ES+) m/z 246.1,
248.1 (M+1).
Step 3. Preparation of (R)-tert-butyl
5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)morpholino)
methyl)-2-fluorobenzoate
##STR01182##
[2038] To a microwave vial was charged with tert-butyl
5-cyclopropyl-2-fluoro-4-(iodomethyl)benzoate (0.14 g, 0.37 mmol),
(R)-2-(3,5-dichlorobenzyl)morpholine (0.18 g, 0.75 mmol), potassium
phosphate (0.16 mg, 0.75 mmol) and N,N-dimethyl formamide (8 mL).
The suspension was heated in the microwave reactor at 80.degree. C.
for 2 hours. The reaction mixture was cooled to ambient temperature
and diluted with water (200 mL) and ethyl acetate (100 mL). The
aqueous layer was isolated and extracted with ethyl acetate
(3.times.50 mL). The combined organics were concentrated and the
residue was purified by flash chromatography (0% to 10% ethyl
acetate in hexanes) to yield the title compound (0.18 g, 98%):
MS(ES+) m/z 494.2, 496.2 (M+1).
Step 4. Preparation of
(R)-5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)morpholino)
methyl)-2-fluorobenzoic acid hydrochloride
##STR01183##
[2040] Following the procedure as described in Example 458 step 5
and making non-critical variations as required to replace
(R)-tert-butyl 5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)
methyl)-2-fluorobenzoate with (R)-tert-butyl
5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)morpholino)
methyl)-2-fluorobenzoate, the title compound was obtained as a
colorless solid (0.08 g, 49%): MS(ES+) m/z 437.9, 439.9 (M+1);
MS(ES-) m/z 436.0, 438.0 (M-1).
Step 5. Preparation of
(R)-5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)morpholino)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide
##STR01184##
[2042] Following the procedure as described in Example 458 step 6
and making non-critical variations as required to replace
(R)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluorobe-
nzoic acid hydrochloride
(R)-5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)morpholino)methyl)-2-fluorobe-
nzoic acid hydrochloride, the title compound was obtained as a
colorless solid (0.05 g, 24%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.95-8.69 (m, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.34-7.20 (m,
2H), 7.14-7.11 (m, 2H), 3.92-3.83 (m, 1H), 3.81-3.31 (m, 2H), 3.67
(s, 2H), 3.42 (s, 3H), 2.82-2.59 (m, 4H), 2.27 (dt, J=3.1, 11.2 Hz,
1H), 2.11-1.89 (m, 2H), 1.02-0.92 (m, 2H), 0.70-0.59 (m, 2H);
MS(ES+) m/z 515.1, 517.1 (M+1), MS(ES-) m/z 513.1, 515.1 (M+1).
Example 464
Preparation of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((2-(3,5-dichlorobenzyl)
morpholino)methyl)-2-fluorobenzamide
##STR01185##
[2044] Following the procedure as described in Example 458 step 6
and making non-critical variations as required to replace
(R)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluorobe-
nzoic acid hydrochloride with
(R)-5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)morpholino)
methyl)-2-fluorobenzoic acid hydrochloride, and to replace
methanesulfonamide with cyclopropanesulfonamide, the title compound
was obtained as a colorless solid (0.03 g, 22%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.78 (d, J=15.7 Hz, 1H), 7.74 (d, J=7.8
Hz, 1H), 7.33-7.19 (m, 2H), 7.11-7.07 (m, 2H), 3.92-3.85 (m, 1H),
3.81-3.71 (m, 1H), 3.67 (s, 2H), 3.65-3.60 (m, 1H), 3.16-3.04 (m,
1H), 2.82-2.62 (m, 4H), 2.27 (dr, J=3.1, 11.2 Hz, 1H), 2.05 (t,
J=10.4 Hz, 2H), 2.01-1.90 (m, 1H), 1.51-1.44 (m, 2H), 1.21-1.11
2H), 1.01-0.94 (m, 2H), 0.71-0.64 (m, 2H); MS(ES+) m/z 541.1, 543.0
(M+1), MS(ES-) m/z 539.1, 541.1 (M-1).
Example 465
Preparation of
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)mor-
pholino) methyl)-2-fluorobenzamide, trifluoroacetic acid salt
##STR01186##
[2046] Following the procedure as described in Example 458 step 6
and making non-critical variations as required to replace
(R)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluorobe-
nzoic acid hydrochloride with
(R)-5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)morpholino)methyl)-2-fluorobe-
nzoic acid hydrochloride, and to replace methanesulfonamide with
azetidine-1-sulfonamide, the title compound was obtained by
reverse-phase HPLC purification as a colorless solid (0.04 g, 37%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.77 (d, J=7.4 Hz, 1H),
7.43 (d, J=11.5 Hz, 1H), 7.27-7.26 (m, 1H), 7.07 (s, 2H), 4.49 (s,
2H), 4.25 (t, J=7.7 Hz, 4H), 4.15-3.88 (m, 3H), 3.55 d, J=11.1 Hz,
2H), 2.97-2.77 (m, 2H), 2.75-2.64 (m, 1H), 2.63-2.49 (m, 1H),
2.36-2.22 (m, 2H), 1.51-1.44 (m, 2H), 1.93-1.79 (m, 1H), 1.17-1.03
(m, 2H), 0.84-0.70 (m, 2H); MS(ES+) m/z 556.1, 558.1 (M+1), MS(ES-)
m/z 554.2, 556.2 (M-1).
Example 466
Synthesis of (R)-4-((2-(2-(2-chloro-4-fluorobenzyl)morpholino)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
trifluoroacetic acid salt
##STR01187##
[2047] Step 1. Preparation of
(R)-1-chloro-3-(2-chloro-4-fluorophenyl)propan-2-ol
##STR01188##
[2049] Following the procedure as described in Example 458 step 1
and making non-critical variations as required to replace
4-bromo-1,2-dichlorobenzene with 1-bromo-2-chloro-4-fluorobenzene,
the title compound was obtained as a colorless oil (3.22 g, 55%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.28 (dd, J=6.2 Hz, 1H),
7.12 (dd, J=2.6, 8.5 Hz, 2H), 6.95 (dt, J=2.6, 8.3 Hz, 1H),
4.19-4.09 (m, 1H), 3.72-3.66 (m, 1H), 3.59-3.50 (m, 1H), 3.06-2.90
(m, 2H), 2.17 (br s, 1H).
Step 2. Preparation of
(R)-2-(2-chloro-4-fluorobenzyl)morpholine
##STR01189##
[2051] Following the procedure as described in Example 458 step 2
and making non-critical variations as required to replace
(R)-1-chloro-3-(3,4-dichlorophenyl)propan-2-ol with
(R)-1-chloro-3-(2-chloro-4-fluorophenyl) propan-2-ol, the title
compound was obtained as a colorless oil (0.66 g, 20%): MS(ES+) m/z
230.2, 232.2 (M+1).
Step 3. Preparation of (R)-tert-butyl
5-cyclopropyl-4-((-2-(2-chloro-4-fluorobenzyl)morpholino)
methyl)-2-fluorobenzoate
##STR01190##
[2053] Following the procedure as described in Example 455 step 4
and making non-critical variations as required to replace
(R)-2-(3,4-dichlorobenzyl)morpholine with
(R)-2-(2-chloro-4-fluorobenzyl)morpholine, the title compound was
obtained (0.47 g, quant. yield): MS(ES+) m/z 478.2, 480.2
(M+1).
Step 4. Preparation of
(R)-4-((2-(2-chloro-4-fluorobenzyl)morpholino)
methyl)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride
##STR01191##
[2055] Following the procedure as described in Example 458 step 5
and making non-critical variations as required to replace
(R)-tert-butyl 5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)
methyl)-2-fluorobenzoate with (R)-tert-butyl
5-cyclopropyl-4-((2-(2-chloro-4-fluorobenzyl)morpholino)
methyl)-2-fluorobenzoate, the title compound was obtainned as a
colorless solid (0.45 g, 97%): MS(ES+) m/z 422.0, 424.0(M+1);
MS(ES-) m/z 420.1, 422.1 (M-1).
Step 5. Preparation of
(R)-4-((-2-(2-chloro-4-fluorobenzyl)morphlino)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01192##
[2057] Following the procedure as described in Example 458 step 6
and making non-critical variations as required to replace
(R)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholine)methyl)-2-fluorobe-
nzoic acid hydrochloride with
(R)-4-((2-(2-chloro-4-fluorobenzyl)morpholino)methyl)-5-cyclopropyl-2-flu-
orobenzoic acid hydrochloride, the title compound was obtained as a
colorless solid (0.07 g, 38%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.71 (d, J=7.7 Hz, 1H), 7.38 (d, J=11.5 Hz, 1H), 7.27-7.16
(m, 1H), 7.14-7.07 (m, 1H), 6.98-6.90 (m, 1H), 4.51 (s, 2H),
4.19-4.09 (m, 1H), 4.09-3.88 (m, 2H), 3.57 (dd, J =11.5, 26.0 Hz,
2H), 3.39 (s, 3H), 3.02-2.88 (m, 3H), 2.68 (t, J=11.0 Hz, 1H),
1.94-1.83 (m, 1H), 1.16-1.06 (m, 2H), 0.82-0.75 (m, 2H); MS(ES+)
m/z 499.1, 501.1 (M+1); MS(ES-) m/z 497.1, 499.1 (M-1).
Example 467
Preparation of (R)-4-((2-(2-chloro-4-fluorobenzyl)morpholino)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01193##
[2059] Following the procedure as described in Example 458 step 6
and making non-critical variations as required to replace
(R)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluorobe-
nzoic acid hydrochloride with
(R)-4-((2-(2-chloro-4-fluorobenzyl)morpholino)methyl)-5-cyclopropyl-2-flu-
orobenzoic acid hydrochloride, and to replace methanesulfonamide
with cyclopropanesulfonamide, the title compound was obtained as a
colorless solid (0.06 g, 32%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.73 (d, J=7.3 Hz, 1H), 7.37 (d, J=11.5 Hz, 1H), 7.20 (dd,
J=6.2, 8.4 Hz, 1H), 7.11 (dd, J=2.3, 8.4 Hz, 1H), 6.94 (dt, J=2.4,
8.2 Hz, 1H), 4.52 (s, 2H), 4.21-3.81 (m, 3H), 3.59 (dd, J=11.2,
26.5 Hz, 2H), 3.14-2.95 (m, 1H), 3.01-2.93 (m, 3H), 2.70 (t, J=10.8
Hz, 1H), 1.95-1.80 (m, 1H), 1.49-1.37 (m, 2H), 1.23-1.37 (m, 4H),
0.80-0.68 (m, 2H); MS(ES+) m/z 525.1, 527.1 (M+1); MS(ES-) m/z
523.1, 525.1 (M-1).
Example 468
Preparation of
(R)-N-(azetidin-1-ylsulfonyl)-4-((2-(2-chloro-4-fluorobenzyl)morpholino)
methyl)-5-cyclopropyl-2-fluorobenzamide, trifluoroacetic acid
salt
##STR01194##
[2061] Following the procedure as described in Example 458 step 6
and making non-critical variations as required to replace
(R)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluorobe-
nzoic acid hydrochloride with
(R)-4-((2-(2-chloro-4-fluorobenzyl)morpholino)methyl)-5-cyclopropyl-2-flu-
orobenzoic acid hydrochloride, and to replace methanesulfonamide
with azetidine-1-sulfonamide, the title cumpouad was obtanied as a
colorless solid (0.06 g, 37%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.77 (d, J=7.2 Hz, 1H), 7.42 (d, J=11.6 Hz, 1H), 7.25-7.20
(m, 1H), 7.14-7.10 (m, 1H), 6.98-6.91 (m, 1H), 4.49 (s, 2H), 4.25
(t, J=7.7 Hz, 4H), 4.20-4.15 (m, 1H), 4.05-3.92 (m, 2H), 3.55 (dd,
J=11.2, 26.5 Hz, 2H), 3.02-2.82 (m, 3H), 2.65 (t, J=10.6 Hz, 1H),
2.37-2.22 (m, 2H), 1.96-1.82 (m, 1H), 1.16-1.03 (m, 2H), 0.82-0.69
(m, 2H); MS(ES+) m/z 540.1, 542.1 (M+1); MS(ES-) m/z 538.1, 540.1
(M-1).
Example 469
Synthesis of
(R)-5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)-5,5-dimethylmorpholino)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01195##
[2062] Step 1. Preparation of
(R)-1-amino-3-(3,5-dichlorophenyl)propan-2-ol
##STR01196##
[2064] To a solution of
(R)-1-chloro-3-(3,5-dichlorophenyl)propan-2-ol (1.44 g, 6.01 mmol)
at N,N-dimethyl formamide (45 mL) was added sodium azide (1.95 g,
30.05 mmol) and sodium iodide (0.54 g, 3.60 mmol). The resulting
suspension was heated at 75.degree. C. overnight, cooled to ambient
temperature, diluted with ethyl acetate (150 mL) and washed with
water (50 mL), 5% aqueous lithium chloride solution (50 mL) and
brine (50 mL). The organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated. The residue was dissolved in
tetrahydrofuran (55 mL) and water (18 mL), and to this solution was
added triphenylphosphine (1.85 g, 7.07 mmol). The resulting
reaction mixture was heated at 50.degree. C. for 24 hours. Upon
cooling to ambient temperature, the reaction mixture was diluted
with dichloromethane (200 mL) and 10% aqueous sodium bicarbonate
solution (100 mL). The aqueous layer was isolated and extracted
with dichloromethane (2.times.100 mL). The combined organics were
washed with brine (100 mL), dried over anhydrous sodium sulfate,
filtered and concentrated. The residue was purified by flash
chromatography [0% to 100% (85:14:1
dichloromethane/ethanol/ammonium hydroxide) in dichloromethane] to
yield the title compound (0.93 g, 70% over 2 steps): MS(ES+) m/z
220.1, 222.1 (M+1).
Step 2. Preparation of
(R)-2-chloro-N-(3-(3,5-dichlorophenyl)-2-hydroxypropyl)acetamide
##STR01197##
[2066] To a cooled (0.degree. C.) solution of
(R)-1-amino-3-(3,5-dichlorophenyl)propan-2-ol (0.86 g, 3.91 mmol)
and triethylamine (0.718 mL, 5.08 mmol) in 9:1
dichloromethane/acetonitrile (60 mL) was added 2-chloroacetyl
chloride (340 .mu.L, 4.29 mmol) dropwise. The resulting solution
was stirred at 0.degree. C. for 1.5 hours, and then warmed to
ambient temperature and stirred for 30 minutes. The reaction
mixture was re-cooled (0.degree. C.) and quenched with 5% aqueous
hydrochloric acid solution (15 mL). The aqueous layer was isolated
and extracted with dichloromethane (2.times.30 mL). The combined
organics were washed with brine (20 mL), dried over sodium sulfate,
filtered and concentrated. The residue was triturated with diethyl
ether to yield the title compound as a colorless solid (0.87 g,
75%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.27-7.26 (m, 2H),
7.13-7.11 (m, 1H), 6.98 (br s, 1H), 4.09 (s, 2H), 4.05-3.95 (m,
1H), 3.64-3.53 (m, 1H), 3.33-3.21 (m, 1H), 2.84-2.64 (m, 2H), 1.58
(br s, 1H); MS(ES+) m/z 296.0, 298.0 (M+1).
Step 3. Prepartion of (R)-6-(3,5-dichlorobenzyl)morpholin-3-one
##STR01198##
[2068] To a cooled (0.degree. C.) solution of
(R)-2-chloro-N-(3-(3,5-dichlorophenyl)-2-hydroxypropyl)acetamide
(0.31 g, 1.03 mmol) in isopropanol (2 mL) and toluene (1 mL) was
added a solution of potassium tert-butoxide (0.32 g, 2.88 mmol) in
isopropanol (3 mL). The reaction was stirred at 0.degree. C. for 1
hour, and then slowly warmed to ambient temperature and stirred
overnight. The reaction mixture was neutralized to pH=6 with 5%
aqueous hydrochloric acid solution, and then concentrated. The
aqueous residue was diluted with toluene (75 mL) and saturated
aqueous sodium bicarbonate solution (25 mL). The toluene layer was
isolated, washed with brine (20 mL) and then concentrated. The
combined aqueous layers were extracted with ethyl acetate
(2.times.50 mL). The combined organics were dried over sodium
sulfate, filtered and concentrated. The residue was purified using
flash chromatography [0% to 5% methanol in dichloromethane] to
yield the title compound as a colorless solid (0.23 g, 87%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.32-7.12 (m, 2H), 7.11
(s, 1H), 6.32 (br s, 1H), 4.29 (d, J=16.9 Hz, 1H), 4.13 (d, J=16.9
Hz, 1H), 3.96-3.82 (m, 1H), 3.41-3.22 (m, 2H), 2.88 (dd, J =7.4,
14.2 Hz, 1H), 2.74 (dd, J=5.1, 14.2 Hz, 1H), 1.87 (br s, 1H).
Step 4. Preparation of
(R)-6-(3,5-dichlorobenzyl)-4-(4-methoxybenzyl)morpholin-3-one
##STR01199##
[2070] To a cooled (0.degree. C.) solution of
(R)-6-(3,5-dichlorobenzyl)morpholin-3-one (0.23 g, 0.89 mmol) in
N,N-dimethyl formamide (3 mL) was added sodium hydride (60%
dispersion, 0.04 g, 1.08 mmol). The resulting suspension was warmed
to ambient temperature and stirred for 15 minutes. The pink slurry
was re-cooled (0.degree. C.) before 4-methoxybenzylchloride (0.15
mL, 1.08 mmol) was added dropwisely. At this point the slurry was
too thick to stir and N,N-dimethyl formamide (2 mL) was added
before the reaction mixture was slowly warmed to ambient
temperature and stirred overnight. The reaction was cooled
(0.degree. C.), quenched with saturated aqueous ammonium chloride
solution (5 mL) and diluted with ethyl acetate (50 mL). The aqueous
layer was isolated and extracted with ethyl acetate (2.times.20
mL). The combined organics were washed with brine (20 mL), dried
over sodium sulfate, flitered and concentrated. The residue was
purified using flash chromatography [0% to 20% to 40% ethyl acetate
in hexanes] to yield the title compound as a colourless oil (0.27
g, 79): .sup.1H NMR (300 CDCl.sub.3) .delta.7.28-7.16 (m, 3H),
7.08-7.03 (m, 2H), 6.91-6.84 (m, 2H), 4.62 (d, J=14.5 Hz, 1H), 4.43
(d, J=14.5 Hz, 1H), 4.19-4.07 (m, 1H), 3.94-3.81 (m, 1H), 3.80 (s,
3H), 3.24-3.02 (m, 2H), 2.96 (s, 1H), 2.88 (s, 1H), 2.77 (dd,
J=7.8, 14.3 Hz, 1H), 2.67 (dd, J=4.6, 14.3 Hz, 1H).
Step 5. Preparation of
(R)-2-(3,5-dichlorobenzyl)-4-(4-methoxybenzyl)-5,5-dimethylmorpholine
##STR01200##
[2072] To a cooled (-10.degree. C.) solution of
(R)-6-(3,5-dichlorobenzyl)-4-(4-methoxybenzyl)morpholin-3-one (0.27
g, 0.71 mmol) tetrahydrofuran (1.5 mL) was added anhydrous
zirconium(IV) chloride (0.17 g, 0.72 mmol). After 30 minutes, a
solution of methylmagnesium bromide (3.0M in diethyl ether, 1.4
4.26 mmol) was added dropwisely. After 1 hour at -10.degree. C.,
the slurry was too thick to stir, so tetrahydrofuran (2 mL) was
added. The resulting suspension was stirred -10.degree. C. for an
additional 1 hour, and then slowly warmed to ambient temperature
and stirred overnight. The reaction was cooled (0.degree. C.),
diluted with diethyl ether (10 mL) and saturated aqueous
sodium/potassium tartarate solution (5 mL). The thick slurry was
stirred for 15 minutes, resulting in a cloudy yellow biphasic
solution. The solid was removed by filtration and rinsed with ethyl
acetate and water. The organic layer was isolated and the aqueous
layer was extracted with ethyl acetate (2.times.50 mL). The
combined organics were washed with water (20 mL) then brine (20
mL), dried over sodium sulfate, and concentrated. The residue was
purified using flash chromatography [0% to 15% to 30% ethyl acetate
in hexanes] to yield the title compound as a colourless oil (0.13
g, 46%): MS(ES+) m/z 394.0, 396.0 (M+1).
Step 6. Preparation of
(R)-2-(3,5-dichlorobenzyl)-5,5-dimethylmorpholine
##STR01201##
[2074] To a solution of
(R)-2-(3,5-dichlorobenzyl)-4-(4-methoxybenzyl)-5,5-dimethylmorpholine
(0.13 g, 0.32 mmol) in water/acetonitrile (1:1, v/v, 7 mL) was
added a solution of ceric ammonium nitrate (535 mg, 0.975 mmol) in
methanol (56 mL). The resulting orange solution was stirred at
ambient temperature overnight, quenched with 5% aqueous
hydrochloric acid solution (20 mL), and then extracted with diethyl
ether (3.times.20 mL). The combined aqueous layer was basified with
solid sodium bicarbonate to pH=9 and extracted with ethyl acetate
(3.times.75 mL). The combined ethyl acetate extracts were washed
with brine (20 mL), dried ever sodium sulfate, filtered and
concentrated to give the title compound as a colorless solid (0.08
g, 98%): MS(ES+) m/z 274.1, 276.1 (M+1).
Step 7. Preparation of (R)-tert-butyl
5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)-5,5-dimethyl
morpholino)methyl)-2-fluorobenzoate
##STR01202##
[2076] To a suspension of
(R)-2-(3,5-dichlorobenzyl)-5,5-dimethylmorpholine (0.08 g, 0.30
mmol) and potassium carbonate (0.05 g, 0.34 mmol) in N,N-dimethyl
formamide (2 mL) was added tert-butyl
5-cyclopropyl-2-fluoro-4-(((methylsulfonyl)oxy)methyl) benzoate
(0.12 g, 0.34 mmol). The suspension was stirred at ambient
temperature overhight, diluted with water (30 mL ) and ethyl
acetate (75 mL). The aqueous layer was isolated and extracted with
ethyl acetate (3.times.50 mL). The combined organics were washed
with brine (50 mL), and concentrated. The residue was purified by
flash chromatogpaphy [0% to 10% ethyl acetate in hexanes] to yield
the title compound (0.08 g, 54%): MS(ES+) m/z 522.1, 524.1
(M+1).
Step 8. Preparation of
(R)-5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)-5,5dimethylmorpholino)
methyl)-2-fluorobenzoic acid hydrochloride
##STR01203##
[2078] Following the procedure as described in Example 458 step 5
and making non-critical variations as required to replace
(R)-tert-butyl 5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)
methyl)-2-fluorobenzoate with (R)-tert-butyl
5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)-5,5-dimethyl
morpholino)methyl)-2-fluorobenzoate, the title compound was
obtained as a colorless solid (0.08 g, quant. yield): MS(ES+) m/z
466.0, 468.0 (M+1); MS(ES-) m/z 464.1, 466.1 (M-1).
Step 9. Preparation of
(R)-5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)-5,5-dimethylmorpholino)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic
acid
##STR01204##
[2080] Following the procedure as described in Example 458 step 6
and making non-critical variations as required to replace
(R)-5-cyclopropyl-4-((2-(3,4-dichlorobenzyl)morpholino)methyl)-2-fluorobe-
nzoic acid hydrochloride with
(R)-5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)-5,5-dimethylmorpholino)
methyl)-2-fluorobenzoic acid hydrochloride, the title compound was
obtained by reverse-phase HPLC purification as a colorless solid
(0.06 g, 56%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.46 (d,
J=7.0 Hz, 1H), 7.31-7.19 (m, 2H), 7.09-7.03 (m, 2H), 4.58 (d,
J=13.2 Hz, 1H), 4.06-3.96 (m, 1H), 3.91 (d, J=13.2 Hz, 1H), 3.84
(d, J=12.7 Hz, 1H), 3.58 (d, J=12.6 Hz, 1H), 3.36 (s, 3H), 3.20 (d,
J=11.9 Hz, 1H), 2.78 (dd, J=14.5 Hz, 1H), 1.90-1.77 (m, 1H), 1.50
(s, 3H), 1.42 (s, 3H), 1.10-0.94 (m, 2H), 0.88-0.79 (m, 2H),
0.61-0.51 (m, 2H); MS(ES+) m/z 543.0, 545.0 (M+1); MS(ES-) m/z
541.0, 543.0 (M-1).
Example 470
Synthesis of
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)
phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-N-(cycloprop-
ylsulfonyl)-2-fluorobenzamide, trifluoroacetic acid salt
##STR01205##
[2081] Step 1. Preparation of (1R,3s,5S)-tert-butyl
3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR01206##
[2083] To a cold (0.degree. C.) mixture of (1R,3s,5S)-tert-butyl
3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (7.68 g, 33.80
mmol) and triethylamine (7.1 mL, 50.70 mmol) in anhydrous
dichloromethane (100 mL) was added methanesulfonyl chloride (3.1
mL, 40.60 mmol) and the reaction mixture was stirred for 1 hour at
0.degree. C. The organic phase was washed with hydrochloric acid
solution (1 N, 10 mL), water (20 mL), and brine (20 mL); dried over
anhydrous sodium sulfate. Filtration and concentration of filtrate
in vacuo provided the title compound as a yellowish solid (10.40
Hz, quant. yield): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
5.09-4.96 (m, 1H), 4.29-4.17 (m, 2H), 2.97 (s, 3H), 2.10-1.93 (m,
4H), 1.90-1.75 (m, 2H), 1.68-1.59 (m, 2H) 1.44 (s, 9H).
Step 2. Preparation of (1R,3s,5S)-tert-butyl
3-(3-chloro-2-fluoro-5-(trifluoromethyl)
phenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR01207##
[2085] To a mixture or (1R,3s,5S)-tert-butyl
3-hydroxy-8-azabicyclo[3.2.1]octane-8-8-carboxylate (1.44 g, 4.70
mmol) in anhydrous dimethylformamide (10 mL) was added cesium
carbonate (3.06 g, 9.40 mmol) and
3-chloro-2-fluoro-5-(trifluoromethyl)phenol (1.10 g, 4.70 mmol) and
the reaction mixture was heated at 80.degree. C. for 16 hours.
After cooling to ambient temperature, the reaction mixture was
diluted with ethyl acetate (150 mL) and water (20 mL). The organic
phase was washed with water (2.times.15 mL), brine (15 mL), and
dried over anhydrous sodium sulfate. After filtration and
concentration of the filtrate in vacuo, the residue was purified by
flash chromatography (0 to 30% ethyl acetate in hexanes) to afford
the title compound as a colorless oil (2.00 g, quant. yield):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.19 (d, J=6.5 Hz, 1H),
6.98-6.93 (m, 1H), 4.71-4.65 (m, 1H), 4.25-4.19 (m, 2H), 2.24-2.09
(m, 4H), 2.06-1.90 (m, 4H), 1.46 (s, 9H); MS(ES+) m/z 368.0, 370.0
(M-55).
Step 3. Preparation of
(1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)
phenoxy)-8-azabicyclo[3.2.1]octane
##STR01208##
[2087] To a mixture of (1R,3r,5S)-tert-butyl
3-(3-chloro-2-fluoro-5-(trifluoromethyl)
phenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (2.00 g, 4.70
mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2
mL) and the reaction mixture was stirred at ambient temperature for
16 hours. After evaporation of all volatiles in vacuo, the residue
was dissolved in dichloromethane (100 mL). The organic phase was
washed with sodium hydroxide solution (1 N, 10 mL), water (10 mL),
and brine (10 mL), and dried over anhydrous sodium sulfate.
Filtration and concentration of the filtrate in vacuo yielded the
title compound as a colorless oil (1.50 g, quant. yield): MS(ES+)
m/z 324.1, 326.1 (M+1).
Step 4. Preparation of tert-butyl
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)-phenoxy)-8-azabic-
yclo[3.2.1]octane-8-yl)methyl)-5- cyclopropyl-2-fluorobenzoate
##STR01209##
[2089] To a mixture of
(1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)
phenoxy)-8-azabicyclo[3.2.1]octane (1.50 g, 4.70 mmol) in anhydrous
dimethylformamide (10 mL) was added potassium carbonate (1.30 g,
9.40 mmol) and tert-butyl
5-cyclopropyl-2-fluoro-4-(((methylsulfonyl) oxy)methyl)benzoate
(1.62 g, 4.70 mmol) and the reaction mixture was stirred at ambient
temperature for 16 hours. After dilution with ethyl acetate (150
mL) and addition of water (20 mL), the organic phase was washed
with water (2.times.15 mL), brine (15 mL), and dried over anhydrous
sodium sulfate. Filtration and concentration of the filtrate in
vacuo gave a residue which was purified by flash chromatography (0
to 20% ethyl acetate in hexanes) to afford the title compound as a
colorless oil (1.30 g, 48%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.48 (d, J=7.2 Hz, 1H), 7.35-7.28 (m, 1H), 7.24-7.20 (m,
1H), 4.68-4.60 (m, 1H), 6.98-6.94 (m, 1H), 3.73-3.61 (m, 2H),
3.25-3.08 (m, 2H), 2.27-1.85 (m, 9H), 1.57 (s, 9H), 0.95-0.85 (m,
2H), 0.64-0.58 0 (m,2H); MS(ES+) m/z 572.1, 574.1 (M +1).
Step 5. 4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)
phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenz-
oic acid hydrochloride
##STR01210##
[2091] A mixture of tert-butyl
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)-phenoxy)-8-azabic-
yclo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzozte (1.30
g, 2.27 mmol) and concentrated hydrochloric acid (3 mL) in dioxane
(20 mL) was stirred at ambient temperature for 16 hours.
Concentration of the reaction mixture in vacuo followed by
co-evaporation with toluene (2.times.10 mL) provided the title
compound as an off-white solid containing traced of toluene (1.30
g, quant. yield): MS(ES+) m/z 514.1, 516.1 (M+1).
Step 6. Preparation of
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)
phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-N-(cycloprop-
ylsulfonyl)-2-fluorobenzamide, trifluoroacetic acid salt
##STR01211##
[2093] A mixture of
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)
phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenz-
oic acid hydrochloride (0.63 g, 1.10 mmol), cyclopropanesulfonamide
(0.34 g, 3.60 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (0.69 g, 3.60 mmol), and 4-dimethylaminopyridine
(0.88 g, 7.20 mmol) in anhydrous dichloromethane (10 mL) was
stirred at ambient temperature for 16 hours. The reaction mixture
was diluted with ethyl acetate (150 mL) and washed with aqueous
hydrochloric acid solution (1 M, 10 mL), water (10 mL) and brine
(10 mL). The organic phase was dried over anhydrous sodium sulfate,
filtered, and the filtrate concentrated in vacuo. The residue was
purified reverse phase HPLC (acetonitrile in water with 0.1%
trifluoroacetic acid) to give the title compound as a colorless
solid (0.38 g, 47%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
12.24 (br s, 1H), 9.58 (br s, 1H), 7.67-7.53 (m, 3H), 7.27 (d,
J=7.1 Hz, 1H), 5.00-4.92 (m, 1H), 4.42 (brs, 2H), 4.01 (br s, 2H),
3.12-2.99 (m, 1H), 2.46-2.23 (m, 6H), 2.22-2.05 (m, 3H), 1.15-1.05
(m, 4H), 1.04-0.94 (m, 2H), 0.82-0.73 (m, 2H); MS(ES-) m/z 617.1,
619.1 (M-1).
Example 471
Synthesis of
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)
phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluoro-N-(-
methylsulfonyl)benzamide 2,2,2-trifluoroacetate
##STR01212##
[2095] Following the procedure as described in Example 470 step 6,
and making variation as required to replace cyclopropanesulfonamide
with methanesulfonamide, the title compound was obtained as a
colorless solid (0.35 g, 45%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 12.32 (br s, 1H), 9.46 (br s, 1H), 7.67-7.51 (m, 3H), 7.29
(d, J=7.2 Hz, 1H), 4.97 (s, 1H), 4.42 (s, 2H), 4.01 (s, 2H), 3.34
(s, 3H), 2.44-2.26 (m, 6H), 2.22-2.06 (m, 3H), 1.03-0.96 (m, 2H),
0.81-0.74 (m, 2H); MS(ES-) m/z 591.1, 593.1 (M-1).
Example 472
Synthesis of
4-((4-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)-4-methylpiperidin-1--
yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01213##
[2096] Step 1. Preparation of tert-butyl
4-(bromomethyl)-5-cyclopropyl-2-fluorobenzoate
##STR01214##
[2098] To a cold (0.degree. C.) mixture of tert-butyl
5-cyclopropyl-2-fluoro-4-(hydroxymethyl)benzoate (1.0 g, 3.80 mmol)
and triphenylphosphine (1.48 g, 5.60 mmol) in anhydrous
tetrahydrofuran (20 mL) was added tetrabromomethane (1.87 g, 5.60
mmol) and the reaction mixture was stirred for 3 hours at 0.degree.
C. After concentration in vacuo, the residue was purified by flash
chromatography (0 to 20% ethyl acetate in hexanes) to afford the
title compound as an off-white solid (1.24 g, quant. yield):
.sup.1H NMR (300 MHz, CDCl.sub.3) 7.52 (d, J=7.2 Hz, 1H), 7.06 (d,
J=10.8 Hz, 1H), 4.62. (s, 2H), 2.04-1.92 (m, 1H), 1.56 (s, 9H),
1.04-0.90 (m, 2H), 0.74-0.67. (m, 2H).
Step 2. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-hydroxy-4-methylpiperidin-1-yl)methyl)benzoa-
te
##STR01215##
[2100] Following the procedure as described in Example 470 step 4,
and making variations as required to replace
(1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicyclo[-
3.2.1]-octane with 4-hydroxy-methylpiperidine, and to replace
tert-butyl 5-cyclopropyl-2-fluoro-4-(((methylsulfonyl)
oxy)methyl)benzoate with tert-butyl
4-(bromomethyl)-5-cyclopropyl-2-fluorobenzoate, the title compound
was obtained as an orange oil (1.10 g, 81%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.47 (d, J=7.2 Hz, 1H), 7.17 (d, J=11.9 Hz,
1H), 3.64 (s, 2H), 2.59-2.49 (m, 2H), 2.47-2.36 (m, 2H), 1.99-1.88
(m, 1H), 1.73-1.51 (m, 14H), 1.24 (s, 3H), 0.93-0.85 (m, 2H),
0.63-0.57 (m, 2H).
Step 3. Preparation of tert-butyl
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)
oxy)-4-methylpiperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoate
##STR01216##
[2102] To a mixture of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-hydroxy-4-methylpiperidin-1-yl)
methyl)benzoate (1.08 g, 2.96 mmol) and
2,5-dichloro-4-(trifluoromethyl)pyridine (0.96 g, 4.40 mmol) in
anhydrous tetrahydrofuran (5 mL) was added lithium
bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 4.4 mL, 4.4
mmol) and the reaction mixture was heated at 80-100.degree. C. for
48 hours. After cooling to ambient temperature, the reaction
mixture was diluted with ethyl acetate (100 mL). The organic phase
was washed with 1 M aqueous hydrochloric acid solution (10 ml),
water (2.times.10 mL), brine (10 mL), and dried over anhydrous
sodium sulfate. Filtration and concentration of the filtrate
provided a residue which was purified by flash chromatography (0 to
20% ethyl acetate in hexanes) to afford the title compound as a
colorless oil (0.19 g, 12%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.8.16 (s, 1H), 7.47 (d, J=7.3 Hz, 1H), 7.17 (d, J=11.8 Hz,
1H), 6.98 (s, 1H), 3.62 (s, 2H), 2.62-2.53 (m, 2H), 2.43-2.30 (m,
4H), 1.99-1.88 (m, 1H), 1.83-1.71 (m, 2H), 1.60 (s, 3H), 1.58 (d,
J=13.7 Hz, 9H), 0.93-0.85 (m, 2H), 0.63-0.57 (m, 2H); MS(ES+) m/z
543.2, 545.2 (M+1).
Step 4. Preparation of
4-((4-(-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)
oxy)-4-methylpiperidin-1-yl)methyl)-5cyclopropyl-2-fluorobenzoic
acid
##STR01217##
[2104] Following the procedure as described in Example 470 step 5,
and making variation as required to replace tert-butyl
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)-phenoxy)-8-azabic-
yclo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoate with
tert-butyl 4-((4-((5-chloro-4-(trifluoromethyl)
pyridin-2-yl)oxy)-4-methylpiperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobe-
nzoate, the title compound was obtained as a yellowish solid (0.17
g, quant. yield): MS(ES+) m/z 485.2, 487.1 (M+1).
Step 5. Preparation of
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)-4-methylpiperidin-1-
-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
2,2,2,-trifluoroacetate
##STR01218##
[2106] Following the procedure as described in Example 470 Step 6,
and making variation as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with 4-((4-((5-chloro-4-(trifluoromethyl)
pyridin-2-yl)oxy)-4-methylpiperidin-1-yl)methyl)-5-cyclopropyly2-fluorobe-
nzoic acid, the title compound was obtained as a colorless solid
(0.07 mg, 31%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.47
(br s, 1H), 9.24 (br s, 1H), 8.22 (s, 1H), 7.74 (d, J=7.4 Hz, 1H),
7.49 (d, J=11.8 Hz, 1H), 7.03 (s, 1H), 4.46 (s, 2H), 3.58-3.44 (m,
2H), 3.12-2.97 (m, 3H), 2.78-2.67 (m, 2H), 2.28-2.11 (m, 2H),
1.91-1.80 (m, 1H), 1.59 (s, 3H), 1.48-1.40 (m, 2H), 1.19-1.11 (m,
2H), 1.10-1.02 (m, 2H), 0.76-0.60 (m, 2H); MS(ES-) m/z 588.1, 590.0
(M-1).
Example 473
Synthesis of
4-((4-((5-bromo-3-chloropyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoracetic acid saLt
##STR01219##
[2107] Step 1. Preptiration of tert-butyl
4-((5-bromo-3-chloropyridin-2-yl)oxy)piperidine-1-carboxylate
##STR01220##
[2109] To a mixture of sodium hydride (60% dispersion in mineral
oil, 0.44 g, 11.00 mmol) in anhydrous dimethylformamide (20 mL) was
added 1-Boc-4-hydroxypiperidine (2.00 g, 10.00 mmol). The reaction
mixture was stirred for 1 hour at ambient temperature, after which
5-bromo-2,3-dichloropyridine (2.27 g, 10.00 mmol) was added. The
reaction mixture was heated to 70.degree. C. for 16 hours. After
cooling to ambient temperature, the reaction mixture was
partitioned between water (50 mL) and ethyl acetate (200 mL). The
organic phase was washed with brine (20 mL), dried over anhydrous
sodium sulfate, and filtered. Concentration of the filtrate in
vacuo provided the title compound as yellowish oil (3.90 g, quant.
yield), which was used without further purification: MS(ES+) m/z
335.0, 337.0 (M-55).
Step 2. Preparation of
5-bromo-3-chloro-2-(piperidin-4-yloxy)pyridine
##STR01221##
[2111] Following the procedure as described in Example 470 step 3,
and making variation as required to replace (1R,3r,5S)-tert-butyl
3-(3-chloro-2-fluoro-5-(trifluoromethyl)
phenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate with tert-butyl
4-((5-bromo-3-chloropyridin-2-yl) oxy)piperidine-1-carboxylate, the
title compound was isolated as a yellowish oil (2.90 g, quant.
yield): MS(ES+) m/z 291.0, 293.0, 295.0 (M+1).
Step 3. Preparation of tert-butyl
4-((4-((5-bromo-3-chloropyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoate
##STR01222##
[2113] Following the procedure as described in Example 470 Step 4,
and making variation as required to replace
(1R,3r5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicyclo[3-
.2.1]-octane with 5-bromo-3-chloro-2-(piperidin-4-yloxy)pyridine,
the title compound was obtined as a yellowish solid (2.70 g, quant.
yield): MS(ES+) m/z 539.2, 541.2 (M+1).
Step 4: Preparation of
4-((4-((5-bromo-3-chloropyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride
##STR01223##
[2115] Following the procedure as described in Example 470 step 5,
and making variation as required to replace tert-butyl
4-(((1R,3r5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)-phenoxy)-8-azabicy-
clo[3.2.1]-octan-80-yl) methyl)-5-cyclopropyl-2-fluorobenzoate with
tert-butyl 4-((4-((5-bromo-3-chloropyridin-2-yl)
oxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoate, the
title compound was isolated as an off-white solid (1.09 g, quant.
yield): MS(ES+) m/z 483.0, 485.00 (M+1).
Step 5: Preparation of
4-((4-((5-bromo-3-chloropyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01224##
[2117] To a mixture of
4-((4-((5-bromo-3-chloropyridin-2-yl)oxy)piperidin-1-yl)methyl)-5-cyclopr-
opyl-2-fluorobenzoic acid hydrochloride (1.09 g, 2.10 mmol) in
anhydrous tetrahydrofuran (10 mL) was added
1,1'-carbonyldiimidazole (0.68 g, 4.20 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (0.63 mL, 4.20 mmol) and the
reaction mixture was heated at 70.degree. C. for 30 minutes. After
cooling to ambient temperature, cyclopropanesulfonamide (0.51 g,
4.20 mmol) and 1,8-diazabicylo[5.4.0]undec-7-ene (0.63 mL, 4.20
mmol) was added and the reaction mixture was heated at 70.degree.
C. for 4 hours. After cooling to ambient temperature, the reaction
mixture was diluted with ethyl acetate (200 mL). The organic phase
washed with hydrochloric acid (1 N, mL), water (10 mL), brine (10
mL), and dried over anhydrous sodium sulfate. Filtration and
concentration of the filtrate in vacuo provided the crude product
(0.78 g). Half of the crude material (0.39 g) was purified by
reverse phase preparative HPLC to give the title compound as a
colorless solid (0.20 g, 14%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 12.38 (br s, 1H), 9.38 (br s, 1H), 8.07 (s, 1H), 7.79 (d,
J=2.1 Hz, 1H), 7.74 (d, J =7.3 Hz, 1H), 7.47 (d, J=11.8 Hz, 1H),
5.45 (s, 1H), 4.52 (s, 2H), 3.61-3.45 (m, 2H), 3.27-3.11 (m, 2H),
3.11-3.00 (m, 1H), 2.43-2.27 (m, 2H), 2.27-2.14 (m, 2H), 1.95-1.83
(m, 1H), 1.48-1.38 (m, 2H), 1.18-1.05 (m, 4H), 0.79-0.72 (m, 2H);
MS(ES-) m/z 584.0, 586.0, 588.0 (M-1).
Example 474
Synthesis of
4-((4-((3-chloro-5-cyclopropylpyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluurobenzamide
hydrochloride
##STR01225##
[2119] To a mixture of
4-((4-((5-bromo-3-chloropyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
(0.39 g, 0.67 mmol), cyclopropylboronic acid (0.17 g, 2.00 mmol),
potassium phosphate tribasic (0.57 g, 2.7 mmol) in dioxane (10 mL)
was added tetrakis(triphenylphosphine)palladium(0) (0.08 g, 0.07
mmol). The reaction mixture was degassed by passing a stream of
argon through it and then heated at 110.degree. C. in a sealed vial
for 16 hours. After cooling to ambient temperature, the reaction
mixture was filtered over diatomaceous earth. The filter cake was
washed with dichloromethane (50 mL), and the combined filtrate was
concentrated in vacuo. The residue was purified by reverse phase
HPLC (acetonitrile in water with 0.1% ammonium hydroxide). The
combined fractions were adjusted to pH 1-2 with 1 N hydrochloric
acid, and extracted with dichloromethane (3.times.30 mL). The
orgrmic phase was dried over anhydrous sodium sulfate, filtered,
and the filtrate concentrated in vacuo to give the title compound
as an off-white solid (0.11 g, 29%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 12.66 (br s, 1H), 9.22 (br s, 1H), 8.15 (d,
J=11.6 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H),
7.29 (d, J=2.1 Hz, 1H), 5.40 (s, 1H), 4.39 (s, 2H), 3.37-3.00 (m,
5H), 2.70-2.50 (m, 2H), 2.24-2.07 (m, 2H), 2.01-1.88 (m, 1H),
1.80-1.75 (m, 1H), 1.50-1.40 (m, 2H), 1.19-1.03 (m, 4H), 1.00-0.92
(m, 2H), 0.77-0.70 (m, 2H), 0.64-0.57 (m, 2H); MS(ES+) m/z 548.2,
550.2 (M+1).
Example 475
Synthesis of
5-cyclopropyL-N-(cyclopropylsulfonyl)-4-(((1R,3r,5S)-3-(3,5-dichloropheno-
xy)-8-azabicyclo[3.2.1]octan-8-yl) methyl)-2-fluorobenzamide
hydrochloride
##STR01226##
[2120] Step 1. Preparation of (1R,3r,5S)-tert-butyl
(3,5-dichlorophenoxy)-8-azabicyclo[3.2.1]octan-8-carboxylate
##STR01227##
[2122] To a mixture of (1R,3r,5S)-tert-butyl
3-hydroxy-8-azabicyclo[3.2.1]octan-8-carboxylate (5.00 g, 22.00
mmol) in toluene (50 mL) was added 3,5-dichloroiodobenzene (6.00 g,
22.00 mmol), cesium carbonate (21.50 g, 66.00 mmol), copper(I)
iodide (0.63 g, 3.30 mmol), 3,4,7,8-tetramethyl-1,10-phenantroline
(1.60 g, 6.60 mmol) and molecular sieves (4 A, 5.00 g). The
reaction mixture was degassed by passing a stream of argon through
it and then heated at 80.degree. C. in a sealed vial for 120 hours.
After cooling to ambient temperature, the reaction mixture was
diluted with ethyl acetate (150 mL) and filtered over diatomaceous
earth. Concentration of the filtrate in vacuo gave a residue which
was purified by flash chromatography (0 to 20% ethyl acetate in
hexanes) to afford the title compound as a yellowish oil (3.80 g,
46%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.6.93-6.90 (m, 1H),
6.71-6.69 (m, 2H), 4.59-4.53 (m, 1H), 4.28-4.09 (m, 2H), 2.24-1.85
(m, 8H), 1.45 (s, 9H); MS(ES+) m/z 316.1, 318.1 (M -55).
Step 2. Preparation of
(1R,3r,5S)-3-(3,5-dichlorophenoxy)-8-azabicyclo[3.2.1]octane
##STR01228##
[2124] Following the procedure as described in Example 470 Step 3,
and making variation as required to replace (1R,3r,5S)-tert-butyl
3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-aziabicyclo[3.2.1]octa-
ne-8-carboxylate with (1R,3r,5S)-tert-butyl
3-(3,5-dichlorophenoxy)-8-aziabicyclo[3.2.1]octane-8-carboxylate,
the title compound was isolated as an off-white solid (2.80 g,
quant. yield): MS(ES+) m/z 272.1, 274.1 (M+1).
Step 3. Preparation of tert-butyl
5-cyclopropyl-4-(((1R,3r,5S)-3-(3,5-dichlorophenoxy)-8-azabicyclo[3.2.1]o-
ctan-8-yl) methyl)-2-fluorobenzoate
##STR01229##
[2126] Following the procedure as described in Example 470 step 4,
and making variation as required to replace
(1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicyclo[-
3.2.1]-octane with
(1R,3r,5S)-3-(3,5-dichlorophenoxy)-8-azabicyclo[3.2.1]octane, the
title compound was obtained as an off-white foam (4.50 g, 86%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.47 (d, J=7.3 Hz, 1H),
7.32 (d, J=12.1 Hz, 1H), 6.92-6.89 (m, 1H), 6.72-6.69 (m, 2H),
4.54-4.46 (m, 1H), 3.65 (s, 2H), 3.14 (s, 2H), 2.19-2.09 (m, 2H),
2.07-1.99 (m, 4H), 1.95-1.85 (m, 3H), 1.57 (s, 9H), 0.93-0.85 (m,
2H), 0.64-0.58 (m, 2H); MS(ES+) m/z 520.2, 522.2 (M+1).
Step 4. Preparation of
5-cyclopropyl-4-(((1R,3r,5S)-3-(3,5-dichlorophenoxy)-8-azabicyclo[3.2.1]--
octan-8-yl) methyl)-2-fluorobenzoic acid hydrochloride
##STR01230##
[2128] Following the procedure as described in Example 470 Step 5,
and making variation as required to replace tert-butyl
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)-phenoxy)-8-azabic-
yclo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoate with
tert-butyl
5-cyclopropyl-4-(((1R,3r,5S)-3-(3,5-dichlorophenoxy)-8-azabicyclo[3.2.1]o-
ctan-8-yl)methyl)-2-fluorobenzoate, the title compound was obtained
as a colorless solid after trituration with diethyl ether (4.40 g,
quant. yield): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.13.43 (br
s, 1H), 10.56 (br s, 1H), 7.92 (d, J=11.6 Hz, 1H), 7.49 (d, J=7.3
Hz, 1H), 7.17-7.09 (m, 3H), 4.84-4.78 (m, 1H), 4.48-4.38 (m, 2H),
3.98 (s, 2H), 2.77-2.65 (m, 2H), 2.40-2.02 (m, 7H), 1.07-0.97 (m,
2H), 0.76-0.66 (m, 2H); MS(ES+) m/z 464.1, 466.1 (M+1).
Step 5. Preparation of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-(((1R,3r,5S)-3-(3,5-dichloropheno-
xy)-8-azabicyclo[3.2.1]octan-8-yl) methyl)-2-fluorobenzamide
hydrochloride
##STR01231##
[2130] A mixture of
5-cyclopropyl-4-(((1R,3r,5S)-3-(3,5-dichlorophenoxy)-8-azabicyclo[3.2.1]o-
ctan-8-yl) methyl)-2-fluorobenzoic acid hydrochloride (4.00 g, 8.00
mmol), cyclopropanesulfonamide (1.16 g, 9.60 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.84
g, 9.60 mmol), and 4-dimethylaminopyridine (3.52 g, 28.80 mmol) in
anhydrous dichloromethane (50 mL) and anhydrous tetrahydrofuran (50
mL) was stirred at ambient temperature for 16 hours. Additional
cyclopropanesulfonamide (1.16 g, 9.60 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.84
g, 9.60 mmol), and 4-dimethylaminopyridine (3.52 g, 28.80 mmol) was
added and the reaction mixture was stirred for another 16 hours at
ambient temperature. The reaction mixture was partitioned between
ethyl acetate (300 mL) and 1M aqueous hydrochloric acid solution
(20 mL). The organic phase was washed with hydrochloric acid (1 N,
20 mL), water (20 mL) and brine (2.times.10 mL), dried over
anhydrous sodium sulfate and filtered. After concentration of the
filtrate in vacuo, the obtained solid residue was triturated with
acetonitrile (100 mL) and filtered off. The solid was re-dissolved
in dichloromethane (50 mL), filtered and concentrated in vacuo. The
residue was dryed in vacuo at 40-50.degree. C. provided the title
compound as a colorless solid (2.45 g, 51%): .sup.1H NMR (300 MHz,
CDCl.sub.3/CDCl.sub.3OD) .delta. 8.42 (d, J=12.3 Hz, 1H), 7.73 (d,
J=7.4 Hz, 1H), 6.97 (t, J=1.6, 1H), 6.71 (d, J=1.7 Hz, 2H),
4.73-4.67 (m, 1H), 4.45 (s, 2H), 3.84 (br s, 2H), 3.33-3.21 (m,
2H), 3.12-3.02 (m, 1H), 2.52-2.42 (m, 2H), 2.33-2.21 (m, 2H),
2.18-2.09 (m, 2H), 1.93-1.82 (m, 1H), 1.50-1.42 (m, 2H), 1.19-1.10
(m, 2H), 1.10-1.01 (m, 2H), 0.78-0.70 (m, 2H); MS(ES-) 567.1, 559.0
(M +1).
Example 476
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((4-((5-(trifluoromethyl)
pyridin-2-yl)oxy)piperidin-1-yl)methyl)benzamide, trifluoroacetic
acid salt
##STR01232##
[2131] Step 1. Preparation of tert-butyl
4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate
##STR01233##
[2133] Following the procedure as described in Example 470 step 1,
and making variation as required to replace
5-bromo-2,3-dichloropyridine with
2-chloro-5-trifluoromethylpyridine, the title compound was isolated
as a colorless solid (3.65 g, quant. yield): MS(ES+) m/z 291.1
(M-55).
Step 2. Preparation of
2-(piperidin-4-yloxy)-5-(trifluoromethyl)pyridine
##STR01234##
[2135] Following the procedure as described in Example 470 step 3,
and making variation as required to replace (1R,3r,5S)-tert-butyl
3-(3-chloro-2-fluoro-5-(trifluoromethyl)
phenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate with tert-butyl
4-((5-(trifluoromethyl) pyridin-2-yl)oxy)piperidine-1-carboxylate,
the title compound was obtained as an off-white solid (2.40 g,
quant. yield): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.8.38 (d,
J=0.7 Hz, 1H), 7.75 (dd, J=8.7, 2.4 Hz, 1H), 6.78 (d, J=8.7 Hz,
1H), 6.48 (s, 1H), 5.36-5.22 (m, 1H), 3.30-3.16 (m, 2H), 3.06-2.93
(m, 2H), 2.22-2.10 (m, 2H), 1.97-1.83 (m, 2H); MS(ES+) m/z 247.2
(M+1).
Step 3. Preparation of tert-butyl 5-cyclopropyl-2-fluoro-4
4-((4-((5-(trifluoromethyl)
pyridin-2-yl)oxy)piperidin-1-yl)methyl)benzoate
##STR01235##
[2137] Following the procedure as described in Example 470 step 4,
and making variation as required to replace
(1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicyclo[-
3.2.1]-octane with
2-(piperidin-4-yloxy)-5-(trifluoromethyl)pyridine, the title
compound was obtained as light yellowish oil (2.50 g, quant.
yield): MS(ES+) m/z 495.2 (M+1).
Step 4. Preparation of
5-cyclopropyl-2-fluoro-4-((4-((5-(trifluoromethyl)pyridin-2-yl)
oxy)piperidin-1-yl)methyl)benzoic acid hydrochloride
##STR01236##
[2139] Following the procedure as described in Example 470 step 5,
and making variation as required to replace tert-butyl
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)-phenoxy)-8-azabic-
yclo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoate with
tert-butyl 5-cyclopropyl-2-fluoro-4-((4-((5-(trifluoromethyl)
pyridin-2-yl)oxy)piperidin-1-yl)methyl)benzoate, the title compound
was obtained au a colorless solid (1.10 g, 95%): MS(ES+) m/z 439.1
(M+1).
Step 5. Preparation of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((4-((5-(trifluoromethyl)
pyridin-2-yl)oxy)piperidin-1-yl)methyl)benzamide, trifluoroacetic
acid salt
##STR01237##
[2141] Following the procedure as described in Example 470 Step 6,
and making variations as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with
5-cyclopropyl-2-fluoro-4-((4-((5-(trifluoromethyl)
pyridin-2-yl)oxy)piperidin-1-yl)methyl)benzoic acid hydrochloride
and cyclopropanesulfonamide with methanesulfonamide, the title
compound was obtained as a colorless solid (0.24 g, 33%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 12.44 (br s, 1H), 9.94 (br s,
1H), 8.40 (s, 1H), 7.80 (dd, J=8.7, 1.9 Hz, 1H), 7.68 (d, J=7.3 Hz,
1H), 7.48 (d, J=11.7 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 5.46 (s, 1H),
4.52 (s, 2H), 3.81-3.42 (m, 2H), 3.37 (s, 3H), 3.31-2.88 (m, 2H),
2.44-2.29 (m, 2H), 2.29-2.14 (m, 2H), 1.96-1.84 (m, 1H), 1.16-1.02
(m, 2H), 0.80-0.71 (m, 2H); MS(ES-) m/z 514.2 (M-1).
Example 477
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((4-((5-(trifluoromethyl-
) pyridin-2-yl)oxy)piperidin-1-yl)methyl)benzamide, trifluoroacetic
acid salt
##STR01238##
[2143] Following the procedure as described in Example 470 step 6,
and making variation as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with
5-cyclopropyl-2-fluoro-4-((4-((5-(trifluoromethl)
pyridin-2-yl)oxy)piperidin-1-yl)methyl)benzoic acid hydrochloride,
the title compound was obtained as a colorless solid (0.31 g, 40%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.12.88 (br s, 1H), 9.49
(br s, 1H), 8.40 (s, 1H), 7.80 (dd, J=8.7, 2.1 Hz, 1H), 7.72 (d,
J=7.4 Hz, 1H), 7.49 (d, J =11.9 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H),
5.45 (s, 1H) 4.50 (s, 2H), 3.75-3.31 (m, 2H), 3.28-2.83 (m, 3H),
2.46-2.29 (m, 2H), 2.28-2.14 (m, 2H), 1.98-1.83 (m, 1H), 1.47-1.37
(m, 2H), 1.19-1.04 (m, 4H), 0.79-0.71 (m, 2H); MS(ES-) m/z 540.2
(M+1).
Example 478
Synthesis of 4-((4-((2-chloro-4-fluorobenzyl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01239##
[2144] Step 1. Preparation of tert-butyl
4-((2-chloro-4-fluorobenzyl)oxy)piperidine-1-carboxylate
##STR01240##
[2146] To a mixture of 1-Boc-4-hydroxypiperidine (2.00 g, 10.00
mmol) in anhydrous dimethylformamide (20 mL) was added sodium
hydride (60% dispersion in mineral oil, 0.40 g, 10.10 mmol) at
0.degree. C. The reaction mixture was allowed to warm to ambient
temperature and stirred for 1 hour. To this reaction mixture was
added 2-chloro-4-fluorobenzylbromide (2.45 g, 11.00 mmol) and
tetrabutylammonium iodide (0.37 g, 1.00 mmol) and the reaction
mixture was stirred for 48 hours at ambient temperature. After
addition of water (20 mL) and dilution with ethyl acetate (200 mL),
the organic phase was washed with water (3.times.20 mL), brine (20
mL), and dried over anhydrous sodium sulfate. Filtration and
concentration of the filtrate in vacuo provided the title compound
as yellowish oil (3.50 g, quant. yield), which was used without
further putificaton: MS(ES+) m/z 288.1, 290.1 (M-55).
Step 2. Preparation of
4-((2-chloro-4-fluorobenzyl)oxy)piperidine
##STR01241##
[2148] Following the procedure as described in Example 470 step 3,
and making variation as required to replace (1R,3r,5S)-tert-butyl
3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxyy)-8-azabicyclo[3.2.1]octa-
ne-8-carboxylate with tert-butyl
4-((2-chloro-4-fluorobenzyl)oxy)piperidine-1-carboxylate, the title
compound was obtained as a yellowish oil (1.70 g, 71%): .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.46 (dd, J=8.4, 6.4 Hz, 1H), 7.08
(dd, J=8.5, 2.6 Hz, 1H), 6.96 (dt, J=8.4, 8.3, 2.6 Hz, 1H), 4.56
(s, 2H), 3.56-3.43 (m, 1H), 3.14-3.04 (m, 2H), 2.68-2.54 (m, 2H),
2.02-1.91 (m, 2H), 1.88-1.79 (m, 1H), 1.58-1.43 (m, 2H).
Step 3. Preparation of tert-butyl
4-((4-((2-chloro-4-fluorobenzyl)oxy)piperidin-1-yl)
methyl-5-cyclopropyl-2-fluorobenzoate
##STR01242##
[2150] Following the procedure as described in Example 470 step 4,
and making variation as required to replace
(1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicyclo[-
3.2.1]-octane with 4-((2-chloro-4-fluorobenzyl)oxy)piperidine, the
title compound was obtained as a yellowish oil (3.40 g, 97%):
MS(ES+) m/z 492.2, 494.2 (M+1).
Step 4. Preparation of
4-((4-((2-chloro-4-fluorobenzyl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoic acid, trifluoroacetic acid
salt
##STR01243##
[2152] To a mixture of tert-butyl
4-((4-((2-chloro-4-fluorobenzyl)oxy)piperidin-1-yl)methyl)-5-cyclopropyl--
2-fluorobenzoate (3.41 g, 6.90 mmol) na dichloromethane (40 mL) was
added trifluoroacetic acid (5 mL) and the reaction mixture was
stirred at ambient temperature for 16 hours. Concentration of the
reaction mixture in vacuo provided the title compound as an
off-white solid (3.20 g, 84%): MS(ES+) m/z 436.1, 438.1 (M+1).
Step 5. Preparation of
4-((4-((2-chloro-4-fluorobenzyl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01244##
[2154] Following the procedure as described in Example 470 step 6,
and making variations as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with 4-((4-((2-chloro-4-fluorobenzyl)
oxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoic acid,
trifluoroacetic acid salt and to replace cyclopropanesulfonamide
with methanesulfonamide, the title compound was obtained as a
colorless solid (0.52 g, 53%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta.11.46 (br s, 1H), 9.97 (br s, 1H), 7.68 (d, J=7.4 Hz, 1H),
7.43 (d, J=11.9 Hz, 1H), 7.37 (dd, J=8.4, 6.3 Hz, 1H), 7.13 (dd,
J=8.4, 2.3 Hz, 1H), 6.99 (dt, J=8.3, 8.3, 2.4 Hz, 1H), 4.52 (s,
2H), 4.46 (s, 2H), 3.85 (br s, 1H), 3.50-3.40 (m, 2H) 3.37 (s, 3H),
3.25-3.09 (m, 2H), 2.24-2.02 (m, 4H), 1.91-1.80 (m, 1H), 1.12-1.03
(m, 2H), 0.77-0.69 (m, 2H); MS(ES+) m/z 513.2, 515.2 (M+1).
Example 479
Synthesis of
N-(azetidin-1-ylsulfonyl)-4-((4-((2-chloro-4-fluorobenzyl)oxy)piperidin-1-
-yl) methyl)-5-cyclopropyl-2-fluorobenzamide, triflouroacetic acid
salt
##STR01245##
[2156] Following the procedure as described in Example 470 step 6,
and making variations as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-6-(trifluoromethyl)
phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)
methyl)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride with
4-((4-((2-chloro-4-fluorobenzyl)
oxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoic acid,
trifluoroacetic acid salt and to replace cyclopropanesulfonamide
with azetidine-1-sulfonamide, the title compound was obtained as a
colorless solid (0.18 g, 17%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta.13.04 (br s, 1H), 9.04 (br s, 1H), 7.75 (d, J=7.5 Hz, 1H),
7.52 (d, J=12.1 Hz, 1H), 7.37 (dd, J=8.4, 6.2 Hz, 1H), 7.13 (dd,
J=8.4, 2.5 Hz, 1H), 6.99 (dt, J=8.3, 8.3, 2.6 Hz, 1H), 4.53 (s,
2H), 4.43 (s, 2H), 4.23 (t, J=7.7, 7.7 Hz, 4H), 3.84 (br s, 1H),
3.48-3.33 (m, 2H), 3.22-3.05 (m, 2H), 2.34-2.14 (m, 4H), 2.13-2.01
(m, 3H), 1.13-1.04 (m, 2H), 0.78-0.71 (m, 2H); MS(ES+) m/z 554.2,
556.2 (M+1).
Example 480
Synthesis of 4-((4-((2-chloro-4-fluorobenzyl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01246##
[2158] Following the procedure described in Example 470 step 6, and
making variation as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with 4-((4-((2-chloro-4-fluorobenzyl)
oxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoic acid
2,2,2-trifluoroacetate, the title compound was obtained as a
colorless solid (0.62 g, 60%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta.12.13 (br s, 1H), 9.34 (br s, 1H), 7.72 (d, J=7.4 Hz, 1H),
7.46 (d, J=11.9 Hz, 1H), 7.37 (dd, J=8.5, 6.1 Hz, 1H), 7.13 (dd,
J=8.4, 2.4 Hz, 1H), 6.99 (dt, J=8.3, 8.3, 2.6 Hz, 1H), 4.52 (s,
2H), 4.45 (s, 2H), 3.85 (s, 1H), 3.50-3.37 (m, 2H), 3.22-2.99 (m,
3H), 2.28-2.01 (m, 4H), 1.92-1.80 (m, 1H), 1.48-1.39 (m, 2H),
1.19-1.03 (m, 4H), 0.77-0.70 (m, 2H); MS(ES+) m/z 539.2, 541.1
(M+1).
Example 481
Synthesis of
4-((1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR01247##
[2159] Step 1. Preparation of tert-butyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)-3-methylazet-
idine-1-carboxylate
##STR01248##
[2161] Following the procedure as described in Example 3 step 1,
and making as required to (R)-tert-butyl
3-hydroxypiperidine-1-carboxlate with
1-Boc-3-(hydroxymethyl)-3-methylazetidine and purification by flash
chromatography (0 to 40% ethyl acetate in hexanes), the title
compound was obtained as a yellowish oil (12.40 g, 81%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.86 (d, J=7.6 Hz, 1H), 6.62 (d,
J=11.9 Hz, 1H), 3.95 (s, 2H), 3.90 (d, J=8.5 Hz, 2H), 3.66 (d,
J=8.5 Hz, 2H), 1.56 (s, 9H), 1.42 (s, 9H), 1.41 (s, 3H); MS(ES+)
m/z 430.1, 432.1 (M+1).
Step 2. Preparation of tert-butyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-3-methylazetidine-1-carboxylate
##STR01249##
[2163] Following the procedure as described in Example 3 step 2,
and making variation as required to (R)-tert-butyl
3-(4-tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)piperidine-
1-carboxylate with tert-butyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)-3-methylazet-
idine-1-carboxylate, the title compound was obtained as a brownish
gum (10.80 g, 86%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.40
(d, J=8.3 Hz, 1H), 6.50 (d, J=12.4 Hz, 1H), 3.95 (d, J=8.4 Hz, 2H),
3.90 (s, 2H), 3.64 (d, J =8.4 Hz, 2H), 1.98-1.87 (m, 1H), 1.55 (s,
9H), 1.41 (s, 9H), 1.40 (s, 3H), 0.91-0.82 (m, 2H), 0.62-0.56 (m,
2H).
Step 3. Preparation of methyl
5-cyclopropyl-2-fluoro-4-((3-methylazetidin-3-yl)methoxy)benzoate
hydrochloride
##STR01250##
[2165] Thionyl chloride (9.0 mL) was added slowly methanol (200 mL)
at 0.degree. C. and the mixture was stirred for 1 hour at 0.degree.
C. A solution of tert-butyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluoromethoxy)
methyl)-3-methylazetidine-1-carboxylate (10.80 g, 24.80 mmol) in
methanol (20 mL) was then added and the reaction mixture was heated
under reflux for 6 hours. After cooling to ambient temperature, the
reaction mixture was stirred for 16 hours and then concentrated in
vacuo. The residue was co-evaporated with toluene (3.times.10 mL)
and triturated in hexanes (20 mL) to provide the title compound as
a brownish gum (8.20 g, quant. yield): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.9.98 (br s, 1H), 9.79 (br s, 1H), 7.47 (d, J=8.2
Hz, 1H), 6.57 (d, J=12.2 Hz, 1H), 4.26-4.15 (m, 2H), 4.01 (s, 2H),
3.86 (s, 3H), 3.86-3.79 (m, 2H), 2.11-2.01 (m, 1H), 1.55 (s, 3H),
1.01-0.93 (m, 2H), 0.62-0.56 (m, 2H); MS(ES+) m/z 294.2 (M+1).
Step 4. Preparation of methyl 4-((1-(3-chloro-5-(trifluoromethyl)
pyridin-2-yl)-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoa-
te
##STR01251##
[2167] To a mixture of methyl
5-cyclopropyl-2-fluoro-4-((3-methylazetidin-3-yl)methoxy)benzoate
hydrochloride (0.60 g, 1.82 mmol) in toluene (10 mL) was added
2-bromo-3-chloro-5-(trifluoromethyl) pyridine (0.71 g, 2.73 mmol),
cesium carbonate (1.78 g, 5.46 mmol),
bis(dibenzylideneacetone)palladium(0) (0.21 g, 0.30 mmol) and
2,2'-bis(diphenyl-phosphino)-1,1'-binaphthalene (0.22 g, 0.36
mmol). The reaction mixture was degassed by passing a stream of
argon through it and then heated at 110.degree. C. in a sealed vial
for 16 hours. After cooling to ambient temperature, the reaction
mixture was filtered over diatomaceous earth. The filter cake was
washed with ethyl acetate (50 mL) and the combined filtrate was
concentrated in vacuo. Purification of the residue by purification
by flash chromatography (0 to 25% ethyl acetate in hexanes)
provided the title compound as an orange gum (0.60 g, 70%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta.8.24-8.22 (m, 1H), 7.56 (d, J=2.0
Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 6.56 (d, J=12.5 Hz, 1H), 4.39 (d,
J=9.0 Hz, 2H), 4.08 (d, J=9.0 Hz, 2H), 4.00 (s, 2H), 3.86 (s, 3H),
1.88-1.74 (m, 1H), 1.48 (s, 3H), 0.75-0.68 (m, 2H), 0.59-0.53 (m,
2H).
Step 5. Preparation of 4-((1-(3-chloro-5-(trifluoromethyl)
pyridin-2-yl)-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoi-
c acid
##STR01252##
[2169] To a mixture of methyl
4-((1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate (0.60 g, 1.27 mmol) in
tetrahydrofuran (5 mL) was added a solution of lithium hydroxide
monohydrate (0.29 g, 6.95 mmol) in water (5 mL) and the reaction
mixture was heated at 80.degree. C. for 3 hours. After cooling to
ambient temperature, the reaction mixture was partitioned between
dichloromethane (50 mL) and 1 M aqueous hydrochloric acid solution
(10 mL). The organic phase was dried over anhydrous sodium sulfate,
filtered, and the filtrate concentrated in vacuo to provide the
title compound as an off-white solid (0.58 g, 99%): MS(ES+) m/z
459.0, 461.0 (M+1).
Step 6. Preparation of
4-((1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR01253##
[2171] Following the procedure as described in Example 470 Step 6,
and making variation as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with 4-((1-(3-chloro-5-(trifluoromethyl)
pyridin-2-yl)-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoi-
c acid and purification by flash chromatography (0 to 50% ethyl
acetate containing 0.1% trifluoroacetic acid in hexanes), the title
compound was obtained as an off-white solid (0.19 g, 54%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta.11.85 (br s, 1H), 8.40-8.38 (m,
1H), 7.99 (d, J=1.9 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 7.01 (d,
J=12.9 Hz, 1H), 4.35 (d, J=9.0 Hz, 2H), 4.12 (s, 2H), 4.06 (d,
J=9.0 Hz, 2H), 3.12-3.02 (m, 1H), 1.80-1.69 (m, 1H), 1.43 (s, 3H),
1.15-1.07 (m, 4H), 0.64-0.58 (m, 4H); MS(ES-) m/z 560.1, 562.1
(M-1).
Example 482
Synthesis of
4-((1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-N-(ethylsulfonyl)-2-fluorobenzamide
##STR01254##
[2173] Following the procedure as described in Example 470 step 6,
and making variation as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with 4-((1-(3-chloro-5-(trifluoromethyl)
pyridin-2-yl)-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoi-
c acid and cyclopropanesulfonamide with ethanesulfonamide and
purification by flash chromatography (0 to 50% ethyl acetate
containing 0.1% trifluoracetic acid in hexanes), the title compound
was obtained as an off-white solid (0.19 g, 56%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta.11.83 (br s, 1H), 8.40-8.38 (m, 1H), 7.99
(d, J=2.1 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 7.00 (d, J=12.8 Hz, 1H),
4.35 (d, J=9.0 Hz, 2H), 4.12 (s, 2H), 4.06 (d, J=9.0 Hz, 2H), 3.46
(d, J=7.3 Hz, 2H), 1.81-1.68 (m, 1H), 1.43 (s, 3H), 1.24 (t, J=7.3
Hz, 3H), 0.64-0.58 (m, 4H); MS(ES-) m/z 548.1, 550.1 (M-1).
Example 483
Synthesis of
4-((1-(5-chloro-3-fluoropyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR01255##
[2174] Step 1. Preparation of methyl
4-((1-(5-chloro-3-fluoropyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR01256##
[2176] Following the procedure as described in Example 481 step 4,
and making variation as required to replace
2-bromo-3-chloro-5-(trifluoromethyl)pyridine with
2-bromo-5-chloro-3-fluoropyridine, the title compound was obtained
as an orange gum (0.43 g, 56%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.7.87-7.85 (m, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.16 (d, J=11.2
Hz, 1H), 6.56 (d, J=12.5 Hz, 1H), 4.18 (d, J =8.3 Hz, 2H), 4.01 (s,
2H), 3.89 (d, J=7.9 Hz, 2H), 3.86 (s, 3H), 1.87-1.75 (m, 1H), 1.48
(s, 1H), 0.77-0.68 (m, 2H), 0.60-0.53 (m, 2H).
Step 2. Preparation of
4-((1-(5-chloro-3-fluoropyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR01257##
[2178] Following the procedure as described in Example Example 481
step 5, and making variation as required to replace methyl
4-((1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate with methyl
4-((1-(5-chloro-3-fluoropyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained as an off-white solid (0.41 g, 98%): MS(ES-) m/z 409.0,
411.0 (M-1).
Step 3. Preparation of
4-((1-(5-chloro-3-fluoropyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR01258##
[2180] Following the procedure as described in Example 470 step 6,
and making variation as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with
4-((1-(5-chloro-3-fluoropyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid and purification by
flash chromatography (0 to 50% ethyl acetate containing 0.1%
trifluoroacetic acid in hexanes), the title compound was obtained
as an off-white solid (0.13 g, 51%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta.11.85 (s, 1H), 7.97 (dd, J=2.0, 0.6 Hz, 1H),
7.74 (dd, J=11.8, 2.1 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 7.00 (d,
J=12.9 Hz, 1H), 4.16-4.10 (m, 4H), 3.85 (dd, J=8.3, 1.2 Hz, 2H),
3.12-3.02 (m, 1H), 1.80-1.69 (m, 1H), 1.43 (s, 3H), 1.16-1.07 (m,
4H), 0.68-0.58 (m, 4H); MS(ES-) m/z 510.1, 512.1 (M-1).
Example 484
Synthesis of
4-((1-(5-chloro-3-fluoropyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-N-(ethylsulfonyl)-2-fluorobenzamide
##STR01259##
[2182] Following the procedure as described in Example 470 step 6,
and making variation as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with
4-((1-(5-chloro-3-fluoropyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid and
cyclopropanesulfonamide with ethanesulfonamide, the title compound
was obtained as an off-white solid (0.08 g, 30%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta.11.83 (br s, 1H), 7.97 (d, J=1.9 Hz, 1H),
7.74 (dd, J=11.8, 2.0 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 7.00 (d,
J=12.9 Hz, 1H), 4.17-4.09 (m, 4H), 3.85 (dd, J=8.3, 1.2 Hz, 2H),
3.46 (q, J=7.4, 7.3, 7.3 Hz, 2H), 1.81-1.70 (m, 1H), 1.43 (s, 3H),
1.24 (t, J=7.3 Hz, 3H), 0.68-0.58 (m, 4H); MS(ES-) m/z 498.1, 500.1
(M-1).
Example 485
Synthesis of
4-((1-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR01260##
[2183] Step 1. Preparation of methyl
4-((1-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR01261##
[2185] Following the procedure as described in Example 481 step 4,
and making variation as required to replace
2-bromo-3-chloro-5-(trifluoromethyl)pyridine with
3,6-dichloro-2-(trifluoromethyl)pyridine, the title compound was
obtained as an orange gum (0.66 g, 51%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.7.48 (d, J=8.8 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H),
6.55 (d, J=12.4 Hz, 1H), 6.36 (d, J=8.8 Hz, 1H), 4.10 (d, J=8.2 Hz,
2H), 3.99 (s, 2H), 3.86 (s, 3H), 3.81 (d, J=8.2 Hz, 2H), 1.82-1.70
(m, 1H), 1.50 (s, 3H), 0.74-0.65 (m, 2H), 0.58-0.52 (m, 2H).
Step 2. Preparation of
4-((1-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR01262##
[2187] Following the procedure as described in Example 481 Step 5,
and making variation as required to replace methyl
4-((1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate with methyl
4-((1-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained as an off-white solid (0.63 g, 99%): MS(ES+) m/z 459.0,
461.0 (M+1).
Step 3. Preparation of
4-((1-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR01263##
[2189] Following the procedure as described in Example 470 step 6,
and making variation as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with -((1-(5-chloro-6-(trifluoromethyl)
pyridin-2-yl)-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoi-
c acid and purification by flash chromatography (0 to 50% ethyl
acetate containing 0.1% trifluoroacetic acid in hexanes), the title
compound was obtained as a colorless solid (0.11 g, 28%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta.11.85 (br s, 1H), 7.81 (d, J=8.9
Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.99 (d, J=12.9 Hz, 1H), 6.78-6.68
(m, 1H), 4.10 (s, 2H), 4.05 (d, J=8.5 Hz, 2H), 3.81 (d, J=8.5 Hz,
2H), 3.13-3.00 (m, 1H), 1.72-1.61 (m, 1H), 1.44 (s, 3H), 1.15-1.06
(m, 4H), 0.62-0.55 (m, 4H); MS(ES-) m/z 560.1, 562.1 (M-1).
Example 486 and Example 487
Synthesis of
4-((1-(4-chloro-5-(trifluoromethyl)pyridin-3-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01264##
[2190] And
4-((2-(2-chloro-5-(trifluoromethyl)pyridin-4-yl)-3-methylazetid-
in-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01265##
[2191] Step 1. Prepapation of methyl
4-((1-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate and methyl
4-((1-(2-chloro-5-(trifluoromethyl)pyridin-4-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR01266##
[2193] Following the procedure as described in Example 481 Step 4,
and making variation as required to replace
2-bromo-3-chloro-5-(trifluoromethyl)pyridine with
2,4-dichloro-5-(trifluoromethyl)pyridine, a 2.5:1 mixture of the
title compounds was obtained as an orange gum (0.40 g, 31%). Major
isomer: .sup.19F NMR (282 MHz, CDCl.sub.3) .delta. -55.5 (s, 3F),
-108.8 (s, 1F). Minor isomer: .sup.19F NMR (2.82 MHz, CDCl.sub.3)
.delta. -60.5 (s, 3F), -108.9 (s, 1F).
Step 2. Prepartion of
4-((1-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid and
4-((1-(2-chloro-5-(trifluoromethyl)pyridin-4-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR01267##
[2195] Following the procedure as described in Example 481 Step 5,
and making variation as required to replace methyl
4-((1-(3-chloro-5-(trifluoromethlyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate with a mixture of methyl
4-((1-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate and methyl
4-((1-(2-chloro-5-trifluoromethyl)
pyridin-4-yl)-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoa-
te, a mixture of the title compounds was obtained as a yellowish
solid (0.33 g, 76%): MS(ES+) m/z 459.1, 461.1 (M+1).
Step 3. Preparation of
4-((1-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-N-cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01268##
[2196] And
4-((1-(2-chloro-5-(trifluoromethyl)pyridin-4-yl)-3-methylazetid-
in-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01269##
[2198] Following the procedure as described in Example 470 step 6,
and making variation as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with a mixture of 4-((1-(4-chloro-5-(trifluoromethyl)
pyridin-2-yl)-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoi-
c acid and
4-((1-(2-chloro-5-(trifluoromethyl)pyridin-4-yl)-3-methylazetid-
in-3-yl) methoxy)-5-cyclopropyl-2-fluorobenzoic acid, the compounds
were obtained after reverse phase HPLC purification: the first
fraction is
4-((1-(2-Chloro-5-(trifluoromethyl)pyridin-4-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt (0.07 g, 18%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.86 (br s, 1H), 8.27 (s, 1H), 7.14 (d,
J=8.3 Hz, 1H), 7.02 (d, J=12.9 Hz, 1H), 6.58 (s, 1H), 4.19 (d,
J=8.9 Hz, 2H), 4.14 (s, 2H), 3.96 (d, J=8.9 Hz, 2H), 3.13-3.02 (m,
1H), 1.88-1.76 (m, 1H), 1.42 (s, 3H), 1.16-1.07 (m, 4H), 0.66-0.58
(m, 4H); MS(ES+) m/z 562.1, 564.1 (M+1). The second fraction is
4-((1-(4-Chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt (0.19 g, 46%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.85 (s, 1H), 8.39 (s, 1H), 7.11 (d, J=8.3
Hz, 1H), 7.01 (d, J=12.9 Hz, 1H), 6.75 (s, 1H), 4.14-4.07 (m, 4H),
3.86 (d, J=8.9 Hz, 2H), 3.12-3.02 (m, 1H), 1.76-1.64 (m, 1H), 1.44
(s, 3H), 1.14-1.07 (m, 4H), 0.64-0.58 (m, 4H); MS(ES+) m/z 562.1,
564.1 (M+1).
Example 488
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((3-methyl-1-(5-(trifluo-
romethyl)pyridin-2-yl) azetidin-3-yl)methoxy)benzamide,
trifluoroacetic acid salt
##STR01270##
[2200] To a mixture of
4-((1-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluorcacetic acid salt (0.10 g, 0.18 mmol) in ethyl acetate (5
mL) and acetic acid (1mL) was added palladium on carbon (10 wt %,
wet, 50 mg) and the reaction mixture was stirred under an
atmosphere of hydrogen the 16 hours. The reaction mixture was
filtered over diatomaceous earth, the filter cake washed with ethyl
acetate (20 mL), and the combined filtrate concentrated in vacuo.
Purification of the residue by reverse phase HPLC provided the
title compound as a colorless solid (0.02 g, 16%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 8.67 (d, J=16.3 Hz, 1H), 8.43(s, 1H),
7.80 (d, J=8.2 Hz, 1H), 7.61 (d, J=9.1 Hz, 1H), 6.61 (d, J=13.3 Hz,
1H), 6.51 (d, J=8.8 Hz, 1H), 4.41 (d, J=8.7 Hz, 2H), 4.12 (d, J=8.8
Hz, 2H), 4.07 (s, 2H), 3.14-3.02 (m, 1H), 1.86-1.73 (m, 1H), 1.57
(s, 3H), 1.48-1.40 (m, 2H), 1.19-1.09 (m, 2H), 0.78-0.70 (m, 2H),
0.63-0.55 (m, 2H); MS(ES+) m/z 528.0 (M+1).
Example 489
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((3-methyl-1-(3-(trifluo-
romethyl) pyridin-4-yl)azetidin-3-yl)methoxy)benzamide,
trifluoroacetic acid salt (
##STR01271##
[2202] Following the procedure as described in Example 488, and
making variation as required to replace
4-((1-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt with 4-((1-(2-chloro-5-trifluoromethyl)
pyridin-4-yl)-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-N-(cyclopropyl-
sulfonyl)-2-fluorobenzamide, trifluoroacetic acid salt, the title
compound was obtained as a colorless solid (0.01 g, 33%): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 8.79-8.55 (m, 2H), 8.36 (br s,
1H), 7.63 (d, J=8.9 Hz, 1H), 6.62. (d, J=13.7 Hz, 1H), 6.53 (br s,
1H), 4.53 (br s, 2H), 4.19 (br s, 2H), 4.07 (s, 2H), 3.13-3.00 (m,
1H), 1.84-1.72 (m, 1H), 1.59 (s, 3H), 1.48-1.38 (m, 2H), 1.17-1.08
(m, 2H), 0.77-0.68 (m, 2H), 0.62-0.54 (m, 2H); MS(ES+) m/z 528.1
(M+1).
Example 490
Synthesis of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(5-(trifluoromethyl)p-
yridin-2-yl) piperidin-3-yl)oxy)benzamide, trifluoroacetic acid
salt
##STR01272##
[2203] Step 1. Preparation of (R) methyl
5-cyclopropyl-2-fluoro-4-((1-(5-(trifluoromethyl)
pyridin-2-yl)piperidin-3-yl)oxy)benzoate
##STR01273##
[2205] Following the procedure as described in Example 481 Step 4
and making variation as required to replace methyl
5-cyclopropyl-2-fluoro-4-((3-methylazetidin-3-yl)methoxy)benzoate
hydrochloride with (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate and
2-bromo-3-chloro-5-(trifluoromethyl)pyridine with
2-chloro-5-(trifluoromethyl)pyridine, the title compound was
obtained as a yellowish oil (0.58 g, 55%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.8.35-8.33 (m, 1H), 7.56 (dd, J=9.1, 2.5 Hz, 1H),
7.36 (d, J=8.3 Hz, 1H), 6.74 (d, J=12.9 Hz, 1H), 6.61 (d, J=9.0 Hz,
1H), 4.47-4.38 (m, 1H), 4.17 (dd, J=13.5, 2.7 Hz, 1H), 3.86 (s,
3H), 3.80-3.64 (m, 3H), 2.18-2.05 (m, 1H), 2.04-1.87 (m, 2H),
1.78-1.57 (m, 2H), 0.74-0.67 (m, 2H), 0.55-0.46 (m, 2H); MS(ES+)
m/z 439.2 (M+1).
Step 2. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-((1-(5-(trifluoromethl)
pyridin-2-yl)piperidin-3-yl)oxy)benzoic acid
##STR01274##
[2207] Following the procedure as described in Example 481 Step 5
and making variation as required to replace methyl
4-((1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate with (R)-methyl
5-cyclopropyl-2-fluoro-4-((1-(5-(trifluoromethyl)
pyridin-2-yl)piperidin-3-yl)oxy)benzoate, the title compound was
obtained as an orange gum (0.55 g, quant. yield): MS(ES+) m/z 425.1
(M+1).
Step 3. Preparation of
(R)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(5-(trifluoromethyl)
pyridin-2-yl)piperidin-3-yl)oxy)benzanmde, trifluoroacetic acid
salt
##STR01275##
[2209] Following the procedure as described in Example 470 Step 6,
and making variation as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with
(R)-5-cyclopropyl-2-fluoro-4-((1-(5-(trifluoromethyl)
pyridin-2-yl)piperidin-3-yl)oxy)benzoic acid and
cyclopropanesulfonamide with methanesulfonamide, the title compound
was obtained as a colorless solid (0.16 g, 39%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta.10.59 (br s, 1H), 8.86-8.71 (m, 1H),
8.37-8.34 (m, 1H), 7.73 (dd, J=9.3, 2.3 Hz, 1H), 7.47 (d, J=9.0 Hz,
1H), 6.83 (d, J=9.3 Hz, 1H), 6.76-6.69 (m, 1H), 4.65-4.56 (m, 1H),
4.10 (dd, J=14.0, 5.3 Hz, 1H), 4.02 (dd, J=14.0, 2.7 Hz, 1H), 3.90
(ddd, J=13.5, 5.9, 3.2 Hz, 1H), 3.63 (ddd, J=13.7, 8.6, 3.4 Hz,
1H), 3.39 (s, 3H), 2.15-1.94 (m, 3H), 1.81-1.60 (m, 2H), 0.78-0.61
(m, 2H), 0.58-0.41 (m, 2H); MS(ES-) m/z 500.2 (M-1).
Example 491
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(5-(trifluoromet-
hyl)pyridin-2-yl) piperidin-3-yl)oxy)benzamide, trifluoroacetic
acid salt
##STR01276##
[2211] Following the proocedure as described in Example 470 step 6,
and making variation as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with
(R)-5-cyclopropyl-2-fluoro-4-((1-(5-(trifluoromethyl)
pyridin-2-yl)piperidin-3-yl)oxy)benzoic acid, the title compound
was obtained as a colorless solid (0.16 g, 39%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta.9.89 (br s, 1H), 8.75 (d, J=15.1 Hz, 1H),
7.72 (dd, J=9.3, 2.3 Hz, 1H), 7.48 (d, J=9.0 Hz, 1H), 6.82 (d,
J=9.3 Hz, 1H), 6.73 (d, J=14.2 Hz, 1H), 4.64-4.53 (m, 1H),
4.12-3.99 (m, 2H), 3.89 (ddd, J=13.4, 6.3, 3.3 Hz, 1H), 3.63 (ddd,
J=13.7, 8.2, 3.3 Hz, 1H), 3.07 (tt, J=8.1, 8.1, 4.8, 4.8 Hz, 1H),
2.15-1.92 (m, 3H), 1.80-1.60 (m, 3H), 1.47-1.38 (m, 2H), 1.18-1.08
(m, 2H), 0.79-0.61 (m, 2H), 0.58-0.43 (m, 2H); MS(ES-) m/z 526.2
(M-1).
Example 492
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(pyridin-2-yl)pi-
peridin-3-yl)oxy)benzamide
##STR01277##
[2212] Step 1. Preparation of (R)-tert-butyl
5-cyclopropyl-2-fluoro-4-((1-(pyridin-2-yl)piperidin-3-yl)oxy)benzoate
##STR01278##
[2214] Following the procedure as described in Example 481 Step 4
and making variations as required to replace methyl
5-cyclopropyl-2-fluoro-4-((3-methylazetidin-3-yl)methoxy)benzoate
hydrochloride with (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate, and to
replace 2-bromo-3-chloro-5-(trifluoromethyl)pyridine with
2-bromopyridine, and to replace cesium carbonate with potassium
tert-butoxide, the title compound was obtained as a yellowish oil
(0.27 g, 32%): MS(ES+) m/z 413.3 (M+1).
Step 2. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-((1-(pyridin-2-yl)piperidin-3-yl)oxy)benzoic
acid
##STR01279##
[2216] Following the procedure as described in Example 478 step 4,
and making variation as required to replace tert-butyl
4-((4-((2-chloro-4-fluorobenzyl)oxy)piperidin-1-yl)methyl-5-cyclopropyl-2-
-fluorobenzoate with (R)-tert-butyl
5-cyclopropyl-2-fluoro-4-((1-(pyridin-2-yl)piperidin-3-yl)oxy)benzoate,
the title compound was obtained as a yellowish oil (0.23 g, quant.
yield): MS(ES+) m/z 357.2 (M+1).
Step 3. Preparation of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(pyridin-2-yl)
piperidin-3-yl)oxy)benzamide
##STR01280##
[2218] Following the procedure as described in Example 470 Step 6,
and making variation as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with (R)-5-cyclopropyl-2-fluoro-4-((1-(pyridin-2-yl)
piperidin-3-yl)oxy)benzoic acid and purification by flash
chromatography (0-100% ethyl acetate in hexanes), the title
compound was obtained as a colorless solid (0.03 g, 20%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.71 (s, 1H), 8.15 (ddd, J=5.0,
1.9, 0.6 Hz, 1H), 7.52 (d, J=9.1 Hz, 1H), 7.44 (ddd, J=8.9, 7.1 Hz,
1H), 6.95 (d, J=15.0 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H), 6.59 (dd,
J=7.1, 5.0 Hz, 1H), 4.46-4.32 (m, 2H), 3.81-3.71 (m, 1H), 3.45-3.32
(m, 2H), 3.13-3.01 (m, 1H), 2.23-2.11 (m, 1H), 1.97-1.81 (m, 3H),
1.70-1.60 (m, 1H), 1.47-1.39 (m, 2H), 1.16-1.08 (m, 2H), 0.85-0.76
(m, 2H), 0.60-0.53 (m, 2H); MS(ES-) m/z 458.3 (M-1).
Example 493
Synthesis of
(R)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluoro-4-((1-(pyridin-2-yl)-
piperidin-3-yl)oxy)benzamide
##STR01281##
[2220] Following the procedore as described in Example 470 Step 6,
and making variations as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with (R)-5-cyclopropyl-2-fluoro-4-((1-(pyridin-2-yl)
piperidin-3-yl)oxy)benzoic acid, and to replace
cyclopropanesulfonamide with azetidine-1-sulfonamide and
purification by flash chromatography (0-100% ethyl acetate in
hexanes), the title compound was obtained as colorless solid (0.04
g, 28%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.8.67 (d, J=14.1
Hz, 1H), 8.15 (dd, J=4.9, 1.8 Hz, 1H), 7.53 (d, J=9.1 Hz, 1H), 7.44
(ddd, J=8.8, 7.2, 1.9 Hz, 1H), 6.96 (d, J=14.7 Hz, 1H), 6.65 (d,
J=8.6 Hz, 1H), 6.59 (dd, J=7.1, 5.0 Hz, 1H), 4.46-4.33 (m, 2H),
4.23 (t, J=8.1, 8.1 Hz, 4H), 3.81-3.71 (m, 1H), 3.45-3.33 (m, 2H),
2.31-2.12 (m, 3H), 1.97-1.82 (m, 3H), 1.72-1.60 (m, 1H), 0.85-0.77
(m, 2H), 0.62-0.55 (m, 2H); MS(ES-) m/z 473.3 (M-1).
Example 494
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((1-(5-fluoropyridin-
-2-yl) piperidin-3-yl)oxy)benzamide, trifluoroacetic acid salt
##STR01282##
[2221] Step 1. Preparation of (R)-tert-butyl
5-cyclopropyl-2-fluoro-4-((1-(5-fluoropyridin-2-yl)
piperidin-3-yl)oxy)benzoate
##STR01283##
[2223] Following the procedure as described in Example 481 step 4
and making variation as required to replace methyl
5-cyclopropyl-2-fluoro-4-((3-methylazetidin-3-yl)methoxy)benzoate
hydrochloride with (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate,
2-bromo-3-chloro-5-(trifluoromethyl) pyridine with
2-chloro-5-fluoropyridine, and cesium carbonate with potassium
tert-butoxide, the title compound was obtained as a yellowish oil
(0.22 g, 26%): MS(ES+) m/z 431.1 (M+1).
Step 2. Preparation of
(R)-5-cyclopropyl-2-fluoro-4-((1-(5-fluoropyridin-2-yl)piperidin-3-yl)oxy-
)benzoic acid
##STR01284##
[2225] Following the procedure as described in Example 478 step 4,
and making variation as required to replace tert-butyl
4-((4-((2-chloro-4-fluorobenzyl)oxy)piperidin-1-yl)methyl)-5-cyclopropyl--
2-fluorobenzoate with (R)-tert-butyl
5-cyclopropyl-2-fluoro-4-((1-(5-fluoropyridin-2-yl)piperidin-3-yl)
oxy)benzoate, the title compound was obtained as an orange oil
(0.04 g, quant. yield): MS(ES+) m/z 374.9 (M+1).
Step 3. Preparation of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-((1-(5-fluoropyridin-2-
-yl) piperidin-3-yl)oxy)benzamide, trifluoroacetic acid salt
##STR01285##
[2227] Following the procedure as described in Example 470 step 6,
and making variation as required to replace
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride with
(R)-5-cyclopropyl-2-fluoro-4-((1-(5-fluoropyridin-2-yl)
ppieridin-3-yl)oxy)benzoic acid and purification by flash
chromatoaraphy (50% ethyl acetate in hexanes, then 0-10% methanol
in dichloromethane) and treatment with trifluoroacetic acid, the
title compound was obtained as a colorless solid (0.12 g, 39%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.72 (d, J=15.5 Hz,
1H), 8.01 (d, J=2.8 Hz, 1H), 7.51 (d, J=9.1 Hz, 1H), 7.32-7.25 (m,
1H), 6.86 (d, J=14.5 Hz, 1H), 6.66 (dd, J=9.3, 3.2 Hz, 1H), 5.06
(br s, 1H), 4.51-4.42 (m, 1H), 4.19 (dd, J=13.2, 2.0 Hz, 1H),
3.72-3.61 (m, 1H), 3.54-3.39 (m, 2H), 3.15-3.02 (m, 1H), 2.21-2.08
(m, 1H), 2.00-1.78 (m, 3H), 1.75-1.60 (m, 1H), 1.47-1.37 (m, 2H),
1.20-1.08 (m, 2H), 0.84-0.76 (m, 2H), 0.61-0.52 (m, 2H); MS(ES+)
m/z 478.2 (M+1).
Example 495
Synthesis of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(2-(3,5-dichlorophenyl)pr-
opan-2-yl) piperidin-3-yl)oxy)-2-fluorobenzamide, trifluoroacetic
acid salt
##STR01286##
[2228] Step 1. Preparation of (R)-methyl
5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)propan-2-yl)
piperidin-3-yl)oxy)-2-fluorobenzoate
##STR01287##
[2230] To a mixture of (R)-methyl
5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate (1.00 g, 3.41
mmol) in anhydrous tetrahydrofuran (20 mL) was added
4-dimethylaminopyridine (0.08 g, 0.68 mmol), triethylamine (0.95
mL, 6.82 mmol) and 3,5-dichlorobenzoyl chloride (0.86 g, 4.11
mmol). After stirring at ambient temperature for 16 hours, the
reaction mixture was diluted with ethyl acetate (200 mL), washed
with aqueous hydrochloric acid solution (1 N, 10 mL), water (10
mL), brine (10 mL), and dried over anhydrous sodium sulfate.
Filtration and concentration of filtrate in vacuo gave a residue
which was purified by flash chromatography (0-100% ethyl acetate in
hexanes) to provide (R)-methyl
5-cyclopropyl-4-((1-(3,5-dichlorobenzoyl)piperidin-3-yl)oxy)-2-fluorobenz-
oate as yellowish oil (1.31 g, 82%).
[2231] To a mixture of (R)-methyl
5-cyclopropyl-4-((1-(3,5-dichlorobenzoyl)piperidin-3-yl)oxy)-2-fluorobenz-
oate (1.31 g, 2.81 mmol) and 2,6-di-tert-butyl-4-methylpyridine
(0.69 g, 3.37 mmol) in anhydrous dichloromethane (40 mL) was added
trifluoromethanesulfonic anhydride (0.57 ml, 3.37 mmol) at
-78.degree. C. The reaction mixture was stirred for 2 hours at
-78.degree. C. after which methyl lithium (1.6 M solution in
diethyl ether, 8.8 mL 14.10 mmol) was added to it. After stirring
for 1 hour at -78.degree. C., the reaction mixture was warmed to
-60.degree. C., and stirred for additional 2 hours. After addition
of saturated ammonium chloride solution (20 mL) and dichloromethane
(200 mL), the mixture was allowed to warm to ambient temperature.
The organic phase was washed with aqueous hydrochloric acid
solution (1 N, 10 mL), water (10 mL), brine (10 mL), and dried over
anhydrous sodium sulfate. Filtration and concentration of the
filtrate in vacuo gave a residue which was purified by flash
chromatography (0-30% ethyl acetate in hexanes) to provide the
title compound as a colorless oil (0.23 g, 17%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta.7.42-7.37 (m, 3H), 7.19 (t, J=1.9, 1.9 Hz,
1H), 6.42 (d, J=12.9 Hz, 1H), 4.37-4.28 (m, 1H), 3.85 (s, 3H),
2.93-2.85 (m, 1H), 2.67-2.58 (m, 1H), 2.39-2.21 (m, 2H), 2.09-1.97
(m, 2H), 1.86-1.74 (m, 1H), 1.64-1.48 (m, 2H), 1.29 (s, 3H), 1.27
(s, 3H), 0.94-0.82 (m, 2H), 0.66-0.59 (m, 2H); MS(ES+) m/z 480.2,
482.2 (M+1).
Step 2. Preparation of
(R)-5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)propan-2-yl)
piperidin-3-yl)oxy)-2-fluorobenzoic acid
##STR01288##
[2233] Following the procedure as described in Example 481 Step 5
and making variation as required to replace methyl
4-((1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate with (R)-methyl
5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)propan-2-yl)
piperidin-3-yl)oxy)-2-fluorobenzoate, the title compound was
obtained as a yellowish oil (0.23 g, quant. yield): MS(ES-) m/z
466.2, 468.2 (M-1).
Step 3. Preparation of
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(2-(3,5-dichlorophenyl)
propan-2-yl)piperidin-3-yl)oxy)-2-fluorobenzamide, trifluoroacetic
acid salt
##STR01289##
[2235] Following the procedure as described in Example 473 Step 5,
and making variation as required to replace
4-((4-((5-bromo-3-chloropyridin-2-yl)oxy)piperidin-1-yl)methyl)-5-cyclopr-
opyl-2-fluorobenzoic acid hydrochloride with
(R)-5-cyclopropyl-4-((1-(2-(3,5-dichlorophenyl)propan-2-yl)
piperidin-3-yl)oxy)-2-fluorobenzoic acid, the title compound was as
a colorless solid (0.19 g, 67%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.74 (d, J=13.3 Hz, 1H), 7.55 (d, J=1.7 Hz, 2H), 7.53 (d,
J=9.0 Hz, 1H), 7.45 (t, J=1.7 Hz, 1H), 6.92 (d, J=14.1 Hz, 1H),
5.15-5.04 (m, 1H), 3.75-3.65 (m, 1H), 3.43-3.35 (m, 1H), 3.11-3.01
(m, 1H), 2.67-2.50 (m, 2H), 2.39-1.89 (m, 4H), 1.89 (s, 3H), 1.86
(s, 3H), 1.60-1.48 (m, 1H), 1.47-1.38 (m, 2H), 1.16-1.08 (m, 2H),
0.93-0.84 (m, 2H), 0.65-0.58 (m, 2H); MS(ES-) m/z 567.2, 569.2
(M-1)
Example 496
Synthesis of
4-(((1R,3r,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.-
1]octan-8-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01290##
[2236] Step 1. Preparation of (1R,3r,5S)-tert-butyl
3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.1]octane-8-carb-
oxylate
##STR01291##
[2238] Following the procedure as described in Example 470 step 2,
and making variation as required to replace
3-chloro-2-fluoro-5-(trifluoromethyl)phenol with
3-chloro-5-(trifluoromethoxy)-phenol, the title compound was
obtained as a colorless oil (2.0 t, quant. yield): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta.6.82-6.79 (m, 1H), 6.75-6.72 (m, 1H),
6.57-6.53 (m, 1H), 4.60-4.54 (m, 1H), 4.23-4.17 (m, 2H), 2.19-1.87
(m, 8H), 1.46 (s, 9H); MS(ES+) m/z 366.0, 368.0 (M-55).
Step 2. Preparation of
(1R,3r,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.1]oc-
tane
##STR01292##
[2240] Following the procedure as described in Example 470 step 3,
and making variation as required to replace (1R,3r,5S)-tert-butyl
3-(3-chloro-2-fluoro-5-(trifluoromethoxy)
phenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate with
(1R,3r,5S)-tert-butyl 3-(3-chloro-5-(trifluoromethoxy-)
phhenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate, the title
compound was isolaled as a colorless oil (1.50 g, quant. yield):
MS(ES+) m/z 322.1, 324.1 (M+1).
Step 3. Preparation of tert-butyl
4-(((1R,3r,5S)-3-(3-chloro-5-(trifluoromethoxy)
phhenoxy)-8-azabicyclo[3.2.1]octane-8-yl)methyl)-5-cyclopropyl-2-fluorobe-
nzoate
##STR01293##
[2242] Following the procedure as described in Example 470 Step 4,
and making variation as required to replace
(1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicyclo[-
3.2.1]-octane with
(1R,3r,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.1]-o-
ctane, the title compound was isolated as a colorless oil (1.75 g,
65%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.48 (d, J=7.1 Hz,
1H), 7.36-7.28 (m, 1H), 6.81-6.77 (m, 1H), 6.74 (t, J=2.0 Hz, 1H),
6.58-6.53 (m, 1H), 4.58-4.46 (m, 1H), 3.74-3.58 (m, 2H), 3.23-3.05
(m, 2H), 2.23-1.83 (m, 9H), 1.57 (s, 9H), 0.95-0.83 (m, 2H),
0.65-0.57 (m, 2H); MS(ES+) m/z 570.1, 572.1 (M+1).
Step 4. Preparation of
4-(((1R,3r,5S)-3-(3-chloro-5-(trifluoromethoxy)
phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenz-
oic acid hydrochloride
##STR01294##
[2244] Following the procedure as described in Example 470 Step 5,
and making variation as required to replace tert-butyl
4-(((1R,3r,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)-phenoxy)-8-azabic-
yclo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoate with
tert-butyl
4-(((1R,3r,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.-
1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoate, the title
compound was isolated as a colorless solid (1.64 g, 96%): MS(ES+)
m/z 516.1, 518.1 (M+1).
Step 5. Preparation of
4-(((1R,3r,5S)-3-(3-chloro-5-(trifluoromethoxy)
phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-N-(cycloprop-
ylsulfonyl)-2-fluorobenzamide, trifluoroacetic acid salt
##STR01295##
[2246] Following the procedure as described in Example 473 step 5,
and making variation as required to replace
4-((4-((5-bromo-3-chloropyridin-2-yl)oxy)piperidin-1-yl)methyl)-5-cyclopr-
opyl-2-fluorobenzoic acid hydrochloride with (of
4-(((1R,3r,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.-
1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride, the title compound was as a colorless solid (0.45 g,
62%): .sup.1H NMR (300 MHz, CDCl.sub.3+10% CD.sub.3OD) .delta. 7.47
(d, J=7.3 Hz, 1H), 7.41 (d, J=11.2 Hz, 1H), 6.79 (br s, 1H),
6.74-6.71 (m, 1H), 6.53 (br s, 1H), 4.62-4.55 (m, 1H), 4.37 (s,
2H), 3.88 (br s, 2H), 3.04-2.93 (m, 1H), 2.75-2.62 (m, 2H),
2.49-2.38 (m, 2H), 2.33-2.22 (m, 2H), 2.12 (d, J=15.6 Hz, 2H),
1.85-1.74 (m, 1H), 1.37-1.28 (m, 2H), 1.11-0.94 (m, 4H), 0.71-0.62
(m, 2H); MS(ES+) m/z 617.1, 619.1 (M+1).
Example 497
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((4-(2-(trifluoromethyl)pheno-
xy)piperidin-1-yl)methyl)benzamide
##STR01296##
[2247] Step 1. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)m-
ethyl)benzoate
##STR01297##
[2249] Following the procedure as described to Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-(2-(trifluoromethyl)phenoxy)piperidine, hydrochloride salt,
the title compound was obtained as an oil (1.38 g, 66%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.55 (d, J=8.3 Hz, 1H), 7.50-7.39
(m, 2H), 7.20 (d, J =12.1 Hz, 1H), 6.99-6.90 (m, 2H), 4.58-4.47 (m,
1H), 3.64 (s, 2H), 2.74-2.62 (m, 2H), 2.50-2.35 (m, 2H), 2.03-1.83
(m, 5H), 1.56 (s, 9H), 0.96-0.86 (m, 2H), 0.64-0.56 (m, 2H);
MS(ES+) m/z 494.3 (M+1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-4-((4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)
methyl)benzoic acid, trifluoroacetic acid salt
##STR01298##
[2251] Following the procedure as described in Example 53 step 4,
and making variation as required to replace (S)-tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)
methyl)-2-fluorobenzoate with tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(2-(trifluoromethyl)
phenoxy)piperidin-1-yl)methyl)benzoate, tne title compound was
obtained as an colorless solid (1.54 g, quant. yield): MS(ES+) m/z
438.1 (M+1).
Step 3. Preparation of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((4-(2-(trifluoromethyl)
phenoxy)piperidin-1-yl)methyl)benzamide
##STR01299##
[2253] Following the procedure as described in Example 53 step 5,
and making variation as required to replace cyclopropanesulfonamide
with methylsulfonamide and to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)
piperidin-1-yl)methyl)-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((4-(2-(trifluoromethyl)
phenoxy)piperidin-1-yl)methyl)benzoic acid, trifluoroacetic acid
salt, and purification by flash chromatography (0-75% methanol+0.4%
ammonium hydroxide in dichloromethane), the title compound was
obtained as a colorless solid (0.20 g, 53%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.69 (d, J=7.6 Hz, 1H), 7.57 (d, J=7.7 Hz, 1H),
7.51-7.37 (m, 2H), 7.04-6.93 (m, 2H), 6.50 (br s, 1H), 4.77-4.68
(m, 1H), 4.09 (s, 2H), 3.29 (s, 3H), 3.04-2.89 (m, 4H), 2.36-2.22
(m, 2H), 2.12-2.00 (m, 2H), 1.94-1.82 (m, 1H), 1.05-0.97 (m, 2H),
0.70-0.63 (m, 2H); MS(ES+) m/z 515.2 (M+1H).
Example 498
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((4-(2-(trifluoromethyl)
phenoxy)piperidin-1-yl)methyl)benzamide
##STR01300##
[2255] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-2-fluoro-4-((4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)m-
ethyl)benzoic acid, trifluoroacetic acid salt the title compound
was obtained as a colorless solid (0.22 g, 56%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.70 (d, J=7.7 Hz, 1H), 7.56 (d, J=7.7 Hz,
1H), 7.50-7.37 (m, 2H), 7.02-6.92 (m, 2H), 6.57 (br s, 1H),
4.73-4.62 (m, 1H), 3.99 (s, 2H), 3.08-2.97 (m, 1H), 2.95-2.76 (m,
4H), 2.27-2.12 (m, 2H), 2.08-1.96 (m, 2H), 1.95-1.84 (m, 1H),
1.45-1.36 (m, 2H), 1.16-1.05 (m, 2H), 1.04-0.94 (m, 2H), 0.70-0.61
(m, 2H); MS(ES+) m/z 541.2 (M+1).
Example 499
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((4-(4-(trifluoromethyl)
phenoxy)piperidin-1-yl)methyl)benzamide
##STR01301##
[2256] Step 1. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(4-(trifluoromethyl)
phenoxy)piperidin-1-yl)methyl)benzoate
##STR01302##
[2258] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-(4-(trifluoromethyl)phenoxy)piperidine, hydrochloride salt,
the title compound was obtained as an oil (1.24 g, 60%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.54-7.45 (m, 3H), 7.18 (d,
J=11.8 Hz, 1H), 6.94 (d, J=9.1 Hz, 2H), 4.46-4.34 (m, 1H), 3.65 (s,
2H), 2.79-2.67 (m, 2H), 2.44-2.27 (m, 2H), 2.07-1.90 (m, 3H),
1.89-1.75 (m, 2H), 1.56 (s, 9H), 0.95-0.87 (m, 2H), 0.65-0.57 (m,
2H); MS(ES+) m/z 494.1 (M+1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)
methyl)benzoic acid, 2trifluoroacetic acid
##STR01303##
[2260] Following the procedure as described in Example 53 step 4,
and making variation as required to replace (S)-tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoate with tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)m-
ethyl)benzoate, the title compound was obtained a an colorless
solid (1.38 g, quant. yield): MS(ES+) m/z 438.2 (M+1).
Step 3. Preparation of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((4-(4-(trifluoromethyl)
phenoxy)piperidin-1-yl)methyl)benzamide
##STR01304##
[2262] Following the procedure as described in Example 53 step 5,
and making variation as required to replace cyclopropanesulfonamide
with methylsulfonamide and to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)
piperidin-1-yl)methyl)-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)m-
ethyl)benzoic acid, trifluoroacetic acid salt, the title compound
was obtained as a colorless solid (0.18 g, 48%): .sup.1H NMR (300
mHz, CDCl.sub.3) .delta. 7.69 (d, J=7.6 Hz, 1H), 7.52 (d, J=8.6 Hz,
2H), 7.39 (d, J=13.1 Hz, 1H), 6.94 (d, J=8.6 Hz, 2H), 6.22 (br s,
1H), 4.56-4.43 (m, 1H), 3.88 (s, 2H), 3.37 (s, 3H), 2.90-2.79 (m,
2H), 2.72-2.59 (m, 2H), 2.21-2.08 (m, 2H), 1.99-1.86 (m, 3H),
1.03-0.94 (m, 2H), 0.70-0.62 (m, 2H); MS(ES+) m/z 515.2 (M+1).
Example 500
Synthesis of
5-cyclopropyl-N-cyclopropylsulfonyl)-2-fluoro-4-((4-(4-(trifluoromethyl)
phenoxy)piperidin-1-yl)methyl)benzamide
##STR01305##
[2264] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-2-fluoro-4-((4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)m-
ethyl)benzoic acid, trifluoroacetic acid salt, the title compound
was obtained as a colorless solid (0.20 g, 51%): 7.69 (d, J =7.6
Hz, 1H), 7.53 (d, J=8.6 Hz, 2H), 7.46 (d, J=12.5 Hz, 1H), 6.95 (d,
J=8.6 Hz, 2H), 4.67-4.55 (m, 1H), 4.17 (s, 2H), 3.16-2.91 (m, 5H),
2.37-2.18 (m, 2H), 2.11-1.97 (m, 2H), 1.96-1.85 (m, 1H), 1.46-1.37
(m, 2H), 1.18-0.99 (m, 4H), 0.74-0.65 (m, 2H); MS(ES+) m/z 541.2
(M+1).
Example 501
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((4-(3-(trifluoromethyl)pheno-
xy) piperidin-1-yl)methyl)benzamide, trifluoroacetic acid salt
##STR01306##
[2265] Step 1. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(3-(trifluoromethyl)
phenoxy)piperidin-1-yl)methyl)benzoate
##STR01307##
[2267] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-(3-(trifluoromethyl) phenoxy)piperidine, the title compound
was obtained as an oil (0.69 g, 79%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.48 (d, J=7.3 Hz, 1H), 7.35 (dd, J=8.0, 8.0
Hz, 1H), 7.22-7.09 (m, 3H), 7.07-7.02 (m, 1H), 4.43-4.34 (m, 1H),
3.67 (s, 2H), 2.79-2.68 (m, 2H), 2.43-2.32 (m, 2H), 2.05-1.92 (m,
3H), 1.89-1.76 (m, 2H), 1.56 (s, 9H), 0.95-0.88 (m, 2H), 0.65-0.58
(m, 2H); MS(ES+) m/z 494.3 (M+1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-4-((4-(3-(trifluoromethyl)phenoxy)
piperidin-1-yl)methyl)benzoic acid, trifluoroacetic acid salt
##STR01308##
[2269] Following the procedure as described in Example 53 step 4,
and making variation as required to replace (S)-tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoate of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(3-(trifluoromethyl)phenoxy)
piperidin-1-yl)methyl)benzoate, the title compound was obtained as
an colorless solid (0.77 g, quant. yield): MS(ES+) m/z 438.2
(M+1).
Step 3. Preparation of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((4-(3-(trifluoromethyl)
phenoxy)piperidin-1-yl)methyl)benzamide, trifluoroacetic acid
salt
##STR01309##
[2271] Following the procedure as described in Example 53 step 5,
and making variations as required to replace
cyclopropanesulfonamide with methylsulfonamide and to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)
piperidin-1-yl)methyl)-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((4-(3-(trifluoromethyl)
phenoxy)piperidin-1-yl)methyl)benzoic acid trifluoroacetic acid
salt and purification by preparative HPLC, the title compound was
obtained as a colorless solid (0.06 g, 14%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 12.24 (br s, 1H), 9.49 (br s, 1H), 7.65-7.45
(m, 2H), 7.34-7.22 (m, 4H), 4.92-4.74 (m, 1H), 4.52 (br s, 2H),
3.78-3.49 (m, 2H), 3.33 (s, 3H), 3.27-3.15 (m, 2H), 2.25-1.95 (m,
5H), 1.03-0.95 (m, 2H), 0.81-0.73 (m, 2H); MS(ES+) m/z 515.0
(M+1).
Example 502
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((4-(3-(trifluoromethyl)
phenoxy)piperidin-1-yl)methyl)benzamide, trifluoroacetic acid
salt
##STR01310##
[2273] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-2-fluoro-4-((4-(3-(trifluoromethyl)phenoxy)piperidin-1-yl)m-
ethyl)benzoic acid trifluoroacetic acid salt and purification by
preparative HPLC, the title compound was obtabled as a colorless
solid (0.10 g, 22%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
12.78 (br s, 1H), 9.24 (br s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.63 (d,
J=11.9 Hz, 1H), 7.46-7.38 (m, 1H), 7.28-7.21 (m, 1H), 7.14-7.10 0
(m, 1H), 7.07-7.02 (m, 1H), 4.78-4.69 (m, 1H), 4.49 (s, 2H),
3.55-3.42 (m, 2H), 3.25-3.11 (m, 2H), 3.11-3.00 (m, 1H), 2.56-2.38
(m, 2H), 2.23-2.10 (m, 2H), 1.97-1.86 (m, 1H), 1.48-1.40 (m, 2H),
1.19-1.07 (m, 4H), 0.80-0.72 (m, 2H); MS(ES+) m/z 541.0 (M+1).
Example 503
Synthesis of
4-((4-(4-chlorophenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluoro-N-(m-
ethylsulfonyl) benzmide, trifluoroacetic acid salt
##STR01311##
[2274] Step 1. Preparation of tert-butyl
4-((4-(4-chlorophenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzo-
ate
##STR01312##
[2276] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-(4-chlorophenoxy)piperidine, the title compound was obtained
as an oil (0.85 g, 93%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.48 (d, J=7.4 Hz, 1H), 7.23-7.14 (m, 3H), 6.84-6.78 (m, 2H),
4.33-4.23 (m, 1H), 3.65 (s, 2H), 2.77-2.66 (m, 2H), 2.40-2.28 (m,
2H), 2.03-1.90 (m, 3H), 1.86-1.72 (m, 2H), 1.56 (s, 9H), 0.94-0.87
(m, 2H), 0.64-0.57 (m, 2H); MS(ES+) m/z 460.3, 462.2 (M+1).
Step 2. Preparation of
4-((4-(4-chlorophenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzo-
ic acid, trifluoroacetic acid salt
##STR01313##
[2278] Following the procedure as described in Example 53 step 4,
and making variation as required to replace (S)-tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoate with tert-butyl
4-((4-(4-chlroophenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzo-
ate, the title compound was obtained as an colorless solid (0.96 g,
quant. yield): MS(ES+) m/z 404.2, 406.2 (M+1).
Step 3. Preparation of
4-((4-(4-chlorophenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluoro-N-(m-
ethylsulfonyl) benzamide, trifluoroacetic acid salt
##STR01314##
[2280] Following the procedure as described in Example 53 step 5,
and making variations as required to replace
cyclopropanesulfonamide with methylsulfonamide and to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)
piperidin-1-yl)methyl)-2-fluorobenzoic acid with
4-((4-(4-chlorophenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoic acid, trifluoroacetic acid
salt, and purification by preparative HPLC, the title compound was
obtained as a colorless solid (0.06 g, 11%): .sup.1H NMR (300 MHz,
CDCl.sub.3+10% CD.sub.3OD) .delta. 7.35-7.28 (m, 2), 7.14-7.07 (m,
2H), 6.76-6.69 (m, 2H), 4.51-4.45 (m, 1H), 4.36 (s, 2H), 3.23 (s,
3H), 3.21-3.09 (m, 4H), 2.19-2.07 (m, 2H), 2.05-1.94 (m, 2H),
1.88-1.77 (m, 1H), 1.00-0.92 (m, 2H), 0.64-0.57 (m, 2H); MS(ES+)
m/z 481.1, 483.2 (M+1).
Example 504
Synthesis of 4-((4-(4-chlorophenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01315##
[2282] Following the procedure as described in Example 53 step 5,
and making variations as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((4-(4-chlorophenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzo-
ic acid, trifluoroacetic acid salt, and purification by preparative
HPLC, the title compound was obtained as a colorless solid (0.07 g,
12%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.19 (br s, 1H),
9.49 (br s, 1H), 7.49 (d, J=11.1 Hz, 1H), 7.32 (d, J=8.6 Hz, 2H),
7.23 (d, J=7.0 Hz, 1H), 7.01 (d, J=8.5 Hz, 2H), 4.77-4.35 (m, 3H),
3.71-3.16 (m, 4H), 3.09-2.99 (m, 1H), 2.28-1.93 (m, 4H), 1.86-1.67
(m, 1H), 1.15-1.06 (m, 4H), 1.02-0.94 (m, 2H), 0.79-0.72 (m, 2H);
MS(ES+) m/z 507.2, 509.1 (M+1).
Example 505
Synthesis of 4-((4-(2-chloro-4-fluorophenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01316##
[2283] Step 1. Preparation of tert-butyl
4-((4-(2-chloro-4-fluorophenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoate
##STR01317##
[2285] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-(2-chloro-4-fluorophenoxy)piperidine, the title compound was
obtained as an oil (1.42 g, 68%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.48 (d, J=7.3 Hz, 1H), 7.22-7.15 (m, 1H), 6.98-6.80 (m,
3H), 4.33-4.18 (m, 1H), 3.65 (s, 2H), 2.80-2.68 (m, 2H), 2.41-2.26
(m, 2H), 2.02-1.72 (m, 5H), 1.56 (s, 9H), 0.95-0.87 (m, 2H),
0.65-0.57 (m, 2H); MS(ES+) m/z 478.3, 480.2 (M+1).
Step 2. Preparation of
4-((4-(2-chloro-4-fluorophenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoic acid, trifluoroacetic acid
salt
##STR01318##
[2287] Following the procedure as described in Example 53 step 4,
and making variation as required tb replace (S)-tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoate with tert-butyl
4-((4-(2-chloro-4-fluorophenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fl-
uorobenzoate, the title compound was obtained as an colorless solid
(1.59 g, quant. yield): MS(ES+) m/z 4.22, 424.1 (M+1).
Step 3. Preparation of
4-((4-(2-chloro-4-fluorophenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyrl)benzamide,
trifluoroacetic acid salt
##STR01319##
[2289] Following the procedure as described in Example 53 step 5,
and making variations as required to replace
cyclopropanesulfonamide with methylsulfonamide and to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)
piperidin-1-yl)methyl)-2-fluorobenzoic acid with
-((4-(2-chloro-4-fluorophenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoic acid, trifluoroacetic acid
salt and purification by preparative HPLC, the title compound was
obtained as a colorless solid (0.10 g, 23%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 12.19 (br s, 1H), 9.81 (br s, 1H), 7.53-7.41
(m, 2H), 7.31-7.23 (m, 2H), 7.21-7.13 (m, 1H), 4.74-4.38 (m, 3H),
3.77-3.44 (m, 2H), 3.32 (s, 3H), 3.29-3.17 (m, 2H), 2.18-2.03 (m,
3H), 2.00-1.80 (m, 2H), 1.02-0.94 (m, 2H), 0.80-0.72 (m, 2H);
MS(ES+) m/z 499.2, 501.1 (M+1).
Example 506
Synthesis of 4-((4-(2-chloro-4-fluorophenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01320##
[2291] Following the procedure as described in Example 53 step 5,
and making variations as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((4-(2-chloro-4-fluorophenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fl-
uorobenzoic acid, trifluoroacetic acid salt, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.13 g, 29%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
12.28 (br s, 1H), 9.92 (br s, 1H), 7.56-7.49 (m, 1H), 7.44 (dd,
J=8.4, 3.1 Hz, 1H), 7.31-7.22 (m, 2H), 7.21-7.13 (m, 1H), 4.76-4.68
(m, 1H), 4.56 (s, 2H), 3.53-3.33 (m, 2H), 3.31-3.15 (m, 2H),
3.11-3.00 (m, 1H), 2.31-1.97 (m, 4H), 1.91-1.77 (m, 1H), 1.15-1.06
(m, 4H), 1.03-0.94 (m, 2H), 0.81-0.73 (m, 2H); MS(ES+) m/z 525.2,
527.2 (M+1).
Example 507
Synthesis of 4-((4-(2-chloro-4-fluorophenoxy)piperidin-1-yl)
methyl)-5-(cyclopropylsulfonyl)-2-fluorobenzamide, trifluoroacetic
acid salt
##STR01321##
[2292] Step 1. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(4-fluorophenoxy)
piperidin-1-yl)methyl)benzoate
##STR01322##
[2294] Following the prccedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-(4-fluorophenoxy)piperidine, the title compound was obtained
as an oil (1.92 g, quant. yield): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.47 (d, J=7.5 Hz, 1H), 7.17 (d, J=11.8 Hz, 1H), 6.97-6.88
(m, 2H), 6.86-6.79 (m, 2H), 4.27-4.17 (m, 1H), 3.63 (s, 2H),
2.77-2.67 (m, 2H), 2.36-2.25 (m, 2H), 2.00-1.89 (m, 3H),
1.1.84-1.71 (m2H), 1.55 (s, 9H), 0.94-0.86 (m, 2H), 0.63-0.57 (m,
2H); MS(ES+) m/z 444.2 (M+1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-4-((4-(4-fluorophenoxy)piperidin-1-yl)
methyl)benzoic acid, trifluoroacetic acid salt
##STR01323##
[2296] Following the procedure as described in Example 53 step 4,
and making variatin as required to replace (S)-tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoate with tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(4-fluorophenoxy)piperidin-1-yl)
methyl)benzoate, the title compound was obtained as an colorless
solid (2.43 g, quant. yield): MS(ES+) m/z 388.2 (M+1).
Step 3. Preparation of
4-((4-(2-chloro-4-fluorophenoxy)piperidin-1-yl)
methyl-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01324##
[2298] Following the procedure as described in Example 53 step 5,
and making variations as required to replace
cyclopropanesulfonamide with methylsulfonamide and to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)
piperidin-1-yl)methyl)-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((4-(4-fluorophenoxy)
piperidin-1-yl)methyl)benzoic acid, trifluoroacetic acid salt, and
purification by preparative HPLC the title compound was obtained as
a colorless solid (0.05 g, 12%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 12.28 (br s, 1H), 9.68 (br s, 1H), 7.51 (d,
J=11.2 Hz, 1H), 7.25 (d, J=6.9 Hz, 1H), 7.16-7.06 (m, 2H),
7.05-6.94 (m, 2H), 4.71-4.41 (m, 3H), 4.21-3.72 (m, 4H), 3.33 (s,
3H), 2.26-2.09 (m, 2H), 2.07-1.93 (m, 2H), 1.86-1.70 (m, 1H),
1.04-0.95 (m, 2H), 0.81-0.73 (m, 2H); MS(ES+) m/z 465.2 (M+1).
Example 508
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((4-(4-fluorophenoxy)pip-
eridin-1-yl) methyl)benzamide, trifluoroacetic acid salt
##STR01325##
[2300] Following the procedure as described in Example 53 step 5,
and making variations as required replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-2-fluoro-4-((4-(4-fluorophenoxy)piperidin-1-yl)methyl)benzo-
ic acid, trifluoroacetic acid salt and purification by preparative
HPLC, the title compound was obtained as a colorless solid (0.06 g,
14%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.26 (br s, 1H),
9.86 (br s, 1H), 7.52 (d, J=11.1 Hz, 1H), 7.23 (d, J=7.2 Hz, 1H),
7.16-7.06 (m, 2H), 7.05-6.95 (m, 2H), 4.73-4.70 (m, 3H), 4.13-3.70
(m, 2H), 3.50-3.31 (m, 2H), 3.11-3.00 (m, 1H), 2.27-1.93 (m, 4H),
1.88-1.70 (m, 1H), 1.15-1.06 (m, 4H), 1.03-0.94 (m, 2H), 0.80-0.72
(m, 2H); MS(ES+) m/z 491.2 (M+1).
Example 509
Synthesis of
5-cyclopropyl-4-((4-(3,4-dichlorophenoxy)piperidin-1-yl)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01326##
[2301] Step 1. Preparation of tert-butyl
5-cyclopropyl-4-((4-(3,4-dichlorophenoxy)
piperidin-1-yl)methyl)-2-fluorobenzoate
##STR01327##
[2303] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-(3,4-dichlorophenoxy)piperidine, the title compound was
obtained as an oil (1.75 g, quant.): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.47 (d, J=7.2 Hz, 1H), 7.26 (d, J=8.9 Hz, 1H),
7.15 (d, J=11.8 Hz, 1 H), 6.97 (d, J=2.7 Hz, 1H), 6.72 (dd, J=8.9,
2.8 Hz, 1H), 4.32-4.21 (m, 1H), 3.63 (s, 2H), 2.74-2.64 (m, 2H),
2.38-2.27 (m, 2H), 2.00-1.88 (m, 3H), 1.84-1.71 (m, 2H), 1.55 (s,
9H), 0.94-0.85 (m, 2H), 0.64-0.56 (m, 2H); MS(ES+) m/z 494.1, 406.1
(M+1).
Step 2. Preparation of
5-cyclopropyl-4-((4-(3,4-dichlorophenoxy)piperidin-1-yl)
methyl-2-fluorobenzoic acid, trifluoroacetic acid salt
##STR01328##
[2305] Following the procedure as described in Example 53 step 4,
and making variation as required to replace (S)-tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoate with tert-butyl
5-cyclopropyl-4-((4-(3,4-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoate and purification by trituration with diethyl ether, the
title compound was obtained as an colorless solid (1.54 g, 69%):
MS(ES+) m/z 438.1, 440.1 (M+1).
Step 3. Preparation of
5-cyclopropyl-4-((4-(3,4-dichlorophenoxy)piperidin-1-yl)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01329##
[2307] Following the procedure as described in Example 53, step 5,
and making variation as required to replace cyclopropanesulfonamide
with methylsulfonamide and
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)
piperidin-1-yl)methyl)-2-fluorobenzoic acid with
5-cyclopropyl-4-((4-(3,4-dichlorophenoxy)
piperidin-1-yl)methyl)-2-fluorobenzoic acid, difluoroacetic acid
salt and purification by preparative HPLC, the title compound was
obtained as a colorless solid (0.40 g, 69%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 12.28 (br s, 1H), 10.00 (br s, 1H), 7.55-7.47
(m, 2H), 7.32 (d, J=2.4 Hz, 1H), 7.25 (d, J=7.1 Hz, 1H), 7.07-6.98
(m, 1H), 4.82-4.65 (m, 1H), 4.56 (s, 2H), 4.38-3.94 (m, 2H), 3.34
(s, 3H), 3.30-3.18 (m, 2H), 2.24-2.09 (m, 3H), 2.01-1.76 (m, 2H),
1.05-0.94 (m, 2H), 0.80-0.72 (m, 2H); MS(ES+) m/z 515.7, 517.1
(M+1).
Example 510
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4-(3,4-dichlorophenoxy)
piperidin-1-yl)methyl)-2-fluorobenzamide, trifluoroacetic acid
salt
##STR01330##
[2309] Following the procedure as described in Example 53 step 5,
and making variations as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-(3,4-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoic acid, trifluoroacetic acid salt and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.45 g, 69%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
12.28 (br s, 1H), 9.98 (br s, 1H), 7.57-7.47 (m, 2H), 7.36-7.28 (m,
1H), 7.23 (d, J=7.0 Hz, 1H), 7.08-6.94 (m, 1H), 4.85-4.69 (m, 1H),
4.57 (s, 2H), 3.59-3.16 (m, 4H), 3.10-2.98 (m, 1H), 2.26-2.09 (m,
2H), 2.09-1.94 (m, 2H), 1.89-1.71 (m, 1H), 1.15-1.06 (m, 4H),
1.03-0.94 (m, 2H), 0.81-0.72 (m, 2H); MS(ES+) m/z 541.1, 543.1
(M+1).
Example 511
Synthesis of
5-cyclopropyl-4-((4-((3,5-dichlorobenzyl)oxy)piperidin-1-yl)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01331##
[2310] Step 1. Preparation of tert-butyl 4-((3,5
dichlorobenzyl)oxy)piperidin-1-yl)carboxylate
##STR01332##
[2312] Following the procedure as described in Example 478 step 1,
and making variation as required to replace
2-chloro-4-fluorobenzylbromide with 3,5-dichlorobenzyl chloride,
the title compound was isolated as a yellowish oil (1.29 g,
77%).
Step 2. Preparation of 4-((3,5-dichlorobenzyl)oxy)piperidine,
trifluoroacetic acid salt
##STR01333##
[2314] A solution of tert-butyl
4-((3,5-dichlorobenzyl)oxy)piperidine-1-carboxylate (1.98 g, 5.50
mmol) in dichloromethane (50 mL) was treated with trifluoroacetic
acid (15 mL). The resulting solution was stirred at ambient
temperature for 1 hour and then concentrated to vacuo. The residue
was used in the next step without further purification.
Step 3. Preparation of tert-butyl
5-cyclopropyl-4-((4-((3,5-dichlorobenzyl)oxy)
piperidin-1-yl)methyl)-4-fluorobenzoate
##STR01334##
[2316] Following the procedure as described in Example 53 step 3,
and-making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-((3,5-dichlorobenzyl) oxy)piperidine, trifluoroacetic acid
salt, the title compound was obtained as an oil (1.44 g, 51% in 2
steps): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.47 (d, J=7.3
Hz, 1H), 7.25-7.19 (m, 3H), 7.16 (d, J=11.8 Hz, 1H), 4.46 (s, 2H),
3.61 (s, 2H), 3.48-3.37 (m, 1H), 2.78-2.68 (m, 2H), 2.27-2.14 (m,
2H), 1.99-1.84 (m, 3H), 1.74-1.60 (m, 2H), 1.56 (s, 9H), 0.94-0.85
(m, 2H), 0.63-0.56 (m, 2H); MS(ES+) m/z 508.2, 510.2 (M+1).
Step 4. Preparation of
5-cyclopropyl-4-((4-((3,5-dichlorobenzyl)oxy)piperidin-1-yl)
methyl)-2-fluorobenzoic acid, trifluoroacetic acid salt
##STR01335##
[2318] Following the procedure as described in Example 53 step 4,
and making variation as required to replace (S)-tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoate with tert-butyl
5-cyclopropyl-4-((4-((3,5-dichlorobenzyl)oxy)piperidin-1-yl)methyl)-2-flu-
orobenzoate, the title compound was obtained as an colorless solid
(1.29 g, 81%): MS(ES+) m/z 452.1, 454.1 (M+1).
Step 5. Preparation of
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)oxy)piperidin-1-yl)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01336##
[2320] Following the procedure as described in Example 53 step 5,
and making variations as required to replace
cyclopropanesulfonamide with methylsulfonamide and to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)
piperidin-1-yl)methyl)-2-fluorobenzoic acid with
5-cyclopropyl-4-((4-((3,5-dichlorobenzyl)oxy)
piperidin-1-yl)methyl)-2-fluorobenzoic acid, trifluoroacetic acid
salt and purification by preparative HPLC, the title compound was
obtained as a colorless solid (0.25 g, 51%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 12.26 (br s, 1H), 9.63 (br s, 1H), 7.54-7.45
(m, 2H), 7.42-7.32 (m, 2H), 7.24 (d, J=7.3 Hz, 3H), 4.51 (br s,
4H), 3.81-3.66 (m, 1H), 3.34 (s, 3H), 3.30-3.20 (m, 2H), 3.18-3.07
(m, 1H), 2.24-1.97 (m, 3H), 1.93-1.80 (m, 2H), 1.73-1.54 (m, 1H),
1.02-0.93 (m, 2H), 0.80-0.71 (m, 2H); MS(ES+) m/z 529.1, 531.1
(M+1).
Example 512
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4-((3,5-dichlorobenzyl)oxy)
piperidin-1-yl)methyl)-2-fluorobenzamide, trifluoroacetic acid
salt
##STR01337##
[2322] Following the procedure as described in Example 53 step 5,
and making variations as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)oxy)piperidin-1-yl)methyl)-2-fluo-
robenzoic acid, trifluoroacetic acid salt and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.31 g, 61%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
12.24 (br s, 1H), 9.53 (br s, 1H), 7.53-7.45 (m, 2H), 7.42-7.33 (m,
2H), 7.23 (d, J=7.3 Hz, 1H), 4.51 (br s, 3H), 3.79-3.66 (m, 1H),
3.64-3.49 (m, 1H), 3.42-3.12 (m, 3H), 3.11-3.00 (m, 1H), 2.21-1.98
(m, 3H), 1.93-1.79 (m, 1H), 1.53 (m, 1H), 1.16-1.06 (m, 4H),
1.01-0.93 (m, 2H), 0.79-0.71 (m, 2H); MS(ES+) m/z 555.2, 557.2
(M+1).
Example 513
Synthesis of
5-cyclopropyl-2-fluoro-4-((4-(fluoromethyl)-4-(4-fluorophenyl)piperidin-1-
-yl) methyl)-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01338##
[2323] Step 1. Preparation of
(4-(4-fluorophenyl)piperidin-4-yl)methanol, trifluoroacetic acid
salt
##STR01339##
[2325] To a solution of tert-butyl
4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (1.51
g, 4.88 mmol) in dichloromethane (50 mL) was added trifluoracetic
acid (15 mL). The resulting solution was stirred at ambient
temperature for 1.5 hours and then concentrated in vacuo to
provided the title compound (1.58 g, quant. yield): MS(ES+) m/z
210.2 (M+1).
Step 2. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(4-fluorophenyl)-4-(hydroxymethyl)
piperidin-1-yl)methyl)benzoate
##STR01340##
[2327] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with (4-(4-fluorophenyl) piperidin-4-yl)methanol, trifluoroacetic
acid salt, the title compound was obtained as an oil (0.78 g, 35%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.45 (d, J=7.3 Hz, 1H),
7.33-7.26 (m, 2H), 7.17 (d, J=11.9 Hz, 1H), 7.12-7.00 (m, 2H),
4.19-4.11 (m, 1H), 3.60-3.50 (m, 4H), 3.32-3.21 (m, 1H), 3.14-3.03
(m, 1H), 2.68-2.57 (m, 2H), 2.33-2.21 (m, 1H), 2.20-2.10 (m, 1H),
1.98-1.79 (m, 3H), 1.55 (s, 9H), 0.90-0.82 (m, 2H), 0.61-0.54 (m,
2H); MS(ES+) m/z 458.3 (M+1).
Step 3. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-fluoromethyl)-4-(4-fluorophenyl)
piperidin-1-yl)methyl)benzoate
##STR01341##
[2329] To a solution of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(4-fluorophenyl)-4-(hydroxymethyl)
piperidin-1-yl)methyl)benzoate (0.78 g, 1.70 mmol) in
dichloromethane (40 mL) under nitrogen, was added with
diethylaminosulfur trifluoride (0.45 mL, 3.4 mmol) at 0.degree. C.
The resulting solution was stirred at 0.degree. C. for 2.5 hours
and then quenched with saturated sodium bicarbonate (30 mL). The
mixture was extracted with ethyl acetate (80 mL) and the combied
organic extracts were washed with saturated sodium bicarbonate
(3.times.30 mL), saturated ammonium chloride (40 mL), brine (40
mL), dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by flash
chromatography (0-25% ethyl acetate in hexanes) to provide the
title compound as a colorless oil (0.39 g, 50%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.47 (d, J=7.2 Hz, 1H), 7.21-7.09 (m, 3H),
7.01-6.91 (m, 2H), 3.64 (s, 2H), 2.85 (d, J=22.9 Hz, 2H), 2.71-2.59
(m, 2H), 2.41-2.28 (m, 2H), 1.97-1.85 (m, 1H), 1.79-1.61 (m, 4H),
1.55 (s, 9H), 0.93-0.85 (m, 2H), 0.63-0.55 (m, 2H); MS(ES+) m/z
460.3 (M+1).
Step 4. Preparation of
5-cyclopropyl-2-fluoro-4-((4-(fluoromethyl)-4-(4-fluorophenyl)
piperidin-1-yl)methyl)benzoic acid
##STR01342##
[2331] To a solution of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(fluoromethyl)-4-(4-fluorophenyl)
piperidin-1-yl)methyl)benzoate (0.39 g, 0.85 mmol) in 1,4-dioxane
(10 mL) was added concentrated hydrochloric acid (5 mL). The
resulting solution was stirred at ambient temperature for 4 hours.
The reaction mixture was diluted with ethyl acetate (60 mL), washed
with water (60 mL), saturated ammonium chloride (50 mL), brine
(2.times.40 mL), dried over anhydrous sodium sulfate, filtered the
solid, and concentrated in vacuo to provide the title compound
(0.24 g, 71%): MS(ES+) m/z 404.2 (M+1).
Step 5. Preparation of
5-cyclopropyl-2-fluoro-4-((4-(fluoromethyl)-4-(4-fluorophenyl)
piperidin-1-yl)methyl)-N-(methylsulfonyl)benzamide, trifluoroacetic
acid salt
##STR01343##
[2333] Following the procedure as described in Example 53 step 5,
and making variations as required to replace
cyclopropanesulfonaimde with methylsulfonamide and to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)
piperidin-1-yl)methyl)-2-fluorobenzoic acid with
5-cyclopropyl-2-fluoro-4-((4-(fluoromethyl)-4-(4-fluorophenyl)
piperidin-1-yl)methyl)benzoic acid and purification by preparative
HPLC, the title compoind was obtained as a colorless solid (0.045
g, 26%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.22 (br s,
1H), 9.49 (br s, 1H), 7.45 (d, J=10.8 Hz, 1H), 7.28-7.19 (m, 3H),
7.17-7.08 (m, 2H), 4.50 (s, 2H), 4.14-3.60 (m, 2H), 3.33 (s, 3H),
3.30-3.10 (m, 2H), 2.96 (d, J=20.6 Hz, 2H), 2.17-2.05 (m, .sub.1H),
2.02-1.75 (m, 4H), 1.03-0.89 (m, 2H), 0.78-0.69 (m, 2H); MS(ES+)
m/z 481.2 (M +1).
Example 514
Synthesis of
5-Cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((4-(fluoromethyl)-4-(4--
flurorophenyl) piperidin-1-yl)methyl)benzamide, trifluoroacetic
acid salt
##STR01344##
[2335] Following the procedure as described in Example 53 step 5,
and making variations as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-2-fluoro-4-((4-(fluoromethyl)-4-(4-fluorophenyl)piperidin-1-
-yl)methyl)benzoic acid, and purification by preparative HPLC s),
the title compound was obtained as a colorless solid (0.07 g, 39%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.24 (br s, 1H), 9.53
(br s, 1H), 7.46 (d, J=11.1 Hz, 1H), 7.27-7.18 (m, 3H), 7.17-7.08
(m, 2H), 4.52 (s, 2H), 4.09-3.64 (m, 2), 3.37-3.13 (m, 2H),
3.09-3.02 (m, 1H), 2.96 (d, J=19.7 Hz, 2H), 2.17-2.05 (m, 1H),
2.02-1.73 (m, 4H), 1.16-1.04 (m, 4H), 1.01-0.91 (m, 2H), 0.79-0.68
(m, 2H); MS(ES+) m/z 507.2 (M+1).
Example 515
Synthesis of
5-cyclopropyl-2-fluoro-4-((4-(4-fluorephenyl)-4-(methoxymethyl)
piperidin-1-yl)methyl)-N-(methylsulfonyl)benzamide, trifluoroacetic
acid salt
##STR01345##
[2336] Step 1. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(4-fluorophenyl)-4-(methoxymethyl)
piperidin-1-yl)methyl)benzoate
##STR01346##
[2338] To a solution of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(4-fluorophenyl)-4-(hydroxymethyl)
piperidin-1-yl)methyl)benzoate (1.39 g, 3.04 mmol) and methyliodide
(0.53 mL, 8.5 mmol) in anhydrous tetrahydrofuran (40 mL) at
-78.degree. C. was treated with 1.0 M lithium
bis(trimethylsilyl)amide in tetrahydrofuran (8.5 mL, 8.5 mmol)
under nitrogen. The reulting solution was stirred -78.degree. C.
for 30 minutes and then warmed to ambient temperature and stirred
for 18 hours. The reaction mixture was diluted with ethyl acetate
(100 mL), washed with saturated ammonium chloride (2.times.50 mL),
brine (2.times.40 mL), dried over anhydrous sodium sulfate,
filtered the solid, and concentrated iu vacuo. The residue was
purified by flash chromatography (0-25% ethyl acetate in hexanes)
to provide the title compound as a colorless oil (0.48 g, 34%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.45 (d, J=7.3 Hz, 1H),
7.33-7.26 (m, 2H), 7.17 (d, J=11.8 Hz, 1H), 7.05-6.96 (m, 2H), 3.54
(s, 2H), 3.31 (s, 2H), 3.19 (s, 3H), 2.66-2.54 (m, 2H), 2.33-2.21
(m, 2H), 2.17-2.06 (m, 2H), 2.02-1.84 (m, 3H), 1.56 (s, 9H),
0.90-0.81 (m, 2H), 0.61-0.53 (m, 2H); MS(ES+) m/z 472.3 (M+1).
Step 2. Preparation of
5-cyclopropyl-2-fluoro-4-((4-(4-fluorophenyl)-4-(methoxymethyl)
piperidin-1-yl)methyl)benzoic acid
##STR01347##
[2340] Following the procedure as described in Example 513 step 4,
and making variation as required to replace tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(fluoromethyl)-4-(4-fluorophenyl)piperidin-1-
-yl) methyl)benzoate with tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(4-fluorophenyl)-4-(methoxymethyl)
piperidin-1-yl)methyl)benzoate, the title compound was obtained a
colorless solid (0.26 g, 62%): MS(ES+) m/z 461.2 (M+1).
Step 3. Preparation of
5-cyclopropyl-2-fluoro-4-((4-(4-fluorophenyl)-4-(methoxymethyl)
piperidin-1-yl)methyl)-N-methylsulfonyl)benzamide, trifluoroacetic
acid salt
##STR01348##
[2342] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with with
5-cyclopropyl-2-fluoro-4-((4-(4-fluorophenyl)-4-(methoxymethyl)piperidin--
1-yl) methyl)benzoic acid, and to replace cyclopropanesulfonamide
with methylsulfonamide, and purification by preparative HPLC, the
title compound was obtained as a colorless solid (0.04 g, 21%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.31 (br s, 1H), 9.54
(br s, 1H), 7.54-7.30 (m, 3H), 7.25-7.02 (m, 3H), 5.74-4.82 (m,
1H), 4.63-4.34 (m, 2H), 3.73-3.55 (m, 1H), 3.38-3.27 (m, 5H),
3.18-3.08 (m, 4H), 2.92-2.74 (m, 1H), 2.43-2.37 (m1H), 2.28-2.02
(m, 3H), 1.99-1.84 (m, 1H), 1.04-0.85 (m, 2H), 0.81-0.66 (m, 2H),
MS(ES+) m/z 493.2 (M+1).
Example 516
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluoro-4-((4-(4-fluorophenyl)-4-(-
methoxymethyl) piperidin-1-yl)methyl)benzamide, trifluoroacetic
acid salt
##STR01349##
[2344] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-2-fluoro-4-((4-(4-fluorophenyl)-4-(methoxymethyl)piperidin--
1-yl) methyl)benzoic acid, and purification by preparative HPLC,
the title compound was obtained as a colorless solid (0.045 g,
23%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.24 (br s, 1H),
9.51 (br s, 1H), 7.54-7.31 (m, 3H), 7.26-7.07 (m, 3H), 4.64-4.53
(m, 2H), 3.72-3.57 (m, 1H), 3.42-3.26 (m, 2H), 3.19-3.09 (m, 4H),
3.08-3.00 (m, 1H), 2.92-2.75 (m, 1H), 2.44-2.35 (m, 1H), 2.29-2.01
(m, 3H), 2.00-1.85 (m, 1H), 1.17-1.06 (m, 4H), 1.04-0.84 (m, 2H),
0.82-0.65 (m, 2H); MS(ES+) m/z 519.2 (M+1).
Example 517
Synthesis of
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)piperazin-1-yl)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01350##
[2345] Step 1. Preparation of tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate
##STR01351##
[2347] To a mixture of tert-butyl piperazine-1-carboxylate (1.00 g,
5.37 mmol) and potassium carbonate (1.34 g, 9.76 mmol) in anhydrous
dimethylformamide (50 mL) was added
1,3-dichloro-5-(chloromethyl)benzene (0.95 g, 4.88 mmol) under
nitrogen. The resulting mixture was stirred at ambient temperature
for 2 days. The reaction mixture was diluted with ethyl acetate
(200 mL), washed with water (100 mL), saturated ammonium chloride
(2.times.50 mL), brine (2.times.40 mL), dried over anhydrous sodium
sulfate, filtered and concentrated in vacuo. The residue purified
by flash chromatography (3:1 hexanes:ethyl acetate) to provide the
title compound as a colorless oil (1.22 g, 73%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.25-7.17 (m, 3H), 3.45-3.35 (m, 6H),
2.39-2.30 (m, 4H), 1.42 (s, 9H); MS(ES+) m/z 345.1, 347.1
(M+1).
Step 2. Preparation of 1-(3,5-dichlorobenzyl)piperazine
dihydrochloride
##STR01352##
[2349] To a mixture of tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate (1.22 g, 3.53 mmol)
in 1,4-dioxane (20 mL) was added concentrated hydrochloric acid (5
mL). The mixture was stirred for 2 hours and then concentrated in
vacuo to provide the title compound as a colorless solid (1.12
quant. yield): MS(ES+) m/z 245.1, 247.1 (M+1).
Step 3. Preparation of tert-butyl
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)piperazin-1-yl)
methyl)-2-fluorobenzoate
##STR01353##
[2351] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 1-(3,5-dichlorobenzyl)piperazine dihydrochloride, the title
compound was obtained as an oil (1.74 g, quant. yield): .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.46 (d, J=7.2 Hz, 1H), 7.25-7.10 (m,
4H), 3.63 (s, 2H), 3.43 2H), 2.59-2.35 (m, 8H), 1.98-1.87 (m, 1H),
1.55 (s, 9H), 0.94-0.86 (m, 2H), 0.67-0.55 (m, 2H); MS(ES+) m/z
508.2, 510.2 (M+1).
Step 4. Preparation of
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)piperazin-1-yl)
methyl)-2-fluorobenzoic acid dihydrochloride
##STR01354##
[2353] To a solution tert-butyl
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)piperazin-1-yl)methyl)-2-fluorobe-
nzoate, (1.81 g, 3.67 mmol) in 1,4-dioxane (35 mL) was added
concentrated hydrochloric acid (15 mL). The resulting mixture was
stirred for 2 hours and then concentrated in vacuo. The residue was
triturated with water to provide the title compound as a colorless
solid (1.5 g, 94%:) MS(ES+) m/z 437.0, 439.0 (M+1).
Step 5. Preparation of
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)piperazin-1-yl)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01355##
[2355] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)piperazin-1-yl)methyl)-2-fluorobe-
nzoic acid dihydrochloride, and to replace cyclopropanesulfonamide
with methylsulfonamide, and purification by preparative HPLC, the
title compound was obtained as colorless solid (0.08 g, 21%):
.sup.1NMR (300 MHz, DMSO-d.sub.6) .delta. 12.19 (br s, 1H), 9.74
(br s, 1H), 7.66 (s, 1H), 7.51 (s, 2H), 7.32 (d, J=11.6 Hz, 1H),
7.22 (d, J=7.1 Hz, 1H), 5.76 (br s, 1H), 4.11 (br s, 2H), 3.97 (br
s, 2H), 3.33 (s, 3H), 3.27-2.65 (m, 8H), 2.11-1.98 (m, 1H),
1.01-0.86 (m, 2H), 0.77-0.59 (m, 2H); MS(ES+) m/z 514.1, 516.1
(M+1).
Example 518
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4-(3,5-dichlorobenzyl)
piperazin-1-yl)methyl)-2-fluorobenzamide, trifluoroacetic acid
salt
##STR01356##
[2357] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)piparazin-1-yl)methyl)-2-fluorobe-
nzoic acid dihydrochloride, and purification by preparative HPLC,
the title compound was obtained as a colorless solid (0.20 g, 34%):
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.13 (br s, 1H), 7.65
(s, 1H), 7.54-7.49 (m, 2H), 7.33 (d, J=11.3 Hz, 1H), 7.20 (d, J=7.6
Hz, 1H), 4.10 (br s, 2H), 3.97 (br s, 2H), 3.33-2.59 (m, 9H),
2.10-1.99 (m, 1H), 1.15-1.03 (m, 4H), 0.96-0.87 (m, 2H), 0.72-0.63
(m, 2H); MS(ES+) m/z 540.2, 542.2 (M+1).
Example 519
Synthesis of
4-((4-(4-chloro-3-(trifluoromethyl)phenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01357##
[2358] Step 1. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-hydroxypiperidin-1-yl)methyl)benzoate
##STR01358##
[2360] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with piperidin-4-ol, the title compound was obtained as an oil
(0.98 g, 94%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.45 (d,
J=7.3 Hz, 1H), 7.16 (d, J=11.8 Hz, 1H), 3.57-3.64 (m, 1H), 3.61 (s,
2H), 2.77-2.68 (m, 2H), 2.25-2.13 (m, 2H), 1.97-1.76 (m, 4H),
1.64-1.57 (m, 1H), 1.54 (s, 9H), 0.92-0.84 (m, 2H), 0.62-0.55 (m,
2H); MS(ES+) m/z 350.3 (M+1).
Step 2. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-((methylsulfonyl)oxy)piperidin-1-yl)methyl)b-
enzoate
##STR01359##
[2362] To a solution of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-hydroxypiperidin-1-yl)methyl)benzoate
(0.98 g, 2.80 mmol) and triethylamine (0.59 mL, 4.2 mmol) in
dichloromethane (40 mL) at 0.degree. C. was added methanesulfonyl
chloride (0.26 mL, 3.36 mmol) under nitrogen. The resulting mixture
was stirred at 0.degree. C. for 1 hour. The mixture was washed with
saturated ammonium chloride (40 mL), brine (40 mL), dried over
anhydrous sodium sulfate, filtered the solid, and concentrated in
vacuo to dryness to provide the title compound as a colorless oil
(1.20 g, quant. yield): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.47 (d, J=7.3 Hz, 1H), 7.14 (d, J=11.8 Hz, 1H), 7.81-4.71 (m, 1H),
3.64 (s, 2H), 3.00 (s, 3H), 2.76-2.65 (m, 2H), 2.43-2.28 (m, 2H),
2.09-1.83 (m, 5H), 1.55 (s, 9H), 0.94-0.86 (m, 2H), 0.63-0.56 (m,
2H); MS(ES+) m/z 428.2 (M+1).
Step 3. Preparation of tert-butyl
4-((4-(4-chloro-3-(trifluoromethyl)phenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoate
##STR01360##
[2364] To a mixture of tert-butyl
5-cyclopropyl-2-fluoro-4-((4-((methylsulfonyl)oxy)piperidin-1-yl)
methyl)benzoate (1.20 g, 2.80 mmol) and
4-chloro-3-(trifluoromethyl)phenol (0.61 g, 3.08 mmol) in anhydrous
dimethylformamide (50 mL) was added potassium carbonate (0.43 g,
3.08 mmol). The reaction mixture was heated at 90.degree. C. under
nitrogen for 7 hours, cooled to ambient temperature and diluted
with ethyl acetate (150 mL), washed with water (100 mL), saturated
ammonium chloride (100 mL), brine (100 mL), dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo. The residue was
purified by flash chromatography (0-25% ethyl acetate in hexanes)
to provide the title compound as a colorless oil (0.71 g, 48%):
MS(ES+) m/z 528.1, 530.1 (M+1).
Step 4. Preparation of
4-((4-(4-chloro-3-(trifluoromethyl)phenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride
##STR01361##
[2366] Following the procedure as described in Example 517 step 4,
and making variation as required to replace tert-butyl
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)piperazin-1-yl)methyl)-2-fluorobe-
nzoate with tert-butyl
4-((4-(4-chloro-3-(trifluoromethyl)phenoxy)piperidin-1-yl)methyl)-5-cyclo-
propyl-2-fluorobenzoate and purification by trituration with
diethyl ether, the title compound was obtained as a colorless solid
(0.32 g, 47%): MS(ES+) m/z 472.0, 474.0 (M+1).
Step 5. Preparation of
4-((4-(4-chloro-3-(trifluoromethyl)phenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01362##
[2368] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((4-(4-chloro-3-(trifluoromethyl)phenoxy)piperidin-1-yl)methyl)-5-cyclo-
propyl-2-fluorobenzoic acid hydrochloride, and to replace
cyclopropanesulfonamide with methylsulfonamide, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.05 g, 24%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
12.30 (br s, 1H), 9.67 (br s, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.51 (d,
J=11.1 Hz, 1H), 7.44-7.30 (m, 2H), 7.25 (d, J=7.0 Hz, 1H),
4.95-4.76 (m, 1H), 4.54 (s, 2H), 4.26-3.74 (m, 2H), 3.47-3.12 (m,
6H), 2.28-1.74 (m, 4H), 1.06-0.92 (m, 2H), 0.82-0.71 (m, 2H);
MS(ES+) m/z 549.1, 551.1 (M+1).
Example 520
Synthesis of
4-((4-(4-chloro-3-(trifluoromethyl)phenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01363##
[2370] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((4-(4-chloro-3-(trifluoromethyl)phenoxy)piperidin-1-yl)methyl)-5-cyclo-
propyl-2-fluorobenzoic acid hydrochloride, and purification by
preparative HPLC, the title compound was obtained as a colorless
(0.07 g, 32%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.22
(br s, 1H), 9.69 (br s, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.51 (d,
J=11.1 Hz, 1H), 7.44-7.30 (m, 2H), 7.23 (d, J=7.2 Hz, 1H),
7.92-4.79 (m, 1H), 4.54 (s, 2H), 4.23-3.76 (m, 2H), 3.50-3.31 (m,
2H), 3.10-3.00 (m, 1H), 2.28-1.70 (m, 5H), 1.15-1.06 (m, 4H),
1.03-0.95 (m, 2H), 0.81-0.72 (m, 2H); MS(ES+) m/z 575.2, 577.1
(M+1).
Example 521
Synthesis of
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01364##
[2371] Step 1. Preparation of tert-butyl
4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate
##STR01365##
[2373] To a solution of tert-butyl
4-hydroxypiperidine-1-carboxylate (1.03 g, 5.09 mmol) in anhydrous
1,2-dimethoxyethane (35 mL) was added (60% sodium hydride in
mineral oil, 0.20 g, 5.09 mmol) under nitrogen. The resulting
mixture was stirred for 1 hour at ambient temperature and then
added 2,5-dichloro-4-(trifluoromethyl)pyridine (1.00 g, 4.63 mmol).
The reaction mixture was refluxed for 2 hours and cooled to ambient
temperature. The reaction atixture was diluted with ethyl acetate
(100 mL), washed with water (50 mL), saturated ammonium chloride
(2.times.50 mL), brine (50 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo to provide the title
compound as an oil (1.76 g, quant. yield): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.18 (s, 1H), 6.99 (s, 1H), 5.21-5.11 (m, 1H),
3.80-3.66 (m, 2H), 3.30-3.19 (m, 2H), 1.99-1.88 (m, 2H), 1.75-1.61
(m, 2H), 1.43 (s, 9H); MS(ES+) m/z 325.0, 326.9 (M-55).
Step 2. Preparation of tert-butyl
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)
oxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoate
##STR01366##
[2375] To a mixture of tert-utyl
4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate
(1.76 g, 4.63 mmol) in 1,4-dioxane (30 mL) was added concentrated
hydrochloric acid (10 mL). The resulting mixture was stirred for 5
hours and then concentrated in vacuo. The residue was dissolved in
anhydrous dimethylformamide (70 mL), and to this solution was added
potassium carbonate (2.21 g, 16.00 mmol) and tert-butyl
5-cyclopropyl-2-fluoro-4-(((methylsulfonyl)oxy)methyl)benzoate
(1.38 g, 4.00 mmol). The resulting mixture was stirred under
nitrogen at ambient temperature for 18 hours diluted with ethyl
acetate (150 mL), washed with water (100 mL), saturated ammonium
chloride (2.times.70 mL), brine (70 mL), dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo. The residue was
purified by flash chromatography (0-80% ethyl acetate in hexanes)
to provide the title compound as a colorless oil (1.92 g, 91%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.19 (s. 1H), 7.48 (d,
J=7.1 Hz, 1H), 7.18 (d, J=11.8 Hz, 1H), 7.00 (s, 1H), 5.12-5.02 (m,
1H), 3.64 (s, 2H), 2.78-2.67 (m, 2H), 2.41-2.31 (m, 2H), 2.05-1.90
(m, 3H), 1.86-1.73 (m, 2H), 1.56 (s, 9H), 0.94-0.86 (m, 2H),
0.65-0.58 (m, 2H); MS(ES+) m/z 529.2, 531.2 (M+1H).
Step 3. Preparation of
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride
##STR01367##
[2377] Following the procedure as described in Example 517 step 4,
and making variation as required to replace tert-butyl
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)piperazin-1-yl)methyl)-2-fluorobe-
nzoate with tert-butyl
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained as a colorless solid (1.85 g, quant. yield): MS(ES+) m/z
472.9, 475.1 (M+1H).
Step 4. Preparation of
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01368##
[2379] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride, and to
replace cyclopropanesulfonamide with methylsulfonamide, and
purification by preparative HPLC, the title compound was obtained
as a colorless solid (0.45 g, 67%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 12.28 (br s, 1H), 9.92 (br s, 1H), 8.49 (s,
1H), 7.51 (d, J=10.9 Hz, 1H), 7.30 (s, 1H), 7.25 (d, J=7.1 Hz, 1H),
5.33-5.15 (m, 1H), 4.55 (s, 2H), 3.51-3.24 (m, 7H), 2.34-2.00 (m,
4H), 1.93-1.75 (m, 1H), 1.04-0.91 (m, 2H), 0.81-0.70 (m, 2H);
MS(ES+) m/z 550.1, 552.1 (M+1).
Example 522
Synthesis of
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01369##
[2381] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride, and
purification by preparative HPLC, the title compound was obtained
as a colorless solid (0.35 g, 51%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 12.24 (br s, 1H), 10.16 (br s, 1H), 8.48 (s,
1H), 7.53 (d, J=10.9 Hz, 1H), 7.30 (s, 1H), 7.23 (d, J=7.1 Hz, 1H),
5.32-5.14 (m, 1H), 4.56 (s, 2H), 3.52-3.24 (m, 4H), 3.11-3.00 (m,
1H), 2.33-1.98 (m, 4H), 1.96-1.82 (m, 1H), 1.17-1.06 (m, 4H),
1.03-0.94 (m, 2H), 0.81-0.71 (m, 2H); MS(ES+) m/z 576.1, 578.1
(M+1).
Example 523
Synthesis of
4-((4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01370##
[2382] Step 1. Preparation of tert-butyl
4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate
##STR01371##
[2384] Following the procedure as described in Example 521 step 1,
and making variation as required to replace
2,5-dichloro-4-(trifluoromethyl)pyridine with
3-chloro-2-fluoro-5-(trifluoromethyl)pyridine, the title compound
was obtained as a colorless solid (1.76 g, quant. yield): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.25 (s, 1H), 7.80 (s, 1H),
5.38-5.28 (m, 1H), 3.87-3.72 (m, 4H), 3.04-2.90 (m, 2H), 1.86-1.72
(m, 2H), 1.40 (s, 9H); MS(ES+) m/z 324.9, 326.9 (M-55).
Step 2. Preparation of tert-butyl
4-((4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)
oxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoate
##STR01372##
[2386] Following the procedure as described in Example 521 step 2,
and making vatiation as required to replace tert-butyl
4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate
with tert-butyl
4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)piperidine-1-carboxylate-
, the title compound was obtained as a colorless solid (0.52 g,
25%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.29-8.26 (m, 1H),
7.81 (d, J=2.1 Hz, 1H), 7.48 (d, J=7.1 Hz, 1H), 7.19 (d, J=11.7 Hz,
1H), 5.28-5.19 (m, 1H), 3.66 (s, 2H), 2.79-2.68 (m, 2H), 2.46-2.35
(m, 2H), 2.09-1.82 (m, 5H), 1.56 (s, 9H), 0.96-0.87 (m, 2H),
0.65-0.58 (m, 2H); MS(ES+) m/z 529.3, 531.2 (M+1).
Step 3. Preparation of
4-((4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride
##STR01373##
[2388] Following the procedure as described in Example 517 step 4,
and making variation as required to replace tert-butyl
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)piperazin-1-yl)methyl)-2-fluorobe-
nzoate with tert-butyl
4-((4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained as a colorless solid (0.50 g, quant. yield): MS(ES+) m/z
472.9, 475.1 (M+1).
Step 4. Preparation of
4-((4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01374##
[2390] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)methy-
l)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride, and to replace
cyclopropanesulfonamide with methylsulfonamide, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.11 g, 39%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
12.31 (br s, 1H), 9.87 (br s, 1H), 8.55-8.51 (m1H), 8.43-8.39 (m,
1H), 7.52 (d, J=11.1 Hz, 1H), 7.26 (d, J=7.1 Hz, 1H), 5.49-5.24 (m,
1H), 4.56 (s, 2H), 3.55-3.14 (m, 7H), 2.38-2.06 (m, 4H), 2.03-1.82
(m, 1H), 1.05-0.93 (m, 2H), 0.83-0.70 (m, 2H); MS(ES+) m/z 550.1,
552.1 (M+1).
Example 524
Synthesis of
4-((4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01375##
[2392] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)methy-
l)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride, and
purification by preparative HPLC, the title compound was obtained
as a colorless solid (0.11 g, 38%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 12.22 (br s, 1H), 9.96 (br s, 1H), 8.55-8.51
(m, 1H), 8.43-8.39 (m, 1H), 7.55 (d, J=10.9 Hz, 1H), 7.24 (d, J=7.1
Hz, 1H), 5.48-5.25 (m, 1H), 4.56 (s, 2H), 3.56-3.16 (m, 4H),
3.11-3.00 (m, 1H), 2.38-2.07 (m, 4H), 2.01-1.82 (m, 1H), 1.15-1.06
(m, 4H), 1.04-0.94 (m, 2H), 0.80-0.72 (m, 2H); MS(ES+) m/z 576.1,
578.1 (M+1).
Example 525
Synthesis of
4-((4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01376##
[2393] Step 1. Preparation of methyl
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR01377##
[2395] To a degassed mixture of methyl
5-cyclopropyl-2-fluoro-4-((3-methylazetidin-3-yl)methoxy)benzoate
hydrochloride (0.15 g, 0.46 mmol),
2,5-dichloro-4-(trifluoromethyl)pyridine (0.15 g, 0.68 mmol) and
cesium carbonate (0.58 g, 1.77 mmol) in anhydrous toluene (5.0 mL)
was added rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.06 g,
0.091 mmol) and bis(dibenzylideneacetone)palladium(0) (0.03 g,
0.046 mmol). The resulting mixture was heated at 100.degree. C. in
a sealed tube for 30 hours. The reaction mixture was diluted with
ethyl acetate (30 mL), washed with water (30 mL), saturated
ammonium chloride (30 mL), brine (30 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The residue
was purified by HPLC to provide the title compound as a colorless
solid (0.10 g, 46%): MS(ES+) m/z 473.1, 475.1 (M+1).
Step 2. Preparation of
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR01378##
[2397] To a mixture of methyl
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate (0.10 g, 0.21 mmol) and
lithium hydroxide monohydrate (0.09 g, 2.10 mmol) in
tetrahydrofuran (20 mL) and water (10 mL) was refluxed for 7 hours.
The mixture was diluted with ethyl acetate (50 mL), washed with 1.0
N hydrochloride acid solution (30 mL), brine (3.times.30 mL), dried
over anhydrous sodium sulfate, filtered, and concentrated in vacuo
to provide the title compound as a colorless solid (0.07 g, 67%):
MS(ES+) m/z 458.9, 460.9 (M+1).
Step 3. Preparation of
4-((4-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01379##
[2399] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid, (0.03 g, 38%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
11.81 (s, 1H), 8.27 (s, 1H), 7.06 (d, J=8.3 Hz, 1H), 6.96 (d,
J=13.0 Hz, 1H), 6.75 (s, 1H), 4.07 (s, 2H), 4.03 (d, J=8.6 Hz, 2H),
3.79 (d, J=8.6 Hz, 2H), 3.08-2.98 (m, 1H), 1.71-1.59 (m, 1H), 1.40
(s, 3H), 1.12-1.03 (m, 4H), 0.59-0.53 (m, 4H); MS(ES+) m/z 562.1,
564.1 (M+1).
Example 526
Synthesis of
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfonyl)piperazin-1-yl)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01380##
[2400] Step 1. Preparation of tert-butyl
4-((3,5-dichlorophenyl)sulfonyl)piperazine-1-carboxylate
##STR01381##
[2402] To a solution of perfluorophenyl
3,5-dichlorobenzenesulfonate (2.30 g, 5.85 mmol) and triethylamine
(1.63 mL, 11.7 mmol) in dichlocomethane (50 mL) was added with
tert-butyl piperazine-1-carboxylate (1.31 g, 7.02 mmol) at ambient
temperature. The resulting mixture was stirred at ambient
temperature for 18 hours under nitrogen, diluted with ethyl acetate
(100 mL), washed with saturated ammonium chloride (2.times.50 mL),
saturated sodium bicarbonate (50 mL), brine (30 mL), dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo. The
residue was purified by flash chromatography (0-20% ethyl acetate
in hexanes) to provide the compound as a colorless solid (1.87 g,
81%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.60-7.54 (m, 3H),
3.50 (t, J=4.8 Hz, 4H), 2.99 (t, J=5.1 Hz, 4H), 1.39 (s, 9H);
MS(ES+) m/z 294.9, 296.9 (M-Boc+2).
Step 2. Preparation of 1-((3,5-dichlorophenyl)sulfonyl)piperazine
hydrochloride
##STR01382##
[2404] Following the procedure as described in Example 517 step 4,
and making variation as required to replace tert-butyl
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)piperazin-1-yl)methyl)-2-fluorobe-
nzoate with tert-butyl
4-((3,5-dichlorophenyl)sulfonyl)piperazine-1-carboxylate, the title
compound was obtained as a colorless solid (1.57 g, quant. yield):
MS(ES+) m/z 295.0, 297.0 (M+1).
Step 2. Preparation of tert-butyl
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfonyl)
piperazin-1-yl)methyl)-2-fluorobenzoate
##STR01383##
[2406] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 1-(3,5-dichlorophenyl)sulfonyl)piperazine hydrochloride and
purification by flash chromatography (0-20% ethyl acetate in
hexanes), the title compound was obtained as an foam (1.81 g, 70%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.61-7.55 (m, 3H), 7.45
(d, J=7.5 Hz, 1H), 7.04 (d, J=11.7 Hz, 1H), 3.64 (s, 2H), 3.11-3.00
(m, 4H), 2.61-2.51 (m, 4H), 1.92-1.79 (m, 1H), 1.54 (s, 9H),
0.91-0.83 (m, 2H), 0.62-0.54 (m, 2H); MS(ES+) m/z 543.0, 545.0
(M+1).
Step 3. Preparation of
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfonyl)piperazin-1-yl)
methyl)-2-fluorobenzoic acid hydrochloride
##STR01384##
[2408] Following the procedure as described in Example 517 step 4,
and making variation as required to replace tert-butyl
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)piperazin-1-yl)methyl)-2-fluorobe-
nzoate with tert-butyl
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfonyl)piperazin-1-yl)
methyl)-2-fluorobenzoate, the title compound was obtained as a
colorless solid (1.74 g, quant. yield): MS(ES+) m/z 478.0, 489.0
(M+1).
Step 4. Preparation of
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfonyl)piperazin-1-yl)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01385##
[2410] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfonyl)piperazin-1-yl)methyl)--
2-fluorobenzoic acid hydrochloride, and to replace
cyclopropanesulfonamide with methylsulfonamide, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.18 g, 43%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
11.97 (br s, 1H), 8.07-8.04 (m, 1H), 7.74 (d, J=1.7 Hz, 2H), 7.32
(d, J=11.3 Hz, 1H), 7.21 (d, J=7.2 Hz, 1H), 5.68 (br s, 1H), 4.20
(s, 2H), 3.32 (s, 3H), 3.29-2.90 (m, 8H), 2.08-1.97 (m, 1H),
0.97-0.87 (m, 2H), 0.72-0.64 (m, 2H); MS(ES+) m/z 564.0, 566.0
(M+1).
Example 527
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4-((3,5-dichlorophenyl)sulfonyl-
) piperazin-1-yl)methyl)-2-fluorobenzamide, trifluoroacetic acid
salt
##STR01386##
[2412] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-((3,5-dichlorophenoxy)sulfonyl)piperazin-1-yl)methyl)-
-2-fluorobenzoic acid hydrochloride, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.19 g, 43%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
12.01 (br s, 1H), 8.04 (d, J=1.7 Hz, 1H), 7.74 (d, J=1.7 Hz, 2H),
7.31 (d, J=11.4 Hz, 1H), 7.19 (d, J=7.1 Hz, 1H), 5.05 (br s, 1H),
4.13 (s, 2H), 3.29-2.76 (m, 9H), 2.07-1.95 (m, 1H), 1.14-1.05 (m,
4H), 0.96-0.87 (m, 2H), 0.71-0.63 (m, 2H); MS(ES+) m/z 590.0, 592.0
(M+1).
Example 528
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-(((1R,3s,5S)-3-(3,5-dichloropheno-
xy)-8-azabicyclo[3.2.1]octan-8-yl) methyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01387##
[2413] Step 1. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-(((1R,3s,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan--
8-yl) methyl)benzoate
##STR01388##
[2415] Following the procedure as described in Example 470 Step 4,
and making variation as required to replace
(1R,3s,5S)-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-8-azabicyclo[-
3.2.1]-octane with nortropine, the title compound was obtained as a
yellowish solid (2.16 g, 99%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.7.46 (d, J=7.3 Hz, 1H), 7.31 (d, J=12.2 Hz, 1H), 4.09-4.03
(m, 1H), 3.63 (s, 2H), 3.13-3.07 (m, 2H), 2.16-1.94 (m, 6H),
1.92-1.81 (m, 1H), 1.70 (br s, 1H), 1.65 (br s, 1H), 1.57-1.57 (m,
1H), 1.56 (s, 9H), 0.91-0.83 (m, 2H), 0.62-0.56 (m, 2H).
Step 2. Preparation of tert-butyl
5-cyclopropyl-2-fluoro-4-(((1R,3r,5S)-3-((methylsulfonyl)
oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)benzoate
##STR01389##
[2417] Following the procedure as described in Example 519 step 2,
and making variation as required to replace tert-butyl
5-cyclopropyl-2-fluoro-4-((4-hydroxypiperidin-1-yl)methyl)benzoate
with tert-butyl
5-cyclopropyl-2-fluoro-4-(((1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan--
8-yl)methyl)benzoate, the title compound was obtained as an foam
(1.21 g, quant. yield): MS(ES+) m/z 454.2 (M+1).
Step 5. Preparation of tert-butyl
5-cyclopropyl-4-(((1R,3s,5S)-3-(3,5-dichlorophenoxy)-8-azabicyclo[3.2.1]o-
ctan-8-yl) methyl)-2-fluorobenzoate
##STR01390##
[2419] Following the procedure as described in Example 519 step 3,
and making variation as required to replace
4-chloro-3-(trifluoromethyl)phenol with 3,5-dichlorophenol and to
replace tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(methylsulfonyl)oxy)piperidin-1-yl)methyl)be-
nzoate with tert-butyl
5-cyclopropyl-2-fluoro-4-(((1R,3r,5S)-3-((methylsulfonyl)oxy)-8-azabicycl-
o[3.2.1]octan-8-yl) methyl)benzoate, the title compound was
obtained as an colorless oil (0.70 g, 36%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.47 (d, J=7.3 Hz, 1H), 7.30 (d, J=12.1 Hz,
1H), 6.91-6.87 (m, 1H), 6.76-6.69 (m, 2H), 4.53-4.40 (m, 1H), 3.75
(s, 2H), 3.32-3.24 (m, 2H), 2.15-1.76 (m, 7H), 1.72-1.64 (m, 2H),
1.57 (s, 9H), 0.94-0.85 (m, 2H), 0.64-0.56 (m, 2H); MS(ES+) m/z
520.1, 522.2 (M+1).
Step 4. Preparation of
5-cyclopropyl-4-(((1R,3s,5S)-3-(3,5-dichlorophenoxy)-8-azabicyclo[3.2.1]o-
ctan-8-yl) methyl)-2-fluorobenzoic acid hydrochloride
##STR01391##
[2421] Following the procedure as described in Example 517 step 4,
and making variation as required to replace tert-butyl
5-cyclopropyl-4-((4-(3,5-dichlorobenzyl)piperazin-1-yl)methyl)-2-fluorobe-
nzoate with tert-butyl
5-cyclopropyl-4-(((1R,3s,5S)-3-(3,5-dichlorophenoxy)-8-azabicyclo[3.2.1]o-
ctan-8-yl) methyl)-2-fluorobenzoate, the title compound was
obtained as a colorless solid (0.67 g, quant. yield): MS(ES+) m/z
464.1, 466.1 (M+1).
Step 5. Preparation of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-(((1R,3s,5S)-3-(3,5-dichloropheno-
xy)-8-azabicyclo[3.2.1]octan-8-yl) methyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01392##
[2423] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-(((1R,3s,5S)-3-(3,5-dichlorophenoxy)-8-azabicyclo[3.2.1]o-
ctan-8-yl) methyl)-2-fluorobenzoic acid hydrochloride, and
purification by preparative HPLC, the title compound was obtaned as
a colorless solid (0.04 g, 4%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 12.25 (br s, 1H), 9.63 (br s, 1H), 7.57 (d, J=11.4 Hz, 1H),
7.26 (d, J=7.1 Hz, 1H), 7.16-7.09 (m, 3H), 4.97-4.83 (m, 1H), 4.38
(s, 2H), 4.03 (s, 2H), 3.10-2.98 (m, 1H), 2.42-2.17 (m, 6H),
2.15-1.94 (m, 3H), 1.17-1.06 (m, 4H), 1.03-0.93 (m, 2H), 0.82-0.72
(m, 2H); MS(ES+) m/z 567.1, 569.1 (M+1).
Example 529
Synthesis of
(R)-4-((1-(2-(3-chlorophenyl)propan-2-yl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01393##
[2424] Step 1. Preparation of methyl
(R)-4-((1-(2-(3-chlorophenyl)propan-2-yl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluorobenzoate
##STR01394##
[2426] Following the procedure as described in Example 495 step 1
and making variation as required to replace 3,5-dichlorobenzoyl
chloride with 3-chlorobenzoyl chloride, the title compound was
obtained as a yellowish oil (0.72 g, 24% in 2 steps): .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta.7.53-7.48 (m, 1H), 7.42-7.35 (m, 2H),
7.21-7.16 (m, 2H), 6.39 (d, J=13.0 Hz, 1H), 4.35-4.24 (m, 1H), 3.85
(s, 3H), 2.96-2.87 (m, 1H), 2.74-2.64 (m, 1H), 2.34-2.20 (m, 2H),
2.09-1.97 (m, 2H), 1.86-1.77 (m, 1H), 1.63-1.50 (m, 2H), 1.30 (s,
3H), 1.30 (s, 3H), 0.92-0.84 (m, 2H), 0.65-0.59 (m, 2H); MS(ES+)
m/z 446.2, 448.2 (M+1).
Step 2. Preparation of
(R)-4-((1-(2-(3-chlorophenyl)propan-2-yl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR01395##
[2428] Following the procedure as described in Example 481 step 5
and making variation as required to replace methyl
4-((1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate with (R)-methyl
4-((1-(2-(3-chlorophenyl)propan-2-yl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained as an orange amorphous solid (1.47 g, 68%): MS(ES+) m/z
432.2, 434.2 (M+1).
Step 3. Preparation of
(R)-4-((1-(2-(3-chlorophenyl)propan-2-yl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01396##
[2430] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
(R)-4-((1-(2-(3-chlorophenyl)propan-2-yl)piperidin-3-yl)oxy-5-cyclopropyl-
-2-fluorobenzoic acid, and to replace cyclopropanesulfonamide with
methylsulfonamide, and purification by preparative HPLC, the title
compound was obtained as a colorless solid (0.08 g, 24%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 12.12 (br s, 1H), 8.85-8.65 (m,
1H), 7.67-7.58 (m, 1H), 7.57-7.49 (m, 2H), 7.46-7.40 (m, 2H), 6.96
(d, J=14.0 Hz, 1H), 5.18-5.05 (m, 1H), 3.78-3.66 (m, 1H), 3.47-3.32
(m, 4H), 2.60-2.43 (m, 2H), 2.38-2.08. (m, 2H), 2.03-1.93 (m, 2H),
1.90 (s, 3H), 1.88 (s, 3H), 1.57-1.41 (m, 1H), 0.93-0.82 (m, 2H),
0.65-0.56 (m, 2H); MS(ES+) m/z 509.1, 511.1 (M+1).
Example 530
Synthesis of
(R)-4-((1-(2-(3-chlorophenyl)propan-2-yl)piperidin-3-yl)
oxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01397##
[2432] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
(R)-4-((1-(2-(3-chlorophenyl)propan-2-yl)piperidin-3-yl)oxy)-5-cyclopropy-
l-2-fluorobenzoic acid, and purification by preparative HPLC, the
title compound was obtained as a colorless solid (0.08 g, 23%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 11.92 (br s, 1H), 8.72
(d, J=15.5 Hz, 1H), 7.67-7.58 (m, 1H), 7.57-7.49 (m, 2H), 7.47-7.40
(m, 2H), 6.96 (d, J=14.0 Hz, 1H), 5.18-5.04 (m, 1H), 3.78-3.65 (m,
1H), 3.46-3.34 (m, 1H), 3.11-3.01 (m, 1H), 2.61-2.43 (m, 2H),
2.37-2.10 (m, 2H), 2.04-1.93 (m, 2H), 1.91 (s, 3H), 1.87 (s, 3H),
1.57-1.39 (m, 3H), 1.16-1.07 (m, 2H), 0.92-0.84 (m, 2H), 0.64-0.57
(m, 2H); MS(ES+) m/z 535.2, 537.1 (M+1).
Example 531
Synthesis of 5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4-((3,5
dichlorophenyl)thio)piperidin-1-yl) methyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01398##
[2433] Step 1. Preparation of tert-butyl
4-((methylsulfonyl)oxy)piperidine-1-carboxylate
##STR01399##
[2435] Following the procedure as described in Example 519 step 2,
and making variation as required to replace tert-butyl
5-cyclopropyl-2-fluoro-4-((4-hydroxypiperidin-1-yl)methyl)benzoate
with tert-buzyl 4-hydroxypiperidine-1-carboxylate, the title
compound was obtained as a colorless solid (7.32 g, quant. yield):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 4.88-4.78 (m, 1H),
3.71-3.60 (m, 2H), 3.30-3.19 (m, 2H), 2.99 (s, 3H), 1.97-1.86 (m,
2H), 1.82-1.70 (m, 2H) 1.41 (s, 9H); MS(ES+) m/z 302.1 (M+23).
Step 2. Preparation of tert-butyl
4-((3,5-dichlorophenyl)thio)piperidine-1-carboxylate
##STR01400##
[2437] Following the procedure as described in Example 519 step 3,
and making variation as required to replace
4-chloro-3-(trifluoromethyl)phenol with 3,5-dichiorobenzenethiol
and tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(methylsulfonyl)oxy)piperidin-1-yl)methyl)be-
nzoate with tert-butyl
4-((methylsulfonyl)oxy)piperidine-1-carboxylate, the title compound
was obtained as a colorless solid (3.66 g, 64%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.22-7.16 (m, 3H), 3.99-3.81 (m, 2H),
3.29-3.17 (m, 1H), 2.98-2.85 (m, 2H), 1.94-1.83 (m, 2H), 1.58-1.45
(m, 2H), 1.41 (s, 9H); MS(ES+) m/z 306.0, 308.0 (M-Boc+2H).
Step 3. Preparation of 4-((3,5-dichlorophenyl)thio)piperidine
hydrochloride
##STR01401##
[2439] Following the procedare as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
4-(3,5-dichlorophenyl) thio)piperidine-1-carboxylate, the title
compound was obtained as a colorless solid (0.19 g, quant. yield):
MS(ES+) m/z: 262.1, 264.1 (M+1).
Step 4. Preparation of tert-butyl
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)
thio)piperidin-1-yl)methyl)-2-fluorobenzoate
##STR01402##
[2441] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-(3,5-dichlorophenyl) thio)piperidine hydrochloride, the
title compound was obtained as an oil (0.29 g, quant. yield):
MS(ES+) m/z 510.0, 512.0 (M+1).
Step 5. Preparation of
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)thio)
piperidin-1-yl)methyl)-2-fluorobenzoic acid hydrochloride
##STR01403##
[2443] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)
thio)piperidin-1-yl)methyl)-2-fluorobenzoate, the title compound
was obtained as a colorless solid (0.28 g, quant. yield): MS(ES+)
m/z 454.0, 456.1 (M+1).
Step 6. Preparation of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4-((3,5-dichlorophenyl)
thio)piperidin-1-yl)methyl)-2-fluorobenzamide, trifluoroacetic acid
salt
##STR01404##
[2445] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)thio)piperidin-1-yl)methyl)-2-fl-
uorobenzoic acid hydrochloride, and purification by preparative
HPLC, the title compound was obtained as a colorless solid (0.09 g,
22%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.43 (br s, 2H),
7.71 (d, J=7.2 Hz, 1H), 7.43 (d, J=12.1 Hz, 1H), 7.27-7.20 (m, 3H),
4.43 (s, 2H), 3.61-3.15 (m, 5H), 3.09-2.99 (m, 1H), 2.50-2.20 (m,
2H), 2.07-1.91 (m, 2H), 1.91-1.81 (m, 1H), 1.46-1.37 (m, 2H),
1.19-1.04 (m, 4H), 0.79-0.69 (m, 2H); MS(ES+) m/z 557.1, 559.1
(M+1).
Example 532
Synthesis of
5-cyclopropyl-4-((4-(3,5-dichlorophenyl)sulfonyl)piperidin-1-yl)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01405##
[2446] Step 1. Preparation of tert-butyl
4-((3,5-dichlorophenyl)sulfonyl)piperidine-1-carboxylate and
tert-butyl
4-((3,5-dichlorophenyl)sulfinyl)piperidine-1-carboxylate
##STR01406##
[2448] To a solution of tert-butyl
4-((3,5-dichlorophenyl)thio)piperidine-1-carboxylate (3.66 g, 10.10
mmol) in dichloromethane (100 mL) at 0.degree. C. was added
m-chloroperoxybenzoic acid (77%, 3.40 g, 15.15 mmol). The resulting
mixture was stirred at 0.degree. C. for 3 hours and then
concentrated in vacuo to about 40 mL volume. The mixture was
diluted with ethyl acetate (150 mL), washed with saturated sodium
thiosulfate (100 mL), 1.0 M aqueous sodium hydroxide solution
(3.times.50 mL), brine (50 mL), dried over anhydrous sodium
sulfate, filtered the solid, and concentrated in vacuo. The residue
was purified by flash chromatography (0-50% ethyl acetate in
hexanes) to provide tert-butyl
4-((3,5-dichlorophenyl)sulfonyl)piperidine-1-carboxylate (2.12 g,
53%) and tert-butyl
4-((3,5-dichlorophenyl)sulfonyl)piperidine-1-carboxylate (1.35 g,
34%) as a colorless solids. Analytical data for tert-butyl
4-((3,5-dichlorophenyl)sulfonyl)piperidine-1-carboxylate: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.73-7.68 (m, 2H), 7.64-7.60 (m,
1H), 4.31-4.15 (m, 2H), 3.10-2.97 (m, 1H), 2.72-2.56 (m, 2H),
1.99-1.89 (m, 2H), 1.67-1.51 (m, 2H), 1.41 (s, 9H); MS(ES+) m/z
294.0, 296.0 (M-Boc+H). Analytical data for tert-butyl
4-((3,5-dichlorophenyl)sulfonyl)piperidine-1-carboxylate: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.46-7.44 (m, 1H), 7.43-7.41 (m,
2H), 4.27-4.12 (m, 2H), 2.76-2.59 (m, 3H), 1.86-1.76 (m, 1H),
1.68-1.54 (m, 3H), 1.40 (s, 9H); MS(ES+) m/z 378.0, 380.0
(M+1).
Step 2. Preparation of 4-((3,5-dichlorophenyl)sulfonyl)piperidine
hydrochloride
##STR01407##
[2450] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
4-(3,5-dichlorophenyl)sulfonyl)piperidine-1-carboxylate, the title
compound was obtained as a colorless solid (1.78 g, quant. yield):
MS(ES+) m/z 294.1, 296.1 (M+1).
Step 3. Preparation of tert-butyl
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfonyl)
piperidin-1-yl)methyl)-2-fluorobenzoate
##STR01408##
[2452] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-((3,5-dichlorophenyl) sulfonyl)piperidine hydrochloride, the
title compound was obtained as a colorless solid (2.63 quant.
yield): MS(ES+) m/z 542.0, 544.0 (M+1).
Step 4. Preparation of
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfonyl)piperidin-1-yl)
methyl)-2-fluorobenzoic acid hydrochloride
##STR01409##
[2454] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)
sulfonyl)piperidin-1-yl)methyl)-2-fluorobenzoate, the title
compoond was obtained as a colorless solid (2.59 g, 90%): MS(ES+)
m/z 486.0, 488.1 (M+1).
Step 5. Preparation of
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfonyl)
piperidin-1-yl)methyl)-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01410##
[2456] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfonyl)piperidin-1-yl)methyl)--
2-fluorobenzoic acid hydrochloride, and to replace
cyclopropanesulfonamide with methylsulfonamide, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.11 g, 20%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
12.17 (br s, 1H), 9.85 (br s, 1H), 8.12 (dd, J=1.7, 1.7 Hz, 1H),
7.84 (d, J=1.7 Hz, 2H), 7.39 (d, J=11.1 Hz, 1H), 7.23 (d, J=7.1 Hz,
1H), 4.32 (s, 2H), 3.75-3.59 (m, 3H), 3.32 (s, 3H), 2.98-2.75 (m,
2H), 2.10-1.96 (m, 3H), 1.88-1.68 (m, 2H), 0.98-0.88 (m, 2H),
0.76-0.66 (m, 2H); MS(ES+) m/z 563.0, 565.0 (M+1).
Example 533
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4-((3,5-dichlorophenyl)
sulfonyl)piperidin-1-yl)methyl)-2-fluorobenzamide, trifluoroacetic
acid salt
##STR01411##
[2458] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopopyl-4-((4-((3,5-dichlorophenyl)sulfonyl)piperidin-1-yl)methyl)-2-
-fluorobenzoic acid hydrochloride, and purification by preparative
HPLC, the the compound was obtained as a colorless solid (0.04 g,
7%): .sup.1H NMR (300 MHz, CDCl.sub.3+10% CD.sub.3OD) .delta.
7.65-7.61 (m, 2H), 7.60-7.57 (m, 1H), 7.38 (d, J=7.1 Hz, 1H), 7.16
(d, J=11.4 Hz, 1H), 4.02 (s, 2H), 3.28-3.20 (m, 2H), 3.17-3.06 (m,
1H), 3.02-2.91 (m, 1H), 2.66-2.51 (m, 2H), 2.11-2.00 (m, 2H),
1.97-1.74 (m, 3H), 1.34-1.25 (m, 2H), 1.08-0.98 (m, 2H), 0.95-0.86
(m, 2H), 0.62-0.54 (m, 2H); MS(ES+) m/z 589.1, 591.1 (M+1).
Example 534
Synthesis of
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfinyl)pipperidin-1-yl)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01412##
[2459] Step 1. Preparation of
4-((3,5-dichlorophenyl)sulfinyl)pipperidine hydrochloride
##STR01413##
[2461] Following the procedure described in Example 517 step 2, and
making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
4-((3,5-dichlorophenyl) sulfinyl)piperidine-1-carboxylate, the
title compound was obtained as a colorless solid (1.12 g, quant.
yield): MS(ES+) m/z 278.1, 280.1 (M+1).
Step 2. Preparation of tert-butyl
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfinyl)
piperidin-1-yl)methyl)-2-fluorobenzoate
##STR01414##
[2463] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-((3,5-dichlorophenyl) sulfinyl)piperidine, hydrochloride,
the title compound was obtained as a colorless solid (1.40 g, 80%):
MS(ES+) m/z 526.1, 528.1 (M+1).
Step 3. Preparation of
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfinyl)
piperidin-1-yl)methyl)-2-fluorobenzoic acid hydrochloride
##STR01415##
[2465] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)
sulfinyl)piperidin-1-yl)methyl)-2-fluorobenzoate, the title
compound was obtained as a colorless solid (1.35 g, quant. yield):
MS(ES+) m/z 470.0, 472.1 (M+1).
Step 4. Preparation of
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfinyl)piperidin-1-yl)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01416##
[2467] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfinyl)piperidin-1-yl)methyl)--
2-fluorobenzoic acid hydrochloride, and to replace
cyclopropanesulfonamide with methylsulfonamide, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.05 g, 9%): .sup.1H NMR (300 MHz, CDCl.sub.310% CD.sub.3OD)
.delta. 7.46-7.37 (m, 3H), 7.26-7.20 (m, 2H), 4.19 (s, 2H),
3.42-3.33 (m, 2H), 3.31-3.24 (m, 4H), 2.88-2.70 (m, 2H), 2.08-1.87
(m, 4H), 1.86-1.76 (m, 1H), 1.00-0.91 (m, 2H), 0.66-0.58 (m, 2H)
(Note: Note: exchangeable protons not observed.); MS(ES+) m/z
547.0, 549.0 (M+1).
Example 535
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4-((3,5-dichlorophenyl)sulfinyl-
) piperidin-1-yl)methyl)-2-fluorobenzamide, trifluoroacetic acid
salt
##STR01417##
[2469] Following the prooedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-((3,5-dichlorophenyl)sulfinyl)piperidin-1-yl)methyl)--
2-fluorobenzoic acid hydrochloride, and purification by preparative
HPLC, the title compound was obtained as a colorless solid (0.05 g,
8%): .sup.1H NMR (300 MHz, CDCl.sub.3+10% CD.sub.3OD) .delta.
7.47-7.42 (m, 2H), 7.42-7.39 (m, 2H), 7.29-7.23 (m, 1H), 4.26 (s,
2H), 3.33-3.27 (m, 2H), 3.05-2.95 (m, 1H), 2.94-2.84 (m, 2H),
2.82-2.72 (m, 1H), 2.13-2.03 (m, 2H), 2.02-1.93 (m, 2H), 1.88-1.77
(m, 1H), 1.39-1.30 (m, 2H), 1.12-1.03 (m, 2H), 1.02-0.95 (m, 2H),
0.68-0.60 (m, 2H); MS(ES+) m/z 573.1, 575.1. (M+1).
Example 536
Synthesis of
4-((4-(3-Chloro-2-fluoro-5-(trifluoromethyl)phenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifuoroacetic acid salt
##STR01418##
[2470] Step 1. Preparation of tert-butyl
4-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)piperidine-1-carboxylate
##STR01419##
[2472] Following the procedure as described in Example 519 step 3,
and making variation as required to replace
4-chloro-3-(trifluoromethyl)phenol with
3-chloro-2-fluoro-5-(trifluoromethyl)phenol and tert-butyl
5-cyclopropyl-2-fluoro-4-((4-((methylsulfonyl)oxy)piperidin-1-yl)methyl)b-
enzoate with tert-butyl
4-((methylsulfonyl)oxy)piperidine-1-carboxylate, the title compound
was obtained as an colorless oil (2.07 g, 69%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.29-7.25 (m, 1H), 7.11-7.06 (m, 1H),
4.55-4.46 (m, 1H), 3.74-3.61 (m, 2H), 3.41-3.29 (m, 2H), 1.97-1.85
(m, 2H), 1.83-1.71 (m, 2H), 1.44 (s, 9H); MS(ES+) m/z 342.0, 344.0
(M-55 ).
Step 2. Preparation of
4-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)piperidine
hydrochloride
##STR01420##
[2474] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
4-(3-chloro-2-fluoro-5-(trifluoromethyl)
phenoxy)piperidine-1-carboxylate, the title compound was obtained
as a colorless solid (2.24 g, quant. yield): MS(ES+) m/z 298.1,
300.1 (M+1).
Step 3. Preparation of tert-butyl
4-((4-(3-chloro-2-fluoro-5-(trifluoromethyl)
phenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoate
##STR01421##
[2476] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-(3-chloro-2-fluoro-5-(trifluoromethyl) phenoxy)piperidine
hydrochloride, the title compound was obtained as a colorless solid
(2.00, 66%): MS(ES+) m/z: 546.2, 548.2 (M+1).
Step 4. Preparation of
4-((4-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)
piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride
##STR01422##
[2478] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
4-((4-(3-chloro-2-fluoro-5-(trifluoromethyl)
phenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoate, the
title compound was obtained as a colorless solid (1.93 g, quant.
yield): MS(ES+) m/z 490.1, 492.1 (M+1).
Step 5. Preparation of
-((4-(3-Chloro-2-fluoro-5-(trifluoromethyl)phenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01423##
[2480] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((4-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)piperidin-1-yl)methyl-
)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride, and to replace
cyclopropanesulfonamide with methylsulfonamide, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.22 g, 38%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
12.19 (br s, 1H), 10.27 (br s, 1H), 7.68-7.61 (m, 2H), 7.52 (d,
J=11.1 Hz, 1H), 7.25 (d, J=7.1 Hz, 1H), 4.95-4.77 (m, 1H), 4.57 (s,
2H), 3.45-3.36 (m, 2H), 3.34 (s, 3H), 3.31-3.23 (m, 2H), 2.24-2.10
(m, 3H), 2.06-1.98 (m, 2H), 1.03-0.95 (m, 2H), 0.81-0.73 (m, 2H);
MS(ES+) m/z 567.1, 569.1 (M+1).
Example 537
Synthesis of
4-((4-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01424##
[2482] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((4-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)piperidin-1-yl)methyl-
)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride, and
purification by preparative HPLC, the title compound was obtained
as a colorless solid (0.25 g, 43%): .sup.1H NMR (300 MHz,
CDCl.sub.3+10% CD.sub.3OD) .delta. 7.40 (d, J =7.1 Hz, 1H),
7.34-7.25 (m, 2H), 7.13-7.08 (m, 1H), 4.67-4.59 (m, 1H), 4.41 (s,
2H), 3.42-3.30 (m, 2H), 3.29-3.15 (m, 2H), 3.02-2.91 (m, 1H),
2.32-2.17 (m, 2H), 2.13-2.01 (m, 2H), 1.90-1.79 (m, 1H), 1.34-1.26
(m, 2H), 1.08-0.96 (m, 4H), 0.69-0.61 (m, 2H); MS(ES+) m/z 593.1,
595.1 (M+1).
Example 538
Synthesis of
(R)-4-((1-(tert-butyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-N-(methylsulfon-
yl)benzamide
##STR01425##
[2483] Step 1. Preparation of methyl
(R)-4-((1-acetylpiperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate
##STR01426##
[2485] To a solution of methyl
(R)-5-cyclopropyl-2-fluoro-4-(piperidin-3-yloxy)benzoate (2.00 g,
6.82 mmol), triethylamine (1.90 mL, 13.64 mmol), and
4-dimethylaminopyridine (0.20 g, 1.64 mmol) in dichloromethane (60
mL) was added acetic anhydride (1.29 m.L, 13.64 mmol) under
nitrogen. The resulting solution was stirred at ambient temperature
for 18 hours. The reaction mixture was concentrated in vacuo,
diluted with ethyl acetate (100 mL), washed with aqueous saturated
ammonium chloride solution (2.times.50 mL), aqueous saturated
sodium bicarbonate solution (2.times.50 mL), and brine (30 mL);
dried over anhydrous sodium sulfate, filtered and concentrated in
vacuo. The residue was purified by flash chromatography (50-100%
ethyl acetate hexanes) to provide the title compound as a colorless
solid (1.28 g, 56%): MS(ES+) m/z 336.1 (M+1).
Step 2. Preparation of methyl
(R)-4-((1-(tert-butyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate
##STR01427##
[2487] To a solution of methyl
(R)-4-((1-acetylpiperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate
(1.28 g, 3.82 mmol) and 2,6-di-tert-butyl-4-methylpyridine (0.94 g,
4.58 mmol) in anhydrous dichloromethane (70 mL) at -78.degree. C.
under nitrogen was added trifluoromethanesulfonic anhydride (0.77
mL, 4.58 mmol) dropwise. The resulting mixture was stirred at
-78.degree. C. for 2 hours and then added methyl lithium (1.6 M in
diethyl ether, 11.9 mL, 19.04 mmol) dropwise. The resulting mixture
was stirred at -78.degree. C. for 1 hour and then quenched cold
with aqueous saturated ammonium chloride solution (50 mL). The
mixture was warmed to ambient temperature, the organic layer was
washed with brine (50 mL), dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo. The residue was purified by
preparative HPLC to provide the title compound as a colorless solid
(0.40 g, 30%): .sup.1H NMR (300 MHz, CDC.sub.3) .delta. 7.39 (d,
J=8.4 Hz, 1H), 6.46 (d, J=12.8 Hz, 1H), 4.67-4.39 (m, 1H), 3.84 (s,
3H), 3.46-3.31 (m, 1H), 3.16-2.98 (m, 1H), 2.32-2.11 (m, 3H),
2.05-1.93 (m, 1H), 1.91-1.69 (m, 2H), 1.50-1.34 (m, 1H), 1.15 (s,
9H), 0.90-0.81 (m, 2H), 0.66-0.55 (m, 2H); MS(ES+) m/z 350.3
(M+1).
Step 3. Preparation of
(R)-4-((1-(tert-butyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluoro-N-(methy-
lsulfonyl)benzamide
##STR01428##
[2489] To a mixture of
(R)-4-((1-(tert-butyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate
(0.14 g, 0.40 mmol) and sodium hydroxide (0.12 g, 2.85 mmol) in
tetrahydrofuran (10 mL) and water (2.5 mL) was refluxed for 6
hours. The reaction mixture was cooled to ambient temperature and
added 1.0 N aqueous hydrochloride acid solution (5 mL) and
concentrated in vacuo. The residue was dissolved in anhydrous
dimethylformamide (5 mL), and dichloromethane (5 mL). To this
solution was added methanesulfonamide (0.06 g, 0.60 mmol),
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.12
g, 0.60 mmol) and 4-dimethylaminopyridine (0.20 g, 1.60 mmol). The
resulting mixture was stirred for 20 hours at ambient temperature,
and diluted with 1.0 N aqueous hydrochloric acid solution (15 mL)
and brine (15 mL); extracted with dichloromethane:methanol (20:1
v/v, 2.times.50 mL); dried dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo. The residue was purified by
preparative HPLC to provide the title compound as a colorless solid
(0.03 g, 18%): .sup.1H NMR (300 MHz, CDCl.sub.3+10% CD.sub.3OD)
.delta. 7.29 (d, J=8.9 Hz, 1H), 6.54 (d, J=13.1 Hz, 1H), 4.51-4.38
(m, 1H), 3.47-3.37 (m, 1H), 3.29-3.18 (m, 1H), 3.09 (s, 3H),
2.37-2.23 (m, 2H), 2.19-2.07 (m, 1H), 1.94-1.73 (m, 3H), 1.44-1.29
(m, 1H), 1.19 (s, 9H), 0.81-0.73 (m, 2H), 0.58-0.49 (m, 2H);
MS(ES+) m/z 413.2 (M+1).
Example 539
Synthesis of
(R)-4-((1-(tert-butyl)piperidin-3-yl)oxy)-5-cyclopropyl-N-(cyclopropysulf-
onyl)-2-fluorobenzamide
##STR01429##
[2491] Following the procedure as described in Example 538 step 3,
and making variation as required to replace methylsulfonamide with
cyclopropanesulfonamide, the title compound was obtained as a
colorless solid (0.04 g, 23%): .sup.1H NMR (300 MHz, CDCl.sub.3+10%
CD.sub.3OD) .delta. 7.33 (d, J=8.7 Hz, 1H), 6.58 (d, J=13.4 Hz,
1H), 4.44-4.31 (m, 1H), 3.36-3.24 (m, 1H), 3.11-2.98 (m, 1H),
2.95-2.84 (m, 1H), 2.23-2.05 (m, 3H), 1.98-1.87 (m, 1H), 1.85-1.57
(m, 2H), 1.43-1.29 (m, 1H), 1.27-1.20 (m, 2H), 1.09 (s, 9H),
1.01-0.92 (m, 2H), 0.84-0.74 (m, 2H), 0.58-0.50 (m, 2H); MS(ES+)
m/z 439.2 (M+1).
Example 540
Synthesis of
5-cyclopropyl-4-((4-(1-(3,5-dichlorophenyl)ethyl)piperazin-1-yl)methyl)-2-
-fluoro-N-(methylsulfonyl)benzamide
##STR01430##
[2492] Step 1. Preparation of tert-butyl
4-(1-(3,5-dichlorophenyl)ethyl)piperazine-1-carboxylate
##STR01431##
[2494] To a solution of tert-butyl piperazine-1-carboxylate (3.13
g, 16.38 mmol) and 1-(3,5-dichlorophenyl)ethan-1-one (3.50 g, 18.51
mmol) in anhydrous tetrahydrofuran (80 mL) was added titanitium
isopropoxide (IV) (10.2 mL, 33.06 mmol) under nitrogen. The
resulting mixture was reflux for 18 hours, cooled to -42 .degree.
C. and added anhydrous methanol (3.0 mL) and sodium
triacetoxyborohydride (7.13 g, 33.66 mmol). After stirring for 5
hours at -42.degree. C., the reaction mixture was added acetic acid
(3.85 mL, 67.32 mmol) and allowed to warm to ambient temperature.
The reaction mixture was stirred for 18 hours and then refluxed for
16 hours, cooled to ambient temperature and diluted with ethyl
acetate (200 mL) and 1.0 M aqueous sodium hydroxide solution (100
mL). The mixture was filtered and the layers were separated. The
organic layer was washed with 1.0 M aqueous sodium hydroxide
solution (3.times.50 mL) and brine (3.times.50 mL); dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo. The
residue was purified by flash chromatography (0-50% ethyl acetate
in hexanes) to provide the title compound as an oil (2.70 g, 45%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.21-7.15 (m, 3H),
3.43-3.33 (m, 4H), 3.29 (q, J=6.7 Hz, 1H), 2.45-2.21 (m, 4H), 1.41
(s, 9H), 1.27 (d, J=6.6 Hz, 3H); MS(ES+) m/z 359.1, 361.1
(M+1).
Step 2. Preparation of
1-(1-(3,5-dichlorophenyl)ethyl)piperazine
##STR01432##
[2496] To a solution of tert-butyl
4-(1-(3,5-dichlorophenyl)ethyl)piperazine-1-carboxylate (2.70 g,
7.51 mmol) in dichloromethane (100 mL) was added trifluoroacetic
acid (25 mL). The resulting solution was stirred at ambient
temperature for 1 hour and then concentrated in vacuo. To the
residue was added 1.0 M aqueous sodium hydroxide solution (50 mL)
and extracted with dichloromethane (2.times.80 mL). The combined
organic extracts were washed with brine (50 mL), dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo to
provide the title compound as a colorless oil (1.80 g, 92%):
MS(ES+) m/z 259.1, 261.2 (M+1).
Step 3. Preparation of tert-butyl
5-cyclopropyl-4-((4-(1-(3,5-diclorophenyl)
ethyl)-piperazin-1-yl)methyl)-2-fluorobenzoate
##STR01433##
[2498] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 1-(1-(3,5-dichlorophenyl) ethyl)piperazine, the title compound
was obtained as a colorless oil (3.53 g, quant. yield): .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.51-7.43 (m, 1H), 7.27-7.09 (m, 2H),
3.61 (s, 2H), 3.34-3.22 (m, 1H), 2.58-2.28 (m, 8H), 1.98-1.85 (m,
1H), 1.55 (s, 9H), 1.33-1.23 (m, 3H), 0.94-0.83 (m, 2H), 0.66-0.53
(m, 2H); MS(ES+) m/z 507.2, 509.2 (M+1).
Step 4. Preparation of
5-cyclopropyl-4-((4-(1-(3,5-dichlorophenyl)ethyl)
piperazin-1-yl)methyl)-2-fluorobenzoic acid dihydrochloride
##STR01434##
[2500] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
5-cyclopropyl-4-((4-(1-(3,5-dichlorophenyl)
ethyl)piperazin-1-yl)methyl)-2-fluorobenzoate, the title compound
was obtained as a colorless solid (1.82 g, quant. yield): MS(ES+)
m/z 451.0, 453.0 (M+1).
Step 5. Preparation of
5-cyclopropyl-4-((4-(1-(3,5-dichlorophenyl)ethyl)piperazin-1-yl)
methyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01435##
[2502] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-(1-(3,5-dichlorophenyl)ethyl)piperazin-1-yl)methyl)-2-
-fluorobenzoic acid dihydrochloride, and to replace
cyclopropanesulfonamide with methylsulfonamide, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.01, g, 1%): .sup.1H NMR (300 MHz, CDCl.sub.3+10%
CO.sub.3OD) .delta. 7.50-7.43 (m, 1H), 7.18-7.09 (m, 4H), 3.59 (s,
2H), 3.31-3.19 (m, 4H), 2.56-2.25 (m, 8H), 1.18-1.79 (m, 1H),
1.29-1.20 (m, 3H), 0.90-0.81 (m, 2H), 0.59-0.50 (m, 2H); MS(ES+)
m/z 528.1, 530.1 (M+1).
Example 541
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((4-(1-(3,5-dichlorophenyl)
ethyl)piperazin-1-yl)methyl)-2-fluorobenzamide
##STR01436##
[2504] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-(1-(3,5-dichlorophenyl)ethyl)piperazin-1-yl)methyl)-2-
-fluorobenzoic acid dihydrochloride, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.08 g, 8%): .sup.1H NMR (300 MHz, CDCl.sub.3+10%
CO.sub.3OD) .delta. 7.47 (d, J=7.9 Hz, 1H), 7.17-7.09 (m, 4H)
3.28-3.18 (m, 3H), 3.01-2.91 (m, 1H), 2.55-2.39 (m, 8H), 1.89-1.78
(m, 1H), 1.35-1.26 (m, 2H), 1.24 (d, J=6.8 Hz, 3H), 1.07-0.98 (m,
2H), 0.89-0.80 (m, 2H), 0.57-0.49 (m, 2H); MS(ES+) m/z 554.1, 556.1
(M+1).
Example 542
Synthesis of
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)methoxy)-5--
cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01437##
[2505] Step 1. Preparation of tert-butyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)azetidine-1-c-
arboxylate
##STR01438##
[2507] To a mixture of tert-butyl
3-(hydroxymethyl)azetidine-1-carboxylate (8.96 g, 47.86 mmol),
tert-butyl 5-chloro-2,4-difluorobenzoate (14.28 g, 57.43 mmol)
anhydrous dimethylsulfoxide (250 mL) was added cesium carbonate
(28.10 g, 86.15 mmol). The reaction mixture was heated at
85.degree.0 C. under nitrogen for 6 hours, cooled to ambient
temperature and diluted with ethyl acetate (500 mL), washed with
water (250 mL), aqueous saturated ammonium chloride solution
(2.times.200 mL) and brine (2.times.100 mL); dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo. The residue was
purified by flash chromatography (0-25% ethyl acetate in hexanes)
to provide the title compound as a colorless solid (19.30 g, 81%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.83 (d, J=7.7 Hz, 1H),
6.61 (d, J=11.8 Hz, 1H), 4.13-.4.07 (m, 2H), 4.4 (d, J=8.4 Hz, 2H),
3.80 (dd, J=8.6, 5.2 Hz, 2H), 3.07-2.91 (m, 1H), 1.53 (s, 9H), 1.40
(s, 9H); MS(ES+) m/z 416.2, 418.2 (M+1).
Step 2. Preparation of tert-butyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)azetidin-
e-1-carboxylate
##STR01439##
[2509] To a degassed mixture of tert-butyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)
methyl)azetidine-1-carboxylate (8.45 g, 20.32 mmol),
cyclopropylboronic acid (43.49 g, 40.64 mmol), and potassium
phosphate (tribasic, 17.30 g, 81.28 mmol) in toluene (200 mL) and
water (20 mL) was added tricyclohexylphosphine tetrafluoroborate
(1.50 g, 4.06 mmol) and palladium (II) acetate (0.46 g, 2.03 mmol).
The resulting mixture was refluxed under nitrogen for 18 hours,
cooled to ambient temperature and filtered. The filtrate was
diluted with ethyl acetate (200 mL), washed with water (100 mL),
aqueous saturated ammonium chloride solution (100 mL) and brine
(100 mL); dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by flash
chromatography (0-18% ethyl acetate in hexanes) to provide the
title compound as a colorless solid (8.35 g, 93%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.37 (d, J=8.3 Hz, 1H), 6.49 (d, J=12.4
Hz, 1H), 4.10-4.01 (m, 4H), 3.86 (dd, J=8.6, 5.5 Hz, 2H), 3.07-2.91
(m, 1H), 1.99-1.87 (m, 1H), 1.54 (s, 9H), 1.40 (s, 9H), 0.90-0.30
(m, 2H), 0.63-0.53 (m, 2H); MS(ES+) m/z 422.2 (M+1).
Step 3. Preparation of methyl
4-(azetidin-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate
hydrochloride
##STR01440##
[2511] To anhydrous methanol (80 mL) under nitrogen was added
thionyi chloride (5.00 mL, 68.97 mmol) dropwise at 0.degree. C. The
resulting mixture was stirred at 0.degree. C. for 1 hour and then
added a solution of tert-butyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)azetidin-
e-1-carboxylate (8.35 g, 19.81 mmol) in anhydrous methanol (10 mL).
The resulting mixture was stirred at 0.degree. C. for 2 hours, at
ambient temperature for 18 hours and refluxed for 4 hours, and then
concentrated in vacuo. The residue was dissolved in anhydrous
toluene (50 mL) and concentrated in vacuo to provide the title
compound as a colorless solid (6.26 g, quant. yield): MS(ES+) m/z
280.2 (M+1).
Step 4. Preparation of methyl
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR01441##
[2513] Following the procedure as described in Example 525 step 1,
and making variation as required to replace methyl
5-cyclopropyl-2-fluoro-4-((3-methylazetidin-3-yl)methoxy)benzoate
hydrochloride with methyl
4-(azetidin-(3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate
hydrochloride and purification by flash chromatography (2:1 of
hexanes:ethyl acetate), the title compound was obtained as a
colorless oil (0.51 g, 53%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.18 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 6.56 (d, J=12.4 Hz,
1H), 6.48 (s, 1H), 4.28-4.20 (m, 2H), 4.18 (d, J=5.7 Hz, 2H), 4.02
(d, J=8.2, 5.3 Hz, 2H), 3.86 (s, 3H), 3.34-3.20 (m, 1H), 1.86-1.75
(m, 1H), 0.77-0.69 (m, 2H), 0.60-0.53 (m, 2H); MS(ES+) m/z 459.1,
461.0 (M+1).
Step 5. Preparation of
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)
azetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR01442##
[2515] Following the procedure as described in Example 525 step 2,
and making variation as required to replace methyl
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate with methyl
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained as a colorless solid (0.49 g, quant. yield): MS(ES+) m/z
445.1, 447.0 (M+1).
Step 6. Preparation of
-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01443##
[2517] Following the procedure asd described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)methoxy)-5--
cyclopropyl-2-fluorobenzoic acid, and to replace
cyclopropanesulfonamide with methylsulfonamide, the title compound
was obtained as a colorless solid (0.12 g, 42%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.70 (d, J=14.0 Hz, 1H), 8.17 (s, 1H),
7.54 (d, J=9.1 Hz, 1H), 6.59 (d, J=14.2 Hz, 1H), 6.48 (s, 1H),
4.28-4.19 (m, 4H), 4.06-3.98 (m, 2H), 3.38 (s, 3H), 3.33-3.23 (m,
1H), 1.87-1.76 (m, 1H), 0.80-0.72 (m, 2H), 0.61-0.54 (m, 2H);
MS(ES+) m/z 522.0, 524.0 (M+1).
Example 543
Synthesis of
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR01444##
[2519] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenxy)piperidin-1-yl)methyl)-2-fluo-
robenzoic acid with
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)methoxy)-5--
cyclopropyl-2-fluorobenzoic acid, the title compound was obtained
as a colorless solid (0.07 g, 23%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.66 (d, J=15.9 Hz, 1H), 8.18 (s, 1H), 7.56 (d,
J=8.9 Hz, 1H), 6.59 (d, J=14.1 Hz, 1H), 6.49 (s, 1H), 4.30-4.19 (m,
4H), 4.06-3.98 (m, 2H), 3.35-3.22 (m, 1H), 3.12-3.02 (m, 1H),
1.89-1.77 (m, 1H), 1.47-1.39 (m, 2H), 1.17-1.08 (m, 2H), 0.81-0.72
(m, 2H), 0.64-0.54 (m, 2H); MS(ES+) m/z 548.0, 550.0 (M+1).
Example 544
Synthesis of 5-cyclopropyl-4-(3,5-dichlorophenoxy)azetidin-1-)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01445##
[2520] Step 1. Preparation of tert-butyl
3-((methylsulfonyl)oxy)azetidin-1-carboxylate
##STR01446##
[2522] Following the procedure as described in Example 519 step 2,
and making variation as required to replace tert-butyl
5-cyclopropyl-2-fluoro-4-((4-hydroxypiperidin-1-yl)methyl)benzoate
with tert-butyl 3-hydroxyazetidine-1-carboxylate, the title
compound was obtained as a colorless oil (16.76 g, quant. yield):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 5.18-5.08 (m, 1H), 4.21
(dd, J=11.1, 6.7 Hz, 2H), 4.02 (dd, J =4.1, 11.0 Hz, 2H), 3.00 (s,
3H), 1.37 (s, 9H).
Step 2. Preparation of tert-butyl
3-(3,5-dichlorphenoxy)azetidin-1-carboxylate
##STR01447##
[2524] Following the procedure as described in Example 519 step 3,
and making variation as required to replace
4-chloro-3-(trifluoromethyl)phenol with 3,5-dichlorophenol, and to
replace tert-butyl
5-cyclopropyl-2-fluoro-4-((4-((methylsulfonyl)oxy)piperidin-1-yl)methyl)b-
enzoate with tert-butyl
3-((methylsulfonyl)oxy)azetidin-1-carboxylate, the title compound
was obtained as an colorless solid (7.06 g, 97%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 6.98-6.93 (m, 1H), 6.62-6.57 (m, 2H),
4.84-4.75 (m, 1H), 4.26 (dd, J=9.8, 6.4 Hz, 2H), 3.94 (dd, J=9.9,
4.1 Hz, 2H), 1.41 (s, 9H); MS(ES+) m/z 262.1, 264.1 (M-55).
Step 3. Preparation of 3-(3,5-dichlorophenoxy)azetidine
##STR01448##
[2526] Following the procedure as described in Example 540 step 2,
and making variation as required to replace tert-butyl
4-(1-(3,5-dichlorophenyl)ethyl)piperazine-1-carboxylate with
tert-butyl 3-(3,5-dichlorophenoxy)azetidine-1-carboxylate, the
title compound was obtained as an colorless oil (4.84 g, quant.
yield): MS(ES+) m/z 218.1, 220.1 (M+1).
Step 4. Preparation of tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)azetidin-1-yl)methyl)-2-fluorobe-
nzoate
##STR01449##
[2528] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 3-(3,5-dichlorophenoxy)azetidine, the title compound was
obtained as a colorless oil (1.81 g, 65%): .sup.1H NMR (300 MHz,
CDC.sub.3) .delta. 7.47 (d, J=7.3 Hz, 1H), 7.09 (d, J=11.7 Hz, 1H),
6.95-6.92 (m, 1H), 6.67-6.62 (m, 2H), 4.81-4.71 (m, 1H), 3.91-3.80
(m, 4H), 3.22-3.11 (m, 2H), 1.90-1.76 (m, 1H), 1.55 (s, 9H),
0.96-0.85 (m, 2H), 0.66-0.55 (m, 2H); MS(ES+) m/z 466.1, 468.1
(M+1).
Step 5. Preparation of
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)azetidin-1-yl)
methyl)-2-fluorobenzoic acid hydrochloride
##STR01450##
[2530] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)
azetidin-1-yl)methyl)-2-fluorobenzoate, the title compound was
obtained as a colorless solid (1.73 g, quant. yield): MS(ES+) m/z
410.0, 412.0 (M+1).
Step 6. Preparation of
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)azetidin-1-yl)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01451##
[2532] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)azetidin-1-yl)methyl)-2-fluorobe-
nzoic acid hydrochloride, and to replace cyclopropanesulfonamide
with methylsulfonamide, and purification by preparative HPLC, the
title compound was obtained as a colorless solid (0.60 g, 99%):
.sup.1H NMR (300 MHz, CDCl.sub.3+50% CD.sub.3OD) .delta. 8.00-7.93
(m, 1H), 7.78-7.68 (m, 1H), 7.55-7.49 (m, 1H), 7.26-7.18 (m, 2H),
5.66-5.55 (m, 1H), 5.24-5.08 (m, 4H), 4.60-4.49 (m, 2H), 3.84 (s,
3H), 2.46-2.35 (m, 1H), 1.62-1.49 (m, 2H), 1.26-1.16 (m, 2H);
MS(ES+) m/z 487.0, 489.0 (M+1).
Example 545
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((3-(3,5-dichlorophenoxy)azetidin-
-1-yl) methyl)-2-fluorobenzamide, trifluoroacetic acid salt
##STR01452##
[2534] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)azetidin-1-yl)methyl)-2-fluorobe-
nzoic acid hydrochloride, and purification by preparative HPLC, the
title compound was obtained as a colorless solid (0.40 g, 64%):
.sup.1H NMR (300 MHz, CDCl.sub.3+10% CD.sub.3OD) .delta. 7.48 (d,
J=7.1 Hz, 1H), 7.17 (d, J =10.8 Hz, 1H), 7.00-6.95 (m, 1H),
6.67-6.62 (m, 2H), 5.10-5.00 (m, 1H), 4.67-4.66 (m, 2H), 4.59 (s,
2H), 3.99-3.90 (m, 2H), 3.05-2.94 (m, 1H), 1.88-1.76 (m, 1H),
1.38-1.30 (m, 2H), 1.12-0.96 (m, 4H), 0.69-0.62 (m, 2H) (Note:
exchangeable protons not observed.); MS(ES+) m/z 513.0, 515.0
(M+1).
Example 546
Synthesis of
5-cyclopropyl-4-((4-(2,4-dichlorophenoxy)piperidin-1-yl)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoracetic acid
salt
##STR01453##
[2535] Step 1. Preparation of tert-butyl
4-(2,4-dichlorophenoxy)piperidine-1-carboxylate
##STR01454##
[2537] Following the procedure as described in Example 519 step 3,
and making variation as required to replace
4-chloro-3-(trifluoromethyl)phenol with 2,4-dichlorophenol, and to
replace tert-butyl
5-cyclopropyl-2-fluoro-4-((4-((methylsulfonyl)oxy)piperidin-1-yl)methyl)b-
enozoate with tert-butyl
4-((methylsulfonyl)oxy)piperidine-1-carboxylate, the title compound
was obtained as an colorless solid (3.16 g, 81%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.33 (d, J=2.4 Hz, 1H), 7.12 (dd, J=8.7,
2.6 Hz, 1H), 6.84 (d, J=8.7 Hz, 1H), 4.50-4.41 (m, 1H), 3.60 (ddd,
J=1.13, 8.0, 3.9 Hz, 2H), 3.48-3.35 (m, 2H), 1.91-1.71 (m, 4H),
1.42 (s, 9H); MS(ES+) m/z 290.1, 292.1 (M-t-Bu+2H).
Step 2. Preparation of 4-(2,4-dichlorophenoxy)piperidine
##STR01455##
[2539] Following the procedure as described in Example 540 step 2,
and making variation as required to replace tert-butyl
4-(1-(3,5-dichlorophenyl)ethyl)piperazine-1-carboxylate with
tert-butyl 4-(2,4-dichlorophenoxy)piperidine-1-carboxylate, the
title compound was obtained as an colorless oil (1.96 g, 87%):
MS(ES+) m/z 246.1, 248.1 (M+1).
Step 3. Preparation of tert-butyl
5-cyclopropyl-4-((4-(2,4-dichlorophenoxy)piperidin-1-yl)
methyl)-2-fluorobenzoate
##STR01456##
[2541] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-(2,4-dichlorophenoxy)piperidine, the title compound was
obtained as a colorless oil(2.76 g, 93%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.47 (d, J=7.3 Hz, 1H), 7.34 (d, J=2.3 Hz, 1H),
7.21-7.10 (m, 2H), 6.85 (d, J=8.9 Hz, 1H), 4.4-4.30 (m, 1H), 3.64
(s, 2H), 2.78-2.67 (m, 2H), 2.42-2.30 (m, 2H), 2.01-1.80 (m, 5H),
1.56 (s, 9H), 0.94-0.86 (m, 2H), 0.65-0.56 (m, 2H); MS(ES+) m/z
494.1, 496.1 (M+1).
Step 4. Preparation of
5-cyclopropyl-4-((4-(2,4-dichlorophenoxy)piperidin-1-yl)
methyl)-2-fluorobenzoic acid hydrochloride
##STR01457##
[2543] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
5-cyclopropyl-4-((4-(2,4-dichlorophenoxy)
piperidin-1-yl)methyl)-2-fluorobenzoate, the title compound was
obtained as a colorless solid (2.65 g, quant. yield): MS(ES+) m/z
438.1, 440.1 (M+1).
Step 5. Preparation of
5-cyclopropyl-4-(2,4-dichlorophenoxy)piperidin-1-yl)
methyl)-2-fluoro-N-(methylsulfonyl)benzamide, trifluoroacetic acid
salt
##STR01458##
[2545] Following the procedure as described in Example 53 step 5
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-(2,4-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoic acid hydrochloride, and to replace cyclopropanesulfonamide
with methylsulfonamide, and purification by preparative HPLC, the
title compound was obtained as a colorless solid (0.25 g, 40%):
.sup.1H NMR (300 MHz, CD.sub.3+10% CD.sub.3OD) .delta. 7.42 (d,
J=7.1 Hz, 1H), 7.36-7.28 (m, 2H), 7.16-7.09 (m, 1H), 6.86-6.80 (m,
1H), 4.69-4.59 (m, 2H), 3.40-3.17 (m, 7H), 2.27-2.00 (m, 4H),
1.89-1.77 (m, 1H), 1.06-0.95 (m, 2H), 0.70-0.61 (m, 2H); MS(ES+)
m/z 515.0, 517.0 (M+1).
Example 547
Synthesis of
5-cyclopropyl-N-(cyclopropyl-N-(cyclopropylsulfonyl)-4-((4-(2,4-dichlorop-
henoxy) piperidin-1-yl)methyl)-2-fluorobenzamide, trifluoroacetic
acid salt
##STR01459##
[2547] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-((4-(2,4-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluorob-
enzoic acid hydrochloride, and purification by preparative HPLC,
the title compound was obtained as a colorless solid (0.33 g, 50%):
.sup.1H NMR (300 MHz, CDCl.sub.3+10% CD.sub.3OD) .delta. 7.49-7.43
(m, 1H), 7.37-7.28 (m, 2H), 7.16-7.10 (m, 1 H), 6.87-6.80 (m, 1H),
4.69-4.61 (m, 1H), 4.43 (s, 2H), 3.48-3.15 (m, 4H), 3.04-2.92 (m,
1H), 2.30-2.14 (m, 2H), 2.13-2.01 (m, 2H), 1.89-1.77 (m, 1H),
1.39-1.28 (m, 2H), 1.13-0.94 (m, 4H), 0.72-0.63 (m, 2H); MS(ES+)
m/z 541.1, 543.1 (M+1).
Example 548
Synthesis of
4-((4-(3-chloro-5-(trifluoromethoxy)phenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01460##
[2548] Step 1. Preparation of tert-butyl
4-(3-chloro-5-(trifluoromethoxy)phenoxy)piperidine-1-carboxylate
##STR01461##
[2550] Following the procedure as described in Example 519 step 3,
and making variation as required to replace
4-chloro-3-(trifluoromethyl)phenol with
3-chloro-5-(trifluoromethoxy)phenol, and to replace tert-butyl
5-cyclopropyl-2-fluoro-4-((4-(methylsulfonyl)oxy)piperidin-1-yl)
methyl)benzoate with tert-butyl
4-(methylsulfonyl)oxy)piperidine-1-carboxylate, the title compound
was obtaitied as an colorless solid (2.41 g, 65%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 6.82-6.78 (m, 2H), 6.64-6.61 (m, 1H),
4.46-4.37 (m, 1H), 3.64 (ddd, J=13.4, 7.6, 3.9 Hz, 2H), 3.33 (ddd,
J=13.5, 7.6, 3.9 Hz, 2H), 1.95-1.82 (m, 2H), 1.77-1.64 (m, 2H),
1.44 (s, 9H); MS(ES+) m/z 340.1, 342.1 (M-t-Bu+2H).
Step 2. Preparation of
4-(3-chloro-5-(trifluoromethoxy)phenoxy)piperidine
##STR01462##
[2552] Following the procedure as described in Example 540 step 2,
and making variation as required to replace tert-butyl
4-(1-(3,5-dichlorophenyl)ethyl)piperazine-1-carboxylate with
tert-butyl
4-(3-chloro-5-(trifluoromethoxy)phenoxy)piperidine-1-carboxylate,
the title compound was obtained as an colorless oil (1.55 g, 86%):
MS(ES+) m/z 296.1, 298.1 (M+1).
Step 3. Preparation of tert-butyl
4-((4-(3-chloro-5-(trifluoromethoxy)phenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoate
##STR01463##
[2554] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 4-(3-chloro-5-(trifluoromethoxy) phenoxy)piperidine, the title
compound was obtained as a colorless oil (2.15 g, 76%): .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.48 (d, J=7.1 Hz, 1H), 7.17 (d,
J=11.6 Hz, 1H), 6.84-6.76 (m, 2H), 6.67-6.61 (m, 1H), 4.35-4.26 (m,
1H), 3.64 (s, 2H), 2.76-2.64 (m, 2H), 2.41-2.29 (m, 2H), 2.03-1.89
(m, 3H), 1.87-1.74 (m, 2H), 1.56 (s, 9H), 0.96-0.87 (m, 2H),
0.65-0.57 (m,2H); MS(ES+) m/z 544.2, 546.2 (M+1).
Step 4. Preparation of
4-((4-(3-chloro-5-(trifluoromethoxy)phenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride
##STR01464##
[2556] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate tert-butyl
4-((4-(3-chloro-5-(trifluoromethoxy)
phenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoate, the
title compound was obtained as a colorless solid (2.07 g, quant.
yield): MS(ES+) m/z 488.1, 490.1 (M+1).
Step 5. Preparation of
4-((4-(3-chloro-5-(trifluoromethoxy)phenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01465##
[2558] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlororphenoxy)piperidin-1-yl)methyl)-2-fl-
uorobenzoic acid with
4-((4-(3-chloro-5-(trifluoromethoxy)phenoxy)piperidin-1-yl)methyl)-5-cycl-
opropyl-2-fluorobenzoic acid hydrochloride, and to replace
cyclopropanesulfonamide with methylsulfonamide, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.15 g, 22%): .sup.1H NMR (300 MHz, CDCl.sub.3+10%
CD.sub.3OD) .delta. 7.42 (d, J=7.3 Hz, 1H), 7.33 (d, J=11.1 Hz,
1H), 6.84-6.78 (m, 2H), 6.65-6.60 (m, 1H), 4.64-4.55 (m, 1H), 4.41
(s, 2H), 3.45-3.33 (m, 2H), 3.30 (s, 3H), 3.24-3.11 (m, 2H),
2.33-2.19 (m, 2H), 2.15-2.03 (m, 2H), 1.91-1.80 (m, 1H), 1.08-0.99
(m, 2H), 0.71-0.64 (m, 2H); MS(ES+) m/z 565.2, 567.2 (M+1).
Example 549
Synthesis of
4-((4-(3-chloro-5-(trifluoromethoxy)phenoxy)piperidin-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01466##
[2560] Following the procedure as described in Example 53 step 5,
and making variation as required tO replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((4-(3-chloro-5-(trifluoromethoxy)phenoxy)piperidin-1-yl)methyl)-5-cycl-
opropyl-2-fluorobenzoic acid hydrochloride, and purification by
preparative HPLC, the title compound was obtaned as a colorless
solid (0.15 g, 21%): .sup.1H NMR (300 MHz, CDCl.sub.3+10%
CD.sub.3OD) .delta. 7.43 (d, J=7.0 Hz, 1H), 7.32 (d, 10.9 Hz, 1H),
6.82-6.77 (m, 2H), 6.64-6.59 (m, 1H), 4.62-4.57 (m, 1H), 4.41 (s,
2H), 3.35-3.25 (m, 2H), 3.23-3.09 (m, 2H), 3.04-2.93 (m, 1H),
2.32-2.17 (m, 2H), 2.13-2.01 (m, 2H), 1.91-1.79 (m, 1H), 1.37-1.28
(m, 2H), 1.11-0.97 (m, 4H), 0.71-0.62 (m, 2H); MS(ES+) m/z 591.1,
593.1 (M+1).
Example 550
Synthesis of
4-(((1R,3r,5S)-3-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)
oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluoro-N-(meth-
ylsulfonyl)benzamide, trifluoroacetic acid salt
##STR01467##
[2561] Step 1. Preparation of tert-butyl
(1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR01468##
[2563] To a mixture of (1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-ol
(4.20 g, 33.02 mmol) and 1.0 M aqueous sodium hydroxide solution
(50 mL, 50.0 mmol) in tetrahydrofuran (100 mL) was added
di-tert-butyl dicarbonate (8.65 g, 39.62 mmol). The resulting
mixture was stirred at ambient temperature for 18 hours, and
diluted with diethyl ether (200 mL); washed with brine (4.times.70
mL); dried over anhydrous sodium sulfate, filtered concentrated in
vacuo. The residue was triturated with hexanes to provide the title
compound as a colorless solid (6.87 g, 91%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 4.24-4.02 (m, 2.19-1.95 (m, 4H), 1.95-1.83 (m,
2H), 1.76-1.59 (m, 3H), 1.41 (s, 9H).
Step 2. Preparation tert-butyl
(1R,3r,5S)-3-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)
oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR01469##
[2565] Following the procedure as described in Example 521 step 1,
and making variation as required to replace tert-butyl
4-hydroxypiperidine-1-carboxylate with tert-butyl
(1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate, the
title compound was obtained as a colorless solid (1.57 g, 84%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.20 (s, 1H), 6.95 (s,
1H), 5.37-5.29 (m, 1H), 4.29-4.08 (m, 2H), 2.26-1.82 (m, 8H), 1.45
(s, 9H); MS(ES+) m/z 351.1, 353.1 (M-55).
Step 3. Preparation of
(1R,3r,5S)-3-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)
oxy)-8-azabicyclo[3.2.1]octane
##STR01470##
[2567] Following the procedure as described in Example 540 step 2,
and making variation as required to replace tert-butyl
4-(1-(3,5-dichlorophenyl)ethyl)piperazine-1-carboxylate with
tert-butyl
(1R,3r,5S)-3-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)-8-arahicyclo-
[3.2.1]octane-8-carboxylate, the title compound was obtained as an
colorless oil (1.18 g, quant. yield): MS(ES+) m/z 307.2, 309.2
(M+1).
Step 4. Preparation of tert-butyl
4-(((1R,3r,5S)-3-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)
oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoate
##STR01471##
[2569] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidin, trifluoroacetic acid salt
with (1R,3r,5S)-3-((5-chloro-4-(trifluoromethyl)
pyridin-2-yl)oxy)-8-azabicyclo[3.2.1]octane, the title compound was
obtained as a colorless oil (1.62 g, 76%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.20 (s, 1H), 7.47 (d, J=7.3 Hz, 1H), 7.32 (d,
J=12.1 Hz, 1H), 6.95 (s, 1H), 5.30-5.24 (m, 1H), 3.67 (s, 2H),
3.19-3.12 (m, 2H), 2.23-2.13 (m, 2H), 2.10-2.00 (m, 4H), 1.95-1.82.
(m, 3H), 1.56 (s, 9H), 0.93-0.84 (m, 2H), 0.64-0.57 (m, 2H);
MS(ES+) m/z 555.2, 557.2 (M+1).
Step 5. Preparation of
4-(((1R,3r,5S)-3-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)
oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoic
acid hydrochloride
##STR01472##
[2571] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
4-((1R,3r,5S)-3-((5-chloro-4-(trifluoromethyl)
pyridin-2-yl)oxy)-8-aziabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2--
fluorobenzoate, the title compound was obtained as a colorless
solid (1.56 g, quant. yield): MS(ES+) m/z: 499.0, 501.0 (M+1).
Step 6. Preparation of
4-(((1R,3r,5S)-3-((5-chloro-4-(trifluoromethyl)pyrdin-2-yl)
oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluoro-N-(meth-
ylsulfonyl)benzamide, trifluoroacetic acid salt
##STR01473##
[2573] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-(((1R,3r,5S)-3-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)-8-azabic-
yclo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride, and to replace cyclopropanesulfonamide with
methylsulfonamide, and purification by preparative HPLC, the title
compound was obtained as a colorless solid (0.14 g, 20%): .sup.1H
NMR (300 MHz, CDCl.sub.3+10% CD.sub.3OD) .delta. 8.18 (s, 1H),
7.50-7.37 (m, 2H), 6.94 (s, 1H), 5.37-5.27 (m, 1H), 4.40 (d, 2H),
3.98-3.83 (m, 2H), 3.29 (s, 3H), 2.80-2.63 (m, 2H), 2.52-2.41 (m,
2H), 2.38-2.25 (m, 2H), 2.19-2.08 (m, 2H), 1.86-1.75 (m, 1H),
1.05-0.95 (m, 2H), 0.71-0.62 (m, 2H); MS(ES+) m/z 576.1, 578.1
(M+1).
Example 551
Synthesis of 4-(((1R,3r,5S)-3-((5-chloro-4-(trifluoromethyl)
oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-N-(cyclopropylsu-
lfonyl)-2-fluorobenzamide, trifluoroacetic acid salt
##STR01474##
[2575] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-(((1R,3r,5S)-3-((5-chloro-4-(trifluoromethyl)phyridin-2-yl)
oxy-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoic
acid hydrochloride, and purification by preparative HPLC, the title
compound was obtained as a colorless solid (0.16 g, 22%): .sup.1H
NMR (300 MHz, CDCl.sub.3+10% CD.sub.3OD) .delta. 8.18 (s, 1H),
7.51-7.40 (m, 2H), 6.94 (s, 1H), 5.36-5.28 (m, 1H), 4.38 (s, 2H),
3.95-3.85 (m, 2H), 3.04-2.94 (m, 1H), 2.76-2.63 (m, 2H), 2.52-2.41
(m, 2H), 2.37-2.23 (m, 2H), 2.20-2.07 (m, 2H), 1.87-1.74 (m, 1H),
1.39-1.29 (m, 2H), 1.11-0.93 (m, 4H), 0.72-0.63 (m, 2H); MS(ES+)
m/z 602.1, 604.1 (M+1).
Example 552
Synthesis of
4-(((1R,3r,5S)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)
oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluoro-N-(meth-
ylsulfonyl)benzamide, trifluoroacetic acid salt
##STR01475##
[2576] Step 1. Preparation of tert-butyl
(1R,3r,5S)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)
oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR01476##
[2578] Following the procedure as described in Example 521 step 1,
and making variation as required to replace
2,5-dichloro-4-(trifluoromethyl)pryidine with
3-chloro-2-fluoro-5-(trifluoromethyl)pyridine and tert-butyl
4-hydroxypiperidine-1-carboxylate with tert-butyl
(1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate, the
title compound was obtained as a colorless solid (1.22 g, 34%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.77 (s, 1H), 7.71 (s,
1H), 5.53-5.46 (m, 1H), 4.31-4.12 (m, 2H), 2.30-2.08 (m, 4H),
2.05-1.81 (m, 4H), 1.45 (s, 9H); MS(ES+) m/z 351.1, 353.1
(M-55).
Step 2. Preparation of
(1R,3r,5S)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)
oxy)-8-azabicyclo[3.2.1]octane
##STR01477##
[2580] Following the procedure as described in Example 540 step 2,
and making variation as required to replace tert-butyl
4-(1-(3,5-dichlorophenyl)ethly)piperazine-1-carboxylate with
tert-butyl (1R,3r,5S)-3-((3-chloro-5-(trifluoromethyl)pyridin
-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate, the title
compound was obtained as an colorless oil (0.39 g, 42%): MS(ES+)
m/z 307.0, 309.0 (M+1).
Step 3. Preparation of tert-butyl
4-(((1R,3r,5S)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)
oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoate
##STR01478##
[2582] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with (1R,3r,5S)-3-((3-chloro-5-(trifluoromethyl)
pyridin-2-yl)oxy)-8-azabicyclo[3.2.1]octane, the title compound was
obtained as a colorless oil (0.68 g, 97%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.30-8.26 (m, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.48
(d, J=7.3 Hz, 1H), 7.34 (d, J=12.1 Hz, 1H), 5.44 (t, J=5.2 Hz, 1H),
3.68 (s, 2H), 3.21-3.13 (m, 2H), 2.27-2.16 (m, 4H), 2.10-1.99 (m,
2H), 1.96-1.84 (m, 3H), 1.56 (s, 9H), 0.93-0.85 (m, 2H), 0.65-0.57
(m, 2H); MS(ES+) m/z 555.2, 557.2 (M+1).
Step 4. Preparation of
4-(((1R,3r,5S)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)
oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoic
acid hydrochloride
##STR01479##
[2584] Following the procedure as described in Example 517 step 2,
and making variation as required to replace rept-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with in tert-butyl
4-(((1R,3r,5S)-3-((3-chloro-5-trifluoromethyl)
pyridin-2-yl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-f-
luorobenzoate, the title compound was obtained as a colorless solid
(0.66 quant. yield): MS(ES+) m/z 499.1, 501.1 (M+1).
Step 5. Preparation of
4-(((1R3r,5S)-3-((3-chloro-5-trifluoromethyl)pyridin-2-yl)
oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluoro-N-(meth-
ylsulfonyl)benzamide, trifluoroacetic acid salt
##STR01480##
[2586] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
-(((1R,3r,5S)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride, and to replace cyclopropanesulfonamide with
methylsulfonamide, and purification by preparative HPLC, the title
compound was obtained as a colorless solid (0.12 g, 29%): .sup.1H
NMR (300 MHz, CDCl.sub.3+10% CD.sub.3OD) .delta. 8.24 (s,1H), 7.83
(s, 1H), 7.50-7.41 (m, 2H), 5.53-5.46 (m, 1H), 4.42 (s, 2H),
3.97-3.87 (m, 2H), 3.30 (s, 3H), 2.80-2.68 (m, 2H), 2.66-2.54 (m,
2H), 2.38-2.25 (m, 2H), 2.20-2.09 (m, 2H), 1.87-1.75 (m, 1H),
1.05-0.95 (m, 2H), 0.72-0.63 (m, 2H); MS(ES+) m/z 576.0, 578.0
(M+1).
Example 553
Synthesis of
4-(((1R,3r,5S)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)
oxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluoro-N-(meth-
ylsulfonyl)benzamide, trifluoroacetic acid salt
##STR01481##
[2588] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
-(((1R,3r,5S)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-8-azabicy-
clo[3.2.1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride, and purification by preparative HPLC, the title
compound was obtained as a colorless solid (0.12 g, 27%): .sup.1H
NMR (300 MHz, CDCl.sub.3+10% CD.sub.3OD) .delta. 8.24 (s, 1H), 7.83
(s,1H), 7.52-7.41 (m, 2H), 5.53-5.46 (m, 1H), 4.42 (s, 2H),
3.97-3.87 (m, 2H), 3.05-2.95 (m, 1H), 2.80-2.68 (m, 2H), 2.66-2.54
(m, 2H), 2.38-2.25 (m, 2H), 2.20-2.09 (m, 2H), 1.87-1.75 (m, 1H),
1.38-1.29 (m, 2H), 1.13-0.94 (m, 1H), 0.73-0.62 (m, 2H); MS(ES+)
m/z 602.1, 604.0 (M+1).
Example 554
Synthesis of
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01482##
[2589] Step 1. Preparation of tert-butyl
4-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)
methyl)piperidin-1-carboxylate
##STR01483##
[2591] Following the procedure as described in Example 542 step 1,
and making variation as required to replace tert-butyl
3-(hydroxymethyl)azetidine-1-carboxylate with tert-butyl
4-(hydroxymethyl)piperidine-1-carboxylate, the title compound was
obtained as a colorless solid (7.39 g, 69%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.85 (d, J=7.6 Hz, 1H), 6.59 (d, J=11.9 Hz,
1H), 4.23-4.05 (m, 2H), 3.84 (d, J=6.2 Hz, 2H), 2.81-2.64 (m, 2H),
2.10-1.94 (m, 1H), 1.87-1.77 (m, 2H), 1.55 (s, 9H), 1.44 (s, 9H),
1.36-1.20 (m, 2H); MS(ES+) m/z 444.1, 446.2 (M+1).
Step 2. Preparation of tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)piperidine-1-carboxylate
##STR01484##
[2593] Following the procedure as described in Example 542 step 2,
and making variation as required to replace tert-butyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)azetidine-1-c-
arboxylate with tert-butyl
4-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)piperidine-1--
carboxylate, the title compound was obtained as a colorless solid
(8.12 g, 9.7%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.35 (d,
J=8.3 Hz, 1H), 6.47 (d, J=12.4 Hz, 1H), 4.23-4.04 (m, 2H), 3.81 (d,
J=6.2 Hz, 2H), 2.81-2.04 (m, 2H), 2.05-1.91 (m, 2H), 1.85-1.75 (m,
2H), 1.53 (s, 9H), 1.43 (s, 9H), 1.38-1.26 (m, 2H), 0.89-0.81 (m,
2H), 0.63-0.56 (m, 2H); MS(ES+) m/z: 450.2 (M+1).
Step 3. Preparation of methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
hydrochloride
##STR01485##
[2595] Following the procedure as described in Example 542 step 3,
and making variation as required to tert-butyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)azetidin-
e-1-carboxylate with tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)piperidi-
ne-1-carboxylate, the title compound was obtained as a colorless
solid (6.21 g, quant. yield): MS(ES+) m/z 308.2 (M+1).
Step 4. Preparation of methyl
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR01486##
[2597] Following the procedure as described in Example 525 step 1,
and making variation as required to replace methyl
5-cyclopropyl-2-fluoro-4-((3-methylazetidin-3-yl)methoxy)benzoate
hydrochloride with methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
hydrochloride and purification by flash chromatography, the title
compound was obtained as a colorless oil (0.71 g, 56%): .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 8.19 (s, 1H), 7.42 (d, J=8.4 Hz, 1H),
6.86 (s, 1H), 6.52 (d, J=12.5 Hz, 1H), 4.41-4.31 (m, 2H), 3.90-3.83
(m, H), 2.94 (d, J=13.0, 2.6 Hz, 2H), 2.23-2.08 (m, 1H), 2.01-1.90
(m, 3H), 1.44 (dq, J=12.4, 4.0 Hz, 2H), 0.94-0.82 (m, 2H),
0.67-0.57 (m, 2H); MS(ES+) m/z 487.1, 489.1 (M+1).
Step 5. Preparation of
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methoxy)-5-
-cyclopropyl-2-fluorobenzoic acid
##STR01487##
[2599] Following the procedure as described in Example 525 step 2,
and making variation as required, to replace methyl
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)me-
thoxy)-5-cyclopropyl-2-fluorobenzoate with methyl
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was
obtained as a colorless solid (0.49 g, 71%): MS(ES+) m/z 473.1,
475.1 (M+1).
Step 6. Preparation of
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01488##
[2601] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methoxy)-5-
-cyclopropyl-2-fluorobenzoic acid, and to replace
cyclopropanesulfonamide with methylsulfonamide, the title compound
was obtained as a colorless solid (0.15 g, 55%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.68 (br s, 1H), 8.20 (s, 1H), 7.56 (d,
J=8.7 Hz, 1H), 6.86 (s, 1H), 6.55 (d, J=14.1 Hz, 1H), 4.41-4.32 (m,
2H), 3.89 (d, J=6.28 Hz, 1H), 3.39 (s, 3H), 2.95 (dt, J=13.0, 2.6
Hz, 2H), 2.25-2.10 (m, 1H), 2.05-1.91 (m, 3H), 1.45 (dq, J=12.5,
3.6 Hz, 2H), 0.95-0.86 (m, 2H), 0.68-0.58 (m, 2H); MS(ES+) m/z
550.0, 552.0 (M+1).
Example 555
Synthesis of
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)
methoxy)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR01489##
[2603] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methoxy)-5-
-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzoic acid, the
title compound was obtained as a colorless solid (0.14 g, 49%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.67 (br s, 1H), 8.20 (s,
1H), 7.57 (d, J=9.1 Hz, 1H), 6.86 (s, 1H), 6.55(d, J=14.1 Hz, 1H),
4.41-4.31 (m, 2H), 3.89 (d, J=6.1 Hz, 2H), 3.12-3.03 (m, 1H),
3.00-2.89 (m, 2H), 2.25-2.09 (m, 1H), 2.05-1.90 (m, 3H), 1.53-1.37
(m, 4H), 1.17-1.07 (m, 2H), 0.94-0.85 (m, 2H), 0.67-0.59 (m, 2H);
MS(ES+) m/z 576.0, 578.0 (M+1).
Example 556
Synthesis of
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01490##
[2604] Step 1. Preparation of tert-butyl
4-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)
methyl)-4-methylpiperidine-1-carboxylate
##STR01491##
[2606] Following the procedure as described in Example 542 step 1,
and making variation as required to replace tert-butyl
3-(hydroxymethyl)azetidine-1-carboxylate with tert-butyl
4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate, the title
compound was obtained as a colorless solid (15.19 g, 70%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 77.83 (d, J=7.6 Hz, 1H), 6.58 (d,
J=11.9 Hz, 1H), 3.76-3.62 (m, 4H), 3.22-3.10 (m, 2H), 1.65-1.56 (m,
2H), 1.54 (s, 9H), 1.48-1.39 (m, 11H), 1.13 (s, 3H); MS(ES+) m/z
458.1, 460.0 (M+1).
Step 2. Preparation of tert-butyl
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)
methyl)-4-methylpiperidine-1-carboxylate
##STR01492##
[2608] Following the procedure as described in Example 542 step 2,
and making variation as required to replace tert-butyl
3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)azetidine-1-c-
arboxylate with tert-butyl
4-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)
methyl)-4-methylpiperidine-1-carboxylate, the title empoond was
obtained as a colorless solid (9.91 g, 69%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.38 (d, J=8.4 Hz, 1H), 6.47 (d, J=12.5 Hz,
1H), 3.77-3.61 (m, 4H), 3.23-3.09 (m, 2H), 2.00-1.88 (m, 1H),
1.69-1.57 (m, 2H), 1.54 (s, 9H), 1.48-1.38 (m, 11H), 1.13 (s, 3H),
0.89-0.82 (m, 2H), 0.62-0.55 (m, 2H); MS(ES+) m/z: 464.2 (M+1).
Step 3. Preparation of methyl
5-cyclopropyl-2-fluoro-4-((4-methylpiperidin-4-yl) methoxy)benzoate
hydrochloride
##STR01493##
[2610] Following the procedure as described in Example 542 step, 3,
and making variation as required to tert-butyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)azetidin-
e-1-carboxylate with tert-butt
4-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)-4-methy-
lpiperidine-1-carboxylate, the title compound was obtained as a
colorless solid (7.65 g, quant. yield): MS(ES+) m/z 322.2
(M+1).
Step 4. Preparation of methyl
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR01494##
[2612] Following the procedure as described in Example 525 step 1,
and making variation as required to replace methyl
5-cyclopropyl-2-fluoro-4-((3-methylazetidin-3-yl)methoxy)benzoate
hydrochloride with methyl
5-cyclopropyl-2-fluoro-4-((4-methylpiperidin-4-yl)methoxy)benzoate
hydrochloride, the title compound was obtained as a colorless oil
(0.87 g, 67%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.19 (s,
1H), 7.45 (d, J=8.4 Hz, 1H), 6.84 (s, 1H), 6.52 (d, J=12.5 Hz, 1H),
3.94-3.83 (m, 5H), 3.73 (s, 2H), 3.43-3.31 (m, 2H), 1.99-1.86 (m,
1H), 1.84-1.72 (m, 2H), 1.63-1.52 (m, 2H), 1.20 (s, 3H), 0.88-0.79
(m, 2H), 0.64-0.55 (m, 2H); MS(ES+) m/z 501.1, 503.1 (M+1).
Step 5. Preparation of
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid
##STR01495##
[2614] Following the procedure as described in Example 525 step 2,
and making variation as required to replace methyl
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)me-
thoxy)-5-cyclopropyl-2-fluorobenzoate with methyl
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)m-
ethoxy)-5-cyclopropyl-2-fluorobenzoate, the title emnponad was
obtained as a colorless solid (0.85 g, quant. yield): MS(ES+) m/z
487.1, 489.1 (M+1).
Step 6. Preparation of
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01496##
[2616] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, and to replace
cyclopropanesulfonamide with methylsulfonamide, the title compound
was obtained as a colorless solid (0.40 g, 82%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.71 (br s, 1H), 8.18 (s, 1H), 7.65 (d,
J=9.1 Hz, 1H), 8.84 (s, 1H), 6.56 (d, J=14.1 Hz, 1H), 3.95-3.84 (m,
2H), 3.76 (s, 2H), 3.42-3.30 (m, 5H), 1.98-1.87 (m, 1H), 1.84-1.71
(m, 2H), 1.63-1.53 (m, 2H), 1.21 (s, 3H), 0.91-0.82 (m, 2H),
0.64-0.56 (m, 2H); MS(ES+) m/z 564.0, 566.0 (M+1).
Example 557
Synthesis of
4-((1-(5chloro-4-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)
methyoxy)5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR01497##
[2618] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was
obtained as a colorless solid (0.35 g, 68%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.67 (d, J=13.6 Hz, 1H), 8.19 (s, 1H), 7.58 (d,
J=9.1 Hz, 1H), 6.84 (s, 1H), 6.55 (d, J=14.1 Hz, 1H), 3.97-3.84 (m,
2H), 3.76 (s, 2H), 3.43-3.29 (m, 2H), 3.13-3.01 (m, 1H), 1.99-1.87
(m, 1H), 1.85-1.72 (m, 2H), 1.64-1.51 (m, 2H), 1.46-1.38 (m, 2H),
1.21 (s, 3H), 1.16-1.07 (m, 2H), 0.91-0.81 (m, 2H), 0.65-0.56 (m,
2H); MS(ES+) m/z 590.0, 592.0 (M+1).
Example 558
Synthesis of
5-cyclopropyl-4-(((1S,4S)-5-((3,5-dichlorophenyl)sulfonyl)-2,5-diazabicyc-
lo[2.2.1]heptan-2-yl)methyl)-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01498##
[2619] Step 1. Preparation of tert-butyl
(1S,4S)-5-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorobenzyl)-2,5-diaz-
abicyclo[2.2.]heptane-2-carboxylate
##STR01499##
[2621] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoromacetic acid salt
with tert-butyl
(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, the title
compound was obtained as a colorless solid (2.61 g, 67%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.46 (d, J=7.1 Hz, 1H), 7.18 (d,
J=12.1 Hz, 1H), 4.41-4.22 (m, 1H), 3.94-3.77 (m, 2H), 3.65-3.39 (m,
2H), 3.23-3.13 (m, 1H), 2.98-2.82 (m, 1H), 2.75-2.43 (m, 1H),
1.93-1.80 (m, 2H), 1.77-1.60 (m, 1H), 1.55 (s, 9H), 1.44 (s, 9H),
0.94-0.86 (m, 2H), 0.64-0.55 (m, 2H); MS(ES+) m/z 447.2 (M+1).
Step 2. Preparation of methyl
4-((((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)
methyl)-5-cyclopropyl-2-fluorobenzoate hydrochloride
##STR01500##
[2623] Following the procedure as described in Example 542 step 3,
and making variation as required to tert-butyl
3-((4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)azetidin-
e-1-carboxylate with tert-butyl
(1S,4S)-5-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorobenzyl)-2,5-diaz-
abicyclo[2.2.1]heptane-2-carboxylate, the title compound was
obtained as a colorless solid (2.12 g, 96%): MS(ES+) m/z 305.2
(M+1).
Step 3. Preparation of methyl
5-cyclopropyl-4-(((1S,4S)-5-((3,5-dichlorophenyl)
sulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-2-fluorobenzoate
##STR01501##
[2625] To a mixture of of methyl
4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-5-cyclopropyl-2-fl-
uorobenzoate hydrochloride (0.38 g, 1.00 mmol) and
4-dimethyhaminopyridine (0.61 g, 5.00 mmol) in dichloromethane (10
mL) was added 3,5-dichlorobenzenesulfonyl chloride (0.37 g, 1.50
mmol). The reaction mixture was stirred at ambient temperature in a
sealed tube for 5 hours, was diluted with ethyl acetate (50 mL);
washed with water (40 mL), aqueous saturated sodium bicarbonate
solution (50 mL) and brine (50 mL); dried over anhydrous sodium
sulfate, filtered and concentrated in vacuo. The residue was
purified by flash chromatography (0-40% ethyl acetate in hexanes)
to provide the title compound as a colorless solid (0.51 g, quant.
yield): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.73-7.68 (m,
2H), 7.58-7.50 (m, 2H), 7.11 (d, J=11.8 Hz, 1H), 4.34 (s, 1H),
3.93-3.81 (m, 5H), 3.64 (d, J=9.5 Hz, 1H), 3.49 (s, 1H), 3.10 (d,
J=9.5, 2.1 Hz, 1H), 2.89 (dd, J=9.7, 2.1 Hz, 1H), 2.68 (d, J=9.7
Hz, 1H), 1.88-1.76 (m, 2H), 1.30 (d, J=9.7 Hz, 1H), 0.94-0.86 (m,
2H), 0.63-0.56 (m, 2H); MS(ES+) m/z 513.0, 515.0 (M+1).
Step 4. Preparation of
5-cyclopropyl-4-(((1S,4S)-5-((3,5-dichlorophenyl)
sulfonyl)-5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-2-fluorobenzoic
acid
##STR01502##
[2627] Following the procedure as described in Example 525 step 2,
and making variation required to replace methyl
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoate with methyl
5-cyclopropyl-4-(((1S,4S)-5-((3,5-dichlorophenyl)
sulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-2-fluorobenzoate,
the title compound was obtained as a colorless solid (0.51 g,
quant. yield): MS(ES+) m/z 499.0, 501.0 (M+1).
Step 5. Preparation of
5-cyclopropyl-4-(((1S,4S)-5-((3,5-dichlorophenyl)sulfonyl)-2.5-diazabicyc-
lo[2.2.1]heptan-2-yl) methyl)-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid
##STR01503##
[2629] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, and to replace
cyclopropanesulfonamide with methylsulfonamide, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.15 g, 43%): .sup.1H NMR (300 MHz, CDCl.sub.3+10%
CD.sub.3OD) .delta. 7.67-7.62 (m, 2H), 7.57-7.53 (m, 1H), 7.48-7.41
(m, 1H), 7.30-7.22 (m, 1H), 4.55-4.33 (m, 3H), 4.24 (s, 1H), 3.84
(d, J=11.1 Hz, 1H), 3.39-3.20 (m, 6H), 2.14 (d, J=11.1 Hz, 1H),
1.86-1.74 (m, 1H), 1.63 (d, J=11.6 Hz, 1H), 1.05-0.95 (m, 2H),
0.69-0.59 (m, 2H); MS(ES+) m/z 575.9, 577.9 (M+1).
Example 559
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-(((1S,4S)-5-((3,5-dichlorophenyl)
sulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01504##
[2631] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-4-methylpiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzoic acid, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.20 g, 56%): .sup.1H NMR (300 MHz, CDCl.sub.3+10%
CD.sub.3OD) .delta. 7.64 (d, J=1.7 Hz, 2H), 7.57-7.54 (m, 1H), 7.47
(d, J=7.3 Hz, 1H), 7.258 (d, J=11.4 Hz, 1H), 4.49-4.28 (m, 3H),
4.17 (s, 1H), 3.82 (d, J=11.4 Hz, 1H), 3.35-3.20 (m, 3H), 3.05-2.94
(m, 1H), 2.15-2.05 (m, 1H), 1.86-1.74 (m, 1H), 1.60 (d, J=11.3 Hz,
1H), 1.37-1.29 (m, 2H), 1.22-0.94 (m, 4H), 0.67-0.59 (m, 2H);
MS(ES+) m/z 602.3, 603.9 (M+1).
Example 560
Synthesis of
4-(((1R,3r,5s)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.-
1]octan-8-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01505##
[2633] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorphenoxy)piperidin-1-yl)methyl)-2-fluo-
robenzoic acid with
4-(((1R,3r,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.-
1]octan-8-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid
hydrochloride, and to replace cyclopropanesulfonamide with
methylsulfonamide, and purification by preparative HPLC, the title
compound was obtained as a colorless solid (0.36 g, 51%): .sup.1H
NMR (300 MHz, CDCl.sub.3+10% CD.sub.3OD) .delta. 7.47-7.39 (m, 2H),
6.81-6.78 (m, 1H), 6.75-6.72 (m, 1H), 6.56-6.52 (m, 1H), 4.62-4.56
(m, 1H), 4.38 (s, 2H), 3.90 (br s, 2H), 3.29 (s, 3H), 2.75-2.64 (m,
2H), 2.50-2.40 (m, 2H), 2.16-2.24 (m, 2H), 2.13 (d, J=16.4 Hz, 2H),
1.85-1.74 (m, 1H), 1.03-0.95 (m, 2H), 0.70-0.63 (m, 2H); MS(ES+)
m/z 591.1, 593.1 (M+1).
Example 561
Synthesis of
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)-3,3-dimethylpiperid-
in-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01506##
[2634] Step 1. Preparation of tert-butyl
3,3-dimethyl-4-oxopiperidine-1-carboxylate
##STR01507##
[2636] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate
(15.0 g, 75.30 mmol) in anhydrous tetrahydrofuran (400 mL) at
0.degree. C. was added sodium hydride (60% in mineral oil, 6.04 g,
151.00 mmol) under nitrogen. After stirring for 10 minutes, methyl
iodide (11.7 mL, 188.00 mmol) was added; the reaction mixture was
stirred at 0.degree. C. for 1 hour and stirred at ambient
temperature for 3 hours. The reaction mixture was quenched by
slowly addition of water (10 mL) and concentrated in vacuo to
remove about 300 mL tetrahydrofuran. The residue was diluted with
ethyl acetate (300 mL), washed with aqueous saturated ammonium
chloride solution (2.times.250 mL) and brine (100 mL); dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo. The
residue was triturated with hexanes to provide the title compound
as a colorless solid (6.68 g, 39%): .sup.1H NMR (300 MHz,
CDC.sub.3) .delta. 3.68 (t, J=6.2 Hz, 2H), 3.39 (s, 2H), 2.45 (t,
J=6.2 Hz, 2H), 1.45 (s, 9H), 1.07 (s, 6H).
Step 2. Preparaton of tert-butyl
4-hydroxy-3,5-dimethylpiperidine-1-carboxylate
##STR01508##
[2638] To a solution of tert-butyl
3,3-dimethyl-4-oxopiperidine-1-carboxylate (4.88 g, 21.47 mmol) in
anhydrous methanol (50 mL) at 0.degree. C. was added sodium
borohydride (0.87 g, 21.97 mmol) portionwise under nitrogen. The
resulting mixture was stirred at 0.degree. C. for 1 hour and then
stirred at ambient temperature for 2.hours. The reaction mixture
was concentrated in vacuo and the residue was diluted with ethyl
acetate (200 mL), washed with 1.0 M aqueous hydrochloric acid
solution (100 mL) and brine (2.times.70 mL); dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo to provide the
title compound as a colorless solid (4.92 g, quant. yield): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 3.92-3.68 (m, 1H), 3.58-3.41 (m,
1H), 3.37 (dd, J=9.2, 4.0 Hz, 1H), 3.07-2.93 (m, 1H), 2.69 (d,
J=13.3 Hz, 1H), 1.77-1.65 (m, 1H), 1.60-1.46 (m, 1H), 1.42 (s, 9H),
0.92 (s, 3H), 0.85 (s, 3H); MS(ES+) m/z 230.2 (M+1).
Step 3. Preparation of tert-butyl
4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)
oxy)-3,3-dimethylpiperidine-1-carboxylate
##STR01509##
[2640] To a mixture of tert-butyl
4-hydroxy-3,3-dimethylpiperidine-1-carboxylate (4.58 g, 19.97 mmol)
and 2,5-dichloro-4-(trifluoromethyl)pyridine (5.18 g, 23.96 mmol)
in anhydrous dimethylsulfoxide (150 mL) was added cesium carbonate
(19.52 g, 59.91 mmol). The reaction mixture was heated at
90.degree. C. under nitrogen for 18 hours, cooled to ambient
temperature, diluted with ethyl acetate (300 mL), washed with water
(150 mL) and brine (3.times.100 mL), dried over anhydrous sodium
sulfate, filtered and concentrated in vacuo. The residue was
purified by flash chromatography (0-12% ethyl acetate in hexanes)
to provide the title compound as a colorless oil (4.55 g, 56%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.18 (s, 1H), 7.01 (s,
1H), 4.91 (dd, J=8.3, 3.8 Hz, 1H), 3.80-3.60 (m, 1H), 3.55-3.43 (m,
1H), 3.25 (ddd, J=13.5, 8.7, 3.9 Hz, 1H), 2.97 (d, J=13.7 Hz, 1H),
1.98-1.83 (m, 1H), 1.73-1.58 (m, 1H), 1.44 (s, 9H), 0.97 (s, 3H),
0.95 (s, 3H); MS(ES+) m/z 353.0, 355.0 (M-55).
Step 4. Preparation of
5-chloro-2-((3,3-dimethylpiperidin-4-yl)oxy)-4-(trifluoromethyl)pyridine
##STR01510##
[2642] Following the procedure as described in Example 540 step 2,
and making variation as required to replace tert-butyl
4-(1-((3,5-dichlorophenyl)ethyl)piperazine-1-carboxylate with
tert-butyl
4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)-3,3-dimethylpiperidine--
1-carboxylate, the title compound was obtained as an colorless oil
(3.77 g, quant. yield): MS(ES+) m/z 309.1, 311.1 (M+1).
Step 5. Preparation of tert-butyl
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)
oxy)-3,3-dimethylpiperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoate
##STR01511##
[2644] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with 5-chloro-2-((3,3-dimethylpiperidin-4-yl)
oxy)-4-(trifluoromethyl)pyridine, the title compound was obtained
as a colorless solid (5.46 g, 79%): .sup.1H NMR (300 MHz,
CDC.sub.3) .delta. 8.18 (s, 1H), 7.47 (d, J=7.3 Hz, 1H), 7.17 (d,
J=11.9 Hz, 1H), 7.01 (s, 1H), 4.83 (dd, J=8.6, 3.9 Hz, 1H), 3.59
(s, 2H), 2.74-2.62 (m, 1H), 2.43 (d, J=10.9 Hz, 1H), 2.37-2.26 (m,
1H), 2.08-1.91 (m, 3H), 1.83-1.68 (m, 1H), 1.56 (s, 9H), 1.07 (s,
3H), 0.98-0.86 (m, 5H), 0.65-0.58 (m, 2H); MS(ES+) m/z 515.0, 516.9
(M+1).
Step 6. Preparation of
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)-3,3-yl)
methyl)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride
##STR01512##
[2646] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
4-((4-((5-chloro-4-(trifluoromethyl)
pyridin-2-yl)oxy)-3,3-dimethylpiperidin-1-yl)methyl)-5-cyclopropyl-2-fluo-
robenzoate, the title compound was obtained as a colorless solid
(1.59 g, quant. yield): MS(ES+) m/z 501.1, 503.1 (M+1).
Step 7. Preparation of
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)-3,3-dimethylpiperid-
in-1-yl)
methyl)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide,
trifluoroacetic acid salt
##STR01513##
[2648] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)-3,3-dimethylpiperid-
in-1-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride,
and to replace cyclopropanesulfonamide with methylsulfonamide, and
purification by preparative HPLC, the title compound was obtained
as a colorless solid (0.35 g, 34%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6+5% D.sub.2O) .delta. 8.45 (s, 1H), 7.49 (d, J=11.2 Hz,
1H) 7.32 (s, 1H), 7.25 (d, J=7.1 Hz, 1H), 5.06-4.91 (m, 1H), 4.43
(br s, 2H), 3.33 (s, 3H), 3.29-2.91 (m, 4H), 2.20-2.04 (m, 2H),
2.02-1.80 (m, 1H), 1.21-0.86 (m, 8H), 0.81-0.68 (m, 2H); MS(ES+)
m/z 578.1, 580.1 (M+1).
Example 562
Synthesis of
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)-3,3-dimethyipiperid-
in-1-yl)
methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide,
trifluoroacetic acid salt
##STR01514##
[2650] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
4-((4-((5-chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)-3,3-dimethylpiperid-
in-1-yl) methyl)-5-cyclopropyl-2-fluorobenzoic acid hydrochloride,
and purification by preparative HPLC, the title compound was
obtained as a colorless solid (0.50 g, 47%): .sup.1H NMR (300 MHz,
CDC.sub.3+10% CD.sub.3OD) .delta. 8.14 (s, 1H), 7.46 (d, J=7.3 Hz,
1H), 7.39 (d, J=11.2 Hz, 1H), 7.00 (s,1H), 4.99-4.92 (m, 1H),
4.48-4.32 (m, 2H), 3.56-3.32 (m, 1H), 3.21-3.08 (m, 1H), 3.05-2.97
(m, 1H), 2.96-2.88 (m, 1H), 2.87-2.74 (m, 1H), 2.35-2.19 (m, 1H),
2.08-1.95 (m, 1H), 1.92-1.81 (m, 1H), 1.38-1.29 (m, 2H), 1.20-0.89
(m, 10H), 0.70-0.63 (m, 2H); MS(ES+) m/z 604.2, 606.2 (M+1).
Example 563
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-(((1S,4S)-5-((R)-1-(3,5-dichlorop-
henyl)
ethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-2-fluorobenzamide-
, trifluoroacetic acid salt
##STR01515##
[2651] Step 1. Preparation of methyl
5-cyclopropyl-4-(((1S,4S)-5-((R)-1-(3,5-dichlorophenyl)ethyl)-2,5-diazabi-
cyclo[2.2.1]heptan-2-yl) methyl)-2-fluorobenzoate and methyl
5-cyclopropyl-4-((1S,4S)-5-((S)-1-(3,5-dichlorophenyl)
ethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-2-fluorobenzoate
##STR01516##
[2653] To a solution of methyl
4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-5-cyclopropyl-2-fl-
uorobenzoate dihydrochloride (0.38 g, 1.00 mmol) and
1-(3,5-dichlorophenyl)ethyl 4-methylbenzenesulfonate (0.41 g, 1.20
mmol) in anhydrous dimethylformamide (10 mL) was added potassium
carbonate (0.55 g, 4.00 mmol). The reaction mixture was heated at
80.degree. C. in a sealed tube for 6 hours, cooled to ambient
temperature, diluted with ethyl acetate (80 mL), washed with water
(50 mL) and brine (50 mL), dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo. The residue was purified by
preparative HPLC. The first eluting fraction was arbitrarily
assigned as methyl
5-cyclopropyl-4-(((1S,4S)-5-((R)-1-(3,5-dichlorophenyl)ethyl)-2,5-diazabi-
cyclo[2.2.1]heptan-2-yl) methyl)-2-fluorobenzoate as a colorless
oil (0.05 g, 10%)) and the second eluting fraction was arbitrarily
assigned as methyl
5-cyclopropyl-4-(((1S,4S)-5-((S)-(3,5-dichlorophenyl)ethyl)-2,5-di-
azabicyclo[2.2.1]heptan-2-yl) methyl)-2-fluorobenzoate as a
colorless oil (0.05 g, 10%). Analytical data for methyl
5-cyclopropyl-4-(((1S,4S)-5-((R)-1-(3,5-dichlorophenyl)ethyl)-2,5-diazabi-
cyclo[2.2.1]heptan-2-yl) methyl)-2-fluorobenzoate: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.54 (d, J=7.3 Hz, 1H), 7.31-7.17 (m, 4H),
3.97-3.85 (m, 4H), 3.75 (d, J=15.6Hz, 1H), 3.65-3.54 (m, 1H), 3.25
(d, J=11.4 Hz, 2H), 2.94-2.85 (s, 2H), 2.70 (d, J=9.7 Hz, 1H), 2.48
(dd, J=10.2, 2.4 Hz, 1H), 1.93-1.81 (m, 1H), 1.77-1.67 (m, 2H),
1.31 (d, J=6.4 Hz, 3H), 0.96-0.88 (m, 2H), 0.65-0.57 (m, 2H);
MS(ES+) m/z 477.1, 479.1 (M+1). Analytical data for methyl
5-cyclopropyl-4-((1S,4S)-5-((S)-1-(3,5-dichlorophenyl)
ethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-2-fluorobenzoate:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.54 (d, J=7.3 Hz, 1H),
7.30-7.17 (m, 4H), 3.93 (d, J=15.7 Hz, 1H), 3.88 (s, 3H), 3.79 (d,
J=15.7 Hz, 1H), 3.54 (q, J=5.9 Hz, 1H), 3.48 (s, 1H), 3.25 (s, 1H),
2.88 (d, J=9.9 Hz, 1H), 2.72-2.60 (m, 2H), 2.54 (d, J=9.6 Hz, 1H),
1.93-1.82 (m, 1H), 1.81-1.69 (m, 2H), 1.22 (d, J=5.9 Hz, 3H),
0.96-0.88 (m, 2H), 0.68-0.56 (m, 2H); MS(ES+) m/z 477.1, 479.1
(M+1).
Step 2. Prepatation of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-(((1S,4S)-5-((R)-1-(3,5-dichlorop-
henyl)
ethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-2-fluorobenzamide-
, trifluoroacetic acid salt
##STR01517##
[2655] Following the procedure as described in Example 538 step 3,
and making variation as required to replace
(R)-4-((1-(tert-butyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate
with methyl
5-cyclopropyl-4-(((1S,4S)-5-((R)-1-(3,5-dichlorophenyl)ethyl)-2,5-diazabi-
cyclo[2.2.1]heptan-2-yl) methyl)-2-fluorobenzoate, and to replace
methylsulfonamide with cyclopropanesulfonamide, and purification by
HPLC, the title compound was obtained as a colorless solid (0.07 g,
26%): .sup.1H NMR (300 MHz, DMSO-d.sub.6+5% D.sub.2O) .delta.
7.64-7.57 (m, 3H), 7.37 (d, J=11.5 Hz, 1H), 7.19 (d, J=7.1 Hz, 1H),
4.37-3.98 (m, 4H), 3.79 (br s, 1H), 3.38-3.23 (m, 2H), 3.10-2.86
(m, 3H), 2.20-2.03 (m, 2H), 2.02-1.92 (m, 1H), 1.52 (d, J=6.2 Hz,
3H), 1.13-1.04 (m, 4H), 0.95-0.87 (m, 2H), 0.70-0.60 (m, 2H);
MS(ES+) m/z 566.1, 568.1 (M+1).
Example 564
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-(((1S,4S)-5-((S)-1-(3,5-dichlorop-
henyl)
ethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-2-fluorobenzamide-
, trifluoroacetic acid salt
##STR01518##
[2657] Following the procedure as described in Example 538 step 3,
and making variation as required to replace
(R)-4-((1-(tert-butyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoate
with methyl
5-cyclopropyl-4-((1S,4S)-5-((S)-1-(3,5-dichlorophenyl)ethyl)-2,5-diazabic-
yclo[2.2.1]heptan-2-yl) methyl)-2-fluorobenzoate, and to replace
methylsulfonamide with cyclopropanesulfonamide, and purification by
HPLC, the title compound was obtained as a colorless solid (0.07 g,
17%): .sup.1H NMR (300 MHz, DMSO-d.sub.6+5% D.sub.2O) .delta. 7.62
(s, 1H), 7.55 (s, 2H), 7.39 (d, J=11.7 Hz, 1H), 7.21 (d, J=7.1 Hz,
1H), 4.39-4.08 (m, 3H), 3.90 (br s, 2H), 3.39-3.25 (m, 2H),
3.22-3.10 (m, 1H), 3.08-2.99 (m, 1H), 2.98-2.89 (m, 1H), 2.26-2.08
(m, 2H), 2.04-1.93 (m, 1H), 1.41 (d, J=6.5 Hz, 3H), 1.16-1.03 (m,
4H), 0.97-0.87 (m, 2H), 0.73-0.61 (m, 2H) (Note: Exchangeable
protons not observed); MS(ES+) m/z 566.2, 568.2 (M+1).
Example 565
Synthesis of
5-cyclopropyl-4-(((S)-4-((R)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiperaz-
in-1-yl) methyl)-2-fluoro-N-(methylsulfonyl)benzamide
##STR01519##
[2658] Step 1. Preparation of 1-benzyl-4-(tert-butyl)
(S)-2-methylpiperazine-1,4-dicarboxylate
##STR01520##
[2660] To a solution of tert-butyl
(S)-3-methylpiperazine-1-carboxylate (6.35 g, 31.71 mmol),
triethylamine (4.98 mL, 34.88 mmol) and 4-dimethylaminopyridine
(0.10 g, 0.82 mmol) in dichloromethane (80 mL) under nitrogen at
0.degree. C. was added dropwise benzyl chloroformate (8.84 mL,
63.42 mmol). The resulting mixture was stirred at 0.degree. C. for
2 hours and then at ambient temperature for 18 hours, quenched with
water (10 mL) and stirred for 1 hour. The mixture was diluted with
diluted with ethyl acetate (150 mL), washed with aqueous saturated
ammonium chloride solution (2.times.80 mL) and brine (80 mL), dried
over anhydrous sodium sulfate, filtered and concentrated in vacuo
to provide the title compound as an oil (10.45 g, 99%): .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.39-7.25 (m, 5H), 5.11 (s, 2H),
4.37-4.23 (m, 1H), 4.10-3.71 (m, 3H), 3.15-2.91 (m, 2H), 2.86-2.69
(m, 1H), 1.43 (s, 9H), 1.14 (d, J=6.8 Hz, 3H); MS(ES+) m/z 235.2
(M-99).
Step 2. Preparation of benzyl
(S)-2-methylpiperazine-1-carboxylate
##STR01521##
[2662] To a solution of 1-benzyl 4-(tert-butyl)
(S)-2-methylpiperazine-1,4-dicarboxylate (10.45 g, 31.25 mmol) in
dichloromethane (70 mL) was added trifluoroacetic acid (35 mL).
After stirring at ambient temperature for 5 hours, the reaction
mixture was concentrated in vacuo and the residue was dissolved in
diethyl ether (80 mL) and extracted with 1.0 M aqueous hydrochloric
acid solution (2.times.25 mL).
[2663] The combined aqueous layers were basified with 2.0 M aqueous
sodium hydroxide solution to pH=9, and extracted with diethyl ether
(2.times.100 mL), the combined organic layers were washed with
brine (2.times.50 mL), dried over anhydrous sodium sulfate;
filtered and concentrated in vacuo to provide the title compound as
an oil (6.28 g, 86%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.36-7.23 (m, 5H), 5.13 (d, J=12.7 Hz, 1H), 5.08 (d, J=12.7 Hz,
1H), 4.27-4.16 (m, 1H), 3.88-3.79 (m, 1H), 3.02 (td, J=12.7, 3.3
Hz, 1H), 2.95-2.83 (m, 2H), 2.76-2.70 (m, 1H), 2.64 (td, J=12.7,
3.4 Hz, 1H), 1.21 (d, J=7.0 Hz, 3H); MS(ES+) m/z 235.1 (M+1).
Step 3. Preparation of benzyl
(S)-4-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorobenzyl)-2-methylpipe-
razine-1-carboxylate
##STR01522##
[2665] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with benzyl (S)-2-methylpiperazine-1-carboxylate, the title
compound was obtained as a colorless solid (6.58 g, 84%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.47 (d, J=7.3 Hz, 1H), 7.38-7.25
) (m, 5H), 7.14 (d, J=11.7 Hz, 1H), 5.17-5.07 (m, 2H), 4.34-4.23
(m, 1H), 3.95-3.85 (m, 1H), 3.58 (s, 2H), 3.17 (td, J=12.4-3.0 Hz,
1H), 2.74 (d, J=11.1 Hz, 1H), 2.59 (d, J=11.1 Hz, 1H), 2.22 (dd,
J=11.1, 3.8 Hz, 1H), 2.08 (td, J=11.8, 3.3 Hz, 1H), 2.01-1.90 (m,
1H), 1.56 (s, 9H), 1.26 (d, J=6.7 Hz, 3H), 0.94-0.86 (m, 2H),
0.64-0.57 (m, 2H); MS(ES+) m/z 483.1 (M+1).
Step 4. Preparation of tert-butyl
(S)-5-cyclopropyl-2-fluoro-4-((3-methylpiperazin-1-yl)methyl)benzoate
##STR01523##
[2667] To a degassed mixture of 10% palladium on carbon (50% wetted
powder, 2.0 g) in methanol (50 mL) was added a solution of benzyl
(S)-4-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorobenzyl)-2-methylpipe-
razine-1-carboxylate (5.51 g, 11.42 mmol) in methanol (50 mL). The
resulting mixture was bubbled with hydrogen gas for 2 minutes and
then held under 1 atmosphere of hydrogen for 2 hours. The reaction
mixture was bubbled with nitrogen, filtered through diatomaceous
earth, and concentrated in vacuo to provide the title compound as a
colorless oil (3.98 g, quant. yield): MS(ES+) m/z: 349.3 (M+1).
Step 5. Preparation of tert-butyl
5-cyclopropyl-4-(((S)-4-((R)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiperaz-
in-1-yl) methyl)-2-fluorobenzoate and tert-butyl
5-cyclopropyl-4-(((S)-4-((S)-1-(3,5-dichlorophenyl)
ethyl)-3-methylpiperazin-1-yl)methyl)-2-fluorobenzoate
##STR01524##
[2669] Following the procedure as described in Example 563 step 1,
and making variation as required to replace methyl
4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-5-cyclopropyl-2-fl-
uorobenzoate dihydrochloride with tert-butyl
(S)-5-cyclopropyl-2-fluoro-4-((3-methylpiperazin-1-yl)
methyl)benzoate and purification by flash chromatography (0-15%
ethyl acetate (+10% isopropanol, 10% triethylamine) in hexanes. The
first eluting fraction was arbitrarily assigned as tert-butyl
5-cyclopropyl-4-(((S)-4-((R)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiperaz-
in-1-yl) methyl)-2-fluorobenzoate (1.44 g, 29%): MS(ES+) m/z:
521.3, 523.2 (M+1). The second eluting fraction was arbitrarily
assigned as tert-butyl
5-cycloproppyl-4-(((S)-4-((S)-1-(3,5-dichlorophenyl)
ethyl)-3-methylpiperazin-1-yl)methyl)-2-fluorobenzoate (3.27 g,
66%) MS(ES+) m/z: 521.2, 523.2 (M+1).
Step 6. Preparation of
5-cyclopropyl-4-(((S)-4-((R)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiperaz-
in-1-yl) methyl)-2-fluorobenzoic acid hydrochloride
##STR01525##
[2671] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
5-cyclopropyl-4-(((S)-4-((R)-1-(3,5-dichlorophenyl)
ethyl)-3-methylpiperazin-1-yl)methyl)-2-fluorobenzoate, the title
compound was obtained as a colorless solid (1.49 g, quant. yield):
MS(ES+) m/z 465.0, 467.0 (M+1).
Step 7. Preparation of
5-cyclopropyl-4-(((S)-4-((R)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiperaz-
in-1-yl) methyl)-2-fluoro-N-(methylsulfonyl)benzamide
##STR01526##
[2673] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-(((S)-4-((R)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiperaz-
in-1-yl) methyl)-2-fluorobenzoic acid hydrochloride, and to replace
cyclopropanesulfonamide with methylsulfonamide, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.07 g, 9%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.69
(d, J=7.7 Hz, 1H), 7.32-7.25 (m, 3H), 7.20-7.18 (m, 1H), 3.98-3.85
(m, 1H), 3.62 (s, 2H), 3.39 (s, 3H), 3.04-2.92 (m, 1H), 2.65-2.57
(m, 1H), 2.50-2.41 (m, 1H), 2.36-2.19 (m, 4H), 1.98-1.87 (m, 1H),
1.24 (d, J=6.7 Hz, 3H), 1.10 (d, J=6.3 Hz, 3H), 0.98-0.91 (m, 2H),
0.66-0.59 (m, 2H); MS(ES+) m/z 542.1, 544.1 (M+1).
Example 566
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-(((S)-4-((R)-1-(3,5-dichloropheny-
l)ethyl)-3-methylpiperazin-1-yl) methyl)-2-fluorobenzamide
##STR01527##
[2675] Following the ptocedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-(((S)-4-((R)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiperaz-
in-1-yl) methyl)-2-fluorobenzoic acid hydrochloride, and
purification by preparative HPLC, the title compound was obtained
as a colorless solid (0.11 g, 14%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.74 (br s, 1H), 7.70 (d, J=7.8 Hz, 1H),
7.34-7.25 (m, 3H), 7.21-7.17 (m, 1H), 3.97-3.84 (m, 1H), 3.61 (m,
2H), 3.13-3.03 (m, 1H), 3.02-2.91 (m, 1H), 2.65-2.57 (m, 1H),
2.50-2.40 (m, 1H), 2.35-2.17 (m, 4H), 1.98-1.87 (m, 1H), 1.48-1.40
(m, 2H), 1.24 (d, J=6.5 Hz, 3H), 1.17-1.06 (m, 5H), 0.98-0.90 (m,
2H), 0.66-0.59 (m, 2H); MS(ES+) m/z 568.2, 570.2 (M+1).
Example 567
Synthesis of
5-cyclopropyl-4-(((S)-4-((S)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiperaz-
in-1-yl) methyl)-2-fluoro-N-(methytsulfonyl)benzamide
##STR01528##
[2676] Step 1. Preparation of
5-cyclopropyl-4-(((S)-4-((S)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiperaz-
in-1-yl) methyl)-2-fluorobenzoic acid dihydrochloride
##STR01529##
[2678] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
5-cyclopropyl-4-(((S)-4-((S)-(3,5-dichlorophenyl)
ethyl)-3-methylpiperazin-1-yl)methyl)-2-fluorobenzoate, the title
compound was obtained as a colorless solid (3.38 g, quant.):
MS(ES+) m/z 465.0, 467.0 (M+1).
Step 2. Preparation of
5-cyclopropyl-4-(((S)-4-((S)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiperaz-
in-yl) methyl)-2-fluoro-N-(methylsulfonyl)benzamide
##STR01530##
[2680] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzeic acid with
5-cyclopropyl-4-(((S)-4-((S)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiperaz-
in-1-yl) methyl)-2-fluorobenzoic acid hydrochloride, and to replace
cyclopropanesulfonamide with methylsulfonamide, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.003 g, 0.2%): MS(ES+) m/z 542.2, 544.2 (M+1).
Example 568
Synthesis of
5-cyclopropyl-N-cyclopropylsulfonyl)-4-(((S)-4-((S)-1-(3,5-dichlorophenyl-
)ethyl)-3-)methylpiperazin-1-yl) methyl)-2-fluorobenzamide
##STR01531##
[2682] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-(((S)-4-((S)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiperaz-
in-1-yl) methyl)-2-fluorobenzoic acid hydrochloride, and
purification by preparative HPLC, the title compound was obtained
as a colorless solid (0.004 g, 0.2%): MS(ES+) m/z 568.2, 570.2
(M+1).
Example 569
Synthesis of
5-cyclopropyl-4-(((R)-4-((R)-1-(3,5-dichlorophenyl)ethyl-3-methylpiperazi-
n-1-yl) methyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01532##
[2683] Step 1. Preparation of 1-benzyl 4-(tert-butyl)
(R)-2-methylpiperazine-1,4-dicarboxylate
##STR01533##
[2685] Following the procedure as described in Example 565 step 1,
and making variation as required to replace tert-butyl
(S)-3-methylpiperazine-1-carboxylate with tert-butyl
(R)-3-methylpiperazine-1-carboxylate, the title compound was
obtained as a colorless oil (10.60 g, quant. yield): .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.39-7.26 (m, 5H) 5.16-5.06 (m, 2H),
4.37-4.23 (m, 1), 4.12-3.70 (m, 3H), 3.16-2.91 (m, 2H), 2.88-2.68
(m, 1H), 1.43 (s, 9H), 1.14 (d, J=6.7 Hz, 3H); MS(ES+) m/z 235.2
(M-Boc+H).
Step 2. Preparation of benzyl
(R)-2-methylpiperazine-1-carboxylate
##STR01534##
[2687] Following the procedure as described in Example 565 step 2,
and making variation as required to replace 1-benzyl 4-(tert-butyl)
(S)-2-methylpiperazine-1,4-dicarboxylate with 1-benzyl
4-(tert-butyl) (R)-2-methylpiperazine-1,4-dicarboxylate, the title
compound was obtained as a colorless oil (6.80 g, 82%): .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.36-7.24 (m, 5H), 5.16-5.05 (m, 2H),
4.27-4.17 (m, 1H), 3.88-3.79 (m, 1H), 3.02. (td, J=12.5, 3.3 Hz,
1H), 2.95-2.82 (m, 2H), 2.77-2.70 (m, 1H), 2.64 (td, J=12.3, 3.5
Hz, 1H), 1.49 (br s, 1H), 1.21 (d, J=6.5 Hz, 3H); MS(ES+) m/z:
235.1 (M+1).
Step 3. Preparation of benzyl
(R)-4-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorobenzyl)-2-methylpipe-
razine-1-carboxylate
##STR01535##
[2689] Following the procedure as described in Example 53 step 3,
and making variation as required to replace
(S)-3-(3,5-dichlorophenoxy)piperidine, trifluoroacetic acid salt
with benzyl (R)-2-methylpiperazine-1-carboxylate, the title
compound was obtained as a colorless solid (7.04 g, 90%): .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.47 (d, J=7.4 Hz, 1H), 7.36-7.25
(m, 5H), 7.14 (d, J=11.8 Hz, 1H), 5.17-5.07 (m, 2H), 4.34-4.23 (m,
1H), 3.95-3.86 (m, 1H), 3.58 (s, 2H), 3.17 (td, J=12.7, 3.2 Hz,
1H), 2.74 (d, J=11.0 Hz, 1H), 2.59 (d, J=11.1 Hz, 1H), 2.22 (dd,
J=11.0, 3.5 Hz, 1H), 2.08 (td, J=11.6, 3.3 Hz, 1H), 2.01-1.90 (m,
1H), 1.56 (s, 9H), 1.26 (d, J=6.8 Hz, 3H), 0.94-0.86 (m, 2H),
0.65-0.57 (m, 2H); MS(ES+) m/z 483.1 (M+1).
Step 4. Preparation of tert-butyl
(R)-5-cyclopropyl-2-fluoro-4-((3-methylpiperazin-1-yl)methyl)benzoate
##STR01536##
[2691] Following the procedure as described in Example 565 step 4,
and making variation as required to replace benzyl
(S)-4-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorobenzyl)-2-methylpipe-
razine-1-carboxylate with benzyl
(R)-4-(4-(tert-butoxycarbonyl)-2-cyclopropyl-5-fluorobenzyl)-2-methylpipe-
razine-1-carboxylate, the title compound was obtained as a
colorless oil (4.19 g, 98%): MS(ES+) m/z 349.1 (M+1).
Step 5. Preparation of tert-butyl
5-cyclopropyl-4-(((R)-4-((R)-1-(3,5-dichlorophenyl)
ethyl)-3-methylpiperazin-1-yl)methyl)-2-fluorobenzoate and
tert-butyl 5-cyclopropyl-4-(((R)-4-((S)-1-(3,5-dichlorophenyl)
ethyl)-3-methylpiperazin-1-yl)methyl-2-fluorobenzoate
##STR01537##
[2693] Following the procedure as described in Example 563 step 1,
and making variation as required to replace methyl
4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-5-cyclopropyl-2-fl-
uorobenzoate dihydrochloride with tert-butyl
(R)-5-cyclopropyl-2-fluoro-4-((3-methylpiperazin-1-yl)
methyl)benzoate and purification by flash chromatography (0-15%
ethyl acetate (+10% isopropanol, +10% triethylamine) in hexanes.
The first eluting fraction was arbitrarily assigned as tert-butyl
5-cyclopropyl-4-(((R)-4-((R)-1-(3,5-dichlorophenyl)ethyl)-3-piperazin-1-y-
l) methyl)-2-fluorobenzoate (1.12 g, 24%)): MS(ES+) m/z: 521.2,
523.2 (M+1). The second eluting fraction was arbitrarily assigned
as tert-butyl 5-cyclopropyl-4-(((R)-4-((S)-1-(3,5-dichlorephenyl)
ethyl)-3-methylpiperazin-1-yl)methyl-2-fluorobenzoate (2.07 g,
44%): MS(ES+) m/z 521.2, 523.2 (M+1).
Step 6. Preparation of
5-cyclopropyl-4-(((R)-4-((R)-1-(3,5-dichlorophenyl)
ethyl)-3-methylpiperazin-1-yl)methyl)-2-fluorobenzoic acid
dihydrochloride
##STR01538##
[2695] Following the procedure as described in Example 517 step 2,
and making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
5-cyclopropyl-4-(((R)-4-((R)-1-(3,5-dichlorophenyl)
ethyl)-3-methylpiperazin-1-yl)methyl)-2-fluorobenzoate, the title
compound was obtained as a colorless solid (1.16 g, quant. yield):
MS(ES+) m/z 465.1, 467.1 (M+1).
Step 7. Preparation of
5-cyclopropyl-4-(((R)-4-((R)-1-(3,5-dichlorophenyl)
ethyl)-3-methylpiperazin-1-yl)methyl)-2-fluoro-N-(methylsulfonyl)benzamid-
e
##STR01539##
[2697] Following the procedure as described in Example 53 step 5,
and making variation as required to replace (S
)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-fluor-
obenzoic acid with
5-cyclopropyl-4-(((R)-4-((R)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiperaz-
in-1-yl)methyl)-2-fluorobenzoic acid hydrochloride, and to replace
cyclopropanesulfonamide with methylsulfonamide, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.13 g, 22%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.44
(d, J=7.7 Hz, 1H), 7.27 (d, J=1.6 Hz, 2H), 7.17 (dd, J=1.7 Hz, 1H),
7.02 (d, J=12.2 Hz, 1H), 6.78 (br s, 1H), 3.93-3.81 (m, 1H), 3.52
(s, 2H), 3.02 (s, 3H), 2.96-2.84 (m, 1H), 2.61-2.51 (m, 1H),
2.45-2.35 (m, 1H), 2.31-2.11 (m, 3H), 1.99-1.96 (m, 1H), 1.93-1.84
(m, 1H), 1.20 (d, J=1.05, 3H), (d, J=6.2Hz, 3H), 0.87-0.80 (m, 2H),
0.60-0.52 (m, 2H); MS(ES+) m/z 542.1, 544.1 (M+1).
Example 570
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-(((R)-4-((R)-1-(3,5-dichloropheny-
l) ethyl)-3-methylpiperazin-1-yl)methyl)-2-fluorobenamide
##STR01540##
[2699] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl-2-fluo-
robenzoic acid with
5-cyclopropyl-4-(((R)-4-((R)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiparaz-
in-1-yl) methyl)-2-fluorobenzoic acid hydrochloride, and
purificafion by preparative HPLC, the title compound was obtained
as a colorless solid (0.18 g, 30%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.69 (d, J=7.8 Hz, 1H), 7.32-7.23 (m, 3H),
7.21-7.17 (m, 1H), 3.98-3.83 (m, 1H), 3.61 (s, 2H), 3.12-3.02 (m,
1H), 3.02-2.92 (m, 1H), 2.65-2.57 (m, 1H), 2.51-2.40 (m, 1H),
2.35-2.19 (m, 4H), 2.00-1.87 (m, 1H), 1.47-1.39 (m, 2H), 1.24 (d,
J=6.5 Hz, 3H), 1.17-1.06 (m, 5H), 0.98-0.90 (m, 2H) 0.66-0.59 (m,
2H); MS(ES+) m/z 568.2, 570.2 (M+1).
Example 571
Synthesis of 5-cyclopropyl-4-(((R)-4-((S)-1-(3,5-dichlorophenyl)
ethyl)-3-methylpiperazin-1-yl)methyl)-2-fluoro-N-(methylsulfonyl)benzamid-
e
##STR01541##
[2700] Step 1. Preparation of
5-cyclopropyl-4-(((R)-4-((S)-1-(3,5-dichlorophenyl)
ethyl)-3-methylpiperazin-1-yl)methyl)-2-fluorobenzoic acid
hydrochloride
##STR01542##
[2702] Following the procedure described in Example 517 step 2, and
making variation as required to replace tert-butyl
4-(3,5-dichlorobenzyl)piperazine-1-carboxylate with tert-butyl
5-cyclopropyl-4-(((R)-4-((S)-1-(3,5-dichlorophenyl)
ethyl)-3-methylpiperazin-1-yl)methyl)-2-fluorobenzoate, the title
compound was obtained as a colorless solid (2.14 g, quant.):
MS(ES+) m/z 465.1, 467.1 (M+1).
Step 2. Preparation of
5-cyclopropyl-4-(((R)-4-((S)-1-(3,5-dichlorophenyl)
ethyl)-3-methylpiperazin-1-yl)methyl)-2-fluoro-N-(methylsulfonyl)benzamid-
e
##STR01543##
[2704] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-(((R)-4-((S)-1-(3,5-dichlorophenyl)ethyl)-3-methylpiperaz-
in-1-yl)methyl)-2-fluorobenzoic acid hydrochloride, and to replace
cyclopropanesulfonamide with methylsulfonamide, and purification by
preparative HPLC, the title compound was obtained as a colorless
solid (0.005 g, 0.5%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.46 (d, J=7.5 Hz, 1H), 7.22-7.18 (m, 1H), 7.17-7.13 (m, 2H), 6.99
(d, J=12.2 Hz, 1H), 3.91-3.78 (m, 1H), 3.51 (s, 2H), 3.02 (s, 3H),
2.79-2.67 (m, 1H), 2.54-2.35 (m, 3H), 2.21-2.11 (m, 2H), 1.94-1.82
(m, 1H), 1.31 (d, J=6.8 Hz, 3H), 1.25-1.20 (m, 2H), 1.00 (d, J =6.1
Hz, 3H), 0.88-0.78 (m, 2H), 0.59-0.52 (m, 2H); MS(ES-) m/z 540.2,
542.2 (M-1).
Example 572
Synthesis of
5-cyclopropyl-N-(cyclopropylsulfonyl)-4-(((R)-4-((S)-1-(3,5-dichloropheny-
l) ethyl)-3-methylpiperazin-1-yl)methyl)-2-fluorobenzamide
##STR01544##
[2706] Following the procedure as described in Example 53 step 5,
and making variation as required to replace
(S)-5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)piperidin-1-yl)methyl)-2-flu-
orobenzoic acid with
5-cyclopropyl-4-(((R)-4-((S)-1-(3,5-dichlorophenyl)ethyl-3-methylpiperazi-
n-1-yl)methyl)-2-fluorobenzoic acid hydrochloride, and purification
by preparative HPLC, the title compound was obtained as a colorless
solid (0.01 g, 1%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.74
(br s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.28-7.20 (m, 2H), 7.19-7.13
(m, 2H), 3.94-3.81 (m, 1H), 3.59 (s, 2H), 3.12-3.02 (m, 1H),
2.93-2.72 (m, 1H), 2.58-2.42 (m, 3H), 2.25-2.16 (m, 1H), 1.97-1.86
(m, 1H), 1.66-1.49 (m, 2H), 1.47-1.40 (m, 2H), 1.33 (d, J=6.5 Hz,
3H), 1.17-1.08 (m, 2H), 1.05 (d, J=6.3 Hz, 3H), 0.97-0.89 2H),
0.65-0.57 (m, 2H); MS(ES+) m/z 568.2, 570.2 (M+1).
Example 573
Synthesis of (S)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)
oxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)
##STR01545##
[2708] Following the procedure as described in Example 3 step 5,
and making variation as required to replace
(R)-5-cyclopropyl-4-((1-(3,5-dichlorobenzyl)piperidin-3-yl)-2-fluorobenzo-
ic acid with
(S)-1-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy-5-cyclopropyl-2-flu-
orobenzoic acid, and to replace cyclopropylsulfonamide with
methanesulfonamide, the title compound was obtained as a colorless
solid (0.09 g, 55%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.55
(d, J=9.2 Hz, 1H), 7.46-7.41 (m, 1H), 7.11-7.08 (m, 1H), 6.96-6.89
(m, 1H), 6.58 (d, J=14.6 Hz, 1H), 4.46-4.41 (m, 1H), 3.63 (s, 2H),
3.41 (s, 3H), 2.99-2.96 (m, 1H), 2.73-2.70 (m, 1H), 2.48-2.42 (m,
1H), 2.36-2.29 (m, 1H), 2.10-2.02 (m, 2H), 1.92-1.86 (m, 1H),
1.72-1.56 (m, 2H), 0.96-0.90 (m, 2H), 0.69-0.64 (m, 2H); MS(ES+)
m/z 498.9, 500.9 (M+1); MS(ES-) m/z 497.2, 499.2 (M-1).
Example 574
Synthesis of 4-((1-benzhydryl-4-methylpiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01546##
[2709] Steps 1-2: Preparation of tert-butyl
4-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)
carbamoyl)-phenoxy)methyl)-4-methylpiperidine-1-carboxylate
[2710] The compound was prepared in a similar manner to Example 598
starting from 5-chloro-2,4-difluoro-N-methylsulfonyl-benzamide and
tert-butyl 3-(hydroxymethyl)-3-methylazetidine-1-carboxylate.
Step 3: Preparation of 4-((1-benzhydryl-4-methylpiperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[2711] A mixture of
4-((1-benzhydryl-4-methylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluoro-N-
-(methylsulfonyl)benzamide (55 mg), trifluoroacetic acid (0.23 mL)
in dichloromethane (0.68 mL) was stirred at 0.degree. C. for 10 min
then at rt for 1 h. The contents were concentrated under vacuum. To
the residue were added acetonitrile (2.3 mL), benzhydryl bromide
(29 mg), and cesium carbonate (266 mg). The mixture was heated at
50.degree. C. for 4 hr. Extra benzhydryl bromide (6 mg) was added.
The mixture was heated at 50.degree. C. for 16 hr. Acidified with
0.5M NaH.sub.2PO.sub.4, the contents were extracted with DCM
(2.times.). The combined extracts were dried (Na.sub.2SO.sub.4).
The crude was purified with HPLC (19.8 mg). LCMS (Method F):
RT=4.71 min, m/z: 551.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 11.84 (s, 1H), 7.49-7.36 (m, 4H), 7.36-7.24 (m, 4H),
7.24-7.11 (m, 3H), 6.93 (d, J=12.9 Hz, 1H), 4.35 (s, 1H), 3.84 (s,
2H), 2.31-2.15 (m, 2H), 2.04-1.94 (m, 1H), 1.76-1.60 (m, 2H),
1.55-1.35 (m, 1H), 1.06 (s, 3H), 0.92-0.80 (m, 2H), 0.68-0.58 (m,
2H).
Example 575
Synthesis of
5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)-4-methylpiperidin-4-yl)methoxy)--
2-fluoro-N-(methylsulfonyl)benzamide
##STR01547##
[2713] The compound was prepared in a similar manner to Example 73
starting from tert-butyl
4-((2-cyclopropyl-5-fluporo-4-((methylsulfonyl)carbamoyl)phenoxy)methyl)--
4-methylpiperidin-1-carboxylate (Example 73 step 1-2) and
3,4-dichlorobenzaldehyde. LCMS (Method F): RT=4.73 min, m/z: 543.2
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.67-7.58 (m,
2H), 7.35 (dd, J=8.3, 2.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.87 (d,
J=12.8 Hz, 1H), 3.83 (s, 2H), 3.72 (s, 2H), 3.15 (s, 3H), 2.78-2.62
(m, 2H), 2.07-1.95 (m, 1H), 1.76-1.64 (m, 2H), 1.57-1.43 (m, 2H),
1.09 (s, 3H), 0.94-0.83 (m, 2H), 0.68-0.55 (m, 2H).
Example 576
Synthesis of 5-cyclopropyl-2-fluoro-4-((1-((6-methoxypyridin-2-yl)
methyl)-4-methylpiperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
##STR01548##
[2715] The compound was prepared in a similar manner to Example 73
starting from tert-butyl
4-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)carbamoyl)phenoxy)methyl)-4-
-methylpiperidine-1-carboxylate (Example 73 step 1-2) and
6-methoxypicolinaldehyde.
[2716] LCMS (Method F): RT=4.25 min, m/z: 506.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.77-7.69 (m, 1H), 7.22 (d,
J=8.5 Hz, 1H), 7.06 (d, J=7.3 Hz, 1H), 6.80 (dd, J=26.4, 10.5 Hz,
2H), 4.02-3.89 (m, 2H), 3.86 (s, 3H), 3.85 (d, J=1.2 Hz, 2H), 3.05
(s, 3H), 3.01-2.75 (m, 4H), 2.06-1.97 (m, 1H), 1.87-1.74 (m, 2H),
1.58 (s, 2H), 1.12 (s, 3H), 0.91-0.83 (m, 2H), 0.63-0.56 (m,
2H).
Example 577
Synthesis of
5-cyclopropyl-4-((1-(4,5-dichloro-2-fluorobenzoyl)-4-methylpiperidin-4-yl-
) methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR01549##
[2718] To a solution of tert-butyl
4-((2-cyclopropyl-5-fluoro-4-(methylsulfonyl)carbamoyl)-phenoxy)
methyl)-4-methylpiperidine-1-carboxylate (Example 73 steps 1-2, 56
mg) in dichloromethane (0.7 mL) at 0.degree. C. was added
trifluoroacetic acid (0.17 mL). The mixture was stirred at
0.degree. C. for 10 min then at rt for 1 h. The contents were
concentrated under vacuum. To the residue was added dichloromethane
(2.3 mL), 4,5-dichloro-2-fluorobenzoic acid (28 mg), DIPEA (0.09
mL, cooled with ice-bath), and HBTU (30 mg). The mixture was
stirred at rt for 1 hr. Acidified with 1:4 mixture of 0.5 M HCl and
0.5 M NaH.sub.2PO.sub.4, the contents were extracted with DCM
(2.times.). The combined DCM solutions were dried
(Na.sub.2SO.sub.4). After filtration and concentration. The crude
was purified with HPLC (41 mg). LCMS (Method. F): RT=6.50 min, m/z:
575.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.85 (s,
1H), 7.83 (d, J=8.9 Hz, 1H), 7.73 (d, J=6.4 Hz, 1H), 7.18 (d, J=8.3
Hz, 1H), 7.00-6.91 (m, 1H), 4.01-3.85 (m, 3H), 3.49-3.38 (m, 1H),
2.05-1.95 (m, 1H), 1.74-1.55 (m, 2H), 1.56-1.45 (m, 1H), 1.45-1.35
(m, 1H), 1.15 (s, 3H), 0.93-0.84 (m, 2H), 0.70-0.61 (m, 2H).
Example 578
Synthesis of
5-cyclopropyl-4-((1-(2,5-dichlorobenzoyl)-4-methylpiperidin-4-yl)
methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR01550##
[2720] The compound was prepared in a similar manner to Example 589
from tert-butyl 4-((2-cyclopropyl-5-fluoro-4-((methylsulfonyl)
carbamoyl)phenoxy)methyl)-4-methylpiperidine-1-carboxylate and
2,5-dichlorobenzoic acid. LCMS (Method F): RT=6.256 min, m/z: 557.2
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.85 (s, 1H),
7.62-7.43 (m, 3H), 7.19 (t, J=8.0 Hz, 1H), 6.93 (dd, J=12.9, 6.2
Hz, 1H), 3.99 (s, 1H), 3.89 (d, J=4.9 Hz, 1H), 3.41 (d, J=13.9 Hz,
1H), 3.26-3.17 (m, 4H), 2.01 (d, J=4.9 Hz, 1H), 1.78-1.46 (m, 4H),
1.40 (d, J=13.6 Hz, 1H), 1.14 (d, J=9.5 Hz, 3H), 0.93-0.82 (m, 2H),
0.70-0.58 (m, 2H).
Example 579
Synthesis of
4-((1-(4-chloro-2-(trifluoromethyl)piperidin)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01551##
[2722] To a solution of
5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-(4-piperidylmethoxy)benzamide
hydrochloride (60 mg) in 1,2-dichloroethane (2.2 mL) at 0.degree.
C. was added DIPEA (0.075 mL), followed by
4-fluoro-2-(trifluoromethyl)benzaldehyde (39 mg) and sodium
triacetoxyborohydride (91 mg). The mixture was stirred at rt for 20
hr. Diluted with 0.5 M NaH.sub.2PO.sub.4, the contents were
extracted with DCM (3.times.). The combined org solutions were
dried (Na.sub.2SO.sub.4). After filtration and concentration, the
residue was purified with HPLC (55 mg). LCMS (Method G): RT=4.36
min, m/x: 563.14 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 11.74 (s, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.78-7.72 (m, 2H),
7.15 (d, J =8.4 Hz, 1H), 6.92 (d, J=12.9 Hz, 1H), 3.95 (d, J=6.0
Hz, 2H), 3.62 (s, 2H), 3.27 (s, 3H), 2.83 (d, J =11.1 Hz, 2H),
2.16-1.97 (m, 3H), 1.90-1.74 (m, 3H), 1.46-1.31 (m, 2H), 0.92-0.85
(m, 2H), 0.69-0.62 (m, 2H).
Example 580
Synthesis of
4-((1-(2-chloro-5-(trifluoromethyl)piperidin)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01552##
[2724] The compound was prepared in a similar manner to Example 591
from
5-cyclopropyl-2-fluoro-N-methylsuifonyl-4-(4-piperidylmethoxy)benzamide
hydrochloride and 2-chloro-5-(trifluoromethyl)benzaldehyde. LCMS
(Method G): RT=4.25 min, m/z: 563.14 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 11.61 (s, 1H), 7.86 (d, J=2.0 Hz, 1H),
7.73-7.64 (m, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.91 (d, J=12.9 Hz, 1H),
3.97 (d, J=6.0 Hz, 2H), 3.72 (s, 2H), 3.26 (s, 3H), 2.92 (d, J=11.2
Hz, 2H), 2.24 (t, J=11.6 Hz, 2H), 2.08-1.96 (m, 1H), 1.92-1.75 (m,
3H), 1.51-1.35 (m, 2H), 0.92-0.83 (2H), 0.69-0.61 (m, 2H).
Example 581
Synthesis of
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01553##
[2725] Step 1: Preparation of methyl
4-[[1-[[3-chloro-2-fluoro-5-(trifluoromethyl)
phenyl]methyl]-4-piperidyl]methoxy]-5-cyclopropyl-2-fluoro-benzoate
[2726] To a solution of methyl
5-cyclopropyl-2-fluoro-4-(4-piperidylmethoxy)benzoate hydrochloride
(A, 0.362 g, 1.00 mmol, .about.95% pure) in 1,2-dichloroethane (6.0
mL) at 0.degree. C. was added DIPEA (2.0 equiv., 2.00 mmol, 100
mass %), followed by
3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde (350 mg) and
sodium triacetoxyborohydride (636 mg). The mixture was stirred at
rt for 20 hr. Diluted with aqueous sodium bicarbonate solution, the
contents were extracted with DCM (3.times.). The combined org
solutions were dried (Na.sub.2SO.sub.4). After filtration and
concentration, the crude was purified with flash chromatography
(0-40% EtOAc/heptane) to afford the product (498 mg).
Step 2: Preparation of
4-[[1-[[3-chloro-2-fluoro-5-(trifluoromethyl)
phenyl]methyl]-4-piperidyl]methoxy]-5-cyclopropyl-2-fluoro-benzoic
acid
[2727] To a mixture of methyl
4-[[1-[[3-chloro-2-fluoro-5-(trifluoromethyl)
phenyl]methyl]-4-piperidyl]methoxy]-5-cyclopropyl-2-fluoro-benzoate
(A, 0.480 g, 0.927 mmol) and KOH (57 mg) in methanol (4.6 mL) was
slowly added water (0.46 mL). The resulting mixture was stirred at
40.degree. C. for 16 hr. Extra 0.1 eq of KOH was added. The mixture
was heated at 60.degree. C. for 20 hr. LCMS showed completion. The
contents were concentrated under vacuum. Used as-is.
Step 3: Preparation of
4-[[1-[[3-chloro-2-fluoro-5-(trifluoromethyl)
phenyl]methyl]-4-piperidyl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfon-
yl-benzamide
[2728] A mixture of crude
4-[[1-[[3-chloro-2-fluoro-5-(trifluoromethyl)
phenyl]methyl]-4-piperidyl]methoxy]-5-cyclopropyl-2-fluoro-benzoic
acid potassium salt (60.0 mg) from the previous step,
methanesulfonamide (41 mg), HBTU (62 mg) and DIPEA (0.037 mL) in
1,2-dichloroethane (1.6 mL) was stirred at 4.degree. C. for 16 hr.
LCMS showed completion. Acidified with 0.5M NaH.sub.2PO.sub.4, the
contents were extracted with DCM (3.times.). The combined extracts
were dried (Na.sub.2SO.sub.4). The crude was purified with HPLC
(16.2 mg). LCMS (Method G): RT=5.71 min, m/z: 581.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.59 (s, 1H), 8.05-7.98 (m,
1H), 7.83-7.75 (m, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.89 (d, J=12.9 Hz,
1H), 3.94 (d, J=5.9 Hz, 2H), 3.73 (s, 2H), 3.24 (s, 3H), 2.91 (d,
J=11.2 Hz, 2H), 2.25-2.10 (m, 2H), 2.05-1.96 (m, 1H), 1.80 (d,
J=11.9 Hz, 3H), 1.39 (d, J=11.9 Hz, 2H), 0.93-0.83 (m, 2H),
0.69-0.61 (m, 2H).
Example 582
Synthesis of
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)piperidin-4-yl)
methoxy-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide
##STR01554##
[2730] The compound was prepared in a similar manner to Example 587
from 4-[[1-[[3-chloro-2-fluoro-5-(trifluoromethyl)
phenyl]methyl]-4-piperidyl]methoxy]-5-cyclopropyl-2-fluoro-benzoic
acid and cyclopropanesulfonamide. LCMS (Method F): RT=4.98 min,
m/z: 607.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
11.69 (s, 1H), 8.03-7.97 (m, 1H), 7.80-7.74 (m, 1H), 7.16 (d, J=8.5
Hz, 1H), 6.83 (d, J=12.9 Hz, 1H), 3.92 (d, J=5.8 Hz, 2H), 3.70-3.63
(m, 2H), 3.04-2.93 (m, 1H), 2.86 (d, J=11.1 Hz, 2H), 2.14-2.05 (m,
3H), 2.04-1.96 (m, 1H), 1.78 (d, J=10.9 Hz, 3H), 1.44-1.31 (m, 2H),
1.04-0.91 (m, 3H), 0.90-0.83 (m, 2H), 0.65-0.58 (m, 2H).
Example 583
Synthesis of
N-(azetidin-1-ylsulfonyl)-4-((1-(3-chloro-2-fluoro)-5-(trifluoromethyl)pi-
peridin)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluorobenzamide
##STR01555##
[2732] The compound was prepared in a similar manner to Example 587
from 4-[[1-[[3-chloro-2-fluoro-5-(trifluoromethyl)
phenyl]methyl]-4-piperidyl]methoxy]-5-cyclopropyl-2-fluoro-benzoic
acid and azetidine-1-sulfonamide. LCMS (Method F): RT=5.04 min,
m/z: 622.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSP-d6) .delta.
11.41 (s, 1H), 8.03-7.97 (m, 1H), 7.81-7.74 (m, 1H), 7.15 (d, J=8.3
Hz, 1H), 6.90 (d, J=12.8 Hz, 1H), 4.06-3.90 (m, 6H), 3.68 (s, 2H),
2.88 (d, J=11.1 Hz, 2H), 2.19-2.06 (m, 4H), 2.06-1.97 (m, 1H), 1.79
(d, J=11.4 Hz, 3H), 1.46-1.31 (m, 2H), 0.93-0.84 (m, 2H), 0.69-0.61
(m, 2H).
Example 584
Synthesis of
4-((1-(4-chloro-2-(trifluoromethyl)piperidin)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01556##
[2734] The compound was prepared in a similar manner to Example 585
from
5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-(4-piperidylmethoxy)benzamide
hydrochloride and 4-chloro-2-(trifluoromethyl)benzaldehyde. LCMS
(Method G): RT=4.36 min, m/z: 563.14 [M+H].sup.+.
[2735] .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.74 (s, 1H), 7.81
(d, J=8.5 Hz, 1H), 7.78-7.72 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 6.92
(d, J=12.9 Hz, 1H), 3.95 (d, J=6.0 Hz, 2H), 3.62 (s, 2H), 3.27 (s,
3H), 2.83 (d, J=11.1 Hz, 2H), 2.16-1.97 (m, 3H), 1.90-1.74 (m, 3H),
1.46-1.31 (m, 2H), 0.92-0.85 (m, 2H), 0.69-0.62 (m, 2).
Example 585
Synthesis of
4-((1-(4-bromo-2-(trifluoromethyl)piperidin)piperadin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01557##
[2737] The compound was prepared in a similar manner to Example 585
from
5-cyclopropyl-2-fluror-N-methylsulfonyl-4-(4-piperidylmethoxy)benzamide
hydrochloride and 4-bromo-2-(trifluoromethyl)benzaldehyde. LCMS
(Method G): RT=4.44 min, m/z: 609.09 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 11.74 (s, 1H), 7.93-7.82 (m, 2H), 7.74 (d,
J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.92 (d, J=13.0 Hz, 1H),
3.96 (d, J=6.1 Hz, 2H), 3.61 (s, 2H), 3.28 (s, 3H), 2.89-2.77 (m,
2H), 2.17-1.96 (m, 3H), 1.90-1.72 (m, 3H), 1.46-1.31 (m, 2H),
0.94-0.82 (m, 2H), 0.71-0.61 (m, 2H).
Example 586
Synthesis of
5-cyclopropyl-2-fluoro-4-((1-(4-fluoro-2-(trifluoromethyl)
benzyl)piperidin-4-yl)methoxy)-N-(methylsulfonyl)benzamide
##STR01558##
[2739] The compound was prepared in a similar manner to Example 585
from
5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-(4-piperidylmethyoxy)benzamide
hydrochloride and 4-fluoro-2-(trifluoromethyl)benzaldehyde. LCMS
(Method G): RT=4.18 min, m/z: 547.17 [M+H].sup.+.
[2740] .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.71 (s, 1H), 7.82
(dd, J=8.6, 5.8 Hz, 1H), 7.61-7.49 (m, 2H), 7.15 (d, J=8.3 Hz, 1H),
6.92 (d, J=13.0 Hz, 1H), 3.95 (d, J=6.2 Hz, 2H), 3.62 (s, 2H), 2.84
(d, J=11.1 Hz, 2H), 2.17-1.96 (m, 3H), 1.90-1.73 (m, 3H), 1.46-1.31
(m, 2H), 0.93-0.84 (m, 2H), 0.69-0.62 (m, 2H).
Example 587
Synthesis of 4-((1-(4-bromo-3-chlorobenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01559##
[2742] The compound was prepared in a similar manner of Example 585
from 5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-(4-piperidylmethoxy)
benzamide hydrochloride and 4-bromo-2-chlorobenzaldehyde. LCMS
(Method G): RT=4.13 min, m/z: 575.06 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.76 (d, J =8.2 Hz, 1H), 7.61 (d, J=2.0 Hz,
1H), 7.27 (dd, J=8.2, 2.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.86 (d,
J=12.9 Hz, 1H), 3.94 (d, J=5.9 Hz, 2H), 3.67 (s, 2H), 3.16 (s, 3H),
2.97 (d, J=11.2 Hz, 2H), 2.25 (s, 2H), 2.06-1.96 (m, 1H), 1.83 (d,
J=12.8 Hz, 3H), 1.42 (d, J=12.2 Hz, 2H), 0.92-0.83 (m, 2H),
0.67-0.58 (m, 2H).
Example 588
Synthesis of
4-((1-(4-bromo-2,5-difluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-
-fluoro-N-(methylsulfonyl)benzamide
##STR01560##
[2744] The compound was prepared in a similar manner to Example 585
from
5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-(4-piperidylmethoxy)benzamide
hydrochloride and 4-bromo2,5-difluorobenzaldehyde. LCMS (Method G):
RT=4.19 min, m/z: 577.08 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 11.46 (s, 1H), 7.71 (dd, J=8.9, 5.7 Hz, 1H), 7.44
(dd, J=9.1, 6.2 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.89 (d, J=12.9
Hz, 1H), 3.94 (d, J=5.9 Hz, 2H), 3.62 (s, 2H), 3.23 (s, 3H), 2.93
(d, J=11.2 Hz, 2H), 2.19 (t, J=11.5 Hz, 2H), 2.05-1.96 (m, 1H),
1.80 (d, J=12.4 Hz, 3H), 1.48-1.32 (m, 2H), 0.92-0.83 (m, 2H),
0.68-0.60 (m, 2H).
Example 589
Synthesis of 4-((1-(4-bromo-2-fluorobenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benazamide
##STR01561##
[2746] The compound was prepared in a similar manner to Example 585
from
5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-(4-piperidylmethoxy)benzamide
hydrochloride and 4-bromo-2,5-difluorobenzaldehyde. LCMS (Method
G): RT=4.18 min, m/z: 559.09 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 7.54 (dd, J=9.7, 1.8 Hz, 1H), 7.47-7.37 (m, 2H),
7.16 (d, J=8.5 Hz, 1H), 6.87 (d, J=12.9 Hz, 1H), 3.93 (d, J=5.97
Hz, 2H), 3.67 (s, 2H), 3.19 (s, 3H), 2.96 (d, J=11.2 Hz, 2H), 2.24
(s, 2H), 2.05-1.96 (m, 1H), 1.81 (d, J=11.8 Hz, 3H), 1.47-1.32 (m,
2H), 0.92-0.83 (m, 2H), 0.67-0.59 (m, 2H).
Example 590
Synthesis of 4-((1-(3-chloro-5-cyanobenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01562##
[2748] The compound was prepared in a similar manner to Example 585
from 5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-(4-piperidylmethoxy)
benzamide hydrochloride and 3-chloro-5-formylbenzonitrile. LCMS
(Method G): RT=3.96 min, m/z: 520.15 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 11.42 (s, 1H), 7.96 (t, J=1.8 Hz, 1H),
7.81-7.74 (m, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.89 (d, J=11.6 Hz, 2H),
3.95 (d, J=5.9 Hz, 2H), 3.68 (s, 2H), 3.22 (s, 3H), 2.92 (d, J=11.2
Hz, 2H), 2.19 (t, J=11.6 Hz, 2H), 2.06-1.95 (m, 1H), 1.91-1.74 (m,
3H), 1.50-1.32 (m, 2H), 0.94-0.82 (m, 2H), 0.69-0.60 (m, 2H).
Example 591
Synthesis of 4-((1-(3-cyano-4-fluorobenzyl)piperidin-4-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01563##
[2750] The compound was prepared in a similar manner to Example 585
from 5-cyclopropyl-2-fluoro-N-methylsulfonyl-4-(4-piperidylmethoxy)
benzamide hydrochloride and 2-fluoro-5-formylbenzonitrile.
[2751] LCMS (Method G): RT=3.85 min, m/z: 504.17 [M+H].sup.+.
[2752] .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.87 (dd, J=6.3, 2.2
Hz, 1H), 7.80-7.72 (m, 1H), 7.57-7.48 (m, 1H), 7.16 (d, J=8.4 Hz,
1H), 6.88 (d, J=12.9 Hz, 1H), 3.94 (d, J=6.0 Hz, 2H), 3.70 (s, 2H),
3.19 (s, 3H), 2.96 (d, J=11.3 Hz, 2H), 2.24 (t, J=11.6 Hz, 2H),
2.05-1.96 (m, 1H), 1.92-1.76 (m, 3H), 1.49-1.33 (m, 2H), 0.92-0.83
(m, 2H), 0.68-0.60 (m, 2H).
Example 592
Synthesis of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(6-(trifluorormethyl)
pyridin-2-yl)piperidin-4-yl)methoxy)benzamide
##STR01564##
[2753] Step 1: Preparation of
5-chloro-2-fluoro-N-methylsulfonyl-4-[[1-[6-(trifluoromethyl)-2-pyridyl]--
4-piperidyl]methoxy]benzamide
[2754] To solution of
(1-[6-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl)methanol (169
mg) and 5-chloro-2,4-difluoro-N-methylsulfonyl-benzamide (175 mg)
in DMSO (2.5 mL) at 14.degree. C. (bath) was added potassium
tert-butoxide (175 mg). The mixture was stirred at rt for 1 hr.
Diluted with EtOAc, the contents were washed with 1/4 mixture of
0.5M HCl and 0.5M NaH.sub.2PO.sub.4 (2.times.) and brine
(1.times.), dried (Na.sub.2PO.sub.4). After filtration and
concentration, the crude was purified with flash chromatography
(0-2% MeOH/DCM with 0.5% HCO.sub.2H) to give the product (205
mg).
Step 2: Preparation of
5-cyclopropyl-2-fluoro-N-(methylsulfonyl)-4-((1-(6-(trifluoromethyl)
pyridin-2-yl)piperidin-4-yl)methoxy)benzamide
[2755] A mixture of
5-chloro-2-fluoro-N-methylsulfonyl-4-[[1-[6-(trifluoromethyl)-2-pyridyl]--
4-piperidly]methoxy]benzamide (205 mg), cyclopropylboronic acid
(109 mg), and potassium phosphate (523 mg) in water (0.4 mL) and
toluene (8.0 mL) was purged with nitrogen for 10 min.
Tricyclohexylphosphoniumtetrafluoroborate (46 mg) and palladium
acetate (14 mg) were added. The resulting mixture was stirred under
nitrogen at 95.degree. C. for 40 hr. Acidified with 1/4 mixture of
0.5 M HCl and 0.5 M NaH.sub.2PO.sub.4, the contents were extracted
with DCM (2.times.). The combined DCM solutions were dried
(Na.sub.2SO.sub.4). Afier filtration and concentration, the crude
was purified with HPLC (37.5 mg). LCMS (Method G): RT=7.99 min,
m/z: 516.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
11.84 (s, 1H), 7.76-7.67 (m, 1H), 7.15 (dd, J=9.8, 8.6 Hz, 2H),
6.98 (d, J=7.2 Hz, 1H), 6.90 (d, J=12.9 Hz, 1H), 4.38 (d, J=13.2
Hz, 2H), 3.98 (d, J=6.2 Hz, 2H), 3.23 (s, 3H), 2.94 (td, J=12.7,
2.6 Hz, 2H), 2.12 (s, 1H), 2.04-1.94 (m, 1H), 1.92-1.81 (m, 2H),
1.43-1.28 (m, 2H), 0.88-0.80 (m, 2H), 0.68-0.59 (m, 2H).
Example 593
Synthesis of
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-3-methylazetidin-3-
-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01565##
[2756] Steps 1-2: Preparation of tert-butyl
3-[[2-cyclopropyl-5-fluoro-4-(methylsulfonylcarbamoyl)phenoxy]methyl]-3-m-
ethyl-azetidine-1-carboxylate
[2757] The compound was prepared in a similar manner to Example 598
starting 5-chloro-2,4-difluoro-N-methylsulfonyl-benzamide and
tert-butyl 3-(hydroxymethyl)-3-methylazetidine-1-carboxylate
Step 3: Preparation of
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-3-methylazetidin-3-
-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
[2758] The compound was prepared in a similar manner to Example 73
starting from tert-butyl
3-[[2-cyclopropyl-5-fluoro-4-(methylsulfonylcarbamoyl)phenoxy]methyl]-3-m-
ethyl-azetidine-1-carboxylate and
3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde. LCMS (Method G):
RT=5.66 min, m/z: 567.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 11.68 (s, 1H), 8.01 (dd, J=6.5, 2.2 Hz, 1H), 7.74 (dd,
J=5.9, 2.3 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 6.94 (d, J=12.8 Hz,
1H), 4.06 (s, 2H), 3.84 (s, 2H), 3.39 (d, J=7.3 Hz, 2H), 3.23 (s,
3H), 3.14 (d, J=7.3 Hz, 2H), 2.09-1.98 (m, 1H), 1.36 (s, 3H),
0.92-0.82 (m, 2H), 0.70-0.61 (m, 2H).
Example 594
Synthesis of
5-Cyclopropyl-4-((1-(3,5-dichloro-2-cyanobenzyl)piperidin-4-yl)
methoxy)-2-fluoro-N-(mehylsulfonyl)benzamide
##STR01566##
[2759] Step 1: Preparation of
1-(bromomethyl)-3,5-dichloro-2-iodobenzene
##STR01567##
[2761] 2,2'-azobis(2-methylpropionitrile) (149 mg, 0.91 mmol) was
added to a solution of 1,5-dichloro-2-iodo-3-methylbenzene (2.6 g,
9.1 mmol) and N-bromosuccinimide (1.8 g, 10.0 mmol) in acetonitrile
(70 mL), the reaction mixture was stirred at 80.degree. C. for 16
h, diluted with water (50 mL) and extracted with ethyl acetate (100
mL.times.3), the combined organic layers were washed with brine (50
mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by silica gel column
chromatography (eluting with petroleum ether) to afford the target
compound (1.26 g, yield: 38%) as a white solid. .sup.1H NMR (500
MHz, CDCl.sub.3): .delta. 7.44-7.43 (m, 1H), 7.41-7.40 (m, 1H),
4.61 (s, 2H).
Step 2: Preparation of methyl
5-cyclopropyl-4-((1-(3,5-dichloro-2-iodobenzyl)
piperidin-4-yl)methoxy)-2-fluorobenzoate
##STR01568##
[2763] A mixture of 1-(bromomethyl)-3,5-dichloro-2-iodobenzene (200
mg, 0.55 mmol), methyl
5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate
hydrochloride (188.7 mg, 0.55 mmo), sodium iodide (245.9 mg, 1.65
mmol) and potassium carbonate (227.7 mg, 1.65 mmol) in acetonitrile
(40 mL) was stirred at 80.degree. C. for 16 h. The reaction mixture
was diluted with ethyl acetate (100 mL) and brine (50 mL), and the
organic layer was separated, washed with brine (20 mL), dried over
anhydrous sodium sulfate, filtered and concentrated. The residue
was purified by silica gel chromatography (eluting with 20% ethyl
acetate in petroleum ether), to give the target compound (240 mg,
74%) as a pale yellow oil. LCMS (ESI) m/z: 592.0 [M+H].sup.+.
Step 3: Preparation of methyl
5-cyclopropyl-4-((1-(3,5-dichloro-2-cyanobenzyl)
piperidin-4-yl)methoxy)-2-fluorobenzoate
##STR01569##
[2765] A mixture of methyl
5-cyclopropyl-4-((1-(3,5-dichloro-2-iodobenzyl)piperidin-4-yl)
methoxy)-2-fluorobenzoate (150 mg, 0.25 mmol) and copper cyanide
(45.0 mg, 0.50 mmo) in N-methylpyrolidone (5.0 mL) was stirred
under microwave at 150.degree. C. for 1.0 h. The reaction mixture
was diluted with ethyl acetate (300 mL), filtered, the filtrate was
washed with water (50 mL) and brine (50 mL), dried over anhydrous
sodium sulfate, filtered and concentrated. The residue was purified
by silica gel chromatography (eluting with 20% ethyl acetate in
petroleum ether to give the target compound (35.0 mg, 14%) as a
pale yellow oil. LCMS(ESI) m/z: 491.1 [M+H].sup.+.
Step 4: Preparation of
5-cyclopropyl-4-((1-(3,5-dichloro-2-cyanobenzyl)
piperidin-4-yl)methoxy)-2-fluorobenzoic acid
##STR01570##
[2767] A mixture of methyl
5-cyclopropyl-4-((1-(3,5-dichloro-2-cyanobenzyl)piperidin-4-yl)methoxy)-2-
-fluorobenzoate (35 mg, 0.07 mmol) and lithium hydroxide (42 mg,
1.75 mmol) in THF (5 mL) and water (5 mL) was stirred at room
temperature for 16 h. The mixture was adjusted to pH 2-3 with HCl
(2M), extracted with ethyl acetate (10.times.2 mL), the combined
organic layers were washed with brine (10 mL), dried over anhydtous
sodium sulfate, filtered and concentrated to give the crude product
as a pale yellow solid. The solid was used in next step without
further purification. LCMS(ESI) m/z: 477.1 [M+H].sup.+.
Step 5: Preparation of
5-Cyclopropyl-4-((1-(3,5-dichloro-2-cyanobenzyl)
piperidin-4-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide
##STR01571##
[2769] A mixture of
5-cyclopropyl-4-((1-(3,5-dichloro-2-cyanobenzyl)piperidin-4-yl)methoxy)-2-
-fluorobentzoic acid (30 mg, 0.07 mmol), methanesulfonamide (11 mg,
0.11 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide
hydrochloride (27 mg, 0.14 mmol) and N,N-dimethyl-4-aminopyridine
(17 mg, 0.14 mmol) in DCM (4 mL) was stirred at room temperature
for 16 h. The reaction mixture was diluted with DCM (30 mL), washed
with HCl (2.0 M, 5 mL), water (5 mL) and brine (10 mL), dried over
anhydrous sodium sulfate, filtered and concentrated. The residue
was purified by reverse phase Combiflash (30-40% MeCN in 0.1%
NH.sub.4HCO.sub.3) to give the target product (23 mg, 38%) as a
white solid. LCMS(ESI) Method A. RT=5.68 min, m/z: 554.1
[M+H].sup.+..sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.91 (d,
J=4.0 Hz, 1H), 7.65 (d, J=4.0 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.90
(d, J=16.0 Hz, 1H), 3.95 (d, J=4.0 Hz, 2H), 3.67 (s, 2H), 3.23 (s,
3H), 2.87-2.84 (m, 2H), 2.18-2.12 (m, 2H), 1.99-2.02 (m, 1H),
1.80-1.77 (m, 3H), 1.39-1.36 (m, 2H), 0.90-0.87 (m, 2H), 0.67-0.64
(m, 2H).
Example 595
Synthesis of
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-cyanopiperidin-4-
-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01572## ##STR01573##
[2770] Step 1: Preparation of 1-(tert-butyl) 4-ethyl
4-cyanopiperidine-1,4-dicarboxylate
##STR01574##
[2772] Lithium hexamethyldisilazide (1 M, 20 mL, 20 mmol) was added
dropwise to a solution of tert-butyl
4-cyanopiperidine-1-carboxylate (2.1 g, 10 mmol) in anhydrous THF
(30 mL) at -78.degree. C. The resulting mixture was stirred at this
temperature for 1 h, then ethyl carbonochloridate (2.2 g, 20 mmol)
was added at -78.degree. C. and stirred at this temperature for 1
h. The reaction was quenched with sodium bicarbonate aqueous
solution (1 M, 30 mL) and extracted with ethyl acetate (100
mL.times.3), the combined organic layers were washed with brine (20
mL). dried over anhydrous sodium sulfate, filtered and
concentrated. The crode product was purified by silica column
chromatography (eluting with 10-25% ethyl acetate of petroleum
ether) to give product as colorless tui (2.8 g, 99%). LCMS (ESI)
m/z: 1.83 [M-99].sup.+.
Step 2: Preparation of tert-butyl
4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate
##STR01575##
[2774] Sodium borohydride (1.5 g, 40 mmol) was added to a solution
of 1-tert-butyl 4-ethyl 4-cyanopiperidine-1,4-dicarboxylate (2.8 g,
10 mmol) in MeOH (30 mL) at 0.degree. C., the reaction mixture was
stirred at room temperature for 1 h. The solvent was removed under
reduced pressure and the crude was diluted with water (30 ml),
extracted with ethyl acetate (50 mL.times.3), washed with brine (20
mL), dried over anhydrous sodium sulfate, filtered and concentrated
to get crude product (2.4 g, 99%). The crude was used directly in
the next step without further purification.
Step 3: Preparation of tert-butyl
4-cyano-4-(tosyloxymethyl)piperidine-1-carboxylate
##STR01576##
[2776] Sodium hydride (2.0 g, 50 mmol) was added to an ice-cooled
solution of tert-butyl 4-cyano-4-(hydroxymethyl)
piperidine-1-carboxylate (2.4 g, 10 mmol) in anhydrous THF (20 mL)
and stirred for 1 h, then a solution of tosyl chloride (3.8 g, 20
mmol) in THF (10 mL) was added and the mixture was stirred at room
temperature for 16 h. The mixture was quenched with water (40 mL),
extracted with ethyl acetate (50 mL.times.3), washed with brine (40
mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The crude product was purified by silica column
chromatography (eluting with 25% ethyl acetate in petroleum ether)
to give product as white solid (2.0 g, 50%). LCMS(ESI) m/z: 295.1
[M-99].sup.+.
Step 4: Preparation of tert-butyl
4-cyano-4-((2-cyclopropyl-5-fluoro-4-(methoxycarbonyl)-phenoxy)
methyl) piperidine-1-carboxylate
##STR01577##
[2778] A mixture of tert-butyl
4-cyano-4-(tosyloxymethyl)piperidine-1-carboxylate (1.0 g, 2.5
mmol), methyl 5-cyclopropyl-2-fluoro-4-hydroxybenzoate (525 mg, 2.5
mmol) and potassium carbonate (1.1 g, 7.5 mmol) in DMF (10 mL) in a
sealed tube was stirred at 120.degree. C. for 4 h. The reaction
mixture was diluted with water (40 mL), extracted with ethyl
acetate (50 mL.times.3), washed with brine (20 mL), dried over
anhydrous sodium sulfate, filtered and concentrated to get crude
product (1.0 g, 93%). The crude was used directly in the next step
without further purification. LCMS(ESI) m/z: 433.1 [M+H].sup.+.
Step 5: Preparation of methyl
4-((4-cyanopiperidin-4-yl)methyoxy)-5-cyclopropyl-2-fluorobenzoate
hydrochloride
##STR01578##
[2780] Hydrochloride in 1,4-dioxane (4 M, 20 mL) was added to a
solution of tert-butyl
4-cyano-4-((2-cyclopropyl-5-fluoro-4-(methoxycarbonyl)phenoxy)methyl)pipe-
ridine-1-carboxylate (1.0 g, 2.3 mmol) in 1,4-dioxane, the reaction
mixture was stirred at room temperature for 1 h. The solution was
concentrated to give a brown solid, which was recrystallized in
ethyl acetate (4 mL) to give the target compound as a gray solid
(0.6 g, 74%). LCMS(ESI) m/z: 333.1 [M-HCl+1].sup.+.
Step 6: Preparation of
(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)methanol
##STR01579##
[2782] Borane-tehrahydrofuran complex (1M, 20 mL, 20 mmol) was
mixed with 3-chloro-2-fluoro-5-(trifluoromethyl)benzoic acid (480
mg, 2 mmol) at 0.degree. C. The reaction mixture was stirred at
room temperature the 1 h, quenched with MeOH (20 mL). The solvents
were removed under reduced pressure to give crude product (400 mg,
87%) which was used directly in the next step without further
purification. LCMS(ESI) m/z: 227.1 [M-1].sup.+.
Step 7: Preparation of
3-chloro-2-fluoro-5-(trifluoromethyl)piperidin methanesulfonate
##STR01580##
[2784] Methanesulfonyl chloride (60 mg, 0.52 mmol) was added
dropwise to a mixture of (3-chloro-2-fluoro-5-(trifluoromethyl)
phenyl)methanol (100 mg, 0.44 mmol) and triethylamine (90 mg, 0.88
mmol) in DCM (10 mL) at 0.degree. C. The reaction mixture was
stirred at room temperature for 16 h, diluted with DCM (20 mL),
washed with water (10 mL.times.2), dried over anhydrous sodium
sulfate, filtered and concentrated to get crude product (130 mg,
96%). The crude was used directly in the next step without further
purification. LCMS(ESI) m/z: 307.1 [M+1].sup.+.
Step 8: Preparation of methyl
4-((1-(3chloro-2-fluoro-5-(trifluoromethyl)
benzyl)-4-cyanopiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate
##STR01581##
[2786] A mixture of 3-chloro-2-fluoro-5-(trifluoromethyl)piperidin
methanesulfonate (100 mg, 0.33 mmol), methyl
4-((4-cyanopiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate
hydrochloride (122 mg, 0.33 mmol) and potassium carbonate (137 mg,
0.99 mmol) in acetonitrile (10 mL) was stirred at 80.degree. C. for
16 h. The reaction mixture was diluted with ethyl acetate (100 mL)
and brine (50 mL), washed with brine (50 mL), dried over anhydrous
sodium sulfate, filtered and concentrated. The residue was purified
by silica gel chromatography (eluting with 20% ethyl acetate in
petroleum ether) to give the target compound (80 mg, 45%) as a pale
yellow oil. LCMS(ESI) m/z: 543.0 [M+H].sup.+.
Step 9: Preparation of 4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)
benzyl)-4-cyanopiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic
acid
##STR01582##
[2788] A mixture of methyl
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-cyanopiperidin-4-
-yl) methoxy)-5-cyclopropyl-2-fluorobenzoate (80 mg, 0.15 mmol) and
lithium hydroxide (36 mg, 1.5 mmol) in THF (3 mL) and water (3 mL)
was stirred at 50 .degree. C. for 3 h. The reaction mixture was
adjusted pH 2-3 with HCl (2M), extracted with ethyl acetate
(10.times.2 mL), washed with brine (10 mL), dried over anhydrous
sodium sulfate, filtered and concentrated to give the product (77
mg, 99%) as a pale yellow solid. LCMS(ESI) m/z: 529.1 [M+H].sup.30
.
Step 10: Preparation of
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-cyanopiperidin-4-
-yl)
methoxy)-5-cyclopropyl-2-fluoro-N-(methylsulfonyl)benzamide
##STR01583##
[2790] A mixture of
4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)piperidin)-4-cyanopiperidin-4-
-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid (77 mg, 0.16 mmol),
methanesulfonamide (23 mg, 0.24 mmol),
1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg,
0.32 mmol) and N,N-dimethyl-4-aminopyridine (39 mg, 0.32 mmol) in
DCM (4 mL) was stirred at room temperature for 16 h. The reaction
mixture was diluted with DCM (100 mL), washed with HCl (2.0 M, 20
mL) and brine (50 mL), dried over anhydrous sodium sulfate,
filtered and concentrated. The residue was purified by reverse
phase combiflash (40-50% MeCN in 0.1% NH.sub.4HCO.sub.3) to give
the target product (40 mg, 41%) as white solid. LCMS(ESI) Method A:
RT=5.91 min, m/z: 606.0 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.03 (d, J=5.2 Hz, 1H), 7.8 (d, J=3.2 Hz,
1H), 7.21 (d, J=7.6 Hz, 1H), 6.92-6.87 (m, 1H), 4.21 (s, 2H), 3.72
(s, 2H), 3.14 (s, 3H), 2.91-2.88 (m, 2H), 2.33-2.76 (m, 2H),
2.06-2.03 (m, 3H), 1.77-1.71 (m, 2H), 0.90-0.87 (m, 2H), 0.65-0.62
(m, 2H).
Examples 596-598
[2791] Using procedures similar to those described herein the
following compounds of fornula (I) were also prepared.
##STR01584##
[2792] Example 596: M+H 588.23; Example 597: M+H 568.22; and
Example 598: M+H 568.22
Example 599
Electrophysiological Assay (EP) (In Vitro Assay)
[2793] Patch voltage clamp electrophysiology allows for the direct
measurement and quantification of block of voltage-gated sodium
channels (NaV's), and allows the determination of the time- and
voltage-dependence of block which has been interpreted as
differential binding to the resting, open, and inactivated states
of the sodium channel (Hille B., Journal of General Physiology
(1977), 69: 497-515).
[2794] The following patch voltage clamp electrophysiology studies
were performed on representative compounds of the invention using
human embryonic kidney cells (HEK), permanently transfected with an
expression vector containing the full-length cDNA coding for the
desired human sodium channel .alpha.-subunit, grown in culture
media containing 10% FBS, 1% PSG, and 0.5 mg/mL G418 at 37.degree.
C. with 5% CO2. HEK cells used for the electrophysiology (EP)
recordings had a passage number of less than 40 for all studies and
were used within three days from the time of plating. NaV1.7 and
NaV1.5 cDNAs (NM_002977 and AC137587; SCN5A, respectively) were
stably expressed in HEK-293 cells. The .beta.1 subunit was
coexpressed in both the NaV1.7 and NaV1.5 cell lines.
[2795] Sodium currents were measured using the patch clamp
technique in the whole-cell configuration using either a
PatchXpress automated voltage clamp or manually using an Axopatch
200B (Axon Instruments) or Model 2400 (A-M systems) amplifier. The
manual voltage clamp protocol was as follows: Borosilicate glass
micropipettes were fire-polished to a tip diameter yielding a
resistance of 2-4 Mohms in the working solutions. The pipette was
filled with a solution comprised of: 5 mMNaCl, 10 mMCsCl, 120
mMCsF, 0.1 mM CaCl2, 2 mM MgCl2, 10 mM HEPES, 10 mM EGTA; and
adjusted to pH 7.2 with CsOH. The external solution had the
following composition: 140 mMNaCl, 5 mMKCl, 2 mM CaCl2, 1 mM MgCl2,
10 mM HEPES; and adjusted to pH 7.4 with NaOH. In some studies, the
external sodium was reduced by equimolar replacement with choline.
Osmolarity in the CsF internal and NaCl external solutions was
adjusted to 300 mOsm/kg and 310 mOsm/kg with glucose, respectively.
All recordings were performed at ambient temperature in a bath
chamber with a volume of 150 .mu.L. Control sodium currents were
measured in 0.5% DMSO. Controls and representative compounds of the
invention were applied to the recording chamber through a 4-pinch
or 8-pinch valve bath perfusion system manufactured by ALA
Scientific Instruments.
[2796] Currents were recorded at 40 kHz sampling frequency,
filtered at 5 Hz, and stored using a Digidata-1322A
analogue/digital interface with the pClamp software (Axon
Instruments). Series resistance compensation was applied (60-80%).
Cells were rejected if currents showed inadequate voltage control
(as judged by the IV relationship during stepwise activation). All
statistics in this study are given as mean .+-.SD.
[2797] The membrane potential was maintained at a voltage where
inactivation of the channel is complete (which was -60 mV for both
NaV1.7 and NaV1.5). The voltage is then stepped back to a very
negative (Vhold=150 mV) voltage for 20 ms and then a test pulse is
applied to quantify the compound block. The 20 ms brief
repolarization was long enough for compound-free channels to
completely recover from fast inactivation, but the compound-bound
channels recovered more slowly such that negligible recovery could
occur during this interval. The percent decrease in sodium current
following wash-on of compound was taken as the percent block of
sodium channels. Data for representative compounds of fornula (I)
is provided in Table 1.
Example 600
Tritiated Sulfonamide Binding to Membranes Isolated from Cells that
Heterologously Express hNav1.7 and the .beta.1 Subunit
[2798] Preparation of membranes containing recombinantly expressed
sodium channels: Frozen recombinant cell pellets were thawed on ice
and diluted to 4 times the cell pellet weight with ice cold 50
mMTrisHCl, pH 7.4 buffer. The cell suspensions were homogenized on
ice using a motorized glass douncehomogeniser. Homogenates were
further diluted 8.4 times with ice cold 50 mMTrisHCl, pH 7.4 buffer
and then centrifuged at 200.times.g, at 4.degree. C. for 15 min.
The supetnatants were collected and centrifuged at 10000.times.g,
at 4.degree. C. for 50 min. The pellets were then re-suspended in
100 mMNaCl, 20 mMTrisHCl, pH 7.4 buffer containing 1% v/v protease
inhibitor (Calbiochem) and re-homogenized on ice. The homogenized
membranes were then processed through a syringe equipped with a 26
gauge needle. Protein concentrations were determined by Bradford
Assay and the membranes were stored at -80.degree. C.
[2799] Radioligand Binding Studies: Saturation experiments. A
representative compound of formula (I) having a methyl group was
tritiated. Three tritiums were incorporated in place of methyl
hydrogens to generate [.sup.3H] compound. Binding of this
radioligand was preformed in 5 mL borosilicate glass test tubes at
room temperature. Binding was initiated by adding membranes to
increasing concentrations of [.sup.3H] compound in 100 mMNaCl, 20
mMTrisHCl, pH 7.4 buffer containing 0.01% w/v bovine serum albumin
(BSA) for 18 h. Non-specific binding was determined in the presence
of 1 .mu.M unlabelled compound. After 18 h, the reactants were
filtered through GF/C glass fiber filters presoaked in 0.5% w/v
polyethylene imine. Filters were washed with 15 mL ice cold 100
mMNaCl, 20 mMTrisHCl, pH 7.4 buffer containing 0.25% BSA to
separate bound from free ligand. [.sup.3H] compound bound to
filters was quantified by liquid scintillation counting.
[2800] Competitive binding experiments: Binding reactions were
preformed in 96-well polypropylene plates at room temperature for
18 h. In 360 .mu.L, membranes were incubated with 100 pM [.sup.3H]
compound and increasing concentrations of Test Compound.
Non-specific binding was defined in the presence of 1 .mu.M
unlabelled compound. Reactions were transferred and filtered
through 96-well glass fiber/C filter plates presoaked with 0.5%
polyethylene imine. The filtered reactions were washed 5 times with
200 .mu.L ice cold buffer containing 0.25% BSA. Bound radioactivity
was determined by liquid scintillation counting.
[2801] Data Analysis: For saturation experiments, non-specific
binding was subtracted from total binding to provide specific
binding and these values were recalculated in terms of pmol ligand
bound per mg protein. Saturation curves were constructed and
dissociation constants were calculated using the single site ligand
binding model: Beq=(Bmax*X)/(X+Kd), where Beq is the amount of
ligand bound at equilibrium, Bmax is the maximum receptor density,
Kd is the dissociation constant for the ligand, and X is the free
ligand concentration. For competition studies percent inhibition
was determined and IC.sub.50 values were calculated using a 4
parameter logistic model (% inhibition=(A+((B-A)
/(l+((x/C){circumflex over ( )}D)))) using XLfit, where A and B are
the maximal and minimum inhibitin respectively, C is the IC.sub.50
concentration and D is the (Hill) slope.
[2802] Representative compounds, when tested in this model,
demonstrated affinities as set forth in Table 1.
TABLE-US-00001 TABLE 1 Ligand Binding NaV1.7 NaV1.5 Assay EP EP
Example Structure (.mu.M) (.mu.M) (.mu.M) 1 ##STR01585## 0.0356
0.0226 2.7559 2 ##STR01586## 4.1167 1.0769 3 ##STR01587## 0.0026 4
##STR01588## 6.5995 5 ##STR01589## 0.0071 6 ##STR01590## 0.0030
0.0009 0.0331 7 ##STR01591## 0.0035 8 ##STR01592## 0.0081 9
##STR01593## 0.0035 10 ##STR01594## 0.0041 11 ##STR01595## 0.0474
12 ##STR01596## 0.0113 13 ##STR01597## 1.4894 14 ##STR01598##
0.3181 15 ##STR01599## 0.0048 16 ##STR01600## 0.0034 17
##STR01601## 0.0048 18 ##STR01602## 0.0026 19 ##STR01603## 0.0049
20 ##STR01604## 0.0309 21 ##STR01605## 0.0112 22 ##STR01606##
0.0182 23 ##STR01607## 0.0017 24 ##STR01608## 0.0060 25
##STR01609## 0.0032 26 ##STR01610## 0.0061 27 ##STR01611## 0.0036
0.1689 28 ##STR01612## 0.0074 29 ##STR01613## 0.0017 30
##STR01614## 0.0027 31 ##STR01615## 0.0026 32 ##STR01616## 0.0054
33 ##STR01617## 0.0132 34 ##STR01618## 0.0019 35 ##STR01619##
0.0024 36 ##STR01620## 0.0036 37 ##STR01621## 0.0151 38
##STR01622## 0.0039 39 ##STR01623## 0.0068 40 ##STR01624## 0.0084
41 ##STR01625## 0.0134 42 ##STR01626## 0.0021 43 ##STR01627##
0.0049 44 ##STR01628## 0.0036 45 ##STR01629## 4.5841 46
##STR01630## 0.9205 47 ##STR01631## 0.0251 48 ##STR01632## 2.8179
49 ##STR01633## 0.0043 0.0054 0.199 50 ##STR01634## 0.0019 51
##STR01635## 0.0021 52 ##STR01636## <0.0016 53 ##STR01637##
0.0080 54 ##STR01638## 0.0220 55 ##STR01639## 0.0233 56
##STR01640## 0.0635 57 ##STR01641## 0.0038 ##STR01642## 58
##STR01643## ##STR01644## 59 ##STR01645## 0.076 60 ##STR01646## 1.6
61 ##STR01647## 0.057 62 ##STR01648## 0.047 63 ##STR01649## 0.046
64 ##STR01650## 0.0047 65 ##STR01651## 0.034 66 ##STR01652## 0.091
67 ##STR01653## 0.0079 68 ##STR01654## 0.0064 69 ##STR01655##
0.0061 70 ##STR01656## 0.006 71 ##STR01657## 0.0031 72 ##STR01658##
0.75 73 ##STR01659## 1.3 74 ##STR01660## 3.6 75 ##STR01661## 0.074
76 ##STR01662## 0.042 77 ##STR01663## 0.0064 78 ##STR01664## 0.49
79 ##STR01665## 0.0099 80 ##STR01666## 0.00405 81 ##STR01667## 0.63
82 ##STR01668## 0.408 83 ##STR01669## 0.059 84 ##STR01670## 1.24 85
##STR01671## 1.86 86 ##STR01672## 0.0495 87 ##STR01673## 0.278 88
##STR01674## 0.0928 89 ##STR01675## 0.0223 90 ##STR01676## 0.00287
91 ##STR01677## 0.0147 92 ##STR01678## 0.0305 93 ##STR01679## 0.173
94 ##STR01680## 0.15 95 ##STR01681## 1.06 96 ##STR01682## 0.429 97
##STR01683## 0.00269 98 ##STR01684## 0.00751 99 ##STR01685##
0.00389 100 ##STR01686## 0.00419 0.0058 0.552 101 ##STR01687##
0.00376 102 ##STR01688## 0.00254 103 ##STR01689## 0.00524 104
##STR01690## 0.0451 105 ##STR01691## 0.0163 106 ##STR01692## 0.0048
107 ##STR01693## 0.0021 108 ##STR01694## 0.094 109 ##STR01695##
0.0536 110 ##STR01696## 0.0411 111 ##STR01697## 0.0204 112
##STR01698## 0.00335 113 ##STR01699## 0.0111 114 ##STR01700##
0.00727 115 ##STR01701## 0.0042 116 ##STR01702## 0.0775 117
##STR01703## 0.411 118 ##STR01704## 0.417 119 ##STR01705##
0.306
120 ##STR01706## 0.0206 121 ##STR01707## 0.0301 122 ##STR01708##
0.0024 123 ##STR01709## 0.0029 124 ##STR01710## 0.0713 125
##STR01711## 0.025 126 ##STR01712## 0.282 127 ##STR01713## 0.578
128 ##STR01714## 0.0056 129 ##STR01715## 1.37 130 ##STR01716##
0.0035 131 ##STR01717## 0.00299 132 ##STR01718## 0.014 133
##STR01719## 0.118 134 ##STR01720## 0.346 135 ##STR01721## 0.0155
136 ##STR01722## 0.00188 137 ##STR01723## 0.00205 138 ##STR01724##
0.0112 139 ##STR01725## 0.0049 140 ##STR01726## 0.0035 141
##STR01727## 0.0039 142 ##STR01728## 0.00657 143 ##STR01729##
0.0026 144 ##STR01730## 0.00915 145 ##STR01731## 0.00622 146
##STR01732## 0.276 147 ##STR01733## 0.00603 148 ##STR01734## 0.015
149 ##STR01735## 0.0737 150 ##STR01736## 0.100 151 ##STR01737##
0.00994 152 ##STR01738## 0.443 153 ##STR01739## 0.439 154
##STR01740## 0.00912 155 ##STR01741## 0.00202 156 ##STR01742##
0.021 157 ##STR01743## 0.0351 158 ##STR01744## 0.0123 159
##STR01745## 0.00542 160 ##STR01746## 0.0628 161 ##STR01747## 0.284
162 ##STR01748## 0.0039 0.0028 163 ##STR01749## 0.0036 164
##STR01750## 0.0043 0.0033 165 ##STR01751## 0.0023 0.0024 0.049 166
##STR01752## 0.0039 167 ##STR01753## 0.0049 0.0042 168 ##STR01754##
0.0062 0.003 0.078 169 ##STR01755## 0.0063 0.003 0.28 170
##STR01756## 0.005 171 ##STR01757## 0.005 172 ##STR01758## 0.0039
173 ##STR01759## 0.0039 174 ##STR01760## 0.012 175 ##STR01761##
0.0052 176 ##STR01762## 0.0091 177 ##STR01763## 0.0083 178
##STR01764## 0.0076 179 ##STR01765## 1.8 180 ##STR01766## 9.9 181
##STR01767## 0.011 182 ##STR01768## 0.014 183 ##STR01769## 0.047
184 ##STR01770## 0.0051 185 ##STR01771## 0.007 186 ##STR01772##
0.004 187 ##STR01773## 0.005 188 ##STR01774## 0.0052 189
##STR01775## 0.016 190 ##STR01776## 0.056 191 ##STR01777## 0.032
192 ##STR01778## 0.034 193 ##STR01779## 0.052 194 ##STR01780## 0.18
195 ##STR01781## 0.35 196 ##STR01782## 0.043 197 ##STR01783## 3.2
198 ##STR01784## 0.55 199 ##STR01785## 1.4 200 ##STR01786## 9.4 201
##STR01787## 0.005 202 ##STR01788## 0.0016 203 ##STR01789## 0.0036
204 ##STR01790## 0.0027 205 ##STR01791## 0.0025 206 ##STR01792##
0.0018 207 ##STR01793## 0.0017 208 ##STR01794## 0.0016 0.003 0.013
209 ##STR01795## 0.0017 0.0158 210 ##STR01796## 0.0019 211
##STR01797## 0.0017 212 ##STR01798## 0.0027 213 ##STR01799## 0.0025
214 ##STR01800## 0.0031 215 ##STR01801## 0.0048 216 ##STR01802##
0.005 217 ##STR01803## 0.0056 0.0025 0.19 218 ##STR01804## 0.0078
219 ##STR01805## 0.0083 220 ##STR01806## 0.017 221 ##STR01807## 1.8
222 ##STR01808## 0.16 223 ##STR01809## 0.25 224 ##STR01810## 0.0045
225 ##STR01811## 0.017 226 ##STR01812## 0.012 227 ##STR01813##
0.0081 228 ##STR01814## 0.0051 0.031 4.1 229 ##STR01815## 0.0073
230 ##STR01816## 0.0044 231 ##STR01817## 0.0059 232 ##STR01818##
0.064 233 ##STR01819## 0.031 234 ##STR01820## 0.17 235 ##STR01821##
0.21 236 ##STR01822## 0.0016 237 ##STR01823## 0.0029 238
##STR01824## 0.0022 239 ##STR01825## 0.0034 240 ##STR01826## 0.0024
241 ##STR01827## 0.0027 242 ##STR01828## 0.003 243 ##STR01829##
0.011 244 ##STR01830## 0.012 245 ##STR01831## 0.0079
246 ##STR01832## 0.0077 247 ##STR01833## 0.0089 248 ##STR01834##
0.01 249 ##STR01835## 0.039 250 ##STR01836## 0.043 251 ##STR01837##
0.049 252 ##STR01838## 0.05 253 ##STR01839## 0.02 254 ##STR01840##
0.026 255 ##STR01841## 1.1 256 ##STR01842## 0.29 257 ##STR01843##
0.27 258 ##STR01844## 0.065 259 ##STR01845## 0.0022 0.023 0.11 260
##STR01846## 0.0048 261 ##STR01847## 0.0048 262 ##STR01848## 0.018
263 ##STR01849## 0.02 264 ##STR01850## 0.0092 265 ##STR01851## 0.10
266 ##STR01852## 0.091 267 ##STR01853## 0.047 268 ##STR01854##
0.006 0.0028 269 ##STR01855## 0.0034 270 ##STR01856## 0.005 0.0058
271 ##STR01857## 0.0037 272 ##STR01858## 0.0042 273 ##STR01859##
0.0085 274 ##STR01860## 0.068 275 ##STR01861## 0.0069 276
##STR01862## 0.0057 277 ##STR01863## 0.004 278 ##STR01864## 0.0033
279 ##STR01865## 0.004 280 ##STR01866## 0.0081 281 ##STR01867##
0.0047 282 ##STR01868## 0.0044 283 ##STR01869## 0.004 284
##STR01870## 0.0036 285 ##STR01871## 0.0033 286 ##STR01872## 0.0054
287 ##STR01873## 0.0035 288 ##STR01874## 0.0035 289 ##STR01875##
0.0035 290 ##STR01876## 0.0048 291 ##STR01877## 0.011 292
##STR01878## 0.0029 293 ##STR01879## 0.0052 294 ##STR01880## 0.0038
295 ##STR01881## 0.0023 296 ##STR01882## 0.0081 297 ##STR01883##
0.0108 298 ##STR01884## 0.0046 299 ##STR01885## 0.0019 300
##STR01886## 0.0016 301 ##STR01887## 0.003 302 ##STR01888## 0.0057
303 ##STR01889## 0.0065 304 ##STR01890## 0.0037 305 ##STR01891##
0.0039 306 ##STR01892## 0.0060 307 ##STR01893## 0.0067 308
##STR01894## 0.0060 309 ##STR01895## 0.0027 0.003 0.38 310
##STR01896## 0.0023 311 ##STR01897## 0.0029 312 ##STR01898## 0.0022
<0.001 0.31 313 ##STR01899## 0.0091 314 ##STR01900## >10 315
##STR01901## 0.0191 316 ##STR01902## 0.0372 317 ##STR01903## 0.0060
318 ##STR01904## 0.0026 319 ##STR01905## 0.0054 320 ##STR01906##
0.2133 321 ##STR01907## 0.1907 322 ##STR01908## 0.0019 323
##STR01909## 0.0019 324 ##STR01910## 0.0027 325 ##STR01911## 0.0024
326 ##STR01912## 0.0029 327 ##STR01913## 0.0027 328 ##STR01914##
0.0064 329 ##STR01915## 0.0033 330 ##STR01916## 0.0319 331
##STR01917## 0.0322 332 ##STR01918## 0.0352 333 ##STR01919## 0.0207
334 ##STR01920## 0.0071 335 ##STR01921## 0.0143 336 ##STR01922##
0.0049 337 ##STR01923## 0.01108 338 ##STR01924## 0.0074 339
##STR01925## 0.0165 340 ##STR01926## 0.0047 341 ##STR01927## 0.0044
342 ##STR01928## 0.0057 343 ##STR01929## 0.0084 344 ##STR01930##
0.0069 345 ##STR01931## 0.0078 346 ##STR01932## 0.0044 0.0022 682
347 ##STR01933## 0.0063 348 ##STR01934## 0.0045 349 ##STR01935##
0.0040 350 ##STR01936## 0.0045 351 ##STR01937## 0.0053 352
##STR01938## 0.0020 353 ##STR01939## 0.011 354 ##STR01940## 2.6695
355 ##STR01941## 0.11876 356 ##STR01942## 0.0058 357 ##STR01943##
0.0130 358 ##STR01944## 0.0140 359 ##STR01945## 0.0114 360
##STR01946## 0.0128 361 ##STR01947## 0.0020 362 ##STR01948## 0.0029
363 ##STR01949## 0.0058 364 ##STR01950## 0.0806 365 ##STR01951##
0.3272 366 ##STR01952## 0.0091 367 ##STR01953## 0.0083 368
##STR01954## 0.0251 369 ##STR01955## 0.0145 370 ##STR01956## 0.0308
371 ##STR01957## 0.0203
372 ##STR01958## 0.04923 373 ##STR01959## 0.0197 374 ##STR01960##
0.0231 375 ##STR01961## 0.0146 376 ##STR01962## 2.4491 377
##STR01963## 1.2589 378 ##STR01964## 0.0459 379 ##STR01965## 0.0172
380 ##STR01966## 0.0409 381 ##STR01967## 0.0148 382 ##STR01968##
0.0407 383 ##STR01969## 0.0148 384 ##STR01970## 0.0163 385
##STR01971## 0.0100 386 ##STR01972## 0.0521 387 ##STR01973## 0.0133
388 ##STR01974## 0.0163 389 ##STR01975## 0.0088 390 ##STR01976##
0.0185 391 ##STR01977## 0.0101 392 ##STR01978## 2.0625 393
##STR01979## 1.3750 394 ##STR01980## 6.0057 395 ##STR01981## >10
396 ##STR01982## 0.0148 397 ##STR01983## 0.0057 398 ##STR01984##
0.0051 399 ##STR01985## 0.0046 400 ##STR01986## 0.0021 401
##STR01987## 0.0031 402 ##STR01988## 0.0224 403 ##STR01989## 0.0170
404 ##STR01990## 0.0201 405 ##STR01991## 0.0150 406 ##STR01992##
0.0176 407 ##STR01993## 0.0067 408 ##STR01994## 0.0227 409
##STR01995## 0.0540 410 ##STR01996## 0.0109 411 ##STR01997## 0.0008
412 ##STR01998## 0.0015 413 ##STR01999## 0.0060 414 ##STR02000##
0.0038 415 ##STR02001## 0.0061 416 ##STR02002## 0.0053 417
##STR02003## 0.0057 418 ##STR02004## 0.0032 419 ##STR02005## 0.0052
420 ##STR02006## 0.0024 421 ##STR02007## 0.0025 422 ##STR02008##
0.0013 423 ##STR02009## 0.0021 424 ##STR02010## 0.0025 425
##STR02011## 0.0029 426 ##STR02012## 0.0031 427 ##STR02013## 0.0190
428 ##STR02014## 0.0234 429 ##STR02015## 0.0519 430 ##STR02016##
0.5327 431 ##STR02017## 0.0032 432 ##STR02018## 0.0033 433
##STR02019## 0.0062 434 ##STR02020## 0.0050 0.0128 435 ##STR02021##
0.0054 436 ##STR02022## 0.0054 437 ##STR02023## 0.0073 438
##STR02024## 0.0095 439 ##STR02025## 0.0110 440 ##STR02026## 0.0003
441 ##STR02027## 0.1378