U.S. patent application number 13/084718 was filed with the patent office on 2011-08-04 for benzimidazole modulators of vr1.
Invention is credited to Derek A. Beauchamp, Michael Richard Brandt, Raul R. Calvo, Wing S. Cheung, Scott L. Dax, Michele C. Jetter, Yu-Kai Lee, Jian Liu, Wenxi Pan, William H. Parsons, Sharmila Patel, Mark R. Player, Kenneth M. Wells, Mark A. Youngman.
Application Number | 20110190364 13/084718 |
Document ID | / |
Family ID | 38566108 |
Filed Date | 2011-08-04 |
United States Patent
Application |
20110190364 |
Kind Code |
A1 |
Player; Mark R. ; et
al. |
August 4, 2011 |
BENZIMIDAZOLE MODULATORS OF VR1
Abstract
The invention is directed to compounds of Formula (I):
##STR00001## to pharmaceutical compositions containing such
compounds and to methods of treatment using them.
Inventors: |
Player; Mark R.;
(Phoenixville, PA) ; Dax; Scott L.; (Landenberg,
PA) ; Parsons; William H.; (Belle Mead, NJ) ;
Brandt; Michael Richard; (Flemington, NJ) ; Calvo;
Raul R.; (Royersford, PA) ; Patel; Sharmila;
(Jamison, PA) ; Liu; Jian; (Manalapan, NJ)
; Cheung; Wing S.; (Plainsboro, NJ) ; Jetter;
Michele C.; (Norristown, PA) ; Lee; Yu-Kai;
(Exton, PA) ; Youngman; Mark A.; (Warminster,
PA) ; Pan; Wenxi; (Glenmoore, PA) ; Wells;
Kenneth M.; (Hillsborough, NJ) ; Beauchamp; Derek
A.; (Watchung, NJ) |
Family ID: |
38566108 |
Appl. No.: |
13/084718 |
Filed: |
April 12, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11734984 |
Apr 13, 2007 |
7951829 |
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13084718 |
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Current U.S.
Class: |
514/394 |
Current CPC
Class: |
A61P 1/04 20180101; A61P
25/04 20180101; A61P 25/22 20180101; A61P 13/10 20180101; C07D
403/06 20130101; C07D 235/08 20130101; A61P 29/00 20180101; C07D
401/06 20130101; A61P 25/00 20180101; A61P 9/12 20180101; A61P
43/00 20180101; A61P 11/00 20180101 |
Class at
Publication: |
514/394 |
International
Class: |
A61K 31/4184 20060101
A61K031/4184; A61P 29/00 20060101 A61P029/00 |
Claims
1-14. (canceled)
15. A method for treating a VR1 ion channel mediated disease in a
subject in need thereof comprising administering to the subject an
effective amount of the compound of claim Formula (I): ##STR00210##
and a salt, stereoisomer, tautomer or ester thereof, wherein: the
dashed lines between positions 1, 2 and 3 in Formula (I) indicate
the positions of a tautomeric double bond, wherein when a double
bond is formed between positions 1 and 2, then R.sub.3b is present,
and wherein, when a double bond is formed between postions 2 and 3,
then R.sub.3a is present; p is 1 or 2; q is 0 or 1; r is 0, 1, 2 or
3; L is C.sub.1-3alkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl or
cyclopropyl; A.sub.1 is selected from the group consisting of
phenyl, biphenyl, naphthyl, pyridinyl, quinolinyl and indole;
R.sub.1 is each selected from the group consisting of hydroxy,
cyano, halogen, formyl, carboxy, C.sub.1-6alkyl,
haloC.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkoxy,
C.sub.1-6alkylcarbonyl, C.sub.1-6alkoxycarbonyl,
C.sub.1-6alkylthio, C.sub.1-6alkylsulfonyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-4alkyl,
C.sub.3-8cycloalkyl-C.sub.1-4alkoxy, C.sub.3-8cycloalkyl-oxy,
amino, (C.sub.1-6alkyl).sub.1-2-amino,
(C.sub.3-8cycloalkyl).sub.1-2-amino,
(C.sub.3-8cycloalkyl-C.sub.1-4alkyl).sub.1-2-amino, aminocarbonyl,
(C.sub.1-6alkyl).sub.1-2-aminocarbonyl,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkoxycarbonylamino,
aminocarbonylamino, (C.sub.1-6alkyl).sub.1-2-aminocarbonylamino,
C.sub.1-6alkylsulfonylamino, C.sub.1-6alkylsulfinylamino,
aminosulfonyl, (C.sub.1-4alkyl).sub.1-2-aminosulfonyl,
aminosulfonylamino and (C.sub.1-6alkyl).sub.1-2-aminosulfonylamino,
wherein alkyl is optionally substituted with C.sub.1-8alkoxy,
amino, (C.sub.1-4alkyl).sub.1-2-amino, C.sub.1-6alkylcarbonylamino,
C.sub.1-6alkoxycarbonylamino, aminocarbonylamino,
(C.sub.1-6alkyl).sub.1-2-aminocarbonylamino,
C.sub.1-6alkylsulfonylamino, aminosulfonylamino,
(C.sub.1-6alkyl).sub.1-2-aminosulfonylamino hydroxy and phenyl,
wherein phenyl is optionally substituted with one, two or three
substituents independently selected from the group consisting of
halogen, cyano, nitro, C.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.1-6alkylthio and C.sub.1-6alkylsulfonyl, and wherein, each
instance of alkyl and alkoxy is optionally perfluorinated; R.sub.2
is selected from the group consisting of halogen, C.sub.1-4alkyl,
C.sub.1-4alkoxy, C.sub.1-4alkylsulfonyl, nitro, amino,
(C.sub.1-4alkyl).sub.1-2-amino and cyano, wherein each instance of
alkyl and alkoxy is optionally perfluorinated; R.sub.3a and
R.sub.3b are each selected from the group consisting of hydrogen
and optionally perfluorinated C.sub.1-4alkyl; and R.sub.4 is each
selected from the group consisting of halogen, nitro, cyano,
carboxy, C.sub.1-6alkyl, C.sub.1-6alkoxy, haloC.sub.1-6alkyl,
haloC.sub.1-6alkoxy, C.sub.1-6alkoxy-C.sub.1-6alkyl,
C.sub.1-6alkylcarbonyl, C.sub.1-6alkylthio, haloC.sub.1-6alkylthio,
C.sub.1-6alkylsulfonyl, haloC.sub.1-6alkylsulfonyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-4alkyl,
C.sub.3-8cycloalkyl-C.sub.1-4alkoxy, C.sub.3-8cycloalkyl-oxy,
amino, (C.sub.1-6alkyl).sub.1-2-amino,
(C.sub.3-8cycloalkyl).sub.1-2-amino,
(C.sub.3-8cycloalkyl-C.sub.1-4alkyl).sub.1-2-amino, aminocarbonyl,
(C.sub.1-6alkyl).sub.1-2-aminocarbonyl,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkoxycarbonylamino,
aminocarbonylamino, (C.sub.1-6alkyl).sub.1-2-aminocarbonylamino,
C.sub.1-6alkylsulfonylamino, haloC.sub.1-6alkylsulfonylamino,
C.sub.1-6alkylsulfinylamino, aminosulfonyl and
(C.sub.1-4alkyl).sub.1-2-aminosulfonyl, wherein each instance of
alkyl is optionally substituted with one, two or three substituents
independently selected from the group consisting of
C.sub.1-8alkoxy, amino, (C.sub.1-4alkyl).sub.1-2-amino,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkoxycarbonylamino,
aminocarbonylamino, (C.sub.1-6alkyl).sub.1-2-aminocarbonylamino,
C.sub.1-6alkylsulfonylamino, oxo and hydroxy, and wherein, each
instance of alkyl and alkoxy is optionally perfluorinated.
16. The method of claim 15, wherein the VR1 ion channel mediated
disease is chronic or acute pain due to disease that causes
inflammatory pain, burning pain or post-operative pain.
17. The method of claim 15, wherein the effective amount of the
compound of claim 1 is in a range of from about 0.001 mg/kg/day to
about 300 mg/kg/day.
18-20. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefits of the filing of
U.S. application Ser. No. 11/734,984 filed Apr. 13, 2007, and U.S.
Provisional Application No. 60/797,504 filed May 3, 2006. The
complete disclosures of the aforementioned related patent
applications are hereby incorporated herein by reference for all
purposes.
BACKGROUND OF THE INVENTION
[0002] Noxious chemical, thermal and mechanical stimuli excite
peripheral nerve endings of small diameter sensory neurons
(nociceptors) deriving from sensory ganglia (e.g., dorsal root,
nodose and trigeminal ganglia) and initiate signals that are
perceived as pain. Such nociceptive neurons (i.e., nociceptors) are
crucial for the detection of harmful or potentially harmful stimuli
(e.g., noxious thermal, chemical, and/or mechanical) that arise
from changes in the extracellular environment during inflammatory,
ischemic or otherwise traumatic conditions and that cause or have
the potential to cause tissue damage (Wall, P. D., and Melzack, R.,
Textbook of Pain, 1994, New York: Churchill Livingstone).
[0003] Nociceptors transduce noxious stimuli into membrane
depolarization that leads to an action potential, its subsequent
conduction to the CNS, and ultimately to the perception of pain,
discomfort, etc. as well as to certain responses thereto. At the
molecular level, nociception is carried out by ion channels and/or
receptors. Plant-derived vanilloid compounds (e.g., capsaicin and
resiniferatoxin) are known to selectively depolarize nociceptors
and elicit sensations of burning pain: the sensation that is
typically evoked by capsaicin-containing hot chili peppers.
Therefore, capsaicin mimics the action of physiological/endogenous
stimuli that activate the "nociceptive pathway". Recent advances in
pain biology have identified a receptor, called VR1 (a.k.a.
capsaicin receptor or TRPV1) for vanilloids, protons and noxious
heat. Because nociceptors are drivers of unwanted pain and
inflammatory conditions in human beings and animals, modulation of
their function is a validated strategy for palliative and other
analgesic therapies.
[0004] Compounds that are modulators (competitive and
non-competitive agonists or antagonists [with respect to capsaicin
and/or its recognition site] and allosteric modulators) at VR1 have
broad therapeutic potential, as demonstrated by the clinical
usefulness of marketed, VR1-targeted pharmaceutical agents or the
efficacy of VR1 modulators in animal models of disease.
Furthermore, it is recognized that agonist modulators of VR1 may
possess clinical utility deriving from their agonist properties,
per se, and/or from their ability to produce an agonist-mediated
desensitization, which would indirectly manifest as a functional
antagonism. Similarly, antagonist modulators could exhibit direct
antagonist (competitive or non-competitive) properties and/or
indirect antagonist properties via the aforementioned
desensitization mechanism. It is further recognized that positive
and negative allosteric modulators may produce any or all of the
aforementioned functional consequences and, as such, may also have
clinical utility. Accordingly, this invention is directed to each
of these types of modulators.
[0005] The effective use of VR1 agonists has been demonstrated in
inflammatory, neuropathic, and visceral pain states. In an
experimental human pain model, dermal capsaicin pretreatment
reduced the pain caused by intradermal injection of an acidic
solution (Bianco, E. D.; Geppetti, P.; Zippi, P.; (solani, D.;
Magini, B.; Cappugi, P. Brit J of Clin Pharmacol 1996, 41, 1-6),
suggesting the benefit of VR1 agonists in the treatment of
inflammatory pain. A particular role for VR1 agonists has been
shown in inflammation and inflammatory pain: for example,
resiniferatoxin prevented inflammatory hypersensitivity and edema
induction by carrageenan (Kissin, I.; Bright, C. A.; Bradley, E.
L., Jr. Anesth Analg 2002, 94, 1253-1258).
[0006] Additionally, capsaicin-containing creams (for example,
Axcain.RTM. and Lidocare.RTM.) are marketed for dermal relief of
pain related to diabetic neuropathy and postherpetic neuralgia,
indicative of the usefulness of VR1 agonists in the treatment of
neuropathic pain states. Furthermore, such creams have been shown
to reduce postsurgical neuropathic pain (Ellison, N., Loprinzi, C.
L., Kugler, J., Hatfield, A. K., Miser, A., Sloan, J. A., Wender,
D. B., Rowland, K. M., Molina, R., Cascino, T. L., Vukov, A. M.,
Dhaliwal, H. S, and Ghosh, C. J. Clin. Oncol. 15:2974-2980, 1997).
In cancer patients, capsaicin contained in a taffy vehicle, was
shown to substantially reduce oral mucositis pain caused by
chemotherapy and radiation therapy (Berger, A., Henderson, M.,
Naadoolman, W., Duffy, V., Cooper, D., Saberski, L. and Bartoshuk,
L. J. Pain Sympt. Mgmt 10:243-248, 1995.
[0007] VR1 also plays a role in the physiology of bladder emptying.
VR1 is expressed by bladder sensory neurons, where it modulates
bladder responsivity to liquid filling. The VR1 agonist
resiniferatoxin desensitized bladder afferents in a dose-dependent
manner (Avelino, A.; Cruz, F.; Coimbra, A. Eur. J. Pharmacol. 1999,
378, 17-22), supporting its usefulness for the treatment of
overactive bladder (Chancellor, M. B.; De Groat, W. C. J. Urol.
(Baltimore) 1999, 162, 3-11). Indeed, intravesicular administration
of capsaicin or resiniferatoxin inhibited bladder contraction in
both normal and spinal cord injured rats (Komiyama, I.; Igawa, Y.;
Ishizuka, O.; Nishizawa, O.; Andersson, K.-E. J. Urol. (Baltimore)
1999, 161, 314-319), indicative of the usefulness of VR1 agonists
in nerve-injured incontinent patients. The effectiveness of
capsaicin or resiniferatoxin treatment on incontinence in spinal
cord injured patients was confirmed in a clinical study (de Seze,
M.; Wiart, L.; de Seze, M.-P.; Soyeur, L.; Dosque, J.-P.;
Blajezewski, S.; Moore, N.; Brochet, B.; Mazaux, J.-M.; Barat, M.;
Joseph, P.-A. Journal of Urology (Hagerstown, Md., United States)
2003, 171, 251-255).
[0008] The effectiveness of VR1 agonists in the reduction of
elevated blood pressure is suggested by capsaicin reduction in
blood pressure in SHR and WKY rats (Li, J.; Kaminski, N. E.; Wang,
D. H. Hypertension 2003, 41, 757-762.). Capsaicin was also
gastroprotective with respect to gastric antral ulcers (Yamamoto,
H.; Horie, S.; Uchida, M.; Tsuchiya, S.; Murayama, T.; Watanabe, K.
Eur. J. Pharmacol. 2001, 432, 203-210).
[0009] VR1 antagonists also may be useful in the treatment of
inflammatory, neuropathic and visceral pain. For example, the
therapeutic utility of VR1 antagonists has been demonstrated in
visceral inflammatory conditions. VR1 is elevated in colonic nerve
fibers in patients with inflammatory bowel disease, and VR1
antagonists relieved pain and dysmotility (Yiangou, Y.; Facer, P.;
Dyer, N. H.; Chan, C. L.; Knowles, C.; Williams, N. S.; Anand, P.
Lancet 2001, 357, 1338-1339). Intestinal inflammation induced by
toxin A or dextran sulfate sodium in rodents was attenuated by VR1
antagonists (McVey, D. C.; Schmid, P. C.; Schmid, H. H. O.; Vigna,
S. R. J. Pharmacol. Exp. Ther. 2003, 304, 713-722). In addition, a
synthetic VR1 antagonist reduced colitis disease scores at several
important endpoints, including macroscopic damage, microscopic
epithelial damage, myeloperoxidase levels, and diarrhea scores,
strongly supporting the therapeutic use of VR1 antagonists in
inflammatory bowel diseases (Kimball, E. S.; Wallace, N. H.;
Schneider, C. R.; D'Andrea, M. R.; Hornby, P. J.
Neurogasteroenterology 2004, 16, 811-818). The VR1 antagonists
capsazepine and BCTC reversed mechanical hyperalgesia in models of
inflammatory and neuropathic pain in guinea pigs (Walker, K. M.;
Urban, L.; Medhurst, S. J.; Patel, S.; Panesar, M.; Fox, A. J.;
McIntyre, P. J. Pharmacol. Exp. Ther. 2003, 304, 56-62) and rats
(Pomonis, J. D.; Harrison, J. E.; Mark, L.; Bristol, D. R.;
Valenzano, K. J.; Walker, K. J. Pharmacol. Exp. Ther. 2003, 306,
387-393).
[0010] LPS-induced fever was attenuated in VR1 knock out mice
(Lida, T.; Shimizu, I.; Nealen, M. L.; Campbell, A.; Caterina, M.
Neurosci. Lett. 2005, 378, 28-33). VR1 agonist-induced rises in
core body temperature were suppressed by capsazepine, indicative of
the usefulness of VR1 antagonists in the treatment of pyresis
(Ohnluki, K.; Haramizu, S.; Watanabe, T.; Yazawa, S.; Fushiki, T.
J. Nutr. Sci. Vitaminol. (Tokyo) 2001, 47, 295-298).
[0011] VR1 agonists also modulate body temperature and fever. In
ferret, rat and mouse, administration of resiniferatoxin-induced
hypothermia (Woods, A. J.; Stock, M. J.; Gupta, A. N.; Wong, T. T.
L.; Andrews, P. L. R. Eur. J. Pharmacol. 1994, 264, 125-133).
Additionally, phase I of LPS (lipopolysaccharide)-induced fever did
not occur in animals desensitized with low intraperitoneal doses of
capsaicin (Romanovsky, A. A. Frontiers in Bioscience 2004, 9,
494-504).
[0012] The therapeutic potential of VR1 antagonists in inflammatory
bronchial conditions is demonstrated by the finding that they
antagonize capsaicin- and acid-induced bronchoconstriction (Nault,
M. A.; Vincent, S. G.; Fisher, J. T. J. Physiol. 1999, 515,
567-578). Related findings demonstrate that the VR1 antagonist
capsazepine attenuates anandamide-induced cough in guinea pigs
(Jia, Y.; McLeod, R. L.; Wang, X.; Parra, L. E.; Egan, R. W.; Hey,
J. A. Brit. J. Pharmacol. 2002, 137, 831-836).
[0013] The VR1 antagonist capsazepine was demonstrated to
significantly reduce anxiety-like behaviors in rats using the
elevated plus maze (Kasckow, J. W.; Mulchahey, J. J.; Geracioti, T.
D. Jr. Progress in Neuro-Psychopharmacol. and Biological Psychiatry
2004, 28, 291-295). Thus, VR1 antagonists may have utility in the
treatment of anxiety, panic disorders, phobias or other
non-adaptive stress responses.
[0014] U.S. Pat. No. 6,299,796B1 discloses electroluminescent
elements comprising units of the formula:
##STR00002##
[0015] Thus, there is a need for potent modulators of VR1, and in
particular, for novel benzimidazole compounds that exhibit potent
binding affinity for the human and rat VR1 ion channel. There is
also a need for novel benzimidazole compounds that act as potent
functional antagonists and/or agonists of the human and rat VR1 ion
channel. Finally, there is a need for novel benzimidazoles that
bind with high affinity to VR1 and also act as potent functional
antagonists of the human and rat VR1 ion channel.
SUMMARY OF THE INVENTION
[0016] The present invention is directed to a compound of Formula
(I):
##STR00003##
and a form thereof, wherein R.sub.1, R.sub.2, R.sub.3a, R.sub.3b,
R.sub.4, p, q, r, L and A.sub.1 are as defined herein, and their
use as potent modulators of VR.sub.1.
[0017] The present invention is also directed to a method for
treating a VR.sub.1 ion channel mediated disease in a subject in
need thereof comprising administering to the subject an effective
amount of a compound of Formula (I). The present invention is
further directed to a process for making a compound of Formula (I)
and salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention is directed to compounds of Formula
(I):
##STR00004##
and a form thereof, wherein: [0019] the dashed lines between
positions 1, 2 and 3 in Formula (I) indicate the positions of a
tautomeric double bond, [0020] wherein when a double bond is formed
between positions 1 and 2, then R.sub.3b is present, and [0021]
wherein, when a double bond is formed between positions 2 and 3,
then R.sub.3a is present; [0022] p is 1 or 2; [0023] q is 0 or 1;
[0024] r is 0, 1, 2 or 3; [0025] L is C.sub.1-3alkyl,
C.sub.2-3alkenyl, C.sub.2-3alkynyl or cyclopropyl; [0026] A.sub.1
is selected from the group consisting of phenyl, biphenyl,
naphthyl, pyridinyl, quinolinyl and indole; [0027] R.sub.1 is each
selected from the group consisting of hydroxy, cyano, halogen,
formyl, carboxy, C.sub.1-6alkyl, haloC.sub.1-6alkyl,
C.sub.1-6alkoxy, haloC.sub.1-6alkoxy, C.sub.1-6alkylcarbonyl,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkylthio,
C.sub.1-6alkylsulfonyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-4alkyl,
C.sub.3-8cycloalkyl-C.sub.1-4alkoxy, C.sub.3-8cycloalkyl-oxy,
amino, (C.sub.1-6alkyl).sub.1-2-amino,
(C.sub.3-8cycloalkyl).sub.1-2-amino,
(C.sub.3-8cycloalkyl-C.sub.1-4alkyl).sub.1-2-amino, aminocarbonyl,
(C.sub.1-6alkyl).sub.1-2-aminocarbonyl,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkoxycarbonylamino,
aminocarbonylamino, (C.sub.1-6alkyl).sub.1-2-aminocarbonylamino,
C.sub.1-6alkylsulfonylamino, C.sub.1-6alkylsulfinylamino,
aminosulfonyl, (C.sub.1-4alkyl).sub.1-2-aminosulfonyl,
aminosulfonylamino and (C.sub.1-6alkyl).sub.1-2-aminosulfonylamino,
[0028] wherein alkyl is optionally substituted with
C.sub.1-8alkoxy, amino, (C.sub.1-4alkyl).sub.1-2-amino,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkoxycarbonylamino,
aminocarbonylamino, (C.sub.1-6alkyl).sub.1-2-aminocarbonylamino,
C.sub.1-6alkylsulfonylamino, aminosulfonylamino,
(C.sub.1-6alkyl).sub.1-2-aminosulfonylamino hydroxy and phenyl,
[0029] wherein phenyl is optionally substituted with one, two or
three substituents independently selected from the group consisting
of halogen, cyano, nitro, C.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.1-6alkylthio and C.sub.1-6alkylsulfonyl, and [0030] wherein,
each instance of alkyl and alkoxy is optionally perfluorinated;
[0031] R.sub.2 is selected from the group consisting of halogen,
C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkylsulfonyl, nitro,
amino, (C.sub.1-4alkyl).sub.1-2-amino and cyano, wherein each
instance of alkyl and alkoxy is optionally perfluorinated; [0032]
R.sub.3a and R.sub.3b are each selected from the group consisting
of hydrogen and optionally perfluorinated C.sub.1-4alkyl; and
[0033] R.sub.4 is each selected from the group consisting of
halogen, nitro, cyano, carboxy, C.sub.1-6alkyl, C.sub.1-6alkoxy,
haloC.sub.1-6alkyl, haloC.sub.1-6alkoxy,
C.sub.1-6alkoxy-C.sub.1-6alkyl, C.sub.1-6alkylcarbonyl,
C.sub.1-6alkylthio, haloC.sub.1-6alkylthio, C.sub.1-6alkylsulfonyl,
haloC.sub.1-6alkylsulfonyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-4alkyl,
C.sub.3-8cycloalkyl-C.sub.1-4alkoxy, C.sub.3-8cycloalkyl-oxy,
amino, (C.sub.1-6alkyl).sub.1-2-amino,
(C.sub.3-8cycloalkyl).sub.1-2-amino,
(C.sub.3-8cycloalkyl-C.sub.1-4alkyl).sub.1-2-amino, aminocarbonyl,
(C.sub.1-6alkyl).sub.1-2-aminocarbonyl,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkoxycarbonylamino,
aminocarbonylamino, (C.sub.1-6alkyl).sub.1-2-aminocarbonylamino,
C.sub.1-6alkylsulfonylamino, haloC.sub.1-6alkylsulfonylamino,
C.sub.1-6alkylsulfinylamino, aminosulfonyl and
(C.sub.1-4alkyl).sub.1-2-aminosulfonyl, [0034] wherein each
instance of alkyl is optionally substituted with one, two or three
substituents independently selected from the group consisting of
C.sub.1-8alkoxy, amino, (C.sub.1-4alkyl).sub.1-2-amino,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkoxycarbonylamino,
aminocarbonylamino, (C.sub.1-6alkyl).sub.1-2-aminocarbonylamino,
C.sub.1-6alkylsulfonylamino, oxo and hydroxy, and [0035] wherein,
each instance of alkyl and alkoxy is optionally perfluorinated.
[0036] An example of the present invention includes a compound of
Formula (I) or a form thereof, wherein q is 0.
[0037] An example of the present invention includes a compound of
Formula (I) or a form thereof, wherein A.sub.1 is selected from the
group consisting of phenyl, biphenyl, naphthyl, quinolinyl and
indole.
[0038] An example of the present invention includes a compound of
Formula (I) or a form thereof, wherein [0039] R.sub.1 is each
selected from the group consisting of hydroxy, halogen, formyl,
C.sub.1-6alkyl, haloC.sub.1-6alkyl, haloC.sub.1-6alkoxy,
C.sub.1-6alkylcarbonyl, C.sub.1-6alkoxycarbonyl,
C.sub.1-6alkylthio, C.sub.1-6alkylsulfonyl, amino, aminocarbonyl,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkoxycarbonylamino,
C.sub.1-6alkylsulfonylamino, aminosulfonyl,
(C.sub.1-4alkyl).sub.1-2-aminosulfonyl and aminosulfonylamino,
[0040] wherein alkyl is optionally substituted with amino,
(C.sub.1-4alkyl).sub.1-2-amino, aminosulfonylamino or hydroxy, and
wherein, alkyl is optionally perfluorinated.
[0041] An example of the present invention includes a compound of
Formula (I) or a form thereof, wherein R.sub.2 is selected from the
group consisting of halogen and C.sub.1-4alkyl, wherein alkyl is
optionally perfluorinated.
[0042] An example of the present invention includes a compound of
Formula (I) or a form thereof, wherein R.sub.3a and R.sub.3b are
each selected from the group consisting of hydrogen and
C.sub.1-4alkyl.
[0043] An example of the present invention includes a compound of
Formula (I) or a form thereof, wherein R.sub.4 is each selected
from the group consisting of halogen, carboxy, C.sub.1-6alkyl,
C.sub.1-6alkoxy, haloC.sub.1-6alkyl, haloC.sub.1-6alkoxy,
C.sub.1-6alkylcarbonyl, haloC.sub.1-6alkylthio,
C.sub.1-6alkylsulfonyl, haloC.sub.1-6alkylsulfonyl,
(C.sub.1-6alkyl).sub.1-2-amino,
(C.sub.1-6alkyl).sub.1-2-aminocarbonyl,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkylsulfonylamino and
haloC.sub.1-6alkylsulfonylamino, wherein alkyl and alkoxy are
optionally perfluorinated.
[0044] An example of the present invention includes a compound of
Formula (I) or a form thereof, wherein [0045] p is 1 or 2; [0046] q
is 0; [0047] r is 0, 1, 2 or 3; [0048] L is C.sub.1-3alkyl,
C.sub.2-3alkenyl, C.sub.2-3alkynyl or cyclopropyl; [0049] A.sub.1
is selected from the group consisting of phenyl, biphenyl,
naphthyl, quinolinyl and indole; [0050] R.sub.1 is each selected
from the group consisting of hydroxy, halogen, formyl,
C.sub.1-6alkyl, haloC.sub.1-6alkyl, haloC.sub.1-6alkoxy,
C.sub.1-6alkylcarbonyl, C.sub.1-6alkoxycarbonyl,
C.sub.1-6alkylthio, C.sub.1-6alkylsulfonyl, amino, aminocarbonyl,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkoxycarbonylamino,
C.sub.1-6alkylsulfonylamino, aminosulfonyl,
(C.sub.1-4alkyl).sub.1-2-aminosulfonyl and aminosulfonylamino,
[0051] wherein alkyl is optionally substituted with amino,
(C.sub.1-4alkyl).sub.1-2-amino, aminosulfonylamino or hydroxy, and
wherein, alkyl is optionally perfluorinated; [0052] R.sub.2 is
selected from the group consisting of halogen and C.sub.1-4alkyl,
wherein alkyl is optionally perfluorinated; [0053] R.sub.3a and
R.sub.3b are each selected from the group consisting of hydrogen
and C.sub.1-4alkyl; and [0054] R.sub.4 is each selected from the
group consisting of halogen, carboxy, C.sub.1-6alkyl,
C.sub.1-6alkoxy, haloC.sub.1-6alkyl, haloC.sub.1-6alkoxy,
C.sub.1-6alkylcarbonyl, haloC.sub.1-6alkylthio,
C.sub.1-6alkylsulfonyl, haloC.sub.1-6alkylsulfonyl,
(C.sub.1-6alkyl).sub.1-2-amino,
(C.sub.1-6alkyl).sub.1-2-aminocarbonyl,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkylsulfonylamino and
haloC.sub.1-6alkylsulfonylamino, wherein alkyl and alkoxy are
optionally perfluorinated.
[0055] The present invention is further directed to compounds of
Formula Ia or Ib:
##STR00005##
wherein: [0056] R.sub.1 is independently hydroxyl; halogen,
C.sub.1-6alkanyl; fluorinated C.sub.1-6alkanyl;
C.sub.1-6alkanyloxy; fluorinated C.sub.1-6alkanyloxy;
C.sub.1-6alkanylthio; fluorinated C.sub.1-6alkanylthio;
C.sub.1-6alkanylsulfonyl; fluorinated C.sub.1-6alkanylsulfonyl;
C.sub.3-8cycloalkanyl; C.sub.3-8cycloalkanyl; C.sub.1-4alkanyl;
C.sub.3-8cycloalkanyloxy; C.sub.3-8cycloalkanyl;
C.sub.1-4alkanyloxy; amino; (C.sub.1-6alkanyl).sub.1-2-amino;
(C.sub.3-8cycloalkanyl).sub.1-2-amino; (C.sub.3-8cycloalkanyl;
C.sub.1-4alkanyl).sub.1-2-amino; cyano; aminocarbonyl;
(C.sub.1-6alkanyl).sub.1-2-aminocarbonyl;
C.sub.1-6alkanylcarbonylamino; fluorinated
C.sub.1-6alkanylcarbonylamino; C.sub.1-6alkanyloxycarbonylamino;
C.sub.0-6alkanylaminocarbonylamino; C.sub.1-6alkanylsulfonylamino;
fluorinated C.sub.1-6alkanylsulfonylamino; aminosulfonyl;
(C.sub.1-8alkanyl).sub.1-2-aminosulfonyl; fluorinated
(C.sub.1-8alkanyl).sub.1-2-aminosulfonyl; wherein the alkanyl in
any alkanyl-containing substituent of R.sub.1 is optionally
substituted with 1 to 3 substituents independently selected from
the group consisting of amino, (C.sub.1-8alkanyl).sub.1-2-amino,
C.sub.1-6alkanylcarbonylamino; fluorinated
C.sub.1-6alkanylcarbonylamino; C.sub.1-6alkanyloxycarbonylamino;
C.sub.0-6alkanylaminocarbonylamino; C.sub.1-6alkanylsulfonylamino;
fluorinated C.sub.1-6alkanylsulfonylamino; halogen, oxo, hydroxyl,
fluorinated alkanyl, and C.sub.1-8alkanyloxy; [0057] p is 1 or 2;
[0058] R.sub.2 is independently selected from the group consisting
of halogen; C.sub.1-4alkanyl; fluorinated C.sub.1-4alkanyl;
C.sub.1-4alkanyloxy; fluorinated C.sub.1-6alkanyloxy;
C.sub.1-4alkanylsulfonyl; fluorinated C.sub.1-4alkanylsulfonyl;
nitro; (C.sub.1-4alkanyl).sub.1-2-amino; cyano; [0059] n is 0, or
1; [0060] R.sub.3 is independently selected from the group
consisting of hydrogen, C.sub.1-4alkanyl, and fluorinated
C.sub.1-4alkanyl; [0061] L is C.sub.2-3alkyldiyl, [0062] A.sub.1 is
selected from the group consisting of phenyl and naphthyl; [0063]
R.sub.4 is independently halogen, C.sub.1-6alkanyl; fluorinated
C.sub.1-6alkanyl; C.sub.1-6alkanyloxy; fluorinated
C.sub.1-6alkanyloxy; C.sub.1-6alkanylthio; fluorinated
C.sub.1-6alkanylthio; C.sub.1-6alkanylsulfonyl; fluorinated
C.sub.1-6alkanylsulfonyl; C.sub.3-8cycloalkanyl;
C.sub.3-8cycloalkanyl; C.sub.1-4alkanyl; C.sub.3-8cycloalkanyloxy;
C.sub.3-8cycloalkanyl; C.sub.1-4alkanyloxy; amino;
(C.sub.1-6alkanyl).sub.1-2-amino;
(C.sub.3-8cycloalkanyl).sub.1-2-amino; (C.sub.3-8cycloalkanyl;
C.sub.1-4alkanyl).sub.1-2-amino; cyano; aminocarbonyl;
(C.sub.1-6alkanyl).sub.1-2-aminocarbonyl;
C.sub.0-6alkanylcarbonylamino; fluorinated
C.sub.1-6alkanylcarbonylamino; C.sub.1-6alkanyloxycarbonylamino;
C.sub.0-6alkanylaminocarbonylamino; C.sub.1-6alkanylsulfonylamino;
fluorinated C.sub.1-6alkanylsulfonylamino; aminosulfonyl;
(C.sub.1-8alkanyl).sub.1-2-aminosulfonyl; fluorinated
(C.sub.1-8alkanyl).sub.1-2-aminosulfonyl; wherein the alkanyl in
any alkanyl-containing substituent of R1 is optionally substituted
with 1 to 3 substituents independently selected from the group
consisting of halogen, oxo, hydroxyl, fluorinated alkanyl, and
C.sub.1-8alkanyloxy; phenyl optionally substituted with 1 to 3
substituents independently selected from the group consisting of
halogen; C.sub.1-4alkanyl; fluorinated C.sub.1-4alkanyl;
C.sub.1-4alkanyloxy; fluorinated C.sub.1-4alkanyloxy;
C.sub.1-4alkanylsulfonyl; fluorinated C.sub.1-4alkanylsulfonyl;
nitro; cyano; [0064] r is 0, 1 or 2; and [0065] enantiomers,
diastereomers, tautomers, solvates, and pharmaceutically acceptable
salts thereof.
[0066] An example of the present invention includes compounds and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof selected from the group
consisting of:
##STR00006## ##STR00007## ##STR00008## ##STR00009## ##STR00010##
##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015##
##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020##
##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025##
##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030##
##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035##
##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040##
##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045##
##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050##
##STR00051## ##STR00052## ##STR00053## ##STR00054## ##STR00055##
##STR00056## ##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## ##STR00155##
##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160##
##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165##
##STR00166## ##STR00167## ##STR00168## ##STR00169## ##STR00170##
##STR00171##
[0067] As modulators of the vanilloid VR1 ion channel, the
compounds of Formula (I) are useful in methods for treating a VR1
ion channel mediated disease in a subject which disease is affected
by the modulation of one or more vanilloid receptors.
[0068] Accordingly, the present invention is directed to a method
of treating a VR1 ion channel mediated disease in a subject in need
thereof comprising administering to the subject an effective amount
of a compound of Formula (I) or a salt or solvate thereof.
Compound Forms
[0069] The term "form" means, in reference to compounds of the
present invention, such may exist as, without limitation, a salt,
stereoisomer, tautomer, crystalline, polymorph, amorphous, solvate,
hydrate, ester, prodrug or metabolite form. The present invention
encompasses all such compound forms and mixtures thereof.
[0070] The term "isolated form" means, in reference to compounds of
the present invention, that such may exist in an essentially pure
state such as, without limitation, an enantiomer, a racemic
mixture, a geometric isomer (such as a cis or trans stereoisomer),
a mixture of geometric isomers, and the like. The present invention
encompasses all such isolated forms and mixtures thereof.
[0071] Certain compounds of Formula (I) may exist in various
stereoisomeric or tautomeric forms and mixtures thereof. The
invention encompasses all such compounds and mixtures thereof.
[0072] The compounds of the present invention may be present in the
form of pharmaceutically acceptable salts. For use in medicines,
the "pharmaceutically acceptable salts" of the compounds of this
invention refer to non-toxic acidic/anionic or basic/cationic salt
forms.
[0073] Suitable pharmaceutically acceptable salts of the compounds
of this invention include acid addition salts which may, for
example, be formed by mixing a solution of the compound according
to the invention with a solution of a pharmaceutically acceptable
acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic
acid, succinic acid, acetic acid, benzoic acid, citric acid,
tartaric acid, carbonic acid or phosphoric acid.
[0074] Furthermore when the compounds of the present invention
carry an acidic moiety, suitable pharmaceutically acceptable salts
thereof may include alkali metal salts, e.g. sodium or potassium
salts; alkaline earth metal salts, e.g. calcium or magnesium salts;
and salts formed with suitable organic ligands, e.g. quaternary
ammonium salts.
[0075] Thus, representative pharmaceutically acceptable salts
include the following: acetate, adipate, benzenesulfonate,
benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide,
calcium, camsylate (or camphorsulphonate), carbonate, chloride,
choline, clavulanate, citrate, dihydrochloride, disodium, edetate,
fumarate, gluconate, glutamate, hydrabamine, hydrobromine,
hydrochloride, iodide, isothionate, lactate, malate, maleate,
mandelate, mesylate, nitrate, oleate, pamoate, palmitate,
phosphate/diphosphate, salicylate, sodium, stearate, sulfate,
succinate, tartrate, tromethane, tosylate, trichloroacetate,
trifluoroacetate and the like.
[0076] An example of the present invention includes compounds of
Formula (I) and a salt form thereof wherein the salt is selected
from the group consisting of disodium, hydrochloride and
sodium.
[0077] The invention includes compounds of various isomers and
mixtures thereof. The term "isomer" refers to compounds that have
the same composition and molecular weight but differ in physical
and/or chemical properties. Such substances have the same number
and kind of atoms but differ in structure. The structural
difference may be in constitution (geometric isomers) or in an
ability to rotate the plane of polarized light (stereoisomers).
[0078] The term "optical isomer" means isomers of identical
constitution that differ only in the spatial arrangement of their
groups. Optical isomers rotate the plane of polarized light in
different directions. The term "optical activity" means the degree
to which an optical isomer rotates the plane of polarized
light.
[0079] The term "racemate" or "racemic mixture" means an equimolar
mixture of two enantiomeric species, wherein each of the isolated
species rotates the plane of polarized light in the opposite
direction such that the mixture is devoid of optical activity.
[0080] The term "enantiomer" means an isomer having a
nonsuperimposable mirror image. The term "diastereomer" means
stereoisomers that are not enantiomers.
[0081] The term "chiral" means a molecule, which in a given
configuration, cannot be superimposed on its mirror image. This is
in contrast to achiral molecules, which can be superimposed on
their mirror images.
[0082] The invention is considered to include the tautomeric forms
of all compounds of Formula (I). In addition, for chiral
embodiments of the invention, the invention is considered to
include pure enantiomers, racemic mixtures, as well as mixtures of
enantiomers having 0.001% to 99.99% enantiomeric excess. In
addition, some of the compounds represented by Formula (I) may be
prodrugs, i.e., derivatives of a drug that possess superior
delivery capabilities and therapeutic value as compared to the
active drug. Prodrugs are transformed into active drugs by in vivo
enzymatic or chemical processes.
[0083] The two distinct mirror image versions of the chiral
molecule are also known as levo (left-handed), abbreviated L, or
dextro (right handed), abbreviated D, depending on which way they
rotate polarized light. The symbols "R" and "S" represent the
configuration of groups around a stereogenic carbon atom(s).
[0084] An example of an enantiomerically enriched form isolated
from a racemic mixture includes a dextrorotatory enantiomer,
wherein the mixture is substantially free of the levorotatory
isomer. In this context, substantially free means the levorotatory
isomer may, in a range, comprise less than 25% of the mixture, less
than 10%, less than 5%, less than 2% or less than 1% of the mixture
according to the formula:
% levorotatory = ( mass levorotatory ) ( mass dextrorotatory ) + (
mass levorotatory ) .times. 100 ##EQU00001##
[0085] Similarly, an example of an enantiomerically enriched form
isolated from a racemic mixture includes a levorotatory enantiomer,
wherein the mixture is substantially free of the dextrorotatory
isomer. In this context, substantially free means the
dextrorotatory isomer may, in a range, comprise less than 25% of
the mixture, less than 10%, less than 5%, less than 2% or less than
1% of the mixture according to the formula:
% dextrorotatory = ( mass dextrorotatory ) ( mass dextrorotatory )
+ ( mass levorotatory ) .times. 100 ##EQU00002##
[0086] "Geometric isomer" means isomers that differ in the
orientation of substituent atoms in relationship to a carbon-carbon
double bond, to a cycloalkyl ring, or to a bridged bicyclic system.
Substituent atoms (other than hydrogen) on each side of a
carbon-carbon double bond may be in an E or Z configuration. In the
"E" configuration, the substituents are on opposite sides in
relationship to the carbon-carbon double bond. In the "Z"
configuration, the substituents are oriented on the same side in
relationship to the carbon-carbon double bond. The scope of the
present invention is intended to include all such "E" and "Z"
isomers.
[0087] Substituent atoms (other than hydrogen) attached to a ring
system may be in a cis or trans configuration. In the "cis"
configuration, the substituents are on the same side in
relationship to the plane of the ring; in the "trans"
configuration, the substituents are on opposite sides in
relationship to the plane of the ring. Compounds having a mixture
of "cis" and "trans" species are designated "cis/trans". The scope
of the present invention is intended to include all such "cis" and
"trans" isomers.
[0088] The isomeric descriptors ("R," "S," "E," and "Z") indicate
atom configurations relative to a core molecule and are intended to
be used as defined in the literature.
[0089] Furthermore, compounds of the present invention may have at
least one crystalline, polymorph or amorphous form. The plurality
of such forms is included in the scope of the invention. In
addition, some of the compounds may form solvates with water (i.e.,
hydrates) or common organic solvents (e.g., organic esters such as
ethanolate and the like). The plurality of such solvates is also
intended to be encompassed within the scope of this invention.
Chemical Nomenclature and Definitions
[0090] Bond lines drawn into a ring system from a substituent
variable indicate that the substituent may be attached to any of
the substitutable ring atoms.
[0091] As used herein, the following terms are intended to have the
following meanings (additional definitions are provided where
prophetic throughout the Specification). The definitions herein may
specify that a chemical term has an indicated formula. The
particular formula provided is not intended to limit the scope of
the invention, but is provided as an illustration of the term and
is intended to include the plurality of variations expected to be
included by one of ordinary skill in the art.
Definitions
[0092] The term "C.sub.1-6alkyl" or "alkyl" means a straight or
branched chain hydrocarbon alkyl radical, comprising from 1 to 6
carbon atoms. Non-limiting examples include methyl, ethyl,
1-propyl, 2-propyl, 1-butyl, 2-butyl, tertiary butyl (also referred
to as t-butyl or tert-butyl), 1-pentyl, 2-pentyl, 3-pentyl,
1-hexyl, 2-hexyl, 3-hexyl and the like. The term further includes
alkyl groups in any combination thereof (e.g. C.sub.1-2, C.sub.1-3,
C.sub.1-4 and the like). An alkyl radical may be attached to a core
molecule where allowed by available valences.
[0093] The terms "C.sub.2-3alkenyl" and "C.sub.2-3alkynyl" mean
straight or branched carbon chains having 2 to 3 carbon atoms,
wherein a C.sub.2-3alkenyl chain has at least one double bond in
the chain and a C.sub.2-3alkynyl chain has at least one triple bond
in the chain. An alkenyl and alkynyl radical may be attached to a
core molecule where allowed by available valences.
[0094] The term "C.sub.1-6alkoxy" or "alkoxy" means a straight or
branched chain hydrocarbon alkyl radical or alkyldiyl linking group
of the formula --O--C.sub.1-6alkyl, comprising from 1 to 6 carbon
atoms. Examples include methoxy, ethoxy, propoxy, isopropoxy,
butoxy and the like. The term further includes alkoxy groups in any
combination thereof (e.g. C.sub.1-2, C.sub.1-3, C.sub.1-4 and the
like). An alkoxy radical may be attached to a core molecule where
allowed by available valences.
[0095] The term "cycloalkyl" refers to a saturated or partially
unsaturated, monocyclic, polycyclic or benzofused hydrocarbon ring
system composed of from 3 to 14 carbon atoms. Except when
specified, the term includes a C.sub.3-8cycloalkyl,
C.sub.3-10cycloalkyl, C.sub.5-6cycloalkyl, C.sub.5-8cycloalkyl,
C.sub.5-12cycloalkyl, C.sub.8-10cycloalkyl, C.sub.9-13cycloalkyl,
C.sub.3-14cycloalkyl or benzofused C.sub.3-14cycloalkyl ring
system. Examples include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, 1H-indenyl,
indanyl, adamantanyl, 9H-fluorenyl,
1,2,3,4-tetrahydro-naphthalenyl, acenaphthenyl,
bicyclo[2.2.1]heptenyl and the like. C.sub.3-14cycloalkyl radicals
may be attached to a core molecule and further substituted on any
atom when allowed by available valences.
[0096] The term "benzofused," used as a prefix for a ring system,
means a radical formed by any ring system radical fused with a
benzene ring. The benzofused radical may be attached to a core
molecule via either ring of the bicyclic system and further
substituted on any atom where allowed by available valences.
[0097] The term "aryl" refers to monocyclic or bicyclic aromatic
ring systems containing from 6 to 12 carbons in the ring. Examples
include phenyl, biphenyl, naphthalene, azulenyl, anthracenyl and
the like. Aryl radicals may be attached to a core molecule and
further substituted on any atom when allowed by available
valences.
[0098] The term "aromatic" refers to a cycloalkylic hydrocarbon
ring system having an unsaturated, conjugated .pi. electron
system.
[0099] The term "hetero," used as a prefix for a ring system,
refers to the replacement of at least one ring carbon atom with one
or more heteroatoms independently selected from a nitrogen, oxygen
or sulfur atom, wherein the nitrogen and sulfur atoms can exist in
any allowed oxidation state. Examples include rings wherein 1, 2, 3
or 4 ring members are a nitrogen atom; or, 0, 1, 2 or 3 ring
members are nitrogen atoms and 1 member is an oxygen or sulfur
atom. When allowed by available valences, up to two adjacent ring
members may be heteroatoms; wherein one heteroatom is nitrogen and
the other is one heteroatom selected from N, S or O.
[0100] The term "heterocyclyl" refers to a nonaromatic (i.e.
saturated or partially unsaturated) monocyclic, polycyclic or
benzofused ring system radical. Heteroatom ring members are
selected from at least one of N, O, S, S(O) or SO.sub.2, wherein
the nitrogen and sulfur atoms can exist in any allowed oxidation
state. Examples include 2H-pyrrole, 2-pyrrolinyl, 3-pyrrolinyl,
pyrrolidinyl, 2-imidazolinyl (also referred to as
4,5-dihydro-1H-imidazolyl), imidazolidinyl, 2-pyrazolinyl,
pyrazolidinyl, oxazolidinyl, tetrazolinyl, tetrazolidinyl,
piperidinyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,
piperazinyl, azetidinyl, azepanyl, dihydro-pyranyl,
tetrahydro-furanyl, tetrahydro-thienyl, tetrahydro-pyranyl,
tetrahydro-pyridazinyl, hexahydro-1,4-diazepinyl,
hexahydro-1,4-oxazepanyl, 1,3-dioxolanyl, 1,4-dioxanyl,
1,3-benzodioxolyl (also referred to as benzo[1,3]dioxolyl),
2,3-dihydro-1,4-benzodioxinyl (also referred to as
2,3-dihydro-benzo[1,4]dioxinyl) and the like. Heterocyclyl radicals
may be attached to a core molecule and further substituted on any
atom when allowed by available valences.
[0101] The term "heteroaryl" means an aromatic monocyclic,
polycyclic or benzofused ring system radical. Heteroatom ring
members are selected from at least one of N, O, S, S(O) or
SO.sub.2, wherein the nitrogen and sulfur atoms can exist in any
allowed oxidation state.
[0102] Examples include furanyl, thienyl, pyrrolyl, pyrazolyl,
1H-imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl,
oxadiazolyl, triazolyl, thiadiazolyl, 1H-tetrazolyl, 2H-tetrazolyl,
1H-[1,2,3]triazolyl, 2H-[1,2,3]triazolyl, 4H-[1,2,4]triazolyl,
pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,
indolyl, azaindolyl, indazolyl, azaindazolyl, isoindolyl,
benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl,
benzoxazolyl, benzoisoxazolyl, benzothiadiazolyl, benzotriazolyl,
purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,
phthalzinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,
pteridinyl and the like. Heteroaryl radicals may be attached to a
core molecule and further substituted on any atom when allowed by
available valences.
[0103] The term "C.sub.1-6alkoxy-C.sub.1-6alkyl" means a radical of
the formula: --C.sub.1-6alkyl-O--C.sub.1-6alkyl.
[0104] The term "C.sub.1-6alkoxycarbonyl" means a radical of the
formula: --C(O)--O--C.sub.1-6alkyl. Examples include
C.sub.1-4alkoxycarbonyl.
[0105] The term "C.sub.1-6alkoxycarbonylamino" means a radical of
the formula: --NH--C(O)--O--C.sub.1-6alkyl. Examples include
C.sub.1-4alkylcarbonylamino.
[0106] The term "(C.sub.1-6alkyl).sub.1-2-amino" means a radical of
the formula: --NH--C.sub.1-6alkyl or --N(C.sub.1-6alkyl).sub.2.
Examples include (C.sub.1-4alkyl).sub.1-2-amino.
[0107] The term "(C.sub.1-6alkyl).sub.1-2-amino-C.sub.1-6alkyl"
means a radical of the formula: --C.sub.1-6alkyl-NH--C.sub.1-6alkyl
or --C.sub.1-6alkyl-N(C.sub.1-6alkyl).sub.2. Examples include
(C.sub.1-4alkyl).sub.1-2-amino-C.sub.1-6alkyl.
[0108] The term "(C.sub.1-6alkyl).sub.1-2-aminocarbonyl" means a
radical of the formula: --C(O)--NH--C.sub.1-6alkyl or
--C(O)--N(C.sub.1-6alkyl).sub.2. Examples include
(C.sub.1-4alkyl).sub.1-2-aminocarbonyl.
[0109] The term "(C.sub.1-6alkyl).sub.1-2-aminocarbonylamino" means
a radical of the formula: --NH--C(O)--NH--C.sub.1-6alkyl or
--NH--C(O)--N(C.sub.1-6alkyl).sub.2. Examples include
(C.sub.1-4alkyl).sub.1-2-aminocarbonylamino.
[0110] The term "(C.sub.1-4alkyl).sub.1-2-aminosulfonyl" means a
radical of the formula: --SO.sub.2--NH--C.sub.1-4alkyl or
--SO.sub.2--N(C.sub.1-4alkyl).sub.2.
[0111] The term "C.sub.1-6alkylcarbonyl" means a radical of the
formula: --C(O)--C.sub.1-6alkyl. Examples include
C.sub.1-4alkylcarbonyl.
[0112] The term "C.sub.1-6alkylcarbonylamino" means a radical of
the formula: --NH--C(O)--C.sub.1-6alkyl. Examples include
C.sub.1-4alkylcarbonylamino.
[0113] The term "C.sub.1-6alkylsulfonyl" means a radical of the
formula: --SO.sub.2--C.sub.1-6alkyl. Examples include
C.sub.1-4alkylsulfonyl.
[0114] The term "C.sub.1-6alkylsulfinylamino" means a radical of
the formula: --NH--S(O)--C.sub.1-6alkyl.
[0115] The term "C.sub.1-6alkylsulfonylamino" means a radical of
the formula: --NH--SO.sub.2--C.sub.1-6alkyl.
[0116] The term "C.sub.1-6alkylthio" means a radical of the
formula: --S--C.sub.1-6alkyl. Examples include
C.sub.1-4alkylthio.
[0117] The term "amino" means a radical of the formula:
--NH.sub.2.
[0118] The term "amino-C.sub.1-6alkyl" means a radical of the
formula: --C.sub.1-6alkyl-NH.sub.2.
[0119] The term "aminocarbonyl" means a radical of the formula:
--C(O)--NH.sub.2.
[0120] The term "aminocarbonylamino" means a radical of the
formula: --NH--C(O)--NH.sub.2.
[0121] The term "aminosulfonyl" means a radical of the formula:
--SO.sub.2--NH.sub.2.
[0122] The term "aminosulfonylamino" means a radical of the
formula: --NH--SO.sub.2--NH.sub.2.
[0123] The term "(C.sub.1-6alkyl).sub.1-2-aminosulfonylamino" means
a radical of the formula: --NH--SO.sub.2--NH--C.sub.1-6alkyl or
--NH--SO.sub.2--N(C.sub.1-6alkyl).sub.2. Examples include
(C.sub.1-4alkyl).sub.1-2-aminosulfonylamino.
[0124] The term "aminosulfonylamino-C.sub.1-6alkyl" means a radical
of the formula: --C.sub.1-6alkyl-NH--SO.sub.2--NH.sub.2.
[0125] The term
"(C.sub.1-6alkyl).sub.1-2-aminosulfonylamino-C.sub.1-6alkyl" means
a radical of the formula:
--C.sub.1-6alkyl-NH--SO.sub.2--NH--C.sub.1-6alkyl or
--C.sub.1-6alkyl-NH--SO.sub.2--N(C.sub.1-6alkyl).sub.2.
[0126] The term "carboxy" means a radical of the formula:
--C(O)OH.
[0127] The term "C.sub.3-8cycloalkyl-C.sub.1-6alkyl" means a
radical of the formula: --C.sub.1-6alkyl-C.sub.3-8cycloalkyl.
Examples include C.sub.3-8cycloalkyl-C.sub.1-4alkyl.
[0128] The term "C.sub.3-8cycloalkyl-C.sub.1-6alkoxy" means a
radical of the formula: --O--C.sub.1-6alkyl-C.sub.3-8cycloalkyl.
Examples include C.sub.3-8cycloalkyl-C.sub.1-4alkoxy.
[0129] The term "C.sub.3-8cycloalkyl-oxy" means a radical of the
formula: --O--C.sub.3-8cycloalkyl.
[0130] The term "(C.sub.3-8cycloalkyl).sub.1-2-amino" means a
radical of the formula: --NH--(C.sub.3-8cycloalkyl) or
--N(C.sub.3-8cycloalkyl).sub.2.
[0131] The term
"(C.sub.3-8cycloalkyl-C.sub.1-4alkyl).sub.1-2-amino" means a
radical of the formula: --NH--C.sub.1-4alkyl-C.sub.3-8cycloalkyl or
--N(C.sub.1-4alkyl-C.sub.3-8cycloalkyl).sub.2.
[0132] The term "formyl" means a radical of the formula:
--C(O)H.
[0133] The term "oxo" means a radical of the formula: .dbd.O.
[0134] The term "halogen" or "halo" means the group chloro, bromo,
fluoro or iodo.
[0135] The term "haloC.sub.1-6alkyl" means a radical of the
formula: --C.sub.1-6alkyl(halo).sub.n, wherein "n" represents that
amount of available valences on C.sub.1-6alkyl, which may be
substituted with one or more halogen atoms while remaining stable.
Examples include difluoromethyl, trifluoromethyl, trifluoroethyl,
chloromethyl and the like.
[0136] The term "haloC.sub.1-6alkoxy" means a radical of the
formula: --O--C.sub.1-6alkyl(halo).sub.n, wherein "n" represents
that amount of available valences on C.sub.1-6alkoxy, which may be
substituted with one or more halogen atoms while remaining stable.
Examples include difluoromethoxy, trifluoromethoxy,
trifluoroethoxy, chloromethoxy and the like.
[0137] The term "haloC.sub.1-6alkylsulfonyl" means a radical of the
formula: --SO.sub.2--C.sub.1-6alkyl(halo).sub.n, wherein "n"
represents that amount of available valences on C.sub.1-6alkyl,
which may be substituted with one or more halogen atoms while
remaining stable. Examples include trifluoromethylsulfonyl and the
like.
[0138] The term "haloC.sub.1-6alkylsulfonylamino" means a radical
of the formula: --NH--SO.sub.2--C.sub.1-6alkyl(halo).sub.n, wherein
"n" represents that amount of available valences on C.sub.1-6alkyl,
which may be substituted with one or more halogen atoms while
remaining stable. Examples include trifluoromethylsulfonyl and the
like.
[0139] The term "haloC.sub.1-6alkylthio" means a radical of the
formula: --S--C.sub.1-6alkyl(halo).sub.n, wherein "n" represents
that amount of available valences on C.sub.1-6alkyl, which may be
substituted with one or more halogen atoms while remaining stable.
Examples include trifluoromethylsulfonyl and the like.
[0140] The term "perfluorinated" means a radical that is
substituted with fluoro atoms to the extent allowed by available
valences while remaining stable.
[0141] The term "substituted," refers to a core molecule on which
one or more hydrogen atoms have been replaced with one or more
functional radical moieties. The number that is allowed by
available valences limits the amount of substituents. Substitution
is not limited to the core molecule, but may also occur on a
substituent radical, whereby the substituent radical becomes a
linking group.
Therapeutic Use
[0142] As modulators of the vanilloid VR1 ion channel, the
compounds of Formula (I) are useful in methods for treating a VR1
ion channel mediated disease in a subject which disease is affected
by the modulation of one or more vanilloid receptors.
[0143] Accordingly, the present invention is directed to a method
of treating a VR1 ion channel mediated disease in a subject in need
thereof comprising administering to the subject an effective amount
of a compound of Formula (I) or a salt or solvate thereof.
[0144] The term "VR1 ion channel mediated disease" refers to
chronic or acute pain due to disease that causes inflammatory pain,
burning pain or post-operative pain.
[0145] An example of a use of the compound of Formula (I) or a salt
or solvate thereof includes use in the manufacture of a medicament
for treating a VR1 ion channel mediated disease, wherein the VR1
ion channel mediated disease is chronic or acute pain due to
disease that causes inflammatory pain, burning pain or
post-operative pain.
[0146] An example of a use of the compound of Formula (I) or a salt
or solvate thereof includes use as a medicine for treating a VR1
ion channel mediated disease, wherein the VR1 ion channel mediated
disease is chronic or acute pain due to disease that causes
inflammatory pain, burning pain or post-operative pain.
[0147] The term "prodrug" means a compound of Formula (I) or a form
thereof that is converted in vivo into a functional derivative form
that may contribute to therapeutic biological activity, wherein the
converted form may be: 1) a relatively active form; 2) a relatively
inactive form; 3) a relatively less active form; or, 4) any form
which results, directly or indirectly, from such in vivo
conversions.
[0148] Prodrugs are useful when said compound may be either too
toxic to administer systemically, absorbed poorly by the digestive
tract or broken down by the body before it reaches its target.
Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described in, for example, "Design
of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
[0149] The term "metabolite" means a form of a compound of Formula
(I) or a form thereof converted by in vivo metabolism or a
metabolic process to a derivative of said compound.
[0150] The term "subject" as used herein, refers to a patient, such
as an animal, a mammal or a human, who has been the object of
treatment, observation or experiment and is at risk of (or
susceptible to) developing a disease that has or will result in VR1
ion channel mediated chronic or acute pain, wherein the pain caused
by the disease is inflammatory pain, burning pain or post-operative
pain.
[0151] The term "effective amount" refers to that amount of a
compound of Formula (I) or a form, pharmaceutical composition,
medicine or medicament thereof that elicits the biological or
medicinal response (such as inhibiting, preventing or ameliorating
VR1 ion channel mediated chronic or acute pain) in a tissue system,
animal or human, that is being sought by a researcher,
veterinarian, medical doctor, or other clinician, which includes
alleviation of the symptoms of the inflammatory pain, burning pain
or post-operative pain being treated.
[0152] The effective amount of a compound of Formula (I) or a form
thereof is from about 0.001 mg/kg/day to about 300 mg/kg/day.
[0153] The term "pharmaceutical composition" refers to a product
containing a compound of Formula (I) or a form thereof, such as a
product comprising the specified ingredients in the specified
amounts, as well as any product that results, directly or
indirectly, from such combinations of the specified ingredients in
the specified amounts.
[0154] The term "medicament" or "medicine" refers to a product
containing a compound of Formula (I) or a form thereof. The present
invention includes use of such a medicament for treating VR1 ion
channel mediated chronic or acute pain.
[0155] The term "pharmaceutically acceptable" refers to molecular
entities and compositions that are of sufficient purity and quality
for use in the formulation of a pharmaceutical composition,
medicine or medicament of the present invention. Since both human
use (clinical and over-the-counter) and veterinary use are equally
included within the scope of the present invention, a
pharmaceutically acceptable formulation would include a
pharmaceutical composition, medicine or medicament for either human
or veterinary use.
[0156] The term "treating" refers, without limitation, inhibiting,
ameliorating, facilitating the eradication of, inhibiting the
progression of or promoting the stasis of VR1 ion channel mediated
chronic or acute pain.
[0157] For oral administration, the pharmaceutical composition,
medicine or medicament is preferably in the form of a tablet
containing, e.g., 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,
25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of a compound of
formula (I) or a form thereof for the symptomatic adjustment of the
dosage to the patient to be treated. Optimal dosages will vary
depending on factors associated with the particular patient being
treated (e.g., age, weight, diet and time of administration), the
severity of the condition being treated, the particular compound
being used, the mode of administration and the strength of the
preparation. The use of either daily administration or
post-periodic dosing may be employed.
[0158] A representative compound of Formula (I) or a form thereof
includes a compound selected from the group consisting of:
TABLE-US-00001 Cpd Name 1
(E)-1-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)-ethanone, 2
(E)-1-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanol, 3
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenol,
4
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)-acetamide, 5
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzamide-
, 6
(E)-3-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzamide-
, 7
(E)-4-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzamide-
, 8
(E)-N-(4-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)-acetamide, 9
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- methanesulfonamide, 10
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
- carbamic acid tert-butyl ester, 11
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenylam-
ine, 12
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
- methanol, 13
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzamide, 14
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phe-
nol, 15
(E)-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanone, 16
(E)-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanol, 17
(E)-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide, 18
(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-propan-2-ol, 19
(E)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-be-
nzamide, 20
(E)-1-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-ethanone, 21
(E)-1-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-ethanol, 22
(E)-N-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanesulfonamide, 23
(E)-2-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol, 24
(E)-N-(2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- acetamide, 25
(E)-N-(3-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)-acetamide, 26
(E)-2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzamid-
e, 27
(E)-1-(2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)-ethanone, 28
(E)-N-(2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- methanesulfonamide, 29
2-{2-[3-(4-tert-butyl-phenyl)-propyl]-1H-benzimidazol-5-yl}-phenol,
30 2-[3-(4-tert-butyl-phenyl)-propyl]-5-m-tolyl-1H-benzimidazole,
31
N-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phen-
yl)- methanesulfonamide, 32
2-{2-[2-(4-tert-butyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenol,
33
3-{2-[2-(4-tert-butyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenol,
34
4-{2-[2-(4-tert-butyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenol,
35
(E)-(2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- phenyl)-methanol, 36
(E)-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}-phenol, 37
(E)-N-(2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-phenyl)-acetamide, 38
(E)-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}- benzamide, 39
(E)-1-(2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-phenyl)-ethanone, 40
(E)-1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-ethanone, 41
(E)-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-phenol, 42
(E)-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-phenyl)-methanol, 43
(E)-N-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-acetamide, 44
(E)-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-benzamide, 45
(E)-1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-ethanol, 46
1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-
- yl}-phenyl)-ethanol, 47
(E)-2-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-propan-2-ol, 48
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimida-
zol-5- yl}-phenol, 49
(E)-3-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimida-
zol-5- yl}-phenol, 50
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-
benzimidazol-5-yl}-phenyl)-acetamide, 51
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimid-
azol- 5-yl}-phenyl)-methanol, 52
(E)-2-[2-(4-tert-butyl-phenyl)-vinyl]-5-(2-fluoro-phenyl)-6-trifluorome-
thyl- 1H-benzimidazole, 53
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimida-
zol-5- yl}-benzamide, 54
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimid-
azol- 5-yl}-phenyl)-carbamic acid tert-butyl ester, 55
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 56
(E)-N-(2-{6-trifluoromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-acetamide, 57
(E)-1-(2-{6-trifluoromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-ethanone, 58
(E)-(2-{6-trifluoromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanol, 59
(E)-2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- phenol, 60
(E)-3-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- phenol, 61
(E)-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-phenyl)-methanol, 62
(E)-1-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidaz-
ol-5- yl}-phenyl)-ethanone, 63
(E)-2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- benzamide, 64
(E)-N-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidaz-
ol-5- yl}-phenyl)-acetamide, 65
(E)-N-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidaz-
ol-5- yl}-phenyl)-methanesulfonamide, 66
(E)-(2-{6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-phenyl)-methanol, 67
(E)-1-(2-{6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidaz-
ol-5- yl}-phenyl)-ethanone, 68
(E)-2-{6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-phenol, 69
(E)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 70
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 71
(E)-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-benzenesulfonamide, 72
(E)-C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 73
(E)-C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 74
(E)-C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-viny-
l]- 1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 75
(E)-1-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanone, 76
(E)-1-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanol, 77
(E)-N-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 78
(E)-2-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
propan-2-ol, 79
(E)-2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 80
(E)-N-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
C,C,C-trifluoro-methanesulfonamide, 81
(E)-1-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanone, 82
(E)-1-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanol, 83
(E)-N-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide, 84
(E)-2-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-propan-2-ol, 85
(E)-2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 86
(E)-C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 87
(E)-1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-vi-
nyl}-1H- benzimidazol-5-yl)-phenyl]-ethanone, 88
(E)-1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-vi-
nyl}-1H- benzimidazol-5-yl)-phenyl]-ethanol, 89
(E)-N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-vi-
nyl}- 1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 90
(E)-2-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-vi-
nyl}-1H- benzimidazol-5-yl)-phenyl]-propan-2-ol, 91
(E)-2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-vinyl-
}-1H- benzimidazol-5-yl)-benzenesulfonamide, 92
(E)-C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-et-
hoxy)-
phenyl]-vinyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 93
(E)-1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimidaz-
ol-5- yl)-phenyl]-ethanone, 94
(E)-1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimidaz-
ol-5- yl)-phenyl]-ethanol, 95
(E)-N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimidaz-
ol-5- yl)-phenyl]-methanesulfonamide, 96
(E)-2-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimidaz-
ol-5- yl)-phenyl]-propan-2-ol, 97
(E)-2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimidazol--
5-yl)- benzenesulfonamide, 98
(E)-C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-viny-
l}-1H- benzimidazol-5-yl)-phenyl]-methanesulfonamide, 99
(E)-1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanone, 100
(E)-1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanol, 101
(E)-N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-phenyl]-methanesulfonamide, 102
(E)-2-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-phenyl]-propan-2-ol, 103
(E)-2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-benzenesulfonamide, 104
(E)-C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phen-
yl]- vinyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 105
(E)-1-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanone, 106
(E)-1-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanol, 107
(E)-N-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 108
(E)-2-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
propan-2-ol, 109
(E)-2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 110
(E)-N-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
C,C,C-trifluoro-methanesulfonamide, 111
(E)-1-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-ethanone, 112
(E)-1-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-ethanol, 113
(E)-N-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanesulfonamide, 114
(E)-2-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol, 115
(E)-2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 116
(E)-C,C,C-trifluoro-N-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 117
(E)-N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-vinyl}-phenyl)-
methanesulfonamide, 118
(E)-N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-yl}-viny-
l)- phenyl]-methanesulfonamide, 119
(E)-N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-phenyl)-methanesulfonamide, 120
(E)-N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-
- yl}-vinyl)-phenyl]-methanesulfonamide, 121
(E)-2-{2-[2-(4-methanesulfonylamino-phenyl)-vinyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 122
(E)-C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-vinyl]--
1H- benzimidazol-5-yl}-phenyl)-methanesulfonamide, 123
(E)-N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-vinyl}-phenyl)-
C,C,C-trifluoro-methanesulfonamide, 124
(E)-C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-
benzimidazol-2-yl}-vinyl)-phenyl]-methanesulfonamide, 125
(E)-C,C,C-trifluoro-N-(4-{2-[5-(2-methanesulfonylamino-phenyl)-1H-
benzimidazol-2-yl]-vinyl}-phenyl)-methanesulfonamide, 126
(E)-C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1-
H- benzimidazol-2-yl}-vinyl)-phenyl]-methanesulfonamide, 127
(E)-2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 128
(E)-C,C,C-trifluoro-N-(4-{2-[5-(2-trifluoromethanesulfonylamino-phenyl-
)- 1H-benzimidazol-2-yl]-vinyl}-phenyl)-methanesulfonamide, 129
2-{2-[2-(4-trifluoromethoxy-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 130
2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 131
2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 132
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethoxy-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 133
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 134
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-ethyl]--
1H- benzimidazol-5-yl}-phenyl)-methanesulfonamide, 135
1-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanone, 136
1-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-etha-
nol, 137
N-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 138
2-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-prop-
an- 2-ol, 139
2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 140
N-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-C,C,-
C- trifluoro-methanesulfonamide, 141
1-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanone, 142
1-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanol, 143
N-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide, 144
2-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
phenyl)-propan-2-ol, 145
2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 146
C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 147
1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl-
}-1H- benzimidazol-5-yl)-phenyl]-ethanone, 148
1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl-
}-1H- benzimidazol-5-yl)-phenyl]-ethanol, 149
N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl-
}-1H- benzimidazol-5-yl)-phenyl]-methanesulfonamide, 150
2-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl-
}-1H- benzimidazol-5-yl)-phenyl]-propan-2-ol, 151
2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl}-1-
H- benzimidazol-5-yl)-benzenesulfonamide, 152
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethox-
y)-
phenyl]-ethyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide,
153
1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol--
5-yl)- phenyl]-ethanone, 154
1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol--
5-yl)- phenyl]-ethanol, 155
N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol--
5-yl)- phenyl]-methanesulfonamide, 156
2-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol--
5-yl)- phenyl]-propan-2-ol, 157
2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol-5-y-
l)- benzenesulfonamide, 158
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}--
1H- benzimidazol-5-yl)-phenyl]-methanesulfonamide, 159
1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanone, 160
1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanol, 161
N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-
benzimidazol-5-yl)-phenyl]-methanesulfonamide, 162
2-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-
benzimidazol-5-yl)-phenyl]-propan-2-ol, 163
2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-benzimida-
zol- 5-yl)-benzenesulfonamide, 164
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-
ethyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 165
1-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanone, 166
1-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-etha-
nol, 167
N-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 168
2-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-prop-
an- 2-ol, 169
2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 170
N-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-C,C,-
C- trifluoro-methanesulfonamide, 171
1-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- ethanone, 172
1-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- ethanol, 173
N-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- methanesulfonamide, 174
2-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- propan-2-ol, 175
2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 176
C,C,C-trifluoro-N-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 177
N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-ethyl}-phenyl)-
methanesulfonamide, 178
N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-yl}-ethyl)-
phenyl]-methanesulfonamide, 179
N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-ethyl]-1H-benzimidazol-5-yl-
}- phenyl)-methanesulfonamide, 180
N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-yl}-
- ethyl)-phenyl]-methanesulfonamide, 181
2-{2-[2-(4-methanesulfonylamino-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 182
C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 183
N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-ethyl}-phenyl)-C,C,-
C- trifluoro-methanesulfonamide, 184
C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazo-
l-2- yl}-ethyl)-phenyl]-methanesulfonamide, 185
C,C,C-trifluoro-N-(4-{2-[5-(2-methanesulfonylamino-phenyl)-1H-
benzimidazol-2-yl]-ethyl}-phenyl)-methanesulfonamide, 186
C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-
benzimidazol-2-yl}-ethyl)-phenyl]-methanesulfonamide, 187
2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-ethyl]-1H-benzimidazo-
l- 5-yl}-benzenesulfonamide, 188
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-et-
hyl]- 1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 189
2-{2-[2-(4-trifluoromethoxy-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
- benzenesulfonamide, 190
2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 191
2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidaz-
ol- 5-yl}-benzenesulfonamide, 192
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethoxy-phenyl)-cyclopropyl]-1H-
- benzimidazol-5-yl}-phenyl)-methanesulfonamide, 193
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 194
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-cyclopr-
opyl]-
1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 195
1-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanone, 196
1-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanol, 197
N-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- methanesulfonamide, 198
2-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- propan-2-ol, 199
2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 200
N-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- C,C,C-trifluoro-methanesulfonamide, 201
1-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanone, 202
1-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanol, 203
N-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-methanesulfonamide, 204
2-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-propan-2-ol, 205
2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 206
C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 207
1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-cyclo-
propyl}- 1H-benzimidazol-5-yl)-phenyl]-ethanone, 208
1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-cyclo-
propyl}- 1H-benzimidazol-5-yl)-phenyl]-ethanol, 209
N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-cyclo-
propyl}- 1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 210
2-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-cyclo-
propyl}- 1H-benzimidazol-5-yl)-phenyl]-propan-2-ol, 211
2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-cyclopro-
pyl}- 1H-benzimidazol-5-yl)-benzenesulfonamide, 212
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethox-
y)-
phenyl]-cyclopropyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide,
213
1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-benzimi-
dazol- 5-yl)-phenyl]-ethanone, 214
1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-benzimi-
dazol- 5-yl)-phenyl]-ethanol, 215
N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-methanesulfonamide, 216
2-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-benzimi-
dazol- 5-yl)-phenyl]-propan-2-ol, 217
2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-benzimidaz-
ol-5- yl)-benzenesulfonamide, 218
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopr-
opyl}- 1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 219
1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanone, 220
1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanol, 221
N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-methanesulfonamide, 222
2-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-propan-2-ol, 223
2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-benzenesulfonamide, 224
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-
cyclopropyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 225
1-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanone, 226
1-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanol, 227
N-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- methanesulfonamide, 228
2-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- propan-2-ol, 229
2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 230
N-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- C,C,C-trifluoro-methanesulfonamide, 231
1-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanone, 232
1-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanol, 233
N-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-methanesulfonamide, 234
2-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-propan-2-ol, 235
2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 236
C,C,C-trifluoro-N-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 237
N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-cyclopropyl}-phenyl-
)- methanesulfonamide, 238
N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-yl}-cyclopro-
pyl)- phenyl]-methanesulfonamide, 239
N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 240
N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-yl}-
- cyclopropyl)-phenyl]-methanesulfonamide, 241
2-{2-[2-(4-methanesulfonylamino-phenyl)-cyclopropyl]-1H-benzimidazol-5-
- yl}-benzenesulfonamide, 242
C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-cyclopropyl-
]- 1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 243
N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-cyclopropyl}-phenyl-
)- C,C,C-trifluoro-methanesulfonamide, 244
C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazo-
l-2- yl}-cyclopropyl)-phenyl]-methanesulfonamide, 245
C,C,C-trifluoro-N-(4-{2-[5-(2-methanesulfonylamino-phenyl)-1H-
benzimidazol-2-yl]-cyclopropyl}-phenyl)-methanesulfonamide, 246
C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-
benzimidazol-2-yl}-cyclopropyl)-phenyl]-methanesulfonamide, 247
2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 248
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-
cyclopropyl]-1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 249
2-[2-(4-trifluoromethoxy-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 250
2-[2-(4-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 251
2-[2-(4-trifluoromethanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 252
C,C,C-trifluoro-N-{2-[2-(4-trifluoromethoxy-phenylethynyl)-1H-
benzimidazol-5-yl]-phenyl}-methanesulfonamide, 253
C,C,C-trifluoro-N-{2-[2-(4-trifluoromethyl-phenylethynyl)-1H-benzimida-
zol- 5-yl]-phenyl}-methanesulfonamide, 254
C,C,C-trifluoro-N-{2-[2-(4-trifluoromethanesulfonyl-phenylethynyl)-1H-
benzimidazol-5-yl]-phenyl}-methanesulfonamide, 255
1-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-ethanon-
e, 256
1-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-ethanol-
, 257
N-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 258
2-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-propan--
2- ol, 259
2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-benzenesulfonamide-
, 260
N-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-C,C,C-
trifluoro-methanesulfonamide, 261
1-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- ethanone, 262
1-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- ethanol, 263
N-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- methanesulfonamide, 264
2-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- propan-2-ol, 265
2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 266
C,C,C-trifluoro-N-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-
benzimidazol-5-yl]-phenyl}-methanesulfonamide, 267
1-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1-
H- benzimidazol-5-yl}-phenyl)-ethanone, 268
1-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1-
H- benzimidazol-5-yl}-phenyl)-ethanol, 269
N-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1-
H- benzimidazol-5-yl}-phenyl)-methanesulfonamide, 270
2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1-
H- benzimidazol-5-yl}-phenyl)-propan-2-ol, 271
2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 272
C,C,C-trifluoro-N-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-
phenylethynyl]-1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide,
273
1-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanone, 274
1-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanol, 275
N-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-y-
l}- phenyl)-methanesulfonamide, 276
2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-y-
l}- phenyl)-propan-2-ol, 277
2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 278
C,C,C-trifluoro-N-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 279
1-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-ethanone, 280
1-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-ethanol, 281
N-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 282
2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, 283
2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 284
C,C,C-trifluoro-N-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethyn-
yl]- 1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 285
1-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-ethanon-
e, 286
2-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-propan--
2-
ol, 287
N-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 288
1-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-ethanol-
, 289
2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-benzenesulfonamide-
, 290
N-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-C,C,C-
trifluoro-methanesulfonamide, 291
1-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- ethanone, 292
1-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- ethanol, 293
N-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- methanesulfonamide, 294
2-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- propan-2-ol, 295
2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 296
C,C,C-trifluoro-N-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimida-
zol- 5-yl]-phenyl}-methanesulfonamide, 297
N-{4-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl-ethynyl]-phenyl}-
methanesulfonamide, 298
N-(4-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-yl-ethynyl}-
phenyl)-methanesulfonamide, 299
N-{2-[2-(4-methanesulfonylamino-phenylethynyl)-1H-benzimidazol-5-yl]-
phenyl}-methanesulfonamide, 300
N-(4-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-yl-
ethynyl}-phenyl)-methanesulfonamide, 301
2-[2-(4-methanesulfonylamino-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 302
C,C,C-trifluoro-N-{2-[2-(4-methanesulfonylamino-phenylethynyl)-1H-
benzimidazol-5-yl]-phenyl}-methanesulfonamide, 303
N-{4-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl-ethynyl]-phenyl}-C,C,C-
trifluoro-methanesulfonamide, 304
C,C,C-trifluoro-N-(4-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-
-yl- ethynyl}-phenyl)-methanesulfonamide, 305
C,C,C-trifluoro-N-{4-[5-(2-methanesulfonylamino-phenyl)-1H-
benzimidazol-2-yl-ethynyl]-phenyl}-methanesulfonamide, 306
C,C,C-trifluoro-N-(4-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-
benzimidazol-2-yl-ethynyl}-phenyl)-methanesulfonamide, 307
2-[2-(4-trifluoromethanesulfonylamino-phenylethynyl)-1H-benzimidazol-5-
- yl]-benzenesulfonamide, 308
C,C,C-trifluoro-N-{2-[2-(4-trifluoromethanesulfonylamino-phenylethynyl-
)- 1H-benzimidazol-5-yl]-phenyl}-methanesulfonamide, 309
(E)-N-tert-butyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol-5- yl}-benzenesulfonamide, 310
(E)-N-methyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 311
(E)-2-hydroxy-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol- 5-yl}-phenyl)-ethanone, 312
(E)-2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 314
(E)-N-methyl-2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 315
(E)-2-{2-[2-(4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 316
(E)-2-{2-[2-(3,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 317
(E)-2-{2-[2-(3-bromo-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 318
(E)-2-{2-[2-(4-dimethylamino-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 319
(E)-2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 320
(E)-2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 321
(E)-2-{2-[2-(3-chloro-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 322
(E)-2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 323
(E)-N-methyl-2-{2-[2-(2,3,4-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}- benzenesulfonamide, 324
(E)-N-methyl-2-{2-[2-(2,4,5-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}- benzenesulfonamide, 325
(E)-2-{2-[2-(2,3-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 326
(E)-2-{2-[2-(2,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 327
(E)-2-{2-[2-(2,6-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 328
(E)-2-{2-[2-(3,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 329
(E)-2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 330
(E)-2-{2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 331
(E)-2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 332
(E)-2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 333
(E)-2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}-N- methyl-benzenesulfonamide, 334
(E)-2-{2-[2-(2,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}-N- methyl-benzenesulfonamide, 335
(E)-2-{2-[2-(3-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 336
(E)-2-{2-[2-(2-chloro-6-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 337
(E)-2-{2-[2-(2,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 338
(E)-2-{2-[2-(3-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 339
(E)-2-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 340
(E)-2-{2-[2-(4-chloro-2-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-N-methyl-benzenesulfonamide, 341
(E)-N-methyl-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 342
(E)-N-methyl-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 343
(E)-N-methyl-2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 344
(E)-N-methyl-2-{2-[2-(3-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 345
(E)-N-methyl-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 346
(E)-2-{2-[2-(2-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 347
(E)-2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 348
(E)-2-{2-[2-(2-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 349
(E)-2-{2-[2-(2,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 350
N-methyl-2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 351
(E)-2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 357
(E)-2-{2-[2-(2,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 358
(E)-2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 359
(E)-2-{2-[2-(2,3-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 360
(E)-2-{2-[2-(2,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 361
(E)-2-{2-[2-(3,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 362
(E)-2-{2-[2-(3-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 363
(E)-2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 364
(E)-2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 365
(E)-2-{2-[2-(2-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 366
(E)-2-{2-[2-(2-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 367
(E)-2-{2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 368
(E)-2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 369
(E)-2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 370
(E)-2-{2-[2-(2,3,4-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 371
(E)-2-{2-[2-(2,4,5-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 372
(E)-2-{2-[2-(2,6-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 373
(E)-2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 374
(E)-2-{2-[2-(2,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 375
(E)-2-{2-[2-(4-chloro-2-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 376
(E)-2-{2-[2-(3-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 378
(E)-2-{2-[2-(4-chloro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 379
(E)-2-{2-[2-(5-bromo-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 380
(E)-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- benzenesulfonamide, 383
2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 384
2-{2-[2-(2,3,4-trifluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 385
2-{2-[2-(2,4,5-trifluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 386
2-{2-[2-(2,6-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 387
2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 388
2-{2-[2-(2,5-bis-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 389
2-{2-[2-(4-chloro-2-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 390
2-{2-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 391
2-{2-[2-(3-trifluoromethoxy-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 392
2-{2-[2-(2,4-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 393
2-{2-[2-(3,4-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 394
2-{2-[2-(2,3-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 395
2-{2-[2-(2,5-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 396
2-{2-[2-(3,5-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 397
2-(2-phenethyl-1H-benzimidazol-5-yl)-benzenesulfonamide, 398
(E)-N,N-dimethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol- 5-yl}-benzenesulfonamide, 399
N,N-dimethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 400
N-methyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 402
2-{2-[2-(2-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 404
2-{2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 405
2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 406
(E)-N-(2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 407
(E)-N-(2-{2-[2-(4-isopropyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- methanesulfonamide, 408
(E)-N-(2-{2-[2-(3-chloro-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanesulfonamide, 409
(E)-N-(2-{2-[2-(3-bromo-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide, 410
(E)-N-(2-{2-[2-(4-difluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanesulfonamide, 411
(E)-N-(2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol-5- yl}-phenyl)-methanesulfonamide, 412
(E)-N-{2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 413
(E)-N-(2-{2-[2-(4-dimethylamino-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide, 414
(E)-N-(2-{2-[2-(4-ethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 415
(E)-N-{2-[2-(2-naphthalen-2-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 416
(E)-N-(2-{2-[2-(3,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phen-
yl)- methanesulfonamide, 417
(E)-N-(2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol-5- yl}-phenyl)-methanesulfonamide, 418
(E)-N-(2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol-5- yl}-phenyl)-methanesulfonamide, 419
2-{2-[2-(2-fluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 420
2-{2-[2-(4-fluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 421
2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 422
(E)-5-(2-methanesulfonyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-vinyl-
]-1H- benzimidazole, 423
(E)-2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 424
(E)-2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 425
(E)-2-{2-[2-(3-ethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 426
(E)-2-(2-styryl-1H-benzimidazol-5-yl)-benzenesulfonamide, 427
(E)-2-{2-[2-(3,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 428
(E)-2-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 429
(E)-2-{2-[2-(4-isopropyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 430
(E)-2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-benzenesulfonamide,
431
(E)-2-{2-[2-(3-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 432
(E)-2-{2-[2-(3-chloro-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 433
(E)-2-[2-(2-naphthalen-2-yl-vinyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 434
(E)-2-{2-[2-(4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 435
(E)-2-{2-[2-(4-difluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 436
(E)-2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 437
(E)-2-{2-[2-(2,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 438
(E)-2-{2-[2-(2-chloro-6-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 439
(E)-2-{2-[2-(3-bromo-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 440
(E)-2-{2-[2-(4-ethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 441
(E)-4-fluoro-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 442
2-{2-[2-(4-isopropyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 443
(E)-N-(2-{3-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-3H-benzimida-
zol- 5-yl}-phenyl)-methanesulfonamide, 444
(E)-4-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 445
4-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimi-
dazol- 5-yl}-benzenesulfonamide, 446
(E)-5-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 447
5-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimi-
dazol- 5-yl}-benzenesulfonamide, 448
(E)-1-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-
-yl}- vinyl)-phenyl]-ethanone, 449
(E)-2-{2-[2-(2-quinolin-6-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-prop-
an-2- ol, 450
(E)-N-isopropyl-4-{2-[5-(2-methylsulfamoyl-phenyl)-1H-benzimidazol-2-y-
l]- vinyl}-benzamide, 451
(E)-2-{2-[2-(4-cyano-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 452
(E)-N-(4-{2-[5-(2-methylsulfamoyl-phenyl)-1H-benzimidazol-2-yl]-vinyl}-
- phenyl)-acetamide, 453
(E)-4-{2-[5-(2-methylsulfamoyl-phenyl)-1H-benzimidazol-2-yl]-vinyl}-
benzoic acid, 454
(E)-2-{2-[2-(1H-indol-6-yl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 455
(E)-2-{2-[2-(2,4-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}-N- methyl-benzenesulfonamide, 456
(E)-2-{2-[2-(4-acetyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 457
N-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- acetamide, 458
(E)-2,2,2-trifluoro-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-acetamide, 459
(E)-2,2,2-trifluoro-ethanesulfonic acid
(2-{2-[2-(4-trifluoromethyl-phenyl)-
vinyl]-1H-benzimidazol-5-yl}-phenyl)-amide, 460
(E)-2,2-dimethyl-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-propionamide, 461 (E)-ethanesulfonic
acid (2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-amide, 462
(E)-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-carbamic acid methyl ester, 463
(E)-2-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phen-
yl)- propan-2-ol, 464
2-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- propan-2-ol, 465
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenylamine, 466
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-be-
nzoic acid ethyl ester, 467
N-(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-methanesulfonamide, 468
(E)-2-[2-(2-styryl-1H-benzimidazol-5-yl)-phenyl]-propan-2-ol, 469
(Z)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol, 470
(E)-5-(2-aminosulfonylamino-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-vi-
nyl]- 1H-benzimidazole, 471
2-(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-propan-2-ol, 472
2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
phenol, 473
(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
- phenyl)-carbamic acid tert-butyl ester, 474
(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanol, 475
(E)-N-{2-[2-(2-biphenyl-4-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 476
(E)-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanol, 477
(E)-N-(2-{1-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol- 5-yl}-phenyl)-methanesulfonamide, 478
(E)-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-acetamide, 479
(E)-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-carbamic acid tert-butyl ester, 480
(E)-5-(2-methylsulfanyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-
-1H- benzimidazole, 481
(E)-2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-5-(2-trifluorometh-
yl- phenyl)-1H-benzimidazole, 482
(E)-2-(2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol, 483
(E)-dimethyl-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-benzyl)-amine, 484
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzaldehyde, 485
(E)-methyl-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- benzyl)-amine, 486
2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzylamine, 487
(E)-5-(2-trifluoromethyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-vinyl-
]-1H- benzimidazole, 488
(E)-5-(2-trifluoromethoxy-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-viny-
l]-1H- benzimidazole, 489
2-[2-(2-phenylethynyl-1H-benzimidazol-5-yl)-phenyl]-propan-2-ol,
490 2-(2-phenylethynyl-1H-benzimidazol-5-yl)-benzenesulfonamide,
491
(E)-5-(2-aminosulfonylamino-methylphenyl)-2-[2-(4-trifluoromethyl-
phenyl)-vinyl]-1H-benzimidazole, 492
2-{2-[2-(4-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- propan-2-ol, 494
2-(2-{2-[2-(4-methoxy-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-pheny-
l)- propan-2-ol, 497
2-(2-{2-[2-(4-trifluoromethoxy-phenyl)-cyclopropyl]-1H-benzimidazol-5--
yl}- phenyl)-propan-2-ol, 498
2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzamide, 499
N-tert-butyl-2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 500
5-(2-methanesulfonyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-cycloprop-
yl]-
1H-benzimidazole, 501
2-(2-{2-[(1R,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, 502
2-{2-[(1R,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 503
2-(2-{2-[(1S,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, 504
2-{2-[(1S,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 505
2-(2-{2-[(1S,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, 506
2-{2-[(1R,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 507
2-(2-{2-[(1R,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, and 508
2-{2-[(1S,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide.
[0159] A representative compound of Formula (I) or a form thereof
includes a compound selected from the group consisting of:
TABLE-US-00002 Cpd Name 1
(E)-1-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- ethanone, 2
(E)-1-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- ethanol, 3
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenol,
4
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- acetamide, 5
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzamid-
e, 6
(E)-3-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzamid-
e, 7
(E)-4-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzamid-
e, 8
(E)-N-(4-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- acetamide, 9
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- methanesulfonamide, 10
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- carbamic acid tert-butyl ester, 11
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyla-
mine, 12
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- methanol, 13
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzamide, 14
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-ph-
enol, 15
(E)-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-ethanone, 16
(E)-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-ethanol, 17
(E)-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanesulfonamide, 18
(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol, 19
(E)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzamide, 20
(E)-1-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl-
}- phenyl)-ethanone, 21
(E)-1-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl-
}- phenyl)-ethanol, 22
(E)-N-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl-
}- phenyl)-methanesulfonamide, 23
(E)-2-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl-
}- phenyl)-propan-2-ol, 24
(E)-N-(2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phen-
yl)- acetamide, 25
(E)-N-(3-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phen-
yl)- acetamide, 26
(E)-2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzami-
de, 27
(E)-1-(2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phen-
yl)- ethanone, 28
(E)-N-(2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phen-
yl)- methanesulfonamide, 29
2-{2-[3-(4-tert-butyl-phenyl)-propyl]-1H-benzimidazol-5-yl}-phenol,
30 2-[3-(4-tert-butyl-phenyl)-propyl]-5-m-tolyl-1H-benzimidazole,
31
N-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- methanesulfonamide, 32
2-{2-[2-(4-tert-butyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenol,
33
3-{2-[2-(4-tert-butyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenol,
34
4-{2-[2-(4-tert-butyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenol,
35
(E)-(2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- phenyl)-methanol, 36
(E)-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- phenol, 37
(E)-N-(2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidaz-
ol-5- yl}-phenyl)-acetamide, 38
(E)-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- benzamide, 39
(E)-1-(2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidaz-
ol-5- yl}-phenyl)-ethanone, 40
(E)-1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimida-
zol- 5-yl}-phenyl)-ethanone, 41
(E)-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-phenol, 42
(E)-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-phenyl)-methanol, 43
(E)-N-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimida-
zol- 5-yl}-phenyl)-acetamide, 44
(E)-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzamide, 45
(E)-1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimida-
zol- 5-yl}-phenyl)-ethanol, 46
1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-ethyl]-1H-benzimidazol--
5- yl}-phenyl)-ethanol, 47
(E)-2-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimida-
zol- 5-yl}-phenyl)-propan-2-ol, 48
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimid-
azol-5- yl}-phenol, 49
(E)-3-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimid-
azol-5- yl}-phenol, 50
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-
benzimidazol-5-yl}-phenyl)-acetamide, 51
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimi-
dazol- 5-yl}-phenyl)-methanol, 52
(E)-2-[2-(4-tert-butyl-phenyl)-vinyl]-5-(2-fluoro-phenyl)-6-trifluorom-
ethyl- 1H-benzimidazole, 53
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimid-
azol-5- yl}-benzamide, 54
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimi-
dazol- 5-yl}-phenyl)-carbamic acid tert-butyl ester, 55
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 56
(E)-N-(2-{6-trifluoromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-acetamide, 57
(E)-1-(2-{6-trifluoromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-ethanone, 58
(E)-(2-{6-trifluoromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanol, 59
(E)-2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- phenol, 60
(E)-3-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- phenol, 61
(E)-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-phenyl)-methanol, 62
(E)-1-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol-5- yl}-phenyl)-ethanone, 63
(E)-2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzamide, 64
(E)-N-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol-5- yl}-phenyl)-acetamide, 65
(E)-N-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol-5- yl}-phenyl)-methanesulfonamide, 66
(E)-(2-{6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-phenyl)-methanol, 67
(E)-1-(2-{6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol-5- yl}-phenyl)-ethanone, 68
(E)-2-{6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-phenol, 69
(E)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 70
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 71
(E)-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 77
(E)-N-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 78
(E)-2-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
propan-2-ol, 79
(E)-2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 83
(E)-N-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanesulfonamide, 84
(E)-2-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol, 85
(E)-2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 95
(E)-N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimida-
zol-5- yl)-phenyl]-methanesulfonamide, 101
(E)-N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-phenyl]-methanesulfonamide, 113
(E)-N-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl-
}- phenyl)-methanesulfonamide, 114
(E)-2-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl-
}- phenyl)-propan-2-ol, 129
2-{2-[2-(4-trifluoromethoxy-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 130
2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 131
2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 139
2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 145
2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 175
2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 190
2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
- benzenesulfonamide, 198
2-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-pheny-
l)- propan-2-ol, 234
2-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5--
yl}- phenyl)-propan-2-ol, 250
2-[2-(4-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 294
2-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-pheny-
l}- propan-2-ol, 295
2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 309
(E)-N-tert-butyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimi-
dazol-5-
yl}-benzenesulfonamide, 310
(E)-N-methyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 311
(E)-2-hydroxy-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimi-
dazol- 5-yl}-phenyl)-ethanone, 312
(E)-2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 314
(E)-N-methyl-2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 315
(E)-2-{2-[2-(4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 316
(E)-2-{2-[2-(3,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-meth-
yl- benzenesulfonamide, 317
(E)-2-{2-[2-(3-bromo-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 318
(E)-2-{2-[2-(4-dimethylamino-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 319
(E)-2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5-yl}- N-methyl-benzenesulfonamide, 320
(E)-2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5-yl}- N-methyl-benzenesulfonamide, 321
(E)-2-{2-[2-(3-chloro-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
- methyl-benzenesulfonamide, 322
(E)-2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5-yl}- N-methyl-benzenesulfonamide, 323
(E)-N-methyl-2-{2-[2-(2,3,4-trifluoro-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- benzenesulfonamide, 324
(E)-N-methyl-2-{2-[2-(2,4,5-trifluoro-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- benzenesulfonamide, 325
(E)-2-{2-[2-(2,3-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-meth-
yl- benzenesulfonamide, 326
(E)-2-{2-[2-(2,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-meth-
yl- benzenesulfonamide, 327
(E)-2-{2-[2-(2,6-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-meth-
yl- benzenesulfonamide, 328
(E)-2-{2-[2-(3,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-meth-
yl- benzenesulfonamide, 329
(E)-2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-meth-
yl- benzenesulfonamide, 330
(E)-2-{2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5-yl}- N-methyl-benzenesulfonamide, 331
(E)-2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5-yl}- N-methyl-benzenesulfonamide, 332
(E)-2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5-yl}- N-methyl-benzenesulfonamide, 333
(E)-2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}-N- methyl-benzenesulfonamide, 334
(E)-2-{2-[2-(2,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}-N- methyl-benzenesulfonamide, 335
(E)-2-{2-[2-(3-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
- methyl-benzenesulfonamide, 336
(E)-2-{2-[2-(2-chloro-6-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
- methyl-benzenesulfonamide, 337
(E)-2-{2-[2-(2,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-meth-
yl- benzenesulfonamide, 338
(E)-2-{2-[2-(3-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 339
(E)-2-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
- methyl-benzenesulfonamide, 340
(E)-2-{2-[2-(4-chloro-2-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-N-methyl-benzenesulfonamide, 341
(E)-N-methyl-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 342
(E)-N-methyl-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 343
(E)-N-methyl-2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 344
(E)-N-methyl-2-{2-[2-(3-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidaz-
ol-5- yl}-benzenesulfonamide, 345
(E)-N-methyl-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidaz-
ol-5- yl}-benzenesulfonamide, 346
(E)-2-{2-[2-(2-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 347
(E)-2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 348
(E)-2-{2-[2-(2-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 349
(E)-2-{2-[2-(2,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-meth-
yl- benzenesulfonamide, 350
N-methyl-2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 351
(E)-2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
- methyl-benzenesulfonamide, 357
(E)-2-{2-[2-(2,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 358
(E)-2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 359
(E)-2-{2-[2-(2,3-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 360
(E)-2-{2-[2-(2,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 361
(E)-2-{2-[2-(3,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 362
(E)-2-{2-[2-(3-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 363
(E)-2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 364
(E)-2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 365
(E)-2-{2-[2-(2-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 366
(E)-2-{2-[2-(2-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 367
(E)-2-{2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5-yl}- benzenesulfonamide, 368
(E)-2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5-yl}- benzenesulfonamide, 369
(E)-2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5-yl}- benzenesulfonamide, 370
(E)-2-{2-[2-(2,3,4-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 371
(E)-2-{2-[2-(2,4,5-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 372
(E)-2-{2-[2-(2,6-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 373
(E)-2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}- benzenesulfonamide, 374
(E)-2-{2-[2-(2,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}- benzenesulfonamide, 375
(E)-2-{2-[2-(4-chloro-2-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 376
(E)-2-{2-[2-(3-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 378
(E)-2-{2-[2-(4-chloro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 379
(E)-2-{2-[2-(5-bromo-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 380
(E)-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 383
2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 384
2-{2-[2-(2,3,4-trifluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 385
2-{2-[2-(2,4,5-trifluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 386
2-{2-[2-(2,6-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 387
2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
- benzenesulfonamide, 388
2-{2-[2-(2,5-bis-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
- benzenesulfonamide, 389
2-{2-[2-(4-chloro-2-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 390
2-{2-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 391
2-{2-[2-(3-trifluoromethoxy-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 392
2-{2-[2-(2,4-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 393
2-{2-[2-(3,4-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 394
2-{2-[2-(2,3-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 395
2-{2-[2-(2,5-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 396
2-{2-[2-(3,5-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 397
2-(2-phenethyl-1H-benzimidazol-5-yl)-benzenesulfonamide, 398
(E)-N,N-dimethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimi-
dazol- 5-yl}-benzenesulfonamide, 399
N,N-dimethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 400
N-methyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 402
2-{2-[2-(2-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 404
2-{2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 405
2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 406
(E)-N-(2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 407
(E)-N-(2-{2-[2-(4-isopropyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phen-
yl)- methanesulfonamide, 408
(E)-N-(2-{2-[2-(3-chloro-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl-
}- phenyl)-methanesulfonamide, 409
(E)-N-(2-{2-[2-(3-bromo-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanesulfonamide, 410
(E)-N-(2-{2-[2-(4-difluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl-
}- phenyl)-methanesulfonamide, 411
(E)-N-(2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol-5- yl}-phenyl)-methanesulfonamide, 412
(E)-N-{2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 413
(E)-N-(2-{2-[2-(4-dimethylamino-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide, 414
(E)-N-(2-{2-[2-(4-ethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
- methanesulfonamide, 415
(E)-N-{2-[2-(2-naphthalen-2-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 416
(E)-N-(2-{2-[2-(3,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phe-
nyl)- methanesulfonamide,
417
(E)-N-(2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol-5- yl}-phenyl)-methanesulfonamide, 418
(E)-N-(2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol-5- yl}-phenyl)-methanesulfonamide, 419
2-{2-[2-(2-fluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 420
2-{2-[2-(4-fluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 421
2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 422
(E)-5-(2-methanesulfonyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-viny-
l]-1H- benzimidazole, 423
(E)-2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5-yl}- benzenesulfonamide, 424
(E)-2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5-yl}- benzenesulfonamide, 425
(E)-2-{2-[2-(3-ethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 426
(E)-2-(2-styryl-1H-benzimidazol-5-yl)-benzenesulfonamide, 427
(E)-2-{2-[2-(3,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 428
(E)-2-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 429
(E)-2-{2-[2-(4-isopropyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 430
(E)-2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-benzenesulfonamide,
431
(E)-2-{2-[2-(3-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 432
(E)-2-{2-[2-(3-chloro-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 433
(E)-2-[2-(2-naphthalen-2-yl-vinyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 434
(E)-2-{2-[2-(4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 435
(E)-2-{2-[2-(4-difluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 436
(E)-2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5-yl}- benzenesulfonamide, 437
(E)-2-{2-[2-(2,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 438
(E)-2-{2-[2-(2-chloro-6-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 439
(E)-2-{2-[2-(3-bromo-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 440
(E)-2-{2-[2-(4-ethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 441
(E)-4-fluoro-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5-yl}- benzenesulfonamide, 442
2-{2-[2-(4-isopropyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 443
(E)-N-(2-{3-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-3H-benzimid-
azol- 5-yl}-phenyl)-methanesulfonamide, 444
(E)-4-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 445
4-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzim-
idazol- 5-yl}-benzenesulfonamide, 446
(E)-5-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 447
5-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzim-
idazol- 5-yl}-benzenesulfonamide, 448
(E)-1-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol--
2-yl}- vinyl)-phenyl]-ethanone, 449
(E)-2-{2-[2-(2-quinolin-6-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-pro-
pan-2- ol, 450
(E)-N-isopropyl-4-{2-[5-(2-methylsulfamoyl-phenyl)-1H-benzimidazol-2--
yl]- vinyl}-benzamide, 451
(E)-2-{2-[2-(4-cyano-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 452
(E)-N-(4-{2-[5-(2-methylsulfamoyl-phenyl)-1H-benzimidazol-2-yl]-vinyl-
}- phenyl)-acetamide, 453
(E)-4-{2-[5-(2-methylsulfamoyl-phenyl)-1H-benzimidazol-2-yl]-vinyl}-
benzoic acid, 454
(E)-2-{2-[2-(1H-indol-6-yl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 455
(E)-2-{2-[2-(2,4-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}-N- methyl-benzenesulfonamide, 456
(E)-2-{2-[2-(4-acetyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 457
N-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-ph-
enyl)- acetamide, 458
(E)-2,2,2-trifluoro-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-acetamide, 459
(E)-2,2,2-trifluoro-ethanesulfonic acid
(2-{2-[2-(4-trifluoromethyl-phenyl)-
vinyl]-1H-benzimidazol-5-yl}-phenyl)-amide, 460
(E)-2,2-dimethyl-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-propionamide, 461 (E)-ethanesulfonic
acid (2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-amide, 462
(E)-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-carbamic acid methyl ester, 463
(E)-2-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phe-
nyl)- propan-2-ol, 464
2-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-ph-
enyl)- propan-2-ol, 465
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenylamine, 466
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-b-
enzoic acid ethyl ester, 467
N-(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5--
yl}- phenyl)-methanesulfonamide, 468
(E)-2-[2-(2-styryl-1H-benzimidazol-5-yl)-phenyl]-propan-2-ol, 469
(Z)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl-
}- phenyl)-propan-2-ol, 470
(E)-5-(2-aminosulfonylamino-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-v-
inyl]- 1H-benzimidazole, 471
2-(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5--
yl}- phenyl)-propan-2-ol, 472
2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
- phenol, 473
(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl-
}- phenyl)-carbamic acid tert-butyl ester, 474
(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl-
}- phenyl)-methanol, 475
(E)-N-{2-[2-(2-biphenyl-4-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 476
(E)-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanol, 477
(E)-N-(2-{1-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol- 5-yl}-phenyl)-methanesulfonamide, 478
(E)-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl-
}- phenyl)-acetamide, 479
(E)-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-carbamic acid tert-butyl ester, 480
(E)-5-(2-methylsulfanyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-vinyl-
]-1H- benzimidazole, 481
(E)-2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-5-(2-trifluoromet-
hyl- phenyl)-1H-benzimidazole, 482
(E)-2-(2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl-
}- phenyl)-propan-2-ol, 483
(E)-dimethyl-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidaz-
ol-5- yl}-benzyl)-amine, 484
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzaldehyde, 485
(E)-methyl-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzyl)-amine, 486
2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzylamine, 487
(E)-5-(2-trifluoromethyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-viny-
l]-1H- benzimidazole, 488
(E)-5-(2-trifluoromethoxy-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-vin-
yl]-1H- benzimidazole, 489
2-[2-(2-phenylethynyl-1H-benzimidazol-5-yl)-phenyl]-propan-2-ol,
490 2-(2-phenylethynyl-1H-benzimidazol-5-yl)-benzenesulfonamide,
491
(E)-5-(2-aminosulfonylamino-methylphenyl)-2-[2-(4-trifluoromethyl-
phenyl)-vinyl]-1H-benzimidazole, 492
2-{2-[2-(4-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-pheny-
l}- propan-2-ol, 494
2-(2-{2-[2-(4-methoxy-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phen-
yl)- propan-2-ol, 497
2-(2-{2-[2-(4-trifluoromethoxy-phenyl)-cyclopropyl]-1H-benzimidazol-5-
-yl}- phenyl)-propan-2-ol, 498
2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
- benzamide, 499
N-tert-butyl-2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 500
5-(2-methanesulfonyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-cyclopro-
pyl]- 1H-benzimidazole, 40333774 501
2-(2-{2-[(1R,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, 40334255 502
2-{2-[(1R,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-
- yl}-benzenesulfonamide, 503
2-(2-{2-[(1S,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, 504
2-{2-[(1S,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidaz-
ol-5- yl}-benzenesulfonamide, 505
2-(2-{2-[(1S,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, 506
2-{2-[(1R,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidaz-
ol-5- yl}-benzenesulfonamide, 507
2-(2-{2-[(1R,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, and 508
2-{2-[(1S,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidaz-
ol-5- yl}-benzenesulfonamide.
[0160] A representative compound of Formula (I) or a form thereof
includes a compound selected from the group consisting of:
TABLE-US-00003 Cpd Name 1
(E)-1-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanone, 2
(E)-1-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanol, 3
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenol,
4
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- acetamide, 5
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzamide-
, 9
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- methanesulfonamide, 10
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
- carbamic acid tert-butyl ester, 11
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenylam-
ine, 12
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
- methanol, 13
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzamide, 15
(E)-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanone, 16
(E)-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanol, 17
(E)-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide, 18
(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-propan-2-ol, 22
(E)-N-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanesulfonamide, 27
(E)-1-(2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- ethanone, 28
(E)-N-(2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- methanesulfonamide, 31
N-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phen-
yl)- methanesulfonamide, 32
2-{2-[2-(4-tert-butyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenol,
34
4-{2-[2-(4-tert-butyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenol,
35
(E)-(2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- phenyl)-methanol, 38
(E)-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}- benzamide, 39
(E)-1-(2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-phenyl)-ethanone, 40
(E)-1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-ethanone, 41
(E)-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-phenol, 42
(E)-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-phenyl)-methanol, 44
(E)-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-benzamide, 45
(E)-1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-ethanol, 46
1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-
- yl}-phenyl)-ethanol, 47
(E)-2-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-propan-2-ol, 50
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-
benzimidazol-5-yl}-phenyl)-acetamide, 51
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimid-
azol- 5-yl}-phenyl)-methanol, 53
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimida-
zol-5- yl}-benzamide, 56
(E)-N-(2-{6-trifluoromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-acetamide, 58
(E)-(2-{6-trifluoromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanol, 59
(E)-2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- phenol, 61
(E)-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-phenyl)-methanol, 62
(E)-1-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidaz-
ol-5- yl}-phenyl)-ethanone, 63
(E)-2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- benzamide, 66
(E)-(2-{6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-phenyl)-methanol, 67
(E)-1-(2-{6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidaz-
ol-5- yl}-phenyl)-ethanone, 68
(E)-2-{6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-phenol, 69
(E)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 70
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 71
(E)-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-benzenesulfonamide, 77
(E)-N-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 78
(E)-2-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
propan-2-ol, 79
(E)-2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 84
(E)-2-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-propan-2-ol, 95
(E)-N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimidaz-
ol-5- yl)-phenyl]-methanesulfonamide, 114
(E)-2-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol, 129
2-{2-[2-(4-trifluoromethoxy-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 130
2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 131
2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 139
2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 175
2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 190
2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 198
2-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- propan-2-ol, 250
2-[2-(4-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 294
2-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- propan-2-ol, 295
2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 309
(E)-N-tert-butyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol-5- yl}-benzenesulfonamide, 310
(E)-N-methyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 311
(E)-2-hydroxy-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol- 5-yl}-phenyl)-ethanone, 312
(E)-2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 314
(E)-N-methyl-2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 315
(E)-2-{2-[2-(4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 316
(E)-2-{2-[2-(3,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 317
(E)-2-{2-[2-(3-bromo-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 318
(E)-2-{2-[2-(4-dimethylamino-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 319
(E)-2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 320
(E)-2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 321
(E)-2-{2-[2-(3-chloro-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 322
(E)-2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 323
(E)-N-methyl-2-{2-[2-(2,3,4-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}- benzenesulfonamide, 324
(E)-N-methyl-2-{2-[2-(2,4,5-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}- benzenesulfonamide, 325
(E)-2-{2-[2-(2,3-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 326
(E)-2-{2-[2-(2,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 327
(E)-2-{2-[2-(2,6-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 328
(E)-2-{2-[2-(3,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 329
(E)-2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 330
(E)-2-{2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 331
(E)-2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 332
(E)-2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 333
(E)-2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}-N- methyl-benzenesulfonamide, 334
(E)-2-{2-[2-(2,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}-N- methyl-benzenesulfonamide, 335
(E)-2-{2-[2-(3-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 336
(E)-2-{2-[2-(2-chloro-6-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 337
(E)-2-{2-[2-(2,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 338
(E)-2-{2-[2-(3-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 339
(E)-2-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 340
(E)-2-{2-[2-(4-chloro-2-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-
-5-
yl}-N-methyl-benzenesulfonamide, 341
(E)-N-methyl-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 342
(E)-N-methyl-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 343
(E)-N-methyl-2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 344
(E)-N-methyl-2-{2-[2-(3-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 345
(E)-N-methyl-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 346
(E)-2-{2-[2-(2-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 347
(E)-2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 348
(E)-2-{2-[2-(2-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 349
(E)-2-{2-[2-(2,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 350
N-methyl-2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 357
(E)-2-{2-[2-(2,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 358
(E)-2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 359
(E)-2-{2-[2-(2,3-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 360
(E)-2-{2-[2-(2,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 361
(E)-2-{2-[2-(3,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 362
(E)-2-{2-[2-(3-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 363
(E)-2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 364
(E)-2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 365
(E)-2-{2-[2-(2-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 366
(E)-2-{2-[2-(2-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 367
(E)-2-{2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 368
(E)-2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 369
(E)-2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 370
(E)-2-{2-[2-(2,3,4-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 371
(E)-2-{2-[2-(2,4,5-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 372
(E)-2-{2-[2-(2,6-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 373
(E)-2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 374
(E)-2-{2-[2-(2,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 375
(E)-2-{2-[2-(4-chloro-2-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 376
(E)-2-{2-[2-(3-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 378
(E)-2-{2-[2-(4-chloro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 379
(E)-2-{2-[2-(5-bromo-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 380
(E)-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- benzenesulfonamide, 383
2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 384
2-{2-[2-(2,3,4-trifluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 385
2-{2-[2-(2,4,5-trifluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 386
2-{2-[2-(2,6-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 387
2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 388
2-{2-[2-(2,5-bis-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 390
2-{2-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 391
2-{2-[2-(3-trifluoromethoxy-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 392
2-{2-[2-(2,4-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 393
2-{2-[2-(3,4-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 394
2-{2-[2-(2,3-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 395
2-{2-[2-(2,5-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 396
2-{2-[2-(3,5-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 397
2-(2-phenethyl-1H-benzimidazol-5-yl)-benzenesulfonamide, 398
(E)-N,N-dimethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol- 5-yl}-benzenesulfonamide, 399
N,N-dimethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 402
2-{2-[2-(2-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 404
2-{2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 405
2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 406
(E)-N-(2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 407
(E)-N-(2-{2-[2-(4-isopropyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- methanesulfonamide, 410
(E)-N-(2-{2-[2-(4-difluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanesulfonamide, 411
(E)-N-(2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol-5- yl}-phenyl)-methanesulfonamide, 412
(E)-N-{2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 413
(E)-N-(2-{2-[2-(4-dimethylamino-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide, 414
(E)-N-(2-{2-[2-(4-ethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 415
(E)-N-{2-[2-(2-naphthalen-2-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 416
(E)-N-(2-{2-[2-(3,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phen-
yl)- methanesulfonamide, 417
(E)-N-(2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol-5- yl}-phenyl)-methanesulfonamide, 418
(E)-N-(2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol-5- yl}-phenyl)-methanesulfonamide, 419
2-{2-[2-(2-fluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 420
2-{2-[2-(4-fluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 421
2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 422
(E)-5-(2-methanesulfonyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-vinyl-
]-1H- benzimidazole, 423
(E)-2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 424
(E)-2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 426
(E)-2-(2-styryl-1H-benzimidazol-5-yl)-benzenesulfonamide, 427
(E)-2-{2-[2-(3,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 428
(E)-2-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 429
(E)-2-{2-[2-(4-isopropyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 430
(E)-2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-benzenesulfonamide,
431
(E)-2-{2-[2-(3-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 432
(E)-2-{2-[2-(3-chloro-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 433
(E)-2-[2-(2-naphthalen-2-yl-vinyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 434
(E)-2-{2-[2-(4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 435
(E)-2-{2-[2-(4-difluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 436
(E)-2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 437
(E)-2-{2-[2-(2,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 438
(E)-2-{2-[2-(2-chloro-6-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 439
(E)-2-{2-[2-(3-bromo-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 440
(E)-2-{2-[2-(4-ethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 442
2-{2-[2-(4-isopropyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 444
(E)-4-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 445
4-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimi-
dazol- 5-yl}-benzenesulfonamide, 446
(E)-5-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 447
5-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimi-
dazol- 5-yl}-benzenesulfonamide, 448
(E)-1-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-
-yl}- vinyl)-phenyl]-ethanone, 449
(E)-2-{2-[2-(2-quinolin-6-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-prop-
an-2- ol, 451
(E)-2-{2-[2-(4-cyano-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 455
(E)-2-{2-[2-(2,4-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}-N- methyl-benzenesulfonamide, 456
(E)-2-{2-[2-(4-acetyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 461 (E)-ethanesulfonic acid
(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-amide, 462
(E)-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-carbamic acid methyl ester, 463
(E)-2-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phen-
yl)- propan-2-ol, 464
2-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- propan-2-ol, 465
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenylamine, 466
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-be-
nzoic acid ethyl ester, 467
N-(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-methanesulfonamide, 468
(E)-2-[2-(2-styryl-1H-benzimidazol-5-yl)-phenyl]-propan-2-ol, 469
(Z)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol, 470
(E)-5-(2-aminosulfonylamino-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-vi-
nyl]- 1H-benzimidazole, 471
2-(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-propan-2-ol, 475
(E)-N-{2-[2-(2-biphenyl-4-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 476
(E)-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanol, 482
(E)-2-(2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol, 489
2-[2-(2-phenylethynyl-1H-benzimidazol-5-yl)-phenyl]-propan-2-ol,
490 2-(2-phenylethynyl-1H-benzimidazol-5-yl)-benzenesulfonamide,
491
(E)-5-(2-aminosulfonylamino-methylphenyl)-2-[2-(4-trifluoromethyl-
phenyl)-vinyl]-1H-benzimidazole, 492
2-{2-[2-(4-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- propan-2-ol, 494
2-(2-{2-[2-(4-methoxy-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-pheny-
l)- propan-2-ol, 497
2-(2-{2-[2-(4-trifluoromethoxy-phenyl)-cyclopropyl]-1H-benzimidazol-5--
yl}- phenyl)-propan-2-ol, 498
2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzamide, 500
5-(2-methanesulfonyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-cycloprop-
yl]- 1H-benzimidazole, 501
2-(2-{2-[(1R,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, 502
2-{2-[(1R,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 503
2-(2-{2-[(1S,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, and 504
2-{2-[(1S,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide.
[0161] A representative compound of Formula (I) or a form thereof
includes a compound selected from the group consisting of:
TABLE-US-00004 Cpd Name 1
(E)-1-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanone, 2
(E)-1-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanol, 5
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzamide-
, 9
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- methanesulfonamide, 12
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
- methanol, 16
(E)-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanol, 17
(E)-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide, 18
(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-propan-2-ol, 22
(E)-N-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanesulfonamide, 31
N-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phen-
yl)- methanesulfonamide, 35
(E)-(2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- phenyl)-methanol, 40
(E)-1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-ethanone, 42
(E)-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-phenyl)-methanol, 45
(E)-1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-ethanol, 46
1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-
- yl}-phenyl)-ethanol, 47
(E)-2-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-propan-2-ol, 51
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimid-
azol- 5-yl}-phenyl)-methanol, 53
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimida-
zol-5- yl}-benzamide, 58
(E)-(2-{6-trifluoromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanol, 61
(E)-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-phenyl)-methanol, 66
(E)-(2-{6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-phenyl)-methanol, 69
(E)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 70
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 71
(E)-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-benzenesulfonamide, 77
(E)-N-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 78
(E)-2-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
propan-2-ol, 79
(E)-2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 84
(E)-2-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-propan-2-ol, 114
(E)-2-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol, 129
2-{2-[2-(4-trifluoromethoxy-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 130
2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 131
2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 139
2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 175
2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 190
2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 198
2-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- propan-2-ol, 250
2-[2-(4-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 294
2-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- propan-2-ol, 295
2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 310
(E)-N-methyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 311
(E)-2-hydroxy-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol- 5-yl}-phenyl)-ethanone, 312
(E)-2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 314
(E)-N-methyl-2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 315
(E)-2-{2-[2-(4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 316
(E)-2-{2-[2-(3,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 317
(E)-2-{2-[2-(3-bromo-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 318
(E)-2-{2-[2-(4-dimethylamino-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 319
(E)-2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 320
(E)-2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 321
(E)-2-{2-[2-(3-chloro-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 322
(E)-2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 323
(E)-N-methyl-2-{2-[2-(2,3,4-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}- benzenesulfonamide, 324
(E)-N-methyl-2-{2-[2-(2,4,5-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}- benzenesulfonamide, 328
(E)-2-{2-[2-(3,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 329
(E)-2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 331
(E)-2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 332
(E)-2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 333
(E)-2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}-N- methyl-benzenesulfonamide, 335
(E)-2-{2-[2-(3-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 337
(E)-2-{2-[2-(2,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 339
(E)-2-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide, 340
(E)-2-{2-[2-(4-chloro-2-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-N-methyl-benzenesulfonamide, 341
(E)-N-methyl-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 342
(E)-N-methyl-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 344
(E)-N-methyl-2-{2-[2-(3-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 345
(E)-N-methyl-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide, 347
(E)-2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 349
(E)-2-{2-[2-(2,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide, 350
N-methyl-2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 357
(E)-2-{2-[2-(2,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 358
(E)-2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 359
(E)-2-{2-[2-(2,3-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 360
(E)-2-{2-[2-(2,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 361
(E)-2-{2-[2-(3,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 362
(E)-2-{2-[2-(3-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 363
(E)-2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 364
(E)-2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 365
(E)-2-{2-[2-(2-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 366
(E)-2-{2-[2-(2-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 367
(E)-2-{2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 368
(E)-2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 369
(E)-2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 370
(E)-2-{2-[2-(2,3,4-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 371
(E)-2-{2-[2-(2,4,5-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 372
(E)-2-{2-[2-(2,6-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 373
(E)-2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 374
(E)-2-{2-[2-(2,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide, 376
(E)-2-{2-[2-(3-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 378
(E)-2-{2-[2-(4-chloro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 379
(E)-2-{2-[2-(5-bromo-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 380
(E)-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}- benzenesulfonamide, 383
2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 384
2-{2-[2-(2,3,4-trifluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 385
2-{2-[2-(2,4,5-trifluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 386
2-{2-[2-(2,6-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide,
387
2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 388
2-{2-[2-(2,5-bis-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 390
2-{2-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 391
2-{2-[2-(3-trifluoromethoxy-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 392
2-{2-[2-(2,4-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 393
2-{2-[2-(3,4-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 394
2-{2-[2-(2,3-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 395
2-{2-[2-(2,5-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 396
2-{2-[2-(3,5-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 397
2-(2-phenethyl-1H-benzimidazol-5-yl)-benzenesulfonamide, 398
(E)-N,N-dimethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol- 5-yl}-benzenesulfonamide, 399
N,N-dimethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 402
2-{2-[2-(2-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 404
2-{2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 405
2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 407
(E)-N-(2-{2-[2-(4-isopropyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- methanesulfonamide, 417
(E)-N-(2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol-5- yl}-phenyl)-methanesulfonamide, 418
(E)-N-(2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol-5- yl}-phenyl)-methanesulfonamide, 419
2-{2-[2-(2-fluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 420
2-{2-[2-(4-fluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 421
2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 422
(E)-5-(2-methanesulfonyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-vinyl-
]-1H- benzimidazole, 423
(E)-2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 424
(E)-2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 426
(E)-2-(2-styryl-1H-benzimidazol-5-yl)-benzenesulfonamide, 427
(E)-2-{2-[2-(3,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 428
(E)-2-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 429
(E)-2-{2-[2-(4-isopropyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 430
(E)-2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-benzenesulfonamide,
431
(E)-2-{2-[2-(3-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 432
(E)-2-{2-[2-(3-chloro-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 433
(E)-2-[2-(2-naphthalen-2-yl-vinyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 434
(E)-2-{2-[2-(4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 435
(E)-2-{2-[2-(4-difluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 436
(E)-2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 437
(E)-2-{2-[2-(2,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 438
(E)-2-{2-[2-(2-chloro-6-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 439
(E)-2-{2-[2-(3-bromo-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 440
(E)-2-{2-[2-(4-ethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 442
2-{2-[2-(4-isopropyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 444
(E)-4-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 445
4-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimi-
dazol- 5-yl}-benzenesulfonamide, 446
(E)-5-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 447
5-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimi-
dazol- 5-yl}-benzenesulfonamide, 448
(E)-1-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-
-yl}- vinyl)-phenyl]-ethanone, 449
(E)-2-{2-[2-(2-quinolin-6-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-prop-
an-2- ol, 451
(E)-2-{2-[2-(4-cyano-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 455
(E)-2-{2-[2-(2,4-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}-N- methyl-benzenesulfonamide, 456
(E)-2-{2-[2-(4-acetyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 461 (E)-ethanesulfonic acid
(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-amide, 462
(E)-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-carbamic acid methyl ester, 463
(E)-2-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phen-
yl)- propan-2-ol, 464
2-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- propan-2-ol, 466
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-be-
nzoic acid ethyl ester, 468
(E)-2-[2-(2-styryl-1H-benzimidazol-5-yl)-phenyl]-propan-2-ol, 469
(Z)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol, 470
(E)-5-(2-aminosulfonylamino-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-vi-
nyl]- 1H-benzimidazole, 471
2-(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-propan-2-ol, 475
(E)-N-{2-[2-(2-biphenyl-4-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 476
(E)-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanol, 482
(E)-2-(2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol, 489
2-[2-(2-phenylethynyl-1H-benzimidazol-5-yl)-phenyl]-propan-2-ol,
490 2-(2-phenylethynyl-1H-benzimidazol-5-yl)-benzenesulfonamide,
491
(E)-5-(2-aminosulfonylamino-methylphenyl)-2-[2-(4-trifluoromethyl-
phenyl)-vinyl]-1H-benzimidazole, 492
2-{2-[2-(4-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- propan-2-ol, 494
2-(2-{2-[2-(4-methoxy-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-pheny-
l)- propan-2-ol, 497
2-(2-{2-[2-(4-trifluoromethoxy-phenyl)-cyclopropyl]-1H-benzimidazol-5--
yl}- phenyl)-propan-2-ol, 498
2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzamide, 500
5-(2-methanesulfonyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-cycloprop-
yl]- 1H-benzimidazole, 501
2-(2-{2-[(1R,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, 503
2-(2-{2-[(1S,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, and 504
2-{2-[(1S,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazo-
l-5- yl}-benzenesulfonamide.
[0162] A representative compound of Formula (I) or a form thereof
includes a compound selected from the group consisting of:
TABLE-US-00005 Cpd Name 9
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- methanesulfonamide, 12
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
- methanol, 17
(E)-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide, 18
(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-propan-2-ol, 69
(E)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 70
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 78
(E)-2-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
propan-2-ol, 79
(E)-2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 114
(E)-2-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol, 130
2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 310
(E)-N-methyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 312
(E)-2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide, 319
(E)-2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- N-methyl-benzenesulfonamide, 341
(E)-N-methyl-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 357
(E)-2-{2-[2-(2,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 358
(E)-2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 362
(E)-2-{2-[2-(3-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 369
(E)-2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide, 384
2-{2-[2-(2,3,4-trifluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 390
2-{2-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 391
2-{2-[2-(3-trifluoromethoxy-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 394
2-{2-[2-(2,3-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 398
(E)-N,N-dimethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol- 5-yl}-benzenesulfonamide, 399
N,N-dimethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 407
(E)-N-(2-{2-[2-(4-isopropyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- methanesulfonamide, 421
2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 422
(E)-5-(2-methanesulfonyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-vinyl-
]-1H- benzimidazole, 428
(E)-2-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 429
(E)-2-{2-[2-(4-isopropyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 430
(E)-2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-benzenesulfonamide,
434 (E)-2-{2-[2-(4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 442
2-{2-[2-(4-isopropyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 449
(E)-2-{2-[2-(2-quinolin-6-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-prop-
an-2- ol, 461 (E)-ethanesulfonic acid
(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-amide, 464
2-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- propan-2-ol, 468
(E)-2-[2-(2-styryl-1H-benzimidazol-5-yl)-phenyl]-propan-2-ol, 469
(Z)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol, 471
2-(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-propan-2-ol, 489
2-[2-(2-phenylethynyl-1H-benzimidazol-5-yl)-phenyl]-propan-2-ol,
492
2-{2-[2-(4-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- propan-2-ol, and 503
2-(2-{2-[(1S,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol.
[0163] A representative prophetic compound of Formula (I) or a form
thereof includes a compound selected from the group consisting
of:
TABLE-US-00006 Cpd Name 72
(E)-C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 73
(E)-C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 74
(E)-C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-viny-
l]- 1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 75
(E)-1-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanone, 76
(E)-1-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanol, 80
(E)-N-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
C,C,C-trifluoro-methanesulfonamide, 81
(E)-1-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanone, 82
(E)-1-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanol, 86
(E)-C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 87
(E)-1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-vi-
nyl}-1H- benzimidazol-5-yl)-phenyl]-ethanone, 88
(E)-1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-vi-
nyl}-1H- benzimidazol-5-yl)-phenyl]-ethanol, 89
(E)-N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-vi-
nyl}- 1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 90
(E)-2-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-vi-
nyl}-1H- benzimidazol-5-yl)-phenyl]-propan-2-ol, 91
(E)-2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-vinyl-
}-1H- benzimidazol-5-yl)-benzenesulfonamide, 92
(E)-C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-et-
hoxy)-
phenyl]-vinyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 93
(E)-1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimidaz-
ol-5- yl)-phenyl]-ethanone, 94
(E)-1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimidaz-
ol-5- yl)-phenyl]-ethanol, 96
(E)-2-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimidaz-
ol-5- yl)-phenyl]-propan-2-ol, 97
(E)-2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimidazol--
5-yl)- benzenesulfonamide, 98
(E)-C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-viny-
l}-1H- benzimidazol-5-yl)-phenyl]-methanesulfonamide, 99
(E)-1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanone, 100
(E)-1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanol, 102
(E)-2-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-phenyl]-propan-2-ol, 103
(E)-2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-benzenesulfonamide, 104
(E)-C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phen-
yl]- vinyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 105
(E)-1-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanone, 106
(E)-1-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanol, 107
(E)-N-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 108
(E)-2-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
propan-2-ol, 109
(E)-2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 110
(E)-N-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
C,C,C-trifluoro-methanesulfonamide, 111
(E)-1-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-ethanone, 112
(E)-1-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-ethanol, 115
(E)-2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 116
(E)-C,C,C-trifluoro-N-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 117
(E)-N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-vinyl}-phenyl)-
methanesulfonamide, 118
(E)-N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-yl}-viny-
l)- phenyl]-methanesulfonamide, 119
(E)-N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-phenyl)-methanesulfonamide, 120
(E)-N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-
- yl}-vinyl)-phenyl]-methanesulfonamide, 121
(E)-2-{2-[2-(4-methanesulfonylamino-phenyl)-vinyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide, 122
(E)-C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-vinyl]--
1H- benzimidazol-5-yl}-phenyl)-methanesulfonamide, 123
(E)-N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-vinyl}-phenyl)-
C,C,C-trifluoro-methanesulfonamide, 124
(E)-C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-
benzimidazol-2-yl}-vinyl)-phenyl]-methanesulfonamide, 125
(E)-C,C,C-trifluoro-N-(4-{2-[5-(2-methanesulfonylamino-phenyl)-1H-
benzimidazol-2-yl]-vinyl}-phenyl)-methanesulfonamide, 126
(E)-C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1-
H- benzimidazol-2-yl}-vinyl)-phenyl]-methanesulfonamide, 127
(E)-2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 128
(E)-C,C,C-trifluoro-N-(4-{2-[5-(2-trifluoromethanesulfonylamino-phenyl-
)- 1H-benzimidazol-2-yl]-vinyl}-phenyl)-methanesulfonamide, 132
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethoxy-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 133
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 134
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-ethyl]--
1H- benzimidazol-5-yl}-phenyl)-methanesulfonamide, 135
1-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanone, 136
1-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-etha-
nol, 137
N-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 138
2-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-prop-
an- 2-ol, 140
N-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-C,C,-
C- trifluoro-methanesulfonamide, 141
1-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanone, 142
1-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanol, 143
N-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide, 144
2-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
phenyl)-propan-2-ol, 146
C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 147
1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl-
}-1H- benzimidazol-5-yl)-phenyl]-ethanone, 148
1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl-
}-1H- benzimidazol-5-yl)-phenyl]-ethanol, 149
N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl-
}-1H- benzimidazol-5-yl)-phenyl]-methanesulfonamide, 150
2-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl-
}-1H- benzimidazol-5-yl)-phenyl]-propan-2-ol, 151
2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl}-1-
H- benzimidazol-5-yl)-benzenesulfonamide, 152
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethox-
y)-
phenyl]-ethyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide,
153
1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol--
5-yl)- phenyl]-ethanone, 154
1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol--
5-yl)- phenyl]-ethanol, 155
N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol--
5-yl)- phenyl]-methanesulfonamide, 156
2-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol--
5-yl)- phenyl]-propan-2-ol, 157
2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol-5-y-
l)- benzenesulfonamide, 158
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}--
1H- benzimidazol-5-yl)-phenyl]-methanesulfonamide, 159
1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanone, 160
1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanol, 161
N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-
benzimidazol-5-yl)-phenyl]-methanesulfonamide, 162
2-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-
benzimidazol-5-yl)-phenyl]-propan-2-ol, 163
2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-benzimida-
zol- 5-yl)-benzenesulfonamide, 164
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-
ethyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 165
1-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanone, 166
1-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-etha-
nol, 167
N-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 168
2-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-prop-
an- 2-ol, 169
2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 170
N-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-C,C,-
C- trifluoro-methanesulfonamide, 171
1-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- ethanone, 172
1-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- ethanol, 173
N-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- methanesulfonamide, 174
2-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- propan-2-ol, 176
C,C,C-trifluoro-N-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 177
N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-ethyl}-phenyl)-
methanesulfonamide, 178
N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-yl}-ethyl)-
phenyl]-methanesulfonamide, 179
N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-ethyl]-1H-benzimidazol-5-yl-
}- phenyl)-methanesulfonamide, 180
N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-yl}-
- ethyl)-phenyl]-methanesulfonamide, 181
2-{2-[2-(4-methanesulfonylamino-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 182
C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide,
183
N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-ethyl}-phenyl)-C,C,-
C- trifluoro-methanesulfonamide, 184
C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazo-
l-2- yl}-ethyl)-phenyl]-methanesulfonamide, 185
C,C,C-trifluoro-N-(4-{2-[5-(2-methanesulfonylamino-phenyl)-1H-
benzimidazol-2-yl]-ethyl}-phenyl)-methanesulfonamide, 186
C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-
benzimidazol-2-yl}-ethyl)-phenyl]-methanesulfonamide, 187
2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-ethyl]-1H-benzimidazo-
l- 5-yl}-benzenesulfonamide, 188
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-et-
hyl]- 1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 189
2-{2-[2-(4-trifluoromethoxy-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
- benzenesulfonamide, 191
2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidaz-
ol- 5-yl}-benzenesulfonamide, 192
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethoxy-phenyl)-cyclopropyl]-1H-
- benzimidazol-5-yl}-phenyl)-methanesulfonamide, 193
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 194
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-cyclopr-
opyl]- 1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 195
1-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanone, 196
1-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanol, 197
N-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- methanesulfonamide, 199
2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 200
N-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- C,C,C-trifluoro-methanesulfonamide, 201
1-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanone, 202
1-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanol, 203
N-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-methanesulfonamide, 204
2-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-propan-2-ol, 205
2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 206
C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 207
1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-cyclo-
propyl}- 1H-benzimidazol-5-yl)-phenyl]-ethanone, 208
1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-cyclo-
propyl}- 1H-benzimidazol-5-yl)-phenyl]-ethanol, 209
N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-cyclo-
propyl}- 1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 210
2-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-cyclo-
propyl}- 1H-benzimidazol-5-yl)-phenyl]-propan-2-ol, 211
2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-cyclopro-
pyl}- 1H-benzimidazol-5-yl)-benzenesulfonamide, 212
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethox-
y)-
phenyl]-cyclopropyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide,
213
1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-benzimi-
dazol- 5-yl)-phenyl]-ethanone, 214
1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-benzimi-
dazol- 5-yl)-phenyl]-ethanol, 215
N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-methanesulfonamide, 216
2-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-benzimi-
dazol- 5-yl)-phenyl]-propan-2-ol, 217
2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-benzimidaz-
ol-5- yl)-benzenesulfonamide, 218
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopr-
opyl}- 1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 219
1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanone, 220
1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanol, 221
N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-methanesulfonamide, 222
2-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-propan-2-ol, 223
2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-benzenesulfonamide, 224
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-
cyclopropyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 225
1-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanone, 226
1-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanol, 227
N-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- methanesulfonamide, 228
2-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- propan-2-ol, 229
2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 230
N-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- C,C,C-trifluoro-methanesulfonamide, 231
1-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanone, 232
1-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanol, 233
N-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-methanesulfonamide, 235
2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 236
C,C,C-trifluoro-N-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 237
N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-cyclopropyl}-phenyl-
)- methanesulfonamide, 238
N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-yl}-cyclopro-
pyl)- phenyl]-methanesulfonamide, 239
N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 240
N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-yl}-
- cyclopropyl)-phenyl]-methanesulfonamide, 241
2-{2-[2-(4-methanesulfonylamino-phenyl)-cyclopropyl]-1H-benzimidazol-5-
- yl}-benzenesulfonamide, 242
C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-cyclopropyl-
]- 1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 243
N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-cyclopropyl}-phenyl-
)- C,C,C-trifluoro-methanesulfonamide, 244
C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazo-
l-2- yl}-cyclopropyl)-phenyl]-methanesulfonamide, 245
C,C,C-trifluoro-N-(4-{2-[5-(2-methanesulfonylamino-phenyl)-1H-
benzimidazol-2-yl]-cyclopropyl}-phenyl)-methanesulfonamide, 246
C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-
benzimidazol-2-yl}-cyclopropyl)-phenyl]-methanesulfonamide, 247
2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 248
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-
cyclopropyl]-1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 249
2-[2-(4-trifluoromethoxy-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 251
2-[2-(4-trifluoromethanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 252
C,C,C-trifluoro-N-{2-[2-(4-trifluoromethoxy-phenylethynyl)-1H-
benzimidazol-5-yl]-phenyl}-methanesulfonamide, 253
C,C,C-trifluoro-N-{2-[2-(4-trifluoromethyl-phenylethynyl)-1H-benzimida-
zol- 5-yl]-phenyl}-methanesulfonamide, 254
C,C,C-trifluoro-N-{2-[2-(4-trifluoromethanesulfonyl-phenylethynyl)-1H-
benzimidazol-5-yl]-phenyl}-methanesulfonamide, 255
1-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-ethanon-
e, 256
1-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-ethanol-
, 257
N-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 258
2-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-propan--
2- ol, 259
2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-benzenesulfonamide-
, 260
N-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-C,C,C-
trifluoro-methanesulfonamide, 261
1-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- ethanone, 262
1-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- ethanol, 263
N-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- methanesulfonamide, 264
2-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- propan-2-ol, 265
2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 266
C,C,C-trifluoro-N-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-
benzimidazol-5-yl]-phenyl}-methanesulfonamide, 267
1-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1-
H- benzimidazol-5-yl}-phenyl)-ethanone, 268
1-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1-
H- benzimidazol-5-yl}-phenyl)-ethanol, 269
N-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1-
H- benzimidazol-5-yl}-phenyl)-methanesulfonamide, 270
2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1-
H- benzimidazol-5-yl}-phenyl)-propan-2-ol, 271
2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 272
C,C,C-trifluoro-N-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-
phenylethynyl]-1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide,
273
1-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanone, 274
1-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanol, 275
N-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-y-
l}- phenyl)-methanesulfonamide, 276
2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-y-
l}- phenyl)-propan-2-ol, 277
2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 278
C,C,C-trifluoro-N-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 279
1-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-ethanone, 280
1-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-ethanol, 281
N-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 282
2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, 283
2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide, 284
C,C,C-trifluoro-N-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethyn-
yl]- 1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 285
1-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-ethanon-
e, 286
2-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-propan--
2- ol, 287
N-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 288
1-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-ethanol-
, 289
2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-benzenesulfonamide-
, 290
N-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-C,C,C-
trifluoro-methanesulfonamide, 291
1-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- ethanone, 292
1-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- ethanol, 293
N-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- methanesulfonamide, 296
C,C,C-trifluoro-N-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimida-
zol- 5-yl]-phenyl}-methanesulfonamide, 297
N-{4-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl-ethynyl]-phenyl}-
methanesulfonamide, 298
N-(4-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-yl-ethynyl}-
phenyl)-methanesulfonamide, 299
N-{2-[2-(4-methanesulfonylamino-phenylethynyl)-1H-benzimidazol-5-yl]-
phenyl}-methanesulfonamide, 300
N-(4-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-yl-
ethynyl}-phenyl)-methanesulfonamide, 301
2-[2-(4-methanesulfonylamino-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 302
C,C,C-trifluoro-N-{2-[2-(4-methanesulfonylamino-phenylethynyl)-1H-
benzimidazol-5-yl]-phenyl}-methanesulfonamide, 303
N-{4-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl-ethynyl]-phenyl}-C,C,C-
trifluoro-methanesulfonamide, 304
C,C,C-trifluoro-N-(4-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-
-yl- ethynyl}-phenyl)-methanesulfonamide, 305
C,C,C-trifluoro-N-{4-[5-(2-methanesulfonylamino-phenyl)-1H-
benzimidazol-2-yl-ethynyl]-phenyl}-methanesulfonamide, 306
C,C,C-trifluoro-N-(4-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-
benzimidazol-2-yl-ethynyl}-phenyl)-methanesulfonamide, 307
2-[2-(4-trifluoromethanesulfonylamino-phenylethynyl)-1H-benzimidazol-5-
- yl]-benzenesulfonamide, and 308
C,C,C-trifluoro-N-{2-[2-(4-trifluoromethanesulfonylamino-phenylethynyl-
)- 1H-benzimidazol-5-yl]-phenyl}-methanesulfonamide.
General Synthetic Methods
[0164] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described below and are illustrated in the schemes that follows.
Since the schemes are an illustration, the invention should not be
construed as being limited by the chemical reactions and conditions
expressed. The preparation of the various starting materials used
in the schemes is well within the skill of persons versed in the
art.
[0165] Compounds of the present invention can be synthesized using
the methods described in the schemes that follow.
[0166] The terms used in describing the invention are commonly used
and known to those skilled in the art. As used herein, the
following abbreviations and formulas have the indicated
meanings:
TABLE-US-00007 Abbreviation Meaning Boc tert-butoxycarbonyl BOP
benzotriazol-1-yloxy- tris(dimethylamino)phosphonium
hexafluorophosphate AcOH acetic acid Cpd compound DBU
1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIEA
N,N-diisopropyl ethyl amine DME ethylene glycol dimethyl ether DMF
N,N-dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate
EtOH ethanol HPLC high performance liquid chromatography LiOH
lithium hydroxide min minute(s) n-BuLi n-butyl lithium h/hr/hrs
hour(s) mCPBA m-chloroperbenzoic acid MeOH methanol MTBE
methyl-t-butyl ether PdCl.sub.2(dppf) or
[1,1'-bis-(diphenylphosphino)ferroceno]
Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 dichloropalladium (II)
dichloromethane complex Pd(PPh.sub.3).sub.4 palladium
tetrakistriphenylphosphine RT or rt room temperature TBAB
tetrabutylammonium bromide TBSOTf t-butyldimethylsilyl
trifluoromethane sulfonate Et.sub.3N triethylamine TFA
trifluoroacetic acid THF tetrahydrofuran TLC thin layer
chromatography
Reaction Scheme AA
[0167] Scheme AA illustrates a general synthesis of benzimidazoles
of formula AA5, representative of a compound of Formula (I).
##STR00172##
[0168] Typically, a solution of 4-bromobenzene-1,2-diamine AA1 and
a suitable carboxylic acid AA2 in phosphorous oxychloride
(POCl.sub.3) is heated at reflux to obtain bromobenzimidazole
AA3.
[0169] Alternatively, the acid can be converted to an acid chloride
using oxalyl chloride and a catalytic amount of DMF in a solvent
such as methylene chloride.
[0170] The acid chloride AA2 is heated with
4-bromobenzene-1,2-diamine AA1 in acetic acid to give AA3. A
suitably substituted phenyl group can be appended to AA3 by a
variety of coupling reactions (Suzuki, Stille) that are well known
to those versed in the art. A particularly useful substitution
method employs a palladium catalyzed cross-coupling Suzuki reaction
(Huff, B. et. al. Org. Syn. 1997, 75: 53-60; and, Goodson, F. E.
et. al. Org. Synth. 1997, 75: 61-68).
##STR00173##
[0171] As an example, a mixture of bromobenzimidazole AA3 is
reacted with a suitable phenyl boronic acid AA4 in the presence of
a reagent such as cesium carbonate and a catalytic amount of a
palladium catalyst such as PdCl.sub.2dppf in a solvent such as a
mixture of dioxane and ethanol at elevated temperatures to give
AA5. The reaction times can be reduced by carrying out this
procedure at similar (about 100.degree. C.) or lower temperatures
in a microwave synthesizer. Other palladium catalysts suitable for
this type of reaction include Pd(PPh.sub.3).sub.4.
Reaction Scheme BB
[0172] Cinnamic acids, as required, can be synthesized via
procedures described in reaction Scheme BB.
##STR00174##
[0173] A solution of arylaldehyde BB1 and
(carbethoxymethylene)triphenyl phosphorane in a solvent such as
toluene or benzene in the presence of a base such as NaOH is
stirred usually at elevated temperatures to give the corresponding
cinnamate ester. The ester is hydrolyzed under standard conditions
to provide the corresponding cinnamic acid BB2.
##STR00175##
[0174] Phenylpropionic acid BB3, as required, can be synthesized
from cinnamic acid BB2 by hydrogenation using a variety of standard
procedures. As shown above, a mixture of BB2 in ethanol with a
catalytic amount of palladium on carbon (10%) is stirred at room
temperature in an atmosphere of hydrogen (50 psi) to provide acid
BB3.
Reaction Scheme BB'
[0175] Reaction Scheme BB' is a variation of Reaction Scheme
BB.
##STR00176##
[0176] Reaction of aldehyde BB1 with malonic acid and a catalytic
amount of piperidine in pyridine at elevated temperatures produces
cinnamic acid BB2 in high yield.
##STR00177##
[0177] Acid BB2 is converted to the acid chloride by reaction with
oxalyl chloride and a catalytic amount of DMF in a solvent such as
methylene chloride. The acid chloride is then heated with AA1 in
acetic acid to give BB'1, which is further elaborated in place of
AA3 as described in reaction Scheme AA.
Reaction Scheme CC
[0178] Reaction Scheme CC provides a method to prepare substituted
4-bromobenzene-1,2-diamine intermediates.
##STR00178##
[0179] As an example, to a solution of a suitably substituted
4-bromoaniline CC1 in trifluoroacetic anhydride is added KNO.sub.3
portionwise at a suitable temperature. The reaction mixture may
then be warmed to room temperature for optimal conversion to
nitroamide CC2.
##STR00179##
[0180] Sequentially, using standard procedures, the amide is
hydrolyzed and the nitro group is reduced to give bromodiamine CC3.
Intermediate CC3 is further elaborated as described in reaction
Scheme AA.
Reaction Scheme DD
[0181] An alternative synthetic sequence to produce compounds of
the present invention is described in reaction Scheme DD.
##STR00180##
[0182] A substituted bromobenzimidazole DD1 (representative of AA3
in Scheme AA) is protected (using a protecting group such as Boc),
then converted to a pinicolboronate ester DD2 under standard Suzuki
coupling conditions (Prieto, M. et. al., J. Org. Chem. 2004, 69:
6812-6820; McDonald, D. et. al., Bioorg. Med. Chem. Lett. 2005, 15:
5241-5246; and, Poon, S. F. et. al. Bioorg. Med. Chem. Lett. 2004,
14, 5477-5480).
[0183] In a typical procedure, a mixture of bromo-benzimidazole
DD1, bis-(pinacolato)diboron, potassium carbonate and a catalytic
amount of a palladium catalyst such as PdCl.sub.2dppf in DMF is
heated at elevated temperatures to give boronate ester DD2.
Frequently, the reaction durations can be reduced by carrying out
this procedure at similar or lower temperatures in a microwave
irradiation apparatus.
##STR00181##
[0184] Boronate ester DD2 can be converted to compounds of the
present invention (Boc protected DD3) by Suzuki coupling with a
phenyl halide, mesylate or triflate (R.sub.1).sub.pPh-X. In this
instance, borane DD2 is reacted with a suitable aryl halide,
tetrakis (triphenylphosphine) palladium (0) and
tri-tert-butylphosphonium tetrafluoroborate in 2M aqueous potassium
carbonate in toluene at 100.degree. C. to give the protected form
of DD3. Deprotection with an acid such as TFA gives DD3.
Reaction Scheme EE
[0185] Reaction Scheme EE describes methods to prepare
representative compounds of the present invention.
##STR00182##
[0186] Aniline EE1 can be converted to a variety of amides,
carbamates or ureas EE2 by utilizing any number of acylation
methods that are commonly used by persons versed in the art. As an
example, reaction of EE1 in a solvent such as THF with a
substituted acid chloride and a base such as triethylamine gives
the corresponding amide of EE2. As a further example, reaction of
EE1 in THF with a substituted chloroformate and triethylamine gives
the corresponding substituted carbamate of EE2.
[0187] EE1 can be converted to sulfonamides by utilizing various
sulfonylation conditions. For instance, reaction of EE1 in a
solvent such as THF with an alkylsulfonyl chloride and
triethylamine gives the alkylsulfonamide EE3. EE1 can be
selectively, and successively substituted to give EE3. An efficient
method of achieving this is via reductive alkylation with aldehydes
or ketones (see Mattson, R. J. et. al. J. Org. Chem. 1990, 55,
2552-2554) and references cited therein]. In this procedure, equal
amounts of EE1 and an aldehyde or ketone are stirred with titanium
(IV) isopropoxide, followed the addition of sodium cyanoborohydride
in a solvent such as ethanol to give substituted amine EE3.
Reaction Scheme FF
[0188] A synthetic sequence to produce compounds of the present
invention wherein L is cyclopropyl is described in reaction Scheme
FF.
##STR00183##
[0189] Reaction of cinnamate ester FF1, in this case a methyl
ester, with trimethylsulfonium iodide methylide in a solvent such
as DMSO and sodium hydride (as exemplified by Burger, A. et. al. J.
Med. Chem. 1970, 13, 33-35), gives cyclopropyl ester FF2.
Hydrolysis of FF2 gives acid FF3, which is further elaborated into
the benzimidazoles described in Scheme AA.
Reaction Scheme GG
[0190] Reaction Scheme GG describes an alternative method to
prepare cyclopropyl acid intermediates.
##STR00184##
[0191] Cinnamic acids are converted to the corresponding Weinreb
amide, by conversion to the acid chloride as described in Reaction
Scheme AA and BB'. The acid chloride is reacted with
N,N-dimethylhydroxylamine hydrochloride and a base such as
triethylamine in methylene chloride to give amide GG2.
[0192] Amide GG2 is converted to cyclopropyl amide GG3 as described
in Scheme FF. The amide GG3 is then hydrolyzed to give acid GG4,
typically by reaction with potassium tertiary butoxide in THF.
Reaction Scheme HH
[0193] A synthetic sequence to produce compounds of the present
invention wherein R.sub.1Ar is benzenesulfonamide is described in
reaction Scheme HH.
##STR00185##
[0194] Coupling by Suzuki reaction of boronate ester DD2 from
reaction Scheme DD and bromobenzene-t-butylsulfonamide HH1 followed
by deprotection with TFA gives the product HH2.
Reaction Scheme II
[0195] A synthetic sequence to produce compounds of the present
invention wherein R is an ether group is described in reaction
Scheme II.
##STR00186##
[0196] An ester of commercially available 4-hydroxycinnamic acid
II1 can be converted to ether analogs by a number of routes
including the Williamson reaction. In this well-known procedure,
II1 and an alkyl halide is reacted with a base such as cesium
carbonate in a solvent such as acetonitrile to give the product
II2.
[0197] More effective electrophiles can be derivatives of alcohols
such as mesylates, p-toluene sulfonates or
trifluoromethanesulfonates (triflates). An effective alternative
method is the conversion of II1 to ether analogs II2 via the
Mitsunobu reaction (as reviewed by Mitsunobu, O., Synthesis, 1981,
1-28).
##STR00187##
[0198] Ether analogs II2 can be further reduced to acid II3 using
standard techniques.
Reaction Scheme JJ
[0199] Reaction Scheme JJ describes methods to prepare cinnamic
acids that contain substituted amino groups.
##STR00188##
[0200] Cinnamate ester JJ1 can be converted to a variety of amides,
carbamates or ureas JJ2 by utilizing any number of acylation
methods that are commonly used by persons versed in the art. As an
example, reaction of JJ1 in a solvent such as THF with a
substituted acid chloride and a base such as triethylamine gives
the corresponding amide of JJ2. As a further example, reaction of
JJ1 in THF with a substituted chloroformate and triethylamine gives
the corresponding substituted carbamate of JJ2. JJ1 can be
converted to sulfonamides by utilizing various sulfonylation
conditions.
[0201] For instance, reaction of JJ1 in a solvent such as THF with
an alkylsulfonyl chloride and triethylamine gives the
alkylsulfonamide JJ3. JJ1 can be selectively, and successively
substituted to give JJ4. An efficient method of substitution is via
reductive alkylation with aldehydes or ketones (see Mattson, R. J.
et. al. J. Org. Chem., 1990, 55, 2552-2554 and references cited
therein). In this procedure, equal amounts of JJ1 and an aldehyde
or ketone are stirred with titanium (IV) isopropoxide, followed the
addition of sodium cyanoborohydride in a solvent such as ethanol to
give substituted amine JJ4.
Reaction Scheme KK
[0202] A synthetic sequence to prepare compounds of the present
invention wherein L is acetylene is described in Reaction Scheme
KK.
##STR00189##
[0203] When not commercially available, propiolic acids KK2 are
prepared by reaction of acetylenes KK1 with n-butyl lithium in THF
at -78.degree. C. warming to 0.degree. C. for 30 min. The mixture
is cooled to -78.degree. C., and transferred to a saturated
solution of carbon dioxide in THF at -78.degree. C. The reaction is
slowly warmed to rt to give the corresponding propiolic acid
KK2.
##STR00190##
[0204] Reaction of the propiolic acid KK2 with
4-bromobenzene-1,2-diamine dihydrochloride KK3 in refluxing
ethylene glycol gives chlorovinylbenzimidazole KK4.
##STR00191##
[0205] Reaction of KK3 with a phenyl boronic acid under Suzuki
conditions in a microwave synthesizer and thermal conditions as
described in Reaction Scheme AA gives acetylene compounds KK4.
Reaction Scheme LL
[0206] An alternative synthetic sequence to produce compounds of
the present invention is described in reaction Scheme LL.
##STR00192##
[0207] Protected bromodiamine LL1 is coupled with a suitable
boronic acid via Suzuki coupling as described in previous reaction
schemes to give the diamine LL2.
##STR00193##
[0208] LL2 is then reacted with an acid or acid chloride to give
LL3 (as described in reaction Schemes AA or BB').
Reaction Scheme MM
[0209] A synthetic sequence to produce compounds of the present
invention wherein L is vinyl or ethyl that may be used as an
alternative to Scheme BB' is described in reaction Scheme MM.
##STR00194##
[0210] A solution of AA1 and dichloroimine MM1 (as described in
McElvain, S. M. et. al. J. Am. Chem. Soc. 1942, 64, 1825) in
ethanol is heated to give chloromethyl benzimidazole MM2 (as
described in Komoriya et. al. Bioorg. Med. Chem., 2004, 12,
2099-2114).
##STR00195##
[0211] Heating in dichloroethane with triphenylphosphine converts
MM2 to the phosphonium salt MM3.
##STR00196##
[0212] Reaction of MM3 with various aldehydes or ketones in a
solution of anhydrous THF and EtOH with a base such as DBU
(1,8-diazabicyclo[4.5.0]undec-7-ene) gives bromobenzimidazole BB'1,
which is further elaborated as described in reaction Scheme AA.
Reaction Scheme NN
[0213] An alternative synthetic sequence to produce compounds of
the present invention is described in reaction Scheme NN.
##STR00197##
[0214] The biaryldiamine LL2 is reacted with dichloroimine MM1 as
described in reaction Scheme MM to give NN1.
##STR00198##
[0215] As described in reaction Scheme MM, NN1 is carried forward
to give NN2.
Reaction Scheme OO
[0216] Compounds of the present invention wherein L is ethylene can
be prepared by the alternate route described in Reaction Scheme
OO.
##STR00199##
[0217] Compounds of the present invention such as NN3, wherein L is
vinyl, are dissolved in a solvent such as methanol, and are
hydrogenated using a catalyst such as 10% Pd on carbon to give
001.
Reaction Scheme PP
[0218] A synthetic sequence to produce compounds of the present
invention wherein L is cyclopropyl is described in reaction Scheme
PP.
##STR00200##
[0219] Reaction of olefin PP1 with an alkyl diazoacetate, such as
ethyl diazoacetate, in the presence of a catalyst, such as
copper(I) trifluoromethane sulfonate and Evans' chiral ligand
(Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am.
Chem. Soc. 1991, 113, 726-728) in a solvent such as chloroform,
gives a cyclopropyl ester enantiomer PP2.
[0220] The (R,R)-cyclopropyl ester PP2 enantiomer is obtained when
a chiral ligand such as
2,2-bis-[2-((4S)-(1,1-dimethylethyl)-1,3-oxazolinyl)]propane
Compound 38b is used. The (S,S)-cyclopropyl ester enantiomer is
obtained when the chiral ligand
2,2-bis-[2-((4R)-(1,1-dimethylethyl)-1,3-oxazolinyl)]propane
Compound 38a is used. The configurations of the cyclopropyl moiety
were predicted based on Evans' J. Am. Chem. Soc. 1991 report.
Hydrolysis of the ester PP2 gives acid PP3, which is further
elaborated into the benzimidazoles of Scheme AA.
##STR00201##
[0221] To determine the enantiomeric excess of the asymmetric
cyclopropanation products PP2, acid PP3 is reacted with
N,O-dimethylhydroxylamine in the presence of a base such as
diisopropylethylamine, and an amide coupling reagent such as BOP,
in a solvent such as DMF to produce the methoxy methyl amide
PP4.
[0222] The resulting .sup.1H NMR of amide PP4 in the presence of an
appropriate amount of chiral shifting agent, such as
(R)-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol, gives base line
resolution of the resulting methoxy singlets. The ratio of the
integration of the methoxy singlets gives the ee value. Thus, the
NMR showed methoxy singlets around 3.47 and 3.45 ppm. The
integration of the singlets was 1 and 99, respectively; thus
providing an ee value of 99%.
Reaction Scheme QQ
[0223] A synthetic sequence to produce compounds of the present
invention wherein R.sub.1 is an alcohol is described in reaction
Scheme QQ.
##STR00202##
[0224] As elaborated in Scheme BB', the aldehyde QQ1 is reacted
with malonic acid and a catalytic amount of piperidine in pyridine
at elevated temperatures to provide an acid QQ2. Acid QQ2 is
converted to an acid chloride QQ3 by reaction with oxalyl chloride
and a catalytic amount of DMF in a solvent such as methylene
chloride.
##STR00203##
[0225] As elaborated in Scheme AA, the acid chloride QQ3 is heated
with 4-bromobenzene-1,2-diamine AA1 in acetic acid to give a
bromobenzimidazole QQ4.
##STR00204##
[0226] As elaborated in Scheme AA, a suitably substituted phenyl
boronic acid is reacted with benzimidazole QQ4 in the presence of a
reagent and a catalytic amount of a palladium catalyst in a solvent
to give an alcohol substituted benzimidazole QQ5, representative of
a compound of Formula (I).
Example 1
(E)-1-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)--
ethanone (Cpd 1)
Step A.
(E)-5-bromo-2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazole
[0227] To a solution of 3-(4-tert-butyl-phenyl)-acrylic acid (12 g,
58.7 mmol) in POCl.sub.3 (200 mL), was slowly added
4-bromo-benzene-1,2-diamine (10 g, 53.4 mmol). The solution was
heated at reflux for 18 h. The solution was concentrated, and the
residual POCl.sub.3 was azeotropically removed with toluene. The
residue was partitioned between EtOAc and 10% Na.sub.2CO.sub.3. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and the filtrate was concentrated. The residue was
purified by chromatography (silica, EtOAc: hexanes, 3:7) to give
the title Compound Ia (7.1 g, 31% yield). .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 7.64 (d, 1H, J=13.9 Hz) 7.62 (s, 1H)
7.41 (d, 2H, J=8.4 Hz) 7.36 (d, 1H, J=8.5 Hz) 7.33 (d, 2H, J=8.4
Hz) 7.28 (s, 1H) 7.22 (dd, 1H, J=1.8 Hz, J=8.5 Hz) 7.02 (d, 1H,
J=16.5 Hz) 1.25 (s, 9H).
Step B.
(E)-1-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}--
phenyl)-ethanone
[0228] A solution of Compound 1a (0.106 g, 0.30 mmol),
2-acetylbenzeneboronic acid (136 mg; 0.76 mmol), PdCl.sub.2dppf
(0.06 mmol) and Cs.sub.2CO.sub.3 (0.244 g, 0.75 mmol) in
1,4-dioxane:EtOH 5:1 was heated to 115.degree. C. After 18 h, the
solution was cooled and concentrated. The residue was purified
using preparative TLC plates (silica gel, 20.times.20 cm, 2000
microns, EtOAc:hexanes 3:7) to give the title Compound 1 (0.0146
g). .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 7.54 (m, 11H)
7.23 (dd, 1H, J=1.6 Hz, J=8.3 Hz) 7.15 (d, 1H, J=16.5 Hz) 2.02 (s,
3H) 1.36 (s, 9H). MS (ESI, pos. ion) m/z: 395.3 (M+1).
[0229] Using the procedures described in Example 1 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00008 Cpd Name and Data 3
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenol
The title compound (0.0048 g) was prepared from
2-hydroxybenzeneboronic acid (0.0345 g, 0.25 mmol) and Compound 1a
(0.029 g, 0.1 mmol). .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
(ppm): 7.56 (s, 1H) 7.31 (dd, 2H, J = 12.2 Hz, J = 24.1 Hz) 7.10
(m, 8H) 6.86 (t, 1H, J = 7.3 Hz) 6.78 (d, 1H, J = 16.4 Hz) 1.19 (s,
9H). MS (ESI, pos. ion) m/z: 368.3 (M + 1). 4
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- acetamide The title compound (0.001 g) was prepared from
2-N-acetyl-benzeneboronic acid (0.136 g, 0.76 mmol) and Compound 1a
(0.106 g, 0.3 mmol). .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm) 7.44 (m, 4H) 7.24 (m, 6H) 6.91 (d, 1H, J = 12.4 Hz) 6.47 (d,
1H, J = 12.4 Hz) 1.86 (s, 1H) 1.20 (s, 9H). MS (ESI, pos. ion) m/z:
410.2 (M + 1). 5
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzamide
The title compound (0.001 g) was prepared from 2-aminocarbonyl
benzeneboronic acid (0.136 g, 0.76 mmol) and Compound 1a (0.106 g,
0.3 mmol). .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm) 7.48 (m,
6H) 7.37 (m, 5H) 7.26 (dd, 1H, J = 1.6 Hz, J = 8.3 Hz) 7.04 (d, 1H,
J = 16.5 Hz) 1.26 (s, 9H). MS (ESI, pos. ion) m/z: 396.1 (M + 1). 6
(E)-3-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzamide
The title compound (0.001 g) was prepared from
3-aminocarbonylbenzene boronic acid (0.136 g, 0.76 mmol) and
Compound 1a (0.106 g, 0.3 mmol). .sup.1H- NMR (400 MHz, CD.sub.3OD)
.delta. (ppm) 8.22 (t, 1H, J = 1.7 Hz) 7.88 (m, 3H) 7.62 (m, 6H)
7.51 (m, 2H) 7.17 (d, 1H, J = 16.5 Hz) 1.38 (s, 9H). MS (ESI, pos.
ion) m/z: 396.1 (M + 1). 7
(E)-4-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzamide
The title compound (0.002 g) was prepared from
4-aminocarbonylbenzene boronic acid (0.136 g, 0.76 mmol) and
Compound 1a (0.106 g, 0.3 mmol). .sup.1H- NMR (400 MHz, CD.sub.3OD)
.delta. (ppm) 7.97 (m, 2H) 7.77 (m, 4H) 7.60 (m, 4H) 7.47 (d, 2H, J
= 8.4 Hz) 7.13 (d, 1H, J = 16.5 Hz) 1.36 (s, 9H). MS (ESI, pos.
ion) m/z: 410.2 (M + 1). 8
(E)-N-(4-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- acetamide The title compound 0.0038 g) was prepared from
4-N-acetylbenzeneboronic acid (0.136 g, 0.76 mmol) and Compound 1a
(0.106 g, 0.3 mmol) to give the title compound (0.0038 g).
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm) 7.73 (m, 2H) 7.61
(m, 7H) 7.49 (m, 3H) 7.12 (d, 1H, J = 16.5 Hz) 2.17 (s, 3H) 1.36
(s, 9H). MS (ESI, pos. ion) m/z: 410.2 (M + 1). 9
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl-
)- methanesulfonamide The title compound (0.0045 g) was prepared
from 2-methanesulfonamide benzeneboronic acid (0.163 g, 0.76 mmol)
and Compound 1a (0.106 g, 0.3 mmol). .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm) 7.62 (m, 6H) 7.50 (d, 2H, J = 8.5 Hz)
7.41 (m, 2H) 7.34 (m, 2H) 7.17 (d, 1H, J = 16.5 Hz) 2.75 (s, 3H)
1.37 (s, 9H). MS (ESI, pos. ion) m/z: 446.2 (M + 1). 10
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
- carbamic acid tert-butyl ester The title compound (0.0016 g) was
prepared from 2-N-Boc-benzeneboronic acid (0.180 g, 0.76 mmol) and
(E)-5-bromo-2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-
aminobenzimidazole Compound 1b (0.106 g, 0.3 mmol). .sup.1H-NMR
(400 MHz, CD.sub.3OD) .delta. (ppm) 7.62 (m, 5H) 7.50 (m, 2H) 7.33
(dd, 1H, J = 1.6 Hz, J = 8.3 Hz) 7.14 (m, 3H) 6.83 (m, 2H) 3.37 (s,
9H) 1.37 (s, 9H). MS (ESI, pos. ion) m/z: 468.1 (M + 1). 11
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenylam-
ine A solution of
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-carbamic acid tert-butyl ester (0.005 g, 0.01 mmol) in
methylene chloride (1 mL) was treated with trifluoroacetic acid
(0.5 mL). The solution was stirred at room temperature for 4 h,
then concentrated to give the title compound (0.003 g). .sup.1H-NMR
(400 MHz, CD.sub.3OD) .delta. (ppm) 8.03 (d, 1H, J = 16.5 Hz) 7.90
(d, 1H, J = 8.5 Hz) 7.85 (s, 1H) 7.74 (d, 2H, J = 8.4 Hz) 7.65 (dd,
1H, J = 1.5 Hz, J = 8.5 Hz) 7.59 (d, 2H, J = 8.4 Hz) 7.43 (m, 5H)
1.39 (s, 9H). MS (ESI, pos. ion) m/z: 368.1 (M + 1). 12
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
- methanol The title compound (0.0046 g) was prepared from
2-hydroxymethylbenzene boronic acid (0.102 g, 0.76 mmol) and
Compound 1a (0.106 g, 0.3 mmol). .sup.1H- NMR (400 MHz, CD.sub.3OD)
.delta. (ppm) 7.59 (m, 5H) 7.49 (d, 2H, J = 8.4 Hz) 7.40 (m, 2H)
7.34 (m, 2H) 7.27 (dd, 1H, J = 1.6 Hz, J = 8.3 Hz) 7.16 (d, 1H, J =
16.6 Hz) 4.58 (s, 2H) 1.37 (s, 9H). MS (ESI, pos. ion) m/z: 383.2
(M + 1). 24
(E)-N-(2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- acetamide Using the procedure of Example 1, Step B, the title
compound (0.001 g) was prepared from 2-N-acetylbenzeneboronic acid
(0.136 g, 0.76 mmol) and (E)-5-
bromo-2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazole Compound
1c (0.10 g, 0.30 mmol). .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm) 7.61 (m, 5H) 7.39 (m, 6H) 7.18 (d, 1H, J = 16.5 Hz) 1.99 (s,
3H). MS (ESI, pos. ion) m/z: 390.2 (M + 1). 25
(E)-N-(3-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- acetamide The title compound (0.0102 g) was prepared from
3-N-acetylbenzeneboronic acid (0.136 g, 0.76 mmol) and Compound 1c
(0.10 g, 0.30 mmol). .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm) 7.78 (d, 1H, J = 0.9 Hz) 7.63 (s, 1H) 7.44 (m, 5H) 7.26 (m,
4H) 7.01 (d, 1H, J = 16.5 Hz) 2.06 (s, 3H). MS (ESI, pos. ion) m/z:
390.1 (M + 1). 26
(E)-2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzamid-
e The title compound (0.0031 g) was prepared from
2-aminocarbonylbenzene boronic acid (0.125 g, 0.76 mmol) and
Compound 1c (0.10 g, 0.30 mmol). .sup.1H- NMR (400 MHz, CDCl.sub.3
+ CD.sub.3OD) .delta. (ppm) 7.62 (s, 1H) 7.40 (m, 9H) 7.18 (td, 1H,
J = 8.4 Hz, J = 10.1 Hz) 7.01 (d, 1H, J = 16.5 Hz). MS (ESI, pos.
ion) m/z: 376.2 (M + 1). 27
(E)-1-(2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- ethanone The title compound (0.001 g) was prepared from
2-acetylbenzeneboronic acid (0.125 g, 0.76 mmol) and Compound 1c
(0.10 g, 0.30 mmol). .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm) 7.49 (m, 5H) 7.37 (m, 4H) 7.23 (td, 1H, J = 8.4 Hz, J = 10.3
Hz) 7.14 (dd, 1H, J = 1.7 Hz, J = 8.3 Hz) 7.06 (d, 1H, J = 16.5 Hz)
1.91 (s, 3H). MS (ESI, pos. ion) m/z: 375.2 (M + 1). 28
(E)-N-(2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- methanesulfonamide The title compound (0.0021 g) was prepared
from 2-methylsulfonylamino benzeneboronic acid (0.163 g, 0.76 mmol)
and Compound 1c (0.10 g, 0.30 mmol). .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm) 7.50 (m, 5H) 7.36 (m, 1H) 7.26 (m, 5H)
7.07 (d, 1H, J = 16.5 Hz) 2.64 (s, 3H). MS (ESI, pos. ion) m/z:
426.1 (M + 1). 30
(E)-2-[3-(4-tert-butyl-phenyl)-propyl]-5-m-tolyl-1H-benzimidazole
The title compound (0.0182 g) was prepared from
3-methylphenylbenzene boronic acid (0.052 g, 0.38 mmol) and
5-bromo-2-[3-(4-tert-butyl-phenyl)- propyl]-1H-benzimidazole
Compound 5a (0.055 g, 0.15 mmol). .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. (ppm) 7.33 (m, 3H) 7.18 (m, 5H) 7.03 (d, 1H, J = 7.4 Hz)
6.95 (d, 2H, J = 8.3 Hz) 2.85 (m, 2H) 2.57 (t, 2H, J = 7.5 Hz) 2.30
(s, 3H) 2.06 (m, 2H) 1.17 (s, 9H). MS (ESI, pos. ion) m/z: 383.2 (M
+ 1).
Example 2
(E)-1-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)--
ethanol (Cpd 2)
[0230] A solution of
(E)-1-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
-ethanone Cpd 1 (0.005 g, 0.01 mmol) in ethanol (0.5 mL) was
treated with NaBH.sub.4 (0.003 g, 0.08 mmol). After 3 h, the
reaction mixture was applied to a preparative TLC plate (2000
microns, silica gel, 20.times.20) and developed using EtOAc:
hexanes, 1:1. The desired band was extracted and concentrated to
give the title compound (0.002 g). .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm) 7.69 (m, 1H) 7.62 (m, 3H) 7.50 (m, 3H)
7.41 (ddd, 2H, J=2.5 Hz, J=10.1 Hz, J=14.1 Hz) 7.32 (dt, 1H, J=1.4
Hz, J=7.5 Hz) 7.23 (m, 2H) 7.17 (d, 1H, J=16.5 Hz) 4.99 (q, 1H,
J=6.3 Hz) 1.38 (s, 9H) 1.35 (d, 1.5H, J=6.1 Hz) 1.33 (d, 1.5H,
J=6.1 Hz). MS (ESI, pos. ion) m/z: 397.2 (M+1).
Example 3
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzam-
ide (Cpd 13)
Step A.
(E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
e
[0231] Using the procedure of Example 1, Step A, the title Compound
10c (0.910 g) was prepared from
3-(4-trifluoromethyl-phenyl)-acrylic acid Compound 10a (1.5 g, 6.9
mmol) and 4-bromo-benzene-1,2-diamine (1.3 g, 6.9 mmol).
.sup.1H-NMR (400 MHz, CDCl.sub.3+DMSO(d6)) .delta. (ppm) 7.78 (d,
1H, J=16.5 Hz) 7.73 (d, 1H, J=1.7 Hz) 7.66 (m, 4H) 7.48 (d, 2H,
J=8.0 Hz) 7.33 (dd, 1H, J=1.8 Hz, J=8.5 Hz) 7.23 (d, 1H, J=16.5
Hz).
Step B.
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl-
}-benzamide
[0232] Using the procedure of Example 1, Step B, the title compound
(0.001 g) was prepared from 2-carboxamidophenylbenzeneboronic acid
(0.120 g, 0.76 mmol) and Compound 10c (0.110 g, 0.30 mmol).
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm) 7.74 (d, 2H, J=8.2
Hz) 7.63 (m, 3H) 7.57 (s, 1H) 7.40 (m, 6H) 7.22 (d, 1H, J=16.5 Hz).
MS (ESI, pos. ion) m/z: 408.1 (M+1).
[0233] Using the procedures described in Example 3 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00009 Cpd Name and Data 14
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phe-
nol The title compound (0.001 g) was prepared from
2-hydroxybenzeneboronic acid (0.105 g, 0.38 mmol) and Compound 10c
(0.110 g, 0.30 mmol). .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm) 7.74 (d, 2H, J = 8.3 Hz) 7.63 (dd, 3H, J = 8.7 Hz, J = 17.1
Hz) 7.56 (s, 1H) 7.50 (d, 1H, J = 8.3 Hz) 7.38 (dd, 1H, J = 1.5 Hz,
J = 8.4 Hz) 7.22 (m, 2H) 7.06 (m, 1H) 6.82 (m, 2H). MS (ESI, pos.
ion) m/z: 381.3 (M + 1). 15
(E)-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanone The title compound (0.001 g) was prepared from
2-acetylbenzeneboronic acid (0.125 g, 0.76 mmol) and Compound 10c
(0.110 g, 0.30 mmol). .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm) 7.75 (d, 2H, J = 8.2 Hz) 7.60 (m, 4H) 7.48 (m, 2H) 7.38 (m,
3H) 7.23 (d, 1H, J = 16.6 Hz) 7.16 (dd, 1H, J = 1.7 Hz, J = 8.3 Hz)
1.92 (s, 3H). MS (ESI, pos. ion) m/z: 407.3 (M + 1). 16
(E)-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanol A solution of
(E)-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-
yl}-phenyl)-ethanone Compound 15 (0.005 g, 0.01 mmol) in ethanol
(0.5 mL) was treated with NaBH.sub.4 (0.003 g, 0.08 mmol). After 3
h, the solution was applied to a preparative TLC plate (2000
microns, silica gel, 20 .times. 20) and developed using EtOAc:
hexanes, 1:1. The desired band was extracted and concentrated to
give the title compound (0.001 g). .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm) 7.87 (d, 1H, J = 8.2 Hz) 7.76 (d, 1H, J =
8.0 Hz) 7.67 (m, 1H) 7.51 (s, 1H) 7.42 (m, 1H) 7.32 (m, 1H) 7.25
(m, 1H) 4.98 (q, 1H, J = 6.4 Hz) 1.35 (d, 1H, J = 6.4 Hz). MS (ESI,
pos. ion) m/z: 409.2 (M + 1). 17
(E)-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide The title compound (0094 g) was prepared
from 2-methylsulfonyl aminobenzeneboronic acid (0.163 g, 0.76 mmol)
and Compound 10c (0.110 g, 0.30 mmol). .sup.1H-NMR (400 MHz,
DMSO(d6)) .delta. (ppm) 12.82 (s, 1H) 8.89 (s, 1H) 7.91 (d, 2H, J =
8.1 Hz) 7.80 (m, 2H) 7.75 (s, 1H) 7.70 (m, 1H) 7.58 (d, 1H, J = 6.9
Hz) 7.37 (m, 6H) 2.73 (d, 3H, J = 28.8 Hz). MS (ESI, pos. ion) m/z:
458.2 (M + 1). 31
N-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phen-
yl)- methanesulfonamide Using the procedure of Example 1, Step A.,
5-bromo-2-[2-(4-trifluoroethyl- phenyl)-ethyl]-1H-benzimidazole
Compound 3b was prepared from 3-(4-
trifluoromethyl-phenyl)-propionic acid (1.04 g, 5.04 mmol) and
4-bromo- benzene-1,2-diamine (0.946 g, 5.06 mmol). Using the
procedure of Example 1, Step B., the title compound was prepared
from 2-methylsulfonylaminobenzeneboronic acid (0.367 g, 1.7 mmol)
and Compound 3b (0.188 g, 0.51 mmol). .sup.1H-NMR (400 MHz,
(CD.sub.3OD) .delta. (ppm) 7.64-7.50 (m, 5H), 7.47-7.34 (m, 4H),
7.34-7.27 (m, 2H), 3.27 (s, 4H), 2.71 (s, 3H). MS (ESI, pos. ion)
m/z: 460.16 (M + 1).
Example 4
(E)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benza-
mide (Cpd 19)
Step A. 3-(4-trifluoromethoxy-phenyl)-acrylic acid
[0234] A solution of 4-trifluoromethoxybenzaldehyde (26.3 mmol),
malonic acid (5.6 g, 53.8 mmol) and piperidine (0.265 mL, 2.7 mmol)
in pyridine (15 mL) was heated to 70.degree. C. for 18 h. Water
(200 mL) was added to the reaction solution. The mixture was
acidified to pH 4 using concentrated hydrochloric acid. The
solution was filtered. The solid was washed with water. The solid
was dried in vacuo to give the title Compound 4a (1.2 g).
.sup.1H-NMR (d6-DMSO) .delta. (ppm): 6.80 (d, J=16.02 Hz, 1H), 6.72
(m, 2H), 6.38 (m, 2H), 5.55 (d, J=16.00 Hz, 1H).
Step B. 3-(4-trifluoromethoxy-phenyl)-acryloyl chloride
[0235] A solution of Compound 4a (1.2 g, 5.2 mmol) in methylene
chloride (20 mL) was treated with oxalyl chloride (7.8 mL, 3.6
mmol). To the solution was added DMF (0.02 mL). The reaction
solution was stirred at room temperature for 2 h. The reaction
solution was concentrated. The residue was dried in vacuo to
provide Compound 4b, which was used without further purification in
the next step.
Step C.
(E)-5-bromo-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazo-
le
[0236] A solution of Compound 4b (1 g, 4 mmol) in acetic acid (10
mL) was added slowly to a solution of 4-bromo-benzene-1,2-diamine
(0.744 g, 4 mmol) in acetic acid (10 mL). The solution was heated
to 100.degree. C. for 18 h. The solution was cooled to room
temperature. To the solution was added ethyl acetate:hexanes 3:7
(100 mL). The solution was filtered. The solid was dried in vacuo
to give the title Compound 4c (1.1 g). .sup.1H-NMR (400 MHz, DMSO
d6) ppm 8.12 (d, J=16.60 Hz, 1H), 7.98 (m, 1H), 7.87 (m, 2H),
7.82-7.68 (m, 1H), 7.67-7.37 (m, 4H), 7.34 (d, J=16.58 Hz, 1H). MS
(ESI pos. ion) m/z: 383.2 and 385.2.
Step D.
(E)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-y-
l}-benzamide
[0237] Using the procedure of Example 1, Step B, the title Compound
19 was prepared from 2-carboxamido-phenylbenzene boronic acid and
Compound 4c.
[0238] Using the procedures described in Example 4 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00010 Cpd Name and Data 20
(E)-1-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-ethanone The title compound (0.001 g) was prepared from
2-acetylbenzeneboronic acid (0.280 g, 1.7 mmol) and Compound 4c
(0.195 g, 0.51 mmol). .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm) 7.66 (d, J = 8.72 Hz, 2H), 7.61-7.43 (m, 4H), 7.43-7.32 (m,
3H), 7.24 (d, J = 8.19 Hz, 2H), 7.19-7.06 (m, 2H), 1.96-1.86 (m,
3H). MS (ESI, pos. ion) m/z: 423.14 (M + 1). 21
(E)-1-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-ethanol Using the procedure of Example 2, the title
compound was prepared from Compound 20. .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm) 7.76-7.80 (d, J = 8.84 Hz, 2H) 7.60-7.70
(m, 3H) 7.50 (bs, 1H) 7.40-7.44 (ddd, J = 1.26, 7.32 Hz, 1H)
7.29-7.37 (m, 3H) 7.20-7.25 (m, 3H) 4.96-5.02 (q, J = 6.57 Hz, 1H)
1.34-1.36 (d, J = 6.32 Hz, 3H). MS (ESI, pos. ion) m/z: 425.2 (M +
1). 22
(E)-N-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanesulfonamide The title compound (0.05 g) was
prepared from 2-methylsulfonyl aminobenzeneboronic acid (0.521 g,
2.4 mmol) and Compound 4c (0.463 g, 1.2 mmol). .sup.1H-NMR (400
MHz, DMSO(d6)) .delta. (ppm) 12.76 (d, J = 5.43 Hz, 1H), 8.90 (d, J
= 4.68 Hz, 1H), 7.83 (d, J = 8.72 Hz, 2H), 7.65 (m, 1H), 7.50-7.22
(m, 8H), 2.76 (s, 1.5H), 2.69 (s, 1.5H). MS (ESI, pos. ion) m/z:
474.2 (M + 1).
Example 5
2-{2-[3-(4-tert-butyl-phenyl)-propyl]-1H-benzimidazol-5-yl}-phenol
(Cpd 29)
Step A.
5-bromo-2-[3-(4-tert-butyl-phenyl)-propyl]-1H-benzimidazole
[0239] Using the procedure of Example 1, Step A, the title Compound
5a (0.512 g) was prepared from 4-(4-tert-butyl-phenyl)-butyric acid
(2.0 g, 10.7 mmol) and 4-bromo-benzene-1,2-diamine (2.0 g, 10.7
mmol). .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm) 7.73 (d, 1H,
J=1.6 Hz) 7.45 (d, 1H, J=8.5 Hz) 7.38 (dd, 1H, J=1.8 Hz, J=8.5 Hz)
7.32 (m, 3H) 7.12 (d, 2H, J=8.3 Hz) 2.97 (m, 2H) 2.73 (t, 2H, J=7.4
Hz) 2.23 (m, 2H) 1.33 (s, 9H).
Step B.
2-{2-[3-(4-tert-butyl-phenyl)-propyl]-1H-benzimidazol-5-yl}-phenol
[0240] Using the procedure outlined in Example 1, Step B, the title
Compound 29 (0.0083 g) was prepared from 2-hydroxybenzeneboronic
acid (0.07 g, 0.5 mmol) and Compound 5a (0.074 g, 0.2 mmol).
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm) 7.51 (s, 1H) 7.39
(d, 1H, J=8.1 Hz) 7.16 (m, 6H) 6.95 (d, 3H, J=8.2 Hz) 6.88 (t, 1H,
J=7.4 Hz) 2.73 (t, 2H, J=7.5 Hz) 2.52 (t, 2H, J=7.3 Hz) 2.00 (m,
2H) 1.20 (s, 9H). MS (ESI, pos. ion) m/z: 385.3 (M+1).
Example 6
2-{2-[2-(4-tert-butyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenol
(Cpd 32)
Step A. 3-(4-tert-butyl-phenyl)-propionic acid
[0241] A mixture of 3-(4-tert-butyl-phenyl)-acrylic acid (12.28 g,
60.1 mmol) and 10% palladium on carbon (0.6 g) in ethanol was
hydrogenated at 50 psi hydrogen for 2 hours. The reaction mixture
was filtered over a pad of celite, a nylon disk, and the solvents
were removed in vacuo to yield the title Compound 6a (12.36 g, 59.9
mmol) as a white crystalline powder. .sup.1H-NMR (d6-DMSO) .delta.
(ppm): 12.10 (s, 1H), 7.29 (d, 2H), 7.12 (d, 2H), 2.88 (t, 2H),
2.50 (t, 2H), 1.25 (s, 9H). MS (ESI pos. ion) m/z: 228.9
(M+Na.sup.+)
Step B.
5-bromo-2-[2-(4-tert-butyl-phenyl)-ethyl]-1H-benzimidazole
[0242] To a solution of Compound 6a (1.04 g, 5.04 mmol), in 25 mL
of POCl.sub.3 was added 4-bromo-benzene-1,2-diamine (0.946 g, 5.06
mmol). The reaction mixture was refluxed under a nitrogen
atmosphere for 2.5 h then concentrated in vacuo. The residue was
treated with 25 mL benzene and evaporated in vacuo. The residue was
partitioned between 50 mL EtOAc and 50 mL saturated NaHCO.sub.3.
The organic fractions were washed with 50 mL of saturated
NaHCO.sub.3 and with 50 mL brine. The organic fraction was dried
with Na.sub.2SO.sub.4, filtered and the filtrate was concentrated
in vacuo. The residue was purified by chromatography (silica gel,
EtOAc:Heptane, 2:8-4:6)) to yield the title Compound 6b (0.726 g,
2.03 mmol) as a tan powder. .sup.1H-NMR (d6-DMSO) .delta. (ppm):
12.48-12.32 (m, 1H), 7.74-7.58 (m, 1H), 7.51-7.38 (m, 1H),
7.33-7.22 (m, 3H), 7.17 (d, 2H), 3.10 (m, 4H), 1.27 (s, 9H).
[0243] MS (ESI pos. ion) m/z: 357.1/359.1 (M+H.sup.+).
Step C.
2-{2-[2-(4-tert-butyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenol
[0244] A mixture of Compound 6b, (0.036 g, 0.10 mmol), 2-hydroxy
phenyl boronic acid (0.022 g, 0.16 mmol), Cs.sub.2CO.sub.3 (0.074
g, 0.23 mmol), and PdCl.sub.2(dppf) (0.008 g, 0.01 mmol) in 2 mL
5:1 dioxane/EtOH in a sealed tube was heated at 100.degree. C. for
15 minutes in a microwave synthesizer. More 2-hydroxy phenyl
boronic acid (0.024 g, 0.17 mmol) and more PdCl.sub.2(dppf) (0.010
g, 0.01 mmol) were added and the reaction was heated at 120.degree.
C. for 20 minutes. The reaction mixture was partitioned between 20
mL EtOAc, 20 mL water, and 2 mL brine. The organic fraction was
evaporated, and the residue was purified by chromatography.
(reverse-phase, acetonitrile:water+0.1% TFA, 25:75-95:5). The
relevant fractions were frozen and lyophilized to give the product
Compound 32 (0.013 g, 0.04 mmol) as a tan powder. .sup.1H-NMR
(d6-DMSO) .delta. (ppm): 14.55 (br s, 1H), 9.69 (s, 1H), 7.87 (s,
1H), 7.77 (d, 1H), 7.65 (d, 1H), 7.36-7.30 (m, 3H), 7.24-7.15 (m,
3H), 6.98 (d, 1H), 6.92 (t, 1H), 3.40 (t, 2H), 3.17 (t, 2H), 1.25
(s, 9H). MS (ESI pos. ion) m/z: 371.2 (M+H.sup.+).
[0245] Using the procedures described in Example 6 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00011 Cpd Name and Data 33
3-{2-[2-(4-tert-butyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenol
The title compound (0.016 g) was prepared from 3-hydroxy phenyl
boronic acid (0.037 g) and Compound 6b (0.036 g). .sup.1H-NMR
(d6-DMSO) .delta. (ppm): 14.62 (br s, 1H), 9.62 (s, 1H), 7.88 (s,
1H), 7.81 (d, 1H), 7.71 (dd, 1H), 7.36-7.27 (m, 3H), 7.18 (d, 2H),
7.13 (d, 1H), 7.08 (t, 1H), 6.82 (dd, 1H), 3.40 (t, 2H), 3.16 (t,
2H), 1.25 (s, 9H). MS (ESI pos. ion): 371.2 (M + H.sup.+). 34
4-{2-[2-(4-tert-butyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenol
The title compound (0.022 g) was prepared from 4-hydroxy phenyl
boronic acid (0.032 g) and Compound 6b (0.036 g). .sup.1H-NMR
(d6-DMSO) .delta. (ppm): 14.61 (br s, 1H), 9.65 (s, 1H), 7.85 (s,
1H), 7.78 (d, 1H), 7.71 (dd, 1H), 7.56 (d, 2H), 7.33 (d, 2H), 7.18
(d, 2H), 6.89 (d, 2H), 3.39 (t, 2H), 3.16 (t, 2H), 1.25 (s, 9H). MS
(ESI pos. ion) m/z: 371.2 (M + H.sup.+).
Example 7
(E)-(2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol-5-y-
l}-phenyl)-methanol (Cpd 35)
Step A. (E)-3-(4-trifluoromethylsulfanyl-phenyl)-acrylic acid ethyl
ester
[0246] To a solution of 4-trifluoromethylsulfanyl-benzaldehyde
(15.46 g, 75.0 mmol) in 350 mL of benzene was added
(carbethoxymethylene)triphenyl-phosphorane (26.14 g, 75.0 mmol).
The reaction mixture was refluxed under a nitrogen atmosphere for 6
hours. The solvents were removed in vacuo and the resulting
material was triturated with 350 mL of diethyl ether and filtered.
The filtrate was concentrated in vacuo and triturated once more
with 50 mL diethyl ether and filtered. The filtrate was evaporated
in vacuo and purified by chromatography (silica, EtOAc:heptane,
0:10-1:9) to obtain the title Compound 7a (15.8 g, 57.3 mmol) as a
white solid. .sup.1H-NMR (400 MHz, d6-DMSO) .delta. (ppm): 7.89 (d,
2H), 7.75 (d, 2H), 7.70 (d, 1H), 6.77 (d, 1H), 4.21 (q, 2H), 1.27
(t, 3H). MS (ESI pos. ion) m/z: 277.0 (M+H.sup.+).
Step B. (E)-3-(4-trifluoromethylsulfanyl-phenyl)-acrylic acid
[0247] To a solution of Compound 7a (10.31 g, 37.3 mmol), in 300 mL
of ethanol was added 3N aqueous NaOH solution (13.0 mL, 39.0 mmol).
The reaction mixture was stirred for 21 hours, then evaporated in
vacuo. The residue was dissolved in 250 mL water, and to it was
added 1N aqueous HCl (45 mL, 45 mmol). The resulting precipitate
was filtered, rinsed with water and dried under a stream of air to
yield the title Compound 7b (8.967 g, 36.1 mmol) as a white powder.
.sup.1H-NMR (400M Hz, d6-DMSO) .delta. (ppm): 12.58 (s, 1H), 7.85
(d, 2H), 7.74 (d, 2H), 7.63 (d, 1H), 6.66 (d, 1H).
Step C.
(E)-5-bromo-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benz-
imidazole
[0248] To a suspension of Compound 7b (1.240 g, 5.00 mmol) in 100
mL of CH.sub.3CN was added POCl.sub.3 (2.3 mL, 25.1 mmol) and
4-bromo-benzene-1,2-diamine (0.938 g, 5.01 mmol). The reaction
mixture was heated at reflux under a nitrogen atmosphere for 18
hours, cooled slightly then additional 4-bromo-benzene-1,2-diamine
(0.468 g, 2.50 mmol) was added. Refluxing was continued for 6
hours, then a final amount of 4-bromo-benzene-1,2-diamine (0.468 g,
2.50 mmol) was added. After heating for an additional 15 hours, the
reaction mixture was concentrated in vacuo. The residue was
purified by chromatography (silica, NH.sub.3 in MeOH
(2M):CH.sub.2Cl.sub.2, 1:99-5:95) then a second time
(EtOAc:heptane, 1:9-1:1)) to afford the title Compound 7c (1.255 g,
3.14 mmol) as a tan powder. .sup.1H-NMR (400 MHz, d6-DMSO) .delta.
(ppm): 12.96-12.83 (br d, 1H), 7.87-7.68 (m, 6H), 7.60-7.45 (m,
1H), 7.39-7.29 (m, 2H). MS (ESI pos. ion) m/z: 398.9/400.9
(M+H.sup.+).
Step D.
(E)-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimida-
zol-5-yl}-phenyl)-methanol
[0249] To a solution of Compound 7c (0.040 g, 0.10 mmol) and
2-hydroxymethyl phenyl boronic acid (0.029 g, 0.19 mmol) in 3 mL
dioxane in a small pressure tube was added aqueous Na.sub.2CO.sub.3
solution (0.13 mL, 2M, 0.26 mmol) followed by PdCl.sub.2(dppf)
(0.008 g, 0.01 mmol). The vessel was flushed with argon, capped and
heated in an oil bath at 120.degree. C. for 1 hour. The reaction
mixture was partitioned between 20 mL EtOAc, 20 mL water, and 2 mL
brine. The organic fractions were dried with Na.sub.2SO.sub.4,
filtered and the filtrate was evaporated. The residue was purified
by chromatography (reverse-phase, acetonitrile:water+0.1% TFA,
1:3-95:5). The relevant fractions were mixed with
poly(vinylpyridine), filtered, frozen and lyophilized to give the
title Compound 35 (0.027 g, 0.063 mmol) as a yellow powder.
.sup.1H-NMR (400 MHz, d6-DMSO) .delta. (ppm): 7.89-7.78 (m, 5H),
7.71-7.57 (m, 3H), 7.44-7.28 (m, 5H), 4.44 (s, 2H). MS (ESI pos.
ion) m/z: 426.7 (M+H.sup.+).
[0250] Using the procedures described in Example 7 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00012 Cpd Name and Data 36
(E)-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}- phenol The title compound (0.029 g) was prepared from
2-hydroxy phenyl boronic acid (0.028 g) and Compound 7c (0.040 g).
.sup.1H-NMR (400 MHz, d6-DMSO) .delta. (ppm): 9.61 (s, 1H),
7.90-7.79 (m, 6H), 7.70 (d, 1H), 7.54 (d, 1H), 7.42 (d, 1H), 7.33
(dd, 1H), 7.19 (dt, 1H), 6.98 (d, 1H), 6.91 (dt, 1H). MS (ESI pos.
ion) m/z: 412.8 (M + H.sup.+). 37
(E)-N-(2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-phenyl)-acetamide The title compound (0.016 g) was
prepared from N-[2-(4,4,5,5-tetramethyl-
[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide (0.052 g) and Compound
7c (0.040 g). .sup.1H-NMR (400 MHz, d6-DMSO) .delta. (ppm): 9.24
(s, 1H), 7.86 (d, 2H), 7.82-7.75 (m, 3H), 7.67 (d, 1H), 7.57 (s,
1H), 7.51 (d, 1H), 7.44-7.24 (m, 5H), 1.89 (s, 3H). MS (ESI pos.
ion) m/z: 453.8 (M + H.sup.+). 38
(E)-2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}- benzamide The title compound (0.031 g) was prepared from
2-benzamido boronic acid (0.034 g) and Compound 7c (0.040 g).
.sup.1H-NMR (400 MHz, d6-DMSO) .delta. (ppm): 7.91-7.79 (m, 5H),
7.73-7.66 (m, 3H), 7.54-7.38 (m, 6H), 7.31 (s, 1H). MS (ESI pos.
ion) m/z: 439.8 (M + H.sup.+). 39
(E)-1-(2-{2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-phenyl)-ethanone The title compound (0.027 g) was prepared
from 2-acetyl phenyl boronic acid (0.034 g) and Compound 7c (0.040
g). .sup.1H-NMR (400 MHz, d6-DMSO) .delta. (ppm): 7.87 (d, 2H),
7.84-7.77 (m, 3H), 7.69 (d, 1H), 7.55-7.47 (m, 2H), 7.64-7.58 (m,
3H), 7.40 (d, 1H), 7.21 (dd, 1H), 2.09 (s, 3H). MS (ESI pos. ion)
m/z: 438.7 (M + H.sup.+).
Example 8
(E)-1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}-phenyl)-ethanone (Cpd 40)
Step A. (E)-3-(4-trifluoromethanesulfonyl-phenyl)-acrylic acid
[0251] To a suspension of Compound 7b (2.483 g, 10.01 mmol), in 50
mL of TFA was added 30% H.sub.2O.sub.2 solution (8 mL, 83 mmol).
The reaction mixture was stirred for 21 h, then poured into 250 mL
of ice water. The resulting precipitate was filtered off, rinsed
with water and dried under vacuum at 50.degree. C. to yield the
title Compound 8a (2.281 g, 8.14 mmol) as a white powder.
.sup.1H-NMR (400 MHz, d6-DMSO) .delta. (ppm): 12.80 (s, 1H), 8.15
(s, 4H), 7.73 (d, 1H), 6.83 (d, 1H). MS (ESI pos. ion) m/z: 278.9
(M-H.sup.+).
Step B.
(E)-5-bromo-2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-ben-
zimidazole
[0252] To a suspension of Compound 8a (1.405 g, 5.01 mmol) in 100
mL of acetonitrile was added POCl.sub.3 (2.3 mL, 25.1 mmol). The
reaction mixture was refluxed under a nitrogen atmosphere for 30
minutes, then cooled slightly. To this reaction mixture was added
4-bromo-benzene-1,2-diamine (0.946 g, 5.06 mmol) and the reaction
was refluxed for 2 h before additional 4-bromo-benzene-1,2-diamine
(0.942 g, 5.04 mmol) was added. After an hour of heating, the
reaction mixture was cooled and filtered over a pad of celite. The
filter cake was rinsed with acetonitrile, ethyl acetate, and
methanol. The filtrate was stirred with aqueous NaHCO.sub.3/EtOAc.
The organic fraction was evaporated, and partitioned between 100 mL
EtOAc and 100 mL saturated NaHCO.sub.3. The organic fraction was
dried with Na.sub.2SO.sub.4, filtered, and the filtrate was
evaporated. The residue was purified by chromatography (silica gel,
EtOAc:heptane, 1:4-1:1)) to yield the title Compound 8b (1.595 g,
3.70 mmol) as a tan powder. .sup.1H-NMR (400 MHz, d6-DMSO) .delta.
(ppm): 13.00 (d, 1H), 8.14 (q, 4H), 7.87-7.73 (m, 2H), 7.63-7.50
(m, 2H), 7.40-7.33 (m, 1H). MS (ESI pos. ion) m/z: 430.8/432.8
(M+H.sup.+).
Step C.
(E)-1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzi-
midazol-5-yl}-phenyl)-ethanone
[0253] A solution of Compound 8b (0.043 g, 0.10 mmol), and 2-acetyl
phenyl boronic acid (0.035 g, 0.21 mmol) in 3 mL dioxane was
stirred in a small pressure tube. Aqueous Na.sub.2CO.sub.3 solution
(0.13 mL, 2M, 0.26 mmol) was added followed by PdCl.sub.2(dppf)
(0.007 g, 0.01 mmol). The vessel was flushed with argon, capped and
heated in an oil bath at 120.degree. C. for 1 h. The reaction
mixture was partitioned between 20 mL EtOAc, 20 mL water, and 2 mL
brine. The organic fraction was dried with Na.sub.2SO.sub.4,
filtered, and the filtrate was evaporated. The residue was flushed
over a plug of silica gel with 100% EtOAc then evaporated. The
crude material was purified by chromatography (reverse-phase,
acetonitrile/water+0.1% TFA, 1:3-95:5). The appropriate fractions
were mixed with poly(vinylpyridine), filtered, frozen and
lyophilized to give the title Compound 40 (0.022 g, 0.047 mmol) as
a yellow powder. .sup.1H-NMR (400 MHz, d6-DMSO) .delta. (ppm): 8.16
(q, 4H), 7.87 (d, 1H), 7.70 (d, 1H), 7.64-7.56 (m, 3H), 7.55-7.47
(m, 3H), 7.21 (d, 1H), 2.09 (s, 3H). MS (ESI pos. ion): 471.0
(M+H.sup.+).
[0254] Using the procedures described in Example 8 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00013 Cpd Name and Data 41
(E)-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-phenol The title compound (0.024 g) was prepared from
2-hydroxy phenyl boronic acid (0.029 g) and Compound 8b (0.043 g).
.sup.1H-NMR (400 MHz, d6-DMSO) .delta. (ppm): 9.53 (s, 1H), 8.16
(q, 4H), 7.85 (d, 1H), 7.77 (s, 1H), 7.65 (d, 1H), 7.58 (d, 1H),
7.47 (d, 1H), 7.33 (d, 1H), 7.17 (dt, 1H), 6.97 (d, 1H), 6.90 (dt,
1H). MS (ESI pos. ion) m/z: 445.0 (M + H.sup.+). 42
(E)-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-phenyl)-methanol The title compound (0.030 g) was prepared
from 2-hydroxymethyl phenyl boronic acid (0.027 g) and Compound 8b
(0.043 g). .sup.1H-NMR (400 MHz, d6- DMSO) .delta. (ppm): 8.16 (q,
4H), 7.89 (d, 1H), 7.69 (d, 1H), 7.62 (d, 2H), 7.58 (d, 1H),
7.43-7.33 (m, 2H), 7.30 (dd, 2H), 4.44 (s, 2H). MS (ESI pos. ion)
m/z: 459.0 (M + H.sup.+). 43
(E)-N-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-acetamide The title compound (0.011 g) was
prepared from N-[2-(4,4,5,5-tetramethyl-
[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide (0.053 g) and Compound
8b (0.043 g). .sup.1H-NMR (400 MHz, d6-DMSO) .delta. (ppm): 9.23
(s, 1H), 8.15 (q, 4H), 7.85 (d, 1H), 7.67 (d, 1H), 7.62-7.55 (m,
2H), 7.51 (d, 1H), 7.42-7.23 (m, 4H), 1.89 (s, 3H). MS (ESI pos.
ion) m/z: 486.1 (M + H.sup.+). 44
(E)-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-benzamide The title compound (0.018 g) was prepared from
2-benzamido boronic acid (0.034 g) and Compound 8b (0.043 g).
.sup.1H-NMR (400 MHz, d6-DMSO) .delta. (ppm): 8.16 (q, 4H), 7.88
(d, 1H), 7.70-7.64 (m, 3H), 7.59 (d, 1H), 7.54-7.39 (m, 4H), 7.36
(dd, 1H), 7.30 (s, 1H). MS (ESI pos. ion) m/z: 472.0 (M +
H.sup.+).
Example 9
(E)-1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}-phenyl)-ethanol (Cpd 45)
1-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl-
}-phenyl)-ethanol (Cpd 46)
[0255] To a solution of Compound 40 (0.047 g, 0.10 mmol) in 5 mL
EtOH was added NaBH.sub.4 (0.028 g, 0.74 mmol). After 1 h, an
additional amount of NaBH.sub.4 (0.024 g, 0.63 mmol) was added.
After an additional 4.5 h, the reaction was diluted into 25 mL
EtOAc and washed twice with 25 mL water/brine. The organic
fractions were dried with Na.sub.2SO.sub.4, filtered and the
filtrate was evaporated. The residue was purified by chromatography
(reverse-phase (acetonitrile/water with 0.1% TFA, 1:3-95:5). The
two products were isolated, frozen and lyophilized to give the
products Compound 45 (0.024 g, 0.051 mmol) as a yellow powder and
Compound 46 (0.020 g, 0.042 mmol) as a white powder.
[0256] Compound 45: .sup.1H-NMR (400 MHz, d6-DMSO) .delta. (ppm):
8.18 (dd, 4H), 7.93 (d, 1H), 7.74 (d, 1H), 7.67 (d, 1H), 7.64-7.57
(m, 2H), 7.43 (dt, 1H), 7.35-7.27 (m, 2H), 7.21 (dd, 1H), 4.80 (q,
1H), 1.22 (d, 3H). MS (ESI pos. ion) m/z: 472.8 (M+H.sup.+).
[0257] Compound 46: .sup.1H-NMR (400 MHz, d6-DMSO) .delta. (ppm):
8.12 (d, 2H), 7.82-7.74 (m, 3H), 7.70-7.63 (m, 2H), 7.47-7.37 (m,
2H), 7.32 (dt, 1H), 7.18 (dd, 1H), 4.72 (q, 1H), 3.47 (t, 2H), 3.40
(t, 2H), 1.19 (d, 3H). MS (ESI pos. ion) m/z: 474.8
(M+H.sup.+).
Example 10
(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phe-
nyl)-propan-2-ol(Cpd 18)
##STR00205##
[0258] Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid
[0259] A solution of 4-trifluoromethylbenzaldehyde (7.7 mL, 57.7
mmol), malonic acid (12.0 g, 115.4 mmol), 0.567 .mu.L piperidine
(5.75 mmol) in 30 mL of pyridine was stirred at 70.degree. C. for
18 h. The reaction solution was cooled to room temperature. Water
(300 mL) was added and the resulting mixture was acidified to pH 4
(litmus) using concentrated hydrochloric acid to give a
precipitate. The solid was filtered, and washed with water until
the filtrate was neutral. The solid product was dried in vacuo to
give the title Compound 10a as a white powder (11.2 g, 90%).
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 12.60 (bs, 1H),
7.92 (d, 2H, J=8.2 Hz), 7.77 (d, 2H, J=8.2 Hz), 7.66 (d, 1H, J=16.0
Hz), 6.70 (d, 1H, J=16.0 Hz).
##STR00206##
Step B.
(E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
le
[0260] A solution of Compound 10a (20.6 g, 95.4 mmol) in anhydrous
methylene chloride (200 mL) was treated with oxalyl chloride (16.6
mL, 190 mmol) and "3 drops" of anhydrous dimethylformamide. The
resulting solution was stirred at room temperature under an argon
atmosphere for 18 h. The solvent was concentrated to give
3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b as a
solid, which was used without further purification in the next
step.
[0261] To a solution of 4-bromo-benzene-1,2-diamine (16.1 g, 86.7
mmol) in acetic acid (100 mL) was added dropwise a solution of
Compound 10b (assumed 95.4 mmol) in acetic acid (100 mL). The
reaction mixture was stirred at 100.degree. C. for 18 h. The
reaction mixture was cooled to room temperature, and a mixture of
ethyl acetate and hexanes 3:7 (500 mL) was added. The mixture was
triturated at room temperature for 3 h to give a precipitate. The
solid was filtered, and dried in vacuo to give the title Compound
10c (23.2 g, 73%). .sup.1H NMR (400 MHz, DMSO-d.sub.6/CDCl.sub.3)
.delta. (ppm): 8.45 (d, 1H, J=16.7 Hz), 7.84-7.90 (m, 1H), 7.74 (d,
2H, J=8.3 Hz), 7.56-7.62 (m, 3H), 7.50-7.52 (m, 1H), 7.34 (d, 1H,
16.7 Hz).
##STR00207##
Step C. 2-(2-bromo-phenyl)-propan-2-ol
[0262] To a solution of methyl 2-bromobenzoate (20.76 g, 96 mmol)
in 120 mL of anhydrous ether under Argon at 0.degree. C. was slowly
added methylmagnesium bromide (77 mL, 3.26 M) at a rate that the
internal temperature of the mixture was below 20.degree. C. A white
suspension resulted, and the mixture was stirred at room
temperature for 2 h. The mixture was cooled in an ice-water bath.
To the reaction mixture was very slowly added hydrochloric acid
(400 mL, 0.5 M). The pH of the final mixture was adjusted to less
than about 6 with few drops of 2M hydrochloric acid. The layers
were separated, and the aqueous layer was extracted twice with
ether. The organic layers were combined and dried over magnesium
sulfate. The organic fraction was filtered, and the filtrate was
concentrated to yield the title compound as a pale yellow liquid,
which was distilled under vacuum to afford the title Compound 10d
as a colorless liquid (16.9 g, 82%, b.p. about 65-70.degree. C./0.3
mmHg). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 7.67 (dd,
1H, J=1.7, 7.9 Hz), 7.58 (dd, 1H, J=1.3, 7.9 Hz), 7.30 (ddd, 1H,
J=1.4, 7.4, 7.9 Hz), 7.10 (ddd, 1H, J=1.7, 7.4, 7.8 Hz), 2.77 (br
s, 1H), 1.76 (s, 6H).
##STR00208##
Step D. 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol
[0263] To a solution of n-BuLi (166 mL, 2.6 M, 432 mmol) in 200 mL
of THF at -78.degree. C. under argon was slowly added a solution of
Compound 10d (42.2 g, 196 mmol) in 60 mL of THF at a rate that the
internal temperature remained below -70.degree. C. The mixture was
stirred at -75.degree. C. for 2 h. To the reaction mixture was then
added triisopropylborate (59 mL, 255 mmol) in three portions. The
mixture was allowed to warm slowly to room temperature overnight.
The mixture was then cooled to 0.degree. C., and was carefully
quenched with dilute hydrochloric acid (250 mL, 2N). The mixture
was then stirred at room temperature for 1 h. The pH of the mixture
was checked and adjusted to acidic using additional 2N HCl if
prophetic. The two layers were separated, and the aqueous layer was
extracted twice with ether. The organic layers were combined, and
dried with magnesium sulfate and filtered. The filtrate was
concentrated under reduced pressure to yield a pale yellow oil. The
residue was then diluted with ethyl acetate (400 mL) and, washed
with 1N sodium hydroxide solution (150 mL.times.3). The basic
aqueous layers were combined and acidified with 2N HCl. The clear
solution turned cloudy when the acid was added. The mixture was
extracted with ether (150 mL.times.3). The organic layers were
combined and dried with magnesium sulfate. The solution was
filtered, and the filtrate was concentrated under reduced pressure
to yield the title Compound 10e as a colorless oil (26.2 g, 82%)
which was used without further purification in the next step.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 9.00 (s, 1H),
7.66 (dm, 1H, J=7.3 Hz), 7.45 (dt, 1H, J=1.1, 7.7 Hz), 7.40 (dm,
1H, J=7.6 Hz), 7.31 (dt, 1H, J=1.2, 7.1 Hz), 1.44 (s, 6H).
##STR00209##
Step E.
(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}-phenyl)-propan-2-ol
[0264] To a mixture of Compound 10e (11.7 g, 71 mmol), Compound 10c
(19.9 g, 54 mmol), sodium carbonate (46 g, 435 mmol) and
PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (8.9 g, 11 mmol) in a 1 L round
bottom flask equipped with water condenser was added 400 mL of
anhydrous DME and 200 mL of water. The mixture was evacuated and
filled with Argon three times. The mixture was heated to
100.degree. C. for 20 h. The mixture was then cooled to room
temperature. The biphasic system was transferred to a 1 L
separatory funnel and the two layers were separated. The organic
layer was washed with brine (2.times.300 mL). The aqueous layers
were combined and extracted with ethyl acetate once (about 300 mL).
The organic layers were combined, dried with sodium sulfate, and
filtered. The volume of the filtrate was reduced to about 170 mL
under reduced pressure. The mixture was then filtered through a pad
of silica gel and the pad was washed with ethyl acetate until the
filtrate did not contain any product. After concentration, a light
pink/beige solid was obtained. The solid was triturated with 50 mL
ethyl acetate, and the mixture was heated to 85.degree. C. for 5
min. The mixture was slowly cooled to r.t., then cooled at
0.degree. C. for 0.5 h. The mixture was filtered, and the solid was
washed with cold ethyl acetate twice, and dried under vacuum at
40.degree. C. to yield the title Compound 18 as a light beige solid
(7.58 g, 33%). RP-HPLC 95% pure. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 12.73 (m, 1H,), 7.90 (d, 2H, J=8.2
Hz), 7.85 (dd, 1H, J=8.0, 0.6 Hz), 7.78 (d, 2H, J=8.4 Hz), 7.74 (d,
1H, J=16.8 Hz), 7.59-7.47 (m, 1H), 7.41 (s, 1H), 7.37-7.32 (m, 2H),
7.21 (dt, 1H, J=1.2, 7.4 Hz), 7.06 (s, 1H), 7.02 (d, 1H, J=7.4 Hz),
4.85 (s, 1H), 1.21 (s, 6H). Mass Spectrum (LCMS, APCI pos.) Calcd.
For C.sub.25H.sub.21F.sub.3N.sub.2O: 423.2 (M+H), Found 423.3. m.p.
(uncorr.) 250-251.degree. C.
[0265] Using the procedures described in Example 10 and
corresponding reagents, starting materials and conditions known to
those skilled in the art, the following compounds representative of
the present invention were prepared:
TABLE-US-00014 Cpd Name and Data 23
(E)-2-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol .sup.1H-NMR (400 MHz, DMSO d6) .delta. (ppm)
7.84 (dd, J = 1.26, 8.084 Hz, 1H) 7.75-7.85 (m, 2H) 7.66 (d, J =
16.4 Hz) 7.53-7.58 (m, 1H) 7.45 (bs, 1H) 7.34-7.38 (m, 3H)
7.17-7.26 (m, 3H) 7.09 (dd, J = 1.58, 7.58 Hz, 1H) 1.36 (s, 6H). MS
(ESI, pos. ion) m/z: 439.2 (M + 1). 47
(E)-2-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-propan-2-ol .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.07 (d, 2H, J = 8.6 Hz), 7.98 (d, 2H, J = 8.6 Hz),
7.78 (dd, 1H, J = 1.1, 8.1 Hz), 7.69 (d, 1H, J = 16.5 Hz), 7.54 (d,
1H, J = 8.2 Hz), 7.44 (d, 1H, J = 16.5 Hz), 7.42 (br s, 1H), 7.31
(ddd, 1H, J = 1.5, 7.8, 8.1 Hz), 7.18 (dt, 1H, J = 1.3, 7.4 Hz),
7.16 (dd, 1H, J = 1.5, 8.3 Hz), 7.03 (dd, 1H, J = 1.4, 7.5 Hz),
1.31 (s, 6H). Mass Spectrum (LCMS, APCI pos.) Calcd. For
C.sub.25H.sub.21F.sub.3N.sub.2O.sub.3S: 487.1 (M + H), Found 487.1.
78
(E)-2-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
propan-2-ol .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 7.79
(dd, 1H, J = 8.1, 1.1 Hz), 7.63-7.54 (m, 3H), 7.51 (br d, 1H, J =
9.7, 7.4 Hz), 7.40-7.38 (m, 3H), 7.31 (m, 1H), 7.19 (dt, 1H, J =
1.4, 7.4 Hz), 7.15 (d, 1H, J = 16.5 Hz), 7.13 (dd, 1H, J = 7.9, 1.8
Hz), 7.04 (dd, 1H, J = 7.5, 1.4 Hz), 1.30 (s, 6H). Mass Spectrum
(LCMS, APCI pos.) Calcd. For C.sub.24H.sub.21ClN.sub.2O: 389.1 (M +
H), Found 389.3. 84
(E)-2-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-propan-2-ol .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.00 (d, J = 8 Hz, 2H), 7.91 (d, J = 8 Hz, 2H), 7.82 (dd, J
= 1.6, 8 Hz, 1H), 7.70 (d, J = 16.4 Hz, 2H), 7.41 (s, 1H), 7.36
(dt, J = 1.6, 8 Hz, 1H), 7.34 (s, 1H), 7.23 (dt, J = 1.6, 8 Hz,
1H), 7.19 (dd, J = 1.6, 8 Hz, 1H), 7.07 (dd, J = 1.6, 8 Hz, 1H),
3.16 (s, 3H), 1.26 (s, 6H). Mass Spectrum (LCMS, ESI pos.) Calcd.
For C.sub.25H.sub.24N.sub.2O.sub.3S: 433.1 (M + H), Found 433.4.
114
(E)-2-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 7.89-7.87 (m, 2H), 7.79 (dd, 1H, J = 8.1, 1.1 Hz), 7.67-7.56
(m, 3H), 7.52 (m, 1H), 7.40 (br s, 1H), 7.31 (m, 1H), 7.27 (d, 1H,
J = 16.6 Hz), 7.18 (dt, 1H, J = 1.3, 7.4 Hz), 7.14 (dd, 1H, J =
8.3, 1.4 Hz, 1H), 7.04 (dd, 1H, J = 7.52, 1.38 Hz), 1.31 (s, 6H).
Mass Spectrum (LCMS, APCI pos.) Calcd. For
C.sub.25H.sub.21F.sub.3N.sub.2O: 423.2 (M + H), Found 423.3. 458
(E)-2,2,2-trifluoro-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-acetamide. The title compound (0.0195 g)
was prepared from Compound 465 (0.10 g, 0.26 mmol) and
trifluoroacetylimidazolide (0.047 g, 0.29 mmol). .sup.1H-NMR (400
MHz, DMSO d6) .delta. (ppm): 12.7-12.9 (bs, 1H) 11.0 (s, 1H)
7.90-7.94 (d, J = 8.59 Hz, 2H)) 7.78-7.81 (d, J = 8.59 Hz, 2H)
7.37-7.76 (m, 7H) 7.20 (d, J = 9.34 Hz, 1H) MS (ESI, pos. ion) m/z:
476.2 (M + 1). 459 (E)-2,2,2-trifluoro-ethanesulfonic acid
(2-{2-[2-(4-trifluoromethyl-phenyl)-
vinyl]-1H-benzimidazol-5-yl}-phenyl)-amide The title compound
(0.0015 g) was prepared from Compound 465 (0.034 g, 0.09 mmol) and
trifluoromethylsulfonylchloride (0.018 g, 0.10 mmol). .sup.1H-NMR
(400 MHz, DMSO d6) .delta. (ppm) 12.75-12.82 (bs, 1H) 9.70-9.80
(bs, 1H) 7.90-7.96 (d, J = 8.08 Hz, 2H) 7.78-7.84 (m, 3H) 7.54-7.77
(m, 2H) 7.40-7.50 (m, 2H) 7.24-7.40 (m, 6H) 4.0 (bs, 2H)MS (ESI,
pos. ion) m/z: 526.1 (M + 1). 460
(E)-2,2-dimethyl-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-propionamide The title compound (0.0014
g) was prepared from Compound 465 (0.034 g, 0.09 mmol) and
trimethylacetylchloride (0.012 mL, 0.036 mmol). .sup.1H-NMR (400
MHz, CD.sub.3OD) .delta. (ppm) 7.80-7.84 (m, 3H) 7.58-7.78 (m, 6H)
7.38-7.42 (m, 2H) 7.24-7.35 (m, 3H) 1.20 (s, 9H) MS (ESI, pos. ion)
m/z: 464.3 (M + 1). 461 (E)-ethanesulfonic acid
(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-amide The title compound (0.0018 g) was
prepared from Compound 465 (0.10 g, 0.26 mmol) and ethylsulfonyl
chloride (0.027 mL, 0.29 mmol). .sup.1H-NMR (400 MHz, DMSO d6)
.delta. (ppm) 12.88 (d, J = 9.1 Hz, 1H) 8.92 (d, J = 7.3 Hz, 1H)
7.78 (d, J = 8.08 Hz, 2H)) 7.85 (d, J = 8.08 Hz, 2H) 7.72-7.82 (m,
3H) 7.63-7.68 (m, 1H) 7.30-7.53 (m, 6H) 2.78-2.92 (qq, J = 7.33 Hz,
2H) 1.00 (tt, J = 7.33 Hz, 3H). MS (ESI, pos. ion) m/z: 472.1 (M +
1). 462
(E)-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-carbamic acid methyl ester The title compound (0.0056 g)
was prepared from Compound 465 (0.10 g, 0.26 mmol) and
chloromethylformate (0.022 mL, 0.29 mmol). .sup.1H-NMR (400 MHz,
DMSO d6) .delta. (ppm) 7.82-7.84 (d, J = 8.59 Hz, 2H) 7.76-7.78 (d,
J = 8.59 Hz, 2H) 7.62-7.70 (m, 3H) 7.59 (bs, 1H) 7.36-7.41 (m, 3H)
7.24-7.34 (m, 3H). MS (ESI, pos. ion) m/z: 438.4 (M + 1). 463
(E)-2-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phen-
yl)- propan-2-ol .sup.1H-NMR (400 MHz, DMSO d6) .delta. (ppm)
7.82-7.84 (m, 1H) 7.35-7.64 (m, 8H) 7.10-7.30 (m, 4H) 1.38 (s,
15H). MS (ESI, pos. ion) m/z: 411.3 (M + 1). 465
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenylamine The title compound was prepared from Compound 479 by
stirring in TFA with heating. .sup.1H-NMR (400 MHz, DMSO d6)
.delta. (ppm) 12.78 (s, 0.5H) 12.75 (s, 0.5H) 7.91 (d, J = 8.08 Hz,
2H) 7.78-7.81 (m, 3H) 7.74 (d, J = 4.55 Hz, 1H) 7.68 (d, J = 8.08
Hz, 1H) 7.56-7.62 (m, 1H) 7.52 (bs, 1H) 7.41 (d, J = 16.4 Hz, 1H)
7.20-7.29 (m, 1H) 7.05 (t, J = 7.6 Hz, 2H) 6.78 (d, J = 8.34 Hz,
1H) 6.65 (t, J = 6.8 Hz, 1H) 4.81 (s, 1H) 4.74 (s, 1H)MS (ESI, pos.
ion) m/z: 526.1 (M + 1). 466
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-be-
nzoic acid ethyl ester .sup.1H-NMR (400 MHz, DMSO d6) .delta. (ppm)
7.82-7.84 (d, J = 8.59 Hz, 2H) 7.76-7.78 (d, J = 8.59 Hz, 2H)
7.62-7.70 (m, 3H) 7.59 (bs, 1H) 7.36-7.41 (m, 3H) 7.24-7.34 (m,
3H). MS (ESI, pos. ion) m/z: 438.4 (M + 1). 468
(E)-2-[2-(2-styryl-1H-benzimidazol-5-yl)-phenyl]-propan-2-ol
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm) 8.18 (bs, 2H) 7.70
(m, 3H) 7.44 (m, 3H) 7.30 (m, 3H) 7.22 (m, 2H) 7.19 (m, 1H) 1.28
(s, 9H). MS (ESI, pos. ion) m/z: 412.2 (M + 1). 470
(E)-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)sulfamide The title compound (0.0023 g) was prepared from
Compound 465 (0.0175 g, 0.046 mmol) and sulfamide (0.5 g, 5.2
mmol). .sup.1H-NMR (400 MHz, DMSO d6) .delta. (ppm) 7.86 (d, J =
8.61 Hz, 2H) 7.62-7.78 (m, 6H) 7.31-7.41 (m, 4H) 7.21-7.25 (m, 1H).
MS (ESI, pos. ion) m/z: 459.2 (M + 1). 476
(E)-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanol .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm)
7.83 (d, J = 8.59 Hz, 2H) 7.77 (d, J = 8.34 Hz, 2H)7.56-7.74 (m,
5H)7.24-7.42 (m, 5H) 4.56 (s, 2H)MS (ESI, pos. ion) m/z: 395.1 (M +
1). 478
(E)-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-acetamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm)
7.80-7.84 (m, 3H) 7.56-7.78 (m, 5H) 7.30-7.44 (m, 5H) 1.97 (s, 3H).
MS (ESI, pos. ion) m/z: 422.3 (M + 1). 479
(E)-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-carbamic acid tert-butyl ester .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm) 7.76-8.00 (d, J = 8.1 Hz, 2H) 7.82-7.90
(d, J = 8.8 Hz, 2H) 7.68-7.79 (m, 4H) 7.36-7.48 (5H) 1.44 (s, 9H).
MS (ESI, pos. ion) m/z: 480.2 (M + 1). 480
(E)-5-(2-methylsulfanyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-
-1H- benzimidazole .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm)
7.84-7.87 (d, J = 8.1 Hz, 2H) 7.56-7.78 (m, 5H) 7.20-7.40 (m, 6H).
MS (ESI, pos. ion) m/z: 411.2 (M + 1). 481
(E)-2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-5-(2-trifluorometh-
yl- phenyl)-1H-benzimidazole .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.10 (d, 2H, J = 8.5 Hz, 1H), 8.02 (d, 2H, J = 8.5
Hz), 7.77 (d, 1H, J = 7.8 Hz, 1H), 7.73 (d, 1H, J = 16.5 Hz), 7.64
(d, 1H, J = 7.4 Hz), 7.60 (d, 1H, J = 8.4 Hz), 7.54 (d, 1H, J = 7.7
Hz), 7.50 (s, 1H), 7.46 (d, 1H, J = 16.5 Hz), 7.42 (d, 1H, J = 7.6
Hz), 7.22 (dd, 1H, J = 8.4, 1.0 Hz). Mass Spectrum (LCMS, APCI
pos.) Calcd. For C.sub.23H.sub.14F.sub.6N.sub.2O.sub.2S: 497.1 (M +
H), Found 497.1. 482
(E)-2-(2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-propan-2-ol .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.00-7.94 (m, 2H), 7.79 (dd, 1H, J = 8.1, 1.1 Hz), 7.73 (d,
1H, J = 7.9 Hz), 7.66 (t, 1H, J = 7.7 Hz), 7.53 (br s, 1H), 7.50
(t, 1H, J = 7.67, 7.67 Hz), 7.41 (br s, 1H), 7.31 (m, 1H),
7.21-7.13 (m, 3H), 7.04 (dd, 1H, J = 7.5, 1.4 Hz), 1.31 (s, 6H).
Mass Spectrum (LCMS, APCI pos.) Calcd. For
C.sub.25H.sub.21F.sub.3N.sub.2O: 423.2 (M + H), Found 423.3. 483
(E)-dimethyl-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazo-
l-5- yl}-benzyl)-amine To a solution of Compound 484 (20.7 mg,
0.053 mmol) in DMF (10 mL) was added dimethylamine 2.0 M in THF (66
.mu.L, 0.132 mmol). The mixture was stirred for 45 min and sodium
triacetoxyborohydride (17 mg, 0.080 mmol) was added. The mixture
was stirred at rt for 2.5 d and then concentrated under reduced
pressure. The residue was purified using preparative TLC plates
(silica gel, 20 .times. 20 cm, 2000 microns, EtOAc:hexanes:methanol
5:5:1) to give the title compound (18.2 mg, 81%). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. (ppm): 7.81 (d, 2H, J = 8.2 Hz), 7.70 (d,
2H, J = 8.0 Hz), 7.67 (d, 1H, J = 16.3 Hz), 7.60 (d, 1H, J = 8.2
Hz), 7.55-7.47 (m, 2H), 7.40-7.26 (m, 4H), 7.19 (dd, 1H, J = 8.3,
1.5 Hz), 3.58 (s, 2H), 2.14 (s, 6H). Mass Spectrum (LCMS, APCI
pos.) Calcd. For C.sub.25H.sub.22F.sub.3N.sub.3: 422.2 (M + H),
Found 422.1. 484
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzaldehyde .sup.1H NMR (400 MHz, DMSO-d6) .delta. (ppm): 12.93
(d, 1H, J = 12.5 Hz), 9.93 (s, 1H), 7.93 (d, 3H, J = 8.4 Hz),
7.82-7.56 (m, 8H), 7.44 (d, 1H, J = 16.5 Hz), 7.28 (dd, 1H, J =
10.1, 9.3 Hz). Mass Spectrum (LCMS, APCI pos.) Calcd. For
C.sub.23H.sub.15F.sub.3N.sub.2O: 393.1 (M + H), Found 393.3. 485
(E)-methyl-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-benzyl)-amine The title compound was prepared according to
the procedure used for Compound 483, with the exception that
methylamine was used. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 7.82 (d, 2H, J = 8.3 Hz, 1H), 7.71 (d, 2H, J = 8.3 Hz), 7.69
(d, 1H, J = 16.6 Hz), 7.63 (d, 1H, J = 8.1 Hz), 7.52-7.47 (m,
2H),
7.39 (tdd, 2H, J = 9.1, 7.2, 3.6, 3.6 Hz), 7.35-7.29 (m, 2H), 7.23
(dd, 1H, J = 8.3, 1.6 Hz), 3.86 (s, 2H), 2.30 (s, 3H). Mass
Spectrum (LCMS, APCI pos.) Calcd. For
C.sub.24H.sub.20F.sub.3N.sub.3: 408.2 (M + H), Found 408.1. 487
(E)-5-(2-trifluoromethyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-vinyl-
]-1H- benzimidazole .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 7.80 (d, 2H, J = 8.2 Hz), 7.76 (d, 1H, J = 7.9 Hz),
7.70-7.60 (m, 4H), 7.57 (d, 1H, J = 8.3 Hz), 7.52 (t, 1H, J = 7.7
Hz), 7.47 (s, 1H), 7.40 (d, 1H, J = 7.6 Hz), 7.29 (d, 1H, J = 16.6
Hz), 7.19 (dd, 1H, J = 8.3, 1.0 Hz). Mass Spectrum (LCMS, APCI
pos.) Calcd. For C.sub.23H.sub.14F.sub.6N.sub.2: 433.1 (M + H),
Found 433.3. 488
(E)-5-(2-trifluoromethoxy-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-viny-
l]-1H- benzimidazole .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 7.78 (d, 2H, J = 8.3 Hz), 7.68-7.66 (m, 3H), 7.63-7.58 (m,
2H), 7.50 (m, 1H), 7.43-7.35 (m, 3H), 7.33 (dd, 1H, J = 8.4, 1.6
Hz), 7.27 (d, 1H, J = 16.6 Hz). Mass Spectrum (LCMS, APCI pos.)
Calcd. For C.sub.23H.sub.14F.sub.6N.sub.2O: 449.1 (M + H), Found
449.3.
Example 10.1
Scale Up Preparation of
(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-ph-
enyl)-propan-2-ol (Cpd 18)
Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid
[0266] A 2-L 4-neck round bottom flask equipped with an air
condenser/argon inlet, mechanical stirrer, thermocouple and a
stopper was charged with 4-(trifluoromethyl)benzaldehyde (250 g,
196.2 mL, 1.44 mol), malonic acid (302.6 g, 2.87 mol), and pyridine
(750 mL). An exotherm developed (about 38-40.degree. C.), which was
maintained for 30 min. Piperidine (14.202 mL, 143.58 mmol) was then
added to the reaction and a second exotherm developed (T.sub.max
about 42.degree. C. after about 10 min.). The reaction was stirred
for 30 min and then heated to 60.degree. C. for 18 h (overnight).
The reaction appeared to be complete by TLC, and was cooled to
about 40.degree. C., diluted into water (2 L; done to prevent
reaction freezing), cooled to room temperature, and further diluted
with water (4 L, 6 L total). The slurry was acidified to pH=2.0-3.0
with concentrated hydrochloric acid (about 675-700 mL). The
material was stirred for 30 min., and a white solid was collected
by filtration. The filter cake was washed with water until the
filtrate was neutral (pH about 5.5-6, 2.5 L), air-dried in a
Buchner funnel for 2 h, and then further dried in a vacuum oven at
60.degree. C. overnight to provide 300.5 g (96%) of the title
Compound 10a as a white solid.
Step B.
(E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
e
[0267] To a 5-L 4-neck round bottom flask equipped with a magnetic
stirrer, argon inlet-argon outlet to a carbonate scrub, two
stoppers, and a room temperature water bath was charged with
4-(trifluoromethyl)cinnamic acid (315 g, 1.46 mol) and
dichloromethane (3.15 L) to give a slurry. To the slurry was added
oxalyl chloride (151.71 mL, 1.75 mol) and DMF (1.13 mL, 14.57
mmol). Upon addition of DMF, gas evolution commenced, and the
reaction was continued for about 3 h during which time a solution
developed. When the reaction was complete (LC-MS), it was
concentrated to dryness to give 342.4 g of
3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b
(>100%) as a yellow oily solid.
[0268] A 5-L 4-neck round bottom flask equipped with mechanical
stirrer, thermocouple, air condenser with argon inlet, and a
stopper was charged with 4-bromo-benzene-1,2-diamine (244 g, 1.27
mol) and acetic acid (2.13 L). To this solution was added a
solution of Compound 10b (327 g, 1.39 mol) in toluene (237 mL).
After this addition, the temperature spiked to 45.degree. C. in
about 30 seconds and then subsided. The reaction was then heated to
90.degree. C. for 16 h (overnight). The reaction was cooled to
40.degree. C., and poured into a mixed solution of EtOAc and
heptane (about 1:3, 5.75 L) and a precipitate occurred. The
resulting slurry was stirred for 3 h, and the solid was collected
by filtration, washed with EtOAc: heptane (1:3, 3 L), and then
dried in a vacuum oven (60.degree. C.) to give 324.3 g (65%) of the
title Compound 10c as a partial acetate salt.
Step C. 2-(2-bromo-phenyl)-propan-2-ol
[0269] A 12-Liter 4-neck flask equipped with a thermocouple,
condenser, septum, addition funnel and overhead mechanical stirrer
under argon was charged with methyl-2-bromobenzoate (226.5 g, 1.05
mol) and THF (1.6 L, 19.66 mol). The mixture was cooled to a
temperature between 2 and 5.degree. C. with stirring and held for
30 min. To the solution was slowly added methyl magnesium bromide
in diethyl ether (3M, 1.05 L; 3.15 mol) via the addition funnel at
a rate to maintain the reaction temperature below 15.degree. C. An
exotherm was observed during the addition, the reaction temperature
warmed from 3 to 15.degree. C. The addition of 1.05 L Grignard was
complete in 4 h (approximate feed rate was 4.17 mL/min). The
reaction mixture appeared to be off-white/yellow slurry. The
reaction was allowed to warm to room temperature and stirred
overnight (15 h). The reaction was sampled by HPLC/TLC and showed
no starting material present. The ice bath was again applied to the
reaction flask and a 0.5 M HCl solution (4.5 L; 2.25 mol) was
slowly added over a period of 2 h. The temperature increased
dramatically from 0 to 15.degree. C. After the quench was complete,
the reaction was stirred at room temperature for 30 min. Additional
2 N HCl (500 mL; 1.00 mol) was slowly added to maintain a pH less
than 6. MTBE (1 L) was added to help with the phase split. The
reaction was stirred at room temperature for 1 to 2 h to dissolve
the solid material into the aqueous phase (most likely Mg(OH).sub.2
which is very basic). The pH must be checked and adjusted with
additional acid when necessary. The phases were separated and the
aqueous layer was washed with an additional 1 L MTBE (2.times.500
mL). The organic phases were combined, washed with NaHCO.sub.3
solution (2.times.300 mL), dried over MgSO.sub.4, filtered and the
filtrate was concentrated under vacuum to yield the title Compound
10d (220.83 g, 97.48% yield) as a clear yellow oil.
Step D. 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol
[0270] A 12-Liter 4-neck round bottom flask equipped with a
thermocouple, condenser, addition funnel and overhead mechanical
stirrer under dry Argon was charged with anhydrous THF, (3 L) and
chilled to -70 to -78.degree. C. via a dry ice/acetone bath.
n-Butyl lithium (2.5N in hexanes, 860 mL, 2.15 mol) was slowly
added via addition funnel. An exotherm was observed as the
temperature rose from -78 to -70.degree. C. To the addition funnel
was added a solution of Compound 10d (220 g, 979.97 mmol) in
anhydrous THF (1 L). The 2-(2-bromophenyl)propan-2-ol solution was
slowly added to the n-BuLi solution. The addition took 90 min in
order to maintain a reaction temperature below -70.degree. C. After
the addition was complete, the reaction mixture was stirred at -70
to -75.degree. C. for 30 min. The triethylborate (230 mL, 1.35 mol)
was quickly added in 3 portions at -70.degree. C. An exotherm was
observed, the batch temperature rose from -70 to -64.degree. C. The
reaction was stirred at -70.degree. C. and slowly warmed to room
temperature over night. After the reaction was cooled to
0-5.degree. C., the reaction was slowly quenched with 2 M HCl (1 L,
2.00 mol) added via the addition funnel while maintaining the batch
temperature 0-5.degree. C. The reaction mixture was stirred for 1
h. The aqueous phase pH was 9-10. The pH was then adjusted to
acidic (4-5) with 2 M HCl (200 mL). The two phases were separated
and the aqueous layer was extracted with MTBE (2.times.500 mL). The
combined organic phases were dried with anhydrous magnesium
sulfate. The solution was filtered and concentrated to yield a
yellow oil. The yellow oil was diluted with MTBE (1.5 L) and washed
with 1M NaOH (3.times.500 mL). The product containing basic aqueous
phases were combined and acidified with 2 M HCl (800 mL) (the clear
solution turns turbid with the addition of acid). After stirring
the turbid solution for 15 min (pH=4-5) (Note 1), it was extracted
with MTBE (2.times.500 mL). The organic phases were combined and
dried over MgSO.sub.4. The solution was filtered and the filtrate
was concentrated to yield the title Compound 10e as a clear yellow
oil (121.78 grams, 77% yield).
Step E.
(E)-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}-phenyl)-propan-2-ol
[0271] A 5-L 4-neck flask equipped with a thermocouple controller,
condenser, overhead mechanical stirrer, Firestone valve.RTM. and a
nitrogen inlet/outlet was charged with dimethoxyethane (2 L), DI
water (1 L) and sodium carbonate (230.9 g, 2.18 mol). The solution
was degassed and purged with N.sub.2 three times. Compound 10e
(71.7 g, 0.35 mol) and Compound 10c (100.0 g, 0.27 mol) were added
to the degassed solution. The solution was degassed and purged with
N.sub.2 three times. PdCl.sub.2(dppf) (44.48 g, 54.4 mmol) was
added to the solution, and the solution was degassed and purged
with N.sub.2 three times. The resulting two-phase suspension was
heated to reflux for 18 h, and then cooled to room temperature. The
reaction mixture was transferred to a 12-L separatory funnel, and
the layers were separated. The organic layer was washed with brine
(1 L). The two aqueous layers were combined and extracted with
EtOAc (1 L). The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered, and the filtrate was concentrated to
an oil. Two separate 100 g coupling reactions were combined and
purified by chromatography in 10 successive chromatography runs on
an ISCO preparative chromatography system (10.times.1.5 Kg
SiO.sub.2, 5 column volumes of EtOAc, 250 mL/min flow rate). The
combined fractions were transferred to two 22 L 4-neck round bottom
flasks, and Silicycle Si-thiol functionalized silica gel (2 g) was
added to each solution. The solutions were warmed to 40.degree. C.
and aged for 1 h. The solutions were filtered thru a medium glass
funnel and washed with EtOAc (4 L) and combined. The filtrate was
evaporated to a semi solid, which was transferred to a 2 L round
bottom flask, to which EtOAc (0.4 L) was added. The resulting white
precipitate slurry was cooled to -5.degree. C. and stirred for 1 h.
The slurry was filtered and washed twice with cold EtOAc (100 mL).
The solids were dried in a vacuum oven at 40.degree. C. for 40 h to
afford 84.0 g (36.5% yield, 98.8 area % purity) of the title
Compound 18 as a white solid. Anal. Calcd for
C.sub.25H.sub.21N.sub.2OF.sub.3 0.04% H.sub.2O 0.15 mol MeOH: C,
70.48; H, 5.14: N, 6.42; F, 13.06 Found: C, 70.54; H, 4.83: N,
6.18; F, 13.33
Example 10.2
(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phe-
nyl)-propan-2-ol monosodium salt (Cpd 18)
[0272] A 5-L 4-neck flask equipped with a thermocouple controller,
an overhead mechanical stirrer, and a nitrogen inlet/outlet was
charged with
(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-ph-
enyl)-propan-2-ol. Compound 18 (125.0 g, 0.510 mol) and MeOH (1.25
L). A solution of sodium methoxide in methanol (0.5 M, 592 mL, 0.3
mol) was added. The reaction was heated to 65.degree. C. for 30 min
and all solids dissolved. The solution was cooled and evaporated to
dryness. The foam was collected by scraping it out of the flask.
The solids were placed in vacuum oven for 24 h at 40.degree. C. to
afford 139 g (about 100% isolated yield) of the title Compound 18
monosodium salt as a yellowish solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.80-7.84 (m, 3H), 7.74 (d, 2H, J=8.59 Hz),
7.65 (d, 1H, J=16.4 Hz), 7.40-7.44 (m, 2H), 7.25-7.37 (m, 2H),
7.16-7.20 (m, 1H), 7.01-7.05 (m, 1H), 6.84-6.87 (m, 1H), 1.23 (s,
6H). Mass Spectrum (LCMS, APCI pos.) Calcd. For
C.sub.25H.sub.21F.sub.3N.sub.2O: 423.2 (M+H), Found 423.3. m.p.
(uncorr.) 258-259.degree. C.
Example 10.3
(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phe-
nyl)-propan-2-ol hydrochloride salt (Cpd 18)
[0273] A 250-mL separatory funnel was charged with
(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-ph-
enyl)-propan-2-ol. Compound 18 (1.0 g, 2.4 mmol) and EtOAc (20 mL).
Aqueous HCl (1M, 20 mL) was added to the white slurry, and the
separatory funnel was shaken. The solid product quickly dissolved,
and a white precipitate started to form. The organic layer was
transferred to a 100 mL round bottom flask equipped with a magnetic
stir bar, and was stirred for 2 h. The thick slurry was filtered,
rinsed with EtOAc (2.times.5 mL), and put into a vacuum oven at
40.degree. C. for 36 h to afford 0.95 g (87.5%) of the title
Compound 18 hydrochloride salt.
Example 11
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimidazol-
-5-yl}-phenol (Cpd 48)
Step A.
N-(4-bromo-2-nitro-5-trifluoromethyl-phenyl)-2,2,2-trifluoro-aceta-
mide
[0274] 4-bromo-3-trifluoromethyl aniline (4.8 g, 0.02 mol) was
added in portions to a stirred ice-cold trifluoroacetic anhydride
(50 mL). To the resulting solution was added KNO.sub.3 (2.22 g,
0.022 mol, 1.1 eq) in portions. The reaction mixture was stirred at
0.degree. C. for 1 h, and then allowed to warm to room temperature
overnight. The reaction mixture was diluted with ice water (150
mL), and the solid was collected by vacuum filtration. The solid
was washed with water (50 mL) and dried in vacuo to provide the
title Compound 11 a as a bright yellow solid (6.4 g). .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. (ppm): 9.19 (s, 1H) 8.64 (s, 1H) MS
(ESI, pos. ion) m/z: 381.4 (M+1).
Step B. 4-bromo-2-nitro-5-trifluoromethyl-phenylamine
[0275] Compound 11a (5.7 g, 0.015 mol) was dissolved in a mixture
of methanol (25 mL) and saturated aqueous K.sub.2CO.sub.3 (15 mL).
The reaction mixture was then stirred at room temperature for 10 h.
The reaction mixture was diluted with water (25 mL) and the product
was collected by vacuum filtration to provide the title Compound
11b as a yellow solid (2.99 g). .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. (ppm): 8.44 (s, 1H) 7.21 (s, 1H), 6.21 (bs, 2H). MS (ESI,
pos. ion) m/z: 285.0 (M+1).
Step C. 4-bromo-5-trifluoromethyl-benzene-1,2-diamine
[0276] Compound 11b (2.85 g, 0.01 mol) was dissolved in 30 mL of
ethanol. Zinc powder (5.9 g, 0.09 mol) was added in portions
followed by the addition of ammonium chloride (1.07 g, 0.02 mol, 2
eq). The reaction mixture was stirred at room temperature overnight
(16 h). The reaction mixture was filtered over a pad of celite and
the solvent was evaporated in vacuo. The residue was taken up in
ethyl acetate (40 mL), washed with 35 mL of brine, dried over
Na.sub.2SO.sub.4, and evaporated in vacuo. The residue was purified
by chromatography (silica gel, CH.sub.2Cl.sub.2: MeOH, 96:4-94:6))
to provide the title Compound 11c as a bright yellow solid (1.53
g), which was used without further purification in the next step.
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 6.99 (s, 1H) 6.92
(s, 1H) MS (ESI, pos. ion) m/z: 254.7 (M+1).
Step D.
(E)-5-bromo-2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-
-benzimidazole
[0277] 4-t-butyl acrylic acid (1.02 g, 0.0055, 1.1 eq) was
dissolved in 30 mL of POCl.sub.3. To this was added Compound 11c
(1.27 g, 0.005 mol), and the reaction mixture was heated at reflux
for 6 h. (The reaction mixture was quite dark). The reaction
mixture was cooled to room temperature and concentrated in vacuo.
The residue was taken up in 50 mL of ethyl acetate, washed with 50
mL of brine, dried over Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated in vacuo. The residue was purified by
chromatography (silica gel, hexanes: EtOAc, 1:3-2:3) to provide the
title Compound 11d as a light brown solid (0.84 g). .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. (ppm): 7.91 (d, 2H, J=18.5 Hz) 7.69
(d, 1H, J=16.4 Hz), 7.32 (m, 4H) 7.09 (d, 1H, J=16.5 Hz) 1.28 (s,
9H). MS (ESI, pos. ion) m/z: 423.7 (M+1).
Step E.
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benz-
imidazol-5-yl}-phenol
[0278] Compound 11d (0.00026 mol, 0.10 g) was dissolved in 5 mL of
dioxane. 2-hydroxyphenyl boronic acid (0.00052 mol, 0.072 g, 2.0
equiv) was added followed by aqueous Na.sub.2CO.sub.3 (0.00055 mol,
0.28 mL of 2M solution) and
dichlorobis(tricyclohexylphosphine)-palladium(II) (0.011 g, 6 mol
%). The reaction mixture was heated in a microwave synthesizer at
110.degree. C. for 20 minutes. The reaction mixture was cooled and
the solvent was concentrated in vacuo. The residue was taken up in
10 mL of CH.sub.2Cl.sub.2, and washed sequentially with 10 mL of
saturated aqueous NaHCO.sub.3 and 10 mL of brine. The organic
fractions were dried over Na.sub.2SO.sub.4, filtered, and the
filtrate was concentrated in vacuo. The residue purified by
chromatography (silica gel, CH.sub.2Cl.sub.2: MeOH, 98:2-95:5) to
provide the title Compound 48 as a white solid. .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. (ppm): 7.29-7.56 (m, 8H) 7.15 (d, 1H,
J=6.7 Hz) 6.89-7.05 (m, 3H)) 1.34 (s, 9H). MS (ESI, pos. ion) m/z:
437.1 (M+1).
[0279] Using the procedures described in Example 11 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00015 Cpd Name and Data 49
(E)-3-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimida-
zol- 5-yl}-phenol The title compound was prepared from
3-hydroxyphenyl boronic acid (0.00052 mol, 0.072 g) and Compound 1a
(0.00026 mol, 0.10 g). .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
(ppm): 7.25-7.61 (m, 8H) 7.19 (d, 1H, J = 7.0 Hz) 6.90-7.11 (m,
3H)) 1.28 (s, 9H). MS (ESI, pos. ion) m/z: 437.1 (M + 1). 50
(E)--N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-
benzimidazol-5-yl}-phenyl)-acetamide The title compound was
prepared from 2-acetamidophenyl boronic acid (0.00052 mol, 0.093 g)
and Compound 1a (0.00026 mol, 0.10 g) to give the product as an
off-white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm):
8.15 (d, 2H, J = 8.1 Hz) 7.73-7.76 (m, 2H) 7.35-7.52 (m, 4H)
7.0-7.14 (m, 3H) 6.77 (s, 1 H) 1.45 (s, 9H) 1.35 (s, 3H). MS (ESI,
pos. ion) m/z: 478.2 (M + 1). 51
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimid-
azol- 5-yl}-phenyl)-methanol The title compound was prepared from
2-hydroxymethyl phenylboronic acid (0.00052 mol, 0.070 g) and
Compound 1a (0.00026 mol, 0.10 g) to give the product as a white
solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 6.9-7.5 (m,
12H) 4.39 (m, 2H) MS (ESI, pos. ion) m/z: 451.2 (M + 1). 52
(E)-2-[2-(4-tert-butyl-phenyl)-vinyl]-5-(2-fluoro-phenyl)-6-trifluorome-
thyl- 1H-benzimidazole The title compound was prepared from
2-fluorophenylboronic acid (0.00052 mol, 0.073 g) and Compound 1a
(0.00026 mol, 0.10 g) to give the product as a beige solid.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 8.1 (m, 2H) 7.72
(d, 2H, J = 16 5 Hz) 7.42-7.53 (m, 4H) 7.05-7.20 (m, 4H) 1.34 (s,
9H). MS (ESI, pos. ion) m/z: 440.1 (M + 1). 53
(E)-2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimida-
zol- 5-yl}-benzamide The title compound was prepared from
2-aminocarbonyl phenylboronic acid (0.00052 mol, 0.086 g) and
Compound 1a (0.00026 mol, 0.10 g) to give the product as a yellow
solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 7.2-7.8 (m,
9H) 6.91 (d, 2H, J = 5.4 Hz) 6.68 (d, 1H, J = 19.5 Hz) 1.32 (s,
9H). MS (ESI, pos. ion) m/z: 465.25 (M + 1). 54
(E)-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-benzimid-
azol- 5-yl}-phenyl)-carbamic acid tert-butyl ester The title
compound was prepared from t-butyl-N-[2-4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl) phenylcarbamate (0.00052 mol, 0.166 g) and
Compound 1a (0.00026 mol, 0.10 g) to give the product as a beige
solid. .sup.1H-NMR (400 MHz, DMSO-d6) .delta. (ppm): 8.0 (s, 1H),
7.89 (s, 1H), 7.62-7.79 (m, 4H), 7.42-7.55 (m, 3H), 7.36-7.41 (m,
2H), 7.15-7.30 (m, 2H))) 1.32 (s, 18H) MS (ESI, pos. ion) m/z:
536.2 (M + 1). 55
(E)-N-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-6-trifluoromethyl-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide The title compound
was prepared from 2-methylsulfonylaminophenyl boronic acid (0.00052
mol, 0.111 g) and Compound 1a (0.00026 mol, 0.10 g) to give the
product as a bright yellow solid. .sup.1H-NMR (400 MHz, DMSO-d6)
.delta. (ppm): 8.0 (s, 1H) 7.79 (d, 1H, J = 16.5 Hz) 7.65 (d, 2H, J
= 8.4 Hz) 7.5 (m, 3H) 7.41 (t, 1H, J = 7.7 Hz) 7.23-7.28 (m, 3H)
7.10 (d, 1H, J = 12.1 Hz) 2.5 (s, 3H) 1.31 (s, 9H). MS (ESI, pos.
ion) m/z: 514.2 (M + 1).
Example 12
(E)-N-(2-{6-trifluoromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benz-
imidazol-5-yl}-phenyl)-acetamide (Cpd 56)
Step A.
(E)-5-bromo-6-trifluoromethyl-2-[2-(4-trifluoromethyl-phenyl)-viny-
l]-1H-benzimidazole
[0280] Using the procedure of Example 11, Step D, 4-trifluoromethyl
acrylic acid (1.19 g, 0.0055, 1.1 eq) was dissolved in 30 mL of
POCl.sub.3. To this solution was added Compound 11c (1.27 g, 0.005
mol), and the reaction mixture was heated at reflux for 6 h (The
reaction mixture was quite dark). The reaction mixture was cooled
to room temperature and then concentrated in vacuo. The residue was
taken up in 50 mL of ethyl acetate, washed with 50 mL of brine,
dried over Na.sub.2SO.sub.4, filtered, and the filtrate was
concentrated in vacuo. The residue was purified by chromatography
(silica gel, hexanes: EtOAc, 3:1-3:2) to provide the title Compound
12a as a light yellow solid (1.02 g). .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 7.92 (d, 2H, J=14.1 Hz) 6.67-7.76 (m,
5H) 7.21 (d, 1H, J=16.5 Hz) MS (ESI, pos. ion) m/z: 368.3
(M+1).
Step B.
(E)-N-(2-{6-trifluoromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-
-1H-benzimidazol-5-yl}-phenyl)-acetamide
[0281] Compound 12a (0.00025 mol, 0.10 g) was dissolved in 5 mL of
dioxane. 2-acetamidophenyl boronic acid (0.0005 mol, 0.089 g, 2.0
equiv) was added followed by aqueous Na.sub.2CO.sub.3 (0.00055 mol,
0.28 mL of 2M solution) and
dichlorobis(tricyclohexylphosphine)-palladium(II) (0.011 g, 6 mol
%). The reaction mixture was heated in a microwave synthesizer at
110.degree. C. for 20 minutes. The reaction mixture was cooled and
the reaction mixture was concentrated in vacuo. The residue was
taken up in 10 mL of CH.sub.2Cl.sub.2, and washed sequentially with
10 mL of saturated aqueous NaHCO.sub.3 and 10 mL of brine. The
organic fractions were dried over Na.sub.2SO.sub.4, filtered and
the filtrate was concentrated in vacuo. The residue was purified by
chromatography (silica gel CH.sub.2Cl.sub.2: MeOH, 98:2-95:5) to
provide the title Compound 56 as a white solid. .sup.1H-NMR (400M
Hz, DMSO-d6) .delta. (ppm): 8.68 (s, 1H) 8.03 (s, 1H) 7.80-7.96 (m,
6H) 7.35-7.50 (m, 3H) 7.20 (d, 2H, J=4.1 Hz) 1.8 (s, 3H) MS (ESI,
pos. ion) m/z: 490.0 (M+1).
[0282] Using the procedures described in Example 12 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00016 Cpd Name and Data 57
(E)-1-(2-{6-trifluoromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-ethanone The title compound was prepared
from 2-acetylphenyl boronic acid (0.0005 mol, 0.082 g) and Compound
12a (0.00025 mol, 0.10 g) to give the product as a whitish-yellow
solid. .sup.1H-NMR (400 MHz, DMSO-d6) .delta. (ppm): 7.81-8.0 (m,
8H) 7.42-7.62 (m, 3H) 7.30 (d, 1H, J = 6.8 Hz) 2.49 (s, 3H) MS
(ESI, pos. ion) m/z: 475.0 (M + 1). 58
(E)-(2-{6-trifluoromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanol The title compound was prepared
from 2-hydroxymethyl phenylboronic acid (0.0005 mol, 0.067 g) and
Compound 12a (0.00025 mol, 0.10 g) to give the product as a light
yellow powder. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 8.0
(d, 2H, J = 8.1 Hz) 7.8 (d, 2H, J = 8.2 Hz) 7.0-7.59 (m, 8H)
4.91-5.07 (m, 1H) 4.09-4.22 (m, 2H) (s, 9H). MS (ESI, pos. ion)
m/z: 463.0 (M + 1).
Example 13
(E)-2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-y-
l}-phenol (Cpd 59)
Step A.
N-(4-bromo-5-fluoro-2-nitro-phenyl)-2,2,2-trifluoro-acetamide
[0283] 4-bromo-3-fluoromethyl aniline (3.8 g, 0.02 mol) was added
in portions to a stirred ice-cold trifluoroacetic anhydride (50
mL). To the solution was added KNO.sub.3 (2.22 g, 0.022 mol, 1.1
eq) in portions. The reaction mixture was stirred at 0.degree. C.
for 1 h and then allowed to warm to room temperature overnight. The
reaction mixture was diluted with ice water (150 mL) and the solid
was collected by vacuum filtration. The solid was washed with water
(50 mL) and dried in vacuo to provide the title Compound 13a as a
bright yellow solid (5.42 g). .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. (ppm): 8.66 (d, 1H, J=10.0 Hz) 8.60 (d, 1H, J=11.3 Hz). MS
(ESI, pos. ion) m/z: 402.0 (M+Na).
Step B. 4-bromo-5-fluoro-2-nitro-phenylamine
[0284] Compound 13a (5.0 g, 0.015 mol) was dissolved in a mixture
of methanol (25 mL) and saturated aqueous K.sub.2CO.sub.3 (15 mL)
and the mixture was stirred at room temperature for 10 h. The
reaction mixture was diluted with water (25 mL) and the product was
collected by vacuum filtration to provide the title Compound 13b as
a yellow solid (2.5 g). .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
(ppm): 8.39 (d, 1H, J=7.1 Hz) 6.75 (d, 1H, J=9.6 Hz) 6.19 (bs, 2H).
MS (ESI, pos. ion) m/z: 236.9 (M+1).
Step C. 4-bromo-5-fluoro-benzene-1,2-diamine
[0285] Compound 13b (1.88 g, 0.008 mol) was dissolved in 20 mL of
ethanol. Zinc powder (4.71 g, 0.072 mol) was added in portions
followed by the addition of the ammonium chloride (0.86 g, 0.016
mol). The reaction mixture was stirred at room temperature
overnight (16 h). The reaction mixture was filtered over a pad of
celite and the solvent was evaporated in vacuo. The residue was
taken up in ethyl acetate (30 mL) and washed with 25 mL of brine.
The organic fractions were dried over Na.sub.2SO.sub.4, filtered
and the filtrate was concentrated in vacuo. The residue was
purified by flash chromatography (silica gel, CH.sub.2Cl.sub.2:
MeOH, 96:4-94:6)) to provide the title Compound 13c as a dark
yellow solid (1.02 g) that was used immediately in the next
reaction. MS (ESI, pos. ion) m/z: 235.7 (M+1).
Step D.
(E)-5-bromo-6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-ben-
zimidazole
[0286] 4-trifluoromethyl cinnamic acid (1.2 g, 0.0055, 1.1 eq) was
dissolved in 30 mL of POCl.sub.3. To the solution was added
Compound 13c (1.02 g, 0.005 mol), and the reaction mixture was
heated at reflux for 6 h. The reaction mixture was cooled to room
temperature and then evaporated in vacuo. The residue was taken up
in 50 mL of ethyl acetate, and washed with 50 mL of brine. The
organic fractions were dried over Na.sub.2SO.sub.4 and concentrated
in vacuo. The residue was purified by chromatography (silica gel,
hexanes: EtOAc, 3:1-3:2) to provide the title
[0287] Compound 13d as a light brown solid (0.80 g). .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta. (ppm): 7.63-8.09 (m, 4H) 7.4 (d,
1H, J=20.7 Hz) 6.69 (d, 1H, J=20.7 Hz) MS (ESI, pos. ion) m/z:
386.0 (M+1).
Step E.
(E)-2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol-5-yl}-phenol
[0288] Compound 13d (0.00025 mol, 0.096 g) was dissolved in 5 mL of
dioxane. 2-hydroxyphenyl boronic acid (0.0005 mol, 0.069 g) was
added followed by aqueous Na.sub.2CO.sub.3 (0.00055 mol, 0.28 mL of
2M solution) and dichlorobis(tricyclohexylphosphine)-palladium(II)
(0.011 g, 6 mol %). The reaction mixture was heated in a microwave
synthesizer at 110.degree. C. for 20 minutes. The reaction mixture
was cooled and the solvent was evaporated in vacuo. The residue was
taken up in 10 mL of CH.sub.2Cl.sub.2, and washed sequentially with
10 mL of saturated aqueous NaHCO.sub.3 and 10 mL of brine. The
organic fractions were dried over Na.sub.2SO.sub.4, filtered and
the filtrate was concentrated in vacuo. The residue was purified by
chromatography (silica gel (CH.sub.2Cl.sub.2: MeOH, 98:2-95:5) to
provide the title Compound 59 as a tan solid. .sup.1H-NMR (400 MHz,
DMSO-d6) .delta. (ppm): 7.90 (d, 2H, J=8.0 Hz) 7.79 (d, 2H, J=7.8
Hz) 7.22-7.53 (m, 4H) 6.88-6.96 (m, 4H) MS (ESI, pos. ion) m/z:
399.1 (M+1).
[0289] Using the procedures described in Example 13 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00017 Cpd Name and Data 60
(E)-3-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-phenol The title compound was prepared from 3-hydroxyphenyl
boronic acid (0.0005 mol, 0.069 g) and Compound 13d (0.00025 mol,
0.096 g) to give the product as an off-white solid. .sup.1H-NMR
(400 MHz, DMSO-d6) .delta. (ppm): 7.76-8.0 (m, 4H) 7.24-7.64 (m,
5H) 6.96-7.03 (m, 1H) 6.75-6.8 (m, 2H) MS (ESI, pos. ion) m/z:
399.3 (M + 1). 61
(E)-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-phenyl)-methanol The title compound was prepared from
2-hydroxymethyl phenylboronic acid (0.0005 mol, 0.067 g) and
Compound 13d (0.00025 mol, 0.096 g) to give the product as a
yellowish solid. .sup.1H-NMR (400 MHz, CD3OD) .delta. (ppm): 7.83
(d, 2H, J = 8.2 Hz) 7.70-7.73 (m, 2H) 7.64 (t, 2H, J = 7.9, 7.5
Hz)) 7.55 (d, 1H, J = 7.2 Hz) 7.25-7.46 (m, 4H) 7.10 (dd, 1H, J =
1.2 Hz) 4.29 (d, 2H, J = 0.85 Hz) MS (ESI, pos. ion) m/z: 413.1 (M
+ 1). 62
(E)-1-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-ethanone The title compound was prepared from
2-acetylphenyl boronic acid (0.0005 mol, 0.082 g) and Compound 13d
(0.00025 mol, 0.096 g) to give the product as a bright yellow
solid. .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 7.75-7.91
(m, 5 H) 7.55-7.68 (m, 4H) 7.41-7.47 (m, 3H) 2.46 (s, 3H) MS (ESI,
pos. ion) m/z: 425.1 (M + 1). 63
(E)-2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-benzamide The title compound was prepared from
2-aminocarbonyl phenylboronic acid (0.0005 mol, 0.083 g) and
Compound 13d (0.00025 mol, 0.096 g) to give the product as a sticky
tan solid. .sup.1H-NMR (400 MHz, DMSO-d6) .delta. (ppm): 7.93 (d,
2H, J = 8.6 Hz) 7.83 (d, 2H, J = 8.6 Hz) 7.40-7.71 (m, 8H) MS (ESI,
pos. ion) m/z: 426.0 (M + 1). 64
(E)-N-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-acetamide The title compound was prepared from
2-acetamidophenyl boronic acid (0.0005 mol, 0.089 g) and Compound
13d (0.00025 mol, 0.096 g) to give the product as an off-white
solid. .sup.1H-NMR (400 MHz, DMSO-d6) .delta. (ppm): 8.68 (s, 1H)
8.03 (s, 1H) 7.80-7.96 (m, 6H) 7.35-7.50 (m, 3H) 7.20 (d, 2H, J =
4.1 Hz) 1.8 (s, 3H) MS (ESI, pos. ion) m/z: 440.1 (M + 1). 65
(E)-N-(2-{6-fluoro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-methanesulfonamide The title compound was
prepared from 2 methylsulfonylaminophenyl boronic acid (0.0005 mol,
0.108 g) and Compound 13d (0.00025 mol, 0.096 g) to give the
product as an off-white solid. .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 7.65 (s, 1 H) 7.59 (d, 1H, J = 6.7 Hz) 7.26-7.48 (m,
10 H) 2.95 (s, 3H) MS (ESI, pos. ion) m/z: 476.1 (M + 1).
Example 14
(E)-(2-{6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}-phenyl)-methanol (Cpd 66)
Step A.
N-(4-bromo-5-chloro-2-nitro-phenyl)-2,2,2-trifluoro-acetamide
[0290] 4-Bromo-3-chloromethyl aniline (4.1 g, 0.02 mol) was added
in portions to a stirred ice cold trifluoroacetic anhydride (50
mL). To the resulting solution was added KNO.sub.3 (2.22 g, 0.022
mol, 1.1 eq) in portions. The reaction mixture was stirred at
0.degree. C. for 1 hour and then allowed to warm to room
temperature overnight.
[0291] The reaction mixture was diluted with ice water (150 mL) and
the solid was collected by vacuum filtration. The solid was washed
with water (50 mL) and dried in vacuo to provide the title Compound
14a as a pale yellow solid (5.55 g).
Step B. 4-bromo-5-chloro-2-nitro-phenylamine
[0292] Compound 14a (5.2 g, 0.015 mol) was dissolved in a mixture
of methanol (25 mL) saturated aqueous K.sub.2CO.sub.3 (15 mL). The
reaction mixture was stirred at room temperature for 10 hours. The
reaction mixture was diluted with water (25 mL) and the product was
collected by vacuum filtration to provide the title Compound 14b as
a yellow solid (2.71 g). .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
(ppm): 8.39 (s, 1H) 6.98 (s, 1H) 6.08 (bs, 2H). MS (ESI, pos. ion)
m/z: 250.9 (Br, Cl pattern).
Step C. 4-bromo-5-chloro-benzene-1,2-diamine
[0293] Compound 14b (2.0 g, 0.008 mol) was dissolved in 20 mL of
ethanol. Zinc powder (4.7 g, 0.072 mol) was added in portions
followed by the addition of the ammonium chloride (0.88 g, 0.016
mol, 2 eq). The reaction mixture was stirred at room temperature
overnight (16 hours). The reaction mixture was filtered over a pad
of celite and the solvent was evaporated in vacuo. The residue was
taken up in ethyl acetate (30 mL) and washed with 25 mL of brine.
The organic fractions were dried over Na.sub.2SO.sub.4, filtered
and the filtrate was concentrated in vacuo. The residue was
purified by flash chromatography (silica gel, CH.sub.2Cl.sub.2:
MeOH, 96:4-94:6) to provide the title Compound 14c as a dark
yellowish-brown solid (1.08 g) and was used immediately in the next
reaction. MS (ESI, pos. ion) m/z: 220.9 (Br, Cl pattern).
Step D.
(E)-5-bromo-6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-ben-
zimidazole
[0294] 4-trifluoromethyl cinnamic acid (1.2 g, 0.0055, 1.1 eq) was
dissolved in 30 mL of POCl.sub.3. To this solution was added
Compound 14c (1.08 g, 0.005 mol), and the reaction mixture was
heated to reflux for 6 hours (The reaction mixture was quite dark).
The reaction mixture was cooled to room temperature and the
evaporated in vacuo. The residue was taken up in 50 mL of ethyl
acetate, and washed with 50 mL of brine. The organic fractions were
dried over Na.sub.2SO.sub.4, filtered and the filtrate was
evaporated in vacuo. The residue was purified by chromatography
(silica gel hexanes: EtOAc, 3:1-3:2) to provide the title Compound
14d as a light brown solid (0.80 g). .sup.1H-NMR (400 MHz, DMSO-d6)
.delta. (ppm): 7.57-8.21 (m, 4H) 7.35 (d, 1H, J=19 Hz) 6.72 (d, 1H,
J=18.5 Hz). MS (ESI, pos. ion) m/z: 401.0.
Step E.
(E)-(2-{6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimi-
dazol-5-yl}-phenyl)-methanol
[0295] Compound 14d (0.00025 mol, 0.100 g) was dissolved in 5 mL of
dioxane. 2-hydroxymethyl phenylboronic acid (0.0005 mol, 0.067 g,
2.0 equiv) was added followed by aqueous Na.sub.2CO.sub.3 (0.00055
mol, 0.28 mL of 2M solution) and
dichlorobis(tricyclohexylphosphine)-palladium(II) (0.011 g, 6 mol
%). The reaction mixture was heated in a microwave at 110.degree.
C. for 20 minutes. The reaction mixture was cooled and the solvent
was evaporated in vacuo. The residue was taken up in 10 mL of
CH.sub.2Cl.sub.2, and washed sequentially with 10 mL of saturated
aqueous NaHCO.sub.3 and 10 mL of brine. The organic fractions were
dried over Na.sub.2SO.sub.4, filtered and the solvent was
evaporated in vacuo. The residue was purified by chromatography
(silica gel, CH.sub.2Cl.sub.2: MeOH, 98:2-95:5) to provide the
title Compound 66 as a yellow sticky solid. .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 7.82-7.85 (d, 2H, J=8.4 Hz) 7.72-7.74
(d, 2H, J=8.3 Hz) 7.56-7.66 (m, 3H) 7.26-7.43 (m, 5H) 5.05 (s, 1H)
4.58 (s, 2H). MS (ESI, pos. ion) m/z: 395.3 (--CH.sub.2OH).
[0296] Using the procedures described in Example 14 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00018 Cpd Name and Data 67
(E)-1-(2-{6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidaz-
ol- 5-yl}-phenyl)-ethanone The title compound was prepared from
2-acetylphenyl boronic acid (0.0005 mol, 0.082 g) and Compound 14d
(0.00025 mol, 0.100 g) to give the product as a pale yellow solid.
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 7.80-7.84 (m, 2H)
7.70-7.74 (m, 2H) 7.67 (s, 1H), 7.50-7.7.64 (m, 2H) 7.27-7.43 (m,
5H), 1.36 (s, 9H). MS (ESI, pos. ion) m/z: 441.1 (M + 1). 68
(E)-2-{6-chloro-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-phenol The title compound was prepared from 2-hydroxyphenyl
boronic acid (0.0005 mol, 0.108 g) and Compound 14d (0.00025 mol,
0.069 g) to give the product as a dark yellow solid. .sup.1H-NMR
(400 MHz, CD.sub.3OD) .delta. (ppm): 6.2-6.6 (m, 5H) 5.99-6.05 (m,
5H) 5.59-5.66 (2H) 7.80-7.84 (m, 2H). MS (ESI, pos. ion) m/z: 415.0
(M + 1).
Example 15
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzen-
esulfonamide (Cpd 70)
(E)-N-tert-butyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}-benzenesulfonamide (Cpd 309)
Step A.
(E)-N-tert-butyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benz-
imidazol-5-yl}-benzenesulfonamide
[0297] A mixture of 2-(t-butylamino)sulfonylphenyl boronic acid
(12.4 g, 0.048 mol), Compound 10c (13.6 g, 0.037 mol),
Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (3.00 g, 3.70 mmol), TBAB (11.9 g,
0.037 mmol), and Na.sub.2CO.sub.3 (31.4, 0.296 mol) in 750 mL of
mixed solvent (DME: water, 4:1) was heated at 90.degree. C. for 12
hours. The reaction mixture was concentrated, and the residue was
purified by chromatography (silica gel, hexanes: EtOAc, 1:1) to
provide the title Compound 309 as a yellow oil. .sup.1H-NMR (400
MHz, CD.sub.3OD) .delta. (ppm): 8.14 (dd, 1H, J=1.6 and 7.6 Hz)
7.84 (d, 2H, J=8.4 Hz) 7.73 (d, 2H, J=8.4 Hz) 7.70-7.62 (m, 4H)
7.54 (dt, 1H, J=1.6 and 8.6 Hz) 7.41 (dd, 1H, J=1.2 and 7.6 Hz)
7.37-7.31 (m, 2H) 1.00 (s, 9H) MS (ESI, pos. ion) m/z: 490.3
(M+1).
Step B.
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl-
}-benzenesulfonamide
[0298] A solution of Compound 309 in 60 mL TFA was heated at
70.degree. C. for 2 hours.
[0299] The reaction was concentrated, the residue was dissolved in
EtOAc, and washed with sat'd NaHCO.sub.3. The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and the residue was
concentrated. The residue was purified by chromatography (silica
gel, hexanes: EtOAc, 1:2) to provide the title Compound 70 as a
light brown solid. M.p. 168-170.degree. C. .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.16 (dd, 1H, J=1.2 and 8.0 Hz)
7.95-7.91 (m, 3H) 7.82-7.76 (m, 4H) 7.70-7.56 (m, 3H) 7.44 (s, 1H)
7.16 (d, 1H, J=9.6 Hz) MS (ESI, pos. ion) m/z: 444.3 (M+1).
[0300] Using the procedures described in Example 15 and reagents,
starting materials and conditions known to those skilled in the
art, the following compound representative of the present invention
was prepared:
TABLE-US-00019 Cpd Name and Data 71
(E)-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-benzimidazol--
5- yl}-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.14 (dd, 1H, J = 1.2 and 7.6 Hz) 8.10 (d, 2H, J = 8.4 Hz)
8.01 (d, 2H, J = 8.4 Hz) 7.71-7.53 (m, 5H) 7.44 (d, 1H, J = 16.4
Hz) 7.41 (dd, 1H, J = 1.2 and 7.6 Hz) 7.35 (dd, 1H, J = 1.2 and 8.4
Hz) MS (ESI, pos. ion) m/z: 508.3 (M + 1). 398
(E)-N,N-dimethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide The title compound was
prepared from 2-N,N-dimethylaminosulfonylphenyl boronic acid and
Compound 10c. .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.08
(dd, 1H, J = 1.2 and 8.4 Hz) 7.84 (d, 2H, J = 8.4 Hz) 7.73 (d, 2H,
J = 8.8 Hz) 7.69-7.56 (m, 5H) 7.43 (dd, 1H, J = 1.2 and 7.2 Hz)
7.33 (d, 1H, J = 16.4 Hz) 7.28 (dd, 1H, J = 1.6 and 8.4 Hz) 2.34
(s, 6H) MS (ESI, pos. ion) m/z: 472.5 (M + 1). 441
(E)-4-fluoro-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide The title compound was prepared from
2-tert-butylaminosulfonyl-5- fluorophenylboronic acid and Compound
10c. .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.18 (dd, J =
5.6, 8 Hz, 1H), 7.94 (d, J = 5.6, 8 Hz, 1H), 7.84 (d, J = 8 Hz,
2H), 7.73 (s, 1H), 7.71-7.69 (m, 2H), 7.63 (d, J = 8 Hz, 1H),
7.35-7.32 (m, 1H), 7.28-7.22 (m, 2H), 7.14 (dd, J = 2, 9 Hz, 1H).
Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.22H.sub.15F.sub.4N.sub.3O.sub.2S: 462.4 (M + H), Found 462.2.
444
(E)-4-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide The title compound was
prepared from 2-tert-butylaminosulfonyl-5- trifluoromethylphenyl
boronic acid and Compound 10c. .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.33 (d, J = 8 Hz, 1H), 7.88 (s, 1H), 7.85 (d, J = 8
Hz, 2H), 7.74-7.68 (m, 6H), 7.36-7.32 (m, 1H), 7.34 (d, J = 16.4
Hz, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.23H.sub.15F.sub.6N.sub.3O.sub.2S: 512.5 (M + H), Found 512.3.
446
(E)-5-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide The title compound was
prepared from 2-tert-butylaminosulfonyl-4- trifluoromethylphenyl
boronic acid and Compound 10c. .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.42 (s, 1H), 7.94 (d, J = 8 Hz, 1H), 7.85 (d, J = 8
Hz, 2H), 7.73 (d, J = 8 Hz, 2H), 7.71 (d, J = 8 Hz, 2H), 7.64 (d, J
= 8 Hz, 2H), 7.34 (d, J = 16.4 Hz, 2H). Mass Spectrum (LCMS, ESI
pos.) Calcd. For C.sub.23H.sub.15F.sub.6N.sub.3O.sub.2S: 512.1 (M +
H), Found 512.2.
Example 16
(E)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benze-
nesulfonamide (Cpd 69)
Step A. (5-bromo-2-tert-butoxycarbonylamino-phenyl)-carbamic acid
tert-butyl ester
[0301] 4-bromo-phenylenediamine (25 g, 0.134 mol) was added
portionwise to di-t-butyl dicarbonate (175 g, 0.802 mol) at
25.degree. C., and the reaction mixture was stirred for 10 hours.
The mixture was purified by chromatography (silica gel, hexanes to
hexanes: EtOAc, 1:1) to provide the title Compound 16a as a light
brown solid.
[0302] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 7.76 (brs,
1H) 7.32 (brs, 1H) 7.22 (dd, 1H, J=2.0 and 8.8 Hz) 6.72 (brs, 1H)
6.53 (brs, 1H).
Step B.
(3-tert-butoxycarbonylamino-2'-tert-butylsulfamoyl-biphenyl-4-yl)--
carbamic acid tert-butyl ester
[0303] A mixture of 2-(t-butylamino)sulfonylphenyl boronic acid
(4.7 g, 0.018 mmol), Compound 16a (4.7 g, 0.012 mmol),
Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (0.99 g, 0.0012 mmol), TBAB (3.90
g, 0.012 mmol), and 20 mL of 1M Na.sub.2CO.sub.3 (aq) in 100 mL of
DME was heated at 100.degree. C. for 12 hours. The reaction mixture
was concentrated, and the residue was purified by chromatography
(silica gel, hexanes: EtOAc, 2:1) to provide the title Compound 16b
as a yellow oil.
Step C. 3',4'-diamino-biphenyl-2-sulfonic acid tert-butylamide
[0304] A mixture of Compound 16b in 20 mL of 4M HCl in dioxane was
stirred for 3 hours. The reaction mixture was concentrated, diluted
with EtOAc and washed with sat'd NaHCO.sub.3 (aq), then dried over
Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated to
provide the title Compound 16c as a brown oil. .sup.1H-NMR (400
MHz, CD.sub.3OD) .delta. (ppm): 8.04 (dd, 1H, J=1.2 and 7.6 Hz)
7.56 (dt, 1H, J=1.2 and 8.2 Hz) 7.44 (dt, 1H, J=1.2 and 8.4 Hz)
7.33 (dd, 1H, J=1.2 and 7.6 Hz) 6.86 (d, 1H, J=1.6 Hz) 6.77 (d, 1H,
J=7.6 Hz) 6.73 (dd, 1H, J=2.0 and 8.0 Hz) 0.97 (s, 9H). MS (ESI,
pos. ion) m/z: 319.9 (M+1).
Step D.
(E)-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-y-
l}-benzenesulfonamide
[0305] A mixture of Compound 16c (0.120 g, 0.376 mmol), trans
4-(trifluoromethoxy)-cinnamic acid (0.105 g, 0.451 mmol), and 0.4
mL of 4N HCl (aq) in 4 mL of ethylene glycol was heated at
180.degree. C. for 1 hour. The reaction mixture was purified
directly by HPLC (YMC ODS-A, H.sub.2O: MeCN, 90:10 to 40:60, over
10 min) to provide the title Compound 69 as an off-white solid.
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.14 (dd, 1H,
J=1.2 and 8.0 Hz) 7.75 (d, 2H, J=8.4 Hz) 7.68-7.53 (m, 5H) 7.41
(dd, 1H, J=1.2 and 7.6 Hz) 7.37-7.33 (m, 3H) 7.19 (d, 1H, J=16.8
Hz) MS (ESI, pos. ion) m/z: 460.3 (M+1).
[0306] Using the procedures described in Example 16 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00020 Cpd Name and Data 79
(E)-2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzene
sulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.14
(dd, 1H, J = 1.2 and 7.6 Hz) 7.68-7.54 (m, 7H) 7.46-7.40 (m, 3H)
7.38 (dd, 1H, J = 1.2 and 8.4 Hz) 7.19 (d, 1H, J = 16.8 Hz) MS
(ESI, pos. ion) m/z: 410.4 (M + 1). 85
(E)-2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, J = 1.2 and 7.6 Hz) 7.99 (d, 2H, J = 8.4 Hz) 7.89 (d,
2H, J = 8.4 Hz) 7.71-7.53 (m, 5H) 7.41 (dd, 1H, J = 1.6 and 7.6 Hz)
7.36 (d, 1H, J = 16.4 Hz) 7.34 (dd, 1H, J = 1.6 and 8.4 Hz) MS
(ESI, pos. ion) m/z: 453.4 (M + 1). 357
(E)-2-{2-[2-(2,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.13 (d, 1H, J = 8.0 Hz) 7.83-7.75 (m, 2H) 7.67-7.53 (m, 4H) 7.38
(t, 2H, J = 9.2 Hz) 7.22 (d, 1H, J = 16.8 Hz) 7.08-7.03 (m, 2H) MS
(ESI, pos. ion) m/z: 412.4 (M + 1). 358
(E)-2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, J = 1.2 and 7.6 Hz) 7.72-7.55 (m, 6H) 7.48-7.35 (m,
4H) 7.20 (d, 1H, J = 16.4 Hz) MS (ESI, pos. ion) m/z: 412.4 (M +
1). 359
(E)-2-{2-[2-(2,3-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, J = 1.2 and 8.0 Hz) 7.84 (d, 1H, J = 16.8 Hz)
7.70-7.54 (m, 5H) 7.41 (dd, 2H, J = 1.6 and 8.4 Hz) 7.33 (d, 1H, J
= 16.8 Hz) 7.29-7.23 (m, 2H) MS (ESI, pos. ion) m/z: 412.4 (M + 1).
360 (E)-2-{2-[2-(2,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, J = 1.2 and 8.0 Hz) 7.81 (d, 1H, J = 16.8 Hz)
7.69-7.54 (m, 5H) 7.46-7.38 (m, 2H) 7.33 (d, 1H, J = 16.8 Hz)
7.26-7.14 (m, 2H) MS (ESI, pos. ion) m/z: 412.4 (M + 1). 361
(E)-2-{2-[2-(3,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, J = 1.6 and 8.0 Hz) 7.71-7.55 (m, 5H) 7.42 (td, 2H, J
= 1.4 and 8.4 Hz) 7.34-7.28 (m, 3H) 7.04-6.99 (m, 1H) MS (ESI, pos.
ion) m/z: 412.4 (M + 1). 362
(E)-2-{2-[2-(3-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, J = 1.2 and 7.6 Hz) 7.37-7.51 (m, 8H) 7.41 (dd, 1H, J
= 1.2 and 8.0 Hz) 7.35 (dd, 1H, J = 1.6 and 8.0 Hz) 7.29 (d, 1H, J
= 8.8 Hz) 7.25 (d, 1H, J = 16.8 Hz) 7.34 (dd, 1H, J = 1.6 and 8.4
Hz) MS (ESI, pos. ion) m/z: 460.4 (M + 1). 363
(E)-2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.13 (dd, 1H, J = 1.2 and 7.6 Hz) 7.93 (d, 1H, J = 1.2 and 7.6 Hz)
7.65-7.47 (m, 6H) 7.42-7.29 (m, 4H) 7.22 (d, 1H, J = 16.8 Hz) MS
(ESI, pos. ion) m/z: 454.3 (M + 1). 364
(E)-2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, J = 1.2 and 8.0 Hz) 8.10 (dd, 1H, J = 2.0 and 16.4
Hz) 8.01 (d, 1H, J = 7.6 Hz) 7.80 (d, 1H, J = 7.6 Hz) 7.75-7.55 (m,
6H) 7.42 (dd, 2H, J = 1.2 and 8.4 Hz) 7.25 (d, 1H, J = 16.4 Hz) MS
(ESI, pos. ion) m/z: 444.3 (M + 1). 365
(E)-2-{2-[2-(2-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.16 (d, 1H, J = 7.6 Hz) 8.13 (s, 1H) 7.90 (d, 1H, J = 9.2 Hz) 7.68
(d, 1H, J = 14.4 Hz) 7.65-7.49 (m, 4H) 7.43-7.38 (m, 4H) 7.25 (d,
1H, J = 16.4 Hz) MS (ESI, pos. ion) m/z: 410.3 (M + 1). 366
(E)-2-{2-[2-(2-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.35 (d, 1H, J = 16.4 Hz) 8.16 (dd, 1H, J = 1.6 and 8.0 Hz) 7.97
(dd, 1H, J = 1.6 and 7.6 Hz) 7.84 (s, 1H) 7.80 (d, 1H, J = 9.2 Hz)
7.76 (dd, 1H, J = 1.2 and 8.0 Hz) 7.70-7.60 (m, 3H) 7.52 (dt, 1H, J
= 1.2 and 8.2 Hz) 7.45-7.39 (m, 2H) 7.32 (d, 1H, J = 16.4 Hz) MS
(ESI, pos. ion) m/z: 454.3 (M + 1). 367
(E)-2-{2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.15 (dd, 1H, J = 1.2 and 7.6 Hz) 8.12-8.08 (m, 2H)
7.76-7.41 (m, 8H) 7.25 (d, 1H, J = 16.4 Hz) MS (ESI, pos. ion) m/z:
461.4 (M + 1). 368
(E)-2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.14 (dd, 1H, J = 1.2 and 7.6 Hz) 8.10 (t, 1H, 7.0
Hz) 7.91 (d, 1H, J = 16.4 Hz) 7.75-7.54 (m, 5H) 7.46-7.34 (m, 4H)
MS (ESI, pos. ion) m/z: 461.4 (M + 1). 369
(E)-2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.16 (dd, 1H, J = 1.6 and 8.0 Hz) 8.12-8.10 (m, 2H)
7.94 (d, 1H, J = 16.8 Hz) 7.85 (dd, 1H, J = 0.8 and 1.6 Hz) 7.80
(dd, 1H, J = 0.8 and 8.8 Hz) 7.70-7.59 (m, 3H) 7.52 (t, 1H, J = 9.8
Hz) 7.43 (dd, 1H, J = 1.6 and 7.6 Hz) 7.39 (d, 1H, J = 16.8 Hz) MS
(ESI, pos. ion) m/z: 462.3 (M + 1). 370
(E)-2-{2-[2-(2,3,4-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (d, 1H, J = 8.0 Hz) 7.79 (d, 1H, J = 16.8 Hz) 7.68 (d, 1H, J =
16.0 Hz) 7.64-7.55 (m, 4H) 7.43-7.40 (m, 2H) 7.31 (d, 1H, J = 16.8
Hz) 7.23 (q, 1H, J = 8.1 Hz) MS (ESI, pos. ion) m/z: 430.4 (M + 1).
371
(E)-2-{2-[2-(2,4,5-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, J = 1.2 and 8.0 Hz) 7.84-7.79 (m, 1H) 7.75 (d, 1H, J
= 15.6 Hz) 7.68-7.53 (m, 4H) 7.41 (dd, 1H, J = 1.2 and 7.6 Hz) 7.37
(dd, 1H, J = 1.6 and 8.4 Hz) 7.33-7.25 (m, 2H) MS (ESI, pos. ion)
m/z: 430.3 (M + 1). 372
(E)-2-{2-[2-(2,6-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, J = 0.8 and 7.6 Hz) 7.85 (d, 1H, J = 16.8 Hz)
7.70-7.54 (m, 4H) 7.49 (d, 1H, J = 16.8 Hz) 7.46-7.40 (m, 3H) 7.10
(t, 2H, J = 8.8 Hz) MS (ESI, pos. ion) m/z: 412.3 (M + 1). 373
(E)-2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.25 (s, 2H) 8.14 (dd, 1H, J = 1.2 and 7.6 Hz) 7.95 (s, 1H)
7.71 (d, 1H, J = 16.8 Hz) 7.68-7.53 (m, 4H) 7.44 (d, 1H, J = 16.8
Hz) 7.42 (dd, 1H, J = 1.2 and 7.6 Hz) 7.35 (dd, 1H, J = 1.6 and 8.0
Hz) MS (ESI, pos. ion) m/z: 512.4 (M + 1). 374
(E)-2-{2-[2-(2,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.36 (s, 1H) 8.24 (dd, 1H, J = 2.0 and 16.4 Hz) 8.16 (dd,
1H, J = 1.2 and 8.0 Hz) 8.06 (d, 1H, J = 8.4 Hz) 7.84 (d, 1H, J =
8.4 Hz) 7.83 (s, 1H) 7.79 (d, 1H, J = 8.8 Hz) 7.69-7.57 (m, 3H)
7.48-7.42 (m, 2H) MS (ESI, pos. ion) m/z: 512.4 (M + 1). 375
(E)-2-{2-[2-(4-chloro-2-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.51 (d, 1H, J = 16.0 Hz) 8.16-8.10 (m, 2H) 8.03 (d,
1H, J = 8.4 Hz) 7.82 (dd, 1H, J = 1.6 and 8.0 Hz) 7.75-7.55 (m, 4H)
7.49-7.36 (m, 2H) 7.28 (d, 1H, J = 16.4 Hz) MS (ESI, pos. ion) m/z:
488.1 (M + 1). 376
(E)-2-{2-[2-(3-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.15 (d, 1H, J = 7.6 Hz) 7.89 (s, 1H) 7.74-7.58 (m, 7H) 7.48-7.37
(m, 3H) 7.27 (d, 1H, J = 16.4 Hz) MS (ESI, pos. ion) m/z: 454.3
(M). 378
(E)-2-{2-[2-(4-chloro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.14 (dd, 1H, J = 1.6 and 8.0 Hz) 8.04 (d, 1H, J =
2.0 Hz) 7.93 (dd, 1H, J = 2.0 and 8.4 Hz) 7.71-7.54 (m, 6H)
7.43-7.38 (m, 2H) 7.32 (d, 1H, J = 16.8 Hz) MS (ESI, pos. ion) m/z:
478.4 (M + 1). 379
(E)-2-{2-[2-(5-bromo-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.15 (dd, 1H, J = 1.2 and 8.0 Hz) 8.00 (dd, 1H, J = 2.4 and 6.4 Hz)
7.88 (d, 1H, J = 16.4 Hz) 7.76-7.57 (m, 5H) 7.51 (dd, 1H, J = 1.6
and 8.8 Hz) 7.42 (dd, 1H, J = 1.2 and 8.0 Hz) 7.38 (d, 1H, J = 16.4
Hz) 7.20 (dd, 1H, J = 8.8 and 10.4 Hz) MS (ESI, pos. ion) m/z:
472.3 (M + 1). 423
(E)-2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.14 (dd, J = 1.2, 8.2 Hz, 1H), 7.74-7.62 (m, 7H),
7.43-7.34 (m, 3H), 6.64 (d, J = 16.0 Hz, 1H). Mass Spectrum (LCMS,
ESI pos.) Calcd. For C.sub.22H.sub.15F.sub.4N.sub.3O.sub.2S: 462.1
(M + H), Found 462.2. 424
(E)-2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.13 (dd, J = 1.6, 8.0 Hz, 1H), 7.99 (t, J = 7.2 Hz,
1H), 7.83 (d, J = 16.8 Hz, 1H), 7.67-7.52 (m, 4H), 7.45 (s, 1H),
7.43-7.40 (m, 3H), 7.34 (dd, J = 1.6, 7.6 Hz, 1H). Mass Spectrum
(LCMS, ESI pos.) Calcd. For C.sub.22H.sub.15F.sub.4N.sub.3O.sub.2S:
462.1 (M + H), Found 462.2. 425
(E)-2-{2-[2-(3-ethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzene
sulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.13
(dd, J = 1.6, 8.0 Hz, 1H), 7.99 (t, J = 7.2 Hz, 1H), 7.57 (d, J =
16 Hz, 1H), 7.67-7.60 (m, 2H), 7.45 (s, 1H), 7.43-7.40 (m, 2H),
7.25 (t, J = 4 Hz, 1H), 7.11 (d, J = 8 Hz, 1H), 7.07-7.08 (m, 1H),
6.92-6.89 (m, 1H), 6.45 (d, J = 16 Hz, 1H). Mass Spectrum (LCMS,
ESI pos.) Calcd. For C.sub.23H.sub.21N.sub.3O.sub.3S: 420.1 (M +
H), Found 420.2. 426
(E)-2-(2-styryl-1H-benzimidazol-5-yl)-benzenesulfonamide 1H-NMR
(400 MHz, CD.sub.3OD) .delta. (ppm): 8.13 (dd, J = 1.6, 7.8 Hz,
1H), 7.66-7.58 (m, 6H), 7.54 (dt, J = 1.6, 7.6 Hz, 1H), 7.44-7.40
(m, 3H), 7.38-7.34 (m, 1H), 7.31 (dd, J = 1.6, 8 Hz, 1H), 7.18 (d,
J = 16.4 Hz, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.21H.sub.17N.sub.3O.sub.2S: 376.1 (M + H), Found 376.3. 427
(E)-2-{2-[2-(3,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzene
sulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.13
(dd, J = 1.6, 8 Hz, 1H), 7.82 (s, 1H), 7.65-7.61 (m, 3H), 7.60-7.54
(m, 3H), 7.52 (s, 1H), 7.41 (dd, J = 1.6, 8 Hz, 1H), 7.32 (dd, J =
1.6, 8 Hz, 1H), 7.22 (d, J = 16.4 Hz, 1H). Mass Spectrum (LCMS, ESI
pos.) Calcd. For C.sub.21H.sub.15Cl.sub.2N.sub.3O.sub.2S: 444.0 (M
+ H), Found 444.1.
428
(E)-2-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.13 (dd, J = 1.6, 8 Hz, 1H), 7.78 (d, J = 8 Hz, 1H), 7.75 (d, J =
8 Hz, 1H), 7.72 (s, 1H), 7.55-7.54 (m, 1H), 7.62 (dd, J = 1.6, 8
Hz, 1H), 7.54 (dt, J = 1.6, 8 Hz, 1H), 7.41 (dd, J = 1.6, 8 Hz,
1H), 7.34-7.26 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.21H.sub.15ClFN.sub.3O.sub.2S: 428.9 (M + H), Found 430.2. 429
(E)-2-{2-[2-(4-isopropyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.13 (dd, J = 1.6, 8 Hz, 1H), 7.65-7.60 (m, 4H), 7.58-7.52 (m, 3H),
7.41 (dd, J = 1.6, 8 Hz, 1H), 7.32-7.29 (m, 3H), 7.13 (d, J = 16.8
Hz, 1H), 2.94 (h, J = 2.4 Hz, 1H), 1.27 (d, J = 8 Hz, 6H). Mass
Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.24H.sub.23N.sub.3O.sub.2S: 418.1 (M + H), Found 418.4. 430
(E)-2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-benzenesulfonamide
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.13 (dd, J = 1.6,
8 Hz, 1H), 7.65-7.58 (m, 5H), 7.53 (d, J = 7.6 Hz, 2H), 7.41 (dd, J
= 1.6, 8 Hz, 1H), 7.30 (dd, J = 1.6, 8 Hz, 1H), 7.23 (d, J = 8 Hz,
2H), 7.11 (d, J = 16.8 Hz, 1H), 2.36 (s, 3H). Mass Spectrum (LCMS,
ESI pos.) Calcd. For C.sub.22H.sub.19N.sub.3O.sub.2S: 390.1 (M +
H), Found 390.5. 431
(E)-2-{2-[2-(3-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.13 (dd, J = 1.6, 8 Hz, 1H), 7.80 (d, J = 16 Hz, 1H), 7.73 (t, J =
7.2 Hz, 1H), 7.66-7.60 (m, 4H), 7.57-7.52 (m, 1H), 7.51-7.46 (m,
1H), 7.42 (dd, J = 1.6, 8 Hz, 1H), 7.33 (dd, J = 1.6, 8 Hz, 1H),
7.22 (d, J = 16.8 Hz, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd.
For C.sub.21H.sub.15ClFN.sub.3O.sub.2S: 428.9 (M + H), Found 428.3.
432
(E)-2-{2-[2-(3-chloro-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.13 (dd, J = 1.6, 8 Hz, 1H), 7.80 (dd, J = 2, 7.2 Hz, 1H),
7.65-7.52 (m, 6H), 7.41 (dd, J = 1.6, 8 Hz, 1H), 7.33-7.28 (m, 2H),
7.16 (d, J = 16.8 Hz, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd.
For C.sub.21H.sub.15ClFN.sub.3O.sub.2S: 428.9 (M + H), Found 428.3.
433
(E)-2-[2-(2-naphthalen-2-yl-vinyl)-1H-benzimidazol-5-yl]-benzene
sulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.13
(dd, J = 1.6, 8 Hz, 1H), 8.01 (s, 1H), 7.91-7.82 (m, 4H), 7.80 (d,
J = 16.8 Hz, 1H), 7.66-7.59 (m, 3H), 7.55 (dd, J = 1.6, 8 Hz, 1H),
7.52-7.48 (m, 2H), 7.42 (dd, J = 2, 7.6 Hz, 1H), 7.32 (dd, J = 1.6,
8 Hz, 1H), 7.30 (d, J = 16.8 Hz, 1H). Mass Spectrum (LCMS, ESI
pos.) Calcd. For C.sub.25H.sub.19N.sub.3O.sub.2S: 426.5 (M + H),
Found 426.3. 434
(E)-2-{2-[2-(4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzene
sulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.13
(dd, J = 1.6, 8 Hz, 1H), 7.69-7.66 (m, 2H), 7.65-7.52 (m, 5H), 7.41
(dd, J = 1.6, 8 Hz, 1H), 7.31 (dd, J = 1.6, 8 Hz, 1H), 7.18-7.10
(m, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.21H.sub.16FN.sub.3O.sub.2S: 394.4 (M + H), Found 394.3. 435
(E)-2-{2-[2-(4-difluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-ben-
zene sulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.13 (dd, J = 1.6, 8 Hz, 1H), 7.70 (d, J = 8 Hz, 2H), 7.66-7.61 (m,
4H), 7.54 (dt, J = 1.6, 8 Hz, 1H), 7.42 (dd, J = 1.6, 8 Hz, 1H),
7.32 (d, J = 8 Hz, 1H), 7.20 (d, J = 8 Hz, 2H), 7.15 (d, J = 16 Hz,
1H), 6.89 (s, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.22H.sub.17F.sub.2N.sub.3O.sub.2S: 426.5 (M + H), Found 426.3.
436
(E)-2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.13 (dd, J = 1.6, 8 Hz, 1H), 7.78 (s, 1H), 7.73
(dd, J = 1.6, 8 Hz, 1H), 7.66-7.61 (m, 4H), 7.54 (dt, J = 1.6, 8
Hz, 1H), 7.44 (d, J = 8 Hz, 1H), 7.41 (dd, J = 1.6, 8 Hz, 1H), 7.33
(d, J = 8 Hz, 1H), 7.34 (d, J = 16 Hz, 1H). Mass Spectrum (LCMS,
ESI pos.) Calcd. For C.sub.22H.sub.15F.sub.4N.sub.3O.sub.2S: 461.4
(M + H), Found 462.2. 437
(E)-2-{2-[2-(2,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzene
sulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.13
(dd, J = 1.6, 8 Hz, 1H), 7.97 (d, J = 16.8 Hz, 1H), 7.84 (d, J = 8
Hz, 1H), 7.66-7.51 (m, 5H), 7.41-7.37 (m, 2H), 7.32 (dd, J = 1.6, 8
Hz, 1H), 7.20 (d, J = 16 Hz, 1H). Mass Spectrum (LCMS, ESI pos.)
Calcd. For C.sub.21H.sub.15Cl.sub.2N.sub.3O.sub.2S: 445.3 (M + H),
Found 446.1. 438
(E)-2-{2-[2-(2-chloro-6-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzene sulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.13 (dd, J = 1.6, 8 Hz, 1H), 7.89 (d, J = 16.8 Hz, 1H),
7.66-7.60 (m, 3H), 7.54 (dt, J = 1.6, 8 Hz, 1H), 7.45 (d, J = 16
Hz, 1H), 7.43 (s, 1H), 7.41-7.32 (m, 3H), 7.24-7.18 (m, 1H). Mass
Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.21H.sub.15ClFN.sub.3O.sub.2S: 428.9 (M + H), Found 428.3. 439
(E)-2-{2-[2-(3-bromo-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.13 (dd, J = 1.6, 8 Hz, 1H), 7.94 (dd, J = 1.6, 8 Hz, 1H),
7.68-7.62 (m, 6H), 7.41 (dd, J = 1.6, 8 Hz, 1H), 7.32 (d, J = 1.6,
8 Hz, 1H), 7.28 (t, J = 8 Hz, 1H), 7.16 (d, J = 16.8 Hz, 1H). Mass
Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.21H.sub.15BrFN.sub.3O.sub.2S: 473.3 (M + H), Found 473.2. 440
(E)-2-{2-[2-(3-bromo-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.13 (dd, J = 1.6, 8 Hz, 1H), 7.94 (dd, J = 1.6, 8 Hz, 1H),
7.68-7.62 (m, 6H), 7.41 (dd, J = 1.6, 8 Hz, 1H), 7.32 (d, J = 1.6,
8 Hz, 1H), 7.28 (t, J = 8 Hz, 1H), 7.16 (d, J = 16.8 Hz, 1H). Mass
Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.21H.sub.15BrFN.sub.3O.sub.2S: 473.3 (M + H), Found 473.2.
Prophetic Example 17
[0307] Using the procedures described in Example 15 or 16 and
reagents, starting materials and conditions known to those skilled
in the art, the following prophetic compounds representative of the
present invention may be prepared:
TABLE-US-00021 Cpd Name and Data 91
(E)-2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-
vinyl}-1H-benzimidazol-5-yl)-benzenesulfonamide, 97
(E)-2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-benzenesulfonamide, 103
(E)-2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-benzenesulfonamide, 109
(E)-2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 115
(E)-2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-
yl}-benzenesulfonamide, 121
(E)-2-{2-[2-(4-methanesulfonylamino-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, and 127
(E)-2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide.
Example 18
(E)-N-Methyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-y-
l}-benzenesulfonamide (Cpd 310)
Step A. N-methylbenzenesulfonamide-2-boronic acid
[0308] To a solution of N-methylbenzenesulfonamide (2.00 g, 0.0117
mmol) in 20 mL THF at 0.degree. C. was added dropwise n-butyl
lithium (1.6 M in hexanes, 14.6 mL, 0.0234 mmol). After 30 min.,
triisopropyl borate (3.1 mL, 0.0164 mmol) was added, and the
mixture was stirred at 0.degree. C. for 2 hours. The reaction was
quenched by addition of 20 mL of 1M HCl (aq). The mixture was
extracted with EtOAc, and the organic fractions were washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and the filtrate was
concentrated to provide the title Compound 18a as a yellow oil.
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 7.81 (d, 1H)
7.62-7.56 (m, 2H) 2.52 (s, 3H).
Step B.
(3-tert-butoxycarbonylamino-2'-methylsulfamoyl-biphenyl-4-yl)-carb-
amic acid tert-butyl ester
[0309] A mixture of the freshly prepared Compound 18a (9.3 g,
0.0434 mol), Compound 16a (11.2 g, 0.289 mol),
Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (4.7 g, 6.42 mmol), TBAB (9.3 g,
0.0289 mol), in 120 mL of 1M Na.sub.2CO.sub.3 (aq) and 600 mL DME
was heated at 85.degree. C. for 10 hours. The reaction mixture was
cooled, and concentrated. The residue was purified by
chromatography (silica gel, hexanes: EtOAc, 2:1) to provide the
title Compound 18b as a yellow oil. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 8.12 (d, 1H) 7.86 (d, 1H) 7.62-7.46 (m,
3H) 7.22 (d, 1H) 7.14 (d, 1H) 2.62 (d, 3H) 1.55 (s, 9H) 1.44 (s,
9H).
Step C. 3',4'-diamino-biphenyl-2-sulfonic acid methylamide
[0310] A solution of Compound 18b (21.4 g, 0.0995 mol) in 210 mL of
4M HCl in dioxane was stirred for 4 hours. The reaction mixture was
concentrated, made basic with 1M NaOH (aq), and extracted with
EtOAc. The organic fraction was dried over Na.sub.2SO.sub.4,
filtered, and the filtrate was concentrated to provide the
title
[0311] Compound 18c as a brown oil. .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.00 (dd, 1H, J=1.6 and 8.0 Hz) 7.59
(dt, 1H, J=1.6 and 8.4 Hz) 7.48 (dt, 1H, J=1.2 and 8.4 Hz) 7.33
(dd, 1H, J=1.2 and 8.0 Hz) 6.79 (d, 1H, J=2.0 Hz) 6.75 (d, 1H,
J=8.4 Hz) 6.68 (d, 1H, J=2.0 and 7.6 Hz) 2.93 (s, 3H) MS (ESI, pos.
ion) m/z: 277.9 (M+1).
Step D.
(E)-N-methyl-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimid-
azol-5-yl}-benzenesulfonamide
[0312] A mixture of Compound 18c (0.100 g, 0.361 mmol) and
4-trifluoromethyl cinnamic acid (0.324 mmol) in 2 mL of POCl.sub.3
was heated to 100.degree. C. for 14 hours. Evaporation of the
reaction mixture provided a residue, which was then purified by
HPLC(H.sub.2O:MeCN, 90:10 to 30:70, over 15 min) to provide the
title Compound 310 as a white solid. .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.07 (dd, 1H, J=1.2 and 8.4 Hz) 7.85 (d,
2H, J=8.4 Hz) 7.73 (d, 2H, J=8 Hz) 7.69-7.63 (m, 3H) 7.58 (dt, 2H,
J=1.6 and 7.2 Hz) 7.44 (dd, 1H, J=1.2 and 7.2 Hz) 7.34 (d, J=16.4
Hz) 2.37 (s, 3H) MS (ESI, pos. ion) m/z: 499.2 (M+MeCN+1).
[0313] Using the procedures described in Example 18 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00022 Cpd Name and Data 312
(E)-2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.06 (dd, 1H, J = 1.2 and 8.0 Hz) 7.68-7.60 (m, 3H) 7.59-7.55 (m,
6H) 7.43 (dd, 1H, J = 1.2 and 7.2 Hz) 7.30 (dd, 1H, J = 1.6 and 8.0
Hz) 7.21 (d, 1H, J = 16.4 Hz) 2.38 (s, 3H) MS (ESI, pos. ion) m/z:
509.2 (M + MeCN). 314
(E)-N-methyl-2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-benzene
sulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.04
(dd, 1H, J = 1.2 and 8.0 Hz) 7.77 (d, 1H, J = 16.4 Hz) 7.70 (d, 1H,
J = 15.2 Hz) 7.66-7.64 (m, 2H) 7.61-7.55 (m, 3H) 7.46 (dd, 1H, J =
1.6 and 8.4 Hz) 7.41 (dd, 1H, J = 1.2 and 7.6 Hz) 7.26 (d, 2H, J =
7.6 Hz) 7.15 (d, 1H, J = 16.8 Hz) 2.42 (s, 3H) 2.36 (s, 3H) MS
(ESI, pos. ion) m/z: 404.2 (M + 1). 315
(E)-2-{2-[2-(4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.05 (dd, 1H, J = 1.2 and 7.6 Hz) 7.82-7.73 (m, 4H) 7.70-7.66 (m,
2H) 7.61 (dd, 1H, J = 1.2 and 7.6 Hz) 7.45 (dd, 1H, J = 1.2 and 8.0
Hz) 7.43 (dd, 1H, J = 1.2 and 7.2 Hz) 7.22 (d, 1H, J = 8.4 Hz) 7.21
(s, 2H) 7.18 (d, 1H, J = 7.6 Hz) 2.42 (s, 3H) MS (ESI, pos. ion)
m/z: 408.3 (M + 1). 316
(E)-2-{2-[2-(3,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.05 (dd, 1H, J = 1.2 and 7.6 Hz) 7.84 (s, 1H) 7.70-7.66 (m,
2H) 7.64 (d, 1H) 7.60 (d, 2H, J = 7.6 Hz) 7.59 (s, 2H) 7.42 (dt,
2H, J = 1.6 and 9.2 Hz) 7.25 (d, 1H, J = 16.4 Hz) 2.42 (s, 3H) MS
(ESI, pos. ion) m/z: 408.3 (M + 1). 317
(E)-2-{2-[2-(3-bromo-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.05 (dd, 1H, J = 1.2 and 7.6 Hz) 7.96 (dd, 1H, J = 2 and 5
Hz) 7.69-7.62 (m, 4H) 7.61-7.57 (m, 2H) 7.43 (dd, 1H, J = 1.2 and
7.2 Hz) 7.39 (dd, 1H, J = 1.6 and 8.0 Hz) 7.29 (t, 1H, J = 8.4 Hz)
7.18 (d, 1H, J = 16.4 Hz) 2.40 (s, 3H) MS (ESI, pos. ion) m/z:
486.2 (M). 318
(E)-2-{2-[2-(4-dimethylamino-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.05 (dd, 1H, J = 1.6 and 7.6 Hz) 7.96 (d, 1H, J = 16.4 Hz)
7.73-7.67 (m, 3H) 7.63 (dd, 1H, J = 1.2 and 8.0 Hz) 7.59 (d, 2H, J
= 9.2 Hz) 7.52 (dd, 1H, J = 1.6 and 8.4 Hz) 7.44 (dd, 1H, J = 1.6
and 7.6 Hz) 6.90 (d, 1H, J = 16 Hz) 6.81 (d, 2H, J = 8.8 Hz) 3.06
(s, 6H) 2.45 (s, 3H) MS (ESI, pos. ion) m/z: 433.4 (M + 1). 319
(E)-2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-N-methyl-benzenesulfonamide .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.05 (dd, 1H, J = 1.6 and 6.4 Hz) 7.77
(q, 1H, J = 5.3 Hz) 7.73-7.63 (m, 5H) 7.60 (dt, 1H, J = 1.6 and 8.4
Hz) 7.51 (dd, 1H, J = 1.6 and 6.4 Hz) 7.43 (d, 2H, J = 8.4 Hz) 7.39
(d, 1H, J = 16.8 Hz) 2.41 (s, 3H) MS (ESI, pos. ion) m/z: 476.3 (M
+ 1). 320
(E)-2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-N-methyl-benzenesulfonamide .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.06 (dd, 1H, J = 1.2 and 6.4 Hz) 8.01
(t, 1H, J = 7.8 Hz) 7.90 (d, 1H, J = 16.4 Hz) 7.70-7.65 (m, 3H)
7.61-7.56 (m, 3H) 7.45 (d, 1H, J = 16.8 Hz) 7.28 (dd, 1H, J = 1.2
and 7.2 Hz) 7.40 (d, 1H, J = 1.2 and 7.2 Hz) 2.40 (s, 3H) MS (ESI,
pos. ion) m/z: 476.3 (M + 1). 321
(E)-2-{2-[2-(3-chloro-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.05 (dd, 1H, J = 1.6 and 6.0 Hz) 7.86 (t, 1H, J = 2.0 and
6.2 Hz) 7.73-7.65 (m, 5H) 7.61 (dd, 1H, J = 1.6 and 7.6 Hz) 7.46
(dd, 1H, J = 1.6 and 8.8 Hz) 7.43 (dd, 1H, J = 1.2 and 7.2 Hz) 7.34
(t, 1H, J = 8.8 Hz) 7.22 (d, 1H, J = 16.4 Hz) 2.42 (s, 3H) MS (ESI,
pos. ion) m/z: 442.3 (M + 1). 322
(E)-2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-N-methyl-benzenesulfonamide .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.05 (dd, 1H, J = 1.6 and 6.0 Hz) 7.86
(t, 1H, J = 2.0 and 6.2 Hz) 7.73-7.65 (m, 5H) 7.61 (dd, 1H, J = 1.6
and 7.6 Hz) 7.46 (dd, 1H, J = 1.6 and 8.8 Hz) 7.43 (dd, 1H, J = 1.2
and 7.2 Hz) 7.34 (t, 1H, J = 8.8 Hz) 7.22 (d, 1H, J = 16.4 Hz) 2.42
(s, 3H) MS (ESI, pos. ion) m/z: 442.3 (M + 1). 323
(E)-N-methyl-2-{2-[2-(2,3,4-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.06 (d, 1H, J = 7.6 Hz) 7.75 (d, 1H, J = 16.8 Hz) 7.68-7.56
(m, 5H) 7.43 (d, 1H, J = 3.2 Hz) 7.34 (d, 1H, J = 1.2 and 8.0 Hz)
7.33 (d, 1H, J = 4.0 Hz) 7.22 (q, 1H, J = 8.8 Hz) 2.38 (s, 3H) MS
(ESI, pos. ion) m/z: 444.4 (M + 1). 324
(E)-N-methyl-2-{2-[2-(2,4,5-trifluoro-phenyl)-vinyl]-1H-benzimidazol-5-
-yl}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.05 (dd, 1H, J = 1.2 and 8.0 Hz) 7.87-7.82 (m, 2H)
7.72-7.58 (m, 5H) 7.46-7.42 (m, 2H) 7.31 (d, 1H, J = 16.4 Hz) 2.41
(s, 3H) MS (ESI, pos. ion) m/z: 444.4 (M + 1). 325
(E)-2-{2-[2-(2,3-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.06 (dd, 1H, J = 1.2 and 7.6 Hz) 7.95 (d, 1H, J = 16.8 Hz)
7.74-7.66 (m, 3H) 7.63-7.59 (m, 2H) 7.47 (dd, 1H, J = 1.6 and 8.0
Hz) 7.44 (dd, 1H, J = 1.6 and 8.0 Hz) 7.39 (d, 1H, J = 16.8 Hz)
7.34-7.70 (m, 2H) 2.42 (s, 3H) MS (ESI, pos. ion) m/z: 426.4 (M +
1). 326
(E)-2-{2-[2-(2,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.06 (dd, 1H, J = 1.2 and 7.6 Hz) 7.82 (d, 1H, J = 16.4 Hz)
7.69-7.64 (m, 3H) 7.61-7.55 (m, 2H) 7.43 (dd, 1H, J = 1.6 and 7.6
Hz) 7.37 (dd, 1H, J = 1.6 and 8.8 Hz) 7.33 (d, 1H, J = 16.8 Hz)
7.26-7.15 (m, 2H) 2.39 (s, 3H) MS (ESI, pos. ion) m/z: 426.4 (M +
1). 327
(E)-2-{2-[2-(2,6-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.06 (dd, 1H, J = 1.2 and 7.6 Hz) 7.90 (d, 1H, J = 16.8 Hz)
7.71-7.58 (m, 4H) 7.51 (d, 1H, J = 16.8 Hz) 7.46-7.43 (m, 3H) 7.12
(t, 2H, J = 9.0 Hz) 2.41 (s, 3H) MS (ESI, pos. ion) m/z: 426.4 (M +
1). 328
(E)-2-{2-[2-(3,5-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.05 (dd, 1H, J = 1.2 and 8.0 Hz) 7.68-7.56 (m, 5H) 7.43
(dd, 1H, J = 1.2 and 7.2 Hz) 7.36 (dd, 1H, J = 1.6 and 8.8 Hz)
7.31-7.25 (m, 3H) 6.99-6.96 (m, 1H) 2.39 (s, 3H) MS (ESI, pos. ion)
m/z: 426.3 (M + 1). 329
(E)-2-{2-[2-(3,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.06 (dd, 1H, J = 1.2 and 7.6 Hz) 7.66-7.56 (m, 6H)
7.48-7.42 (m, 2H) 7.36-7.32 (m, 2H) 7.17 (d, 1H, J = 16.8 Hz) 2.38
(s, 3H) MS (ESI, pos. ion) m/z: 426.4 (M + 1). 330
(E)-2-{2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-N-methyl-benzenesulfonamide .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.25 (dd, 1H, J = 1.6 and 16.4 Hz) 8.16
(dd, 1H, J = 1.2 and 9.2 Hz) 8.06 (dd, 1H, J = 1.2 and 7.6 Hz) 8.4
(d, 1H, J = 1.2 Hz) 8.25 (dd, 1H, J = 0.8 and 8.0 Hz) 7.73-7.56 (m,
5H) 7.46 (dd, 1H, J = 1.6 and 8.0 Hz) 7.65 (d, 1H, J = 16.4 Hz)
2.46 (s, 3H) MS (ESI, pos. ion) m/z: 476.4 (M + 1). 331
(E)-2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-N-methyl-benzenesulfonamide .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.06 (dd, 1H, J = 1.2 and 8.0 Hz)
8.02-7.98 (m, 2H) 7.18-7.56 (m, 4H) 7.45-7.40 (m, 2H) 7.38 (dd, 1H,
J = 1.6 and 8.4 Hz) 7.26 (d, 1H, J = 16.8 Hz) 2.39 (s, 3H) MS (ESI,
pos. ion) m/z: 476.4 (M + 1). 332
(E)-2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-N-methyl-benzenesulfonamide .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.10-8.05 (m, 2H) 7.84 (d, 1H, J = 16.8
Hz) 7.71-7.55 (m, 5H) 7.43 (dd, 1H, J = 1.6 and 7.2 Hz) 7.37 (d,
1H, J = 16.8 Hz) 7.32 (dd, 1H, J = 1.2 and 8.4 Hz) 2.37 (s, 3H) MS
(ESI, pos. ion) m/z: 476.5 (M + 1). 333
(E)-2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}-N- methyl-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.24 (s, 2H) 7.06 (dd, 1H, J = 1.2 and 8.0 Hz) 7.94
(s, 1H) 7.73-7.55 (m, 5H) 7.45-7.40 (m, 2H) 7.32 (dd, 1H, J = 1.6
and 8.4 Hz) 2.38 (s, 3H) MS (ESI, pos. ion) m/z: 526.4 (M + 1). 334
(E)-2-{2-[2-(2,5-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}-N- methyl-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.27 (s, 1H) 8.08-7.92 (m, 3H) 8.87 (d, 1H, J = 8.4
Hz) 7.69-7.56 (m, 4H) 7.44 (dd, 1H, J = 1.6 and 8.0 Hz) 7.36-7.32
(m, 2H) 2.37 (s, 3H) MS (ESI, pos. ion) m/z: 526.4 (M + 1). 335
(E)-2-{2-[2-(3-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.06 (d, 1H, J = 8.4 Hz) 7.93 (d, 1H, J = 8.0 Hz) 7.81 (d,
1H, J = 16.4 Hz) 7.74-7.56 (m, 4H) 7.50-7.23 (m, 5H) 2.37 (s, 3H)
MS (ESI, pos. ion) m/z: 442.4 (M + 1). 336
(E)-2-{2-[2-(2-chloro-6-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.06 (dd, 1H, J = 1.2 and 8.0 Hz) 7.89 (d, 1H, J = 16.8 Hz)
7.68-7.55 (m, 4H) 7.45 (d, 1H, J = 16.8 Hz) 7.43 (dd, 1H, J = 1.2
and 7.6 Hz) 7.38-7.31 (m, 3H) 7.23-7.18 (m, 1H) 2.37 (s, 3H) MS
(ESI, pos. ion) m/z: 442.4 (M + 1). 337
(E)-2-{2-[2-(2,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.05 (dd, 1H, J = 1.2 and 8.0 Hz) 8.51 (d, 1H, J = 16.8 Hz)
7.88 (d, 1H, J = 8.0 Hz) 7.68-7.56 (m, 5H) 7.45-7.41 (m, 2H) 7.32
(dd, 1H, J = 1.6 and 8.4 Hz) 7.24 (d, 1H, J = 16.4 Hz) 2.37 (s, 3H)
MS (ESI, pos. ion) m/z: 458.3 (M + 1). 338
(E)-2-{2-[2-(3-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.06 (dd, 1H, J = 1.2 and 7.6 Hz) 7.82 (t, 1H, J = 1.8 Hz)
7.68-7.49 (m, 7H) 7.43 (dd, 1H, J = 1.2 and 7.2 Hz) 7.35 (d, 1H, J
= 7.6 Hz) 7.30 (dd, 1H, J = 0.8 and 8.0 Hz) 7.21 (d, 1H, J = 16.4
Hz) 2.37 (s, 3H) MS (ESI, pos. ion) m/z: 468.3 (M + 1).
339
(E)-2-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.40 (d, 1H, J = 16.4 Hz) 8.08-8.06 (m, 2H) 8.01 (d, 1H, J =
8.4 Hz) 7.89 (dd, 1H, J = 2.4 and 8.4 Hz) 7.80-7.56 (m, 4H) 7.44
(dd, 1H, J = 1.2 and 7.2 Hz) 7.33 (dd, 1H, J = 1.6 and 7.2 Hz) 7.26
(d, 1H, J = 16.4 Hz) 2.37 (s, 3H) MS (ESI, pos. ion) m/z: 442.3 (M
+ 1). 340
(E)-2-{2-[2-(4-chloro-2-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-
- 5-yl}-N-methyl-benzenesulfonamide .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.06 (dd, 1H, J = 1.2 and 7.6 Hz)
7.76-7.72 (m, 2H) 7.66-7.54 (m, 4H) 7.42 (dd, 1H, J = 0.8 and 7.2
Hz) 7.32-7.26 (m, 4H) 2.37 (s, 3H) MS (ESI, pos. ion) m/z: 502.3 (M
+ 1). 341
(E)-N-methyl-2-{2-[2-(4-trifluoromethylthio-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.12 (d, 2H, J = 8.8 Hz) 8.06 (dd, 1H, J
= 1.2 and 8.4 Hz) 8.06 (d, 2H, J = 8.8 Hz) 7.75-7.56 (m, 5H) 7.47
(d, 1H, J = 16.4 Hz) 7.44 (dd, 1H, J = 1.2 and 7.2 Hz) 7.34 (dd,
1H, J = 1.2 and 8.4 Hz) 2.38 (s, 3H) MS (ESI, pos. ion) m/z: 522.3
(M + 1). 342
(E)-N-methyl-2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.06 (dd, 1H, J = 1.2 and 8.4 Hz) 7.75
(q, 4H, J = 10.6 Hz) 7.44-7.55 (m, 5H) 7.43 (dd, 1H, J = 1.2 and
7.6 Hz) 7.33-7.28 (m, 2H) 2.37 (s, 3H) MS (ESI, pos. ion) m/z:
490.3 (M + 1). 343
(E)-N-methyl-2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.07 (dd, 1H, J = 1.2 and 8.0 Hz) 8.02 (dd, 1H, J =
12.0 and 16.0 Hz) 7.98 (d, 1H, J = 8.0 Hz) 7.77 (d, 1H, J = 8.4 Hz)
7.72-7.62 (m, 4H) 7.57 (dt, 1H, J = 1.6 and 8.4 Hz) 7.54 (t, 1H, J
= 7.6 Hz) 7.44 (dd, 1H, J = 1.2 and 7.2 Hz) 7.32 (dd, 1H, J = 1.6
and 8.4 Hz) 7.21 (d, 1H, J = 16.4 Hz) 2.37 (s, 3H) MS (ESI, pos.
ion) m/z: 458.4 (M + 1). 344
(E)-N-methyl-2-{2-[2-(3-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazo-
l- 5-yl}-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.06 (dd, 1H, J = 1.2 and 8.0 Hz) 7.66-7.62 (m, 4H)
7.60-7.54 (m, 3H) 7.51 (d, 1H, J = 8.0 Hz) 7.43 (dd, 1H, J = 1.2
and 7.2 Hz) 7.31 (dd, 1H, J = 1.2 and 8.0 Hz) 7.28 (d, 1H, J = 8.4
Hz) 7.25 (d, 1H, J = 16.8 Hz) 2.37 (s, 3H) MS (ESI, pos. ion) m/z:
474.4 (M + 1). 345
(E)-N-methyl-2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-benzimidazo-
l- 5-yl}-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.06 (dd, 1H, J = 1.2 and 7.6 Hz) 7.75 (d, 2H, J =
8.4 Hz) 7.69-7.64 (m, 3H) 7.61 (d, 1H, J = 8.0 Hz) 7.57 (dt, 1H, J
= 1.2 and 8.4 Hz) 7.42 (dd, 1H, J = 1.6 and 8.4 Hz) 7.33 (d, 3H, J
= 10.0 Hz) 7.20 (d, 1H, J = 16.4 Hz) 2.38 (s, 3H) MS (ESI, pos.
ion) m/z: 474.4 (M + 1). 346
(E)-2-{2-[2-(2-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.03-8.05 (m, 2H) 7.87 (dd, 2H, J = 1.68 and 7.6 Hz) 7.66-7.55 (m,
4H) 7.45 (dd, 1H, J = 1.6 and 7.6 Hz) 7.43 (dd, 1H, J = 1.2 and 7.2
Hz) 7.38-7.30 (m, 3H) 7.22 (d, 1H, J = 16.4 Hz) 2.37 (s, 3H) MS
(ESI, pos. ion) m/z: 425.3 (M + 1). 347
(E)-2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.06 (dd, 1H, J = 1.2 and 8.0 Hz) 7.36-7.63 (m, 4H) 7.62-7.55 (m,
3H) 7.44 (d, 3H, J = 8.0 Hz) 7.31 (dd, 1H, J = 1.6 and 8.0 Hz) 7.19
(d, 1H, J = 16.4 Hz) 2.36 (s, 3H) MS (ESI, pos. ion) m/z: 425.3 (M
+ 1). 348
(E)-2-{2-[2-(2-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.07 (dd, 1H, J = 1.2 and 8.0 Hz) 8.02 (d, 1H, J = 16.4 Hz) 7.84
(dd, 1H, J = 1.6 and 8.4 Hz) 7.68-7.55 (m, 5H) 7.44-7.40 (m, 2H)
7.31 (dd, 1H, J = 1.2 and 6.8 Hz) 7.02 (dt, 1H, J = 1.6 and 8.4 Hz)
7.17 (d, 1H, J = 16.4 Hz) 2.37 (s, 3H) MS (ESI, pos. ion) m/z:
469.5 (M + 1). 349
(E)-2-{2-[2-(2,4-difluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methy-
l- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.06 (dd, 1H, J = 1.2 and 8.0 Hz) 7.80 (q, 1H, J = 8.0 Hz)
7.74 (d, 1H, J = 16.8 Hz) 7.67-7.54 (m, 5H) 7.42 (dd, 1H, J = 1.2
and 7.6 Hz) 7.30 (dd, 1H, J = 1.6 and 8.4 Hz) 7.23 (d, 1H, J = 16.8
Hz) 7.05 (t, 1H, J = 8.8 Hz) 2.37 (s, 3H) MS (ESI, pos. ion) m/z:
426.4 (M + 1). 351
(E)-2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-
methyl-benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.07 (dd, 1H, J = 1.2 and 8.0 Hz) 8.01 (d, 2H, J = 8.4 Hz)
7.90 (d, 2H, J = 8.8 Hz) 7.72 (d, 1H, J = 16.4 Hz) 7.67-7.56 (m,
4H) 7.44 (dd, 1H, J = 1.6 and 7.2 Hz) 7.38 (d, 1H, J = 16.4 Hz)
7.33 (dd, 1H, J = 1.6 and 8.4 Hz) 3.15 (s, 3H) 2.37 (s, 3H) MS
(ESI, pos. ion) m/z: 468.4 (M + 1).
Example 19
(E)-N-(2-{2-[2-(4-ethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-meth-
anesulfonamide (Cpd 414)
Step A.
(3-tert-butoxycarbonylamino-2'-methanesulfonylamino-biphenyl-4-yl)-
-carbamic acid tert-butyl ester
[0314] To a solution of Compound 16a (2.0 g, 5.1 mmol),
2-methylsulfonylphenyl boronic acid (1.1 g, 5.1 mmol), and
K.sub.2CO.sub.3 (2.1 g, 15.3 mmol) in 1,4-dioxane:water (4:1, 120
mL), was added Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (0.42 g, 0.51 mmol)
under an argon atmosphere. The mixture was heated at 95.degree. C.
for 12 h. The reaction mixture was cooled to room temperature and
concentrated under reduced pressure. The residue was purified by
chromatography (silica, EtOAc: hexanes, 3:7) to provide the title
Compound 19a as a yellow solid (1.7 g, 70% yield). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. (ppm): 7.64 (d, J=8.4 Hz, 1H), 7.57 (d,
J=14.4 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 7.26-7.15 (m, 3H), 7.07 (s,
1H), 7.04 (d, J=8 Hz, 1H), 6.87 (s, 1H), 6.63 (s, 1H), 2.90 (s,
3H), 1.51 (s, 9H), 1.49 (s, 9H). Mass Spectrum (LCMS, ESI pos.)
Calcd. For C.sub.23H.sub.31N.sub.3O.sub.6S: 478.19 (M+H), Found
478.0.
Step B. N-(3',4'-diamino-biphenyl-2-yl)-methanesulfonamide
[0315] A solution of Compound 19a (1.0 g, 2.1 mmol) in a mixture of
4M HCl in 1,4-dioxane (10 mL) was heated at 70.degree. C. for 2 h.
After concentration of the reaction, the residue was dissolved in
dichloromethane (20 mL), and to the solution was added
K.sub.2CO.sub.3 (0.5 g) and the mixture was stirred at room
temperature for 20 min. After filtration and removal of solvents,
the residue was dried to provide the title Compound 19b as a brown
solid (0.58 g, quantitative yield). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 7.47 (d, J=8.4 Hz, 1H), 7.40-7.35 (m,
1H), 7.32-7.29 (m, 2H), 7.16-7.09 (m, 3H), 2.80 (s, 3H). Mass
Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.13H.sub.15N.sub.3O.sub.2S: 278.09 (M+H), Found 278.1.
Step C.
(E)-N-(2-{2-[2-(4-ethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phen-
yl)-methanesulfonamide
[0316] A solution of Compound 19b (50 mg, 0.18 mmol) and
commercially available 3-(4-ethoxy-phenyl)-acrylic acid (34.6 mg,
0.18 mmol) in POCl.sub.3 (1.5 mL) was heated to 100.degree. C. for
12 h. The reaction was cooled, the excess POCl.sub.3 was removed
under reduced pressure, and the residue was purified by HPLC
(Gilson, C-18 column, CH.sub.3CN: H.sub.2O (gradient of CH.sub.3CN:
5%-80%)) to provide the title Compound 414 as an off-white solid
(25 mg, 32% yield). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
(ppm):7.62-7.59 (m, 4H), 7.54-7.52 (m, 1H), 7.41-7.37 (m, 2H),
7.35-7.30 (m, 2H), 7.03 (d, J=16.8 Hz, 2H), 6.97 (d, J=12 Hz, 2H),
4.09 (q, J=7.2 Hz, 2H), 2.72 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). Mass
Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.24H.sub.23N.sub.3O.sub.3S: 434.1 (M+H), Found 434.1.
[0317] Using the procedures described in Example 19 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00023 Cpd Name and Data 77
(E)-N-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm)
7.40-7.56 (m, 6H) 7.24-7.33 (m, 4H) 7.19-7.22 (m, 2H) 7.05 (d, J =
16.4 Hz, 1H) 2.61 (s, 3H). MS (ESI, pos. ion) m/z: 424.1 (M + 1).,
83
(E)-N-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 7.99-7.96 (m, 2H), 7.89-7.86 (m, 4H), 7.78 (dd, J =
6.4, 15.8 Hz, 2H), 7.60 (dd, J = 1.2, 8.2 Hz, 1H), 7.46-7.39 (m,
2H), 7.33 (dt, J = 1.6, 8.2 Hz, 2H), 6.99 (dd, J = 6.4, 15.8 Hz,
2H), 3.10 (s, 3H), 3.09 (s, 3H). Mass Spectrum (LCMS, ESI pos.)
Calcd. For C.sub.23H.sub.21N.sub.3O.sub.4S.sub.2: 468.1 (M + H),
Found 468.0., 95
(E)-N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimidaz-
ol-5- yl)-phenyl]-methanesulfonamide .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 7.67-7.62 (m, 5H), 7.54-7.52, (m, 1H),
7.42-7.33 (m, 4H), 7.09 (d, J = 16.4 Hz, 2H), 7.08 (d, J = 12 Hz,
1H), 4.60 (q, J = 8.4 Hz, 2H), 2.74 (s, 3H). Mass Spectrum (LCMS,
ESI pos.) Calcd. For C.sub.24H.sub.20F.sub.3N.sub.3O.sub.3S: 488.1
(M + H), Found 488.3, 101
(E)-N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-phenyl]-methanesulfonamide .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 7.65-7.60 (m, 5H), 7.54-7.52 (m, 1H),
7.41-7.37 (m, 2H), 7.34-7.30 (m, 2H), 7.10-7.06 (m, 3H), 4.68 (t, J
= 12.8 Hz, 2H), 2.74 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd.
For C.sub.25H.sub.20F.sub.5N.sub.3O.sub.3S: 538.1 (M + H), Found
538.2., 113
(E)-N-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanesulfonamide .sup.1H-NMR (400 MHz, CD3OD) .delta.
(ppm) 7.90-7.96 (m, 2H) 7.54-7.76 (m, 6H) 7.26-7.42 (m, 5H) 2.76
(s, 3H). MS (ESI, pos. ion) m/z: 458.1 (M + 1)., 406
(E)-N-(2-{2-[2-(4-bromo-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
7.87-7.80 (m, 2H), 7.58-7.30 (m, 9H), 2.85 (s, 3H). Mass Spectrum
(LCMS, ESI pos.) Calcd. For C.sub.22H.sub.18BrN.sub.3O.sub.2S:
468.0 (M + H), Found 469.1., 407
(E)-N-(2-{2-[2-(4-isopropyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- methanesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 7.67-7.52) (m, 6H), 7.14 (d, J = 16.4 Hz, 1H), 3.13-3.12 (m,
1H), 2.72 (s, 3H), 1.27 (d, J = 6.8 Hz, 6H). Mass Spectrum (LCMS,
ESI pos.) Calcd. For C.sub.25H.sub.25N.sub.3O.sub.2S: 432.2 (M +
H), Found 432.2., 408
(E)-N-(2-{2-[2-(4-isopropyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-pheny-
l)- methanesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 7.82 (dd, J = 2.4, 7.2 Hz, 1H) 7.66-7.60 (m, 4H), 7.56-7.52
(m, 2H), 7.41-7.39 (m, 6H), 7.18 (d, J = 16.4 Hz, 1H), 2.73 (s,
3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.22H.sub.17ClFN.sub.3O.sub.2S: 442.1 (M + H), Found 442.3.,
409
(E)-N-(2-{2-[2-(3-bromo-4-fluoro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 7.95 (dd, J-2.4, 6.8 Hz, 1H), 7.69-7.68 (m, 1H),
7.67-7.63 (m, 2H), 7.58 (d, J = 16.4 Hz, 1H), 7.53-7.51 (m, 1H),
7.40-7.26 (m, 5H), 7.18 (d, J = 16.4 Hz, 1H), 2.72 (s, 3H). Mass
Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.22H.sub.17BrFN.sub.3O.sub.2S: 486.0 (M + H), Found 486.3.,
410
(E)-N-(2-{2-[2-(4-difluoromethoxy-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 7.73 (d, J = 12.8 Hz, 2H), 7.54-7.52 (m, 1H),
7.48-7.45 (m, 1H), 7.41-7.39 (m, 2H), 7.34-7.30 (m, 2H), 7.21 (d, J
= 8.8 Hz, 2H), 7.16 (d, J = 17.2 Hz, 1H), 6.90 (s, 1H), 2.73 (s,
3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.23H.sub.19F.sub.2N.sub.3O.sub.3S: 456.1 (M + H), Found
456.1., 411
(E)-N-(2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol- 5-yl}-phenyl)-methanesulfonamide .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 7.77 (s, 1H), 7.75 (d, J = 12 Hz, 1H),
7.68 (s, 1H), 7.67-7.64 (m, 2H), 7.52 (d, J = 12 Hz, 1H), 7.46 (d,
J = 12 Hz, 1H), 7.40-7.25 (m, 5H), 2.74 (s, 3H). Mass Spectrum
(LCMS, ESI pos.) Calcd. For C.sub.23H.sub.17F.sub.4N.sub.3O.sub.2S:
476.1 (M + H), Found 476.2, 412
(E)-N-{2-[2-(2-p-tolyl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
7.65-7.60 (m, 3H), 7.41-7.36 (m, 3H), 7.41-7.36 (m, 2H), 7.33-7.30
(m, 2H), 7.26 (d, J = 10 Hz, 2H), 7.18 (d, J = 20 Hz, 1H), 2.74 (s,
3H), 2.39 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.23H.sub.21N.sub.3O.sub.2S: 404.1 (M + H), Found 404.3, 413
(E)-N-(2-{2-[2-(4-dimethylamino-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 7.69-7.61 (m, 2H) 7.57-7.51 (m, 2H), 7.46-7.39 (m,
3H), 7.29 (d, J = 16.2 Hz, 2H), 7.05 (d, J = 12 Hz, 1H), 6.67 (d, J
= 16.2 Hz, 2H), 6.33 (d, J = 12 Hz, 1H), 3.01 (s, 3H), 2.97 (s,
6H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.24H.sub.24N.sub.4O.sub.2S: 433.2 (M + H), Found 433.3, 415
(E)-N-{2-[2-(2-naphthalen-2-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.09 (s, 1H), 7.96-7.88, (m, 4H), 7.74-7.72 (m, 2H), 7.57-7.52 (m,
3H), 7.51-7.33 (m, 6H), 2.80 (s, 3H). Mass Spectrum (LCMS, ESI
pos.) Calcd. For C.sub.26H.sub.21N.sub.3O.sub.2S: 440.1 (M + H),
Found 440.3, 416
(E)-N-(2-{2-[2-(3,4-dichloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phen-
yl)- methanesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.03-8.00 (m, 1H), 7.93 (s, 1H), 7.77 (s, 1H), 7.74 (d, J =
11.2 Hz, 1H), 7.69 (s, 1H), 7.57-7.52 (m, 2H), 7.47 (d, J = 8 Hz,
1H), 7.44 (d, J = 7.6 Hz, 2H), 7.40-7.36 (m, 1H), 7.32 (d, J = 17.2
Hz, 1H), 2.84 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.22H.sub.17Cl.sub.2N.sub.3O.sub.2S: 458.0 (M + H), Found
458.2., 417
(E)-N-(2-{2-[2-(3-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol- 5-yl}-phenyl)-methanesulfonamide .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.03-8.00 (m, 1H), 7.76 (t, J = 8.0 Hz,
1H), 7.71-7.67 (m, 3H), 7.63 (d, J = 8.4 Hz, 1H), 7.54-7.52 (m,
1H), 7.78-7.44 (m, 1H), 7.43-7.38 (m, 3H), 7.38-7.32 (m, 1H), 2.77
(s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.23H.sub.17F.sub.4N.sub.3O.sub.2S: 476.1 (M + H), Found
476.2., 418
(E)-N-(2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-1H-benzimida-
zol- 5-yl}-phenyl)-methanesulfonamide .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.00 (t, J = 8.4 Hz, 1H), 7.84 (d, J =
17.2 Hz, 1H), 7.62-7.58 (m, 2H), 7.55-7.52 (m, 2H), 7.46 (s, 1H),
7.44-7.38 (m, 3H), 7.38-7.32 (m, 2H), 2.74 (s, 3H). Mass Spectrum
(LCMS, ESI pos.) Calcd. For C.sub.23H.sub.17F.sub.4N.sub.3O.sub.2S:
476.1 (M + H), Found 476.2, 475
(E)-N-{2-[2-(2-biphenyl-4-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm)
7.44-7.65 (m, 10H) 7.22-7.40 (m, 5H) 7.10-7.20 (m, 3H) 2.76 (s,
3H). MS (ESI, pos. ion) m/z: 466.2 (M + 1).,
Prophetic Example 20
[0318] Using the procedures described in Example 19, or using the
procedures in Example 1 and the corresponding bromobenzimidazole
and boronic acid or boronate ester, and reagents, starting
materials and conditions known to those skilled in the art, the
following prophetic compounds representative of the present
invention may be prepared:
TABLE-US-00024 Cpd Name and Data 89
(E)-N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-
phenyl]-vinyl}-1H-benzimidazol-5-yl)-phenyl]- methanesulfonamide,
107 (E)-N-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide, 119
(E)-N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 125
(E)-C,C,C-trifluoro-N-(4-{2-[5-(2-methanesulfonylamino-
phenyl)-1H-benzimidazol-2-yl]-vinyl}-phenyl)-
methanesulfonamide,
Prophetic Example 21
[0319] Using the procedures described in Example 1 or Example 19
and reagents, starting materials and conditions known to those
skilled in the art, the following prophetic compounds
representative of the present invention may be prepared:
TABLE-US-00025 Cpd Name and Data 72
(E)-C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 73
(E)-C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 74
(E)-C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-viny-
l]-1H- benzimidazol-5-yl}-phenyl)-methanesulfonamide. 75
(E)-1-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanone, 76
(E)-1-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanol, 80
(E)-N-(2-{2-[2-(4-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
C,C,C-trifluoro-methanesulfonamide. 81
(E)-1-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanone, 82
(E)-1-(2-{2-[2-(4-methanesulfonyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanol, 87
(E)-1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-vi-
nyl}- 1H-benzimidazol-5-yl)-phenyl]-ethanone, 88
(E)-1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-vi-
nyl}- 1H-benzimidazol-5-yl)-phenyl]-ethanol, 90
(E)-2-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-vi-
nyl}- 1H-benzimidazol-5-yl)-phenyl]-propan-2-ol, 92
(E)-C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-et-
hoxy)-
phenyl]-vinyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 93
(E)-1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimidaz-
ol-5-yl)- phenyl]-ethanone, 94
(E)-1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimidaz-
ol-5-yl)- phenyl]-ethanol, 96
(E)-2-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-vinyl}-1H-benzimidaz-
ol-5-yl)- phenyl]-propan-2-ol, 98
(E)-C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-viny-
l}-1H- benzimidazol-5-yl)-phenyl]-methanesulfonamide, 99
(E)-1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanone, 100
(E)-1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanol, 102
(E)-2-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-vinyl}-1H-
benzimidazol-5-yl)-phenyl]-propan-2-ol, and 104
(E)-C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phen-
yl]- vinyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide. 105
(E)-1-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanone, 106
(E)-1-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanol, 108
(E)-2-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
propan-2-ol, 110
(E)-N-(2-{2-[2-(3-chloro-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-
C,C,C-trifluoro-methanesulfonamide, 111
(E)-1-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-ethanone, 112
(E)-1-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-
- phenyl)-ethanol, 116
(E)-C,C,C-trifluoro-N-(2-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide. 117
(E)-N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-vinyl}-phenyl)-
methanesulfonamide, 118
(E)-N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-yl}-viny-
l)- phenyl]-methanesulfonamide, 120
(E)-N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-
- yl}-vinyl)-phenyl]-methanesulfonamide, 122
(E)-C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-vinyl]--
1H- benzimidazol-5-yl}-phenyl)-methanesulfonamide, 123
(E)-N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-vinyl}-phenyl)-
C,C,C-trifluoro-methanesulfonamide, 124
(E)-C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-
benzimidazol-2-yl}-vinyl)-phenyl]-methanesulfonamide, 126
(E)-C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1-
H- benzimidazol-2-yl}-vinyl)-phenyl]-methanesulfonamide, and 128
(E)-C,C,C-trifluoro-N-(4-{2-[5-(2-trifluoromethanesulfonylamino-phenyl-
)- 1H-benzimidazol-2-yl]-vinyl}-phenyl)-methanesulfonamide.
Example 22
2-{2-[2-(2-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-benzenesul-
fonamide (Cpd 401)
[0320] A mixture of
(E)-2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benze-
nesulfonamide Cpd 364 (0.020 g, 0.045 mmol) and 10% palladium on
charcoal (0.005 g, 0.0045 mmol) in 2 mL MeOH was hydrogenated under
H.sub.2 gas (1 atm) for 1 hour. The catalyst was removed by
filtration, the filtrate was concentrated to dryness, and the
residue was purified by chromatography (silica gel, MeOH:
CH.sub.2Cl.sub.2=10:1) to give the title compound as a white solid.
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.14 (dd, 1H,
J=1.2 and 7.6 Hz) 7.74-7.53 (m, 4H) 7.60-7.56 (m, 2H) 7.51-7.40 (m,
4H) 3.41 (m, 4H) MS (ESI, pos. ion) m/z: 446.5 (M+1).
[0321] Using the procedures described in Example 22 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared from the corresponding vinyl
derivatives:
TABLE-US-00026 Cpd Name and Data 129
2-{2-[2-(4-trifluoromethoxy-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, 1.2 and 8.0 Hz) 7.65-7.54 (m, 4H) 7.44-7.31 (m, 4H)
7.20 (d, 2H, J = 8.8 Hz) 3.26-3.23 (m, 4H) MS (ESI, pos. ion) m/z:
462.4 (M + 1). 130
2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.12 (dd, 1H, J = 1.2 and 8.4 Hz) 7.64-7.51 (m, 6H) 7.42 (d, 2H, J
= 8.0 Hz) 7.39 (dd, 1H, J = 1.2 and 7.6 Hz) 7.27 (dd, 1H, J = 1.6
and 8.4 Hz) 3.24 (m, 4H) MS (ESI, pos. ion) m/z: 446.4 (M + 1). 131
2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.15 (dd, 1H, J = 1.2 and 8.0 Hz) 8.02 (d, 2H, J = 8.8 Hz)
7.70-7.55 (m, 7H) 7.42 (dd, 1H, J = 1.6 and 7.2 Hz) 7.36 (dd, 1H, J
= 1.6 and 8.4 Hz) 3.41-3.48 (m, 4H) MS (ESI, pos. ion) m/z: 510.2
(M + 1). 139
2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-benzene
sulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.12
(dd, 1H, 1.6 and 8.0 Hz) 7.64-7.59 (m, 2H) 7.55-7.51 (m, 2H) 7.39
(dd, 1H, J = 0.8 and 7.6 Hz) 7.32-7.14 (m, 5H) 3.20-3.13 (m, 4H) MS
(ESI, pos. ion) m/z: 412.3 (M + 1). 145
2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, 1.2 and 7.6 Hz) 7.87 (d, 2H, J = 8.4 Hz) 7.66-7.50
(m, 6H) 7.41 (dd, 1H, J = 1.2 and 8.0 Hz) 7.30 (dd, 1H, J = 1.6 and
8.4 Hz) 3.10 (m, 4H) MS (ESI, pos. ion) m/z: 456.3 (M + 1). 175
2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.13 (dd, 1H, J = 1.2 and 7.6 Hz) 7.70-7.48 (m, 8H) 7.44 (dd, 1H, J
= 1.6 and 8.0 Hz) 7.39 (dd, 1H, J = 1.2 and 7.2 Hz) 3.40-3.30 (m,
4H) MS (ESI, pos. ion) m/z: 446.4 (M + 1). 383
2-{2-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.02 (dd, 1H, J = 1.2 and 8.0 Hz) 7.52-7.49 (m, 2H)
7.45-7.41 (m, 4H) 7.31-7.26 (m, 1H) 7.18 (dd, 1H, J = 1.2 and 8.0
Hz) 7.13 (t, 1H, J = 7.2 Hz) 3.20-3.15 (m, 4H) MS (ESI, pos. ion)
m/z: 446.4 (M + 1). 384
2-{2-[2-(2,3,4-trifluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, J = 1.2 and 8.0 Hz) 7.66-7.53 (m, 4H) 7.42 (dd, 1H, J
= 1.6 and 7.6 Hz) 7.29 (dd, 1H, J = 1.6 and 8.4 Hz) 7.04-6.99 (m,
2H) 3.24 (m, 4H) MS (ESI, pos. ion) m/z: 432.5 (M + 1). 385
2-{2-[2-(2,4,5-trifluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, J = 1.2 and 8.4 Hz) 7.67-7.53 (m, 4H) 7.42 (dd, 1H, J
= 1.2 and 7.6 Hz) 7.30 (dd, 1H, J = 1.6 and 8.4 Hz) 7.26-7.10 (m,
2H) 3.23-3.20 (m, 4H) MS (ESI, pos. ion) m/z: 432.3 (M + 1). 386
2-{2-[2-(2,6-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, J = 1.2 and 8.0 Hz) 7.67-7.53 (m, 4H) 7.42 (dd, 1H, J
= 1.2 and 7.6 Hz) 7.31-7.25 (m, 2H) 6.97-6.93 (m, 2H) 3.26-3.19 (m,
4H) MS (ESI, pos. ion) m/z: 414.3 (M + 1). 387
2-{2-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.12 (dd, 1H, 1.6 and 8.0 Hz) 7.92 (dd, 1H, 1.2 and 8.4 Hz) 7.80
(s, 1H) 7.64-7.51 (m, 4H) 7.40-7.33 (m, 2H) 7.28 (dd, 1H, J = 1.6
and 8.0 Hz) 3.38-3.25 (m, 4H) MS (ESI, pos. ion) m/z: 514.4 (M +
1). 388
2-{2-[2-(2,5-bis-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.15 (dd, 1H, J = 1.2 and 7.6 Hz) 7.94 (d, 1H, J = 8.0 Hz)
7.76-7.72 (m, 2H) 7.67-7.54 (m, 4H) 7.42 (dd, 1H, J = 1.2 and 7.6
Hz) 7.33 (dd, 1H, J = 1.6 and 8.4 Hz) 3.50-3.45 (m, 2H) 3.31-3.26
(m, 2H) MS (ESI, pos. ion) m/z: 514.5 (M + 1). 390
2-{2-[2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.12 (dd, 1H, 1.6 and 8.0 Hz) 7.54-7.60 (m, 3H) 7.54 (dd,
1H, J = 1.2 and 8.0 Hz) 7.52-7.48 (m, 2H) 7.43 (dd, 1H, J = 2.0 and
8.4 Hz) 7.39 (dd, 1H, J = 1.6 and 7.2 Hz) 7.27 (d, 1H, J = 8.0 Hz)
3.23 (m, 4H) MS (ESI, pos. ion) m/z: 480.4 (M + 1). 391
2-{2-[2-(3-trifluoromethoxy-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.15 (dd, 1H, 1.2 and 8.0 Hz) 7.65-7.54 (m, 4H) 7.43-7.37 (m, 2H)
7.33 (dd, 1H, J = 2.0 and 8.0 Hz) 7.26 (d, 1H, J = 8.8 Hz) 7.17 (s,
1H) 7.13 (d, 1H, J = 9.6 Hz) 3.26 (m, 4H) MS (ESI, pos. ion) m/z:
462.4 (M + 1). 392
2-{2-[2-(2,4-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.15 (dd, 1H, 1.6 and 6.4 Hz) 7.67-7.53 (m, 4H) 7.42 (dd, 1H, 1.6
and 8.0 Hz) 7.30 (dd, 1H, J = 1.2 and 6.8 Hz) 7.28-7.23 (m, 1H)
6.96-6.85 (m, 2H) 3.22 (m, 4H) MS (ESI, pos. ion) m/z: 414.2 (M +
1). 393 2-{2-[2-(3,4-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.15 (dd, 1H, 1.2 and 7.6 Hz) 7.65-7.53 (m, 4H) 7.42 (dd, 1H, 1.2
and 7.2 Hz) 7.32 (dd, 1H, J = 1.2 and 8.4 Hz) 7.22-7.13 (m, 2H)
7.04-7.01 (m, 1H) 3.22 (m, 4H) MS (ESI, pos. ion) m/z: 414.4 (M +
1). 394 2-{2-[2-(2,3-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, 1H, 1.6 and 8.0 Hz) 7.68-7.53 (m, 4H) 7.42 (dd, 1H, 1.6
and 7.6 Hz) 7.32 (dd, 1H, J = 1.6 and 8.0 Hz) 7.15-7.01 (m, 3H)
3.28 (m, 4H) MS (ESI, pos. ion) m/z: 414.3 (M + 1). 395
2-{2-[2-(2,5-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.15 (dd, 1H, 2.4 and 7.6 Hz) 7.67-7.53 (m, 4H) 7.43-7.39 (m, 1H)
7.33-7.29 (m, 1H) 7.12-6.94 (m, 3H) 3.26 (m, 4H) MS (ESI, pos. ion)
m/z: 414.4 (M + 1). 396
2-{2-[2-(3,5-difluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-benzene
sulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.15
(dd, 1H, 2.0 and 8.0 Hz) 7.67-7.54 (m, 4H) 7.42 (dd, 1H, 1.6 and
7.6 Hz) 7.36 (dd, 1H, 1.6 and 8.4 Hz) 6.91-6.77 (m, 3H) 3.26-3.20
(m, 4H) MS (ESI, pos. ion) m/z: 414.6 (M + 1). 397
2-(2-phenethyl-1H-benzimidazol-5-yl)-benzenesulfonamide .sup.1H-NMR
(400 MHz, CD.sub.3OD) .delta. (ppm): 8.14 (dd, 1H, 1.6 and 7.6 Hz)
7.67-7.54 (m, 4H) 7.42 (dd, 1H, 1.6 and 7.6 Hz) 7.30-7.17 (m, 7H)
3.25-3.06 (m, 4H) MS (ESI, pos. ion) m/z: 378.3 (M + 1). 399
N,N-dimethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-
-5- yl}-benzenesulfonamide The title compound was prepared by
hydrogenation using Compound 398. .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.07 (dd, 1H, J = 1.2 and 8.0 Hz) 7.65 (dt, 1H, J =
1.6 and 8.2 Hz) 7.58-7.53 (m, 5H) 7.41-7.38 (m, 3H) 7.20 (dd, 1H, J
= 1.6 and 8.4 Hz) 3.25 (m, 4H) 2.27 (s, 6H) MS (ESI, pos. ion) m/z:
474.4 (M + 1). 402
2-{2-[2-(2-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.12 (d, 1H) 7.64-7.52 (m, 4H) 7.41-7.38 (m, 2H) 7.26-7.19 (m, 4H)
3.22-3.18 (m, 4H) MS (ESI, pos. ion) m/z: 412.3 (M + 1). 404
2-{2-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.12 (dd, 1H, J = 1.6 and 8.0 Hz) 7.64-7.60 (m, 2H)
7.56-7.51 (m, 2H) 7.46-7.38 (m, 3H) 7.30-7.27 (m, 2H) 3.33-3.30 (m,
2H) 3.35-3.32 (m, 2H) MS (ESI, pos. ion) m/z: 464.4 (M + 1). 405
2-{2-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.15 (dd, 1H, J = 1.2 and 8.0 Hz) 7.66-7.62 (m, 2H)
7.59-7.50 (m, 4H) 7.41 (dd, 1H, J = 1.2 and 7.6 Hz) 7.31 (dd, 1H, J
= 1.6 and 8.0 Hz) 7.26-7.21 (m, 1H) 3.26 (m, 4H) MS (ESI, pos. ion)
m/z: 464.3 (M + 1). 419
2-{2-[2-(2-fluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-benzene
sulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.14
(d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.68-7.64 (m, 2H), 7.60-7.57 (m,
1H), 7.40 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.29-7.24
(m, 2H), 7.12-7.06 (m, 2H), 3.41 (t, J = 8.0 Hz, 2H), 3.28 (t, J =
8.0 Hz, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.21H.sub.18FN.sub.3O.sub.2S: 396.1 (M + H), Found 396.3. 420
2-{2-[2-(4-fluoro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.14 (dd, J = 1.6, 8.0 Hz, 1H), 7.73 (s, 1H), 7.69 (d, J = 8.0 Hz,
1H), 7.65 (dd, J = 1.6, 8.0 Hz, 1H), 7.58 (dt, J = 1.6, 8.0 Hz,
1H), 7.51 (d, J = 1.6, 8.0 Hz, 1H), 7.40 (dd, J = 1.2, 7.2 Hz, 1H),
7.27-7.24 (m, 2H), 7.04-7.00 (m, 2H), 3.42 (t, J = 8.0 Hz, 2H),
3.23 (t, J = 8.0 Hz, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.21H.sub.18FN.sub.3O.sub.2S: 396.1 (M + H), Found 396.3. 421
2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.12 (d, J = 8.0 Hz, 1H), 7.64-7.60 (m, 2H), 7.56-7.51 (m,
2H), 7.40-7.36 (m, 2H), 7.32-7.29 (m, 3H), 3.27-3.25 (m, 4H). Mass
Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.22H.sub.17F.sub.4N.sub.3O.sub.2S: 464.1 (M + H), Found 464.3.
442
2-{2-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-y-
l}- benzenesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 8.12 (dd, J = 1.6, 8 Hz, 1H), 8.01 (d, J = 1.6, 8 Hz, 1H),
7.65-7.60 (m, 3H), 7.58-7.53 (m, 3H), 7.48-7.44 (m, 1H), 7.40 (dd,
J = 1.6, 8 Hz, 1H), 7.33 (dd, J = 1.6, 8 Hz, 1H), 3.13 (m, 1H),
2.86 (t, J = 7.6 Hz, 2H), 2.83 (t, J = 7.6 Hz, 2H), 1.21 (d, J =
7.6 Hz, 6H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.24H.sub.25N.sub.3O.sub.2S: 420.5 (M + H), Found 420.4. 445
4-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide The title compound was
prepared by hydrogenation using Compound 444. .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.33 (d, J = 8 Hz, 1H), 7.83 (dd, J = 2,
8 Hz, 1H), 7.63 (d, J = 8 Hz, 2H), 7.58-7.54 (m, 3H), 7.42 (d, J =
8 Hz, 2H), 7.29 (dd, J = 2, 8 Hz, 1H), 3.28-3.24 (m, 4H). Mass
Spectrum (LCMS, ESI pos.) Calcd.
For C.sub.23H.sub.17F.sub.6N.sub.3O.sub.2S: 514.5 (M + H), Found
514.3. 447
4-trifluoromethyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide The title compound was
prepared by hydrogenation using Compound 446. .sup.1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.42 (s, 1H), 7.94 (d, J = 8 Hz, 1H),
7.63-7.56 (m, 5H), 7.42 (d, J = 8 Hz, 2H), 7.29 (d, J = 1.6, 8 Hz,
1H), 3.27-3.25 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.23H.sub.17F.sub.6N.sub.3O.sub.2S: 514.1 (M + H), Found
514.2.
Example 23
N-methyl-2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-b-
enzenesulfonamide (Cpd 400)
[0322] Using the procedure of Example 18, the title compound was
prepared from Compound 18c and 4-trifluoromethylphenyl propionic
acid. .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.04 (dd,
1H, J=1.2 and 8.0 Hz) 7.66-7.53 (m, 6H) 7.42-7.38 (m, 3H) 7.29 (dd,
1H, J=1.6 and 8.4 Hz) 3.27 (m, 4H) MS (ESI, pos. ion) m/z: 460.4
(M+1).
Example 24
N-methyl-2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-b-
enzenesulfonamide (Cpd 350)
[0323] Using the procedure of Example 18, the title compound was
prepared from Compound 18c and 3-trifluoromethylphenyl propionic
acid. .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.05 (dd,
1H, J=1.2 and 7.6 Hz) 7.64 (td, 1H, 1.2 and 8.2 Hz) 7.58-7.53 (m,
4H) 7.50-7.44 (m, 3H) 7.40 (dd, 1H, J=1.2 and 7.2 Hz) 7.25 (dd, 1H,
J=1.6 and 8.0 Hz) 3.26-3.22 (m, 4H) MS (ESI, pos. ion) m/z: 460.4
(M+1).
Example 25
2-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-
-propan-2-ol (Cpd 464)
[0324] Using the procedure of Example 10, the title Compound 464
(0.013 g) was prepared from
5-bromo-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazole
Compound 25a (0.048 g, 0.13 mmol) and Compound 10e (0.032 g, 0.20
mmol).
[0325] .sup.1H-NMR (400 MHz, DMSO d6) .delta. (ppm) 7.71 (dd,
J=1.26, 8.08 Hz, 1H) 7.45 (d, J=7.8 Hz, 2H) 7.37 (d, J=8.34 Hz, 1H)
7.31 (d, J=8.08 Hz, 2H) 7.20-7.26 (m, 2H) 7.10 (ddd, J=1.51, 7.33,
7.58 Hz, 1H) 6.93-7.20 (m, 2H) 3.14 (m, 4H) 1.21 (s, 6H).
[0326] MS (ESI, pos. ion) m/z: 425.1 (M+1).
[0327] Using the procedures described in Example 25 and Compound
25a, and reagents, starting materials and conditions known to those
skilled in the art, the following compounds representative of the
present invention were prepared from the corresponding vinyl
derivatives:
TABLE-US-00027 Cpd Name and Data 457
N-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-
yl}-phenyl)-acetamide .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm): 7.50-7.60 (m, 5H) 7.32-7.44 (m, 5H) 7.22-7.26 (d, J = 8.6
Hz, 1H) 3.24-3.30 (s, 4H) 1.96 (s, 3H). MS (ESI, pos. ion) m/z:
424.2 (M + 1).
Prophetic Example 26
[0328] Using the procedures of Examples 22, 23, 24 or 25, and
reagents, starting materials and conditions known to those skilled
in the art, the following prophetic compounds representative of the
present invention may be prepared.
TABLE-US-00028 Cpd Name and Data 133
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 134
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-ethyl]--
1H- benzimidazol-5-yl}-phenyl)-methanesulfonamide, 135
1-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanone, 136
1-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-etha-
nol, 137
N-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 138
2-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-prop-
an-2-ol, 140
N-(2-{2-[2-(4-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-C,C,-
C- trifluoro-methanesulfonamide, 141
1-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanone, 142
1-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
phenyl)-ethanol, 143
N-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
phenyl)-methanesulfonamide, 144
2-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
phenyl)-propan-2-ol, 146
C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonyl-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 147
1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl-
}-1H- benzimidazol-5-yl)-phenyl]-ethanone, 148
1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl-
}-1H- benzimidazol-5-yl)-phenyl]-ethanol, 149
N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl-
}-1H- benzimidazol-5-yl)-phenyl]-methanesulfonamide, 150
2-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl-
}-1H- benzimidazol-5-yl)-phenyl]-propan-2-ol, 151
2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-ethyl}-1-
H- benzimidazol-5-yl)-benzenesulfonamide, 152
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethox-
y)-
phenyl]-ethyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide,
153
1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol--
5-yl)- phenyl]-ethanone, 154
1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol--
5-yl)- phenyl]-ethanol, 155
N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol--
5-yl)- phenyl]-methanesulfonamide, 156
2-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol--
5-yl)- phenyl]-propan-2-ol, 157
2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}-1H-benzimidazol-5-y-
l)- benzenesulfonamide, 158
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-ethyl}--
1H- benzimidazol-5-yl)-phenyl]-methanesulfonamide, 159
1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanone, 160
1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanol, 161
N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-
benzimidazol-5-yl)-phenyl]-methanesulfonamide, 162
2-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-
benzimidazol-5-yl)-phenyl]-propan-2-ol, 163
2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-ethyl}-1H-
benzimidazol-5-yl)-benzenesulfonamide, 164
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-
ethyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 165
1-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-
ethanone, 166
1-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-etha-
nol, 167
N-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-
methanesulfonamide, 168
2-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-prop-
an- 2-ol, 169
2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 170
N-(2-{2-[2-(3-chloro-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phenyl)-C,C,-
C- trifluoro-methanesulfonamide, 171
1-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- ethanone, 172
1-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- ethanol, 173
N-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- methanesulfonamide, 174
2-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-phe-
nyl)- propan-2-ol, 176
C,C,C-trifluoro-N-(2-{2-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 177
N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-ethyl}-phenyl)-
methanesulfonamide, 178
N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-yl}-ethyl)-
phenyl]-methanesulfonamide, 179
N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-ethyl]-1H-benzimidazol-5-
yl}-phenyl)-methanesulfonamide, 180
N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-yl}-
- ethyl)-phenyl]-methanesulfonamide, 181
2-{2-[2-(4-methanesulfonylamino-phenyl)-ethyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 182
C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-ethyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 183
N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-ethyl}-phenyl)-C,C,-
C- trifluoro-methanesulfonamide, 184
C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazo-
l- 2-yl}-ethyl)-phenyl]-methanesulfonamide, 185
C,C,C-trifluoro-N-(4-{2-[5-(2-methanesulfonylamino-phenyl)-1H-
benzimidazol-2-yl]-ethyl}-phenyl)-methanesulfonamide, 186
C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-
benzimidazol-2-yl}-ethyl)-phenyl]-methanesulfonamide, 187
2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-ethyl]-1H-benzimidazo-
l- 5-yl}-benzenesulfonamide, and 188
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-
ethyl]-1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide.
Example 27
2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-benz-
enesulfonamide (Cpd 190)
Step A. 2-(4-trifluoromethyl-phenyl)-cyclopropanecarboxylic acid
methyl ester
[0329] To a solution of trimethylsulfonium iodide (0.53 g, 2.39
mmol) in 8 mL of DMSO was added sodium hydride (0.06 g, 2.39 mmol)
at 25.degree. C. After stirring for one hour, a solution of methyl
4-trifluoromethylcinnamate (0.50 g, 2.17 mmol) in 4 mL DMSO was
added. The reaction mixture was stirred for six hours, when it was
quenched by sat'd NH.sub.4Cl solution. The resulting mixture was
extracted with CH.sub.2Cl.sub.2, the organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The
residue was purified by chromatography (silica gel, hexanes: EtOAc,
2:1) to provide the title Compound 27a as a solid.
Step B. 2-(4-trifluoromethyl-phenyl)-cyclopropanecarboxylic
acid
[0330] A solution of Compound 27a in 10 mL MeOH and 4 mL of 1N LiOH
(aq) was heated at 70.degree. C. for 4 h. The mixture was then
acidified by 4N HCl (aq) and extracted with EtOAc. The organic
layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered,
and filtrate was concentrated to provide the title Compound 27b.
.sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 7.56 (d, 2H) 7.25
(d, 2H) 2.39 (m, 1H) 1.80 (m, 1H) 1.47 (m, 1H) 1.18 (m, 1H).
Step C.
2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5--
yl}-benzenesulfonamide
[0331] To a solution of Compound 16c (0.140 g, 0.438 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
Compound 27c (0.060 g, 0.313 mmol) in 4 mL acetonitrile at rt was
slowly added a solution of Compound 27b (0.072 g, 0.313 mmol) in 2
mL of acetonitrile. After stirring for 2 hours, the mixture was
passed through a short column (silica gel, hexanes: EtOAc, 2:1).
The collected eluent was concentrated, and the residue was
dissolved in AcOH. The reaction was heated at 80.degree. C. for 3
h. The reaction was concentrated and the residue was purified by
chromatography (silica gel, hexanes: EtOAc, 2:1). This material was
dissolved in TFA, and the mixture was heated at 60.degree. C. for 2
h. The reaction was concentrated, and the residue was purified by
chromatography (silica gel, hexanes: EtOAc, 1:1) to provide the
title Compound 190 as a solid. .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm): 8.14 (dd, 1H, J=1.2 and 7.6 Hz) 7.74-7.63 (m, 6H)
7.60-7.47 (m, 5H) 7.40 (dd, 1H, J=1.6 and 7.2 Hz) 2.97-2.92 (m, 1H)
2.76-2.71 (m, 1H) 2.12-2.00 (m, 2H) MS (ESI, pos. ion) m/z: 458.3
(M+1).
Example 28
2-(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-p-
henyl)-propan-2-ol (Cpd 471)
Step A.
N-methoxy-N-methyl-3-(4-trifluoromethyl-phenyl)-acrylamide
[0332] To a solution of 4-trifluoromethyl cinnamic acid (3.6 g,
16.7 mmol) in anhydrous methylene chloride (40 mL) was slowly added
oxalyl chloride (1.7 mL, 19.5 mmol). To the solution was added
anhydrous dimethylformamide (10 .mu.L) and the reaction was stirred
at room temperature under an argon atmosphere. After 18 h, the
reaction was concentrated. A solution of the residue Compound 10b
(16.7 mmol) in methylene chloride (40 mL) was added dropwise to a
solution of N,N-dimethylhydroxylamine hydrochloride (1.6 g, 16.7
mmol) and triethylamine (5.8 mL, 41.7 mmol) in methylene chloride
(40 mL) at 0.degree. C. The reaction mixture was stirred at
0.degree. C. for 30 min, then warmed to room temperature. After 6
h, the reaction was successively washed with sodium carbonate (10%
in water), water and brine. The organic fraction was dried over
magnesium sulfate, filtered and the filtrate was concentrated. The
compound was purified by chromatography (silica, EtOAc: hexanes,
1:1) to provide the title Compound 28a (2.2 g, 50% over two steps)
.sup.1H-NMR (400 MHz, DMSO d6) .delta. (ppm) 7.96 (d, J=8.3 Hz, 2H)
7.78 (d, J=8.08 Hz, 2H) 7.64 (d, J=15.9 Hz, 1H) 7.24 (d, J=15.9 Hz,
1H) 3.77 (s, 3H) 3.23 (s, 3H).
Step B. 2-(4-trifluoromethyl-phenyl)-cyclopropanecarboxylic acid
methoxy-methyl-amide
[0333] Anhydrous dimethylsulfoxide (8 mL) was added dropwise under
an argon atmosphere to a mixture of sodium hydride (60% suspension
in oil, 0.369 g, 9.2 mmol) and trimethylsulfoxonium iodide (2 g,
9.1 mmol). To the solution was added dropwise Compound 28a (1.2 g,
4.6 mmol) in DMSO (8 mL). The reaction mixture was stirred at room
temperature for 18 h. The reaction was poured into ethyl
ether:water (1:1, 50 mL). The organic layer was separated and
washed successively with water and brine. The organic fraction was
dried over magnesium sulfate, filtered and the filtrate was
concentrated to provide the title Compound 28b (1.9 g, 90%).
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm) 7.55 (d, J=8.08 Hz,
2H) 7.25 (d, J=8.3 Hz, 2H) 3.72 (s, 3H) 3.26 (s, 3H) 2.54-2.59 (m,
1H) 2.43-2.52 (m, 1H) 1.68-1.74 (m, 1H) 1.33-1.38 (m, 1H).
Step C. 2-(4-trifluoromethyl-phenyl)-cyclopropanecarboxylic
acid
[0334] To a solution of Compound 28b (3.6 g, 13.2 mmol) in
tetrahydrofuran (45 mL) was added a solution of
potassium-t-butoxide (1M in tetrahydrofuran, 50 mL, 50 mmol). To
the reaction was added water (1.5 mL, 83.3 mmol), and the reaction
was stirred at room temperature under an argon atmosphere. After 18
h, ice was added to the reaction until it became homogeneous. To
the solution was added ethyl ether, and the layers were separated.
The aqueous layer was cooled and acidified with 1 M HCl until the
pH was 4. The aqueous layer was extracted with ethyl acetate. The
ethyl acetate layer was washed successively with water and brine.
The organic layer was dried over magnesium sulfate, filtered and
the filtrate was concentrated to provide the title Compound 28c
(2.2 g, 73%). .sup.1H-NMR (400 MHz, DMSO d6) .delta. (ppm) 12.4 (s,
1H) 7.62 (d, J=8.08 Hz, 2H) 7.40 (d, J=8.08 Hz, 2H) 2.46-2.54 (m,
1H) 1.88-1.96 (m, 1H) 1.46-1.52 (m, 1H) 1.38-1.44 (m, 1H).
Step D.
5-bromo-2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidaz-
ole
[0335] Using the procedure of Example 1, the title Compound 28d was
prepared from Compound 28c and 4-bromobenzene-1,2-diamine.
.sup.1H-NMR (400 MHz, DMSO d6) .delta. (ppm) 7.96 (s, 1H) 7.68-7.75
(m, 3H) 7.60-7.64 (dd, J=1.5, 8.6 Hz, 1H) 7.46-7.56 (m, 4H)
7.10-7.14 (d, J=8.4 Hz, 2H) 2.96-3.02 (m, 1H) 2.70-2.78 (m, 1H)
2.10-2.16 (m, 1H) 2.00-2.08 (m, 1H).
Step E.
2-(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-
-5-yl}-phenyl)-propan-2-ol
[0336] Using the procedure of Example 10, the title Compound 471
was prepared from Compound 28d and Compound 10e. .sup.1H-NMR (400
MHz, CD.sub.3OD) .delta. (ppm) 12.4 (s, 0.5H) 12.32 (s, 0.5H) 7.88
(m, 1H) 7.65 (d, 2H, J=8.084 Hz) 7.46 (m, 2H) 7.35 (m, 2H) 7.20 (m,
1H) 6.95 (m, 2H) 4.85 (s, 1H) 2.70 (m, 1H) 2.46 (m, 1H) 1.90 (m,
1H) 1.70 (m, 1H) 1.20 (d, 6H). MS (ESI, pos. ion) m/z: 437.2
(M+1).
[0337] Using the procedures described in Example 28 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared from the corresponding vinyl
derivatives:
TABLE-US-00029 Cpd Name and Data 198
2-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
phenyl)-propan-2-ol, .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.
(ppm) 7.83-7.86 (m, 1H) 7.44-7.49 (bs, 1H) 7.31-7.36 (m, 4H)
7.21-7.26 (m, 3H) 7.055-7.13 (m, 2H) 2.60-2.65 (m, 1H) 2.40-2.44
(m, 1H) 1.84-1.90 (m, 1H) 1.62-1.70 (m, 1H) 1.32 (s, 6H). MS (ESI,
pos. ion) m/z: 403.2 (M + 1). 234
2-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-
yl}-phenyl)-propan-2-ol .sup.1H-NMR (400 MHz, CD3OD) .delta. (ppm)
7.71-7.74 (dd, J = 1.01, 8.08 Hz, 1H) 7.40-7.45 (m, 4H) 7.33-7.38
(d, J = 8.34 Hz) 7.21-7.26 (m, 2H) 7.08-7.13 (ddd, J = 1.52, 7.58
Hz, 1H) 6.99-7.02 (dd, J = 1.52, 8.34 Hz) 6.93-6.97 (dd, J = 1.52,
7.58 Hz, 1H) 2.60-2.66 (m, 1H) 2.37-2.42 (m, 1H) 1.78-1.84 (m, 1H)
1.59-1.65 (m, 1H) 1.22 (s, 6H). MS (ESI, pos. ion) m/z: 437.3 (M +
1). 467
N-(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-
yl}-phenyl)-methanesulfonamide .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta. (ppm) 7.52-7.62 (m, 5H) 7.33-7.41 (m, 4H) 7.24-7.32 (m, 2H)
2.70 (m, 4H) 2.48-2.53 (m, 1H) 1.90-1.96 (m, 1H) 1.69-1.75 (m, 1H).
MS (ESI, pos. ion) m/z: 472.2 (M + 1), 472
2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
phenol .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm) 7.70 (bs,
1H) 7.61 (d, 2H, J = 8.34 Hz) 7.51 (m, 3H) 7.42 (m, 3H) 7.30 (m,
1H) 7.15 (m, 1H) 6.93 (m, 2H) 2.72 (m, 1H) 2.50 (m, 1H) 1.93 (m,
1H) 1.74 (m, 1H). MS (ESI, pos. ion) m/z: 395.2 (M + 1), 474
(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
- phenyl)-methanol .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm)
7.62 (m, 3H)7.50 (m, 4H) 7.35 (m, 3H) 7.20 (m, 1H) 4.50 (s, 2H)
2.73 (m, 1H) 2.52 (m, 1H) 1.95 (m, 1H) 1.78 (m, 1H). MS (ESI, pos.
ion) m/z: 409.1 (M + 1). 494
2-(2-{2-[2-(4-methoxy-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
phenyl)-propan-2-ol .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm)
7.83-7.86 (m, 1H) 7.44-7.49 (d, J = 8.08 Hz, 1H) 7.34-7.40 (m, 2H)
7.14-7.28 (m, 3H) 7.12-7.18 (m, 2H) 3.80 (s, 3H) 2.60-2.65 (m, 1H)
2.31-2.35 (m, 1H) 1.78-1.82 (m, 1H) 1.62-1.70 (m, 1H) 1.34 (s, 6H).
MS (ESI, pos. ion) m/z: 399.1 (M + 1). 497
2-(2-{2-[2-(4-trifluoromethoxy-phenyl)-cyclopropyl]-1H-benzimidazol-5-
yl}-phenyl)-propan-2-ol .sup.1H-NMR (400 MHz, DMSO d6) .delta.
(ppm) 12.30-12.40 (d, 1H) 7.84-7.87 (d, J = 7.83 Hz, 1H) 7.45-7.48
(d, J = 7.83 Hz, 1H) 7.29-7.40 (m, 6H) 7.17-7.23 (m, 1H) 6.96-7.10
(m, 2H) 2.60-2.67 (m, 1H) 2.38-2.43 (m, 1H) 1.81-1.86 (m, 1H)
1.62-1.68 (m, 1H) 1.20 (s, 6H). MS (ESI, pos. ion) m/z: 453.3 (M +
1). 498
2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzamide .sup.1H-NMR (400 MHz, DMSO d6) .delta. (ppm) 12.5 (bs,
1H) 7.68-7.72 (d, J = 8.08 Hz, 2H) 7.40-7.60 (m, 7H) 7.28 (s, 1H)
7.21-7.25 (dd, J = 1.77, 8.34 Hz, 1H) 2.70-2.78 (m, 1H) 2.44-2.53
(m, 1H) 1.90-1.99 (m, 1H) 1.70-1.80 (m, 1H). MS (ESI, pos. ion)
m/z: 422.2 (M + 1). 499
N-tert-butyl-2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide .sup.1H-NMR (400 MHz, DMSO
d6) .delta. (ppm) 12.40 (s, 1H) 8.2-8.3 (d, J = 9.34 Hz, 1H)
7.30-7.70 (m, 9H) 7.10-7.15 (m, 1H) 6.28-6.32 (m, 1H) 2.64-2.72 (m,
1H) 1.90-1.94 (m, 1H) 1.70-1.75 (m, 1H) 0.90 (s, 9H). MS (ESI, pos.
ion) m/z: 514.2 (M + 1). 500
5-(2-methanesulfonyl-phenyl)-2-[2-(4-trifluoromethyl-phenyl)-
cyclopropyl]-1H-benzimidazole .sup.1H-NMR (400 MHz, DMSO d6)
.delta. (ppm) 8.12-8.15 (dd, J = 1.26, 7.83 Hz, 1H) 7.70-7.83 (m,
6H) 7.53-7.57 (d, J = 8.08 Hz, 2H) 7.42-7.47 (ddd, J = 1.26, 7.32
Hz, 2H) 2.93-3.00 (m, 1H) 2.66-2.74 (m, 1H) 2.06-2.13 (m, 1H)
1.97-2.03 (m, 1H). MS (ESI, pos. ion) m/z: 457.1 (M + 1).
Prophetic Example 29
[0338] Using the procedures of Examples 27 or 28, and reagents,
starting materials and conditions known to those skilled in the
art, the following prophetic compounds representative of the
present invention may be prepared.
TABLE-US-00030 Cpd Name and Data 189
2-{2-[2-(4-trifluoromethoxy-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
- benzenesulfonamide, 191
2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidaz-
ol- 5-yl}-benzenesulfonamide, 192
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethoxy-phenyl)-cyclopropyl]-1H-
- benzimidazol-5-yl}-phenyl)-methanesulfonamide, 193
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 194
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonyl-phenyl)-
cyclopropyl]-1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 195
1-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanone, 196
1-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanol, 197
N-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- methanesulfonamide, 199
2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 200
N-(2-{2-[2-(4-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- C,C,C-trifluoro-methanesulfonamide, 201
1-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-
yl}-phenyl)-ethanone, 202
1-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-
yl}-phenyl)-ethanol, 203
N-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-
yl}-phenyl)-methanesulfonamide, 204
2-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-
yl}-phenyl)-propan-2-ol, 205
2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 206
C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 207
1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-cyclo-
propyl}- 1H-benzimidazol-5-yl)-phenyl]-ethanone, 208
1-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-cyclo-
propyl}- 1H-benzimidazol-5-yl)-phenyl]-ethanol, 209
N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-
cyclopropyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 210
2-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-cyclo-
propyl}- 1H-benzimidazol-5-yl)-phenyl]-propan-2-ol, 211
2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenyl]-cyclopro-
pyl}- 1H-benzimidazol-5-yl)-benzenesulfonamide, 212
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethox-
y)-
phenyl]-cyclopropyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide,
213 1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanone, 214
1-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanol, 215
N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-methanesulfonamide, 216
2-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-propan-2-ol, 217
2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopropyl}-1H-benzimidaz-
ol-5- yl)-benzenesulfonamide, 218
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-cyclopr-
opyl}- 1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 219
1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanone, 220
1-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-ethanol, 221
N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-methanesulfonamide, 222
2-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-phenyl]-propan-2-ol, 223
2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-cyclopropyl}-1H-
benzimidazol-5-yl)-benzenesulfonamide, 224
C,C,C-trifluoro-N-[2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-
cyclopropyl}-1H-benzimidazol-5-yl)-phenyl]-methanesulfonamide, 225
1-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanone, 226
1-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- ethanol, 227
N-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- methanesulfonamide, 228
2-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- propan-2-ol, 229
2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 230
N-(2-{2-[2-(3-chloro-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-phenyl-
)- C,C,C-trifluoro-methanesulfonamide, 231
1-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanone, 232
1-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanol, 233
N-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-y-
l}- phenyl)-methanesulfonamide, 235
2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 236
C,C,C-trifluoro-N-(2-{2-[2-(3-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 237
N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-cyclopropyl}-phenyl-
)- methanesulfonamide, 238
N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-yl}-
cyclopropyl)-phenyl]-methanesulfonamide, 239
N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 240
N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-yl}-
- cyclopropyl)-phenyl]-methanesulfonamide, 241
2-{2-[2-(4-methanesulfonylamino-phenyl)-cyclopropyl]-1H-benzimidazol-
5-yl}-benzenesulfonamide, 242
C,C,C-trifluoro-N-(2-{2-[2-(4-methanesulfonylamino-phenyl)-cyclopropyl-
]- 1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 243
N-(4-{2-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl]-cyclopropyl}-phenyl-
)- C,C,C-trifluoro-methanesulfonamide, 244
C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazo-
l- 2-yl}-cyclopropyl)-phenyl]-methanesulfonamide, 245
C,C,C-trifluoro-N-(4-{2-[5-(2-methanesulfonylamino-phenyl)-1H-
benzimidazol-2-yl]-cyclopropyl}-phenyl)-methanesulfonamide, 246
C,C,C-trifluoro-N-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-
benzimidazol-2-yl}-cyclopropyl)-phenyl]-methanesulfonamide, 247
2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, and 248
C,C,C-trifluoro-N-(2-{2-[2-(4-trifluoromethanesulfonylamino-phenyl)-
cyclopropyl]-1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide.
Example 30
2-[2-(2-phenylethynyl-1H-benzimidazol-5-yl)-phenyl]-propan-2-ol
(Cpd 489)
Step A.
(E)-5-bromo-2-(2-chloro-2-phenyl-vinyl)-1H-benzimidazole
[0339] A mixture of 4-bromo-benzene-1,2-diamine dihydrochloride
(1.3 g, 5 mmol), phenylpropiolic acid (0.73 g, 5 mmol) in 4 mL of
ethylene glycol was heated to reflux for 5 h. The mixture was
cooled to rt and poured into water. The mixture was neutralized
with 2N sodium hydroxide and filtered. The solid was suspended in
water and extracted with ethyl acetate. The organic layers were
combined, dried with anhydrous sodium sulfate, and filtered. The
filtrate was concentrated to yield a red oil. The residue was
purified using preparative TLC plates twice (silica gel,
20.times.20 cm, 2000 microns, EtOAc: hexanes 3:7 and silica gel,
20.times.20 cm, 2000 microns, EtOAc: dichloromethane 3:97) to
provide a mixture of cis and trans isomers of the title Compound
30a (0.345 g). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm):
12.59 (m, 1H), 7.86-7.78 (m, 3H), 7.64-7.56 (m, 1H), 7.54-7.49 (m,
3H), 7.46 (s, 1H), 7.40-7.34 (m, 1H). Mass Spectrum (LCMS, APCI
pos.) Calcd. For C.sub.16H.sub.10BrClN.sub.2: 333.0 (M+H), Found
333.1.
Step B.
2-[2-(2-phenylethynyl-1H-benzimidazol-5-yl)-phenyl]-propan-2-ol
[0340] A mixture of Compound 30a (25 mg, 0.075 mmol), Compound 10e
(18 mg, 0.113 mmol) and Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (12 mg,
0.015 mmol) in 3 mL of DME and sodium carbonate solution (1.0 M,
0.6 mL) was heated at 150.degree. C. for 1 h in a Biotage
Initiator.TM. microwave synthesizer. The mixture was filtered
through a pad of silica gel. The reaction was repeated total three
times. The residues were combined and purified using preparative
TLC plates twice (silica gel, 20.times.20 cm, 2000 microns, EtOAc:
hexanes 3:7 and then silica gel, 20.times.20 cm, 2000 microns,
EtOAc: hexanes: methanol 2:8:1) to provide the title Compound 489
(8.4 mg). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 7.78
(dd, 1H, J=8.1, 1.1 Hz, 1H), 7.62-7.60 (m, 2H), 7.52 (d, 1H, J=8.3
Hz), 7.46-7.38 (m, 4H), 7.31 (dt, 1H, J=1.5, 8.0 Hz), 7.21-7.17 (m,
2H), 7.02 (dd, J=7.5, 1.3 Hz, 1H), 1.30 (s, 6H). Mass Spectrum
(LCMS, APCI pos.) Calcd. For C.sub.24H.sub.20N.sub.2O: 353.2 (M+H),
Found 353.3.
Example 31
2-(2-phenylethynyl-1H-benzimidazol-5-yl)-benzenesulfonamide (Cpd
490)
Step A.
N-tert-butyl-2-(2-phenylethynyl-1H-benzimidazol-5-yl)-benzenesulfo-
namide
[0341] A mixture of Compound 30a (25 mg, 0.075 mmol),
2-(tert-butylamino)sulfonylphenyl boronic acid (29 mg, 0.113 mmol),
and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (12 mg, 0.015 mmol) in 3 mL
of DME and sodium carbonate solution (1.0 M, 0.6 mL) was heated at
150.degree. C. for 1 h in a Biotage Initiator.TM. microwave
synthesizer. The mixture was filtered through a pad silica gel. The
residue was purified by preparative TLC (silica gel, 20.times.20
cm, 2000 microns, EtOAc: hexanes 3:7) to provide the title Compound
31a (12.8 mg). Mass Spectrum (LCMS, APCI pos.) Calcd. For
C.sub.25H.sub.23N.sub.3O.sub.2S: 430.2 (M+H), Found 430.3.
Step B.
2-(2-phenylethynyl-1H-benzimidazol-5-yl)-benzenesulfonamide
[0342] A mixture of Compound 31a (14.9 mg, 0.034 mmol) in
trifluoroacetic acid and 1,2-dichloroethane (2 mL, 1:1) was heated
at 90.degree. C. for 3 h. The reaction was cooled to rt, and
concentrated under reduced pressure. The residue was dissolved in
dichloromethane, and washed with saturated sodium bicarbonate
solution. The aqueous layer was extracted twice with ethyl acetate.
The organic layers were combined, dried with anhydrous magnesium
sulfate, filtered, and the filtrate was removed under reduced
pressure. The residue was purified using preparative TLC plates
(silica gel, 20.times.20 cm, 2000 microns, EtOAc: hexanes: methanol
5:5:1) to provide the title Compound 490 (12.1 mg). .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. (ppm): 8.11 (dd, 1H, J=8.0, 1.2 Hz),
7.67-7.56 (m, 5H), 7.52 (ddd, 1H, J=7.6, 6.4, 1.4 Hz), 7.48-7.33
(m, 5H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.21H.sub.15N.sub.3O.sub.2S: 374.1 (M+H), Found 374.2.
[0343] Using the procedures described in Examples 30 and 31, and
reagents, starting materials and conditions known to those skilled
in the art, the following compounds representative of the present
invention were prepared from the corresponding vinyl
derivatives:
TABLE-US-00031 Cpd Name and Data 250
2-[2-(4-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
8.04 (dd, 1H, J = 8.0, 1.2 Hz), 7.76 (d, J2H, = 8.2 Hz), 7.69 (d,
2H, J = 8.2 Hz), 7.58-7.53 (m, 2H), 7.54 (dt, 1H, J = 1.4, 7.5 Hz),
7.46 (dt, 1H, J = 1.4, 7.7 Hz), 7.31 (dd, 1H, J = 7.5, 1.3 Hz),
7.30 (dd, 1H, J = 8.4, 0.9 Hz). Mass Spectrum (LCMS, ESI pos.)
Calcd. For C.sub.22H.sub.14F.sub.3N.sub.3O.sub.2S: 442.1 (M + H),
Found 442.2. 294
2-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- propan-2-ol .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
7.94 (s, 1H), 7.89 (d, 1H, J = 7.7 Hz), 7.80-7.74 (m, 2H), 7.66 (t,
1H, J = 7.8 Hz, 1H), 7.60-7.39 (m, 2H), 7.33 (m, 1H), 7.28-7.18 (m,
2H), 7.04 (dd, 1H, J = 7.5, 1.4 Hz, 1H), 1.32 (s, 6H). Mass
Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.25H.sub.19F.sub.3N.sub.2O: 421.1 (M + H), Found 421.3. 295
2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide .sup.1H NMR (400 MHz, CD.sub.3OD .delta. (ppm):
8.11 (dd, 1H, J = 8.0, 1.2 Hz), 7.94 (s, 1H), 7.89 (dm, 1H, J = 7.6
Hz), 7.77 (dm, 1H, J = 7.9 Hz), 7.67-7.58 (m, 4H), 7.52 (m, 1H),
7.38 (dd, J = 7.5, 1.3 Hz, 1H), 7.37 (br s, 1H). Mass Spectrum
(LCMS, ESI pos.) Calcd. For C.sub.22H.sub.14F.sub.3N.sub.3O.sub.2S:
442.1 (M + H), Found 442.2 492
2-{2-[2-(4-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- propan-2-ol .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
7.83 (d, 2H, J = 8.2 Hz), 7.79 (dd, 1H, J = 8.2 1.1 Hz, 1H), 7.76
(d, 2H, J = 8.3 Hz), 7.64-7.37 (m, 2H), 7.33 (m, 1H), 7.22 (br d,
1H, J = 7.2 Hz), 7.20 (dt, 1H, J = 1.3, 7.4 Hz), 7.04 (dd, 1H, J =
7.5, 1.4 Hz), 1.32 (s, 6H). Mass Spectrum (LCMS, ESI pos.) Calcd.
For C.sub.25H.sub.19F.sub.3N.sub.2O: 421.1 (M + H), Found 421.3.
Preparation of (4-trifluoromethylphenyl)propynoic acid. To a
solution of 4- ethynyl-.alpha.,.alpha.,.alpha.-trifluorotoluene (5
g, 29 mmol) in anhydrous THF (25 mL), was slowly added
n-butyllithium 2.6M in hexanes (14.5 mL, 47 mmol). The mixture was
stirred at -78.degree. C. for 30 min and then at 0.degree. C. for
an additional 30 min. The mixture was cooled to -78.degree. C. and
transferred via a cannula to a saturated solution of carbon dioxide
in anhydrous THF (25 mL) at -78.degree. C. The mixture was stirred
and allowed to warm to rt over 18 h. The mixture was quenched with
saturated sodium chloride solution, and the two layers were
separated. The aqueous layer was washed with hexanes and then
acidified with 2N hydrochloric acid. The aqueous layer was
extracted twice with ethyl acetate. The organic layers were
combined and dried with anhydrous sodium sulfate and magnesium
sulfate. The mixture was filtered and the filtrate was concentrated
under reduced pressure to yield the title Compound 31b as a white
solid (5.4 g, 87%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
(ppm): 7.81 (s, 4H). Compound 31b was carried forward using the
procedure of Example 31 to provide the title Compound 492.
Prophetic Example 32
[0344] Using the procedures of Examples 30 or 31, the corresponding
bromobenzimidazole and, when not commercially available, the
arylacetylenic acid precursors prepared as described in Reaction
Scheme KK and reagents, starting materials and conditions known to
those skilled in the art, the following prophetic compounds
representative of the present invention may be prepared.
Alternatively, the following compounds may be prepared from their
corresponding vinyl compounds by hydrogenation:
TABLE-US-00032 Cpd Name and Data 249
2-[2-(4-trifluoromethoxy-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 251
2-[2-(4-trifluoromethanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 252
C,C,C-trifluoro-N-{2-[2-(4-trifluoromethoxy-phenylethynyl)-1H-
benzimidazol-5-yl]-phenyl}-methanesulfonamide, 253
C,C,C-trifluoro-N-{2-[2-(4-trifluoromethyl-phenylethynyl)-1H-benzimida-
zol- 5-yl]-phenyl}-methanesulfonamide, 254
C,C,C-trifluoro-N-{2-[2-(4-trifluoromethanesulfonyl-phenylethynyl)-1H-
benzimidazol-5-yl]-phenyl}-methanesulfonamide, 255
1-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-ethanon-
e, 256
1-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-ethanol-
, 257
N-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 258
2-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-propan--
2- ol, 259 2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 260
N-{2-[2-(4-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-C,C,C-
trifluoro-methanesulfonamide, 261
1-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- ethanone, 262
1-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- ethanol, 263
N-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-
phenyl}-methanesulfonamide, 264
2-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- propan-2-ol, 265
2-[2-(4-methanesulfonyl-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 266
C,C,C-trifluoro-N-{2-[2-(4-methanesulfonyl-phenylethynyl)-1H-
benzimidazol-5-yl]-phenyl}-methanesulfonamide, 267
1-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1-
H- benzimidazol-5-yl}-phenyl)-ethanone, 268
1-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1-
H- benzimidazol-5-yl}-phenyl)-ethanol, 269
N-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1-
H- benzimidazol-5-yl}-phenyl)-methanesulfonamide, 270
2-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1-
H- benzimidazol-5-yl}-phenyl)-propan-2-ol, 271
2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-benzenesulfonamide, 272
C,C,C-trifluoro-N-(2-{2-[4-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-
phenylethynyl]-1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide,
273
1-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanone, 274
1-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-y-
l}- phenyl)-ethanol, 275
N-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-y-
l}- phenyl)-methanesulfonamide, 276
2-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-y-
l}- phenyl)-propan-2-ol, 277
2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-benzimidazol-5-yl}-
benzenesulfonamide, 278
C,C,C-trifluoro-N-(2-{2-[4-(2,2,2-trifluoro-ethoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 279
1-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-ethanone, 280
1-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-ethanol, 281
N-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-methanesulfonamide, 282
2-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol, 283
2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethynyl]-1H-benzimidazol-
- 5-yl}-benzenesulfonamide, 284
C,C,C-trifluoro-N-(2-{2-[4-(2,2,3,3,3-pentafluoro-propoxy)-phenylethyn-
yl]- 1H-benzimidazol-5-yl}-phenyl)-methanesulfonamide, 285
1-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-ethanon-
e, 286
2-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-propan--
2- ol, 287
N-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-
methanesulfonamide, 288
1-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-ethanol-
, 289 2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 290
N-{2-[2-(3-chloro-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl}-C,C,C-
trifluoro-methanesulfonamide, 291
1-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- ethanone, 292
1-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- ethanol, 293
N-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimidazol-5-yl]-phenyl-
}- methanesulfonamide, 296
C,C,C-trifluoro-N-{2-[2-(3-trifluoromethyl-phenylethynyl)-1H-benzimida-
zol- 5-yl]-phenyl}-methanesulfonamide, 297
N-{4-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl-ethynyl]-phenyl}-
methanesulfonamide, 298
N-(4-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-yl-ethynyl}-
phenyl)-methanesulfonamide, 299
N-{2-[2-(4-methanesulfonylamino-phenylethynyl)-1H-benzimidazol-5-yl]-
phenyl}-methanesulfonamide, 300
N-(4-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-yl-
ethynyl}-phenyl)-methanesulfonamide, 301
2-[2-(4-methanesulfonylamino-phenylethynyl)-1H-benzimidazol-5-yl]-
benzenesulfonamide, 302
C,C,C-trifluoro-N-{2-[2-(4-methanesulfonylamino-phenylethynyl)-1H-
benzimidazol-5-yl]-phenyl}-methanesulfonamide, 303
N-{4-[5-(2-acetyl-phenyl)-1H-benzimidazol-2-yl-ethynyl]-phenyl}-C,C,C-
trifluoro-methanesulfonamide, 304
C,C,C-trifluoro-N-(4-{5-[2-(1-hydroxy-ethyl)-phenyl]-1H-benzimidazol-2-
-yl- ethynyl}-phenyl)-methanesulfonamide, 305
C,C,C-trifluoro-N-{4-[5-(2-methanesulfonylamino-phenyl)-1H-
benzimidazol-2-yl-ethynyl]-phenyl}-methanesulfonamide, 306
C,C,C-trifluoro-N-(4-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-
benzimidazol-2-yl-ethynyl}-phenyl)-methanesulfonamide, 307
2-[2-(4-trifluoromethanesulfonylamino-phenylethynyl)-1H-benzimidazol-5-
- yl]-benzenesulfonamide, and 308
C,C,C-trifluoro-N-{2-[2-(4-trifluoromethanesulfonylamino-phenylethynyl-
)- 1H-benzimidazol-5-yl]-phenyl}-methanesulfonamide.
Example 33
(E)-2-{2-[2-(2-quinolin-6-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}-propan-2-
-ol (Cpd. 449)
Step A. 5-bromo-2-chloromethyl-1H-benzimidazole
[0345] A mixture of 4-bromo-benzene-1,2-diamine (200 mg, 1.07 mmol)
and 2-chloroacetimidic acid ethyl ester hydrochloride salt (168 mg,
1.07 mmol; prepared according to the procedure described in J. Med.
Chem. 1986, 29, 2280) in anhydrous ethanol (200 proof, 5 mL) was
stirred at room temperature for 4 h. The reaction mixture was
concentrated under reduced pressure and extracted with ethyl
acetate and water. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated in
vacuo to provide the title Compound 33a as an off-white solid (240
mg, 92% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm):
7.75 (d, 1H, J=1.4 Hz), 7.47 (d, 1H, J=8.6 Hz), 7.42 (dd, 1H, J=8.6
Hz, J=1.3 Hz), 4.84 (s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd.
For C.sub.18H.sub.20ClN.sub.3O.sub.2S: 247.50 (M+H), Found
247.0.
Step B. (5-bromo-1H-benzimidazol-2-ylmethyl)-triphenyl-phosphonium
chloride
[0346] A mixture of Compound 33a (240 mg, 0.98 mmol) and
triphenylphosphine (385 mg, 1.47 mmol), in 1,2-dichloroethane (10
mL) was heated at 140.degree. C. for 1 h. The reaction mixture was
concentrated under reduced pressure to provide the title Compound
33b, which was used in the next step without further
purification.
Step C.
(E)-6-[2-(5-bromo-1H-benzimidazol-2-yl)-vinyl]-quinoline
[0347] A mixture of Compound 33b (100 mg, 0.204 mmol),
6-quinolinecarboxaldehyde (32 mg, 0.29 mmol) and DBU (39.6 uL,
0.265 mmol) in ethanol:tetrahydrofuran (1:1, 2 mL) was stirred at
room temperature for 12 h. The reaction mixture was concentrated
under reduced pressure, and the residue was purified by reverse
phase preparative HPLC (10-100% gradient acetonitrile/water over 10
min) to provide the title Compound 33c as an off-white solid (50
mg, 72 yield). Calcd. For C.sub.18H.sub.12BrN.sub.3: 350.21 (M+H),
Found 350.2.
Step D.
(E)-2-{2-[2-(2-quinolin-6-yl-vinyl)-1H-benzimidazol-5-yl]-phenyl}--
propan-2-ol
[0348] A mixture of Compound 33c (50.0 mg, 0.143 mmol), Compound
10e (46 mg, 0.29 mmol), PdCl.sub.2(dppf) (23.4 mg, 0.029 mmol) and
1M sodium bicarbonate solution (1.15 mL, 1.15 mmol) in
1,2-dimethoxyethane (1 mL) was heated at reflux for 12 h. The
reaction mixture was concentrated under reduced pressure. The
residue was purified by chromatography (silica, EtOAc) to provide
the title Compound 449 as an off-white solid (11.8 mg, 20% yield).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 9.01 (br s, 1H),
8.68 (d, 1H, J=8.1 Hz), 8.35 (m, 2H), 8.12-8.21 (m, 2H), 7.76 (m,
3H), 7.67 (s, 1H), 7.53 (m, 2H), 7.38-7.43 (m, 1H), 7.28 (m, 1H),
7.09 (m, 1H), 1.42 (s, 6H). Calcd. For C.sub.27H.sub.23N.sub.3O:
406.5 (M+H), Found 406.3.
[0349] Using the procedures described in Example 33 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00033 Cpd Name and Data 448
(E)-1-[4-(2-{5-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-1H-benzimidazol-2-
- yl}-vinyl)-phenyl]-ethanone The title compound was prepared from
Compound 33b (100 mg, 0.204 mmol) and 4-acetylbenzaldehyde (30.2
mg, 0.204 mmol) as an off-white solid (3.75 mg, 10% yield). .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.06 (d, 1H, J = 8.8 Hz),
7.96 (m, 1H), 7.80 (m, 3H), 7.68 (m, 1H), 7.55 (m, 1H), 7.43 (m,
1H), 7.34 (m, 2H), 7.17-7.24 (m, 2H), 7.07 (m, 1H), 2.63 (s, 3H),
1.35 (s, 6H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.26H.sub.24N.sub.2O.sub.2: 397.5 (M + H), Found 397.3. 450
(E)-N-isopropyl-4-{2-[5-(2-methylsulfamoyl-phenyl)-1H-benzimidazol-2-
yl]-vinyl}-benzamide The title compound was prepared from
[5-(2-methylsulfamoyl-phenyl)-1H-
benzimidazol-2-ylmethyl]-triphenyl-phosphonium chloride Compound
33c (90 mg, 0.15 mmol) and 4-carboxyaldehyde-N-isopropylbenzamide
(24.3 mg, 0.15 mmol) as an off-white solid (10.5 mg, 15% yield).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 8.06 (dd, 1H, J =
8.1, Hz, J = 1.5 Hz), 7.87 (m, 2H), 7.55-7.74 (m, 7H), 7.43 (dd,
1H, J = 8.1 Hz, J = 1.5 Hz), 7.29 (m, 2H), 4.22 (m, 1H), 2.37 (s,
3H), 1.26 (s, 6H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.26H.sub.26N.sub.4O.sub.3S: 475.5 (M + H), Found 475.2. 451
(E)-2-{2-[2-(4-cyano-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide The title compound was prepared from Compound
33c (90 mg, 0.15 mmol) and 4-cyanobenzaldehyde (19.6 mg, 0.15 mmol)
as an off-white solid (7.4 mg, 12% yield). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.07 (dd, 1H, J = 8.0 Hz, J = 1.0 Hz),
7.49-7.69 (m. 8H), 7.37 (m, 2H), 7.20 (m, 2H), 2.32 (s, 3H). Mass
Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.23H.sub.18N.sub.4O.sub.2S: 415.5 (M + H), Found 415.2. 452
(E)-N-(4-{2-[5-(2-methylsulfamoyl-phenyl)-1H-benzimidazol-2-yl]-vinyl}-
- phenyl)-acetamide The title compound was prepared from Compound
33c (90 mg, 0.15 mmol) and 4-acetamidobenzaldehyde (24.3 mg, 0.15
mmol) as an off-white solid (11.3 mg, 17% yield). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. (ppm): 8.04 (dd, 1H, J = 8.0 Hz, J = 1.3
Hz), 7.63 (td, 1H, J = 7.4 Hz, J = 1.4 Hz), 7.55 (m, 5H), 7.26-7.39
(m, 5H), 7.19 (dd, 1H, J = 8.1 Hz, J = 1.5 Hz), 2.22 (s, 3H), 2.03
(s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.24H.sub.22N.sub.4O.sub.3S: 447.5 (M + H), Found 447.2. 453
(E)-4-{2-[5-(2-methylsulfamoyl-phenyl)-1H-benzimidazol-2-yl]-vinyl}-
benzoic acid The title compound was prepared from Compound 33c (90
mg, 0.15 mmol) and 4-carboxybenzaldehyde (22.4 mg, 0.15 mmol) as an
off-white solid (3.4 mg, 5% yield). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.02 (m, 2H), 7.53-7.77 (m, 6H),
7.18-7.45 (m, 5H), 2.36 (s, 3H). Mass Spectrum (LCMS, ESI pos.)
Calcd. For C.sub.23H.sub.19N.sub.3O.sub.4S: 434.5 (M + H), Found
434.2. 454
(E)-2-{2-[2-(1H-indol-6-yl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide The title compound was prepared from Compound
33c (90 mg, 0.15 mmol) and indole-6-carboxaldehyde (21.6 mg, 0.15
mmol) as an off-white solid (6.5 mg, 10% yield). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. (ppm): 8.06 (m, 1H), 7.05-7.73 (m, 11H),
6.48 (m, 2H), 2.36 (m, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd.
For C.sub.24H.sub.20N.sub.4O.sub.2S: 429.5 (M + H), Found 429.2.
455
(E)-2-{2-[2-(2,4-bis-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5--
yl}-N- methyl-benzenesulfonamide The title compound was prepared
from Compound 33c (90 mg, 0.15 mmol) and
2,4-bis(trifluoromethyl)benzaldehyde (24.4 uL, 0.15 mmol) as an
off-white solid (8.62 mg, 11% yield). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 7.14-8.17 (m, 12H), 2.44 (s, 3H). Mass
Spectrum (LCMS, ESI pos.) Calcd. For
C.sub.24H.sub.17F.sub.6N.sub.3O.sub.2S: 526.5 (M + H), Found 526.3.
456
(E)-2-{2-[2-(4-acetyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-N-methyl-
benzenesulfonamide The title compound was prepared from Compound
33c (90 mg, 0.15 mmol) and 4-acetylbenzaldehyde (22.1 mg, 0.15
mmol) as an off-white solid (8.32 mg, 13% yield). .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. (ppm): 8.06 (m, 3H), 7.56-7.79 (m, 9H),
7.44 (m, 1H), 2.62 (s, 3H), 2.37 (s, 3H). Mass Spectrum (LCMS, ESI
pos.) Calcd. For C.sub.24H.sub.21N.sub.3O.sub.3S: 432.5 (M + H),
Found 432.2.
Example 34
2-{2-[2-(4-trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-benzylamin-
e (Cpd 486)
Step A.
(E)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl-
}-benzonitrile
[0350] A mixture of Compound 10c (52 mg, 0.14 mmol),
2-cyanophenylboronic acid (38 mg, 0.26 mmol),
Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (36 mg, 0.044 mmol),
tetrabutylammonium bromide (55 mg, 0.17 mmol), and sodium carbonate
(1 mL, 1.0 M) in DME (5 mL) was heated at 90.degree. C. for 18 h.
The mixture was cooled to rt, filtered through a pad of Celite and
concentrated under reduced pressure. The residue was purified using
preparative TLC plates (silica gel, 20.times.20 cm, 2000 microns,
EtOAc:hexanes 1:1 and hexanes: dichloromethane: methanol 6:14:1) to
provide the title Compound 34a (20 mg, 37%). .sup.1H NMR (400 MHz,
CD.sub.3OD+CDCl.sub.3) .delta. (ppm): 7.72-7.47 (m, 10H), 7.40-7.30
(m, 3H), 7.14 (d, 1H, J=16.55 Hz). Mass Spectrum (LCMS, APCI pos.)
Calcd. For C.sub.23H.sub.14F.sub.3N.sub.3:.390.1 (M+H), Found
390.3.
Step B.
2-{2-[2-(4-Trifluoromethyl-phenyl)-ethyl]-1H-benzimidazol-5-yl}-be-
nzylamine
[0351] A mixture of Compound 34a (20 mg, 0.051 mmol),
Raney.RTM.-Nickel, ammonium hydroxide (0.1 mL) in ethanol was
hydrogenated under 50 psi for 18 h. The mixture was filtered
through a pad of Celite and washed with ethanol. The filtrate was
concentrated under reduced pressure. The residue was purified using
preparative TLC plates (silica gel, 20.times.20 cm, 2000 microns,
NH.sub.3 in methanol: EtOAc 1:9) to provide the title Compound 486
(6.3 mg, 31%). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. (ppm):
7.57-7.52 (m, 4H), 7.46-7.34 (m, 6H), 7.14 (dd, J=8.2, 1.5 Hz, 1H),
4.05 (s, 2H), 3.24 (s, 4H). Mass Spectrum (LCMS, APCI pos.) Calcd.
For C.sub.23H.sub.20F.sub.3N.sub.3: 396.2 (M+H), Found 396.2.
Example 35
(Z)-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phe-
nyl)-propan-2-ol (Cpd 469)
[0352] A solution of Compound 18 (0.030 g, 0.07 mmol) in DMSO (5
mL) was stirred at room temperature for 5 days under a 60 W light
bulb. The reaction was then applied to a 2000 micron prep TLC plate
(20.times.20 cm) and developed using ethyl acetate:hexanes 4:6. The
desired band was extracted with MeOH, filtered and concentrated to
provide the title Compound 469 (0.001 g). .sup.1H-NMR (400 MHz,
DMSO d6) .delta. (ppm) 7.71 (dd, J=1.01, 8.34 Hz, 1H) 7.53 (s, 4H)
7.37-7.41 (m, 1H) 7.21-7.28 (m, 2H) 7.11 (dt, J=1.26, 7.33 Hz, 1H)
7.05 (dd, J=1.52, 8.34 Hz, 1H), 6.94-7.10 (m, 4H) 6.67 (d, 12.6 Hz,
1H) 1.23 (s, 6H). MS (ESI, pos. ion) m/z: 423.2 (M+1).
Example 36
(E)-N-(2-{3-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-3H-benzimidazol--
5-yl}-phenyl)-methanesulfonamide (Cpd 443)
(E)-N-(2-{1-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol--
5-yl}-phenyl)-methanesulfonamide (Cpd 477)
Step A.
(E)-5-bromo-1-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-ben-
zimidazole and
(E)-6-bromo-1-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidaz-
ole
[0353] To a solution of sodium hydride (60% suspension in oil,
0.131 g, 3.2 mmol) in anhydrous tetrahydrofuran (10 mL) was added
Compound 10c (1 g, 2.7 mmol). The solution was stirred at room
temperature under an argon atmosphere. After five minutes methyl
iodide was added (0.205 mL, 3.2 mmol), and the solution was stirred
at room temperature for 3 h. The reaction mixture was partitioned
between ethyl acetate (10 mL) and ice water (20 mL). The organic
fraction was washed with brine, dried over magnesium sulfate, then
filtered and concentrated to give a 1:1 mixture of the title
Compound 36a and 36b (0.38 g).
Step B.
(E)-N-(2-{3-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-3H-benzi-
midazol-5-yl}-phenyl)-methanesulfonamide and
(E)-N-(2-{1-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}-phenyl)-methanesulfonamide
[0354] Using the procedure of Example 1, Step B, the title
compounds were prepared from a mixture of
(E)-5-bromo-1-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidaz-
ole and
(E)-6-bromo-1-methyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-ben-
zimidazole and 2-methylsulfonylaminophenyl boronic acid.
[0355] Cpd 443: .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm)
7.82-7.80 (m, 3H) 7.75 (d, J=8.1 Hz, 3H) 7.52-7.62 (m, 3H)
7.34-7.42 (m, 4H) 4.00 (s, 3H) 2.76 (s, 3H). MS (ESI, pos. ion)
m/z: 472.1 (M+1).
[0356] Cpd 477: .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm)
7.88-7.95 (m, 3H) 7.72-7.77 (m, 3H) 7.56-7.67 (m, 4H) 7.40-7.44 (m,
3H) 4.10 (s, 3H) 2.73 (s, 3H). MS (ESI, pos. ion) m/z: 472.1
(M+1).
Example 37
(E)-2-hydroxy-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-
-5-yl}-phenyl)-ethanone (Cpd 311)
Step A.
(E)-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-5-[2-(1-trimethylsilany-
loxy-vinyl)-phenyl]-1H-benzimidazole
[0357] To a solution of Compound 15 (0.20 g, 0.492 mmol) in 16 mL
1,2-dichloroethane was added TBSOTf (0.19 mL, 1.08 mmol) and
Et.sub.3N (0.27 mL, 1.97 mmol) at 0.degree. C. After 5 min., the
mixture was warmed to 25.degree. C. and stirred for 8 hours. The
reaction was concentrated and the residue was purified by
chromatography (silica gel, hexanes: EtOAc, 4:1) to provide the
title Compound 37a as a colorless oil.
Step B.
(E)-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-5-[2-(2-trimethylsilany-
loxy-oxiranyl)-phenyl]-1H-benzimidazole
[0358] A mixture of Compound 37a (0.124 g, 0.238 mmol) and mCPBA
(0.053 g, 0.238 mmol) in 10 mL CH.sub.2Cl.sub.2 was stirred for two
hours. The reaction was concentrated and the residue was purified
by chromatography (silica gel, hexanes: EtOAc, 4:1) to provide the
title Compound 37b as a yellow oil.
Step C.
(E)-2-hydroxy-1-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benz-
imidazol-5-yl}-phenyl)-ethanone
[0359] A mixture of Compound 37b (0.026 g, 0.048 mmol) and
p-toluenesulfonic acid monohydrate (p-TsOHH.sub.2O, 0.018 g, 0.0968
mmol) in 4 mL THF was stirred for four hours. The reaction was
concentrated and the residue was purified by chromatography (silica
gel, hexanes: EtOAc, 1:2) to provide the title Compound 311 as a
brown solid. .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 7.85
(d, 2H, J=8.8 Hz) 7.74 (d, 2H, J=7.6 Hz) 7.71 (d, 1H, J=16.4 Hz)
7.63-7.47 (m, 6H) 7.33 (d, 1H, J=16.0 Hz) 7.25 (dd, 1H, J=1.6 and
8.4 Hz) 4.08 (s, 2H) MS (ESI, pos. ion) m/z: 423.3 (M+1).
Example 38
2-(2-{2-[(1R,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazol-
-5-yl}-phenyl)-propan-2-ol (Cpd 501)
Step A. (1R,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropanecarboxylic
acid ethyl ester
[0360] To a suspension of copper(I) trifluoromethanesulfonate
toluene complex (31.0 mg, 0.12 mmol) in anhydrous CHCl.sub.3 (3.0
mL) was added a solution of
2,2-bis-[(4S)-(1,1-dimethylethyl)-1,3-oxazolin-2-yl]propane (35 mg,
0.12 mmol) in chloroform (1.2 mL). After stirring at ambient
temperature for 1 h, the resulting green solution was filtered
through glass wool under argon atmosphere into a flask previously
charged with a solution of 4-(trifluoromethyl)-styrene (0.887 mL,
6.00 mmol) in chloroform (0.9 mL). To this solution was added a
solution of ethyl diazoacetate (1.56 mL, 15.0 mmol) in chloroform
(12.0 mL) at ambient temperature through a dropping funnel over a
period of 6 h. The resulting mixture was stirred for 24 h,
concentrated to dryness, and purified by flash chromatography on a
silica gel column (45 mm.times.140 mm silica gel), eluting with
ethyl acetate/hexane (1, 1.5, 2%) to provide the title Compound 38a
(892 mg, 58% yield, 98% ee) as a colorless liquid, and cis isomer
(1R,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropanecarboxylic acid
ethyl ester Compound 38b (128 mg, 5% yield calculated based on 34
wt % contamination of ethyl fumarate as analyzed by 1 NMR). The
enantiomeric excess of the product was determined as described in
Step E below.
[0361] .sup.1H-NMR of Compound 38a (400 MHz, CDCl.sub.3) .delta.
(ppm): 7.53 (d, 2H, J=8.3 Hz), 7.23 (d, 2H, J=8.1 Hz), 4.18 (q, 2H,
J=7.1 Hz), 2.55 (dd, 1H, J=2.6, 4.3, & 6.6 Hz), 1.94 (ddd, 1H,
J=4.3, 5.6, & 9.6 Hz), 1.68-1.53 (m, 1H), 1.34 (1H, ddd, 4.8,
6.7, & 1.1 Hz), 1.29 (t, 2H, J=7.0 Hz).
[0362] 1H-NMR of Compound 38b (400 MHz, CDCl.sub.3) .delta. (ppm):
7.51 (d, 2H, J=7.9 Hz), 7.37 (d, 2H, J=7.8 Hz), 3.92-3.86 (m, 2H),
2.62-2.56 (m, 1H), 2.14 (ddd, 1H, J=5.8, 8.1 & 9.3 Hz), 1.73
(td, 1H, J=5.3 & 7.6 Hz), 1.39 (ddd, 1H, J=5.1, 7.8 & 8.6
Hz), 0.99 (t, 3H, J=7.1 Hz).
Step B. (1R,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropanecarboxylic
acid
[0363] To a solution of Compound 38a (750 mg, 2.91 mmol) in ethanol
(7.27 mL) was added a 1M aqueous solution of NaOH (7.27 mL). The
resulting mixture was stirred at ambient temperature for 16 h,
concentrated to about 4 g, acidified with 2M HCl to pH 3, and
extracted with ethyl acetate (15 mL.times.2). The extracts were
combined, washed with brine, dried over Na.sub.2SO.sub.4,
concentrated to provide the title Compound 38c (611 mg, 91% yield)
as a white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3 with a drop of
CD.sub.3OD) .delta. (ppm): 7.51 (d, 2H, J=8.3 Hz), 7.18 (d, 2H,
J=8.1 Hz), 2.57 (ddd, 1H, J=4.2, 6.6, & 10.3 Hz), 1.90 (ddd,
1H, J=4.0, 5.3, & 8.3 Hz), 1.65 (dt, 1H, J=4.9 & 9.3 Hz),
1.35 (ddd, 1H, J=4.9, 6.4, & 11.1 Hz).
Step C:
2-(2-{2-[(1R,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benz-
imidazol-5-yl}-phenyl)-propan-2-ol
[0364] Using the procedure of Example 10, Steps B and E, the title
Compound 501 was prepared from Compound 38c. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6) .delta. (ppm): 12.40 (s, 0.5 H), 12.32 (s, 0.5 H),
7.87-7.84 (m, 1H), 7.66 (d, 2H, J=8.0 Hz), 7.49-7.17 (m, 6H),
7.00-6.96 (m, 2H), 4.84 (s, 1H), 2.72-2.67 (m, 1H), 2.50-2.46 (m,
1H), 1.92-1.86 (m, 1H), 1.74-1.68 (m, 1H), 1.19 (s, 3H), 1.18 (s,
3H). Mass Spectrum (LCMS, ESI pos.) Calcd for
C.sub.26H.sub.24F.sub.3N.sub.2O: 437.2. Found 437.3.
Step D: (1R,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropanecarboxylic
acid methoxy-methyl-amide
[0365] To a mixture of Compound 38c (50 mg, 0.216 mmol),
N,O-dimethylhydroxylamine hydrochloride (30 mg, 0.30 mmol), BOP
(134 mg, 0.30 mmol), and DMF (0.4 mL) was added DIEA (0.15 mL). The
resulting mixture was stirred at ambient temperature for 48 h,
concentrated to dryness, and partitioned between saturated
NaHCO.sub.3 (2 mL) and ethyl acetate (4 mL). The ethyl acetate
layer was separated, and the aqueous layer was extracted with ethyl
acetate (5 mL.times.2). All ethyl acetate layers were combined,
washed with brine, dried over Na.sub.2SO.sub.4, concentrated, and
purified by prep-TLC, developed with 10% ethyl acetate/DCM to
provide Compound 38d (46 mg, 78% yield) as a white solid.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 7.52 (d, 2H, J=8.4
Hz), 7.23 (d, 2H, J=8.1 Hz), 3.70 (s, 3H), 3.24 (s, 3H), 2.56-2.52
(m, 1H), 2.45 (bs, 1H), 2.17-1.67 (m, 1H), 1.34 (ddd, 1H, J=4.6,
6.3, & 8.7 Hz).
Step E: Determination of ee
[0366] To a solution of Compound 38d (0.8 mg) in CDCl.sub.3 (0.6
mL) was added (R)-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol
portion-wise and the amount of addition was monitored by .sup.1HNMR
until base line resolution of the resulting methoxy singlets was
achieved. Thus, the enantiomer methoxy singlets were around 3.47
and 3.45 ppm. The integration of these singlets was 99 and 1,
respectively; thus providing an ee value of 99%.
[0367] Using the procedure described in Example 38 and reagents,
starting materials and conditions known to those skilled in the
art, the following compounds representative of the present
invention were prepared:
TABLE-US-00034 Cpd Name and Data 502
2-{2-[(1R,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazo-
l- 5-yl}-benzenesulfonamide Using the procedure of Example 38, the
title compound was prepared from Compound 38c and
2-(t-butylamino)sulfonylphenyl boronic acid. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. (ppm): 12.42 (s, 0.5H), 12.40 (s, 0.5H), 8.04
(dd, 1H, J = 1.3 & 7.8 Hz), 7.66 (d, 2H, J = 8.3 Hz), 7.63-7.34
(m, 7H), 7.17-7.11 (m, 1H), 7.06 (s, 1H), 7.03 (s, 1H), 2.71-2.65
(m, 1H), 2.50-2.46 (m, 1H), 1.92-1.87 (m, 1H), 1.75-1.70 (m, 1H).
Mass Spectrum (LCMS, ESI pos.) Calcd for
C.sub.23H.sub.19F.sub.3N.sub.3O.sub.2S: 458.1 (M + 1). Found 458.2.
503 2-(2-{2-[(1S,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol monosodium salt Using the
procedure of Example 38, the title compound was prepared from 2,2-
bis-[(4R)-(1,1-dimethylethyl)-1,3-oxazolin-2-yl]propane and
4-(trifluoromethyl)- styrene. To a suspension of
N,N'-bis-[(2R)-3,3-dimethyl-1-hydroxybutyl]-2,2-dimethyl-
1,3-propanediamide (83 mg, 0.25 mmol, prepared according to the
procedure described in J. Am. Chem. Soc. 1991, 113, 726) in DCM
(2.5 mL) was added (diethylamino)sulfur trifluoride (0.066 mL, 0.50
mmol, as described in J. Org. Chem. 2002, 67, 8566 for the
formation of oxazoline from hydroxyamide) dropwise at ambient
temperature. The resulting mixture was stirred at ambient
temperature for 16 h, and poured into saturated NaHCO.sub.3 (4.0
mL). The mixture was extracted with DCM (3 .times. 5 mL). The
extracts were combined and dried over Na.sub.2SO.sub.4, then
concentrated and flash chromatographed with ethyl acetate/ DCM (0,
5, 10, and 20%) to provide
2,2-bis-[2-((4R)-(1,1-dimethylethyl)-1,3- oxazolinyl)]propane (53
mg, 72% yield) as a white solid. .sup.1H-NMR was identical to the
literature as reported by Evans. .sup.1H-NMR (400 MHz, DMSO-d6)
.delta. (ppm): 7.82 (dd, 1H, J = 1.5 & 8.1 Hz), 7.61 (d, 2H, J
= 8.1 Hz), 7.37 (d, 2H, J = 8.1 Hz), 7.24 (dt, 1H, J = 1.8 &
7.3 Hz), 7.15-7.11 (m, 2H), 7.00 (d, 1H, J = 1.5 Hz), 6.98 (dd, 1H,
J = 1.5 & 7.3 Hz), 6.52 (d, 1H, J = 7.8 Hz), 4.63 (bs, 1H),
2.52-2.47 (m, 1H), 2.33 (ddd, 1H, J = 4.1, 5.8 & 8.8 Hz), 1.75
(ddd, 1H, J = 3.7, 5.8, & 8.8 Hz), 1.45-1.40 (m, 1H), 1.22 (s,
6H). Mass Spectrum (LCMS, ESI pos.) Calcd for
C.sub.26H.sub.24F.sub.3N.sub.2O: 437.2. Found 437.2. Analogous to
Example 38, step A, both the trans isomer (1S,2S)-2-(4-
trifluoromethyl-phenyl)-cyclopropanecarboxylic acid ethyl ester
Compound 38e and the cis isomer
(1S,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropanecarboxylic acid
ethyl ester Compound 38f were isolated. 504
2-{2-[(1S,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazo-
l- 5-yl}-benzenesulfonamide Using the procedure described for
Compound 503, the title compound was prepared from Compound 38e,
4-(trifluoromethyl)-styrene and 2-(t- butylamino)sulfonylphenyl
boronic acid. .sup.1H-NMR (400 MHz, DMSO-d6) .delta. (ppm): 12.41
(s, 0.5H), 12.40 (s, 0.5H), 8.04 (dd, 1H, J = 1.3 & 7.8 Hz),
7.66 (d, 2H, J = 8.3 Hz), 7.63-7.34 (m, 7H), 7.17-7.11 (m, 1H),
7.06 (s, 1H), 7.03 (s, 1H), 2.71-2.65 (m, 1H), 2.50-2.46 (m, 1H),
1.92-1.87 (m, 1H), 1.75-1.70 (m, 1H). MS (ESI, pos. ion) m/z: 458.2
(M + 1). Mass Spectrum (LCMS, ESI pos.) Calcd for
C.sub.23H.sub.19F.sub.3N.sub.3O.sub.2S: 458.1 (M + 1). Found 458.2.
505 2-(2-{2-[(1S,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol Using the procedure
described for Compound 503, the title compound was prepared from
Compound 38f. 1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 7.79 (dd,
1H, J = 1.0 & 8.1 Hz), 7.36-7.15 (m, 8H), 7.01 (t, 1H, J = 1.5
Hz), 6.99 (d, 1H, J = 1.5 Hz), 2.83-2.73 (m, 2H), 2.08-2.03 (m,
1H), 1.71 (td, 1H, J = 8.6 & 5.6 Hz), 1.23 (s, 3H), 1.22 (s,
3H). Mass Spectrum (LCMS, ESI pos.) Calcd for
C.sub.26H.sub.24F.sub.3N.sub.2O: 437.2. Found 437.3. Determination
of ee: To a mixture of (1S,2R)-2-(4-trifluoromethyl-phenyl)-
cyclopropanecarboxylic acid (14 mg, 0.0.061 mmol), (S)-(-)-.alpha.-
methylbenzylamine (10.0 mg, 0.0609 mmol), BOP (27 mg, 0.0609 mmol),
and DMF (0.2 mL) was added DIEA (0.023 mL, 0.13 mmol). The
resulting solution was stirred at room temperature for 48 h,
concentrated to dryness, and partitioned between saturated
NaHCO.sub.3 (1 mL) and ethyl acetate (3 mL). Ethyl acetate layer
was separated, and aqueous was extracted with ethyl acetate (5 mL
.times. 2). All ethyl acetate layers were combined, washed with
brine, dried over Na.sub.2SO.sub.4, concentrated, and purified by
prep-TLC, developed with 10% ethyl acetate/DCM to give the title
compound (10.1 mg, 70% yield) as a white solid. 1H-NMR (400 MHz,
C.sub.6D.sub.6) .delta. (ppm): 7.26 (d, 2H, J = 8.1 Hz), 7.03-6.95
(m, 5H), 6.68-6.65 (m, 2H), 4.96-4.89 (m, 1H), 4.79 (bd, 1H, J =
7.6 Hz), 1.80-1.73 (m, 2H), 1.23-1.17 (m, 1H), 1.00 (d, 3H, J = 6.8
Hz), 0.82-0.79 (m, 1H).). In the 1H-NMR doublet of the Me in (1R,
2S, 1'S)-N-(1'-phenethyl)-2-(4-trifluoromethyl-
phenyl)-cyclopropanecarboxamide appeared at 0.85 ppm. Integration
of this methyl doublet and that of the title compound was 2.5 and
97.5, respectively. 506
2-{2-[(1R,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazo-
l- 5-yl}-benzenesulfonamide Using the procedure of Example 38, the
title compound was prepared from Compound 38b and
2-(t-butylamino)sulfonylphenyl boronic acid. 1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.09 (dd, 1H, J = 1.3 & 7.9 Hz),
7.59 (dt, 1H, J = 1.6 & 7.6 Hz), 7.51 (dt, 1H, J = 1.5 &
7.8 Hz), 7.47 (bs, 1H), 7.42-7.29 (m, 6H), 7.19 (dd, 1H, J = 1.7
& 8.3 Hz), 2.84-2.74 (m, 2H), 2.05 (q, 1H, J = 6.3 Hz), 1.72
(td, 1H, J = 8.5 & 5.7 Hz). Mass Spectrum (LCMS, ESI pos.)
Calcd for C.sub.23H.sub.19F.sub.3N.sub.3O.sub.2S: 458.1 (M + 1).
Found 458.2. 507
2-(2-{2-[(1R,2S)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-
benzimidazol-5-yl}-phenyl)-propan-2-ol Using the procedure of
Example 38, the title compound was prepared using Compound 38b.
1H-NMR (400 MHz, CD.sub.3OD) .delta. (ppm): 7.79 (dd, 1H, J = 1.0
& 8.1 Hz), 7.36-7.15 (m, 8H), 7.01 (t, 1H, J = 1.5 Hz), 6.99
(d, 1H, J = 1.5 Hz), 2.83-2.73 (m, 2H), 2.08-2.03 (m, 1H), 1.71
(td, 1H, J = 8.6 & 5.6 Hz), 1.23 (s, 3H), 1.22 (s, 3H). Mass
Spectrum (LCMS, ESI pos.) Calcd for
C.sub.26H.sub.24F.sub.3N.sub.2O: 437.2. Found 437.3. Determination
of ee: Using the procedure described for Compound 506, the amide
intermediate of Compound 507 was prepared from (1R,2S)-2-(4-
trifluoromethyl-phenyl)-cyclopropanecarboxylic acid Compound 38 g
and (S)-(-)- .alpha.-methylbenzylamine. 1H-NMR (400 MHz,
C.sub.6D.sub.6) .delta. (ppm): 7.37 (d, 2H, J = 8.1 Hz), 7.35-7.02
(m, 5H), 6.97-6.95 (m, 2H), 4.95-4.88 (m, 1H), 4.82 (bd, 1H, J =
7.8 Hz), 1.81-1.75 (m, 1H), 1.70 (ddd, 1H, J = 4.8, 5.8 & 7.3
Hz), 1.14 (ddd, 1H, J = 5.6, 7.8 & 9.0 Hz), 0.85 (d, 3H, J =
6.6 Hz), 0.80-0.75 (m, 1H). In the 1H-NMR doublet of the Me in (1S,
2R, 1'S)-N-(1'-phenethyl)-2-(4-
trifluoromethyl-phenyl)-cyclopropanecarboxamide appeared at 1.00
ppm. Integration of this methyl doublet and that of the title
compound was 3 and 97, respectively. 508
2-{2-[(1S,2R)-2-(4-trifluoromethyl-phenyl)-cyclopropyl]-1H-benzimidazo-
l- 5-yl}-benzenesulfonamide Using the procedure described for
Compound 503, the title compound was prepared from Compound 38f and
2-(t-butylamino)sulfonylphenyl boronic acid. 1H-NMR (400 MHz,
CD.sub.3OD) .delta. (ppm): 8.09 (dd, 1H, J = 1.3 & 7.9 Hz),
7.59 (dt, 1H, J = 1.6 & 7.6 Hz), 7.51 (dt, 1H, J = 1.5 &
7.8 Hz), 7.47 (bs, 1H), 7.42-7.29 (m, 6H), 7.19 (dd, 1H, J = 1.7
& 8.3 Hz), 2.84-2.74 (m, 2H), 2.05 (q, 1H, J = 6.3 Hz), 1.72
(td, 1H, J = 8.5 & 5.7 Hz). Mass Spectrum (LCMS, ESI pos.)
Calcd for C.sub.23H.sub.19F.sub.3N.sub.3O.sub.2S: 458.1 (M + 1).
Found 458.2.
BIOLOGICAL EXAMPLES
Example 1
Human VR1 (hVR1) Binding Assay
[0368] Compounds of the present invention were tested for their
ability to inhibit the binding of [.sup.3H] RTX to hVR1 receptors
in a [.sup.3H] RTX binding assay as previously described (Zhang,
Sui-Po. Improved ligand binding assays for vanilloid receptors. PCT
Int. Appl. (2002), WO 0233411 A1 20020425 AN 2002:315209, and
Elfrida G. R. et al., J. Pharmacol. Exp. Ther., 2002, 300(1):
9-17.)
[0369] HEK293 cells were transfected with hVR1 vanilloid receptors
and washed with Hank's balanced Salt Solution, dissociated with
cell dissociation buffer (Sigma), and then centrifuged at
1000.times.g for 5 min. Cell pellets were homogenized in cold 20 mM
HEPES buffer (pH=7.4), containing 5.8 mM NaCl, 320 mM sucrose, 2 mM
MgCl.sub.2, 0.75 CaCl.sub.2 and 5 mM KCl and centrifuged at
1000.times.g for 15 min. The resultant supernatant was then
centrifuged at 40,000.times.g for 15 min. The pelleted membranes
were stored in a freezer at -80.degree. C.
[0370] Approximately 120 .mu.g protein/ml from membranes were
incubated with indicated concentrations of [.sup.3H]RTX in 0.5 ml
of the HEPES buffer (pH 7.4) containing 0.25 mg/mL fatty acid-free
bovine serum albumin at 37.degree. C. for 60 min. The reaction
mixture was then cooled to 4.degree. C., and 0.1 mg of a, acid
glycoprotein was added to each sample, which was then incubated at
4.degree. C. for 15 min. The samples were centrifuged at
18,500.times.g for 15 min. The tip of the microcentrifuge tube
containing the pellet was cut off. Bound radioactivity was
quantified by scintillation counting. Non-specific binding was
measured in the presence of 200 nM unlabeled RTX.
[0371] Data were calculated according to the equation:
% inhibition=100%.times.[(total binding-binding)/(total binding-non
specific binding)]
[0372] K.sub.i values were calculated using a Prism program.
TABLE-US-00035 TABLE 1 Cpd Ki (nM) 1 9.7 3 20 4 31 5 17 9 0.9 14
380 15 41 17 8.7 18 6.5 27 1800 32 100 36 820 40 81 50 16 51 6.4 56
120 69 6 70 8.6 71 22 78 6.4 79 18 310 10 312 19 319 6 407 5.7 434
39
Example 2
Human VR1 (hVR1) Functional Assay
[0373] The functional activity of the test compounds was determined
by measuring changes in intracellular calcium concentration using a
Ca.sup.++-sensitive fluorescent dye and FLIPR.TM. technology.
Increases in Ca.sup.++ concentration were readily detected upon
challenge with capsaicin.
[0374] HEK293 cells expressing hVR1 were grown on poly-D-lysine
coated 384 well black-walled plates (BD 354663) and 1 day later
loaded with Calcium 3 Dye for 35 min at 37.degree. C., 5% CO.sub.2
and then for 25 min at room temperature, and subsequently tested
for agonist-induced increases in intracellular Ca.sup.2+ levels
using FLIPR.TM. technology. Cells were challenged with test
compounds (at varying concentrations) and intracellular Ca.sup.2+
was measured for 5 min prior to the addition of capsaicin to all
wells to achieve a final concentration of 0.030 .mu.M eliciting
about 80% maximal response. IC.sub.50 values were determined from
concentration-response studies, which were generated using the
average of quadruplicate wells for each data point.
[0375] For those compounds tested, an IC.sub.50 (nM) value and
percent inhibition value is shown in Table 2. Except where
indicated, the percent inhibition values were obtained at a test
concentration of 1 .mu.M; otherwise: .sup.(1)the test concentration
was 5 .mu.M. The percent inhibition value is provided for those
compounds where an IC.sub.50 value was not obtained. The term "NA"
means that the data is "not available" because it was not obtained
for a particular compound.
TABLE-US-00036 TABLE 2 Cpd % Inh IC.sub.50 1 100 27 2 100 12 3 NA
140 4 78 400 5 100 71 6 12 NA 7 10 NA 8 10 NA 9 99 2 10 94 280 11
100 210 12 100 10 13 82 310 14 49 1000 15 100 120 16 100 45 17 100
8 18 100 4 19 32 NA 20 NA 320 22 NA 18 24 8 NA 25 4 NA 26 6 NA 27
100 260 28 96 250 29 6 NA 30 10 NA 31 NA 13 32 77 380 33 NA 1700 34
.sup.(1)75 NA 35 100 41 36 44 NA 37 18 NA 38 89 270 39 98 200 40 99
54 41 90 280 42 100 22 43 58 890 44 95 300 45 100 16 46 100 46 47
100 20 48 33 NA 49 16 NA 50 100 100 51 100 66 52 28 NA 53 98 47 54
20 NA 55 14 NA 56 100 110 57 15 NA 58 87 95 59 80 440 60 7 NA 61
100 75 62 100 200 63 97 260 64 41 NA 65 0 NA 66 98 48 67 98 130 68
NA 329 69 98 6 70 100 7 71 99 22 77 100 76 78 99 5 79 100 7 83 NA
>500 84 100 40 85 16 NA 95 81 301 101 NA >500 113 48 NA 114
99 3 129 96 34 130 100 6 131 96 31 139 98 31 145 19 NA 175 100 16
190 94 38 198 95 10 234 7 NA 250 98 19 294 101 9.1 295 100 16 309
73 NA 310 100 6 311 99 54 312 100 6 314 100 18 315 100 11 316 101
12 317 101 11 318 100 50 319 100 10 320 100 13 321 100 18 322 101
14 323 97 40 324 98 33 325 73 NA 326 89 157 327 77 343 328 99 35
329 98 27 330 85 131 331 97 43 332 98 49 333 98 27 334 94 178 335
100 47 336 89 240 337 96 14 338 96 104 339 99 27 340 98 62 341 99 6
342 98 24 343 82 243 344 101 24 345 101 13 346 87 264 347 100 44
348 86 162 349 99 59 350 100 33 351 NA >500 357 100 8 358 99 9
359 98 24 360 98 46 361 97 27 362 99 8 363 98 12 364 97 65 365 99
17 366 99 35 367 98 53 368 99 15 369 99 8 370 98 13 371 98 18 372
97 71 373 99 20 374 99 34 375 97 139 376 100 28 378 100 12 379 99
40 380 99 12 383 96 11 384 98 7 385 97 21 386 96 43 387 98 41 388
99 54 389 23 NA 390 96 7 391 95 8 392 97 10 393 98 10 394 98 6 395
99 15 396 99 13 397 99 23 398 97 3 399 97 3 402 93 38 404 94 47 405
95 20 406 97 170 407 96 9 408 64 NA 409 43 NA 410 91 156 411 85 350
412 86 190 413 82 240 414 98 140 415 95 150 416 96 120 417 100 11
418 100 18 419 93 32 420 93 15 421 95 10 422 98 7 423 99 11 424 99
11 425 2 NA 426 99 22 427 98 13 428 100 7 429 98 6 430 100 9 431 97
35 432 98 15 433 98 10 434 98 7 435 97 20 436 96 10 437 97 24 438
96 71 439 97 23 440 98 40 441 40 NA 442 96 4 444 98 28 445 96 20
446 97 76 447 98 44 448 99 17 449 100 9 450 27 NA 451 101 28 452 5
NA 453 22 NA 454 36 NA 455 100 17 456 100 45 457 22 NA 458 15 NA
459 0 NA 460 21 NA 461 99 5 462 98 97 463 100 14 464 100 3 465 75
363 466 98 71 467 86 182 468 97 8 469 99 7 470 97 45 471 100 10 472
NA >500 473 NA >500 474 NA >500 475 NA 77
476 NA 68 477 44 NA 478 NA >500 479 12 NA 480 NA >500 481 42
NA 482 100 13 483 21 NA 484 NA >500 485 NA >500 486 NA
>500 487 20 NA 488 4 NA 489 96 2 490 99 26 491 NA 77 492 99 5
494 93 52 497 94 39 498 100 19 499 7 NA 500 97 19 501 99 85 502 82
190 503 93 10 504 95 22
Example 3
Chemically-Induced Models of Inflammatory Pain
[0376] Compounds of the present invention were tested in animal
models of inflammation and inflammatory pain. To assess the ability
of test compounds to reverse thermal hyperalgesia, baseline
response latencies on a radiant heat (RH) paw stimulator were
obtained before an intraplantar injection of 100 .mu.L (1
.mu.g/.mu.L) CFA (1:1 CFA:saline) in male Sprague-Dawley rats. Only
withdrawal responses that were quick hind paw movements (with or
without licking of the hind paw) were recorded. Paw movements
associated with locomotion or a shifting of weight were not
considered a withdrawal response. The stimulus intensity that
produced 10-15 sec baseline withdrawal latencies was used and a
maximum cutoff of 20 sec was imposed. Hypersensitivity was
evaluated 24 hr after CFA. Only rats that exhibited at least a 25%
reduction in response latency from baseline (i.e. hyperalgesia)
were included in further analysis.
[0377] Following the post-inflammogen latency assessment, rats were
orally dosed (2.5 mL/kg) with test compound (10 mg/kg) or vehicle
(20% hydroxypropyl beta cyclodextran). To determine the time of
peak effect, latencies were redetermined 30, 60, 100, 180 and 300
min after compound administration.
[0378] Data are presented as the maximal percent reversal of
hypersensitivity obtained during the 300 min test, which was
calculated for each animal according to the formula:
% reversal=100%.times.(treatment response-post-inflammogen
response)/(pre-inflammogen response-post-inflammogen response)
TABLE-US-00037 TABLE 3 Cpd % Reversal 17 104 18 133 22 18 23 31 31
72 47 58 70 76 78 19 114 56 310 23 464 65
Example 4
Incision-Induced Model of Postoperative Surgery
[0379] Compounds of the present invention were tested in animal
models of postoperative surgery, as previously described (Brennan,
T. J. et al., Pain, 1996, 64: 493-501). Male Sprague-Dawley rats
were anaesthetized with 2-3 isoflurane and the plantar surface of
the hindpaw was sterilized using three alternating betadine and
alcohol scrubs. A 1 cm longitudinal incision through the skin of
the plantar paw was made using a number 10 scalpel beginning 0.5 cm
from the proximal heel and extending toward the toes. The plantaris
muscle was excised using a forcep and incised longitudinally. The
skin was then sutured in two locations using 5-0 silk. The wound
site was then covered with antibiotic ointment and the animals were
returned to their individual home cages. Changes in thermal
sensitivity were evaluated before surgery and 24 hr after surgery.
Vehicle (20% HP.beta.CD) or test compound was orally administered
and thermal sensitivity was re-assessed 30, 60, 100, 180 and 300
min later.
[0380] Data are presented as the maximal percent reversal of
hypersensitivity obtained during the 300 min test, which was
calculated for each animal according to the formula:
% reversal=100% (treatment response-post-inflammogen
response)/(pre-inflammogen response-post-inflammogen response)
TABLE-US-00038 TABLE 4 Cpd % Reversal 18 132
[0381] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
[0382] All publications disclosed in the above specification are
hereby incorporated by reference in full.
* * * * *