U.S. patent application number 15/369029 was filed with the patent office on 2017-05-25 for pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels.
The applicant listed for this patent is Vertex Pharmaceuticals Incorporated. Invention is credited to Corey ANDERSON, Vijayalaksmi ARUMUGAM, Peter Diederik Jan GROOTENHUIS, Sara Sabina HADIDA RUAH, Licong JIANG, Edward Adam KALLEL, Jason McCARTNEY, Mark Thomas MILLER.
Application Number | 20170145011 15/369029 |
Document ID | / |
Family ID | 45689011 |
Filed Date | 2017-05-25 |
United States Patent
Application |
20170145011 |
Kind Code |
A1 |
HADIDA RUAH; Sara Sabina ;
et al. |
May 25, 2017 |
Pyrrolopyrazine-Spirocyclic piperidine amides as modulators of ion
channels
Abstract
The invention relates to pyrrolopyrazine-spirocyclic piperidine
amide compounds useful as inhibitors of ion channels. The invention
also provides pharmaceutically acceptable compositions comprising
the compounds of the invention and methods of using the
compositions in the treatment of various disorders.
Inventors: |
HADIDA RUAH; Sara Sabina;
(La Jolla, CA) ; KALLEL; Edward Adam; (Escondido,
CA) ; MILLER; Mark Thomas; (San Diego, CA) ;
ARUMUGAM; Vijayalaksmi; (San Marcos, CA) ; McCARTNEY;
Jason; (Cardiff by the Sea, CA) ; ANDERSON;
Corey; (San Diego, CA) ; GROOTENHUIS; Peter Diederik
Jan; (San Diego, CA) ; JIANG; Licong; (San
Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vertex Pharmaceuticals Incorporated |
Boston |
MA |
US |
|
|
Family ID: |
45689011 |
Appl. No.: |
15/369029 |
Filed: |
December 5, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14578628 |
Dec 22, 2014 |
9511067 |
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15369029 |
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13364586 |
Feb 2, 2012 |
8916565 |
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14578628 |
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61438685 |
Feb 2, 2011 |
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61440987 |
Feb 9, 2011 |
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61495538 |
Jun 10, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/04 20180101; A61P
25/04 20180101; A61P 13/00 20180101; A61P 21/00 20180101; A61P
25/02 20180101; C07D 471/20 20130101; A61P 27/16 20180101; A61P
5/00 20180101; A61P 25/18 20180101; A61P 7/06 20180101; A61P 15/00
20180101; A61P 1/18 20180101; A61P 21/02 20180101; A61P 17/02
20180101; A61P 25/00 20180101; A61P 17/04 20180101; A61K 31/506
20130101; A61P 25/28 20180101; A61K 31/499 20130101; A61P 1/00
20180101; A61P 25/06 20180101; A61P 25/22 20180101; A61P 25/24
20180101; A61P 43/00 20180101; A61P 9/10 20180101; C07D 519/00
20130101; A61P 13/08 20180101; A61P 9/12 20180101; A61P 25/08
20180101; A61P 19/02 20180101; A61P 13/10 20180101; A61P 9/00
20180101; A61P 25/14 20180101; A61P 9/06 20180101; A61P 1/02
20180101; A61P 11/02 20180101; A61P 29/00 20180101 |
International
Class: |
C07D 471/20 20060101
C07D471/20; A61K 31/499 20060101 A61K031/499 |
Claims
1. (canceled)
2. A compound of formula ##STR00890## or a pharmaceutically
acceptable salt thereof.
3. A compound of formula ##STR00891##
4. The compound of claim 2, wherein said pharmaceutically
acceptable salt is selected from acid addition salts of suitable
inorganic and organic acids.
5. The compound of claim 4, wherein said pharmaceutically
acceptable salt is selected from the group consisting of adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts.
6. The compound of claim 4, wherein said pharmaceutically
acceptable salt is selected from hydrochloride, hydrobromide,
phosphate, sulfate, perchlorate, acetate, oxalate, maleate,
tartarate, citrate, succinate and malonate salts.
7. A pharmaceutical composition comprising the compound of claim 2
and a pharmaceutically acceptable carrier.
8. The composition of claim 7 further comprising an additional
therapeutic agent.
9. The composition of claim 8, wherein the additional therapeutic
agent is selected from the group consisting of: nonopioid
analgesics selected from indoles, naphthylalkanones, oxicams,
para-aminophenol derivatives, propionic acids, salicylates,
fenamates, and pyrazoles; and opioid (narcotic) agonists selected
from Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine,
Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene,
Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and
Pentazocine.
10. A method of inhibiting a voltage-gated sodium ion channel in: a
patient; or a biological sample; comprising administering to the
patient, or contacting the biological sample, with the compound of
claim 2.
11. The method of claim 10, wherein the voltage-gated sodium ion
channel is NaV 1.7.
12. A method of treating or lessening the severity of acute pain,
chronic pain, neuropathic pain, inflammatory pain, visceral pain,
osteoarthritis pain, radicular pain, sciatica, back pain, head
pain, neck pain, severe pain, intractable pain, nociceptive pain,
breakthrough pain, postsurgical pain, pain associated with cancer
in a subject, comprising administering to said subject an effective
amount of a compound of claim 2.
13. The method of claim 12, wherein said pharmaceutically
acceptable salt is selected from the group consisting of acid
addition salts of suitable inorganic and organic acids.
14. The method of claim 13, wherein said pharmaceutically
acceptable salt is selected from the group consisting of adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts.
15. The method of claim 13, wherein said pharmaceutically
acceptable salt is selected from the group consisting of
hydrochloride, hydrobromide, phosphate, sulfate, perchlorate,
acetate, oxalate, maleate, tartarate, citrate, succinate and
malonate salts.
16. The method of claim 12 wherein an additional therapeutic agent
is administered concurrently with, prior to, or subsequent to the
compound of claim 2.
17. The method of claim 16, wherein the additional therapeutic
agent is selected from the group consisting of: nonopioid
analgesics selected from indoles, naphthylalkanones, oxicams,
para-aminophenol derivatives, propionic acids, salicylates,
fenamates, and pyrazoles; and opioid (narcotic) agonists selected
from Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine,
Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene,
Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and
Pentazocine.
18. A method of treating or lessening the severity of acute pain,
chronic pain, neuropathic pain, inflammatory pain, visceral pain,
osteoarthritis pain, radicular pain, sciatica, back pain, head
pain, neck pain, severe pain, intractable pain, nociceptive pain,
breakthrough pain, postsurgical pain, pain associated with cancer
in a subject, comprising administering to said subject an effective
amount of a composition comprising a compound of claim 2.
19. The method of claim 18, wherein the composition comprises the
compound of claim 2 and a pharmaceutically acceptable carrier.
20. The method of claim 19, wherein the composition further
comprises an additional therapeutic agent.
21. The method of claim 20, wherein the additional therapeutic
agent is selected from the group consisting of: nonopioid
analgesics selected from indoles, naphthylalkanones, oxicams,
para-aminophenol derivatives, propionic acids, salicylates,
fenamates, and pyrazoles; and opioid (narcotic) agonists selected
from Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine,
Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene,
Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional patent
application Ser. No. 61/438,685, filed Feb. 2, 2011, 61/440,987,
filed Feb. 9, 2011, and 61/495,538, filed Jun. 10, 2011, the entire
contents of all applications are incorporated herein by
reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The invention relates to compounds useful as inhibitors of
ion channels. The invention also provides pharmaceutically
acceptable compositions comprising the compounds of the invention
and methods of using the compositions in the treatment of various
disorders.
BACKGROUND OF THE INVENTION
[0003] Pain is a protective mechanism that allows healthy animals
to avoid tissue damage and to prevent further damage to injured
tissue. Nonetheless there are many conditions where pain persists
beyond its usefulness, or where patients would benefit from
inhibition of pain. Voltage-gated sodium channels are believed to
play a critical role in pain signaling. This belief is based on the
known roles of these channels in normal physiology, pathological
states arising from mutations in sodium channel genes, preclinical
work in animal models of disease, and the clinical usefulness of
known sodium channel modulating agents (Cummins, T. R., Sheets, P.
L., and Waxman, S. G., The roles of sodium channels in nociception:
Implications for mechanisms of pain. Pain 131 (3), 243 (2007);
England, S., Voltage-gated sodium channels: the search for
subtype-selective analgesics. Expert Opin Investig Drugs 17 (12),
1849 (2008); Krafte, D. S. and Bannon, A. W., Sodium channels and
nociception: recent concepts and therapeutic opportunities. Curr
Opin Pharmacol 8 (1), 50 (2008)).
[0004] Voltage-gated sodium channels (NaV's) are key biological
mediators of electrical signaling. NaV's are the primary mediators
of the rapid upstroke of the action potential of many excitable
cell types (e.g. neurons, skeletal myocytes, cardiac myocytes), and
thus are critical for the initiation of signaling in those cells
(Hille, Bertil, Ion Channels of Excitable Membranes, Third ed.
(Sinauer Associates, Inc., Sunderland, Mass., 2001)). Because of
the role NaV's play in the initiation and propagation of neuronal
signals, antagonists that reduce NaV currents can prevent or reduce
neural signaling. Thus NaV channels are considered likely targets
in pathologic states where reduced excitability is predicted to
alleviate the clinical symptoms, such as pain, epilepsy, and some
cardiac arrhythmias (Chahine, M., Chatelier, A., Babich, O., and
Krupp, J. J., Voltage-gated sodium channels in neurological
disorders. CNS Neurol Disord Drug Targets 7 (2), 144 (2008)).
[0005] The NaV's form a subfamily of the voltage-gated ion channel
super-family and comprises 9 isoforms, designated NaV 1.1-NaV 1.9.
The tissue localizations of the nine isoforms vary greatly. NaV 1.4
is the primary sodium channel of skeletal muscle, and NaV 1.5 is
primary sodium channel of cardiac myocytes. NaV's 1.7, 1.8 and 1.9
are primarily localized to the peripheral nervous system, while
NaV's 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both
the central and peripheral nervous systems. The functional
behaviors of the nine isoforms are similar but distinct in the
specifics of their voltage-dependent and kinetic behavior
(Catterall, W. A., Goldin, A. L., and Waxman, S. G., International
Union of Pharmacology. XLVII. Nomenclature and structure-function
relationships of voltage-gated sodium channels. Pharmacol Rev 57
(4), 397 (2005)).
[0006] NaV channels have been identified as the primary target for
some clinically useful pharmaceutical agents that reduce pain
(Cummins, T. R., Sheets, P. L., and Waxman, S. G., The roles of
sodium channels in nociception: Implications for mechanisms of
pain. Pain 131 (3), 243 (2007)). The local anesthetic drugs such as
lidocaine block pain by inhibiting NaV channels. These compounds
provide excellent local pain reduction but suffer the drawback of
abolishing normal acute pain and sensory inputs. Systemic
administration of these compounds results in dose limiting side
effects that are generally ascribed to block of neural channels in
the CNS (nausea, sedation, confusion, ataxia). Cardiac side effects
can also occur, and indeed these compounds are also used as class 1
anti-arrhythmics, presumably due to block of NaV1.5 channels in the
heart. Other compounds that have proven effective at reducing pain
have also been suggested to act by sodium channel blockade
including carbamazepine, lamotragine, and tricyclic antidepressants
(Soderpalm, B., Anticonvulsants: aspects of their mechanisms of
action. Eur J Pain 6 Suppl A, 3 (2002); Wang, G. K., Mitchell, J.,
and Wang, S. Y., Block of persistent late Na+ currents by
antidepressant sertraline and paroxetine. J Membr Biol 222 (2), 79
(2008)). These compounds are likewise dose limited by adverse
effects similar to those seen with the local anesthetics.
Antagonists that specifically block only the isoform(s) critical
for nocioception are expected to have increased efficacy since the
reduction of adverse effects caused by block of off-target channels
should enable higher dosing and thus more complete block of target
channels isoforms.
[0007] Four NaV isoforms, NaV 1.3, 1.7, 1.8, and 1.9, have been
specifically indicated as likely pain targets. NaV 1.3 is normally
found in the pain sensing neurons of the dorsal root ganglia (DRG)
only early in development and is lost soon after birth both in
humans and in rodents. Nonetheless, nerve damaging injuries have
been found to result in a return of the NaV 1.3 channels to DRG
neurons and this may contribute to the abnormal pain signaling in
various chronic pain conditions resulting from nerve damage
(neuropathic pain). These data have led to the suggestion that
pharmaceutical block of NaV 1.3 could be an effective treatment for
neuropathic pain. In opposition to this idea, global genetic
knockout of NaV 1.3 in mice does not prevent the development of
allodynia in mouse models of neuropathic pain (Nassar, M. A. et
al., Nerve injury induces robust allodynia and ectopic discharges
in NaV 1.3 null mutant mice. Mol Pain 2, 33 (2006)). It remains
unknown whether compensatory changes in other channels allow for
normal neuropathic pain in NaV 1.3 knockout mice, though it has
been reported that knockout of NaV 1.1 results in drastic
upregulation of NaV 1.3. The converse effect in NaV 1.3 knockouts
might explain these results.
[0008] NaV 1.7, 1.8, and 1.9 are highly expressed in DRG neurons,
including the neurons whose axons make up the C-fibers and A.delta.
nerve fibers that are believed to carry most pain signals from the
nocioceptive terminals to the central nervous. Like NaV 1.3, NaV
1.7 expression increases after nerve injury and may contribute to
neuropathic pain states. The localization of NaV 1.7, 1.8, and 1.9
in nocioceptors led to the hypothesis that reducing the sodium
currents through these channels might alleviate pain. Indeed,
specific interventions that reduce the levels of these channels
have proven effective in animal models of pain.
[0009] Specific reduction of NaV 1.7 in rodents by multiple
different techniques has resulted in the reduction of observable
pain behaviors in model animals. Injection of a viral antisense NaV
1.7 cDNA construct greatly reduces normal pain responses due to
inflammation or mechanical injury (Yeomans, D. C. et al., Decrease
in inflammatory hyperalgesia by herpes vector-mediated knockdown of
NaV 1.7 sodium channels in primary afferents. Hum Gene Ther 16 (2),
271 (2005)). Likewise, a genetic knockout of NaV 1.7 in a subset of
nociceptor neurons reduced acute and inflammatory pain in mouse
models (Nassar, M. A. et al., Nociceptor-specific gene deletion
reveals a major role for NaV 1.7 (PN1) in acute and inflammatory
pain. Proc Natl Acad Sci USA 101 (34), 12706 (2004)). Global
knockouts of NaV 1.7 in mice lead to animals that die on the first
day after birth. These mice fail to feed and this is the presumed
cause of death.
[0010] Treatments that specifically reduce NaV 1.8 channels in
rodent models effectively reduce pain sensitivity. Knockdown of NaV
1.8 in rats by intrathecal injection of antisense
oligodeoxynucleotides reduces neuropathic pain behaviors, while
leaving acute pain sensation intact (Lai, J. et al., Inhibition of
neuropathic pain by decreased expression of the
tetrodotoxin-resistant sodium channel, NaV1.8. Pain 95 (1-2), 143
(2002); Porreca, F. et al., A comparison of the potential role of
the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2,
in rat models of chronic pain. Proc Natl Acad Sci USA 96 (14), 7640
(1999)). Global genetic knockout of NaV 1.8 in mice or specific
destruction of NaV 1.8 expressing neurons greatly reduces
perception of acute mechanical, inflammatory, and visceral pain
(Akopian, A. N. et al., The tetrodotoxin-resistant sodium channel
SNS has a specialized function in pain pathways. Nat Neurosci 2
(6), 541 (1999); Abrahamsen, B. et al., The cell and molecular
basis of mechanical, cold, and inflammatory pain. Science 321
(5889), 702 (2008); Laird, J. M., Souslova, V., Wood, J. N., and
Cervero, F., Deficits in visceral pain and referred hyperalgesia in
NaV 1.8 (SNS/PN3)-null mice. J Neurosci 22 (19), 8352 (2002)). In
contrast to the antisense experiments in rats, genetic knockout
mice appear to develop neuropathic pain behaviors normally after
nerve injury (Lai, J. et al., Inhibition of neuropathic pain by
decreased expression of the tetrodotoxin-resistant sodium channel,
NaV1.8. Pain 95 (1-2), 143 (2002); Akopian, A. N. et al., The
tetrodotoxin-resistant sodium channel SNS has a specialized
function in pain pathways. Nat Neurosci 2 (6), 541 (1999);
Abrahamsen, B. et al., The cell and molecular basis of mechanical,
cold, and inflammatory pain. Science 321 (5889), 702 (2008); Laird,
J. M., Souslova, V., Wood, J. N., and Cervero, F., Deficits in
visceral pain and referred hyperalgesia in NaV 1.8 (SNS/PN3)-null
mice. J Neurosci 22 (19), 8352 (2002)).
[0011] NaV 1.9 global knock out mice have decreased sensitivity to
inflammation induced pain, despite normal acute, and neuropathic
pain behaviors (Amaya, F. et al., The voltage-gated sodium channel
Na(v)1.9 is an effector of peripheral inflammatory pain
hypersensitivity. J Neurosci 26 (50), 12852 (2006); Priest, B. T.
et al., Contribution of the tetrodotoxin-resistant voltage-gated
sodium channel NaV1.9 to sensory transmission and nociceptive
behavior. Proc Natl Acad Sci USA 102 (26), 9382 (2005)). Spinal
knockdown of NaV 1.9 had no apparent effect on pain behavior in
rats (Porreca, F. et al., A comparison of the potential role of the
tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in
rat models of chronic pain. Proc Natl Acad Sci USA 96 (14), 7640
(1999)).
[0012] The understanding of the role of NaV channels in human
physiology and pathology has been greatly advanced by the discovery
and analysis of naturally occurring human mutations. NaV 1.1 and
NaV 1.2 mutations result in various forms of epilepsy (Fujiwara,
T., Clinical spectrum of mutations in SCN1A gene: severe myoclonic
epilepsy in infancy and related epilepsies. Epilepsy Res 70 Suppl
1, S223 (2006); George, A. L., Jr., Inherited disorders of
voltage-gated sodium channels. J Clin Invest 115 (8), 1990 (2005);
Misra, S. N., Kahlig, K. M., and George, A. L., Jr., Impaired
NaV1.2 function and reduced cell surface expression in benign
familial neonatal-infantile seizures. Epilepsia 49 (9), 1535
(2008)). Mutations of the NaV 1.4 cause muscular disorders like
paramyotonia congenital (Vicart, S., Sternberg, D., Fontaine, B.,
and Meola, G., Human skeletal muscle sodium channelopathies. Neurol
Sci 26 (4), 194 (2005)). NaV 1.5 mutations result in cardiac
abnormalities like Brugada Syndrome and long QT syndrome (Bennett,
P. B., Yazawa, K., Makita, N., and George, A. L., Jr., Molecular
mechanism for an inherited cardiac arrhythmia. Nature 376 (6542),
683 (1995); Darbar, D. et al., Cardiac sodium channel (SCNSA)
variants associated with atrial fibrillation. Circulation 117 (15),
1927 (2008); Wang, Q. et al., SCNSA mutations associated with an
inherited cardiac arrhythmia, long QT syndrome. Cell 80 (5), 805
(1995)).
[0013] Recent discoveries have demonstrated that mutations in the
gene that encodes the NaV 1.7 channel (SCN9A) can cause both
enhanced and reduced pain syndromes. Work by Waxman's group and
others have identified at least 15 mutations that result in
enhanced current through NaV 1.7 and are linked to dominant
congenital pain syndromes. Mutations that lower the threshold for
NaV 1.7 activation cause inherited erythromelalgia (IEM). IEM
patients exhibit abnormal burning pain in their extremities.
Mutations that interfere with the normal inactivation properties of
NaV 1.7 lead to prolonged sodium currents and cause paroxysmal
extreme pain disorder (PEPD). PEPD patients exhibit periocular,
perimandibular, and rectal pain symptoms that progresses throughout
life (Drenth, J. P. et al., SCN9A mutations define primary
erythermalgia as a neuropathic disorder of voltage gated sodium
channels. J Invest Dermatol 124 (6), 1333 (2005); Estacion, M. et
al., NaV 1.7 gain-of-function mutations as a continuum: A1632E
displays physiological changes associated with erythromelalgia and
paroxysmal extreme pain disorder mutations and produces symptoms of
both disorders. J Neurosci 28 (43), 11079 (2008)).
[0014] NaV 1.7 null mutations in human patients were recently
described by several groups (Ahmad, S. et al., A stop codon
mutation in SCN9A causes lack of pain sensation. Hum Mol Genet 16
(17), 2114 (2007); Cox, J. J. et al., An SCN9A channelopathy causes
congenital inability to experience pain. Nature 444 (7121), 894
(2006); Goldberg, Y. P. et al., Loss-of-function mutations in the
NaV 1.7 gene underlie congenital indifference to pain in multiple
human populations. Clin Genet 71 (4), 311 (2007)). In all cases
patients exhibit congenital indifference to pain. These patients
report no pain under any circumstances. Many of these patients
suffer dire injuries early in childhood since they do not have the
protective, normal pain that helps to prevent tissue damage and
develop appropriate protective behaviors. Aside from the striking
loss of pain sensation and reduced or absent of smell (Goldberg, Y.
P. et al., Loss-of-function mutations in the NaV 1.7 gene underlie
congenital indifference to pain in multiple human populations. Clin
Genet 71 (4), 311 (2007)), these patients appear completely normal.
Despite the normally high expression of NaV 1.7 in sympathetic
neurons (Toledo-Aral, J. J. et al., Identification of PN1, a
predominant voltage-dependent sodium channel expressed principally
in peripheral neurons. Proc Natl Acad Sci USA 94 (4), 1527 (1997))
and adrenal chromafin cells (Klugbauer, N., Lacinova, L.,
Flockerzi, V., and Hofmann, F., Structure and functional expression
of a new member of the tetrodotoxin-sensitive voltage-activated
sodium channel family from human neuroendocrine cells. EMBO J 14
(6), 1084 (1995)), these NaV 1.7-null patients show no sign of
neuroendocrine or sympathetic nervous dysfunction.
[0015] The gain of NaV 1.7 function mutations that cause pain,
coupled with the loss of NaV 1.7 function mutations that abolish
pain, provide strong evidence that NaV 1.7 plays an important role
in human pain signaling. The relative good health of NaV 1.7-null
patients indicates that ablation of NaV 1.7 is well tolerated in
these patients.
[0016] Unfortunately, the efficacy of currently used sodium channel
blockers for the disease states described above has been to a large
extent limited by a number of side effects. These side effects
include various CNS disturbances such as blurred vision, dizziness,
nausea, and sedation as well more potentially life threatening
cardiac arrhythmias and cardiac failure. Accordingly, there remains
a need to develop additional Na channel antagonists, preferably
those with higher potency and fewer side effects.
SUMMARY OF THE INVENTION
[0017] It has now been found that compounds of this invention, and
pharmaceutically acceptable compositions thereof, are useful as
inhibitors of voltage-gated sodium channels. These compounds have
the general formula I:
##STR00001##
or a pharmaceutically acceptable salt thereof.
[0018] These compounds and pharmaceutically acceptable compositions
are useful for treating or lessening the severity of a variety of
diseases, disorders, or conditions, including, but not limited to,
acute, chronic, neuropathic, or inflammatory pain, arthritis,
migraine, cluster headaches, trigeminal neuralgia, herpetic
neuralgia, general neuralgias, epilepsy or epilepsy conditions,
neurodegenerative disorders, psychiatric disorders such as anxiety
and depression, myotonia, arrhythmia, movement disorders,
neuroendocrine disorders, ataxia, multiple sclerosis, irritable
bowel syndrome, incontinence, visceral pain, osteoarthritis pain,
postherpetic neuralgia, diabetic neuropathy, radicular pain,
sciatica, back pain, head or neck pain, severe or intractable pain,
nociceptive pain, breakthrough pain, postsurgical pain, or cancer
pain.
DETAILED DESCRIPTION OF THE INVENTION
[0019] In one aspect, the invention provides compounds of formula
I:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein,
independently for each occurrence: [0020] R.sup.1 is H, C1-C8
alkyl, C3-C8 cycloalkyl, halo, CN, NR.sup.8SO.sub.2R.sup.8,
SO.sub.2R.sup.8, SR.sup.8, SOR.sup.8, NR.sup.8COR.sup.8,
NR.sup.8CO.sub.2R.sup.8, CON(R.sup.8).sub.2,
SO.sub.2N(R.sup.8).sub.2, CF.sub.3, heterocycloalkyl, or a straight
chain, branched, or cyclic (C1-C8)-R.sup.9 wherein up to two
CH.sub.2 units may be replaced with O, CO, S, SO, SO.sub.2 or
NR.sup.8, or two R.sup.1 taken together form an oxo group, or a 3
to 7 membered fused cycloalkyl ring, or a 3 to 7 membered
spirocyclic ring; [0021] R.sup.2 is H, C1-C8 alkyl, halo, C1-C8
haloalkyl, CN, OH, SO.sub.2R.sup.8, SR.sup.8, SOR.sup.8,
CO.sub.2R.sup.8, CON(R.sup.8).sub.2, COR.sup.8,
SO.sub.2N(R.sup.8).sub.2, CF.sub.3, CHF.sub.2, or a straight chain,
branched, or cyclic (C1-C8)-R.sup.9 wherein up to two CH.sub.2
units may be replaced with O, CO, S, SO, SO.sub.2, CF.sub.2, or
NR.sup.8; [0022] R.sup.3 is H, C1-C8 alkyl, C3-C8 cycloalkyl,
CO.sub.2R.sup.8, COR.sup.8, COH, CON(R.sup.8).sub.2, CF.sub.3,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, or a straight chain, branched,
or cyclic (C1-C8)-R.sup.9 wherein up to two CH.sub.2 units may be
replaced with O, CO, S, SO, SO.sub.2, CF.sub.2, or NR.sup.8; [0023]
R.sup.4 is H, C1-C8 alkyl, halo, C3-C8 cycloalkyl, wherein up to
two CH.sub.2 units may be replaced by O, CO, S, SO, SO.sub.2, or
NR.sup.8, or 2 R.sup.4 taken together form a fused 3 to 7 membered
cycloalkyl ring; [0024] R.sup.8 is H, C1-C8 alkyl, CF.sub.3, C3-C8
cycloalkyl, fluoroalkyl, aryl, heteroaryl, or a straight chain,
branched, or cyclic (C1-C8)-R.sup.9 wherein up to two CH.sub.2
units may be replaced with O, CO, S, SO, SO.sub.2 or NR, or 2
R.sup.8 taken together with the atoms to which they are attached
form a ring; [0025] R.sup.9 is H, CF.sub.3, CO.sub.2R, OH, aryl,
heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R).sub.2, NRCOR,
CON(R).sub.2, CN, halo, or SO.sub.2R; [0026] R is H, C1-C8 alkyl,
aryl, heteroaryl, C3-C8 cycloalkyl, or heterocycloalkyl; [0027] A
is an optionally substituted aryl, heteroaryl or heterocyclic;
[0028] m is an integer from 0 to 4 inclusive; [0029] n is an
integer from 0 to 3 inclusive; and [0030] o is an integer from 0 to
4 inclusive.
[0031] In another aspect, the invention provides compounds of
formula I, or a pharmaceutically acceptable salt thereof, wherein,
independently for each occurrence: [0032] R.sup.1 is H, C1-C6
alkyl, C3-C8 cycloalkyl, halo, CN, NR.sup.8SO.sub.2R.sup.8,
SO.sub.2R.sup.8, SR.sup.8, SOR.sup.8, NR.sup.8COR.sup.8,
NR.sup.8CO.sub.2R.sup.8, CON(R.sup.8).sub.2,
SO.sub.2N(R.sup.8).sub.2, CF.sub.3, heterocycloalkyl, or a straight
chain, branched, or cyclic (C1-C8)-R.sup.9 wherein up to two
CH.sub.2 units may be replaced with O, CO, S, SO, SO.sub.2 or
NR.sup.8, or two R.sup.1 taken together form an oxo group, or a 3
to 7 membered fused cycloalkyl ring, or a 3 to 7 membered
spirocyclic ring; [0033] R.sup.2 is H, C1-C6 alkyl, C1-C6
haloalkyl, CN, OH, SO.sub.2R.sup.8, SR.sup.8, SOR.sup.B,
CO.sub.2R.sup.8, CON(R.sup.8).sub.2, SO.sub.2N(R.sup.8).sub.2,
CF.sub.3, CHF.sub.2, or a straight chain, branched, or cyclic
(C1-C8)-R.sup.9 wherein up to two CH.sub.2 units may be replaced
with O, CO, S, SO, SO.sub.2, CF.sub.2, or NR.sup.8; [0034] R.sup.3
is H, C1-C6 alkyl, C3-C8 cycloalkyl, CO.sub.2R.sup.8, COR.sup.8,
COH, CON(R.sup.8).sub.2, CF.sub.3, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, or a straight chain, branched, or cyclic
(C1-C8)-R.sup.9 wherein up to two CH.sub.2 units may be replaced
with O, CO, S, SO, SO.sub.2 or NR.sup.8; [0035] R.sup.4 is H, C1-C6
alkyl, halo, C3-C8 cycloalkyl, wherein up to two CH.sub.2 units may
be replaced by O, CO, S, SO, SO.sub.2, or NR.sup.8, or 2 R.sup.4
taken together form a fused 3 to 7 membered cycloalkyl ring; [0036]
R.sup.8 is H, C1-C6 alkyl, CF.sub.3, C3-C8 cycloalkyl, or a
straight chain, branched, or cyclic (C1-C8)-R.sup.9 wherein up to
two CH.sub.2 units may be replaced with O, CO, S, SO, SO.sub.2 or
NR, or 2 R.sup.8 taken together with the atoms to which they are
attached form a ring; [0037] R.sup.9 is H, CF.sub.3, CO.sub.2R, OH,
aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R).sub.2,
NRCOR, CON(R).sub.2, CN, or SO.sub.2R; [0038] R is H, C1-C6 alkyl,
aryl, heteroaryl, C3-C8 cycloalkyl, or heterocycloalkyl; [0039] A
is an optionally substituted aryl, heteroaryl or heterocyclic;
[0040] m is an integer from 0 to 4 inclusive; [0041] n is an
integer from 0 to 3 inclusive; and [0042] o is an integer from 0 to
4 inclusive.
[0043] For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed.
Additionally, general principles of organic chemistry are described
in "Organic Chemistry", Thomas Sorrell, University Science Books,
Sausalito: 1999, and "March's Advanced Organic Chemistry", 5.sup.th
Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New
York: 2001, the entire contents of which are hereby incorporated by
reference.
[0044] As described herein, compounds of the invention can
optionally be substituted with one or more substituents, such as
are illustrated generally above, or as exemplified by particular
classes, subclasses, and species of the invention. The phrase
"optionally substituted" is used interchangeably with the phrase
"substituted or unsubstituted." As described herein, the variables
R.sup.1-R.sup.9 in formula I encompass specific groups, such as,
for example, alkyl and aryl. Unless otherwise noted, each of the
specific groups for the variables R.sup.1-R.sup.8 can be optionally
substituted with one or more substituents of halo, cyano,
oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. For
instance, an alkyl group can be optionally substituted with one or
more of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl,
haloalkyl, and alkyl. As an additional example, an aryl group can
be optionally substituted with one or more of halo, cyano, alkoxy,
hydroxy, nitro, haloalkyl, and alkyl. As one of ordinary skill in
the art will recognize, combinations of substituents envisioned by
this invention are those combinations that result in the formation
of stable or chemically feasible compounds. The term "stable", as
used herein, refers to compounds that are not substantially altered
when subjected to conditions to allow for their production,
detection, and preferably their recovery, purification, and use for
one or more of the purposes disclosed herein. In some embodiments,
a stable compound or chemically feasible compound is one that is
not substantially altered when kept at a temperature of 40.degree.
C. or less, in the absence of moisture or other chemically reactive
conditions, for at least a week. When two alkoxy groups are bound
to the same atom or adjacent atoms, the two alkoxy groups can form
a ring together with the atom(s) to which they are bound.
[0045] In general, the term "substituted," whether preceded by the
term "optionally" or not, refers to the replacement of hydrogen
radicals in a given structure with the radical of a specified
substituent. Specific substituents are described above in the
definitions and below in the description of compounds and examples
thereof. Unless otherwise indicated, an optionally substituted
group can have a substituent at each substitutable position of the
group, and when more than one position in any given structure can
be substituted with more than one substituent selected from a
specified group, the substituent can be either the same or
different at every position. A ring substituent, such as a
heterocycloalkyl, can be bound to another ring, such as a
cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings
share one common atom. As one of ordinary skill in the art will
recognize, combinations of substituents envisioned by this
invention are those combinations that result in the formation of
stable or chemically feasible compounds.
[0046] The phrase "up to", as used herein, refers to zero or any
integer number that is equal or less than the number following the
phrase. For example, "up to 3" means any one of 0, 1, 2, and 3.
[0047] The term "aliphatic", "aliphatic group" or "alkyl" as used
herein, means a straight-chain (i.e., unbranched) or branched,
substituted or unsubstituted hydrocarbon chain that is completely
saturated or that contains one or more units of unsaturation.
Unless otherwise specified, aliphatic groups contain 1-20 aliphatic
carbon atoms. In some embodiments, aliphatic groups contain 1-10
aliphatic carbon atoms. In other embodiments, aliphatic groups
contain 1-8 aliphatic carbon atoms. In still other embodiments,
aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet
other embodiments aliphatic groups contain 1-4 aliphatic carbon
atoms. Suitable aliphatic groups include, but are not limited to,
linear or branched, substituted or unsubstituted alkyl, alkenyl,
alkynyl groups. The term "cycloaliphatic" or "cycloalkyl" mean a
monocyclic hydrocarbon, bicyclic, or tricyclic hydrocarbon that is
completely saturated or that contains one or more units of
unsaturation, but which is not aromatic and has a single point of
attachment to the rest of the molecule. In some embodiments,
"cycloaliphatic" refers to a monocyclic C.sub.3-C.sub.8 hydrocarbon
or bicyclic C.sub.8-C.sub.12 hydrocarbon that is completely
saturated or that contains one or more units of unsaturation, but
which is not aromatic, that has a single point of attachment to the
rest of the molecule wherein any individual ring in said bicyclic
ring system has 3-7 members.
[0048] The term "electron withdrawing group", as used herein means
an atom or a group that is electronegative relative to hydrogen.
See, e.g., "Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure," Jerry March, 4.sup.th Ed., John Wiley & Sons
(1992), e.g., pp. 14-16, 18-19, etc. Exemplary such substituents
include halo such as Cl, Br, or F, CN, COOH, CF.sub.3, etc.
[0049] Unless otherwise specified, the term "heterocycle",
"heterocyclyl", "heterocycloaliphatic", "heterocycloalkyl" or
"heterocyclic" as used herein means non-aromatic, monocyclic,
bicyclic, or tricyclic ring systems in which one or more ring atoms
in one or more ring members is an independently selected
heteroatom. Heterocyclic ring can be saturated or can contain one
or more unsaturated bonds. In some embodiments, the "heterocycle",
"heterocyclyl", "heterocycloaliphatic", "heterocycloalkyl" or
"heterocyclic" group has three to fourteen ring members in which
one or more ring members is a heteroatom independently selected
from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the
ring system contains 3 to 7 ring members.
[0050] The term "heteroatom" means oxygen, sulfur, nitrogen,
phosphorus, or silicon (including, any oxidized form of nitrogen,
sulfur, phosphorus, or silicon; the quaternized form of any basic
nitrogen or; a substitutable nitrogen of a heterocyclic ring, for
example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl)
or NR.sup.+ (as in N-substituted pyrrolidinyl)).
[0051] The term "unsaturated", as used herein, means that a moiety
has one or more units of unsaturation but is not aromatic.
[0052] The term "alkoxy", or "thioalkyl", as used herein, refers to
an aliphatic group, as previously defined, attached to the
principal carbon chain through an oxygen ("alkoxy") or sulfur
("thioalkyl") atom. As used herein, alkoxy group includes
alkenyloxy and aklkynyloxy groups.
[0053] The term "aryl" used alone or as part of a larger moiety as
in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic,
bicyclic, and tricyclic ring systems having a total of five to
fourteen ring carbon atoms, wherein at least one ring in the system
is aromatic and wherein each ring in the system contains 3 to 7
ring carbon atoms. The term "aryl" may be used interchangeably with
the term "aryl ring".
[0054] The term "heteroaryl", used alone or as part of a larger
moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to
monocyclic, bicyclic, and tricyclic ring systems having a total of
five to fourteen ring members, wherein at least one ring in the
system is aromatic, at least one ring in the system contains one or
more heteroatoms, and wherein each ring in the system contains 3 to
7 ring members. The term "heteroaryl" may be used interchangeably
with the term "heteroaryl ring" or the term "heteroaromatic".
[0055] The term "alkylidene chain" refers to a straight or branched
carbon chain that may be fully saturated or have one or more units
of unsaturation and has two points of attachment to the rest of the
molecule.
[0056] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, (Z)
and (E) double bond isomers, and (Z) and (E) conformational
isomers. Therefore, single stereochemical isomers as well as
enantiomeric, diastereomeric, and geometric (or conformational)
mixtures of the present compounds are within the scope of the
invention.
[0057] Unless otherwise stated, all tautomeric forms of the
compounds of the invention are within the scope of the invention.
Thus, included within the scope of the invention are tautomers of
compounds of formula I.
[0058] Additionally, unless otherwise stated, structures depicted
herein are also meant to include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds of formula I, wherein one or more hydrogen atoms are
replaced deuterium or tritium, or one or more carbon atoms are
replaced by a .sup.13C- or .sup.14C-enriched carbon are within the
scope of this invention. Such compounds are useful, for example, as
analytical tools, probes in biological assays, or sodium channel
blockers with improved therapeutic profile.
[0059] In the formulas and drawings, a line transversing a ring and
bonded to an R group such as in
##STR00003##
means that the R group can be bonded to any carbon, or if
applicable, heteroatom such as N, of that ring as valency
allows.
[0060] Within a definition of a term as, for example, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, or R.sup.7 when a
CH.sub.2 unit or, interchangeably, methylene unit may be replaced
by O, CO, S, SO, SO.sub.2 or NR.sup.8, it is meant to include any
CH.sub.2 unit, including a CH.sub.2 within a terminal methyl group.
For example, --CH.sub.2CH.sub.2CH.sub.2SH is within the definition
of C1-C8 alkyl wherein up to two CH.sub.2 units may be replaced by
S because the CH.sub.2 unit of the terminal methyl group has been
replaced by S.
[0061] In another embodiment, the invention features a compound of
formula I and the attendant definitions, wherein R.sup.1 is C1-C8
alkyl or two R.sup.1 taken together with the atoms to which they
are attached form a 3 to 7 membered fused cycloalkyl or spirocyclic
ring. In another embodiment, R.sup.1 is CH.sub.3 or two R.sup.1
taken together form a fused cyclohexyl ring.
[0062] In another embodiment, the invention features a compound of
formula I and the attendant definitions, wherein R.sup.2 is H,
C1-C8 alkyl, halo, CF.sub.3, CN, CON(R.sup.8).sub.2, or a straight
chain, branched, or cyclic (C1-C8)-R.sup.9 wherein up to two
CH.sub.2 units may be replaced with O, CO, S, SO, SO.sub.2,
CF.sub.2, or NR.sup.8. In another embodiment, R.sup.2 is
COCF.sub.3, COtBu, Cl, COCH.sub.3, CF.sub.2CF.sub.3,
CH.sub.2CF.sub.3, CF.sub.3, CN, Br, COCH(CH.sub.3).sub.2,
COCH.sub.2CH.sub.3, CH(OH)CF.sub.3, SO.sub.2CH.sub.3,
##STR00004##
[0063] In another embodiment, the invention features a compound of
formula I and the attendant definitions, wherein R.sup.3 is H,
C1-C8 alkyl, CO.sub.2R.sup.8, COR.sup.8, COH, CON(R.sup.8).sub.2 or
a straight chain, branched, or cyclic (C1-C8)-R.sup.9 wherein up to
two CH.sub.2 units may be replaced with O, CO, CF.sub.2, S, SO,
SO.sub.2 or NR.sup.8. In another embodiment, R.sup.3 is H,
CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2OCH.sub.3, benzyl,
CH.sub.2CH(CH.sub.2).sub.2, CH(CH.sub.2).sub.2, cyclobutyl,
COCH.sub.3, CO.sub.2CH.sub.3, CO.sub.2CH.sub.2CH.sub.3,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, COH, CON(CH.sub.3).sub.2, or
CONHCH.sub.3.
[0064] In another embodiment, the invention features a compound of
formula I and the attendant definitions, wherein R.sup.4 is H,
halo, or C1-C8 alkyl. In another embodiment, R.sup.4 is H, F, or
CH.sub.3.
[0065] In another embodiment, the invention features a compound of
formula I and the attendant definitions, wherein m is 0, 1, or 2.
In another embodiment, n is 0, 1 or 2. In another embodiment, O is
0 or 1.
[0066] In another embodiment, the invention features a compound of
formula I and the attendant definitions, wherein A is
##STR00005##
wherein: [0067] R.sup.5 is H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8
alkoxy, halo, CN, OH, OR.sup.8, N(R.sup.8).sub.2,
NR.sup.8SO.sub.2R.sup.8, SO.sub.2R.sup.8, SOR.sup.8, SR.sup.8,
CO.sub.2R.sup.8, NR.sup.8COR.sup.8, NR.sup.8CO.sub.2R.sup.8,
CON(R.sup.8).sub.2, SO.sub.2N(R.sup.8).sub.2, CHF.sub.2, CF.sub.3,
OCF.sub.3, OCHF.sub.2, R.sup.9, heterocycloalkyl,
heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched,
or cyclic (C1-C8)-R.sup.9 wherein up to three CH.sub.2 units may be
replaced with O, CO, S, SO, SO.sub.2, or NR.sup.8; [0068] R.sup.6
is H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C3-C8
cycloalkoxy, halo, CN, OH, OR.sup.8, N(R.sup.8).sub.2,
NR.sup.8SO.sub.2R.sup.8, SO.sub.2R.sup.8, SOR.sup.8, SR.sup.8,
CO.sub.2R.sup.8, NR.sup.8COR.sup.8, NR.sup.8CO.sub.2R.sup.8,
CON(R.sup.8).sub.2, SO.sub.2N(R.sup.8).sub.2, CF.sub.3, OCF.sub.3,
OCHF.sub.2, R.sup.9, heterocycloalkyl, heterocycloalkoxy, aryl,
heteroaryl, or a straight chain, branched, or cyclic
(C1-C8)-R.sup.9 wherein up to three CH.sub.2 units may be replaced
with O, CO, S, SO, SO.sub.2, or NR.sup.8; [0069] R.sup.7 is H,
C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, halo, CN, OH,
OR.sup.8, N(R.sup.8).sub.2, NR.sup.8SO.sub.2R.sup.8,
SO.sub.2R.sup.8, OSO.sub.2R.sup.8, SOR.sup.8, SR.sup.8,
CO.sub.2R.sup.8, NR.sup.8COR.sup.8, NR.sup.8CO.sub.2R.sup.8,
CON(R).sub.2, SO.sub.2N(R.sup.8).sub.2, CF.sub.3, OCF.sub.3,
OCHF.sub.2, R.sup.9, heterocycloalkyl, heterocycloalkoxy, aryl,
heteroaryl, or a straight chain, branched, or cyclic
(C1-C8)-(R.sup.9).sub.p, wherein p is 1 or 2 and wherein up to
three CH.sub.2 units may be replaced with O, CO, S, SO, SO.sub.2,
or NR.sup.8; or [0070] two occurrences of R.sup.5 and R.sup.6, or
R.sup.6 and R.sup.7 are both C1-C8 alkyl and together with the
carbons to which they are attached form an optionally substituted
ring comprising up to 2 heteroatoms.
[0071] In another embodiment, the invention features a compound of
formula I and the attendant definitions, wherein R.sup.5 is H,
C1-C8 alkyl, C1-C8 alkoxy, halo, OCF.sub.3, OCHF.sub.2, R.sup.9, or
a straight chain, branched, or cyclic (C1-C8)-R.sup.9 wherein up to
three CH.sub.2 units may be replaced with O, CO, S, SO, SO.sub.2,
or NR.sup.7. In another embodiment, R.sup.5 is H, CH.sub.3,
OCH.sub.3, OCF.sub.3, OPh, Ph, OCHF.sub.2, or F.
[0072] In another embodiment, the invention features a compound of
formula I and the attendant definitions, wherein R.sup.6 is H,
C1-C8 alkyl, C1-C8 alkoxy, halo, R.sup.9, or a straight chain,
branched, or cyclic (C1-C8)-R.sup.9 wherein up to three CH.sub.2
units may be replaced with O, CO, S, SO, SO.sub.2, or NR.sup.8. In
another embodiment, R.sup.6 is H, CH.sub.3, OCH.sub.3,
OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
CF.sub.3, CN, Ph, SO.sub.2CH.sub.3, OH, CH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.3, F, Cl, or CH.sub.2OH.
[0073] In another embodiment, the invention features a compound of
formula I and the attendant definitions, wherein R.sup.7 is H,
C1-C8 alkyl, C1-C8 alkoxy, SO.sub.2R.sup.8, OSO.sub.2R.sup.8,
SO.sub.2N(R.sup.8).sub.2, R.sup.9, or a straight chain, branched,
or cyclic (C1-C8)-(R.sup.9).sub.p, wherein p is 1 or 2 and wherein
up to three CH.sub.2 units may be replaced with O, CO, S, SO,
SO.sub.2, or NR.sup.8. In another embodiment, R.sup.7 is H,
CH.sub.2CH.sub.3, tBu, Cl, F, OH, C(.dbd.CH.sub.2)CH.sub.3,
OC(.dbd.CH.sub.2)CH.sub.3, OCH.sub.3,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2OH, OCH.sub.2CH.sub.2OH,
OCH.sub.2CH.sub.2CH.sub.2OH, OtBu, OCH(CH.sub.3)(CH.sub.2CH.sub.3),
OCH.sub.2C(CH.sub.3).sub.2OH, C(CH.sub.3).sub.2OH,
CH.sub.2C(CH.sub.3).sub.2OH, CH(OH)CH(CH.sub.3).sub.2,
C(CH.sub.3).sub.2CH.sub.2OH, OCH.sub.2CH.sub.2CH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2OCH.sub.3, SO.sub.2CH.sub.3,
##STR00006##
SO.sub.2tBu, SO.sub.2CH.sub.2CH.sub.3,
SO.sub.2CH.sub.2CH(CH.sub.3).sub.2, SO.sub.2CH(CH.sub.3).sub.2,
##STR00007##
SO.sub.2NH(CH.sub.3), SO.sub.2NH(CH(CH.sub.2).sub.2),
SO.sub.2NH(CH.sub.2CH.sub.3), SO.sub.2NH(CH(CH.sub.3).sub.2),
SO.sub.2N(CH.sub.3).sub.2,
##STR00008##
OCH.sub.2CH.sub.2OCH.sub.3, CH(CH.sub.3).sub.2,
SO.sub.2N(CH.sub.2CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3, OPh,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2OPh,
##STR00009##
OCH.sub.2Ph, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
OCH.sub.2CH.sub.3, OCH.sub.2CH(CH.sub.3).sub.2, CH.sub.2CH.sub.3,
CH.sub.2Ph,
##STR00010##
CCCH.sub.2OCH.sub.3, SO.sub.2CHF.sub.2, OCF.sub.3,
##STR00011##
CH.sub.2CH(CH.sub.3).sub.2, OCH.sub.2tBu,
##STR00012##
CH.sub.2OCH.sub.2CH.sub.2CF.sub.3, CH.sub.2OCH.sub.2CF.sub.3,
SO.sub.2CF.sub.3, C(CH.sub.3).sub.2CH.sub.2CH.sub.3,
C(CH.sub.2CH.sub.3).sub.3, CH(OCH.sub.2CF.sub.3).sub.2,
##STR00013##
CF.sub.3, OCH.sub.2C(CH.sub.3).sub.2F,
##STR00014##
CH(OH)CH.sub.2OCH.sub.2CF.sub.3, CH(OCH.sub.2CF.sub.3)CH.sub.2OH,
OSO.sub.2CF.sub.3,
##STR00015##
or OCH.sub.2CH.sub.2OCF.sub.3.
[0074] In another embodiment, the invention features a compound of
formula I and the attendant definitions, wherein A is
##STR00016##
and is selected from:
##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##
[0075] In another embodiment, the invention features a compound of
formula I and the attendant definitions, wherein A is heteroaryl or
heterocyclic. In another embodiment, A is a monocyclic heteroaryl
comprising 1 to 3 heteroatoms independently selected from N, O, or
S. In another embodiment, A is selected from a bicyclic heteroaryl
comprising from 1 to 3 heteoratoms independently selected from N,
O, or S.
[0076] In another embodiment, the invention features a compound of
formula I and the attendant definitions, wherein A is selected from
the following:
##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047##
##STR00048## ##STR00049##
[0077] In another embodiment, the compounds of the invention have
formula IA:
##STR00050##
wherein: [0078] R.sup.2 is H, C1-C8 alkyl, halo, C1-C8 haloalkyl,
CN, OH, SO.sub.2R.sup.8, SR.sup.8, SOR.sup.8, COR.sup.8,
CO.sub.2R.sup.8, CON(R.sup.8).sub.2, SO.sub.2N(R.sup.8).sub.2,
CF.sub.3, CHF.sub.2, or a straight chain, branched, or cyclic
(C1-C8)-R.sup.9 wherein up to two CH.sub.2 units may be replaced
with O, CO, S, SO, SO.sub.2 CF.sub.2, or NR.sup.8; [0079] R.sup.3
is H, C1-C8 alkyl, CO.sub.2R.sup.8, COR.sup.8, COH,
CON(R.sup.8).sub.2, CF.sub.3, or a straight chain, branched, or
cyclic (C1-C8)-R.sup.9 wherein up to two CH.sub.2 units may be
replaced with O, CO, CF.sub.2, S, SO, SO.sub.2 or NR.sup.8; [0080]
R.sup.6 is H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C3-C8
cycloalkoxy, halo, CN, OH, OR.sup.8, N(R.sup.8).sub.2,
NR.sup.8SO.sub.2R.sup.8, SO.sub.2R.sup.8, SOR.sup.8, SR.sup.8,
CO.sub.2R.sup.8, NR.sup.8COR.sup.8, NR.sup.8CO.sub.2R.sup.8,
CON(R.sup.8).sub.2, SO.sub.2N(R.sup.8).sub.2, CF.sub.3, OCF.sub.3,
OCHF.sub.2, R.sup.9, heterocycloalkyl, heterocycloalkoxy, aryl,
heteroaryl, or a straight chain, branched, or cyclic
(C1-C8)-R.sup.9 wherein up to three CH.sub.2 units may be replaced
with O, CO, S, SO, SO.sub.2, or NR.sup.8; [0081] R.sup.7 is H,
C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, halo, CN, OH,
OR.sup.8, N(R.sup.8).sub.2, NR.sup.8SO.sub.2R.sup.8,
SO.sub.2R.sup.8, SOR.sup.8, SR.sup.8, CO.sub.2R.sup.8,
NR.sup.8COR.sup.8, NR.sup.8CO.sub.2R.sup.8, CON(R.sup.8).sub.2,
SO.sub.2N(R.sup.8).sub.2, CF.sub.3, OCF.sub.3, OCHF.sub.2, R.sup.9,
heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a
straight chain, branched, or cyclic (C1-C8)-R.sup.9 wherein up to
three CH.sub.2 units may be replaced with O, CO, S, SO, SO.sub.2,
or NR.sup.8.
[0082] In another embodiment, the invention features a compound of
formula IA and the attendant definitions, wherein R.sup.2 is is H,
COCF.sub.3, COtBu, Cl, COCH.sub.3, CF.sub.2CF.sub.3,
CH.sub.2CF.sub.3, CF.sub.3, CN, Br, COCH(CH.sub.3).sub.2,
COCH.sub.2CH.sub.3, CH(OH)CF.sub.3, SO.sub.2CH.sub.3,
##STR00051##
[0083] In another embodiment, the invention features a compound of
formula IA and the attendant definitions, wherein R.sup.3 is H,
CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH.sub.2OCH.sub.3,
CH.sub.2CH.sub.2OH, CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
CH.sub.2CON(CH.sub.3).sub.2, CH.sub.2CONH.sub.2, CH.sub.2CN,
benzyl, cyclobutyl, CH.sub.2CH(CH.sub.2).sub.2, CH(CH.sub.2).sub.2,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, COCH.sub.3,
COCH.sub.2CH.sub.3, CO.sub.2CH.sub.3, CO.sub.2CH.sub.2CH.sub.3,
COH, CONH(CH.sub.3).sub.2, or CONHCH.sub.3.
[0084] In another embodiment, the invention features a compound of
formula IA and the attendant definitions, wherein R.sup.6 is H,
CH.sub.3, OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.3,
OCH(CH.sub.3).sub.2, CF.sub.3, CN, Ph, SO.sub.2CH.sub.3, OH,
CH(CH.sub.3).sub.2, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3, F, Cl, or
CH.sub.2OH.
[0085] In another embodiment, the invention features a compound of
formula IA and the attendant definitions, wherein R.sup.7 is H,
CH.sub.3, CH.sub.2CH.sub.3, tBu, Cl, F, OH,
C(.dbd.CH.sub.2)CH.sub.3, OC(.dbd.CH.sub.2)CH.sub.3, OCH.sub.3,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2OH, OCH.sub.2CH.sub.2OH,
OCH.sub.2CH.sub.2CH.sub.2OH, OtBu, OCH(CH.sub.3)(CH.sub.2CH.sub.3),
OCH.sub.2C(CH.sub.3).sub.2OH, C(CH.sub.3).sub.2OH,
CH.sub.2C(CH.sub.3).sub.2OH, CH(OH)CH(CH.sub.3).sub.2,
C(CH.sub.3).sub.2CH.sub.2OH, OCH.sub.2CH.sub.2CH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2OCH.sub.3,
##STR00052##
SO.sub.2CH.sub.3, SO.sub.2tBu, SO.sub.2CH.sub.2CH.sub.3,
SO.sub.2CH.sub.2CH(CH.sub.3).sub.2, SO.sub.2CH(CH.sub.3).sub.2,
##STR00053##
SO.sub.2NH(CH.sub.3), SO.sub.2NH(CH(CH.sub.2).sub.2),
SO.sub.2NH(CH.sub.2CH.sub.3), SO.sub.2NH(CH(CH.sub.3).sub.2),
SO.sub.2N(CH.sub.3).sub.2,
##STR00054##
OCH.sub.2CH.sub.2OCH.sub.3, CH(CH.sub.3).sub.2,
SO.sub.2N(CH.sub.2CH.sub.2CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.3, CH.sub.2OPh,
##STR00055##
OCH.sub.2Ph, CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
OCH.sub.2CH.sub.3, OCH.sub.2CH(CH.sub.3).sub.2, CH.sub.2Ph,
##STR00056##
CCCH.sub.2OCH.sub.3, SO.sub.2CHF.sub.2, OCF.sub.3,
##STR00057##
CH.sub.2CH(CH.sub.3).sub.2, OCH.sub.2tBu,
##STR00058##
CH.sub.2OCH.sub.2CH.sub.2CF.sub.3, CH.sub.2OCH.sub.2CF.sub.3,
SO.sub.2CF.sub.3, C(CH.sub.3).sub.2CH.sub.2CH.sub.3,
C(CH.sub.2CH.sub.3).sub.3, CH(OCH.sub.2CF.sub.3).sub.2,
##STR00059##
CH(OH)CH.sub.2OCH.sub.2CF.sub.3, CH(OCH.sub.2CF.sub.3)CH.sub.2OH,
OSO.sub.2CF.sub.3,
##STR00060##
or OCH.sub.2CH.sub.2OCF.sub.3.
[0086] In another embodiment, the invention features a compound of
formula IA and the attendant definitions, wherein R.sup.2 is H,
CF.sub.3, COCF.sub.3, COtBu, Cl, COCH.sub.3, CF.sub.2CF.sub.3,
CH.sub.2CF.sub.3 or CN; R.sup.3 is H, CH.sub.2CH.sub.2OCH.sub.3,
benzyl, CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2CH(CH.sub.2).sub.2,
cyclobutyl, COCH.sub.3, CO.sub.2CH.sub.3, COH, CH(CH.sub.2).sub.2,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CO.sub.2CH.sub.2CH.sub.3,
CON(CH.sub.3).sub.2, or CONHCH.sub.3; R.sup.6 is CH.sub.3,
OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2OH, F, or Cl; and R.sup.7 is F, CH.sub.2CH.sub.3, tBu, OH,
OCH.sub.3, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3, OtBu,
OCH(CH.sub.3)(CH.sub.2CH.sub.3), OCH.sub.2CH.sub.2OH,
OCH.sub.2CH.sub.2CH.sub.2OH, OCH.sub.2C(CH.sub.3).sub.2OH,
C(CH.sub.3).sub.2OH, C(.dbd.CH.sub.2)CH.sub.3,
OC(.dbd.CH.sub.2)CH.sub.3, CH.sub.2OH,
C(CH.sub.3).sub.2CH.sub.2OH,
##STR00061##
OCH.sub.2CH.sub.2CH(CH.sub.3).sub.2, OCH.sub.2CH.sub.2CH.sub.3,
OCH(CH.sub.3).sub.2, OCH.sub.2CH.sub.2OCH.sub.3, SO.sub.2CH.sub.3,
SO.sub.2CH.sub.2CH.sub.3, SO.sub.2CH(CH.sub.3).sub.2,
##STR00062##
SO.sub.2NH(CH.sub.3), SO.sub.2NH(CH(CH.sub.2).sub.2),
SO.sub.2NH(CH.sub.2CH.sub.3), SO.sub.2NH(CH(CH.sub.3).sub.2),
SO.sub.2N(CH.sub.3).sub.2, or OCH.sub.2CH.sub.2OCF.sub.3.
[0087] In another embodiment, the invention features a compound of
formula IA and the attendant definitions, wherein the
##STR00063##
moiety is selected from:
##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##
[0088] In another embodiment, the invention features a compound of
formula I, wherein the compound is selected from Table 1:
TABLE-US-00001 ##STR00089## 1 ##STR00090## 2 ##STR00091## 3
##STR00092## 4 ##STR00093## 5 ##STR00094## 6 ##STR00095## 7
##STR00096## 8 ##STR00097## 9 ##STR00098## 10 ##STR00099## 11
##STR00100## 12 ##STR00101## 13 ##STR00102## 14 ##STR00103## 15
##STR00104## 16 ##STR00105## 17 ##STR00106## 18 ##STR00107## 19
##STR00108## 20 ##STR00109## 21 ##STR00110## 22 ##STR00111## 23
##STR00112## 24 ##STR00113## 25 ##STR00114## 26 ##STR00115## 27
##STR00116## 28 ##STR00117## 29 ##STR00118## 30 ##STR00119## 31
##STR00120## 32 ##STR00121## 33 ##STR00122## 34 ##STR00123## 35
##STR00124## 36 ##STR00125## 37 ##STR00126## 38 ##STR00127## 39
##STR00128## 40 ##STR00129## 41 ##STR00130## 42 ##STR00131## 43
##STR00132## 44 ##STR00133## 45 ##STR00134## 46 ##STR00135## 47
##STR00136## 48 ##STR00137## 49 ##STR00138## 50 ##STR00139## 51
##STR00140## 52 ##STR00141## 53 ##STR00142## 54 ##STR00143## 55
##STR00144## 56 ##STR00145## 57 ##STR00146## 58 ##STR00147## 59
##STR00148## 60 ##STR00149## 61 ##STR00150## 62 ##STR00151## 63
##STR00152## 64 ##STR00153## 65 ##STR00154## 66 ##STR00155## 67
##STR00156## 68 ##STR00157## 69 ##STR00158## 70 ##STR00159## 71
##STR00160## 72 ##STR00161## 73 ##STR00162## 74 ##STR00163## 75
##STR00164## 76 ##STR00165## 77 ##STR00166## 78 ##STR00167## 79
##STR00168## 80 ##STR00169## 81 ##STR00170## 82 ##STR00171## 83
##STR00172## 84 ##STR00173## 85 ##STR00174## 86 ##STR00175## 87
##STR00176## 88 ##STR00177## 89 ##STR00178## 90 ##STR00179## 91
##STR00180## 92 ##STR00181## 93 ##STR00182## 94 ##STR00183## 95
##STR00184## 96 ##STR00185## 97 ##STR00186## 98 ##STR00187## 99
##STR00188## 100 ##STR00189## 101 ##STR00190## 102 ##STR00191## 103
##STR00192## 104 ##STR00193## 105 ##STR00194## 106 ##STR00195## 107
##STR00196## 108 ##STR00197## 109 ##STR00198## 110 ##STR00199## 111
##STR00200## 112 ##STR00201## 113 ##STR00202## 114 ##STR00203## 115
##STR00204## 116 ##STR00205## 117 ##STR00206## 118 ##STR00207## 119
##STR00208## 120 ##STR00209## 121 ##STR00210## 122 ##STR00211## 123
##STR00212## 124 ##STR00213## 125
##STR00214## 126 ##STR00215## 127 ##STR00216## 128 ##STR00217## 129
##STR00218## 130 ##STR00219## 131 ##STR00220## 132 ##STR00221## 133
##STR00222## 134 ##STR00223## 135 ##STR00224## 136 ##STR00225## 137
##STR00226## 138 ##STR00227## 139 ##STR00228## 140 ##STR00229## 141
##STR00230## 142 ##STR00231## 143 ##STR00232## 144 ##STR00233## 145
##STR00234## 146 ##STR00235## 147 ##STR00236## 148 ##STR00237## 149
##STR00238## 150 ##STR00239## 151 ##STR00240## 152 ##STR00241## 153
##STR00242## 154 ##STR00243## 155 ##STR00244## 156 ##STR00245## 157
##STR00246## 158 ##STR00247## 159 ##STR00248## 160 ##STR00249## 161
##STR00250## 162 ##STR00251## 163 ##STR00252## 164 ##STR00253## 165
##STR00254## 166 ##STR00255## 167 ##STR00256## 168 ##STR00257## 169
##STR00258## 170 ##STR00259## 171 ##STR00260## 172 ##STR00261## 173
##STR00262## 174 ##STR00263## 175 ##STR00264## 176 ##STR00265## 177
##STR00266## 178 ##STR00267## 179 ##STR00268## 180 ##STR00269## 181
##STR00270## 182 ##STR00271## 183 ##STR00272## 184 ##STR00273## 185
##STR00274## 186 ##STR00275## 187 ##STR00276## 188 ##STR00277## 189
##STR00278## 190 ##STR00279## 191 ##STR00280## 192 ##STR00281## 193
##STR00282## 194 ##STR00283## 195 ##STR00284## 196 ##STR00285## 197
##STR00286## 198 ##STR00287## 199 ##STR00288## 200 ##STR00289## 201
##STR00290## 202 ##STR00291## 203 ##STR00292## 204 ##STR00293## 205
##STR00294## 206 ##STR00295## 207 ##STR00296## 208 ##STR00297## 209
##STR00298## 210 ##STR00299## 211 ##STR00300## 212 ##STR00301## 213
##STR00302## 214 ##STR00303## 215 ##STR00304## 216 ##STR00305## 217
##STR00306## 218 ##STR00307## 219 ##STR00308## 220 ##STR00309## 221
##STR00310## 222 ##STR00311## 223 ##STR00312## 224 ##STR00313## 225
##STR00314## 226 ##STR00315## 227 ##STR00316## 228 ##STR00317## 229
##STR00318## 230 ##STR00319## 231 ##STR00320## 232 ##STR00321## 233
##STR00322## 234 ##STR00323## 235 ##STR00324## 236 ##STR00325## 237
##STR00326## 238 ##STR00327## 239 ##STR00328## 240 ##STR00329## 241
##STR00330## 242 ##STR00331## 243 ##STR00332## 244 ##STR00333## 245
##STR00334## 246 ##STR00335## 247 ##STR00336## 248 ##STR00337## 249
##STR00338## 250
##STR00339## 251 ##STR00340## 252 ##STR00341## 253 ##STR00342## 254
##STR00343## 255 ##STR00344## 256 ##STR00345## 257 ##STR00346## 258
##STR00347## 259 ##STR00348## 260 ##STR00349## 261 ##STR00350## 262
##STR00351## 263 ##STR00352## 264 ##STR00353## 265 ##STR00354## 266
##STR00355## 267 ##STR00356## 268 ##STR00357## 269 ##STR00358## 270
##STR00359## 271 ##STR00360## 272 ##STR00361## 273 ##STR00362## 274
##STR00363## 275 ##STR00364## 276 ##STR00365## 277 ##STR00366## 278
##STR00367## 279 ##STR00368## 280 ##STR00369## 281 ##STR00370## 282
##STR00371## 283 ##STR00372## 284 ##STR00373## 285 ##STR00374## 286
##STR00375## 287 ##STR00376## 288 ##STR00377## 289 ##STR00378## 290
##STR00379## 291 ##STR00380## 292 ##STR00381## 293 ##STR00382## 294
##STR00383## 295 ##STR00384## 296 ##STR00385## 297 ##STR00386## 298
##STR00387## 299 ##STR00388## 300 ##STR00389## 301 ##STR00390## 302
##STR00391## 303 ##STR00392## 304 ##STR00393## 305 ##STR00394## 306
##STR00395## 307 ##STR00396## 308 ##STR00397## 309 ##STR00398## 310
##STR00399## 311 ##STR00400## 312 ##STR00401## 313 ##STR00402## 314
##STR00403## 315 ##STR00404## 316 ##STR00405## 317 ##STR00406## 318
##STR00407## 319 ##STR00408## 320 ##STR00409## 321 ##STR00410## 322
##STR00411## 323 ##STR00412## 324 ##STR00413## 325 ##STR00414## 326
##STR00415## 327 ##STR00416## 328 ##STR00417## 329 ##STR00418## 330
##STR00419## 331 ##STR00420## 332 ##STR00421## 333 ##STR00422## 334
##STR00423## 335 ##STR00424## 336 ##STR00425## 337 ##STR00426## 338
##STR00427## 339 ##STR00428## 340 ##STR00429## 341 ##STR00430## 342
##STR00431## 343 ##STR00432## 344 ##STR00433## 345 ##STR00434## 346
##STR00435## 347 ##STR00436## 348 ##STR00437## 349 ##STR00438## 350
##STR00439## 351 ##STR00440## 352 ##STR00441## 353 ##STR00442## 354
##STR00443## 355 ##STR00444## 356 ##STR00445## 357 ##STR00446## 358
##STR00447## 359 ##STR00448## 360 ##STR00449## 361 ##STR00450## 362
##STR00451## 363 ##STR00452## 364 ##STR00453## 365 ##STR00454## 366
##STR00455## 367 ##STR00456## 368 ##STR00457## 369 ##STR00458## 370
##STR00459## 371 ##STR00460## 372 ##STR00461## 373 ##STR00462## 374
##STR00463## 375 ##STR00464## 376
##STR00465## 377 ##STR00466## 378 ##STR00467## 379 ##STR00468## 380
##STR00469## 381 ##STR00470## 382 ##STR00471## 383 ##STR00472## 384
##STR00473## 385 ##STR00474## 386 ##STR00475## 387 ##STR00476## 388
##STR00477## 389 ##STR00478## 390 ##STR00479## 391 ##STR00480## 392
##STR00481## 393 ##STR00482## 394 ##STR00483## 395 ##STR00484## 396
##STR00485## 397 ##STR00486## 398 ##STR00487## 399 ##STR00488## 400
##STR00489## 401 ##STR00490## 402 ##STR00491## 403 ##STR00492## 404
##STR00493## 405 ##STR00494## 406 ##STR00495## 407 ##STR00496## 408
##STR00497## 409 ##STR00498## 410 ##STR00499## 411 ##STR00500## 412
##STR00501## 413 ##STR00502## 414 ##STR00503## 415 ##STR00504## 416
##STR00505## 417 ##STR00506## 418 ##STR00507## 419 ##STR00508## 420
##STR00509## 421 ##STR00510## 422 ##STR00511## 423 ##STR00512## 424
##STR00513## 425 ##STR00514## 426 ##STR00515## 427 ##STR00516## 428
##STR00517## 429 ##STR00518## 430 ##STR00519## 431 ##STR00520## 432
##STR00521## 433 ##STR00522## 434 ##STR00523## 435 ##STR00524## 436
##STR00525## 437 ##STR00526## 438 ##STR00527## 439 ##STR00528## 440
##STR00529## 441 ##STR00530## 442 ##STR00531## 443 ##STR00532## 444
##STR00533## 445 ##STR00534## 446 ##STR00535## 447 ##STR00536## 448
##STR00537## 449 ##STR00538## 450 ##STR00539## 451 ##STR00540## 452
##STR00541## 453 ##STR00542## 454 ##STR00543## 455 ##STR00544## 456
##STR00545## 457 ##STR00546## 458 ##STR00547## 459 ##STR00548## 460
##STR00549## 461 ##STR00550## 462 ##STR00551## 463 ##STR00552## 464
##STR00553## 465 ##STR00554## 466 ##STR00555## 467 ##STR00556## 468
##STR00557## 469 ##STR00558## 470 ##STR00559## 471 ##STR00560## 472
##STR00561## 473 ##STR00562## 474 ##STR00563## 475 ##STR00564## 476
##STR00565## 477 ##STR00566## 478 ##STR00567## 479 ##STR00568## 480
##STR00569## 481 ##STR00570## 482 ##STR00571## 483 ##STR00572## 484
##STR00573## 485 ##STR00574## 486 ##STR00575## 487 ##STR00576## 488
##STR00577## 489 ##STR00578## 490 ##STR00579## 491 ##STR00580## 492
##STR00581## 493 ##STR00582## 494 ##STR00583## 495 ##STR00584## 496
##STR00585## 497 ##STR00586## 498 ##STR00587## 499 ##STR00588## 500
##STR00589## 501
##STR00590## 502 ##STR00591## 503 ##STR00592## 504 ##STR00593## 505
##STR00594## 506 ##STR00595## 507 ##STR00596## 508 ##STR00597## 509
##STR00598## 510 ##STR00599## 511 ##STR00600## 512 ##STR00601## 513
##STR00602## 514 ##STR00603## 515 ##STR00604## 516 ##STR00605## 517
##STR00606## 518 ##STR00607## 519 ##STR00608## 520 ##STR00609## 521
##STR00610## 522 ##STR00611## 523 ##STR00612## 524 ##STR00613## 525
##STR00614## 526 ##STR00615## 527 ##STR00616## 528 ##STR00617## 529
##STR00618## 530 ##STR00619## 531 ##STR00620## 532 ##STR00621## 533
##STR00622## 534 ##STR00623## 535 ##STR00624## 536 ##STR00625## 537
##STR00626## 538 ##STR00627## 539 ##STR00628## 540 ##STR00629## 541
##STR00630## 542 ##STR00631## 543 ##STR00632## 544 ##STR00633## 545
##STR00634## 546 ##STR00635## 547 ##STR00636## 548 ##STR00637## 549
##STR00638## 550 ##STR00639## 551 ##STR00640## 552 ##STR00641## 553
##STR00642## 554 ##STR00643## 555 ##STR00644## 556 ##STR00645## 557
##STR00646## 558 ##STR00647## 559 ##STR00648## 560 ##STR00649## 561
##STR00650## 562 ##STR00651## 563 ##STR00652## 564 ##STR00653## 565
##STR00654## 566 ##STR00655## 567 ##STR00656## 568 ##STR00657## 569
##STR00658## 570 ##STR00659## 571 ##STR00660## 572 ##STR00661## 573
##STR00662## 574 ##STR00663## 575 ##STR00664## 576 ##STR00665## 577
##STR00666## 578 ##STR00667## 579 ##STR00668## 580 ##STR00669## 581
##STR00670## 582 ##STR00671## 583 ##STR00672## 584 ##STR00673## 585
##STR00674## 586 ##STR00675## 587 ##STR00676## 588 ##STR00677## 589
##STR00678## 590 ##STR00679## 591 ##STR00680## 592 ##STR00681## 593
##STR00682## 594 ##STR00683## 595 ##STR00684## 596 ##STR00685## 597
##STR00686## 598 ##STR00687## 599 ##STR00688## 600 ##STR00689## 601
##STR00690## 602 ##STR00691## 603 ##STR00692## 604 ##STR00693## 605
##STR00694## 606 ##STR00695## 607 ##STR00696## 608 ##STR00697## 609
##STR00698## 610 ##STR00699## 611 ##STR00700## 612 ##STR00701## 613
##STR00702## 614 ##STR00703## 615 ##STR00704## 616 ##STR00705## 617
##STR00706## 618 ##STR00707## 619 ##STR00708## 620 ##STR00709## 621
##STR00710## 622 ##STR00711## 623 ##STR00712## 624 ##STR00713## 625
##STR00714## 626 ##STR00715## 627
##STR00716## 628 ##STR00717## 629 ##STR00718## 630 ##STR00719## 631
##STR00720## 632 ##STR00721## 633 ##STR00722## 634 ##STR00723## 635
##STR00724## 636 ##STR00725## 637 ##STR00726## 638 ##STR00727## 639
##STR00728## 640 ##STR00729## 641 ##STR00730## 642 ##STR00731## 643
##STR00732## 644 ##STR00733## 645 ##STR00734## 646 ##STR00735## 647
##STR00736## 648 ##STR00737## 649 ##STR00738## 650 ##STR00739## 651
##STR00740## 652 ##STR00741## 653 ##STR00742## 654 ##STR00743## 655
##STR00744## 656 ##STR00745## 657 ##STR00746## 658 ##STR00747## 659
##STR00748## 660 ##STR00749## 661 ##STR00750## 662 ##STR00751## 663
##STR00752## 664 ##STR00753## 665 ##STR00754## 666 ##STR00755## 667
##STR00756## 668 ##STR00757## 669 ##STR00758## 670 ##STR00759## 671
##STR00760## 672 ##STR00761## 673 ##STR00762## 674 ##STR00763## 675
##STR00764## 676 ##STR00765## 677 ##STR00766## 678 ##STR00767## 679
##STR00768## 680 ##STR00769## 681 ##STR00770## 682 ##STR00771## 683
##STR00772## 684 ##STR00773## 685 ##STR00774## 686 ##STR00775## 687
##STR00776## 688 ##STR00777## 689 ##STR00778## 690 ##STR00779## 691
##STR00780## 692 ##STR00781## 693 ##STR00782## 694 ##STR00783## 695
##STR00784## 696 ##STR00785## 697 ##STR00786## 698 ##STR00787## 699
##STR00788## 700 ##STR00789## 701 ##STR00790## 702 ##STR00791## 703
##STR00792## 704 ##STR00793## 705 ##STR00794## 706 ##STR00795## 707
##STR00796## 708 ##STR00797## 709 ##STR00798## 710 ##STR00799## 711
##STR00800## 712 ##STR00801## 713 ##STR00802## 714 ##STR00803## 715
##STR00804## 716 ##STR00805## 717 ##STR00806## 718 ##STR00807## 719
##STR00808## 720 ##STR00809## 721 ##STR00810## 722 ##STR00811## 723
##STR00812## 724 ##STR00813## 725 ##STR00814## 726 ##STR00815## 727
##STR00816## 728 ##STR00817## 729 ##STR00818## 730 ##STR00819## 731
##STR00820## 732 ##STR00821## 733 ##STR00822## 734 ##STR00823## 735
##STR00824## 736 ##STR00825## 737 ##STR00826## 738 ##STR00827## 739
##STR00828## 740 ##STR00829## 741 ##STR00830## 742 ##STR00831## 743
##STR00832## 744 ##STR00833## 745 ##STR00834## 746 ##STR00835## 747
##STR00836## 748 ##STR00837## 749 ##STR00838## 750 ##STR00839## 751
##STR00840## 752
[0089] In another aspect, the invention features a pharmaceutical
composition comprising the compound of the invention and a
pharmaceutically acceptable carrier.
[0090] In another aspect, the invention features a method of
inhibiting a voltage-gated sodium ion channel in:
[0091] a patient; or
[0092] a biological sample;
[0093] comprising administering to the patient, or contacting the
biological sample, with the compound or composition of the
invention. In another embodiment, the voltage-gated sodium ion
channel is NaV 1.7.
[0094] In another aspect, the invention features a method of
treating or lessening the severity in a subject of acute, chronic,
neuropathic, or inflammatory pain, arthritis, migraine, cluster
headaches, trigeminal neuralgia, herpatic neuralgia, general
neuralgias, epilepsy or epilepsy conditions, neurodegenerative
disorders, psychiatric disorders, anxiety, depression, dipolar
disorder, myotonia, arrhythmia, movement disorders, neuroendocrine
disorders, ataxia, multiple sclerosis, irritable bowel syndrome,
incontinence, visceral pain, osteoarthritis pain, postherpetic
neuralgia, diabetic neuropathy, radicular pain, sciatica, back
pain, head or neck pain, severe or intractable pain, nociceptive
pain, breakthrough pain, postsurgical pain, cancer pain, stroke,
cerebral ischemia, traumatic brain injury, amyotrophic lateral
sclerosis, stress- or exercise induced angina, palpitations,
hypertension, migraine, or abnormal gastro-intestinal motility,
comprising administering an effective amount of a compound or
composition of the invention.
[0095] In another embodiment, the method is used for treating or
lessening the severity of femur cancer pain; non-malignant chronic
bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis;
neuropathic low back pain; neuropathic low back pain; myofascial
pain syndrome; fibromyalgia; temporomandibular joint pain; chronic
visceral pain, abdominal pain; pancreatic; IBS pain; chronic and
acute headache pain; migraine; tension headache, including, cluster
headaches; chronic and acute neuropathic pain, post-herpatic
neuralgia; diabetic neuropathy; HIV-associated neuropathy;
trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary
sensory neuropathies; peripheral nerve injury; painful neuromas;
ectopic proximal and distal discharges; radiculopathy; chemotherapy
induced neuropathic pain; radiotherapy-induced neuropathic pain;
post-mastectomy pain; central pain; spinal cord injury pain;
post-stroke pain; thalamic pain; complex regional pain syndrome;
phantom pain; intractable pain; acute pain, acute post-operative
pain; acute musculoskeletal pain; joint pain; mechanical low back
pain; neck pain; tendonitis; injury/exercise pain; acute visceral
pain, abdominal pain; pyelonephritis; appendicitis; cholecystitis;
intestinal obstruction; hernias; chest pain, cardiac pain; pelvic
pain, renal colic pain, acute obstetric pain, labor pain; cesarean
section pain; acute inflammatory, burn and trauma pain; acute
intermittent pain, endometriosis; acute herpes zoster pain; sickle
cell anemia; acute pancreatitis; breakthrough pain; orofacial pain
including sinusitis pain, dental pain; multiple sclerosis (MS)
pain; pain in depression; leprosy pain; Behcet's disease pain;
adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful
legs and moving toes; Haglund syndrome; erythromelalgia pain;
Fabry's disease pain; bladder and urogenital disease, including,
urinary incontinence; hyperactivity bladder; painful bladder
syndrome; interstitial cyctitis (IC); prostatitis; complex regional
pain syndrome (CRPS), type I and type II; widespread pain,
paroxysmal extreme pain, pruritis, tinnitis, or angina-induced
pain.
[0096] The compounds of the invention may be prepared readily using
the following methods. Illustrated below in Scheme 1 through Scheme
4 are methods for preparing the compounds of the invention.
##STR00841##
##STR00842##
##STR00843##
##STR00844##
Uses, Formulation and Administration
[0097] Pharmaceutically Acceptable Compositions
[0098] As discussed above, the invention provides compounds that
are inhibitors of voltage-gated sodium ion channels, and thus the
present compounds are useful for the treatment of diseases,
disorders, and conditions including, but not limited to acute,
chronic, neuropathic, or inflammatory pain, arthritis, migraine,
cluster headaches, trigeminal neuralgia, herpetic neuralgia,
general neuralgias, epilepsy or epilepsy conditions,
neurodegenerative disorders, psychiatric disorders such as anxiety
and depression, myotonia, arrhythmia, movement disorders,
neuroendocrine disorders, ataxia, multiple sclerosis, irritable
bowel syndrome, and incontinence. Accordingly, in another aspect of
the invention, pharmaceutically acceptable compositions are
provided, wherein these compositions comprise any of the compounds
as described herein, and optionally comprise a pharmaceutically
acceptable carrier, adjuvant or vehicle. In certain embodiments,
these compositions optionally further comprise one or more
additional therapeutic agents.
[0099] It will also be appreciated that certain of the compounds of
invention can exist in free form for treatment, or where
appropriate, as a pharmaceutically acceptable derivative thereof.
According to the invention, a pharmaceutically acceptable
derivative includes, but is not limited to, pharmaceutically
acceptable salts, esters, salts of such esters, or any other adduct
or derivative which upon administration to a subject in need is
capable of providing, directly or indirectly, a compound as
otherwise described herein, or a metabolite or residue thereof.
[0100] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgement, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. A "pharmaceutically acceptable salt" means any
non-toxic salt or salt of an ester of a compound of this invention
that, upon administration to a recipient, is capable of providing,
either directly or indirectly, a compound of this invention or an
inhibitorily active metabolite or residue thereof. As used herein,
the term "inhibitorily active metabolite or residue thereof" means
that a metabolite or residue thereof is also an inhibitor of a
voltage-gated sodium ion channel.
[0101] Pharmaceutically acceptable salts are well known in the art.
For example, S. M. Berge, et al. describe pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66,
1-19, incorporated herein by reference. Pharmaceutically acceptable
salts of the compounds of this invention include those derived from
suitable inorganic and organic acids and bases. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid or
malonic acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4alkyl).sub.4 salts. This
invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersable products may be obtained by such
quaternization. Representative alkali or alkaline earth metal salts
include sodium, lithium, potassium, calcium, magnesium, and the
like. Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and
aryl sulfonate.
[0102] As described above, the pharmaceutically acceptable
compositions of the invention additionally comprise a
pharmaceutically acceptable carrier, adjuvant, or vehicle, which,
as used herein, includes any and all solvents, diluents, or other
liquid vehicle, dispersion or suspension aids, surface active
agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants and the like, as suited to
the particular dosage form desired. Remington's Pharmaceutical
Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co.,
Easton, Pa., 1980) discloses various carriers used in formulating
pharmaceutically acceptable compositions and known techniques for
the preparation thereof. Except insofar as any conventional carrier
medium is incompatible with the compounds of the invention, such as
by producing any undesirable biological effect or otherwise
interacting in a deleterious manner with any other component(s) of
the pharmaceutically acceptable composition, its use is
contemplated to be within the scope of this invention. Some
examples of materials which can serve as pharmaceutically
acceptable carriers include, but are not limited to, ion
exchangers, alumina, aluminum stearate, lecithin, serum proteins,
such as human serum albumin, buffer substances such as phosphates,
glycine, sorbic acid, or potassium sorbate, partial glyceride
mixtures of saturated vegetable fatty acids, water, salts or
electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol or polyethylene glycol;
esters such as ethyl oleate and ethyl laurate; agar; buffering
agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
[0103] Uses of Compounds and Pharmaceutically Acceptable
Compositions
[0104] In yet another aspect, a method for the treatment or
lessening the severity of acute, chronic, neuropathic, or
inflammatory pain, arthritis, migraine, cluster headaches,
trigeminal neuralgia, herpetic neuralgia, general neuralgias,
epilepsy or epilepsy conditions, neurodegenerative disorders,
psychiatric disorders such as anxiety and depression, dipolar
disorder, myotonia, arrhythmia, movement disorders, neuroendocrine
disorders, ataxia, multiple sclerosis, irritable bowel syndrome,
incontinence, visceral pain, osteoarthritis pain, postherpetic
neuralgia, diabetic neuropathy, radicular pain, sciatica, back
pain, head or neck pain, severe or intractable pain, nociceptive
pain, breakthrough pain, postsurgical pain, or cancer pain is
provided comprising administering an effective amount of a
compound, or a pharmaceutically acceptable composition comprising a
compound to a subject in need thereof.
[0105] In certain embodiments, a method of treatment or lessening
the severity of stroke, cerebral ischemia, traumatic brain injury,
amyotrophic lateral sclerosis, stress- or exercise induced angina,
palpitations, hypertension, migraine, or abnormal gastro-intestinal
motility is provided comprising administering an effective amount
of a compound, or a pharmaceutically acceptable composition
comprising a compound to a subject in need thereof.
[0106] In certain embodiments, a method for the treatment or
lessening the severity of acute, chronic, neuropathic, or
inflammatory pain is provided comprising administering an effective
amount of a compound or a pharmaceutically acceptable composition
to a subject in need thereof. In certain other embodiments, a
method for the treatment or lessening the severity of radicular
pain, sciatica, back pain, head pain, or neck pain is provided
comprising administering an effective amount of a compound or a
pharmaceutically acceptable composition to a subject in need
thereof. In still other embodiments, a method for the treatment or
lessening the severity of severe or intractable pain, acute pain,
postsurgical pain, back pain, tinnitis or cancer pain is provided
comprising administering an effective amount of a compound or a
pharmaceutically acceptable composition to a subject in need
thereof.
[0107] In certain embodiments, a method for the treatment or
lessening the severity of femur cancer pain; non-malignant chronic
bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis;
neuropathic low back pain; neuropathic low back pain; myofascial
pain syndrome; fibromyalgia; temporomandibular joint pain; chronic
visceral pain, including, abdominal; pancreatic; IBS pain; chronic
and acute headache pain; migraine; tension headache, including,
cluster headaches; chronic and acute neuropathic pain, including,
post-herpetic neuralgia; diabetic neuropathy; HIV-associated
neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy;
hereditary sensory neuropathies; peripheral nerve injury; painful
neuromas; ectopic proximal and distal discharges; radiculopathy;
chemotherapy induced neuropathic pain; radiotherapy-induced
neuropathic pain; post-mastectomy pain; central pain; spinal cord
injury pain; post-stroke pain; thalamic pain; complex regional pain
syndrome; phantom pain; intractable pain; acute pain, acute
post-operative pain; acute musculoskeletal pain; joint pain;
mechanical low back pain; neck pain; tendonitis; injury/exercise
pain; acute visceral pain, including, abdominal pain;
pyelonephritis; appendicitis; cholecystitis; intestinal
obstruction; hernias; etc; chest pain, including, cardiac Pain;
pelvic pain, renal colic pain, acute obstetric pain, including,
labor pain; cesarean section pain; acute inflammatory, burn and
trauma pain; acute intermittent pain, including, endometriosis;
acute herpes zoster pain; sickle cell anemia; acute pancreatitis;
breakthrough pain; orofacial pain including sinusitis pain, dental
pain; multiple sclerosis (MS) pain; pain in depression; leprosy
pain; behcet's disease pain; adiposis dolorosa; phlebitic pain;
Guillain-Barre pain; painful legs and moving toes; Haglund
syndrome; erythromelalgia pain; Fabry's disease pain; bladder and
urogenital disease, including, urinary incontinence; hyperactivity
bladder; painful bladder syndrome; interstitial cyctitis (IC); or
prostatitis; complex regional pain syndrome (CRPS), type I and type
II; angina-induced pain is provided, comprising administering an
effective amount of a compound or a pharmaceutically acceptable
composition to a subject in need thereof.
[0108] In certain embodiments of the invention an "effective
amount" of the compound or pharmaceutically acceptable composition
is that amount effective for treating or lessening the severity of
one or more of acute, chronic, neuropathic, or inflammatory pain,
arthritis, migraine, cluster headaches, trigeminal neuralgia,
herpetic neuralgia, general neuralgias, epilepsy or epilepsy
conditions, neurodegenerative disorders, psychiatric disorders such
as anxiety and depression, myotonia, arrhythmia, movement
disorders, neuroendocrine disorders, ataxia, multiple sclerosis,
irritable bowel syndrome, incontinence, visceral pain,
osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,
radicular pain, sciatica, back pain, head or neck pain, severe or
intractable pain, nociceptive pain, breakthrough pain, postsurgical
pain, tinnitis or cancer pain.
[0109] The compounds and compositions, according to the method of
the invention, may be administered using any amount and any route
of administration effective for treating or lessening the severity
of one or more of acute, chronic, neuropathic, or inflammatory
pain, arthritis, migraine, cluster headaches, trigeminal neuralgia,
herpetic neuralgia, general neuralgias, epilepsy or epilepsy
conditions, neurodegenerative disorders, psychiatric disorders such
as anxiety and depression, myotonia, arrhythmia, movement
disorders, neuroendocrine disorders, ataxia, multiple sclerosis,
irritable bowel syndrome, incontinence, visceral pain,
osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,
radicular pain, sciatica, back pain, head or neck pain, severe or
intractable pain, nociceptive pain, breakthrough pain, postsurgical
pain, tinnitis or cancer pain. The exact amount required will vary
from subject to subject, depending on the species, age, and general
condition of the subject, the severity of the infection, the
particular agent, its mode of administration, and the like. The
compounds of the invention are preferably formulated in dosage unit
form for ease of administration and uniformity of dosage. The
expression "dosage unit form" as used herein refers to a physically
discrete unit of agent appropriate for the subject to be treated.
It will be understood, however, that the total daily usage of the
compounds and compositions of the invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific effective dose level for any particular subject or
organism will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the subject; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed, and like
factors well known in the medical arts. The term "subject" or
"patient", as used herein, means an animal, preferably a mammal,
and most preferably a human.
[0110] The pharmaceutically acceptable compositions of this
invention can be administered to humans and other animals orally,
rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments, or drops),
bucally, as an oral or nasal spray, or the like, depending on the
severity of the infection being treated. In certain embodiments,
the compounds of the invention may be administered orally or
parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg
and preferably from about 1 mg/kg to about 25 mg/kg, of subject
body weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[0111] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0112] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0113] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0114] In order to prolong the effect of a compound of the
invention, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
[0115] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0116] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0117] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polethylene
glycols and the like.
[0118] The active compounds can also be in microencapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
[0119] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, eardrops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the invention contemplates the use of
transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
are prepared by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0120] As described generally above, the compounds of the invention
are useful as inhibitors of voltage-gated sodium ion channels. In
one embodiment, the compounds and compositions of the invention are
inhibitors of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4,
NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9, and thus, without
wishing to be bound by any particular theory, the compounds and
compositions are particularly useful for treating or lessening the
severity of a disease, condition, or disorder where activation or
hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4,
NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 is implicated in the
disease, condition, or disorder. When activation or hyperactivity
of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8,
or NaV1.9 is implicated in a particular disease, condition, or
disorder, the disease, condition, or disorder may also be referred
to as a "NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,
NaV1.8 or NaV1.9-mediated disease, condition or disorder".
Accordingly, in another aspect, the invention provides a method for
treating or lessening the severity of a disease, condition, or
disorder where activation or hyperactivity of one or more of
NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or
NaV1.9 is implicated in the disease state.
[0121] The activity of a compound utilized in this invention as an
inhibitor of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6,
NaV1.7, NaV1.8, or NaV1.9 may be assayed according to methods
described generally in the Examples herein, or according to methods
available to one of ordinary skill in the art.
[0122] In certain exemplary embodiments, compounds of the invention
are useful as inhibitors of NaV1.7 and/or NaV1.8.
[0123] It will also be appreciated that the compounds and
pharmaceutically acceptable compositions of the invention can be
employed in combination therapies, that is, the compounds and
pharmaceutically acceptable compositions can be administered
concurrently with, prior to, or subsequent to, one or more other
desired therapeutics or medical procedures. The particular
combination of therapies (therapeutics or procedures) to employ in
a combination regimen will take into account compatibility of the
desired therapeutics and/or procedures and the desired therapeutic
effect to be achieved. It will also be appreciated that the
therapies employed may achieve a desired effect for the same
disorder (for example, an inventive compound may be administered
concurrently with another agent used to treat the same disorder),
or they may achieve different effects (e.g., control of any adverse
effects). As used herein, additional therapeutic agents that are
normally administered to treat or prevent a particular disease, or
condition, are known as "appropriate for the disease, or condition,
being treated". For example, exemplary additional therapeutic
agents include, but are not limited to: nonopioid analgesics
(indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin;
naphthylalkanones such sa Nabumetone; oxicams such as Piroxicam;
para-aminophenol derivatives, such as Acetaminophen; propionic
acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen,
Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Asprin,
Choline magnesium trisalicylate, Diflunisal; fenamates such as
meclofenamic acid, Mefenamic acid; and pyrazoles such as
Phenylbutazone); or opioid (narcotic) agonists (such as Codeine,
Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone,
Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine,
Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally,
nondrug analgesic approaches may be utilized in conjunction with
administration of one or more compounds of the invention. For
example, anesthesiologic (intraspinal infusion, neural blocade),
neurosurgical (neurolysis of CNS pathways), neurostimulatory
(transcutaneous electrical nerve stimulation, dorsal column
stimulation), physiatric (physical therapy, orthotic devices,
diathermy), or psychologic (cognitive methods-hypnosis,
biofeedback, or behavioral methods) approaches may also be
utilized. Additional appropriate therapeutic agents or approaches
are described generally in The Merck Manual, Seventeenth Edition,
Ed. Mark H. Beers and Robert Berkow, Merck Research Laboratories,
1999, and the Food and Drug Administration website, www.fda.gov,
the entire contents of which are hereby incorporated by
reference.
[0124] In another embodiment, additional appropriate therapeutic
agents are selected from the following:
[0125] (1) an opioid analgesic, e.g. morphine, heroin,
hydromorphone, oxymorphone, levorphanol, levallorphan, methadone,
meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone,
hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone,
naltrexone, buprenorphine, butorphanol, nalbuphine or
pentazocine;
[0126] (2) a nonsteroidal antiinflammatory drug (NSAID), e.g.
aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen,
flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen,
ketorolac, meclofenamic acid, mefenamic acid, meloxicam,
nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,
oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac,
tolmetin or zomepirac;
[0127] (3) a barbiturate sedative, e.g. amobarbital, aprobarbital,
butabarbital, butabital, mephobarbital, metharbital, methohexital,
pentobarbital, phenobartital, secobarbital, talbutal, theamylal or
thiopental;
[0128] (4) a benzodiazepine having a sedative action, e.g.
chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam,
oxazepam, temazepam or triazolam;
[0129] (5) an antagonist having a sedative action, e.g.
diphenhydramine, pyrilamine, promethazine, chlorpheniramine or
chlorcyclizine;
[0130] (6) a sedative such as glutethimide, meprobamate,
methaqualone or dichloralphenazone;
[0131] (7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol,
chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;
[0132] (8) an NMDA receptor antagonist, e.g. dextromethorphan
((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan
((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine,
pyrroloquinoline quinine,
cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,
EN-3231 (MorphiDex.RTM., a combination formulation of morphine and
dextromethorphan), topiramate, neramexane or perzinfotel including
an NR2B antagonist, e.g. ifenprodil, traxoprodil or
(-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl--
3,4-dihydro-2(1H)-quinolinone;
[0133] (9) an alpha-adrenergic, e.g. doxazosin, tamsulosin,
clonidine, guanfacine, dexmetatomidine, modafinil, or
4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,
2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;
[0134] (10) a tricyclic antidepressant, e.g. desipramine,
imipramine, amitriptyline or nortriptyline;
[0135] (11) an anticonvulsant, e.g. carbamazepine, lamotrigine,
topiratmate or valproate;
[0136] (12) a tachykinin (NK) antagonist, particularly an NK-3,
NK-2 or NK-I antagonist, e.g.
([alpha]R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-m-
ethyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13--
dione (TAK-637),
5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorop-
henyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one
(MK-869), aprepitant, lanepitant, dapitant or
3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine
(2S,3S);
[0137] (13) a muscarinic antagonist, e.g oxybutynin, tolterodine,
propiverine, tropsium chloride, darifenacin, solifenacin,
temiverine and ipratropium;
[0138] (14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib,
parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;
[0139] (15) a coal-tar analgesic, in particular paracetamol;
[0140] (16) a neuroleptic such as droperidol, chlorpromazine,
haloperidol, perphenazine, thioridazine, mesoridazine,
trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone,
ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole,
blonanserin, iloperidone, perospirone, raclopride, zotepine,
bifeprunox, asenapine, lurasidone, amisulpride, balaperidone,
palindore, eplivanserin, osanetant, rimonabant, meclinertant,
Miraxion.RTM. or sarizotan;
[0141] (17) a vanilloid receptor agonist (e.g. resinferatoxin) or
antagonist (e.g. capsazepine);
[0142] (18) a beta-adrenergic such as propranolol;
[0143] (19) a local anaesthetic such as mexiletine;
[0144] (20) a corticosteroid such as dexamethasone;
[0145] (21) a 5-HT receptor agonist or antagonist, particularly a
5-HT.sub.1B/1D.sub.[h3] agonist such as eletriptan, sumatriptan,
naratriptan, zolmitriptan or rizatriptan;
[0146] (22) a 5-HT2A receptor antagonist such as
R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidin-
emethanol (MDL-100907);
[0147] (23) a cholinergic (nicotinic) analgesic, such as
ispronicline (TC-1734),
(E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403),
(R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or
nicotine;
[0148] (24) Tamadol.RTM.;.sub.[h4]
[0149] (25) a PDEV inhibitor, such as
5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-prop-
yl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil),
(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)--
pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione (IC-351 or
tadalafil),
2-[2-ethoxy-5-(4-ethylpiperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-prop-
yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil),
5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-di-
hydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2-
,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2--
methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-
-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,
3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)--
N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;
[0150] (26) an.sub.[h5] alpha-2-delta ligand such as gabapentin,
pregabalin, 3-methyl gabapentin,
(1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acet-
ic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,
(3S,5R)-3-amino-5-methyl-heptanoic acid,
(3S,5R)-3-amino-5-methyl-octanoic acid,
(2S,4S)-4-(3-chlorophenoxy)proline,
(2S,4S)-4-(3-fluorobenzyl)-proline,
[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,
3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,
C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,
(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,
(3S,5R)-3-aminomethyl-5-methyl-octanoic acid,
(3S,5R)-3-amino-5-methyl-nonanoic acid,
(3S,5R)-3-amino-5-methyl-octanoic acid,
(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and
(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;
[0151] (27) a cannabinoid;
[0152] (28) metabotropic glutamate subtype 1 receptor (mGluR1)
antagonist;
[0153] (29) a serotonin reuptake inhibitor such as sertraline,
sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine
(fluoxetine desmethyl metabolite), fluvoxamine, paroxetine,
citalopram, citalopram metabolite desmethylcitalopram,
escitalopram, d,l-fenfluramine, femoxetine, ifoxetine,
cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and
trazodone;
[0154] (30) a noradrenaline (norepinephrine) reuptake inhibitor,
such as maprotiline, lofepramine, mirtazepine, oxaprotiline,
fezolamine, tomoxetine, mianserin, buproprion, buproprion
metabolite hydroxybuproprion, nomifensine and viloxazine
(Vivalan.RTM.), especially a selective noradrenaline reuptake
inhibitor such as reboxetine, in particular (S,S)-reboxetine;
[0155] (31) a dual serotonin-noradrenaline reuptake inhibitor, such
as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,
clomipramine, clomipramine metabolite desmethylclomipramine,
duloxetine, milnacipran and imipramine;
[0156] (32) an inducible nitric oxide synthase (iNOS) inhibitor
such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,
S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,
S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,
(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,
2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butylJthioJ-S-chloro-S-pyri-
dinecarbonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonit-
rile,
(2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiaz-
olebutanol,
2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluorometh-
yl)-3 pyridinecarbonitrile,
2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonit-
rile,
N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine,
or guanidinoethyldisulfide;
[0157] (33) an acetylcholinesterase inhibitor such as
donepezil;
[0158] (34) a prostaglandin E2 subtype 4 (EP4) antagonist such as
7V-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]eth-
yl}amino)-carbonyl]-4-methylbenzenesulfonamide or
4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethy-
l]benzoic acid;
[0159] (35) a leukotriene B4 antagonist; such as
1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic
acid (CP-105696),
5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valer-
ic acid (ONO-4057) or DPC-11870,
[0160] (36) a 5-lipoxygenase inhibitor, such as zileuton,
6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methy-
l]-1-methyl-2-quinolone (ZD-2138), or
2,3,5-trimethyl-6-(3-pyridylmethyl),1,4-benzoquinone (CV-6504);
[0161] (37) a sodium channel blocker, such as lidocaine;
[0162] (38) a 5-HT3 antagonist, such as ondansetron; and the
pharmaceutically acceptable salts and solvates thereof.
[0163] The amount of additional therapeutic agent present in the
compositions of this invention will be no more than the amount that
would normally be administered in a composition comprising that
therapeutic agent as the only active agent. Preferably the amount
of additional therapeutic agent in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
[0164] The compounds of this invention or pharmaceutically
acceptable compositions thereof may also be incorporated into
compositions for coating an implantable medical device, such as
prostheses, artificial valves, vascular grafts, stents and
catheters. Accordingly, the invention, in another aspect, includes
a composition for coating an implantable device comprising a
compound of the invention as described generally above, and in
classes and subclasses herein, and a carrier suitable for coating
said implantable device. In still another aspect, the invention
includes an implantable device coated with a composition comprising
a compound of the invention as described generally above, and in
classes and subclasses herein, and a carrier suitable for coating
said implantable device. Suitable coatings and the general
preparation of coated implantable devices are described in U.S.
Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are
typically biocompatible polymeric materials such as a hydrogel
polymer, polymethyldisiloxane, polycaprolactone, polyethylene
glycol, polylactic acid, ethylene vinyl acetate, and mixtures
thereof. The coatings may optionally be further covered by a
suitable topcoat of fluorosilicone, polysaccarides, polyethylene
glycol, phospholipids or combinations thereof to impart controlled
release characteristics in the composition.
[0165] Another aspect of the invention relates to inhibiting one or
more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,
NaV1.8, or NaV1.9, activity in a biological sample or a subject,
which method comprises administering to the subject, or contacting
said biological sample with a compound of formula I or a
composition comprising said compound. The term "biological sample",
as used herein, includes, without limitation, cell cultures or
extracts thereof; biopsied material obtained from a mammal or
extracts thereof; and blood, saliva, urine, feces, semen, tears, or
other body fluids or extracts thereof.
[0166] Inhibition of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4,
NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9, activity in a biological
sample is useful for a variety of purposes that are known to one of
skill in the art. Examples of such purposes include, but are not
limited to, the study of sodium ion channels in biological and
pathological phenomena; and the comparative evaluation of new
sodium ion channel inhibitors.
Examples
[0167] General methods. .sup.1H NMR (400 MHz) and .sup.13C NMR (100
MHz) spectra were obtained as solutions in deuterioacetonitrile
(CD.sub.3CN), chloroform-d (CDCl.sub.3) or dimethyl
sulfoxide-D.sub.6 (DMSO). Mass spectra (MS) were obtained using an
Applied Biosystems API EX LC/MS system equipped with a Phenomenex
50.times.4.60 mm luna-5.mu., C18 column. The LC/MS eluting system
was 1-99% or 10-99% acetonitrile in H.sub.2O with 0.035% v/v
trifluoroacetic acid, 0.035% v/v formic acid, 5 mM HCl or 5 mM
ammonium formate using a 3 or 15 minute linear gradient and a flow
rate of 12 mL/minute. Silica gel chromatography was performed using
silica gel-60 with a particle size of 230-400 mesh. Pyridine,
dichloromethane (CH.sub.2Cl.sub.2), tetrahydrofuran (THF),
dimethylformamide (DMF), acetonitrile (ACN), methanol (MeOH), and
1,4-dioxane were from Aldrich Sure-Seal bottles kept under dry
nitrogen. All reactions were stirred magnetically unless otherwise
noted.
trans-5a',6',7',8',9',9a'-Hexahydro-5'H-spiro[piperidine-4,4'-pyrrolo[1,2--
a]quinoxaline]dihydrochloride
##STR00845##
[0169] Step 1:
[0170] tert-Butyl N-[(1R,2R)-2-aminocyclohexyl]carbamate (1.06 g,
4.93 mmol), sodium acetate (1.70 g, 20.7 mmol) and
2,5-dimethoxytetrahydrofuran (764 .mu.L, 5.91 mmol) were combined
in acetic acid (10.6 mL). The reaction mixture was heated at
80.degree. C. for 16 hours. The reaction mixture was then
evaporated to dryness and the residue was partitioned between ethyl
acetate and a saturated aqueous solution of sodium bicarbonate. The
layers were separated, and the organic layer was washed twice with
a saturated aqueous solution of sodium chloride, dried over sodium
sulfate, and evaporated to dryness to yield a brown solid. This
solid was then dissolved in HCl in dioxane (10.3 mL of 4.0 M, 41.1
mmol) and was allowed to stand for 3 hours. The solvent was then
removed to yield trans-2-(1H-pyrrol-1-yl)cyclohexanamine hydrogen
chloride (989 mg, 99%) as a brown solid. ESI-MS m/z calc. 164.1,
found 165.2 (M+1)+; Retention time: 0.27 minutes (4 min run).
[0171] Step 2:
[0172] trans-2-(1H-Pyrrol-1-yl)cyclohexanamine hydrogen chloride
(989 mg, 4.93 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (982
mg, 4.93 mmol), and maleic acid (56.2 mg, 0.493 mmol) were combined
in ethanol (12 mL). The reaction mixture was heated at 80.degree.
C. for 4 hours. The reaction mixture was cooled to room temperature
and the solvent was evaporated. The residue was dissolved in
dichloromethane and was then purified on 80 g of silica gel
utilizing a gradient of 0-10% methanol in dichloromethane to give
trans-tert-butyl
5a',6',7',8',9',9a'-hexahydro-5'H-spiro[piperidine-4,4'-pyrrolo[1,2-a]qui-
noxaline]-1-carboxylate. ESI-MS m/z calc. 345.2, found 346.2
(M+1)+; Retention time: 1.63 minutes (4 min run).
[0173] Step 3:
[0174] trans-tert-Butyl
5a',6',7',8',9',9a'-hexahydro-5'H-spiro[piperidine-4,4'-pyrrolo[1,2-a]qui-
noxaline]-1-carboxylate (0.311 g, 0.901 mmol) was suspended in
hydrogen chloride in dioxane (2.0 mL of 4.0 M, 8.0 mmol). The
reaction mixture was allowed to stand for 2 hours. The reaction
mixture was then evaporated to dryness to give
trans-5a',6',7',8',9',9a'-hexahydro-5'H-spiro[piperidine-4,4'-pyrrolo[1,2-
-a]quinoxaline]. ESI-MS m/z calc. 245.2, found 246.3 (M+1)+;
Retention time: 0.32 minutes (3 min run).
2'-Methyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyr-
rolo[1,2-a]pyrazine]dihydrochloride
##STR00846##
[0176] Step 1:
[0177] A mixture of 2,5-dimethoxytetrahydrofuran (15 g, 113.5
mmol), 2-chloroethanamine hydrochloride (44.76 g, 385.9 mmol), and
sodium acetate (46.55 g, 567.5 mmol) in acetic acid (55 mL) was
heated at 110.degree. C. After 2 h, the reaction was poured into
brine and the product was extracted with dichloromethane. The
organics were washed with brine, saturated Na.sub.2CO.sub.3, and
brine again. The organics were dried over sodium sulfate and
evaporated. The crude material was filtered through a plug of
Florisil (80 g) using hexane as the eluent to give
1-(2-chloroethyl)pyrrole (10.1 g, 69%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 6.70 (t, J=1.9 Hz, 2H), 6.18 (t, J=1.9 Hz, 2H),
4.20 (t, J=6.5 Hz, 2H), 3.73 (t, J=6.5 Hz, 2H).
[0178] Step 2:
[0179] 1-(2-Chloroethyl)pyrrole (2.0 g, 15.43 mmol) was combined
with a solution of 33% methylamine in ethanol (7.3 mL of 33% w/v,
77.15 mmol). The mixture was heated at 90.degree. C. for 16 h
before it was concentrated under reduced pressure to provide
N-methyl-2-pyrrol-1-yl-ethanamine (2.19 g, 88%) which was used
directly in next reaction, ESI-MS m/z calc. 124.1, found 125.3
(M+1)+; Retention time: 0.22 minutes (3 min run). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 6.73-6.68 (m, 2H), 6.22-6.14 (m, 2H), 4.05
(t, J=5.9 Hz, 2H), 2.94 (t, J=5.9 Hz, 2H), 2.45 (s, 3H).
[0180] Step 3:
[0181] N-Methyl-2-pyrrol-1-yl-ethanamine (2.19 g, 17.64 mmol),
tert-butyl 4-oxopiperidine-1-carboxylate (3.51 g, 17.64 mmol), and
pTsOH.H.sub.2O (0.334 g, 1.76 mmol) were combined in ethanol (87.60
mL) and heated at 70.degree. C. for 4 h. The reaction was
concentrated and the residue was dissolved in dichloromethane. The
organics were washed with a saturated NaHCO.sub.3 solution and
brine. The organics were dried over sodium sulfate and evaporated.
The crude material was purified by silica gel chromatography
eluting with 0-10% methanol in dichloromethane with 2%
triethylamine to give tert-butyl
2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carbo-
xylate (4.2 g, 78%). ESI-MS m/z calc. 305.4, found 306.3 (M+1)+;
Retention time: 0.97 minutes (3 min run). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 6.55-6.52 (m, 1H), 6.15-6.11 (m, 1H), 5.92-5.89
(m, 1H), 3.92 (t, J=6.0 Hz, 2H), 3.91-3.75 (m, 2H), 3.29 (t, J=6.0
Hz, 2H), 3.26-3.12 (m, 2H), 2.36 (s, 3H), 2.10-1.99 (m, 2H),
1.83-1.69 (m, 2H), 1.47 (s, 9H).
[0182] Step 4:
[0183] Method A: tert-Butyl
2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carbo-
xylate (1.0 g, 3.27 mmol), potassium carbonate (497.7 mg, 3.60
mmol) and trifluoromethanesulfonate;
5-(trifluoromethyl)dibenzothiophen-5-ium (1.32 g, 3.27 mmol) were
combined in acetonitrile (10 mL). The reaction mixture was heated
at 60.degree. C. for 16 h. The reaction was evaporated to dryness
and the residue was dissolved in dichloromethane. The organics were
washed with water and brine, dried over sodium sulfate and
evaporated. The crude material was purified by silica gel
chromatography eluting with 0-50% ethyl acetate in hexanes to give
tert-butyl
2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'--
piperidine]-1'-carboxylate (812 mg, 66%). ESI-MS m/z calc. 373.2,
found 374.5 (M+1)+; Retention time: 1.21 minutes (3 min run).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.52 (d, J=3.8 Hz, 1H),
5.91 (d, J=3.8 Hz, 1H), 3.98 (t, J=6.0 Hz, 2H), 3.93-3.76 (m, 2H),
3.32 (t, J=6.0 Hz, 2H), 3.26-3.08 (m, 2H), 2.36 (s, 3H), 2.11-1.99
(m, 2H), 1.81-1.65 (m, 2H), 1.47 (s, 9H).
[0184] Method B: To tert-butyl
2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carbo-
xylate (10.0 g, 32.7 mmol) in DMSO (164 mL) was added ferrous
sulfate heptahydrate (9.8 mL of 1.0 M, 9.8 mmol) followed by
CF.sub.3I (6.41 g, 32.7 mmol) by slow bubbling through the solution
and taking the weight difference of the canister. The mixture was
cooled with a ice-water bath before H.sub.2O.sub.2 (3.71 mL of 30%
w/v, 32.7 mmol) dropwise over 15 min keeping the internal
temperature <20.degree. C. The mixture was poured onto 300 mL of
ice water and was extracted with EtOAc (2.times.400 mL). The
combined organic phases were washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuo. The crude material
was purified column chromatography eluting with 0-10% methanol in
dichloromethane with 2% iPr.sub.2NEt to give tert-butyl
2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'--
piperidine]-1'-carboxylate (7.8 g, 64%).
[0185] Step 5:
[0186] tert-Butyl
2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'--
piperidine]-1'-carboxylate (7.8 g, 20.89 mmol) was stirred in 4M
HCl in dioxane (26.10 mL of 4 M, 104.4 mmol) and methanol (22 mL)
at room temperature for 1 h. The reaction mixture was evaporated to
dryness and the residue was co-evaporated with 100 mL of MTBE to
afford
2'-methyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-py-
rrolo[1,2-a]pyrazine]dihydrochloride as a yellow foam/solid (7.23
g, quantitative). ESI-MS m/z calc. 273.2, found 274.5 (M+1)+;
Retention time: 0.44 minutes (3 min run).
2'-Methyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]--
6'-carbonitrile dihydrochloride
##STR00847##
[0188] Step 1:
[0189] A solution of chlorosulfonyl isocyanate (590.9 mg, 363.4
.mu.L, 4.175 mmol) in tetrahydrofuran (2 mL) was slowly added to a
solution of tert-butyl
2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carbo-
xylate (1020 mg, 3.340 mmol) in tetrahydrofuran (9 mL) held at
-78.degree. C. (bath temperature) under an atmosphere of argon. The
reaction mixture was allowed to stir for 1 hour at -78.degree. C.
N,N-dimethylformamide (732.4 mg, 775.8 .mu.L, 10.02 mmol) was then
slowly added to the cold reaction mixture. The reaction mixture was
then allowed to slowly warm to room temperature. After stirring for
3 hours at room temperature the crude material was diluted with 25
mL of tetrahydrofuran, washed with a 1M solution of sodium
hydroxide, followed by three washes of a saturated aqueous solution
of sodium chloride. The organic layer was dried over sodium
sulfate, filtered, and evaporated to dryness to yield the crude
product. The crude material was purified on 80 g of silica gel
utilizing a gradient of 0-70% ethyl acetate in hexanes to yield
tert-butyl
6-cyano-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-
-1'-carboxylate (280 mg, 25%) as a white solid. ESI-MS m/z calc.
330.2, found 331.1 (M+1)+; Retention time: 0.94 minutes. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 6.76 (d, J=4.0 Hz, 1H), 5.97 (d,
J=4.0 Hz, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.98-3.76 (m, 2H), 3.36 (t,
J=6.0 Hz, 2H), 3.30-3.08 (m, 2H), 2.36 (s, 3H), 2.09-1.98 (m, 2H),
1.84-1.66 (m, 2H), 1.47 (s, 9H).
[0190] Step 2:
[0191] tert-Butyl
6-cyano-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-
-1'-carboxylate (280 mg, 0.8474 mmol) was dissolved in a mixture of
hydrochloric acid in dioxane (8 mL of 4 M, 32.00 mmol) and dioxane
(8 mL). The reaction mixture was allowed to stir for 30 minutes and
then evaporated to dryness to yield
2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-carbon-
itrile dihydrochloride (258 mg, 99%) as a white solid. ESI-MS m/z
calc. 230.2, found 231.5 (M+1)+; Retention time: 0.50 minutes (3
min run). .sup.1H NMR (400 MHz, D.sub.2O) .delta. 7.10 (d, J=4.2
Hz, 1H), 6.59 (d, J=4.3 Hz, 1H), 4.51 (t, J=6.4 Hz, 2H), 4.02 (t,
J=6.3 Hz, 2H), 3.66-3.56 (m, 2H), 3.49-3.36 (m, 2H), 2.95 (s, 3H),
2.69-2.59 (m, 2H), 2.54-2.40 (m, 2H).
N-methyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrr-
olo[1,2-a]pyrazine]-2'-carboxamide hydrochloride
##STR00848##
[0193] Step 1:
[0194] To tert-butyl
6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piper-
idine]-1'-carboxylate (600 mg, 1.67 mmol), THF (3 mL) and Et.sub.3N
(698 .mu.L, 5.01 mmol) was added methyl isocyanate (199 .mu.L, 3.34
mmol). The mixture was allowed to stir at room temperature for 2 h.
The mixture was charged with additional Et.sub.3N (698 .mu.L, 5.01
mmol) and methyl isocyanate (199 .mu.L, 3.34 mmol), and the
reaction was stirred at room temperature for 3 d. The solvent was
evaporated under reduced pressure. The residue was dissolved in
ethyl acetate (40 mL) and washed with water (3.times.10 mL). The
organic layer was dried over sodium sulfate, filtered, and
concentrated in vacuo to yield tert-butyl
2-(methylcarbamoyl)-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyr-
azine-1,4'-piperidine]-1'-carboxylate (680 mg, 97%). ESI-MS m/z
calc. 416.2, found 417.4 (M+1)+; Retention time: 1.73 minutes (3
min run). .sup.1H NMR (400 MHz, DMSO) .delta. 7.14 (q, J=4.3 Hz,
1H), 6.56 (d, J=3.4 Hz, 1H), 6.03 (d, J=3.9 Hz, 1H), 3.88 (t, J=5.4
Hz, 2H), 3.73 (t, J=5.4 Hz, 2H), 3.69-3.55 (m, 2H), 3.23-3.03 (m,
2H), 2.78-2.62 (m, 2H), 2.56 (d, J=4.4 Hz, 3H), 1.76-1.60 (m, 2H),
1.40 (s, 9H).
[0195] Step 2:
[0196] To tert-butyl
2-(methylcarbamoyl)-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyr-
azine-1,4'-piperidine]-1'-carboxylate (0.66 g, 1.6 mmol) and
acetonitrile (5 mL) was added a solution of HCl in dioxane (5.2 mL
of 4.0 M, 21 mmol). The reaction mixture was stirred at room
temperature for 60 minutes. The solvent was evaporated under
reduced pressure to yield
N-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'--
piperidine]-2-carboxamide hydrochloride as a brown solid (99%).
ESI-MS m/z calc. 316.2, found 317.2 (M+1)+; Retention time: 0.77
minutes (3 min run).
[0197] The following compounds were synthesized using the
procedures described above:
[0198]
2'-(2-methoxyethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo-
[1,2-a]pyrazine]dihydrochloride, [0199]
2'-benzyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-
dihydrochloride, [0200]
2'-(2-methoxyethyl)-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidi-
ne-4,1'-pyrrolo[1,2-a]pyrazine]dihydrochloride, [0201]
6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2--
a]pyrazine]dihydrochloride, [0202]
2'-ethyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyr-
rolo[1,2-a]pyrazine]dihydrochloride, [0203]
3',3'-dimethyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,-
1'-pyrrolo[1,2-a]pyrazine]dihydrochloride, [0204]
3'-methyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-py-
rrolo[1,2-a]pyrazine]dihydrochloride, [0205]
4',4'-dimethyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,-
1'-pyrrolo[1,2-a]pyrazine]dihydrochloride, [0206]
2',3'-dimethyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,-
1'-pyrrolo[1,2-a]pyrazine]dihydrochloride, [0207]
3-methyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyr-
rolo[1,2-a]pyrazine]dihydrochloride, [0208]
2'-cyclopropyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,-
1'-pyrrolo[1,2-a]pyrazine]dihydrochloride, [0209]
2'-(cyclopropylmethyl)-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piper-
idine-4,1'-pyrrolo[1,2-a]pyrazine]dihydrochloride, [0210]
2',3-dimethyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1-
'-pyrrolo[1,2-a]pyrazine]dihydrochloride, [0211]
2'-methyl-6'-(2,2,2-trifluoroethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,-
1'-pyrrolo[1,2-a]pyrazine]dihydrochloride, [0212]
2'-methyl-6'-(perfluoroethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyr-
rolo[1,2-a]pyrazine]dihydrochloride, [0213]
2'-methyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-
dihydrochloride,
3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]dihydrochl-
oride, [0214]
N,N-dimethyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-
-pyrrolo[1,2-a]pyrazine]-2'-carboxamide, [0215]
2'-(2,2,2-trifluoroethyl)-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[pi-
peridine-4,1'-pyrrolo[1,2-a]pyrazine]hydrochloride, [0216]
3-fluoro-2'-methyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidin-
e-4,1'-pyrrolo[1,2-a]pyrazine]dihydrochloride, [0217]
2,2'-dimethyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1-
'-pyrrolo[1,2-a]pyrazine]dihydrochloride, [0218] methyl
2'-methyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-py-
rrolo[1,2-a]pyrazine]-4'-carboxylate, [0219]
2'-(2,2-difluoroethyl)-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piper-
idine-4,1'-pyrrolo[1,2-a]pyrazine]hydrochloride, [0220]
2'-cyclobutyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1-
'-pyrrolo[1,2-a]pyrazine]dihydrochloride, [0221] ethyl
2-(6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1-
,2-a]pyrazine]-2'-yl)acetate, and [0222] methyl
6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2--
a]pyrazine]-2'-carboxylate.
2,2,2-Trifluoro-1-(2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-pi-
peridine]-6-yl)ethanone dihydrochloride
##STR00849##
[0224] Step 1:
[0225] (2,2,2-Trifluoroacetyl) 2,2,2-trifluoroacetate (910 .mu.L,
6.55 mmol) was added dropwise to a solution of tert-butyl
2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carbo-
xylate (1.0 g, 3.27 mmol), pyridine (1.06 mL, 13.10 mmol) and
CH.sub.2Cl.sub.2 (6.5 mL) at room temperature. The mixture was
heated at 35.degree. C. for 2 h. The reaction mixture was
partitioned between 1N HCl and CH.sub.2Cl.sub.2. The layers were
separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2
(2.times.). The combined organics were dried over sodium sulfate
and filtered. The filtrate was concentrated to give tert-butyl
2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-
-1,4'-piperidine]-1'-carboxylate (1.38 g, 94%) as a yellowish
solid. ESI-MS m/z calc. 401.2, found 402.5 (M+1)+; Retention time:
1.36 minutes. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.21 (dd,
J=4.4, 2.1 Hz, 1H), 6.14 (d, J=4.5 Hz, 1H), 4.34 (t, J=6.0 Hz, 2H),
3.93 (s, 2H), 3.33 (t, J=6.0 Hz, 2H), 3.19 (s, 2H), 2.39 (s, 3H),
2.13-2.05 (m, 2H), 1.79 (t, J=11.6 Hz, 2H), 1.48 (s, 9H).
[0226] Step 2:
[0227] Hydrogen chloride (6.01 mL of 4 M, 24.07 mmol) was added to
a solution of tert-butyl
2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-
-1,4'-piperidine]-1'-carboxylate (1.38 g, 3.44 mmol) in
CH.sub.2Cl.sub.2 (9.7 mL) at room temperature. The mixture was
stirred at room temperature for 1.5 h. The reaction mixture was
concentrated under reduced pressure to give
2,2,2-trifluoro-1-(2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazin-
e-1,4'-piperidine]-6-yl)ethanone dihydrochloride (1.34 g, 99%) as a
tan solid. ESI-MS m/z calc. 301.1, found 302.5 (M+1).sup.+;
Retention time: 1.02 minutes.
2,2-Dimethyl-1-(2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piper-
idine]-6-yl)propan-1-one dihydrochloric acid
##STR00850##
[0229] Step 1:
[0230] 2,2-Dimethylpropanoyl chloride (1.22 mL, 9.90 mmol) was
added to a mixture of tert-butyl
2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carbo-
xylate (2.75 g, 9.0 mmol), DBN (1.22 mL, 9.90 mmol) and
dichloroethane (6.9 mL) at room temperature. The mixture was
allowed to stir for 18 h at 115.degree. C. The mixture was cooled
to room temperature before it was partitioned between
CH.sub.2Cl.sub.2 and 1N HCl. The layers were separated and the
organic layer was washed with 1N NaOH. The organic layer was dried
over sodium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by column chromatography (0-100%
ethyl acetate/hexanes) to give tert-butyl
6-(2,2-dimethylpropanoyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-
e-1,4'-piperidine]-1'-carboxylate (1.8 g, 41%) as an off-white
solid. ESI-MS m/z calc. 389.3, found 390.5 (M+1)+; Retention time:
1.46 minutes.
[0231] Step 2:
[0232] Hydrogen chloride (5.1 mL of 4 M, 20.22 mmol) was added to a
solution of tert-butyl
6-(2,2-dimethylpropanoyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazin-
e-1,4'-piperidine]-1'-carboxylate (1.75 g, 4.49 mmol) in
CH.sub.2Cl.sub.2 (12.3 mL) at room temperature. The mixture was
stirred at room temperature for 1.5 h. The reaction mixture was
concentrated under reduced pressure to give
2,2-dimethyl-1-(2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-pipe-
ridine]-6-yl)propan-1-one dihydrochloride (1.8 g, 99%) as a tan
solid. ESI-MS m/z calc. 289.2, found 290.5 (M+1)+; Retention time:
0.97 minutes.
1-(2'-Methyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazin-
e]-6'-yl)ethanone dihydrochloride
##STR00851##
[0234] Step 1:
[0235] To tert-butyl
2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carbo-
xylate (10 g, 32.74 mmol) in methylene chloride (73.5 mL) at
0.degree. C. was added N-bromosuccinimide (5.53 g, 31.10 mmol)
portionwise. The reaction was stirred at 0.degree. C. After 30
minutes, additional N-bromosuccinimide (291.4 mg, 1.64 mmol) was
added and the reaction was stirred for 1 hour. The reaction was
diluted with 0.5 M Na.sub.2S.sub.2O.sub.3 (135 mL) and the aqueous
phase was removed. The organic layer was washed with brine (135
mL). The organic layer was dried over sodium sulfate, filtered and
the solvent was evaporated under reduced pressure to yield
tert-butyl
6-bromo-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-
-1'-carboxylate as a red viscous liquid that was used in the next
step without further purification. 1H NMR (400 MHz, DMSO) .delta.
6.09 (d, J=3.7 Hz, 1H), 5.99 (d, J=3.7 Hz, 1H), 3.78-3.65 (m, 4H),
3.27 (t, J=6.0 Hz, 2H), 3.17-2.92 (m, 2H), 2.21 (s, 3H), 2.03-1.93
(m, 2H), 1.65-1.53 (m, 2H), 1.40 (s, 9H). ESI-MS m/z calc. 383.1,
found 386.0 (M+1)+; Retention time: 1.13 minutes (3 minute
run).
[0236] Step 2:
[0237] A solution of tert-butyl
6-bromo-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-
-1'-carboxylate (2 g, 5.2 mmol) and
N-cyclohexyl-N-methyl-cyclohexanamine (1.67 mL, 7.81 mmol) in
1,4-dioxane (8.0 mL) was purged with N.sub.2 for 5 minutes.
1-Vinyloxybutane (7.04 mL, 52.04 mmol), Pd(dba).sub.3 (1.078 g,
1.04 mmol) and tri tert-butylphosphane (642.0 .mu.L, 2.60 mmol)
were added and the reaction was heated at 80.degree. C. for 5 hours
in a pressure vessel. The reaction was filtered through a plug of
celite using ethyl acetate. The solvent was evaporated under
reduced pressure. The crude product was purified by silica gel
chromatography utilizing a gradient of 1-100% ethyl acetate in
hexane to yield tert-butyl
6-acetyl-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine-
]-1'-carboxylate (672.1 mg, 1.93 mmol, 37%) as a yellow solid.
.sup.1H NMR (400 MHz, DMSO) .delta. 7.04 (d, J=4.1 Hz, 1H), 6.12
(d, J=4.2 Hz, 1H), 4.17 (t, J=6.0 Hz, 2H), 3.83-3.68 (m, 2H), 3.21
(t, J=6.0 Hz, 2H), 3.17-2.91 (m, 2H), 2.31 (s, 3H), 2.24 (s, 3H),
2.07-1.97 (m, 2H), 1.72-1.59 (m, 2H), 1.41 (s, 9H). ESI-MS m/z
calc. 347.2, found 348.5 (M+1)+; Retention time: 0.95 minutes (3
minute run).
[0238] Step 3:
[0239] To tert-butyl
6-acetyl-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine-
]-1'-carboxylate (300 mg, 0.86 mmol) and methylene chloride (1.7
mL) was added hydrogen chloride in dioxane (1.60 mL of 4 M, 6.40
mmol) The reaction was stirred at room temperature for 0.5 hours.
The solvent was evaporated under reduced pressure to yield
1-(2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl)-
ethanone dihydrochloride as a light green solid in quantitative
yield. ESI-MS m/z calc. 247.2, found 248.2 (M+1)+; Retention time:
0.17 minutes (3 minute run).
[0240] The following compounds were synthesized using the
procedures described above: [0241]
1-(2'-methyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazi-
ne]-6'-yl)propan-1-one dihydrochloride, [0242]
2-methyl-1-(2'-methyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-
-a]pyrazine]-6'-yl)propan-1-one dihydrochloride, [0243]
cyclopropyl(2'-methyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-
-a]pyrazine]-6'-yl)methanone dihydrochloride, [0244]
(2'-methyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine-
]-6'-yl)(phenyl)methanone dihydrochloride, [0245]
1-(3',3'-dimethyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]p-
yrazine]-6'-yl)-2,2,2-trifluoroethanone dihydrochloride, [0246]
1-(3',3'-dimethyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]p-
yrazine]-6'-yl)ethanone dihydrochloride, [0247]
1-(3',3'-dimethyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]p-
yrazine]-7'-yl)ethanone dihydrochloride, [0248]
2,2,2-trifluoro-1-(2',4',4'-trimethyl-3',4'-dihydro-2'H-spiro[piperidine--
4,1'-pyrrolo[1,2-a]pyrazine]-6'-yl)ethanone dihydrochloride, [0249]
2,2,2-trifluoro-1-(2',4',4'-trimethyl-3',4'-dihydro-2'H-spiro[piperidine--
4,1'-pyrrolo[1,2-a]pyrazine]-7'-yl)ethanone dihydrochloride, [0250]
1-(2',4',4'-trimethyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-
-a]pyrazine]-6'-yl)ethanone dihydrochloride, [0251]
1-(2',3'-dimethyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]p-
yrazine]-6'-yl)-2,2,2-trifluoroethanone dihydrochloride, [0252]
2,2,2-trifluoro-1-(3'-methyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrr-
olo[1,2-a]pyrazine]-6'-yl)ethanone dihydrochloride, [0253]
2,2,2-trifluoro-1-(4'-methyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrr-
olo[1,2-a]pyrazine]-6'-yl)ethanone dihydrochloride, [0254]
1-(2',4'-dimethyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]p-
yrazine]-6'-yl)-2,2,2-trifluoroethanone dihydrochloride, and [0255]
(2'-methyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine-
]-6'-yl)(1-methylcyclopropyl)methanone.
2'-Methyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyr-
rolo[1,2-a]pyrazine]-8'-carbonitrile dihydrochloride
##STR00852##
[0257] Step 1:
[0258] To a solution of tert-butyl
2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'--
piperidine]-1'-carboxylate (1.86 g, 5.0 mmol) in acetonitrile (50
mL) was added N-bromosuccinimide (930.4 mg, 5.25 mmol). The mixture
was stirred at room temperature overnight. The solvent was
evaporated under reduced pressure. The residue was partitioned
between ethyl acetate and water. The layers were separated and the
aqueous layer was extracted with ethyl acetate (2.times.). The
combined organic layers were washed with brine, dried over
MgSO.sub.4 and concentrated to dryness. The crude material was
purified by column chromatography (10-20% Ethyl acetate-Hexanes) to
provide a the product as light yellow solid (1.7 g, 75%). ESI-MS
m/z calc. 451.1, found 452.1 (M+1)+; Retention time: 1.59 minutes
(3 minute run).
[0259] Step 2:
[0260] A mixture of tert-butyl
8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazi-
ne-1,4'-piperidine]-1'-carboxylate (1.67 g, 3.7 mmol) and
dicyanozinc (234.9 .mu.L, 3.7 mmol) in DMF (10 mL) was purged with
N.sub.2 for 5 min. Pd(PPh.sub.3).sub.4 (427.6 mg, 0.37 mmol) was
added. The mixture was heated in a sealed microwave vial at
150.degree. C. overnight. The mixture was partitioned between ethyl
acetate and water. The layers were separated. The aqueous layer was
extracted with ethyl acetate (3.times.). All organic layers were
combined, washed with water (3.times.), brine, dried over
MgSO.sub.4, filtered and concentrated to dryness. The crude
material was purified by column chromatography (10-20%
EtOAc/hexanes) to provide tert-butyl
8-cyano-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazi-
ne-1,4'-piperidine]-1'-carboxylate (510 mg, 35%) as a white solid.
ESI-MS m/z calc. 398.2, found 399.3 (M+1)+; Retention time: 1.56
minutes (3 minute run).
[0261] Step 3:
[0262] To a solution of tert-butyl
8-cyano-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazi-
ne-1,4'-piperidine]-1'-carboxylate (278.9 mg, 0.7 mmol) in DCM (4
mL) was added HCl in dioxane (2 mL of 4 M, 8.0 mmol). The mixture
was stirred at room temperature for 30 min. The solvent was
evaporated and the crude material was used directly in next step
without further purification. ESI-MS m/z calc. 298.1, found 299.5
(M+1)+; Retention time: 0.88 minutes (3 minute run).
6'-Chloro-2'-methyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]-
pyrazine]dihydrochloride
##STR00853##
[0264] Step 1:
[0265] To tert-butyl
2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carbo-
xylate (5 g, 16.37 mmol) in dichloromethane (50.00 mL) at 0.degree.
C. was added trifluoromethanesulfonyl chloride (3.64 mL, 34.38
mmol) and the reaction was stirred from 0.degree. C. to room
temperature overnight. The reaction was diluted with
dichloromethane and washed with water. The layers were separated
and the organics were dried over sodium sulfate, filtered and
concentrated. Purification of the residue by silica gel
chromatography eluting with 10-100% ethylacetate in hexanes
afforded tert-butyl
6-chloro-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine-
]-1'-carboxylate (4.3 g, 77%), as a yellow solid. ESI-MS m/z calc.
339.2, found 340.3 (M+1)+; Retention time: 1.13 minutes (3 min
run). .sup.1H NMR (400 MHz, CDCl3) .delta. 6.01 (d, J=3.8 Hz, 1H),
5.91 (d, J=3.7 Hz, 1H), 3.77 (t, J=6.1 Hz, 2H), 3.34 (s, 2H), 3.24
(s, 2H), 2.34 (s, 3H), 2.03 (d, J=13.1 Hz, 2H), 1.74 (t, J=11.1 Hz,
2H), 1.47 (s, 9H).
[0266] Step 2:
[0267] HCl (1.84 mL of 4 M in dioxanes, 7.34 mmol) was added to a
solution of tert-butyl
6-chloro-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine-
]-1'-carboxylate (624 mg, 1.84 mmol) in dichloromethane (2 mL) and
was stirred at 40.degree. C. for 1 hour. The reaction was
evaporated to dryness to yield
6'-chloro-2'-methyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a-
]pyrazine]dihydrochloride (quantitative) that was used without
further purification. ESI-MS m/z calc. 239.1, found 240.3 (M+1)+;
Retention time: 0.22 minutes (3 min run).
Ethyl
6'-cyano-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyraz-
ine]-2'-carboxylate hydrochloride
##STR00854##
[0269] Step 1:
[0270] Ethyl chloroformate (328.2 .mu.L, 3.43 mmol) was added to a
solution of tert-butyl
spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carboxyla-
te (500 mg, 1.72 mmol) and K.sub.2CO.sub.3 (474.3 mg, 3.43 mmol) in
acetonitrile (5.0 mL) and the reaction was stirred at room
temperature overnight. The reaction was filtered using acetonitrile
and the solvent was evaporated under reduced pressure. The compound
was dissolved in ethyl acetate and washed with 1N hydrochloric acid
and brine. The organic layer was dried over sodium sulfate,
filtered, and concentrated under reduced pressure to yield
1-tert-butyl 2'-ethyl
3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-1,2'-dica-
rboxylate (395 mg, 63%) as an amber oil that was used in the next
step without further purification. ESI-MS m/z calc. 363.2, found
364.3 (M+1)+; Retention time: 1.78 minutes (3 minute run).
[0271] Step 2:
[0272] A solution of N-(oxomethylene)sulfamoyl chloride (23.9
.mu.L, 0.27 mmol) in THF (200.0 .mu.L) was slowly added to a
solution of 1-tert-butyl 2'-ethyl
3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]--
1,2'-dicarboxylate (100 mg, 0.27 mmol) in THF (1.0 mL) at
-78.degree. C. under nitrogen. The reaction mixture was stirred for
1 hour at -78.degree. C. N,N-dimethylformamide (39.9 .mu.L, 0.51
mmol) was then slowly added to the cold reaction mixture. The
reaction mixture was then allowed to slowly warm to room
temperature. The reaction was filtered and purified by reverse
phase preparatory-LC-MS (10-99% CH.sub.3CN/H.sub.2O) using HCl
modifier to give 1-tert-butyl 2'-ethyl
6'-cyano-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]--
1,2'-dicarboxylate. ESI-MS m/z calc. 388.2, found 389.3 (M+1)+;
Retention time: 1.82 minutes (3 minute run).
[0273] Step 3:
[0274] 4 N HCl in dioxane (8.7 mL, 34.7 mmol) was added to a
solution of 1-tert-butyl 2'-ethyl
6'-cyano-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]--
1,2'-dicarboxylate (0.27 mmol) in dichloromethane (5 mL) and the
mixture was stirred at 40.degree. C. for 1 hour. The reaction
mixture was evaporated to dryness to give ethyl
6'-cyano-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]--
2'-carboxylate hydrochloride. ESI-MS m/z calc. 288.2, found 289.3
(M+1)+; Retention time: 0.75 minutes (3 minute run).
8'-Fluoro-2'-methyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidin-
e-4,1'-pyrrolo[1,2-a]pyrazine]dihydrochloride
##STR00855##
[0276] Step 1:
[0277] To a solution of tert-butyl
2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'--
piperidine]-1'-carboxylate (5.60 g, 15.0 mmol) in acetonitrile (50
mL) was added NBS (2.80 g, 15.8 mmol). The mixture was stirred at
room temperature overnight. The solvent was removed and the residue
was partitioned between EtOAc and water. The aqueous layer was
extracted with EtOAc (2.times.). The combined organic layers were
washed with brine, dried over MgSO.sub.4 and concentrated to
dryness. The crude material was purified by column chromatography
(10-20% EtOAc-Hex) to provide tert-butyl
8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazi-
ne-1,4'-piperidine]-1'-carboxylate (5.40 g, 73%) as a light yellow
solid. ESI-MS m/z calc. 452.3 found 454.5 (M+1)+; Retention time:
1.60 minutes (3 minute run).
[0278] Step 2:
[0279] A solution of tert-butyl
8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazi-
ne-1,4'-piperidine]-1'-carboxylate (15.0 g, 33.2 mmol) in THF (200
mL) was purged with Argon for 5 min. The mixture was cooled to
-78.degree. C. before nBuLi (42.5 mL of 1.6 M, 68 mmol) was added
dropwise. The mixture was stirred at -78.degree. C. for 30 min
before a solution of
N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (20.9 g, 66.3 mmol)
in THF (100 mL) was added dropwise. The mixture was allowed to warm
to room temperature overnight. The reaction mixture was quenched
with sat. aq. NH.sub.4Cl. The layers were separated and the aqueous
layer was extracted with EtOAc (2.times.). The organic layers were
combined and washed with brine, dried over MgSO.sub.4, filtered and
concentrated to dryness. CH.sub.2Cl.sub.2 was added and the solid
was removed via filtration. The filtrate was concentrated to
dryness and the residue was purified by column chromatography
(10-20% EtOAc-Hex) to provide tert-butyl
8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrol[1,2-a]pyrazi-
ne-1,4'-piperidine]-1'-carboxylatete (5.52 g, 43%) as a light brown
oil that solidified upon standing. ESI-MS m/z calc. 391.4, found
392.5 (M+1)+; Retention time: 1.35 minutes (3 minute run).
[0280] Step 3:
[0281] To tert-butyl
8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyraz-
ine-1,4'-piperidine]-1'-carboxylate (310 mg, 0.80 mmol) in
CH.sub.2Cl.sub.2 (2 mL) was added a solution of HCl (2.0 mL of 4 M,
8.0 mmol) in 1,4-dioxane. The reaction mixture was allowed to stir
at room temperature for 1 hour. The volatiles were removed under
reduced pressure providing
8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1-
,2-a]pyrazine-1,4'-piperidine]dihydrochloride (290 mg, 99%) as a
pink solid. ESI-MS m/z calc. 291.1, found 292.3 (M+1)+; Retention
time: 0.75 minutes (3 minute run).
8'-Chloro-2'-methyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidin-
e-4,1'-pyrrolo[1,2-a]pyrazine]dihydrochloride
##STR00856##
[0283] Step 1:
[0284] To a solution of tert-butyl
8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazi-
ne-1,4'-piperidine]-1'-carboxylate (5.00 g, 11.1 mmol) in anhydrous
THF (125 mL) at -78.degree. C. was added nBuLi (8.84 mL of 2.5 M,
22.1 mmol) slowly. The reaction mixture was allowed to stir at -78
for 20 minutes before 1,1,1,2,2,2-hexachloroethane (5.36 g, 22.7
mmol) was added dropwise as a solution in THF (12 mL). The reaction
mixture was allowed to slowly warm to room temperature and was
stirred overnight. The reaction mixture was quenched with the
addition of saturated aqueous ammonium chloride (100 mL). The
volatiles were removed under reduced pressure to half volume. The
remaining aqueous suspension was extracted with EtOAc (2.times.100
mL). The combined organic layers were dried over sodium sulfate,
filtered and concentrated under reduced pressure to afford a thick
brown oil. The crude product was purified by silica gel column
chromatography: 10-20% EtOAc/hexane gradient to provide tert-butyl
8-chloro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyraz-
ine-1,4'-piperidine]-1'-carboxylate (2.40 g, 53%) as a yellow oil
that crystallized upon standing. ESI-MS m/z calc. 407.2, found
407.9 (M+1)+; Retention time: 1.70 minutes (3 min run). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 6.47 (s, 1H), 3.97 (t, J=5.5 Hz, 4H),
3.28 (s, 2H), 3.13 (s, 2H), 2.51-2.28 (m, 5H), 1.93 (d, J=13.7 Hz,
2H), 1.47 (d, J=9.5 Hz, 9H).
[0285] Step 2:
[0286] To a solution of tert-butyl
8-chloro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyraz-
ine-1,4'-piperidine]-1'-carboxylate (750 mg, 1.84 mmol) in
CH.sub.2Cl.sub.2 (2 mL) was added a prepared solution of 1:1
trifluoroacetic acid (2.0 mL, 26 mmol) in CH.sub.2Cl.sub.2 (2 mL).
After stirring at room temperature for 2 hours, saturated aqueous
sodium bicarbonate solution (75 mL) was slowly added. The mixture
was extracted with EtOAc (2.times.75 mL). The organic layers were
combined, dried over sodium sulfate, filtered and concentrated
under reduced pressure to provide
8-chloro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-
-a]pyrazine-1,4'-piperidine](555 mg, 98%) as a yellow-brown solid.
ESI-MS m/z calc. 307.1, found 307.9 (M+1)+; Retention time: 1.12
minutes (3 min run). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.72
(s, 1H), 9.38 (s, 1H), 6.49 (s, 1H), 3.98 (t, J=5.6 Hz, 2H), 3.36
(d, J=11.6 Hz, 2H), 3.26 (d, J=6.1 Hz, 4H), 2.78 (s, 2H), 2.40 (s,
3H), 2.11 (d, J=14.4 Hz, 2H), 1.69 (s, 2H).
2'-Methyl-6',7'-bis(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,-
1'-pyrrolo[1,2-a]pyrazine]
##STR00857##
[0288] Step 1:
[0289] Ferrous sulfate heptahydrate (803 .mu.L of 1.00 M, 0.803
mmol) was added to a mixture of tert-butyl
2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'--
piperidine]-1'-carboxylate (1.00 g, 2.68 mmol) and DMSO (15 mL) at
room temperature. The vessel was then charged with CF.sub.3I (gas)
before H.sub.2O.sub.2 (304 .mu.L of 30% w/v, 2.68 mmol) was added
dropwise. The mixture was allowed to stir overnight at room
temperature before it was partitioned between ethyl acetate and
water. The layers were separated and the aqueous layer was
extracted with ethyl acetate (3.times.). The combined organics were
washed with brine, dried over sodium sulfate, filtered and
concentrated. The reside was purified by column chromatography
(0-100% ethyl acetate/hexanes) to give tert-butyl
2-methyl-6,7-bis(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine--
1,4'-piperidine]-1'-carboxylate. ESI-MS m/z calc. 441.2, found
442.5 (M+1)+; Retention time: 1.36 minutes (3 min run).
[0290] Step 2:
[0291] tert-Butyl
2-methyl-6,7-bis(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine--
1,4'-piperidine]-1'-carboxylate (from step 1) was taken up in
CH.sub.2Cl.sub.2 (2 mL) and HCl (1.7 mL of 4 M, 6.8 mmol) was
added. The mixture was allowed to stir for 30 min before it was
concentrated under reduced pressure. The residue was taken up in
ethyl acetate and was washed with sat. aq. NaHCO.sub.3, then brine.
The organic layer was dried over sodium sulfate, filtered and
concentrated to give
2-methyl-6,7-bis(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine--
1,4'-piperidine] (22 mg, 2% over 2 steps). ESI-MS m/z calc. 341.1,
found 342.3 (M+1)+; Retention time: 1.29 minutes.
2'-Methyl-6'-(methylsulfonyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrr-
olo[1,2-a]pyrazine]
##STR00858##
[0293] Step 1:
[0294] To benzyl
2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carbo-
xylate (3.00 g, 8.84 mmol) in CH.sub.2Cl.sub.2 (30 mL) at 0.degree.
C. was added NBS (1.57 g, 8.84 mmol) portionwise. The reaction
mixture was stirred at 0.degree. C. for 2 h. Additional NBS (157
mg) was added and the reaction mixture was stirred at 0.degree. C.
for 15 minutes (repeated 6 additional times until starting material
was consumed). The reaction mixture was diluted with 0.5 M
Na.sub.2S.sub.2O.sub.3 (30 mL) and the aqueous phase was removed.
The organic phase was washed with brine (30 mL). The organic layer
was dried over sodium sulfate, filtered and the solvent was
evaporated under reduced pressure. The crude product was purified
by column chromatography utilizing a gradient of 0-30% ethyl
acetate in CH.sub.2Cl.sub.2 to yield benzyl
6-bromo-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-
-1'-carboxylate (2.34 g, 63%) as a cream solid. ESI-MS m/z calc.
417.1, found 418.1 (M+1)+; Retention time: 1.49 minutes (3 min
run). .sup.1H NMR (400 MHz, DMSO) .delta. 7.43-7.26 (m, 5H), 6.09
(d, J=3.7 Hz, 1H), 5.99 (d, J=3.7 Hz, 1H), 5.08 (s, 2H), 3.89-3.74
(m, 2H), 3.68 (t, J=5.8 Hz, 2H), 3.27 (t, J=5.8 Hz, 2H), 3.22-2.99
(m, 2H), 2.21 (s, 3H), 2.09-1.94 (m, 2H), 1.73-1.52 (m, 2H).
[0295] Step 2:
[0296] A mixture of sodium methanesulfinate (293 mg, 2.87 mmol),
benzyl
6-bromo-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-
-1'-carboxylate (1.00 g, 2.39 mmol), CuI (296 mg, 1.55 mmol) and
DMSO (5 mL) was heated at 90.degree. C. in a pressure vessel for 20
hours. The mixture was cooled and was partitioned between ether (10
mL) and water (10 mL). The organic layer was separated and the
aqueous layer was extracted with ether (3.times.5 mL). The combined
organic layers were washed with brine (2.times.10 mL), dried over
sodium sulfate, filtered and concentrated in vacuo. The crude
product was purified by column chromatography utilizing a gradient
of 0-50% ethyl acetate in CH.sub.2Cl.sub.2 to yield benzyl
2-methyl-6-methyl
sulfonyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carb-
oxylate (520 mg, 52%) as a white solid. ESI-MS m/z calc. 417.2,
found 418.3 (M+1)+; Retention time: 1.27 minutes (3 min run).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.45-7.30 (m, 5H), 6.88
(d, J=4.1 Hz, 1H), 6.01 (d, J=3.9 Hz, 1H), 5.15 (s, 2H), 4.28-4.15
(m, 2H), 4.09-3.89 (m, 2H), 3.40-3.16 (m, 4H), 3.10 (s, 3H), 2.37
(s, 3H), 2.20-2.02 (m, 2H), 1.89-1.66 (m, 2H).
[0297] Step 3:
[0298] To a solution of benzyl
2-methyl-6-methylsulfonyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-pi-
peridine]-1'-carboxylate (520 mg, 1.25 mmol) in EtOH (13 mL) was
added 10% palladium-carbon (66 mg, 0.062 mmol) under nitrogen
atmosphere. The reaction mixture was stirred at room temperature
for 16 h under a hydrogen atmosphere. The mixture was filtered
through a plug of celite and the solvent was evaporated under
reduced pressure to yield
2-methyl-6-methylsulfonyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-pi-
peridine] (342 mg, 97%) as an off-white solid. ESI-MS m/z calc.
283.1, found 284.3 (M+1)+; Retention time: 0.30 minutes (3 min
run).
3-Methyl-4-(methylsulfamoyl)benzoic acid
##STR00859##
[0300] Step 1:
[0301] A solution of 4-amino-3-methyl-benzoic acid (4.00 g, 26.5
mmol) in conc. HCl (15 mL) was cooled to 0.degree. C. in an ice
bath before a solution of sodium nitrite (1.97 g, 910 .mu.L, 28.6
mmol) in water (5 mL) was added dropwise while keeping the
temperature below 5.degree. C. SO.sub.2 was bubbled through a
solution of acetic acid (60 mL) and CuCl.sub.2 (889 mg, 6.62 mmol)
for 20 min before the cold diazonium solution was added. The
reaction mixture was stirred for 1 h before it was poured onto ice.
The solid was collected by filtration and was washed with water.
The solid was further dried to give
4-chlorosulfonyl-3-methyl-benzoic acid (2.30 g, 37%). .sup.1H NMR
(400 MHz, DMSO) .delta. 7.81 (d, J=7.8 Hz, 1H), 7.74-7.66 (m, 2H),
2.57 (s, 3H).
[0302] Step 2:
[0303] 4-Chlorosulfonyl-3-methyl-benzoic acid (0.99 g, 4.2 mmol),
methanamine (2.0 mL of 33% w/v, 21 mmol), and triethylamine (1.8
mL, 13 mmol) were stirred for 45 min at rt. The reaction mixture
was evaporated and the resultant oil was partitioned between ethyl
acetate and 1N HCl. The organics were separated and washed with
another portion of 1N HCl and then brine. The organics were dried
over sodium sulfate and evaporated to give
3-methyl-4-(methylsulfamoyl)benzoic acid (841 mg, 87%). ESI-MS m/z
calc. 229.0, found 230.5 (M+1)+; Retention time: 0.64 minutes (3
min run).
[0304] The following compounds were synthesized using the
procedures described above:
[0305] 4-(N-ethylsulfamoyl)-3-methylbenzoic acid,
4-(N-cyclopropylsulfamoyl)-3-methylbenzoic acid,
4-(N-isopropylsulfamoyl)-3-methylbenzoic acid, and
4-(N,N-dimethylsulfamoyl)-3-methylbenzoic acid.
7-(Ethyl(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid
##STR00860##
[0307] Step 1:
[0308] To a stirred suspension ethyl
7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (0.95 g, 4.6 mmol)
in POCl.sub.3 (8.0 mL, 86 mmol) was added dimethyl aniline (0.8
.mu.L, 0.006 mmol) and the mixture was heated at 80.degree. C. for
2 hours. The mixture was slowly poured onto ice, and the pH was
carefully adjusted to .about.7 with 1N NaOH, then to pH 10 with
solid Na.sub.2CO.sub.3. The mixture was then extracted with
dichloromethane (3.times.). The organics were combined, washed with
brine, dried (MgSO.sub.4) and evaporated to dryness. Trituration of
the solids with hexanes gave ethyl
7-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (260 mg, 25%) as a
tan solid. ESI-MS m/z calc. 225.0, found 226.5 (M+1)+; Retention
time: 0.87 minutes (3 min run).
[0309] Step 2:
[0310] To a solution of ethyl
7-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (68 mg, 0.30 mmol)
in CH.sub.3CN (1 mL) was added N-methylethanamine (18 mg, 0.30
mmol) and the mixture was stirred at ambient temperature for 16 h.
The mixture was evaporated and the residue was purified by column
chromatography (0-10% MeOH in dichloromethane) to give a solid. The
solid was taken up in EtOH (0.5 mL) and water (0.1 mL) before NaOH
(12 mg, 0.30 mmol) was added. The mixture was stirred at 50.degree.
C. for 4 h. The pH of the mixture was adjusted to 4 with conc. HCl,
and the solvents were removed. The residue was co-evaporated with
MeOH (3.times.) to provide
7-(ethyl(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
ESI-MS m/z calc. 220.1, found 221.5 (M+1)+; Retention time: 0.29
minutes (3 min run).
[0311] The following compounds were synthesized using the
procedures described above:
[0312] 7-(ethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid,
7-(isopropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid,
7-(ethyl(methyl)amino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic
acid,
5-methyl-7-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid, and
7-(ethylamino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic
acid.
4-(1-Hydroxy-1-methyl-ethyl)-3-methyl-benzoic acid
##STR00861##
[0314] 4-Bromo-3-methyl-benzoic acid (3.96 g, 18.4 mmol) was
dissolved in tetrahydrofuran (100 mL) and the solution was cooled
to -78.degree. C. n-Butyllithium in hexanes (16.2 mL of 2.5 M, 41
mmol) was added dropwise over 20 minutes. The reaction mixture was
allowed to stir for 30 minutes at -78.degree. C. and then acetone
(1.35 mL, 18.4 mmol) was added in a drop-wise manner. The reaction
mixture was allowed to stir for 30 minutes at -78.degree. C., and
then it was allowed to warm to room temperature. The reaction
mixture was then diluted with 100 mL of 1M aqueous sodium
hydroxide. The organic layer was discarded and then the aqueous
layer was made acidic with 4M aqueous hydrochloric acid. The
aqueous layer was then extracted 3 times with ethyl acetate. The
combined extracts were dried over sodium sulfate and then
evaporated to dryness. The crude material was further purified on
silica gel utilizing a gradient of 0-10% methanol in
dichloromethane to give
4-(1-hydroxy-1-methyl-ethyl)-3-methyl-benzoic acid (1.51 g, 42%).
.sup.1H NMR (400 MHz, DMSO) .delta. 12.74 (s, 1H), 7.68 (dd, J=3.9,
2.5 Hz, 2H), 7.55 (d, J=8.7 Hz, 1H), 5.06 (s, 1H), 2.56 (s, 3H),
1.51 (s, 6H).
[0315] The following compounds were synthesized using the
procedures described above:
[0316] 4-(1-hydroxycyclopentyl)-3-methylbenzoic acid,
4-(1-hydroxycyclopentyl)benzoic acid,
4-(1-hydroxycyclohexyl)-3-methylbenzoic acid,
4-(1-hydroxycyclohexyl)benzoic acid,
3-fluoro-4-(1-hydroxycyclohexyl)benzoic acid, and
4-(1-hydroxycyclohexyl)-3-methoxybenzoic acid.
5-Isopropoxy-6-methylpicolinic acid
##STR00862##
[0318] Step 1:
[0319] 2-Methyl-3-pyridinol (8.3 g, 76.1 mmol) was suspended in
acetonitrile (125 mL). A solution of NBS (27.7 g, 155.6 mmol, 2.05
equiv) in acetonitrile (275 mL) was added to the suspension
drop-wise over 1 hour. The mixture was heated at reflux for 1.5 h.
The mixture was concentrated and the residue was purified by column
chromatography (DCM) to give 4,6-dibromo-2-methylpyridin-3-ol (15.8
g, 78%) as a yellow solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 2.41
(s, 3H), 7.70 (s, 1H), 9.98 (s, 1H).
[0320] Step 2:
[0321] 4,6-Dibromo-2-methylpyridin-3-ol (15.8 g, 59.4 mmol) was
dissolved in THF (200 mL). The solution was cooled to -78.degree.
C. and n-BuLi (50 mL, 125 mmol, 2.5 M in hexane) was added
drop-wise keeping the temperature below -78.degree. C. The mixture
was allowed to stir at that temperature for 2 h. The mixture was
quenched with water (50 mL) and was neutralized with 2 N HCl. The
aqueous mixture was extracted with dichloromethane (2.times.). The
combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated to give 6-bromo-2-methylpyridin-3-ol (10.5 g, 95%) as
a yellow oil. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 2.29 (s, 3H),
7.08 (d, 1H), 7.26 (d, 1H), 10.08 (s, 1H).
[0322] Step 3:
[0323] 6-Bromo-2-methylpyridin-3-ol (10.5 g, 55.9 mmol) was
dissolved in DMF (100 mL). K.sub.2CO.sub.3 (19.3 g, 139.6 mmol) and
2-bromopropane (13.1 ml, 139.6 mmol) were added to the solution and
the mixture was heated at 100.degree. C. overnight. The mixture was
poured into a mixture of water and EtOAc (200 mL). The layers were
separated and the aqueous layer was extracted with EtOAc
(2.times.). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated. The crude oil was purified by
column chromatography (0-20% ethyl acetate/heptanes) to give
6-bromo-3-isopropoxy-2-methylpyridine (10.9 g, 85) as a yellow oil.
.sup.1H-NMR (300 MHz, CDCl.sub.3) 1.42 (d, 6H), 2.48 (s, 3H), 4.65
(m, 1H), 7.20 (d, 1H), 8.04 (d, 1H).
[0324] Step 4:
[0325] 6-Bromo-3-isopropoxy-2-methylpyridine (2.00 g, 8.70 mmol),
PdCl.sub.2(PPh.sub.3).sub.2 (0.18 g, 0.26 mmol) and Et.sub.3N (1.8
ml, 13.04 mmol) were added to MeOH (5.2 mL) and acetonitrile (20
mL) in a Berghoff reactor. The reactor was charged with 10 bar CO
(g) and was heated at 60.degree. C. overnight. The mixture was
concentrated and the residue was partitioned between DCM and water.
The layers were separated and the organic layer was washed with
brine and dried (Na.sub.2SO.sub.4). The mixture was concentrated
and purified by column chromatography to give methyl
5-isopropoxy-6-methylpicolinate (1.3 g, 71%) as a yellow oil.
.sup.1H-NMR (300 MHz, CDCl.sub.3) 1.40 (d, 6H), 2.53 (s, 3H), 3.98
(s, 3H), 4.62 (m, 1H), 7.12 (d, 1H), 7.98 (d, 1H).
[0326] Step 5:
[0327] 5-Isopropoxy-6-methylpicolinate (1.3 g, 6.22 mmol) was
dissolved in THF/water 2:1 (9 mL). LiOH*H.sub.2O (0.26 g, 6.22
mmol) was added and the mixture was stirred at room temperature
overnight. The mixture was poured into a mixture of water and EtOAc
and the layers were separated. The aqueous layer was acidified to
pH 4 with 2 N HCl and was extracted with EtOAc (2.times.). The
combined organics were dried (Na.sub.2SO.sub.4) and concentrated to
give 5-isopropoxy-6-methylpicolinic acid (860 mg, 74%) as a beige
solid. .sup.1H-NMR (300 MHz, DMSO-d.sub.6) 1.31 (d, 6H), 4.73 (m,
1H), 7.44 (d, 1H), 7.86 (d, 1H). 1H NMR (400 MHz, DMSO) .delta.
12.61 (s, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.44 (d, J=8.7 Hz, 1H), 4.74
(dt, J=12.0, 6.0 Hz, 1H), 2.37 (s, 3H), 1.32 (d, J=6.0 Hz, 6H).
[0328] The following compound was synthesized using the procedures
described above:
[0329] 5-methoxy-6-methylpicolinic acid.
4-Isopropoxy-3-methoxybenzoic acid
##STR00863##
[0331] Step 1:
[0332] Under a balloon of N.sub.2, tert-butyllithium (2.14 mL of
1.6 M, 3.43 mmol) was added drop-wise to a solution of
4-bromo-1-isopropoxy-2-methoxy-benzene (400 mg, 1.63 mmol) in THF
(6.0 mL) at -78.degree. C. The mixture was allowed to stir for 1 h
at -78.degree. C. before it was added drop-wise to a flask
containing CO.sub.2 (1.80 g, 40.8 mmol)(solid, dry ice) in THF (2.0
mL). The mixture was allowed to stir for 30 min as it warmed to
room temperature (caution: CO.sub.2 gas evolution). Water (20 mL)
was added and the volatiles were removed under reduced pressure.
The resultant aqueous layer was acidified with 1N HCl to pH
.about.1-2 and the mixture was extracted with ethyl acetate
(3.times.15 mL). The combined organics were washed with brine,
dried over sodium sulfate, filtered and concentrated to give
4-isopropoxy-3-methoxy-benzoic acid (>94% pure, 310 mg, 85%) as
a white solid. ESI-MS m/z calc. 210.1, found 210.9 (M+1).sup.+;
Retention time: 1.23 min. .sup.1H NMR (400 MHz, DMSO) .delta. 12.63
(s, 1H), 7.53 (dd, J=8.4, 2.0 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.04
(d, J=8.7 Hz, 1H), 4.67 (dt, J=12.1, 6.0 Hz, 1H), 3.78 (s, 3H),
1.28 (d, J=6.0 Hz, 6H).
3-Methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoic acid
##STR00864##
[0334] Step 1:
[0335] To sodium hydride (200 mg, 5.0 mmol) in DMF (6 mL) under
N.sub.2 was added methyl 4-hydroxy-3-methoxy-benzoate (920 mg, 5.0
mmol) and the mixture was stirred for 10 min.
2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (1.2 g, 4.6
mmol) was then added dropwise and the solution was stirred at room
temperature for 2 h, then at 50.degree. C. for 2 h. The mixture was
concentrated to a solid, and the residue was taken up in 50 mL of
CH.sub.2Cl.sub.2 before it was washed with brine (20 mL), dried
over MgSO.sub.4 and purified by column chromatography (0-25%
EtOAc/hexane) to give methyl
3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoate as a white solid.
ESI-MS m/z calc. 294.1, found 295.3 (M+1).sup.+; Retention time:
1.63 minutes (3 min run).
[0336] Step 2:
[0337] Methyl 3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoate
(obtained in Step 1) was dissolved in THF (5 mL) and a suspension
of LiOH (550 mg, 23 mmol) in water (5 mL) was added. The mixture
was stirred vigorously and heated at 60.degree. C. for 6 h before
it was concentrated to half volume. Water (5 mL) was added and the
mixture was extracted with diethyl ether (1.times.10 mL). The
aqueous layer was acidified with 4N HCl to pH 2. The resulting
mixture was extracted with ethyl acetate (3.times.10 mL) and the
combined organics were washed (1.times.10 mL H.sub.2O, 1.times.10
mL brine), dried over MgSO.sub.4 and evaporated to give
3-methoxy-4-(2-(trifluoromethoxy)ethoxy)benzoic acid (1.0 g, 82%)
as a white solid. ESI-MS m/z calc. 280.1, found 281.3 (M+1).sup.+;
Retention time: 1.34 minutes (3 min run).
4-tert-Butoxy-3-methoxybenzoic acid
##STR00865##
[0339] Step 1:
[0340] 4-Hydroxy-3-methoxy-benzaldehyde (500 mg, 3.29 mmol),
Boc.sub.2O (1.74 g, 7.97 mmol), and Sc(OTf).sub.3 (0.080 g, 0.16
mmol) were combined in dichloromethane (5 mL). The reaction mixture
was allowed to stir at room temperature for 24 h. Water (5 mL) and
dichloromethane (5 mL) were added and the two phases were
separated. The aqueous layer was extracted with dichloromethane
(3.times.5 mL) and the combined organics were stirred with 10%
aqueous potassium hydroxide until all remaining starting material
was not observed in the organic phase (TLC, 40% ethyl acetate in
hexanes). The two phases were separated and the dichloromethane
layer was then washed twice with a saturated aqueous solution of
sodium chloride, dried over sodium sulfate, filtered, and
evaporated to dryness to give 4-tert-butoxy-3-methoxybenzaldehyde
(130 mg, 19%) as a yellow oil. Rf=0.66 (SiO.sub.2, 40% ethyl
acetate in hexanes); ESI-MS m/z calc. 208.1, found 209.2
(M+1).sup.+. Retention time: 0.96 minutes (6 min run).
[0341] Step 2:
[0342] 4-tert-Butoxy-3-methoxybenzaldehyde (130 mg, 0.62 mmol) was
suspended in a mixture of dioxane (520 .mu.L) and potassium
hydroxide (6.5 mL of 0.20 M, 1.3 mmol). KMnO.sub.4 (150 mg, 0.93
mmol) was added and the reaction was stirred vigorously for 16 h.
The reaction mixture was filtered and then concentrated to 3 mL.
Hydrochloric acid (1M, 4 mL) was added and the resulting
precipitate was filtered (after standing for 15 minutes) and washed
with 1M HCl and a small amount of water to yield
4-tert-butoxy-3-methoxy-benzoic acid (68 mg, 49%) as a white solid.
Rf=0.23 (SiO.sub.2, 40% ethyl acetate in hexanes); ESI-MS m/z calc.
224.1, found 225.2 (M+1).sup.+. Retention time: 1.66 minutes (3 min
run). .sup.1H NMR (400 MHz, DMSO) .delta. 12.80 (s, 1H), 7.66-7.41
(m, 2H), 7.09 (d, J=8.8 Hz, 1H), 3.78 (s, 3H), 1.32 (s, 9H).
[0343] The following compounds were synthesized using the
procedures described above:
[0344] 4-tert-butoxy-3-methylbenzoic acid from
4-hydroxy-3-methylbenzaldehyde, 2-fluoro-4,5-dimethoxybenzoic acid
from 2-fluoro-4,5-dimethoxybenzaldehyde,
4-tert-butoxy-2-methoxybenzoic acid from
4-hydroxy-2-methoxybenzaldehyde, 4-tert-butoxy-2-fluorobenzoic acid
from 2-fluoro-4-hydroxybenzaldehyde, and 4-tert-butoxybenzoic acid
from 4-hydroxybenzaldehyde.
4-Ethyl-3-methoxybenzoic acid
##STR00866##
[0346] A mixture of 4-bromo-3-methoxy-benzoic acid (2.49 g, 10.9
mmol) and Pd(dppf)Cl.sub.2 (158 mg, 0.216 mmol) were stirred in
dioxane (25 mL) and Et.sub.2Zn (22 mL, 1 M in hexanes, 22 mmol) was
added. The reaction mixture was heated at 70.degree. C. for 1 h.
The mixture was cooled to room temperature and was quenched with
MeOH (1.1 mL). The solution was diluted with ethyl acetate (20 mL)
and was washed with 1 N HCl (10 mL). The combined organics were
washed with brine, dried over sodium sulfate and evaporated to
dryness to give 4-ethyl-3-methoxybenzoic acid. ESI-MS m/z calc.
180.1, found 179.1 (M-1).sup.-; Retention time: 1.77 minutes (3 min
run).
4-(Isopropylsulfonyl)-3-methylbenzoic acid
##STR00867##
[0348] Step 1.
[0349] Butyllithium (16 mL of 1.6 M, 26 mmol) was added drop-wise
to a mixture of 4-bromo-3-methyl-benzoic acid (2.5 g, 12 mmol) and
THF (63 mL) at -78.degree. C. The mixture was allowed to stir at
-78.degree. C. for 30 minutes before a solution of
2-isopropyldisulfanylpropane (1.7 g, 12 mmol) in THF (2 mL) was
added drop-wise. The mixture was allowed to stir at -78.degree. C.
for 30 min, then 30 min at rt. The reaction mixture was then
diluted with 100 mL of 1M aqueous sodium hydroxide. The organic
layer was discarded and the aqueous layer was made acidic with 4M
aqueous hydrochloric acid. The aqueous layer was then extracted 3
times with ethyl acetate. The combined extracts were dried over
sodium sulfate and then evaporated to dryness. The crude material
was purified by column chromatography using a gradient of 0-5% MeOH
in dichloromethane to give 4-(isopropylthio)-3-methylbenzoic acid
(870 mg, 18%). MS m/z calc. 210.3, found 211.2 (M+1).sup.+.
Retention time: 2.32 minutes (3 min run).
[0350] Step 2:
[0351] 3-Chlorobenzenecarboperoxoic acid (930 mg, 4.2 mmol) was
added to a mixture of 4-(isopropylthio)-3-methylbenzoic acid (250
mg, 1.2 mmol) and dichloromethane (5.0 mL) at 25.degree. C. The
mixture was allowed to stir at 25.degree. C. for 2 h before it was
concentrated in vacuo. The white solid material was taken up in
dichloromethane and was subjected to column chromatography (0-2%
MeOH/dichloromethane) to give 4-isopropylsulfonyl-3-methyl-benzoic
acid (90 mg, 31%) as a white solid. ESI-MS m/z calc. 242.3, found
243.2 (M+1).sup.+. Retention time: 1.57 minutes (3 min run).
.sup.1H NMR (400 MHz, DMSO) .delta. 13.50 (s, 1H), 8.50-7.66 (m,
3H), 3.50-3.47 (m, 1H), 2.67 (s, 3H), 1.19 (d, J=1.16 Hz, 6H).
[0352] The following compounds were synthesized using the
procedures described above:
[0353] 4-(isopropylsulfonyl)-2-methylbenzoic acid and
4-(ethylsulfonyl)-3-methylbenzoic acid,
4-(2-Hydroxypropan-2-yl)-3-methoxybenzoic acid
##STR00868##
[0355] 4-Bromo-3-methoxy-benzoic acid (2.00 g, 8.67 mmol) was
dissolved in THF (50 mL) and the solution was cooled to -78.degree.
C. n-BuLi in hexanes (7.6 mL of 2.5 M, 19 mmol) was added dropwise
over 15 minutes. The reaction mixture was allowed to stir for 30
minutes at -78.degree. C. and then acetone (640 .mu.L, 8.9 mmol)
was added in a dropwise manner. The reaction mixture was allowed to
stir for 30 minutes at -78.degree. C., and then it was allowed to
warm to room temperature. The reaction mixture was then diluted
with 100 mL of 1M aqueous sodium hydroxide. The organic layer was
discarded and the aqueous layer was made acidic with 4M aqueous
hydrochloric acid. The aqueous layer was then extracted 3 times
with ethyl acetate. The combined extracts were dried over sodium
sulfate and then evaporated to dryness. The crude material was
purified by column chromatography utilizing a gradient of 0-5%
methanol in dichloromethane to give
4-(2-hydroxypropan-2-yl)-3-methoxybenzoic acid (618 mg, 34%).
ESI-MS m/z calc. 210.1, found 209.1 (M-1).sup.-; Retention time:
0.68 minutes (3 min run).
3-Fluoro-4-isopropoxybenzoic acid
##STR00869##
[0357] Step 1:
[0358] To methyl 3-fluoro-4-hydroxy-benzoate (2.00 g, 11.8 mmol) in
DMF (12.5 mL) was added K.sub.2CO.sub.3 (6.50 g, 47.0 mmol)
followed by 2-iodopropane (2.35 mL, 23.5 mmol). The mixture was
heated at 60.degree. C. for 1.5 h. The mixture was filtered using
EtOAc and the filtrate was evaporated under reduced pressure. The
residue was dissolved in EtOAc and was washed with water and brine.
The organic layer was dried over sodium sulfate, filtered and
concentrated under reduced pressure to give methyl
3-fluoro-4-isopropoxybenzoate. ESI-MS m/z calc 212.1, found 213.3
(M+1).sup.+. Retention time: 1.70 minutes (3 min run).
[0359] Step 2:
[0360] Methyl 3-fluoro-4-isopropoxybenzoate (from step 1),
1,4-dioxane (31 mL), and NaOH (31 mL of 1.0 M, 31 mmol) were
combined and the mixture was heated at 80.degree. C. for 20 min.
The solvent was evaporated under reduced pressure. The crude
mixture was dissolved in water and was washed with EtOAc
(3.times.). The combined organics were discarded. The aqueous layer
was acidified and was extracted with EtOAc (3.times.). The organic
layer was dried over sodium sulfate, filtered and the concentrated
under reduced pressure to yield 3-fluoro-4-isopropoxy-benzoic acid
(1.25 g, 72%) as a white solid. ESI-MS m/z calc 198.1, found 199.3
(M+1).sup.+. Retention time: 1.34 minutes (3 min run).
[0361] The following compounds were synthesized using the
procedures described above:
[0362] 2-fluoro-4-isopropoxybenzoic acid and
4-isopropoxy-3-methylbenzoic acid, 3-cyano-4-isopropoxybenzoic acid
and 4-isopropoxy-3-(trifluoromethyl)benzoic acid.
4-(tert-Butylsulfonyl)benzoic acid
##STR00870##
[0364] Step 1:
[0365] Ethyl 4-fluorobenzoate (1.5 g, 8.9 mmol) and
tert-butylsulfanylsodium (2.00 g, 17.8 mmol) were combined in DMF
(10 mL). The reaction mixture was heated at 80.degree. C. for 2
hours. A large amount of precipitate formed and an additional 15 mL
of DMF was added and the reaction mixture was stirred for an
additional 20 hours at 80.degree. C. The reaction mixture was
partitioned between ethyl acetate (100 mL) and water (100 mL). The
organic layer was discarded, and the water layer was made acidic
with 4M hydrochloric acid. The water layer was extracted two times
with ethyl acetate. The combined extracts were dried over sodium
sulfate, filtered, and evaporated to dryness to yield
4-(tert-butylthio)benzoic acid as a colorless oil. ESI-MS m/z calc.
210.3, found 211.1 (M+1).sup.+. Retention time: 1.74 minutes (3 min
run).
[0366] Step 2:
[0367] 4-(tert-Butylthio)benzoic acid (from Step 1) was dissolved
in AcOH (10 mL) and hydrogen peroxide (5.0 mL of 30% w/w, 52 mmol)
was added to the reaction mixture. The resulting mixture was heated
at 80.degree. C. for 2 hours. The reaction mixture was then allowed
to cool to room temperature, and was diluted with 50 mL of water
and 100 mL of ethyl acetate. The layers were separated and the
aqueous layer was extracted with ethyl acetate. The combined ethyl
acetate extracts were dried over sodium sulfate, filtered, and
evaporated to dryness to yield a white solid. The white solid was
then dissolved in dichloromethane and was evaporated to dryness.
The solid was then dried under vacuum for 16 hours to give
4-tert-butylsulfonylbenzoic acid (2.2 g, 92%) as a white solid.
ESI-MS m/z calc. 242.1, found 243.1 (M+1).sup.+. Retention time:
1.15 minutes (3 min run). .sup.1H NMR (400 MHz, DMSO) .delta. 8.18
(d, J=8.0 Hz, 2H), 7.94 (d, J=7.6 Hz, 2H), 1.25 (s, 9H).
[0368] The following compound was synthesized using the procedures
described above:
[0369] 4-(ethyl sulfonyl)benzoic acid.
4-(Isobutylsulfonyl)benzoic acid
##STR00871##
[0371] Step 1:
[0372] K.sub.2CO.sub.3 (1.23 g, 8.92 mmol) was added to a mixture
of methyl 4-sulfanylbenzoate (1.00 g, 5.95 mmol),
1-bromo-2-methyl-propane (970 .mu.L, 8.92 mmol), and DMF (10 mL) at
rt. The mixture was allowed to stir for 4 h at rt before the solids
were filtered off. The solids were washed with ethyl acetate, and
then were discarded. The combined filtrates were partitioned
between ethyl acetate (100 mL) and water (100 mL). The layers were
separated and the organic layer was washed with brine, dried over
sodium sulfate, filtered and concentrated to give methyl
4-(isobutylthio)benzoate (82%) as a clear oil. ESI-MS m/z calc.
224.1, found 225.2 (M+1).sup.+. Retention time: 1.59 minutes (3 min
run).
[0373] Step 2:
[0374] m-CPBA (3.59 g, 15.6 mmol) was added to a solution of methyl
4-(isobutylsulfanyl)benzoate (1.00 g, 4.46 mmol) in
CH.sub.2Cl.sub.2 (20 mL) at rt. The mixture was allowed to stir for
2 h before it was concentrated in vacuo. Column chromatography
(0-100% ethyl acetate/hexanes) on the residue gave methyl
4-(isobutylsulfonyl)benzoate. ESI-MS m/z calc. 256.1, found 257.2
(M+1)+; Retention time: 1.96 minutes (3 min run). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.23 (d, J=8.4 Hz, 2H), 8.00 (d, J=8.3 Hz,
2H), 3.98 (s, 3H), 3.02 (d, J=6.5 Hz, 2H), 2.25 (dp, J=13.3, 6.6
Hz, 1H), 1.07 (d, J=6.7 Hz, 6H).
[0375] Step 3:
[0376] A mixture of methyl 4-isobutylsulfonylbenzoate (1.00 g, 3.90
mmol), NaOH (10 mL of 1.0 M, 10 mmol), and 1,4-dioxane (10 mL) was
heated at 80.degree. C. for 1.5 h. The mixture was cooled to rt
before it was concentrated in vacuo. The solid residue was taken up
in water and was washed with ethyl acetate which was discarded. The
aqueous layer was acidified with 1N HCl and was extracted with
ethyl acetate (2.times.). The combined organics were washed with
brine, dried over sodium sulfate, and were concentrated in vacuo.
Column chromatography (0-100% ethyl acetate/hexanes) on the residue
gave 4-(isobutylsulfonyl)benzoic acid (98%). ESI-MS m/z calc.
242.1, found 243.2 (M+1)+; Retention time: 1.73 minutes (3 min
run). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.30 (d, J=8.3 Hz,
2H), 8.05 (d, J=8.3 Hz, 2H), 3.03 (d, J=6.5 Hz, 2H), 2.27 (dt,
J=13.3, 6.6 Hz, 1H), 1.08 (d, J=6.7 Hz, 6H).
3-(Hydroxymethyl)-4-isopropoxy-benzoic acid
##STR00872##
[0378] Step 1:
[0379] To methyl 3-formyl-4-hydroxy-benzoate (10.0 g, 55.5 mmol),
potassium carbonate (30.7 g, 222 mmol) and DMF (63 mL) was added
2-iodopropane (11.1 mL, 111 mmol). The mixture was heated at
60.degree. C. for 18 hours. The mixture was filtered using ethyl
acetate (200 mL) and the solvent was evaporated under reduced
pressure. The residue was dissolved in ethyl acetate (150 mL) and
was washed with water (3.times.75 mL) and a saturated aqueous
solution of sodium chloride (1.times.75 mL). The organic layer was
dried over sodium sulfate, filtered and the solvent was evaporated
under reduced pressure to yield methyl
3-formyl-4-isopropoxy-benzoate (98%) as a yellow viscous liquid.
ESI-MS m/z calc. 222.2, found 223.3 (M+1)+; Retention time: 1.51
minutes (3 min run). .sup.1H NMR (400 MHz, DMSO) .delta. 10.35 (s,
1H), 8.23 (d, J=2.3 Hz, 1H), 8.17 (dd, J=8.8, 2.3 Hz, 1H), 7.39 (d,
J=8.9 Hz, 1H), 4.98-4.83 (m, 1H), 3.85 (s, 3H), 1.38 (d, J=6.0 Hz,
6H).
[0380] Step 2:
[0381] Methyl 3-formyl-4-isopropoxy-benzoate (180 mg, 0.81 mmol)
was dissolved in tetrahydrofuran (4.8 mL) and LiBH.sub.4 (35 mg,
1.6 mmol) was added. The reaction was stirred at room temperature
for 30 minutes before it was quenched with methanol (3 mL). The
reaction was neutralized by the addition of a saturated aqueous
solution of sodium bicarbonate (3 mL) and was then extracted with
ethyl acetate (3.times.10 mL). The combined organics were washed
with a saturated aqueous solution of sodium chloride (1.times.10
mL), dried over sodium sulfate, filtered and the solvent was
evaporated under reduced pressure to yield methyl
3-(hydroxymethyl)-4-isopropoxy-benzoate (99%) as a viscous liquid.
ESI-MS m/z calc. 224.3, found 225.3 (M+1)+; Retention time: 1.26
minutes (3 min run). .sup.1H NMR (400 MHz, DMSO) .delta. 8.09 (s,
1H), 7.89 (d, J=8.6 Hz, 1H), 7.13 (d, J=8.6 Hz, 1H), 5.25 (t, J=5.6
Hz, 1H), 4.86-4.68 (m, 1H), 4.54 (d, J=5.6 Hz, 2H), 3.87 (s, 3H),
1.35 (d, J=6.0 Hz, 6H).
[0382] Step 3:
[0383] To methyl 3-(hydroxymethyl)-4-isopropoxy-benzoate (180 mg,
0.80 mmol) and 1,4-dioxane (1.895 mL) was added sodium hydroxide
(2.1 mL of 1.0 M, 2.1 mmol) and the mixture was heated at
80.degree. C. for 50 minutes. The solvent was evaporated under
reduced pressure. The crude mixture was dissolved in water (10 mL)
and was washed with ethyl acetate (3.times.10 mL) which was
discarded. The aqueous layer was acidified with hydrochloric acid.
The aqueous layer was extracted with ethyl acetate (3.times.10 mL).
The combined organics were dried over sodium sulfate, filtered and
the solvent was evaporated under reduced pressure to yield
3-(hydroxymethyl)-4-isopropoxy-benzoic acid (89%) as a white solid.
ESI-MS m/z calc. 210.2, found 211.3 (M+1)+; Retention time: 1.01
minutes (3 min run).
[0384] The following compounds were synthesized using the
procedures described above:
[0385] 4-ethoxy-3-(hydroxymethyl)benzoic acid,
4-(2-hydroxy-2-methylpropoxy)-3-methylbenzoic acid,
4-isopropoxy-3-methoxy-5-methylbenzoic acid, 5-isobutoxypicolinic
acid, 5-(isopentyloxy)picolinic acid,
5-isopropoxy-4-methylpicolinic acid.
3-Methyl-4-(oxetan-3-yl)benzoic acid
##STR00873##
[0387] Step 1:
[0388] (4-Cyano-2-methyl-phenyl)boronic acid (1.75 g, 10.87 mmol),
diiodonickel (102 mg, 0.326 mmol), (1S,2S)-2-aminocyclohexan-1-ol
hydrochloride (50 mg, 0.33 mmol) and NaHMDS (2.01 g, 11.0 mmol)
were combined in isopropanol (10 mL) under N2 in a pressure vial. A
solution of 3-iodooxetane (1.00 g, 5.44 mmol) in isopropanol (1 mL)
was added. The vial was immersed in a pre-heated 90.degree. C. oil
bath and stirred for 2 h, then cooled, diluted with ethanol (20
mL), filtered over Celite, concentrated, then absorbed onto Celite
and purified by silica gel column chromatography (0-60%
EtOAc/hexane) to give 3-methyl-4-(oxetan-3-yl)benzonitrile (616 mg,
3.556 mmol, 65.42%) as a white solid. ESI-MS m/z calc. 173.1, found
174.3 (M+1)+; Retention time: 1.09 minutes (3 min run).
[0389] Step 2:
[0390] To 3-methyl-4-(oxetan-3-yl)benzonitrile (500 mg, 2.89 mmol)
in ethanol (7.5 mL) was added NaOH (3.0 mL of 5 M, 15 mmol) and the
mixture immersed in a 85.degree. C. oil bath. The mixture was
heated and stirred for 1 h, concentrated, then diluted with ethyl
acetate (20 mL). 6N HCl (.about.3 mL) was added to adjust pH to 6.
The aqueous layer was extracted with ethyl acetate (2.times.20 mL),
then the combined organics washed with brine (10 mL), dried over
MgSO.sub.4 and concentrated to give a white solid, which was
triturated with ether to give a mixture (2:3 by NMR) of acid
3-methyl-4-(oxetan-3-yl)benzoic acid (500 mg, 14%) and amide.
ESI-MS m/z calc. 192.2, found 193.3 (M+1)+; Retention time: 0.87
minutes (3 min run).
5-Isopropoxy-6-methoxypicolinic acid
##STR00874##
[0392] Step 1:
[0393] To a solution of 2-chloro-6-iodo-pyridin-3-ol (5.00 g, 19.57
mmol) in DMF was added finely ground potassium carbonate (5.409 g,
39.14 mmol) followed by 2-bromopropane (4.814 g, 3.675 mL, 39.14
mmol). The reaction mixture was allowed to stir at 70.degree. C.
overnight. The reaction mixture was concentrated under reduced
pressure. The residue was dissolved/suspended in EtOAc (75 mL) and
washed with water (lx 75 mL). The aqueous layer was further
extracted with EtOAc (1.times.75 mL). Both organic layers were
combined, dried over sodium sulfate, filtered and concentrated
under reduced pressure to obtain a yellow oil which was purified by
silica gel column chromatography: 0-30% EtOAc/hexane gradient to
provide 2-chloro-6-iodo-3-isopropoxy-pyridine (5.68 g, 97.%) as a
clear colourless thin oil. ESI-MS m/z calc. 296.9, found 298.4
(M+1)+; Retention time: 1.74 minutes (3 min run). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.55 (d, J=8.3 Hz, 1H), 6.90 (d, J=8.3 Hz,
1H), 4.53 (dt, J=12.1, 6.1 Hz, 1H), 1.39 (d, J=6.1 Hz, 6H).
[0394] Step 2:
[0395] 2-Chloro-6-iodo-3-isopropoxy-pyridine (2.00 g, 6.722 mmol)
was dissolved in DMF (15 mL). Zn(CN).sub.2 (592 mg, 5.04 mmol) was
added, and the mixture was bubbled with nitrogen gas prior to the
addition of Pd(PPh.sub.3).sub.4 (600 mg, 0.519 mmol). The reaction
system was sealed and heated under microwave irradiation at
100.degree. C. for 30 minutes. The reaction mixture was diluted
with EtOAc (75 mL) and washed with saturated aqueous sodium
bicarbonate solution (75 mL) followed by brine (75 mL). The organic
layer was dried over sodium sulfate, filtered and concentrated
under reduced pressure to obtain a clear oil which was purified by
silica gel column chromatography: 0-30% EtOAc/hexane gradient to
provide 6-chloro-5-isopropoxy-pyridine-2-carbonitrile (1.17 g, 88%)
as a clear colourless oil that crystallized upon standing. ESI-MS
m/z calc. 196.0, found 197.3 (M+1)+; Retention time: 1.46 minutes
(3 min run). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.61 (d,
J=8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 4.67 (dt, J=12.1, 6.1 Hz,
1H), 1.45 (d, J=6.1 Hz, 6H).
[0396] Step 3:
[0397] 6-Chloro-5-isopropoxy-pyridine-2-carbonitrile (1.10 g, 5.59
mmol) was dissolved in methanol (11 mL). To the solution was added
a solution of HCl (11 mL of 4 M, 44.00 mmol) in 1,4-dioxane. The
reaction mixture was allowed to stir at 70.degree. C. overnight.
The reaction mixture was cooled to room temperature and
concentrated under reduced pressure. The remaining solids were
suspended in EtOAc (75 mL) and washed with saturated aqueous sodium
bicarbonate solution (lx 75 mL). The organic layer was dried over
sodium sulfate, filtered and concentrated under reduced pressure.
It was purified by silica gel column chromatography: 0-50%
EtOAc/hexane to provide methyl
6-chloro-5-isopropoxy-pyridine-2-carboxylate (894 mg, 69%) as a
clear colourless oil that crystallized upon standing. ESI-MS m/z
calc. 229.1, found 230.3 (M+1)+; Retention time: 1.23 minutes (3
min run). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.06 (d, J=8.4
Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 4.68 (dt, J=12.1, 6.1 Hz, 1H),
3.97 (s, 3H), 1.44 (d, J=6.1 Hz, 6H).
[0398] Step 4:
[0399] Methyl 6-chloro-5-isopropoxy-pyridine-2-carboxylate (330 mg,
1.44 mmol) was dissolved in dioxane (12 mL), and a solution of
sodium methoxide (5.75 mL of 0.5 M, 2.87 mmol) in methanol was
added. The reaction was heated under microwave irradiation at
140.degree. C. for 1.5 hours. Water (52 .mu.L, 2.9 mmol) was added,
and the reaction mixture was heated by microwave irradiation at
100.degree. C. for 30 minutes. The reaction mixture was diluted
with 1 N HCl solution (50 mL) and extracted with EtOAc (2.times.50
mL). Organic layers were combined, dried over sodium sulfate,
filtered and concentrated under reduced pressure to provide
5-isopropoxy-6-methoxy-pyridine-2-carboxylic acid (300 mg, 98%) as
a beige solid. ESI-MS m/z calc. 211.1, found 211.9 (M+1)+;
Retention time: 0.97 minutes (3 min run). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.83 (d, J=8.1 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H),
4.72-4.61 (m, 1H), 4.06 (s, 3H), 1.45 (t, J=7.4 Hz, 7H).
5-tert-Butoxypicolinic acid
##STR00875##
[0401] Step 1:
[0402] To NaOtBu (1.57 g, 16.4 mmol) in HMPA (6 mL) was added DMF
(6 mL) (to facilitate stirring). 5-Fluoropyridine-2-carbonitrile
(1.00 g, 8.19 mmol) was added and the dark mixture was stirred
overnight. The mixture was diluted with water (100 mL), extracted
with DCM (3.times.50 mL) and the organics were washed with water
(50 mL) and sat. aq. NaHCO.sub.3 (50 mL), dried over MgSO.sub.4,
evaporated and purified by column chromatography (0-50% EtOAc/hex)
to give 5-tert-butoxypyridine-2-carbonitrile (0.90 g, 62%) as a
yellow solid. ESI-MS m/z calc. 211.1, found 211.9 (M+1)+; Retention
time: 0.97 minutes (3 min run). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.38 (dd, J=2.7, 0.5 Hz, 1H), 7.67-7.56 (m, 1H), 7.41-7.31
(m, 1H), 1.52-1.38 (m, 10H).
[0403] Step 2:
[0404] To 5-tert-butoxypyridine-2-carbonitrile (751 mg, 4.26 mmol)
in ethanol (10 mL) was added NaOH (4.262 mL of 5 M, 21.31 mmol) and
the mixture immersed in a 85.degree. C. heated bath. The mixture
was heated and stirred for 1 h, concentrated, then diluted with
ethyl acetate (50 mL). 10 mL brine and .about.3 mL of 6N HCl (to
adjust to pH 6) was added. The organic layer was separated, dried
over MgSO.sub.4 and concentrated to give
5-tert-butoxypyridine-2-carboxylic acid (820 mg, 98%) as a yellow
solid. ESI-MS m/z calc. 195.1, found 196.1 (M+1)+; Retention time:
0.62 minutes (3 min run). .sub.1H NMR (400 MHz, DMSO) .delta. 12.74
(s, 1H), 8.29 (d, J=32.6 Hz, 1H), 7.99 (s, 1H), 7.60 (d, J=6.5 Hz,
1H), 3.37 (s, 1H), 1.39 (s, 11H).
4-(N-Methyl-N-(thiazol-2-yl)sulfamoyl)benzoic acid
##STR00876##
[0406] Step 1:
[0407] To methyl 4-chlorosulfonylbenzoate (4 g, 17.05 mmol),
N-methylthiazol-2-amine (1.95 g, 17.05 mmol), 1,2-dichloroethane
(20 mL), and triethylamine (2.38 mL, 17.05 mmol) were added and the
reaction was heated at 100.degree. C. in a pressure vessel for 20.5
hours on a heat block. The solvent was evaporated under reduced
pressure. The crude compound was dissolved in dichloromethane and
filtered. The filtrate was purified by silica gel chromatography
utilizing a gradient of 0-30% ethyl acetate in dichloromethane to
yield methyl 4-[methyl(thiazol-2-yl)sulfamoyl]benzoate (4.22 g,
79.2%). 1H NMR (400 MHz, DMSO) .delta. 8.16 (d, J=8.5 Hz, 2H), 7.95
(d, J=8.5 Hz, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H),
3.89 (s, 3H), 3.39 (s, 3H). ESI-MS m/z calc. 312.0, found 313.3
(M+1)+; Retention time: 1.52 minutes (3 min run).
[0408] Step 2:
[0409] To methyl 4-[methyl(thiazol-2-yl)sulfamoyl]benzoate (4.22 g,
13.5 mmol) and 1,4-dioxane (32 mL) was added aq. NaOH (62 mL of 2.5
M, 155 mmol) and the mixture was stirred at 50.degree. C. for 1
hour. The reaction mixture was cooled to room temperature. Ethyl
acetate (135 mL) was added before acidifying it to pH 1 with HCl
(37%). The organic and aqueous layers were separated. The aqueous
layer was extracted with ethyl acetate (1.times.50 mL). The organic
layers were dried over sodium sulfate, filtered and the solvent was
evaporated under reduced pressure to yield
4-[methyl(thiazol-2-yl)sulfamoyl]benzoic acid (3.63 g, 87%) as a
white solid. ESI-MS m/z calc. 298.0, found 299.1 (M+1)+; Retention
time: 1.31 minutes (3 minutes run). .sup.1H NMR (400 MHz, DMSO)
.delta. 13.56 (s, 1H), 8.14 (d, J=8.6 Hz, 2H), 7.92 (d, J=8.5 Hz,
2H), 7.46 (d, J=3.6 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H), 3.39 (s,
3H).
4-(2-Fluoro-2-methylpropoxy)-3-methoxybenzoic acid
##STR00877##
[0411] Step 1:
[0412] To a solution of methyl
4-(2-hydroxy-2-methyl-propoxy)-3-methoxy-benzoate (509 mg, 2.00
mmol) in DCM (5 mL) at 0.degree. C. was added
2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-sulfanyl)ethanamine (406
.mu.L, 2.20 mmol) dropwise. The mixture was stirred at 0.degree. C.
for 1 h before the cooling bath was removed and the mixture was
stirred for 1 h at room temperature. The mixture was poured into
water and was extracted with EtOAc (3.times.). The organics were
combined, washed with water, brine, dried (Na.sub.2SO.sub.4) and
evaporated to dryness. Purification of the residue by column
chromatography (0-20% EtOAc in Hex) gave methyl
4-(2-fluoro-2-methyl-propoxy)-3-methoxy-benzoate (450 mg, 70%).
ESI-MS m/z calc. 256.1, found 257.1 (M+1)+; Retention time: 1.57
minutes (3 min run).
[0413] Step 2:
[0414] To a solution of methyl
4-(2-fluoro-2-methyl-propoxy)-3-methoxy-benzoate (450 mg, 1.76
mmol) in MeOH (3.6 mL) and water (900 .mu.L) was added NaOH (210
mg, 5.27 mmol) and the mixture was stirred at 40.degree. C. for 1
hour. The MeOH was evaporated and the pH of the solution was
adjusted to 3 with 1N HCl. The precipitate was filtered, washed
with water, and dessicated to give
4-(2-fluoro-2-methylpropoxy)-3-methoxybenzoic acid. ESI-MS m/z
calc. 242.2, found 243.7 (M+1)+; Retention time: 1.25 minutes (3
min run).
3-Methoxy-4-((2,2,2-trifluoroethoxy)methyl)benzoic acid
##STR00878##
[0416] To a solution of 2,2,2-trifluoroethanol (874 .mu.L, 12.0
mmol) at 0.degree. C. was added NaH (60%, 520 mg, 13.0 mmol) and
the mixture was stirred at this temp for 10 min, then at room
temperature for 10 min. The mixture was cooled to 0.degree. C.
before methyl 4-(bromomethyl)-3-methoxybenzoate (2.59 g, 10.0 mmol)
was added. The cooling bath was removed and the mixture was stirred
at room temperature for 3 hours. The mixture was poured into water
and extracted with EtOAc (3.times.). The organics were combined,
washed with water, brine, dried (MgSO.sub.4) and evaporated to
dryness. Crushed NaOH was added to the residue, followed by water
(4 mL) and MeOH (20 mL). The mixture was stirred at room
temperature for 1 hour. The MeOH was evaporated and the residue was
taken up in 1N NaOH (30 ml) and the pH was adjusted to pH 2 with
conc HCl. The precipitate was filtered, washed with water
(2.times.) then hexanes (2.times.) and desiccated to give
3-methoxy-4-((2,2,2-trifluoroethoxy)methyl)benzoic acid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.79 (dd, J=7.8, 1.4 Hz, 1H),
7.61 (d, J=1.4 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 4.80 (s, 2H),
4.00-3.91 (m, 5H).
[0417] The following compound was synthesized using the procedures
described above:
[0418] methyl
3-methoxy-4-((3,3,3-trifluoropropoxy)methyl)benzoate.
4-(1-Hydroxy-2-methylpropan-2-yl)-3-methoxybenzoic acid
##STR00879##
[0420] Step 1:
[0421] 4-Bromo-3-methoxy-benzoic acid (1.50 g, 6.49 mmol),
K.sub.2CO.sub.3 (2.69 g, 19.5 mmol), and DMF (10 mL) were combined
and the mixture was allowed to stir for 10 minutes.
Bromomethylbenzene (849 gL, 7.14 mmol) was added dropwise and the
mixture was allowed to stir at room temperature for 1 h. The
reaction mixture was quenched with brine and was extracted with
EtOAc (3.times.). The organic layers were dried over sodium
sulfate, filter and concentrated. The residue was purified using
silica gel chromatography (5%-70% EtOAc in hexanes) to provide
benzyl 4-bromo-3-methoxybenzoate (91%). ESI-MS m/z calc 320.0,
found 321.0/323.0 (M+I)+. Retention time: 3.24 minutes (4 min
run).
[0422] Step 2:
[0423] To a flask purged with nitrogen was added
Pd(tBu.sub.3P).sub.2 (26 mg, 0.050 mmol), ZnF.sub.2 (52 mg, 0.50
mmol) and DMF (4 mL). The reaction mixture was allowed to stir for
10 minutes before benzyl 4-bromo-3-methoxy-benzoate (323 mg, 1.01
mmol) was added followed by trimethyl(2-methylprop-1-enoxy)silane
(277 .mu.L, 1.51 mmol). The reaction was heated at 80.degree. C.
overnight. The crude mixture was quenched with brine and extracted
with EtOAc 3 times. The organic layer was dried over sodium sulfate
and the solvent was evaporated to give benzyl
3-methoxy-4-(2-methyl-1-oxopropan-2-yl)benzoate. ESI-MS m/z calc.
312.4, found 313.4 (M+1)+; Retention time: 3.27 minutes (4 min
run).
[0424] Step 3:
[0425] Benzyl 3-methoxy-4-(2-methyl-1-oxopropan-2-yl)benzoate
(crude, from step 2) was then treated with MeOH (2 mL) followed by
NaBH.sub.4 (190 mg, 5.03 mmol). The reaction mixture was stirred
for 1 h before it was quenched with brine and extracted with EtOAc.
The organic layers were combined, dried over sodium sulfate, and
evaporated to give benzyl
4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxybenzoate.
[0426] Step 4:
[0427] To the crude benzyl
4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxybenzoate (from step 3)
was added THF (2 mL) followed by aqueous NaOH (1.7 mL of 3.0 M, 5.0
mmol). The reaction mixture was stirred for 3 h. The reaction
mixture was acidified to pH 3 and was extracted with EtOAc 3 times.
The organic layers were dried over sodium sulfate and the solvent
was evaporated to give
4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxybenzoic acid. ESI-MS m/z
calc. 224.1, found 224.2 (M+1)+; Retention time: 2.46 minutes (4
min run).
3-Fluoro-4-(2-hydroxy-2-methylpropyl)benzoic acid
##STR00880##
[0429] Step 1:
[0430] Diazomethyl-trimethyl-silane (11.6 mL of 2.0 M, 23.2 mmol)
was added dropwise to a solution of
2-(4-bromo-2-fluoro-phenyl)acetic acid (4.50 g, 19.3 mmol) in
toluene (7.7 mL) and MeOH (7.7 mL) under a nitrogen atmosphere at
room temperature. A persistent yellow color remained after complete
addition of diazomethane. The reaction was then quenched with a few
drops of acetic acid and the solvents were removed under reduced
pressure. The residue was purified by silica gel flash column
chromatography using 0-10% EtOAc in hexanes to yield methyl
2-(4-bromo-2-fluoro-phenyl)acetate (4.32 g, 91%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.28-7.22 (m, 2H), 7.15 (t, J=8.0 Hz, 1H),
3.71 (s, 3H), 3.63 (d, J=1.0 Hz, 2H).
[0431] Step 2:
[0432] Methyl 2-(4-bromo-2-fluoro-phenyl)acetate (4.00 g, 16.2
mmol) in THF (56 mL) was cooled in an ice water bath under a
nitrogen atmosphere upon which bromo-methyl-magnesium (16.2 mL of 3
M, 48.6 mmol) was added dropwise over 30 minutes. The reaction
mixture was continued to stir for 2 hours under ice water bath
cooling. The reaction mixture was then quenched with saturated
aqueous ammonium chloride and diluted with EtOAc. The layers were
separated, and the aqueous layer was extracted with EtOAc. The
combined organics were dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
silica gel flash column chromatography using 0-15% EtOAc in hexanes
to yield 1-(4-bromo-2-fluoro-phenyl)-2-methyl-propan-2-ol (3.0 g,
75%) as a clear colorless oil. ESI-MS m/z calc. 246.0, found 231.1
(M+1)+; Retention time: 1.53 minutes (3 min run). LC/MS observed
m/z does not show parent mass, but the -17 fragment. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.26-7.21 (m, 2H), 7.14 (t, J=8.1 Hz,
1H), 2.78 (d, J=1.4 Hz, 2H), 1.24 (d, J=0.8 Hz, 6H).
[0433] Step 3:
[0434] 1-(4-Bromo-2-fluoro-phenyl)-2-methyl-propan-2-ol (2.35 g,
9.51 mmol), diacetoxypalladium (214 mg, 0.951 mmol),
3-diphenylphosphanylpropyl-diphenyl-phosphane (404 mg, 0.951 mmol),
and Et.sub.3N (4.24 mL, 30.4 mmol) in DMF (26 mL) were treated with
MeOH (20.0 mL, 495 mmol). The vessel was charged to 50 psi with CO
(266 mg, 9.51 mmol) and then vented. This operation was repeated
twice. The reaction was charged to 50 psi and heated at 80.degree.
C. for 15 h. The reaction mixture was allowed to cool, vented and
partitioned between EtOAc/brine. The layers were separated and the
aqueous layer was extracted with EtOAc. The combined organics were
washed twice with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to an orange oil. The residue was purified by silica
gel flash column chromatography using 0-30% EtOAc in hexanes to
yield methyl 3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoate (1.83
g, 85%) ESI-MS m/z calc. 226.1, found 227.5 (M+1)+; Retention time:
1.29 minutes (3 min run). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.78 (dd, J=7.9, 1.7 Hz, 1H), 7.71 (dd, J=10.3, 1.6 Hz, 1H), 7.34
(t, J=7.6 Hz, 1H), 3.92 (s, 3H), 2.88 (d, J=1.3 Hz, 2H), 1.26 (s,
6H).
[0435] Step 4:
[0436] Methyl 3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoate (1.59
g, 7.03 mmol) was dissolved in THF (40 mL), water (200 mL) and MeOH
(21 mL) before LiOH (1.01 g, 42.2 mmol) was added. The reaction
mixture was heated at 55.degree. C. for 30 minutes. The reaction
mixture was cooled to room temperature and the solvents were
removed under reduced pressure. The residue was dissolved in water
and cooled in an ice water bath and treated with HCl 1M to pH 3.
The resulting precipitate was collected by vacuum filtration,
washed with water and dried under high vacuum to yield
3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoic acid (999 mg, 67%) as
a white solid. ESI-MS m/z calc. 212.1, found 211.1 (M+1)+;
Retention time: 0.98 minutes (3 min run, scanned using negative
ionization mode). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.84
(dd, J=7.9, 1.6 Hz, 1H), 7.77 (dd, J=10.1, 1.6 Hz, 1H), 7.39 (d,
J=15.1 Hz, 1H), 2.91 (s, 2H), 1.28 (s, 6H).
3-Fluoro-4-(3-methoxyprop-1-ynyl)benzoic acid
##STR00881##
[0438] Step 1:
[0439] To methyl 4-bromo-3-fluoro-benzoate (2.50 g, 10.7 mmol),
copper (I) iodide (204 mg, 1.07 mmol) and
Pd(PPh.sub.3).sub.2Cl.sub.2 (753 mg, 1.07 mmol) in a flask under
Argon was added DMF (degassed for 30 min) and reaction cooled to 0
C. Et.sub.3N (1.95 mL, 14.0 mmol) was added followed by
3-methoxyprop-1-yne (997 .mu.L, 11.8 mmol) and the mixture was
allowed to stir at 60.degree. C. for 70 min. The mixture was
cooled, diluted with ethyl acetate and filtered. The filtrate was
washed sequentially with 1 M HCl, 10% NH.sub.4OH and brine
solutions. The organic layer was separated, dried and purified with
silica gel using ethyl acetate-hexanes to give methyl
3-fluoro-4-(3-methoxyprop-1-ynyl)benzoate. ESI-MS m/z calc. 222.2,
found 223.2 (M+1)+; Retention time: 1.53 minutes (3 min run).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.75 (ddd, J=11.2, 8.8,
1.5 Hz, 2H), 7.50 (dd, J=7.9, 7.0 Hz, 1H), 4.37 (s, 2H), 3.92 (s,
3H), 3.47 (s, 3H).
[0440] Step 2:
[0441] To methyl 3-fluoro-4-(3-methoxyprop-1-ynyl)benzoate (1.40 g,
6.30 mmol) in 15 ml of 2:1 THF:MeOH at room temperature was added
NaOH (1.89 mL of 4 M, 7.56 mmol). The mixture was stirred at room
temperature for 1 h before the volatile solvents were removed. The
remainder was extracted with ether. The aqueous layer was acidified
with 1M HCl and was extracted with ether (3.times.). The combined
ether extracts were dried and concentrated to give
3-fluoro-4-(3-methoxyprop-1-ynyl)benzoic acid as a white solid.
ESI-MS m/z calc. 208.2, found 209.2 (M+1)+; Retention time: 1.22
minutes (3 min run). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.85
(dd, J=8.0, 1.4 Hz, 1H), 7.80 (dd, J=9.5, 1.3 Hz, 1H), 7.59-7.49
(m, 1H), 4.39 (s, 2H), 3.48 (s, 3H).
4-(Bis(2,2,2-trifluoroethoxy)methyl)-3-chlorobenzoic acid
##STR00882##
[0443] To a solution of methyl 3-chloro-4-methyl-benzoate (2.00 g,
10.8 mmol) and NBS (2.05 g, 11.5 mmol) in CCl.sub.4 (9 mL) at
reflux was added AIBN (178 mg, 1.08 mmol). The mixture was heated
at reflux for 16 h before additional AIBN (178 mg, 1.08 mmol) was
added. The mixture was heated at reflux for 72 h before it was
cooled. The mixture was concentrated to dryness, the residue was
partitioned between Et.sub.2O and water, the layers were separated,
and the aqueous layer was extracted with Et.sub.2O (2.times.). The
organics were combined, washed with water, brine, dried
(MgSO.sub.4) and concentrated to dryness. Purification of the
residue by column chromatography (0-30% EtOAc in Hex) gave methyl
3-chloro-4-(dibromomethyl)benzoate. ESI-MS m/z calc. 342.5, found
342.9 (M+1)+; Retention time: 1.96 minutes (3 min run).
[0444] Step 2:
[0445] To a solution of 2,2,2-trifluoroethanol (109 .mu.L, 1.50
mmol) in DMF (2.63 mL) was added NaH (64 mg, 1.6 mmol). The mixture
was stirred at room temperature for 1 h before methyl
3-chloro-4-(dibromomethyl)benzoate (342 mg, 1.00 mol) was added.
The mixture was stirred at room temperature for 2 h before it was
poured into water and was extracted with EtOAc (3.times.). The
organics were combined, washed with water, brine, dried
(Na.sub.2SO.sub.4) and evaporated to dryness. The material was
taken up in MeOH and powdered NaOH (160 mg, 4.00 mol) was added and
the mixture was stirred at room temperature for 1 h. The mixture
was evaporated and treated with 1N HCl (until the solution was
strongly acidic). The precipitated product was washed with water
and dried to give
4-(bis(2,2,2-trifluoroethoxy)methyl)-3-chlorobenzoic acid. ESI-MS
m/z calc. 394.4, found 394.5 (M+1)+; Retention time: 1.74 minutes
(3 min run).
4-(1-Hydroxy-2-(2,2,2-trifluoroethoxy)ethyl)benzoic acid and
4-(2-hydroxy-1-(2,2,2-trifluoroethoxy)ethyl)benzoic acid
##STR00883##
[0447] Step 1:
[0448] To a solution of methyl 4-acetylbenzoate (8.91 g, 50.0 mmol)
in AcOH (80 mL) was added Br.sub.2 (2.71 mL, 52.5 mmol) dropwise.
The mixture was stirred at room temperature for 2 h. The mixture
was cooled to 0.degree. C. and the solid was filtered. The
precipitate was washed with 1:1 MeOH in water and was dessicated to
give methyl 4-(2-bromoacetyl)benzoate (10.6 g, 82%) as a tan solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.19-8.12 (m, 2H), 8.04
(d, J=8.5 Hz, 2H), 4.47 (s, 2H), 3.96 (s, 3H).
[0449] Step 2:
[0450] To a stirred solution of methyl 4-(2-bromoacetyl)benzoate
(0.59 g, 2.3 mmol) in MeOH (6 mL) at 0.degree. C. was added
NaBH.sub.4 (92 mg, 2.4 mmol) in portions. The cooling bath was
removed and the mixture was stirred at room temperature for 1 h.
K.sub.2CO.sub.3 (317 mg, 2.30 mmol) was added and the mixture was
stirred at room temperature for 72 h. The mixture was poured into
water and was extracted with Et.sub.2O (3.times.). The organics
were combined, washed with water, brine, dried (MgSO.sub.4) and
evaporated to dryness to give methyl 4-(oxiran-2-yl)benzoate (370
mg, 90%) as a white solid. ESI-MS m/z calc. 178.2, found 179.1
(M+1)+; Retention time: 1.14 minutes (3 min run).
[0451] Step 3:
[0452] To 2,2,2-trifluoroethanol (0.50 mL, 6.9 mmol) was added NaH
(10 mg, 0.24 mmol). The mixture was stirred for 5 min before the
addition of methyl 4-(oxiran-2-yl)benzoate (36 mg, 0.20 mmol) and
heating at 70.degree. C. for 2 h. Crushed NaOH (40 mg, 1.0 mmol)
was added followed by water (0.1 mL) and the mixture was stirred at
40.degree. C. for 3 h. The mixture was evaporated and the residue
was partitioned between 1N HCl and EtOAc. The layers were
separated, and aqueous layer was extracted with EtOAc (2.times.).
The organics were combined and evaporated to dryness to give a
mixture of 4-[1-hydroxy-2-(2,2,2-trifluoroethoxy)ethyl]benzoic acid
and 4-(2-hydroxy-1-(2,2,2-trifluoroethoxy)ethyl)benzoic acid (30
mg, 57%) as an oil. ESI-MS m/z calc. 264.1, found 265.1 (M+1)+;
Retention time: 1.07 minutes (3 min run).
(4-Isopropoxy-3-methoxyphenyl)(2'-methyl-6'-(trifluoromethyl)-3',4'-dihydr-
o-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-1-yl)methanone
##STR00884##
[0454] A mixture of
2'-methyl-6'-(trifluoromethyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-py-
rrolo[1,2-a]pyrazine]dihydrochloride (69 mg, 0.20 mmol),
4-isopropoxy-3-methoxybenzoic acid (42 mg, 0.20 mmol), HATU (76 mg,
0.20 mmol), Et.sub.3N (112 .mu.L, 0.80 mmol) and DMF (2 mL) was
allowed to stir at room temperature for 3 h. The mixture was
filtered and purified by reverse-phase preparatory HPLC (10-99%
ACN/water). The desired fractions were concentrated to give
(4-isopropoxy-3-methoxyphenyl)(2'-methyl-6'-(trifluoromethyl)-3',4'-dihyd-
ro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-1-yl)methanone
as an amorphous white solid. ESI-MS m/z calc. 465.2, found 466.3
(M+1)+; Retention time: 1.23 minutes (3 min run). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.01 (d, J=1.7 Hz, 1H), 6.97 (dd, J=8.2,
1.7 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.53 (d, J=3.0 Hz, 1H), 5.94
(d, J=3.5 Hz, 1H), 4.57 (dt, J=12.2, 6.1 Hz, 1H), 4.52 (s, 1H),
3.99 (s, 2H), 3.87 (s, 3H), 3.69 (s, 1H), 3.40 (s, 1H), 3.34 (t,
J=5.4 Hz, 3H), 2.39 (s, 3H), 2.11 (s, 2H), 1.82 (s, 2H), 1.38 (d,
J=6.1 Hz, 6H).
(4-Isopropoxy-3-methoxyphenyl)(6'-(trifluoromethyl)-3',4'-dihydro-2'H-spir-
o[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-1-yl)methanone
##STR00885##
[0456] To a stirred solution of
6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piper-
idine]dihydrochloride (475 mg, 1.43 mmol),
4-isopropoxy-3-methoxy-benzoic acid (361 mg, 1.72 mmol) and
1-hydroxybenzotriazole (232 mg, 1.72 mmol) in CH.sub.2Cl.sub.2 (5.5
mL) at ambient temperature was added
3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (266 mg,
1.72 mmol) followed by 4-methylmorpholine (786 .mu.L, 7.15 mmol).
The mixture was stirred for 16 h at room temperature. The mixture
was poured into water and was extracted with EtOAc (3.times.). The
organics were combined, washed with 0.1 N HCl, 1N NaOH, water,
brine, dried (Na.sub.2SO.sub.4) and evaporated to dryness. The
residue was purified by column chromatography (0-100% ethyl
acetate/hexanes) to give
(4-isopropoxy-3-methoxy-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H--
pyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone (623 mg,
96%). ESI-MS m/z calc. 451.2, found 452.3 (M+1)+; Retention time:
1.30 minutes (3 min run). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.03 (d, J=1.9 Hz, 1H), 6.98 (dd, J=8.2, 1.9 Hz, 1H), 6.88 (d,
J=8.3 Hz, 1H), 6.54 (d, J=3.7 Hz, 1H), 5.93 (d, J=3.8 Hz, 1H), 4.56
(dd, J=12.2, 6.1 Hz, 1H), 4.52 (s, 1H), 3.94 (s, 2H), 3.88 (s, 3H),
3.69 (s, 1H), 3.47 (s, 2H), 3.27 (s, 2H), 1.87 (s, 4H), 1.38 (d,
J=6.1 Hz, 6H).
[0457] The following compounds were made using the procedures
described above:
TABLE-US-00002 Compound name Amine name Acid name
[(5aR,9aR)-spiro[5a,6,7,8,9,9a- (5aR,9aR)- 4-tert-butyl-3-methoxy-
hexahydro-5H-pyrrolo[1,2- spiro[5a,6,7,8,9,9a- benzoic acid
a]quinoxaline-4,4'-piperidine]-1'-yl]- hexahydro-5H-
(4-tert-butyl-3-methoxy- pyrrolo[1,2- phenyl)methanone
a]quinoxaline-4,4'- piperidine] [(5aS,9aS)-spiro[5a,6,7,8,9,9a-
(5aS,9aS)- 4-tert-butyl-3-methoxy- hexahydro-5H-pyrrolo[1,2-
spiro[5a,6,7,8,9,9a- benzoic acid
a]quinoxaline-4,4'-piperidine]-1'-yl]- hexahydro-5H-
(4-tert-butyl-3-methoxy- pyrrolo[1,2- phenyl)methanone
a]quinoxaline-4,4'- piperidine] (4-isopropoxy-3-methyl-phenyl)-[2-
2-(2- 4-isopropoxy-3-methyl- (2-methoxyethyl)spiro[3,4-
methoxyethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
(2-benzylspiro[3,4- 2-benzylspiro[3,4- 4-isopropoxy-3-methyl-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2- benzoic
acid piperidine]-1'-yl)-(4-isopropoxy-3- a]pyrazine-1,4'-
methyl-phenyl)methanone piperidine] (4-ethyl-3-methoxy-phenyl)-[2-
2-methyl-6- 4-ethyl-3-methoxy- methyl-6-(trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
[3-(hydroxymethyl)-4-isopropoxy- 2-methyl-6- 3-(hydroxymethyl)-4-
phenyl]-[2-methyl-6- (trifluoromethyl)spiro[3,4- isopropoxy-benzoic
acid (trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] [2-methyl-6- 2-methyl-6- 2-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
(trifluoromethoxy)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'-yl]-[2- a]pyrazine-1,4'-
(trifluoromethoxy)phenyl]methanone piperidine]
(4-isopropoxy-3-methoxy-phenyl)- 2-methyl-6-
4-isopropoxy-3-methoxy- [2-methyl-6- (trifluoromethyl)spiro[3,4-
benzoic acid (trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] [4-(1-hydroxy-1-methyl-
2-methyl-6- 4-(1-hydroxy-1-methyl- ethyl)phenyl]-[2-methyl-6-
(trifluoromethyl)spiro[3,4- ethyl)benzoic acid
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(4-ethyl-3-methoxy-phenyl)-[2-(2- 2-(2-methoxyethyl)-6-
4-ethyl-3-methoxy- methoxyethyl)-6- (trifluoromethyl)spiro[3,4-
benzoic acid (trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
[3-(hydroxymethyl)-4-isopropoxy- 2-(2-methoxyethyl)-6-
3-(hydroxymethyl)-4- phenyl]-[2-(2-methoxyethyl)-6-
(trifluoromethyl)spiro[3,4- isopropoxy-benzoic acid
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] [2-(2-methoxyethyl)-6-
2-(2-methoxyethyl)-6- 2- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- (trifluoromethoxy)benzoic
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2- acid
piperidine]-1'-yl]-[2- a]pyrazine-1,4'-
(trifluoromethoxy)phenyl]methanone piperidine]
(4-isopropoxy-3-methoxy-phenyl)- 2-(2-methoxyethyl)-6-
4-isopropoxy-3-methoxy- [2-(2-methoxyethyl)-6-
(trifluoromethyl)spiro[3,4- benzoic acid
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] [4-(1-hydroxy-1-methyl-
2-(2-methoxyethyl)-6- 4-(1-hydroxy-1-methyl-
ethyl)phenyl]-[2-(2-methoxyethyl)- (trifluoromethyl)spiro[3,4-
ethyl)benzoic acid 6-(trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
(4-isopropoxy-3-methoxy-phenyl)- 6- 4-isopropoxy-3-methoxy-
[6-(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydro-2H-pyrrolo[1,2-a]pyrazine- dihydro-2H-pyrrolo[1,2-
1,4'-piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
[3-(hydroxymethyl)-4-isopropoxy- 6- 3-(hydroxymethyl)-4-
phenyl]-[6- (trifluoromethyl)spiro[3,4- isopropoxy-benzoic acid
(trifluoromethyl)spiro[3,4-dihydro- dihydro-2H-pyrrolo[1,2-
2H-pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] [2-ethyl-6- 2-ethyl-6-
4-isopropoxy-3-methoxy- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine]
(3-methyl-4-methylsulfonyl-phenyl)- 2-methyl-6- 3-methyl-4-
[2-methyl-6- (trifluoromethyl)spiro[3,4- methylsulfonyl-benzoic
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] N-methyl-4-[2-methyl-6-
2-methyl-6- 4- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- (methylsulfamoyl)benzoic
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2- acid
piperidine]-1'- a]pyrazine-1,4'- carbonyl]benzenesulfonamide
piperidine] (4-isopropoxy-3-methyl-phenyl)-[2- 2-methyl-6-
4-isopropoxy-3-methyl- methyl-6-(trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
(4-tert-butoxy-3-methoxy-phenyl)- 2-methyl-6-
4-tert-butoxy-3-methoxy- [2-methyl-6- (trifluoromethyl)spiro[3,4-
benzoic acid (trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(4-tert-butoxy-3-methoxy-phenyl)- 6- 4-tert-butoxy-3-methoxy-
[6-(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydro-2H-pyrrolo[1,2-a]pyrazine- dihydro-2H-pyrrolo[1,2-
1,4'-piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
1'-(4-isopropoxy-3-methyl-benzoyl)- 2-methylspiro[3,4-
4-isopropoxy-3-methyl- 2-methyl-spiro[3,4- dihydropyrrolo[1,2-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-carbonitrile piperidine]-6-carbonitrile
(4-tert-butylsulfonylphenyl)-[2- 2-methyl-6- 4-tert-
methyl-6-(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
butylsulfonylbenzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]methanone a]pyrazine-1,4'-
piperidine] N-cyclopropyl-4-[6- 6- 4-(cyclopropylsulfamoyl)-
(trifluoromethyl)spiro[3,4-dihydro- (trifluoromethyl)spiro[3,4-
benzoic acid 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'- a]pyrazine-1,4'-
carbonyl]benzenesulfonamide piperidine]
(4-isopropoxy-3-methyl-phenyl)-[6- 6- 4-isopropoxy-3-methyl-
(trifluoromethyl)spiro[3,4-dihydro- (trifluoromethyl)spiro[3,4-
benzoic acid 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'-yl]methanone
a]pyrazine-1,4'- piperidine] N-cyclopropyl-4-[2-methyl-6-
2-methyl-6- 4-(cyclopropylsulfamoyl)- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'- a]pyrazine-1,4'- carbonyl]benzenesulfonamide
piperidine] N,2-dimethyl-4-[2-methyl-6- 2-methyl-6- 3-methyl-4-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
(methylsulfamoyl)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'- a]pyrazine-1,4'-
carbonyl]benzenesulfonamide piperidine]
(3-ethoxy-4-methoxy-phenyl)-[6- 6- 3-ethoxy-4-methoxy-
(trifluoromethyl)spiro[3,4-dihydro- (trifluoromethyl)spiro[3,4-
benzoic acid 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'-yl]methanone
a]pyrazine-1,4'- piperidine] (4-isopropoxyphenyl)-[6- 6-
4-isopropoxybenzoic acid (trifluoromethyl)spiro[3,4-dihydro-
(trifluoromethyl)spiro[3,4- 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'-yl]methanone
a]pyrazine-1,4'- piperidine] 8-quinolyl-[6- 6-
quinoline-8-carboxylic (trifluoromethyl)spiro[3,4-dihydro-
(trifluoromethyl)spiro[3,4- acid 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'-yl]methanone
a]pyrazine-1,4'- piperidine] (3-butoxy-4-methoxy-phenyl)-[6- 6-
3-butoxy-4-methoxy- (trifluoromethyl)spiro[3,4-dihydro-
(trifluoromethyl)spiro[3,4- benzoic acid
2H-pyrrolo[1,2-a]pyrazine-1,4'- dihydro-2H-pyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
(4-butoxy-3-methoxy-phenyl)-[6- 6- 4-butoxy-3-methoxy-
(trifluoromethyl)spiro[3,4-dihydro- (trifluoromethyl)spiro[3,4-
benzoic acid 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'-yl]methanone
a]pyrazine-1,4'- piperidine] (4-methoxyphenyl)-[6- 6-
4-methoxybenzoic acid (trifluoromethyl)spiro[3,4-dihydro-
(trifluoromethyl)spiro[3,4- 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'-yl]methanone
a]pyrazine-1,4'- piperidine] 4-quinolyl-[6- 6-
quinoline-4-carboxylic (trifluoromethyl)spiro[3,4-dihydro-
(trifluoromethyl)spiro[3,4- acid 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'-yl]methanone
a]pyrazine-1,4'- piperidine] (3,4-dimethoxyphenyl)-[2-methyl-6-
2-methyl-6- 3,4-dimethoxybenzoic (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
(3-ethoxy-4-methoxy-phenyl)-[2- 2-methyl-6- 3-ethoxy-4-methoxy-
methyl-6-(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]methanone a]pyrazine-1,4'-
piperidine] (3-methoxy-4-propoxy-phenyl)-[2- 2-methyl-6-
3-methoxy-4-propoxy- methyl-6-(trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
(3-methoxyphenyl)-[2-methyl-6- 2-methyl-6- 3-methoxybenzoic acid
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
(4-isopropoxyphenyl)-[2-methyl-6- 2-methyl-6- 4-isopropoxybenzoic
acid (trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
[2-methyl-6- 2-methyl-6- quinoline-8-carboxylic
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(8- a]pyrazine-1,4'- quinolyl)methanone
piperidine] (3-butoxy-4-methoxy-phenyl)-[2- 2-methyl-6-
3-butoxy-4-methoxy- methyl-6-(trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
[4-(1-hydroxy-1-methyl-ethyl)-3- 2-methyl-6- 4-(1-hydroxy-1-methyl-
methoxy-phenyl]-[2-methyl-6- (trifluoromethyl)spiro[3,4-
ethyl)-3-methoxy-benzoic (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
[4-(1-hydroxy-1-methyl-ethyl)-3- 2-methyl-6- 4-(1-hydroxy-1-methyl-
methyl-phenyl]-[2-methyl-6- (trifluoromethyl)spiro[3,4-
ethyl)-3-methyl-benzoic (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
(4-butoxy-3-methoxy-phenyl)-[2- 2-methyl-6- 4-butoxy-3-methoxy-
methyl-6-(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
[2-methyl-6- 2-methyl-6- 3-methylbenzoic acid
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(m- a]pyrazine-1,4'- tolyl)methanone piperidine]
[2-methyl-6- 2-methyl-6- 2-(1-piperidyl)pyridine-4-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- carboxylic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-[2-(1-piperidyl)-4- a]pyrazine-1,4'-
pyridyl]methanone piperidine] (3-chlorophenyl)-[2-methyl-6-
2-methyl-6- 3-chlorobenzoic acid (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]methanone a]pyrazine-1,4'-
piperidine] (2-methoxyphenyl)-[2-methyl-6- 2-methyl-6-
2-methoxybenzoic acid (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]methanone a]pyrazine-1,4'-
piperidine] [4-(2-hydroxyethoxy)-3-methoxy- 2-methyl-6-
4-(2-hydroxyethoxy)-3- phenyl]-[2-methyl-6-
(trifluoromethyl)spiro[3,4- methoxy-benzoic acid
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(4-methoxyphenyl)-[2-methyl-6- 2-methyl-6- 4-methoxybenzoic acid
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
(4-fluoro-3-methyl-phenyl)-[2- 2-methyl-6-
4-fluoro-3-methyl-benzoic methyl-6-(trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
[2-methyl-6- 2-methyl-6- quinoline-4-carboxylic
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4- a]pyrazine-1,4'- quinolyl)methanone
piperidine] [4-(1-hydroxy-1-methyl-ethyl)-3- 6-
4-(1-hydroxy-1-methyl- methoxy-phenyl]-[6-
(trifluoromethyl)spiro[3,4- ethyl)-3-methoxy-benzoic
(trifluoromethyl)spiro[3,4-dihydro- dihydro-2H-pyrrolo[1,2- acid
2H-pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(3-methoxy-4-propoxy-phenyl)-[6- 6- 3-methoxy-4-propoxy-
(trifluoromethyl)spiro[3,4-dihydro- (trifluoromethyl)spiro[3,4-
benzoic acid 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'-yl]methanone
a]pyrazine-1,4'- piperidine] [4-(1-hydroxy-1-methyl-ethyl)-3- 6-
4-(1-hydroxy-1-methyl- methyl-phenyl]-[6-
(trifluoromethyl)spiro[3,4- ethyl)-3-methyl-benzoic
(trifluoromethyl)spiro[3,4-dihydro- dihydro-2H-pyrrolo[1,2- acid
2H-pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
N-ethyl-2-methyl-4-[2-methyl-6- 2-methyl-6- 4-(ethylsulfamoyl)-3-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
methyl-benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'- a]pyrazine-1,4'-
carbonyl]benzenesulfonamide piperidine]
N-cyclopropyl-2-methyl-4-[2- 2-methyl-6- 4-(cyclopropylsulfamoyl)-
methyl-6-(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
3-methyl-benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'- a]pyrazine-1,4'-
carbonyl]benzenesulfonamide piperidine]
N-isopropyl-2-methyl-4-[2-methyl- 2-methyl-6-
4-(isopropylsulfamoyl)-3- 6-(trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- methyl-benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'- a]pyrazine-1,4'- carbonyl]benzenesulfonamide
piperidine] N,N,2-trimethyl-4-[2-methyl-6- 2-methyl-6-
4-(dimethylsulfamoyl)-3- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- methyl-benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'- a]pyrazine-1,4'- carbonyl]benzenesulfonamide
piperidine] N,2-dimethyl-4-[6- 6- 3-methyl-4-
(trifluoromethyl)spiro[3,4-dihydro- (trifluoromethyl)spiro[3,4-
(methylsulfamoyl)benzoic 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- acid piperidine]-1'- a]pyrazine-1,4'-
carbonyl]benzenesulfonamide piperidine] (2-phenoxyphenyl)-[6- 6-
2-phenoxybenzoic acid (trifluoromethyl)spiro[3,4-dihydro-
(trifluoromethyl)spiro[3,4- 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'-yl]methanone
a]pyrazine-1,4'- piperidine] (4-phenoxyphenyl)-[6- 6-
4-phenoxybenzoic acid (trifluoromethyl)spiro[3,4-dihydro-
(trifluoromethyl)spiro[3,4- 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'-yl]methanone
a]pyrazine-1,4'- piperidine] (2-phenylphenyl)-[6- 6-
2-phenylbenzoic acid (trifluoromethyl)spiro[3,4-dihydro-
(trifluoromethyl)spiro[3,4- 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'-yl]methanone
a]pyrazine-1,4'- piperidine] [2-methyl-6- 2-methyl-6-
2-phenoxybenzoic acid (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-(2- a]pyrazine-1,4'-
phenoxyphenyl)methanone piperidine] (4-chlorophenyl)-[2-methyl-6-
2-methyl-6- 4-chlorobenzoic acid (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]methanone a]pyrazine-1,4'-
piperidine] [2-methyl-6- 2-methyl-6- 4-phenoxybenzoic acid
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4- a]pyrazine-1,4'- phenoxyphenyl)methanone
piperidine] [2-methyl-6- 2-methyl-6- 4-phenylbenzoic acid
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4- a]pyrazine-1,4'- phenylphenyl)methanone
piperidine] [2-methyl-6- 2-methyl-6- 2-phenylbenzoic acid
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(2- a]pyrazine-1,4'- phenylphenyl)methanone
piperidine] [2-methyl-6- 2-methyl-6- 4-methylbenzoic acid
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(p-tolyl)methanone a]pyrazine-1,4'- piperidine]
N,N,2-trimethyl-4-[6- 6- 4-(dimethylsulfamoyl)-3-
(trifluoromethyl)spiro[3,4-dihydro- (trifluoromethyl)spiro[3,4-
methyl-benzoic acid 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'- a]pyrazine-1,4'-
carbonyl]benzenesulfonamide piperidine] (2'-(cyclopropylmethyl)-6'-
2'-(cyclopropylmethyl)-6'- 4-isopropoxy-3-methoxy-
(trifluoromethyl)-3',4'-dihydro-2'H- (trifluoromethyl)-3',4'-
benzoic acid spiro[piperidine-4,1'-pyrrolo[1,2- dihydro-2'H-
a]pyrazine]-1-yl)(4-isopropoxy-3- spiro[piperidine-4,1'-
methoxyphenyl)methanone pyrrolo[1,2-a]pyrazine]
(2-fluoro-4-isopropoxy-phenyl)-[6- 6- 2-fluoro-4-isopropoxy-
(trifluoromethyl)spiro[3,4-dihydro- (trifluoromethyl)spiro[3,4-
benzoic acid 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'-yl]methanone
a]pyrazine-1,4'- piperidine] (3-fluoro-4-isopropoxy-phenyl)-[6- 6-
3-fluoro-4-isopropoxy- (trifluoromethyl)spiro[3,4-dihydro-
(trifluoromethyl)spiro[3,4- benzoic acid
2H-pyrrolo[1,2-a]pyrazine-1,4'- dihydro-2H-pyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
(3-chloro-4-isopropoxy-phenyl)-[6- 6- 3-chloro-4-isopropoxy-
(trifluoromethyl)spiro[3,4-dihydro- (trifluoromethyl)spiro[3,4-
benzoic acid 2H-pyrrolo[1,2-a]pyrazine-1,4'-
dihydro-2H-pyrrolo[1,2- piperidine]-1'-yl]methanone
a]pyrazine-1,4'- piperidine] (2-fluoro-4-isopropoxy-phenyl)-[2-
2-methyl-6- 2-fluoro-4-isopropoxy-
methyl-6-(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]methanone a]pyrazine-1,4'-
piperidine] (3-fluoro-4-isopropoxy-phenyl)-[2- 2-methyl-6-
3-fluoro-4-isopropoxy- methyl-6-(trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
(3-chloro-4-isopropoxy-phenyl)-[2- 2-methyl-6-
3-chloro-4-isopropoxy- methyl-6-(trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
[3,3-dimethyl-6- 3,3-dimethyl-6- 4-isopropoxy-3-methyl-
(trifluoromethyl)spiro[2,4- (trifluoromethyl)spiro[2,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methyl-phenyl)methanone piperidine] [3,3-dimethyl-6-
3,3-dimethyl-6- 4-isopropoxy-3-methoxy- (trifluoromethyl)spiro[2,4-
(trifluoromethyl)spiro[2,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine] [3,3-dimethyl-6-
3,3-dimethyl-6- 2-fluoro-4-isopropoxy- (trifluoromethyl)spiro[2,4-
(trifluoromethyl)spiro[2,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(2-fluoro-4- a]pyrazine-1,4'-
isopropoxy-phenyl)methanone piperidine]
(3-chloro-4-isopropoxy-phenyl)- 3,3-dimethyl-6-
3-chloro-4-isopropoxy- [3,3-dimethyl-6- (trifluoromethyl)spiro[2,4-
benzoic acid (trifluoromethyl)spiro[2,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(4-tert-butoxy-3-methoxy-phenyl)- 3,3-dimethyl-6-
4-tert-butoxy-3-methoxy- [3,3-dimethyl-6-
(trifluoromethyl)spiro[2,4- benzoic acid
(trifluoromethyl)spiro[2,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] [3,3-dimethyl-6-
3,3-dimethyl-6- 3-fluoro-4-isopropoxy- (trifluoromethyl)spiro[2,4-
(trifluoromethyl)spiro[2,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(3-fluoro-4- a]pyrazine-1,4'-
isopropoxy-phenyl)methanone piperidine]
(2-fluoro-4-isopropoxy-phenyl)-[3- 3-methyl-6-
2-fluoro-4-isopropoxy- methyl-6-(trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydro-2H-pyrrolo[1,2-a]pyrazine- dihydro-2H-pyrrolo[1,2-
1,4'-piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
(4-isopropoxy-3-methoxy-phenyl)- 3-methyl-6-
4-isopropoxy-3-methoxy- [3-methyl-6- (trifluoromethyl)spiro[3,4-
benzoic acid (trifluoromethyl)spiro[3,4-dihydro-
dihydro-2H-pyrrolo[1,2- 2H-pyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
(4-isopropoxy-3-methyl-phenyl)-[3- 3-methyl-6-
4-isopropoxy-3-methyl- methyl-6-(trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydro-2H-pyrrolo[1,2-a]pyrazine- dihydro-2H-pyrrolo[1,2-
1,4'-piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
(3-fluoro-4-isopropoxy-phenyl)-[3- 3-methyl-6-
3-fluoro-4-isopropoxy- methyl-6-(trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydro-2H-pyrrolo[1,2-a]pyrazine- dihydro-2H-pyrrolo[1,2-
1,4'-piperidine]-1'-yl]methanone a]pyrazine-1,4'- piperidine]
[4,4-dimethyl-6- 4,4-dimethyl-6- 4-isopropoxy-3-methoxy-
(trifluoromethyl)spiro[2,3- (trifluoromethyl)spiro[2,3- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine] [7-(difluoromethyl)-5-methyl-
2-methyl-6- 7-(difluoromethyl)-5-
pyrazolo[1,5-a]pyrimidin-3-yl]-[2- (trifluoromethyl)spiro[3,4-
methyl-pyrazolo[1,5- methyl-6-(trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- a]pyrimidine-3-carboxylic
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'- acid
piperidine]-1'-yl]methanone piperidine]
[7-(difluoromethyl)-5-methyl- 6- 7-(difluoromethyl)-5-
pyrazolo[1,5-a]pyrimidin-3-yl]-[6- (trifluoromethyl)spiro[3,4-
methyl-pyrazolo[1,5-
(trifluoromethyl)spiro[3,4-dihydro- dihydro-2H-pyrrolo[1,2-
a]pyrimidine-3-carboxylic 2H-pyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- acid piperidine]-1'-yl]methanone piperidine]
[2,3-dimethyl-6- 2,3-dimethyl-6- 4-isopropoxy-3-methoxy-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine] [4,4-dimethyl-6-
4,4-dimethyl-6- 3-fluoro-4-isopropoxy- (trifluoromethyl)spiro[2,3-
(trifluoromethyl)spiro[2,3- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(3-fluoro-4- a]pyrazine-1,4'-
isopropoxy-phenyl)methanone piperidine] [4,4-dimethyl-6-
4,4-dimethyl-6- 4-isopropoxy-3-methyl- (trifluoromethyl)spiro[2,3-
(trifluoromethyl)spiro[2,3- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methyl-phenyl)methanone piperidine] (3-chloro-4-isopropoxy-phenyl)-
4,4-dimethyl-6- 3-chloro-4-isopropoxy- [4,4-dimethyl-6-
(trifluoromethyl)spiro[2,3- benzoic acid
(trifluoromethyl)spiro[2,3- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
N-cyclopropyl-4-[4,4-dimethyl-6- 4,4-dimethyl-6-
4-(cyclopropylsulfamoyl)- (trifluoromethyl)spiro[2,3-
(trifluoromethyl)spiro[2,3- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'- a]pyrazine-1,4'- carbonyl]benzenesulfonamide
piperidine] [7-(difluoromethyl)-5-methyl- 4,4-dimethyl-6-
7-(difluoromethyl)-5- pyrazolo[1,5-a]pyrimidin-3-yl]-[4,4-
(trifluoromethyl)spiro[2,3- methyl-pyrazolo[1,5- dimethyl-6-
dihydropyrrolo[1,2- a]pyrimidine-3-carboxylic
(trifluoromethyl)spiro[2,3- a]pyrazine-1,4'- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]
piperidine]-1'-yl]methanone [7-[ethyl(methyl)amino]-5-methyl-
2-methyl-6- 7-[ethyl(methyl)amino]-5-
pyrazolo[1,5-a]pyrimidin-3-yl]-[2- (trifluoromethyl)spiro[3,4-
methyl-pyrazolo[1,5- methyl-6-(trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- a]pyrimidine-3-carboxylic
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'- acid
piperidine]-1'-yl]methanone piperidine] [4,4-dimethyl-6-
4,4-dimethyl-6- 4-(1-hydroxy-1-methyl- (trifluoromethyl)spiro[2,3-
(trifluoromethyl)spiro[2,3- ethyl)-3-methyl-benzoic
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2- acid
piperidine]-1'-yl]-[4-(1-hydroxy-1- a]pyrazine-1,4'-
methyl-ethyl)-3-methyl- piperidine] phenyl]methanone
[3-methoxy-4-[(1S)-1- 2-methyl-6- 3-methoxy-4-[(1S)-1-
methylpropoxy]phenyl]-[2-methyl-6- (trifluoromethyl)spiro[3,4-
methylpropoxy]benzoic (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
[3-methoxy-4-[(1R)-1- 2-methyl-6- 3-methoxy-4-[(1R)-1-
methylpropoxy]phenyl]-[2-methyl-6- (trifluoromethyl)spiro[3,4-
methylpropoxy]benzoic (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
[3-methoxy-4-[(1S)-1- 6- 3-methoxy-4-[(1S)-1-
methylpropoxy]phenyl]-[6- (trifluoromethyl)spiro[3,4-
methylpropoxy]benzoic (trifluoromethyl)spiro[3,4-dihydro-
dihydro-2H-pyrrolo[1,2- acid 2H-pyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
[3-methoxy-4-[(1R)-1- 6- 3-methoxy-4-[(1R)-1-
methylpropoxy]phenyl]-[6- (trifluoromethyl)spiro[3,4-
methylpropoxy]benzoic (trifluoromethyl)spiro[3,4-dihydro-
dihydro-2H-pyrrolo[1,2- acid 2H-pyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
(5,7-dimethylpyrazolo[1,5- 2-methyl-6- 5,7-dimethylpyrazolo[1,5-
a]pyrimidin-3-yl)-[2-methyl-6- (trifluoromethyl)spiro[3,4-
a]pyrimidine-3-carboxylic (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine] [7-
2-methyl-6- 7-[ethyl(methyl)amino]-
[ethyl(methyl)amino]pyrazolo[1,5- (trifluoromethyl)spiro[3,4-
pyrazolo[1,5- a]pyrimidin-3-yl]-[2-methyl-6- dihydropyrrolo[1,2-
a]pyrimidine-3-carboxylic (trifluoromethyl)spiro[3,4-
a]pyrazine-1,4'- acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
piperidine] piperidine]-1'-yl]methanone
(5-methyl-7-pyrrolidin-1-yl- 2-methyl-6- 5-methyl-7-pyrrolidin-1-
pyrazolo[1,5-a]pyrimidin-3-yl)-[2- (trifluoromethyl)spiro[3,4-
yl-pyrazolo[1,5- methyl-6-(trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- a]pyrimidine-3-carboxylic
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'- acid
piperidine]-1'-yl]methanone piperidine] [7-(ethylamino)-5-methyl-
2-methyl-6- 7-(ethylamino)-5-methyl-
pyrazolo[1,5-a]pyrimidin-3-yl]-[2- (trifluoromethyl)spiro[3,4-
pyrazolo[1,5- methyl-6-(trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- a]pyrimidine-3-carboxylic
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'- acid
piperidine]-1'-yl]methanone piperidine]
(4-isopropoxy-3-methoxy-phenyl)- 3'-methyl-6-
4-isopropoxy-3-methoxy- [3'-methyl-6- (trifluoromethyl)spiro[3,4-
benzoic acid (trifluoromethyl)spiro[3,4-dihydro-
dihydro-2H-pyrrolo[1,2- 2H-pyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
(7-methylpyrazolo[1,5-a]pyrimidin- 2-methyl-6-
7-methylpyrazolo[1,5- 3-yl)-[2-methyl-6-
(trifluoromethyl)spiro[3,4- a]pyrimidine-3-carboxylic
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
[7-(ethylamino)pyrazolo[1,5- 2-methyl-6- 7-
a]pyrimidin-3-yl]-[2-methyl-6- (trifluoromethyl)spiro[3,4-
(ethylamino)pyrazolo[1,5- (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- a]pyrimidine-3-carboxylic
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'- acid
piperidine]-1'-yl]methanone piperidine]
[7-(isopropylamino)pyrazolo[1,5- 2-methyl-6- 7-
a]pyrimidin-3-yl]-[2-methyl-6- (trifluoromethyl)spiro[3,4-
(isopropylamino)pyrazolo (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- [1,5-a]pyrimidine-3-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'- carboxylic
acid piperidine]-1'-yl]methanone piperidine] [5-cyclopropyl-7-
2-methyl-6- 5-cyclopropyl-7- (difluoromethyl)pyrazolo[1,5-
(trifluoromethyl)spiro[3,4- (difluoromethyl)pyrazolo[1,5-
a]pyrimidin-3-yl]-[2-methyl-6- dihydropyrrolo[1,2- a]pyrimidine-3-
(trifluoromethyl)spiro[3,4- a]pyrazine-1,4'- carboxylic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]
piperidine]-1'-yl]methanone [2-cyclopropyl-6- 2-cyclopropyl-6-
4-isopropoxy-3-methoxy- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine] [2-cyclopropyl-6-
2-cyclopropyl-6- 4-isopropoxy-3-methyl- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methyl-phenyl)methanone piperidine] [2,3'-dimethyl-6-
2,3'-dimethyl-6- 4-isopropoxy-3-methoxy-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine]
[4-(2-hydroxy-1,1-dimethyl-ethyl)- 2-methyl-6- 4-(2-hydroxy-1,1-
3-methoxy-phenyl]-[2-methyl-6- (trifluoromethyl)spiro[3,4-
dimethyl-ethyl)-3- (trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
methoxy-benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
[4-(2-hydroxy-1,1-dimethyl-ethyl)- 6- 4-(2-hydroxy-1,1-
3-methoxy-phenyl]-[6- (trifluoromethyl)spiro[3,4-
dimethyl-ethyl)-3- (trifluoromethyl)spiro[3,4-dihydro-
dihydro-2H-pyrrolo[1,2- methoxy-benzoic acid
2H-pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] 1'-(4-isopropoxy-3-methoxy-
N-methyl-6- 4-isopropoxy-3-methoxy- benzoyl)-N-methyl-6-
(trifluoromethyl)spiro[3,4- benzoic acid
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-2-carboxamide piperidine]-2- carboxamide
1'-(4-isopropoxy-3-methyl-benzoyl)- N-methyl-6-
4-isopropoxy-3-methyl- N-methyl-6- (trifluoromethyl)spiro[3,4-
benzoic acid (trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-2-carboxamide piperidine]-2- carboxamide
1'-(3-chloro-4-isopropoxy-benzoyl)- N-methyl-6-
3-chloro-4-isopropoxy- N-methyl-6- (trifluoromethyl)spiro[3,4-
benzoic acid (trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-2-carboxamide piperidine]-2- carboxamide
1'-(2-fluoro-4-isopropoxy-benzoyl)- N-methyl-6-
2-fluoro-4-isopropoxy- N-methyl-6- (trifluoromethyl)spiro[3,4-
benzoic acid (trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-2-carboxamide piperidine]-2- carboxamide
(5-isopropoxy-6-methyl-2-pyridyl)- 2-methyl-6-
5-isopropoxy-6-methyl- [2-methyl-6- (trifluoromethyl)spiro[3,4-
pyridine-2-carboxylic acid (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
2,2,2-trifluoro-1-[1'-(4- 2,2,2-trifluoro-1-(2-
4-isopropylsulfonyl-3- isopropylsulfonyl-3-methyl- methylspiro[3,4-
methyl-benzoic acid benzoyl)-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(4-
2,2,2-trifluoro-1-(2- 4-isopropylsulfonyl-2-
isopropylsulfonyl-2-methyl- methylspiro[3,4- methyl-benzoic acid
benzoyl)-2-methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-[3-fluoro-4-(1- 2,2,2-trifluoro-1-(2-
3-fluoro-4-(1-hydroxy-1- hydroxy-1-methyl-ethyl)benzoyl]-2-
methylspiro[3,4- methyl-ethyl)benzoic acid methyl-spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-[4-(3-
2,2,2-trifluoro-1-(2- 4-(3-hydroxypropoxy)-3-
hydroxypropoxy)-3-methyl- methylspiro[3,4- methyl-benzoic acid
benzoyl]-2-methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-tert-butoxy-3-methoxy- 2,2,2-trifluoro-1-(2-
4-tert-butoxy-3-methoxy- benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl)ethanone
N,2-dimethyl-4-[2-methyl-6-(2,2,2- 2,2,2-trifluoro-1-(2-
3-methyl-4- trifluoroacetyl)spiro[3,4- methylspiro[3,4-
(methylsulfamoyl)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'- a]pyrazine-1,4'-
carbonyl]benzenesulfonamide piperidine]-6-yl)ethanone
N-cyclopropyl-4-[2-methyl-6-(2,2,2- 2,2,2-trifluoro-1-(2-
4-(cyclopropylsulfamoyl)- trifluoroacetyl)spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'- a]pyrazine-1,4'-
carbonyl]benzenesulfonamide piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-[4-(1-hydroxy- 2,2,2-trifluoro-1-(2-
4-(1-hydroxy-1-methyl- 1-methyl-ethyl)-3-methyl-benzoyl]-
methylspiro[3,4- ethyl)-3-methyl-benzoic 2-methyl-spiro[3,4-
dihydropyrrolo[1,2- acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone
piperidine]-6-yl)ethanone 1-[1'-(4-tert-butylsulfonylbenzoyl)-
2,2,2-trifluoro-1-(2- 4-tert- 2-methyl-spiro[3,4- methylspiro[3,4-
butylsulfonylbenzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(4-isopropoxy- 2,2,2-trifluoro-1-(2-
4-isopropoxy-3-methyl- 3-methyl-benzoyl)-2-methyl- methylspiro[3,4-
benzoic acid spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(4-isopropoxy-
2,2,2-trifluoro-1-(2- 4-isopropoxy-3-methoxy-
3-methoxy-benzoyl)-2-methyl- methylspiro[3,4- benzoic acid
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'-
yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-isopropylsulfonyl-2-methyl- 2,2-dimethyl-1-(2-
4-isopropylsulfonyl-2- benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- methyl-benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2-dimethyl- a]pyrazine-1,4'- propan-1-one
piperidine]-6-yl)propan-1- one 1-[1'-[3-fluoro-4-(1-hydroxy-1-
2,2-dimethyl-1-(2- 3-fluoro-4-(1-hydroxy-1-
methyl-ethyl)benzoyl]-2-methyl- methylspiro[3,4-
methyl-ethyl)benzoic acid spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-6-yl]-2,2-
a]pyrazine-1,4'- dimethyl-propan-1-one piperidine]-6-yl)propan-1-
one 1-[1'-[4-(3-hydroxypropoxy)-3- 2,2-dimethyl-1-(2-
4-(3-hydroxypropoxy)-3- methyl-benzoyl]-2-methyl-spiro[3,4-
methylspiro[3,4- methyl-benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2-dimethyl- a]pyrazine-1,4'- propan-1-one
piperidine]-6-yl)propan-1- one 1-[1'-(4-tert-butoxy-3-methoxy-
2,2-dimethyl-1-(2- 4-tert-butoxy-3-methoxy-
benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2-dimethyl- a]pyrazine-1,4'- propan-1-one
piperidine]-6-yl)propan-1- one 4-[6-(2,2-dimethylpropanoyl)-2-
2,2-dimethyl-1-(2- 3-methyl-4- methyl-spiro[3,4- methylspiro[3,4-
(methylsulfamoyl)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'-carbonyl]-N,2-
a]pyrazine-1,4'- dimethyl-benzenesulfonamide
piperidine]-6-yl)propan-1- one 1-[1'-[4-(1-hydroxy-1-methyl-ethyl)-
2,2-dimethyl-1-(2- 4-(1-hydroxy-1-methyl-
3-methyl-benzoyl]-2-methyl- methylspiro[3,4-
ethyl)-3-methyl-benzoic spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- acid a]pyrazine-1,4'-piperidine]-6-yl]-2,2-
a]pyrazine-1,4'- dimethyl-propan-1-one piperidine]-6-yl)propan-1-
one 1-[1'-(4-isopropoxy-3-methyl- 2,2-dimethyl-1-(2-
4-isopropoxy-3-methyl- benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2-dimethyl-
a]pyrazine-1,4'- propan-1-one piperidine]-6-yl)propan-1- one
1-[1'-(4-isopropoxy-3-methoxy- 2,2-dimethyl-1-(2-
4-isopropoxy-3-methoxy- benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2-dimethyl-
a]pyrazine-1,4'- propan-1-one piperidine]-6-yl)propan-1- one
1-[1'-(3-chloro-4-isopropoxy- 2,2,2-trifluoro-1-(2-
3-chloro-4-isopropoxy- benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl)ethanone
1-[1'-(4-isopropylsulfonyl-3-methyl- 2,2-dimethyl-1-(2-
4-isopropylsulfonyl-3- benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- methyl-benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2-dimethyl- a]pyrazine-1,4'- propan-1-one
piperidine]-6-yl)propan-1- one N-cyclopropyl-4-[6-(2,2-
2,2-dimethyl-1-(2- 4-(cyclopropylsulfamoyl)-
dimethylpropanoyl)-2-methyl- methylspiro[3,4- benzoic acid
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-1'- a]pyrazine-1,4'-
carbonyl]benzenesulfonamide piperidine]-6-yl)propan-1- one
1-[1'-(4-tert-butylsulfonylbenzoyl)- 2,2-dimethyl-1-(2- 4-tert-
2-methyl-spiro[3,4- methylspiro[3,4- butylsulfonylbenzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2-dimethyl- a]pyrazine-1,4'- propan-1-one
piperidine]-6-yl)propan-1- one 1-[1'-(3-chloro-4-isopropoxy-
2,2-dimethyl-1-(2- 3-chloro-4-isopropoxy-
benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2-dimethyl- a]pyrazine-1,4'- propan-1-one
piperidine]-6-yl)propan-1- one (6-chloro-2-methyl-spiro[3,4-
6-chloro-2-methyl- 4-isopropylsulfonyl-3-
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4- methyl-benzoic acid
piperidine]-1'-yl)-(4- dihydropyrrolo[1,2-
isopropylsulfonyl-3-methyl- a]pyrazine-1,4'- phenyl)methanone
piperidine] (6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
4-(1-hydroxy-1-methyl- dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- ethyl)-3-methyl-benzoic
piperidine]-1'-yl)-[4-(1-hydroxy-1- dihydropyrrolo[1,2- acid
methyl-ethyl)-3-methyl- a]pyrazine-1,4'- phenyl]methanone
piperidine] (3-chloro-4-isopropoxy-phenyl)-(6- 6-chloro-2-methyl-
3-chloro-4-isopropoxy- chloro-2-methyl-spiro[3,4- spiro[3,4-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl)methanone a]pyrazine-1,4'-
piperidine] 4-(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
4-(cyclopropylsulfamoyl)- dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- benzoic acid piperidine]-1'-carbonyl)-N-
dihydropyrrolo[1,2- cyclopropyl-benzenesulfonamide a]pyrazine-1,4'-
piperidine] (6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
5-isopropoxy-6-methyl- dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- pyridine-2-carboxylic acid
piperidine]-1'-yl)-(5-isopropoxy-6- dihydropyrrolo[1,2-
methyl-2-pyridyl)methanone a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
4-isopropoxy-3-methoxy- dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- benzoic acid piperidine]-1'-yl)-(4-isopropoxy-3-
dihydropyrrolo[1,2- methoxy-phenyl)methanone a]pyrazine-1,4'-
piperidine] (6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
4-isopropoxy-3-methyl- dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- benzoic acid piperidine]-1'-yl)-(4-isopropoxy-3-
dihydropyrrolo[1,2- methyl-phenyl)methanone a]pyrazine-1,4'-
piperidine] [3-methoxy-4-[(1R)-1- 2-methyl-6-(1,1,2,2,2-
3-methoxy-4-[(1R)-1- methylpropoxy]phenyl]-[2-methyl-6-
pentafluoroethyl)spiro[3,4- methylpropoxy]benzoic (1,1,2,2,2-
dihydropyrrolo[1,2- acid pentafluoroethyl)spiro[3,4-
a]pyrazine-1,4'- dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]
piperidine]-1'-yl]methanone N,2-dimethyl-4-[2-methyl-6-
2-methyl-6-(1,1,2,2,2- 3-methyl-4- (1,1,2,2,2-
pentafluoroethyl)spiro[3,4- (methylsulfamoyl)benzoic
pentafluoroethyl)spiro[3,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'- piperidine] carbonyl]benzenesulfonamide
[4-(3-hydroxypropoxy)-3-methyl- 2-methyl-6-(1,1,2,2,2-
4-(3-hydroxypropoxy)-3- phenyl]-[2-methyl-6-(1,1,2,2,2-
pentafluoroethyl)spiro[3,4- methyl-benzoic acid
pentafluoroethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
[3-fluoro-4-(2-hydroxy-2-methyl- 2-methyl-6-(1,1,2,2,2-
3-fluoro-4-(2-hydroxy-2- propyl)phenyl]-[2-methyl-6-
pentafluoroethyl)spiro[3,4- methyl-propyl)benzoic (1,1,2,2,2-
dihydropyrrolo[1,2- acid pentafluoroethyl)spiro[3,4-
a]pyrazine-1,4'- dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]
piperidine]-1'-yl]methanone N-methyl-4-[2-methyl-6-(1,1,2,2,2-
2-methyl-6-(1,1,2,2,2- 4- pentafluoroethyl)spiro[3,4-
pentafluoroethyl)spiro[3,4- (methylsulfamoyl)benzoic
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2- acid
piperidine]-1'- a]pyrazine-1,4'- carbonyl]benzenesulfonamide
piperidine] [3-methoxy-4-[(1S)-1- 2-methyl-6-(1,1,2,2,2-
3-methoxy-4-[(1S)-1- methylpropoxy]phenyl]-[2-methyl-6-
pentafluoroethyl)spiro[3,4- methylpropoxy]benzoic (1,1,2,2,2-
dihydropyrrolo[1,2- acid pentafluoroethyl)spiro[3,4-
a]pyrazine-1,4'- dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]
piperidine]-1'-yl]methanone (4-tert-butoxy-3-methoxy-phenyl)-
2-methyl-6-(1,1,2,2,2- 4-tert-butoxy-3-methoxy-
[2-methyl-6-(1,1,2,2,2- pentafluoroethyl)spiro[3,4- benzoic acid
pentafluoroethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(4-cyclopropylsulfonylphenyl)-[2- 2-methyl-6-(1,1,2,2,2-
4-cyclopropylsulfonyl- methyl-6-(1,1,2,2,2-
pentafluoroethyl)spiro[3,4- benzoic acid
pentafluoroethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(4-tert-butylsulfonylphenyl)-[2- 2-methyl-6-(1,1,2,2,2- 4-tert-
methyl-6-(1,1,2,2,2- pentafluoroethyl)spiro[3,4-
butylsulfonylbenzoic acid pentafluoroethyl)spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
[3-methoxy-4-(2- 2-methyl-6-(1,1,2,2,2- 3-methoxy-4-(2-
methoxyethoxy)phenyl]-[2-methyl- pentafluoroethyl)spiro[3,4-
methoxyethoxy)benzoic 6-(1,1,2,2,2- dihydropyrrolo[1,2- acid
pentafluoroethyl)spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]
piperidine]-1'-yl]methanone [3-(hydroxymethyl)-4-isopropoxy-
2-methyl-6-(1,1,2,2,2- 3-(hydroxymethyl)-4-
phenyl]-[2-methyl-6-(1,1,2,2,2- pentafluoroethyl)spiro[3,4-
isopropoxy-benzoic acid pentafluoroethyl)spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
[4-(1-hydroxycyclopentyl)phenyl]- 2-methyl-6-(1,1,2,2,2-
4-(1-hydroxycyclopentyl)- [2-methyl-6-(1,1,2,2,2-
pentafluoroethyl)spiro[3,4- benzoic acid
pentafluoroethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
[3-fluoro-4-(1-hydroxy-1-methyl- 2-methyl-6-(1,1,2,2,2-
3-fluoro-4-(1-hydroxy-1- ethyl)phenyl]-[2-methyl-6-
pentafluoroethyl)spiro[3,4- methyl-ethyl)benzoic acid (1,1,2,2,2-
dihydropyrrolo[1,2- pentafluoroethyl)spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]
piperidine]-1'-yl]methanone [4-(1-hydroxy-1-methyl-
2-methyl-6-(1,1,2,2,2- 4-(1-hydroxy-1-methyl-
ethyl)phenyl]-[2-methyl-6- pentafluoroethyl)spiro[3,4-
ethyl)benzoic acid (1,1,2,2,2- dihydropyrrolo[1,2-
pentafluoroethyl)spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]
piperidine]-1'-yl]methanone N-cyclopropyl-4-[2-methyl-6-
2-methyl-6-(1,1,2,2,2- 4-(cyclopropylsulfamoyl)- (1,1,2,2,2-
pentafluoroethyl)spiro[3,4- benzoic acid
pentafluoroethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'- piperidine] carbonyl]benzenesulfonamide
(3-chloro-4-isopropoxy-phenyl)-[2- 2-methyl-6-(1,1,2,2,2-
3-chloro-4-isopropoxy- methyl-6-(1,1,2,2,2-
pentafluoroethyl)spiro[3,4- benzoic acid
pentafluoroethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
[4-(1-hydroxy-1-methyl-ethyl)-3- 2-methyl-6-(1,1,2,2,2-
4-(1-hydroxy-1-methyl- methyl-phenyl]-[2-methyl-6-
pentafluoroethyl)spiro[3,4- ethyl)-3-methyl-benzoic (1,1,2,2,2-
dihydropyrrolo[1,2- acid pentafluoroethyl)spiro[3,4-
a]pyrazine-1,4'- dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]
piperidine]-1'-yl]methanone (4-isopropylsulfonyl-3-methyl-
2-methyl-6-(1,1,2,2,2- 4-isopropylsulfonyl-3-
phenyl)-[2-methyl-6-(1,1,2,2,2- pentafluoroethyl)spiro[3,4-
methyl-benzoic acid pentafluoroethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(4-isopropoxy-3-methoxy-phenyl)- 2-methyl-6-(1,1,2,2,2-
4-isopropoxy-3-methoxy- [2-methyl-6-(1,1,2,2,2-
pentafluoroethyl)spiro[3,4- benzoic acid
pentafluoroethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(4-isopropoxy-3-methyl-phenyl)-[2- 2-methyl-6-(1,1,2,2,2-
4-isopropoxy-3-methyl-
methyl-6-(1,1,2,2,2- pentafluoroethyl)spiro[3,4- benzoic acid
pentafluoroethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] ethyl
1'-(3-chloro-4-isopropoxy- ethyl 6-cyanospiro[3,4-
3-chloro-4-isopropoxy- benzoyl)-6-cyano-spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-2-carboxylate piperidine]-2-carboxylate ethyl
6-cyano-1'-(4-isopropoxy-3- ethyl 6-cyanospiro[3,4-
4-isopropoxy-3-methyl- methyl-benzoyl)spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-2-carboxylate piperidine]-2-carboxylate ethyl
6-cyano-1'-(5-isopropoxy-6- ethyl 6-cyanospiro[3,4-
5-isopropoxy-6-methyl- methyl-pyridine-2- dihydropyrrolo[1,2-
pyridine-2-carboxylic acid carbonyl)spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-2-carboxylate
piperidine]-2-carboxylate 4-(6-acetyl-2-methyl-spiro[3,4-
1-(2-methylspiro[3,4- 4-(cyclopropylsulfamoyl)-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2- benzoic
acid piperidine]-1'-carbonyl)-N- a]pyrazine-1,4'-
cyclopropyl-benzenesulfonamide piperidine]-6-yl)ethanone
1-[1'-(4-isopropylsulfonyl-3-methyl- 1-(2-methylspiro[3,4-
4-isopropylsulfonyl-3- benzoyl)-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- methyl-benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-isopropoxy-3-methyl- 1-(2-methylspiro[3,4-
4-isopropoxy-3-methyl- benzoyl)-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(3-chloro-4-isopropoxy- 1-(2-methylspiro[3,4-
3-chloro-4-isopropoxy- benzoyl)-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-[4-(1-hydroxy-1-methyl-ethyl)- 1-(2-methylspiro[3,4-
4-(1-hydroxy-1-methyl- 3-methyl-benzoyl]-2-methyl-
dihydropyrrolo[1,2- ethyl)-3-methyl-benzoic
spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'- acid
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)ethanone
yl]ethanone 1-[1'-(4-isopropoxy-3-methoxy- 1-(2-methylspiro[3,4-
4-isopropoxy-3-methoxy- benzoyl)-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
[4-(1-hydroxy-1-methyl-ethyl)-3- 2-methylspiro[3,4-
4-(1-hydroxy-1-methyl- methyl-phenyl]-(2-methylspiro[3,4-
dihydropyrrolo[1,2- ethyl)-3-methyl-benzoic
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'- acid
piperidine]-1'-yl)methanone piperidine]
(4-isopropoxy-3-methyl-phenyl)-(2- 2-methylspiro[3,4-
4-isopropoxy-3-methyl- methylspiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- benzoic acid a]pyrazine-1,4'-piperidine]-1'-
a]pyrazine-1,4'- yl)methanone piperidine]
(3-chloro-4-isopropoxy-phenyl)-[2- 2-methyl-6-(2,2,2-
3-chloro-4-isopropoxy- methyl-6-(2,2,2- trifluoroethyl)spiro[3,4-
benzoic acid trifluoroethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
[4-(1-hydroxy-1-methyl-ethyl)-3- 2-methyl-6-(2,2,2-
4-(1-hydroxy-1-methyl- methyl-phenyl]-[2-methyl-6-(2,2,2-
trifluoroethyl)spiro[3,4- ethyl)-3-methyl-benzoic
trifluoroethyl)spiro[3,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(4-isopropylsulfonyl-3-methyl- 2-methyl-6-(2,2,2-
4-isopropylsulfonyl-3- phenyl)-[2-methyl-6-(2,2,2-
trifluoroethyl)spiro[3,4- methyl-benzoic acid
trifluoroethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(4-isopropoxy-3-methoxy-phenyl)- 2-methyl-6-(2,2,2-
4-isopropoxy-3-methoxy- [2-methyl-6-(2,2,2-
trifluoroethyl)spiro[3,4- benzoic acid trifluoroethyl)spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
(4-isopropoxy-3-methyl-phenyl)-[2- 2-methyl-6-(2,2,2-
4-isopropoxy-3-methyl- methyl-6-(2,2,2- trifluoroethyl)spiro[3,4-
benzoic acid trifluoroethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] 1'-(4-isopropoxy-3-methoxy-
2-methyl-6- 4-isopropoxy-3-methoxy- benzoyl)-2-methyl-6-
(trifluoromethyl)spiro[3,4- benzoic acid
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-8-carbonitrile piperidine]-8-carbonitrile
[(5aR,9aR)-spiro[5a,6,7,8,9,9a- (5aR,9aR)-spiro[5a,6,7,8,9,9a-
4-isopentyloxy-3- hexahydro-5H-pyrrolo[1,2- hexahydro-5H-
methoxy-benzoic acid a]quinoxaline-4,4'-piperidine]-1'-yl]-
pyrrolo[1,2- (4-isopentyloxy-3-methoxy- a]quinoxaline-4,4'-
phenyl)methanone piperidine] [(5aS,9aS)-spiro[5a,6,7,8,9,9a-
(5aS,9aS)- 4-isopentyloxy-3- hexahydro-5H-pyrrolo[1,2-
spiro[5a,6,7,8,9,9a- methoxy-benzoic acid
a]quinoxaline-4,4'-piperidine]-1'-yl]- hexahydro-5H-
(4-isopentyloxy-3-methoxy- pyrrolo[1,2- phenyl)methanone
a]quinoxaline-4,4'- piperidine] (4-isopropoxy-3-methoxy-phenyl)-
(3S)-3-methyl-6- 4-isopropoxy-3-methoxy- [(3S)-3-methyl-6-
(trifluoromethyl)spiro[3,4- benzoic acid
(trifluoromethyl)spiro[3,4-dihydro- dihydro-2H-pyrrolo[1,2-
2H-pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(4-isopropoxy-3-methoxy-phenyl)- (3R)-3-methyl-6-
4-isopropoxy-3-methoxy- [(3R)-3-methyl-6-
(trifluoromethyl)spiro[3,4- benzoic acid
(trifluoromethyl)spiro[3,4-dihydro- dihydro-2H-pyrrolo[1,2-
2H-pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] [(3S)-2,3-dimethyl-6-
(3S)-2,3-dimethyl-6- 2-fluoro-4-isopropoxy-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(2-fluoro-4- a]pyrazine-1,4'-
isopropoxy-phenyl)methanone piperidine] [(3R)-2,3-dimethyl-6-
(3R)-2,3-dimethyl-6- 2-fluoro-4-isopropoxy-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(2-fluoro-4- a]pyrazine-1,4'-
isopropoxy-phenyl)methanone piperidine] [(3S)-2,3-dimethyl-6-
(3S)-2,3-dimethyl-6- 4-isopropoxy-3-methoxy-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine] [(3R)-2,3-dimethyl-6-
(3R)-2,3-dimethyl-6- 4-isopropoxy-3-methoxy-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine]
(4-isopropoxy-3-methyl-phenyl)- (3S)-3-methyl-6-
4-isopropoxy-3-methyl- [(3S)-3-methyl-6-
(trifluoromethyl)spiro[3,4- benzoic acid
(trifluoromethyl)spiro[3,4-dihydro- dihydro-2H-pyrrolo[1,2-
2H-pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(4-isopropoxy-3-methyl-phenyl)- (3R)-3-methyl-6-
4-isopropoxy-3-methyl- [(3R)-3-methyl-6-
(trifluoromethyl)spiro[3,4- benzoic acid
(trifluoromethyl)spiro[3,4-dihydro- dihydro-2H-pyrrolo[1,2-
2H-pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(3-fluoro-4-isopropoxy-phenyl)- (3S)-3-methyl-6-
3-fluoro-4-isopropoxy- [(3S)-3-methyl-6-
(trifluoromethyl)spiro[3,4- benzoic acid
(trifluoromethyl)spiro[3,4-dihydro- dihydro-2H-pyrrolo[1,2-
2H-pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(3-fluoro-4-isopropoxy-phenyl)- (3R)-3-methyl-6-
3-fluoro-4-isopropoxy- [(3R)-3-methyl-6-
(trifluoromethyl)spiro[3,4- benzoic acid
(trifluoromethyl)spiro[3,4-dihydro- dihydro-2H-pyrrolo[1,2-
2H-pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
[(1S,3'R)-3'-fluoro-2-methyl-6- (1S,3'R)-3'-fluoro-2-
4-isopropoxy-3-methoxy- (trifluoromethyl)spiro[3,4- methyl-6-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
(trifluoromethyl)spiro[3,4- piperidine]-1'-yl]-(4-isopropoxy-3-
dihydropyrrolo[1,2- methoxy-phenyl)methanone a]pyrazine-1,4'-
piperidine] [(1R,3'R)-3'-fluoro-2-methyl-6- (1R,3'R)-3'-fluoro-2-
4-isopropoxy-3-methoxy- (trifluoromethyl)spiro[3,4- methyl-6-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
(trifluoromethyl)spiro[3,4- piperidine]-1'-yl]-(4-isopropoxy-3-
dihydropyrrolo[1,2- methoxy-phenyl)methanone a]pyrazine-1,4'-
piperidine] [(1R,2'S)-2,2'-dimethyl-6- (1R,2'S)-2,2'-dimethyl-6-
4-isopropoxy-3-methoxy- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine]
[(1R,3'R)-3'-fluoro-2-methyl-6- (1R,3'R)-3'-fluoro-2-
4-isopropoxy-3-methoxy- (trifluoromethyl)spiro[3,4- methyl-6-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
(trifluoromethyl)spiro[3,4- piperidine]-1'-yl]-(4-isopropoxy-3-
dihydropyrrolo[1,2- methoxy-phenyl)methanone a]pyrazine-1,4'-
piperidine] [(1R,3'S)-3'-fluoro-2-methyl-6- (1R,3'S)-3'-fluoro-2-
4-isopropoxy-3-methoxy- (trifluoromethyl)spiro[3,4- methyl-6-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
(trifluoromethyl)spiro[3,4- piperidine]-1'-yl]-(4-isopropoxy-3-
dihydropyrrolo[1,2- methoxy-phenyl)methanone a]pyrazine-1,4'-
piperidine] [(1S,3'R)-3'-fluoro-2-methyl-6- (1S,3'R)-3'-fluoro-2-
4-isopropoxy-3-methoxy- (trifluoromethyl)spiro[3,4- methyl-6-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
(trifluoromethyl)spiro[3,4- piperidine]-1'-yl]-(4-isopropoxy-3-
dihydropyrrolo[1,2- methoxy-phenyl)methanone a]pyrazine-1,4'-
piperidine] [(1S,3'S)-2,3'-dimethyl-6- (1S,3'S)-2,3'-dimethyl-6-
4-isopropoxy-3-methoxy- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine]
[(1S,3'S)-3'-fluoro-2-methyl-6- (1S,3'S)-3'-fluoro-2-
4-isopropoxy-3-methoxy- (trifluoromethyl)spiro[3,4- methyl-6-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
(trifluoromethyl)spiro[3,4- piperidine]-1'-yl]-(4-isopropoxy-3-
dihydropyrrolo[1,2- methoxy-phenyl)methanone a]pyrazine-1,4'-
piperidine] [(1S,3'R)-3'-fluoro-2-methyl-6- (1S,3'R)-3'-fluoro-2-
4-(1-hydroxy-1-methyl- (trifluoromethyl)spiro[3,4- methyl-6-
ethyl)-3-methyl-benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
(trifluoromethyl)spiro[3,4- acid
piperidine]-1'-yl]-[4-(1-hydroxy-1- dihydropyrrolo[1,2-
methyl-ethyl)-3-methyl- a]pyrazine-1,4'- phenyl]methanone
piperidine] [(1S,3'R)-3'-fluoro-2-methyl-6- (1S,3'R)-3'-fluoro-2-
3-(hydroxymethyl)-4- (trifluoromethyl)spiro[3,4- methyl-6-
isopropoxy-benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
(trifluoromethyl)spiro[3,4- piperidine]-1'-yl]-[3-
dihydropyrrolo[1,2- (hydroxymethyl)-4-isopropoxy- a]pyrazine-1,4'-
phenyl]methanone piperidine] N-cyclopropyl-4-[(1S,3'R)-3'-fluoro-
(1S,3'R)-3'-fluoro-2- 4-(cyclopropylsulfamoyl)- 2-methyl-6-
methyl-6- benzoic acid (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'- a]pyrazine-1,4'-
carbonyl]benzenesulfonamide piperidine]
[(1S,3'R)-3'-fluoro-2-methyl-6- (1S,3'R)-3'-fluoro-2-
4-isopropoxy-3-methyl- (trifluoromethyl)spiro[3,4- methyl-6-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
(trifluoromethyl)spiro[3,4- piperidine]-1'-yl]-(4-isopropoxy-3-
dihydropyrrolo[1,2- methyl-phenyl)methanone a]pyrazine-1,4'-
piperidine] [(1R,2'S)-2,2'-dimethyl-6- (1R,2'S)-2,2'-dimethyl-6-
4-isopropoxy-3-methoxy- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine] [(1S,2'R)-2,2'-dimethyl-6-
(1S,2'R)-2,2'-dimethyl-6- 4-isopropoxy-3-methoxy-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine]
[(1S,3'R)-3'-fluoro-2-methyl-6- (1S,3'R)-3'-fluoro-2-
4-(1-hydroxy-1-methyl- (trifluoromethyl)spiro[3,4- methyl-6-
ethyl)-3-methyl-benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
(trifluoromethyl)spiro[3,4- acid
piperidine]-1'-yl]-[4-(1-hydroxy-1- dihydropyrrolo[1,2-
methyl-ethyl)-3-methyl- a]pyrazine-1,4'- phenyl]methanone
piperidine] [(1R,3'S)-3'-fluoro-2-methyl-6- (1R,3'S)-3'-fluoro-2-
4-(1-hydroxy-1-methyl- (trifluoromethyl)spiro[3,4- methyl-6-
ethyl)-3-methyl-benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
(trifluoromethyl)spiro[3,4- acid
piperidine]-1'-yl]-[4-(1-hydroxy-1- dihydropyrrolo[1,2-
methyl-ethyl)-3-methyl- a]pyrazine-1,4'- phenyl]methanone
piperidine] [(1S,3'R)-3'-fluoro-2-methyl-6- (1S,3'R)-3'-fluoro-2-
4-isopropoxy-3-methyl- (trifluoromethyl)spiro[3,4- methyl-6-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
(trifluoromethyl)spiro[3,4- piperidine]-1'-yl]-(4-isopropoxy-3-
dihydropyrrolo[1,2- methyl-phenyl)methanone a]pyrazine-1,4'-
piperidine] [(1R,3'S)-3'-fluoro-2-methyl-6- (1R,3'S)-3'-fluoro-2-
4-isopropoxy-3-methyl- (trifluoromethyl)spiro[3,4- methyl-6-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
(trifluoromethyl)spiro[3,4- piperidine]-1'-yl]-(4-isopropoxy-3-
dihydropyrrolo[1,2- methyl-phenyl)methanone a]pyrazine-1,4'-
piperidine] ethyl 2-[1'-(4-isopropoxy-3- ethyl 2-(2-
4-isopropoxy-3-methoxy- methoxy-benzoyl)-2-methyl- methylspiro[3,4-
benzoic acid spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6-yl]-2- a]pyrazine-1,4'- oxo-acetate
piperidine]-6-yl)-2-oxo- acetate ethyl
2-[1'-(4-isopropoxy-3-methyl- ethyl 2-(2- 4-isopropoxy-3-methyl-
benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2-oxo-acetate a]pyrazine-1,4'-
piperidine]-6-yl)-2-oxo- acetate ethyl
2-[1'-[4-(1-hydroxy-1-methyl- ethyl 2-(2- 4-(1-hydroxy-1-methyl-
ethyl)-3-methyl-benzoyl]-2-methyl- methylspiro[3,4-
ethyl)-3-methyl-benzoic spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- acid a]pyrazine-1,4'-piperidine]-6-yl]-2-
a]pyrazine-1,4'- oxo-acetate piperidine]-6-yl)-2-oxo- acetate ethyl
2-[1'-(3-chloro-4-isopropoxy- ethyl 2-(2- 3-chloro-4-isopropoxy-
benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2-oxo-acetate a]pyrazine-1,4'-
piperidine]-6-yl)-2-oxo- acetate ethyl
2-[1'-(4-isopropylsulfonyl-3- ethyl 2-(2- 4-isopropylsulfonyl-3-
methyl-benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4- methyl-benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2-oxo-acetate a]pyrazine-1,4'-
piperidine]-6-yl)-2-oxo- acetate ethyl 2-[1'-[4- ethyl 2-(2-
4-(cyclopropylsulfamoyl)- (cyclopropylsulfamoyl)benzoyl]-2-
methylspiro[3,4- benzoic acid methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-2-oxo-acetate piperidine]-6-yl)-2-oxo- acetate
[8-bromo-2-methyl-6- 8-bromo-2-methyl-6- 4-isopropoxy-3-methoxy-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine] [8-bromo-2-methyl-6-
8-bromo-2-methyl-6- 4-isopropoxy-3-methyl-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methyl-phenyl)methanone piperidine]
1'-(4-isopropoxy-3-methyl-benzoyl)- 2-methyl-6-
4-isopropoxy-3-methyl- 2-methyl-6- (trifluoromethyl)spiro[3,4-
benzoic acid (trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-8-carbonitrile piperidine]-8-carbonitrile
1'-(3-chloro-4-isopropoxy-benzoyl)- 2-methyl-6-
3-chloro-4-isopropoxy- 2-methyl-6- (trifluoromethyl)spiro[3,4-
benzoic acid (trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-8-carbonitrile piperidine]-8-carbonitrile
1'-[4-(1-hydroxy-1-methyl-ethyl)-3- 2-methyl-6-
4-(1-hydroxy-1-methyl- methyl-benzoyl]-2-methyl-6-
(trifluoromethyl)spiro[3,4- ethyl)-3-methyl-benzoic
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-8-carbonitrile piperidine]-8-carbonitrile
[8-chloro-2-methyl-6- 8-chloro-2-methyl-6- 4-(1-hydroxy-1-methyl-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
ethyl)-3-methyl-benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'-yl]-[4-(1-hydroxy-1-
a]pyrazine-1,4'- methyl-ethyl)-3-methyl- piperidine]
phenyl]methanone [8-chloro-2-methyl-6- 8-chloro-2-methyl-6-
5-isopropoxy-6-methyl- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- pyridine-2-carboxylic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(5-isopropoxy-6- a]pyrazine-1,4'-
methyl-2-pyridyl)methanone piperidine] [8-chloro-2-methyl-6-
8-chloro-2-methyl-6- 4-isopropoxy-3-methoxy-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine] [8-fluoro-2-methyl-6-
8-fluoro-2-methyl-6- 4-isopropoxy-3-methoxy-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine] [8-chloro-2-methyl-6-
8-chloro-2-methyl-6- 4-isopropoxy-3-methyl-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methyl-phenyl)methanone piperidine] [8-fluoro-2-methyl-6-
8-fluoro-2-methyl-6- 4-isopropoxy-3-methyl-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isopropoxy-3- a]pyrazine-1,4'-
methyl-phenyl)methanone piperidine] 2,2,2-trifluoro-1-[1'-(4-
2,2,2-trifluoro-1-(2- 4-isopropylbenzoic acid
isopropylbenzoyl)-2-methyl- methylspiro[3,4-
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-[4-(2-
2,2,2-trifluoro-1-(2- 4-(2- methoxyethoxy)benzoyl]-2-methyl-
methylspiro[3,4- methoxyethoxy)benzoic
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2- acid
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[2-methyl-1'-(4-
2,2,2-trifluoro-1-(2- 4-propoxybenzoic acid
propoxybenzoyl)spiro[3,4- methylspiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 4-[2-methyl-6-(2,2,2-
2,2,2-trifluoro-1-(2- 4-(dipropylsulfamoyl)-
trifluoroacetyl)spiro[3,4- methylspiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-carbonyl]-N,N- a]pyrazine-1,4'-
dipropyl-benzenesulfonamide piperidine]-6-yl)ethanone
1-[1'-(4-butylbenzoyl)-2-methyl- 2,2,2-trifluoro-1-(2-
4-butylbenzoic acid spiro[3,4-dihydropyrrolo[1,2- methylspiro[3,4-
a]pyrazine-1,4'-piperidine]-6-yl]- dihydropyrrolo[1,2-
2,2,2-trifluoro-ethanone a]pyrazine-1,4'- piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[2-methyl-1'-(4- 2,2,2-trifluoro-1-(2-
4-phenylbenzoic acid phenylbenzoyl)spiro[3,4- methylspiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[2-methyl-1'-(4-
2,2,2-trifluoro-1-(2- 4-propylbenzoic acid propylbenzoyl)spiro[3,4-
methylspiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[2-methyl-1'-(4-
2,2,2-trifluoro-1-(2- 4-phenoxybenzoic acid
phenoxybenzoyl)spiro[3,4- methylspiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(4-
2,2,2-trifluoro-1-(2- 4-isopentyloxybenzoic
isopentyloxybenzoyl)-2-methyl- methylspiro[3,4- acid
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 1-[1'-(4-butoxybenzoyl)-2-methyl-
2,2,2-trifluoro-1-(2- 4-butoxybenzoic acid
spiro[3,4-dihydropyrrolo[1,2- methylspiro[3,4-
a]pyrazine-1,4'-piperidine]-6-yl]- dihydropyrrolo[1,2-
2,2,2-trifluoro-ethanone a]pyrazine-1,4'- piperidine]-6-yl)ethanone
1-[1'-(4-tert-butylbenzoyl)-2-methyl- 2,2,2-trifluoro-1-(2-
4-tert-butylbenzoic acid spiro[3,4-dihydropyrrolo[1,2-
methylspiro[3,4- a]pyrazine-1,4'-piperidine]-6-yl]-
dihydropyrrolo[1,2- 2,2,2-trifluoro-ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[2-methyl-1'-[4-
2,2,2-trifluoro-1-(2- 4- (phenoxymethyl)benzoyl]spiro[3,4-
methylspiro[3,4- (phenoxymethyl)benzoic
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2- acid
piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[2-methyl-1'-[4-(1-
2,2,2-trifluoro-1-(2- 4-(1-piperidyl)benzoic
piperidyl)benzoyl]spiro[3,4- methylspiro[3,4- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 1-[1'-(4-tert-butoxybenzoyl)-2-
2,2,2-trifluoro-1-(2- 4-tert-butoxybenzoic acid methyl-spiro[3,4-
methylspiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl)ethanone
1-[1'-(4-benzyloxybenzoyl)-2- 2,2,2-trifluoro-1-(2-
4-benzyloxybenzoic acid methyl-spiro[3,4- methylspiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2,2-trifluoro- a]pyrazine-1,4'- ethanone
piperidine]-6-yl)ethanone 1-[1'-(3-chloro-4-isopropoxy-
2-methyl-1-(2- 3-chloro-4-isopropoxy- benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2-methyl-propan-1-
a]pyrazine-1,4'- one piperidine]-6-yl)propan-1- one
1-[1'-(4-isopropoxy-3-methyl- 2-methyl-1-(2- 4-isopropoxy-3-methyl-
benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2-methyl-propan-1- a]pyrazine-1,4'- one
piperidine]-6-yl)propan-1- one 1-[1'-(4-isopropoxy-3-methoxy-
2-methyl-1-(2- 4-isopropoxy-3-methoxy- benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2-methyl-propan-1-
a]pyrazine-1,4'- one piperidine]-6-yl)propan-1- one
2,2,2-trifluoro-1-[2-methyl-1'-(4- 2,2,2-trifluoro-1-(2-
4-pentylbenzoic acid pentylbenzoyl)spiro[3,4- methylspiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 1-[1'-(3,4-diethoxybenzoyl)-2-
2,2,2-trifluoro-1-(2- 3,4-diethoxybenzoic acid methyl-spiro[3,4-
methylspiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl)ethanone
1-[1'-(4-tert-butyl-3-methoxy- 2,2,2-trifluoro-1-(2-
4-tert-butyl-3-methoxy- benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(4-methoxy-3- 2,2,2-trifluoro-1-(2-
4-methoxy-3-propoxy- propoxy-benzoyl)-2-methyl- methylspiro[3,4-
benzoic acid spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 1-[1'-(4-butoxy-3-methoxy-
2,2,2-trifluoro-1-(2- 4-butoxy-3-methoxy-
benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2,2-trifluoro- a]pyrazine-1,4'- ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(3-methoxy-4-
2,2,2-trifluoro-1-(2- 3-methoxy-4-propoxy-
propoxy-benzoyl)-2-methyl- methylspiro[3,4- benzoic acid
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(3-isopropoxy-
2,2,2-trifluoro-1-(2- 3-isopropoxy-4-methoxy-
4-methoxy-benzoyl)-2-methyl- methylspiro[3,4- benzoic acid
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-[4-(2-hydroxy-
2,2,2-trifluoro-1-(2- 4-(2-hydroxy-2-methyl-
2-methyl-propoxy)-3-methyl- methylspiro[3,4- propoxy)-3-methyl-
benzoyl]-2-methyl-spiro[3,4- dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(3-butoxy-4-methoxy- 2,2,2-trifluoro-1-(2-
3-butoxy-4-methoxy- benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-[4-(1-hydroxy- 2,2,2-trifluoro-1-(2-
4-(1-hydroxy-1-methyl- 1-methyl-ethyl)benzoyl]-2-methyl-
methylspiro[3,4- ethyl)benzoic acid spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'-
yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(4-isobutoxy-3- 2,2,2-trifluoro-1-(2-
4-isobutoxy-3-methoxy- methoxy-benzoyl)-2-methyl- methylspiro[3,4-
benzoic acid spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 1-[1'-(4-ethylbenzoyl)-2-methyl-
2,2,2-trifluoro-1-(2- 4-ethylbenzoic acid
spiro[3,4-dihydropyrrolo[1,2- methylspiro[3,4-
a]pyrazine-1,4'-piperidine]-6-yl]- dihydropyrrolo[1,2-
2,2,2-trifluoro-ethanone a]pyrazine-1,4'- piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(3-fluoro-4- 2,2,2-trifluoro-1-(2-
3-fluoro-4-isopropoxy- isopropoxy-benzoyl)-2-methyl-
methylspiro[3,4- benzoic acid spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'-
yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-ethoxy-3-fluoro-benzoyl)-2- 2,2,2-trifluoro-1-(2-
4-ethoxy-3-fluoro-benzoic methyl-spiro[3,4- methylspiro[3,4- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2,2-trifluoro- a]pyrazine-1,4'- ethanone
piperidine]-6-yl)ethanone 1-[1'-(4-ethyl-3-methoxy-benzoyl)-
2,2,2-trifluoro-1-(2- 4-ethyl-3-methoxy- 2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(4- 2,2,2-trifluoro-1-(2- 4-isopropoxybenzoic
acid isopropoxybenzoyl)-2-methyl- methylspiro[3,4-
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 1-[1'-(4-benzylbenzoyl)-2-methyl-
2,2,2-trifluoro-1-(2- 4-benzylbenzoic acid
spiro[3,4-dihydropyrrolo[1,2- methylspiro[3,4-
a]pyrazine-1,4'-piperidine]-6-yl]- dihydropyrrolo[1,2-
2,2,2-trifluoro-ethanone a]pyrazine-1,4'- piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-[4-isopropoxy- 2,2,2-trifluoro-1-(2-
4-isopropoxy-3- 3-(trifluoromethyl)benzoyl]-2- methylspiro[3,4-
(trifluoromethyl)benzoic methyl-spiro[3,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl- 4-isopropylbenzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
piperidine]-1'-yl)-(4- dihydropyrrolo[1,2-
isopropylphenyl)methanone a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl- 4-propoxybenzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
piperidine]-1'-yl)-(4- dihydropyrrolo[1,2- propoxyphenyl)methanone
a]pyrazine-1,4'- piperidine] 4-(6-chloro-2-methyl-spiro[3,4-
6-chloro-2-methyl- 4-(dipropylsulfamoyl)-
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4- benzoic acid
piperidine]-1'-carbonyl)-N,N- dihydropyrrolo[1,2-
dipropyl-benzenesulfonamide a]pyrazine-1,4'- piperidine]
(4-butylphenyl)-(6-chloro-2-methyl- 6-chloro-2-methyl-
4-butylbenzoic acid spiro[3,4-dihydropyrrolo[1,2- spiro[3,4-
a]pyrazine-1,4'-piperidine]-1'- dihydropyrrolo[1,2- yl)methanone
a]pyrazine-1,4'- piperidine] (6-chloro-2-methyl-spiro[3,4-
6-chloro-2-methyl- 4-phenylbenzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
piperidine]-1'-yl)-(4- dihydropyrrolo[1,2- phenylphenyl)methanone
a]pyrazine-1,4'- piperidine] (6-chloro-2-methyl-spiro[3,4-
6-chloro-2-methyl- 4-propylbenzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
piperidine]-1'-yl)-(4- dihydropyrrolo[1,2- propylphenyl)methanone
a]pyrazine-1,4'- piperidine] (6-chloro-2-methyl-spiro[3,4-
6-chloro-2-methyl- 4-phenoxybenzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
piperidine]-1'-yl)-(4- dihydropyrrolo[1,2- phenoxyphenyl)methanone
a]pyrazine-1,4'- piperidine] (6-chloro-2-methyl-spiro[3,4-
6-chloro-2-methyl- 4-isopentyloxybenzoic
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4- acid
piperidine]-1'-yl)-(4- dihydropyrrolo[1,2-
isopentyloxyphenyl)methanone a]pyrazine-1,4'- piperidine]
(4-butoxyphenyl)-(6-chloro-2- 6-chloro-2-methyl- 4-butoxybenzoic
acid methyl-spiro[3,4- spiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl)methanone a]pyrazine-1,4'- piperidine]
(4-tert-butylphenyl)-(6-chloro-2- 6-chloro-2-methyl-
4-tert-butylbenzoic acid methyl-spiro[3,4- spiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl)methanone a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl- 4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
(phenoxymethyl)benzoic piperidine]-1'-yl)-[4- dihydropyrrolo[1,2-
acid (phenoxymethyl)phenyl]methanone a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
4-(1-piperidyl)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- acid piperidine]-1'-yl)-[4-(1- dihydropyrrolo[1,2-
piperidyl)phenyl]methanone a]pyrazine-1,4'- piperidine]
(4-benzyloxyphenyl)-(6-chloro-2- 6-chloro-2-methyl-
4-benzyloxybenzoic acid methyl-spiro[3,4- spiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl)methanone a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl- 4-pentylbenzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
piperidine]-1'-yl)-(4- dihydropyrrolo[1,2- pentylphenyl)methanone
a]pyrazine-1,4'- piperidine] (6-chloro-2-methyl-spiro[3,4-
6-chloro-2-methyl- 4-cyclohexylbenzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
piperidine]-1'-yl)-(4- dihydropyrrolo[1,2-
cyclohexylphenyl)methanone a]pyrazine-1,4'- piperidine]
(4-tert-butyl-3-methoxy-phenyl)-(6- 6-chloro-2-methyl-
4-tert-butyl-3-methoxy- chloro-2-methyl-spiro[3,4- spiro[3,4-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl)methanone a]pyrazine-1,4'-
piperidine] (6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
4-methoxy-3-propoxy- dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
benzoic acid piperidine]-1'-yl)-(4-methoxy-3- dihydropyrrolo[1,2-
propoxy-phenyl)methanone a]pyrazine-1,4'- piperidine]
(4-butoxy-3-methoxy-phenyl)-(6- 6-chloro-2-methyl-
4-butoxy-3-methoxy- chloro-2-methyl-spiro[3,4- spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl)methanone a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
3-methoxy-4-propoxy- dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
benzoic acid piperidine]-1'-yl)-(3-methoxy-4- dihydropyrrolo[1,2-
propoxy-phenyl)methanone a]pyrazine-1,4'- piperidine]
(3-butoxy-4-methoxy-phenyl)-(6- 6-chloro-2-methyl-
3-butoxy-4-methoxy- chloro-2-methyl-spiro[3,4- spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl)methanone a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl- 3-methoxy-4-[2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
(trifluoromethoxy)ethoxy] piperidine]-1'-yl)-[3-methoxy-4-[2-
dihydropyrrolo[1,2- benzoic acid
(trifluoromethoxy)ethoxy]phenyl]methanone a]pyrazine-1,4'-
piperidine] (6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
3-fluoro-4-(3- dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
methoxyprop-1- piperidine]-1'-yl)-[3-fluoro-4-(3-
dihydropyrrolo[1,2- ynyl)benzoic acid methoxyprop-1-
a]pyrazine-1,4'- ynyl)phenyl]methanone piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
3-fluoro-4-isopropoxy- dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- benzoic acid piperidine]-1'-yl)-(3-fluoro-4-
dihydropyrrolo[1,2- isopropoxy-phenyl)methanone a]pyrazine-1,4'-
piperidine] 4-(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
4-(ethylsulfamoyl)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- acid piperidine]-1'-carbonyl)-N-ethyl-
dihydropyrrolo[1,2- benzenesulfonamide a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
3-fluoro-4-(1-hydroxy-1- dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- methyl-ethyl)benzoic acid
piperidine]-1'-yl)-[3-fluoro-4-(1- dihydropyrrolo[1,2-
hydroxy-1-methyl- a]pyrazine-1,4'- ethyl)phenyl]methanone
piperidine] (6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
4-isopropoxy-3- dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
(trifluoromethyl)benzoic piperidine]-1'-yl)-[4-isopropoxy-3-
dihydropyrrolo[1,2- acid (trifluoromethyl)phenyl]methanone
a]pyrazine-1,4'- piperidine] (6-chloro-2-methyl-spiro[3,4-
6-chloro-2-methyl- 4-isopropoxybenzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
piperidine]-1'-yl)-(4- dihydropyrrolo[1,2-
isopropoxyphenyl)methanone a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
4-isobutoxy-3-methoxy- dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- benzoic acid piperidine]-1'-yl)-(4-isobutoxy-3-
dihydropyrrolo[1,2- methoxy-phenyl)methanone a]pyrazine-1,4'-
piperidine] (6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl- 4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
(difluoromethylsulfonyl)- piperidine]-1'-yl)-[4-
dihydropyrrolo[1,2- benzoic acid
(difluoromethylsulfonyl)phenyl]methanone a]pyrazine-1,4'-
piperidine] (6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
quinoline-8-carboxylic dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- acid piperidine]-1'-yl)-(8- dihydropyrrolo[1,2-
quinolyl)methanone a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
4-(1-hydroxycyclopentyl)- dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- benzoic acid piperidine]-1'-yl)-[4-(1-
dihydropyrrolo[1,2- hydroxycyclopentyl)phenyl]methanone
a]pyrazine-1,4'- piperidine] (6-chloro-2-methyl-spiro[3,4-
6-chloro-2-methyl- 3-methoxy-4-[(1S)-1-
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
methylpropoxy]benzoic piperidine]-1'-yl)-[3-methoxy-4-
dihydropyrrolo[1,2- acid [(1S)-1- a]pyrazine-1,4'-
methylpropoxy]phenyl]methanone piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl- 4-ethyl-3-methoxy-
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4- benzoic acid
piperidine]-1'-yl)-(4-ethyl-3- dihydropyrrolo[1,2-
methoxy-phenyl)methanone a]pyrazine-1,4'- piperidine]
(4-benzylphenyl)-(6-chloro-2- 6-chloro-2-methyl- 4-benzylbenzoic
acid methyl-spiro[3,4- spiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl)methanone a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
3,4-diethoxybenzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- piperidine]-1'-yl)-(3,4- dihydropyrrolo[1,2-
diethoxyphenyl)methanone a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
4-(2-hydroxy-2-methyl- dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- propoxy)-3-methyl- piperidine]-1'-yl)-[4-(2-hydroxy-2-
dihydropyrrolo[1,2- benzoic acid methyl-propoxy)-3-methyl-
a]pyrazine-1,4'- phenyl]methanone piperidine]
1-[1'-(4-isopropylbenzoyl)-2-methyl- 1-(2-methylspiro[3,4-
4-isopropylbenzoic acid spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'-
yl]ethanone piperidine]-6-yl)ethanone 1-[2-methyl-1'-(4-
1-(2-methylspiro[3,4- 4-propoxybenzoic acid
propoxybenzoyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
4-(6-acetyl-2-methyl-spiro[3,4- 1-(2-methylspiro[3,4-
4-(dipropylsulfamoyl)- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- benzoic acid piperidine]-1'-carbonyl)-N,N-
a]pyrazine-1,4'- dipropyl-benzenesulfonamide
piperidine]-6-yl)ethanone 1-[1'-(4-butylbenzoyl)-2-methyl-
1-(2-methylspiro[3,4- 4-butylbenzoic acid
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 1-[2-methyl-1'-(4- 1-(2-methylspiro[3,4-
4-phenylbenzoic acid phenylbenzoyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[2-methyl-1'-(4- 1-(2-methylspiro[3,4- 4-propylbenzoic acid
propylbenzoyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[2-methyl-1'-(4- 1-(2-methylspiro[3,4- 4-phenoxybenzoic acid
phenoxybenzoyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-isopentyloxybenzoyl)-2- 1-(2-methylspiro[3,4-
4-isopentyloxybenzoic methyl-spiro[3,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-butoxybenzoyl)-2-methyl- 1-(2-methylspiro[3,4-
4-butoxybenzoic acid spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'-
yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-tert-butylbenzoyl)-2-methyl- 1-(2-methylspiro[3,4-
4-tert-butylbenzoic acid spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'-
yl]ethanone piperidine]-6-yl)ethanone 1-[2-methyl-1'-[4-
1-(2-methylspiro[3,4- 4- (phenoxymethyl)benzoyl]spiro[3,4-
dihydropyrrolo[1,2- (phenoxymethyl)benzoic
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'- acid
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[2-methyl-1'-[4-(1- 1-(2-methylspiro[3,4- 4-(1-piperidyl)benzoic
piperidyl)benzoyl]spiro[3,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-benzyloxybenzoyl)-2- 1-(2-methylspiro[3,4-
4-benzyloxybenzoic acid methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[2-methyl-1'-(4- 1-(2-methylspiro[3,4- 4-pentylbenzoic acid
pentylbenzoyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-cyclohexylbenzoyl)-2- 1-(2-methylspiro[3,4-
4-cyclohexylbenzoic acid methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-tert-butyl-3-methoxy- 1-(2-methylspiro[3,4-
4-tert-butyl-3-methoxy- benzoyl)-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-methoxy-3-propoxy- 1-(2-methylspiro[3,4-
4-methoxy-3-propoxy- benzoyl)-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-butoxy-3-methoxy- 1-(2-methylspiro[3,4-
4-butoxy-3-methoxy- benzoyl)-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(3-methoxy-4-propoxy- 1-(2-methylspiro[3,4-
3-methoxy-4-propoxy- benzoyl)-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-[3-methoxy-4-[2- 1-(2-methylspiro[3,4- 3-methoxy-4-[2-
(trifluoromethoxy)ethoxy]benzoyl]- dihydropyrrolo[1,2-
(trifluoromethoxy)ethoxy] 2-methyl-spiro[3,4- a]pyrazine-1,4'-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
piperidine]-6-yl)ethanone piperidine]-6-yl]ethanone
1-[1'-[3-fluoro-4-(3-methoxyprop-1- 1-(2-methylspiro[3,4-
3-fluoro-4-(3- ynyl)benzoyl]-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- methoxyprop-1-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'- ynyl)benzoic
acid piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-ethylbenzoyl)-2-methyl- 1-(2-methylspiro[3,4-
4-ethylbenzoic acid spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'-
yl]ethanone piperidine]-6-yl)ethanone 1-[1'-(3-fluoro-4-isopropoxy-
1-(2-methylspiro[3,4- 3-fluoro-4-isopropoxy-
benzoyl)-2-methyl-spiro[3,4- dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
4-(6-acetyl-2-methyl-spiro[3,4- 1-(2-methylspiro[3,4-
4-(ethylsulfamoyl)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'-carbonyl)-N-ethyl-
a]pyrazine-1,4'- benzenesulfonamide piperidine]-6-yl)ethanone
1-[1'-[3-fluoro-4-(1-hydroxy-1- 1-(2-methylspiro[3,4-
3-fluoro-4-(1-hydroxy-1- methyl-ethyl)benzoyl]-2-methyl-
dihydropyrrolo[1,2- methyl-ethyl)benzoic acid
spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)ethanone
yl]ethanone 1-[1'-[4-isopropoxy-3- 1-(2-methylspiro[3,4-
4-isopropoxy-3- (trifluoromethyl)benzoyl]-2-methyl-
dihydropyrrolo[1,2- (trifluoromethyl)benzoic
spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'- acid
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)ethanone
yl]ethanone 1-[1'-(4-isopropoxybenzoyl)-2- 1-(2-methylspiro[3,4-
4-isopropoxybenzoic acid methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-isobutoxy-3-methoxy- 1-(2-methylspiro[3,4-
4-isobutoxy-3-methoxy- benzoyl)-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone 1-[1'-[4-
1-(2-methylspiro[3,4- 4- (difluoromethylsulfonyl)benzoyl]-2-
dihydropyrrolo[1,2- (difluoromethylsulfonyl)- methyl-spiro[3,4-
a]pyrazine-1,4'- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
piperidine]-6-yl)ethanone piperidine]-6-yl]ethanone
1-[2-methyl-1'-(quinoline-8- 1-(2-methylspiro[3,4-
quinoline-8-carboxylic carbonyl)spiro[3,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone 1-[1'-[4-(1-
1-(2-methylspiro[3,4- 4-(1-hydroxycyclopentyl)-
hydroxycyclopentyl)benzoyl]-2- dihydropyrrolo[1,2- benzoic acid
methyl-spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)ethanone
piperidine]-6-yl]ethanone 1-[1'-[3-methoxy-4-[(1S)-1-
1-(2-methylspiro[3,4- 3-methoxy-4-[(1S)-1-
methylpropoxy]benzoyl]-2-methyl- dihydropyrrolo[1,2-
methylpropoxy]benzoic spiro[3,4-dihydropyrrolo[1,2-
a]pyrazine-1,4'- acid a]pyrazine-1,4'-piperidine]-6-
piperidine]-6-yl)ethanone yl]ethanone
1-[1'-(4-ethyl-3-methoxy-benzoyl)- 1-(2-methylspiro[3,4-
4-ethyl-3-methoxy- 2-methyl-spiro[3,4- dihydropyrrolo[1,2- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-benzylbenzoyl)-2-methyl- 1-(2-methylspiro[3,4-
4-benzylbenzoic acid spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'-
yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(3,4-diethoxybenzoyl)-2- 1-(2-methylspiro[3,4-
3,4-diethoxybenzoic acid methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-[4-(2-hydroxy-2-methyl- 1-(2-methylspiro[3,4-
4-(2-hydroxy-2-methyl- propoxy)-3-methyl-benzoyl]-2-
dihydropyrrolo[1,2- propoxy)-3-methyl- methyl-spiro[3,4-
a]pyrazine-1,4'- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
piperidine]-6-yl)ethanone piperidine]-6-yl]ethanone
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
3-methoxy-4-[(1R)-1- dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
methylpropoxy]benzoic piperidine]-1'-yl)-[3-methoxy-4-
dihydropyrrolo[1,2- acid [(1R)-1- a]pyrazine-1,4'-
methylpropoxy]phenyl]methanone piperidine]
1-[1'-[3-methoxy-4-[(1R)-1- 1-(2-methylspiro[3,4-
3-methoxy-4-[(1R)-1- methylpropoxy]benzoyl]-2-methyl-
dihydropyrrolo[1,2- methylpropoxy]benzoic
spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'- acid
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)ethanone
yl]ethanone 2-isopropoxy-5-[2-methyl-6-(2,2,2-
2,2,2-trifluoro-1-(2- 3-cyano-4-isopropoxy-
trifluoroacetyl)spiro[3,4- methylspiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-carbonyl]benzonitrile a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-[4-methoxy-3-
2,2,2-trifluoro-1-(2- 4-methoxy-3-
(trifluoromethyl)benzoyl]-2-methyl- methylspiro[3,4-
(trifluoromethyl)benzoic spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- acid a]pyrazine-1,4'-piperidine]-6-
a]pyrazine-1,4'- yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[2-methyl-1'-[4- 2,2,2-trifluoro-1-(2- 4-
(trifluoromethoxy)benzoyl]spiro[3,4- methylspiro[3,4-
(trifluoromethoxy)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-[3-
2,2,2-trifluoro-1-(2- 3-(hydroxymethyl)-4-
(hydroxymethyl)-4-isopropoxy- methylspiro[3,4- isopropoxy-benzoic
acid benzoyl]-2-methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-[4-(2-hydroxy- 2,2,2-trifluoro-1-(2-
4-(2-hydroxy-2-methyl- 2-methyl-propyl)benzoyl]-2-methyl-
methylspiro[3,4- propyl)benzoic acid spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'-
yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-[3-methoxy-4- 2,2,2-trifluoro-1-(2-
3-methoxy-4-(2- (2-methoxyethoxy)benzoyl]-2- methylspiro[3,4-
methoxyethoxy)benzoic methyl-spiro[3,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
[8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6- 4-isopropoxybenzoic acid
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4- a]pyrazine-1,4'- isopropoxyphenyl)methanone
piperidine] [8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6-
4-propoxybenzoic acid (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-(4- a]pyrazine-1,4'-
propoxyphenyl)methanone piperidine] [8-fluoro-2-methyl-6-
8-fluoro-2-methyl-6- 4-(2- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4-
methoxyethoxy)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'-yl]-[4-(2- a]pyrazine-1,4'-
methoxyethoxy)phenyl]methanone piperidine] [8-fluoro-2-methyl-6-
8-fluoro-2-methyl-6- 4-(1-hydroxy-1-methyl-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
ethyl)benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-[4-(1-hydroxy-1-
a]pyrazine-1,4'- methyl-ethyl)phenyl]methanone piperidine]
[8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6- 4-(1-hydroxy-2-methyl-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
propyl)benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-[4-(1-hydroxy-2-
a]pyrazine-1,4'- methyl-propyl)phenyl]methanone piperidine]
[8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6- 4-(1-hydroxy-1-methyl-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
ethyl)-3-methyl-benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'-yl]-[4-(1-hydroxy-1-
a]pyrazine-1,4'- methyl-ethyl)-3-methyl- piperidine]
phenyl]methanone [3-fluoro-4-(1-hydroxy-1-methyl-
8-fluoro-2-methyl-6- 3-fluoro-4-(1-hydroxy-1-
ethyl)phenyl]-[8-fluoro-2-methyl-6- (trifluoromethyl)spiro[3,4-
methyl-ethyl)benzoic acid (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-1'-yl]methanone piperidine]
[8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6- 4-(2-hydroxy-2-methyl-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
propoxy)-3-methyl- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- benzoic acid
piperidine]-1'-yl]-[4-(2-hydroxy-2- a]pyrazine-1,4'-
methyl-propoxy)-3-methyl- piperidine] phenyl]methanone
[8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6- 4-(1-hydroxycyclobutyl)-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-[4-(1- a]pyrazine-1,4'-
hydroxycyclobutyl)phenyl]methanone piperidine]
(3-fluoro-4-isopropoxy-phenyl)-[8- 8-fluoro-2-methyl-6-
3-fluoro-4-isopropoxy- fluoro-2-methyl-6-
(trifluoromethyl)spiro[3,4- benzoic acid
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] [8-fluoro-2-methyl-6-
8-fluoro-2-methyl-6- 3-methoxy-4-propoxy-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(3-methoxy-4- a]pyrazine-1,4'-
propoxy-phenyl)methanone piperidine] [8-fluoro-2-methyl-6-
8-fluoro-2-methyl-6- 3-methoxy-4-[(1S)-1-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
methylpropoxy]benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'-yl]-[3-methoxy-4-
a]pyrazine-1,4'- [(1S)-1- piperidine]
methylpropoxy]phenyl]methanone [8-fluoro-2-methyl-6-
8-fluoro-2-methyl-6- 3-methoxy-4-(2- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- methoxyethoxy)benzoic
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2- acid
piperidine]-1'-yl]-[3-methoxy-4-(2- a]pyrazine-1,4'-
methoxyethoxy)phenyl]methanone piperidine]
(4-tert-butoxy-3-methoxy-phenyl)- 8-fluoro-2-methyl-6-
4-tert-butoxy-3-methoxy- [8-fluoro-2-methyl-6-
(trifluoromethyl)spiro[3,4- benzoic acid
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] [8-fluoro-2-methyl-6-
8-fluoro-2-methyl-6- 4-isobutoxy-3-methoxy-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-isobutoxy-3- a]pyrazine-1,4'-
methoxy-phenyl)methanone piperidine]
[4-(difluoromethoxy)-3-methoxy- 8-fluoro-2-methyl-6-
4-(difluoromethoxy)-3- phenyl]-[8-fluoro-2-methyl-6-
(trifluoromethyl)spiro[3,4- methoxy-benzoic acid
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] [8-fluoro-2-methyl-6-
8-fluoro-2-methyl-6- 4-(3-hydroxypropoxy)-3-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
methyl-benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-[4-(3- a]pyrazine-1,4'-
hydroxypropoxy)-3-methyl- piperidine] phenyl]methanone
[8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6- 3-(hydroxymethyl)-4-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
isopropoxy-benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-[3- a]pyrazine-1,4'-
(hydroxymethyl)-4-isopropoxy- piperidine] phenyl]methanone
[8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6- 4-methoxy-3-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'-yl]-[4-methoxy-3-
a]pyrazine-1,4'- (trifluoromethyl)phenyl]methanone piperidine]
[8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6- 4-(2-hydroxyethoxy)-3-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
methoxy-benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-[4-(2- a]pyrazine-1,4'-
hydroxyethoxy)-3-methoxy- piperidine] phenyl]methanone
[8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6- 5-isopropoxy-6-methyl-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
pyridine-2-carboxylic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-(5-isopropoxy-6-
a]pyrazine-1,4'- methyl-2-pyridyl)methanone piperidine]
N-cyclopropyl-4-[8-fluoro-2-methyl- 8-fluoro-2-methyl-6-
4-(cyclopropylsulfamoyl)- 6-(trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'- a]pyrazine-1,4'- carbonyl]benzenesulfonamide
piperidine] 4-[8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6- 4-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
(methylsulfamoyl)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'-carbonyl]-N-methyl-
a]pyrazine-1,4'- benzenesulfonamide piperidine]
[4-(difluoromethylsulfonyl)phenyl]- 8-fluoro-2-methyl-6- 4-
[8-fluoro-2-methyl-6- (trifluoromethyl)spiro[3,4-
(difluoromethylsulfonyl)- (trifluoromethyl)spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] [8-fluoro-2-methyl-6-
8-fluoro-2-methyl-6- 4- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- isopropylsulfonylbenzoic
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2- acid
piperidine]-1'-yl]-(4- a]pyrazine-1,4'-
isopropylsulfonylphenyl)methanone piperidine] [8-fluoro-2-methyl-6-
8-fluoro-2-methyl-6- 4-isopropylsulfonyl-3-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
methyl-benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-(4- a]pyrazine-1,4'-
isopropylsulfonyl-3-methyl- piperidine] phenyl)methanone
[8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6- 6-isopropoxypyridine-3-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- carboxylic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'yl]-(6-isopropoxy-3- a]pyrazine-1,4'-
pyridyl)methanone piperidine] [8-fluoro-2-methyl-6-
8-fluoro-2-methyl-6- 4-(2-hydroxy-2-methyl-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
propyl)benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-[4-(2-hydroxy-2-
a]pyrazine-1,4'- methyl-propyl)phenyl]methanone piperidine]
[8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6- 3-methoxy-4-[(1R)-1-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
methylpropoxy]benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'-yl]-[3-methoxy-4-
a]pyrazine-1,4'- [(1R)-1- piperidine]
methylpropoxy]phenyl]methanone 1-[1'-[4-(1-hydroxy-1-methyl-ethyl)-
1-(2-methylspiro[3,4- 4-(1-hydroxy-1-methyl-
3-methyl-benzoyl]-2-methyl- dihydropyrrolo[1,2-
ethyl)-3-methyl-benzoic spiro[3,4-dihydropyrrolo[1,2-
a]pyrazine-1,4'- acid a]pyrazine-1,4'-piperidine]-6-
piperidine]-6-yl)propan-1- yl]propan-1-one one
1-[1'-(4-isopropoxy-3-methoxy- 1-(2-methylspiro[3,4-
4-isopropoxy-3-methoxy- benzoyl)-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]propan-1-one piperidine]-6-yl)propan-1- one
1-[1'-(3-chloro-4-isopropoxy- 1-(2-methylspiro[3,4-
3-chloro-4-isopropoxy- benzoyl)-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]propan-1-one piperidine]-6-yl)propan-1- one
1-[1'-(4-isopropoxy-3-methyl- 1-(2-methylspiro[3,4-
4-isopropoxy-3-methyl- benzoyl)-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]propan-1-one piperidine]-6-yl)propan-1- one
1-[2-methyl-1'-[4-(1- 1-(2-methylspiro[3,4- 4-(1-piperidyl)benzoic
piperidyl)benzoyl]spiro[3,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]propan-1-one piperidine]-6-yl)propan-1- one
1-[1'-(4-cyclopropylbenzoyl)-2- 2,2,2-trifluoro-1-(2-
4-cyclopropylbenzoic acid methyl-spiro[3,4- methylspiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2,2-trifluoro- a]pyrazine-1,4'- ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(4-
2,2,2-trifluoro-1-(2- 4-isobutylbenzoic acid
isobutylbenzoyl)-2-methyl-spiro[3,4- methylspiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[2-methyl-1'-(3-
2,2,2-trifluoro-1-(2- 3-methyl-4-phenyl-
methyl-4-phenyl-benzoyl)spiro[3,4- methylspiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 1-[1'-[4-(2,2- 2,2,2-trifluoro-1-(2-
4-(2,2- dimethylpropoxy)benzoyl]-2- methylspiro[3,4-
dimethylpropoxy)benzoic methyl-spiro[3,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-2,2,2-trifluoro- piperidine]-6-yl)ethanone
ethanone 5-[8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6-
3-cyano-4-isopropoxy- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-carbonyl]-2- a]pyrazine-1,4'-
isopropoxy-benzonitrile piperidine] (4-ethyl-3-methoxy-phenyl)-[8-
8-fluoro-2-methyl-6- 4-ethyl-3-methoxy- fluoro-2-methyl-6-
(trifluoromethyl)spiro[3,4- benzoic acid
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine]
(4-cyclopropylphenyl)-[8-fluoro-2- 8-fluoro-2-methyl-6-
4-cyclopropylbenzoic acid methyl-6-(trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]methanone a]pyrazine-1,4'-
piperidine] 1-[1'-[4- 2,2,2-trifluoro-1-(2- 4-(cyclopropylmethoxy)-
(cyclopropylmethoxy)benzoyl]-2- methylspiro[3,4- benzoic acid
methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-2,2,2-trifluoro- piperidine]-6-yl)ethanone
ethanone 2,2,2-trifluoro-1-[2-methyl-1'-[4- 2,2,2-trifluoro-1-(2-
4-(2,2,2- (2,2,2- methylspiro[3,4- trifluoroethoxy)benzoic
trifluoroethoxy)benzoyl]spiro[3,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(4-methoxy-3- 2,2,2-trifluoro-1-(2-
4-methoxy-3-phenyl- phenyl-benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(4-isopropyl-3- 2,2,2-trifluoro-1-(2-
4-isopropyl-3- methylsulfonyl-benzoyl)-2-methyl- methylspiro[3,4-
methylsulfonyl-benzoic spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- acid a]pyrazine-1,4'-piperidine]-6-
a]pyrazine-1,4'- yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-cyclohexylbenzoyl)-2- 2,2,2-trifluoro-1-(2-
4-cyclohexylbenzoic acid methyl-spiro[3,4- methylspiro[3,4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2,2-trifluoro- a]pyrazine-1,4'- ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-[4-(1-
2,2,2-trifluoro-1-(2- 4-(1-hydroxycyclopentyl)-
hydroxycyclopentyl)-3-methyl- methylspiro[3,4- 3-methyl-benzoic
acid benzoyl]-2-methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
3-(hydroxymethyl)-4- dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
isopropoxy-benzoic acid piperidine]-1'-yl)-[3- dihydropyrrolo[1,2-
(hydroxymethyl)-4-isopropoxy- a]pyrazine-1,4'- phenyl]methanone
piperidine] (6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl-
4-(cyclopropylmethoxy)- dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- benzoic acid piperidine]-1'-yl)-[4- dihydropyrrolo[1,2-
(cyclopropylmethoxy)phenyl]methanone a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl- 4-(2,2,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
trifluoroethoxy)benzoic piperidine]-1'-yl)-[4-(2,2,2-
dihydropyrrolo[1,2- acid trifluoroethoxy)phenyl]methanone
a]pyrazine-1,4'- piperidine] (6-chloro-2-methyl-spiro[3,4-
6-chloro-2-methyl- 4-(2,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- dimethylpropoxy)benzoic piperidine]-1'-yl)-[4-(2,2-
dihydropyrrolo[1,2- acid dimethylpropoxy)phenyl]methanone
a]pyrazine-1,4'- piperidine] 5-(6-chloro-2-methyl-spiro[3,4-
6-chloro-2-methyl- 3-cyano-4-isopropoxy-
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4- benzoic acid
piperidine]-1'-carbonyl)-2- dihydropyrrolo[1,2-
isopropoxy-benzonitrile a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl- 3-methyl-4-phenyl-
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4- benzoic acid
piperidine]-1'-yl)-(3-methyl-4- dihydropyrrolo[1,2-
phenyl-phenyl)methanone a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl- 4-
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
(trifluoromethoxy)benzoic piperidine]-1'-yl)-[4-
dihydropyrrolo[1,2- acid (trifluoromethoxy)phenyl]methanone
a]pyrazine-1,4'- piperidine] (6-chloro-2-methyl-spiro[3,4-
6-chloro-2-methyl- 4-cyclopropylbenzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
piperidine]-1'-yl)-(4- dihydropyrrolo[1,2-
cyclopropylphenyl)methanone a]pyrazine-1,4'- piperidine]
(6-chloro-2-methyl-spiro[3,4- 6-chloro-2-methyl- 4-isobutylbenzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
piperidine]-1'-yl)-(4- dihydropyrrolo[1,2- isobutylphenyl)methanone
a]pyrazine-1,4'- piperidine] (6-chloro-2-methyl-spiro[3,4-
6-chloro-2-methyl- 4-methoxy-3- dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[3,4- (trifluoromethyl)benzoic
piperidine]-1'-yl)-[4-methoxy-3- dihydropyrrolo[1,2- acid
(trifluoromethyl)phenyl]methanone a]pyrazine-1,4'- piperidine]
1-[1'-[3-(hydroxymethyl)-4- 1-(2-methylspiro[3,4-
3-(hydroxymethyl)-4- isopropoxy-benzoyl]-2-methyl-
dihydropyrrolo[1,2- isopropoxy-benzoic acid
spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)ethanone
yl]ethanone 1-[1'-[4- 1-(2-methylspiro[3,4- 4-(cyclopropylmethoxy)-
(cyclopropylmethoxy)benzoyl]-2- dihydropyrrolo[1,2- benzoic acid
methyl-spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)ethanone
piperidine]-6-yl]ethanone 1-[1'-(4-methoxy-3-phenyl-benzoyl)-
1-(2-methylspiro[3,4- 4-methoxy-3-phenyl- 2-methyl-spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[2-methyl-1'-[4-(2,2,2- 1-(2-methylspiro[3,4- 4-(2,2,2-
trifluoroethoxy)benzoyl]spiro[3,4- dihydropyrrolo[1,2-
trifluoroethoxy)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- acid piperidine]-6-yl]ethanone
piperidine]-6-yl)ethanone 1-[1'-[4-(2,2- 1-(2-methylspiro[3,4-
4-(2,2- dimethylpropoxy)benzoyl]-2- dihydropyrrolo[1,2-
dimethylpropoxy)benzoic methyl-spiro[3,4- a]pyrazine-1,4'- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)ethanone
piperidine]-6-yl]ethanone 5-(6-acetyl-2-methyl-spiro[3,4-
1-(2-methylspiro[3,4- 3-cyano-4-isopropoxy-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2- benzoic
acid piperidine]-1'-carbonyl)-2- a]pyrazine-1,4'-
isopropoxy-benzonitrile piperidine]-6-yl)ethanone
1-[2-methyl-1'-(3-methyl-4-phenyl- 1-(2-methylspiro[3,4-
3-methyl-4-phenyl- benzoyl)spiro[3,4- dihydropyrrolo[1,2- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[2-methyl-1'-[4- 1-(2-methylspiro[3,4- 4-
(trifluoromethoxy)benzoyl]spiro[3,4- dihydropyrrolo[1,2-
(trifluoromethoxy)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- acid piperidine]-6-yl]ethanone
piperidine]-6-yl)ethanone 1-[1'-(4-cyclopropylbenzoyl)-2-
1-(2-methylspiro[3,4- 4-cyclopropylbenzoic acid methyl-spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone
piperidine]-6-yl)ethanone 1-[1'-(4-isobutylbenzoyl)-2-methyl-
1-(2-methylspiro[3,4- 4-isobutylbenzoic acid
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone (6-chloro-2-methyl-spiro[3,4-
6-chloro-2-methyl- 4-[(4-methyl-1-
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[3,4-
piperidyl)sulfonyl]benzoic piperidine]-1'-yl)-[4-[(4-methyl-1-
dihydropyrrolo[1,2- acid piperidyl)sulfonyl]phenyl]methanone
a]pyrazine-1,4'- piperidine] 2,2,2-trifluoro-1-[1'-(5-isopropoxy-
2,2,2-trifluoro-1-(2- 5-isopropoxy-6-methyl-
6-methyl-pyridine-2-carbonyl)-2- methylspiro[3,4-
pyridine-2-carboxylic acid methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[2-methyl-1'-[4-[(4- 2,2,2-trifluoro-1-(2-
4-[(4-methyl-1- methyl-1- methylspiro[3,4-
piperidyl)sulfonyl]benzoic piperidyl)sulfonyl]benzoyl]spiro[3,4-
dihydropyrrolo[1,2- acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone
piperidine]-6-yl)ethanone 1-[1'-(3-chloro-4-methoxy-benzoyl)-
2,2,2-trifluoro-1-(2- 3-chloro-4-methoxy- 2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(3-fluoro-4- 2,2,2-trifluoro-1-(2-
3-fluoro-4-methoxy- methoxy-benzoyl)-2-methyl- methylspiro[3,4-
benzoic acid spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(4-
2,2,2-trifluoro-1-(2- 4-isobutoxybenzoic acid
isobutoxybenzoyl)-2-methyl- methylspiro[3,4-
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone (4-cyclohexylphenyl)-[2-methyl-6-
2,2,2-trifluoro-1-(2- 4-cyclohexylbenzoic acid
(2,2,2-trifluoro-1-hydroxy- methylspiro[3,4-
ethyl)spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-1'- a]pyrazine-1,4'- yl]methanone
piperidine]-6-yl)ethanol 2,2,2-trifluoro-1-[1'-(4-methoxy-3-
2,2,2-trifluoro-1-(2- 4-methoxy-3-methyl-
methyl-benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 1-[1'-(4-cyclohexylbenzoyl)-3,3-
1-(3,3-dimethylspiro[2,4- 4-cyclohexylbenzoic acid
dimethyl-spiro[2,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-2,2,2-trifluoro- piperidine]-6-yl)-2,2,2-
ethanone trifluoro-ethanone 2,2,2-trifluoro-1-[1'-(3-fluoro-4-
1-(3,3-dimethylspiro[2,4- 3-fluoro-4-isopropoxy-
isopropoxy-benzoyl)-3,3-dimethyl- dihydropyrrolo[1,2- benzoic acid
spiro[2,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)-2,2,2- yl]ethanone
trifluoro-ethanone 2,2,2-trifluoro-1-[1'-(5-isopropoxy-
1-(3,3-dimethylspiro[2,4- 5-isopropoxy-6-methyl-
6-methyl-pyridine-2-carbonyl)-3,3- dihydropyrrolo[1,2-
pyridine-2-carboxylic acid dimethyl-spiro[2,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)-2,2,2-
piperidine]-6-yl]ethanone trifluoro-ethanone
2,2,2-trifluoro-1-[1'-(4-isopropoxy- 1-(3,3-dimethylspiro[2,4-
4-isopropoxy-3-methoxy- 3-methoxy-benzoyl)-3,3-dimethyl-
dihydropyrrolo[1,2- benzoic acid spiro[2,4-dihydropyrrolo[1,2-
a]pyrazine-1,4'- a]pyrazine-1,4'-piperidine]-6-
piperidine]-6-yl)-2,2,2- yl]ethanone trifluoro-ethanone
2,2,2-trifluoro-1-[1'-(2-fluoro-4- 1-(3,3-dimethylspiro[2,4-
2-fluoro-4-isopropoxy- isopropoxy-benzoyl)-3,3-dimethyl-
dihydropyrrolo[1,2- benzoic acid spiro[2,4-dihydropyrrolo[1,2-
a]pyrazine-1,4'- a]pyrazine-1,4'-piperidine]-6-
piperidine]-6-yl)-2,2,2- yl]ethanone trifluoro-ethanone
1-[1'-(3-chloro-4-isopropoxy- 1-(3,3-dimethylspiro[2,4-
3-chloro-4-isopropoxy- benzoyl)-3,3-dimethyl-spiro[2,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-2,2,2-trifluoro- piperidine]-6-yl)-2,2,2-
ethanone trifluoro-ethanone 2,2,2-trifluoro-1-[1'-(4-isopentyloxy-
1-(3,3-dimethylspiro[2,4- 4-isopentyloxy-3-
3-methoxy-benzoyl)-3,3-dimethyl- dihydropyrrolo[1,2-
methoxy-benzoic acid spiro[2,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)-2,2,2- yl]ethanone
trifluoro-ethanone 2,2,2-trifluoro-1-[1'-(4-isopropoxy-
1-(3,3-dimethylspiro[2,4- 4-isopropoxy-3-methyl-
3-methyl-benzoyl)-3,3-dimethyl- dihydropyrrolo[1,2- benzoic acid
spiro[2,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)-2,2,2- yl]ethanone
trifluoro-ethanone 2,2,2-trifluoro-1-[1'-(4-
1-(3,3-dimethylspiro[2,4- 4-isopentyloxybenzoic
isopentyloxybenzoyl)-3,3-dimethyl- dihydropyrrolo[1,2- acid
spiro[2,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)-2,2,2- yl]ethanone
trifluoro-ethanone [3-fluoro-4-(1- 8-fluoro-2-methyl-6-
3-fluoro-4-(1- hydroxycyclobutyl)phenyl]-[8-
(trifluoromethyl)spiro[3,4- hydroxycyclobutyl)- fluoro-2-methyl-6-
dihydropyrrolo[1,2- benzoic acid (trifluoromethyl)spiro[3,4-
a]pyrazine-1,4'- dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]
piperidine]-1'-yl]methanone [8-fluoro-2-methyl-6-
8-fluoro-2-methyl-6- 4-(1-hydroxycyclobutyl)-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
3-methyl-benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-[4-(1- a]pyrazine-1,4'-
hydroxycyclobutyl)-3-methyl- piperidine] phenyl]methanone
[8-fluoro-2-methyl-6- 8-fluoro-2-methyl-6- 4-(1-hydroxycyclobutyl)-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
3-methoxy-benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-[4-(1- a]pyrazine-1,4'-
hydroxycyclobutyl)-3-methoxy- piperidine] phenyl]methanone
2,2,2-trifluoro-1-[1'-(4-hydroxy-3- 2,2,2-trifluoro-1-(2-
4-hydroxy-3-methyl- methyl-benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 1-[1'-(3-chloro-4-hydroxy-benzoyl)-
2,2,2-trifluoro-1-(2- 3-chloro-4-hydroxy- 2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2,2-trifluoro- a]pyrazine-1,4'- ethanone
piperidine]-6-yl)ethanone (4-isopropoxy-3-methoxy-phenyl)-
2-methyl-6,7- 4-isopropoxy-3-methoxy- [2-methyl-6,7-
bis(trifluoromethyl)spiro[3,4- benzoic acid
bis(trifluoromethyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-yl]methanone piperidine] 1-[2-methyl-1'-[4-(3,3,3-
1-(2-methylspiro[3,4- 4-(3,3,3-
trifluoropropoxymethyl)benzoyl]spiro[3,4- dihydropyrrolo[1,2-
trifluoropropoxymethyl)- dihydropyrrolo[1,2- a]pyrazine-1,4'-
benzoic acid a]pyrazine-1,4'-piperidine]-6-
piperidine]-6-yl)ethanone yl]ethanone 1-[2-methyl-1'-[4-(2,2,2-
1-(2-methylspiro[3,4- 4-(2,2,2-
trifluoroethoxymethyl)benzoyl]spiro[3,4- dihydropyrrolo[1,2-
trifluoroethoxymethyl)- dihydropyrrolo[1,2-a]pyrazine-
a]pyrazine-1,4'- benzoic acid 1,4'-piperidine]-6-yl]ethanone
piperidine]-6-yl)ethanone (4-isopropoxy-3-methyl-phenyl)-(2-
2-methyl-6- 4-isopropoxy-3-methyl-
methyl-6-methylsulfonyl-spiro[3,4- methylsulfonyl-spiro[3,4-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl)methanone a]pyrazine-1,4'-
piperidine] (4-cyclohexylphenyl)-(2-methyl-6- 2-methyl-6-
4-cyclohexylbenzoic acid methylsulfonyl-spiro[3,4-
methylsulfonyl-spiro[3,4- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl)methanone a]pyrazine-1,4'-
piperidine] (3-chloro-4-isopropoxy-phenyl)-(2- 2-methyl-6-
3-chloro-4-isopropoxy- methyl-6-methylsulfonyl-spiro[3,4-
methylsulfonyl-spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl)methanone a]pyrazine-1,4'- piperidine]
2,2,2-trifluoro-1-[1'-(4-methoxy-3- 1-(3,3-dimethylspiro[2,4-
4-methoxy-3-methyl- methyl-benzoyl)-3,3-dimethyl-
dihydropyrrolo[1,2- benzoic acid spiro[2,4-dihydropyrrolo[1,2-
a]pyrazine-1,4'- a]pyrazine-1,4'-piperidine]-6-
piperidine]-6-yl)-2,2,2- yl]ethanone trifluoro-ethanone
2,2,2-trifluoro-1-[1'-[4-methoxy-3- 1-(3,3-dimethylspiro[2,4-
4-methoxy-3- (trifluoromethyl)benzoyl]-3,3- dihydropyrrolo[1,2-
(trifluoromethyl)benzoic dimethyl-spiro[2,4- a]pyrazine-1,4'- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)-2,2,2-
piperidine]-6-yl]ethanone trifluoro-ethanone
2,2,2-trifluoro-1-[1'-[3-fluoro-4-(1- 1-(3,3-dimethylspiro[2,4-
3-fluoro-4-(1-hydroxy-1- hydroxy-1-methyl-ethyl)benzoyl]-
dihydropyrrolo[1,2- methyl-ethyl)benzoic acid
3,3-dimethyl-spiro[2,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)-2,2,2-
piperidine]-6-yl]ethanone trifluoro-ethanone
1-[1'-(3-chloro-4-methoxy-benzoyl)- 1-(3,3-dimethylspiro[2,4-
3-chloro-4-methoxy- 3,3-dimethyl-spiro[2,4- dihydropyrrolo[1,2-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-2,2,2-trifluoro- piperidine]-6-yl)-2,2,2-
ethanone trifluoro-ethanone 2,2,2-trifluoro-1-[1'-(4-methoxy-2-
1-(3,3-dimethylspiro[2,4- 4-methoxy-2-methyl-
methyl-benzoyl)-3,3-dimethyl- dihydropyrrolo[1,2- benzoic acid
spiro[2,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)-2,2,2- yl]ethanone
trifluoro-ethanone 2,2,2-trifluoro-1-[1'-(2-fluoro-4-
1-(3,3-dimethylspiro[2,4- 2-fluoro-4-methoxy-
methoxy-benzoyl)-3,3-dimethyl- dihydropyrrolo[1,2- benzoic acid
spiro[2,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)-2,2,2- yl]ethanone
trifluoro-ethanone 1-[1'-(3-chloro-4-ethoxy-benzoyl)-
1-(3,3-dimethylspiro[2,4- 3-chloro-4-ethoxy-benzoic
3,3-dimethyl-spiro[2,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-2,2,2-trifluoro- piperidine]-6-yl)-2,2,2-
ethanone trifluoro-ethanone 1-[1'-(4-tert-butyl-3-methoxy-
1-(3,3-dimethylspiro[2,4- 4-tert-butyl-3-methoxy-
benzoyl)-3,3-dimethyl-spiro[2,4- dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-2,2,2-trifluoro- piperidine]-6-yl)-2,2,2-
ethanone trifluoro-ethanone 1-[1'-(4-isopropoxy-3-methyl-
1-(3,3-dimethylspiro[2,4- 4-isopropoxy-3-methyl-
benzoyl)-3,3-dimethyl-spiro[2,4- dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-7-yl]ethanone piperidine]-7-yl)ethanone
1-[1'-(4-isopropoxy-3-methyl- 1-(3,3-dimethylspiro[2,4-
4-isopropoxy-3-methyl- benzoyl)-3,3-dimethyl-spiro[2,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-cyclohexylbenzoyl)-3,3- 1-(3,3-dimethylspiro[2,4-
4-cyclohexylbenzoic acid dimethyl-spiro[2,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-7-yl]ethanone piperidine]-7-yl)ethanone
1-[1'-(4-cyclohexylbenzoyl)-3,3- 1-(3,3-dimethylspiro[2,4-
4-cyclohexylbenzoic acid dimethyl-spiro[2,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-methoxy-3-methyl- 1-(3,3-dimethylspiro[2,4-
4-methoxy-3-methyl- benzoyl)-3,3-dimethyl-spiro[2,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-[4-methoxy-3- 1-(3,3-dimethylspiro[2,4- 4-methoxy-3-
(trifluoromethyl)benzoyl]-3,3- dihydropyrrolo[1,2-
(trifluoromethyl)benzoic dimethyl-spiro[2,4- a]pyrazine-1,4'- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)ethanone
piperidine]-6-yl]ethanone 1-[1'-(3-chloro-4-methoxy-benzoyl)-
1-(3,3-dimethylspiro[2,4- 3-chloro-4-methoxy-
3,3-dimethyl-spiro[2,4- dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(2-fluoro-4-isopropoxy- 1-(3,3-dimethylspiro[2,4-
2-fluoro-4-isopropoxy- benzoyl)-3,3-dimethyl-spiro[2,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-[4-isopropoxy-3- 1-(3,3-dimethylspiro[2,4- 4-isopropoxy-3-
(trifluoromethyl)benzoyl]-3,3- dihydropyrrolo[1,2-
(trifluoromethyl)benzoic dimethyl-spiro[2,4- a]pyrazine-1,4'- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-7-yl)ethanone
piperidine]-7-yl]ethanone 1-[1'-[4-isopropoxy-3-
1-(3,3-dimethylspiro[2,4- 4-isopropoxy-3-
(trifluoromethyl)benzoyl]-3,3- dihydropyrrolo[1,2-
(trifluoromethyl)benzoic dimethyl-spiro[2,4- a]pyrazine-1,4'- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)ethanone
piperidine]-6-yl]ethanone 1-[1'-(3-chloro-4-isopropoxy-
1-(3,3-dimethylspiro[2,4- 3-chloro-4-isopropoxy-
benzoyl)-3,3-dimethyl-spiro[2,4- dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-7-yl]ethanone piperidine]-7-yl)ethanone
1-[1'-(3-chloro-4-isopropoxy- 1-(3,3-dimethylspiro[2,4-
3-chloro-4-isopropoxy- benzoyl)-3,3-dimethyl-spiro[2,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(4-tert-butyl-3- 1-(3,3- 4-tert-butyl-3-methoxy-
methoxy-benzoyl)-3,3-dimethyl- dimethylspiro[2,4- benzoic acid
spiro[2,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-7- a]pyrazine-1,4'- yl]ethanone
piperidine]-7-yl)ethanone 1-[1'-(4-tert-butyl-3-methoxy-
1-(3,3-dimethylspiro[2,4- 4-tert-butyl-3-methoxy-
benzoyl)-3,3-dimethyl-spiro[2,4- dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(2-fluoro-4- 2,2,2-trifluoro-1-(2,4,4-
2-fluoro-4-methoxy- methoxy-benzoyl)-2,4,4-trimethyl-
trimethylspiro[3H- benzoic acid spiro[3H-pyrrolo[1,2-a]pyrazine-
pyrrolo[1,2-a]pyrazine- 1,4'-piperidine]-7-yl]ethanone
1,4'-piperidine]-7- yl)ethanone
2,2,2-trifluoro-1-[1'-[4-(1-hydroxy- 2,2,2-trifluoro-1-(2,4,4-
4-(1-hydroxy-1-methyl- 1-methyl-ethyl)-3-methyl-benzoyl]-
trimethylspiro[3H- ethyl)-3-methyl-benzoic
2,4,4-trimethyl-spiro[3H- pyrrolo[1,2-a]pyrazine- acid
pyrrolo[1,2-a]pyrazine-1,4'- 1,4'-piperidine]-7-
piperidine]-7-yl]ethanone yl)ethanone
2,2,2-trifluoro-1-[1'-(4-isopropoxy- 2,2,2-trifluoro-1-(2,4,4-
4-isopropoxy-3-methyl- 3-methyl-benzoyl)-2,4,4-trimethyl-
trimethylspiro[3H- benzoic acid spiro[3H-pyrrolo[1,2-a]pyrazine-
pyrrolo[1,2-a]pyrazine- 1,4'-piperidine]-7-yl]ethanone
1,4'-piperidine]-7- yl)ethanone 1-[1'-(3-chloro-4-methoxy-benzoyl)-
2,2,2-trifluoro-1-(2,4,4- 3-chloro-4-methoxy-
2,4,4-trimethyl-spiro[3H- trimethylspiro[3H- benzoic acid
pyrrolo[1,2-a]pyrazine-1,4'- pyrrolo[1,2-a]pyrazine-
piperidine]-7-yl]-2,2,2-trifluoro- 1,4'-piperidine]-7- ethanone
yl)ethanone 2,2,2-trifluoro-1-[1'-(2-fluoro-4-
2,2,2-trifluoro-1-(2,4,4- 2-fluoro-4-isopropoxy-
isopropoxy-benzoyl)-2,4,4- trimethylspiro[3H- benzoic acid
trimethyl-spiro[3H-pyrrolo[1,2- pyrrolo[1,2-a]pyrazine-
a]pyrazine-1,4'-piperidine]-7- 1,4'-piperidine]-7- yl]ethanone
yl)ethanone 2,2,2-trifluoro-1-[1'-(4-methoxy-3-
2,2,2-trifluoro-1-(2,4,4- 4-methoxy-3-methyl-
methyl-benzoyl)-2,4,4-trimethyl- trimethylspiro[3H- benzoic acid
spiro[3H-pyrrolo[1,2-a]pyrazine- pyrrolo[1,2-a]pyrazine-
1,4'-piperidine]-7-yl]ethanone 1,4'-piperidine]-7- yl)ethanone
2,2,2-trifluoro-1-[1'-(5-isopropoxy- 2,2,2-trifluoro-1-(2,4,4-
5-isopropoxy-6-methyl- 6-methyl-pyridine-2-carbonyl)-
trimethylspiro[3H- pyridine-2-carboxylic acid
2,4,4-trimethyl-spiro[3H- pyrrolo[1,2-a]pyrazine-
pyrrolo[1,2-a]pyrazine-1,4'- 1,4'-piperidine]-7-
piperidine]-7-yl]ethanone yl)ethanone 1-[1'-(3-chloro-4-isopropoxy-
2,2,2-trifluoro-1-(2,4,4- 3-chloro-4-isopropoxy-
benzoyl)-2,4,4-trimethyl-spiro[3H- trimethylspiro[3H- benzoic acid
pyrrolo[1,2-a]pyrazine-1,4'- pyrrolo[1,2-a]pyrazine-
piperidine]-7-yl]-2,2,2-trifluoro- 1,4'-piperidine]-7- ethanone
yl)ethanone 2,2,2-trifluoro-1-[1'-(3-fluoro-4-
2,2,2-trifluoro-1-(2,4,4- 3-fluoro-4-isopropoxy-
isopropoxy-benzoyl)-2,4,4- trimethylspiro[3H- benzoic acid
trimethyl-spiro[3H-pyrrolo[1,2- pyrrolo[1,2-a]pyrazine-
a]pyrazine-1,4'-piperidine]-7- 1,4'-piperidine]-7- yl]ethanone
yl)ethanone 1-[1'-[4-(cyclopropylmethoxy)-3- 2,2,2-trifluoro-1-(2-
4-(cyclopropylmethoxy)- fluoro-benzoyl]-2-methyl-spiro[3,4-
methylspiro[3,4- 3-fluoro-benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2,2-trifluoro- a]pyrazine-1,4'- ethanone
piperidine]-6-yl)ethanone 1-[1'-[4-(cyclopropylmethoxy)-3-
1-(2-methylspiro[3,4- 4-(cyclopropylmethoxy)-
fluoro-benzoyl]-2-methyl-spiro[3,4- dihydropyrrolo[1,2-
3-fluoro-benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone
piperidine]-6-yl)ethanone 1-[1'-[4-(cyclopropylmethoxy)-3-
1-(3,3-dimethylspiro[2,4- 4-(cyclopropylmethoxy)-
fluoro-benzoyl]-3,3-dimethyl- dihydropyrrolo[1,2- 3-fluoro-benzoic
acid spiro[2,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6-yl]- piperidine]-6-yl)-2,2,2-
2,2,2-trifluoro-ethanone trifluoro-ethanone
2,2,2-trifluoro-1-[1'-(4-isopropoxy- 2,2,2-trifluoro-1-(2,4,4-
4-isopropoxy-3-methyl- 3-methyl-benzoyl)-2,4,4-trimethyl-
trimethylspiro[3H- benzoic acid spiro[3H-pyrrolo[1,2-a]pyrazine-
pyrrolo[1,2-a]pyrazine- 1,4'-piperidine]-6-yl]ethanone
1,4'-piperidine]-6- yl)ethanone 2,2,2-trifluoro-1-[1'-[4-methoxy-3-
2,2,2-trifluoro-1-(2,4,4- 4-methoxy-3-
(trifluoromethyl)benzoyl]-2,4,4- trimethylspiro[3H-
(trifluoromethyl)benzoic trimethyl-spiro[3H-pyrrolo[1,2-
pyrrolo[1,2-a]pyrazine- acid a]pyrazine-1,4'-piperidine]-6-
1,4'-piperidine]-6- yl]ethanone yl)ethanone
2,2,2-trifluoro-1-[1'-(3-fluoro-4- 2,2,2-trifluoro-1-(2,4,4-
3-fluoro-4-isopropoxy- isopropoxy-benzoyl)-2,4,4-
trimethylspiro[3H- benzoic acid trimethyl-spiro[3H-pyrrolo[1,2-
pyrrolo[1,2-a]pyrazine- a]pyrazine-1,4'-piperidine]-6-
1,4'-piperidine]-6- yl]ethanone yl)ethanone
(7,8-difluoro-3,3-dimethyl-spiro[2,4- 7,8-difluoro-3,3-dimethyl-
4-isopropoxy-3-methyl-
dihydropyrrolo[1,2-a]pyrazine-1,4'- spiro[2,4- benzoic acid
piperidine]-1'-yl)-(4-isopropoxy-3- dihydropyrrolo[1,2-
methyl-phenyl)methanone a]pyrazine-1,4'- piperidine]
(7,8-difluoro-3,3-dimethyl-spiro[2,4- 7,8-difluoro-3,3-dimethyl-
4-isopentyloxybenzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
spiro[2,4- acid piperidine]-1'-yl)-(4- dihydropyrrolo[1,2-
isopentyloxyphenyl)methanone a]pyrazine-1,4'- piperidine]
2,2,2-trifluoro-1-[1'-(4-methoxy-3- 2,2,2-trifluoro-1-(2,4,4-
4-methoxy-3-methyl- methyl-benzoyl)-2,4,4-trimethyl-
trimethylspiro[3H- benzoic acid spiro[3H-pyrrolo[1,2-a]pyrazine-
pyrrolo[1,2-a]pyrazine- 1,4'-piperidine]-6-yl]ethanone
1,4'-piperidine]-6- yl)ethanone 1-[1'-[4-isopropoxy-3- 1-(2,4,4-
4-isopropoxy-3- (trifluoromethyl)benzoyl]-2,4,4- trimethylspiro[3H-
(trifluoromethyl)benzoic trimethyl-spiro[3H-pyrrolo[1,2-
pyrrolo[1,2-a]pyrazine- acid a]pyrazine-1,4'-piperidine]-6-
1,4'-piperidine]-6- yl]ethanone yl)ethanone
l-[1'-[3-fluoro-4-(1-hydroxy-1- 1-(2,4,4- 3-fluoro-4-(1-hydroxy-1-
methyl-ethyl)benzoyl]-2,4,4- trimethylspiro[3H-
methyl-ethyl)benzoic acid trimethyl-spiro[3H-pyrrolo[1,2-
pyrrolo[1,2-a]pyrazine- a]pyrazine-1,4'-piperidine]-6-
1,4'-piperidine]-6- yl]ethanone yl)ethanone
2,2,2-trifluoro-1-[1'-(4-isopropoxy- 2,2,2-trifluoro-1-(2,4,4-
4-isopropoxy-3-methoxy- 3-methoxy-benzoyl)-2,4,4-trimethyl-
trimethylspiro[3H- benzoic acid spiro[3H-pyrrolo[1,2-a]pyrazine-
pyrrolo[1,2-a]pyrazine- 1,4'-piperidine]-6-yl]ethanone
1,4'-piperidine]-6- yl)ethanone
2,2,2-trifluoro-1-[1'-[3-fluoro-4-(1- 2,2,2-trifluoro-1-(2,4,4-
3-fluoro-4-(1-hydroxy-1- hydroxy-1-methyl-ethyl)benzoyl]-
trimethylspiro[3H- methyl-ethyl)benzoic acid
2,4,4-trimethyl-spiro[3H- pyrrolo[1,2-a]pyrazine-
pyrrolo[1,2-a]pyrazine-1,4'- 1,4'-piperidine]-6-
piperidine]-6-yl]ethanone yl)ethanone 1-[1'-(4-isopropoxy-3-methyl-
1-(2,4,4- 4-isopropoxy-3-methyl- benzoyl)-2,4,4-trimethyl-spiro[3H-
trimethylspiro[3H- benzoic acid pyrrolo[1,2-a]pyrazine-1,4'-
pyrrolo[1,2-a]pyrazine- piperidine]-6-yl]ethanone
1,4'-piperidine]-6- yl)ethanone 1-[1'-(4-cyclohexylbenzoyl)-2,4,4-
1-(2,4,4- 4-cyclohexylbenzoic acid trimethyl-spiro[3H-pyrrolo[1,2-
trimethylspiro[3H- a]pyrazine-1,4'-piperidine]-6-
pyrrolo[1,2-a]pyrazine- yl]ethanone 1,4'-piperidine]-6- yl)ethanone
1-[1'-(4-hydroxy-3-methyl-benzoyl)- 2,2-dimethyl-1-(2-
4-hydroxy-3-methyl- 2-methyl-spiro[3,4- methylspiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2-dimethyl- a]pyrazine-1,4'- propan-1-one
piperidine]-6-yl)propan-1- one 1-[1'-(3-chloro-4-hydroxy-benzoyl)-
2,2-dimethyl-1-(2- 3-chloro-4-hydroxy- 2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2-dimethyl-
a]pyrazine-1,4'- propan-1-one piperidine]-6-yl)propan-1- one
1-[1'-(4-methoxy-3-methyl- 2,2-dimethyl-1-(2- 4-methoxy-3-methyl-
benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2-dimethyl- a]pyrazine-1,4'- propan-1-one
piperidine]-6-yl)propan-1- one 1-[1'-(3-chloro-4-methoxy-benzoyl)-
2,2-dimethyl-1-(2- 3-chloro-4-methoxy- 2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2-dimethyl-
a]pyrazine-1,4'- propan-1-one piperidine]-6-yl)propan-1- one
1-[1'-[4-methoxy-3- 2,2-dimethyl-1-(2- 4-methoxy-3-
(trifluoromethyl)benzoyl]-2-methyl- methylspiro[3,4-
(trifluoromethyl)benzoic spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- acid a]pyrazine-1,4'-piperidine]-6-yl]-2,2-
a]pyrazine-1,4'- dimethyl-propan-1-one piperidine]-6-yl)propan-1-
one 1-[1'-[4-isopropoxy-3- 2,2-dimethyl-1-(2- 4-isopropoxy-3-
(trifluoromethyl)benzoyl]-2-methyl- methylspiro[3,4-
(trifluoromethyl)benzoic spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- acid a]pyrazine-1,4'-piperidine]-6-yl]-2,2-
a]pyrazine-1,4'- dimethyl-propan-1-one piperidine]-6-yl)propan-1-
one 1-[1'-(2-fluoro-4-isopropoxy- 2,2-dimethyl-1-(2-
2-fluoro-4-isopropoxy- benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2-dimethyl-
a]pyrazine-1,4'- propan-1-one piperidine]-6-yl)propan-1- one
1-[1'-(2-fluoro-4-methoxy-benzoyl)- 2,2-dimethyl-1-(2-
2-fluoro-4-methoxy- 2-methyl-spiro[3,4- methylspiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2-dimethyl- a]pyrazine-1,4'- propan-1-one
piperidine]-6-yl)propan-1- one 2,2-dimethyl-1-[2-methyl-1'-(3-
2,2-dimethyl-1-(2- 3-methyl-4- methyl-4-methylsulfonyl-
methylspiro[3,4- methylsulfonyl-benzoic benzoyl)spiro[3,4-
dihydropyrrolo[1,2- acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]propan-1-one
piperidine]-6-yl)propan-1- one 1-[1'-(3-fluoro-4-isopropoxy-
2,2-dimethyl-1-(2- 3-fluoro-4-isopropoxy-
benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2-dimethyl- a]pyrazine-1,4'- propan-1-one
piperidine]-6-yl)propan-1- one 1-[1'-(4-isopropylsulfonylbenzoyl)-
2,2-dimethyl-1-(2- 4- 2-methyl-spiro[3,4- methylspiro[3,4-
isopropylsulfonylbenzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-6-yl]-2,2-dimethyl-
a]pyrazine-1,4'- propan-1-one piperidine]-6-yl)propan-1- one
1-[1'-(4-isopentyloxybenzoyl)-2- 2,2-dimethyl-1-(2-
4-isopentyloxybenzoic methyl-spiro[3,4- methylspiro[3,4- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2-dimethyl- a]pyrazine-1,4'- propan-1-one
piperidine]-6-yl)propan-1- one 1-[1'-(4-ethylsulfonyl-3-methyl-
2,2-dimethyl-1-(2- 4-ethylsulfonyl-3-methyl-
benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2-dimethyl- a]pyrazine-1,4'- propan-1-one
piperidine]-6-yl)propan-1- one 2,2-dimethyl-1-[2-methyl-1'-[4-
2,2-dimethyl-1-(2- 4- (trifluoromethylsulfonyl)benzoyl]spiro[3,4-
methylspiro[3,4- (trifluoromethylsulfonyl)- dihydropyrrolo[1,2-
dihydropyrrolo[1,2- benzoic acid a]pyrazine-1,4'-piperidine]-6-
a]pyrazine-1,4'- yl]propan-1-one piperidine]-6-yl)propan-1- one
1-[1'-[7-(difluoromethyl)-5-methyl- 2,2-dimethyl-1-(2-
7-(difluoromethyl)-5- pyrazolo[1,5-a]pyrimidine-3- methylspiro[3,4-
methyl-pyrazolo[1,5- carbonyl]-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- a]pyrimidine-3-carboxylic
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'- acid
piperidine]-6-yl]-2,2-dimethyl- piperidine]-6-yl)propan-1-
propan-1-one one 1-[1'-(4-isobutylsulfonylbenzoyl)-2-
2,2-dimethyl-1-(2- 4-isobutylsulfonylbenzoic methyl-spiro[3,4-
methylspiro[3,4- acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2-dimethyl-
a]pyrazine-1,4'- propan-1-one piperidine]-6-yl)propan-1- one
1-[1'-[4-(1,1- 1-(3,3-dimethylspiro[2,4- 4-(1,1-
dimethylpropyl)benzoyl]-3,3- dihydropyrrolo[1,2-
dimethylpropyl)benzoic dimethyl-spiro[2,4- a]pyrazine-1,4'- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)-2,2,2-
piperidine]-6-yl]-2,2,2-trifluoro- trifluoro-ethanone ethanone
1-[1'-[4-(1,1- 2,2,2-trifluoro-1-(2- 4-(1,1-
dimethylpropyl)benzoyl]-2-methyl- methylspiro[3,4-
dimethylpropyl)benzoic spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- acid a]pyrazine-1,4'-piperidine]-6-yl]-
a]pyrazine-1,4'- 2,2,2-trifluoro-ethanone piperidine]-6-yl)ethanone
1-[1'-[4-(1,1-diethylpropyl)benzoyl]- 1-(2-methylspiro[3,4- 4-(1,1-
2-methyl-spiro[3,4- dihydropyrrolo[1,2- diethylpropyl)benzoic
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'- acid
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone 1-[1'-[4-(1,1-
1-(2-methylspiro[3,4- 4-(1,1- dimethylpropyl)benzoyl]-2-methyl-
dihydropyrrolo[1,2- dimethylpropyl)benzoic
spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'- acid
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)ethanone
yl]ethanone 1-[1'-[3-methoxy-4-(3,3,3- 1-(2-methylspiro[3,4-
3-methoxy-4-(3,3,3- trifluoropropoxymethyl)benzoyl]-2-
dihydropyrrolo[1,2- trifluoropropoxymethyl)- methyl-spiro[3,4-
a]pyrazine-1,4'- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
piperidine]-6-yl)ethanone piperidine]-6-yl]ethanone
1-[1'-[3-methoxy-4-(2,2,2- 1-(2-methylspiro[3,4-
3-methoxy-4-(2,2,2- trifluoroethoxymethyl)benzoyl]-2-
dihydropyrrolo[1,2- trifluoroethoxymethyl)- methyl-spiro[3,4-
a]pyrazine-1,4'- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
piperidine]-6-yl)ethanone piperidine]-6-yl]ethanone
2,2,2-trifluoro-1-[2-methyl-1'-[4-(3,3,3- 2,2,2-trifluoro-1-(2-
4-(3,3,3- trifluoropropoxymethyl)benzoyl]spiro[3,4-
methylspiro[3,4- trifluoropropoxymethyl)- dihydropyrrolo[1,2-
dihydropyrrolo[1,2- benzoic acid a]pyrazine-1,4'-piperidine]-6-
a]pyrazine-1,4'- yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[2-methyl-1'-[4- 2,2,2-trifluoro-1-(2- 4-(2,2,2-
(2,2,2- methylspiro[3,4- trifluoroethoxymethyl)-
trifluoroethoxymethyl)benzoyl]spiro dihydropyrrolo[1,2- benzoic
acid [3,4-dihydropyrrolo[1,2-a]pyrazine- a]pyrazine-1,4'-
1,4'-piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-[3-methoxy-4- 2,2,2-trifluoro-1-(2-
3-methoxy-4-(3,3,3- (3,3,3- methylspiro[3,4-
trifluoropropoxymethyl)- trifluoropropoxymethyl)benzoyl]-2-
dihydropyrrolo[1,2- benzoic acid methyl-spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)ethanone
piperidine]-6-yl]ethanone 2,2,2-trifluoro-1-[1'-[3-methoxy-4-
2,2,2-trifluoro-1-(2- 3-methoxy-4-(2,2,2- (2,2,2- methylspiro[3,4-
trifluoroethoxymethyl)- trifluoroethoxymethyl)benzoyl]-2-
dihydropyrrolo[1,2- benzoic acid methyl-spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)ethanone
piperidine]-6-yl]ethanone 1-[3,3-dimethyl-1'-[4-(3,3,3-
1-(3,3-dimethylspiro[2,4- 4-(3,3,3-
trifluoropropoxymethyl)benzoyl]spiro[2,4- dihydropyrrolo[1,2-
trifluoropropoxymethyl)- dihydropyrrolo[1,2- a]pyrazine-1,4'-
benzoic acid a]pyrazine-1,4'-piperidine]-6-yl]-
piperidine]-6-yl)-2,2,2- 2,2,2-trifluoro-ethanone
trifluoro-ethanone 1-[3,3-dimethyl-1'-[4-(2,2,2-
1-(3,3-dimethylspiro[2,4- 4-(2,2,2-
trifluoroethoxymethyl)benzoyl]spiro dihydropyrrolo[1,2-
trifluoroethoxymethyl)- [2,4-dihydropyrrolo[1,2-a]pyrazine-
a]pyrazine-1,4'- benzoic acid
1,4'-piperidine]-6-yl]-2,2,2-trifluoro- piperidine]-6-yl)-2,2,2-
ethanone trifluoro-ethanone 2,2,2-trifluoro-1-[1'-[3-methoxy-4-
1-(3,3-dimethylspiro[2,4- 3-methoxy-4-(3,3,3- (3,3,3-
dihydropyrrolo[1,2- trifluoropropoxymethyl)-
trifluoropropoxymethyl)benzoyl]- a]pyrazine-1,4'- benzoic acid
3,3-dimethyl-spiro[2,4- piperidine]-6-yl)-2,2,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- trifluoro-ethanone
piperidine]-6-yl]ethanone 2,2,2-trifluoro-1-[1'-[3-methoxy-4-
1-(3,3-dimethylspiro[2,4- 3-methoxy-4-(2,2,2- (2,2,2-
dihydropyrrolo[1,2- trifluoroethoxymethyl)-
trifluoroethoxymethyl)benzoyl]-3,3- a]pyrazine-1,4'- benzoic acid
dimethyl-spiro[2,4- piperidine]-6-yl)-2,2,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- trifluoro-ethanone
piperidine]-6-yl]ethanone 1-[1'-[4-[bis(2,2,2-
1-(2-methylspiro[3,4- 4-[bis(2,2,2-
trifluoroethoxy)methyl]-3-chloro- dihydropyrrolo[1,2-
trifluoroethoxy)methyl]-3- benzoyl]-2-methyl-spiro[3,4-
a]pyrazine-1,4'- chloro-benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)ethanone
piperidine]-6-yl]ethanone 2,2,2-trifluoro-1-[1'-(4-hydroxy-3-
1-(3,3-dimethylspiro[2,4- 4-hydroxy-3-methyl-
methyl-benzoyl)-3,3-dimethyl- dihydropyrrolo[1,2- benzoic acid
spiro[2,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)-2,2,2- yl]ethanone
trifluoro-ethanone 1-[1'-(3-chloro-4-hydroxy-benzoyl)-
1-(3,3-dimethylspiro[2,4- 3-chloro-4-hydroxy-
3,3-dimethyl-spiro[2,4- dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-2,2,2-trifluoro- piperidine]-6-yl)-2,2,2-
ethanone trifluoro-ethanone 2,2,2-trifluoro-1-[1'-[4-hydroxy-3-
1-(3,3-dimethylspiro[2,4- 4-hydroxy-3-
(trifluoromethyl)benzoyl]-3,3- dihydropyrrolo[1,2-
(trifluoromethyl)benzoic dimethyl-spiro[2,4- a]pyrazine-1,4'- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)-2,2,2-
piperidine]-6-yl]ethanone trifluoro-ethanone
2,2,2-trifluoro-1-[1'-[4-hydroxy-3- 2,2,2-trifluoro-1-(2-
4-hydroxy-3- (trifluoromethyl)benzoyl]-2-methyl- methylspiro[3,4-
(trifluoromethyl)benzoic spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- acid a]pyrazine-1,4'-piperidine]-6-
a]pyrazine-1,4'- yl]ethanone piperidine]-6-yl)ethanone
1-[1'-[4-hydroxy-3- 2,2-dimethyl-1-(2- 4-hydroxy-3-
(trifluoromethyl)benzoyl]-2-methyl- methylspiro[3,4-
(trifluoromethyl)benzoic spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- acid a]pyrazine-1,4'-piperidine]-6-yl]-2,2-
a]pyrazine-1,4'- dimethyl-propan-1-one piperidine]-6-yl)propan-1-
one 2,2,2-trifluoro-1-[1'-(3-hydroxy-4- 2,2,2-trifluoro-1-(2-
3-hydroxy-4-methyl- methyl-benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(4-hydroxy-3,5-
2,2,2-trifluoro-1-(2- 4-hydroxy-3,5-dimethyl-
dimethyl-benzoyl)-2-methyl- methylspiro[3,4- benzoic acid
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(2-fluoro-5-
2,2,2-trifluoro-1-(2- 2-fluoro-5-hydroxy-
hydroxy-benzoyl)-2-methyl- methylspiro[3,4- benzoic acid
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[2-methyl-1'-(4-
2,2,2-trifluoro-1-(2- 4-tetrahydropyran-4- tetrahydropyran-4-
methylspiro[3,4- yloxybenzoic acid yloxybenzoyl)spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone
piperidine]-6-yl)ethanone 1-[1'-(4-chloro-3-hydroxy-benzoyl)-
2,2,2-trifluoro-1-(2- 4-chloro-3-hydroxy- 2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(3-hydroxy-2- 2,2,2-trifluoro-1-(2-
3-hydroxy-2-methyl- methyl-benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(4-fluoro-3-
2,2,2-trifluoro-1-(2- 4-fluoro-3-hydroxy-
hydroxy-benzoyl)-2-methyl- methylspiro[3,4- benzoic acid
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(4-fluoro-3-
2,2,2-trifluoro-1-(2- 4-fluoro-3-methyl-benzoic
methyl-benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 1-[1'-(4-chloro-3-methyl-benzoyl)-2-
2,2,2-trifluoro-1-(2- 4-chloro-3-methyl- methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl)ethanone
[8-chloro-2-methyl-6- 8-chloro-2-methyl-6- 4-(1-hydroxy-1-methyl-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
ethyl)benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-[4-(1-hydroxy-1-
a]pyrazine-1,4'- methyl-ethyl)phenyl]methanone piperidine]
[8-chloro-2-methyl-6- 8-chloro-2-methyl-6- 3-fluoro-4-(1-hydroxy-1-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
methyl-ethyl)benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-[3-fluoro-4-(1-
a]pyrazine-1,4'- hydroxy-1-methyl- piperidine]
ethyl)phenyl]methanone [8-chloro-2-methyl-6- 8-chloro-2-methyl-6-
4-(1-hydroxycyclobutyl)- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-[4-(1- a]pyrazine-1,4'-
hydroxycyclobutyl)phenyl]methanone piperidine]
[8-chloro-2-methyl-6- 8-chloro-2-methyl-6- 3-fluoro-4-(2-hydroxy-2-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
methyl-propyl)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'-yl]-[3-fluoro-4-(2-
a]pyrazine-1,4'- hydroxy-2-methyl- piperidine]
propyl)phenyl]methanone [8-chloro-2-methyl-6- 8-chloro-2-methyl-6-
4-methoxy-3-methyl- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-methoxy-3- a]pyrazine-1,4'-
methyl-phenyl)methanone piperidine] [8-chloro-2-methyl-6-
8-chloro-2-methyl-6- 4-ethoxy-3-methyl- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(4-ethoxy-3- a]pyrazine-1,4'-
methyl-phenyl)methanone piperidine] [8-chloro-2-methyl-6-
8-chloro-2-methyl-6- 2-fluoro-4-isopropoxy-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(2-fluoro-4- a]pyrazine-1,4'-
isopropoxy-phenyl)methanone piperidine] [8-chloro-2-methyl-6-
8-chloro-2-methyl-6- 4-(2,2,2- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- trifluoroethoxymethyl)-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2- benzoic
acid piperidine]-1'-yl]-[4-(2,2,2- a]pyrazine-1,4'-
trifluoroethoxymethyl)phenyl]methanone piperidine]
2,2,2-trifluoro-1-[2-methyl-1'-(5- 2,2,2-trifluoro-1-(2-
5-phenylpyridine-2- phenylpyridine-2- methylspiro[3,4- carboxylic
acid carbonyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[3,3-dimethyl-1'-(5- 1-(3,3-dimethylspiro[2,4-
5-phenylpyridine-2- phenylpyridine-2- dihydropyrrolo[1,2-
carboxylic acid carbonyl)spiro[2,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)-2,2,2-
piperidine]-6-yl]-2,2,2-trifluoro- trifluoro-ethanone ethanone
2,2,2-trifluoro-1-[1'-(3-methoxy-4- 2,2,2-trifluoro-1-(2-
3-methoxy-4-phenyl- phenyl-benzoyl)-2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(3-methoxy-4-
1-(3,3-dimethylspiro[2,4- 3-methoxy-4-phenyl-
phenyl-benzoyl)-3,3-dimethyl- dihydropyrrolo[1,2- benzoic acid
spiro[2,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)-2,2,2- yl]ethanone
trifluoro-ethanone 2,2,2-trifluoro-1-[1'-(3-hydroxy-4-
2,2,2-trifluoro-1-(2- 3-hydroxy-4-phenyl-
phenyl-benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(3-hydroxy-4-
1-(3,3-dimethylspiro[2,4- 3-hydroxy-4-phenyl-
phenyl-benzoyl)-3,3-dimethyl- dihydropyrrolo[1,2- benzoic acid
spiro[2,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)-2,2,2- yl]ethanone
trifluoro-ethanone 2,2,2-trifluoro-1-[1'-(3-fluoro-4-
2,2,2-trifluoro-1-(2- 3-fluoro-4-phenyl-benzoic
phenyl-benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(3-fluoro-4-
1-(3,3-dimethylspiro[2,4- 3-fluoro-4-phenyl-benzoic
phenyl-benzoyl)-3,3-dimethyl- dihydropyrrolo[1,2- acid
spiro[2,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)-2,2,2- yl]ethanone
trifluoro-ethanone 2,2,2-trifluoro-1-[(3R)-1'-(2-fluoro-
1-[(3R)-2,3- 2-fluoro-4-isopropoxy- 4-isopropoxy-benzoyl)-2,3-
dimethylspiro[3,4- benzoic acid dimethyl-spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 1-[(3R)-1'-(3-chloro-4-methoxy- 1-[(3R)-2,3-
3-chloro-4-methoxy- benzoyl)-2,3-dimethyl-spiro[3,4-
dimethylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 2,2,2-trifluoro-1-[(3R)-1'-(4- 1-[(3R)-2,3-
4-methoxy-3-methyl- methoxy-3-methyl-benzoyl)-2,3-
dimethylspiro[3,4- benzoic acid dimethyl-spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 2,2,2-trifluoro-1-[(3R)-1'-[4- 1-[(3R)-2,3-
4-methoxy-3- methoxy-3- dimethylspiro[3,4- (trifluoromethyl)benzoic
(trifluoromethyl)benzoyl]-2,3- dihydropyrrolo[1,2- acid
dimethyl-spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl]-2,2,2-
piperidine]-6-yl]ethanone trifluoro-ethanone
2,2,2-trifluoro-1-[2-methyl-1'-[3- 2,2,2-trifluoro-1-(2-
3-methyl-4- methyl-4- methylspiro[3,4- (trifluoromethyl)benzoic
(trifluoromethyl)benzoyl]spiro[3,4- dihydropyrrolo[1,2- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-[4-ethoxy-3- 2,2,2-trifluoro-1-(2- 4-ethoxy-3-
(trifluoromethyl)benzoyl]-2-methyl- methylspiro[3,4-
(trifluoromethyl)benzoic spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- acid a]pyrazine-1,4'-piperidine]-6-yl]-
a]pyrazine-1,4'- 2,2,2-trifluoro-ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(5-isopropoxy- 2,2,2-trifluoro-1-(2-
5-isopropoxy-4-methyl- 4-methyl-pyridine-2-carbonyl)-2-
methylspiro[3,4- pyridine-2-carboxylic acid methyl-spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone
piperidine]-6-yl)ethanone [6-(cyclopropanecarbonyl)-2-
cyclopropyl-(2- 4-methoxy-3- methyl-spiro[3,4- methylspiro[3,4-
(trifluoromethyl)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'-yl]-[4-methoxy-3-
a]pyrazine-1,4'- (trifluoromethyl)phenyl]methanone piperidine]-6-
yl)methanone (3-chloro-4-methoxy-phenyl)-[6- cyclopropyl-(2-
3-chloro-4-methoxy- (cyclopropanecarbonyl)-2-methyl-
methylspiro[3,4- benzoic acid spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-1'-
a]pyrazine-1,4'- yl]methanone piperidine]-6- yl)methanone
(4-cyclohexylphenyl)-[6- cyclopropyl-(2- 4-cyclohexylbenzoic acid
(cyclopropanecarbonyl)-2-methyl- methylspiro[3,4-
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-1'- a]pyrazine-1,4'- yl]methanone
piperidine]-6- yl)methanone [6-(cyclopropanecarbonyl)-2-
cyclopropyl-(2- 4-isopropoxy-3- methyl-spiro[3,4- methylspiro[3,4-
(trifluoromethyl)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-1'-yl]-[4-isopropoxy-3-
a]pyrazine-1,4'- (trifluoromethyl)phenyl]methanone piperidine]-6-
yl)methanone 2,2,2-trifluoro-1-[(3S)-1'-[4- 1-[(3S)-2,3-
4-methoxy-3- methoxy-3- dimethylspiro[3,4- (trifluoromethyl)benzoic
(trifluoromethyl)benzoyl]-2,3- dihydropyrrolo[1,2- acid
dimethyl-spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl]-2,2,2-
piperidine]-6-yl]ethanone trifluoro-ethanone
2,2,2-trifluoro-1-[(3S)-1'-(4- 1-[(3S)-2,3- 4-methoxy-3-methyl-
methoxy-3-methyl-benzoyl)-2,3- dimethylspiro[3,4- benzoic acid
dimethyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 1-[(3S)-1'-(3-chloro-4-methoxy- 1-[(3S)-2,3-
3-chloro-4-methoxy- benzoyl)-2,3-dimethyl-spiro[3,4-
dimethylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 2,2,2-trifluoro-1-[(3S)-1'-(2-fluoro-
1-[(3S)-2,3- 2-fluoro-4-isopropoxy- 4-isopropoxy-benzoyl)-2,3-
dimethylspiro[3,4- benzoic acid dimethyl-spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone [8-chloro-2-methyl-6- 8-chloro-2-methyl-6-
4-(3,3,3- (trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
trifluoropropoxymethyl)- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- benzoic acid piperidine]-1'-yl]-[4-(3,3,3-
a]pyrazine-1,4'- trifluoropropoxymethyl)phenyl]methanone
piperidine] [8-chloro-2-methyl-6- 8-chloro-2-methyl-6-
3-methoxy-4-(2,2,2- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- trifluoroethoxymethyl)-
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2- benzoic
acid piperidine]-1'-yl]-[3-methoxy-4- a]pyrazine-1,4'- (2,2,2-
piperidine] trifluoroethoxymethyl)phenyl]methanone
[8-chloro-2-methyl-6- 8-chloro-2-methyl-6- 3-methoxy-4-(3,3,3-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
trifluoropropoxymethyl)- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- benzoic acid piperidine]-1'-yl]-[3-methoxy-4-
a]pyrazine-1,4'- (3,3,3- piperidine]
trifluoropropoxymethyl)phenyl]methanone [8-chloro-2-methyl-6-
8-chloro-2-methyl-6- 4-(2-fluoro-2-methyl-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
propoxy)-3-methoxy- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- benzoic acid piperidine]-1'-yl]-[4-(2-fluoro-2-
a]pyrazine-1,4'- methyl-propoxy)-3-methoxy- piperidine]
phenyl]methanone [8-chloro-2-methyl-6- 8-chloro-2-methyl-6-
5-isopropoxy-4-methyl- (trifluoromethyl)spiro[3,4-
(trifluoromethyl)spiro[3,4- pyridine-2-carboxylic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(5-isopropoxy-4- a]pyrazine-1,4'-
methyl-2-pyridyl)methanone piperidine] [6-(cyclopropanecarbonyl)-2-
cyclopropyl-(2- 4-methoxy-3-methyl- methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-(4-methoxy-3-
a]pyrazine-1,4'- methyl-phenyl)methanone piperidine]-6-
yl)methanone [6-(cyclopropanecarbonyl)-2- cyclopropyl-(2-
2-fluoro-4-isopropoxy- methyl-spiro[3,4- methylspiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(2-fluoro-4- a]pyrazine-1,4'-
isopropoxy-phenyl)methanone piperidine]-6- yl)methanone
[6-(cyclopropanecarbonyl)-2- cyclopropyl-(2-
3-fluoro-4-(1-hydroxy-1- methyl-spiro[3,4- methylspiro[3,4-
methyl-ethyl)benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-[3-fluoro-4-(1-
a]pyrazine-1,4'- hydroxy-1-methyl- piperidine]-6-
ethyl)phenyl]methanone yl)methanone [6-(cyclopropanecarbonyl)-2-
cyclopropyl-(2- 4-(3,3,3- methyl-spiro[3,4- methylspiro[3,4-
trifluoropropoxymethyl)- dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- benzoic acid piperidine]-1'-yl]-[4-(3,3,3-
a]pyrazine-1,4'- trifluoropropoxymethyl)phenyl]methanone
piperidine]-6- yl)methanone [6-(cyclopropanecarbonyl)-2-
cyclopropyl-(2- 4-isopropoxy-3-methyl- methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-(4-isopropoxy-3-
a]pyrazine-1,4'- methyl-phenyl)methanone piperidine]-6-
yl)methanone [6-(cyclopropanecarbonyl)-2- cyclopropyl-(2-
3-fluoro-4-isopropoxy- methyl-spiro[3,4- methylspiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-yl]-(3-fluoro-4- a]pyrazine-1,4'-
isopropoxy-phenyl)methanone piperidine]-6- yl)methanone
(3-chloro-4-hydroxy-phenyl)-[6- cyclopropyl-(2- 3-chloro-4-hydroxy-
(cyclopropanecarbonyl)-2-methyl- methylspiro[3,4- benzoic acid
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-1'- a]pyrazine-1,4'- yl]methanone
piperidine]-6- yl)methanone (3-chloro-4-isopropoxy-phenyl)-[6-
cyclopropyl-(2- 3-chloro-4-isopropoxy-
(cyclopropanecarbonyl)-2-methyl- methylspiro[3,4- benzoic acid
spiro[3,4-dihydropyrrolo[1,2- dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-1'- a]pyrazine-1,4'- yl]methanone
piperidine]-6- yl)methanone [6-(cyclopropanecarbonyl)-2-
cyclopropyl-(2- 4-hydroxy-3-methyl- methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-(4-hydroxy-3-
a]pyrazine-1,4'- methyl-phenyl)methanone piperidine]-6-
yl)methanone 1-[1'-(4-methoxy-3-methyl- 2-methyl-1-(2-
4-methoxy-3-methyl- benzoyl)-2-methyl-spiro[3,4- methylspiro[3,4-
benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2-methyl-propan-1-
a]pyrazine-1,4'- one piperidine]-6-yl)propan-1- one
1-[1'-[4-methoxy-3- 2-methyl-1-(2- 4-methoxy-3-
(trifluoromethyl)benzoyl]-2-methyl- methylspiro[3,4-
(trifluoromethyl)benzoic spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- acid a]pyrazine-1,4'-piperidine]-6-yl]-2-
a]pyrazine-1,4'- methyl-propan-1-one piperidine]-6-yl)propan-1- one
1-[1'-(3-chloro-4-methoxy-benzoyl)- 2-methyl-1-(2-
3-chloro-4-methoxy- 2-methyl-spiro[3,4- methylspiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2-methyl-propan-1- a]pyrazine-1,4'- one
piperidine]-6-yl)propan-1- one 1-[1'-(4-hydroxy-3-methyl-benzoyl)-
2-methyl-1-(2- 4-hydroxy-3-methyl- 2-methyl-spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2-methyl-propan-1-
a]pyrazine-1,4'- one piperidine]-6-yl)propan-1- one
1-[1'-(3-chloro-4-hydroxy-benzoyl)- 2-methyl-1-(2-
3-chloro-4-hydroxy- 2-methyl-spiro[3,4- methylspiro[3,4- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2-methyl-propan-1- a]pyrazine-1,4'- one
piperidine]-6-yl)propan-1- one 1-[1'-[3-fluoro-4-(1-hydroxy-1-
2-methyl-1-(2- 3-fluoro-4-(1-hydroxy-1-
methyl-ethyl)benzoyl]-2-methyl- methylspiro[3,4-
methyl-ethyl)benzoic acid spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-6-yl]-2-
a]pyrazine-1,4'- methyl-propan-1-one piperidine]-6-yl)propan-1- one
2-methyl-1-[2-methyl-1'-[4-(3,3,3- 2-methyl-1-(2- 4-(3,3,3-
trifluoropropoxymethyl)benzoyl]spiro[3,4- methylspiro[3,4-
trifluoropropoxymethyl)- dihydropyrrolo[1,2- dihydropyrrolo[1,2-
benzoic acid a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'-
yl]propan-1-one piperidine]-6-yl)propan-1- one
[1'-(4-methoxy-3-methyl-benzoyl)- (2-methylspiro[3,4-
4-methoxy-3-methyl- 2-methyl-spiro[3,4- dihydropyrrolo[1,2- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-phenyl-methanone piperidine]-6-yl)-phenyl-
methanone [1'-[4-methoxy-3- (2-methylspiro[3,4- 4-methoxy-3-
(trifluoromethyl)benzoyl]-2-methyl- dihydropyrrolo[1,2-
(trifluoromethyl)benzoic spiro[3,4-dihydropyrrolo[1,2-
a]pyrazine-1,4'- acid a]pyrazine-1,4'-piperidine]-6-yl]-
piperidine]-6-yl)-phenyl- phenyl-methanone methanone
[1'-(3-chloro-4-methoxy-benzoyl)-2- (2-methylspiro[3,4-
3-chloro-4-methoxy- methyl-spiro[3,4- dihydropyrrolo[1,2- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-phenyl-methanone piperidine]-6-yl)-phenyl-
methanone [1'-(4-hydroxy-3-methyl-benzoyl)-2- (2-methylspiro[3,4-
4-hydroxy-3-methyl- methyl-spiro[3,4- dihydropyrrolo[1,2- benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-phenyl-methanone piperidine]-6-yl)-phenyl-
methanone 2,2,2-trifluoro-1-[1'-(6-isopropoxy-
2,2,2-trifluoro-1-(2- 6-isopropoxy-5-methyl-
5-methyl-pyridine-3-carbonyl)-2- methylspiro[3,4-
pyridine-3-carboxylic acid methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(4-hydroxy-3- 2,2,2-trifluoro-1-(2-
4-hydroxy-3-isopropyl- isopropyl-benzoyl)-2-methyl-
methylspiro[3,4- benzoic acid spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'-
yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(5-ethylpyridine-2-carbonyl)-2- 2,2,2-trifluoro-1-(2-
5-ethylpyridine-2- methyl-spiro[3,4- methylspiro[3,4- carboxylic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2,2-trifluoro- a]pyrazine-1,4'- ethanone
piperidine]-6-yl)ethanone 1-[(3S)-1'-(3-chloro-4-hydroxy-
1-[(3S)-2,3- 3-chloro-4-hydroxy- benzoyl)-2,3-dimethyl-spiro[3,4-
dimethylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 2,2,2-trifluoro-1-[(3S)-1'-(4- 1-[(3S)-2,3-
4-hydroxy-3-methyl- hydroxy-3-methyl-benzoyl)-2,3-
dimethylspiro[3,4- benzoic acid dimethyl-spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 2,2,2-trifluoro-1-[(3S)-1'-[3-fluoro-
1-[(3S)-2,3- 3-fluoro-4-(1-hydroxy-1- 4-(1-hydroxy-1-methyl-
dimethylspiro[3,4- methyl-ethyl)benzoic acid
ethyl)benzoyl]-2,3-dimethyl- dihydropyrrolo[1,2-
spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl]-2,2,2- yl]ethanone
trifluoro-ethanone 1-[(3S)-1'-(4-tert- 1-[(3S)-2,3- 4-tert-
butylsulfonylbenzoyl)-2,3-dimethyl- dimethylspiro[3,4-
butylsulfonylbenzoic acid spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2- a]pyrazine-1,4'-piperidine]-6-yl]-
a]pyrazine-1,4'- 2,2,2-trifluoro-ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 1-[(3S)-1'-[2- 1-[(3S)-2,3- 2-
(difluoromethoxy)benzoyl]-2,3- dimethylspiro[3,4-
(difluoromethoxy)benzoic dimethyl-spiro[3,4- dihydropyrrolo[1,2-
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-2,2,2-trifluoro- piperidine]-6-yl]-2,2,2-
ethanone trifluoro-ethanone 2,2,2-trifluoro-1-[(3S)-1'-(3-fluoro-
1-[(3S)-2,3- 3-fluoro-4-isopropoxy- 4-isopropoxy-benzoyl)-2,3-
dimethylspiro[3,4- benzoic acid dimethyl-spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 2,2,2-trifluoro-1-[(3S)-1'-(2- 1-[(3S)-2,3-
2-methoxy-3-methyl- methoxy-3-methyl-benzoyl)-2,3-
dimethylspiro[3,4- benzoic acid dimethyl-spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 1-[(3S)-2,3-dimethyl-1'-[4-(2,2,2- 1-[(3S)-2,3-
4-(2,2,2- trifluoroethoxy)benzoyl]spiro[3,4- dimethylspiro[3,4-
trifluoroethoxy)benzoic dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- acid piperidine]-6-yl]-2,2,2-trifluoro-
a]pyrazine-1,4'- ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3- 1-[(3S)-2,3-
4-(3,3,3- trifluoropropoxymethyl)benzoyl]spiro[3,4-
dimethylspiro[3,4- trifluoropropoxymethyl)- dihydropyrrolo[1,2-
dihydropyrrolo[1,2- benzoic acid a]pyrazine-1,4'-piperidine]-6-yl]-
a]pyrazine-1,4'- 2,2,2-trifluoro-ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 2,2,2-trifluoro-1-[(3S)-1'-(3-fluoro-
l-[(3S)-2,3- 3-fluoro-2-methoxy- 2-methoxy-benzoyl)-2,3-dimethyl-
dimethylspiro[3,4- benzoic acid spiro[3,4-dihydropyrrolo[1,2-
dihydropyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl]-2,2,2- trifluoro-ethanone
2,2,2-trifluoro-1-[(3S)-1'-(5- l-[(3S)-2,3- 5-methoxy-6-methyl-
methoxy-6-methyl-pyridine-2- dimethylspiro[3,4-
pyridine-2-carboxylic acid carbonyl)-2,3-dimethyl-spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 2,2,2-trifluoro-1-[1'-(5-methoxy-6-
2,2,2-trifluoro-1-(2- 5-methoxy-6-methyl-
methyl-pyridine-2-carbonyl)-2- methylspiro[3,4-
pyridine-2-carboxylic acid methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(5-hydroxy-6- 2,2,2-trifluoro-1-(2-
5-hydroxy-6-methyl- methyl-pyridine-2-carbonyl)-2- methylspiro[3,4-
pyridine-2-carboxylic acid methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(5-isopropoxy-6-methyl- 1-(2-methylspiro[3,4-
5-isopropoxy-6-methyl- pyridine-2-carbonyl)-2-methyl-
dihydropyrrolo[1,2- pyridine-2-carboxylic acid
spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)ethanone
yl]ethanone 1-[1'-(2-fluoro-4-isopropoxy- 1-(2-methylspiro[3,4-
2-fluoro-4-isopropoxy- benzoyl)-2-methyl-spiro[3,4-
dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(5- 2,2,2-trifluoro-1-(2-
5-isobutoxypyridine-2- isobutoxypyridine-2-carbonyl)-2-
methylspiro[3,4- carboxylic acid methyl-spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(5-
2,2,2-trifluoro-1-(2- 5-isopentyloxypyridine-2-
isopentyloxypyridine-2-carbonyl)-2- methylspiro[3,4- carboxylic
acid methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone [4-methoxy-3-
(1-methylcyclopropyl)-(2- 4-methoxy-3-
(trifluoromethyl)phenyl]-[2-methyl- methylspiro[3,4-
(trifluoromethyl)benzoic 6-(1- dihydropyrrolo[1,2- acid
methylcyclopropanecarbonyl)spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine- piperidine]-6-
1,4'-piperidine]-1'-yl]methanone yl)methanone [2-methyl-6-(1-
(1-methylcyclopropyl)-(2- 4-(3,3,3-
methylcyclopropanecarbonyl)spiro[3,4- methylspiro[3,4-
trifluoropropoxymethyl)- dihydropyrrolo[1,2-a]pyrazine-
dihydropyrrolo[1,2- benzoic acid 1,4'-piperidine]-1'-yl]-[4-(3,3,3-
a]pyrazine-1,4'- trifluoropropoxymethyl)phenyl]methanone
piperidine]-6- yl)methanone 2,2,2-trifluoro-1-[1'-[4-[1-hydroxy-
2,2,2-trifluoro-1-(2- 4-[l-hydroxy-2-(2,2,2- 2-(2,2,2-
methylspiro[3,4- trifluoroethoxy)ethyl]-
trifluoroethoxy)ethyl]benzoyl]-2- dihydropyrrolo[1,2- benzoic acid
methyl-spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)ethanone
piperidine]-6-yl]ethanone 2,2,2-trifluoro-1-[1'-[4-[2-hydroxy-
2,2,2-trifluoro-1-(2- 4-[2-hydroxy-1-(2,2,2- 1-(2,2,2-
methylspiro[3,4- trifluoroethoxy)ethyl]-
trifluoroethoxy)ethyl]benzoyl]-2- dihydropyrrolo[1,2- benzoic acid
methyl-spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)ethanone
piperidine]-6-yl]ethanone 2,2,2-trifluoro-1-[1'-(4-
1-(3,3-dimethylspiro[2,4- 4- isopropylsulfonylbenzoyl)-3,3-
dihydropyrrolo[1,2- isopropylsulfonylbenzoic dimethyl-spiro[2,4-
a]pyrazine-1,4'- acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
piperidine]-6-yl)-2,2,2- piperidine]-6-yl]ethanone
trifluoro-ethanone 1-[3,3-dimethyl-1'-[4- 1-(3,3-dimethylspiro[2,4-
4- (trifluoromethylsulfonyl)benzoyl]spiro[2,4- dihydropyrrolo[1,2-
(trifluoromethylsulfonyl)- dihydropyrrolo[1,2- a]pyrazine-1,4'-
benzoic acid a]pyrazine-1,4'-piperidine]-6-yl]-
piperidine]-6-yl)-2,2,2- 2,2,2-trifluoro-ethanone
trifluoro-ethanone N-cyclopropyl-4-[3,3-dimethyl-6-
1-(3,3-dimethylspiro[2,4- 4-(cyclopropylsulfamoyl)-
(2,2,2-trifluoroacetyl)spiro[2,4- dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'- piperidine]-6-yl)-2,2,2-
carbonyl]benzenesulfonamide trifluoro-ethanone
1-[1'-(4-tert-butylsulfonylbenzoyl)- 1-(3,3-dimethylspiro[2,4-
4-tert- 3,3-dimethyl-spiro[2,4- dihydropyrrolo[1,2-
butylsulfonylbenzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]-2,2,2-trifluoro-
piperidine]-6-yl)-2,2,2- ethanone trifluoro-ethanone
2,2,2-trifluoro-1-[(3S)-1'-(4- 1-[(3S)-2,3- 4-
isopropylsulfonylbenzoyl)-2,3- dimethylspiro[3,4-
isopropylsulfonylbenzoic dimethyl-spiro[3,4- dihydropyrrolo[1,2-
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 1-[(3S)-2,3-dimethyl-1'-[4- 1-[(3S)-2,3- 4-
(trifluoromethylsulfonyl)benzoyl]spiro[3,4- dimethylspiro[3,4-
(trifluoromethylsulfonyl)- dihydropyrrolo[1,2- dihydropyrrolo[1,2-
benzoic acid a]pyrazine-1,4'-piperidine]-6-yl]- a]pyrazine-1,4'-
2,2,2-trifluoro-ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone N-cyclopropyl-4-[(3S)-2,3-dimethyl- 1-[(3S)-2,3-
4-(cyclopropylsulfamoyl)- 6-(2,2,2-trifluoroacetyl)spiro[3,4-
dimethylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'- a]pyrazine-1,4'-
carbonyl]benzenesulfonamide piperidine]-6-yl]-2,2,2-
trifluoro-ethanone 1-[1'-(5-cyclohexylpyridine-2-
2,2,2-trifluoro-1-(2- 5-cyclohexylpyridine-2-
carbonyl)-2-methyl-spiro[3,4- methylspiro[3,4- carboxylic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-6-yl]-2,2,2-trifluoro- a]pyrazine-1,4'- ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-[5-(2-
2,2,2-trifluoro-1-(2- 5-(2- fluorophenyl)pyridine-2-carbonyl]-
methylspiro[3,4- fluorophenyl)pyridine-2- 2-methyl-spiro[3,4-
dihydropyrrolo[1,2- carboxylic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[(3S)-1'-[4-(1- 1-[(3S)-2,3-
4-(1-hydroxy-1-methyl- hydroxy-1-methyl-ethyl)benzoyl]-
dimethylspiro[3,4- ethyl)benzoic acid 2,3-dimethyl-spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone piperidine]-6-yl]-2,2,2-
trifluoro-ethanone [4-(1-hydroxy-1-methyl-
(1-methylcyclopropyl)-(2- 4-(1-hydroxy-1-methyl-
ethyl)phenyl]-[2-methyl-6-(1- methylspiro[3,4- ethyl)benzoic acid
methylcyclopropanecarbonyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine- a]pyrazine-1,4'-
1,4'-piperidine]-1'-yl]methanone piperidine]-6- yl)methanone
(5-methoxy-6-methyl-2-pyridyl)-[2- (1-methylcyclopropyl)-(2-
5-methoxy-6-methyl- methyl-6-(1- methylspiro[3,4-
pyridine-2-carboxylic acid methylcyclopropanecarbonyl)spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine- a]pyrazine-1,4'-
1,4'-piperidine]-1'-yl]methanone piperidine]-6- yl)methanone
(3-chloro-4-methoxy-phenyl)-[2- (1-methylcyclopropyl)-(2-
3-chloro-4-methoxy- methyl-6-(1- methylspiro[3,4- benzoic acid
methylcyclopropanecarbonyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine- a]pyrazine-1,4'-
1,4'-piperidine]-1'-yl]methanone piperidine]-6- yl)methanone
(4-hydroxy-3-methyl-phenyl)-[2- (1-methylcyclopropyl)-(2-
4-hydroxy-3-methyl- methyl-6-(1- methylspiro[3,4- benzoic acid
methylcyclopropanecarbonyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine- a]pyrazine-1,4'-
1,4'-piperidine]-1'-yl]methanone piperidine]-6- yl)methanone
N-cyclopropyl-4-[2-methyl-6-(1- (1-methylcyclopropyl)-(2-
4-(cyclopropylsulfamoyl)- methylcyclopropanecarbonyl)spiro[3,4-
methylspiro[3,4- benzoic acid dihydropyrrolo[1,2-a]pyrazine-
dihydropyrrolo[1,2- 1,4'-piperidine]-1'- a]pyrazine-1,4'-
carbonyl]benzenesulfonamide piperidine]-6- yl)methanone
(3-chloro-4-hydroxy-phenyl)-[2- (1-methylcyclopropyl)-(2-
3-chloro-4-hydroxy- methyl-6-(1- methylspiro[3,4- benzoic acid
methylcyclopropanecarbonyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine- a]pyrazine-1,4'-
1,4'-piperidine]-1'-yl]methanone piperidine]-6- yl)methanone
[2-methyl-6-(1- (1-methylcyclopropyl)-(2- 4-
methylcyclopropanecarbonyl)spiro[3,4- methylspiro[3,4-
(trifluoromethylsulfonyl)- dihydropyrrolo[1,2-a]pyrazine-
dihydropyrrolo[1,2- benzoic acid 1,4'-piperidine]-1'-yl]-[4-
a]pyrazine-1,4'- (trifluoromethylsulfonyl)phenyl]methanone
piperidine]-6- yl)methanone [3-(hydroxymethyl)-4-isopropoxy-
(1-methylcyclopropyl)-(2- 3-(hydroxymethyl)-4-
phenyl]-[2-methyl-6-(1- methylspiro[3,4- isopropoxy-benzoic acid
methylcyclopropanecarbonyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine- a]pyrazine-1,4'-
1,4'-piperidine]-1'-yl]methanone piperidine]-6- yl)methanone
(2-fluoro-4-isopropoxy-phenyl)-[2- (1-methylcyclopropyl)-(2-
2-fluoro-4-isopropoxy- methyl-6-(1- methylspiro[3,4- benzoic acid
methylcyclopropanecarbonyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine- a]pyrazine-1,4'-
1,4'-piperidine]-1'-yl]methanone piperidine]-6- yl)methanone
(4-methoxy-3-methyl-phenyl)-[2- (1-methylcyclopropyl)-(2-
4-methoxy-3-methyl- methyl-6-(1- methylspiro[3,4- benzoic acid
methylcyclopropanecarbonyl)spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine- a]pyrazine-1,4'-
1,4'-piperidine]-1'-yl]methanone piperidine]-6- yl)methanone
[4-hydroxy-3- (1-methylcyclopropyl)-(2- 4-hydroxy-3-
(trifluoromethyl)phenyl]-[2-methyl- methylspiro[3,4-
(trifluoromethyl)benzoic 6-(1- dihydropyrrolo[1,2- acid
methylcyclopropanecarbonyl)spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine- piperidine]-6-
1,4'-piperidine]-1'-yl]methanone yl)methanone
2,2,2-trifluoro-1-[1'-(5-methoxy-6- 1-(3,3-dimethylspiro[2,4-
5-methoxy-6-methyl- methyl-pyridine-2-carbonyl)-3,3-
dihydropyrrolo[1,2- pyridine-2-carboxylic acid dimethyl-spiro[2,4-
a]pyrazine-1,4'- dihydropyrrolo[1,2-a]pyrazine-1,4'-
piperidine]-6-yl)-2,2,2- piperidine]-6-yl]ethanone
trifluoro-ethanone (4-tert-butylsulfonylphenyl)-[2-
(1-methylcyclopropyl)-(2- 4-tert- methyl-6-(1- methylspiro[3,4-
butylsulfonylbenzoic acid methylcyclopropanecarbonyl)spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine- a]pyrazine-1,4'-
1,4'-piperidine]-1'-yl]methanone piperidine]-6- yl)methanone
1-[1'-(4- 2,2,2-trifluoro-1-(2- 4-cyclopropylsulfonyl-
cyclopropylsulfonylbenzoyl)-2- methylspiro[3,4- benzoic acid
methyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-2,2,2-trifluoro- piperidine]-6-yl)ethanone
ethanone 1-[(3S)-1'-(4- 1-[(3S)-2,3- 4-cyclopropylsulfonyl-
cyclopropylsulfonylbenzoyl)-2,3- dimethylspiro[3,4- benzoic acid
dimethyl-spiro[3,4- dihydropyrrolo[1,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-2,2,2-trifluoro- piperidine]-6-yl]-2,2,2-
ethanone trifluoro-ethanone 1-[1'-(4- 1-(3,3-dimethylspiro[2,4-
4-cyclopropylsulfonyl- cyclopropylsulfonylbenzoyl)-3,3-
dihydropyrrolo[1,2- benzoic acid dimethyl-spiro[2,4-
a]pyrazine-1,4'- dihydropyrrolo[1,2-a]pyrazine-1,4'-
piperidine]-6-yl)-2,2,2- piperidine]-6-yl]-2,2,2-trifluoro-
trifluoro-ethanone ethanone [4-[2-methyl-6-(2,2,2-
2,2,2-trifluoro-1-(2- 4-(trifluoromethyl-
trifluoroacetyl)spiro[3,4- methylspiro[3,4- sulfonyloxy)benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- dihydropyrrolo[1,2-
piperidine]-1'-carbonyl]phenyl] a]pyrazine-1,4'-
trifluoromethanesulfonate piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(4-methoxy-3- 1-(2,4-dimethylspiro[3,4-
4-methoxy-3-methyl- methyl-benzoyl)-2,4-dimethyl-
dihydropyrrolo[1,2- benzoic acid
spiro[3,4-dihydropyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl)-2,2,2- yl]ethanone
trifluoro-ethanone 1-[1'-(3-chloro-4-methoxy-benzoyl)-
1-(2,4-dimethylspiro[3,4- 3-chloro-4-methoxy-
2,4-dimethyl-spiro[3,4- dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-2,2,2-trifluoro- piperidine]-6-yl)-2,2,2-
ethanone trifluoro-ethanone 2,2,2-trifluoro-1-[1'-[4-methoxy-3-
1-(2,4-dimethylspiro[3,4- 4-methoxy-3-
(trifluoromethyl)benzoyl]-2,4- dihydropyrrolo[1,2-
(trifluoromethyl)benzoic dimethyl-spiro[3,4- a]pyrazine-1,4'- acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)-2,2,2-
piperidine]-6-yl]ethanone trifluoro-ethanone
2,2,2-trifluoro-1-[1'-(4- 1-(2,4-dimethylspiro[3,4-
4-isopentyloxybenzoic isopentyloxybenzoyl)-2,4-dimethyl-
dihydropyrrolo[1,2- acid spiro[3,4-dihydropyrrolo[1,2-
a]pyrazine-1,4'- a]pyrazine-1,4'-piperidine]-6-
piperidine]-6-yl)-2,2,2- yl]ethanone trifluoro-ethanone
2,2,2-trifluoro-1-[1'-(4-isopropoxy- 1-(2,4-dimethylspiro[3,4-
4-isopropoxy-3-methyl- 3-methyl-benzoyl)-2,4-dimethyl-
dihydropyrrolo[1,2- benzoic acid spiro[3,4-dihydropyrrolo[1,2-
a]pyrazine-1,4'- a]pyrazine-1,4'-piperidine]-6-
piperidine]-6-yl)-2,2,2- yl]ethanone trifluoro-ethanone
1-[2,4-dimethyl-1'-[4-(3,3,3- 1-(2,4-dimethylspiro[3,4- 4-(3,3,3-
trifluoropropoxymethyl)benzoyl]spiro[3,4- dihydropyrrolo[1,2-
trifluoropropoxymethyl)- dihydropyrrolo[1,2- a]pyrazine-1,4'-
benzoic acid a]pyrazine-1,4'-piperidine]-6-yl]-
piperidine]-6-yl)-2,2,2- 2,2,2-trifluoro-ethanone
trifluoro-ethanone 1-[1'-(3-chloro-4-isopropoxy-
1-(2,4-dimethylspiro[3,4- 3-chloro-4-isopropoxy-
benzoyl)-2,4-dimethyl-spiro[3,4- dihydropyrrolo[1,2- benzoic acid
dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]-2,2,2-trifluoro- piperidine]-6-yl)-2,2,2-
ethanone trifluoro-ethanone 2,2,2-trifluoro-1-[1'-(5-isopropoxy-
1-(2,4-dimethylspiro[3,4- 5-isopropoxy-6-methyl-
6-methyl-pyridine-2-carbonyl)-2,4- dihydropyrrolo[1,2-
pyridine-2-carboxylic acid dimethyl-spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)-2,2,2-
piperidine]-6-yl]ethanone trifluoro-ethanone
2,2,2-trifluoro-1-[1'-(5- 1-(2,4-dimethylspiro[3,4-
5-isopentyloxypyridine-2- isopentyloxypyridine-2-carbonyl)-
dihydropyrrolo[1,2- carboxylic acid 2,4-dimethyl-spiro[3,4-
a]pyrazine-1,4'- dihydropyrrolo[1,2-a]pyrazine-1,4'-
piperidine]-6-yl)-2,2,2- piperidine]-6-yl]ethanone
trifluoro-ethanone 2,2,2-trifluoro-1-[1'-(4-methoxy-3-
2,2,2-trifluoro-1-(4- 4-methoxy-3-methyl-
methyl-benzoyl)-4-methyl-spiro[3,4- methylspiro[3,4-dihydro-
benzoic acid dihydro-2H-pyrrolo[1,2-a]pyrazine- 2H-pyrrolo[1,2-
1,4'-piperidine]-6-yl]ethanone a]pyrazine-1,4'-
piperidine]-6-yl)ethanone 1-[1'-(3-chloro-4-methoxy-benzoyl)-
2,2,2-trifluoro-1-(4- 3-chloro-4-methoxy-
4-methyl-spiro[3,4-dihydro-2H- methylspiro[3,4-dihydro- benzoic
acid pyrrolo[1,2-a]pyrazine-1,4'- 2H-pyrrolo[1,2-
piperidine]-6-yl]-2,2,2-trifluoro- a]pyrazine-1,4'- ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(4-
2,2,2-trifluoro-1-(4- 4-isopentyloxybenzoic
isopentyloxybenzoyl)-4-methyl- methylspiro[3,4-dihydro- acid
spiro[3,4-dihydro-2H-pyrrolo[1,2- 2H-pyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(4-isopropoxy-
2,2,2-trifluoro-1-(4- 4-isopropoxy-3-methyl-
3-methyl-benzoyl)-4-methyl- methylspiro[3,4-dihydro- benzoic acid
spiro[3,4-dihydro-2H-pyrrolo[1,2- 2H-pyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[4-methyl-1'-[4-
2,2,2-trifluoro-1-(4- 4-(3,3,3- (3,3,3- methylspiro[3,4-dihydro-
trifluoropropoxymethyl)- trifluoropropoxymethyl)benzoyl]spiro[3,4-
2H-pyrrolo[1,2- benzoic acid dihydro-2H-pyrrolo[1,2-
a]pyrazine-1,4'- a]pyrazine-1,4'-piperidine]-6-
piperidine]-6-yl)ethanone yl]ethanone
2,2,2-trifluoro-1-[1'-(5-methoxy-6- 2,2,2-trifluoro-1-(4-
5-methoxy-6-methyl- methyl-pyridine-2-carbonyl)-4-
methylspiro[3,4-dihydro- pyridine-2-carboxylic acid
methyl-spiro[3,4-dihydro-2H- 2H-pyrrolo[1,2-
pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
1-[1'-(3-chloro-4-isopropoxy- 2,2,2-trifluoro-1-(4-
3-chloro-4-isopropoxy- benzoyl)-4-methyl-spiro[3,4-
methylspiro[3,4-dihydro- benzoic acid
dihydro-2H-pyrrolo[1,2-a]pyrazine- 2H-pyrrolo[1,2-
1,4'-piperidine]-6-yl]-2,2,2-trifluoro- a]pyrazine-1,4'- ethanone
piperidine]-6-yl)ethanone 2,2,2-trifluoro-1-[1'-(5-
2,2,2-trifluoro-1-(4- 5-isopentyloxypyridine-2-
isopentyloxypyridine-2-carbonyl)-4- methylspiro[3,4-dihydro-
carboxylic acid methyl-spiro[3,4-dihydro-2H- 2H-pyrrolo[1,2-
pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(5-methoxy-6- 1-(2,4-dimethylspiro[3,4-
5-methoxy-6-methyl- methyl-pyridine-2-carbonyl)-2,4-
dihydropyrrolo[1,2- pyridine-2-carboxylic acid dimethyl-spiro[3,4-
a]pyrazine-1,4'- dihydropyrrolo[1,2-a]pyrazine-1,4'-
piperidine]-6-yl)-2,2,2- piperidine]-6-yl]ethanone
trifluoro-ethanone 2,2,2-trifluoro-1-[1'-[4-methoxy-3-
2,2,2-trifluoro-1-(4- 4-methoxy-3-
(trifluoromethyl)benzoyl]-4-methyl- methylspiro[3,4-dihydro-
(trifluoromethyl)benzoic spiro[3,4-dihydro-2H-pyrrolo[1,2-
2H-pyrrolo[1,2- acid a]pyrazine-1,4'-piperidine]-6-
a]pyrazine-1,4'- yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(5-isopropoxy- 2,2,2-trifluoro-1-(4-
5-isopropoxy-6-methyl- 6-methyl-pyridine-2-carbonyl)-4-
methylspiro[3,4-dihydro- pyridine-2-carboxylic acid
methyl-spiro[3,4-dihydro-2H- 2H-pyrrolo[1,2-
pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-[4-(1-hydroxy- 1-(2,4-dimethylspiro[3,4-
4-(1-hydroxy-1-methyl- 1-methyl-ethyl)-3-methyl-benzoyl]-
dihydropyrrolo[1,2- ethyl)-3-methyl-benzoic 2,4-dimethyl-spiro[3,4-
a]pyrazine-1,4'- acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
piperidine]-6-yl)-2,2,2- piperidine]-6-yl]ethanone
trifluoro-ethanone 2,2,2-trifluoro-1-[1'-[4-(1-hydroxy-
2,2,2-trifluoro-1-(4- 4-(1-hydroxy-1-methyl-
1-methyl-ethyl)-3-methyl-benzoyl]- methylspiro[3,4-dihydro-
ethyl)-3-methyl-benzoic 4-methyl-spiro[3,4-dihydro-2H-
2H-pyrrolo[1,2- acid pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl)ethanone
2,2,2-trifluoro-1-[1'-(5-isopropoxy- 2,2,2-trifluoro-1-(2-
5-isopropoxy-6-methoxy- 6-methoxy-pyridine-2-carbonyl)-2-
methylspiro[3,4- pyridine-2-carboxylic acid methyl-spiro[3,4-
dihydropyrrolo[1,2- dihydropyrrolo[1,2-a]pyrazine-1,4'-
a]pyrazine-1,4'- piperidine]-6-yl]ethanone
piperidine]-6-yl)ethanone [8-chloro-2-methyl-6-
8-chloro-2-methyl-6- 5-isopropoxy-6-methoxy-
(trifluoromethyl)spiro[3,4- (trifluoromethyl)spiro[3,4-
pyridine-2-carboxylic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-yl]-(5-isopropoxy-6-
a]pyrazine-1,4'- methoxy-2-pyridyl)methanone piperidine]
2,2,2-trifluoro-1-[1'-[3-methoxy-4- 1-(2,4-dimethylspiro[3,4-
3-methoxy-4-[2- [2- dihydropyrrolo[1,2- (trifluoromethoxy)ethoxy]
(trifluoromethoxy)ethoxy]benzoyl]- a]pyrazine-1,4'- benzoic acid
2,4-dimethyl-spiro[3,4- piperidine]-6-yl)-2,2,2-
dihydropyrrolo[1,2-a]pyrazine-1,4'- trifluoro-ethanone
piperidine]-6-yl]ethanone 2,2,2-trifluoro-1-[1'-[3-methoxy-4-
2,2,2-trifluoro-1-(4- 3-methoxy-4-[2- [2- methylspiro[3,4-dihydro-
(trifluoromethoxy)ethoxy] (trifluoromethoxy)ethoxy]benzoyl]-
2H-pyrrolo[1,2- benzoic acid 4-methyl-spiro[3,4-dihydro-2H-
a]pyrazine-1,4'- pyrrolo[1,2-a]pyrazine-1,4'-
piperidine]-6-yl)ethanone piperidine]-6-yl]ethanone
2,2,2-trifluoro-1-[1'-[3-methoxy-4- 2,2,2-trifluoro-1-(2-
3-methoxy-4-[2- [2- methylspiro[3,4- (trifluoromethoxy)ethoxy]
(trifluoromethoxy)ethoxy]benzoyl]- dihydropyrrolo[1,2- benzoic acid
2-methyl-spiro[3,4- a]pyrazine-1,4'-
dihydropyrrolo[1,2-a]pyrazine-1,4'- piperidine]-6-yl)ethanone
piperidine]-6-yl]ethanone [4-[2,4-dimethyl-6-(2,2,2-
1-(2,4-dimethylspiro[3,4- 4-(trifluoromethyl-
trifluoroacetyl)spiro[3,4- dihydropyrrolo[1,2- sulfonyloxy)benzoic
acid dihydropyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-1'-carbonyl]phenyl] piperidine]-6-yl)-2,2,2-
trifluoromethanesulfonate trifluoro-ethanone
2,2,2-trifluoro-1-[(3S)-1'-(4- 2,2,2-trifluoro-1-[(3S)-3-
4-methoxy-3-methyl- methoxy-3-methyl-benzoyl)-3-
methylspiro[3,4-dihydro- benzoic acid methyl-spiro[3,4-dihydro-2H-
2H-pyrrolo[1,2- pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl]ethanone
1-[(3S)-1'-(3-chloro-4-methoxy- 2,2,2-trifluoro-1-[(3S)-3-
3-chloro-4-methoxy- benzoyl)-3-methyl-spiro[3,4-
methylspiro[3,4-dihydro- benzoic acid
dihydro-2H-pyrrolo[1,2-a]pyrazine- 2H-pyrrolo[1,2-
1,4'-piperidine]-6-yl]-2,2,2-trifluoro- a]pyrazine-1,4'- ethanone
piperidine]-6-yl]ethanone 2,2,2-trifluoro-1-[(3S)-1'-[4-
2,2,2-trifluoro-1-[(3S)-3- 4-methoxy-3- methoxy-3-
methylspiro[3,4-dihydro- (trifluoromethyl)benzoic
(trifluoromethyl)benzoyl]-3-methyl- 2H-pyrrolo[1,2- acid
spiro[3,4-dihydro-2H-pyrrolo[1,2- a]pyrazine-1,4'-
a]pyrazine-1,4'-piperidine]-6- piperidine]-6-yl]ethanone
yl]ethanone 2,2,2-trifluoro-1-[(3S)-1'-(3-fluoro-
2,2,2-trifluoro-1-[(3S)-3- 3-fluoro-4-isopropoxy-
4-isopropoxy-benzoyl)-3-methyl- methylspiro[3,4-dihydro- benzoic
acid spiro[3,4-dihydro-2H-pyrrolo[1,2- 2H-pyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl]ethanone 1-[(3S)-1'-(4-tert-
2,2,2-trifluoro-1-[(3S)-3- 4-tert- butylsulfonylbenzoyl)-3-methyl-
methylspiro[3,4-dihydro- butylsulfonylbenzoic acid
spiro[3,4-dihydro-2H-pyrrolo[1,2- 2H-pyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6-yl]- a]pyrazine-1,4'-
2,2,2-trifluoro-ethanone piperidine]-6-yl]ethanone
2,2,2-trifluoro-1-[(3S)-3-methyl-1'- 2,2,2-trifluoro-1-[(3S)-3-
4-(3,3,3- [4-(3,3,3- methylspiro[3,4-dihydro-
trifluoropropoxymethyl)- trifluoropropoxymethyl)benzoyl]spiro[3,4-
2H-pyrrolo[1,2- benzoic acid dihydro-2H-pyrrolo[1,2-
a]pyrazine-1,4'- a]pyrazine-1,4'-piperidine]-6-
piperidine]-6-yl]ethanone yl]ethanone
2,2,2-trifluoro-1-[(3S)-1'-(5- 2,2,2-trifluoro-1-[(3S)-3-
5-methoxy-6-methyl- methoxy-6-methyl-pyridine-2-
methylspiro[3,4-dihydro- pyridine-2-carboxylic acid
carbonyl)-3-methyl-spiro[3,4- 2H-pyrrolo[1,2-
dihydro-2H-pyrrolo[1,2-a]pyrazine- a]pyrazine-1,4'-
1,4'-piperidine]-6-yl]ethanone piperidine]-6-yl]ethanone
2,2,2-trifluoro-1-[(3S)-1'-(2-fluoro- 2,2,2-trifluoro-1-[(3S)-3-
2-fluoro-4-isopropoxy- 4-isopropoxy-benzoyl)-3-methyl-
methylspiro[3,4-dihydro- benzoic acid
spiro[3,4-dihydro-2H-pyrrolo[1,2- 2H-pyrrolo[1,2-
a]pyrazine-1,4'-piperidine]-6- a]pyrazine-1,4'- yl]ethanone
piperidine]-6-yl]ethanone 2,2,2-trifluoro-1-[(3S)-1'-(5-
2,2,2-trifluoro-1-[(3S)-3- 5-isopentyloxypyridine-2-
isopentyloxypyridine-2-carbonyl)-3- methylspiro[3,4-dihydro-
carboxylic acid methyl-spiro[3,4-dihydro-2H- 2H-pyrrolo[1,2-
pyrrolo[1,2-a]pyrazine-1,4'- a]pyrazine-1,4'-
piperidine]-6-yl]ethanone piperidine]-6-yl]ethanone
N-methyl-4-[2-methyl-6-(2,2,2- 2,2,2-trifluoro-1-(2-
4-[methyl(thiazol-2- trifluoroacetyl)spiro[3,4- methylspiro[3,4-
yl)sulfamoyl]benzoic acid dihydropyrrolo[1,2-a]pyrazine-1,4'-
dihydropyrrolo[1,2- piperidine]-1'-carbonyl]-N-thiazol-2-
a]pyrazine-1,4'- yl-benzenesulfonamide piperidine]-6-yl)ethanone
1-(1-(4-bromo-3-methylbenzoyl)-2'- 2,2,2-trifluoro-1-(2'-
4-bromo-3-methylbenzoic methyl-3',4'-dihydro-2'H-
methyl-3',4'-dihydro-2'H- acid spiro[piperidine-4,1'-pyrrolo[1,2-
spiro[piperidine-4,1'- a]pyrazine]-6'-yl)-2,2,2-
pyrrolo[1,2-a]pyrazine]- trifluoroethanone 6'-yl)ethanone
(2-chloropyridin-3-yl)(2'-methyl-6'- 2'-methyl-6'-
2-chloronicotinic acid (trifluoromethyl)-3',4'-dihydro-2'H-
(trifluoromethyl)-3',4'- spiro[piperidine-4,1'-pyrrolo[1,2-
dihydro-2'H- a]pyrazine]-1-yl)methanone spiro[piperidine-4,1'-
pyrrolo[1,2-a]pyrazine]
1-(1-(4-Isopropoxy-3-methoxybenzoyl)-6'-(trifluoromethyl)-3',4'-dihydro-2'-
H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-2'-yl)ethanone
##STR00886##
[0459] Acetyl chloride (158 .mu.L, 2.22 mmol) was added drop-wise
to a mixture of
(4-isopropoxy-3-methoxy-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H--
pyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone (100 mg,
0.222 mmol) and pyridine (1 mL) at room temperature. The mixture
was allowed to stir for 16 h at room temperature before it was
partitioned between ethyl acetate and 1N HCl. The layers were
separated and the organic layer was washed with 1N HCl, water, and
then brine. The organic layer was dried over sodium sulfate and
concentrated under reduced pressure. The residue was taken up in
DMF and was purified by preparatory-HPLC (10-99% ACN/water with
ammonium formate modifier) to give
1-[1'-(4-isopropoxy-3-methoxy-benzoyl)-6-(trifluoromethyl)spiro[3,4-dihyd-
ropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-2-yl]ethanone (60 mg,
53%) as a white solid. ESI-MS m/z calc. 493.2, found 494.7 (M+1)+;
Retention time: 1.70 minutes (3 min run). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.06 (d, J=1.8 Hz, 1H), 7.05-6.98 (m, 1H), 6.88
(d, J=8.2 Hz, 1H), 6.55 (d, J=3.3 Hz, 1H), 6.15 (d, J=3.9 Hz, 1H),
4.57 (d, J=6.1 Hz, 1H), 4.19-4.10 (m, 2H), 3.88 (m, s, 5H), 3.79
(s, 2H), 3.70-3.52 (m, J=31.5 Hz, 2H), 3.11 (s, 2H), 2.24 (s, 3H),
1.92-1.75 (m, 2H), 1.38 (d, J=6.1 Hz, 6H).
[0460] The following compounds were synthesized using the procedure
described above: methyl
1-(4-isopropoxy-3-methoxybenzoyl)-6'-(trifluoromethyl)-3',4'-dihydro-2'H--
spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-2'-carboxylate and
ethyl
1-(4-isopropoxy-3-methoxybenzoyl)-6'-(trifluoromethyl)-3',4'-dihydro-2'H--
spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-2'-carboxylate.
2,2,2-Trifluoro-1-[1'-[4-(2-methoxy-3-pyridyl)-3-methyl-benzoyl]-2-methyl--
spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone
##STR00887##
[0462] To a microtube with Pd(dppf)Cl.sub.2 (5.5 mg, 0.075 mmol)
was added 2-methoxypyridin-3-ylboronic acid (0.10 mmol) in NMP (0.2
mL), followed by a solution of
1-(1-(4-bromo-3-methylbenzoyl)-2'-methyl-3',4'-dihydro-2'H-spiro[piperidi-
ne-4,1'-pyrrolo[1,2-a]pyrazine]-6'-yl)-2,2,2-trifluoroethanone
(0.75 mmol) in DMF (0.3 mL) and aq. Na.sub.2CO.sub.3 (2M, 4 mmol).
The reaction mixture was shaken at 80.degree. C. for 16 h.
Filtration followed by purification using preparatory-HPLC (1-99%
ACN in water (HCl modifier)) gave
2,2,2-trifluoro-1-[1'-[4-(2-methoxy-3-pyridyl)-3-methyl-benzoyl]-2-m-
ethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethano-
ne. ESI-MS m/z calc. 526.2, found 527.3 (M+1)+; Retention time:
1.38 minutes (3 min run).
[0463] The following compounds were synthesized using the procedure
described above: [0464]
5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo-
[1,2-a]pyrazine-1,4'-piperidine]-1'-carbonyl]phenyl]pyridine-2-carbonitril-
e, [0465]
1-[1'-[4-(1-ethylimidazol-4-yl)-3-methyl-benzoyl]-2-methyl-spiro-
[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2,2-trifluoro--
ethanone, [0466]
2,2,2-trifluoro-1-[2-methyl-1'-[3-methyl-4-(2-methyl-4-pyridyl)benzoyl]sp-
iro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone,
[0467]
2,2,2-trifluoro-1-[2-methyl-1'-[3-methyl-4-(1-methylpyrazol-3-yl)b-
enzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethan-
one, [0468]
2,2,2-trifluoro-1-[2-methyl-1'-[3-methyl-4-(1-methylpyrazol-4-yl)benzoyl]-
spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone,
[0469]
2,2,2-trifluoro-1-[1'-[4-(4-methoxyphenyl)-3-methyl-benzoyl]-2-met-
hyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone-
, [0470]
1-[1'-[4-(3-chlorophenyl)-3-methyl-benzoyl]-2-methyl-spiro[3,4-di-
hydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2,2-trifluoro-ethanon-
e, [0471]
2,2,2-trifluoro-1-[2-methyl-1'-[3-methyl-4-(2-methylpyrazol-3-yl-
)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]eth-
anone, [0472]
N-[5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrr-
olo[1,2-a]pyrazine-1,4'-piperidine]-1'-carbonyl]phenyl]-2-pyridyl]acetamid-
e, [0473]
1-[1'-[4-[2-(dimethylamino)pyrimidin-5-yl]-3-methyl-benzoyl]-2-m-
ethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2,2-
-trifluoro-ethanone, [0474]
2,2,2-trifluoro-1-[2-methyl-1'-[3-methyl-4-[3-(trifluoromethyl)-1H-pyrazo-
l-4-yl]benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6--
yl]ethanone, and [0475]
2,2,2-trifluoro-1-[2-methyl-1'-(3-methyl-4-pyrimidin-5-yl-benzoyl)spiro[3-
,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone.
(2-(3-Hydroxypyrrolidin-1-yl)pyridin-3-yl)(2'-methyl-6'-(trifluoromethyl)--
3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-1-yl)metha-
none
##STR00888##
[0477] A mixture of
(2-Chloro-3-pyridyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrol-
o[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone (0.1 mol) and
pyrrolidin-3-ol (0.3 mmol) DMF (0.5 mL) was stirred at 80.degree.
C. for 16 h. Additional pyrrolidin-3-ol (0.5 mmol) was added and
the mixture was stirred at 150.degree. C. for 16 h. The mixture was
filtered and was subjected to preparatory-HPLC (10-90% ACN in
water) to give
(2-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)(2'-methyl-6'-(trifluoromethyl)-
-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-1-yl)meth-
anone. ESI-MS m/z calc. 463.5, found 464.3 (M+1)+; Retention time:
0.75 minutes (3 min run).
[0478] The following compounds were synthesized using the procedure
described above:
[0479]
(2-(3-fluoropyrrolidin-1-yl)pyridin-3-yl)(2'-methyl-6'-(trifluorome-
thyl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-1-yl-
)methanone and
(2-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl)(2'-methyl-6'-(trifluorometh-
yl)-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-1-yl)m-
ethanone.
2,2,2-Trifluoro-1-(1-(3-methoxy-4-(prop-1-en-2-yloxy)benzoyl)-2'-methyl-3'-
,4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-6'-yl)ethano-
ne
##STR00889##
[0481] Step 1:
[0482] 4-Methyl morpholine (1.59 mL, 14.4 mmol) was added to a
mixture of
2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'--
piperidine]dihydrochloride (1.00 g, 2.89 mmol),
4-hydroxy-3-methoxy-benzoic acid (486 mg, 2.89 mmol), EDCI (831 mg,
4.33 mmol), HOBt (585 mg, 4.33 mmol) and DMF (10 mL) at room
temperature. The mixture was heated at 60.degree. C. overnight
before it was cooled to room temperature and partitioned between
ethyl acetate and 1N HCl. The layers were separated and the aqueous
layer was extracted with ethyl acetate (3.times.). The combined
organics were washed with brine, dried over sodium sulfate,
filtered and concentrated. The residue was subjected to column
chromatography (0-100% ethyl acetate/hexanes) to give
(4-hydroxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihyd-
ropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone (690 mg,
58%). ESI-MS m/z calc. 423.2, found 424.1 (M+1)+; Retention time:
1.16 minutes (3 min run). .sup.1H NMR (400 MHz, CD.sub.3CN) .delta.
7.04 (d, J=1.8 Hz, 1H), 6.94 (dd, J=8.1, 1.9 Hz, 1H), 6.87 (d,
J=8.1 Hz, 1H), 6.82 (s, 1H), 6.62-6.56 (m, 1H), 6.05 (d, J=3.9 Hz,
1H), 4.35 (s, 1H), 4.00 (t, J=6.0 Hz, 2H), 3.89 (s, 3H), 3.64 (s,
2H), 3.36 (t, J=6.0 Hz, 2H), 3.29 (s, 1H), 2.36 (s, 3H), 2.16-2.04
(m, 2H), 1.81 (dd, J=17.1, 7.3 Hz, 2H). 26-7.21 (m, 2H), 7.14 (t,
J=8.1 Hz, 1H), 2.78 (d, J=1.4 Hz, 2H), 1.24 (d, J=0.8 Hz, 6H).
[0483] Step 2:
[0484] A mixture of Cs.sub.2CO.sub.3 (115 mg, 0.354 mmol),
acetylacetone (12 .mu.L, 0.12 mmol), CuCl (5.8 mg, 0.059 mmol) and
THF (2.5 mL) in a vial was stirred at room temperature for 5 min
before
(4-hydroxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihyd-
ropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone (100 mg,
0.236 mmol) then 2-bromoprop-1-ene (27 .mu.L, 0.31 mmol) were
added. The vial was capped and heated at 70.degree. C. overnight.
The mixture was cooled to room temperature, filtered and
concentrated under reduced pressure. The residue was subjected to
column chromatography (0-100% ethyl acetate/hexanes) to give
(4-isopropenyloxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,-
4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone
(8.9 mg, 8%). ESI-MS m/z calc. 463.2, found 464.3 (M+1)+; Retention
time: 1.47 minutes (3 min run). .sup.1H NMR (400 MHz, CD.sub.3CN)
.delta. 7.12 (d, J=1.8 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.01 (dd,
J=8.0, 1.8 Hz, 1H), 6.60 (d, J=3.4 Hz, 1H), 6.07 (d, J=3.7 Hz, 1H),
4.42 (s, 1H), 4.12 (dd, J=1.6, 0.9 Hz, 1H), 4.01 (t, J=6.0 Hz, 2H),
3.85 (s, 3H), 3.79 (d, J=1.7 Hz, 1H), 3.67-3.40 (m, 2H), 3.36 (t,
J=5.6 Hz, 2H), 3.20 (s, 1H), 2.36 (s, 3H), 2.18 (s, 2H), 2.00 (d,
J=0.7 Hz, 3H), 1.83 (s, 2H).
[0485] Table 2 below recites the analytical data for the compounds
of Table 1.
TABLE-US-00003 TABLE 2 Cmpd. LC/MS LC/RT No. M + 1 min NMR 1 454.50
1.61 1H NMR (400 MHz, DMSO) .delta. 7.89 (d, J = 8.0 Hz, 1H),
7.59-7.45 (m, 2H), 6.58 (d, J = 3.7 Hz, 1H), 6.12 (d, J = 3.9 Hz,
1H), 4.45-4.27 (m, 1H), 3.93 (t, J = 5.8 Hz, 2H), 3.57-3.43 (m,
1H), 3.43-3.01 (m, 5H), 2.65 (s, 3H), 2.27 (s, 3H), 2.23-1.65 (m,
4H), 1.17 (d, J = 6.8 Hz, 6H). 2 498.20 2.57 1H NMR (400 MHz, DMSO)
.delta. 7.11-6.97 (m, 3H), 6.65 (d, J = 3.5 Hz, 1H), 6.33 (d, J =
3.9 Hz, 1H), 4.98-4.69 (m, 1H), 4.67-4.54 (m, 1H), 4.09-3.98 (m,
1H), 3.90- 3.81 (m, 1H), 3.77 (s, 3H), 3.74-3.52 (m, 2H), 3.46-
3.35 (m, 1H), 3.34-3.30 (m, 2H), 3.26-3.08 (m, 1H), 2.32 (s, 3H),
2.14-1.82 (m, 2H), 1.27 (d, J = 6.0 Hz, 6H). 3 484.40 2.83 4 466.30
1.63 5 408.20 2.38 6 478.50 1.55 1H NMR (400 MHz, DMSO) .delta.
7.83 (d, J = 8.0 Hz, 1H), 7.63-7.54 (m, 1H), 7.52-7.39 (m, 2H),
6.58 (d, J = 3.7 Hz, 1H), 6.12 (d, J = 3.9 Hz, 1H), 4.43-4.26 (m,
1H), 3.93 (t, J = 5.6 Hz, 2H), 3.48-3.19 (m, 4H), 3.19-3.01 (m,
1H), 2.59 (s, 3H), 2.45 (d, J = 4.6 Hz, 3H), 2.27 (s, 3H),
2.23-2.12 (m, 1H), 2.06-1.96 (m, 1H), 1.85-1.70 (m, 2H). 7 485.50
1.24 8 546.70 1.64 9 500.50 1.51 10 416.50 1.05 1H NMR (400 MHz,
DMSO) .delta. 7.50 (d, J = 2.1 Hz, 1H), 7.36 (dd, J = 8.5, 2.1 Hz,
1H), 7.20 (d, J = 8.7 Hz, 1H), 5.99 (d, J = 3.5 Hz, 1H), 5.93 (d, J
= 3.6 Hz, 1H), 4.78- 4.64 (m, 1H), 4.38-4.03 (m, 1H), 3.78 (t, J =
5.8 Hz, 2H), 3.63 (q, J = 11.2 Hz, 2H), 3.55-3.03 (m, 5H), 2.24 (s,
3H), 2.12-1.91 (m, 2H), 1.79-1.62 (m, 2H), 1.31 (d, J = 6.0 Hz,
6H). 11 484.50 1.32 12 462.50 1.64 1H NMR (400 MHz, DMSO) .delta.
7.83 (d, J = 8.0 Hz, 1H), 7.57 (q, J = 4.9 Hz, 1H), 7.50-7.41 (m,
2H), 6.57 (s, 1H), 6.19 (d, J = 4.0 Hz, 1H), 4.36 (d, J = 12.5 Hz,
1H), 3.98 (t, J = 5.7 Hz, 2H), 3.44-3.33 (m, 2H), 3.31-3.22 (m,
2H), 3.11 (t, J = 12.6 Hz, 1H), 2.59 (s, 3H), 2.45 (d, J = 4.9 Hz,
3H), 2.28 (s, 3H), 2.19 (d, J = 12.9 Hz, 1H), 2.06-1.99 (m, 1H),
1.80 (t, J = 12.6 Hz, 2H). 13 535.50 1.40 14 464.50 1.47 15 465.50
1.35 16 510.70 1.74 17 548.50 1.73 18 454.50 2.97 19 442.50 1.26 20
414.18 2.84 21 509.50 1.36 22 437.10 1.27 23 510.50 2.68 24 451.20
1.73 25 420.22 2.21 26 434.50 1.54 27 470.50 1.70 1H NMR (400 MHz,
DMSO) .delta. 8.10 (d, J = 1.7 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H),
7.50-7.39 (m, 2H), 6.59 (d, J = 3.6 Hz, 1H), 6.13 (d, J = 3.8 Hz,
1H), 4.36 (d, J = 12.3 Hz, 1H), 3.93 (t, J = 5.2 Hz, 2H), 3.48-3.25
(m, 4H), 3.12 (t, J = 11.7 Hz, 1H), 2.59 (s, 3H), 2.28 (s, 3H),
2.23- 2.10 (m, 2H), 2.07-1.95 (m, 1H), 1.86-1.68 (m, 2H), 0.51-0.42
(m, 2H), 0.38-0.30 (m, 2H). 28 511.70 1.23 1H NMR (400 MHz, CDCl3)
.delta. 7.04-7.00 (m, 1H), 6.97 (dd, J = 8.2, 1.6 Hz, 1H), 6.88 (d,
J = 8.2 Hz, 1H), 6.52 (d, J = 3.6 Hz, 1H), 5.98-5.86 (m, 1H),
4.72-4.26 (m, 2H), 3.88 (s, 3H), 3.86-3.07 (m, 6H), 2.46-1.88 (m,
6H), 1.71-1.46 (m, 1H), 1.38 (d, J = 6.1 Hz, 6H), 1.34- 1.12 (m,
3H). 29 480.30 1.70 30 458.30 1.45 31 428.50 1.22 32 430.23 2.75 1H
NMR (400 MHz, CDCl3) .delta. 8.00-7.94 (m, 2H), 7.61- 7.55 (m, 2H),
7.22 (dd, J = 4.3, 2.1 Hz, 1H), 6.17 (d, J = 4.4 Hz, 1H), 4.91 (s,
1H), 4.63 (d, J = 12.5 Hz, 1H), 4.36 (t, J = 5.8 Hz, 2H), 3.64-3.41
(m, 2H), 3.34 (t, J = 5.7 Hz, 2H), 3.31-3.21 (m, 1H), 2.41 (s, 3H),
2.32-2.18 (m, 2H), 2.08 (d, J = 10.2 Hz, 1H), 1.95 (t, J = 12.2 Hz,
1H), 1.74 (t, J = 11.1 Hz, 1H), 0.68-0.60 (m, 4H). 33 525.50 1.41
34 424.24 2.33 1H NMR (400 MHz, DMSO) .delta. 7.54-7.39 (m, 1H),
7.22- 7.09 (m, 2H), 6.60 (d, J = 3.6 Hz, 1H), 6.10 (s, 1H), 5.20-
4.36 (m, 3H), 4.19-3.99 (m, 1H), 3.92-3.37 (m, 4H), 3.20-2.93 (m,
2H), 2.54 (s, 3H), 2.35-2.14 (m, 4H), 1.95-1.64 (m, 1H), 1.51 (s,
6H). 35 468.20 4.64 36 430.19 2.11 1H NMR (400 MHz, DMSO) .delta.
7.51 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.21 (d,
J = 8.6 Hz, 1H), 6.60 (d, J = 3.8 Hz, 1H), 6.16 (d, J = 3.9 Hz,
1H), 4.86- 4.60 (m, 1H), 4.48-4.08 (m, 1H), 3.70 (s, 2H), 3.62-
2.81 (m, 3H), 2.09 (s, 1H), 1.89-1.61 (m, 4H), 1.31 (d, J = 6.0 Hz,
6H), 1.09 (s, 6H). 37 484.40 1.54 38 446.26 2.26 39 458.70 1.53 40
482.50 1.56 41 532.50 1.62 42 408.50 1.24 43 456.50 1.42 44 450.30
1.10 45 436.20 2.13 46 494.30 1.69 47 476.50 1.52 48 534.20 1.25 49
429.70 1.17 50 464.50 1.42 51 489.50 1.54 52 510.70 1.64 53 511.70
1.28 54 476.50 1.76 55 496.20 1.79 56 438.28 2.52 57 454.50 1.51 58
458.40 1.55 59 534.50 2.04 1H NMR (400 MHz, DMSO) .delta. 7.04-6.87
(m, 3H), 6.57 (d, J = 3.5 Hz, 1H), 6.07 (d, J = 3.9 Hz, 1H),
4.66-4.52 (m, 1H), 4.04-3.83 (m, 2H), 3.77 (s, 3H), 3.60-3.12 (m,
5H), 2.33-2.21 (m, 4H), 2.17-1.65 (m, 3H), 1.42 (d, J = 7.0 Hz,
3H), 1.26 (d, J = 6.0 Hz, 6H). 60 480.40 3.01 61 518.20 1.17 62
476.50 1.81 63 393.50 0.99 64 518.30 1.66 65 446.17 2.37 66 460.50
1.64 67 422.50 1.51 68 450.14 2.52 69 504.50 1.54 70 450.50 1.46 71
496.70 1.69 72 548.30 1.28 73 400.20 2.57 74 478.20 0.98 1H NMR
(400 MHz, CDCl3) .delta. 7.45 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2
Hz, 2H), 6.49 (s, 1H), 4.71 (s, 2H), 4.63 (s, 1H), 3.98 (s, 2H),
3.86 (q, J = 8.7 Hz, 2H), 3.57 (s, 1H), 3.47 (s, 1H), 3.30 (s, 2H),
3.19 (s, 1H), 2.47 (s, 1H), 2.41 (d, J = 24.3 Hz, 4H), 2.16-2.02
(m, 1H), 2.01 (s, 1H), 1.91 (s, 1H), 1.56 (s, 2H), 1.25 (s, 1H). 75
524.00 1.69 1H NMR (400 MHz, DMSO) .delta. 8.07-7.95 (m, 1H), 7.95-
7.81 (m, 2H), 7.76-7.61 (m, 2H), 6.62 (d, J = 4.0 Hz, 1H), 6.12 (d,
J = 4.0 Hz, 1H), 4.45-4.30 (m, 1H), 3.57- 3.08 (m, 3H), 2.97-2.85
(m, 2H), 2.85-2.74 (m, 1H), 2.20-2.07 (m, 1H), 2.01-1.66 (m, 4H),
1.43 (d, J = 6.7 Hz, 6H), 0.56-0.32 (m, 4H). 76 511.50 4.41 1H NMR
(400 MHz, DMSO) .delta. 7.51 (d, J = 2.0 Hz, 1H), 7.37 (dd, J =
8.5, 2.0 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 6.61 (d, J = 4.0 Hz,
1H), 6.11 (d, J = 4.0 Hz, 1H), 4.81- 4.66 (m, 1H), 4.41-4.16 (m,
1H), 3.58-2.99 (m, 3H), 2.91 (d, J = 5.8 Hz, 2H), 2.77 (t, J = 7.1
Hz, 1H), 1.99- 1.68 (m, 4H), 1.43 (s, 6H), 1.31 (d, J = 6.0 Hz,
6H). 77 484.50 6.20 78 444.20 2.34 79 446.50 1.59 1H NMR (400 MHz,
DMSO) .delta. 7.19 (d, J = 7.6 Hz, 1H), 6.96 (s, 1H), 6.93 (d, J =
7.8 Hz, 1H), 6.56 (d, J = 3.7 Hz, 1H), 6.09 (d, J = 3.9 Hz, 1H),
4.33-4.15 (m, 1H), 3.97-3.87 (m, 2H), 3.81 (s, 3H), 3.48 (t, J =
5.5 Hz, 2H), 3.46-3.32 (m, 4H), 3.25 (s, 3H), 3.23-3.08 (m, 1H),
2.70-2.61 (m, 2H), 2.57 (q, J = 7.5 Hz, 2H), 2.29- 1.98 (m, 2H),
1.90-1.63 (m, 2H), 1.13 (t, J = 7.5 Hz, 3H). 80 480.50 1.57 1H NMR
(400 MHz, DMSO) .delta. 7.07-6.91 (m, 3H), 6.60 (d, J = 3.7 Hz,
1H), 6.18-6.04 (m, 1H), 5.14-4.73 (m, 1H), 4.66-4.58 (m, 1H),
4.57-4.19 (m, 1H), 4.19-3.99 (m, 1H), 3.93-3.71 (m, 5H), 3.59-3.43
(m, 1H), 3.40- 3.26 (m, 2H), 3.14-2.97 (m, 1H), 2.30 (s, 3H), 2.26-
2.12 (m, 1H), 1.94-1.75 (m, 1H), 1.27 (d, J = 6.0 Hz, 6H). 81
484.40 5.39 82 446.26 2.37 83 452.20 1.16 84 436.50 1.06 1H NMR
(400 MHz, CDCl3) .delta. 7.06-6.98 (m, 3H), 6.91 (dd, J = 8.1, 1.9
Hz, 1H), 6.00 (d, J = 4.3 Hz, 1H), 4.57 (s, 1H), 4.31 (t, J = 6.0
Hz, 2H), 3.83 (s, 3H), 3.65 (s, 1H), 3.53 (s, 1H), 3.26 (t, J = 6.0
Hz, 2H), 3.26 (s, 1H), 2.42-2.37 (m, 3H), 2.27-2.00 (m, 2H), 1.90
(s, 1H), 1.73 (s, 1H), 1.36 (s, 9H), 1.35 (s, 9H). 85 496.70 1.51
86 432.26 2.02 87 448.20 1.69 1H NMR (400 MHz, DMSO) .delta.
7.07-6.90 (m, 3H), 6.60 (d, J = 3.8 Hz, 1H), 6.18-6.03 (m, 1H),
5.14-4.74 (m, 1H), 4.67-4.52 (m, 1H), 4.54-4.14 (m, 1H), 4.18-3.94
(m, 1H), 3.89-3.69 (m, 5H), 3.60-3.37 (m, 1H), 3.37- 3.27 (m, 2H),
3.17-2.99 (m, 1H), 2.30 (s, 3H), 2.25- 2.08 (m, 1H), 1.96-1.71 (m,
1H), 1.27 (d, J = 6.0 Hz, 6H). 88 484.40 5.32 1H NMR (400 MHz,
DMSO) .delta. 7.30 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 4.2 Hz, 1H),
6.92 (d, J = 8.8 Hz, 2H), 6.16 (d, J = 4.2 Hz, 1H), 4.19 (t, J =
5.9 Hz, 2H), 4.12-3.56 (m, 1H), 3.38-3.29 (m, 2H), 3.27-3.16 (m,
7H), 2.73 (q, J = 7.4 Hz, 2H), 2.27 (s, 3H), 2.15-1.98 (m, 2H),
1.85-1.66 (m, 2H), 1.66-1.50 (m, 6H), 1.04 (t, J = 7.4 Hz, 3H). 89
449.20 1.07 1H NMR (400 MHz, CDCl3) .delta. 7.25-7.18 (m, 1H),
7.08- 6.98 (m, 2H), 6.97-6.88 (m, 1H), 6.25-6.10 (m, 1H), 4.59 (s,
1H), 4.37 (s, 2H), 3.84 (s, 3H), 3.75 (s, 1H), 3.51 (s, 1H), 3.35
(s, 1H), 3.35 (s, 2H), 2.42 (s, 3H), 2.16 (s, 2H), 1.87 (s, 2H),
1.37 (s, 9H). 90 508.70 1.52 91 470.50 1.49 92 422.29 2.67 93
526.30 1.65 94 515.29 2.43 1H NMR (400 MHz, CDCl3) .delta. 7.63 (t,
J = 8.1 Hz, 1H), 7.19 (dd, J = 8.0, 1.6 Hz, 1H), 7.12 (dd, J =
11.9, 1.6 Hz, 1H), 6.49 (s, 1H), 4.60 (s, 1H), 3.99 (s, 2H), 3.72
(q, J = 7.0 Hz, 3H), 3.37 (t, J = 80.3 Hz, 5H), 2.43 (d, J = 16.6
Hz, 5H), 2.25-1.83 (m, 3H), 1.65 (d, J = 0.8 Hz, 7H), 1.29-1.20 (m,
5H). 95 488.50 1.46 1H NMR (400 MHz, DMSO) .delta. 7.28-7.22 (m,
2H), 6.95 (d, J = 8.5 Hz, 1H), 6.58-6.52 (m, 1H), 6.18 (d, J = 4.0
Hz, 1H), 4.54 (t, J = 5.2 Hz, 1H), 4.47-4.13 (m, 1H), 4.07 (t, J =
6.2 Hz, 2H), 3.97 (t, J = 5.7 Hz, 2H), 3.62 (s, 1H), 3.62-3.54 (m,
2H), 3.33 (s, 2H), 3.30-3.03 (m, 2H), 2.28 (s, 3H), 2.16 (s, 3H),
2.14-2.00 (m, 2H), 1.88 (q, J = 6.2 Hz, 2H), 1.81-1.67 (m, 2H). 96
516.50 1.44 97 478.20 1.01 1H NMR (400 MHz, DMSO) .delta. 7.47 (d,
J = 8.7 Hz, 1H), 7.24-7.09 (m, 2H), 6.57 (d, J = 3.2 Hz, 1H), 6.12
(d, J = 3.9 Hz, 1H), 4.97 (s, 1H), 4.45-4.25 (m, 1H), 3.92 (t, J =
5.2 Hz, 2H), 3.60-2.97 (m, 5H), 2.54 (s, 3H), 2.27 (s, 3H),
2.21-1.95 (m, 2H), 1.85-1.63 (m, 2H), 1.50 (s, 6H). 98 450.50 1.21
99 408.10 1.20 100 470.50 1.58 1H NMR (400 MHz, DMSO) .delta. 7.36
(d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.27-7.18 (m, 1H),
6.49 (d, J = 4.6 Hz, 1H), 4.50-4.18 (m, 3H), 3.54-2.99 (m, 5H),
2.58-2.47 (m, 1H), 2.30 (s, 3H), 2.26-1.91 (m, 2H), 1.91-1.65 (m,
7H), 1.50-1.16 (m, 5H). 101 488.50 1.84 1H NMR (400 MHz, CDCl3)
.delta. 7.47-7.41 (m, 2H), 7.38 (d, J = 8.2 Hz, 2H), 6.48 (s, 1H),
4.64 (d, J = 10.0 Hz, 1H), 4.56 (s, 2H), 3.98 (s, 2H), 3.71 (t, J =
6.6 Hz, 2H), 3.58 (s, 1H), 3.46 (s, 1H), 3.29 (s, 2H), 3.18 (s,
1H), 2.61-2.28 (m, 7H), 2.17-2.02 (m, 1H), 2.01 (s, 1H), 1.88 (d, J
= 12.1 Hz, 1H), 1.60 (s, 1H). 102 538.00 1.81 103 546.70 1.63 104
420.10 2.45 1H NMR (400 MHz, DMSO) .delta. 7.06-6.90 (m, 3H), 6.60
(d, J = 3.5 Hz, 1H), 6.17-6.05 (m, 1H), 5.11-4.71 (m, 1H),
4.65-4.55 (m, 1H), 4.53-4.25 (m, 1H), 4.14-4.03 (m, 1H), 3.88-3.69
(m, 5H), 3.58-3.43 (m, 1H), 3.41- 3.28 (m, 2H), 3.15-3.06 (m, 1H),
2.30 (s, 3H), 2.27- 2.10 (m, 1H), 2.00-1.69 (m, 1H), 1.27 (d, J =
6.0 Hz, 6H). 105 484.60 4.79 1H NMR (400 MHz, DMSO) .delta.
7.26-7.19 (m, 2H), 6.96
(d, J = 9.2 Hz, 1H), 6.57 (d, J = 3.8 Hz, 1H), 6.13 (d, J = 3.9 Hz,
1H), 4.71-4.56 (m, 1H), 4.32-3.90 (m, 1H), 3.79 (t, J = 6.0 Hz,
2H), 3.70-3.18 (m, 5H), 3.18-3.02 (m, 1H), 2.19-1.68 (m, 11H),
1.57-1.36 (m, 2H), 1.29 (d, J = 6.0 Hz, 6H). 106 490.40 4.35 1H NMR
(400 MHz, DMSO) .delta. 7.51 (d, J = 2.1 Hz, 1H), 7.38 (dd, J =
8.5, 2.1 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 4.2 Hz,
1H), 6.17 (d, J = 4.2 Hz, 1H), 4.74 (hept, J = 6.0 Hz, 1H),
4.48-4.12 (m, 3H), 3.65-3.28 (m, 2H), 3.28-2.94 (m, 3H), 2.73 (q, J
= 7.4 Hz, 2H), 2.27 (s, 3H), 2.17-1.90 (m, 2H), 1.86-1.68 (m, 2H),
1.31 (d, J = 6.0 Hz, 6H), 1.04 (t, J = 7.4 Hz, 3H). 107 458.20 1.49
108 454.50 1.51 109 392.50 1.31 110 436.20 1.92 1H NMR (400 MHz,
DMSO) .delta. 7.51 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 8.5, 2.1 Hz,
1H), 7.20 (d, J = 8.7 Hz, 1H), 6.73 (d, J = 4.0 Hz, 1H), 6.22 (d, J
= 4.1 Hz, 1H), 4.80- 4.65 (m, 1H), 4.46-4.20 (m, 1H), 4.13 (t, J =
5.8 Hz, 2H), 3.62-3.24 (m, 4H), 3.20 (s, 3H), 3.18-2.93 (m, 1H),
2.29 (s, 3H), 2.23-1.90 (m, 2H), 1.87-1.70 (m, 2H), 1.31 (d, J =
6.0 Hz, 6H). 111 480.30 1.37 1H NMR (400 MHz, CDCl3) .delta. 7.42
(t, J = 7.8 Hz, 1H), 7.17 (ddd, J = 12.5, 9.5, 1.5 Hz, 2H), 6.29
(s, 1H), 4.57 (s, 1H), 3.93 (s, 2H), 3.53 (d, J = 31.9 Hz, 2H),
3.25 (d, J = 38.8 Hz, 3H), 2.65 (dt, J = 11.8, 8.8 Hz, 2H), 2.50-
2.33 (m, 6H), 2.27-2.07 (m, 3H), 2.01 (s, 2H), 1.84- 1.67 (m, 1H).
112 484.30 1.34 113 492.50 2.82 114 578.50 1.62 115 508.70 1.58 116
464.30 0.75 1H NMR (400 MHz, CDCl3) .delta. 7.28-7.20 (m, 3H), 6.82
(d, J = 8.1 Hz, 1H), 6.16 (d, J = 4.5 Hz, 1H), 4.56 (dt, J = 12.1,
6.0 Hz, 1H), 4.56 (s, 1H), 4.35 (t, J = 5.9 Hz, 2H), 3.80 (s, 1H),
3.37 (s, 2H), 3.34 (t, J = 5.9 Hz, 2H), 2.41 (s, 3H), 2.21 (s, 3H),
2.11 (s, 2H), 1.84 (s, 2H), 1.35 (d, J = 6.0 Hz, 6H). 117 478.30
1.64 118 484.70 1.32 1H NMR (400 MHz, CDCl3) .delta. 7.19-7.00 (m,
2H), 6.91 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 3.8 Hz, 1H), 6.02 (d, J
= 3.8 Hz, 1H), 5.92 (s, 1H), 4.71-4.50 (m, 1H), 4.46- 4.23 (m, 2H),
4.16 (t, J = 6.5 Hz, 2H), 3.88 (s, 3H), 3.88- 3.62 (m, 2H), 3.41
(t, J = 6.4 Hz, 2H), 2.71 (s, 3H), 2.59-2.44 (m, 2H), 2.36-1.61 (m,
2H), 1.39 (d, J = 6.1 Hz, 6H). 119 509.60 4.60 120 475.12 2.82 121
454.50 1.42 1H NMR (400 MHz, DMSO) .delta. 7.28-7.20 (m, 2H), 7.05
(d, J = 4.1 Hz, 1H), 6.97 (d, J = 9.1 Hz, 1H), 6.17 (d, J = 4.2 Hz,
1H), 4.73-4.55 (m, 1H), 4.47-4.11 (m, 3H), 3.72-3.28 (m, 2H),
3.28-2.98 (m, 3H), 2.31 (s, 3H), 2.26 (s, 3H), 2.14 (s, 3H),
2.12-1.96 (m, 2H), 1.85- 1.64 (m, 2H), 1.29 (d, J = 6.0 Hz, 6H).
122 424.20 1.22 1H NMR (400 MHz, DMSO) .delta. 7.86 (d, J = 8.4 Hz,
2H), 7.68 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 3.8 Hz, 1H), 6.12 (d, J
= 3.9 Hz, 1H), 4.47-4.28 (m, 1H), 3.93 (t, J = 5.8 Hz, 2H),
3.48-3.25 (m, 4H), 3.25-3.07 (m, 5H), 2.27 (s, 3H), 2.23-1.96 (m,
2H), 1.86-1.73 (m, 2H), 1.71- 1.63 (m, 4H). 123 511.40 2.70 124
454.50 1.37 125 428.20 0.96 126 522.70 1.64 127 464.50 1.54 1H NMR
(400 MHz, DMSO) .delta. 7.53-7.41 (m, 1H), 7.22- 7.10 (m, 2H), 6.61
(d, J = 4.1 Hz, 1H), 6.09 (d, J = 4.0 Hz, 1H), 4.97 (s, 1H),
4.49-4.19 (m, 1H), 3.53-3.01 (m, 3H), 2.96-2.83 (m, 2H), 2.83-2.70
(m, 1H), 2.55 (s, 3H), 2.01-1.61 (m, 4H), 1.51 (s, 6H), 1.43 (s,
6H). 128 464.50 4.17 1H NMR (400 MHz, CDCl3) .delta. 7.50 (d, J =
2.1 Hz, 1H), 7.37 (dd, J = 8.4, 2.1 Hz, 1H), 7.27-7.24 (m, 1H),
6.96 (d, J = 8.5 Hz, 1H), 6.20 (d, J = 4.5 Hz, 1H), 4.57 (s, 1H),
4.20 (s, 2H), 3.94 (s, 3H), 3.63 (s, 2H), 3.32 (s, 1H), 1.92 (s,
2H), 1.78 (s, 2H), 1.18 (s, 6H), 0.97 (s, 1H). 129 484.50 1.50 130
512.40 1.68 131 492.20 1.84 132 476.50 1.39 1H NMR (400 MHz, DMSO)
.delta. 7.27 (d, J = 7.9 Hz, 1H), 6.99 (d, J = 1.4 Hz, 1H),
6.97-6.90 (m, 1H), 6.62-6.53 (m, 1H), 6.18-6.05 (m, 1H), 4.58-4.18
(m, 2H), 3.93- 3.76 (m, 5H), 3.62 (d, J = 4.2 Hz, 2H), 3.54-3.02
(m, 5H), 2.49-2.26 (m, 1H), 2.01-1.63 (m, 4H), 1.27 (s, 6H). 133
466.40 2.99 1H NMR (400 MHz, CDCl3) .delta. 7.68-7.61 (m, 2H),
7.04- 6.97 (m, 1H), 6.29 (s, 1H), 4.70 (dt, J = 12.1, 6.1 Hz, 1H),
4.53 (s, 1H), 3.93 (t, J = 5.7 Hz, 2H), 3.55 (s, 2H), 3.30 (s, 3H),
2.42 (s, 3H), 2.23-1.92 (m, 4H), 1.43 (d, J = 6.1 Hz, 6H). 134
479.50 1.42 135 456.50 1.45 136 548.30 1.30 1H NMR (400 MHz, DMSO)
.delta. 7.09 (d, J = 4.3 Hz, 1H), 7.05-6.92 (m, 3H), 6.17 (d, J =
4.3 Hz, 1H), 4.67-4.51 (m, 1H), 4.47-4.02 (m, 3H), 3.77 (s, 3H),
3.65-3.28 (m, 2H), 3.28-2.95 (m, 3H), 2.28 (s, 3H), 2.17-1.97 (m,
2H), 1.86-1.67 (m, 2H), 1.31-1.24 (m, 15H). 137 482.40 1.28 1H NMR
(400 MHz, CDCl3) .delta. 7.34-7.29 (m, 2H), 6.84 (d, J = 9.0 Hz,
1H), 6.56 (d, J = 3.7 Hz, 1H), 6.02 (d, J = 3.9 Hz, 1H), 4.62-4.52
(m, 1H), 4.51-4.40 (m, 1H), 4.34-4.23 (m, 2H), 4.18 (t, J = 6.5 Hz,
2H), 3.88-3.64 (m, 1H), 3.55-3.31 (m, 2H), 2.85 (s, 6H), 2.62-2.42
(m, 2H), 2.22 (s, 3H), 1.70-1.54 (m, 2H), 1.35 (d, J = 6.0 Hz, 6H).
138 507.40 6.05 139 492.30 1.55 140 410.20 0.80 141 498.70 2.97 142
494.50 1.50 1H NMR (400 MHz, DMSO) .delta. 7.39 (d, J = 8.7 Hz,
2H), 7.27-7.17 (m, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.49 (d, J = 4.6
Hz, 1H), 4.55-4.15 (m, 3H), 4.03 (t, J = 6.6 Hz, 2H), 3.76-2.94 (m,
5H), 2.30 (s, 3H), 2.21-1.97 (m, 2H), 1.94-1.69 (m, 3H), 1.62 (q, J
= 6.7 Hz, 2H), 0.93 (d, J = 6.6 Hz, 6H). 143 492.50 1.73 144 468.70
1.42 1H NMR (400 MHz, DMSO) .delta. 8.02 (d, J = 1.1 Hz, 1H), 7.86
(d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 3.4 Hz,
1H), 6.14 (d, J = 3.9 Hz, 1H), 4.26-4.14 (m, 1H), 3.79 (t, J = 5.9
Hz, 2H), 3.50-3.23 (m, 5H), 3.18-3.04 (m, 1H), 2.26-1.76 (m, 9H),
1.60-1.36 (m, 2H), 0.56-0.35 (m, 4H). 145 537.40 2.89 146 508.70
1.61 147 414.17 2.22 148 494.50 1.36 1H NMR (400 MHz, DMSO) .delta.
7.06-6.90 (m, 3H), 6.57 (d, J = 3.6 Hz, 1H), 6.11 (d, J = 3.9 Hz,
1H), 4.68-4.50 (m, 1H), 3.83-3.63 (m, 5H), 3.18-2.78 (m, 4H), 2.41-
2.20 (m, 1H), 2.13-1.87 (m, 5H), 1.61-1.34 (m, 2H), 1.26 (d, J =
6.0 Hz, 6H), 1.24-1.19 (m, 3H). 149 480.30 1.76 150 450.50 1.28 1H
NMR (400 MHz, DMSO) .delta. 7.27 (d, J = 7.9 Hz, 1H), 6.98 (d, J =
1.2 Hz, 1H), 6.96-6.87 (m, 1H), 6.58 (s, 1H), 6.12 (s, 1H),
4.62-4.19 (m, 2H), 4.01-3.85 (m, 2H), 3.81 (s, 3H), 3.62 (s, 2H),
3.55-2.94 (m, 5H), 2.36- 2.01 (m, 5H), 1.86-1.59 (m, 2H), 1.27 (s,
6H). 151 480.40 2.97 152 468.30 1.91 153 526.50 1.42 154 526.20
1.50 155 470.50 1.70 156 480.50 0.65 1H NMR (400 MHz, DMSO) .delta.
8.46 (s, 1H), 7.61 (t, J = 52.4 Hz, 1H), 7.42 (s, 1H), 6.63 (d, J =
4.0 Hz, 1H), 6.03 (d, J = 4.0 Hz, 1H), 4.50-4.29 (m, 1H), 3.76-3.39
(m, 2H), 3.27-3.07 (m, 1H), 3.03-2.88 (m, 2H), 2.88-2.76 (m, 1H),
2.65 (s, 3H), 2.08-1.66 (m, 4H), 1.44 (s, 6H). 157 497.50 4.05 1H
NMR (400 MHz, DMSO) .delta. 7.05 (d, J = 1.7 Hz, 1H), 7.01 (d, J =
8.0 Hz, 1H), 6.93 (dd, J = 8.0, 1.8 Hz, 1H), 6.58 (d, J = 3.1 Hz,
1H), 6.12 (d, J = 3.9 Hz, 1H), 4.32 (s, 1H), 3.93 (t, J = 5.5 Hz,
2H), 3.76 (s, 3H), 3.58-3.35 (m, 2H), 3.35-3.29 (m, 2H), 3.22-3.02
(m, 1H), 2.28 (s, 3H), 2.11 (s, 2H), 1.76 (t, J = 11.1 Hz, 2H),
1.29 (s, 9H). 158 480.50 1.36 1H NMR (400 MHz, CDCl3) .delta. 8.41
(s, 1H), 7.35 (t, J = 40.0 Hz, 1H), 7.09 (s, 1H), 6.55 (d, J = 3.7
Hz, 1H), 5.97 (d, J = 3.9 Hz, 1H), 4.63 (s, 1H), 3.95 (t, J = 5.3
Hz, 2H), 3.83 (s, 1H), 3.62 (s, 1H), 3.28 (s, 2H), 2.71 (s, 3H),
2.12 (s, 2H), 2.03-1.76 (m, 4H). 159 469.50 1.12 1H NMR (400 MHz,
DMSO) .delta. 7.47 (d, J = 2.1 Hz, 1H), 7.30 (dd, J = 8.4, 2.2 Hz,
1H), 7.26-7.18 (m, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.49 (d, J = 4.6
Hz, 1H), 5.06 (t, J = 5.7 Hz, 1H), 4.75-4.59 (m, 1H), 4.48 (d, J =
5.7 Hz, 2H), 4.44-4.15 (m, 3H), 3.83-2.94 (m, 5H), 2.31 (s, 3H),
2.21-2.00 (m, 2H), 1.94-1.72 (m, 2H), 1.28 (d, J = 6.0 Hz, 6H). 160
494.50 1.44 161 422.50 1.21 162 476.50 1.04 163 428.21 2.32 1H NMR
(400 MHz, DMSO) .delta. 7.36-7.22 (m, 3H), 6.97 (d, J = 8.4 Hz,
1H), 6.48 (d, J = 4.6 Hz, 1H), 4.86-4.72 (m, 1H), 4.43-4.02 (m,
1H), 3.82 (s, 3H), 3.76-3.39 (m, 1H), 3.40-3.29 (m, 2H), 3.29-2.97
(m, 2H), 2.34- 2.13 (m, 7H), 2.06-1.88 (m, 2H), 1.81-1.61 (m, 1H),
1.30 (d, J = 6.0 Hz, 3H). 164 464.50 1.53 1H NMR (400 MHz, DMSO)
.delta. 7.24 (d, J = 6.6 Hz, 2H), 6.97 (d, J = 9.2 Hz, 1H), 6.58
(d, J = 3.8 Hz, 1H), 6.14 (d, J = 3.9 Hz, 1H), 4.64 (dt, J = 12.1,
6.1 Hz, 1H), 4.06 (t, J = 5.9 Hz, 2H), 3.90 (s, 2H), 3.51 (t, J =
6.0 Hz, 2H), 2.14 (s, 3H), 1.83 (t, J = 11.8 Hz, 2H), 1.29 (d, J =
6.0 Hz, 6H). 165 475.30 2.04 166 412.10 1.41 167 480.30 1.49 1H NMR
(400 MHz, CDCl3) .delta. 7.06 (d, J = 1.8 Hz, 1H), 7.00 (dd, J =
8.2, 1.9 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 3.8 Hz,
1H), 5.96 (d, J = 3.9 Hz, 1H), 4.53 (s br, 1H), 4.42-4.23 (m, 4H),
4.06 (s br, 2H), 3.91 (s, 3H), 3.71 (s br, 1H), 3.54 (s br, 1H),
3.43-3.25 (m, 3H), 2.42 (s, 3H), 2.15 (s br, 2H), 1.86 (s br, 2H).
168 536.10 1.58 169 511.26 1.00 1H NMR (400 MHz, CDCl3) .delta.
7.06 (d, J = 1.8 Hz, 1H), 7.05-6.98 (m, 1H), 6.88 (d, J = 8.2 Hz,
1H), 6.55 (d, J = 3.3 Hz, 1H), 6.15 (d, J = 3.9 Hz, 1H), 4.57 (d, J
= 6.1 Hz, 1H), 4.19-4.10 (m, 2H), 3.88 (m, s, 5H), 3.79 (s, 2H),
3.70-3.52 (m, J = 31.5 Hz, 2H), 3.11 (s, 2H), 2.24 (s, 3H),
1.92-1.75 (m, 2H), 1.38 (d, J = 6.1 Hz, 6H). 170 494.70 1.70 1H NMR
(400 MHz, DMSO) .delta. 7.27-7.19 (m, 1H), 7.12- 6.98 (m, 3H), 6.51
(d, J = 4.6 Hz, 1H), 4.82-4.69 (m, 1H), 4.46-4.38 (m, 2H),
4.31-4.23 (m, 2H), 3.80 (s, 3H), 3.62-3.39 (m, 1H), 3.38-3.30 (m,
2H), 3.30-3.08 (m, 2H), 2.94-2.72 (m, 2H), 2.17-2.07 (m, 1H), 2.05-
1.51 (m, 3H), 1.35 (d, J = 6.4 Hz, 3H). 171 564.70 1.60 1H NMR (400
MHz, DMSO) .delta. 7.77-7.68 (m, 4H), 7.58- 7.46 (m, 4H), 7.43-7.37
(m, 1H), 7.29-7.18 (m, 1H), 6.51 (d, J = 4.6 Hz, 1H), 4.56-4.32 (m,
1H), 4.25 (t, J = 5.6 Hz, 2H), 3.63-3.21 (m, 4H), 3.21-2.98 (m,
1H), 2.31 (s, 3H), 2.27-1.98 (m, 2H), 1.95-1.78 (m, 2H). 172 482.50
1.63 173 504.50 1.58 1H NMR (400 MHz, DMSO) .delta. 7.30-7.19 (m,
3H), 6.97 (d, J = 9.0 Hz, 1H), 6.21 (d, J = 4.3 Hz, 1H), 4.73-4.55
(m, 1H), 4.36-3.82 (m, 1H), 3.82-3.42 (m, 1H), 3.42- 3.15 (m, 2H),
3.08 (s, 2H), 2.41 (s, 3H), 2.40 (s, 3H), 2.14 (s, 3H), 2.13-1.95
(m, 2H), 1.86-1.66 (m, 2H), 1.59 (s, 6H), 1.29 (d, J = 6.0 Hz, 6H).
174 452.50 1.53 1H NMR (400 MHz, DMSO) .delta. 7.45 (d, J = 8.7 Hz,
2H), 7.30-7.18 (m, 1H), 7.11 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 4.6
Hz, 1H), 4.82 (q, J = 8.9 Hz, 2H), 4.54-4.12 (m, 3H), 3.61-2.95 (m,
5H), 2.30 (s, 3H), 2.26-1.77 (m, 4H). 175 504.50 1.55 176 500.50
1.34 177 410.50 1.38 178 507.50 1.54 179 466.50 1.41 180 512.20
1.07 181 466.50 1.46 1H NMR (400 MHz, DMSO) .delta. 7.27-7.20 (m,
2H), 7.10 (d, J = 4.2 Hz, 1H), 6.97 (d, J = 9.2 Hz, 1H), 6.18 (d, J
= 4.2 Hz, 1H), 4.71-4.59 (m, 1H), 4.48-4.09 (m, 3H), 3.72-3.28 (m,
3H), 3.28-2.95 (m, 3H), 2.27 (s, 3H), 2.14 (s, 3H), 2.13-1.93 (m,
2H), 1.81-1.64 (m, 2H), 1.29 (d, J = 6.0 Hz, 6H), 1.05 (d, J = 6.8
Hz, 6H). 182 452.70 1.58 183 456.30 0.87 1H NMR (400 MHz, CDCl3)
.delta. 7.37-7.29 (m, 2H), 7.14- 7.06 (m, 2H), 6.29 (s, 1H), 4.59
(s, 1H), 3.92 (t, J = 5.7 Hz, 2H), 3.64 (s, 1H), 3.45 (s, 1H), 3.25
(d, J = 39.3 Hz, 3H), 2.41 (s, 3H), 2.27-1.86 (m, 5H), 1.63 (s,
1H), 1.06- 0.93 (m, 2H), 0.72 (dt, J = 6.6, 4.7 Hz, 2H). 184 436.30
1.44 185 490.30 1.61 186 510.70 1.39 187 500.50 2.44 188 498.50
3.07 189 408.26 2.48 190 466.50 1.41 191 498.23 1.14 192 459.15
1.58 193 454.50 2.30 194 513.50 1.32 195 427.21 1.42 1H NMR (400
MHz, CDCl3) .delta. 8.27 (d, J = 2.3 Hz, 1H), 7.62 (d, J = 9.0 Hz,
1H), 7.52 (s, 1H), 7.39 (dd, J = 8.5, 2.7 Hz, 1H), 7.00 (s, 1H),
6.53 (d, J = 4.1 Hz, 2H), 5.95 (d, J = 3.8 Hz, 2H), 4.52 (s, 2H),
3.95 (dd, J = 23.5, 10.2 Hz, 4H), 3.63-3.44 (m, 4H), 3.40-3.16 (m,
4H), 2.80
(s, 3H), 2.39 (s, 4H), 2.28-2.15 (m, 2H), 2.06 (s, 2H), 1.92 (s,
3H), 1.40 (s, 10H), 1.25 (s, 2H). 196 451.30 1.32 197 524.50 1.38
198 479.50 1.49 1H NMR (400 MHz, DMSO) .delta. 7.28-7.19 (m, 2H),
7.09 (d, J = 4.3 Hz, 1H), 6.97 (d, J = 9.2 Hz, 1H), 6.17 (d, J =
4.3 Hz, 1H), 4.70-4.56 (m, 1H), 4.51-4.04 (m, 3H), 3.83-3.28 (m,
2H), 3.28-2.91 (m, 3H), 2.27 (s, 3H), 2.14 (s, 3H), 2.13-1.96 (m,
2H), 1.84-1.66 (m, 2H), 1.29 (d, J = 6.0 Hz, 6H), 1.27 (s, 9H). 199
466.40 1.48 200 451.50 1.31 1H NMR (400 MHz, CDCl3) .delta. 7.21
(dt, J = 4.2, 2.1 Hz, 1H), 7.19 (d, J = 1.4 Hz, 1H), 7.08 (dd, J =
8.2, 2.0 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.16 (d, J = 4.5 Hz,
1H), 4.57 (s, 1H), 4.35 (t, J = 6.0 Hz, 2H), 3.76 (s, 1H), 3.52 (s,
1H), 3.32 (t, J = 6.0 Hz, 2H), 3.28 (s, 1H), 2.40 (s, 3H), 2.21 (s,
3H), 2.19-2.02 (m, 2H), 2.00 (s, 1H), 1.97- 1.64 (m, 2H). 201
436.30 1.30 1H NMR (400 MHz, DMSO) .delta. 7.47 (d, J = 2.1 Hz,
1H), 7.28 (dd, J = 8.4, 2.1 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.60
(d, J = 3.5 Hz, 1H), 6.16-6.03 (m, 1H), 5.07 (t, J = 5.6 Hz, 1H),
5.02-4.72 (m, 1H), 4.72-4.59 (m, 1H), 4.48 (d, J = 5.6 Hz, 2H),
4.18-4.01 (m, 1H), 3.96-3.26 (m, 5H), 3.21-2.90 (m, 2H), 2.30 (s,
3H), 2.26-2.12 (m, 1H), 1.98-1.75 (m, 1H), 1.28 (d, J = 6.0 Hz,
6H). 202 484.40 4.78 203 480.30 1.55 204 430.50 1.28 205 458.10
2.27 206 469.50 2.74 207 450.50 1.29 208 540.50 1.44 209 430.17
2.69 210 465.14 3.62 211 500.50 1.46 212 480.30 1.52 1H NMR (400
MHz, DMSO) .delta. 7.61 (d, J = 7.8 Hz, 1H), 7.03-6.92 (m, 2H),
6.58 (d, J = 3.9 Hz, 1H), 6.12 (d, J = 3.9 Hz, 1H), 5.00 (s, 1H),
4.45-4.22 (m, 1H), 3.93 (t, J = 5.8 Hz, 2H), 3.82 (s, 3H),
3.57-3.02 (m, 5H), 2.27 (s, 3H), 2.24-1.98 (m, 2H), 1.86-1.67 (m,
2H), 1.48 (s, 6H). 213 466.20 1.24 214 512.70 1.65 215 516.50 2.62
216 522.22 1.33 217 498.70 2.62 218 512.20 1.15 219 438.28 2.55 220
427.20 2.15 221 386.15 2.32 1H NMR (400 MHz, CDCl3) .delta.
7.28-7.20 (m, 2H), 6.82 (d, J = 8.0 Hz, 1H), 6.53 (d, J = 3.7 Hz,
1H), 5.97-5.86 (m, 1H), 4.56 (dt, J = 12.1, 6.0 Hz, 1H), 4.08 (d, J
= 8.9 Hz, 1H), 3.62-3.13 (m, 4H), 2.21 (s, 3H), 2.18-1.84 (m, 2H),
1.78-1.40 (m, 4H), 1.35 (d, J = 6.0 Hz, 6H), 1.27 (d, J = 3.9 Hz,
3H), 0.87 (s, 1H). 222 450.40 1.50 223 478.50 1.65 224 386.15 2.36
225 456.70 1.29 1H NMR (400 MHz, DMSO) .delta. 7.37 (t, J = 7.7 Hz,
1H), 7.26-7.15 (m, 2H), 6.56 (s, 1H), 6.19 (d, J = 4.0 Hz, 1H),
4.44 (s, 1H), 4.42-4.21 (m, 1H), 3.97 (t, J = 5.7 Hz, 2H), 3.41 (s,
2H), 3.30-3.21 (m, 1H), 3.10 (s, 1H), 2.71 (s, 2H), 2.28 (s, 3H),
2.22-2.10 (m, 1H), 2.10- 1.95 (m, 1H), 1.86-1.71 (m, 2H), 1.25 (s,
1H), 1.09 (s, 6H). 226 518.30 1.46 1H NMR (400 MHz, CDCl3) .delta.
7.12-7.03 (m, 2H), 6.91 (d, J = 8.6 Hz, 1H), 6.56 (d, J = 3.8 Hz,
1H), 6.03 (d, J = 3.9 Hz, 1H), 4.67-4.54 (m, 1H), 4.54-4.39 (m,
1H), 4.38-4.23 (m, 2H), 4.18 (t, J = 6.5 Hz, 2H), 3.89 (s, 3H),
3.84-3.63 (m, 1H), 3.50-3.32 (m, 2H), 2.85 (s, 6H), 2.66-2.44 (m,
2H), 1.72-1.48 (m, 2H), 1.39 (d, J = 6.1 Hz, 6H). 227 523.60 4.94
1H NMR (400 MHz, CDCl3) .delta. 7.57 (d, J = 8.3 Hz, 2H), 7.45 (d,
J = 8.3 Hz, 2H), 6.51 (s, 1H), 4.03 (s, 2H), 3.51 (d, J = 111.0 Hz,
5H), 2.65-2.45 (m, 6H), 2.39 (ddd, J = 12.6, 9.5, 7.5 Hz, 3H),
2.19-1.86 (m, 4H), 1.72 (dt, J = 10.1, 7.5 Hz, 1H), 1.55 (s, 5H).
228 482.40 1.43 229 432.13 2.06 230 454.23 2.22 1H NMR (400 MHz,
DMSO) .delta. 8.13-8.00 (m, 1H), 7.32- 7.19 (m, 2H), 6.97 (d, J =
9.1 Hz, 1H), 6.60-6.51 (m, 1H), 4.69-4.57 (m, 1H), 4.32-3.38 (m,
2H), 3.38-3.20 (m, 2H), 3.14 (s, 2H), 2.39 (s, 3H), 2.14 (s, 3H),
2.13- 1.94 (m, 2H), 1.89-1.68 (m, 2H), 1.53 (s, 6H), 1.29 (d, J =
6.0 Hz, 6H). 231 506.50 1.67 232 496.40 1.74 1H NMR (400 MHz, DMSO)
.delta. 7.39 (d, J = 8.7 Hz, 2H), 7.30-7.17 (m, 1H), 6.95 (d, J =
8.7 Hz, 2H), 6.49 (d, J = 4.6 Hz, 1H), 4.74-4.59 (m, 1H), 4.50-4.04
(m, 3H), 3.76-2.94 (m, 5H), 2.30 (s, 3H), 2.22-1.94 (m, 2H),
1.94-1.74 (m, 2H), 1.28 (d, J = 6.0 Hz, 6H). 233 464.50 1.52 234
432.50 1.15 235 478.50 1.41 236 530.15 1.66 1H NMR (400 MHz, DMSO)
.delta. 7.44 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H),
7.26-7.20 (m, 1H), 6.50 (d, J = 4.6 Hz, 1H), 4.55 (s, 2H),
4.47-4.30 (m, 1H), 4.29- 4.19 (m, 2H), 3.67 (t, J = 6.1 Hz, 2H),
3.46-3.24 (m, 4H), 3.18-3.00 (m, 1H), 2.70-2.53 (m, 2H), 2.30 (s,
3H), 2.25-1.76 (m, 4H). 237 532.30 1.70 238 450.50 1.40 239 478.50
1.53 240 518.30 1.64 241 466.50 1.42 1H NMR (400 MHz, CDCl3)
.delta. 7.59-7.53 (m, 2H), 7.47- 7.42 (m, 2H), 6.30 (s, 1H), 4.61
(s, 1H), 3.93 (s, 2H), 3.62 (s, 1H), 3.49 (s, 2H), 3.31 (s, 3H),
2.64-2.51 (m, 2H), 2.51-2.31 (m, 5H), 2.17 (s, 2H), 2.11-1.89 (m,
4H), 1.80-1.64 (m, 1H), 1.56 (s, 1H). 242 466.50 2.45 1H NMR (400
MHz, DMSO) .delta. 7.51 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 8.5, 2.1
Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.09 (d, J = 4.3 Hz, 1H), 6.17
(d, J = 4.3 Hz, 1H), 4.81- 4.67 (m, 1H), 4.45-4.20 (m, 1H), 4.15
(t, J = 5.8 Hz, 2H), 3.60-3.28 (m, 2H), 3.27-2.96 (m, 3H), 2.27 (s,
3H), 2.17-1.94 (m, 2H), 1.87-1.72 (m, 2H), 1.31 (d, J = 6.0 Hz,
6H), 1.27 (s, 9H). 243 486.40 1.44 244 515.40 4.81 245 532.50 1.19
1H NMR (400 MHz, CDCl3) .delta. 8.02 (d, J = 7.9 Hz, 1H), 7.48-7.35
(m, 2H), 6.95 (d, J = 4.1 Hz, 1H), 6.01 (d, J = 4.0 Hz, 1H),
4.67-4.49 (m, 1H), 4.35 (t, J = 5.9 Hz, 2H), 3.64-3.37 (m, 2H),
3.37-3.20 (m, 4H), 2.72 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H),
2.31-2.14 (m, 1H), 2.14- 2.02 (m, 1H), 1.99-1.83 (m, 1H), 1.78-1.64
(m, 1H), 1.32 (d, J = 6.8 Hz, 6H). 246 472.20 0.96 247 466.20 1.96
248 499.20 1.43 249 484.70 2.50 250 436.50 1.38 251 470.50 1.34 252
484.20 1.08 253 504.50 1.22 1H NMR (400 MHz, CDCl3) .delta. 7.64
(t, J = 8.0 Hz, 1H), 7.29-7.26 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H),
7.13 (d, J = 11.9 Hz, 1H), 6.21 (s, 1H), 4.60 (s, 1H), 4.43-4.01
(m, 2H), 3.65 (s, 2H), 3.28 (s, 1H), 2.04 (s, 2H), 1.92-1.72 (m,
2H), 1.65 (s, 6H), 1.19 (s, 6H), 0.99 (s, 1H). (OH not observed).
254 496.70 1.41 255 494.50 2.99 256 432.50 1.49 257 482.50 1.20 1H
NMR (400 MHz, CDCl3) .delta. 7.02 (d, J = 1.8 Hz, 1H), 6.98 (dd, J
= 8.2, 1.8 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.49 (s, 1H), 4.61
(s, 1H), 4.04 (d, J = 10.3 Hz, 1H), 4.02-3.94 (m, 3H), 3.88 (s,
3H), 3.75 (d, J = 43.7 Hz, 1H), 3.43 (s, 1H), 3.30 (s, 2H),
3.25-3.07 (m, 1H), 2.44 (s, 5H), 2.01 (s, 2H), 1.56 (d, J = 13.8
Hz, 4H), 1.49 (s, 3H). 258 532.50 1.73 1H NMR (400 MHz, CDCl3)
.delta. 7.06 (d, J = 1.9 Hz, 1H), 7.00 (dd, J = 8.2, 1.9 Hz, 1H),
6.88 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 3.3 Hz, 1H), 6.11 (d, J =
4.0 Hz, 1H), 4.57 (dt, J = 12.2, 6.1 Hz, 1H), 4.09-4.02 (m, 2H),
3.97- 3.90 (m, 2H), 3.88 (s, 3H), 3.83-3.75 (m, 3H), 3.74 (s, 3H),
3.04-2.89 (m, 2H), 1.87 (dt, J = 14.0, 5.8 Hz, 2H), 1.38 (d, J =
6.1 Hz, 6H), 1.30-1.23 (m, 1H). 259 510.70 1.89 260 442.20 2.40 1H
NMR (400 MHz, CDCl3) .delta. 7.50 (d, J = 8.4 Hz, 1H), 7.13 (d, J =
8.5 Hz, 1H), 6.47 (s, 1H), 4.68-4.51 (m, 2H), 3.99 (dd, J = 16.4,
10.5 Hz, 3H), 3.54 (t, J = 12.8 Hz, 1H), 3.27 (ddd, J = 36.4, 19.3,
9.5 Hz, 3H), 2.48 (dd, J = 28.6, 8.7 Hz, 8H), 2.06 (d, J = 13.3 Hz,
1H), 1.89 (d, J = 14.8 Hz, 1H), 1.59 (s, 1H), 1.37 (d, J = 6.0 Hz,
6H). 261 485.05 3.02 262 468.70 2.48 1H NMR (400 MHz, CDCl3)
.delta. 7.29 (s, 1H), 7.27 (d, J = 2.1 Hz, 1H), 6.83 (d, J = 8.0
Hz, 1H), 6.56 (d, J = 3.8 Hz, 1H), 5.97 (d, J = 3.9 Hz, 1H), 4.53
(s br, 1H, OH), 4.10-3.94 (m, 2H), 3.84 (s, 2H), 3.62 (m br, J =
74.5 Hz, 2H), 3.37 (t, J = 6.0 Hz, 3H), 2.41 (s, 3H), 2.30 (s, 3H),
2.17 (m br, J = 15.0 Hz, 2H), 1.85 (s br, 3H), 1.40 (s, 6H). 263
480.70 1.33 264 468.50 1.37 265 485.50 1.17 1H NMR (400 MHz, CDCl3)
.delta. 7.49 (d, J = 8.1 Hz, 1H), 7.25-7.16 (m, 3H), 6.17 (d, J =
4.5 Hz, 1H), 4.68-4.53 (m, 1H), 4.35 (t, J = 5.9 Hz, 2H), 3.65 (s,
1H), 3.51 (n, 1H), 3.34 (t, J = 5.6 Hz, 2H), 3.24 (s, 1H), 2.61 (s,
3H), 2.41 (s, 3H), 2.18 (s, 1H), 2.06 (s, 1H), 1.93 (s, 1H), 1.73
(s, 1H), 1.70 (s, 1H), 1.66 (s, 6H). 266 478.30 1.38 267 450.50
1.25 268 466.14 1.74 269 426.50 1.27 270 512.20 1.84 1H NMR (400
MHz, DMSO) .delta. 10.48 (s, 1H), 7.39 (d, J = 8.1 Hz, 1H),
7.30-7.16 (m, 1H), 6.99 (d, J = 1.8 Hz, 1H), 6.88 (dd, J = 8.1, 1.9
Hz, 1H), 6.48 (d, J = 4.6 Hz, 1H), 4.45-4.29 (m, 1H), 4.29-4.16 (m,
2H), 3.58-2.96 (m, 5H), 2.30 (s, 3H), 2.25-1.68 (m, 4H). 271 456.50
1.44 272 462.50 1.32 273 422.50 1.32 274 513.70 1.36 275 400.13
2.61 276 436.50 1.37 277 458.50 1.46 278 380.17 1.97 1H NMR (400
MHz, DMSO) .delta. 7.29-7.17 (m, 2H), 6.96 (d, J = 9.1 Hz, 1H),
6.04-5.88 (m, 2H), 4.69-4.57 (m, 1H), 4.46-3.92 (m, 1H), 3.86-3.72
(m, 2H), 3.72-3.55 (m, 2H), 3.42-2.95 (m, 5H), 2.24 (s, 3H), 2.14
(s, 3H), 2.11-1.91 (m, 2H), 1.78-1.57 (m, 2H), 1.29 (d, J = 6.0 Hz,
6H). 279 464.50 1.32 1H NMR (400 MHz, DMSO) .delta. 7.29-7.19 (m,
2H), 7.02- 6.92 (m, 1H), 6.61 (d, J = 4.0 Hz, 1H), 6.08 (d, J = 4.0
Hz, 1H), 4.71-4.58 (m, 1H), 4.46-4.08 (m, 1H), 3.65- 3.00 (m, 3H),
2.91 (d, J = 6.7 Hz, 2H), 2.77 (t, J = 7.2 Hz, 1H), 2.14 (s, 3H),
1.98-1.63 (m, 4H), 1.43 (s, 6H), 1.29 (d, J = 6.0 Hz, 6H). 280
464.50 6.18 281 429.50 1.12 1H NMR (400 MHz, DMSO) .delta. 7.76
(dd, J = 8.6, 2.0 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.32 (d, J =
8.7 Hz, 1H), 7.08 (d, J = 4.1 Hz, 1H), 6.20 (d, J = 4.2 Hz, 1H),
4.48- 4.23 (m, 1H), 4.14 (t, J = 5.8 Hz, 2H), 3.94 (s, 3H), 3.53-
3.29 (m, 2H), 3.23 (t, J = 5.5 Hz, 2H), 3.19-2.96 (m, 1H), 2.28 (s,
3H), 2.23-1.89 (m, 2H), 1.89-1.70 (m, 2H), 1.43 (s, 3H), ?
0.99-0.94 (m, 2H), 0.66-0.61 (m, 2H). 282 490.50 1.47 283 471.50
1.06 284 492.30 1.78 285 435.20 2.02 286 442.40 1.45 287 498.20
1.09 288 561.80 1.76 289 547.50 1.22 290 448.50 1.57 291 479.30
1.53 292 394.22 2.22 293 505.50 1.39 294 446.26 2.27 295 500.24
1.22 296 485.05 3.58 297 423.30 1.19 1H NMR (400 MHz, DMSO) .delta.
7.91 (d, J = 8.0 Hz, 1H), 7.58-7.46 (m, 2H), 6.58 (d, J = 3.4 Hz,
1H), 6.12 (d, J = 3.9 Hz, 1H), 4.43-4.29 (m, 1H), 3.93 (t, J = 5.8
Hz, 2H), 3.46-3.21 (m, 6H), 3.18-3.05 (m, 1H), 2.65 (s, 3H), 2.27
(s, 3H), 2.23-1.70 (m, 4H), 1.12 (t, J = 7.4 Hz, 3H). 298 484.40
2.46 1H NMR (400 MHz, DMSO) .delta. 7.05 (d, J = 1.9 Hz, 1H), 7.01
(d, J = 8.1 Hz, 1H), 6.92 (dd, J = 8.1, 1.9 Hz, 1H), 6.59-6.53 (m,
1H), 6.19 (d, J = 4.0 Hz, 1H), 4.33 (s, 1H), 3.97 (t, J = 5.7 Hz,
2H), 3.76 (s, 3H), 3.62-3.34 (m, 2H), 3.31-2.99 (m, 3H), 2.28 (s,
3H), 2.11 (s, 2H), 1.84-1.71 (m, 2H), 1.29 (s, 9H). 299 530.50 1.56
300 540.50 1.41 301 428.23 1.93 1H NMR (400 MHz, DMSO) .delta. 7.35
(d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 6.73 (d, J = 4.0 Hz,
1H), 6.22 (d, J = 4.1 Hz, 1H), 4.47-4.24 (m, 1H), 4.12 (t, J = 5.8
Hz, 2H), 3.55-3.37 (m, 1H), 3.37-3.26 (m, 3H), 3.20
(s, 3H), 3.18-2.98 (m, 1H), 2.58-2.51 (m, 1H), 2.29 (s, 3H),
2.25-1.91 (m, 2H), 1.88-1.63 (m, 7H), 1.53-1.14 (m, 5H). 302 470.50
1.55 303 554.20 1.34 304 442.10 2.47 305 448.50 0.83 306 466.50
1.41 1H NMR (400 MHz, DMSO) .delta. 7.47 (d, J = 7.9 Hz, 1H),
7.24-7.12 (m, 2H), 6.60 (d, J = 3.7 Hz, 1H), 6.20 (d, J = 3.9 Hz,
1H), 4.97 (s, 1H), 4.27-4.08 (m, 1H), 4.08- 3.93 (m, 2H), 3.51-3.13
(m, 5H), 2.54 (s, 3H), 2.42- 2.13 (m, 2H), 1.97-1.68 (m, 3H), 1.51
(s, 6H), 0.68- 0.47 (m, 4H). 307 476.40 3.77 308 450.50 1.61 309
436.22 1.75 310 505.30 1.55 311 492.30 1.44 1H NMR (400 MHz, CDCl3)
.delta. 7.36 (t, J = 8.2 Hz, 1H), 7.25 (dd, J = 4.9, 2.7 Hz, 1H),
6.76 (dd, J = 8.6, 2.3 Hz, 1H), 6.62 (dd, J = 11.5, 2.4 Hz, 1H),
6.19 (d, J = 4.5 Hz, 1H), 4.66 (d, J = 13.4 Hz, 1H), 4.30-4.08 (m,
2H), 3.83 (s, 3H), 3.68-3.54 (m, 1H), 3.49 (d, J = 13.0 Hz, 1H),
3.25 (t, J = 13.0 Hz, 1H), 2.07-1.96 (m, 1H), 1.85 (t, J = 16.3 Hz,
2H), 1.70 (d, J = 12.7 Hz, 1H), 1.21 (s, 3H), 1.14 (s, 3H), 0.96
(s, 1H). 312 468.30 1.45 313 468.70 2.38 314 438.50 1.43 1H NMR
(400 MHz, CDCl3) .delta. 7.25-7.19 (m, 1H), 7.02 (d, J = 1.8 Hz,
1H), 6.98 (dd, J = 8.2, 1.9 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.17
(d, J = 4.2 Hz, 1H), 4.57 (s, 1H), 4.56 (dd, J = 12.2, 6.1 Hz, 1H),
4.35 (t, J = 5.5 Hz, 2H), 3.88 (s, 3H), 3.74 (s, 1H), 3.34 (t, J =
5.2 Hz, 2H), 3.34 (s, 2H), 2.42 (s, 3H), 2.14 (s, 2H), 1.84 (s,
2H), 1.38 (d, J = 6.1 Hz, 6H). 315 494.50 1.45 1H NMR (400 MHz,
DMSO) .delta. 7.26 (s, 1H), 7.18 (dd, J = 23.4, 7.8 Hz, 2H), 6.57
(s, 1H), 6.12 (d, J = 3.0 Hz, 1H), 5.25 (s, 1H), 4.85 (d, J = 1.1
Hz, 1H), 4.33 (s, 1H), 3.93 (s, 2H), 3.09 (s, 1H), 2.30 (s, 3H),
2.27 (s, 3H), 2.01 (s, 3H), 1.75 (s, 2H). 316 432.70 1.68 1H NMR
(400 MHz, DMSO) .delta. 7.05-6.93 (m, 3H), 6.58 (d, J = 3.8 Hz,
1H), 6.13 (d, J = 3.9 Hz, 1H), 4.65-4.53 (m, 1H), 4.31-3.92 (m,
1H), 3.84-3.73 (m, 5H), 3.60- 3.20 (m, 5H), 3.16-3.03 (m, 1H),
2.17-1.69 (m, 8H), 1.58-1.35 (m, 2H), 1.26 (d, J = 6.0 Hz, 6H). 317
506.40 3.47 318 450.20 0.99 319 392.50 1.37 1H NMR (400 MHz, CDCl3)
.delta. 7.02 (d, J = 1.9 Hz, 1H), 6.98 (dd, J = 8.2, 1.9 Hz, 1H),
6.88 (d, J = 8.2 Hz, 1H), 6.53 (d, J = 3.8 Hz, 1H), 5.91 (d, J =
3.8 Hz, 1H), 4.57 (dt, J = 12.2, 6.1 Hz, 1H), 4.08 (d, J = 8.8 Hz,
1H), 3.88 (s, 3H), 3.67-3.18 (m, 5H), 2.27-1.86 (m, 2H), 1.65 (s,
3H), 1.38 (d, J = 6.1 Hz, 6H), 1.27 (d, J = 5.9 Hz, 3H), 0.79 (s,
1H). 320 466.30 1.24 321 438.20 1.16 322 437.20 0.89 323 428.15
2.27 324 498.50 1.66 325 512.50 1.71 326 548.70 1.24 1H NMR (400
MHz, DMSO) .delta. 7.08-6.95 (m, 3H), 6.65 (d, J = 3.7 Hz, 1H),
6.33 (d, J = 3.9 Hz, 1H), 4.96-4.68 (m, 1H), 4.68-4.53 (m, 1H),
4.08-3.98 (m, 1H), 3.90- 3.84 (m, 1H), 3.77 (s, 3H), 3.74-3.51 (m,
2H), 3.47- 3.35 (m, 1H), 3.35-3.28 (m, 2H), 3.28-3.11 (m, 1H), 2.32
(s, 3H), 2.13-1.86 (m, 2H), 1.27 (d, J = 6.0 Hz, 6H). 327 484.60
2.75 1H NMR (400 MHz, DMSO) .delta. 7.04-6.90 (m, 3H), 6.57 (d, J =
3.5 Hz, 1H), 6.07 (d, J = 3.9 Hz, 1H), 4.66-4.52 (m, 1H), 4.06-3.82
(m, 2H), 3.77 (s, 3H), 3.61-3.11 (m, 5H), 2.30-2.21 (m, 4H),
2.17-1.66 (m, 3H), 1.42 (d, J = 7.0 Hz, 3H), 1.26 (d, J = 6.0 Hz,
6H). 328 480.20 3.02 329 440.30 1.41 330 442.12 2.25 331 435.50
1.28 1H NMR (400 MHz, DMSO) .delta. 7.28-7.20 (m, 2H), 6.91 (d, J =
9.0 Hz, 1H), 6.59 (d, J = 3.6 Hz, 1H), 6.20 (d, J = 3.9 Hz, 1H),
4.65 (s, 1H), 4.25-3.91 (m, 3H), 3.73 (s, 2H), 3.65-3.09 (m, 5H),
2.36-2.14 (m, 5H), 1.92-1.68 (m, 3H), 1.23 (s, 6H), 0.66-0.46 (m,
4H). 332 506.20 3.81 1H NMR (400 MHz, DMSO) .delta. 7.29-7.18 (m,
2H), 7.02- 6.92 (m, 1H), 6.60 (d, J = 3.5 Hz, 1H), 6.20 (d, J = 3.9
Hz, 1H), 4.70-4.53 (m, 1H), 4.27-3.90 (m, 3H), 3.72- 3.04 (m, 5H),
2.42-2.18 (m, 2H), 2.14 (s, 3H), 1.90- 1.64 (m, 3H), 1.29 (d, J =
6.0 Hz, 6H), 0.68-0.48 (m, 4H). 333 476.30 7.37 334 434.25 2.57 335
452.10 1.15 336 510.70 1.32 1H NMR (400 MHz, DMSO) .delta.
7.38-7.27 (m, 1H), 7.27- 7.16 (m, 2H), 6.62 (d, J = 4.1 Hz, 1H),
6.11 (d, J = 4.0 Hz, 1H), 4.75-4.63 (m, 1H), 4.41-4.13 (m, 1H),
3.59- 2.99 (m, 3H), 2.90 (d, J = 6.3 Hz, 2H), 2.77 (t, J = 7.2 Hz,
1H), 1.99-1.69 (m, 4H), 1.43 (s, 6H), 1.30 (d, J = 6.0 Hz, 6H). 337
468.70 5.63 338 424.20 0.95 1H NMR (400 MHz, DMSO) .delta. 7.36 (d,
J = 8.1 Hz, 2H), 7.29-7.14 (m, 3H), 6.50 (d, J = 4.6 Hz, 1H),
4.53-4.13 (m, 3H), 3.62-2.96 (m, 5H), 2.53-2.46 (m, 2H), 2.30 (s,
3H), 2.25-1.93 (m, 2H), 1.93-1.74 (m, 3H), 0.87 (d, J = 6.6 Hz,
6H). 339 462.20 1.78 340 528.06 3.63 341 470.50 1.51 342 410.14
1.98 343 499.30 1.27 344 448.50 1.53 1H NMR (400 MHz, CDCl3)
.delta. 8.43 (d, J = 1.5 Hz, 1H), 7.69-7.51 (m, 2H), 6.53 (d, J =
3.4 Hz, 1H), 5.95 (d, J = 3.5 Hz, 1H), 4.64-4.45 (m, 1H), 4.08-3.92
(m, 2H), 3.92-3.74 (m, 1H), 3.61-3.25 (m, 4H), 2.70 (q, J = 7.6 Hz,
2H), 2.39 (s, 3H), 2.28-1.82 (m, 4H), 1.28 (t, J = 7.6 Hz, 3H). 345
407.00 2.23 346 462.50 1.20 1H NMR (400 MHz, DMSO) .delta. 7.80 (d,
J = 8.1 Hz, 1H), 7.51 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.58 (d, J
= 3.7 Hz, 1H), 6.12 (d, J = 3.9 Hz, 1H), 4.35 (d, J = 12.4 Hz, 1H),
3.93 (t, J = 5.5 Hz, 2H), 3.47-3.31 (m, 4H), 3.11 (t, J = 12.8 Hz,
1H), 2.76 (s, 6H), 2.58 (s, 3H), 2.27 (s, 3H), 2.18 (d, J = 12.5
Hz, 1H), 2.01 (d, J = 13.8 Hz, 1H), 1.84- 1.69 (m, 2H). 347 499.30
1.36 348 544.02 3.17 349 478.50 1.29 1H NMR (400 MHz, DMSO) .delta.
7.59-7.40 (m, 1H), 7.24- 7.08 (m, 2H), 6.60 (d, J = 3.5 Hz, 1H),
6.10 (s, 1H), 5.21- 4.36 (m, 3H), 4.18-3.97 (m, 1H), 3.91-3.64 (m,
2H), 3.63-2.93 (m, 4H), 2.54 (s, 3H), 2.38-2.11 (m, 4H), 1.93-1.68
(m, 1H), 1.51 (s, 6H). 350 468.20 4.52 351 408.10 1.24 352 463.10
1.07 353 452.20 1.69 354 486.30 1.78 355 492.50 1.70 1H NMR (400
MHz, DMSO) .delta. 10.44 (s, 2H), 7.30-7.23 (m, 2H), 7.04-6.97 (m,
1H), 6.74 (d, J = 3.5 Hz, 1H), 6.50 (s, 1H), 4.66 (sept, J = 6.0
Hz, 1H), 4.32-4.17 (m, 2H), 4.18-3.88 (m, 1H), 3.81-3.60 (m, 5H),
2.35-2.19 (m, 2H), 2.19-2.07 (m, 2H), 2.16 (s, 3H), 1.30 (d, J =
6.0 Hz, 6H). 356 436.50 1.39 357 495.50 1.43 1H NMR (400 MHz, DMSO)
.delta. 7.52 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H),
7.28-7.19 (m, 1H), 6.50 (d, J = 4.6 Hz, 1H), 5.08 (s, 1H),
4.49-4.30 (m, 1H), 4.24 (t, J = 5.6 Hz, 2H), 3.55-3.23 (m, 4H),
3.21-3.00 (m, 1H), 2.30 (s, 3H), 2.25-1.96 (m, 2H), 1.95-1.77 (m,
2H), 1.43 (s, 6H). 358 464.50 1.29 359 506.20 1.05 360 564.70 1.54
361 462.70 1.69 1H NMR (400 MHz, CDCl3) .delta. 8.62 (s, 1H), 7.03
(d, J = 1.9 Hz, 1H), 6.98 (dd, J = 8.2, 1.9 Hz, 1H), 6.89 (dd, J =
8.3, 2.4 Hz, 1H), 6.59 (dd, J = 28.9, 3.6 Hz, 1H), 6.17 (dd, J =
112.7, 4.0 Hz, 1H), 4.59 (dt, J = 12.1, 6.1 Hz, 1H), 4.08 (dd, J =
18.9, 5.5 Hz, 3H), 3.88 (d, J = 1.9 Hz, 3H), 3.36 (s, 2H), 2.41 (s,
2H), 2.14 (d, J = 49.0 Hz, 2H), 1.39 (d, J = 6.1 Hz, 6H). 362
480.30 4.65 363 502.30 2.46 364 452.50 1.52 365 421.30 1.20 366
504.50 1.85 367 440.50 1.31 1H NMR (400 MHz, DMSO) .delta.
7.77-7.58 (m, 1H), 7.36- 7.10 (m, 3H), 6.22 (d, J = 4.2 Hz, 1H),
5.35 (s, 1H), 4.43- 4.24 (m, 1H), 4.22-4.09 (m, 2H), 3.46-3.27 (m,
2H), 3.27-2.94 (m, 3H), 2.62-2.53 (m, 1H), 2.26 (s, 3H), 2.21-1.88
(m, 2H), 1.88-1.68 (m, 2H), 1.49 (s, 6H), 0.95-0.67 (m, 4H). 368
454.50 1.22 369 512.40 1.74 1H NMR (400 MHz, CDCl3) .delta. 7.62
(t, J = 8.1 Hz, 1H), 7.18 (dd, J = 8.0, 1.5 Hz, 1H), 7.12 (dd, J =
11.9, 1.5 Hz, 1H), 6.53 (d, J = 3.8 Hz, 1H), 5.94 (d, J = 3.9 Hz,
1H), 4.54 (s br, 1H), 3.99 (d br, J = 5.9 Hz, 2H), 3.57 (s br, 2H),
3.33 (t, J = 6.0 Hz, 2H), 3.27 (s br, 1H), 2.38 (s, 3H), 2.19 (s
br, 1H), 2.14-2.01 (m, 2H), 1.90 (s br, 1H), 1.72 (s br, 1H), 1.65
(s, 6H). 370 454.30 1.23 1H NMR (400 MHz, CDCl3) .delta. 8.40 (s,
1H), 7.45-7.20 (m, 1H), 7.08 (s, 1H), 6.55 (d, J = 3.4 Hz, 1H),
5.98 (d, J = 3.8 Hz, 1H), 4.58 (s, 1H), 4.00 (s, 3H), 3.81 (s, 1H),
3.62 (s, 1H), 3.37 (t, J = 5.8 Hz, 2H), 2.72 (s, 3H), 2.41 (s, 3H),
2.28-2.06 (m, 2H), 1.99 (t, J = 11.6 Hz, 2H). 371 483.70 1.22 1H
NMR (400 MHz, CDCl3) .delta. 7.03 (d, J = 1.9 Hz, 1H), 6.98 (dd, J
= 8.2, 1.9 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 3.7 Hz,
1H), 5.93 (d, J = 3.8 Hz, 1H), 4.56 (dd, J = 12.2, 6.1 Hz, 1H),
4.52 (s, 1H), 3.94 (s, 2H), 3.88 (s, 3H), 3.69 (s, 1H), 3.47 (s,
2H), 3.27 (s, 2H), 1.87 (s, 4H), 1.38 (d, J = 6.1 Hz, 6H). (NH is
not observed.) 372 452.50 1.21 373 508.40 1.47 374 456.50 1.47 375
508.40 1.66 376 438.50 1.54 1H NMR (400 MHz, CDCl3) .delta. 7.70
(d, J = 1.9 Hz, 1H), 7.64 (dd, J = 8.5, 2.1 Hz, 1H), 7.28-7.22 (m,
1H), 7.05 (d, J = 8.6 Hz, 1H), 6.20 (d, J = 4.5 Hz, 1H), 4.61 (s,
1H), 4.20 (s, 2H), 3.95 (s, 3H), 3.70 (s, 2H), 3.34 (s, 1H), 1.97
(s, 2H), 1.79 (s, 2H), 1.18 (s, 6H), 0.97 (s, 1H). 377 518.20 1.69
378 502.50 1.03 379 501.30 1.60 380 466.20 1.92 1H NMR (400 MHz,
DMSO) .delta. 7.86-7.81 (m, 2H), 7.69- 7.64 (m, 2H), 7.55 (q, J =
4.8 Hz, 1H), 6.59-6.55 (m, 1H), 6.19 (d, J = 4.0 Hz, 1H), 4.37 (d,
J = 12.5 Hz, 1H), 3.97 (t, J = 5.8 Hz, 2H), 3.46-3.33 (m, 2H),
3.31-3.23 (m, 2H), 3.12 (t, J = 12.6 Hz, 1H), 2.44 (d, J = 4.9 Hz,
3H), 2.28 (s, 3H), 2.23-2.14 (m, 1H), 2.06-1.98 (m, 1H), 1.80 (t, J
= 13.3 Hz, 2H). 381 521.50 1.35 382 410.21 2.12 383 500.24 1.24 1H
NMR (400 MHz, CDCl3) .delta. 7.32 (d, J = 7.8 Hz, 1H), 7.21 (dd, J
= 12.0, 4.2 Hz, 2H), 6.29 (s, 1H), 4.59 (s, 1H), 3.92 (s, 2H), 3.72
(q, J = 7.0 Hz, 3H), 3.61 (s, 1H), 3.46 (s, 1H), 3.30 (s, 2H), 3.19
(s, 1H), 2.75-2.61 (m, 2H), 2.48-2.35 (m, 8H), 2.25-2.06 (m, 3H),
1.99 (s, 2H), 1.72 (dtt, J = 10.7, 8.9, 5.2 Hz, 2H), 1.24 (t, J =
7.0 Hz, 5H). 384 480.20 1.34 1H NMR (400 MHz, DMSO) .delta. 7.01
(d, J = 1.4 Hz, 1H), 7.00-6.93 (m, 2H), 6.56 (s, 1H), 6.18 (d, J =
4.0 Hz, 1H), 4.42-4.33 (m, 1H), 4.26 (s, 1H), 3.97 (t, J = 5.8 Hz,
2H), 3.77 (s, 3H), 3.59 (s, 2H), 3.31-2.85 (m, 3H), 2.28 (s, 3H),
2.10 (s, 2H), 1.76 (t, J = 13.3 Hz, 2H), 1.71- 1.50 (m, 2H), 1.22
(d, J = 6.1 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H). 385 530.50 1.56 386
416.13 2.51 387 420.22 1.81 388 422.20 2.02 389 446.20 1.59 390
484.70 2.55 391 510.70 1.63 392 484.30 1.33 393 454.30 1.72 1H NMR
(400 MHz, DMSO) .delta. 7.26-7.19 (m, 2H), 6.96 (d, J = 9.1 Hz,
1H), 6.90 (d, J = 4.0 Hz, 1H), 6.20 (d, J = 4.0 Hz, 1H), 4.63
(hept, J = 6.0 Hz, 1H), 4.53-4.06 (m, 1H), 3.97 (t, J = 5.6 Hz,
2H), 3.38-2.87 (m, 5H), 2.27 (s, 3H), 2.14 (s, 3H), 2.11-1.95 (m,
2H), 1.83-1.65 (m, 2H), 1.28 (d, J = 6.0 Hz, 6H). 394 407.70 1.32
395 468.70 2.61 396 552.50 1.56 397 484.70 2.82 1H NMR (400 MHz,
DMSO) .delta. 7.51 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.5, 2.0 Hz,
1H), 7.20 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 4.1 Hz, 1H), 6.18 (d, J
= 4.1 Hz, 1H), 4.80- 4.67 (m, 1H), 4.46-4.08 (m, 3H), 3.62-3.30 (m,
2H), 3.30-2.97 (m, 3H), 2.31 (s, 3H), 2.27 (s, 3H), 2.21- 1.91 (m,
2H), 1.89-1.69 (m, 2H), 1.31 (d, J = 6.0 Hz, 6H). 398 444.40 1.21
399 514.70 1.37 400 384.21 2.16 1H NMR (400 MHz, CDCl3) .delta.
7.32 (t, J = 7.5 Hz, 1H), 7.20-7.12 (m, 2H), 6.49 (s, 1H), 4.61 (s,
1H), 3.99 (s,
2H), 3.72 (q, J = 7.0 Hz, 3H), 3.68-3.09 (m, 5H), 2.85 (s, 2H),
2.43 (d, J = 17.8 Hz, 5H), 2.07 (s, 1H), 1.94 (s, 1H), 1.60 (s,
1H), 1.47-1.30 (m, 2H), 1.25 (dd, J = 11.5, 4.4 Hz, 11H). 401
502.10 1.48 1H NMR (400 MHz, DMSO) .delta. 7.53-7.38 (m, 4H), 7.27-
7.14 (m, 2H), 7.14-6.96 (m, 4H), 6.49 (d, J = 4.6 Hz, 1H),
4.48-4.28 (m, 1H), 4.24 (t, J = 5.8 Hz, 2H), 3.65- 3.23 (m, 4H),
3.23-2.94 (m, 1H), 2.31 (s, 3H), 2.23- 1.95 (m, 2H), 1.95-1.75 (m,
2H). 402 498.30 1.63 403 412.50 1.45 404 496.40 1.79 1H NMR (400
MHz, CDCl3) .delta. 7.06-6.95 (m, 2H), 6.93- 6.85 (m, 1H), 6.63 (d,
J = 4.0 Hz, 1H), 5.91 (d, J = 4.0 Hz, 1H), 4.57 (dt, J = 12.1, 6.1
Hz, 1H), 3.88 (s, 3H), 3.49 (s, 3H), 2.96 (s, 2H), 1.84 (s, 4H),
1.59 (s, 2H), 1.51 (s, 6H), 1.38 (d, J = 6.1 Hz, 6H). 405 480.30
1.78 406 436.09 2.50 407 424.50 1.03 408 490.50 1.79 1H NMR (400
MHz, DMSO) .delta. 7.39 (d, J = 8.7 Hz, 2H), 7.26 (dd, J = 4.4, 2.2
Hz, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.55 (d, J = 4.6 Hz, 1H), 4.33
(s, 1H), 4.11 (s, 2H), 4.03 (t, J = 6.6 Hz, 2H), 3.52 (s, 2H), 3.24
(s, 1H), 2.27 (s, 1H), 1.94-1.83 (m, 2H), 1.83-1.67 (m, 3H), 1.62
(q, J = 6.7 Hz, 2H), 1.08 (s, 6H), 0.93 (d, J = 6.6 Hz, 6H). 409
506.00 1.94 1H NMR (400 MHz, CDCl3) .delta. 7.33 (d, J = 7.7 Hz,
1H), 7.07-6.96 (m, 2H), 6.29 (s, 1H), 5.30 (s, 0H), 4.62 (s, 1H),
3.90 (d, J = 10.6 Hz, 5H), 3.50 (dd, J = 80.7, 48.4 Hz, 6H), 2.50
(ddd, J = 13.9, 8.6, 5.6 Hz, 2H), 2.45- 2.32 (m, 5H), 2.17 (s, 2H),
2.12-1.91 (m, 8H), 1.63 (dt, J = 15.7, 8.6 Hz, 2H). 410 496.30 1.36
411 496.70 1.34 1H NMR (400 MHz, DMSO) .delta. 7.01 (d, J = 1.2 Hz,
1H), 7.00-6.93 (m, 2H), 6.56 (s, 1H), 6.18 (d, J = 4.0 Hz, 1H),
4.42-4.33 (m, 1H), 4.33-4.02 (m, 1H), 3.97 (t, J = 5.7 Hz, 2H),
3.77 (s, 3H), 3.59 (s, 2H), 3.20 (t, J = 20.2 Hz, 3H), 2.28 (s,
3H), 2.10 (s, 2H), 1.76 (t, J = 13.5 Hz, 2H), 1.71-1.51 (m, 2H),
1.22 (d, J = 6.1 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H). 412 530.50 1.57
413 444.20 0.94 414 450.14 2.53 415 489.50 2.26 416 440.19 1.82 417
440.50 1.38 418 438.50 1.44 1H NMR (400 MHz, CDCl3) .delta. 7.55
(d, J = 2.0 Hz, 1H), 7.40 (dd, J = 8.5, 2.1 Hz, 1H), 6.97 (d, J =
8.5 Hz, 1H), 6.56 (d, J = 3.8 Hz, 1H), 6.02 (d, J = 3.8 Hz, 1H),
5.92 (s, 1H), 4.69-4.54 (m, 1H), 4.41-4.20 (m, 2H), 4.15 (t, J =
6.6 Hz, 2H), 4.06-3.56 (m, 2H), 3.41 (t, J = 6.5 Hz, 2H), 2.72 (s,
3H), 2.56-2.44 (m, 2H), 2.44-1.48 (m, 2H), 1.40 (d, J = 6.1 Hz,
6H). 419 513.20 5.54 1H NMR (400 MHz, CDCl3) .delta. 7.25 (dd, J =
9.6, 2.6 Hz, 3H), 6.80 (d, J = 9.0 Hz, 1H), 6.49 (s, 1H), 4.60 (s,
1H), 4.06 (q, J = 7.0 Hz, 2H), 3.99 (s, 2H), 3.72 (q, J = 7.0 Hz,
2H), 3.32 (s, 4H), 2.43 (d, J = 20.3 Hz, 5H), 2.23 (s, 3H), 2.01
(s, 2H), 1.58 (s, 1H), 1.44 (t, J = 7.0 Hz, 3H), 1.25 (dd, J = 8.8,
5.2 Hz, 4H). 420 470.50 1.71 421 506.50 1.41 422 471.10 1.42 423
492.50 1.77 424 434.19 2.62 425 392.20 1.97 426 522.50 2.19 1H NMR
(400 MHz, CDCl3) .delta. 7.38-7.28 (m, 1H), 6.72 (d, J = 8.3 Hz,
1H), 6.59 (d, J = 11.7 Hz, 1H), 6.53 (d, J = 3.7 Hz, 1H), 5.95-5.84
(m, 1H), 4.68-4.46 (m, 2H), 4.07 (dd, J = 11.6, 5.2 Hz, 1H),
3.66-3.14 (m, 5H), 2.29- 1.47 (m, 4H), 1.35 (d, J = 5.9 Hz, 6H),
1.31-1.22 (m, J = 6.1 Hz, 3H), 1.19-0.77 (m, 1H). 427 454.40 1.36
1H NMR (400 MHz, CDCl3) .delta. 7.08 (d, J = 1.9 Hz, 1H), 7.02 (dd,
J = 8.2, 1.9 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 3.1
Hz, 1H), 6.15 (d, J = 3.9 Hz, 1H), 4.56 (dt, J = 12.2, 6.1 Hz, 1H),
4.13 (t, J = 4.4 Hz, 2H), 3.88 (s, 3H), 3.92-3.84 (m, 2H), 3.79 (s,
2H), 3.63 (s, 2H), 3.22-2.96 (m, 2H), 2.46 (dd, J = 14.4, 7.5 Hz,
2H), 1.82 (s, 2H), 1.38 (d, J = 6.1 Hz, 6H), 1.17 (t, J = 7.3 Hz,
3H). 428 508.70 1.83 1H NMR (400 MHz, DMSO) .delta. 6.97 (q, J =
8.3 Hz, 3H), 6.62 (d, J = 3.6 Hz, 1H), 6.37 (d, J = 3.9 Hz, 1H),
4.59 (dt, J = 12.1, 6.0 Hz, 1H), 4.09-3.97 (m, 1H), 3.84 (s, 1H),
3.76 (s, 3H), 3.06 (s, 1H), 2.69 (s, 2H), 2.19 (s, 3H), 2.07 (s,
1H), 1.87 (d, J = 27.8 Hz, 2H), 1.26 (d, J = 6.0 Hz, 6H), 1.11 (t,
J = 7.2 Hz, 1H), 0.88 (s, 3H). 429 480.50 1.28 430 382.16 2.33 431
455.50 2.70 432 464.20 1.08 1H NMR (400 MHz, DMSO) .delta. 7.43 (s,
2H), 7.25 (dd, J = 4.5, 2.2 Hz, 1H), 6.50 (d, J = 4.6 Hz, 1H),
4.73-4.64 (m, 1H), 4.39 (d, J = 12.7 Hz, 1H), 4.11 (s, 2H), 3.76
(d, J = 12.7 Hz, 1H), 3.51 (t, J = 12.3 Hz, 1H), 3.21 (t, J = 11.2
Hz, 1H), 2.34 (s, 3H), 2.29 (s, 1H), 1.94-1.78 (m, 3H), 1.68 (d, J
= 12.4 Hz, 1H), 1.31 (d, J = 6.0 Hz, 6H), 1.09 (d, J = 12.1 Hz,
6H). 433 493.30 1.67 434 480.30 1.36 435 466.50 1.34 436 472.30
2.95 437 506.50 1.84 438 493.20 1.26 439 496.70 1.52 440 468.20
1.03 441 498.50 1.26 442 539.50 1.38 1H NMR (400 MHz, CDCl3)
.delta. 7.01 (d, J = 1.9 Hz, 1H), 6.97 (dd, J = 8.2, 1.9 Hz, 1H),
6.88 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 3.5 Hz, 1H), 5.94 (d, J =
3.7 Hz, 1H), 4.56 (dq, J = 12.2, 6.1 Hz, 1H), 4.52-4.34 (m, 1H),
4.05- 3.94 (m, 2H), 3.87 (s, 3H), 3.69 (s, 1H), 3.50 (s, 1H), 3.34
(s, 1H), 3.34 (t, J = 5.7 Hz, 2H), 2.39 (s, 3H), 2.13 (s, 2H), 1.84
(s, 2H), 1.38 (d, J = 6.1 Hz, 6H). 443 466.50 1.23 444 507.50 1.68
445 468.70 1.42 446 468.70 1.47 447 464.30 1.18 448 437.50 1.21 449
546.70 1.55 1H NMR (400 MHz, DMSO) .delta. 7.88 (d, J = 7.9 Hz,
1H), 7.71 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.42 (d, J = 8.1 Hz,
1H), 6.58 (d, J = 3.6 Hz, 1H), 6.12 (d, J = 3.8 Hz, 1H), 4.35 (d, J
= 11.4 Hz, 1H), 3.96-3.86 (m, 2H), 3.45- 3.34 (m, 2H), 3.29-3.19
(m, 3H), 3.17-3.01 (m, 1H), 2.60 (s, 3H), 2.27 (s, 3H), 2.22-2.10
(m, 1H), 2.06- 1.95 (m, 1H), 1.84-1.67 (m, 2H), 0.97 (d, J = 6.5
Hz, 6H). 450 513.30 1.37 1H NMR (400 MHz, DMSO) .delta. 7.52 (d, J
= 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 6.60 (d, J = 3.8 Hz, 1H),
6.20 (d, J = 3.9 Hz, 1H), 5.07 (s, 1H), 4.26-4.09 (m, 1H), 3.98 (t,
J = 5.8 Hz, 2H), 3.51-3.13 (m, 5H), 2.43-2.12 (m, 2H), 1.95-1.69
(m, 3H), 1.43 (s, 6H), 0.63-0.50 (m, 4H). 451 462.20 3.29 452
415.50 1.06 453 483.20 1.12 454 438.50 1.36 1H NMR (400 MHz, DMSO)
.delta. 7.28-7.17 (m, 1H), 7.06- 6.95 (m, 3H), 6.50 (d, J = 4.6 Hz,
1H), 4.65-4.51 (m, 1H), 4.48-4.05 (m, 3H), 3.78 (s, 3H), 3.67-2.99
(m, 5H), 2.30 (s, 3H), 2.18-1.98 (m, 2H), 1.94-1.75 (m, 2H), 1.25
(d, J = 6.0 Hz, 6H). 455 494.50 1.44 1H NMR (400 MHz, DMSO) .delta.
7.47 (d, J = 8.7 Hz, 1H), 7.21-7.14 (m, 2H), 7.05 (d, J = 4.1 Hz,
1H), 6.18 (d, J = 4.2 Hz, 1H), 4.97 (s, 1H), 4.43-4.25 (m, 1H),
4.18 (t, J = 5.8 Hz, 2H), 3.54-3.29 (m, 2H), 3.29-3.19 (m, 2H),
3.18-2.99 (m, 1H), 2.54 (s, 3H), 2.31 (s, 3H), 2.26 (s, 3H),
2.19-1.94 (m, 2H), 1.86-1.66 (m, 2H), 1.51 (s, 6H). 456 424.20 0.90
457 382.50 0.91 1H NMR (400 MHz, CDCl3) .delta. 7.01 (d, J = 1.8
Hz, 1H), 6.96 (dd, J = 8.2, 1.9 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H),
6.63 (d, J = 3.5 Hz, 1H), 6.06 (d, J = 2.2 Hz, 1H), 4.92 (t, J =
6.3 Hz, 1H), 4.56 (dt, J = 12.1, 6.1 Hz, 1H), 4.36 (s, 1H), 3.87
(s, 3H), 3.76 (s, 3H), 3.50 (d, J = 50.0 Hz, 5H), 2.33 (s, 3H),
2.28 (s, 1H), 2.06 (s, 1H), 1.86 (s, 2H), 1.38 (d, J = 6.1 Hz, 6H).
458 524.70 1.87 1H NMR (400 MHz, DMSO) .delta. 7.76 (dd, J = 8.6,
2.0 Hz, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H),
7.28-7.19 (m, 1H), 6.49 (d, J = 4.6 Hz, 1H), 4.52-4.15 (m, 3H),
3.94 (s, 3H), 3.59-2.96 (m, 5H), 2.31 (s, 3H), 2.26-1.78 (m, 4H).
459 504.50 1.59 1H NMR (400 MHz, DMSO) .delta. 7.29-7.19 (m, 2H),
6.98 (d, J = 9.1 Hz, 1H), 6.63 (d, J = 3.9 Hz, 1H), 6.29 (d, J =
4.0 Hz, 1H), 4.71-4.56 (m, 1H), 4.05 (t, J = 5.0 Hz, 2H), 3.99-3.79
(m, 2H), 3.78-3.44 (m, 7H), 2.98-2.73 (m, 2H), 2.14 (s, 3H),
1.91-1.72 (m, 2H), 1.29 (d, J = 6.0 Hz, 6H). 460 494.20 6.64 1H NMR
(400 MHz, DMSO) .delta. 7.46 (d, J = 2.1 Hz, 1H), 7.29 (dd, J =
8.4, 2.2 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.60-6.50 (m, 1H), 6.18
(d, J = 4.0 Hz, 1H), 5.05 (t, J = 5.7 Hz, 1H), 4.72-4.58 (m, 1H),
4.48 (d, J = 5.7 Hz, 2H), 4.43-4.14 (m, 1H), 3.97 (t, J = 5.7 Hz,
2H), 3.82- 3.42 (m, 1H), 3.40-2.91 (m, 4H), 2.29 (s, 3H), 2.22-
2.01 (m, 2H), 1.86-1.65 (m, 2H), 1.27 (d, J = 6.0 Hz, 6H). 461
516.50 1.26 462 438.20 2.57 463 518.30 1.51 1H NMR (400 MHz,
Acetone) .delta. 7.99-7.93 (m, 2H), 7.76- 7.70 (m, 2H), 6.61-6.54
(m, 1H), 6.18 (d, J = 4.1 Hz, 1H), 4.52 (d, J = 10.5 Hz, 1H), 4.10
(t, J = 5.9 Hz, 2H), 3.63-3.41 (m, 4H), 3.24 (t, J = 11.3 Hz, 1H),
2.43 (s, 3H), 2.38-2.11 (m, 2H), 1.99-1.84 (m, 2H), 1.33 (s, 9H).
464 548.70 1.46 465 422.30 0.80 466 484.07 2.75 467 562.70 1.67 1H
NMR (400 MHz, DMSO) .delta. 7.47-7.38 (m, 2H), 7.27- 7.19 (m, 1H),
6.46 (d, J = 4.6 Hz, 1H), 4.76-4.62 (m, 1H), 4.46-4.30 (m, 1H),
4.24 (t, J = 5.9 Hz, 2H), 3.87- 3.68 (m, 1H), 3.46-3.25 (m, 3H),
3.19-2.98 (m, 1H), 2.35 (s, 3H), 2.31 (s, 3H), 2.26-1.97 (m, 2H),
1.95- 1.72 (m, 2H), 1.30 (d, J = 6.0 Hz, 6H). 468 479.50 1.47 1H
NMR (400 MHz, CDCl3) .delta. 7.59-7.49 (m, 2H), 7.48- 7.37 (m, 2H),
6.50 (s, 1H), 4.64 (s, 1H), 4.00 (s, 2H), 3.72 (q, J = 7.0 Hz, 2H),
3.48 (d, J = 126.2 Hz, 5H), 2.46 (s, 5H), 2.07 (s, 1H), 1.88 (d, J
= 33.9 Hz, 2H), 1.59 (s, 7H), 1.24 (dd, J = 9.2, 4.8 Hz, 4H). 469
470.50 1.36 470 494.50 1.48 471 488.50 1.65 472 403.15 1.35 473
408.26 2.32 1H NMR (400 MHz, CDCl3) .delta. 7.38 (t, J = 8.2 Hz,
1H), 6.73 (d, J = 8.5 Hz, 1H), 6.68-6.50 (m, 2H), 6.06-5.71 (m,
2H), 4.61-4.50 (m, 1H), 4.46-4.30 (m, 2H), 4.15 (t, J = 6.3 Hz,
2H), 4.11-3.93 (m, 1H), 3.59 (t, J = 5.2 Hz, 1H), 3.50-3.33 (m,
2H), 2.79-2.65 (m, 3H), 2.58-2.39 (m, 2H), 2.36-1.47 (m, 2H), 1.35
(d, J = 6.0 Hz, 6H). 474 497.40 5.17 475 468.60 6.38 476 408.50
1.20 477 440.50 1.28 478 500.24 1.24 479 507.14 2.56 480 576.70
1.69 481 462.50 0.94 482 500.50 1.45 483 498.70 2.94 484 442.70
1.28 485 465.50 1.29 486 498.50 1.39 1H NMR (400 MHz, DMSO) .delta.
7.44 (d, J = 8.0 Hz, 1H), 7.29-7.12 (m, 3H), 6.50 (d, J = 4.6 Hz,
1H), 4.69 (s, 1H), 4.49-4.17 (m, 3H), 3.61-2.94 (m, 5H), 2.53 (s,
3H), 2.30 (s, 3H), 2.24-1.59 (m, 12H). 487 504.50 1.49 488 436.50
1.42 489 514.22 1.27 490 465.50 1.34 1H NMR (400 MHz, DMSO) .delta.
10.67 (s, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.32-7.21 (m, 2H), 6.99
(d, J = 8.3 Hz, 1H), 6.56 (d, J = 4.6 Hz, 1H), 5.76 (s, 1H), 4.14
(s, 1H), 4.10 (s, 2H), 3.53 (s, 1H), 2.26 (s, 1H), 1.88 (td, J =
13.1, 4.4 Hz, 2H), 1.73 (d, J = 13.9 Hz, 2H), 1.08 (s, 6H). 491
470.20 0.96 1H NMR (400 MHz, DMSO) .delta. 7.89 (d, J = 8.0 Hz,
1H), 7.58-7.47 (m, 2H), 6.60 (d, J = 3.4 Hz, 1H), 6.21 (d, J = 3.9
Hz, 1H), 4.29-4.14 (m, 1H), 3.98 (t, J = 5.8 Hz, 2H), 3.55-3.44 (m,
1H), 3.44-3.16 (m, 5H), 2.65 (s, 3H), 2.43-2.14 (m, 2H), 1.94-1.68
(m, 3H), 1.17 (d, J = 6.8 Hz, 6H), 0.65-0.48 (m, 4H). 492 524.20
3.40 493 456.50 1.34 494 492.40 1.86 495 450.30 1.64 496 510.70
1.31 497 394.30 1.08 1H NMR (400 MHz, DMSO) .delta. 7.85-7.39 (m,
3H), 6.65- 6.51 (m, 1H), 6.17-6.05 (m, 1H), 4.51-4.32 (m, 1H), 3.92
(t, J = 5.7 Hz, 2H), 3.55-3.38 (m, 1H), 3.41-3.24 (m, 3H),
3.25-2.97 (m, 2H), 2.42-2.29 (m, 3H), 2.26 (s, 3H), 2.24-2.15 (m,
1H), 2.13-1.51 (m, 3H), 1.17 (d, J = 6.8 Hz, 6H). 498 498.20 2.37
1H NMR (400 MHz, DMSO) .delta. 7.29 (dd, J = 24.6, 8.1 Hz,
4H), 6.58 (d, J = 3.7 Hz, 1H), 6.12 (d, J = 3.9 Hz, 1H), 4.35 (s,
1H), 3.92 (t, J = 5.8 Hz, 2H), 3.42 (s, 1H), 3.10 (s, 1H), 2.68 (s,
2H), 2.27 (s, 3H), 2.07 (s, 1H), 1.75 (s, 2H), 1.07 (s, 6H). 499
450.50 1.18 500 526.50 1.35 1H NMR (400 MHz, DMSO) .delta. 7.39 (d,
J = 8.7 Hz, 2H), 7.28-7.17 (m, 1H), 6.97 (d, J = 8.7 Hz, 2H), 6.49
(d, J = 4.6 Hz, 1H), 4.50-4.04 (m, 3H), 3.78 (d, J = 6.5 Hz, 2H),
3.68-2.91 (m, 5H), 2.30 (s, 3H), 2.19-1.93 (m, 3H), 1.91-1.75 (m,
2H), 0.98 (d, J = 6.7 Hz, 6H). 501 478.50 1.67 1H NMR (400 MHz,
CDCl3) .delta. 7.98-7.93 (m, 2H), 7.63- 7.57 (m, 2H), 7.22 (dd, J =
4.3, 2.1 Hz, 1H), 6.17 (d, J = 4.4 Hz, 1H), 4.69-4.57 (m, 1H), 4.36
(t, J = 5.7 Hz, 2H), 3.57 (t, J = 10.0 Hz, 1H), 3.49-3.39 (m, 1H),
3.34 (t, J = 5.3 Hz, 2H), 3.29 (s, 1H), 2.41 (s, 3H), 2.25 (d, J =
13.3 Hz, 1H), 2.08 (d, J = 16.5 Hz, 1H), 1.95 (t, J = 13.8 Hz, 1H),
1.72 (t, J = 13.9 Hz, 1H), 1.36 (s, 9H). 502 526.30 1.45 503 451.30
1.34 504 435.26 1.19 505 532.50 1.61 506 466.50 1.53 507 410.21
2.09 508 526.50 1.40 509 508.50 1.74 1H NMR (400 MHz, DMSO) .delta.
7.28-7.18 (m, 1H), 7.06- 6.93 (m, 3H), 6.49 (d, J = 4.6 Hz, 1H),
4.49-4.16 (m, 3H), 4.11-4.00 (m, 4H), 3.77-3.39 (m, 1H), 3.38-3.26
(m, 3H), 3.24-2.88 (m, 1H), 2.30 (s, 3H), 2.21-1.95 (m, 2H),
1.93-1.73 (m, 2H), 1.40-1.26 (m, 6H). 510 494.70 1.48 511 450.50
1.67 512 402.25 2.29 513 498.30 2.96 514 527.25 1.38 1H NMR (400
MHz, DMSO) .delta. 7.95 (d, J = 8.0 Hz, 1H), 7.54-7.48 (m, 2H),
6.58 (d, J = 3.4 Hz, 1H), 6.12 (d, J = 3.9 Hz, 1H), 4.36 (d, J =
12.9 Hz, 1H), 3.93 (t, J = 5.6 Hz, 2H), 3.46-3.32 (m, 2H),
3.31-3.27 (m, 2H), 3.25 (s, 3H), 3.12 (t, J = 11.9 Hz, 1H), 2.67
(s, 3H), 2.27 (s, 3H), 2.18 (d, J = 13.7 Hz, 1H), 2.01 (d, J = 14.5
Hz, 1H), 1.85-1.69 (m, 2H). 515 470.50 1.13 1H NMR (400 MHz, DMSO)
.delta. 7.34-7.12 (m, 1H), 7.12- 6.93 (m, 3H), 6.50 (d, J = 4.5 Hz,
1H), 4.52-4.14 (m, 3H), 3.89-3.71 (m, 5H), 3.69-2.94 (m, 5H), 2.31
(s, 3H), 2.24-1.95 (m, 3H), 1.95-1.72 (m, 2H), 0.98 (d, J = 6.7 Hz,
6H). 516 508.70 1.61 517 554.10 1.52 518 466.30 0.99 519 394.22
2.19 520 450.10 2.03 521 422.50 1.30 522 466.50 3.36 1H NMR (400
MHz, DMSO) .delta. 7.47 (d, J = 8.7 Hz, 1H), 7.22-7.13 (m, 2H),
7.09 (d, J = 4.3 Hz, 1H), 6.17 (d, J = 4.3 Hz, 1H), 4.97 (s, 1H),
4.47-4.24 (m, 1H), 4.15 (t, J = 5.9 Hz, 2H), 3.53-3.29 (m, 2H),
3.28-3.18 (m, 2H), 3.16-2.97 (m, 1H), 2.54 (s, 3H), 2.27 (s, 3H),
2.19- 1.93 (m, 2H), 1.88-1.62 (m, 2H), 1.51 (s, 6H), 1.27 (s, 9H).
523 466.40 1.18 524 478.50 1.66 525 480.50 4.06 526 475.12 3.70 527
415.50 1.03 1H NMR (400 MHz, CDCl3) .delta. 7.48 (d, J = 2.1 Hz,
1H), 7.32 (dd, J = 8.4, 2.1 Hz, 1H), 7.22 (dd, J = 4.3, 2.1 Hz,
1H), 6.96 (d, J = 8.6 Hz, 1H), 6.16 (d, J = 4.4 Hz, 1H), 4.61 (dt,
J = 12.2, 6.1 Hz, 1H), 4.56 (s, 1H), 4.35 (t, J = 5.8 Hz, 2H),
3.78-3.40 (m, 2H), 3.34 (s, 1H), 3.34 (t, J = 5.4 Hz, 2H), 2.41 (s,
3H), 2.14 (s, 2H), 1.83 (s, 2H), 1.40 (d, J = 6.1 Hz, 6H). 528
498.30 1.61 529 498.30 1.53 530 430.17 2.69 531 446.22 2.08 1H NMR
(400 MHz, CDCl3) .delta. 7.96 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.4
Hz, 2H), 6.95 (d, J = 4.2 Hz, 1H), 6.02 (d, J = 4.1 Hz, 1H), 5.02
(s, 1H), 4.67-4.48 (m, 1H), 4.35 (t, J = 5.9 Hz, 2H), 3.66-3.36 (m,
2H), 3.36-3.21 (m, 3H), 2.40 (s, 3H), 2.38 (s, 3H), 2.32-2.16 (m,
2H), 2.16-2.00 (m, 1H), 2.00-1.84 (m, 1H), 1.82-1.66 (m, 1H),
0.71-0.57 (m, 4H). 532 471.40 0.88 1H NMR (400 MHz, CDCl3) .delta.
7.32-7.28 (m, 2H), 6.92- 6.79 (m, 1H), 6.55 (d, J = 3.8 Hz, 1H),
6.02 (d, J = 3.9 Hz, 1H), 5.90 (s, 1H), 4.63-4.51 (m, 1H),
4.35-4.19 (m, 2H), 4.15 (t, J = 6.6 Hz, 2H), 4.00-3.56 (m, 2H),
3.41 (t, J = 6.5 Hz, 2H), 2.71 (s, 3H), 2.53-2.44 (m, 2H), 2.22 (s,
3H), 2.18-1.38 (m, 2H), 1.35 (d, J = 6.0 Hz, 6H). 533 493.40 5.60
1H NMR (400 MHz, DMSO) .delta. 7.89 (d, J = 8.0 Hz, 1H), 7.55-7.46
(m, 2H), 5.99 (d, J = 3.5 Hz, 1H), 5.93 (d, J = 3.6 Hz, 1H),
4.39-4.24 (m, 1H), 3.83-3.72 (m, 2H), 3.71-3.56 (m, 2H), 3.55-3.42
(m, 1H), 3.42-3.20 (m, 4H), 3.20-3.05 (m, 1H), 2.64 (s, 3H), 2.24
(s, 3H), 2.19- 2.09 (m, 1H), 2.02-1.91 (m, 1H), 1.79-1.62 (m, 2H),
1.17 (d, J = 6.8 Hz, 6H). 534 512.70 1.11 1H NMR (400 MHz, DMSO)
.delta. 7.05 (d, J = 4.2 Hz, 1H), 7.03-6.94 (m, 3H), 6.18 (d, J =
4.1 Hz, 1H), 4.66-4.53 (m, 1H), 4.50-4.11 (m, 3H), 3.77 (s, 3H),
3.70-3.29 (m, 2H), 3.28-3.02 (m, 3H), 2.31 (s, 3H), 2.27 (s, 3H),
2.18-1.96 (m, 2H), 1.86-1.67 (m, 2H), 1.26 (d, J = 6.0 Hz, 6H). 535
440.60 1.00 536 506.50 1.62 537 464.50 1.59 538 494.70 1.51 539
446.17 2.28 540 486.50 2.17 541 510.17 2.18 1H NMR (400 MHz, DMSO)
.delta. 7.27-7.18 (m, 2H), 6.97 (d, J = 9.1 Hz, 1H), 6.73 (d, J =
4.0 Hz, 1H), 6.21 (d, J = 4.1 Hz, 1H), 4.72-4.54 (m, 1H), 4.46-4.01
(m, 3H), 3.80-3.37 (m, 1H), 3.36-3.26 (m, 3H), 3.20 (s, 3H),
3.17-2.89 (m, 1H), 2.29 (s, 3H), 2.14 (s, 3H), 2.14- 1.96 (m, 2H),
1.84-1.64 (m, 2H), 1.29 (d, J = 6.0 Hz, 6H). 542 460.50 1.36 1H NMR
(400 MHz, DMSO) .delta. 7.28-7.18 (m, 2H), 6.98 (d, J = 9.1 Hz,
1H), 6.60 (d, J = 3.8 Hz, 1H), 6.10 (s, 1H), 5.15-4.76 (m, 1H),
4.68-4.57 (m, 1H), 4.52-4.19 (m, 1H), 4.17-4.00 (m, 1H), 3.90-3.73
(m, 2H), 3.60- 2.96 (m, 4H), 2.30 (s, 3H), 2.26-2.18 (m, 1H), 2.14
(s, 3H), 1.93-1.75 (m, 1H), 1.29 (d, J = 6.0 Hz, 6H). 543 468.20
6.35 1H NMR (400 MHz, CDCl3) .delta. 6.89-6.73 (m, 2H), 6.56 (d, J
= 3.1 Hz, 1H), 5.96 (d, J = 3.9 Hz, 1H), 4.53 (s br, 1H), 4.50-4.41
(m, 1H), 4.02 (s, 2H), 3.89 (s, 3H), 3.60 (d, J = 45.1 Hz, 2H),
3.36 (t, J = 6.0 Hz, 2H), 3.34-3.19 (m, 1H), 2.41 (s, 3H), 2.18 (s,
2H), 1.83 (d, J = 51.6 Hz, 2H), 1.34 (d, J = 6.1 Hz, 6H). 544
484.30 1.59 545 480.50 1.30 546 454.50 1.49 1H NMR (400 MHz, DMSO)
.delta. 7.04-6.91 (m, 3H), 5.99 (d, J = 3.5 Hz, 1H), 5.92 (d, J =
3.6 Hz, 1H), 4.65-4.52 (m, 1H), 4.44-3.95 (m, 1H), 3.82-3.71 (m,
5H), 3.71- 3.55 (m, 2H), 3.43-2.97 (m, 5H), 2.24 (s, 3H), 2.13-
1.92 (m, 2H), 1.78-1.59 (m, 2H), 1.26 (d, J = 6.0 Hz, 6H). 547
480.30 1.17 548 495.06 3.68 549 452.50 1.16 550 452.30 1.32 1H NMR
(400 MHz, DMSO) .delta. 7.06-6.89 (m, 3H), 6.60 (d, J = 3.8 Hz,
1H), 6.15 (d, J = 3.9 Hz, 1H), 4.68-4.47 (m, 1H), 4.46-3.89 (m,
1H), 3.77 (s, 3H), 3.70 (s, 2H), 3.66-2.78 (m, 3H), 2.09 (s, 1H),
1.95-1.52 (m, 4H), 1.26 (d, J = 6.0 Hz, 6H), 1.09 (s, 6H). 551
480.40 1.35 552 486.50 1.40 553 518.20 1.67 1H NMR (400 MHz, CDCl3)
.delta. 7.39 (d, J = 7.6 Hz, 1H), 6.99 (dd, J = 7.6, 1.4 Hz, 1H),
6.97 (d, J = 1.2 Hz, 1H), 6.48 (s, 1H), 4.63 (d, J = 11.1 Hz, 1H),
4.58 (s, 2H), 3.98 (t, J = 5.4 Hz, 2H), 3.86 (s, 3H), 3.75 (t, J =
6.7 Hz, 2H), 3.62 (s, 1H), 3.45 (s, 1H), 3.37-3.24 (m, 2H), 3.18
(s, 1H), 2.58-2.33 (m, 8H), 2.08 (d, J = 12.8 Hz, 1H), 2.01 (d, J =
4.6 Hz, 2H), 1.89 (d, J = 12.4 Hz, 1H). 554 568.40 1.86 555 512.20
1.27 556 493.50 1.52 1H NMR (400 MHz, DMSO) .delta. 7.92 (d, J =
8.3 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.32-7.23 (m, 1H), 6.57 (d,
J = 4.6 Hz, 1H), 4.51-4.32 (m, 1H), 4.18-4.00 (m, 2H), 3.63-3.38
(m, 2H), 3.38-3.15 (m, 2H), 2.29 (s, 1H), 2.01-1.57 (m, 4H), 1.17
(d, J = 6.8 Hz, 6H), 1.12 (s, 3H), 1.04 (s, 3H). 557 526.50 1.38
558 440.20 1.76 559 434.25 2.64 560 484.70 1.71 561 501.50 1.31 1H
NMR (400 MHz, CDCl3) .delta. 7.42-7.35 (m, 2H), 6.92- 6.86 (m, 2H),
6.29 (s, 1H), 4.58 (dt, J = 12.1, 6.1 Hz, 1H), 3.93 (s, 2H), 3.30
(s, 3H), 2.42 (s, 3H), 2.09 (s, 4H), 1.56 (s, 1H), 1.35 (d, J = 6.1
Hz, 7H). 562 454.50 2.85 563 502.10 2.01 564 496.20 1.20 565 482.50
1.46 566 492.50 1.61 567 504.20 1.11 568 454.50 1.44 1H NMR (400
MHz, DMSO) .delta. 10.45 (s, 2H), 8.06 (d, J = 2.4 Hz, 1H), 7.90
(d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 6.79-6.73 (m, 1H),
6.51 (s, 1H), 4.32-4.15 (m, 3H), 3.80-3.59 (m, 4H), 3.57-3.42 (m, J
= 37.6 Hz, 1H), 2.44-2.28 (m, 1H), 2.28-2.10 (m, 4H), 0.54- 0.47
(m, 2H), 0.44-0.36 (m, 2H). 569 483.50 1.12 1H NMR (400 MHz, DMSO)
.delta. 7.34-7.17 (m, 3H), 6.92 (d, J = 9.0 Hz, 1H), 6.49 (d, J =
4.6 Hz, 1H), 4.65 (s, 1H), 4.49-4.10 (m, 3H), 3.73 (s, 2H),
3.69-2.93 (m, 5H), 2.30 (s, 3H), 2.21 (s, 3H), 2.18-1.94 (m, 2H),
1.93- 1.73 (m, 2H), 1.23 (s, 6H). 570 508.70 1.42 1H NMR (400 MHz,
DMSO) .delta. 7.43 (s, 1H), 7.24 (t, J = 8.8 Hz, 3H), 7.02-6.93 (m,
1H), 6.58 (d, J = 3.7 Hz, 1H), 6.14 (d, J = 3.9 Hz, 1H), 4.64 (dt,
J = 12.1, 6.0 Hz, 1H), 3.97 (s, 2H), 3.57 (s, 4H), 3.32 (s, 3H),
3.08 (s, 2H), 2.14 (s, 4H), 1.80 (s, 2H), 1.29 (d, J = 6.0 Hz, 6H).
571 493.30 1.79 572 454.23 2.08 1H NMR (400 MHz, DMSO) .delta. 8.24
(s, 1H), 7.47 (s, 1H), 7.26-7.17 (m, 1H), 6.45 (d, J = 4.6 Hz, 1H),
4.86-4.73 (m, 1H), 4.43-4.29 (m, 1H), 4.29-4.18 (m, 2H), 3.89- 3.72
(m, 1H), 3.45-3.21 (m, 3H), 3.18-3.00 (m, 1H), 2.31 (s, 3H),
2.25-2.13 (m, 4H), 2.07-2.00 (m, 1H), 1.90-1.74 (m, 2H), 1.32 (d, J
= 6.0 Hz, 6H). 573 479.50 1.49 574 506.30 1.50 575 482.50 1.37 576
514.20 1.34 577 436.10 2.08 578 442.70 1.38 1H NMR (400 MHz, DMSO)
.delta. 7.42 (d, J = 7.6 Hz, 1H), 7.05-6.92 (m, 2H), 6.58 (d, J =
3.8 Hz, 1H), 6.12 (d, J = 4.0 Hz, 1H), 5.06 (d, J = 5.2 Hz, 1H),
4.51 (d, J = 4.8 Hz, 2H), 4.34 (s, 1H), 4.06 (q, J = 6.8 Hz, 2H),
3.93 (s, 2H), 3.10 (s, 1H), 2.27 (s, 3H), 2.05 (d, J = 19.9 Hz,
3H), 1.76 (s, 2H), 1.33 (t, J = 6.9 Hz, 3H). 579 452.50 1.17 1H NMR
(400 MHz, DMSO) .delta. 7.26-7.19 (m, 2H), 6.97 (d, J = 9.1 Hz,
1H), 6.57 (d, J = 3.5 Hz, 1H), 6.11 (d, J = 3.9 Hz, 1H), 4.64
(sept, J = 6.0 Hz, 1H), 4.51-4.07 (m, 1H), 3.92 (t, J = 5.8 Hz,
2H), 3.80-3.40 (m, 1H), 3.34- 3.28 (m, 2H), 3.26-3.00 (m, 2H), 2.28
(s, 3H), 2.14 (s, 3H), 2.13-1.98 (m, 2H), 1.73 (t, J = 11.5 Hz,
2H), 1.29 (d, J = 6.0 Hz, 6H). 580 450.50 1.47 581 462.20 1.07 1H
NMR (400 MHz, DMSO) .delta. 7.31 (d, J = 8.8 Hz, 2H), 7.27-7.17 (m,
1H), 6.92 (d, J = 8.9 Hz, 2H), 6.49 (d, J = 4.6 Hz, 1H), 4.36-3.57
(m, 4H), 3.35-3.27 (m, 3H), 3.27-3.16 (m, 5H), 2.30 (s, 3H),
2.20-1.99 (m, 2H), 1.93-1.75 (m, 2H), 1.69-1.49 (m, 6H). 582 489.50
1.20 1H NMR (400 MHz, DMSO) .delta. 7.28-7.22 (m, 2H), 6.95 (d, J =
8.8 Hz, 1H), 6.57 (d, J = 3.8 Hz, 1H), 6.11 (d, J = 3.9 Hz, 1H),
4.54 (t, J = 5.2 Hz, 1H), 4.07 (t, J = 6.2 Hz, 2H), 3.92 (t, J =
5.7 Hz, 2H), 3.58 (dd, J = 11.5, 6.2 Hz, 2H), 2.28 (s, 3H), 2.16
(s, 3H), 2.07 (s, 1H), 1.88 (p, J = 6.2 Hz, 2H), 1.75 (d, J = 10.7
Hz, 2H). 583 466.10 1.22 1H NMR (400 MHz, DMSO) .delta. 12.01 (s,
1H), 8.06 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.75-7.63 (m, 2H),
6.78 (s, 1H), 6.55 (s, 1H), 4.42-4.18 (m, 2H), 4.18-3.85 (m, 2H),
3.70-3.52 (m, 3H), 3.36-3.16 (m, 1H), 2.90-2.63 (m, 3H), 2.37-1.96
(m, 5H), 0.54-0.46 (m, 2H), 0.43- 0.35 (m, 2H). 584 497.50 1.16 585
518.30 1.47 586 440.24 1.87 587 512.50 1.26 588 526.50 1.72 589
526.20 1.33 590 402.15 2.25 1H NMR (400 MHz, DMSO) .delta. 7.47 (d,
J = 8.7 Hz, 1H), 7.22-7.12 (m, 2H), 7.06 (d, J = 4.2 Hz, 1H), 6.17
(d, J = 4.2 Hz, 1H), 4.97 (s, 1H), 4.43-4.25 (m, 1H), 4.19 (t, J =
5.9 Hz, 2H), 3.52-3.29 (m, 2H), 3.27-3.19 (m, 2H), 3.19-2.97 (m,
1H), 2.73 (q, J = 7.4 Hz, 2H), 2.54 (s, 3H), 2.26 (s, 3H),
2.20-1.93 (m, 2H), 1.87-1.61 (m, 2H), 1.51 (s, 6H), 1.04 (t, J =
7.4 Hz, 3H). 591 438.40 1.24 592 478.50 1.67 1H NMR (400 MHz, DMSO)
.delta. 7.47 (d, J = 8.7 Hz, 1H), 7.19-7.12 (m, 2H), 5.99 (d, J =
3.5 Hz, 1H), 5.93 (d, J = 3.6 Hz, 1H), 4.96 (s, 1H), 4.39-4.18 (m,
1H), 3.77 (t, J = 5.8 Hz, 2H), 3.63 (q, J = 11.2 Hz, 2H), 3.49-3.30
(m, 2H), 3.29-3.22 (m, 2H), 3.20-2.99 (m, 1H), 2.54 (s,
3H), 2.24 (s, 3H), 2.16-1.91 (m, 2H), 1.77-1.56 (m, 2H), 1.50 (s,
6H). 593 464.50 1.04 1H NMR (400 MHz, DMSO) .delta. 10.45 (s, 2H),
9.47 (s, 1H), 7.02 (s, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.83 (d, J =
8.1 Hz, 1H), 6.75 (s, 1H), 6.51 (s, 1H), 4.24 (s, 2H), 3.80 (s,
4H), 3.69 (s, 4H), 2.20 (d, J = 40.3 Hz, 4H). 594 410.50 0.95 595
450.50 1.50 596 532.50 1.76 1H NMR (400 MHz, DMSO) .delta. 9.54 (s,
1H), 7.29-7.16 (m, 1H), 7.10 (d, J = 7.9 Hz, 1H), 6.81 (d, J = 1.4
Hz, 1H), 6.76 (dd, J = 7.5, 1.5 Hz, 1H), 6.48 (d, J = 4.6 Hz, 1H),
4.48-4.27 (m, 1H), 4.27-4.17 (m, 2H), 3.67-3.41 (m, 1H), 3.41-3.21
(m, 3H), 3.21-2.93 (m, 1H), 2.30 (s, 3H), 2.19-1.97 (m, 5H),
1.93-1.68 (m, 2H). 597 436.30 1.32 1H NMR (400 MHz, DMSO) .delta.
7.29-7.15 (m, 2H), 6.97 (d, J = 9.1 Hz, 1H), 6.60 (d, J = 3.8 Hz,
1H), 6.14 (d, J = 3.9 Hz, 1H), 4.71-4.54 (m, 1H), 4.42-3.97 (m,
1H), 3.70 (s, 2H), 3.61-3.38 (m, 1H), 3.26-3.15 (m, 1H), 3.06-2.73
(m, 1H), 2.14 (s, 3H), 2.08 (s, 1H), 1.88- 1.56 (m, 4H), 1.29 (d, J
= 6.0 Hz, 6H), 1.09 (s, 6H). 598 464.40 1.53 599 470.24 2.68 600
567.50 1.65 601 424.50 1.35 602 488.30 1.72 603 440.50 1.47 604
458.24 2.34 605 427.30 1.18 606 440.24 1.82 1H NMR (400 MHz, DMSO)
.delta. 7.06 (d, J = 4.2 Hz, 1H), 7.03-6.93 (m, 3H), 6.17 (d, J =
4.2 Hz, 1H), 4.66-4.53 (m, 1H), 4.45-4.11 (m, 3H), 3.77 (s, 3H),
3.69-3.29 (m, 2H), 3.29-2.94 (m, 3H), 2.73 (q, J = 7.4 Hz, 2H),
2.27 (s, 3H), 2.18-1.92 (m, 2H), 1.86-1.67 (m, 2H), 1.26 (d, J =
6.0 Hz, 6H), 1.04 (t, J = 7.4 Hz, 3H). 607 454.20 1.32 608 484.50
1.48 609 454.23 2.08 610 492.30 1.60 611 493.50 1.65 1H NMR (400
MHz, CDCl3) .delta. 7.28-7.22 (m, 3H), 6.83 (d, J = 8.2 Hz, 1H),
6.20 (d, J = 4.5 Hz, 1H), 4.57 (s, 1H), 4.19 (s, 2H), 3.86 (s, 3H),
3.77 (s, 1H), 3.38 (n, 2H), 2.23 (s, 3H), 1.97 (s, 2H), 1.76 (s,
2H), 1.18 (s, 6H), 0.98 (s, 1H). 612 464.50 1.50 613 410.50 1.31 1H
NMR (400 MHz, DMSO) .delta. 7.04-6.88 (m, 3H), 6.57 (d, J = 3.4 Hz,
1H), 6.07 (d, J = 3.9 Hz, 1H), 4.66-4.50 (m, 1H), 4.06-3.81 (m,
2H), 3.77 (s, 3H), 3.63-3.43 (m, 1H), 3.35-3.28 (m, 3H), 3.27-3.09
(m, 1H), 2.34- 2.20 (m, 4H), 2.20-1.64 (m, 3H), 1.42 (d, J = 7.0
Hz, 3H), 1.26 (d, J = 6.0 Hz, 6H). 614 480.40 3.08 615 438.17 1.97
1H NMR (400 MHz, CDCl3) .delta. 7.62 (t, J = 8.1 Hz, 1H), 7.19 (dd,
J = 8.0, 1.6 Hz, 1H), 7.12 (dd, J = 11.9, 1.6 Hz, 1H), 6.29 (s,
1H), 4.57 (s, 1H), 3.92 (d, J = 5.5 Hz, 2H), 3.59 (s, 1H), 3.48 (s,
1H), 3.30 (s, 3H), 2.42 (s, 3H), 2.16 (s, 2H), 2.07 (d, J = 2.8 Hz,
1H), 2.01 (s, 2H), 1.65 (d, J = 0.8 Hz, 6H), 1.55 (s, 1H). 616
472.50 2.50 617 520.50 1.65 618 438.40 1.12 619 470.50 1.51 620
430.20 0.81 621 541.29 1.25 1H NMR (400 MHz, CDCl3) .delta. 7.01
(d, J = 1.9 Hz, 1H), 6.97 (dd, J = 8.2, 1.9 Hz, 1H), 6.88 (d, J =
8.3 Hz, 1H), 6.31 (d, J = 3.9 Hz, 1H), 5.91 (d, J = 3.8 Hz, 1H),
4.61- 4.49 (m, 3H), 4.16 (t, J = 5.1 Hz, 2H), 3.87 (s, 3H), 3.69
(s, 1H), 3.49 (s, 1H), 3.37-3.18 (m, 2H), 2.82 (t, J = 12.9 Hz,
2H), 2.40 (s, 3H), 2.13 (s, 2H), 1.86 (s, 1H), 1.73 (d, J = 12.0
Hz, 3H), 1.50-1.42 (m, 1H), 1.38 (d, J = 6.1 Hz, 6H), 1.34-1.14 (m,
5H), 0.90 (d, J = 6.8 Hz, 6H). 622 551.70 1.61 623 478.30 1.20 624
442.12 2.26 625 400.13 2.49 626 426.21 2.81 627 504.50 1.41 628
476.30 0.92 629 436.50 1.41 1H NMR (400 MHz, DMSO) .delta.
7.57-7.40 (m, 1H), 7.23- 7.09 (m, 2H), 6.60 (d, J = 3.5 Hz, 1H),
6.10 (s, 1H), 5.15- 4.35 (m, 3H), 4.15-4.05 (m, 1H), 3.90-3.67 (m,
2H), 3.61-2.96 (m, 4H), 2.55 (s, 3H), 2.39-2.14 (m, 4H), 1.97-1.68
(m, 1H), 1.51 (s, 6H). 630 468.40 4.54 1H NMR (400 MHz, DMSO)
.delta. 7.34 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 6.47
(s, 1H), 6.15-6.00 (m, 1H), 5.94 (d, J = 3.7 Hz, 1H), 5.28-5.06 (m,
1H), 4.42- 4.17 (m, 1H), 3.86 (t, J = 5.8 Hz, 2H), 3.50-3.30 (m,
2H), 3.29-3.21 (m, 2H), 3.20-2.98 (m, 1H), 2.58-2.45 (m, 1H), 2.25
(s, 3H), 2.18-1.89 (m, 2H), 1.88-1.57 (m, 7H), 1.53-1.12 (m, 5H).
631 490.20 1.72 632 444.20 0.86 633 464.50 1.37 634 507.40 4.29 1H
NMR (400 MHz, CDCl3) .delta. 7.47 (d, J = 2.0 Hz, 1H), 7.32-7.25
(m, 1H), 7.22 (dd, J = 4.4, 2.1 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H),
6.16 (d, J = 4.5 Hz, 1H), 5.94 (s, 1H), 4.53 (s, 1H), 4.35 (t, J =
6.0 Hz, 2H), 3.82-3.38 (m, 2H), 3.34 (t, J = 6.0 Hz, 2H), 3.29 (s,
1H), 2.41 (s, 3H), 2.13 (s, 2H), 1.81 (s, 2H). 635 456.50 1.34 1H
NMR (400 MHz, CDCl3) .delta. 7.49 (d, J = 2.1 Hz, 1H), 7.34 (dd, J
= 8.4, 2.1 Hz, 1H), 7.26 (dd, J = 4.0, 1.7 Hz, 1H), 6.94 (d, J =
8.5 Hz, 1H), 6.19 (d, J = 4.5 Hz, 1H), 4.57 (s, 1H), 4.19 (s, 2H),
4.14 (q, J = 7.0 Hz, 2H), 3.92- 3.09 (m, 3H), 1.96 (s, 2H),
1.83-1.67 (m, 2H), 1.49 (t, J = 7.0 Hz, 3H), 1.18 (s, 6H), 0.96 (s,
1H). 636 498.30 1.61 1H NMR (400 MHz, CDCl3) .delta. 7.48-7.35 (m,
2H), 7.02- 6.87 (m, 2H), 6.53 (d, J = 3.8 Hz, 1H), 5.94 (d, J = 3.9
Hz, 1H), 5.30 (s, 1H), 4.49 (s, 1H), 4.17-3.93 (m, 2H), 3.82 (s,
2H), 3.76-3.13 (m, 5H), 2.39 (s, 3H), 2.28- 1.95 (m, 3H), 1.80 (s,
2H), 1.43-1.25 (m, 6H). 637 466.30 1.18 638 489.50 1.57 639 470.50
1.45 640 510.70 1.37 641 444.50 1.33 1H NMR (400 MHz, DMSO) .delta.
7.29-7.17 (m, 2H), 6.98 (d, J = 9.1 Hz, 1H), 6.60 (d, J = 3.8 Hz,
1H), 6.10 (s, 1H), 5.18-4.74 (m, 1H), 4.73-4.59 (m, 1H), 4.59-4.17
(m, 1H), 4.17-4.03 (m, 1H), 3.90-3.75 (m, 2H), 3.62- 2.95 (m, 4H),
2.30 (s, 3H), 2.25-2.16 (m, 1H), 2.14 (s, 3H), 1.94-1.74 (m, 1H),
1.29 (d, J = 6.0 Hz, 6H). 642 468.40 6.38 643 448.50 1.61 644
524.50 1.46 645 506.50 1.48 646 506.50 1.81 1H NMR (400 MHz, DMSO)
.delta. 7.47 (d, J = 8.7 Hz, 1H), 7.21-7.13 (m, 2H), 6.60-6.51 (m,
1H), 6.19 (d, J = 4.0 Hz, 1H), 4.97 (s, 1H), 4.46-4.23 (m, 1H),
3.97 (t, J = 5.5 Hz, 2H), 3.55-3.22 (m, 4H), 3.20-2.96 (m, 1H),
2.54 (s, 3H), 2.28 (s, 3H), 2.23-1.95 (m, 2H), 1.84- 1.63 (m, 2H),
1.51 (s, 6H). 647 500.50 2.74 648 417.30 1.17 649 552.50 1.54 650
502.10 2.31 1H NMR (400 MHz, Acetone) .delta. 8.05-7.94 (m, 2H),
7.77- 7.68 (m, 2H), 6.62-6.53 (m, 1H), 6.18 (d, J = 4.0 Hz, 1H),
4.51 (d, J = 8.8 Hz, 1H), 4.16-4.03 (m, 2H), 3.62- 3.41 (m, 4H),
3.30-3.16 (m, 1H), 2.75 (ddd, J = 9.6, 6.4, 4.0 Hz, 1H), 2.43 (s,
3H), 2.36-2.11 (m, 2H), 1.92 (t, J = 13.9 Hz, 2H), 1.23 (dd, J =
4.5, 2.4 Hz, 2H), 1.10 (dd, J = 7.9, 2.6 Hz, 2H). 651 535.50 1.41
652 422.10 0.88 653 554.20 1.13 654 514.70 1.41 1H NMR (400 MHz,
DMSO) .delta. 7.41-7.26 (m, 1H), 7.26- 7.13 (m, 2H), 6.60 (d, J =
3.8 Hz, 1H), 6.16 (d, J = 3.9 Hz, 1H), 4.80-4.56 (m, 1H), 4.46-4.12
(m, 1H), 3.70 (s, 2H), 3.64-2.81 (m, 3H), 2.09 (s, 1H), 1.93-1.53
(m, 4H), 1.30 (d, J = 6.0 Hz, 6H), 1.09 (s, 6H). 655 468.20 1.45
656 480.50 1.31 1H NMR (400 MHz, CDCl3) .delta. 8.11 (s, 1H), 7.50
(s, 1H), 6.47 (s, 1H), 4.73-4.59 (m, 2H), 4.03 (d, J = 13.4 Hz,
1H), 3.97 (t, J = 5.8 Hz, 2H), 3.55 (t, J = 12.7 Hz, 1H), 3.39-3.16
(m, 3H), 2.56-2.41 (m, 5H), 2.25 (s, 3H), 2.07 (d, J = 14.2 Hz,
1H), 1.90 (d, J = 14.5 Hz, 1H), 1.68 (s, 1H), 1.39 (d, J = 6.0 Hz,
6H). 657 485.40 1.66 1H NMR (400 MHz, CDCl3) .delta. 7.43 (d, J =
7.9 Hz, 1H), 7.30 (dd, J = 7.9, 1.6 Hz, 1H), 7.24 (s, 1H), 6.53 (d,
J = 3.2 Hz, 1H), 5.94 (d, J = 3.9 Hz, 1H), 5.05 (dd, J = 8.4, 5.9
Hz, 2H), 4.84 (dd, J = 7.4, 5.9 Hz, 2H), 4.61-4.41 (m, J = 15.8,
7.9 Hz, 2H), 3.99 (s br, 2H), 3.55 (d br, J = 35.9 Hz, 2H), 3.34
(t, J = 6.0 Hz, 2H), 3.27 (s, 1H), 2.36 (d, J = 20.1 Hz, 3H),
2.26-2.13 (m, 4H), 2.15-2.00 (m, 1H), 1.91 (s, 1H), 1.72 (s, 1H).
658 448.10 1.26 659 454.50 1.71 660 490.50 1.10 661 480.50 1.69 662
506.50 1.55 1H NMR (400 MHz, DMSO) .delta. 7.34-7.17 (m, 3H), 6.97
(d, J = 8.4 Hz, 1H), 6.49 (d, J = 4.6 Hz, 1H), 4.51-4.09 (m, 3H),
3.82 (s, 3H), 3.69-2.96 (m, 5H), 2.30 (s, 3H), 2.17 (s, 3H),
2.15-1.97 (m, 2H), 1.93-1.74 (m, 2H). 663 450.30 1.49 664 520.50
1.51 665 458.24 2.37 666 515.50 2.49 1H NMR (400 MHz, DMSO) .delta.
7.05 (d, J = 1.8 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.92 (dd, J =
8.1, 1.9 Hz, 1H), 6.60 (d, J = 3.7 Hz, 1H), 6.16 (d, J = 3.9 Hz,
1H), 4.50- 4.08 (m, 1H), 3.77 (s, 3H), 3.70 (s, 2H), 3.63-2.76 (m,
3H), 2.09 (s, 1H), 1.92-1.57 (m, 4H), 1.29 (s, 9H), 1.09 (s, 6H).
667 494.40 1.45 1H NMR (400 MHz, CDCl3) .delta. 7.15 (d, J = 7.7
Hz, 1H), 6.95-6.89 (m, 2H), 6.29 (s, 1H), 4.60 (s, 1H), 3.92 (t, J
= 5.7 Hz, 2H), 3.86 (d, J = 11.1 Hz, 3H), 3.67 (s, 1H), 3.46 (s,
1H), 3.30 (s, 3H), 2.64 (q, J = 7.5 Hz, 2H), 2.42 (s, 3H), 2.08 (d,
J = 57.9 Hz, 4H), 1.60 (s, 1H), 1.19 (t, J = 7.5 Hz, 3H). 668
454.50 1.52 669 539.50 1.35 670 458.13 1.91 671 569.20 1.76 672
468.70 1.54 673 447.30 2.07 1H NMR (400 MHz, DMSO) .delta. 7.51 (d,
J = 2.1 Hz, 1H), 7.38 (dd, J = 8.5, 2.1 Hz, 1H), 7.20 (d, J = 8.7
Hz, 1H), 7.11 (d, J = 4.3 Hz, 1H), 6.19 (d, J = 4.2 Hz, 1H), 4.79-
4.69 (m, 1H), 4.44-4.13 (m, 3H), 3.61-3.29 (m, 3H), 3.27-2.98 (m,
3H), 2.27 (s, 3H), 2.23-1.90 (m, 2H), 1.85-1.71 (m, 2H), 1.31 (d, J
= 6.0 Hz, 6H), 1.05 (d, J = 6.8 Hz, 6H). 674 472.50 1.56 675 464.50
1.39 676 532.50 1.73 677 480.30 1.71 678 432.18 1.94 679 395.18
1.56 680 514.70 1.42 681 454.23 1.81 682 486.30 1.40 1H NMR (400
MHz, DMSO) .delta. 7.48 (d, J = 8.6 Hz, 1H), 7.22-7.14 (m, 2H),
6.64 (d, J = 3.5 Hz, 1H), 6.30 (d, J = 4.0 Hz, 1H), 4.97 (s, 1H),
4.08-4.00 (m, 2H), 3.98- 3.42 (m, 9H), 2.98-2.71 (m, 2H), 2.55 (s,
3H), 1.93- 1.71 (m, 2H), 1.51 (s, 6H). 683 494.20 4.87 684 450.30
1.17 685 476.50 1.36 1H NMR (400 MHz, DMSO) .delta. 7.26 (dd, J =
4.5, 2.2 Hz, 1H), 7.02 (d, J = 1.5 Hz, 1H), 7.01-6.95 (m, 2H), 6.56
(d, J = 4.6 Hz, 1H), 4.33 (s, 1H), 4.10 (s, 2H), 4.01 (t, J = 6.7
Hz, 2H), 3.78 (s, 3H), 3.57 (s, 2H), 3.27 (s, 1H), 2.26 (s, 1H),
1.95-1.83 (m, 2H), 1.83-1.66 (m, 3H), 1.62 (q, J = 6.7 Hz, 2H),
1.08 (s, 6H), 0.93 (d, J = 6.6 Hz, 6H). 686 536.40 1.88 1H NMR (400
MHz, CDCl3) .delta. 7.40 (d, J = 7.5 Hz, 1H), 7.03-6.95 (m, 2H),
6.49 (s, 1H), 4.73 (s, 2H), 4.64 (d, J = 10.9 Hz, 1H), 3.98 (t, J =
5.5 Hz, 2H), 3.95-3.82 (m, 5H), 3.60 (s, 1H), 3.47 (d, J = 11.9 Hz,
1H), 3.37-3.26 (m, 2H), 3.20 (d, J = 11.6 Hz, 1H), 2.58-2.31 (m,
5H), 2.08 (d, J = 13.6 Hz, 1H), 2.02-1.99 (m, 2H), 1.90 (d, J =
13.3 Hz, 1H), 1.62 (s, 1H). 687 553.80 1.85 1H NMR (400 MHz, DMSO)
.delta. 7.34 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H),
7.25-7.20 (m, 1H), 6.50 (d, J = 4.6 Hz, 1H), 4.49-4.29 (m, 2H),
4.24 (t, J = 5.7 Hz, 2H), 3.54-3.24 (m, 4H), 3.20-2.97 (m, 1H),
2.68 (s, 2H), 2.30 (s, 3H), 2.25-1.73 (m, 4H), 1.07 (s, 6H). 688
478.50 1.38 689 512.70 1.33 1H NMR (400 MHz, DMSO) .delta.
7.02-6.93 (m, 3H), 6.60 (d, J = 3.4 Hz, 1H), 6.20 (d, J = 3.9 Hz,
1H), 4.67-4.51 (m, 1H), 4.24-3.91 (m, 3H), 3.77 (s, 3H), 3.69-3.12
(m, 5H), 2.38-2.11 (m, 2H), 1.93-1.68 (m, 3H), 1.26 (d, J = 6.0 Hz,
6H), 0.64-0.49 (m, 4H). 690 492.50 6.09 691 425.30 0.91 1H NMR (400
MHz, CDCl3) .delta. 7.24-7.14 (m, 2H), 6.99 (t, J = 8.4 Hz, 1H),
6.53 (d, J = 3.8 Hz, 1H), 5.91 (d, J = 3.5 Hz, 1H), 4.59 (dt, J =
12.1, 6.1 Hz, 1H), 4.09 (d, J = 8.9 Hz, 1H), 3.78-3.17 (m, 5H),
2.28-1.86 (m, 2H), 1.63 (s, 3H), 1.38 (d, J = 6.1 Hz, 6H), 1.28 (d,
J = 4.8 Hz, 3H), 0.78 (s, 1H). 692 454.50 1.52 693 514.50 1.53 694
458.20 1.00 695 496.70 1.58
696 402.25 2.15 1H NMR (400 MHz, DMSO) .delta. 7.54 (d, J = 2.0 Hz,
1H), 7.43 (dd, J = 8.5, 2.1 Hz, 1H), 7.25-7.21 (m, 1H), 7.20 (d, J
= 8.6 Hz, 1H), 6.49 (d, J = 4.6 Hz, 1H), 4.47-4.16 (m, 3H), 3.90
(s, 3H), 3.69-2.92 (m, 5H), 2.30 (s, 3H), 2.19-1.95 (m, 2H),
1.95-1.74 (m, 2H). 697 470.50 1.47 698 432.13 2.12 699 454.28 2.12
700 470.50 1.31 701 480.50 1.19 702 524.50 1.33 703 428.16 1.66 1H
NMR (400 MHz, DMSO) .delta. 7.27-7.19 (m, 2H), 7.05 (d, J = 4.2 Hz,
1H), 6.97 (d, J = 9.2 Hz, 1H), 6.16 (d, J = 4.2 Hz, 1H), 4.64
(hept, J = 5.9 Hz, 1H), 4.50-4.01 (m, 3H), 3.74-3.28 (m, 2H),
3.28-2.90 (m, 3H), 2.73 (q, J = 7.4 Hz, 2H), 2.27 (s, 3H), 2.14 (s,
3H), 2.12-1.95 (m, 2H), 1.85-1.63 (m, 2H), 1.29 (d, J = 6.0 Hz,
6H), 1.04 (t, J = 7.4 Hz, 3H). 704 438.40 1.48 1H NMR (400 MHz,
CDCl3) .delta. 7.26 (dd, J = 5.4, 1.8 Hz, 2H), 6.97 (d, J = 1.6 Hz,
1H), 6.92 (dd, J = 7.9, 1.6 Hz, 1H), 6.19 (d, J = 4.5 Hz, 1H), 4.64
(s, 1H), 4.34-4.04 (m, 2H), 3.88 (s, 3H), 3.77 (s, 1H), 3.57 (s,
1H), 3.27 (s, 1H), 2.01 (s, 1H), 1.93-1.62 (m, 3H), 1.37 (s, 9H),
1.18 (s, 6H), 0.98 (s, 1H). 705 506.50 1.80 706 516.30 2.02 707
497.20 1.18 1H NMR (400 MHz, DMSO) .delta. 8.02 (s, 1H), 7.86 (d, J
= 8.3 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 6.61 (d, J = 3.9 Hz, 1H),
6.21 (d, J = 3.9 Hz, 1H), 4.29-4.12 (m, 1H), 3.98 (t, J = 5.8 Hz,
2H), 3.50-3.17 (m, 5H), 2.43-2.09 (m, 3H), 1.99-1.68 (m, 3H),
0.65-0.35 (m, 8H). 708 523.40 3.83 709 466.50 1.22 710 416.50 1.35
711 482.70 1.35 712 479.20 1.14 1H NMR (400 MHz, CDCl3) .delta.
7.27 (dd, J = 8.6, 2.3 Hz, 2H), 6.83 (d, J = 8.1 Hz, 1H), 6.48 (s,
1H), 4.60 (s, 1H), 3.98 (t, J = 5.7 Hz, 2H), 3.85 (s, 3H), 3.72
(dd, J = 13.8, 7.0 Hz, 2H), 3.30 (s, 5H), 2.42 (d, J = 14.8 Hz,
5H), 2.23 (s, 3H), 2.15-1.82 (m, 2H), 1.58 (s, 2H), 1.25 (dd, J =
8.8, 5.2 Hz, 4H). 713 456.40 1.59 714 436.30 1.24 715 436.30 1.09
1H NMR (400 MHz, DMSO) .delta. 7.83 (d, J = 8.4 Hz, 2H), 7.66 (d, J
= 8.4 Hz, 2H), 7.55 (s, 1H), 6.58 (d, J = 3.2 Hz, 1H), 6.12 (d, J =
3.9 Hz, 1H), 4.36 (d, J = 12.8 Hz, 1H), 3.93 (t, J = 5.7 Hz, 2H),
3.46-3.33 (m, 2H), 3.31- 3.24 (m, 2H), 3.19-3.05 (m, 1H), 2.44 (s,
3H), 2.27 (s, 3H), 2.18 (d, J = 12.9 Hz, 1H), 2.02 (d, J = 13.9 Hz,
1H), 1.87-1.70 (m, 2H). 716 471.50 1.07 717 500.20 1.28 718 436.30
0.98 1H NMR (400 MHz, CDCl3) .delta. 7.02 (d, J = 1.8 Hz, 1H), 6.98
(dd, J = 8.2, 1.9 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.66 (d, J =
3.8 Hz, 1H), 6.15 (d, J = 3.9 Hz, 1H), 4.57 (dt, J = 12.1, 6.0 Hz,
1H), 4.40-4.30 (m, 1H), 4.19 (dd, J = 11.9, 3.8 Hz, 1H), 3.88 (s,
3H), 4.03-3.56 (m, 5H), 3.40 (s, 2H), 3.28 (dd, J = 13.5, 5.2 Hz,
1H), 2.37 (s, J = 20.5 Hz, 3H), 2.34 (s, 1H), 2.04 (s, 1H), 1.86
(s, 2H), 1.38 (d, J = 6.1 Hz, 6H). 719 496.40 2.65 720 440.50 1.36
1H NMR (400 MHz, DMSO) .delta. 7.34 (t, J = 8.2 Hz, 1H), 6.90-6.79
(m, 2H), 6.59 (d, J = 3.8 Hz, 1H), 6.09 (d, J = 3.6 Hz, 1H),
4.79-4.53 (m, 1H), 4.48-4.21 (m, 1H), 3.70 (s, 2H), 3.61-3.42 (m,
1H), 3.28-2.84 (m, 2H), 2.13 (s, 1H), 1.87-1.55 (m, 4H), 1.27 (d, J
= 6.0 Hz, 6H), 1.11 (s, 3H), 1.06 (s, 3H). 721 468.40 1.49 H NMR
(400.0 MHz, CDCl3) .delta. 7.02-6.97 (m, 2H), 6.87 (d, J = 8.2 Hz,
1H), 6.53 (s, 1H), 5.99 (s, 1H), 4.54 (qn, J = 6.1 Hz, 1H), 4.04
(s, 2H), 3.88 (s, 3H), 3.34 (s, 2H), 2.92 (d, J = 5.3 Hz, 4H), 2.40
(s, 3H), 2.14 (s, 2H), 1.82 (s, 2H) and 1.41-1.35 (m, 6H) ppm. 722
516.50 1.28 1H NMR (400 MHz, DMSO) .delta. 7.28-7.19 (m, 2H), 7.01-
6.93 (m, 1H), 6.62 (d, J = 3.6 Hz, 1H), 6.22 (d, J = 3.0 Hz, 1H),
4.64 (dt, J = 12.1, 6.1 Hz, 1H), 4.01 (s, 2H), 3.41 (d, J = 37.7
Hz, 11H), 3.14 (d, J = 20.8 Hz, 3H), 2.87 (s, 3H), 2.14 (s, 4H),
1.86 (s, 2H), 1.29 (d, J = 6.0 Hz, 6H). 723 521.50 1.87 1H NMR (400
MHz, DMSO) .delta. 7.09-6.96 (m, 3H), 6.65 (d, J = 3.5 Hz, 1H),
6.33 (d, J = 3.3 Hz, 1H), 4.94-4.72 (m, 1H), 4.70-4.54 (m, 1H),
4.07-3.82 (m, 2H), 3.77 (s, 3H), 3.75-3.46 (m, 2H), 3.48-3.29 (m,
3H), 3.24- 3.13 (m, 1H), 2.32 (s, 3H), 2.17-1.85 (m, 2H), 1.27 (d,
J = 6.0 Hz, 6H). 724 484.60 2.73 725 501.50 1.47 726 518.30 1.58
727 480.50 4.03 728 526.25 1.59 729 466.12 2.80 730 452.20 1.23 731
433.70 0.92 732 478.17 2.53 733 490.20 1.00 734 428.16 2.06 735
478.20 1.03 736 470.50 2.46 737 476.50 0.98 1H NMR (400 MHz, CDCl3)
.delta. 7.26-7.22 (m, 1H), 7.22- 7.02 (m, 1H), 6.79-6.70 (m, 2H),
6.17 (s, 1H), 4.70 (d, J = 11.6 Hz, 1H), 4.30-4.07 (m, 2H), 3.81
(s, 3H), 3.56- 3.45 (m, 1H), 3.45-3.34 (m, 1H), 3.31-3.15 (m, 1H),
2.44-2.23 (m, 3H), 2.02-1.93 (m, 1H), 1.89-1.71 (m, 2H), 1.71-1.60
(m, 1H), 1.21 (s, 3H), 1.13 (s, 3H), 0.96 (s, 1H). 738 464.50 1.49
739 596.50 1.71 740 462.50 1.71 1H NMR (400 MHz, CDCl3) .delta.
7.06 (d, J = 1.8 Hz, 1H), 7.00 (dd, J = 8.2, 1.9 Hz, 1H), 6.88 (d,
J = 8.3 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 6.11 (d, J = 4.0 Hz,
1H), 4.57 (dt, J = 12.2, 6.1 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H),
4.09- 4.03 (m, 2H), 3.97-3.91 (m, 2H), 3.88 (s, 3H), 3.85- 3.71 (m,
3H), 2.97 (s, 2H), 1.91-1.82 (m, 2H), 1.77- 1.66 (m, 1H), 1.38 (d,
J = 6.1 Hz, 6H), 1.32 (t, J = 7.1 Hz, 3H). 741 524.40 1.96 742
491.50 1.56 1H NMR (400 MHz, DMSO) .delta. 7.52 (d, J = 8.3 Hz,
2H), 7.36 (d, J = 8.3 Hz, 2H), 6.60-6.53 (m, 1H), 6.19 (d, J = 4.0
Hz, 1H), 5.07 (s, 1H), 4.44-4.24 (m, 1H), 3.97 (t, J = 5.7 Hz, 2H),
3.52-3.22 (m, 4H), 3.22-2.98 (m, 1H), 2.28 (s, 3H), 2.23-1.95 (m,
2H), 1.85-1.67 (m, 2H), 1.43 (s, 6H). 743 486.50 1.14 744 454.70
1.36 745 466.50 3.47 1H NMR (400 MHz, DMSO) .delta. 7.48 (d, J =
8.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.26-7.14 (m, 1H), 6.47 (d,
J = 4.6 Hz, 1H), 4.47-4.28 (m, 1H), 4.24 (t, J = 5.9 Hz, 2H), 3.86
(s, 3H), 3.81-3.67 (m, 1H), 3.42-3.35 (m, 1H), 3.35-3.29 (m, 2H),
3.21-2.99 (m, 1H), 2.37 (s, 3H), 2.31 (s, 3H), 2.24-2.12 (m, 1H),
2.12-1.98 (m, 1H), 1.98-1.70 (m, 2H). 746 451.30 1.28 747 484.50
1.54 1H NMR (400 MHz, DMSO) .delta. 7.87-7.60 (m, 1H), 7.60- 7.33
(m, 1H), 7.33-7.06 (m, 2H), 6.54 (d, J = 4.8 Hz, 1H), 5.35 (s, 1H),
4.30-4.06 (m, 1H), 3.62-3.03 (m, 5H), 2.46 (s, 3H), 2.24-1.77 (m,
4H), 1.62 (s, 6H), 1.49 (s, 6H). 748 510.70 1.65 749 468.30 1.91
750 464.30 1.11 1H NMR (400 MHz, DMSO) .delta. 7.89 (d, J = 8.0 Hz,
1H), 7.59-7.45 (m, 2H), 6.58 (d, J = 3.7 Hz, 1H), 6.12 (d, J = 3.9
Hz, 1H), 4.45-4.27 (m, 1H), 3.93 (t, J = 5.8 Hz, 2H), 3.57-3.43 (m,
1H), 3.43-3.01 (m, 5H), 2.65 (s, 3H), 2.27 (s, 3H), 2.23-1.65 (m,
4H), 1.17 (d, J = 6.8 Hz, 6H). 751 454.30 1.47 1H NMR (400 MHz,
CD.sub.3CN) d 7.12 (d, J = 1.8 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H),
7.01 (dd, J = 8.0, 1.8 Hz, 1H), 6.60 (d, J = 3.4 Hz, 1H), 6.07 (d,
J = 3.7 Hz, 1H), 4.42 (s, 1H), 4.12 (dd, J = 1.6, 0.9 Hz, 1H), 4.01
(t, J = 6.0 Hz, 2H), 3.85 (s, 3H), 3.79 (d, J = 1.7 Hz, 1H), 3.67-
3.40 (m, 2H), 3.36 (t, J = 5.6 Hz, 2H), 3.20 (s, 1H), 2.36 (s, 3H),
2.18 (s, 2H), 2.00 (d, J = 0.7 Hz, 3H), 1.83 (s, 2H). [h6] 752
582.20 1.66
Assays for Detecting and Measuring NaV Inhibition Properties of
Compound
[0486] E-VIPR Optical Membrane Potential Assay Method with
Electrical Stimulation
[0487] Sodium channels are voltage-dependent proteins that can be
activated by inducing membrane voltage changes by applying electric
fields. The electrical stimulation instrument and methods of use
are described in Ion Channel Assay Methods PCT/US01/21652, herein
incorporated by reference and are referred to as E-VIPR. The
instrument comprises a microtiter plate handler, an optical system
for exciting the coumarin dye while simultaneously recording the
coumarin and oxonol emissions, a waveform generator, a current- or
voltage-controlled amplifier, and a device for inserting electrodes
in well. Under integrated computer control, this instrument passes
user-programmed electrical stimulus protocols to cells within the
wells of the microtiter plate.
[0488] 24 hours before the assay on E-VIPR, HEK cells expressing
human NaV subtype, like NaV 1.7, are seeded in 384-well poly-lysine
coated plates at 15,000-20,000 cells per well. Other subtypes are
performed in an analogous mode in a cell line expressing the NaV of
interest. HEK cells are grown in media (exact composition is
specific to each cell type and NaV subtype) supplemented with 10%
FBS (Fetal Bovine Serum, qualified; GibcoBRL #16140-071) and 1%
Pen-Strep (Penicillin-Streptomycin; GibcoBRL #15140-122). Cells are
grown in vented cap flasks, in 90% humidity and 10% CO.sub.2, to
100% confluence. They are usually split by trypsinization 1:10 or
1:20, depending on scheduling needs, and grown for 2-3 days before
the next split.
Reagents and Solutions
[0489] 100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO
[0490] Compound Plates: 384-well round bottom plate, e.g. Corning
384-well Polypropylene Round Bottom #3656
[0491] Cell Plates: 384-well tissue culture treated plate, e.g.
Greiner #781091-1B
[0492] 10 mM DiSBAC.sub.6(3) (Aurora #00-100-010) in dry DMSO
[0493] 10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO
[0494] 200 mM ABSC1 in H.sub.20
[0495] Bath1 buffer. Glucose 10 mM (1.8 g/L), Magnesium Chloride
(Anhydrous), 1 mM (0.095 g/L), Calcium Chloride, 2 mM (0.222 g/L),
HEPES 10 mM (2.38 g/L), Potassium Chloride, 4.5 mM (0.335 g/L),
Sodium Chloride 160 mM (9.35 g/L).
[0496] Hexyl Dye Solution: Bath1 Buffer+0.5% .beta.-cyclodextrin
(make this prior to use, Sigma #C4767), 8 .mu.M CC2-DMPE+2.5 .mu.M
DiSBAC.sub.6(3). To make the solution Add volume of 10% Pluronic
F127 stock equal to volumes of CC2-DMPE+DiSBAC.sub.6(3). The order
of preparation is first mix Pluronic and CC2-DMPE, then add
DiSBAC.sub.6(3) while vortexing, then add
Bath1+.beta.-Cyclodextrin.
Assay Protocol
[0497] 1) Pre-spot compounds (in neat DMSO) into compound plates.
Vehicle control (neat DMSO), the positive control (20 mM DMSO stock
tetracaine, 125 .mu.M final in assay) and test compounds are added
to each well at 160.times. desired final concentration in neat
DMSO. Final compound plate volume will be 80 .mu.L (80-fold
intermediate dilution from 1 .mu.L DMSO spot; 160-fold final
dilution after transfer to cell plate). Final DMSO concentration
for all wells in assay is 0.625%.
[0498] 2) Prepare Hexyl Dye Solution.
[0499] 3) Prepare cell plates. On the day of the assay, medium is
aspirated and cells are washed three times with 100 .mu.L of Bath1
Solution, maintaining 25 .mu.L residual volume in each well.
[0500] 4) Dispense 25 .mu.L per well of Hexyl Dye Solution into
cell plates. Incubate for 20-35 minutes at room temp or ambient
conditions.
[0501] 5) Dispense 80 .mu.L per well of Bath1 into compound plates.
Acid Yellow-17 (1 mM) is added and Potassium Chloride can be
altered from 4.5 to 20 mM depending on the NaV subtype and assay
sensitivity.
[0502] 6) Wash cell plates three times with 100 .mu.L per well of
Bath1, leaving 25 .mu.L of residual volume. Then transfer 25 uL per
well from Compound Plates to Cell Plates. Incubate for 20-35
minutes at room temp/ambient condition
[0503] 7) Read Plate on E-VIPR. Use the current-controlled
amplifier to deliver stimulation wave pulses for typically 9
seconds and a scan rate of 400 Hz. A pre-stimulus recording is
performed for 0.5 seconds to obtain the un-stimulated intensities
baseline. The stimulatory waveform is applied for 9 seconds
followed by 0.5 seconds of post-stimulation recording to examine
the relaxation to the resting state. The stimulatory waveform of
the electrical stimulation is specific for each cell type and can
vary the magnitude, duration and frequency of the applied current
to provide an optimal assay signal.
Data Analysis
[0504] Data are analyzed and reported as normalized ratios of
background-subtracted emission intensities measured in the 460 nm
and 580 nm channels. Background intensities are then subtracted
from each assay channel. Background intensities are obtained by
measuring the emission intensities during the same time periods
from identically treated assay wells in which there are no cells.
The response as a function of time is then reported as the ratios
obtained using the following formula:
R ( t ) = ( intensity 460 nm - background 460 nm ) ( intensity 580
nm - background 580 nm ) ##EQU00001##
[0505] The data is further reduced by calculating the initial
(R.sub.1) and final (R.sub.f) ratios. These are the average ratio
values during part or all of the pre-stimulation period, and during
sample points during the stimulation period. The response to the
stimulus R.quadrature..quadrature.=R.sub.f/R.sub.i is then
calculated and reported as a function of time.
[0506] Control responses are obtained by performing assays in the
presence of a compound with the desired properties (positive
control), such as tetracaine, and in the absence of pharmacological
agents (negative control). Responses to the negative (N) and
positive (P) controls are calculated as above. The compound
antagonist activity A is defined as:
A = R - P N - P * 100. ##EQU00002##
where R is the ratio response of the test compound
Electrophysiology Assays for NaV Activity and Inhibition of Test
Compounds
[0507] Patch clamp electrophysiology was used to assess the
efficacy and selectivity of sodium channel blockers in dorsal root
ganglion neurons. Rat neurons were isolated from the dorsal root
ganglions and maintained in culture for 2 to 10 days in the
presence of NGF (50 ng/ml) (culture media consisted of NeurobasalA
supplemented with B27, glutamine and antibiotics). Small diameter
neurons (nociceptors, 8-12 .mu.m in diameter) have been visually
identified and probed with fine tip glass electrodes connected to
an amplifier (Axon Instruments). The "voltage clamp" mode has been
used to assess the compound's IC50 holding the cells at -60 mV. In
addition, the "current clamp" mode has been employed to test the
efficacy of the compounds in blocking action potential generation
in response to current injections. The results of these experiments
have contributed to the definition of the efficacy profile of the
compounds.
IonWorks Assays.
[0508] Sodium currents were recorded using the automated patch
clamp system, IonWorks (Molecular Devices Corporation, Inc.). Cells
expressing Nav subtypes are harvested from tissue culture and
placed in suspension at 0.5-4 million cells per mL Bath1. The
IonWorks instrument measures changes in sodium currents in response
to applied voltage clamp similarly to the traditional patch clamp
assay, except in a 384-well format. Using the IonWorks,
dose-response relationships were determined in voltage clamp mode
by depolarizing the cell from the experiment specific holding
potential to a test potential of about 0 mV before and following
addition of the test compound. The influence of the compound on
currents are measured at the test potential.
1-Benzazepin-2-One Binding Assay
[0509] The sodium channel inhibiting properties of the compounds of
the invention can also be determined by assay methods described in
Williams, B. S. et al., "Characterization of a New Class of Potent
Inhibitors of the Voltage-Gated Sodium Channel NaV 1.7,"
Biochemistry, 2007, 46, 14693-14703, the entire contents of which
are incorporated herein by reference.
[0510] The exemplified compounds of Table 1 herein are active
against one or more sodium channels as measured using the assays
described herein above as presented in Table 3.
TABLE-US-00004 TABLE 3 IC50: +++ <= 2.0 .mu.M < ++ <= 5.0
.mu.M < + Cmpd. No. Binned Activity Data 1 ++ 2 +++ 3 + 4 + 5
+++ 6 +++ 7 +++ 8 +++ 9 +++ 10 +++ 11 +++ 12 +++ 13 +++ 14 +++ 15
+++ 16 ++ 17 +++ 18 +++ 19 +++ 20 +++ 21 + 22 + 23 +++ 24 ++ 25 +
26 ++ 27 +++ 28 +++ 29 +++ 30 + 31 ++ 32 +++ 33 +++ 34 +++ 35 +++
36 + 37 +++ 38 ++ 39 +++ 40 +++ 41 +++ 42 + 43 + 44 ++ 45 +++ 46
+++ 47 +++ 48 +++ 49 +++ 50 +++ 51 +++ 52 + 53 +++ 54 ++ 55 +++ 56
+++ 57 +++ 58 +++ 59 +++ 60 + 61 ++ 62 +++ 63 + 64 +++ 65 +++ 66
+++ 67 + 68 ++ 69 +++ 70 +++ 71 +++ 72 +++ 73 ++ 74 ++ 75 +++ 76 +
77 +++ 78 ++ 79 + 80 +++ 81 +++ 82 +++ 83 +++ 84 +++ 85 +++ 86 + 87
+++ 88 ++ 89 +++ 90 +++ 91 +++ 92 +++ 93 +++ 94 ++ 95 +++ 96 +++ 97
+++ 98 +++ 99 ++ 100 +++ 101 +++ 102 +++ 103 +++ 104 + 105 +++ 106
+++ 107 +++ 108 ++ 109 + 110 +++ 111 + 112 +++ 113 +++ 114 +++ 115
+++ 116 + 117 +++ 118 +++ 119 +++ 120 ++ 121 + 122 +++ 123 +++ 124
+++ 125 ++ 126 ++ 127 +++ 128 +++ 129 +++ 130 ++ 131 +++ 132 +++
133 +++ 134 +++ 135 +++ 136 +++ 137 +++ 138 +++ 139 + 140 +++ 141
+++ 142 +++ 143 +++ 144 +++ 145 + 146 +++ 147 ++ 148 +++ 149 +++
150 +++ 151 +++ 152 +++ 153 + 154 ++ 155 + 156 +++ 157 + 158 +++
159 ++ 160 +++ 161 +++ 162 +++ 163 + 164 +++ 165 +++ 166 + 167 +++
168 +++ 169 +++ 170 + 171 +++ 172 +++ 173 +++ 174 +++ 175 +++ 176
++ 177 + 178 + 179 ++ 180 +++ 181 +++ 182 +++ 183 +++ 184 ++ 185
+++ 186 +++ 187 +++ 188 +++ 189 +++ 190 +++ 191 +++ 192 + 193 +++
194 +++ 195 + 196 + 197 +++ 198 +++ 199 +++ 200 +++ 201 +++ 202 ++
203 +++ 204 + 205 + 206 +++ 207 +++ 208 +++ 209 +++ 210 ++ 211 +++
212 +++ 213 +++ 214 +++ 215 +++ 216 +++ 217 +++ 218 + 219 +++ 220
++ 221 + 222 +++ 223 ++ 224 + 225 + 226 +++ 227 + 228 +++ 229 ++
230 +++ 231 + 232 +++ 233 +++ 234 + 235 +++ 236 +++ 237 +++ 238 +++
239 + 240 +++ 241 + 242 +++ 243 +++ 244 +++ 245 +++
246 + 247 +++ 248 +++ 249 +++ 250 +++ 251 +++ 252 + 253 +++ 254 +++
255 +++ 256 + 257 +++ 258 +++ 259 +++ 260 ++ 261 +++ 262 +++ 263
+++ 264 +++ 265 +++ 266 +++ 267 ++ 268 + 269 +++ 270 +++ 271 + 272
++ 273 ++ 274 +++ 275 ++ 276 +++ 277 +++ 278 + 279 +++ 280 +++ 281
+++ 282 +++ 283 ++ 284 +++ 285 ++ 286 +++ 287 ++ 288 +++ 289 +++
290 +++ 291 +++ 292 + 293 + 294 +++ 295 + 296 +++ 297 +++ 298 +++
299 +++ 300 +++ 301 + 302 ++ 303 + 304 +++ 305 +++ 306 ++ 307 +++
308 +++ 309 + 310 + 311 +++ 312 +++ 313 +++ 314 +++ 315 +++ 316 +++
317 ++ 318 +++ 319 + 320 +++ 321 + 322 +++ 323 + 324 +++ 325 +++
326 +++ 327 +++ 328 + 329 ++ 330 ++ 331 + 332 +++ 333 +++ 334 + 335
+++ 336 +++ 337 +++ 338 +++ 339 +++ 340 +++ 341 +++ 342 + 343 +++
344 ++ 345 + 346 +++ 347 +++ 348 +++ 349 +++ 350 +++ 351 + 352 ++
353 +++ 354 +++ 355 +++ 356 +++ 357 +++ 358 ++ 359 +++ 360 +++ 361
+++ 362 + 363 +++ 364 + 365 +++ 366 +++ 367 +++ 368 +++ 369 +++ 370
+++ 371 +++ 372 +++ 373 +++ 374 + 375 +++ 376 ++ 377 +++ 378 +++
379 +++ 380 +++ 381 +++ 382 ++ 383 ++ 384 +++ 385 +++ 386 +++ 387
+++ 388 + 389 +++ 390 +++ 391 + 392 ++ 393 + 394 ++ 395 +++ 396 +++
397 +++ 398 +++ 399 ++ 400 + 401 +++ 402 ++ 403 + 404 +++ 405 +++
406 ++ 407 ++ 408 +++ 409 +++ 410 +++ 411 +++ 412 +++ 413 +++ 414
++ 415 +++ 416 + 417 + 418 +++ 419 +++ 420 +++ 421 + 422 +++ 423
+++ 424 +++ 425 + 426 +++ 427 +++ 428 +++ 429 ++ 430 + 431 ++ 432
++ 433 +++ 434 + 435 ++ 436 +++ 437 +++ 438 +++ 439 +++ 440 + 441
+++ 442 +++ 443 +++ 444 +++ 445 +++ 446 ++ 447 + 448 +++ 449 +++
450 +++ 451 + 452 ++ 453 ++ 454 + 455 +++ 456 ++ 457 + 458 ++ 459
+++ 460 +++ 461 +++ 462 +++ 463 +++ 464 +++ 465 + 466 +++ 467 +++
468 +++ 469 ++ 470 +++ 471 +++ 472 + 473 + 474 ++ 475 +++ 476 +++
477 +++ 478 + 479 ++ 480 +++ 481 +++ 482 ++ 483 +++ 484 +++ 485 +++
486 +++ 487 +++ 488 +++ 489 +++ 490 +++ 491 +++ 492 +++ 493 +++ 494
+++ 495 +++ 496 ++
497 + 498 +++ 499 +++ 500 +++ 501 +++ 502 + 503 +++ 504 + 505 +++
506 ++ 507 + 508 +++ 509 +++ 510 +++ 511 + 512 ++ 513 +++ 514 + 515
+ 516 +++ 517 +++ 518 +++ 519 + 520 +++ 521 +++ 522 +++ 523 +++ 524
+++ 525 +++ 526 +++ 527 + 528 +++ 529 + 530 +++ 531 +++ 532 + 533
+++ 534 + 535 + 536 ++ 537 +++ 538 +++ 539 + 540 + 541 +++ 542 +
543 +++ 544 +++ 545 ++ 546 +++ 547 + 548 +++ 549 +++ 550 +++ 551
+++ 552 +++ 553 +++ 554 +++ 555 +++ 556 +++ 557 +++ 558 + 559 +++
560 +++ 561 +++ 562 +++ 563 +++ 564 +++ 565 ++ 566 +++ 567 +++ 568
+++ 569 +++ 570 +++ 571 ++ 572 +++ 573 +++ 574 +++ 575 +++ 576 +++
577 + 578 ++ 579 +++ 580 +++ 581 ++ 582 +++ 583 +++ 584 +++ 585 +++
586 ++ 587 +++ 588 + 589 +++ 590 ++ 591 +++ 592 +++ 593 +++ 594 +
595 +++ 596 + 597 + 598 +++ 599 +++ 600 +++ 601 +++ 602 +++ 603 +
604 +++ 605 + 606 + 607 ++ 608 +++ 609 ++ 610 +++ 611 +++ 612 +++
613 + 614 + 615 + 616 +++ 617 +++ 618 + 619 +++ 620 ++ 621 +++ 622
++ 623 +++ 624 ++ 625 + 626 +++ 627 +++ 628 +++ 629 +++ 630 +++ 631
+ 632 +++ 633 + 634 + 635 ++ 636 +++ 637 ++ 638 +++ 639 +++ 640 ++
641 +++ 642 +++ 643 +++ 644 +++ 645 +++ 646 +++ 647 +++ 648 +++ 649
+++ 650 +++ 651 +++ 652 + 653 ++ 654 +++ 655 +++ 656 +++ 657 +++
658 +++ 659 + 660 +++ 661 +++ 662 +++ 663 +++ 664 +++ 665 +++ 666
+++ 667 +++ 668 +++ 669 +++ 670 + 671 +++ 672 +++ 673 +++ 674 +++
675 +++ 676 +++ 677 + 678 ++ 679 ++ 680 +++ 681 ++ 682 + 683 +++
684 + 685 +++ 686 +++ 687 +++ 688 +++ 689 + 690 +++ 691 +++ 692 +++
693 +++ 694 ++ 695 +++ 696 + 697 +++ 698 ++ 699 +++ 700 +++ 701 +++
702 +++ 703 + 704 +++ 705 +++ 706 +++ 707 +++ 708 +++ 709 +++ 710
+++ 711 +++ 712 +++ 713 ++ 714 + 715 +++ 716 +++ 717 +++ 718 ++ 719
++ 720 + 721 +++ 722 +++ 723 +++ 724 +++ 725 + 726 +++ 727 +++ 728
+++ 729 +++ 730 +++ 731 ++ 732 +++ 733 +++ 734 + 735 +++ 736 +++
737 +++ 738 +++ 739 + 740 +++ 741 +++ 742 ++ 743 +++ 744 +++ 745
+++ 746 +++ 747 +++
748 + 749 ++ 750 + 751 +++ 752 +++
[0511] Many modifications and variations of the embodiments
described herein may be made without departing from the scope, as
is apparent to those skilled in the art. The specific embodiments
described herein are offered by way of example only.
* * * * *
References