U.S. patent application number 11/840952 was filed with the patent office on 2008-01-17 for additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Jalaj Arora, Louise Edwards, Methvin Isaac, Martin Johansson, Annika Kers, Johan Malmberg, Donald McLeod, Alexander Mindis, Abdelmalik Slassi, Karin Staaf, Tomislav Stefanac, Thomas Stormann, David Wensbo, Tao Xin.
Application Number | 20080015234 11/840952 |
Document ID | / |
Family ID | 35447957 |
Filed Date | 2008-01-17 |
United States Patent
Application |
20080015234 |
Kind Code |
A1 |
Edwards; Louise ; et
al. |
January 17, 2008 |
ADDITIONAL HETEROPOLYCYCLIC COMPOUNDS AND THEIR USE AS METABOTROPIC
GLUTAMATE RECEPTOR ANTAGONISTS
Abstract
The present invention relates to new compounds of formula I,
##STR1## to pharmaceutical formulations containing the compounds,
and to the use of the compounds in the prevention and/or treatment
of mGluR5 receptor-mediated disorders.
Inventors: |
Edwards; Louise;
(Mississauga, CA) ; Isaac; Methvin; (Brampton,
CA) ; Johansson; Martin; (Sodertalje, SE) ;
Kers; Annika; (Sodertalje, SE) ; Malmberg; Johan;
(Sodertalje, SE) ; McLeod; Donald; (Salt Lake
City, UT) ; Mindis; Alexander; (Sodertalje, SE)
; Staaf; Karin; (Sodertalje, SE) ; Slassi;
Abdelmalik; (Mississauga, CA) ; Stefanac;
Tomislav; (Burlington, CA) ; Stormann; Thomas;
(Salt Lake City, UT) ; Wensbo; David; (Sodertalje,
SE) ; Xin; Tao; (Toronto, CA) ; Arora;
Jalaj; (Cambridge, CA) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
AstraZeneca AB
Sodertalje
UT
NPS PHARMACEUTICALS INC.
Salt Lake City
|
Family ID: |
35447957 |
Appl. No.: |
11/840952 |
Filed: |
August 18, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11053752 |
Feb 9, 2005 |
|
|
|
11840952 |
Aug 18, 2007 |
|
|
|
60608960 |
Feb 18, 2004 |
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Current U.S.
Class: |
514/340 ;
435/377; 514/364; 546/269.1; 548/131 |
Current CPC
Class: |
A61P 25/22 20180101;
A61P 43/00 20180101; A61P 9/00 20180101; A61P 25/06 20180101; A61P
25/24 20180101; A61P 25/00 20180101; A61P 25/16 20180101; C07D
487/04 20130101; A61P 25/28 20180101; A61P 29/00 20180101; A61P
27/02 20180101; A61P 35/00 20180101; A61P 15/00 20180101; A61P
19/06 20180101; A61P 25/08 20180101; A61P 25/04 20180101; A61P
25/30 20180101; C07D 413/12 20130101; C07D 413/14 20130101; C07D
413/06 20130101; A61P 1/00 20180101; A61P 27/06 20180101; A61P
25/18 20180101; A61P 3/08 20180101; A61P 19/02 20180101; A61P 9/10
20180101; A61P 21/02 20180101 |
Class at
Publication: |
514/340 ;
435/377; 514/364; 546/269.1; 548/131 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; A61K 31/4196 20060101 A61K031/4196; A61K 31/4245
20060101 A61K031/4245; A61P 19/06 20060101 A61P019/06; A61P 25/18
20060101 A61P025/18; A61P 25/30 20060101 A61P025/30; A61P 29/00
20060101 A61P029/00; A61P 9/00 20060101 A61P009/00; C07D 413/14
20060101 C07D413/14; C12N 5/00 20060101 C12N005/00; C07D 271/06
20060101 C07D271/06; A61P 35/00 20060101 A61P035/00; A61P 27/02
20060101 A61P027/02; A61P 25/28 20060101 A61P025/28; A61P 25/08
20060101 A61P025/08; A61P 19/02 20060101 A61P019/02; A61K 31/443
20060101 A61K031/443 |
Claims
1. A compound selected from the group consisting the compounds set
forth in the following table: TABLE-US-00062 957 ##STR228## 960
##STR229## 962 ##STR230## 963 ##STR231## 964 ##STR232## 966
##STR233## or a pharmaceutically acceptable salt thereof.
2-11. (canceled)
12. A method of prevention and/or treatment of mGluR5
receptor-mediated disorders, comprising administering to a mammal
in need of such prevention and/or treatment a therapeutically
effective amount of a compound according to claim 1.
13. The method according to claim 12, wherein the disorder is a
neurological disorder.
14. The method according to claim 12, wherein the disorder is a
psychiatric disorder.
15. The method according to claim 12, wherein the disorder is
selected from chronic and acute pain disorders.
16. The method according to claim 12, wherein the disorder is a
gastrointestinal disorder.
17. The method according to claim 12, wherein the disorder is
selected from the group consisting of Alzheimer's disease, senile
dementia, AIDS-induced dementia, Parkinson's disease, amyotrophic
lateral sclerosis, Huntington's Chorea, migraine, epilepsy,
schizophrenia, depression, anxiety, acute anxiety, obsessive
compulsive disorder, opthalmological disorders, diabetic
retinopathies, glaucoma, auditory neuropathic disorders,
chemotherapy induced neuropathies, post-herpetic neuralgia and
trigeminal neuralgia, tolerance, dependency, addiction and craving
disorders, neurodevelopmental disorders, autism, mental
retardation, schizophrenia, Down's Syndrome, pain related to
migraine, inflammatory pain, neuropathic pain disorders, arthritis
and rheumatitiod diseases, low back pain, post-operative pain, pain
associated with angina, renal and billiary colic, menstruation,
migraine gout, stroke, head trauma, anoxic and ischemic injuries,
hypoglycemia, cardiovascular diseases and epilepsy.
18. A method for inhibiting the activation of mGluR5 receptors,
comprising treating a cell containing said receptor with an
effective amount of a compound according to claim 1.
19. A pharmaceutical formulation comprising as active ingredient a
therapeutically effective amount of the compound according to claim
1 in association with one or more pharmaceutically acceptable
diluents, excipients and/or inert carriers.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] This Nonprovisional application claims priority under 35
U.S.C. .sctn. 119(e) on Nonprovisional application Ser. No.
11/053,752 filed on Feb. 9, 2005, which claims priority on U.S.
Provisional Application No. 60/608,960 filed on Feb. 18, 2004, the
entire contents of which are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a new class of compounds,
to pharmaceutical formulations containing said compounds and to the
use of said compounds in therapy. The present invention further
relates to the process for the preparation of said compounds and to
new intermediates prepared therein.
BACKGROUND OF THE INVENTION
[0003] Glutamate is the major excitatory neurotransmitter in the
mammalian central nervous system (CNS). Glutamate produces its
effects on central neurons by binding to and thereby activating
cell surface receptors. These receptors have been divided into two
major classes, the ionotropic and metabotropic glutamate receptors,
based on the structural features of the receptor proteins, the
means by which the receptors transduce signals into the cell, and
pharmacological profiles.
[0004] The metabotropic glutamate receptors (mGluRs) are G
protein-coupled receptors that activate a variety of intracellular
second messenger systems following the binding of glutamate.
Activation of mGluRs in intact mammalian neurons elicits one or
more of the following responses: activation of phospholipase C;
increases in phosphoinositide (PI) hydrolysis; intracellular
calcium release; activation of phospholipase D; activation or
inhibition of adenyl cyclase; increases or decreases in the
formation of cyclic adenosine monophosphate (cAMP); activation of
guanylyl cyclase; increases in the formation of cyclic guanosine
monophosphate (cGMP); activation of phospholipase A.sub.2;
increases in arachidonic acid release; and increases or decreases
in the activity of voltage- and ligand-gated ion channels. Schoepp
et al., Trends Pharmacol. Sci. 14:13 (1993), Schoepp, Neurochem.
Int. 24:439 (1994), Pin et al., Neuropharmacology 34:1 (1995),
Bordi and Ugolini, Prog. Neurobiol. 59:55 (1999).
[0005] Molecular cloning has identified eight distinct mGluR
subtypes, termed mGluR1 through mGluR8. Nakanishi, Neuron 13:1031
(1994), Pin et al., Neuropharmacology 34:1 (1995), Knopfel et al.,
J. Med. Chem. 38:1417 (1995). Further receptor diversity occurs via
expression of alternatively spliced forms of certain mGluR
subtypes. Pin et al., PNAS 89:10331 (1992), Minakami et al., BBRC
199:1136 (1994), Joly et al., J. Neurosci. 15:3970 (1995).
[0006] Metabotropic glutamate receptor subtypes may be subdivided
into three groups, Group I, Group II, and Group III mGluRs, based
on amino acid sequence homology, the second messenger systems
utilized by the receptors, and by their pharmacological
characteristics. Group I mGluR comprises mGluR1, mGluR5 and their
alternatively spliced variants. The binding of agonists to these
receptors results in the activation of phospholipase C and the
subsequent mobilization of intracellular calcium.
Neurological, Psychiatric and Pain Disorders
[0007] Attempts at elucidating the physiological roles of Group I
mGluRs suggest that activation of these receptors elicits neuronal
excitation. Various studies have demonstrated that Group I mGluRs
agonists can produce postsynaptic excitation upon application to
neurons in the hippocampus, cerebral cortex, cerebellum, and
thalamus, as well as other CNS regions. Evidence indicates that
this excitation is due to direct activation of postsynaptic mGluRs,
but it also has been suggested that activation of presynaptic
mGluRs occurs, resulting in increased neurotransmitter release.
Baskys, Trends Pharmacol. Sci. 15:92 (1992), Schoepp, Neurochem.
Int. 24:439 (1994), Pin et al., Neuropharmacology 34:1(1995),
Watkins et al., Trends Pharmacol. Sci. 15:33 (1994).
[0008] Metabotropic glutamate receptors have been implicated in a
number of normal processes in the mammalian CNS. Activation of
mGluRs has been shown to be required for induction of hippocampal
long-term potentiation and cerebellar long-term depression. Bashir
et al., Nature 363:347 (1993), Bortolotto et al., Nature 368:740
(1994), Aiba et al., Cell 79:365 (1994), Aiba et al., Cell 79:377
(1994). A role for mGluR activation in nociception and analgesia
also has been demonstrated, Meller et al., Neuroreport 4: 879
(1993), Bordi and Ugolini, Brain Res. 871:223 (1999). In addition,
mGluR activation has been suggested to play a modulatory role in a
variety of other normal processes including synaptic transmission,
neuronal development, apoptotic neuronal death, synaptic
plasticity, spatial learning, olfactory memory, central control of
cardiac activity, waking, motor control and control of the
vestibulo-ocular reflex. Nakanishi, Neuron 13: 1031 (1994), Pin et
al., Neuropharmacology 34:1, Knopfel et al., J. Med. Chem. 38:1417
(1995).
[0009] Further, Group I metabotropic glutamate receptors and mGluR5
in particular, have been suggested to play roles in a variety of
pathophysiological processes and disorders affecting the CNS. These
include stroke, head trauma, anoxic and ischemic injuries,
hypoglycemia, epilepsy, neurodegenerative disorders such as
Alzheimer's disease and pain. Schoepp et al., Trends Pharmacol.
Sci. 14:13 (1993), Cunningham et al., Life Sci. 54:135 (1994),
Hollman et al., Ann. Rev. Neurosci. 17:31 (1994), Pin et al.,
Neuropharmacology 34:1 (1995), Knopfel et al., J. Med. Chem.
38:1417 (1995), Spooren et al., Trends Pharmacol. Sci. 22:331
(2001), Gasparini et al. Curr. Opin. Pharmacol. 2:43 (2002),
Neugebauer Pain 98:1 (2002). Much of the pathology in these
conditions is thought to be due to excessive glutamate-induced
excitation of CNS neurons. Because Group I mGluRs appear to
increase glutamate-mediated neuronal excitation via postsynaptic
mechanisms and enhanced presynaptic glutamate release, their
activation probably contributes to the pathology. Accordingly,
selective antagonists of Group I mGluR receptors could be
therapeutically beneficial, specifically as neuroprotective agents,
analgesics or anticonvulsants.
[0010] Recent advances in the elucidation of the neurophysiological
roles of metabotropic glutamate receptors generally and Group I in
particular, have established these receptors as promising drug
targets in the therapy of acute and chronic neurological and
psychiatric disorders and chronic and acute pain disorders. Because
of their physiological and pathophysiological significance, there
is a need for new potent mGluR agonists and antagonists that
display a high selectivity for mGluR subtypes, particularly the
Group I receptor subtype, most particularly the mGluR5 subtype.
Gastro Intestinal Disorders
[0011] The lower esophageal sphincter (LES) is prone to relaxing
intermittently. As a consequence, fluid from the stomach can pass
into the esophagus since the mechanical barrier is temporarily lost
at such times, an event hereinafter referred to as "G.I.
reflux".
[0012] Gastro-esophageal reflux disease (GERD) is the most
prevalent upper gastrointestinal tract disease. Current
pharmacotherapy aims at reducing gastric acid secretion, or at
neutralizing acid in the esophagus. The major mechanism behind G.I.
reflux has been considered to depend on a hypotonic lower
esophageal sphincter. However, e.g. Holloway & Dent (1990)
Gastroenterol. Clin. N. Amer. 19, pp. 517-535, has shown that most
reflux episodes occur during transient lower esophageal sphincter
relaxations (TLESRs), i.e. relaxations not triggered by swallows.
It has also been shown that gastric acid secretion usually is
normal in patients with GERD.
[0013] The novel compounds according to the present invention are
assumed to be useful for the inhibition of transient lower
esophageal sphincter relaxations (TLESRs) and thus for treatment of
gastro-esophageal reflux disorder (GERD).
[0014] The wording "TLESR", transient lower esophageal sphincter
relaxations, is herein defined in accordance with Mittal, R. K.,
Holloway, R. H., Penagini, R., Blackshaw, L. A., Dent, J., 1995;
Transient lower esophageal sphincter relaxation. Gastroenterology
109, pp. 601-610.
[0015] The wording "G.I. reflux" is herein defined as fluid from
the stomach being able to pass into the esophagus, since the
mechanical barrier is temporarily lost at such times.
[0016] The wording "GERD", gastro-esophageal reflux disease, is
herein defined in accordance with van Heerwarden, M. A., Smout A.
J. P. M., 2000; Diagnosis of reflux disease. Bailliere's Clin.
Gastroenterol. 14, pp. 759-774.
[0017] Because of their physiological and pathophysiological
significance, there is a need for new potent mGluR agonists and
antagonists that display a high selectivity for mGluR subtypes,
particularly the Group I receptor subtype.
[0018] The object of the present invention is to provide compounds
exhibiting an activity at metabotropic glutamate receptors
(mGluRs), especially at the mGluR5 receptor.
SUMMARY OF THE INVENTION
[0019] The present invention provides a compound of formula Ia
##STR2## wherein:
[0020] P is selected from the group consisting of hydrogen,
C.sub.3-7alkyl or a 3- to 8-membered ring containing one or more
atoms independently selected from C, N, O and S, which ring may
optionally be fused with a 5- or 6-membered ring containing one or
more atoms independently selected from the group consisting of C,
N, O and S;
[0021] R.sup.1 is selected from the group consisting of hydrogen,
hydroxy, halo, nitro, C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo,
C.sub.1-6alkyl, OC.sub.1-6alkyl, C.sub.2-6alkenyl,
OC.sub.2-6alkenyl, C.sub.2-6alkynyl, OC.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl,
OC.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
OC.sub.0-6alkylaryl, CHO, (CO)R.sup.5, O(CO)R.sup.5, O(CO)OR,
O(CN)OR.sup.5, C.sub.1-6alkylOR.sup.5, OC.sub.2-6alkylOR.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, OC.sub.1-6alkyl(CO)R.sup.5,
C.sub.0-6alkylCO.sub.2R.sup.5, OC.sub.1-6alkylCO.sub.2R.sup.5,
C.sub.0-6alkylcyano, OC.sub.2-6alkylcyano,
C.sub.0-6alkylNR.sup.5R.sup.6, OC.sub.2-6alkylNR.sup.5R.sup.6,
C.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.1-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, C.sub.0-6alkylSR.sup.5,
OC.sub.2-6alkylSR.sup.5, C.sub.0-6alkyl(SO)R.sup.5,
OC.sub.2-6alkyl(SO)R.sup.5, C.sub.0-6alkylSO.sub.2R.sup.5,
OC.sub.2-6alkylSO.sub.2R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6, NR.sup.5OR.sup.6,
C.sub.0-6alkylNR.sup.5(CO)OR.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)OR.sup.6, SO.sub.3R.sup.5 and a 5- or
6-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S, wherein said ring may
be substituted by one or more A;
[0022] M.sup.1 is selected from the group consisting of a bond,
C.sub.1-3alkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-4alkyl(CO)C.sub.0-4alkyl, C.sub.0-3alkylOC.sub.0-3alkyl,
C.sub.0-3alkyl(CO)NR.sup.5,
C.sub.0-3alkyl(CO)NR.sup.5C.sub.0-3alkyl, C.sub.0-4alkylNR.sup.5,
C.sub.0-3alkylSC.sub.0-3alkyl, C.sub.0-3alkyl(SO)C.sub.0-3alkyl or
C.sub.0-3alkyl(SO.sub.2)C.sub.0-3alkyl;
[0023] R.sup.2 is selected from the group consisting of hydrogen,
hydroxy, C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-4alkyl, O(CO)C.sub.1-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, OC.sub.1-4alkyl, C.sub.1-4alkylOR.sup.5
and C.sub.0-4alkylNR.sup.5R.sup.6;
[0024] X.sup.1, X.sup.2 and X.sup.3 are independently selected from
the group consisting of CR, CO, N, NR, O and S;
[0025] R is selected from the group consisting of hydrogen,
C.sub.0-3alkyl, halo, C.sub.0-3alkylOR.sup.5,
C.sub.0-3alkylNR.sup.5R.sup.6, C.sub.0-3alkyl(CO)OR.sup.5,
C.sub.0-3alkylNR.sup.5R.sup.6 and C.sub.0-3alkylaryl;
[0026] M.sup.2 is selected from a group consisting of a bond,
C.sub.1-3alkyl, C.sub.3-7cycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, C.sub.0-4alkyl(CO)C.sub.0-4alkyl,
C.sub.0-3alkylOC.sub.0-3alkyl,
C.sub.0-3alkylNR.sup.5C.sub.1-3alkyl, C.sub.0-3alkyl(CO)NR.sup.5,
C.sub.0-4alkylNR.sup.5, C.sub.0-3alkylSC.sub.0-3alkyl,
C.sub.0-3alkyl(SO)C.sub.0-3alkyl and
C.sub.0-3alkyl(SO.sub.2)C.sub.0-3alkyl;
[0027] R.sup.3 is selected from a group consisting of hydrogen,
hydroxy, C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-4alkyl, O(CO)C.sub.1-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, OC.sub.1-4alkyl, C.sub.1-4alkylOR.sup.5
and C.sub.0-4alkylNR.sup.5R.sup.6;
[0028] X.sup.4 is selected from the group consisting of
C.sub.0-4alkylR.sup.5, C.sub.0-4alkyl(NR.sup.5R.sup.6),
C.sub.0-4alkyl(NR.sup.5R.sup.6).dbd.N,
NR.sup.5C.sub.0-4alkyl(NR.sup.5R.sup.6).dbd.N, NOC.sub.0-4alkyl,
C.sub.1-4alkylhalo, C, O, SO, SO.sub.2 and S;
[0029] Q is a 5- or 6-membered ring containing one or more atoms
independently selected from the group consisting of C, N, O and S,
which group may optionally be fused with a 5- or 6-membered ring
containing one or more atoms independently selected from the group
consisting of C, N, O and S and which fused ring may be substituted
by one or more A;
[0030] R.sup.4 is selected from the group consisting of hydrogen,
hydroxy, C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-4alkyl, OC.sub.1-4alkyl,
OC.sub.0-6alkylaryl, O(CO)C.sub.1-4alkyl,
C.sub.0-4alkyl(S)C.sub.0-4alkyl, C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5,
C.sub.0-4alkylNR.sup.5R.sup.6 and a 5- or 6-membered ring
containing one or more atoms independently selected from C, N, O or
S, wherein said ring may be substituted by one or more A;
[0031] R.sup.5 and R.sup.6 are independently selected from the
group consisting of hydrogen, hydroxy, C.sub.1-6alkyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylheteroaryl and a 5- or 6-membered ring containing one
or more atoms independently selected from C, N, O and S, and
wherein R.sup.5 and R.sup.6 may together form a 5- or 6-membered
ring containing one or more atoms independently selected from the
group consisting of C, N, O and S;
[0032] wherein any C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.0-6alkylC.sub.3-6cycloalkyl,
C.sub.0-6alkylaryl and C.sub.0-6alkylheteroaryl defined under
R.sup.1, R.sup.2, R.sup.3R.sup.4, R.sup.4 and R.sup.5 may be
substituted by one or more A;
[0033] A is selected from the group consisting of hydrogen,
hydroxy, oxo, halo, nitro, C.sub.0-6alkylcyano, C.sub.1-4alkyl,
C.sub.0-4alkylC.sub.3-6cycloalkyl, C.sub.1-6alkylhalo,
OC.sub.1-6alkylhalo, C.sub.2-6alkenyl, OC.sub.1-6alkyl,
C.sub.0-3alkylaryl, C.sub.0-6alkylOR.sup.5,
OC.sub.2-6alkylOR.sup.5, C.sub.1-6alkylSR.sup.5,
OC.sub.2-6alkylSR.sup.5, (CO)R.sup.5, O(CO)R.sup.5,
OC.sub.2-6alkylcyano, C.sub.0-6alkylCO.sub.2R.sup.5,
OC.sub.1-6alkylCO.sub.2R.sup.5, O(CO)OR.sup.5,
OC.sub.1-6alkyl(CO)R.sup.5, C.sub.1-6alkyl(CO)R.sup.5,
NR.sup.5OR.sup.6, C.sub.0-6alkylNR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5R.sup.6, C.sub.0-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6,
NR.sup.5(CO)OR.sup.6, C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6, SO.sub.3R.sup.5,
C.sub.1-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)R.sup.5, C.sub.0-6alkyl(SO.sub.2)R.sup.5,
C.sub.0-6alkyl(SO)R.sup.5, OC.sub.2-6alkyl(SO)R.sup.5 and a 5- or
6-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S;
[0034] m is selected from 0, 1, 2, 3 and 4; and
[0035] n is selected from 0, 1, 2 and 3,
[0036] or salt thereof.
[0037] The present invention provides a compound of formula I
##STR3## wherein:
[0038] P is selected from the group consisting of thiophene,
pyridyl, thiazolyl, furyl, pyrrolyl and phenyl, whereby the phenyl
ring is substituted on position 3 or disubstituted on positions 2
and 5;
[0039] R.sup.1 is attached to P via a carbon atom on ring P and is
selected from the group consisting of hydrogen, hydroxy, halo,
nitro, C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo, C.sub.1-6alkyl,
OC.sub.1-6alkyl, C.sub.2-6alkenyl, OC.sub.2-6alkenyl,
C.sub.2-6alkynyl, OC.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl,
OC.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
OC.sub.0-6alkylaryl, CHO, (CO)R.sup.5O(CO)R.sup.5, O(CO)OR.sup.5,
O(CN)OR.sup.5, C.sub.1-6alkylOR.sup.5, OC.sub.2-6alkylOR.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, OC.sub.1-6alkyl(CO)R.sup.5,
C.sub.0-6alkylCO.sub.2R.sup.5, OC.sub.1-6alkylCO.sub.2R.sup.5,
C.sub.0-6alkylcyano, OC.sub.2-6alkylcyano,
C.sub.0-6alkylNR.sup.5R.sup.6, OC.sub.2-6alkylNR.sup.5R.sup.6,
C.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6, C.sub.0-6alkylNR.sup.5
(CO)R.sup.6, OC.sub.2-6alkylNR.sup.5 (CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, C.sub.0-6alkylSR.sup.5,
OC.sub.2-6alkylSR.sup.5, C.sub.0-6alkyl(SO)R.sup.5,
OC.sub.2-6alkyl(SO)R.sup.5, C.sub.0-6alkylSO.sub.2R.sup.5,
OC.sub.2-6alkylSO.sub.2R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6, NR.sup.5OR.sup.6,
C.sub.0-6alkylNR.sup.5(CO)OR.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)OR.sup.6, SO.sub.3R.sup.5 and a 5- or
6-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S;
[0040] M.sup.1 is a bond;
[0041] X.sup.1 selected from the group consisting of C, CO, N, O
and S;
[0042] X.sup.2 is selected from the group consisting of C, N, O and
S;
[0043] X.sup.3 is i) selected from the group consisting of N, O and
S, or
[0044] ii) selected from N, O, S, and C when X.sup.2 is selected
from N, O, or S, and when X.sup.3 is C the substituent R on X.sup.3
is H;
[0045] R is selected from the group consisting of hydrogen,
C.sub.0-3alkyl, halo, C.sub.0-3alkylOR.sup.5,
C.sub.0-3alkylNR.sup.5R.sup.6, C.sub.0-3alkyl(CO)OR.sup.5 and
C.sub.0-3alkylaryl;
[0046] M.sup.2 is selected from a group consisting of a bond,
C.sub.1-3alkyl, C.sub.2-3alkynyl, C.sub.0-4alkyl(CO)C.sub.0-4alkyl,
C.sub.0-3alkylOC.sub.0-3alkyl,
C.sub.0-3alkylNR.sup.5C.sub.1-3alkyl, C.sub.0-3alkyl(CO)NR.sup.5,
C.sub.0-4alkylNR.sup.5, C.sub.0-3alkyl(SO)C.sub.0-3alkyl and
C.sub.0-3alkyl(SO.sub.2)C.sub.0-3alkyl;
[0047] R.sup.3 is selected from a group consisting of hydroxy,
C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-4alkyl, O(CO)C.sub.1-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, OC.sub.1-4alkyl, C.sub.1-4alkylOR.sup.5
and C.sub.0-4alkylNR.sup.5R.sup.6;
[0048] X.sup.4 is selected from the group consisting of
C.sub.0-4alkylR.sup.5R.sup.6, C.sub.3-7cycloalkyl,
C.sub.1-4alkyl(NR.sup.5R.sup.6), NR.sup.5,
C.sub.0-4alkyl(NR.sup.5R.sup.6).dbd.N,
NR.sup.5C.sub.0-4alkyl(NR.sup.5R.sup.6).dbd.N, NOC.sub.0-4alkyl,
C.sub.1-4alkylhalo, O, SO, SO.sub.2 and S, and wherein the bond
between M.sup.2 and X.sup.4 is a single bond;
[0049] Q is i) selected from the group consisting of triazolyl,
imidazolyl, oxadiazolyl, imidazolonyl, oxazolonyl, thiazolonyl,
tetrazolyl and thiadiazolyl, and wherein any substitutable nitrogen
atom in the ring is substituted with R.sup.4 on such nitrogen atom
and any suitable carbon atom is optionally substituted with
R.sup.4; and [0050] R.sup.4 is selected from the group consisting
of C.sub.0-6alkylcyano, .dbd.NC.sub.1-4alkyl, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-6alkyl, OC.sub.1-4alkyl,
C.sub.2-4alkenyl, C.sub.0-2alkylC.sub.3-6cycloalkyl,
C.sub.0-6alkylaryl, C.sub.0-6alkylheteroaryl, OC.sub.0-6alkylaryl,
OC.sub.0-6alkylheteroaryl, NC.sub.0-6alkylaryl,
NC.sub.0-6alkylheteroaryl, C.sub.0-6alkylOaryl,
C.sub.0-6alkylOheteroaryl, C.sub.0-6alkylNaryl,
C.sub.0-6alkylNheteroaryl, OC.sub.0-6alkylOaryl,
OC.sub.0-6alkylOheteroaryl, OC.sub.0-6alkylNaryl,
OC.sub.0-6alkylNheteroaryl, NC.sub.0-6alkylOaryl,
NC.sub.0-6alkylOheteroaryl, NC.sub.0-6alkylNaryl,
NC.sub.0-6alkylNheteroaryl, O(CO)C.sub.1-4alkyl,
C.sub.0-4alkyl(CO)OC.sub.1-4alkyl, C.sub.1-4alkyl(S)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5,
C.sub.0-4alkylN(C.sub.1-4alkyl).sub.2 and a 3- or 6-membered
non-aromatic ring containing one or more atoms independently
selected from C, N, O and S, which ring may optionally be fused
with a 5-membered ring containing one or more atoms independently
selected from the group consisting of C, N and O and wherein said
ring and said fused ring may be substituted by one or two A; or
[0051] ii) selected from the group consisting of benzoimidazolyl,
benzooxazolyl, tetrahydrotriazolopyridyl,
tetrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl,
imidazopyridyl, oxazolopyridyl, thiazolopyridyl,
imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and
purinyl; and [0052] R.sup.4 is selected from the group consisting
of hydrogen, hydroxy, C.sub.0-6alkylcyano, .dbd.NR.sup.5,
.dbd.NOR.sup.5, C.sub.1-4alkylhalo, halo, C.sub.1-6alkyl,
OC.sub.1-4alkyl, OC.sub.0-6alkylaryl, O(CO)C.sub.1-4alkyl,
C.sub.0-4alkyl(S)C.sub.0-4alkyl, C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5,
C.sub.0-4alkylNR.sup.5R.sup.6 and a 5- or 6-membered ring
containing one or more atoms independently selected from C, N, O
and S, which ring may optionally be fused with a 5- or 6-membered
ring containing one or more atoms independently selected from the
group consisting of C, N and O and wherein said ring and said fused
ring may be substituted by one or two A;
[0053] R.sup.5 and R.sup.6 are independently selected from the
group consisting of hydrogen and C.sub.1-6alkyl;
[0054] wherein any C.sub.1-6alkyl defined under R.sup.1, R.sup.2
and R.sup.4 may be substituted by one or more A;
[0055] A is selected from the group consisting of hydrogen,
hydroxy, halo, nitro, oxo, C.sub.0-6alkylcyano,
C.sub.0-4alkylC.sub.3-6cycloalkyl, C.sub.1-6alkyl,
C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo, C.sub.2-6alkenyl,
C.sub.0-3alkylaryl, C.sub.0-6alkylOR.sup.5,
OC.sub.2-6alkylOR.sup.5, C.sub.1-6alkylSR.sup.5,
OC.sub.2-6alkylSR.sup.5, (CO)R.sup.5, O(CO)R.sup.5,
OC.sub.2-6alkylcyano, OC.sub.1-6alkylCO.sub.2R.sup.5,
O(CO)OR.sup.5, OC.sub.1-6alkyl(CO)R.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, NR.sup.5OR.sup.6,
OC.sub.2-6alkylNR.sup.5R.sup.6, C.sub.0-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6, OC.sub.2-6alkylNR.sup.5
(CO)R.sup.6, C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-1alkylNR.sup.5(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6, SO.sub.3R.sup.5,
C.sub.1-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)R.sup.5, C.sub.0-6alkyl(SO.sub.2)R.sup.5,
C.sub.0-6alkyl(SO)R.sup.5, OC.sub.2-6alkyl(SO)R.sup.5 and a
5-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S;
[0056] m1 is selected from 0, 1, 2, 3 and 4;
[0057] m2 is selected from 0, 1, 2 and 3;
[0058] n is selected from 0, 1 and 2; and
[0059] t is 0 or 1,
[0060] and salts thereof,
[0061] with the proviso that the compound is not
5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-3-yl-[1,2,4]-
oxadiazole, 1,2-di{2-(3-amino-phenyl)-[1,3,4]oxadiazole-yl)ethane,
1,2-di
{5-[5-(4-nitro-phenyl)furan-2-yl]-[1,3,4]oxadiazol-yl)ethane,
1,2-di{5-[5-(4-bromo-phenyl)furan-2-yl]-[1,3,4]oxadiazol-yl)ethane,
1,2-di{5-[5-(4-chloro-phenyl)furan-2-yl]-[1,3,4]oxadiazol-yl)ethane
and 1,2-di
{5-[5-(2,4-dibromo-phenyl)furan-2-yl]-[1,3,4]oxadiazol-yl)ethane.
[0062] The present invention provides a compound of formula Ib
##STR4## wherein:
[0063] P is selected from the group consisting of thiophene,
pyridyl, thiazolyl, furyl, pyrrolyl and phenyl, whereby the phenyl
ring is substituted on position 3 or disubstituted on positions 2
and 5;
[0064] R.sup.1 is attached to P via a carbon atom on ring P and is
selected from the group consisting of hydrogen, hydroxy, halo,
nitro, C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo, C.sub.1-6alkyl,
OC.sub.1-6alkyl, C.sub.2-6alkenyl, OC.sub.2-6alkenyl,
C.sub.2-6alkynyl, OC.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl,
OC.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
OC.sub.0-6alkylaryl, CHO, (CO)R.sup.5, O(CO)R.sup.5, O(CO)OR.sup.5,
O(CN)OR.sup.5, C.sub.1-6alkylOR.sup.5, OC.sub.2-6alkylOR.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, OC.sub.1-6alkyl(CO)R.sup.5,
C.sub.0-6alkylCO.sub.2R.sup.5, OC.sub.1-6alkylCO.sub.2R.sup.5,
C.sub.0-6alkylcyano, OC.sub.2-6alkylcyano,
C.sub.0-6alkylNR.sup.5R.sup.6, OC.sub.2-6alkylNR.sup.5R.sup.6,
C.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6, OC.sub.2-6alkylNR.sup.5
(CO)R.sup.6, C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6,
C.sub.0-6alkylSR.sup.5, OC.sub.2-6alkylSR.sup.5,
C.sub.0-6alkyl(SO)R.sup.5, OC.sub.2-6alkyl(SO)R.sup.5,
C.sub.0-6alkylSO.sub.2R.sup.5, OC.sub.2-6alkylSO.sub.2R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6, NR.sup.5OR.sup.6,
C.sub.0-6alkylNR.sup.5(CO)OR.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)OR.sup.6, SO.sub.3R.sup.5 and a 5- or
6-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S;
[0065] M.sup.1 is a bond;
[0066] X.sup.1 selected from the group consisting of C, CO, N, O
and S;
[0067] X.sup.2 is selected from the group consisting of C, N, O and
S;
[0068] X.sup.3 is selected from the group consisting of N, O and S,
or X.sup.3 is CH when X.sup.2 is N, O or S;
[0069] R is selected from the group consisting of hydrogen,
C.sub.0-3alkyl, halo, C.sub.0-3alkylOR.sup.5,
C.sub.0-3alkylNR.sup.5R.sup.6, C.sub.0-3alkyl(CO)OR.sup.5 and
C.sub.0-3alkylaryl;
[0070] M.sup.2 is selected from a group consisting of a bond,
C.sub.1-3alkyl, C.sub.2-3alkynyl, C.sub.0-4alkyl(CO)C.sub.0-4alkyl,
C.sub.0-3alkylOC.sub.0-3alkyl,
C.sub.0-3alkylNR.sup.5C.sub.1-3alkyl, C.sub.0-3alkyl(CO)NR.sup.5,
C.sub.0-4alkylNR.sup.5, C.sub.0-3alkyl(SO)C.sub.0-3alkyl and
C.sub.0-3alkyl(SO.sub.2)C.sub.0-3alkyl;
[0071] R.sup.3 is selected from a group consisting of hydroxy,
C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-4alkyl, O(CO)C.sub.1-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, OC.sub.1-4alkyl, C.sub.1-4alkylOR.sup.5
and C.sub.0-4alkylNR.sup.5R.sup.6;
[0072] X.sup.4 is selected from the group consisting of
C.sub.0-4alkylR.sup.5R.sup.6, C.sub.3-7cycloalkyl,
C.sub.1-4alkyl(NR.sup.5R.sup.6), NR.sup.5,
C.sub.0-4alkyl(NR.sup.5R.sup.6).dbd.N,
NR.sup.5C.sub.0-4alkyl(NR.sup.5R.sup.6).dbd.N, NOC.sub.0-4alkyl,
C.sub.1-4alkylhalo, O, SO, SO.sub.2 and S, and wherein the bond
between M.sup.2 and X.sup.4 is a single bond;
[0073] Q is i) selected from the group consisting of triazolyl,
imidazolyl, oxadiazolyl, imidazolonyl, oxazolonyl, thiazolonyl,
tetrazolyl and thiadiazolyl, and wherein any substitutable nitrogen
atom in the ring is substituted with R.sup.4 on such nitrogen atom;
and [0074] R.sup.4 is selected from the group consisting of
C.sub.0-6alkylcyano, .dbd.NC.sub.1-4alkyl, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-6alkyl, OC.sub.1-4alkyl,
C.sub.2-4alkenyl, C.sub.0-2alkylC.sub.3-6cycloalkyl,
C.sub.0-6alkylaryl, C.sub.0-6alkylheteroaryl, OC.sub.0-6alkylaryl,
OC.sub.0-6alkylheteroaryl, NC.sub.0-6alkylaryl,
NC.sub.0-6alkylheteroaryl, C.sub.0-6alkylOaryl,
C.sub.0-6alkylOheteroaryl, C.sub.0-6alkylNaryl,
C.sub.0-6alkylNheteroaryl, OC.sub.0-6alkylOaryl,
OC.sub.0-6alkylOheteroaryl, OC.sub.0-6alkylNaryl,
OC.sub.0-6alkylNheteroaryl, NC.sub.0-6alkylOaryl,
NC.sub.0-6alkylOheteroaryl, NC.sub.0-6alkylNaryl,
NC.sub.0-6alkylNheteroaryl, O(CO)C.sub.1-4alkyl,
C.sub.0-4alkyl(CO)OC.sub.1-4alkyl, C.sub.1-4alkyl(S)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5,
C.sub.0-4alkylN(C.sub.1-4alkyl).sub.2 and a 3- or 6-membered
non-aromatic ring containing one or more atoms independently
selected from C, N, O and S, which ring may optionally be fused
with a 5-membered ring containing one or more atoms independently
selected from the group consisting of C, N and O and wherein said
ring and said fused ring may be substituted by one or two A; or
[0075] ii) selected from the group consisting of benzoimidazolyl,
benzooxazolyl, tetrahydrotriazolopyridyl,
tetrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl,
imidazopyridyl, oxazolopyridyl, thiazolopyridyl,
imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and
purinyl; and [0076] R.sup.4 is selected from the group consisting
of hydrogen, hydroxy, C.sub.0-6alkylcyano, .dbd.NR.sup.5,
.dbd.NOR.sup.5, C.sub.1-4alkylhalo, halo, C.sub.1-6alkyl,
OC.sub.1-4alkyl, OC.sub.0-6alkylaryl, O(CO)C.sub.1-4alkyl,
C.sub.0-4alkyl(S)C.sub.0-4alkyl, C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5,
C.sub.0-4alkylNR.sup.5R.sup.6 and a 5- or 6-membered ring
containing one or more atoms independently selected from C, N, O
and S, which ring may optionally be fused with a 5- or 6-membered
ring containing one or more atoms independently selected from the
group consisting of C, N and O and wherein said ring and said fused
ring may be substituted by one or two A;
[0077] R.sup.5 and R.sup.6 are independently selected from the
group consisting of hydrogen and C.sub.1-6alkyl;
[0078] wherein any C.sub.1-6alkyl defined under R.sup.1, R.sup.2
and R.sup.4 may be substituted by one or more A;
[0079] A is selected from the group consisting of hydrogen,
hydroxy, halo, nitro, oxo, C.sub.0-6alkylcyano,
C.sub.0-4alkylC.sub.3-6cycloalkyl, C.sub.1-6alkyl,
C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo, C.sub.2-6alkenyl,
C.sub.0-3alkylaryl, C.sub.0-6alkylOR.sup.5,
OC.sub.2-6alkylOR.sup.5, C.sub.1-6alkylSR.sup.5,
OC.sub.2-6alkylSR.sup.5, (CO)R.sup.5, O(CO)R.sup.5,
OC.sub.2-6alkylcyano, OC.sub.1-6alkylCO.sub.2R.sup.5,
O(CO)OR.sup.5, OC.sub.1-6alkyl(CO)R.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, NR.sup.5OR.sup.6,
OC.sub.2-6alkylNR.sup.5R.sup.6, C.sub.0-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6, SO.sub.3R.sup.5,
C.sub.1-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)R.sup.5, C.sub.0-6alkyl(SO.sub.2)R.sup.5,
C.sub.0-6alkyl(SO)R.sup.5, OC.sub.2-6alkyl(SO)R.sup.5 and a
5-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S;
[0080] m1 is selected from 0, 1, 2, 3 and 4;
[0081] m2 is selected from 0, 1, 2 and 3;
[0082] n is selected from 0, 1 and 2; and
[0083] t is 0 or 1,
[0084] and salts thereof,
[0085] with the proviso that the compound is not
5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-3-yl-[1,2,4]-
oxadiazole.
[0086] In a further aspect of the invention there is provided
pharmaceutical formulations comprising a therapeutically effective
amount of a compound of formula I and a pharmaceutically acceptable
carrier.
[0087] In yet a further aspect of the invention there is provided a
pharmaceutical formulation including a compound of formula I for
use in the treatment of mGluR5 receptor-mediated disorders, and
particularly neurological disorders, psychiatric disorders, acute
and chronic pain, and gastrointestinal disorders.
[0088] In still a further aspect of the invention there is provided
a compound of formula I for use in therapy for the treatment of
mGluR5 receptor-mediated disorders, and particularly neurological
disorders, psychiatric disorders, acute and chronic pain, and
gastrointestinal disorders.
[0089] In another aspect of the invention there is provided a
process for the preparation of compounds of formula I, and the
intermediates provided therein.
[0090] These and other aspects of the present invention are
described in greater detail herein below.
DETAILED DESCRIPTION OF THE INVENTION
[0091] Listed below are definitions of various terms used in the
specification and claims to describe the present invention.
[0092] For the avoidance of doubt it is to be understood that where
in this specification a group is qualified by `hereinbefore
defined`, `defined hereinbefore` or `defined above` the said group
encompasses the first occurring and broadest definition as well as
each and all of the other definitions for that group.
[0093] For the avoidance of doubt it is to be understood that in
this specification `C.sub.1-6` means a carbon group having 1, 2, 3,
4, 5 or 6 carbon atoms.
[0094] In this specification "C" means 1 carbon atom.
[0095] In this specification, unless stated otherwise, the term
"alkyl" includes both straight and branched chain alkyl groups and
may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
[0096] s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl,
n-hexyl or i-hexyl, t-hexyl. The term "C.sub.1-3alkyl" refers to an
alkyl group having 1, 2 or 3 carbon atoms, and may be methyl,
ethyl, n-propyl and i-propyl.
[0097] In this specification, unless stated otherwise, the term
"cycloalkyl" refers to an optionally substituted, saturated cyclic
hydrocarbon ring system. The term "C.sub.3-7cycloalkyl" may be
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl.
[0098] In this specification, unless stated otherwise, the term
"alkenyl" includes both straight and branched chain alkenyl groups.
The term "C.sub.2-6alkenyl" refers to an alkenyl group having 2 to
6 carbon atoms and one or two double bonds, and may be, but is not
limited to vinyl, allyl, propenyl, i-propenyl, butenyl, i-butenyl,
crotyl, pentenyl, i-pentenyl and hexenyl.
[0099] In this specification, unless stated otherwise, the term
"alkynyl" includes both straight and branched chain alkynyl groups.
The term C.sub.2-6alkynyl having 2 to 6 carbon atoms and one or two
triple bonds, and may be, but is not limited to ethynyl, propargyl,
butynyl, i-butynyl, pentynyl, i-pentynyl and hexynyl.
[0100] The term "aryl" refers to an optionally substituted
monocyclic or bicyclic hydrocarbon ring system containing at least
one unsaturated aromatic ring. Examples and suitable values of the
term "aryl" are phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl
and indenyl.
[0101] In this specification, unless stated otherwise, the term
"heteroaryl" refer to an optionally substituted monocyclic or
bicyclic unsaturated, aromatic ring system containing at least one
heteroatom selected independently from N, O or S. Examples of
"heteroaryl" may be, but are not limited to thiophene, thienyl,
pyridyl, thiazolyl, furyl, pyrrolyl, triazolyl, imidazolyl,
oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolonyl,
oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl,
benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl,
tetrahydrotriazolopyrimidinyl, benzofuryl, indolyl, isoindolyl,
pyridonyl, pyridazinyl, pyrimidinyl, imidazopyridyl,
oxazolopyridyl, thiazolopyridyl, pyridyl, imidazopyridazinyl,
oxazolopyridazinyl, thiazolopyridazinyl and purinyl.
[0102] In this specification, unless stated otherwise, the term
"alkylaryl", "alkylheteroaryl" and "alkylcycloalkyl" refer to a
substituent that is attached via the alkyl group to an aryl,
heteroaryl and cycloalkyl group.
[0103] In this specification, unless stated otherwise, a 5- or
6-membered ring containing one or more atoms independently selected
from C, N, O or S, includes aromatic and heteroaromatic rings as
well as carbocyclic and heterocyclic rings which may be saturated
or unsaturated. Examples of such rings may be, but are not limited
to furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl,
imidazolyl, imidazolidinyl, imidazolinyl, triazolyl, morpholinyl,
piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl,
pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl,
phenyl, cyclohexyl, cyclopentyl and cyclohexenyl.
[0104] In this specification, unless stated otherwise, a 3- to
8-membered ring containing one or more atoms independently selected
from C, N, O or S, includes aromatic and heteroaromatic rings as
well as carbocyclic and heterocyclic rings which may be saturated
or unsaturated. Examples of such rings may be, but are not limited
to imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl,
piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl,
pyrrolinyl, tetrahydropyranyl or thiomorpholinyl,
tetrahydrothiopyranyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl,
oxazolyl, oxazolidinonyl, pyrazinyl, pyrazolyl, pyridazinyl,
pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl,
triazolyl, phenyl, cyclopropyl, aziridinyl, cyclobutyl, azetidinyl,
cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,
cycloheptenyl, cyclooctyl and cyclooctenyl.
[0105] In this specification, unless stated otherwise, a 3- to
8-membered ring containing one or more atoms independently selected
from C, N, O or S, which group may optionally be fused with a 5- or
6-membered ring containing one or more atoms independently selected
from C, N, O or S, includes aromatic and heteroaromatic rings as
well as carbocyclic and heterocyclic rings which may be saturated
or unsaturated. Examples of such rings may be, but are not limited
to naphthyl, norcaryl, chromyl, isochromyl, indanyl, benzoimidazol
or tetralinyl, benzooxazolyl, benzothiazolyl, benzofuryl,
benzothienyl, benzotriazolyl, indolyl, azaindolyl, indazolyl,
indolinyl, isoindolinyl, benzimidazolyl, oxadiazolyl, thiadiazolyl,
quinolinyl, quinoxalinyl and benzotriazolyl.
[0106] In this specification, unless stated otherwise, the term
".dbd.NR.sup.5" and ".dbd.NOR.sup.5" include imino- and oximogroups
carrying an R.sup.5 substituent and may be, or be part of, groups
including, but not limited to iminoalkyl, iminohydroxy,
iminoalkoxy, amidine, hydroxyamidine and alkoxyamidine.
[0107] In the case where a subscript is the integer 0 (zero) the
group to which the subscript refers, indicates that the group is
absent, i.e. there is a direct bond between the groups.
[0108] In this specification, unless stated otherwise, the term
"bond" is a saturated bond.
[0109] In this specification, unless stated otherwise, the term
"halo" may be fluoro, chloro, bromo or iodo.
[0110] In this specification, unless stated otherwise, the term
"alkylhalo" means an alkyl group as defined above, substituted with
one or more halo. The term "C.sub.1-6alkylhalo" may include, but is
not limited to fluoromethyl, difluoromethyl, trifluoromethyl,
fluoroethyl, difluoroethyl and bromopropyl. The term
"OC.sub.1-6alkylhalo" may include, but is not limited to
fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy and
difluoroethoxy.
[0111] In one embodiments of the invention P may be hydrogen or
C.sub.3-7 alkyl or P may be a 3- to 8-membered ring containing one
or more atoms selected from C, N, O or S said ring may be
optionally fused with a 5- or 6-membered ring containing one or
more atoms independently selected from C, N, O, or S. In a
preferred embodiment of the invention P is selected from 5 and 6
membered aromatic and heteroaromatic rings.
[0112] In a further preferred embodiment P is selected from
thiophene, pyridyl, thiazolyl, furyl, pyrrolyl and phenyl, whereby
the phenyl ring is substituted on position 3 or disubstituted on
positions 2 and 5.
[0113] In yet a further preferred embodiment of the invention P is
phenyl substituted on position 3 or disubstituted on positions 2
and 5.
[0114] P is optionally substituted via a carbon atom with 0, 1, 2,
3 or 4 groups R.sup.1, wherein the number of R.sup.1 substituents
on the P ring is designated by the term m1. In preferred
embodiments of the invention m1 is 1 or 2. In further preferred
embodiments of the invention m1 is 1.
[0115] In suitable embodiments of invention R.sup.1 is selected
from the group consisting of hydrogen, hydroxy, halo, nitro,
C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo, C.sub.1-6alkyl,
OC.sub.1-6alkyl, C.sub.2-6alkenyl, OC.sub.2-6alkenyl,
C.sub.2-6alkynyl, OC.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl,
OC.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
OC.sub.0-6alkylaryl, CHO, (CO)R.sup.5, O(CO)R.sup.5, O(CO)OR.sup.5,
O(CN)OR.sup.5, C.sub.1-6alkylOR.sup.5, OC.sub.2-6alkylOR.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, OC.sub.1-6alkyl(CO)R.sup.5,
C.sub.0-6alkylCO.sub.2R.sup.5, OC.sub.1-6alkylCO.sub.2R.sup.5,
C.sub.0-6alkylcyano, OC.sub.2-6alkylcyano,
C.sub.0-6alkylNR.sup.5R.sup.6, OC.sub.2-6alkylNR.sup.5R.sup.5,
C.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-3alkyl(CO)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.2-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, C.sub.0-6alkylSR.sup.5,
OC.sub.2-6alkylSR.sup.5, C.sub.0-6alkyl(SO)R.sup.5,
OC.sub.2-6alkyl(SO)R.sup.5, C.sub.0-6alkylSO.sub.2R.sup.5,
OC.sub.2-6alkylSO.sub.2R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6, NR.sup.5OR.sup.6,
C.sub.0-6alkylNR.sup.5(CO)OR.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)OR.sup.6, SO.sub.3R.sup.5 and a 5- or
6-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S.
[0116] In a more suitable embodiment of the invention R.sup.1 is
selected from hydrogen, hydroxy, halo, nitro, C.sub.1-6alkylhalo,
OC.sub.1-6alkylhalo, C.sub.1-6alkyl, OC.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.0-6alkylC.sub.3-6cycloalkyl,
C.sub.1-6alkylOR.sup.5, C.sub.1-6alkyl(CO)R.sup.5,
C.sub.0-6alkylCO.sub.2R.sup.5, C.sub.0-6alkylcyano,
C.sub.0-6alkylNR.sup.5R.sup.6, C.sub.0-6alkylSR.sup.5 and a 5- or
6-membered ring containing one or more atoms independently selected
from the group consisting of C and O.
[0117] Any C.sub.1-6alkyl defined under R.sup.1 may be substituted
by one or more A. In one embodiment of the invention R.sup.1 is
ethyl and A is hydroxyl.
[0118] In a further suitable embodiment of the invention R.sup.1 is
selected from hydrogen, methyl, ethyl, cyclopropyl, hydroxy,
methoxy, cyano, fluoro, chloro, bromo, iodo, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, amino, nitro, dimethylamino,
methylsulfanyl, vinyl, acetyl, formic acid methyl ester,
methoxymethyl, ethanol and furyl.
[0119] In a more suitable embodiment of the invention P is selected
from the group consisting of thiophene, pyridyl, thiazolyl, furyl,
pyrrolyl or phenyl, whereby the phenyl ring is substituted on
position 3 or disubstituted on positions 2 and 5 and R.sup.1 is
selected from the group consisting of hydrogen, hydroxy, halo,
nitro, C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo, C.sub.1-6alkyl,
OC.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.1-6alkylOR.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, C.sub.0-6alkylCO.sub.2R.sup.5,
C.sub.0-6alkylcyano, C.sub.0-6alkylNR.sup.5R.sup.6,
C.sub.0-6alkylSR.sup.5 and a 5-membered ring containing one or more
atoms independently selected from the group consisting of C and
O.
[0120] In a further suitable embodiment of the invention P is
phenyl substituted on position 3 or disubstituted on positions 2
and 5 and R.sup.1 is selected from the group consisting of
hydrogen, hydroxy, halo, nitro, C.sub.1-6alkylhalo,
OC.sub.1-6alkylhalo, C.sub.1-6alkyl, OC.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.0-6alkylC.sub.3-6cycloalkyl,
C.sub.1-6alkylOR.sup.5, C.sub.1-6alkyl(CO)R.sup.5,
C.sub.0-6alkylCO.sub.2R.sup.5, C.sub.0-6alkylcyano,
C.sub.0-6alkylNR.sup.5R.sup.6, C.sub.0-6alkylSR.sup.5 and a
5-membered ring containing one or more atoms independently selected
from the group consisting of C and O.
[0121] According to another aspect of the invention the ring P is
connected to the core ring by M.sup.1, wherein M.sup.1 can be a
bond directly joining P to the core ring. M.sup.1 can also be a
linker C.sub.1-3alkyl.
[0122] In a preferred embodiment of the invention M.sup.1 is a
bond.
[0123] When M.sup.1 is not a direct bond M.sup.1 can be further
substituted with 0, 1, 2 or 3 substituents R.sup.2 wherein the
number of substituents R.sup.2 is designated by the term n. The
substituents R.sup.2 may be selected from hydrogen, hydroxy, oxo,
C.sub.1-4alkylhalo, halo and C.sub.1-4alkyl. In a preferred
embodiment of the invention n is 0.
[0124] In another aspect of the invention there is provided
compounds of formula I wherein X.sup.1 is selected from the group
consisting of C, CO, N, O and S. In a further aspect of the
invention X.sup.2 is selected from the group consisting of C, N, O
and S. In yet a further aspect of the invention X.sup.3 is selected
from the group consisting of N, O and S, or X.sup.3 is selected
from N, O, S, and C when X.sup.2 is selected from N, O, or S, and
when X.sup.3 is C the substituent R on X.sup.3 is H.
[0125] X.sup.1, X.sup.2 and X.sup.3 can be further substituted with
0, 1 or 2 substituents R wherein the number of substituents R is
designated by the term t. The substituent R may be selected from
the group consisting of hydrogen, C.sub.0-3alkyl, halo,
C.sub.0-3alkylOR.sup.5, C.sub.0-3alkylNR.sup.5R.sup.6,
C.sub.0-3alkyl(CO)OR.sup.5, C.sub.0-3alkylNR.sup.5R.sup.6 and
C.sub.0-3alkylaryl. In one embodiment of the invention R is
selected from the group consisting of hydrogen, C.sub.0-3alkyl and
halo.
[0126] In a preferred embodiment of the invention X.sup.1 is C, N
or O and R is selected from hydrogen, C.sub.0-3alkyl and halo. In
one embodiment R is selected from hydrogen, chloro or methyl.
[0127] In another preferred embodiment of the invention X.sup.1 is
N.
[0128] In a suitable embodiment X.sup.2 is selected from N, O and
S, and R is hydrogen. In another embodiment of the invention
X.sup.3 is N, O or S. In a further preferred embodiment of the
invention X.sup.1 is O and one of X.sup.2 and X.sup.3 is O and the
other is N. In yet a further preferred embodiment of the invention
X.sup.1 is N and one of X.sup.2 and X.sup.3 is O and the other is
N. In yet another preferred embodiment of the invention X.sup.1 is
C or CR and one of X.sup.2 and X.sup.3 is O and the other is N.
[0129] In another preferred embodiment of the invention X.sup.2 is
O and X.sup.3 is N, and in yet another preferred embodiment of the
invention X.sup.2 is N and X.sup.3 is O.
[0130] In a further preferred embodiment of the invention X.sup.1
is O and X.sup.2 and X.sup.3 are N.
[0131] In another suitable embodiment of the invention the ring
containing X.sup.1, X.sup.2 and X.sup.3 forms an oxadiazole,
isoxazole, oxazole, chloro-isoxazole or a methyl-isoxazole.
[0132] In a preferred embodiment of the invention the ring
containing X.sup.1, X.sup.2 and X.sup.3 forms an oxadiazole. In
another preferred embodiment of the invention the ring containing
X.sup.1, X.sup.2 and X.sup.3 forms an isoxazole.
[0133] The ring containing X.sup.1, X.sup.2 and X.sup.3 should not
be further annulated onto any other ring.
[0134] In a suitable embodiment of the invention M.sup.2 may be a
direct bond from the core ring to the variable X.sup.4 or M.sup.2
may be selected from the group consisting of bond, C.sub.1-3alkyl,
C.sub.2-3alkynyl, C.sub.0-4alkyl(CO)C.sub.0-4alkyl,
C.sub.0-3alkylOC.sub.0-3alkyl,
C.sub.0-3alkylNR.sup.5C.sub.1-3alkyl, C.sub.0-3alkyl(CO)NR.sup.5,
C.sub.0-4alkylNR.sup.5, C.sub.0-3alkyl(SO)C.sub.0-3alkyl and
C.sub.0-3alkyl(SO.sub.2)C.sub.0-3alkyl.
[0135] In preferred embodiments of the invention M.sup.2 is a bond
or C.sub.1-3alkyl. In further preferred embodiments of the
invention M.sup.2 is C.sub.1-3alkyl, preferably methyl or
ethyl.
[0136] When M.sub.2 is not a direct bond M.sup.2 may be further
substituted with 0, 1 or 2 R.sup.3 groups wherein the number of
substituents R.sup.3 is designated by the term n. In one embodiment
of the invention n is 1 or 2. In another embodiment of the
invention n is 0.
[0137] In a suitable embodiment of the invention R.sup.3 is
selected from the group consisting of R.sup.3 is selected from a
group consisting of hydroxy, C.sub.0-6alkylcyano, oxo,
.dbd.NR.sup.5, .dbd.NOR.sup.5, C.sub.1-4alkylhalo, halo,
C.sub.1-4alkyl, O(CO)C.sub.1-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, OC.sub.1-4alkyl, C.sub.1-4alkylOR.sup.5
and C.sub.0-4alkylNR.sup.5R.sup.6.
[0138] In a preferred embodiment R.sup.3 is selected from hydrogen
and C.sub.1-4alkyl, preferably methyl or dimethyl.
[0139] In another preferred embodiment M.sup.2 may be selected from
the group consisting of a bond, C.sub.1-3alkyl, C.sub.2-3alkynyl,
C.sub.0-4alkyl(CO)C.sub.0-4alkyl, C.sub.0-3alkylOC.sub.0-3alkyl,
C.sub.0-3alkylNR.sup.5C.sub.1-3alkyl, C.sub.0-3alkyl(CO)NR.sup.5,
C.sub.0-4alkylNR.sup.5, C.sub.0-3alkyl(SO)C.sub.0-3alkyl and
C.sub.0-3alkyl(SO.sub.2)C.sub.0-3alkyl and R.sup.3 is selected from
hydrogen and C.sub.1-4alkyl.
[0140] In yet another preferred embodiments of the invention
M.sup.2 is a bond or C.sub.1-3alkyl and R.sup.3 is hydrogen, methyl
or dimethyl.
[0141] In a further preferred embodiment M.sup.2 may be selected
from the group consisting of a bond, methyl and ethyl and R.sup.3
is hydrogen, methyl or dimethyl.
[0142] In a further embodiment of the invention M.sup.2 is
nitrogen. In yet a further embodiment of the invention M.sup.2 is
oxygen.
[0143] According to another aspect of the invention X.sup.4 is
selected from the group consisting of C.sub.0-4alkylR.sup.5R.sup.6,
C.sub.3-7cycloalkyl, C.sub.1-4alkyl(NR.sup.5R.sup.6), NR.sup.5,
C.sub.0-4alkyl(NR.sup.5R.sup.6).dbd.N,
NR.sup.5C.sub.0-4alkyl(NR.sup.5R.sup.6).dbd.N, NOC.sub.0-4alkyl,
C.sub.1-4alkylhalo, O, SO, SO.sub.2 and S, and wherein the bond
between M.sup.2 and X.sup.4 is a single bond.
[0144] In a preferred embodiment of the invention X.sup.4 is
selected from the group consisting of C.sub.0-4alkylR.sup.5R.sup.6,
C.sub.3-7cycloalkyl, NR.sup.5, O, SO, SO.sub.2 and S and R.sup.5
and R.sup.6 are independently selected from hydrogen and
C.sub.1-6alkyl.
[0145] In a further preferred embodiment of the invention X.sup.4
is selected from the group consisting of CH.sub.2, CHCH.sub.3,
CH(CH.sub.3).sub.2 and NR.sup.5. In a further preferred embodiment
of the invention X.sup.4 is NR.sup.5 and R.sup.5 is selected from
hydrogen and C.sub.1-6alkyl. In a preferred embodiment of the
invention R.sup.5 is methyl or hydrogen and R.sup.6 is
hydrogen.
[0146] In still a further preferred embodiment of the invention
X.sup.4 is O. In yet another preferred embodiment of the invention
X.sup.4 is S.
[0147] It is to be understood that the bond between M.sup.2 and
X.sup.4 is a single bond in all tautomeric forms.
[0148] Embodiments of the present invention include those wherein Q
is a 5- or 6-membered ring.
[0149] When Q is a 5-membered ring, Q is selected from the group
consisting of the group consisting of triazolyl, imidazolyl,
oxadiazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl and
thiadiazolyl, and wherein any substitutable nitrogen atom in the
ring is substituted with R.sup.4 on such nitrogen atom.
[0150] In one embodiment the 5 membered ring Q is selected from the
group consisting of triazolyl and thiadiazolyl. In another
embodiment the 5 membered ring Q is selected from the group
consisting of tetrazolyl and oxadiazolyl. In a further embodiment
the 5 membered ring Q is imidazolyl.
[0151] When Q is a 6-membered ring, Q is selected from the group
consisting of benzoimidazolyl, benzooxazolyl,
tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl,
pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl,
thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl,
thiazolopyridazinyl and purinyl.
[0152] In a preferred embodiment of the invention the 6 membered
ring Q is selected from the group consisting of pyridonyl,
tetrahydrotriazolopyridyl and tetrahydrotriazolopyrimidinyl. In
another embodiment the 6 membered ring Q is pyridazinyl. In a
further embodiment the 6 membered ring Q is selected from the group
consisting of benzoimidazolyl, benzooxazolyl and
imidazopyridyl.
[0153] Q can be further substituted with 0, 1, 2 or 3 substituents
R.sup.4, wherein the number of R.sup.4 substituents is designated
by the term m2. In a preferred embodiment m2 is 1 or 2. When Q is a
5-membered ring the substituent R.sup.4 is selected from the group
consisting of C.sub.0-6alkylcyano, .dbd.NC.sub.1-4alkyl,
.dbd.NOR.sup.5, C.sub.1-4alkylhalo, halo, C.sub.1-6alkyl,
OC.sub.1-4alkyl, C.sub.2-4alkenyl,
C.sub.0-2alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylheteroaryl, OC.sub.0-6alkylaryl,
OC.sub.0-6alkylheteroaryl, NC.sub.0-6alkylaryl,
NC.sub.0-6alkylheteroaryl, C.sub.0-6alkylOaryl,
C.sub.0-6alkylOheteroaryl, C.sub.0-6alkylNaryl,
C.sub.0-6alkylNheteroaryl, OC.sub.0-6alkylOaryl,
OC.sub.0-6alkylOheteroaryl, OC.sub.0-6alkylNaryl,
OC.sub.0-6alkylNheteroaryl, NC.sub.0-6alkylOaryl,
NC.sub.0-6alkylOheteroaryl, NC.sub.0-6alkylNaryl,
NC.sub.0-6alkylNheteroaryl, O(CO)C.sub.1-4alkyl,
C.sub.0-4alkyl(CO)OC.sub.1-4alkyl, C.sub.1-4alkyl(S)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5,
C.sub.0-4alkylN(C.sub.1-4alkyl).sub.2 and a 3- or 6-membered
non-aromatic ring containing one or more atoms independently
selected from C, N, O and S, which ring may optionally be fused
with a 5-membered ring containing one or more atoms independently
selected from the group consisting of C, N and O and wherein said
ring and said fused ring may be substituted by one or two A.
[0154] In a further embodiment of the invention R.sup.4 on the 5
membered Q ring is selected from the group consisting of
C.sub.1-4alkylhalo, C.sub.1-6alkyl, C.sub.2-4alkenyl,
C.sub.0-2alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylheteroaryl, OC.sub.0-6alkylaryl,
OC.sub.0-6alkylheteroaryl, NC.sub.0-6alkylaryl,
NC.sub.0-6alkylheteroaryl, C.sub.0-6alkylOaryl,
C.sub.0-6alkylOheteroaryl, C.sub.0-6alkylNaryl,
C.sub.0-6alkylNheteroaryl, OC.sub.0-6alkylOaryl,
OC.sub.0-6alkylOheteroaryl, OC.sub.0-6alkylNaryl,
OC.sub.0-6alkylNheteroaryl, NC.sub.0-6alkylOaryl,
NC.sub.0-6alkylOheteroaryl, NC.sub.0-6alkylNaryl,
NC.sub.0-6alkylNheteroaryl, C.sub.0-4alkyl(CO)OC.sub.1-4alkyl,
C.sub.1-4alkyl(S)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5 and a 3- or
6-membered non-aromatic ring containing one or more atoms
independently selected from C, N, O and S, which ring may
optionally be fused with a 5-membered ring containing one or more
atoms independently selected from the group consisting of C, N and
O and wherein said ring and said fused ring may be substituted by
one or two A.
[0155] In one embodiment of the invention Q is selected from the
group consisting of triazolyl, imidazolyl, oxadiazolyl,
imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl,
and wherein any substitutable nitrogen atom in the ring is
substituted with R.sup.4 on such nitrogen atom and R.sup.4 is
selected from the group consisting of C.sub.1-4alkylhalo,
C.sub.1-6alkyl, C.sub.2-4alkenyl,
C.sub.0-2alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylheteroaryl, OC.sub.0-6alkylaryl,
OC.sub.0-6alkylheteroaryl, NC.sub.0-6alkylaryl,
NC.sub.0-6alkylheteroaryl, C.sub.0-6alkylOaryl,
C.sub.0-6alkylOheteroaryl, C.sub.0-6alkylNaryl,
C.sub.0-6alkylNheteroaryl, OC.sub.0-6alkylOaryl,
OC.sub.0-6alkylOheteroaryl, OC.sub.0-6alkylNaryl,
OC.sub.0-6alkylNheteroaryl, NC.sub.0-6alkylOaryl,
NC.sub.0-6alkylOheteroaryl, NC.sub.0-6alkylNaryl,
NC.sub.0-6alkylNheteroaryl, C.sub.0-4alkyl(CO)OC.sub.1-4alkyl,
C.sub.1-4alkyl(S)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5 and a 3- or
6-membered non-aromatic ring containing one or more atoms
independently selected from C, N, O and S, which ring may
optionally be fused with a 5-membered ring containing one or more
atoms independently selected from the group consisting of C, N and
O and wherein said ring and said fused ring may be substituted by
one or two A.
[0156] In another embodiment of the invention Q selected from the
group consisting of triazolyl, imidazolyl, oxadiazolyl, tetrazolyl
and thiadiazolyl, and wherein any substitutable nitrogen atom in
the ring is substituted with R.sup.4 on such nitrogen atom and
R.sup.4 is selected from the group consisting of
C.sub.1-4alkylhalo, C.sub.1-6alkyl, C.sub.2-4alkenyl,
C.sub.0-2alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylheteroaryl, OC.sub.0-6alkylaryl,
OC.sub.0-6alkylheteroaryl, NC.sub.0-6alkylaryl,
NC.sub.0-6alkylheteroaryl, C.sub.0-6alkylOaryl,
C.sub.0-6alkylOheteroaryl, C.sub.0-6alkylNaryl,
C.sub.0-6alkylNheteroaryl, OC.sub.0-6alkylOaryl,
OC.sub.0-6alkylOheteroaryl, OC.sub.0-6alkylNaryl,
OC.sub.0-6alkylNheteroaryl, NC.sub.0-6alkylOaryl,
NC.sub.0-6alkylOheteroaryl, NC.sub.0-6alkylNaryl,
NC.sub.0-6alkylNheteroaryl, C.sub.0-4alkyl(CO)OC.sub.1-4alkyl,
C.sub.1-4alkyl(S)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5 and a 3- or
6-membered non-aromatic ring containing one or more atoms
independently selected from C, N, O and S, which ring may
optionally be fused with a 5-membered ring containing one or more
atoms independently selected from the group consisting of C, N and
O and wherein said ring and said fused ring may be substituted by
one or two A.
[0157] When Q is a 6-membered ring the substituent R.sup.4 is
selected from the group consisting of hydrogen, hydroxy,
C.sub.0-6alkylcyano, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-6alkyl, OC.sub.1-4alkyl,
OC.sub.0-6alkylaryl, O(CO)C.sub.1-4alkyl,
C.sub.0-4alkyl(S)C.sub.0-4alkyl, C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5,
C.sub.0-4alkylNR.sup.5R.sup.6 and a 5- or 6-membered ring
containing one or more atoms independently selected from C, N, O
and S, which ring may optionally be fused with a 5- or 6-membered
ring containing one or more atoms independently selected from the
group consisting of C, N and O and wherein said ring and said fused
ring may be substituted by one or two A.
[0158] In a suitable embodiment of the invention R.sup.4 on the 6
membered Q ring is selected from hydrogen and C.sub.1-6alkyl. In a
further embodiment of the invention R.sup.4 is hydrogen, methyl,
ethyl, propyl, butyl or hexyl.
[0159] In a preferred embodiment of the invention Q selected from
the group consisting of benzoimidazolyl, benzooxazolyl,
tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl,
pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl,
thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl,
thiazolopyridazinyl and purinyl and R.sup.4 is hydrogen or
C.sub.1-6alkyl.
[0160] In another preferred embodiment of the invention Q selected
from the group consisting of benzoimidazolyl, benzooxazolyl,
tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl,
pyridonyl, pyridazinyl and imidazopyridyl, and R.sup.4 is hydrogen
or C.sub.1-6alkyl.
[0161] In a suitable embodiment of the invention R.sup.4 is
selected from the group consisting of benzo[b]thiophenyl,
benzodioxolyl, bromo, bromofuryl, butoxyphenyl,
chloromethoxypyridyl, chlorophenyl, chlorophenylmethanol,
chloropyridyl, chlorothiophene, cyanophenyl, cyclohexyl,
cyclopentyl, dichloro-phenyl, dichloropyridyl, difluorophenyl,
dimethylthiazolyl, ethanol, ethoxymethyl, fluoromethylphenyl,
fluorophenyl, formic acid methyl ester, furyl, hydrogen,
hydroxyphenoxymethyl, hydroxyphenyl, imidazolyl, methoxyethyl,
methoxymethyl, methoxyphenoxymethyl, methoxyphenyl,
methoxyphenylethyl, methoxypyridazinyl, methoxypyridyl,
methoxypyrimidinyl, methoxythiophene, methylimidazolyl,
methylpyridyl, methylsulfanylmethyl, methylthiazolyl,
methylthiophene, nitrofuryl, nitrophenyl, phenyl, p-tolyloxymethyl,
pyridazinyl, pyridine-oxidyl, benzylmorpholinyl, pyridinolyl,
pyridyl, pyridylmethyl, pyrimidinyl, tert-butylphenyl,
tetrahydrofuryl, thiazolyl, thiophene, tolyl, trifluoromethyl,
acetic acid methylester, allyl, amino, benzyl, cyclopropylmethyl,
ethyl, fluorobenzyl, fluoroethyl, furylmethyl, hydroxyethyl,
isobutyl, methyl, methylbenzyl, methylbutyl, methylsulfanylpropyl,
n-butyl, n-hexyl, n-propyl, tetrahydrofurylmethyl, thiophenylmethyl
and trifluoroethyl.
[0162] Ring Q may be substituted by one or more R.sup.4 on a carbon
and/or a nitrogen atom in the ring. When Q is substituted on the
carbon atom, R.sup.4 is selected from benzo[b]thiophenyl,
benzodioxolyl, bromo, bromofuryl, butoxyphenyl,
chloromethoxypyridyl, chlorophenyl, chlorophenylmethanol,
chloropyridyl, chlorothiophene, cyanophenyl, cyclohexyl,
cyclopentyl, dichloro-phenyl, dichloropyridyl, difluorophenyl,
dimethylthiazolyl, ethanol, ethoxymethyl, fluoromethylphenyl,
fluorophenyl, formic acid methyl ester, furyl, hydrogen,
hydroxyphenoxymethyl, hydroxyphenyl, imidazolyl, methoxyethyl,
methoxymethyl, methoxyphenoxymethyl, methoxyphenyl,
methoxyphenylethyl, methoxypyridazinyl, methoxypyridyl,
methoxypyrimidinyl, methoxythiophene, methylimidazolyl,
methylpyridyl, methylsulfanylmethyl, methylthiazolyl,
methylthiophene, nitrofuryl, nitrophenyl, phenyl, p-tolyloxymethyl,
pyridazinyl, pyridine-oxidyl, benzylmorpholinyl, pyridinolyl,
pyridyl, pyridylmethyl, pyrimidinyl, tert-butylphenyl,
tetrahydrofuryl, thiazolyl, thiophene, tolyl and
trifluoromethyl.
[0163] When Q is substituted on the nitrogen atom, R.sup.4 is
selected from acetic acid methylester, allyl, amino, benzyl,
cyclopropyl, cyclopropylmethyl, ethyl, fluorobenzyl, fluoroethyl,
furylmethyl, hydroxyethyl, isobutyl, methoxyethyl, methyl,
methylbenzyl, methylbutyl, methylsulfanylpropyl, n-butyl, n-hexyl,
n-propyl, tetrahydrofurylmethyl, thiophenylmethyl and
trifluoroethyl.
[0164] When R.sup.4 is a ring R.sup.4 can be substituted with one
or more substituents A, wherein A is selected from hydrogen,
hydroxy, halo, nitro, oxo, C.sub.0-6alkylcyano,
C.sub.0-4alkylC.sub.3-6cycloalkyl, C.sub.1-6alkyl,
C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo, C.sub.2-6alkenyl,
C.sub.0-3alkylaryl, C.sub.0-6alkylOR.sup.5,
OC.sub.2-6alkylOR.sup.5, C.sub.1-6alkylSR.sup.5,
OC.sub.2-6alkylSR.sup.5, (CO)R.sup.5, O(CO)R.sup.5,
OC.sub.2-6alkylcyano, OC.sub.1-6alkylCO.sub.2R.sup.5,
O(CO)OR.sup.5, OC.sub.1-6alkyl(CO)R.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, NR.sup.5OR.sup.6,
OC.sub.2-6alkylNR.sup.5R.sup.6, C.sub.0-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6, SO.sub.3R.sup.5,
C.sub.1-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)R.sup.5, C.sub.0-6alkyl(SO.sub.2)R.sup.5,
C.sub.0-6alkyl(SO)R.sup.5, OC.sub.2-6alkyl(SO)R.sup.5 and a
5-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S.
[0165] In a preferred embodiment A is selected from hydroxy, halo,
nitro, oxo, C.sub.0-6alkylcyano, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.0-3alkylaryl, C.sub.0-6alkylOR.sup.5 and a 5-membered ring
containing one or more atoms independently selected from the group
consisting of C and O.
[0166] Specific embodiments of the invention include, [0167]
2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimid-
azole, [0168]
5-(3-Methoxy-phenyl)-3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsu-
lfanylmethyl)-[1,2,4]oxadiazole, [0169]
3-[5-(1-Methyl-5-thiophen-2-yl-1H-imidazol-2-ylsulfanylmethyl)-[1,2,4]oxa-
diazol-3-yl]-benzonitrile, [0170]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-pheny-
l-[1,2,4]oxadiazole, [0171]
2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-methyl-1H--
benzoimidazole, [0172]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tol-
yl-[1,2,4]oxadiazole, [0173]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-tr-
ifluoromethyl-phenyl)-[1,2,4]oxadiazole, [0174]
3-(3-Methoxy-phenyl)-5-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsu-
lfanylmethyl)-[1,2,4]oxadiazole, [0175]
5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-pheny-
l-[1,2,4]oxadiazole, [0176]
5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-m-tol-
yl-[1,2,4]oxadiazole, [0177]
3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2-
,4]oxadiazol-5-yl]-benzonitrile, [0178]
3-[4-Methyl-5-(2-methyl-thiazol-4-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethy-
l]-5-m-tolyl-[1,2,4]oxadiazole, [0179]
3-[5-(2-Methyl-thiazol-4-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-5-m-tol-
yl-[1,2,4]oxadiazole, [0180]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiop-
hen-2-yl-[1,2,4]oxadiazole, [0181]
3-[5-(2,4-Dimethyl-thiazol-5-yl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylm-
ethyl]-5-m-tolyl-[1,2,4]oxadiazole, [0182]
3-[4-Methyl-5-(5-nitro-furan-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]--
5-m-tolyl-[1,2,4]oxadiazole, [0183]
4-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]t-
riazol-3-yl]-pyridine, [0184]
3-[5-(4-tert-Butyl-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-
-5-m-tolyl-[1,2,4]-oxadiazole, [0185]
2-Chloro-5-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-
-[1,2,4]triazol-3-yl]-pyridine, [0186]
2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-benzooxazole-
, [0187]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethy-
l)-5-thiophen-3-yl-[1,2,4]oxadiazole, [0188]
3-(5-Furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl--
[1,2,4]oxadiazole, [0189]
5-(3-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazole, [0190]
2-(5-m-Tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-pyridine, [0191]
2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-imidazo[4-
,5-b]pyridine, [0192]
5-(3-Fluoro-5-methyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazo-
l-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0193]
3-Methyl-5-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmet-
hyl)-[1,2,4]oxadiazol-5-yl]-pyridine, [0194]
3-(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2-
,4]oxadiazole, [0195]
2-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]t-
riazol-3-yl]-pyridine, [0196]
4-Benzyl-2-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-
-[1,2,4]triazol-3-yl]-morpholine, [0197]
4-[4-Methyl-5-(5-thiophen-3-yl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1-
,2,4]triazol-3-yl]-pyridine, [0198]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiaz-
ol-4-yl-[1,2,4]oxadiazole, [0199]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-ni-
tro-phenyl)-[1,2,4]oxadiazole, [0200]
2-Methyl-4-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmet-
hyl)-[1,2,4]oxadiazol-5-yl]-pyridine, [0201]
3-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]t-
riazol-3-yl]-pyridine, [0202]
3-(4-Methyl-5-thiophene-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-to-
lyl-[1,2,4]oxadiazole, [0203]
3-(4-Methyl-5-thiazol-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-toly-
l-[1,2,4]oxadiazole, [0204]
5-(3-Iodo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfa-
nylmethyl)-[1,2,4]oxadiazole, [0205]
5-(3-Ethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulf-
anylmethyl)-[1,2,4]oxadiazole, [0206]
2-[5-(2-Methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benz-
oimidazole, [0207]
2-[5-(3-Iodo-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazo-
le, [0208]
3-(4-Methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-t-
olyl-[1,2,4]oxadiazole, [0209]
2,6-Dichloro-4-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl-
)-4H-[1,2,4]triazol-3-yl]-pyridine, [0210]
3-(4-Methyl-5-p-tolyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,-
2,4]oxadiazole, [0211]
Dimethyl-{3-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylme-
thyl)-[1,2,4]oxadiazol-5-yl]phenyl}-amine, [0212]
5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazole, [0213]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-tr-
ifluoromethoxy-phenyl) [1,2,4]oxadiazole, [0214]
3-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl--
[1,2,4]oxadiazole, [0215]
3-(5-tert-Butyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl--
[1,2,4]oxadiazole, [0216]
5-(3-Bromo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulf-
anylmethyl)-[1,2,4]oxadiazole, [0217]
2-[5-(3-Bromo-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidaz-
ole, [0218]
5-(3-Methoxymethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol--
3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0219]
2-[5-(3-Methoxymethyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-ben-
zoimidazole, [0220]
4-[5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2-
,4]oxadiazol-3-yl]-pyridine, [0221]
2-{1-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-1-methyl-
-1H-imidazo[4,5-b]pyridine, [0222]
2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1-methyl-1H--
imidazo[4,5-b], [0223]
3-[1-Methyl-1-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-e-
thyl]-5-m-tolyl-[1,2,4]oxadiazole, [0224]
3-[1-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m-
-tolyl-[1,2,4]oxadiazole, [0225]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulfonylmethyl)-5-m-toly-
l-[1,2,4]oxadiazole, [0226]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulfinylmethyl)-5-m-toly-
l-[1,2,4]oxadiazole, or [0227]
5-(3-Furan-3-yl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-y-
lsulfanylmethyl)-[1,2,4]oxadiazole, [0228] or salt thereof.
[0229] Further specific embodiments of the invention include,
[0230]
4-(4-Cyclopropyl-5-{1-[5-(2,5-difluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-eth-
ylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine, [0231]
4-(5-{1-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-met-
hyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0232]
4-{4-Methyl-5-[1-(5-m-tolyl-[1,2,4]oxadiazol-3-yl)-ethylsulfanyl]-4H-[1,2-
,4]triazol-3-yl}-pyridine, [0233]
5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-o-tol-
yl-[1,2,4]oxadiazole, [0234]
5-(3-Chloro-phenyl)-3-(4-cyclopropyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3--
ylsulfanylmethyl)-[1,2,4]oxadiazole, [0235]
2-{3-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-
-thiophen-2-yl-[1,2,4]triazol-4-yl}-ethanol, [0236]
4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsul-
fanyl]-4H-[1,2,4]triazol-3-yl}-pyrimidine, [0237]
3-(4-Ethyl-5-furan-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-
-5-methyl-phenyl)-[1,2,4]oxadiazole, [0238]
{3-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-t-
hiophen-2-yl-[1,2,4]triazol-4-yl}-acetic acid methyl ester, [0239]
5-(2-Fluoro-5-methyl-phenyl)-3-[5-furan-2-yl-4-(2-methoxy-ethyl)-4H-[1,2,-
4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0240]
3-(4-Cyclopropyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2--
fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole, [0241]
3-(5-Chloro-2-fluoro-phenyl)-5-(4-cyclopropylmethyl-5-thiophen-2-yl-4H-[1-
,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0242]
4-{5-[3-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-
-ethyl-4H-[1,2,4]triazol-3-yl}-pyrimidine, [0243]
3-(5-Cyclopentyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl--
[1,2,4]oxadiazole, [0244]
3-(3-Chloro-phenyl)-5-{4-ethyl-5-[2-(4-methoxy-phenyl)-ethyl]-4H-[1,2,4]t-
riazol-3-ylsulfanylmethyl}-[1,2,4]oxadiazole, [0245]
5-(3-Chloro-phenyl)-3-(4-ethyl-5-p-tolyloxymethyl-4H-[1,2,4]triazol-3-yls-
ulfanylmethyl)-[1,2,4]oxadiazole, [0246]
5-(3-Chloro-phenyl)-3-[4-(2-methoxy-ethyl)-5-thiophen-2-yl-4H-[1,2,4]tria-
zol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0247]
3-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-methoxymethyl-4H-[1,2,4]triazol-
-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0248]
5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-methoxymethyl-4H-[1,2,4]triazol-
-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0249]
5-(3-Chloro-phenyl)-3-(4-ethyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulf-
anylmethyl)-[1,2,4]oxadiazole, [0250]
3-(3-Chloro-phenyl)-5-(4-ethyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulf-
anylmethyl)-[1,2,4]oxadiazole, [0251]
4-(5-{1-[3-(3-Chloro-phenyl)-isoxazol-5-yl]-ethylsulfanyl}-4-methyl-4H-[1-
,2,4]triazol-3-yl)-pyridine, [0252]
3-(4-Allyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro-
-phenyl)-[1,2,4]oxadiazole, [0253]
3-(4-Allyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen--
3-yl-[1,2,4]oxadiazole, [0254]
5-(4-Allyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-furan-2-y-
l-[1,2,4]oxadiazole, [0255]
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(4-methoxy-phenoxymethyl)-4H-[1,2,4]tria-
zol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0256]
3-(3-Chloro-phenyl)-5-[4-ethyl-5-(4-methoxy-phenoxymethyl)-4H-[1,2,4]tria-
zol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0257]
{5-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-[-
1,2,4]triazol-3-yl}-methanol, [0258]
3-(3-Chloro-phenyl)-5-[4-ethyl-5-(2-methoxy-ethyl)-4H-[1,2,4]triazol-3-yl-
sulfanylmethyl]-[1,2,4]oxadiazole, [0259]
3-(3-Chloro-phenyl)-5-(4-ethyl-5-methylsulfanylmethyl-4H-[1,2,4]triazol-3-
-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0260]
3-(3-Chloro-phenyl)-5-(5-ethoxymethyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfa-
nylmethyl)-[1,2,4]oxadiazole, [0261]
5-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-[1-
,2,4]triazole-3-carboxylic acid methyl ester, [0262]
2-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3--
ylsulfanylmethyl)-[1,3,4]oxadiazole, [0263]
2-(3-Chloro-phenyl)-5-(4-cyclopropyl-5-furan-2-yl-4H-[1,2,4]triazol-3-yls-
ulfanylmethyl)-[1,3,4]oxadiazole, [0264]
5-(3-Chloro-phenyl)-3-{1-[4-ethyl-5-(tetrahydro-furan-2-yl)-4H-[1,2,4]tri-
azol-3-ylsulfanyl]-ethyl}-[1,2,4]oxadiazole, [0265]
4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethy-
l-4H-[1,2,4]triazol-3-yl)-pyridazine, [0266]
4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethy-
l-4H-[1,2,4]triazol-3-ylmethyl)-pyridine, [0267]
5-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethy-
l-4H-[1,2,4]triazol-3-yl)-pyridin-2-ol, [0268]
4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethy-
l-4H-[1,2,4]triazol-3-yl)-phenol, [0269]
5-(3-Chloro-phenyl)-3-[5-(4-methoxy-phenoxymethyl)-4-(tetrahydro-furan-2--
ylmethyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,
[0270]
5-(3-Chloro-phenyl)-3-[4-cyclopropyl-5-(4-methoxy-phenoxymethyl)-4H-[1,2-
,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0271]
5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3--
ylsulfanylmethyl)-[1,2,4]oxadiazole, [0272]
3-(4-Ethyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-toly-
l-[1,2,4]oxadiazole, [0273]
3-[4-Ethyl-5-(tetrahydro-furan-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl-
]-5-m-tolyl-[1,2,4]oxadiazole, [0274]
2-(3-Chloro-phenyl)-5-{1-[4-ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol--
3-ylsulfanyl]-ethyl}-[1,3,4]oxadiazole, [0275]
4-{5-[3-(2,5-Difluoro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethy-
l-4H-[1,2,4]triazol-3-yl}-pyrimidine, [0276]
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-
-methyl-4H-[1,2,4]triazol-3-yl}-pyrimidine, [0277]
3-(3-Chloro-phenyl)-5-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazole, [0278]
5-(3-Methylsulfanyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-
-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0279]
2-[5-(3-Methylsulfanyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-be-
nzoimidazole, [0280]
5-(2,5-Dimethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-y-
lsulfanylmethyl)-[1,2,4]oxadiazole, [0281]
5-(2-Fluoro-5-methyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazo-
l-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0282]
5-(3-Cyclopropyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3--
ylsulfanylmethyl)-[1,2,4]oxadiazole, [0283]
4-{5-[2-(3-Chloro-phenyl)-oxazol-4-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]t-
riazol-3-yl}-pyridine, [0284]
4-[4-Methyl-5-(5-thiophen-2-yl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1-
,2,4]triazol-3-yl]-pyridine, [0285]
4-{4-Methyl-5-[5-(3-methylsulfanyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsul-
fanyl]-4H-[1,2,4]triazol-3-yl}-pyridine, [0286]
4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4-
H-[1,2,4]triazol-3-yl}-pyridine, [0287]
2-Methyl-4-[3-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmeth-
yl)-[1,2,4]oxadiazol-5-yl]-pyridine, [0288]
1-{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[-
1,2,4]oxadiazol-5-yl]-phenyl}-ethanone, [0289]
4-{5-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-
-methyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0290]
2-Methyl-4-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-
-[1,2,4]triazol-3-yl]-pyridine, [0291]
3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl-5-thiophen-2-
-yl-4H-[1,2,4]triazole, [0292]
4-{5-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4-
]triazol-3-yl}-pyridine, [0293]
3-(4-Butyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chl-
oro-phenyl)-[1,2,4]oxadiazole, [0294]
5-(3-Chloro-phenyl)-3-[4-(3-methoxy-propyl)-5-thiophen-2-yl-4H-[1,2,4]tri-
azol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0295]
3-(4-Benzyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-ch-
loro-phenyl)-[1,2,4]oxadiazole, [0296]
5-(3-Chloro-phenyl)-3-(4-furan-2-ylmethyl-5-thiophen-2-yl-4H-[1,2,4]triaz-
ol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0297]
3-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4-
H-[1,2,4]triazol-3-yl}-pyridine, [0298]
5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazole, [0299]
4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4-
H-[1,2,4]triazol-3-yl}-2-methyl-pyridine, [0300]
5-(5-Chloro-2-fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazo-
l-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0301]
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-
-methyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0302]
3-{5-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-
-methyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0303]
5-(3-Chloro-phenyl)-3-(5-thiophen-2-yl-4-thiophen-2-ylmethyl-4H-[1,2,4]tr-
iazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0304]
5-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulf-
anylmethyl)-[1,2,4]oxadiazole, [0305]
3-{5-[3-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-
-methyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0306]
4-{5-[3-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-
-methyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0307]
4-{5-[5-(5-Bromo-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4--
methyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0308]
3-{5-[5-(5-Bromo-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4--
methyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0309]
5-(5-Bromo-2-fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-
-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0310]
5-(4-Methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-pheny-
l-[1,2,4]oxadiazole, [0311]
3-{5-[5-(3-Fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4-
H-[1,2,4]triazol-3-yl}-pyridine, [0312]
4-{5-[5-(3-Fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4-
H-[1,2,4]triazol-3-yl}-pyridine, [0313]
5-(3-Fluoro-phenyl)-3-(4-methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazole, [0314]
3-[4-Methyl-5-(5-thiophen-3-yl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1-
,2,4]triazol-3-yl]-pyridine, [0315]
3-(4-Methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiop-
hen-3-yl-[1,2,4]oxadiazole, [0316]
2-Chloro-4-[3-(4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmeth-
yl)-[1,2,4]oxadiazol-5-yl]-pyridine, [0317]
2-Chloro-4-[3-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmeth-
yl)-[1,2,4]oxadiazol-5-yl]-pyridine, [0318]
2-Chloro-4-[3-(4-methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmet-
hyl)-[1,2,4]oxadiazol-5-yl]-pyridine, [0319]
4-[4-Methyl-5-(5-phenyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]tr-
iazol-3-yl]-pyridine, [0320]
3-(4-Methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-pheny-
l-[1,2,4]oxadiazole, [0321]
5-(5-Bromo-2-fluoro-phenyl)-3-(4-methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-
-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0322]
3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-thiophen-2--
yl-4H-[1,2,4]triazole, [0323]
2-Chloro-4-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmet-
hyl)-[1,2,4]oxadiazol-5-yl]-pyridine, [0324]
4-{5-[3-(3-Fluoro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4-
H-[1,2,4]triazol-3-yl}-pyridine, [0325]
3-(3-Fluoro-phenyl)-5-(4-methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazole, [0326]
3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-toly-
l-[1,2,4]oxadiazole, [0327]
3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-flu-
oro-5-methyl-phenyl)-[1,2,4]oxadiazole, [0328]
4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-furan-2--
ylmethyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0329]
4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-
-[1,2,4]triazol-3-yl}-pyridine, [0330]
3-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-
-[1,2,4]triazol-3-yl}-pyridine, [0331]
5-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulf-
anylmethyl)-[1,2,4]oxadiazole, [0332]
3-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-furan-2--
ylmethyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0333]
3-(4-Furan-2-ylmethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethy-
l)-5-m-tolyl-[1,2,4]oxadiazole, [0334]
5-(5-Fluoro-2-methyl-phenyl)-3-(4-furan-2-ylmethyl-5-thiophen-2-yl-4H-[1,-
2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0335]
5-(3-Chloro-phenyl)-3-(4-furan-2-ylmethyl-4H-[1,2,4]triazol-3-ylsulfanylm-
ethyl)-[1,2,4]oxadiazole, [0336]
3-[3-(4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,-
4]oxadiazol-5-yl]-benzonitrile, [0337]
3-[3-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-oxadi-
azol-5-yl]-benzonitrile, [0338]
3-[3-(4-Methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2-
,4]oxadiazol-5-yl]-benzonitrile, [0339]
5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-
-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0340]
2-Chloro-4-[3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmeth-
yl)-[1,2,4]oxadiazol-5-yl]-pyridine, [0341]
3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thioph-
en-3-yl-[1,2,4]oxadiazole, [0342]
3-(4-Ethyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-toly-
l-[1,2,4]oxadiazole, [0343]
4-[4-Ethyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]tr-
iazol-3-yl]-pyridine, [0344]
3-[4-Ethyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]tr-
iazol-3-yl]-pyridine, [0345]
3-(4-Ethyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-flu-
oro-5-methyl-phenyl)-[1,2,4]oxadiazole, [0346]
4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsul-
fanyl]-4H-[1,2,4]triazol-3-yl}-pyridine, [0347]
3-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsul-
fanyl]-4H-[1,2,4]triazol-3-yl}-pyridine, [0348]
3-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-pyridin-4-y-
l-[1,2,4]triazol-4-ylamine, [0349]
4-{5-[5-(5-Bromo-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4--
ethyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0350]
5-(4-Methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thiop-
hen-2-yl-[1,2,4]oxadiazole, [0351]
3-[3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,-
4]oxadiazol-5-yl]-benzonitrile, [0352]
3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-phenyl-
-[1,2,4]oxadiazole, [0353]
4-[3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,-
4]oxadiazol-5-yl]-2-methoxy-pyridine, [0354]
3-(3-Chloro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulf-
anylmethyl)-[1,2,4]oxadiazole, [0355]
4-{5-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]-
triazol-3-yl}-pyridine, [0356]
2-Methyl-4-[3-(4-methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmet-
hyl)-[1,2,4]oxadiazol-5-yl]-pyridine, [0357]
4-[3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,-
4]oxadiazol-5-yl]-2-methyl-pyridine,
[0358]
5-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
3-thiophen-2-yl-[1,2,4]oxadiazole, [0359]
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-
-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0360]
4-[3-(4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4-
]oxadiazol-5-yl]-2-methyl-pyridine, [0361]
3-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4-
H-[1,2,4]triazol-3-yl}-benzonitrile, [0362]
5-(3-Chloro-phenyl)-3-[5-(3-chloro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-y-
lsulfanylmethyl]-[1,2,4]oxadiazole, [0363]
5-(3-Chloro-phenyl)-3-[5-(4-chloro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-y-
lsulfanylmethyl]-[1,2,4]oxadiazole, [0364]
4-{5-[5-(2,5-Dichloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethy-
l-4H-[1,2,4]triazol-3-yl}-pyridine, [0365]
5-(2,5-Dichloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl-
sulfanylmethyl)-[1,2,4]oxadiazole, [0366]
5-(2,5-Difluoro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl-
sulfanylmethyl)-[1,2,4]oxadiazole, [0367]
4-{5-[5-(2,5-Difluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethy-
l-4H-[1,2,4]triazol-3-yl}-pyridine, [0368]
5-(2,5-Dichloro-phenyl)-3-(4-ethyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-yl-
sulfanylmethyl)-[1,2,4]oxadiazole, [0369]
5-(2,5-Difluoro-phenyl)-3-(4-ethyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-yl-
sulfanylmethyl)-[1,2,4]oxadiazole, [0370]
4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-propyl-4-
H-[1,2,4]triazol-3-yl}-pyridine, [0371]
4-{5-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-
-propyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0372]
3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thioph-
en-2-yl-[1,2,4]oxadiazole, [0373]
3-(4-Methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiop-
hen-2-yl-[1,2,4]oxadiazole, [0374]
4-[4-Methyl-5-(3-thiophen-3-yl-[1,2,4]oxadiazol-5-ylmethylsulfanyl)-4H-[1-
,2,4]triazol-3-yl]-pyridine, [0375]
5-(4-Methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thiop-
hen-3-yl-[1,2,4]oxadiazole, [0376]
5-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thioph-
en-3-yl-[1,2,4]oxadiazole, [0377]
5-[3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,-
4]oxadiazol-5-yl]-thiophene-3-carbonitrile, [0378]
5-(3-Chloro-phenyl)-3-[5-(2-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-y-
lsulfanylmethyl]-[1,2,4]oxadiazole, [0379]
5-(3-Chloro-phenyl)-3-[5-(3-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-y-
lsulfanylmethyl]-[1,2,4]oxadiazole, [0380]
5-(3-Chloro-phenyl)-3-[5-(4-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-y-
lsulfanylmethyl]-[1,2,4]oxadiazole, [0381]
3-(5-Benzo[b]thiophen-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-
-5-(3-chloro-phenyl)-[1,2,4]oxadiazole, [0382]
5-(3-Chloro-phenyl)-3-[5-(3-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3--
ylsulfanylmethyl]-[1,2,4]oxadiazole, [0383]
5-(3-Chloro-phenyl)-3-[5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3--
ylsulfanylmethyl]-[1,2,4]oxadiazole, [0384]
3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-
-5-methyl-phenyl)-[1,2,4]oxadiazole, [0385]
3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[-
1,2,4]oxadiazole, [0386]
3-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-f-
luoro-5-methyl-phenyl)-[1,2,4]oxadiazole, [0387]
3-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-py-
ridin-4-yl-[1,2,4]triazol-4-ylamine, [0388]
3-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-th-
iophen-2-yl-[1,2,4]triazol-4-ylamine, [0389]
3-Pyridin-4-yl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-[1,2,4]t-
riazol-4-ylamine, [0390]
3-Thiophen-2-yl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-[1,2,4]-
triazol-4-ylamine, [0391]
3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen--
3-yl-[1,2,4]oxadiazole, [0392]
5-(3-Chloro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfany-
lmethyl)-[1,2,4]oxadiazole, [0393]
4-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]o-
xadiazol-5-yl]-2-methyl-pyridine, [0394]
5-(2,5-Difluoro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazole, [0395]
4-[4-Ethyl-5-(5-thiophen-3-yl-isoxazol-3-ylmethylsulfanyl)-4H-[1,2,4]tria-
zol-3-yl]-pyridine, [0396]
4-Ethyl-3-furan-2-yl-5-(5-thiophen-3-yl-isoxazol-3-ylmethylsulfanyl)-4H-[-
1,2,4]triazole, [0397]
5-(3-Chloro-phenyl)-3-[5-(3,5-dichloro-phenyl)-4-ethyl-4H-[1,2,4]triazol--
3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0398]
5-(3-Chloro-phenyl)-3-(4-ethyl-5-p-tolyl-4H-[1,2,4]triazol-3-ylsulfanylme-
thyl)-[1,2,4]oxadiazole, [0399]
5-(3-Chloro-phenyl)-3-(4-ethyl-5-m-tolyl-4H-[1,2,4]triazol-3-ylsulfanylme-
thyl)-[1,2,4]oxadiazole, [0400]
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-nitro-phenyl)-4H-[1,2,4]triazol-3-yls-
ulfanylmethyl]-[1,2,4]oxadiazole, [0401]
4-{5-[3-(3-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-4-methyl-4H-[1,2,4-
]triazol-3-yl}-pyridine, [0402]
5-(3-Chloro-phenyl)-3-[5-(2,5-difluoro-phenyl)-4-ethyl-4H-[1,2,4]triazol--
3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0403]
5-(3-Chloro-phenyl)-3-[5-(3-chloro-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-yl-
sulfanylmethyl]-[1,2,4]oxadiazole, [0404]
5-(3-Chloro-phenyl)-3-[5-(4-chloro-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-yl-
sulfanylmethyl]-[1,2,4]oxadiazole, [0405]
4-{5-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]tr-
iazol-3-yl}-pyridine, [0406]
3-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-5-thiophen-2-yl-
-4H-[1,2,4]triazole, [0407]
3-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-5-furan-2-yl-4H-
-[1,2,4]triazole, [0408]
5-(2-Chloro-5-methyl-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-
-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0409]
4-{5-[3-(3-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]-
triazol-3-yl}-pyridine, [0410]
3-[3-(3-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-4-ethyl-5-thiophen-2--
yl-4H-[1,2,4]triazole, [0411]
3-[3-(3-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-4-ethyl-5-furan-2-yl--
4H-[1,2,4]triazole, [0412]
4-{5-[5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl--
4H-[1,2,4]triazol-3-yl}-pyridine, [0413]
5-(2,5-Dichloro-thiophen-3-yl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triaz-
ol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0414]
4-{5-[5-(2,5-Dichloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-
-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0415]
4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-
H-[1,2,4]triazol-3-yl}-pyridine, [0416]
4-Ethyl-3-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-th-
iophen-2-yl-4H-[1,2,4]triazole, [0417]
4-Ethyl-3-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-fu-
ran-2-yl-4H-[1,2,4]triazole, [0418]
5-(3-Chloro-phenyl)-3-(4-ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsu-
lfanylmethyl)-[1,2,4]oxadiazole, [0419]
3-(3-Chloro-phenyl)-5-(4-ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsu-
lfanylmethyl)-[1,2,4]oxadiazole, [0420]
3-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thio-
phen-3-yl-[1,2,4]oxadiazole, [0421]
5-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thio-
phen-3-yl-[1,2,4]oxadiazole, [0422]
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-fluoro-phenyl)-4H-[1,2,4]triazol-3-yl-
sulfanylmethyl]-[1,2,4]oxadiazole, [0423]
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(4-fluoro-phenyl)-4H-[1,2,4]triazol-3-yl-
sulfanylmethyl]-[1,2,4]oxadiazole, [0424]
3-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thio-
phen-2-yl-[1,2,4]oxadiazole, [0425]
3-{3-[5-(3-Chloro-thiophen-2-yl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylme-
thyl]-[1,2,4]oxadiazol-5-yl}-benzonitrile, [0426]
4-{5-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-ethyl-4H-
-[1,2,4]triazol-3-yl}-pyridine, [0427]
2-(3-Chloro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfany-
lmethyl)-[1,3,4]oxadiazole, [0428]
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-y-
lsulfanylmethyl]-[1,2,4]oxadiazole, [0429]
5-(3-Chloro-phenyl)-3-[5-(2-fluoro-5-methyl-phenyl)-4-furan-2-ylmethyl-4H-
-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0430]
4-[3-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,-
2,4]oxadiazol-5-yl]-2-methyl-pyridine, [0431]
3-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-m-
ethoxy-phenyl)-[1,2,4]oxadiazole, [0432]
5-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-(3-m-
ethoxy-phenyl)-[1,2,4]oxadiazole, [0433]
5-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thio-
phen-2-yl-[1,2,4]oxadiazole, [0434]
5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-trifluoromethyl-4H-[1,2,4]triaz-
ol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0435]
3-[3-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,-
2,4]oxadiazol-5-yl]-benzonitrile, [0436]
3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-trifluorome-
thyl-4H-[1,2,4]triazole, [0437]
3-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-5-trifluorometh-
yl-4H-[1,2,4]triazole, [0438]
4-Ethyl-3-(5-thiophen-3-yl-isoxazol-3-ylmethylsulfanyl)-5-trifluoromethyl-
-4H-[1,2,4]triazole, [0439]
4-{3-[5-(3-Fluoro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]--
[1,2,4]oxadiazol-5-yl}-2-methyl-pyridine, [0440]
4-{3-[5-(3-Chloro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]--
[1,2,4]oxadiazol-5-yl}-2-methyl-pyridine, [0441]
4-{3-[5-(4-Chloro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]--
[1,2,4]oxadiazol-5-yl}-2-methyl-pyridine, [0442]
4-{3-[5-(4-Methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-
-[1,2,4]oxadiazol-5-yl}-2-methyl-pyridine, [0443]
4-[3-(4-Ethyl-5-p-tolyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxad-
iazol-5-yl]-2-methyl-pyridine, [0444]
3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-flu-
oro-phenyl)-[1,2,4]oxadiazole, [0445]
4-{4-Ethyl-5-[5-(3-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-
-[1,2,4]triazol-3-yl}-pyridine, [0446]
5-(3-Chloro-phenyl)-3-[5-(3,5-difluoro-phenyl)-4-ethyl-4H-[1,2,4]triazol--
3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0447]
5-(3-Chloro-phenyl)-3-[5-(2,6-difluoro-phenyl)-4-ethyl-4H-[1,2,4]triazol--
3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0448]
2-[3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,-
4]oxadiazol-5-yl]-4-methyl-phenol, [0449]
3-{1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-ethyl-5-furan-2-
-yl-4H-[1,2,4]triazole, [0450]
4-(5-{1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,-
2,4]triazol-3-yl)-pyridine, [0451]
3-[5-(4-Butoxy-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-(3-
-chloro-phenyl)-[1,2,4]oxadiazole, [0452]
3-(5-Benzo[1,3]dioxol-5-yl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
5-(3-chloro-phenyl)-[1,2,4]oxadiazole, [0453]
3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-met-
hyl-thiazol-4-yl)-[1,2,4]oxadiazole, [0454]
3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(4-flu-
oro-phenyl)-[1,2,4]oxadiazole, [0455]
4-Ethyl-3-{1-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethylsulfanyl}--
5-furan-2-yl-4H-[1,2,4]triazole, [0456]
4-(4-Ethyl-5-{1-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethylsulfany-
l}-4H-[1,2,4]triazol-3-yl)-pyridine, [0457]
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-methyl-3H-imidazol-4-yl)-4H-[1,2,4]tr-
iazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0458]
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(1-methyl-1H-imidazol-2-yl)-4H-[1,2,4]tr-
iazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0459]
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(1-methyl-1H-imidazol-4-yl)-4H-[1,2,4]tr-
iazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0460]
4-{5-[5-(3-Chloro-phenyl)-4-methyl-isoxazol-3-ylmethylsulfanyl]-4-ethyl-4-
H-[1,2,4]triazol-3-yl}-pyridine, [0461]
3-[5-(3-Chloro-phenyl)-4-methyl-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-fu-
ran-2-yl-4H-[1,2,4]triazole, [0462]
3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(4-met-
hyl-thiophen-2-yl)-[1,2,4]oxadiazole, [0463]
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-methyl-thiophen-2-yl)-4H-[1,2,4]triaz-
ol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0464]
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1,2,4]triaz-
ol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0465]
4-{5-[4-Chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-4-
H-[1,2,4]triazol-3-yl}-pyridine, [0466]
3-[4-Chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-fu-
ran-2-yl-4H-[1,2,4]triazole, [0467]
2-Chloro-4-{5-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-
-ethyl-4H-[1,2,4]triazol-3-yl}-6-methyl-pyridine, [0468]
3-[5-(5-Bromo-furan-2-yl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-
-(3-chloro-phenyl)-[1,2,4]oxadiazole, [0469]
2-Chloro-4-{5-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-
-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0470]
2-Chloro-4-{5-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-
-ethyl-4H-[1,2,4]triazol-3-yl}-6-methoxy-pyridine, [0471]
2-[3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,-
4]oxadiazol-5-yl]-4-methyl-benzonitrile, [0472]
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-methoxy-thiophen-2-yl)-4H-[1,2,4]tria-
zol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0473]
3-[5-(5-Chloro-thiophen-3-yl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-fura-
n-2-yl-4H-[1,2,4]triazole, [0474]
3-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]o-
xadiazol-5-yl]-5-fluoro-benzonitrile, [0475]
4-Ethyl-3-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-5-thiophen-2-yl-4H-[1,2,-
4]triazole, [0476]
4-Methyl-3-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-5-thiophen-3-yl-4H-[1,2-
,4]triazole, [0477]
4-Ethyl-3-furan-2-yl-5-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-4H-[1,2,4]t-
riazole, [0478]
4-[4-Ethyl-5-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-y-
l]-pyridine, [0479]
4-[4-Methyl-5-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3--
yl]-pyridine, [0480]
2-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[-
1,3,4]oxadiazole, [0481]
4-[4-Methyl-5-(5-m-tolyl-[1,3,4]oxadiazol-2-ylmethylsulfanyl)-4H-[1,2,4]t-
riazol-3-yl]-pyridine, [0482]
4-[4-Ethyl-5-(5-m-tolyl-[1,3,4]oxadiazol-2-ylmethylsulfanyl)-4H-[1,2,4]tr-
iazol-3-yl]-pyridine, [0483]
4-{5-[5-(5-Chloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-e-
thyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0484]
3-[3-(4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-oxadia-
zol-5-yl]-4-fluoro-benzonitrile, [0485]
3-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-oxadiazo-
l-5-yl]-4-fluoro-benzonitrile, [0486]
3-[3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,-
4]oxadiazol-5-yl]-4-fluoro-benzonitrile, [0487]
3-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]o-
xadiazol-5-yl]-benzonitrile, [0488]
3-[5-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]o-
xadiazol-3-yl]-benzonitrile,
[0489]
3-[3-(4-Methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylme-
thyl)-[1,2,4]oxadiazol-5-yl]-benzonitrile, [0490]
5-(5-Chloro-2-fluoro-phenyl)-3-(4-methyl-5-trifluoromethyl-4H-[1,2,4]tria-
zol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0491]
2-Chloro-4-[3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-
-[1,2,4]oxadiazol-5-yl]-pyridine, [0492]
2-Chloro-4-[3-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl-
)-[1,2,4]oxadiazol-5-yl]-pyridine, [0493]
2-(3-Chloro-phenyl)-5-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[1,2,4]triaz-
ol-3-ylsulfanylmethyl]-[1,3,4]oxadiazole, [0494]
2-(3-Chloro-phenyl)-5-(4-methyl-5-thiazol-4-yl-4H-[1,2,4]triazol-3-ylsulf-
anylmethyl)-[1,3,4]oxadiazole, [0495]
2-(3-Chloro-phenyl)-5-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfan-
ylmethyl)-[1,3,4]oxadiazole, [0496]
2-(3-Chloro-phenyl)-5-(4-ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsu-
lfanylmethyl)-[1,3,4]oxadiazole, [0497]
4-{4-Ethyl-5-[5-(4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-ylmethylsulfa-
nyl]-4H-[1,2,4]triazol-3-yl}-pyridine, [0498]
3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(4-methyl-
-thiophen-2-yl)-[1,2,4]oxadiazole, [0499]
3-(3-Chloro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfany-
lmethyl)-[1,2,4]oxadiazole, [0500]
4-{5-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-
-[1,2,4]triazol-3-yl}-pyridine, [0501]
4-{4-Ethyl-5-[5-(3-nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4H--
[1,2,4]triazol-3-yl}-pyridine, [0502]
2-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-nitro--
phenyl)-[1,3,4]oxadiazole, [0503]
4-{5-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-cyclopropyl-4H-[-
1,2,4]triazol-3-yl}-pyridine, [0504]
3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-(4-methoxy--
phenyl)-4H-[1,2,4]triazole, [0505]
5-(3-Chloro-phenyl)-3-[1-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl-
sulfanyl)-ethyl]-[1,2,4]oxadiazole, [0506]
5-(3-Chloro-phenyl)-3-[1-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yls-
ulfanyl)-ethyl]-[1,2,4]oxadiazole, [0507]
4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-meth-
yl-4H-[1,2,4]triazol-3-yl)-pyridine, [0508]
4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethy-
l-4H-[1,2,4]triazol-3-yl)-pyridine, [0509]
3-[5-(4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4-
]oxadiazol-2-yl]-benzonitrile, [0510]
3-[5-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]o-
xadiazol-2-yl]-benzonitrile, [0511]
3-[5-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,-
4]oxadiazol-2-yl]-benzonitrile, [0512]
3-[5-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
[1,3,4]oxadiazol-2-yl]-benzonitrile, [0513]
4-{5-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-methyl-4-
H-[1,2,4]triazol-3-yl}-pyridine, [0514]
4-{5-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-cyclopro-
pyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0515]
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-
-cyclopropyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0516]
2-(5-Chloro-2-fluoro-phenyl)-5-[4-ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]tr-
iazol-3-ylsulfanylmethyl]-[1,3,4]oxadiazole, [0517]
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-
-methyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0518]
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-
-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0519]
2-(3-Chloro-phenyl)-5-[4-ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-y-
lsulfanylmethyl]-[1,3,4]oxadiazole, [0520]
2-(3-Chloro-phenyl)-5-[1-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulf-
anyl)-ethyl]-[1,3,4]oxadiazole, [0521]
5-(5-Chloro-2-fluoro-phenyl)-3-[1-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]tri-
azol-3-ylsulfanyl)-ethyl]-[1,2,4]oxadiazole, [0522]
4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfany-
l}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0523]
4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfany-
l}-4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0524]
2-Chloro-4-[3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfany-
lmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine, [0525]
4-{5-[5-(2-Fluoro-5-methyl-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-
-methyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0526]
4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazol-2-ylmethylsul-
fanyl]-4H-[1,2,4]triazol-3-yl}-pyridine, [0527]
4-{4-Cyclopropyl-5-[5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazol-2-ylmet-
hylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine, [0528]
2-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-
-5-methyl-phenyl)-[1,3,4]oxadiazole, [0529]
2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-(-
2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole, [0530]
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-4-
H-[1,2,4]triazol-3-yl}-pyridine, [0531]
4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-eth-
yl-4H-[1,2,4]triazol-3-yl)-pyridine, [0532]
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl--
4H-[1,2,4]triazol-3-yl}-pyridine, [0533]
4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-met-
hyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0534]
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-cyclopr-
opyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0535]
4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-cyc-
lopropyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0536]
3-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-fu-
ran-2-yl-4H-[1,2,4]triazole, [0537]
3-{1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-ethyl--
5-furan-2-yl-4H-[1,2,4]triazole, [0538]
4-(5-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-meth-
yl-4H-[1,2,4]triazol-3-yl)-pyridine, [0539]
4-(5-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-ethy-
l-4H-[1,2,4]triazol-3-yl)-pyridine, [0540]
4-(5-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-cycl-
opropyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0541]
5-(5-Chloro-2-fluoro-phenyl)-3-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-
-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0542]
5-(5-Chloro-2-fluoro-phenyl)-3-(5-furan-3-yl-4-methyl-4H-[1,2,4]triazol-3-
-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0543]
4-Chloro-2-[3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmeth-
yl)-[1,2,4]oxadiazol-5-yl]-phenol, [0544]
2-Chloro-4-[5-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmeth-
yl)-[1,3,4]oxadiazol-2-yl]-pyridine, [0545]
2-Chloro-4-[5-(4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethy-
l)-[1,3,4]oxadiazol-2-yl]-pyridine, [0546]
2-Chloro-4-[5-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfany-
lmethyl)-[1,3,4]oxadiazol-2-yl]-pyridine, [0547]
2-Chloro-4-[5-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-
-[1,3,4]oxadiazol-2-yl]-pyridine, [0548]
2-Chloro-4-{5-[4-ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfany-
lmethyl]-[1,3,4]oxadiazol-2-yl}-pyridine, [0549]
2-(3-Chloro-phenyl)-5-{1-[5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-
-3-ylsulfanyl]-ethyl}-[1,3,4]oxadiazole, [0550]
4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfany-
l}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0551]
5-(5-Bromo-2-fluoro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-y-
lsulfanylmethyl)-[1,2,4]oxadiazole, [0552]
2-(3-Chloro-phenyl)-5-[5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3--
ylsulfanylmethyl]-[1,3,4]oxadiazole, [0553]
4-{5-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-cyclopro-
pyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0554]
4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-cyclopro-
pyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0555]
4-(5-{1-[5-(2-Fluoro-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfany-
l}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0556]
4-(4-Ethyl-5-{1-[5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-ethy-
lsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine, [0557]
4-(4-Cyclopropyl-5-{1-[5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl-
]-ethylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine, [0558]
4-(4-Cyclopropylmethyl-5-{-[5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazol-
-2-yl]-ethylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine, [0559]
2-(2-Fluoro-5-methyl-phenyl)-5-{1-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H--
[1,2,4]triazol-3-ylsulfanyl]-ethyl}-[1,3,4]oxadiazole, [0560]
4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfany-
l}-4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0561]
4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfany-
l}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0562]
2-(5-Chloro-2-fluoro-phenyl)-5-[1-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-
-3-ylsulfanyl)-ethyl]-[1,3,4]oxadiazole, [0563]
2-(5-Chloro-2-fluoro-phenyl)-5-{1-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H--
[1,2,4]triazol-3-ylsulfanyl]-ethyl}-[1,3,4]oxadiazole, [0564]
4-(4-Cyclopropylmethyl-5-{1-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]--
ethylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine, [0565]
4-(5-{1-[5-(3-Fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-meth-
yl-4H-[1,2,4]triazol-3-yl)-pyridine, [0566]
4-(4-Cyclopropyl-5-{1-[5-(3-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsu-
lfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine, [0567]
4-(5-{1-[5-(4-Methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-et-
hyl}-[1,3,4]oxadiazol-2-yl)-2-methyl-pyridine, [0568]
4-(5-{1-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-eth-
yl}-[1,3,4]oxadiazol-2-yl)-2-methyl-pyridine, [0569]
4-{5-[1-(4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[1-
,3,4]oxadiazol-2-yl}-2-methyl-pyridine, [0570]
4-{5-[1-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-eth-
yl]-[1,3,4]oxadiazol-2-yl}-2-methyl-pyridine, [0571]
4-{5-[1-(5-Furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[1,-
3,4]oxadiazol-2-yl}-2-methyl-pyridine, [0572]
2-(3-Chloro-phenyl)-5-{1-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[1,2,4]tr-
iazol-3-ylsulfanyl]-ethyl}-[1,3,4]oxadiazole, [0573]
3-(5-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-meth-
yl-4H-[1,2,4]triazol-3-yl)-pyridine, [0574]
4-(5-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-meth-
yl-4H-[1,2,4]triazol-3-yl)-2-methyl-pyridine, [0575]
4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-cycl-
opropyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0576]
5-(3-Chloro-phenyl)-3-{1-[5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-
-3-ylsulfanyl]-ethyl}-[1,2,4]oxadiazole, [0577]
4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfany-
l}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0578]
5-(5-Chloro-2-fluoro-phenyl)-3-{1-[5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,-
4]triazol-3-ylsulfanyl]-ethyl}-[1,2,4]oxadiazole, [0579]
4-[5-(4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4-
]oxadiazol-2-yl]-2-methyl-pyridine, [0580]
4-[5-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
[1,3,4]oxadiazol-2-yl]-2-methyl-pyridine, [0581]
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-
-cyclopropyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0582]
4-[5-(5-Furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]-
oxadiazol-2-yl]-2-methyl-pyridine, [0583]
4-(5-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-cycl-
opropylmethyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0584]
4-(5-{1-[5-(4-Fluoro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-eth-
yl}-[1,3,4]oxadiazol-2-yl)-2-methyl-pyridine, [0585]
4-(5-{1-[5-(3-Fluoro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-eth-
yl}-[1,3,4]oxadiazol-2-yl)-2-methyl-pyridine, [0586]
3-[3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
[1,2,4]oxadiazol-5-yl]-4-fluoro-benzonitrile, [0587]
4-Chloro-2-[3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfany-
lmethyl)-[1,2,4]oxadiazol-5-yl]-phenol, [0588]
4-{4-Cyclopropyl-5-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfa-
nyl]-4H-[1,2,4]triazol-3-yl}-pyridine, [0589]
4-{4-Cyclopropyl-5-[5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmet-
hylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine, [0590]
4-{4-Cyclopropyl-5-[5-(3-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfan-
yl]-4H-[1,2,4]triazol-3-yl}-pyridine, [0591]
4-[4-Cyclopropyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,-
2,4]triazol-3-yl]-pyridine, [0592]
3-[3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
[1,2,4]oxadiazol-5-yl]-benzonitrile, [0593]
4-{4-Cyclopropyl-5-[5-(2,5-difluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsu-
lfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine, [0594]
4-{4-Cyclopropyl-5-[1-(5-m-tolyl-[1,2,4]oxadiazol-3-yl)-ethylsulfanyl]-4H-
-[1,2,4]triazol-3-yl}-pyridine, [0595]
4-(4-Cyclopropyl-5-{1-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-ethyls-
ulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine, [0596]
4-{5-[5-(2-Chloro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-
-cyclopropyl-4H-[1,2,4]triazol-3-yl}-pyridine, [0597]
2-[3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
[1,2,4]oxadiazol-5-yl]-4-methyl-phenol, [0598]
4-(5-{1-[5-(2-Chloro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfany-
l}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0599]
{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,-
2,4]oxadiazol-5-yl]-phenyl}-methanol, [0600]
3-[5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2-
,4]oxadiazol-3-yl]-phenol, [0601]
5-(3-Chloro-phenyl)-3-[4-(tetrahydro-furan-2-ylmethyl)-5-thiophen-2-yl-4H-
-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0602]
(2-Chloro-phenyl)-{5-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulf-
anyl]-4-isobutyl-4H-[1,2,4]triazol-3-yl}-methanol, [0603]
5-(2-Fluoro-5-methyl-phenyl)-3-[5-thiophen-2-yl-4-(2,2,2-trifluoro-ethyl)-
-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0604]
3-(2,5-Difluoro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl-
sulfanylmethyl)-[1,2,4]oxadiazole, [0605]
5-Furan-3-yl-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylme-
thyl)-[1,2,4]oxadiazole, [0606]
3-(3-Chloro-phenyl)-5-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfan-
ylmethyl)-[1,2,4]oxadiazole, [0607]
3-(3-Chloro-phenyl)-5-(5-furan-3-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfan-
ylmethyl)-[1,2,4]oxadiazole, [0608]
5-(3-Chloro-phenyl)-3-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfan-
ylmethyl)-[1,2,4]oxadiazole, [0609]
5-(3-Chloro-phenyl)-3-(5-furan-3-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfan-
ylmethyl)-[1,2,4]oxadiazole, [0610]
4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4-
H-[1,2,4]triazol-3-yl}-pyrimidine, [0611]
4-{5-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4-
H-[1,2,4]triazol-3-yl}-pyrimidine, [0612]
3-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-
-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,
[0613]
3-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[1,2,4]tr-
iazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0614]
5-(5-Chloro-thiophen-2-yl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-
-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0615]
5-(5-Chloro-thiophen-2-yl)-3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-yl-
sulfanylmethyl)-[1,2,4]oxadiazole, [0616]
5-(5-Chloro-thiophen-3-yl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-
-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0617]
4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-
-[1,2,4]triazol-3-ylmethoxy}-phenol, [0618]
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-
-ethyl-4H-[1,2,4]triazol-3-ylmethoxy}-phenol, [0619]
3-(2,5-Difluoro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazole, [0620]
3-(2,5-Difluoro-phenyl)-5-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsu-
lfanylmethyl)-[1,2,4]oxadiazole, [0621]
4-(5-{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylsulfanyl}-4-meth-
yl-4H-[1,2,4]triazol-3-yl)-pyridine, [0622]
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-
-cyclopropyl-4H-[1,2,4]triazol-3-yl}-pyrimidine, [0623]
2-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethy-
l-4H-[1,2,4]triazol-3-yl)-5-methoxy-pyrimidine, [0624]
2-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethy-
l-4H-[1,2,4]triazol-3-yl)-pyrimidine, [0625]
4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethy-
l-4H-[1,2,4]triazol-3-yl)-2-methoxy-pyridine, [0626]
5-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethy-
l-4H-[1,2,4]triazol-3-yl)-2-methoxy-pyridine, [0627]
2-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethy-
l-4H-[1,2,4]triazol-3-yl)-5-methoxy-pyridine, [0628]
3-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethy-
l-4H-[1,2,4]triazol-3-yl)-6-methoxy-pyridazine, [0629]
3-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-cycl-
opropyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0630]
4-{5-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4-
H-[1,2,4]triazol-3-yl}-pyridine, [0631]
5-(3-Chloro-phenyl)-3-(5-furan-2-yl-4-isobutyl-4H-[1,2,4]triazol-3-ylsulf-
anylmethyl)-[1,2,4]oxadiazole, [0632]
5-(3-Chloro-phenyl)-3-[4-(3-methylsulfanyl-propyl)-5-thiophen-2-yl-4H-[1,-
2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0633]
5-(3-Chloro-phenyl)-3-(4-hexyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulf-
anylmethyl)-[1,2,4]oxadiazole, [0634]
5-(3-Chloro-phenyl)-3-(4-cyclopropylmethyl-5-thiophen-2-yl-4H-[1,2,4]tria-
zol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0635]
5-(3-Chloro-phenyl)-3-[4-(3-fluoro-benzyl)-5-thiophen-2-yl-4H-[1,2,4]tria-
zol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0636]
5-(3-Chloro-phenyl)-3-[4-(3-methyl-benzyl)-5-thiophen-2-yl-4H-[1,2,4]tria-
zol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0637]
5-(3-Chloro-phenyl)-3-[4-(2-methyl-butyl)-5-thiophen-2-yl-4H-[1,2,4]triaz-
ol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0638]
5-(3-Chloro-phenyl)-3-[4-(3-methyl-butyl)-5-thiophen-2-yl-4H-[1,2,4]triaz-
ol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0639]
5-(3-Chloro-phenyl)-3-[4-(2-fluoro-benzyl)-5-thiophen-2-yl-4H-[1,2,4]tria-
zol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0640]
5-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yloxym-
ethyl)-[1,2,4]oxadiazole, [0641]
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethoxy]-4-methyl-
-4H-[1,2,4]triazol-3-yl}-pyridine, [0642]
4-(5-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethoxy}-4-methyl-4H-[-
1,2,4]triazol-3-yl)-pyridine, [0643]
4-(5-{1-[3-(3-Chloro-phenyl)-isoxazol-5-yl]-ethoxy}-4-methyl-4H-[1,2,4]tr-
iazol-3-yl)-pyridine, [0644]
5-(2-Methoxy-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsu-
lfanylmethyl)-[1,2,4]oxadiazole, [0645]
5-Furan-2-yl-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylme-
thyl)-[1,2,4]oxadiazole, [0646]
3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2-
,4]oxadiazol-5-yl]-benzoic acid methyl ester, [0647]
5-(2-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazole, [0648]
5-(2,5-Difluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-y-
lsulfanylmethyl)-[1,2,4]oxadiazole, [0649]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-vi-
nyl-phenyl)-[1,2,4]oxadiazole, [0650]
5-(3-Difluoromethoxy-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazo-
l-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0651]
5-(4-Methoxy-thiophen-3-yl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-
-3-ylsulfanylmethyl)-[1,2,4]oxadiazole, [0652]
5-(2-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazole, [0653]
5-(4-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazole, [0654]
3-(3-Chloro-phenyl)-5-[1-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl-
sulfanyl)-ethyl]-[1,2,4]oxadiazole,
-(5-{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylsulfanyl}-4-methy-
l-4H-[1,2,4]triazol-3-yl)-pyridine, [0655]
3-(3-Chloro-phenyl)-5-[2-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl)-
-ethyl]-[1,2,4]oxadiazole, [0656]
5-(3-Chloro-phenyl)-3-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylmethyl-
)-[1,2,4]oxadiazole, [0657]
2-(3-Chloro-phenyl)-5-[2-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-yl)-e-
thyl]-[1,3,4]oxadiazole, [0658]
2-(3-Chloro-phenyl)-5-[2-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-yl)-et-
hyl]-[1,3,4]oxadiazole, [0659]
2-(3-Chloro-phenyl)-5-[2-(4-cyclopropyl-5-furan-2-yl-4H-[1,2,4]triazol-3--
yl)-ethyl]-[1,3,4]oxadiazole, [0660]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-4-methyl-4H-[1-
,2,4]triazol-3-yl)-pyridine, [0661]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-4-ethyl-4H-[1,-
2,4]triazol-3-yl)-pyridine, [0662]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-4-cyclopropyl--
4H-[1,2,4]triazol-3-yl)-pyridine, [0663]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-
-4H-[1,2,4]triazol-3-yl)-pyridine, [0664]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-methyl-propyl}-4-cy-
clopropyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0665]
4-(5-{2-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propyl}-4-cyclopropyl-
-4H-[1,2,4]triazol-3-yl)-pyridine, [0666]
8-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,-
8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, [0667]
8-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-thiophen-2-yl-5,6,7-
,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, [0668]
8-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4--
yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, [0669]
5-(5-Bromo-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-(3-chloro-phe-
nyl)-[1,2,4]oxadiazole, [0670]
3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2-
,4]oxadiazol-5-yl]-phenylamine, [0671]
5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulf-
onylmethyl)-[1,2,4]oxadiazole, [0672]
5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulf-
inylmethyl)-[1,2,4]oxadiazole, [0673]
2-Methyl-6-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmet-
hyl)-[1,2,4]oxadiazol-5-yl]-pyridine, [0674]
4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethy-
l-4H-[1,2,4]triazol-3-yl)-pyridin-2-ol, [0675]
4-(5-{2-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-propyl}-4-methyl-4H-[-
1,2,4]triazol-3-yl)-pyridine, [0676]
[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-methyl-(4-methyl-5-pyri-
din-4-yl-4H-[1,2,4]triazol-3-yl)-amine, [0677]
8-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,-
8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine, [0678]
8-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4--
yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine, [0679]
8-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-3-pyridin-4-yl-5,6,7,-
8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine, [0680]
8-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethyl}-3-pyridin-4-yl-5,-
6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine, [0681]
8-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-furan-2-yl-
-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine, [0682]
8-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethyl}-3-pyridin-4-yl-5,-
6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine, [0683]
3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(1H-py-
rrol-3-yl)-[1,2,4]oxadiazole, [0684]
4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4-
H-[1,2,4]triazol-3-yl}-pyridine 1-oxide, [0685]
5-(3-Chloro-phenyl)-3-(2-furan-2-yl-3-methyl-3H-imidazol-4-ylsulfanylmeth-
yl)-[1,2,4]oxadiazole, [0686]
5-(5-Chloro-2-fluoro-phenyl)-3-[4-(2-fluoro-ethyl)-5-thiophen-2-yl-4H-[1,-
2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole, [0687]
5-(5-Chloro-thiophen-3-yl)-3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-yl-
sulfanylmethyl)-[1,2,4]oxadiazole, [0688]
3-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]o-
xadiazol-5-yl]-4-hydroxy-benzonitrile, [0689]
3-(3-Chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl-
)-ethyl]-[1,2,4]oxadiazole, [0690]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-[1,3,4]oxadia-
zol-2-yl)-pyridine, [0691]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-methyl-ethyl}-4-cyc-
lopropyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0692]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopropyl}-4-cyclop-
ropyl-4H-[1,2,4]triazol-3-yl)-pyridine, or [0693]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1,1-dimethyl-ethyl}-[-
1,3,4]oxadiazol-2-yl)-pyridine, [0694]
3-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethoxy}-4-cyclopropyl-
-4H-[1,2,4]triazol-3-yl)-pyridine, [0695]
4-(5-{1-[5-(2-Chloro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfany-
l}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0696]
4-(5-{1-[5-(2,5-Difluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4--
methyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0697]
4-(5-{1-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfany-
l}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0698]
4-(4-Cyclopropyl-5-{1-[5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-yl-
]-ethylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine, [0699]
3-{3-[1-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[-
1,2,4]oxadiazol-5-yl}-benzonitrile, [0700]
3-{3-[1-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-eth-
yl]-[1,2,4]oxadiazol-5-yl}-benzonitrile, [0701]
3-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-5-pyridin-
-4-yl-[1,2,4]triazol-4-ylamine, [0702]
3-(3-Chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl-
)-ethyl]-[1,2,4]oxadiazole, [0703]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-methyl-ethyl}-4-cyc-
lopropyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0704]
cis-4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopropyl}-4-cy-
clopropyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0705]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1,1-dimethyl-ethyl}-[-
1,3,4]oxadiazol-2-yl)-pyridine, [0706]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-methyl-propyl}-[1,3-
,4]oxadiazol-2-yl)-pyridine, [0707]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-methyl-ethyl}-[1,3,-
4]oxadiazol-2-yl)-pyridine, [0708]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopropyl}-[1,3,4]o-
xadiazol-2-yl)-pyridine, [0709]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopropyl}-4-methyl-
-4H-[1,2,4]triazol-3-yl)-pyridine, [0710]
4-(5-{2-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propyl}-4-methyl-4H-[-
1,2,4]triazol-3-yl)-pyridine, [0711]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-[1,3,4]oxadia-
zol-2-yl)-pyridine, [0712]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-methyl-4H-[-
1,2,4]triazol-3-yl)-pyridine, [0713]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-
-4H-[1,2,4]triazol-3-yl)-pyridine, [0714]
(S)-[1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyr-
idin-4-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-carbamic acid tert-butyl
ester, [0715]
(S)-1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropy-
l-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-ethylamine, [0716]
(S)-[1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyr-
idin-4-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-dimethyl-amine, and salts
thereof.
[0717] Additional specific embodiments of the invention include:
[0718]
4-(5-{2-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propyl}-4-cyclopropyl-4H-
-1,2,4-triazol-3-yl)pyridine, [0719]
4-[5-(chloromethyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine, [0720]
4-(5-{2-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propyl}-4-cyclopropyl-4H-
-1,2,4-triazol-3-yl)pyridine, [0721]
4-(5-{2-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-4-cyclopropyl-4H--
1,2,4-triazol-3-yl)pyridine, [0722]
4-(5-{2-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]-1-methylethyl}-4-cyclop-
ropyl-4H-1,2,4-triazol-3-yl)pyridine, [0723]
4-(5-{2-[5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazol-3-yl]propyl}-4-methy-
l-4H-1,2,4-triazol-3-yl)pyridine, [0724]
4-(5-{2-[5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazol-3-yl]propyl}-4-cyclo-
propyl-4H-1,2,4-triazol-3-yl)pyridine, [0725]
4-(4-methyl-5-{2-[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]ethyl}-4H-1,2,4-
-triazol-3-yl)pyridine, [0726]
4-(4-cyclopropyl-5-{1-methyl-2-[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]e-
thyl}-4H-1,2,4-triazol-3-yl)pyridine, [0727]
3-(3-Chloro-phenyl)-5-{2-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol--
4-yl]-ethyl}-[1,2,4]oxadiazole, [0728]
3-(3-Chloro-phenyl)-5-{2-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol--
4-yl]-1-methyl-ethyl}-[1,2,4]oxadiazole, [0729]
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-1-cyclopropyl-
-1H-imidazol-2-yl)-pyridine, [0730]
3-(3-Chloro-phenyl)-5-{2-[2-(4-methoxy-phenyl)-3-methyl-3H-imidazol-4-yl]-
-1-methyl-ethyl}-[1,2,4]oxadiazole, [0731]
(S)-4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopr-
opyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0732]
4-(5-{(2S)-2-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]propyl}-4-cycloprop-
yl-4H-1,2,4-triazol-3-yl)pyridine, [0733]
4-(5-{(2R)-2-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]propyl}-4-cycloprop-
yl-4H-1,2,4-triazol-3-yl)pyridine, [0734]
4-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methyl-4H-1,2,-
4-triazol-3-yl)pyridine, [0735]
5-(3-chlorophenyl)-3-((1R)-1-{[4-methyl-5-(trifluoromethyl)-4H-1,2,4-tria-
zol-3-yl]oxy}ethyl)-1,2,4-oxadiazole, [0736]
3-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-cyclopropyl-4H-
-1,2,4-triazol-3-yl)pyridine, [0737]
3-(5-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methyl-4H-
-1,2,4-triazol-3-yl)pyridine, [0738]
5-(3-chlorophenyl)-3-((1R)-1-{[5-(4-fluorophenyl)-4-methyl-4H-1,2,4-triaz-
ol-3-yl]oxy}ethyl)-1,2,4-oxadiazole, [0739]
5-(3-chlorophenyl)-3-((1R)-1-{[5-(3,5-difluorophenyl)-4-methyl-4H-1,2,4-t-
riazol-3-yl]oxy}ethyl)-1,2,4-oxadiazole, [0740]
(+)-4-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propoxy}-4-methyl-4H-
-1,2,4-triazol-3-yl)pyridine, [0741]
(-)-4-(5-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methy-
l-4H-1,2,4-triazol-3-yl)pyridine, [0742]
(+)-4-(5-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methy-
l-4H-1,2,4-triazol-3-yl)pyridine, [0743]
(-)-4-(5-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}-4-methyl-4H--
1,2,4-triazol-3-yl)pyridine, [0744]
(+)-4-(5-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}-4-methyl-4H--
1,2,4-triazol-3-yl)pyridine, [0745]
4-(5-{1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethoxy}-4-methyl-4H-[1,2,4]tr-
iazol-3-yl)-pyridine, [0746]
N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyrid-
in-3-yl-4H-1,2,4-triazol-3-amine, [0747]
3-Pyridin-4-yl-8-[1-(5-m-tolyl-[1,2,4]oxadiazol-3-yl)-ethyl]-5,6,7,8-tetr-
ahydro-[1,2,4]triazolo[4,3-a]pyrimidine, [0748]
N,4-dimethyl-N-{[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]methyl}-5-pyridi-
n-4-yl-4H-1,2,4-triazol-3-amine, [0749]
N-{[5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-N,4-dimethyl-
-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine, [0750]
N-{[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-N-cyclopropyl-4-methy-
l-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine, [0751]
(+)-N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-5-(3,5-difluorop-
henyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine, [0752]
(-)-N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-5-(3,5-difluorop-
henyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine, [0753]
(+)-8-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-
-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine, [0754]
(-)-8-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-
-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine, [0755]
(-)-N-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}-N,4-dimethyl-5-p-
yridin-4-yl-4H-1,2,4-triazol-3-amine, [0756]
(+)-N-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}-N,4-dimethyl-5-p-
yridin-4-yl-4H-1,2,4-triazol-3-amine, [0757]
(-)-N-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethy-
l-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine, [0758]
(+)-N-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethy-
l-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine, [0759]
3-[5-(3-Pyridin-4-yl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylm-
ethyl)[1,3,4]oxadiazol-2-yl]benzonitrile, [0760]
3-{5-[3-(2-Methoxypyridin-4-yl)-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyri-
midin-8-ylmethyl][1,3,4]oxadiazol-2-yl}benzonitrile, [0761]
3-(5-{[Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amino]-met-
hyl}[1,3,4]oxadiazol-2-yl)benzonitrile, [0762]
3-{5-[3-(2-Methoxy-pyridin-4-yl)-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyr-
imidin-8-ylmethyl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, [0763]
3-{3-[(3-pyridin-4-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl-
)methyl]-1,2,4-oxadiazol-5-yl}benzonitrile, [0764]
3-(3-{[[5-(2-methoxypyridin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]
(methyl)amino]methyl}-1,2,4-oxadiazol-5-yl)benzonitrile, [0765]
3-(3-{[methyl(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)amino]methyl}-
-1,2,4-oxadiazol-5-yl)benzonitrile, [0766]
3-(3-{[3-(2-methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimid-
in-8(5H)-yl]methyl}-1,2,4-oxadiazol-5-yl)benzonitrile, [0767]
N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyrid-
in-4-yl-4H-1,2,4-triazol-3-amine, [0768]
3-{5-[(3-pyridin-4-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl-
)methyl]-1,2,4-oxadiazol-3-yl}benzonitrile, [0769]
3-{5-[3-(2-Hydroxy-pyridin-4-yl)-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyr-
imidin-8-ylmethyl]-[1,2,4]oxadiazol-3-yl}-benzonitrile, [0770]
N-{[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-N,4-dimethyl-5-pyridi-
n-4-yl-4H-1,2,4-triazol-3-amine, [0771]
N-{[3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-4-cyclopropyl-N-methy-
l-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine, [0772]
[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-ethyl-(4-methyl-5-pyrid-
in-4-yl-4H-[1,2,4]triazol-3-yl)-amine, [0773]
[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-ethyl-(4-methyl-5-pyrid-
in-4-yl-4H-[1,2,4]triazol-3-yl)-amine, [0774]
N-{[3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-N-isopropyl-4-methyl--
5-pyridin-4-yl-4H-1,2,4-triazol-3-amine, [0775]
N-{1-[3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}-N-cyclopropyl-4-meth-
yl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine, [0776]
{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-methyl-(4-methyl-5--
pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine, [0777]
[5-(3-Chloro-phenyl)-isoxazol-3-ylmethyl]-methyl-(4-methyl-5-pyridin-4-yl-
-4H-[1,2,4]triazol-3-yl)-amine, [0778]
N-{[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-4-cyclopropyl-N-methy-
l-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine, [0779]
N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]-1-methylethyl}-N,4-dimethy-
l-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine, [0780]
4-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]-1-methylethoxy}-4-methy-
l-4H-1,2,4-triazol-3-yl)pyridine, [0781]
N-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-4-methyl-5-pyri-
din-4-yl-4H-1,2,4-triazol-3-amine, [0782]
5-(3-chlorophenyl)-N-methyl-N-[(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol--
3-yl)methyl]-1,2,4-oxadiazol-3-amine, [0783]
5-(3-chlorophenyl)-N-ethyl-N-[(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-
-yl)methyl]-1,2,4-oxadiazol-3-amine, [0784] Ethyl
8-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-yl-5,6,7-
,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate, and
salts thereof.
[0785] Further feasible examples of compounds of formula I are
provided by compounds of formula Ia ##STR5## wherein:
[0786] P is selected from the group consisting of hydrogen,
C.sub.3-7alkyl and a 3- to 8-membered ring containing one or more
atoms independently selected from the group consisting of C, N, O
and S, which ring may optionally be fused with a 5- or 6-membered
ring containing one or more atoms independently selected from the
group consisting of C, N, O and S;
[0787] R.sup.1 is selected from the group consisting of hydrogen,
hydroxy, halo, nitro, C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo,
C.sub.1-6alkyl, OC.sub.1-6alkyl, C.sub.2-6alkenyl,
OC.sub.2-6alkenyl, C.sub.2-6alkynyl, OC.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl,
OC.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
OC.sub.0-6alkylaryl, CHO, (CO)R.sup.5, O(CO)R.sup.5, O(CO)OR,
O(CN)OR.sup.5, C.sub.1-6alkylOR.sup.5, OC.sub.2-6alkylOR.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, OC.sub.1-6alkyl(CO)R.sup.5,
C.sub.0-6alkylCO.sub.2R.sup.5, OC.sub.1-6alkylCO.sub.2R.sup.5,
C.sub.0-6alkylcyano, OC.sub.2-6alkylcyano,
C.sub.0-6alkylNR.sup.5R.sup.6, OC.sub.2-6alkylNR.sup.5R.sup.6,
C.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6, OC.sub.2-6alkylNR.sup.5
(CO)R.sup.6, C.sub.0-6alkylNR.sup.5 (CO)NR.sup.5R.sup.6,
C.sub.0-6alkylSR.sup.5, OC.sub.2-6alkylSR,
C.sub.0-6alkyl(SO)R.sup.5, OC.sub.2-6alkyl(SO)R.sup.5,
C.sub.0-6alkylSO.sub.2R.sup.5, OC.sub.2-6alkylSO.sub.2R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6, NR.sup.5OR.sup.6,
C.sub.0-6alkylNR.sup.5(CO)OR.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)OR.sup.6, SO.sub.3R.sup.5 and a 5- or
6-membered ring containing one or more atoms independently selected
from the group consisting of C, N, O and S, wherein said ring may
be substituted by one or more A;
[0788] M.sup.1 is selected from the group consisting of a bond,
C.sub.1-3alkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.0-4alkyl(CO)C.sub.0-4alkyl, C.sub.0-3alkylOC.sub.0-3alkyl,
C.sub.0-3alkyl(CO)NR.sup.5,
C.sub.0-3alkyl(CO)NR.sup.5C.sub.0-3alkyl, C.sub.0-4alkylNR.sup.5,
C.sub.0-3alkylSC.sub.0-3alkyl, C.sub.0-3alkyl(SO)C.sub.0-3alkyl and
C.sub.0-3alkyl(SO.sub.2)C.sub.0-3alkyl;
[0789] R.sup.2 is selected from the group consisting of hydrogen,
hydroxy, C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-4alkyl, O(CO)C.sub.1-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, OC.sub.1-4alkyl, C.sub.1-4alkylOR.sup.5
and C.sub.0-4alkylNR.sup.5R.sup.6;
[0790] X.sup.1, X.sup.2 and X.sup.3 are independently selected from
the group consisting of CR, CO, N, NR, O and S;
[0791] R is selected from the group consisting of hydrogen,
C.sub.0-3alkyl, halo, C.sub.0-3alkylOR.sup.5,
C.sub.0-3alkylNR.sup.5R.sup.6, C.sub.0-3alkyl(CO)OR.sup.5,
C.sub.0-3alkylNR.sup.5R.sup.6 and C.sub.0-3alkylaryl;
[0792] M.sup.2 is selected from the group consisting of a bond,
C.sub.1-3alkyl, C.sub.3-7cycloalkyl, C.sub.2-3alkenyl,
C.sub.2-3alkynyl, C.sub.0-4alkyl(CO)C.sub.0-4alkyl,
C.sub.0-3alkylOC.sub.0-3alkyl,
C.sub.0-3alkylNR.sup.5C.sub.1-3alkyl, C.sub.0-3alkyl(CO)NR.sup.5,
C.sub.0-4alkylNR.sup.5, C.sub.0-3alkylSC.sub.0-3alkyl,
C.sub.0-3alkyl(SO)C.sub.0-3alkyl and
C.sub.0-3alkyl(SO.sub.2)C.sub.0-3alkyl;
[0793] R.sup.3 is selected from the group consisting of hydrogen,
hydroxy, C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-4alkyl, O(CO)C.sub.1-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, OC.sub.1-4alkyl, C.sub.1-4alkylOR.sup.5
and C.sub.0-4alkylNR.sup.5R.sup.6;
[0794] X.sup.4 is selected from the group consisting of
C.sub.0-4alkylR.sup.5, C.sub.0-4alkyl(NR.sup.5R.sup.6),
C.sub.0-4alkyl(NR.sup.5R.sup.6).dbd.N,
NR.sup.5C.sub.0-4alkyl(NR.sup.5R.sup.6).dbd.N, NOC.sub.0-4alkyl,
C.sub.1-4alkylhalo, C, O, SO, SO.sub.2 and S;
[0795] Q is a 5- or 6-membered ring containing one or more atoms
independently selected from C, N, O and S, which group may
optionally be fused with a 5- or 6-membered ring containing one or
more atoms independently selected from C, N, O and S and which
fused ring may be substituted by one or more A;
[0796] R.sup.4 is selected from the group consisting of hydrogen,
hydroxy, C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-4alkyl, OC.sub.1-4alkyl,
OC.sub.0-6alkylaryl, O(CO)C.sub.1-4alkyl,
C.sub.0-4alkyl(S)C.sub.0-4alkyl, C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5,
C.sub.0-4alkylNR.sup.5R.sup.6 and a 5- or 6-membered ring
containing one or more atoms independently selected from C, N, O
and S, wherein said ring may be substituted by one or more A;
[0797] R.sup.5 and R.sup.6 are independently selected from the
group consisting of hydrogen, hydroxy, C.sub.1-6alkyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
C.sub.0-6alkylheteroaryl and a 5- or 6-membered ring containing one
or more atoms independently selected from C, N, O and S, and
wherein R.sup.5 and R.sup.6 may together form a 5- or 6-membered
ring containing one or more atoms independently selected from C, N,
O and S;
[0798] wherein any C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.0-6alkylC.sub.3-6cycloalkyl,
C.sub.0-6alkylaryl and C.sub.0-6alkylheteroaryl defined under
R.sup.1, R.sup.2, R.sup.3R.sup.4, R.sup.5 and R.sup.6 may be
substituted by one or more A; and
[0799] A is selected from the group consisting of hydrogen,
hydroxy, oxo, halo, nitro, C.sub.0-6alkylcyano, C.sub.1-4alkyl,
C.sub.0-4alkylC.sub.3-6cycloalkyl, C.sub.1-6alkylhalo,
OC.sub.1-6alkylhalo, C.sub.2-6alkenyl, OC.sub.1-6alkyl,
C.sub.0-3alkylaryl, C.sub.0-6alkylOR.sup.5,
OC.sub.2-6alkylOR.sup.5, C.sub.1-6alkylSR.sup.5,
OC.sub.2-6alkylSR.sup.5, (CO)R.sup.5, O(CO)R.sup.5,
OC.sub.2-6alkylcyano, C.sub.0-6alkylCO.sub.2R.sup.5,
OC.sub.1-6alkylCO.sub.2R.sup.5, O(CO)OR.sup.5,
OC.sub.1-6alkyl(CO)R.sup.5, C.sub.1-6alkyl(CO)R.sup.5,
NR.sup.5OR.sup.6, C.sub.0-6alkylNR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5R.sup.6, C.sub.0-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6,
NR.sup.5(CO)OR.sup.6, C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6, SO.sub.3R.sup.5,
C.sub.1-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)R.sup.5, C.sub.0-6alkyl(SO.sub.2)R.sup.5,
C.sub.0-6alkyl(SO)R.sup.5, OC.sub.2-6alkyl(SO)R.sup.5 and a 5- or
6-membered ring containing one or more atoms independently selected
from C, N, O and S;
[0800] m is selected from 0, 1, 2, 3 and 4; and
[0801] n is selected from 0, 1, 2 and 3,
[0802] or salt thereof.
[0803] The present invention relates to the use of compounds of
formula I and IA as hereinbefore defined as well as to the salts
thereof. Salts for use in pharmaceutical formulations will be
pharmaceutically acceptable salts, but other salts may be useful in
the production of the compounds of formula I and Ia.
[0804] Examples of pharmaceutically acceptable salts may be, but
are not limited to hydrochloride, 4-aminobenzoate, anthranilate,
4-aminosalicylate, 4-hydroxybenzoate, 3,4-dihydroxybenzoate,
3-hydroxy-2-naphthoate, nitrate and trifluoroacetate. Other
pharmaceutically acceptable salts and methods of preparing these
salts may be found in, for example, Remington's Pharmaceutical
Sciences (18.sup.th Edition, Mack Publishing Co.).
[0805] Some compounds of formula I may have chiral centres and/or
geometric isomeric centres (E- and Z-isomers), and it is to be
understood that the invention encompasses all such optical,
diastereoisomers and geometric isomers.
[0806] The invention relates to any and all tautomeric forms of the
compounds of formula I.
[0807] The invention relates to the following compounds, which may
be used as intermediates in the preparation of a compound of
formula I; [0808] 6-Methylpyridine-4-carboxylic acid, [0809]
1-Cyano-3-ethylbenzene, [0810] 3-Ethylbenzoic acid, [0811]
3-Fluoro-5-methyl-benzoic acid, [0812] 3-Methoxymethyl-benzoic
acid, [0813] N-Hydroxy-3-methoxy-benzamidine, [0814]
N-Hydroxy-benzamidine, [0815] N-Hydroxy-3-methyl-benzamidine,
[0816] 5-Chloromethyl-3-(3-methoxy-phenyl)-[1,2,4]oxadiazole,
[0817] 5-Chloromethyl-3-phenyl-[1,2,4]oxadiazole, [0818]
5-Chloromethyl-3-m-tolyl-[1,2,4]oxadiazole, [0819]
3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile, [0820]
3-(5-Chloromethyl-[1,2,4]oxadiazol-3-yl)-benzonitrile, [0821]
3-Chloromethyl-5-m-tolyl-[1,2,4]oxadiazole, [0822]
3-Chloromethyl-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole, [0823]
3-Chloromethyl-5-thiophen-3-yl-[1,2,4]oxadiazole, [0824]
3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-5-methyl-pyridine, [0825]
3-Chloromethyl-5-(3-nitro-phenyl)-[1,2,4]oxadiazole, [0826]
4-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-2-methyl-pyridine, [0827]
3-Chloromethyl-5-(3-ethyl-phenyl)-[1,2,4]oxadiazole, [0828]
3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-dimethyl-amine,
[0829] 3-Chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole, [0830]
3-Chloromethyl-5-(3-trifluoromethoxy-phenyl)-[1,2,4]oxadiazole,
[0831] 5-(3-Bromo-phenyl)-3-chloromethyl-[1,2,4]oxadiazole, [0832]
3-Chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole, [0833]
3-Chloromethyl-5-(3-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole,
[0834] 3-Chloromethyl-5-thiazol-4-yl-[1,2,4]oxadiazole, [0835]
3-Chloromethyl-5-(3-iodo-phenyl)-[1,2,4]oxadiazole, [0836]
3-Chloromethyl-5-(3-methoxymethyl-phenyl)-[1,2,4]oxadiazole, [0837]
5-Furan-2-yl-4-methyl-4H-[1,2,4]triazole-3-thiol, [0838]
4-Methyl-5-phenyl-4H-[1,2,4]triazole-3-thiol, [0839]
4-Methyl-5-pyridin-2-yl-4H-[1,2,4]triazole-3-thiol, [0840]
5-(4-Benzyl-morpholin-2-yl)-4-methyl-4H-[1,2,4]triazole-3-thiol,
[0841] 5-tert-Butyl-4-methyl-4H-[1,2,4]triazole-3-thiol, [0842]
4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol, [0843]
4-Methyl-5-thiophene-3-yl-4H-[1,2,4]triazole-3-thiol, [0844]
4-Methyl-5-thiazol-4-yl-4H-[1,2,4]triazole-3-thiol, [0845]
5-Cyclohexyl-4-methyl-4H-[1,2,4]triazole-3-thiol, [0846]
5-Chloro-thiophene-3-carboxylic acid, [0847]
3-Methylsulfanyl-benzoic acid, [0848] 3-Cyclopropyl-benzoic acid,
[0849] 3-tert-Butoxycarbonylamino-benzoic acid, [0850]
3-Acetyl-benzoic acid, [0851] 2-Methyl-isonicotinic acid hydrazide,
[0852] 5-Chloro-2-fluoro-benzoic acid hydrazide, [0853]
3-Cyano-benzoic acid hydrazide, [0854] 2-Chloro-isonicotinic acid
hydrazide, [0855] 2-Fluoro-5-methyl-benzoic acid hydrazide, [0856]
Pyrimidine-4-carboxylic acid hydrazide, [0857]
3-Fluoro-N-hydroxy-benzamidine, [0858]
N-Hydroxy-thiophene-3-carboxamidine, [0859]
2-Chloro-N-hydroxy-propionamidine, [0860]
3,N-Dihydroxy-benzamidine, [0861] N-Hydroxy-2-methyl-benzamidine,
[0862]
N-Hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ace-
tamidine, [0863] 3-Chloro-N-hydroxy-benzamidine, [0864]
N-Hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ace-
tamidine, [0865] 2,5-Difluoro-N-hydroxy-benzamidine, [0866]
4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol, [0867]
4-Butyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol, [0868]
4-(3-Methoxy-propyl)-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol,
[0869] 4-Benzyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol, [0870]
4-Furan-2-ylmethyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol,
[0871]
5-Thiophen-2-yl-4-thiophen-2-ylmethyl-4H-[1,2,4]triazole-3-thiol,
[0872] 4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol, [0873]
4-Furan-2-ylmethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol,
[0874] 4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol, [0875]
4-Ethyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol, [0876]
4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol, [0877]
4-Furan-2-ylmethyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol,
[0878] 4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazole-3-thiol, [0879]
4-Ethyl-5-(3-fluoro-phenyl)-4H-[1,2,4]triazole-3-thiol, [0880]
4-Ethyl-5-(4-fluoro-phenyl)-4H-[1,2,4]triazole-3-thiol, [0881]
5-(2-Fluoro-5-methyl-phenyl)-4-furan-2-ylmethyl-4H-[1,2,4]triazole-3-thio-
l, [0882]
4-Ethyl-5-(3-methyl-thiophen-2-yl)-4H-[1,2,4]triazole-3-thiol,
[0883]
4-Ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1,2,4]triazole-3-thiol,
[0884]
5-(2-Chloro-6-methyl-pyridin-4-yl)-4-ethyl-4H-[1,2,4]triazole-3-t-
hiol, [0885]
5-(5-Bromo-furan-2-yl)-4-ethyl-4H-[1,2,4]triazole-3-thiol, [0886]
4-Ethyl-5-(3-methoxy-thiophen-2-yl)-4H-[1,2,4]triazole-3-thiol,
[0887]
4-Ethyl-5-(tetrahydro-furan-2-yl)-2,4-dihydro-[1,2,4]triazole-3-t-
hione, [0888]
4-Ethyl-5-thioxo-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylic acid
methyl ester, [0889]
5-(2-Chloro-pyridin-4-yl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,
[0890]
5-(2-Chloro-6-methoxy-pyridin-4-yl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,
[0891]
4-Ethyl-5-(3-methyl-3H-imidazol-4-yl)-4H-[1,2,4]triazole-3-thiol,
[0892] 4-Propyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol, [0893]
4-Ethyl-5-(1-methyl-1H-imidazol-2-yl)-4H-[1,2,4]triazole-3-thiol,
[0894]
4-Ethyl-5-(1-methyl-1H-imidazol-4-yl)-4H-[1,2,4]triazole-3-thiol,
[0895] 3-(5-Mercapto-4-methyl-4H-[1,2,4]triazol-3-yl)-benzonitrile,
[0896] 5-(3-Chloro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol,
[0897] 5-(4-Chloro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol,
[0898] 5-(2-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol,
[0899] 5-(3-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol,
[0900] 5-(4-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol,
[0901] 5-Benzo[b]thiophen-2-yl-4-methyl-4H-[1,2,4]triazole-3-thiol,
[0902] 5-(3-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol,
[0903] 5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol,
[0904] 4-Ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazole-3-thiol,
[0905] 5-(3,5-Difluoro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,
[0906] 5-(2,6-Difluoro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,
[0907] 5-(4-Butoxy-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,
[0908] 5-Benzo[1,3]dioxol-5-yl-4-ethyl-4H-[1,2,4]triazole-3-thiol,
[0909]
4-Ethyl-5-pyrimidin-5-yl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0910] 4-Ethyl-5-furan-3-yl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0911]
4-(Tetrahydrofuran-2-ylmethyl)-5-thiophene-2-yl-2,4-dihydro-[1,2,4]triazo-
le-3-thione, [0912]
5-Cyclopentyl-4-ethyl-2,4-dihydro-[1,2,4]triazole-3-thione, [0913]
4-Ethyl-5-[2-(4-methoxy-phenyl)-ethyl]-2,4-dihydro-[1,2,4]triazole-3-thio-
ne, [0914]
5-(3,5-Dichloro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol, [0915]
5-(3-Methylphenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol, [0916]
5-(4-Methylphenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol, [0917]
4-Ethyl-5-(3-nitrophenyl)-4H-[1,2,4]triazole-3-thiol, [0918]
5-(2,5-Difluorophenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol, [0919]
5-(3-Chlorophenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol, [0920]
5-(4-Chlorophenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol, [0921]
4-Ethyl-5-methoxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0922]
4-Methyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0923] 4-Allyl-5-furan-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0924]
4-Ethyl-5-(4-methoxy-phenoxymethyl)-2,4-dihydro-[1,2,4]triazole-3-thione,
[0925]
4-Ethyl-5-phenoxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0926]
4-Ethyl-5-hydroxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0927]
4-Ethyl-5-(2-methoxy-ethyl)-2,4-dihydro-[1,2,4]triazole-3-thione,
[0928]
4-Ethyl-5-methylsulfanylmethyl-2,4-dihydro-[1,2,4]triazole-3-thi-
one, [0929]
5-Ethoxymethyl-4-ethyl-2,4-dihydro-[1,2,4]triazole-3-thione, [0930]
5-Furan-3-yl-4-methyl-2,4-dihydro-[1,2,4]triazole-3-thione, [0931]
4-Methyl-5-pyrimidin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0932]
4-Ethyl-5-pyridazin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0933]
4-Ethyl-5-pyridin-4-ylmethyl-2,4-dihydro-[1,2,4]triazole-3-thione-
, [0934]
4-Ethyl-5-(6-hydroxy-pyridin-3-yl)-2,4-dihydro-[1,2,4]triazole--
3-thione, [0935]
4-Ethyl-5-(4-hydroxy-phenyl)-2,4-dihydro-[1,2,4]triazole-3-thione,
[0936]
4-Ethyl-5-p-tolyloxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0937]
4-Ethyl-5-(6-methoxy-pyridin-3-yl)-2,4-dihydro-[1,2,4]triazole-3--
thione, [0938]
4-Ethyl-5-(2-methoxy-pyridin-4-yl)-2,4-dihydro-[1,2,4]triazole-3-thione,
[0939]
4-Ethyl-5-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0940]
4-Ethyl-5-(5-methoxy-pyrimidin-2-yl)-2,4-dihydro-[1,2,4]triazole--
3-thione, [0941] 4-Furan-2-ylmethyl-4H-[1,2,4]triazole-3-thiol,
[0942] 4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol,
[0943]
4-Cyclopropylmethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol,
[0944]
4-Cyclopropyl-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0945]
5-Furan-2-yl-4-(2-methoxy-ethyl)-2,4-dihydro-[1,2,4]triazole-3-th-
ione, [0946]
4-Cyclopropyl-5-furan-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0947]
(3-Thiophen-2-yl-5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-acetic
acid methyl ester, [0948]
4-Cyclopropylmethyl-5-thiophene-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione-
, [0949]
4-(2-Methoxy-ethyl)-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-
-3-thione, [0950]
Thiophen-2-yl-4-(2,2,2-trifluoroethyl)-2,4-dihydro-[1,2,4]triazole-3-thio-
ne, [0951]
4-Cyclopropyl-5-pyrimidin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0952]
4-Cyclopropyl-5-pyridin-3-yl-2,4-dihydro-[1,2,4]triazole-3-thione-
, [0953] 4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol,
[0954]
4-Ethyl-3-methanesulfonyl-5-thiophen-2-yl-4H-[1,2,4]triazole,
[0955]
4-(5-Methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,
[0956]
4-(2-Hydroxy-ethyl)-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione,
[0957] 4-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-pyridine, [0958]
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine,
[0959]
3-Pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,
[0960]
3-Furan-2-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,
[0961]
4-Ethyl-5-(6-methoxy-pyridazin-3-yl)-2,4-dihydro-[1,2,4]triazole-
-3-thione, [0962]
4-Ethyl-5-(5-methoxy-pyridin-2-yl)-2,4-dihydro-[1,2,4]triazole-3-thione,
[0963] 5-Chloromethyl-3-phenyl-[1,2,4]oxadiazole, [0964]
5-Chloromethyl-3-(3-fluoro-phenyl)-[1,2,4]oxadiazole, [0965]
5-Chloromethyl-3-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole,
[0966] 5-Chloromethyl-3-thiophen-2-yl-[1,2,4]oxadiazole, [0967]
5-Chloromethyl-3-thiophen-3-yl-[1,2,4]oxadiazole, [0968]
3-(5-Chloromethyl-[1,2,4]oxadiazol-3-yl)-phenol, [0969]
5-Chloromethyl-3-o-tolyl-[1,2,4]oxadiazole, [0970]
5-Chloromethyl-3-(3-chloro-phenyl)-[1,2,4]oxadiazole, [0971]
5-Chloromethyl-3-(2,5-difluoro-phenyl)-[1,2,4]oxadiazole, [0972]
3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile, [0973]
2-Chloro-4-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-pyridine, [0974]
3-Chloromethyl-5-(2,5-dimethyl-phenyl)-[1,2,4]oxadiazole, [0975]
3-Chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole,
[0976] 3-Chloromethyl-5-(2,5-dichloro-phenyl)-[1,2,4]oxadiazole,
[0977]
3-Chloromethyl-5-(2-fluoro-5-bromo-phenyl)-[1,2,4]oxadiazole,
[0978] 3-Chloromethyl-5-(3-methyl-phenyl)-[1,2,4]oxadiazole, [0979]
3-Chloromethyl-5-(2,5-difluoro-phenyl)-[1,2,4]oxadiazole, [0980]
3-Chloromethyl-5-(3-methylsulfanyl-phenyl)-[1,2,4]oxadiazole,
[0981] 3-Chloromethyl-5-(3-cyclopropyl-phenyl)-[1,2,4]oxadiazole,
[0982] 3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-carbamic
acid tert-butyl ester, [0983]
1-[3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-ethanone,
[0984]
5-(5-Chloro-2-fluoro-phenyl)-3-chloromethyl-[1,2,4]oxadiazole,
[0985] 2-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-4-methyl-phenol,
[0986]
3-Chloromethyl-5-(2-chloro-5-methyl-phenyl)-[1,2,4]oxadiazole,
[0987]
3-Chloromethyl-5-(2,5-dichloro-thiophen-3-yl)-[1,2,4]oxadiazole,
[0988] 3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile,
[0989] 3-Chloromethyl-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole, [0990]
3-Chloromethyl-5-(2-methyl-thiazol-4-yl)-[1,2,4]oxadiazole, [0991]
3-Chloromethyl-5-(4-fluoro-phenyl)-[1,2,4]oxadiazole, [0992]
5-(5-Bromo-2-fluoro-phenyl)-3-chloromethyl-[1,2,4]oxadiazole,
[0993] 3-Chloromethyl-5-(4-methyl-thiophen-2-yl)-[1,2,4]oxadiazole,
[0994]
5-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-thiophene-3-carbonitrile,
[0995]
2-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-4-methyl-benzonitrile,
[0996]
3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-5-fluoro-benzonitrile,
[0997]
3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-4-fluoro-benzonitrile,
[0998] 4-Chloro-2-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-phenol,
[0999] 3-(1-Chloro-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole,
[1000] 3-(1-Chloro-ethyl)-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole,
[1001]
3-(1-Chloro-ethyl)-5-(5-chloro-2-fluoro-phenyl)-[1,2,4]oxadiazole,
[1002] [3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanol,
[1003]
3-Chloromethyl-5-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-[1,2,4]o-
xadiazole, [1004] 3-Chloromethyl-5-furan-3-yl-[1,2,4]oxadiazole,
[1005] 3-Chloromethyl-5-(5-chloro-thiophen-2-yl)-[1,2,4]oxadiazole,
[1006] 1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethanol,
[1007]
[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanol,
[1008] 1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethanol,
[1009] [5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanol, [1010]
2-Chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole,
[1011] 2-Chloromethyl-5-(3-chloro-phenyl)-[1,3,4]oxadiazole, [1012]
4-(5-Chloromethyl-[1,3,4]oxadiazol-2-yl)-2-methyl-pyridine, [1013]
2-Chloromethyl-5-m-tolyl-[1,3,4]oxadiazole, [1014]
3-(5-Chloromethyl-[1,3,4]oxadiazol-2-yl)-benzonitrile, [1015]
2-Chloro-4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)-pyridine, [1016]
2-(5-Chloro-2-fluoro-phenyl)-5-chloromethyl-[1,3,4]oxadiazole,
[1017] 2-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole,
[1018]
2-(1-Bromo-ethyl)-5-(5-chloro-2-fluoro-phenyl)-[1,3,4]oxadiazole,
[1019]
4-[5-(1-Bromo-ethyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-pyridine,
[1020]
2-(1-Bromo-ethyl)-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole,
[1021] 2-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole,
[1022] 3-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole,
[1023] 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol, [1024]
1-[5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethanol, [1025]
5-(2-Fluoro-5-methyl-phenyl)-isoxazole-3-carboxylic acid methyl
ester, [1026] 5-Thiophen-3-yl-isoxazole-3-carboxylic acid methyl
ester, [1027] 5-Phenyl-isoxazole-3-carboxylic acid methyl ester,
[1028] 5-(3-Chloro-phenyl)-4-methyl-isoxazole-3-carboxylic acid
ethyl ester, [1029]
5-(5-Chloro-thiophen-3-yl)-isoxazole-3-carboxylic acid methyl
ester, [1030] [5-(3-Chloro-phenyl)-isoxazol-3-yl]-methanol, [1031]
[2-(3-Chloro-phenyl)-oxazol-4-yl]-methanol, [1032]
[3-(3-Chloro-phenyl)-isoxazol-5-yl]-methanol, [1033]
5-(Thiophen-3-yl-isoxazol-3-yl)methanol,
[1034] [5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-yl]-methanol,
[1035] (5-Phenyl-isoxazol-3-yl)-methanol, [1036]
[5-(3-Chloro-phenyl)-4-methyl-isoxazol-3-yl]-methanol, [1037]
[5-(5-Chloro-thiophen-3-yl)-isoxazol-3-yl)]-methanol, [1038]
Methanesulfonic acid 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethyl
ester, [1039] Methanesulfonic acid
2-(3-chloro-phenyl)-oxazol-4-ylmethyl ester, [1040] Methanesulfonic
acid 3-(3-chloro-phenyl)-isoxazol-5-ylmethyl ester, [1041]
Methanesulfonic acid
5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethyl ester, [1042]
Methanesulfonic acid-phenyl)-isoxazol-5-yl]-ethyl ester, [1043]
Methanesulfonic acid
5-(5-chloro-2-fluoro-phenyl)-isoxazol-3-ylmethyl ester, [1044]
Methanesulfonic acid 5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester,
[1045] Methanesulfonic acid 5-thiophen-3-yl-isoxazol-3-ylmethyl
ester, [1046] Methanesulfonic acid
5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethyl ester, [1047]
Methanesulfonic acid 5-phenyl-isoxazol-3-ylmethyl ester, [1048]
Methanesulfonic acid
5-(3-chloro-phenyl)-4-methyl-isoxazol-3-ylmethyl ester, [1049]
Methanesulfonic acid 5-(5-chloro-thiophen-3-yl)-isoxazol-3-ylmethyl
ester, [1050] Methanesulfonic acid
1-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethyl ester, [1051]
Methanesulfonic acid
1-[5-(5-chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethyl ester, [1052]
Methanesulfonic acid
4-chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester, [1053]
Pyrimidine-4-carboxylic acid, [1054]
3-(3-Chloro-phenyl)-isoxazole-5-carboxylic acid methyl ester,
[1055] 2-Bromomethyl-5-(3-chloro-phenyl)-oxazole, [1056]
2-(3-Chloro-phenyl)-oxazole-4-carboxylic acid methyl ester, [1057]
2-(3-Chloro-phenyl)-oxazole-4-carboxylic acid methyl ester, [1058]
1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethanol, [1059]
1-[3-(3-Chloro-phenyl)-isoxazol-5-yl]-ethanol, [1060]
[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-methanol, [1061]
3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid
hydrazide, [1062]
3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid
hydrazide, [1063]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionimidic acid
ethyl ester hydrochloride, [1064]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid
hydrazide, [1065]
[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid hydrazide,
[1066] (R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric
acid hydrazide, [1067]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-butyric acid
hydrazide, [1068]
3-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidin-2-one,
[1069]
3-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-pipe-
ridin-2-one, [1070]
3-Chloromethyl-5-(5-chloro-thiophen-3-yl)-[1,2,4]oxadiazole, [1071]
1-[5-(5-Chloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethoxy]-1H-benzotriaz-
ole, [1072]
(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetonitrile,
[1073]
2-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-propi-
onic acid, [1074]
2-(4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-propionic
acid, [1075]
3-(3-Chloro-phenyl)-5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,-
2,4]oxadiazole or, [1076]
{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,-
2,4]oxadiazol-5-yl-phenyl}-carbamic acid tert-butyl ester.
Pharmaceutical Formulations
[1077] According to one aspect of the present invention there is
provided a pharmaceutical formulation comprising a compound of
formula I, or salt thereof, for use in the prevention and/or
treatment of metabotropic glutamate receptor subtype 5 receptor
(mGluR5) mediated disorders and any disorder listed below.
[1078] The composition may be in a form suitable for oral
administration, for example as a tablet, pill, syrup, powder,
granule or capsule, for parenteral injection (including
intravenous, subcutaneous, intramuscular, intravascular or
infusion) as a sterile solution, suspension or emulsion, for
topical administration as an ointment, patch or cream or for rectal
administration as a suppository.
[1079] In general the above compositions may be prepared in a
conventional manner using one or more conventional excipients,
pharmaceutical diluents and/or inert carriers.
[1080] According to another aspect of the invention there is
provided a pharmaceutical formulation comprising as active
ingredient a therapeutically effective amount of a compound of
formula I in association with one or more pharmaceutically
acceptable diluent, excipients and/or inert carrier.
[1081] Suitable daily doses of the compounds of formula I in the
treatment of a mammal, including man are approximately 0.01 to 250
mg/kg bodyweight at peroral administration and about 0.001 to 250
mg/kg bodyweight at parenteral administration. The typical daily
dose of the active ingredients varies within a wide range and will
depend on various factors such as the relevant indication, the
route of administration, the age, weight and sex of the patient and
may be determined by a physician.
Medical Use
[1082] It has been found that the compounds according to the
present invention, or salts thereof, exhibit a high degree of
potency and selectivity for individual metabotropic glutamate
receptor (mGluR) subtypes. In particular there are compounds
according to the present invention that are potent and selective
for the mGluR Group I receptor and more particularly for mGluR5.
Accordingly, the compounds of the present invention are expected to
be useful in the prevention and/or treatment of conditions
associated with excitatory activation of an mGluR Group I receptor
and for inhibiting neuronal damage caused by excitatory activation
of an mGluR Group I receptor, specifically when the mGluR Group I
receptor is mGluR5. The compounds may be used to produce an
inhibitory effect of mGluR Group I, especially mGluR5, in mammals,
including man.
[1083] mGluR5 is highly expressed in the central and peripheral
nervous system and in other tissues. Thus, it is expected that the
compounds of the invention are well suited for the prevention
and/or treatment of mGluR5 receptor-mediated disorders such as
acute and chronic neurological and psychiatric disorders and
chronic and acute pain disorders.
[1084] Further disorders are Alzheimer's disease, senile dementia,
AIDS-induced dementia, Parkinson's disease, amyotrophic lateral
sclerosis, Huntington's Chorea, migraine, epilepsy, schizophrenia,
depression, anxiety, acute anxiety, obsessive compulsive disorder,
opthalmological disorders such as retinopathies, diabetic
retinopathies, glaucoma, auditory neuropathic disorders such as
tinnitus, chemotherapy induced neuropathies, post-herpetic
neuralgia and trigeminal neuralgia, tolerance, dependency,
addiction and craving disorders, neurodevelopmental disorders
including Fragile X, autism, mental retardation, schizophrenia and
Down's Syndrome.
[1085] The compounds are also well suited for the prevention and/or
treatment of pain related to migraine, inflammatory pain,
neuropathic pain disorders such as diabetic neuropathies, arthritis
and rheumatitiod diseases, low back pain, post-operative pain and
pain associated with various conditions including angina, renal or
billiary colic, menstruation, migraine and gout.
[1086] Other disorders are stroke, head trauma, anoxic and ischemic
injuries, hypoglycemia, cardiovascular diseases and epilepsy.
[1087] The dose required for the therapeutic or preventive
treatment of a particular disorder will necessarily be varied
depending on the host treated, the route of administration and the
severity of the illness being treated.
[1088] The invention relates to compounds of formula I as defined
hereinbefore, for use in therapy.
[1089] The invention relates to compounds of formula I as defined
hereinbefore, for use in prevention and/or treatment of
neurological disorders.
[1090] The invention relates to compounds of formula I as defined
hereinbefore, for use in prevention and/or treatment of psychiatric
disorders.
[1091] The invention relates to compounds of formula I as defined
hereinbefore, for use in prevention and/or treatment of chronic and
acute pain disorders.
[1092] The invention relates to compounds of formula I as defined
hereinbefore, for use in prevention and/or treatment of mGluR5
receptor-mediated disorders.
[1093] The invention relates to compounds of formula I as defined
hereinbefore, for use in prevention and/or treatment of Alzheimer's
disease senile dementia, AIDS-induced dementia, Parkinson's
disease, amylotropic lateral sclerosis, Huntington's Chorea,
migraine, epilepsy, schizophrenia, depression, anxiety, acute
anxiety, opthalmological disorders such as retinopathies, diabetic
retinopathies, glaucoma, auditory neuropathic disorders such as
tinnitus, chemotherapy induced neuropathies, post-herpetic
neuralgia and trigeminal neuralgia, tolerance, dependency, Fragile
X, autism, mental retardation, schizophrenia and Down's
Syndrome.
[1094] The invention relates to compounds of formula I as defined
hereinbefore, for use in prevention and/or treatment of pain
related to migraine, inflammatory pain, neuropathic pain disorders
such as diabetic neuropathies, arthritis and rheumatitiod diseases,
low back pain, post-operative pain and pain associated with various
conditions including angina, renal or billiary colic, menstruation,
migraine and gout.
[1095] The invention relates to compounds of formula I as defined
hereinbefore, for use in prevention and/or treatment of stroke,
head trauma, anoxic and ischemic injuries, hypoglycemia,
cardiovascular diseases and epilepsy.
[1096] The present invention relates to the use of a compound
according to Formula I and Formula II in the treatment of
gastrointestinal disorders.
[1097] Another embodiment of the invention relates to the use of a
compound according to Formula I and Formula II, for the manufacture
of a medicament for the inhibition of transient lower esophageal
sphincter relaxations, for the treatment of GERD, for the
prevention of G.I. reflux, for the treatment regurgitation,
treatment of asthma, treatment of laryngitis, treatment of lung
disease and for the management of failure to thrive.
[1098] The present invention relates also to the use of a compound
of formula I as defined hereinbefore, in the manufacture of a
medicament for the prevention and/or treatment of mGluR5
receptor-mediated disorders and any disorder listed above.
[1099] The invention also provides a method of treatment and/or
prevention of mGluR5 receptor-mediated disorders and any disorder
listed above, in a patient suffering from, or at risk of, said
condition, which comprises administering to the patient an
effective amount of a compound of formula I, as hereinbefore
defined.
[1100] In the context of the present specification, the term
"therapy" includes treatment as well as prevention, unless there
are specific indications to the contrary. The terms "therapeutic"
and "therapeutically" should be construed accordingly.
[1101] In this specification, unless stated otherwise, the term
`antagonist` means a compound that by any means, partly or
completely, blocks the transduction pathway leading to the
production of a response by the ligand.
[1102] The term "disorder", unless stated otherwise, means any
condition and disease associated with metabotropic glutamate
receptor activity.
Non-Medical Use
[1103] In addition to their use in therapeutic medicine, the
compounds of formula I or salt thereof, are also useful as
pharmacological tools in the development and standardisation of in
vitro and in vivo test systems for the evaluation of the effects of
inhibitors of mGluR related activity in laboratory animals such as
cats, dogs, rabbits, monkeys, rats and mice, as part of the search
for new therapeutics agents.
Pharmacology
[1104] The pharmacological properties of the compounds of the
invention can be analyzed using standard assays for functional
activity. Examples of glutamate receptor assays are well known in
the art as described in for example Aramori et al., Neuron 8:757
(1992), Tanabe et al., Neuron 8:169 (1992), Miller et al., J.
Neuroscience 15: 6103 (1995), Balazs, et al., J. Neurochemistry
69:151 (1997). The methodology described in these publications is
incorporated herein by reference. Conveniently, the compounds of
the invention can be studied by means of an assay that measures the
mobilization of intracellular calcium, [Ca.sup.2+].sub.i in cells
expressing mGluR5.
[1105] Intracellular calcium mobilization was measured by detecting
changes in fluorescence of cells loaded with the fluorescent
indicator fluo-3. Fluorescent signals were measured using the FLIPR
system (Molecular Devices). A two addition experiment was used that
could detect compounds that either activate or antagonize the
receptor.
[1106] For FLIPR analysis, cells expressing human mGluR5d were
seeded on collagen coated clear bottom 96-well plates with black
sides and analysis of [Ca.sup.2+].sub.i mobilization was done 24
hours after seeding.
[1107] FLIPR experiments were done using a laser setting of 0.800 W
and a 0.4 second CCD camera shutter speed. Each FLIPR experiment
was initiated with 160 .mu.L of buffer present in each well of the
cell plate. After each addition of the compound, the fluorescence
signal was sampled 50 times at 1 second intervals followed by 3
samples at 5 second intervals. Responses were measured as the peak
height of the response within the sample period.
[1108] EC.sub.50 and IC.sub.50 determinations were made from data
obtained from 8-point concentration response curves (CRC) performed
in duplicate. Agonist CRC were generated by scaling all responses
to the maximal response observed for the plate. Antagonist block of
the agonist challenge was normalized to the average response of the
agonist challenge in 14 control wells on the same plate.
[1109] We have validated a secondary functional assay for mGluR5d
based on Inositol Phosphate (IP.sub.3) turnover. IP.sub.3
accumulation is measured as an index of receptor mediated
phospholipase C turnover. GHEK cells stably expressing the human
mGluR5d receptors were incubated with [3H] myo-inositol overnight,
washed three times in HEPES buffered saline and pre-incubated for
10 minutes with 10 mM LiCl. Compounds (agonists) were added and
incubated for 30 minutes at 37.degree. C. Antagonist activity was
determined by pre-incubating test compounds for 15 minutes, then
incubating in the presence of glutamate (80 .mu.M) or DHPG (30
.mu.M) for 30 minutes. Reactions were terminated by the addition of
perchloric acid (5%). Samples were collected and neutralized, and
inositol phosphates were separated using Gravity-Fed Ion-Exchange
Columns.
[1110] A detailed protocol for testing the compounds of the
invention is provided below in Pharmaceutical Examples.
[1111] Abbreviations
[1112] FLIPR Fluorometric Imaging Plate reader
[1113] CCD Charge Coupled Device
[1114] CRC Concentration Response Curve
[1115] GHEK Human Embrionic Kidney expressing Glutamate
Transporter
[1116] HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
(buffer)
[1117] IP.sub.3 inositol triphosphate
[1118] DHPG 3,5-dihydroxyphenylglycine;
[1119] BSA Bovine Serum Albumin
[1120] EDTA Ethylene Diamine Tetraacetic Acid
Methods of Preparation
[1121] Another aspect of the present invention provides a process
for preparing a compound of formula I, or salt thereof.
[1122] Throughout the following description of such processes it is
understood that, where appropriate, suitable protecting groups will
be added to, and subsequently removed from, the various reactants
and intermediates in a manner that will be readily understood by
one skilled in the art of organic synthesis. Conventional
procedures for using such protecting groups as well as examples of
suitable protecting groups are described, for example, in
"Protective Groups in Organic Synthesis" T. W. Green, P. G. M.
Wuts, Wiley-Interscience, New York, 1999. It is also to be
understood that a transformation of a group or substituent into
another group or substituent by chemical manipulation can be
conducted on any intermediate or final product on the synthetic
path toward the final product, in which the possible type of
transformation is limited only by inherent incompatibility of other
functionalities carried by the molecule at that stage to the
conditions or reagents employed in the transformation. Such
inherent incompatibilities, and ways to circumvent them by carrying
out appropriate transformations and synthetic steps in a suitable
order, will be readily understood to the one skilled in the art of
organic synthesis. Examples of transformations are given below, and
it is to be understood that the described transformations are not
limited only to the generic groups or substituents for which the
transformations are exemplified. References and descriptions on
other suitable transformations are given in "Comprehensive Organic
Transformations--A Guide to Functional Group Preparations" R. C.
Larock, VHC Publishers, Inc. (1989). References and descriptions of
other suitable reactions are described in textbooks of organic
chemistry, for example, "Advanced Organic Chemistry", March,
4.sup.th ed. McGraw Hill (1992) or, "Organic Synthesis", Smith,
McGraw Hill, (1994). Techniques for purification of intermediates
and final products include for example, straight and reversed phase
chromatography on column or rotating plate, recrystallisation,
distillation and liquid-liquid or solid-liquid extraction, which
will be readily understood by the one skilled in the art. The
definitions of substituents and groups are as in formula I except
where defined differently. The term "room temperature" and "ambient
temperature" shall mean, unless otherwise specified, a temperature
between 16 and 25.degree. C.
[1123] Unless specified otherwise, are P, Q, X.sup.1, X.sup.2,
X.sup.3, X.sup.4, R, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5R.sup.6, M.sup.1, M.sup.2, m and n, defined as in formula
I.
[1124] All starting materials are commercially available or earlier
described in the literature.
[1125] The .sup.1H and .sup.13C NMR spectra were recorded either on
Bruker 300, Bruker DPX400 or Varian +400 spectrometers operating at
300, 400 and 400 MHz for .sup.1H NMR respectively, using TMS or the
residual solvent signal as reference, in deuterated chloroform as
solvent unless otherwise indicated. All reported chemical shifts
are in ppm on the delta-scale, and the fine splitting of the
signals as appearing in the recordings (s: singlet, d: doublet, t:
triplet, q: quartet, m: multiplet).
[1126] Analytical in line liquid chromatography separations
followed by mass spectra detections, were recorded on a Waters LCMS
consisting of an Alliance 2795 (LC) and a ZQ single quadropole mass
spectrometer. The mass spectrometer was equipped with an
electrospray ion source operated in a positive or negative ion
mode. The ion spray voltage was .+-.3 kV and the mass spectrometer
was scanned from m/z 100-700 at a scan time of 0.8 s. To the
column, X-Terra MS, Waters, C8, 2.1.times.50 mm, 3.5 .mu.m, was
applied a linear gradient from 5% to 100% acetonitrile in 10 mM
ammonium acetate (aq.), or in 0.1% TFA (aq.).
[1127] Preparative reversed phase chromatography was run on a
Gilson autopreparative HPLC with a diode array detector using an
XTerra MS C8, 19.times.300 mm, 7 .mu.m as column.
[1128] MS-triggered preparative reversed phase chromatograpy was
run on a Waters autopurification LC-MS system with a diode array
detector and a ZQ mass detector using an XTerra MS C8, 19.times.100
mm, 5 .mu.m as column.
[1129] Purification by a chromatotron was performed on rotating
silica gel/gypsum (Merck, 60 PF-254 with calcium sulphate) coated
glass sheets, with coating layer of 1, 2, or 4 mm using a TC
Research 7924T chromatotron.
[1130] Purification of products were also done using Chem Elut
Extraction Columns (Varian, cat #1219-8002), Mega BE-SI (Bond Elut
Silica) SPE Columns (Varian, cat #12256018; 12256026; 12256034), or
by flash chromatography in silica-filled glass columns.
[1131] Microwave heating was performed in a Smith Synthesizer
Single-mode microwave cavity producing continuous irradiation at
2450 MHz (Personal Chemistry AB, Uppsala, Sweden).
[1132] Abbreviations: [1133] atm atmosphere [1134] aq. aqueous
[1135] CDI N,N'-Carbonyldiimidazole [1136] d day(s) [1137] DBU
1,8-diazabicyclo[5.4.0]undec-7-ene [1138] DCC
N,N-Dicyclohexylcarbodiimide [1139] DCM Dichloromethane [1140] DEA
N,N-Diisopropyl ethylamine [1141] DIC N,N'-Diisopropylcarbodiimide
[1142] DMAP N,N-Dimethyl-4-aminopyridine [1143] DMF
N,N-dimethylformamide [1144] DMSO Dimethylsulfoxide [1145] EA Ethyl
acetate [1146] BOPA Benzoyl Peroxide [1147] EDCl
N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride
[1148] EtOH Ethanol [1149] Et.sub.2O Diethylether [1150] h hour(s)
[1151] hep heptane [1152] hex hexane(s) [1153] P-BEMP Polystyrene
bound
2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphospho-
rine [1154] Deoxofluor [Bis(2-methoxyethyl)amino]sulfur trifluoride
[1155] DAST (Diethylamino)sulfur trifluoride [1156] EDCI
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [1157]
HOBt 1-hydroxybenzotriazole hydrate [1158] THF tetrahydrofuran
[1159] TFA trifluoroacetic acid [1160] Et ethyl [1161] Ac acetyl
[1162] DIBAL diisobutylaluminum hydride [1163] M, N molar and
normal [1164] MeOH Methanol [1165] HBTU
O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate [1166] Boc tert-butoxycarbonyloxy [1167] HMDS
hexamethyl disilazide [1168] Ms mesylate or methanesulphonyl [1169]
min minutes [1170] NADPH Nicotinamide-adenine dinucleotide
phosphate, reduced [1171] nBuLi 1-butyl lithium [1172] NBS
N-bromosuccinimid [1173] Novozyme 435.RTM. Trademark name for
polymer supported Candida Antartica Lipase [1174] o.n. over night
[1175] prep preparative [1176] r.t. or rt room temperature [1177]
sat. saturated [1178] TEA Triethylamine [1179] LDA Lithium
diisopropylamine [1180] LHA Lithium aluminium hydride [1181] MCPBA
meta-chloroperoxybenzoic acid [1182] SPE solid phase extraction
[1183] Lawesson's Reagent
[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide
[1184] TFA Trifluoroacetic acid [1185] Ts tosyl or para-toluene
sulphonyl
[1186] General Syntheses of Compounds of Formula V. ##STR6##
[1187] A compound of formula V, wherein R.sup.7 is independently
selected from a group consisting of
M.sup.1-(R.sup.2).sub.n--P--(R.sup.1).sub.m1,
M.sup.2-(R.sup.3).sub.n--X.sup.4-Q-(R.sup.4).sub.m2, and
M.sup.2-(R.sup.3).sub.n-G wherein G is a leaving group or a group
which may subsequently be transformed into a leaving group, may be
prepared through cyclization of a compound of formula IV formed
from a suitably activated compound of formula III, wherein LG is a
leaving group, with a compound of formula II. The compound of
formula II may be prepared from a suitable nitrile by addition of
hydroxylamine in a suitable solvent such as, methanol, ethanol,
water or mixture thereof, using an appropriate base such as
hydroxide, carbonate or acetate.
[1188] The compound of formula III may be activated as follows; i)
as the acid chloride formed from the acid using a suitable reagent
such as oxalyl chloride or thionyl chloride; ii) as an anhydride or
mixed anhydride formed from treatment with a reagent such as alkyl
chloroformate; iii) using traditional methods to activate acids in
amide coupling reactions such as EDCI with HOBt or uronium salts
like HBTU; iv) as an alkyl ester when the hydroxyamidine is
deprotonated using a strong base like tert-butoxide; v) by any
other suitable method of activation for the desired substrate.
[1189] The ester formation may be accomplished using an appropriate
aprotic solvent such as dichloromethane, tetrahydrofuran,
N,N-dimethylformamide or toluene, with optionally an appropriate
organic base such as triethylamine, diisopropylethylamine and the
like or an inorganic base such sodium bicarbonate or potassium
carbonate.
[1190] The cyclization of the ester to form an oxadiazole may be
carried out on the crude ester, with evaporation and replacement of
the solvent with a higher boiling solvent such as DMF, or with
aqueous extraction to provide a semi-purified material or with
material purified by standard chromatographic methods. The
cyclization may be accomplished by heating conventionally or by
microwave irradiation (100-180.degree. C.), in a suitable solvent
such as pyridine or N,N-dimethylformamide or using a lower
temperature method employing reagents like tetrabutylammonium
fluoride in tetrahydrofuran or by any other suitable known
literature method.
[1191] Other compatible non-reacting functional groups suitably
protected may also be present in the substrates.
[1192] Further examples of the above described reactions can be
found in Poulain et al., Tetrahedron Lett., (2001), 42, 1495-98,
Ganglott et al., Tetrahedron Lett., (2001), 42, 1441-43, which are
hereby included as references.
[1193] Synthesis of Nitriles and Acids for Use in Preparation of
Compounds of Formula II and III
[1194] Aryl nitrites are available by a variety of methods
including cyanation of an aryl halide or triflate under palladium
or nickel catalysis using an appropriate cyanide source such as
zinc cyanide in an appropriate solvent such as
N,N-dimethylformamide. The corresponding acid is available from the
nitrile by hydrolysis under either acidic or basic conditions in an
appropriate solvent such as aqueous alcohols. Aryl acids are also
available from a variety of other sources, including iodo- or
bromo-lithium exchange followed by trapping with CO.sub.2 to give
directly the acid.
[1195] The acid may be converted to the primary amide using any
compatible method to activate the acid, including via the acid
chloride or mixed anhydride, followed by trapping with any source
of ammonia, including ammonium chloride in the presence of a
suitable base, ammonium hydroxide, methanolic ammonia or ammonia in
an aprotic solvent such as dioxane. This amide intermediate may be
converted to the nitrile using a variety of dehydration reagents
such as oxalyl chloride or thionyl chloride. This reaction sequence
to convert an acid into a nitrile may also be applied to
non-aromatic acids, including suitably protected amino acid
derivatives. A suitable protecting group for an amine, in an amino
acid or in a remote position of any other acid starting material,
may be any group which removes the basicity and nucleophilicity of
the amine functionality, including such carbamate protecting group
as Boc.
[1196] Some acids are more easily prepared taking advantage of
commercially available analogs. For example,
6-methylpyridine-4-carboxylic acid is prepared by dechlorination of
2-chloro-6-methylpyridine-4-carboxylic acid. Certain types of
substituted fluoro-benzonitriles and benzoic acids are available
from bromo-difluoro-benzene via displacement of one fluoro group
with a suitable nucleophile such as imidazole in the presence of a
base such as potassium carbonate in a compatible solvent such as
N,N-dimethylformamide at elevated temperatures (80-120.degree. C.)
for extended periods of time. The bromo group may subsequently be
elaborated into the acid or nitrile as above.
[1197] 1,3-Disubstituted and 1,3,5-trisubstituted benzoic acids and
benzonitriles may be prepared by taking advantage of readily
available substituted isophthalic acid derivatives. Monohydrolysis
of the diester allows selective reaction of the acid with a variety
of reagents, most typically activating agents such as thionyl
chloride, oxalyl chloride or isobutyl chloroformate and the like.
From the activated acid, a number of products are available. In
addition to the primary amide used to form the nitrite by
dehydration as mentioned above, reduction to the hydroxymethyl
analog may be carried out on the mixed anhydride or acid chloride
using a variety of reducing agents such as sodium borohydride in a
compatible solvent such as tetrahydrofuran. The hydroxymethyl
derivative may be further reduced to the methyl analog using
catalytic hydrogenation with an appropriate source of catalyst such
as palladium on carbon in an appropriate solvent such as ethanol.
The hydroxymethyl group may also be used in any reaction suitable
for benzylic alcohols such as acylation, alkylation, transformation
to halogen and the like. Halomethylbenzoic acids of this type may
also be obtained from bromination of the methyl derivative when not
commercially available. Ethers obtained by alkylation of the
hydroxymethyl derivatives may also be obtained from the
halomethylaryl benzoate derivatives by reaction with the
appropriate alcohol using an appropriate base such as potassium
carbonate or sodium hydroxide in an appropriate solvent such as
tetrahydrofuran or the alcohol. When other substituents are
present, these may also be employed in standard transformation
reactions. Treatment of an aniline with acid and sodium nitrite may
yield a diazonium salt, which may be transformed into a halide such
as fluoride using tetrafluoroboric acid. Phenols react in the
presence of a suitable base such as potassium carbonate with
alkylating agents to form aromatic ethers.
[1198] Formation of Compounds of Formula IX ##STR7##
[1199] A compound of formula IX, wherein R.sup.7 is independently
selected from a group consisting of
M.sup.1-(R.sup.2).sub.n--P--(R.sup.1).sub.m1,
M.sup.2-(R.sup.3).sub.n--X.sup.4-Q-(R.sup.4).sub.m2, and
M.sup.2-(R.sup.3).sub.n-G wherein G is a leaving group or a group
which may subsequently be transformed into a leaving group, may be
prepared by a 1,3-dipolar cycloaddition between compounds of
formula VI and VII under basic conditions using a suitable base
such as sodium bicarbonate or triethylamine at suitable
temperatures (0.degree. C.-100.degree. C.) in solvents such as
toluene. Synthesis of compounds of type VI has previously been
described in the literature, e.g. Kim, Jae Nyoung; Ryu, Eung K; J.
Org. Chem. (1992), 57, 6649-50. 1,3-Dipolar cycloaddition with
acetylenes of type VII can also be effected using substituted
nitromethanes of type VIII via activation with an electrophilic
reagent such as PhNCO in the presence of a base such as
triethylamine at elevated temperatures (50-100.degree. C.). Li,
C-S.; Lacasse, E.; Tetrahedron Lett. (2002) 43; 3565-3568. Several
compounds of type VII are commercially available, or may be
synthesized by standard methods as known by one skilled in the
art.
[1200] Alternatively, compounds of formula X, which are available
from a Claisen condensation of a methyl keone and an ester using
basic conditions using such bases as sodium hydride or potassium
tert-butoxide, may yield compounds of formula IX via condensation
and subsequent cyclization using hydroxylamine, for example in the
form of the hydrochloric acid salt, at elevated temperatures
(60-120.degree. C.).
[1201] It is understood that for both methods subsequent functional
group transformations may be necessary. In the case of an ester
group, these transformations may include, but is not limited to
either of following three procedures: a) Complete reduction using a
suitable reducing agent such as LAH in solvents such as THF. b)
Partial reduction using a suitable selective reducing agent such as
DIBAL followed by alkylation with an alkylhalide. c) Alkylation
using an alkylmetal reagent such as an alkyl magnesium halide in
solvents such as toluene or THF, followed by reduction with for
example sodium borohydride in methanol.
[1202] Formation of Compounds of Formula XIV ##STR8##
[1203] A compound of formula XIV, wherein R.sup.7 is independently
selected from a group consisting of
M.sup.1-(R.sup.2).sub.n--P--(R.sup.1).sub.m1,
M.sup.2-(R.sup.3).sub.n--X.sup.4-Q-(R.sup.4).sub.m2, and
M.sup.2-(R.sup.3).sub.n-G wherein G is a leaving group or a group
which may subsequently be transformed into a leaving group, may be
prepared from tetrazole compounds of type XI via acylation using an
isolable compound of type III such as an acid chloride or
anhydride, or a compound of type III wherein the LG may be formed
in situ, for example from activation of an acid using a reagent
such as DCC or EDCI, followed by rearrangement to the
1,3,4-oxadizaole. Jursic, B. S.; Zdravkovski, Z.; Synth. Commun.;
(1994) 24; 1575-1582.
[1204] Alternatively, compounds of formula XIV may also be prepared
from acyl hydrazide of type XII via heating in the presence of
compounds of formula XIII or III, wherein LG is a leaving group
such as chloride or alkoxide, at elevated temperatures
(60-130.degree. C.) in one step. The reaction of compounds of
Formula XIII may be carried out neat or using a suitable aprotic
solvent such as benzene or xylene, or a protic solvent such as
ethanol or n-butanol, and may be facilitated by the presence of
abase such as KOtBu or a acid such as p-toluene sulfonic acid or
acetic acid. Se references: Saunders, J.; Cassidy, M.; Freedman, S.
B.; Harley, E. A.; Iversen, L. L. J. Med. Chem.; (1990) 33;
1128-1138; Peet, N. P.; Sunder, S. J. Heterocycl. Chem.; (1984) 21;
1807-1816. For compounds of formula III a dehydrating agent such as
phosphorous pentoxide may be used to increase cyclization of the
formed reaction intermediate as has been previously been described
for example by Kakefuda, Akio; et al.; Bioorg. Med. Chem. (2002),
10; 1905-1912.
[1205] Formation of Compounds of Formula XVI ##STR9##
[1206] A compound of formula XVI, wherein R.sup.8 as defined above
is independently selected from a group consisting of
M.sup.1-(R.sup.2).sub.n--P--(R.sup.1).sub.m1,
M.sup.2-(R.sup.3).sub.n--X.sup.4-Q-(R.sup.4).sub.m2, and
M.sup.2-(R.sup.3).sub.n-G wherein G is a leaving group or a group
which may subsequently be transformed into a leaving group, may be
prepared by the reaction of compounds of formula XVa and XVb in the
presence of in situ generated T1(OTf)3 under acidic conditions
according to the procedure of Lee and Hong; Tetrahedron Lett.,
(1997), 38, 8959-60.
[1207] Alternatively compounds of formula III and XVII are reacted
as described above for formula V to give an intermediate of formula
XVIII. Such an intermediate may give the required oxazole by
cyclodehydration with to generate the oxazoline followed by
dehydrogenation using BrCCl.sub.3 in the same reaction pot.
Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J. and Williams, D.
R., Organic Letters, (2000) 2, 1165-8.
[1208] Formation of the Bond Between X.sup.4 and M.sup.2 or Q and
M.sup.2 Through Nucleophilic Displacement of a Leaving Group:
##STR10##
[1209] A compound of formula XX, may be used to displace the
leaving group LG in compounds of formula XIX (R.sup.7 is
M.sup.1-(R.sup.2).sub.n--P--(R.sup.1).sub.m1). When X.sup.4 is
represented by a heteroatom such as N and S, the reaction is
carried out in the presence of an appropriate base such as
potassium carbonate, cesium carbonate, sodium hydride,
triethylamine or the like, which may facilitate the reaction by
deprotonation of the X.sup.4 residue and prevent the formation of
any excess acid that would be generated by the reaction in the
absence of a base. The reaction may be accomplished using any
appropriate solvent such as acetonitrile or DMF, and may be carried
out at room temperature or at elevated temperature (35-100.degree.
C.) to accelerate the reaction.
[1210] Such conditions may be used with appropriate modifications
of employed equipment for parallel synthesis, using standard
techniques known to the one skilled in the art.
[1211] Similarly these reaction conditions may be carried out for
compounds of formula XX when X.sup.4=bond and ring Q is a fused
bicycle containing a heteroatom such as N as defined above. In
either the latter or the above described case with X.sup.4=N, NaH
in DMF is preferred as described in literature precedences, for
example Murdoch, Robert; Tully, W. Roger; Westwood, Robert; J.
Heterocycl. Chem.; (1986), 23; 833-841.
[1212] For compounds of formula XX containing X.sup.4=C a stronger
base needs to be employed to achieve deprotonation, such as for
example LDA, n-butyllithium or any other alkyl metal base in
appropriate aprotic solvents such as THF, hexane or toluene at
temperatures generally below ambient temperatures, e.g. at
-78.degree. C. or 0.degree. C. ##STR11##
[1213] An alternative procedure for the synthesis of above
described type of thiomethyl oxadiazole is to form an acyclic ester
IVa and IVb from the combination of a suitably substituted
hydroxyamidine and activated acid coupling partner also suitably
substituted. Displacement of the chloride using the thiol
nucleophile may occur immediately prior to cyclization using one of
the methods of oxadiazole formation described above. The
displacement can also be carried out on the chloromethyl
hydroxyamidine or chloromethyl acid starting materials followed by
the two step esterification and cyclization as above. The
conditions described may be used with appropriate modifications of
employed equipment for parallel synthesis using standard techniques
known to the one skilled in the art.
[1214] Formation of 4-alkyl-triazoles thiols/thiones: ##STR12##
[1215] Any suitable acylating agent such as an acid chloride or an
activated acid or the corresponding acid under amide coupling
conditions as mentioned above, is reacted with a suitable
4-alkyl-3-thiosemicarbazide in the presence of a base such as
pyridine or non-nucleophilic amines to form the acyclic
intermediate compound of formula XXV, wherein R.sup.4 is as defined
above. The same intermediate is also available through reaction of
an acyl hydrazide with an alkyl isothiocyanate. Cyclization to give
a compound of formula XXVI is easily effected by treatment with an
appropriate inorganic base such as hydroxide or bicarbonate at
elevated temperature in an appropriate solvent such as water,
water-dioxane, an aqueous alcohol or mixture thereof.
[1216] Such conditions may be used with appropriate modifications
of employed equipment when using a solid phase base instead of
above-mentioned ones, such as for example P-BEMP for parallel
synthesis using standard techniques known to the one skilled in the
art.
[1217] The compound of formula XXV reacts through its tautomeric
form under the conditions described above with compounds of formula
XIX to yield the S-alkylation compounds of the formula Ia.
[1218] The triazole thiones XXIX and XXXI alkylated on the other
nitrogen atoms of the ring (1 and 2) are available through similar
procedures. The 2-alkyl triazole thione XXVIII may be obtained by
treatment of an aroyl isothiocyanate with an alkyl hydrazine in
toluene at elevated temperatures, e.g. 85.degree. C., followed by
heating with aqueous bicarbonate. The same product may also be
obtained through treatment of the analogous
2-alkyl-3-thiosemicarbazide with an activated acid in the presence
of a suitable base such as pyridine or triethylamine followed by
alkaline ring closure in a manner similar to the alkaline ring
closure yielding product XXVI above. ##STR13##
[1219] The 1-alkyl triazole thiones XXXI may be prepared by the
reaction of a suitable N-alkyl-N-acylhydrazide with potassium
thiocyanate in the presence of an acid such as HCl or other
compatible strong acid via the 1-acyl-1-alkyl-3-thoisemicarbazide
intermediate which undergoes alkaline ring closure in a manner the
alkaline ring closure yielding compounds of formula XXVI above.
[1220] Formation of Compounds of Formula XXXIII ##STR14##
[1221] A compound of formula XXXIII may be prepared by alkylation
of cyclic thioureas of formula XXXIIa, wherein n is defined as 0, 1
or 2, resulting in compound of formula XXXIIb, e.g.
2-methylthio-1,4,5,6-tetrahydropyrimidine in case of n=1. The
alkylation with for example methyliodide as alkylating agent can be
done in several solvents (DMF, acetone, CH.sub.2Cl.sub.2 etc.) at
room temperature or elevated temperatures and will give the product
as its hydroiodide salt as has been previously described by
Kennedy, Kevin J.; Simandan, Tiberiu L.; Dix, Thomas A.; Synth.
Commun.; (1998); 24; 741-746. Cyclic thioureas are readily
available either through synthesis as known by the one skilled in
the art, or commercial sources. Compounds of formula XXXIIc result
from the hydrazinolysis of the corresponding compounds of type
XXXIIb. The hydrazinolysis is preferably done in refluxing EtOH
with hydrazine hydrate as described previously by Krezel, Izabella;
Pharmazie; (1994); 94, 27-31. Finally, fused triazoles of formula
XXXIII may be formed through the thermal acylation and condensation
reaction between compounds of formula XXI wherein LG is a leaving
group as for example a halide, and compounds of formula XXXIIc.
Such reactions may be conducted in pyridine or in EtOH or toluene
in the presence of base. Normal heating or microwave irradiation
may be used. Similarly, XXXIII may be prepared in the presence of a
base, such as sodium methoxide in a suitable solvent such as
methanol or ethanol at elevated temperatures where XXI may also be
an ester or carboxylic acid.
[1222] Acyclic thioureas of formula XXXIId, wherein R.sup.8 is
defined as in the scheme and R.sup.3 and R.sup.4 are as defined in
Formula I, may also be employed using a similar method to obtain
compounds of formula XXXIIIa, wherein the introduction of the
hydrazine portion may be carried out using either hydrazine
followed by acylation, or by using a preformed acyl hydrazine.
[1223] Formation of Compounds of Formula XXXV ##STR15##
[1224] Compounds of formula XXXIVb may be prepared by using similar
methods as above, e.g. by activation of XXXIVa to give the
corresponding imidoyl chloride by using oxalyl chloride or
pentachlorophosphine in the optional presence of a base such as
triethylamine. The intermediate may be used in-situ or may be
isolated prior to trapping by a compound of formula XXIII as has
been used above. The subsequent product may be cyclized under
acidic or basic conditions in a suitable solvent such as DMF to
give compounds of formula XXXV. XXXV may be an intermediate used in
the formation of compounds of Formula I, or may be the final
bioactive compound of Formula I.
[1225] A compound of formula XXXV, wherein R.sup.8 is selected
independently from a group as depicted above may also be prepared
through reaction of compounds of formula XXXVIa (ethyl imidoate is
depicted as example) and XXXVIb followed by cyclization at elevated
temperatures (40-80.degree. C.) in the presence of an amine,
whereas the amine preferably should have, but is not limited to, a
low boiling point such as that it can be used in excess and
simplify the work-up procedure. Examples for such amines may be,
but are not limited to methylamine or ethylamine which may be used
as solutions in for example methanol, THF or dichloromethane.
[1226] Formation of Compounds of Formula XXXVIa and XXXVIb
##STR16##
[1227] A compound of formula XXXVIa, wherein R.sup.8 is selected
independently from a group as depicted above may be prepared
through reaction of a nitrile of formula XXXVIe in an alcohol such
as ethanol in the presence of a protic acid, for example
hydrochloric acid. The nitrile may be obtained from an acid XXXVId
as described above. Compounds of formula XXXVId may also be used to
prepare acyl hydrazides of formula XXXVIb, wherein R.sup.8 is
selected independently from a group as depicted above. This type of
substance XXXVIb may also be formed directly from an acid. There
may be advantages to react an intermediate ester of type XXXVIf
with either neat hydrazine, hydrazine salt in the presence of a
base or hydrazine hydrate in facilitating a simpler workup.
However, the direct route via the acid using in situ activation may
be advantageous in substrates sensitive to nucleophilic attack and
also give the product in a shorter sequence of steps.
[1228] Formation of Compounds of Formula XXXVId and XXXVIf
##STR17##
[1229] Compound of formula XXXVId & XXXVIf, wherein R.sup.7 is
a group consisting of M.sup.1-(R.sup.2).sub.n--P--(R.sup.1).sub.m,
may be prepared by either of the non-limiting methods: a) reaction
of acyl hydrazide compounds of formula XII with a cyclic anhydride
or monoesterified diacid followed by the cyclization of the formed
intermediate would lead to 1,3,4-oxadiazoles of type XXXVId and
XXXVIf respectively (X.sup.1=O, X.sup.2 and X.sup.3=N); b) reaction
and cyclization of an hydroxyamidine of Formula II with a cyclic
anhydride or with the monoesterified diacid may be used to provide
the 1,2,4-oxaziazole analogs XXXVId and XXXVIf wherein X.sup.1 and
X.sup.2=N, X.sup.3=O; c) reaction of a compound of type III with an
hydroxamidine type compound, with the exception of the succinyl
derivative, may be used to provide the 1,2,4-oxaziazole analogs
XXXVIf wherein X.sup.1 and X.sup.3=N, X.sup.2=O. Compounds XXXVId
and XXXVIf may be interconverted independent of the nature of
X.sup.1, X.sup.2 or X.sup.3 as described above.
[1230] Formation of Compounds of Formula Ib ##STR18##
[1231] A compound of formula Ib, wherein R.sup.7 is selected from a
group M.sup.1-(R.sup.2).sub.n--P--(R.sup.1).sub.m1 may be prepared
from compounds of formula XXXVII, generated from XIV as described
below, through selective O alkylation using Me.sub.3OBF.sub.4 or
dimethyl sulfate (as described in literature precedences, for
example: a) Sheu, Jennline; Smith, Michael B.; Oeschger, Thomas R.;
Satchell, Jacqueline; Org. Prep. Proced. Int.; (1992); 24, 147-158;
or b) Hutchinson, Ian S.; Matlin, Stephen A.; Mete, Antonio,
Tetrahedron Lett.; (2001); 42; 1773-1776). The methoxy group may
then be displaced by an acyl hydrazide of type XXIII, followed by a
ring closing condensation to form the triazole heterocycle. This
may be done in ethanol, toluene, DMF or pyridine under thermal
conditions with regular heating or microwave irradiation, as has
been previously described by for example Lawson, Edward C.;
Hoekstra, William J.; Addo, Michael F.; Andrade-Gordon, Patricia;
Damiano, Bruce P.; Kauffman, Jack A.; Mitchell, John A.; Maryanoff,
Bruce E.; Bioorg. Med. Chem. Lett.; (2001); 11; 2619-2622.
[1232] One preferred subset of compounds of formula Ib are those of
formula g and can be made according to the following scheme:
##STR19##
[1233] Compounds of formula b may be generated through selective O
alkylation of a cyclic lactam a using Me.sub.3OBF.sub.4 or dimethyl
sulfate (as described in literature precedences, for example: a)
Sheu, Jennline; Smith, Michael B.; Oeschger, Thomas R.; Satchell,
Jacqueline; Org. Prep. Proced. Int.; (1992); 24, 147-158; or b)
Hutchinson, Ian S.; Matlin, Stephen A.; Mete, Antonio, Tetrahedron
Lett.; (2001); 42; 1773-1776). The methoxy group may then be
displaced by or hydrazine to form intermediate c which can be
acylated to provide intermediate d. Alternatively the methoxy group
may be displaced using an acyl hydrazide to yield d directly. Ring
closing condensation to form the triazole heterocycle e may be done
in ethanol, toluene, DMF or pyridine under thermal conditions with
regular heating or microwave irradiation, as has been previously
described by for example Lawson, Edward C.; Hoekstra, William J.;
Addo, Michael F.; Andrade-Gordon, Patricia; Damiano, Bruce P.;
Kauffman, Jack A.; Mitchell, John A.; Maryanoff, Bruce E.; Bioorg.
Med. Chem. Lett.; (2001); 11; 2619-2622.
[1234] A compound of formula g, wherein R.sup.7 is selected from a
group M.sup.1-(R.sup.2).sub.n--P--(R.sup.1)m.sub.1 may be prepared
from compounds of formula e, by deprotonation and reaction with
compounds of formula f. Although this can be accomplished using a
strong base due to the stabilization of the aromatic triazole ring,
the reaction is facilitated when R is a group which provides
additional stabilization of the resulting carbanions, such as an
ester, nitrile or sulfone.
[1235] Compounds of type XXXVII may be prepared by the reaction of
cyclic amides, lactams, which are readily alkylated in the
.alpha.-position to the carbonyl by successive treatment with 2
equivalents of a strong base e.g. n-Buli to generate the dianion
followed by addition of 1 equivalent of compounds of formula XIX,
in an aprotic solvent such as THF, as has been previously described
by for example Grieco, Paul A.; Kaufman, Michael D.; J. Org. Chem.;
(1999); 64; 6041-6048). Alternatively, a N-protected lactam may be
used in which only 1 equivalent base e.g. LDA is needed to generate
the anion for the alkylation as has been previously described by
for example Padwa, Albert; Beall, L. Scott; Heidelbaugh, Todd M.;
Liu, Bing; Sheehan, Scott M.; J. Org. Chem.; (2000); 65;
2684-2695.
[1236] General Synthesis of Compounds of Formula Ic ##STR20##
[1237] A compound of formula Ic, wherein R.sup.7 is consisting of
M.sup.1-(R.sup.2).sub.n--P--(R.sup.1).sub.m1, may be prepared
through reaction with subsequent cyclization of compounds of
formula XXXVIII, with a compound of formula XXXIX. The compound of
formula XXXIX may be prepared from a suitable secondary amide using
oxalyl chloride or pentachlorophosphine in the optional presence of
a base such as triethylamine and used either in-situ or as isolated
material as described above from XXXIVa.
[1238] Compounds of formula XXXVIII, may be prepared from the
corresponding alcohol by reacting it with phosgene or preferably a
phosgene analog such as carbonyldiimidazole followed by coupling to
hydrazine. ##STR21##
[1239] Other means of synthesizing a compound of formula Ic or Id,
wherein X.sup.4=O and wherein R.sup.7 is
M.sup.1-(R.sup.2).sub.n--P--(R.sup.1).sub.m1, may be by the
O-alkylation of compounds of type XL with compounds of type XLI
wherein the leaving group may consist of a tosyl-, mesyl-, halo- or
any other appropriate group, in the a suitable base such as cesium
or potassium carbonate, sodium hydride in solvents such as for
example DMF or DMSO.
[1240] Compounds of type XLI may be synthesized as exemplified with
triazole XXVI by alkylation or arylation of the sulfur group using
an appropriate alkylating or arylating reagent followed by double
oxidation of the thiogroup to the corresponding sulfone using
oxidants such as MCPBA, hydrogen peroxide in acetic acid or
potassium permanganate. Such a sequence has previously been
described for example by .ANG.kerblom et al. J. Med. Chem. 16, 312
(1973). Alternatively, triazole halides may be synthesized as
previously described in the literature by for example Ashton, W. T.
et al. J. Med. Chem. 36, 591 (1993).
[1241] The alcohols may be prepared either directly upon synthesis
of the oxadiazole or isoxazole part as described above under
general synthesis of compounds of formula V. Alternatively they may
be prepared from an oxadiazole or isoxazole unit with an
appropriate leaving group such as a halide, e.g. chloride, using a
three step sequence as described by Palazzo et al. J. Heterocycl.
Chem. (1979) 16:1469, followed by a standard reduction protocol of
the resulting aldehyde (or hydrate thereof) using for example
sodium borohydride in methanol. ##STR22##
[1242] Yet another method may involve the reaction of a compound of
structure XIV unit containing an appropriate leaving group such as
a halide, e.g. chloride with hydroxybenzotriazole in the presence
of a suitable base such as potassium carbonate or triethylamine in
a suitable solvent such as DMSO, acetonitrile, acetone, DMF to give
compounds of type XLa. Alternatively XLa may be obtained if
hydroxybenzotriazole is present during cyclization to the
oxadiazole, either as a co-activator with EDCI or as a result of a
byproduct from a coupling reagent such as HBTU as described above
under the reaction of compounds of formula II-V. XLa may be
converted to the alcohol by the addition of samarium diiode,
preferably over an elongated period of time (5-360 minutes) in a
suitable solvent such as tetrahydrofuran, methanol, water or
mixtures thereof, with THF being a preferred solvent, at an
appropriate temperature (-75.degree. C.-+75.degree. C.).
[1243] The cleavage of the N--O bond can alternatively be done
using commonly used hydrogenation methods in the presence of a
suitable catalyst such as raney-nickel as known by the one skilled
in the art. In compounds of formula XLa the oxobenzotriazole
functionality may also serve as a leaving group. Thus compounds XLa
may react with compounds XX as described above.
[1244] Formation of Compounds of Type Ie ##STR23##
[1245] A compound of formula Ie, wherein R.sup.7 is
M.sup.1-(R.sup.2).sub.n--P--(R.sup.1).sub.m1, may be prepared
through nucleophilic substitution of compounds of type XLIIIb with
compounds of type XIX as described above. Compounds of type XLIIIb
may be prepared by reaction of their oxo-analogues XLIIIa using
P.sub.2S.sub.10 or Lawesson's reagent under thermal conditions.
Synthesis of compounds of type XLIIIa has been described by
Takeuchi, H., Hagiwara, S., Eguchi, S., Tetrahedron (1989); 45;
6375-6386.
[1246] Introduction of Substitution in the Q Ring:
[1247] If substitution on the Q ring is desired, one may choose an
appropriately substituted aryl or heteroaryl thiol to use for the
displacement reaction. The same is valid for other nucleophilic
reagents other than substituted or non-substituted aryl or
heteroaryl thiols serving to substitute the same in the final
compounds. If the aryl or heteroaryl residue has an amenable
reactive moiety, either directly introduced or as a result of a
deprotection reaction, including but not limited to a free NH site
as in aniline, imidazole, benzimidazole, indole and the like, a
compound of formula If (R.sup.7 is
M.sup.1-(R.sup.2).sub.n--P--(R.sup.1).sub.m1) may be substituted
with R.sup.4 using a suitable base such as an alkyllithium or
alkali-metal hydride or hydroxide to deprotonate the NH residue,
followed by the addition of a suitable electrophilic reagent such
as an alkyl halides, acid chlorides or anhydrides, chloroformates,
carbamoyl chlorides, sulfonyl chlorides, isocyanates,
isothiocyanates and the like to provide the substituted product of
Formula Ia. ##STR24##
[1248] Introduction of the M.sup.2 Substituent(s) and of the X
Substituent(s):
[1249] When the most acidic protons are positioned on the atom
adjacent to X.sup.4, or on X.sup.4 itself, substitution may be
achieved by deprotonation of compound of Formula Ia with a strong
base such as an alkyllithium or an alkali-metal hydride in a
suitable aprotic non-acidic solvent like THF or diethylether
followed by trapping of the resulting anion with a suitable
electrophile such as alkyl halides, acid chlorides or anhydrides,
chloroformates, carbamoyl chlorides, sulfonyl chlorides,
isocyanates, isothiocyanates and the like. When an excess of base
and electrophile are employed and the reaction is left for
sufficient time, two hydrogens may be replaced by the electrophile
as illustrated below for the introduction of two
R.sup.3-substituents (M.sup.2 exemplified as carbon). Two or more,
different or same substituents, might also be introduced
accordingly by subsequent deprotonations and reactions with
appropriate electrophiles to yield compounds of Formula Ig.
##STR25##
[1250] Oxidation of S Atom of Chain (when X is S) or N Atoms on
Substituents:
[1251] Oxidation of the sulfur atom to give sulfones (Y=O) and
sulfoxides (Y=":", i.e. a lone pair) may be achieved by direct
oxidation using any suitable oxidizing agent including peroxyacids
such as MCPBA. In the case of MCPBA oxidation, it is possible to
obtain a mixture of products from a single reaction and separate
them by standard column chromatography or to obtain selectively the
sulfoxide or sulfone by controlling the stoichiometry and
temperature of the reaction. ##STR26##
[1252] If one of the substitutents, e.g. R.sup.4 contains one or
more nitrogen atoms as for example a pyridine moiety or any other
substituent as defined above, then oxidation of this nitrogen may
occur in the above reaction of Ia with an oxidant such as MCPBA to
give the corresponding N-oxide. It is understood to the one skilled
in the art that such products may be obtained by separation via
standard column chromatography or any other standard purification
protocol even in the case of mixtures containing for example Ih and
N-oxide. It is also understood to the skilled in the art that the
formation of N-oxides may be reduced by choice of suitable reaction
conditions such as using acidic media to protect the nasic
amine.
[1253] Other Miscellaneous Reactions:
[1254] When the intermediate compounds contain a suitable reactive
functionality such as an aryl halide or triflate, the functionality
may be employed to further elaborate the product. For example, when
3-halo-phenyl is present in P--(R.sup.1).sub.m1, it is possible to
use standard Suzuki conditions to couple an aryl boronic acid to
yield a diaryl coupling product. Miyaura, N., Yanagi, T., Suzuki,
A., Synth. Commun., (1981), 11; 7, 513-520.
[1255] Other functionalities such as an aliphatic alcohol may for
example be converted to a fluoro group by the use of a fluorinating
agent such as DAST, or other halide groups by the use of for
example triphenylphosphine and either iodine, N-bromosuccinimide or
N-chlorosuccinimide These halides may serve as leaving groups for
further elaboration or may remain as substituent in active
compounds of formula Ia.
[1256] In a similar fashion alcohols may be transformed to leaving
grous such as the non-limiting examples mesyl or tosyl by employing
the appropriate sulfonyl halide or sulfonyl anhydride in the
presence of a non-nucleophilic base together with the alcohol to
obtain the sulfonic ester derivative.
[1257] Other functionalities which may be further elaborated are
depicted in the following, non-limiting example (R.sup.7 is
M.sup.1-(R.sup.2).sub.n--P--(R.sup.1).sub.m1), where halogenation
may be undergone on a carbon-atom of an oxazole unit employing a
chlorinating agent such as sulfuryl chloride. ##STR27##
[1258] Additional Reactions for the Preparation of Intermediate and
Final Compounds
[1259] More specific reaction types useful for the preparation of
compounds of formula I and their intermediates, where applicable,
are given below in the synthetic schemes and their corresponding
descriptions. The definitions in the following formula are as
defined in formula unless otherwise specified. Other starting
materials are either commercially available or can be prepared via
methods described in the literature.
[1260] Intermediate Compounds
[1261] Alkylsulphonyl[1,2,4]triazoles ##STR28##
[1262] With reference to scheme 1, alkylsulphonyl[1,2,4]triazoles
can be prepared from the corresponding [1,2,4]triazolethiones by
initial alkylation of the sulphur atom with primary alkyl halides
such as MeI and EtI (alkyl is Me and Et respectively) in MeOH,
EtOH, THF, acetone or the like at -30 to 100.degree. C., followed
by oxidation of the sulphur atom using for example KMnO.sub.4 in
mixtures of water and acetic acid, or mCPBA in DCM, at -20 to
120.degree. C., or by using any other suitable oxidant.
[1,2,4]triazolethiones are for example prepared by N-acylation of a
thiosemicarbazide, using any suitable acylating agent such as acid
chlorides (LG is Cl) in for example pyridine, or acids (LG is OH),
that are activated by the treatment with standard activating
reagents as described herein below, in DMF, THF, DCM or the like at
-20 to 120.degree. C., followed by ring closure of the initially
formed acyclic intermediate either spontaneously under the
conditions of the acylation, or by heating at 50 to 150.degree. C.
in pyridine or in aqueous solvents in the presence of a base, such
as NaHCO.sub.3 or Na.sub.2CO.sub.3, with or without co-solvents
such as dioxane, THF, MeOH, EtOH or DMF. This acyclic intermediate
can also be formed by treatment of the proper acyl hydrazide with a
suitable isothiocyanate in for example 2-propanol, DCM, THF or the
like at -20 to 120.degree. C.
[1263] Amino[1, 2, 4]triazoles ##STR29##
[1264] With reference to scheme 2, amino[1,2,4]triazoles are
obtained by treating carbonohydrazonic diamides with a proper
acylating agent carrying a leaving group LG in suitable solvent
such as THF, pyridine or DMF at -20 to 100.degree. C. The reaction
initially leads to an open intermediate that either forms a
triazole ring spontaneously, or can be made to do so by heating at
50 to 200.degree. C. in for example pyridine or DMF. The leaving
group LG may be chloro or any other suitable leaving group as for
example generated by in situ treatment of the corresponding acid
(LG is OH) with standard activating reagents as described herein
below. Carbonohydrazonic diamides may be generated from
isothioureas, in which the S-alkyl (for example S-Me or S-Et)
moiety acts as a leaving group upon treatment with hydrazine in
solvents such as pyridine, methanol, ethanol, 2-propanol, THF or
the like at -20 to 180.degree. C. The open intermediate can also be
directly generated by treatment of isothioureas with acylhydrazines
under the same conditions as described for the reaction with
hydrazine. Isothioureas are obtained by S-alkylation of the
corresponding thioureas with for example MeI or EtI in acetone,
EtOH, THF, DCM or the like at -100 to 100.degree. C.
[1265] Carbon Substituted [1,2,4]triazoles ##STR30##
[1266] With reference to scheme 3, imidoyl chlorides react with
acyl hydrazides in suitable solvents, such as THF, pyridine or DMF
at -20 to 100.degree. C. to initially form an open intermediate
that either forms a triazole ring spontaneously, or can be made to
do so by heating at 50 to 200.degree. C. in for example pyridine,
DMF or water, with or without the presence of a base such as
NaHCO.sub.3 or Na.sub.2CO.sub.3. Imidoylchlorides may in turn be
obtained from the corresponding amides by standard methods such as
by treatment with oxalyl chloride or thionyl chloride.
[1267] Imidazole-4-carbaldehydes and [1,2,4]triazolecarbaldehydes
##STR31##
[1268] With reference to scheme 4, Imidazole-4-carbaldehydes
(X.sup.5 is C) are for example prepared by reacting suitably
substituted amidines with 2-bromo-3-isopropoxyacrylaldehyde in for
example well-stirred mixtures of an organic solvent, such as
chloroform, DCM, or toluene and water in the presence of a base
such as a carbonate at 10 to 100.degree. C. The amidine starting
material might be prepared using standard methods from the
corresponding nitrile via the imidate ester (alkyl is for example
Me or Et), by treatment with for example a hydrochloric acid
solution in the corresponding alcohol solvent followed by treatment
with an amine substituted with the group R.sup.5, or directly from
the corresponding nitrile by reacting with the same amine together
with trimethylaluminum. [1,2,4]triazolecarbaldehydes (X.sup.5 is N)
can be prepared by oxidizing the corresponding primary alcohols,
using for example MnO.sub.2 or any other standard oxidant for this
type of transformation. These alcohols, in turn, may be prepared by
hydroxymethylation of the corresponding C unsubstituted triazoles
using for example formaline at elevated temperature. C
unsubstituted triazoles are for example prepared through standard
desulphurization of [1,2,4]triazolethiones with Raney-Ni.
[1269] Isoxazole-5-carboxylic Acid Esters ##STR32##
[1270] In reference to scheme 5, isoxazoles are formed by reaction
and in-situ cyclization of dioxo butyric ester derivatives with
hydroxylamine hydrochloride in solvents such as ethanol, 2-propanol
or DMF at temperatures from 40 to 140.degree. C. Dioxo butyric
esters are formed through the reaction of acetophenones with
dialkyl oxolates (alkyl is for example Me or Et) in the presence of
a strong base such as sodium hydride in solvents such as DMF or
toluene at temperatures from -20 to 120.degree. C.
[1271] Carbon Substituted [1,2,4]oxadiazoles ##STR33##
[1272] With reference to scheme 6, [1,2,4]oxadiazoles with a carbon
alpha to the heterocycle, wherein G.sup.1, G.sup.2 and G.sup.3 are
defined as described in scheme 6, are formed by cyclization of
G.sup.1- and G.sup.2-substituted-acyloxyimidamides in solvents such
as pyridine, DMF, or water containing mixtures thereof, at 40 to
140.degree. C., alternatively in aqueous alcoholic solvents in the
presence of sodium acetate at temperatures from 40 to 140.degree.
C., with the later method being preferred if one of the groups
G.sup.1 or G.sup.2 contains a chiral stereocenter.
Acyloxyimidamides are formed by coupling with a proper acylating
agent carrying a leaving group LG with a G.sup.1-substituted
hydroxamidine. The leaving group LG may be chloro or any other
suitable leaving group as for example generated by in situ
treatment of the corresponding acid (LG is OH) with standard
activating reagents as described herein below. G.sup.1-substituted
hydroxamidines are formed by reaction of the corresponding nitrile
with the free base of hydroxylamine, or hydroxylamine hydrochloride
in the presence of a base such as triethylamine, pyridine or sodium
carbonate, in solvents such as ethanol, water or pyridine at
temperatures from -20 to 120.degree. C.
[1273] Amino[1, 2, 4]oxadiazoles ##STR34##
[1274] With reference to scheme 7, amino[1,2,4]oxadiazoles are
obtained from the corresponding bromo[1,2,4]oxadiazoles by reaction
with an excess alkylamine in solvents such as methanol or ethanol
at elevated temperatures. Intermediate bromo[1,2,4]oxadiazoles are
obtained by reaction of benzonitrile derivatives with
hydroxycarbonimidic dibromide in the presence of a base such as
NaHCO.sub.3 in solvents such as toluene or DMF at elevated
temperatures.
[1275] Carbon substituted [1,3,4]oxadiazoles ##STR35##
[1276] With reference to scheme 8, starting from acid hydrazides,
coupling with an aliphatic acid chloride derivative in THF, DMF,
toluene or the like, optionally in the presence of a base such as
triethylamine or a carbonate, leads to the formation of an acyl
benzohydrazide derivative, which is cyclized at elevated
temperatures in the presence of a dehydrating agent such as
phosphorous pentoxide in solvents such as toluene or DMF or
mixtures thereof to yield the [1,3,4]oxadiazole product.
Alternatively, [1,3,4]oxadiazoles may be made directly from the
acid hydrazide using trialkyl ortho esters either neat or in
solvents such as toluene or xylenes at elevated temperatures.
[1277] Functional Group Transformations ##STR36##
[1278] With reference to scheme 9, aliphatic alcohols may for
example be converted by standard methods to the corresponding
halides by the use of for example triphenylphosphine in combination
with either iodine, N-bromosuccinimide or N-chlorosuccinimide, or
alternatively by treatment with tribromo phosphine or
thionylchloride. In a similar fashion alcohols may be transformed
to other leaving groups such as mesylates or tosylates by employing
the appropriate sulfonyl halide or sulfonyl anhydride in the
presence of a non-nucleophilic base together with the alcohol to
obtain the corresponding sulfonates. Clorides or sulphonates can be
converted to the corresponding bromides or iodides by treatment
with bromide salts, for example LiBr, or iodide salts. Further
standard methods to obtain alcohols include the reduction of the
corresponding carbonyl containing groups such as methyl or ethyl
esters, aldehydes (R.sup.3 is H) or ketones (R.sup.3 is not H), by
employing common reducing agents such as boranes, lithium
borohydride, lithium aluminumhydride, or hydrogen in the presence
of a transition metal catalyst such as complexes of for example
ruthenium or iridium, or alternatively palladium on charcoal.
[1279] Stereoselective Preparation of Chiral Secondary Alcohols
##STR37##
[1280] Enantiomerically pure or enriched products as depicted in
scheme 10 (R.sup.3 is Me or Et) are obtained by kinetic resolution
of racemic or scalemic secondary alcohols using enzyme-catalyzed
acetylation with for example polymer bound Candida Antarctica
Lipase (Novozyme 435.RTM.), or other esterases, for example Candida
rugosa or Pseudomonas fluorescens, in organic solvents such as
toluene, tert-butyl methyl ether, tert-butanol or DCM at
temperatures from 0 to 90.degree. C., using acetylating reagents
such as vinyl acetate, other substituted alkyl acetates,
pentafluorophenyl acetate or nitro- or halophenyl acetates, which
yields the enriched (R)-acetate and the enriched (S)-alcohol. The
(R)-acetate may be hydrolyzed to the corresponding alcohol by e.g.
lithium hydroxide in mixtures of THF and water or by any other
methods as described herein below, to yield the opposite
enantiomerically enriched or pure alcohol.
[1281] Isothioureas ##STR38##
[1282] Isothioureas, as depicted in scheme 11, may be obtained by
substitution of a leaving group LG (LG is for example Cl, Br or
OMs) by a R.sup.4-substituted amine in solvents such as MeOH or
EtOH at temperatures from 0 to 150.degree. C. The product is added
to an isocyanate substituted with R.sup.5 in solvents such as
chloroform, ethanol, methanol or DMF at temperatures from -20 to
100.degree. C., yielding a thiourea intermediate, which may be
alkylated by an alkylating agent such as methyl- or ethyliodide or
any other suitable primary alkyl halide or sulphonate, in solvents
such as methanol, ethanol, acetonitrile or acetone, in the presence
or absence of a base such as triethylamine or potassium
carbonate.
[1283] Propionic Acid Derivatives ##STR39##
[1284] Propionic acid derivatives such as saturated alkyl esters,
saturated free carboxylic acids or saturated acyl hydrazides may be
prepared as depicted in scheme 12. Carboxylic acids are obtained
upon hydrolysis of the corresponding esters for example under basic
conditions such as sodium hydroxide in methanol or any other method
known to the one skilled in the art. The corresponding saturated
alkyl esters in turn may be obtained from the unsaturated ester by
reduction of the carbon-carbon double bond using hydrogen at
atmospheric pressure or elevated pressures up to 100 bars in the
presence of a metal catalyst such as palladium on charcoal or any
other selective reducing agent suitable for this type of compounds
as known to the one skilled in the art. During aforementioned
hydrogenation, any halide substituents attached to aromatic groups
R.sup.6 will be removed by hydro-dehalogenation. Unsaturated esters
in turn may be obtained by an olefination reaction such as the
Wittig or Horner-Wadsworth-Emmons type by reacting an aldehyde or
ketone in the presence of a suitable base such as n-BuLi or DBU
with appropriately substituted phosphor ylides or phosphonates such
as triethyl-2-phosphonopropionate, or
2-(diethoxy-phosphoryl)-propionic acid ethyl ester in suitable
solvents such as acetonititrile or THF at temperatures from -90 to
100.degree. C. Acyl hydrazides may be obtained from the
corresponding esters by reaction with hydrazine, or from the free
carboxylic acids by activation as described herein below and
coupling with hydrazine.
[1285] Preparation of Final Compounds
[1286] Several non-limiting methods for preparing the final
compounds are illustrated and exemplified by drawings in which the
generic groups, or other structural elements of the intermediates
correspond to those of formula I. It is to be understood that an
intermediate containing any other generic group or structural
element than those of formula I can be used in the exemplified
reactions, provided that this group or element does not hinder the
reaction and that it can be chemically converted to the
corresponding group or element of formula I at a later stage which
is known to the one skilled in the art.
[1287] By Connection to Nucleophilic X.sup.4 ##STR40##
[1288] With reference to scheme 13, compounds of formula I can be
prepared by bond formation through nucleophilic replacement of a
leaving group (LG) in which X.sup.4 is acting as nucleophile.
X.sup.4 can be a carbon or nitrogen atom in it's anionic form,
generated by treatment of the corresponding protonated neutral atom
with bases in suitable solvents such as LDA or nBuLi in THF,
diethylether or toluene, or NaH in for example DMF, or
K.sub.2CO.sub.3 in acetonitile or ketones such as 2-butanone at a
temperature from -100 to 150.degree. C. When X.sup.4 is carbon, LG
is preferable bromo, and when X.sup.4 is nitrogen examples of
suitable leaving groups LG are chloro, bromo, OMs and OTs. When
X.sup.4 is N, the reaction may also be undertaken in a
stereoselective manner by employing enantiomerically pure or
enriched starting materials in which the leaving group LG is
attached to the stereocenter. Optionally, catalytic or
stoichiometric amounts of an alkali metal iodide, such as LiI, can
be present in the reaction to facilitate the same through in situ
displacement of the leaving group to iodo.
[1289] By Connection to Nucleophilic Oxygen ##STR41##
[1290] With reference to scheme 14, compounds of formula I can be
prepared by bond formation through nucleophilic replacement of a
leaving group (LG) in which an alcohol is acting as O-nucleophile
under basic conditions to facilitate the reaction. As base, for
example NaH or Cs.sub.2CO.sub.3 is used, the latter being preferred
for obtaining enantiomerically pure products, at temperatures from
0 to 100.degree. C. in polar aprotic solvents such as DMF or
acetonitrile. Examples of suitable leaving groups are sulphonates
such as OMs and halogens such as chloro.
[1291] By Alpha-Alkylation Relative to Ring Q ##STR42##
[1292] With reference to scheme 15, compounds of formula I
substituted with no group R.sup.3 can be either mono- or
dialkylated at the position alpha to ring Q. Dialkylation can be
performed sequentially for the introduction of two different or
same groups R.sup.3. Preferably, primary alkyl halides, mesylates,
or tosylates are used as alkylating reagents (R.sup.3-LG) in the
reaction with an intermediate carbanionic nucleophile generated
upon treatment of compounds of formula I, substituted with no or
one group R.sup.3, with strong bases such as NaH, LDA or HMDS
alkali metal salts in solvents such as for example THF,
diethylether, hexanes or toluene at a temperature of -100 to
50.degree. C.
[1293] By Formation of a Triazole Ring ##STR43##
[1294] With reference to scheme 16, intermediates carrying a
leaving group LG.sup.1, such as SMe or SEt, can undergo reaction
with hydrazine in solvents such as pyridine, methanol, ethanol,
2-propanol, THF or the like at -20 to 180.degree. C. Subsequent
acylation with an acylating agent carrying a leaving group LG.sup.2
in suitable solvent such as THF, pyridine or DMF at 0 to
100.degree. C. leads to an open intermediate that either forms a
triazole ring spontaneously, or can be whipped to do so by heating
at 50 to 200.degree. C., resulting in the formation of a compound
of formula I. LG.sup.2 may be chloro or any other suitable leaving
group as for example generated by in situ treatment of the
corresponding acid (LG.sup.2=OH) with standard activating reagents
such as DCC, DIC, EDCI or HBTU, with or without the presence of
co-reagents such as HOBt or DMAP in suitable solvents such as DMF,
DCM, THF, or acetonitrile at a temperature from -20 to 100.degree.
C. Alternatively, acylhydrazines can be directly reacted with
intermediates carrying a leaving group LG.sup.1 under the
conditions described above to yield compounds of formula I.
[1295] By Formation of the Ring Q ##STR44##
[1296] With reference to scheme 17, the ring Q of compounds of
formula I may be formed by reaction of esters (G is for example OMe
or OEt) or activated acid derivatives, such as acid chlorides (G is
Cl) or else as generated upon treatment of the corresponding acids
(G is OH) with standard activating reagents as described herein
above, with N-hydroxyamidines. When employing esters, suitable
conditions include the use of the solvents 1-propanol, 2-propanol,
EtOH or toluene, together with a stoichiometric amount of a base
such as potassium tert-butoxide at 0 to 180.degree. C. When
employing activated acid derivatives the reaction can for example
be run in DMF, DCM, THF, pyridine or the like at -20 to 120.degree.
C. The initially formed acyclic intermediate may ringclose
spontaneously to form an [1,2,4]oxadiazole, or may be heated in
pyridine, DMF, EtOH, MeOH or aqueous mixtures thereof, with or
without additives such as sodium acetate, at 50 to 200.degree. C.
Upon reaction of acyl hydrazides (G is NHNH.sub.2) with imidate
esters (alkyl is for example Me or Et), or the corresponding salts,
in MeOH, EtOH, THF, DMF or the like at 0 to 150.degree. C.,
compounds of formula I in which the ring Q is [1,3,4]oxadiazole are
generated.
[1297] By N-alkylation of Heterocyclic Amines ##STR45##
[1298] With reference to scheme 18, compounds of formula I are
prepared by bond formation through nucleophilic replacement of a
leaving group (LG) in which the nitrogen atom, to which the group
R.sup.3 is attached, is acting as nucleophile. The reaction is
facilitated by deprotonation of this nitrogen atom to generate a
stronger nucleophile by treatment with bases in suitable solvents
such as LDA, alkali metal salts of HMDS or nBuLi in THF,
diethylether or toluene, or NaH in for example DMF at a temperature
from -100 to 150.degree. C. Suitable leaving groups include for
example chloro, bromo, iodo, OMs or OTs. Useful intermediates
carrying such a leaving group can for example be prepared by
halogenation of the corresponding compound in which LG is hydrogen.
For example, alpha-chloro triazoles (LG is Cl and X.sup.5 is N) can
be prepared by treatment with SO.sub.2Cl.sub.2 in solvents such as
DCM and DMF.
[1299] By Cytochrome P450 Mediated Dealkylation
[1300] Compounds of formula I in which X.sup.4 is nitrogen and
R.sup.4 is alkyl, preferably methyl, can be converted to the
corresponding compounds in which R.sup.4 is hydrogen by incubation
with human liver microsome protein, or other sources of cytochrome
P450 isoenzymes including preferably the 3A4 isoenzyme, at
35-40.degree. C. in for example aqueous phosphate buffer in the
presence of NADPH.
[1301] By Chromatographic Separation of Enantiomers
[1302] Practically pure (>95%) enantiomers of compounds of
formula I can be obtained by chromatographic separation of the
corresponding racemic or scalemic mixtures by using for example
Chiralpak AD.RTM. or Chiracel OJ.RTM. as stationary phase and for
example 2-propanol or ethanol, and mixtures of hexanes and ethanol
respectively, as eluants.
EXAMPLES
[1303] Suitable embodiments of the invention will now be
illustrated by the following non-limiting examples.
[1304] NMR measurements were made on the delta scale (.delta.).
[1305] The compounds prepared according to Examples 1 to 39 and 100
to 328 are intermediates.
[1306] The compounds prepared according to Examples 40 to 99 and
329 to 794 are end products.
[1307] Intermediates
Example 1
6-Methylpyridine-4-carboxylic acid
[1308] A hydrogen filled balloon was attached to a flask containing
2-chloro-6-methylpyridine-4-carboxylic acid (2 g, 12.0 mmol),
palladium 10 wt. % on activated carbon (0.5 g), triethyl amine (4.8
ml) and ethanol (24 ml) and then stirred overnight at room
temperature. The reaction mixture was filtered through celite,
washed with methanol and concentrated. The residue was titurated
with dichloromethane and then filtered to afford
6-methylpyridine-4-carboxylic acid as a white solid; 1.05 g (66%).
.sup.1H NMR (MeOD) .delta. (ppm): 8.62 (d, 1H), 7.68 (s, 1H), 7.60
(d, 1H), 2.55 (s, 3H).
Example 2
1-Cyano-3-ethylbenzene
[1309] Argon was bubbled into a solution of 1-bromo-3-ethylbenzene
(2.5 g, 13.5 mmol) in DMF (37 ml) for 10 min. and then zinc cyanide
(1.75 g, 14.9 mmol) and tetrakis(triphenylphosphine)palladium(0)
(1.56 g, 1.35 mmol) were added. After stirring at 80.degree. C.
overnight the reaction mixture was diluted with ethyl acetate (35
ml) then filtered through celite to remove the precipitate. The
filtrate was washed with water (3.times.), saturated brine, dried
over anhydrous sodium sulfate, filtered and concentrated. The
product was purified by flash column chromatography using 2% ethyl
acetate in hexane affording a colorless liquid (1.42 g). GC-MS
(M+): 131.18.
Example 3
3-Ethylbenzoic acid
[1310] 6 M Sodium hydroxide (25 ml) was added to
1-cyano-3-ethylbenzene (1 g, 7.62 mmol) in methanol (25 ml) and
then heated at 100.degree. C. overnight. After concentrating the
reaction mixture, the aqueous layer was washed with dichloromethane
(2.times.), then acidified pH about 3 with 12 M HCl. The
precipitate was extracted with ethyl acetate then washed with water
and saturated brine, dried over anhydrous sodium sulfate, filtered
and concentrated to afford 3-ethylbenzoic acid as a colorless oil;
0.770 g (28% yield over 2 steps). .sup.1H NMR (CDCl.sub.3), .delta.
(ppm): 7.76 (d, 2H), 7.43 (m, 2H), 2.67 (m, 2H), 1.19 (t, 3H).
Example 4
3-Fluoro-5-methyl-benzoic acid
[1311] Concentrated HCl (30 ml) was added to a cooled (-5.degree.
C.) suspension of dimethyl 5-amino isophthalate (20 g, 95.6 mmol)
in water (75 ml), followed by portionwise addition of NaNO.sub.2
(7.5 g, 109 mmol). The reaction mixture was then stirred for 15
min., after which HBF.sub.4 (18 ml, 100 mmol, 48% aqueous solution)
was added. The resulting mixture was stirred at 0.degree. C. for 30
min. and the precipitate formed was collected by filtration and
washed with cold methanol (60 ml) and ether (60 ml). The residue
was then decomposed by heating in an oil bath (.about.110.degree.
C.). The cooled mixture was then diluted with ether, concentrated
onto silica gel and purified by flash chromatography with 5% ethyl
acetate hexane as eluant giving 9.0 g (44%) of product as a white
fluffy solid. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.57 (s,
1H), 7.95 (d, 2H), 3.97 (s, 6H).
[1312] A suspension of 5-fluoro-isophthalic acid dimethyl ester
(1.7 g, 8.0 mmol) in methanol (41 ml) was treated with 1.0 N sodium
hydroxide (7.2 ml, 7.2 mmol). The reaction was left stirring
overnight at room temperature. After the solution was concentrated,
the residue was dissolved in water and transferred to a separatory
funnel. The aqueous layer was washed with dichloromethane (3 times)
and then acidified with 1.0 N HCl to pH 2. Ethyl acetate was used
to extract the precipitate, which was then washed with brine and
dried over anhydrous sodium sulphate. After removal of solvent in
vacuo, a total of 1.3 g (83%) of 5-fluoro-isophthalic acid
monomethyl ester was isolated as a white solid. .sup.1H NMR (DMSO),
.delta. (ppm): 8.31 (t, 1H), 7.96 (m, 2H), 3.91 (s, 3H).
[1313] Triethylamine (2.2 ml, 16.0 mmol) and isobutyl chloroformate
(1.0 ml, 8.0 mmol) were added to an ice-cooled solution of
5-fluoro-isophthalic acid monomethyl ester (1.3 g, 6.7 mmol) in
dichloromethane (20 ml) and then warmed to room temperature. After
stirring for 2 h, the reaction mixture was filtered and
concentrated. The residue was re-dissolved tetrahydrofuran (10 ml)
and then sodium borohydride (1.1 g, 29.02 mmol) in water (3 ml) was
added drop-wise. After 1 h, the reaction was quenched with methanol
and then diluted with ethyl acetate, washed with water and brine,
dried over anhydrous sodium sulfate, filtered and concentrated.
Flash column chromatography on silica gel using 30% ethyl acetate
in hexanes afforded 667 mg (54%) of
3-fluoro-5-hydroxymethyl-benzoic acid methyl ester as a colorless
oil. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.82 (s, 1H), 7.63
(d, 1H), 7.32 (d, 1H), 4.76 (s, 2H), 3.93 (s, 3H).
[1314] Ethanol (2 ml) was added to round bottom flask containing
3-fluoro-5-hydroxymethyl-benzoic acid methyl ester (667 mg, 3.6
mmol) and palladium (10 wt. % on activated carbon, 300 mg) under
argon. The flask was evacuated using a water aspirator and then
filled with hydrogen from a balloon. After stirring for 2 h, the
palladium on carbon was removed by filtration through celite. The
filtrate was then concentrated to afford 520 mg (87%) of
3-fluoro-5-methyl-benzoic acid methyl ester. .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 7.65 (s, 1H), 7.51 (d, 1H), 7.08 (d,
1H), 3.91 (s, 3H), 2.40 (s, 3H).
[1315] 0.5 N Lithium hydroxide (7.4 ml, 3.7 mmol) was added to a
solution 3-fluoro-5-methyl-benzoic acid methyl ester (520 mg, 3.1
mmol) in tetrahydrofuran (7.4 ml). The reaction was stirred at
75.degree. C. for 2 h and then the solvent was removed in vacuo.
The residue was dissolved in a small amount of water and then
acidified (pH about 2) by the addition of 10% HCl (aq.). Following
extraction of the aqueous layer with ethyl acetate, the organic
layer was then washed with water and saturated brine, dried over
anhydrous sodium sulfate, filtered, and concentrated to afford 469
mg (98%) of 3-fluoro-5-methyl-benzoic acid as a white solid. 1H NMR
(DMSO), d (ppm): 7.62 (s, 1H), 7.45 (d, 1H), 7.32 (d, 1H), 2.38 (s,
3H).
Example 5
3-Methoxymethyl-benzoic acid
[1316] A mixture of 3-bromomethyl-benzoic acid methyl ester (556
mg, 2.4 mmol) and potassium carbonate (670 mg, 4.9 mmol) in
methanol (10 ml) and tetrathydrofuran (10 ml) was heated at
55.degree. C. for 2 h. After cooling, the reaction mixture was
diluted with water and then extracted with ethyl acetate. The
organic layer was washed with water and saturated brine, dried over
anhydrous sodium sulfate, filtered and concentrated. After drying
in vacuo, 3-methoxymethyl-benzoic acid methyl ester (436 mg,
quantitative) was isolated as a white solid. .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 8.01 (s, 1H), 7.98 (d, 1H), 7.55 (d,
1H), 7.43 (t, 1H), 4.50 (s, 2H), 3.92 (s, 3H), 3.41 (s, 3H).
[1317] 1 N Sodium hydroxide (3.6 ml, 3.6 mmol) was added to a
3-methoxymethyl-benzoic acid methyl ester (436 mg, 2.4 mmol) in
methanol (5 ml) and tetrahydrofuran (5 ml). The reaction was
stirred at 70.degree. C. for 30 min. and then the solvent was
removed in vacuo. The residue was dissolved in a small amount of
water and then acidified (pH about 2) by the addition of 1 N HCl
(aq.). Following extraction of the aqueous layer with ethyl
acetate, the organic layer was then washed with water and saturated
brine, dried over anhydrous sodium sulfate, filtered, and
concentrated to afford 395 mg (98%) of 3-methoxymethyl-benzoic acid
as a white solid. .sup.1H NMR (DMSO), .delta. (ppm): 7.90 (s, 1H),
7.87 (d, 1H), 7.56 (d, 1H), 7.48 (t, 1H), 4.48 (s, 2H), 3.31 (s,
3H).
Example 6
N-Hydroxy-3-methoxy-benzamidine
[1318] Using the general procedure of Shine et al., J. Heterocyclic
Chem. (1989) 26:125-128, hydroxylamine hydrochloride (22 ml, 5 M,
110 mmol) and sodium hydroxide (11 ml, 10 M, 110 mmol) were added
to a solution of 3-methoxybenzonitrile (11.5 ml. 94 mmol) in
ethanol (130 ml). The reaction mixture was then heated at reflux
(80.degree. C.) for 12 h. After the mixture was cooled, most of the
solvent was removed in vacuo. The crude product was partitioned
between ethyl acetate and water, washed with saturated brine, dried
over anhydrous sodium sulfate and the solvent was removed in vacuo.
Flash chromatography on silica gel using 35-50% ethyl acetate in
hexane yielded the title compound (8.05 g, 52%). Examples 7-9 were
prepared in an analogous method to the procedure given in Example
6.
Example 7
N-Hydroxy-benzamidine
[1319] N-hydroxy-benzamidine (4.83 g, 91%, white solid) was
obtained from benzonitrile (4 g, 38.9 mmol), hydroxylamine
hydrochloride (8.89 ml, 44.0 mmol) and sodium hydroxide (4.49 ml,
45.0 mmol) in ethanol (30 ml). .sup.1H NMR (CDCl.sub.3), .delta.
(ppm): 8.81 (broad peak, 1H), 7.63 (m, 2H), 7.39 (m, 3H), 4.91 (s,
2H).
Example 8
N-Hydroxy-3-methyl-benzamidine
[1320] N-Hydroxy-3-methyl-benzamidine (3.65 g, 94%, white solid)
was obtained from m-tolunitrile (3 g, 26.0 mmol), hydroxylamine
hydrochloride (5.9 ml, 29.6 mmol), and sodium hydroxide (3.0 ml,
29.9 mmol) in ethanol (20 ml). .sup.1H NMR (CDCl.sub.3), .delta.
(ppm): 8.25 (broad peak, 1H), 7.36 (m, 2H), 7.25 (m, 2H), 4.88 (s,
2H), 2.38 (s, 3H).
Example 9
3-Cyano-N-hydroxy-benzamidine
[1321] 3-Cyano-N-hydroxy-benzamidine (1.32 g, 52%, white solid) was
obtained from isophthalonitrile (2 g, 15.6 mmol), hydroxylamine
hydrochloride (3.12 ml, 5 M, 15.6 mmol) and sodium hydroxide (15.6
ml, 1 M, 15.6 mmol) in ethanol (20 ml). Purification was performed
by flash column chromatography using 20-50% ethyl acetate in
hexanes. .sup.1H NMR (DMSO), .delta. (ppm): 9.91 (s, 1H), 8.06 (s,
1H), 8.01 (d, 1H), 7.85 (d, 1H), 7.59 (t, 1H), 6.01 (bs, 2H).
Example 10
5-Chloromethyl-3-(3-methoxy-phenyl)-[1,2,4]oxadiazole
[1322] Chloroacetyl chloride (0.72 ml, 9.03 mmol) and triethylamine
(1.50 ml, 10.23 mmol) were added to N-hydroxy-3-methoxy-benzamidine
(1 g, 6.02 mmol) in dichloromethane (12.0 ml) at 0.degree. C. and
the resulting mixture was stirred for 20 min. To effect cyclization
to oxadiazole, the solution was concentrated and DMF (20 ml) was
added to the residue and heated at 120.degree. C. for 5 h. The
product was purified by flash chromatography using 10-20% ethyl
acetate in hexane affording 0.90 g (66% yield over 2 steps) of the
title compound (yellow oil). .sup.1H NMR (CDCl.sub.3), .delta.
(ppm): 7.68 (m, 1H), 7.60 (d, 1H), 7.40 (t, 1H), 7.07 (m, 1H), 4.76
(s, 2H), 3.88 (s, 3H).
[1323] Examples 11-14 were prepared in an analogous method to the
procedure given in Example 10.
Example 11
5-Chloromethyl-3-phenyl-[1,2,4]oxadiazole
[1324] 5-Chloromethyl-3-phenyl-[1,2,4]oxadiazole (1.62 g, 57% yield
over 2 steps, yellow oil) was obtained from chloroacetyl chloride
(1.76 ml, 22.05 mmol) and triethylamine (3.32 ml, 24.99 mmol) with
N-hydroxy-benzamidine (2 g, 14.7 mmol) in dichloromethane (29.3
ml). Purification was performed by flash chromatography using 10%
ethyl acetate in hexane. .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
8.08 (m, 2H), 7.51 (m, 3H), 4.76 (s, 2H).
Example 12
5-Chloromethyl-3-m-tolyl-[1,2,4]oxadiazole
[1325] 5-Chloromethyl-3-m-tolyl-[1,2,4]oxadiazole (1.75 g, 62%
yield over 2 steps, yellow oil) was obtained from chloroacetyl
chloride (1.59 ml, 20.0 mmol) and triethylamine (3.00 ml, 22.7
mmol) with N-hydroxy-3-methyl-benzamidine (2 g, 13.3 mmol) in
dichloromethane (26.6 ml). Purification was performed by flash
chromatography using 10% ethyl acetate in hexane. .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 7.90 (s, 1H), 7.87 (s, 1H), 7.36 (m,
2H), 4.75 (s, 2H), 2.34 (s, 3H)
Example 13
3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile
[1326] 3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile (3.57
g, 43%) was obtained from 2-chloro-N-hydroxy-acetamidine (4.05 g,
37.4 mmol) and 3-cyanobenzoyl-chloride (6.2 g, 37.4 mmol) in
dichloromethane (60 ml) with triethylamine (6.5 ml, 46.7 mmol).
Purification was performed by silica gel chromatography. .sup.1H
NMR (CDCl.sub.3), .delta. (ppm): 8.47 (bs, 1H), 8.41 (dd, 1H), 7.91
(dd, 1H), 7.72 (t, 1H), 4.70 (s, 2H); GC-MS (M+): 219.
Example 14
3-(5-Chloromethyl-[1,2,4]oxadiazol-3-yl)-benzonitrile
[1327] 3-(5-Chloromethyl-[1,2,4]oxadiazol-3-yl)-benzonitrile (1.2
g, 87%, light brown solid): 3-cyano-N-hydroxy-benzamidine (1.0 g,
6.2 mmol), triethylamine (1.5 ml, 10.6 mmol) and chloroacetyl
chloride (0.74 ml, 9.3 mmol) in dichloromethane (12 ml).
Purification was performed by decolorizing with silica gel. 1H NMR
(CDCl.sub.3), d (ppm): 8.40 (s, 1H), 8.32 (d, 1H), 7.82 (d, 1H),
7.64 (t, 1H), 4.77 (s, 2H).
Example 15
3-Chloromethyl-5-m-tolyl-[1,2,4]oxadiazole
[1328] 3-Methyl-benzoyl chloride (0.80 ml, 6.1 mmol) was added to a
solution of 2-chloro-N-hydroxy-acetamidine (440 mg, 4.1 mmol) in
dichloromethane (10 ml) at room temperature and the resulting
mixture was stirred for 30 min. Then triethylamine (0.62 ml, 4.5
mmol) was added and the resulting mixture was stirred for 30 min.
The product was partitioned into dichloromethane and the organic
layer was washed with water and brine and dried over sodium
sulfate. Evaporation of the solvent and flash chromatography on
silica (10-20% ethyl acetate in hexanes) yielded the acyclic ester
intermediate (814 mg). A solution of this intermediate in DMF (10
ml) was heated at 135.degree. C. for 4 h. The product was
partitioned into ethyl acetate and the organic layer was washed
with water and brine and dried over sodium sulfate. Evaporation of
the solvent and flash chromatography on silica (5% ethyl acetate in
hexanes) yielded 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (469
mg, 54% over 2 steps, white solid). .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 7.99 (s, 1H), 7.97 (m, 1H), 7.43 (d, 2H), 4.68 (s,
2H), 2.45 (s, 3H).
Example 16
3-Chloromethyl-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole
[1329] DMF (10 ml) was added to a mixture of 3-fluorobenzoic acid
(710 mg, 5.07 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI) (972 mg, 5.07 mmol), 1-hydroxybenzotriazole
hydrate (HOBt) (685 mg, 5.07 mmol) and
2-chloro-N-hydroxy-acetamidine (500 mg, 4.61 mmol) at room
temperature and then stirred overnight. The reaction mixture was
diluted with ethyl acetate, washed with water (3 times) and brine,
dried over anhydrous sodium sulfate, filtered and concentrated. DMF
(14 ml) was added to the residue and the resulting solution was
heated at 135.degree. C. for 3.5 h to effect cyclization to
oxadiazole. After cooling the reaction mixture was washed with
water (3 times) and brine, dried over anhydrous sodium sulfate,
filtered and concentrated.
3-Chloromethyl-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole (383 mg, 35%
yield over 2 steps, yellow oil) was obtained by flash
chromatography on silica gel, using 5% ethyl acetate in hexane.
.sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.96 (d, 1H), 7.86 (m,
1H), 7.54 (m, 1H), 7.33 (m, 1H), 4.68 (s, 2H).
[1330] Examples 17-30 were prepared in an analogous method to the
procedure given in Example 16.
Example 17
3-Chloromethyl-5-thiophen-3-yl-[1,2,4]oxadiazole
[1331] 3-Chloromethyl-5-thiophen-3-yl-[1,2,4]oxadiazole (197 mg,
20% yield over 2 steps, white solid) was obtained from
3-thiophenecarboxylic acid (700 mg, 4.96 mmol), EDCI (950 mg, 4.96
mmol), HOBt (670 mg, 4.96 mmol) and 2-chloro-N-hydroxy-acetamidine
(538 mg, 5.46 mmol) in DMF (10 ml). The acyclic product was
purified by flash column chromatography eluting with 2:1.2:0.8
dichloromethane:hexane:ethyl acetate. The title compound was
purified by flash column chromatography using 5% ethyl acetate in
hexane. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.28 (s, 1H), 7.70
(d, 1H), 7.48 (m, 1H).
Example 18
3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-5-methyl-pyridine
[1332] 3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-5-methyl-pyridine
(25 mg, 4% yield over 2 steps) was obtained from 5-methynicotinic
acid (472 mg, 3.44 mmol), EDCI (652 mg, 3.44 mmol), HOBt (465 mg,
3.44 mmol) and 2-chloro-N-hydroxy-acetamidine (340 mg, 3.13 mmol)
in DMF (10 ml). The acyclic intermediate was purified by flash
column chromatography using 100% ethyl acetate; 200 mg (30%) of the
acyclic ester was also isolated as side product.
Example 19
3-Chloromethyl-5-(3-nitro-phenyl)-[1,2,4]oxadiazole
[1333] 3-Chloromethyl-5-(3-nitro-phenyl)-[1,2,4]oxadiazole (335 mg,
30% yield over 2 steps, yellow solid) was obtained from
3-nitrobenzoic acid (847 mg, 5.07 mmol), EDCI (972 mg, 5.07 mmol),
HOBt (685 mg, 5.07 mmol) and 2-chloro-N-hydroxy-acetamidine (500
mg, 4.61 mmol) in DMF (10 ml). The acyclic intermediate was
purified by flash column chromatography using 100% ethyl acetate.
Purification was performed by flash column chromatography using 15%
ethyl acetate in hexane. .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
9.03 (t, 1H), 8.50 (t, 2H), 7.79 (t, 1H), 4.71 (s, 2H)
Example 20
4-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-2-methyl-pyridine
[1334] 4-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-2-methyl-pyridine
(316 mg, 28% yield over 2 steps, yellow oil) was obtained from
6-methylpyridine-4-carboxylic acid (800 mg, 5.8 mmol), EDCI (1.12
g, 5.8 mmol), HOBt (788 mg, 5.8 mmol) and
2-chloro-N-hydroxy-acetamidine (575 mg, 5.3 mmol) in DMF (10 ml)
plus triethylamine (536 mg, 5.3 mmol). Purification was performed
by flash column chromatography using 30% ethyl acetate in hexane.
.sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.75 (d, 1H), 7.88 (s,
1H), 7.79 (d, 1H), 4.70 (s, 2H), 2.70 (s, 3H)
Example 21
3-Chloromethyl-5-(3-ethyl-phenyl)-[1,2,4]oxadiazole
[1335] 3-Chloromethyl-5-(3-ethyl-phenyl)-[1,2,4]oxadiazole (446 mg,
52% yield over 2 steps, yellow oil) was obtained from
3-ethylbenzoic acid (770 mg, 3.81 mmol), EDCI (803 mg, 4.19 mmol),
HOBt (566 mg, 4.19 mmol) and 2-chloro-N-hydroxy-acetamidine (454
mg, 4.19 mmol) in DMF (10 ml). Purification was performed by flash
column chromatography using 5% ethyl acetate in hexane. .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 7.96 (t, 2H), 7.42 (m, 2H), 4.68 (s,
2H), 2.74 (m, 2H), 1.28 (m, 3H).
Example 22
3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-dimethyl-amine
[1336]
3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-dimethyl-amine (40
mg, 4% yield over 2 steps, yellow solid) was obtained from
3-(dimethylamino)benzoic acid (656 mg, 3.97 mmol), EDCI (761 mg,
3.97 mmol), HOBt (536 mg, 3.97 mmol) and
2-chloro-N-hydroxy-acetamidine (500 mg, 3.6 mmol) in DMF (10 ml).
Purification was performed by flash column chromatography using 5%
ethyl acetate in hexane. .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
7.46 (t, 2H), 7.37 (t, 1H), 6.94 (d, 1H), 4.68 (s, 2H), 3.04 (s,
6H).
Example 23
3-Chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole
[1337] 3-Chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole (406
mg, 43% yield over 2 steps, white solid) was obtained from
3-chlorobenzoic acid (708 mg, 4.52 mmol), EDCI (866 mg, 4.52 mmol),
HOBt (611 mg, 4.52 mmol) and 2-chloro-N-hydroxy-acetamidine (446
mg, 4.11 mmol) in DMF (10 ml). Purification was performed by flash
column chromatography using 5% ethyl acetate in hexane. .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 8.17 (t, 1H), 8.05 (d, 1H), 7.59 (t,
1H), 7.50 (t, 1H), 4.68 (s, 2H).
Example 24
3-Chloromethyl-5-(3-trifluoromethoxy-phenyl)-[1,2,4]oxadiazole
[1338]
3-Chloromethyl-5-(3-trifluoromethoxy-phenyl)-[1,2,4]oxadiazole (707
mg, 55% yield over 2 steps, light yellow oil) was obtained from
3-trifluoromethoxybenzoic acid (1.05 g, 5.07 mmol), EDCI (972 mg,
5.07 mmol), HOBt (685 mg, 5.07 mmol) and
2-chloro-N-hydroxy-acetamidine (500 mg, 4.61 mmol) in DMF (10 ml).
Purification was performed by flash column chromatography using 5%
ethyl acetate in hexane. .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
8.10 (m, 1H), 8.03 (s, 1H), 7.61 (t, 1H), 7.48 (d, 1H), 4.69 (s,
2H).
Example 25
5-(3-Bromo-phenyl)-3-chloromethyl-[1,2,4]oxadiazole
[1339] 5-(3-Bromo-phenyl)-3-chloromethyl-[1,2,4]oxadiazole (707 mg,
55% yield over 2 steps, white solid) was obtained from
3-bromobenzoic acid (1.05 g, 5.07 mmol), EDCI (972 mg, 5.07 mmol),
HOBt (685 mg, 5.07 mmol) and 2-chloro-N-hydroxy-acetamidine (500
mg, 4.61 mmol) in DMF (10 ml). Purification was performed by flash
column chromatography using 5% ethyl acetate in hexane. 1H NMR
(CDCl.sub.3) d (ppm): 8.10 (m, 1H), 8.03 (s, 1H), 7.61 (t, 1H),
7.48 (d, 1H), 4.69 (s, 2H).
Example 26
3-Chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole
[1340] 3-Chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole (202 mg,
20%, off-white solid) was obtained from thiophene-2-carboxylic acid
(649 mg, 5.1 mmol), 2-chloro-N-hydroxy-acetamidine (500 mg, 4.6
mmol), EDCI (972 mg, 5.1 mmol) and HOBt (684 mg, 5.1 mmol) in DMF
(5 ml). Purification was performed by SPE (flash) chromatography
using 5% ethyl acetate in hexanes. .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 8.00 (s, 1H), 7.83 (d, 1H), 7.19 (t, 1H), 4.13 (s,
2H).
Example 27
3-Chloromethyl-5-(3-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole
[1341]
3-Chloromethyl-5-(3-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole (312
mg, 46%, colorless oil) was obtained from 3-fluoro-5-methyl-benzoic
acid (469 mg, 3.0 mmol), 2-chloro-N-hydroxy-acetamidine (363 mg,
3.3 mmol), EDCI (641 mg, 3.3 mmol) and HOBt (452 mg, 3.3 mmol) in
DMF (5 ml). Purification was performed by SPE (flash)
chromatography using 5% ethyl acetate in hexanes. .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 7.79 (s, 1H), 7.65 (d, 1H), 7.15 (d,
1H), 4.67 (s, 2H), 2.46 (s, 3H).
Example 28
3-Chloromethyl-5-thiazol-4-yl-[1,2,4]oxadiazole
[1342] 3-Chloromethyl-5-thiazol-4-yl-[1,2,4]oxadiazole (37 mg, 5%,
yellow solid) was obtained from thiazole-4-carboxylic acid (500 mg,
3.9 mmol), 2-chloro-N-hydroxy-acetamidine (462 mg, 4.3 mmol), EDCI
(817 mg, 4.3 mmol) and HOBt (575 mg, 4.3 mmol) in DMF (5 ml).
Purification was performed by SPE (flash) chromatography using 30%
ethyl acetate in hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
9.02 (d, 1H), 8.42 (d, 1H), 4.70 (s, 2H).
Example 29
3-Chloromethyl-5-(3-iodo-phenyl)-[1,2,4]oxadiazole
[1343] 3-Chloromethyl-5-(3-iodo-phenyl)-[1,2,4]oxadiazole (2.9 g,
44%, white solid) was obtained from 3-iodo-benzoic acid (5.0 g,
20.2 mmol), 2-chloro-N-hydroxy-acetamidine (2.4 g, 22.2 mmol), EDCI
(4.3 g, 22.2 mmol) and HOBt (3.0 g, 22.2 mmol) in DMF (10 ml). The
acyclic ester intermediate was purified by flash column
chromatography using 50-80% ethyl acetate in hexanes. The title
compound was purified by SPE (flash) chromatography using 5% ethyl
acetate in hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.52
(s, 1H), 8.13 (d, 1H), 7.96 (d, 1H), 7.29 (t, 1H), 4.68 (s,
2H).
Example 30
3-Chloromethyl-5-(3-methoxymethyl-phenyl)-[1,2,4]oxadiazole
[1344] 3-Chloromethyl-5-(3-methoxymethyl-phenyl)-[1,2,4]oxadiazole
(193 mg, 34%, light yellow oil) was obtained from
3-methoxymethyl-benzoic acid (395 mg, 2.4 mmol),
2-chloro-N-hydroxy-acetamidine (284 mg, 2.6 mmol), EDCI (501 mg,
2.6 mmol) and HOBt (353 mg, 2.6 mmol) in DMF (5 ml). Purification
was performed by SPE (flash) chromatography using 5% ethyl acetate
in hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.14 (s, 1H),
8.08 (d, 1H), 7.61 (d, 1H), 7.53 (t, 1H), 4.68 (s, 2H), 4.54 (s,
2H), 3.44 (s, 3H).
Example 31
5-Furan-2-yl-4-methyl-4H-[1,2,4]triazole-3-thiol
[1345] 2-Furoyl chloride (0.76 ml, 7.66 mmol) was added in a
dropwise manner to a solution of 4-methyl-3-thiosemicarbazide (732
mg, 6.96 mmol) and pyridine (7 ml) and the resulting solution was
stirred at room temperature for 4 h. The reaction mixture was
diluted with ethyl acetate (100 ml), successively washed with water
(3.times.100 ml) and brine (100 ml). The organic phase was dried
(sodium sulfate), filtered and concentrated in-vacuo. The residue
was suspended in sodium bicarbonate (70 ml, 69.6 mmol, 1 M water)
and left stirring at 100.degree. C. overnight. The reaction mixture
was cooled to 0.degree. C., then brought to pH about 6 using
hydrochloric acid (70 ml, 1 N water). The title compound (298 mg)
was collected by filtration as a white solid. .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 11.4 (bs, 1H), 7.63 (d, 1H), 7.02 (d,
1H), 6.60 (dd, 1H), 3.83 (s, 3H).
[1346] Examples 32-35 were prepared in an analogous method to the
procedure given in Example 31.
Example 32
4-Methyl-5-phenyl-4H-[1,2,4]triazole-3-thiol
[1347] 4-Methyl-5-phenyl-4H-[1,2,4]triazole-3-thiol (478 mg,
off-white solid) was obtained from 4-methyl-3-thiosemicarbazide
(732 mg, 6.96 mmol) and pyridine (7 ml) with benzoyl chloride (0.89
ml, 7.66 mmol). Then sodium bicarbonate (70 ml, 69.6 mmol, 1 M
water) was added at 100.degree. C. overnight and the title compound
was collected by filtration. .sup.1H NMR (CDCl.sub.3), .delta.
(ppm): 12.3 (bs, 1H), 7.55 (m, 5H), 3.65 (s, 3H).
Example 33
4-Methyl-5-pyridin-2-yl-4H-[1,2,4]triazole-3-thiol
[1348] 4-Methyl-5-pyridin-2-yl-4H-[1,2,4]triazole-3-thiol (44 mg,
greenish solid) was obtained from 4-methyl-3-thiosemicarbazide (537
mg, 5.11 mmol) and pyridine (7 ml) with 2-pyridinecarbonyl chloride
hydrochloride (1.00 g, 5.62 mmol). Then sodium bicarbonate (51 ml,
1 M water) was added at 100.degree. C. overnight and the title
compound was collected using extraction and evaporation. .sup.1H
NMR (CDCl.sub.3), .delta. (ppm): 11.1 (bs, 1H), 8.70 (d, 1H), 8.02
(d, 1H), 7.84 (m, 1H), 7.41 (dd, 1H), 4.05 (s, 3H).
Example 34
5-(4-Benzyl-morpholin-2-yl)-4-methyl-4H-[1,2,4]triazole-3-thiol
[1349] (83.3 mg, dirty yellow solid) was obtained from
4-methyl-3-thiosemicarbazide (346 mg, 3.29 mmol) and pyridine (7
ml) with 4-benzyl-2-morpholinecarbonyl chloride hydrochloride (1.00
g, 3.62 mmol). Then sodium bicarbonate (33 ml, 1 M water) was added
at 100.degree. C. overnight and the title compound was collected
using extraction and evaporation. .sup.1H NMR (CDCl.sub.3), .delta.
(ppm): 9.48 (bs, 1H), 7.25 (m, 5H), 4.68 (dd, 1H), 3.86 (dAb, 1H),
3.68 (tAB, 1H), 3.59-3.64 (m, 5H), 3.07 (d, 1H), 2.88 (d, 1H), 2.61
(t, 1H), 2.37 (dt, 1H).
Example 35
5-tert-Butyl-4-methyl-4H-[1,2,4]triazole-3-thiol
[1350] 5-tert-Butyl-4-methyl-4H-[1,2,4]triazole-3-thiol (2.21 g,
83%, off-white solid) was obtained from
4-methyl-3-thiosemicarbazide (1.80 g, 17.2 mmol) and pyridine (20
ml) with trimethylacetyl chloride (1.92 ml, 15.6 mmol). Then sodium
hydroxide (200 ml, 5% water) was added and left stirring at
60.degree. C. overnight and the title compound was collected
extraction and evaporation. .sup.1H NMR (CDCl.sub.3), .delta.
(ppm): 11.7 (bs, 1H), 3.72 (s, 3H) 1.40 (s, 9H).
Example 36
4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol
[1351] A solution of 4-methyl-3-thiosemicarbazide (902 mg, 8.58
mmol), nicotinic acid (960 mg, 7.80), EDCI (1.64 g, 8.58 mmol),
HOBt (1.16 g, 8.58 mmol) in DMF (10 ml) was stirred at room
temperature overnight. The reaction mixture was diluted with ethyl
acetate (100 ml), successively washed with hydrochloric acid (50
ml, 10% aqueous), water (50 ml), saturated sodium carbonate (50 ml,
aqueous), water (50 ml) and brine (50 ml). The organic phase was
dried (sodium sulfate), filtered and concentrated in-vacuo. The
residue was stirred in sodium hydroxide (53.4 ml, 66.7 mmol, 5%
aqueous) at 60.degree. C. overnight. The reaction mixture was
cooled to room temperature, then carefully brought to pH about 6
using hydrochloric acid (1 N water). The aqueous phase was
saturated with solid sodium chloride, then extracted with ethyl
acetate (4.times.50 ml). The combined organic phase was washed with
brine (100 ml), dried (sodium sulfate), filtered and concentrated
in-vacuo (180 mg, off-white solid). .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 11.6 (bs, 1H), 8.94 (s, 1H), 8.83 (dd, 1H), 7.98 (m,
1H), 7.51 (dd, 1H), 3.69 (s, 3H).
[1352] Examples 37-39 were prepared in an analogous method to the
procedure given in Example 36.
Example 37
4-Methyl-5-thiophene-3-yl-4H-[1,2,4]triazole-3-thiol
[1353] 4-Methyl-5-thiophene-3-yl-4H-[1,2,4]triazole-3-thiol (693
mg, white solid) was obtained from 4-methyl-3-thiosemicarbazide
(902 mg, 8.58 mmol), 3-thiophenecarboxylic acid (1 g, 7.80 mmol),
EDCI (1.64 g, 8.58 mmol), HOBt (1.16 g, 8.58 mmol) in DMF (10 ml).
Then sodium hydroxide (88 ml, 110 mmol, 5% aqueous) at 60.degree.
C. overnight and the title compound was product collected
extraction and evaporation. .sup.1H NMR (CDCl.sub.3), .delta.
(ppm): 11.4 (bs, 1H), 7.77 (dd, 1H), 7.51 (dd, 1H), 7.42 (dd, 1H),
3.61 (s, 3H).
Example 38
4-Methyl-5-thiazol-4-yl-4H-[1,2,4]triazole-3-thiol
[1354] 4-Methyl-5-thiazol-4-yl-4H-[1,2,4]triazole-3-thiol (71.2 mg,
sticky yellow oil) was obtained from 4-methyl-3-thiosemicarbazide
(902 mg, 8.58 mmol), 4-carboxythiazole (1.01 g, 7.80), EDCI (1.64
g, 8.58 mmol), HOBt (1.16 g, 8.58 mmol) in DMF (10 ml). Then sodium
hydroxide (43 ml, 54 mmol, 5% aqueous) at 60.degree. C. overnight
and the title compound was collected extraction and
evaporation.
Example 39
5-Cyclohexyl-4-methyl-4H-[1,2,4]triazole-3-thiol
[1355] 5-Cyclohexyl-4-methyl-4H-[1,2,4]triazole-3-thiol (403 mg,
beige solid) was obtained from 4-methyl-3-thiosemicarbazide (1.80
g, 17.2 mmol), cyclohexane carboxylic acid (2 g, 15.6 mmol), EDCI
(2.99 g, 17.2 mmol) and HOBt (2.10 g, 17.2 mmol) in DMF (20 ml);
then sodium hydroxide (195 ml, 244 mmol, 5% aqueous) at 60.degree.
C. overnight.
Example 40
2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimida-
zole
[1356] 1H-Benzoimidazole-2-thiol (150 mg, 1 mmol) was added to a
solution of the
3-chloromethyl-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole (30 mg, 0.13
mmol) and potassium carbonate (50 mg, 0.36 mmol) in DMF (2 ml) at
room temperature. The solvent was removed in vacuo and the product
obtained by flash chromatography using 20-100% ethyl acetate in
hexane. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.71 (d, 1H), 7.62
(d, 1H), 7.53 (m, 2H), 7.42 (t, 1H), 7.18 (overlapping, m, 3H),
4.52 (s, 2H), 3.87 (s, 3H).
[1357] Examples 41-92 were prepared in an analogous method to the
procedure given in Example 40.
Example 41
5-(3-Methoxy-phenyl)-3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazole
[1358] The title compound was prepared from
3-chloromethyl-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole (50 mg, 0.22
mmol), potassium carbonate (92.4 mg, 0.67 mmol),
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (52.8 mg, 0.27
mmol) in acetonitrile (1 ml) at room temperature. Purification was
performed by SPE (flash) chromatography using 30-40% ethyl acetate
in hexanes afforded 76 mg (90%) of the title compound as a white
solid. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.68 (d, 1H), 7.57
(t, 1H), 7.49 (m, 2H), 7.41 (t, 1H), 7.15 (m, 2H), 4.53 (s, 2H),
3.85 (s, 3H), 3.72 (s, 3H). LC-MS (M+1).sup.+ 386.3.
Example 42
3-[5-(1-Methyl-5-thiophen-2-yl-1H-imidazol-2-ylsulfanylmethyl)-[1,2,4]oxad-
iazol-3-yl]-benzonitrile
[1359]
3-[5-(1-Methyl-5-thiophen-2-yl-1H-imidazol-2-ylsulfanylmethyl)-[1,-
2,4]oxadiazol-3-yl]-benzonitrile (39 mg, 47%, white solid) was
obtained from
3-chloromethyl-3-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-benzonitrile
(50 mg, 0.22 mmol), potassium carbonate (92.4 mg, 0.67 mmol),
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (52.8 mg, 0.27
mmol) in acetonitrile (1 ml) at room temperature. Purification was
performed by SPE (flash) chromatography using 50-70% ethyl acetate
in hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.34 (s, 1H),
8.28 (d, 1H), 7.79 (d, 1H), 7.60 (t, 1H), 7.53 (d, 1H), 7.49 (d,
1H), 7.19 (m, 1H), 4.70 (s, 2H), 3.74 (s, 3H). LS-MS (ES+full scan,
C.sub.17H.sub.12N.sub.6OS.sub.2) M.sup.+ calc. 380.05, found
(M+1).sup.+ 381.04.
Example 43
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-phenyl-
-[1,2,4]oxadiazole
[1360]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
5-phenyl-[1,2,4]oxadiazole (41.2 mg, 44%, off-white solid) was
obtained from 3-chloromethyl-5-phenyl-[1,2,4]oxadiazole (50 mg,
0.26 mmol), potassium carbonate (106 mg, 0.77 mmol),
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (60.8 mg, 0.31
mmol) in acetonitrile (2 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 50% ethyl acetate in
hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.09 (m, 2H),
7.57 (m, 5H), 7.17 (dd, 1H), 4.53 (s, 2H), 3.72 (s, 3H).
Example 44
2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-methyl-1H-b-
enzoimidazole
[1361]
2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-met-
hyl-1H-benzoimidazole (75.5 mg, 70.5%, white foam) was obtained
from 3-chloromethyl-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole (82 mg,
0.365 mmol), potassium carbonate (210 mg, 1.520 mmol),
2-thiol-5-methyl-1H-benzoimidazole (50 mg, 0.305 mmol) in
acetonitrile (3 ml) at room temperature. Purification was performed
by SPE flash chromatography using 50% ethyl acetate in hexanes
followed by trituration with ethyl acetate. .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 11.95 (bs, 1H), 7.80 (d, 1H), 7.70 (s,
1H), 7.52 (m, 2H), 7.21 (dd, 2H), 7.17 (d, 1H), 4.40 (s, 2H), 3.95
(s, 3H), 2.50 (s, 3H).
Example 45
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-toly-
l-[1,2,4]oxadiazole
[1362]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
5-m-tolyl-[1,2,4]oxadiazole (76 mg, 85%, white solid) was obtained
from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol),
potassium carbonate (99.4 mg, 0.72 mmol),
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (56.7 mg, 0.27
mmol) in acetonitrile (1 ml) at room temperature. Purification was
performed by SPE (flash) chromatography using 50-70% ethyl acetate
in hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.89 (m, 2H),
7.50 (m, 2H), 7.40 (m, 2H), 7.18 (t, 1H), 4.52 (s, 2H), 3.71 (s,
3H), 2.41 (s, 3H).
Example 46
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-tri-
fluoromethyl-phenyl)-[1,2,4]oxadiazole
[1363]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
5-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazole (84 mg, 86%, white
solid) was obtained from
3-chloromethyl-5-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazole (60
mg, 0.23 mmol), potassium carbonate (95 mg, 0.69 mmol),
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (54 mg, 0.27
mmol) in acetonitrile (1 ml) at room temperature. Purification was
performed by SPE (flash) chromatography using 40-60% ethyl acetate
in hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.38 (s, 1H),
7.29 (d, 1H), 7.86 (d, 1H), 7.68 (t, 1H), 7.50 (t, 2H), 7.19 (m,
1H), 4.57 (s, 2H), 3.75 (s, 3H).
Example 47
3-(3-Methoxy-phenyl)-5-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazole
[1364]
3-(3-Methoxy-phenyl)-5-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-
-3-ylsulfanylmethyl)-[1,2,4]oxadiazole (74.3 mg, 88%, white solid)
was obtained from
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (53.3 mg, 0.27
mmol), 5-chloromethyl-3-(3-methoxy-phenyl)-[1,2,4]oxadiazole (50
mg, 0.22) mmol), and potassium carbonate (92.6 mg, 0.67 mmol) in
acetonitrile (1 ml) at room temperature. Purification was performed
by SPE (flash) chromatography using 40-70% ethyl acetate in hexane.
.sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.62 (d, 1H), 7.52 (d,
2H), 7.48 (d, 1H), 7.37 (t, 1H), 7.18 (t, 1H), 7.06 (m, 1H), 4.64
(s, 2H), 3.84 (s, 3H), 3.71 (s, 3H). LC-MS (MH+): 386.06.
Example 48
5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-
-[1,2,4]oxadiazole
[1365]
5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
3-phenyl-[1,2,4]oxadiazole (79.9 mg, 87%, white solid) was obtained
from 4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (86.8 mg,
0.44 mmol), 5-chloromethyl-3-phenyl-[1,2,4]oxadiazole (50 mg, 0.26
mmol), and potassium carbonate (152.0 mg, 1.1 mmol) in acetonitrile
(1 ml) at room temperature. Purification was performed by SPE
(flash) chromatography using 40-70% ethyl acetate in hexane.
.sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.02 (d, 2H), 7.47 (m,
5H), 7.18 (t, 1H).
Example 49
5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-m-toly-
l-[1,2,4]oxadiazole
[1366]
5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
3-m-tolyl-[1,2,4]oxadiazole (71.8 mg, 91%, white solid) was
obtained from 4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol
(78.9 mg, 0.40 mmol), 5-chloromethyl-3-m-tolyl-[1,2,4]oxadiazole
(50 mg, 0.24 mmol) and potassium carbonate (138.2 mg, 1.0 mmol) in
acetonitrile (1 ml) at room temperature. Purification was performed
by SPE (flash) chromatography using 45-65% ethyl acetate in hexane.
.sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.82 (d, 2H), 7.52 (d,
1H), 7.47 (d, 1H), 7.31 (m, 2H), 7.18 (m, 1H), 4.64 (s, 2H), 3.70
(s, 3H), 2.39 (s, 3H). LC-MS (MH.sup.+): 370.06.
Example 50
3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,-
4]oxadiazol-5-yl]-benzonitrile
[1367]
3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethy-
l)-[1,2,4]oxadiazol-5-yl]-benzonitrile (130 mg, 75%) was obtained
from 3-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile (100 mg,
0.45 mmol) with K.sub.2CO.sub.3 (189 mg, 1.36 mmol) and
4-methyl-5-(2-thienyl) 1,2,4-triazole-3-thiol (110 mg, 0.54 mmol)
in acetonitrile at room temperature. Purification was performed by
flash chromatography using 50% ethyl acetate in dichloromethane.
.sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.38 (bs, 1H), 8.32 (d,
1H), 7.88 (d, 1H), 7.68 (t, 1H), 7.51 (dd, 2H), 7.18 (dd, 1H), 4.56
(s, 2H), 3.75 (s, 3H); LC-MS (M+H).sup.+: 381.
Example 51
3-[4-Methyl-5-(2-methyl-thiazol-4-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl-
]-5-m-tolyl-[1,2,4]oxadiazole
[1368]
3-[4-Methyl-5-(2-methyl-thiazol-4-yl)-4H-[1,2,4]triazol-3-ylsulfan-
ylmethyl]-5-m-tolyl-[1,2,4]oxadiazole (82.8 mg, 90%, white solid)
was obtained from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50
mg, 0.24 mmol), potassium carbonate (99 mg, 0.72 mmol),
4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[1,2,4]triazole-3-thiol (61
mg, 0.29 mmol) in acetonitrile (2 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 80% ethyl acetate in
hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.96 (s, 1H),
7.88 (m, 2H), 7.38 (m, 2H), 4.53 (s, 2H), 3.91 (s, 3H), 2.75 (s,
3H), 2.41 (s, 3H).
Example 52
3-[5-(2-Methyl-thiazol-4-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-5-m-toly-
l-[1,2,4]oxadiazole
[1369]
3-[5-(2-Methyl-thiazol-4-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]--
5-m-tolyl-[1,2,4]oxadiazole (89 mg, 99%, off-white solid) was
obtained from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg,
0.24 mmol), potassium carbonate (99 mg, 0.72 mmol),
5-(2-methyl-thiazol-4-yl)-[1,3,4]oxadiazole-2-thiol (57.3 mg, 0.29
mmol) in acetonitrile (2 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 80% ethyl acetate in
hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.97 (s, 1H),
7.90 (m, 2H), 7.40 (m, 2H), 4.66 (s, 2H), 2.80 (s, 3H), 2.42 (s,
3H).
Example 53
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thioph-
en-2-yl-[1,2,4]oxadiazole
[1370]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
5-thiophen-2-yl-[1,2,4]oxadiazole (80 mg, 88%, white solid) was
obtained from 3-chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole (50
mg, 0.25 mmol), potassium carbonate (103 mg, 0.75 mmol),
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (59 mg, 0.30
mmol) in acetonitrile (1 ml) at room temperature. Purification was
performed by SPE (flash) chromatography using 50-70% ethyl acetate
in hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.89 (d, 1H),
7.65 (m, 1H), 7.51 (m, 2H), 7.19 (m, 2H), 4.50 (t, 2H), 3.74 (s,
3H).
Example 54
3-[5-(2,4-Dimethyl-thiazol-5-yl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylme-
thyl]-5-m-tolyl-[1,2,4]oxadiazole
[1371]
3-[5-(2,4-Dimethyl-thiazol-5-yl)-4-methyl-4H-[1,2,4]triazol-3-ylsu-
lfanylmethyl]-5-m-tolyl-[1,2,4]oxadiazole (54.2 mg, 57%, off-white
solid) was obtained from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole
(50 mg, 0.24 mmol), potassium carbonate (99 mg, 0.72 mmol),
5-(2,4-dimethyl-thiazol-5-yl)-4-methyl-4H-[1,2,4]triazole-3-thiol
(65.1 mg, 0.29 mmol) in acetonitrile (2 ml) at 60.degree. C.
overnight. Purification was performed on silica gel using 80% ethyl
acetate in hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.88
(m, 2H), 7.39 (m, 2H), 4.57 (s, 2H), 3.49 (s, 3H), 2.73 (s, 3H),
2.43 (d, 6H).
Example 55
3-[4-Methyl-5-(5-nitro-furan-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-
-m-tolyl-[1,2,4]oxadiazole
[1372]
3-[4-Methyl-5-(5-nitro-furan-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylm-
ethyl]-5-m-tolyl-[1,2,4]oxadiazole (77.9 mg, 81%, yellow solid) was
obtained from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg,
0.24 mmol), potassium carbonate (99 mg, 0.72 mmol),
4-methyl-5-(5-nitro-furan-2-yl)-4H-[1,2,4]triazole-3-thiol (65.1
mg, 0.29 mmol) in acetonitrile (2 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 80% ethyl acetate
in. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.90 (m, 2H), 7.46 (d,
1H), 7.40 (m, 2H), 7.33 (d, 1H), 4.59 (s, 2H), 3.91 (s, 3H), 2.42
(s, 3H).
Example 56
4-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]tr-
iazol-3-yl]-pyridine
[1373]
4-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[-
1,2,4]triazol-3-yl]-pyridine (66 mg, 75%, white solid) was obtained
from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol),
potassium carbonate (99 mg, 0.72 mmol),
4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (55.3 mg, 0.29
mmol) in acetonitrile (2 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 80% ethyl acetate in
hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.79 (dd, 2H),
7.89 (m, 2H), 7.63 (dd, 2H), 7.40 (m, 2H), 4.59 (s, 2H), 3.69 (s,
3H), 2.41 (s, 3H).
Example 57
3-[5-(4-tert-Butyl-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]--
5-m-tolyl-[1,2,4]-oxadiazole
[1374]
3-[5-(4-tert-Butyl-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl-
methyl]-5-m-tolyl-[1,2,4]-oxadiazole (100 mg, 99%, white waxy
solid) was obtained from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole
(50 mg, 0.24 mmol), potassium carbonate (99 mg, 0.72 mmol),
5-(4-tert-butyl-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol (71.1
mg, 0.29 mmol) in acetonitrile (2 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 80% ethyl acetate in
hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.89 (m, 2H),
7.57 (m, 4H), 7.39 (d, 2H), 4.55 (s, 2H), 3.61 (s, 3H), 2.40 (s,
3H), 1.35 (s, 9H).
Example 58
2-Chloro-5-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H--
[1,2,4]triazol-3-yl]-pyridine
[1375]
2-Chloro-5-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfa-
nyl)-4H-[1,2,4]triazol-3-yl]-pyridine (53.8 mg, 56%, white solid)
was obtained from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50
mg, 0.24 mmol), potassium carbonate (99 mg, 0.72 mmol),
5-(6-chloro-pyridin-3-yl)-4-methyl-4H-[1,2,4]triazole-3-thiol (65.2
mg, 0.29 mmol) in acetonitrile (2 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 80% ethyl acetate in
hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.67 (d, 1H),
8.02 (dd, 1H), 7.88 (m, 2H), 7.49 (d, 1H), 7.40 (m, 2H), 4.58 (s,
2H), 3.65 (s, 3H), 2.42 (s, 3H).
Example 59
2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-benzooxazole
[1376]
2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-benzo-
oxazole (138 mg, 62%) was obtained from
3-chloromethyl-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole (225.9 mg,
1.1 mmol), benzooxazole-2-thiol (167 mg, 1.00 mmol), potassium
carbonate (180 mg, 1.3 mmol) in DMF (4.5 ml) at room temperature
overnight. Purification was performed on silica gel using 10-20%
ethyl acetate in hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
7.67 (d, 1H), 7.57 (m, 3H), 7.43 (t, 1H), 7.21 (m, 2H), 7.14 (m,
1H), 4.50 (s, 2H), 3.86 (s, 3H).
Example 60
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thioph-
en-3-yl-[1,2,4]oxadiazole
[1377]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
5-thiophen-3-yl-[1,2,4]oxadiazole (73.6 mg, 73%, white solid) was
obtained from 4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol
(61 mg, 0.31 mmol),
3-chloromethyl-5-thiophen-3-yl-[1,2,4]oxadiazole (50 mg, 0.28
mmol), and potassium carbonate (15 mg, 0.83 mmol) in acetonitrile
(1 ml) at room temperature. Purification was performed by SPE
(flash) chromatography using 50-70% ethyl acetate in hexane.
.sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.20 (d, 1H), 7.64 (d,
1H), 7.48 (m, 3H), 7.18 (m, 1H), 4.52 (s, 2H), 3.72 (s, 3H)
Example 61
3-(5-Furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[-
1,2,4]oxadiazole
[1378]
3-(5-Furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-
-tolyl-[1,2,4]oxadiazole (51.0 mg, 76%, white solid) was obtained
from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (40.0 mg, 0.19
mmol), potassium carbonate (79 mg, 0.58 mmol),
5-furan-2-yl-4-methyl-4H-[1,2,4]triazole-3-thiol (41.7 mg, 0.23
mmol) in acetonitrile (2 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 80% ethyl acetate in
hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.88 (m, 2H),
7.58 (s, 1H), 7.40 (m, 2H), 7.10 (d, 1H), 6.58 (dd, 1H), 4.51 (s,
2H), 3.77 (s, 3H), 2.41 (s, 3H).
Example 62
5-(3-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulf-
anylmethyl)-[1,2,4]oxadiazole
[1379]
5-(3-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol--
3-ylsulfanylmethyl)-[1,2,4]oxadiazole (75.4 mg, 83%, white solid)
was obtained from
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (51 mg, 0.26
mmol), 3-chloromethyl-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole (50 mg,
0.24 mmol) and potassium carbonate (98 mg, 0.71 mmol) in
acetonitrile (1 ml) at room temperature. Purification was performed
by SPE (flash) chromatography using 55-60% ethyl acetate in hexane.
.sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.89 (d, 1H), 7.78 (m,
1H), 7.51 (m, 3H), 7.32 (m, 1H), 7.18 (m, 1H), 4.55 (s, 2H), 3.74
(s, 3H)
Example 63
2-(5-m-Tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-pyridine
[1380] 2-(5-m-Tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-pyridine
(27.3 mg, 96.5%) was obtained from
3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (20.8 mg, 0.1 mmol) with
pyridine-2-thiol (12.2 mg, 0.11 mmol) and potassium carbonate in
DMF (0.8 ml) at room temperature for 15 h. Purification was
performed by flash chromatography on silica gel using 20% ethyl
acetate in hexane. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.47
(dd, 1H), 7.94 (s, 1H), 7.90 (t, 1H), 7.51 (dt, 1H), 7.38 (d, 2H),
7.26 (dd, 1H), 7.02 (dd, 1H), 4.61 (s, 2H), 2.42 (s, 3H).
Example 64
2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]1-H-imidazo[4,-
5-b]pyridine
[1381]
2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-im-
idazo[4,5-b]pyridine (74.5 mg, 96%) was obtained from
3-chloromethyl-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole (51.2 mg,
0.25 mmol), 1H-imidazo[4,5-b]pyridine-2-thiol (37.5 mg, 0.23 mmol)
and potassium carbonate (80 mg, 0.58 mmol) in DMF (1.5 ml) at room
temperature overnight. Purification was performed on silica gel
using 25-50% ethyl acetate in dichloromethane. .sup.1H-NMR
(DMSO-d.sub.6), .delta. (ppm): 8.24 (br s, 1H), 7.88 br s, 1H),
7.66 (d, 1H), 7.55 (m, 3H), 7.29 (d, 1H), 7.19 (m, 1H), 4.82 (s,
2H), 3.85 (s, 3H).
Example 65
5-(3-Fluoro-5-methyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-
-3-ylsulfanylmethyl)-[1,2,4]oxadiazole
[1382]
5-(3-Fluoro-5-methyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4-
]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole (58 mg, 68%, white
solid) was obtained from
3-chloromethyl-5-(3-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole (50
mg, 0.22 mmol), potassium carbonate (91.5 mg, 0.66 mmol),
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (52.2 mg, 0.26
mmol) in acetonitrile (1 ml) at room temperature. Purification was
performed by SPE (flash) chromatography using 40-100% ethyl acetate
in hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.70 (s, 1H),
7.58 (d, 1H), 7.52 (m, 1H), 7.49 (m, 1H), 7.18 (m, 1H), 7.12 (d,
1H), 4.53 (s, 2H), 3.73 (s, 3H), 2.42 (s, 3H).
Example 66
3-Methyl-5-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmeth-
yl)-[1,2,4]oxadiazol-5-yl]-pyridine
[1383]
3-Methyl-5-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulf-
anylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine (19.0 mg, 43%, light
yellow solid) was obtained from
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (26 mg, 0.13
mmol), 3-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-5-methyl-pyridine
(25 mg, 0.12 mmol) and potassium carbonate (50 mg, 0.36 mmol) in
acetonitrile (1 ml) at room temperature. Purification was performed
by SPE (flash) chromatography using 100% ethyl acetate. .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 9.13 (s, 1H), 8.65 (s, 1H), 8.16 (s,
1H), 7.50 (m, 2H), 7.19 (t, 1H) 4.57 (s, 2H), 3.74 (s, 3H), 2.43
(s, 3H)
Example 67
3-(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,-
4]oxadiazole
[1384]
3-(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tol-
yl-[1,2,4]oxadiazole (55.8 mg, 67%, white solid) was obtained from
3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (48.4 mg, 0.23 mmol),
potassium carbonate (96 mg, 0.70 mmol),
4-methyl-5-phenyl-4H-[1,2,4]triazole-3-thiol (44.4 mg, 0.23 mmol)
in acetonitrile (2 ml) at 60.degree. C. overnight. Purification was
performed on silica gel using 50% ethyl acetate in hexanes. .sup.1H
NMR (CDCl.sub.3), .delta. (ppm): 7.89 (m, 2H), 7.64 (m, 2H), 7.50
(m, 3H), 7.39 (m, 2H), 4.56 (s, 2H), 3.61 (s, 3H), 2.41 (s,
3H).
Example 68
2-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]tr-
iazol-3-yl]-pyridine
[1385]
2-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[-
1,2,4]triazol-3-yl]-pyridine (42.8 mg, 51%, off-white solid) was
obtained from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (48.4 mg,
0.23 mmol), potassium carbonate (96 mg, 0.70 mmol),
4-methyl-5-pyridin-2-yl-4H-[1,2,4]triazole-3-thiol (44.6 mg, 0.23
mmol) in acetonitrile (2 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 50% ethyl acetate in
hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.62 (d, 1H),
8.30 (d, 1H), 7.85 (m, 3H), 7.36 (m, 3H), 4.59 (s, 2H), 4.02 (s,
3H), 2.40 (s, 3H).
Example 69
4-Benzyl-2-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H--
[1,2,4]triazol-3-yl]-morpholine
[1386]
4-Benzyl-2-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfa-
nyl)-4H-[1,2,4]triazol-3-yl]-morpholine (95.8 mg, 83%, clear oil)
was obtained from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (59.9
mg, 0.29 mmol), potassium carbonate (119 mg, 0.86 mmol),
5-(4-benzyl-morpholin-2-yl)-4-methyl-4H-[1,2,4]triazole-3-thiol
(83.3 mg, 0.29 mmol) in acetonitrile (2 ml) at 60.degree. C.
overnight. Purification was performed on silica gel using 10%
methanol in ethyl acetate. .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
7.88 (m, 2H), 7.31 (m, 7H), 4.75 (dd, 1H), 4.47 (dd, 2H), 3.84 (m,
2H), 3.59 (bs, 5H), 3.20 (d, 1H), 2.72 (m, 2H), 2.43 (s, 3H), 2.30
(dt, 1H).
Example 70
4-[4-Methyl-5-(5-thiophen-3-yl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,-
2,4]triazol-3-yl]-pyridine
[1387]
4-[4-Methyl-5-(5-thiophen-3-yl-[1,2,4]oxadiazol-3-ylmethylsulfanyl-
)-4H-[1,2,4]triazol-3-yl]-pyridine (24 mg, 34%, white solid) was
obtained from 3-chloromethyl-5-thiophen-3-yl-[1,2,4]oxadiazole (40
mg, 0.20 mmol), potassium carbonate (82.5 mg, 0.60 mmol),
4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (38.3 mg, 0.20
mmol) in acetonitrile (2 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 10% methanol in
ethyl acetate. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.80 (bs,
2H), 8.20 (dd, 1H), 7.62 (m, 3H), 7.45 (dd, 1H), 4.59 (s, 2H), 3.70
(s, 3H).
Example 71
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiazo-
l-4-yl-[1,2,4]oxadiazole
[1388]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
5-thiazol-4-yl-[1,2,4]oxadiazole (44 mg, 67%, white solid) was
obtained from 3-chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole (37
mg, 0.18 mmol), potassium carbonate (75.3 mg, 0.54 mmol),
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (43 mg, 0.22
mmol) in acetonitrile (1 ml) at room temperature. Purification was
performed by SPE (flash) chromatography using 50-100% ethyl acetate
in hexanes. .sup.1H NMR (DMSO), .delta. (ppm): 9.37 (d, 1H), 8.86
(d, 1H), 7.80 (d, 1H), 7.65 (d, 1H), 7.26 (t, 1H), 4.54 (s, 2H),
3.75 (s, 3H).
Example 72
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-nit-
ro-phenyl)-[1,2,4]oxadiazole
[1389]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
5-(3-nitro-phenyl)-[1,2,4]oxadiazole (21.1 mg, 13%, white solid)
was obtained from
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (91 mg, 0.46
mmol), 3-chloromethyl-5-(3-nitro-phenyl)-[1,2,4]oxadiazole (100 mg,
0.42 mmol) and potassium carbonate (173 mg, 1.25 mmol) in
acetonitrile (2 ml) at room temperature. Purification was performed
by SPE (flash) chromatography using 60% ethyl acetate in hexane.
.sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.96 (s, 1H), 8.44 (t,
2H), 7.75 (t, 1H), 7.51 (m, 2H), 7.19 (t, 1H), 4.59 (s, 2H), 3.76
(s, 3H)
Example 73
2-Methyl-4-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmeth-
yl)-[1,2,4]oxadiazol-5-yl]-pyridine
[1390]
2-Methyl-4-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulf-
anylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine (59.2 mg, 66%, white
solid) was obtained from
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (51 mg, 0.26
mmol), 4-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-2-methyl-pyridine
(50 mg, 0.24 mmol), and potassium carbonate (100 mg, 0.72 mmol) in
acetonitrile (1 ml) at room temperature. Purification was performed
by SPE (flash) chromatography using 100% ethyl acetate. .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 8.71 (d, 1H), 7.79 (s, 1H), 7.73 (d,
1H), 7.49 (m, 2H), 7.19 (t, 1H), 4.58 (s, 2H), 3.73 (s, 3H), 2.65
(s, 3H)
Example 74
3-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]tr-
iazol-3-yl]-pyridine
[1391]
3-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[-
1,2,4]triazol-3-yl]-pyridine (30 mg, off-white solid) was obtained
from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol),
potassium carbonate (100 mg, 0.72 mmol),
4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol (46.1 mg, 0.24
mmol) in acetonitrile (2 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 5% methanol in ethyl
acetate. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.90 (bs, 1H),
8.76 (bs, 1H), 8.03 (m, 1H), 7.88 (m, 2H), 7.46 (dd, 1H), 7.40 (m,
2H), 4.58 (s, 2H), 3.66 (s, 3H), 2.42 (s, 3H).
Example 75
3-(4-Methyl-5-thiophene-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tol-
yl-[1,2,4]oxadiazole
[1392]
3-(4-Methyl-5-thiophene-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-
-5-m-tolyl-[1,2,4]oxadiazole (60 mg, white solid) was obtained from
3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol),
potassium carbonate (100 mg, 0.72 mmol),
4-methyl-5-thiophene-3-yl-4H-[1,2,4]triazole-3-thiol (47.3 mg, 0.24
mmol) in acetonitrile (2 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 40% ethyl acetate in
dichloromethane. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.87 (m,
2H), 7.71 (dd, 1H), 7.48 (m, 2H), 7.38 (m, 2H), 4.52 (s, 2H), 3.67
(s, 3H), 2.41 (s, 3H).
Example 76
3-(4-Methyl-5-thiazol-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
-[1,2,4]oxadiazole
[1393]
3-(4-Methyl-5-thiazol-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-
-m-tolyl-[1,2,4]oxadiazole (30 mg, off-white solid) was obtained
from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol),
potassium carbonate (100 mg, 0.72 mmol),
4-methyl-5-thiazol-4-yl-4H-[1,2,4]triazole-3-thiol (47.5 mg, 0.24
mmol) in acetonitrile (2 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 60% ethyl acetate in
dichloromethane. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.89 (d,
1H), 8.22 (d, 1H), 7.88 (m, 2H), 7.38 (m, 2H), 4.55 (s, 2H), 3.94
(s, 3H), 2.41 (s, 3H).
Example 77
5-(3-Iodo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfan-
ylmethyl)-[1,2,4]oxadiazole
[1394]
5-(3-Iodo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3--
ylsulfanylmethyl)-[1,2,4]oxadiazole (725 mg, 97%, white solid) was
obtained from 3-chloromethyl-5-(3-iodo-phenyl)-[1,2,4]oxadiazole
(500 mg, 1.56 mmol), potassium carbonate (647 mg, 4.68 mmol),
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (369 mg, 1.87
mmol) in acetonitrile (10 ml) at room temperature. Purification was
performed by flash column chromatography on silica gel using 40%
ethyl acetate in hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
8.44 (d, 1H), 8.06 (d, 1H), 7.93 (d, 1H), 7.51 (m, 2H), 7.26 (t,
1H), 7.19 (m, 1H), 4.54 (s, 2H), 3.73 (s, 3H).
Example 78
5-(3-Ethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfa-
nylmethyl)-[1,2,4]oxadiazole
[1395]
5-(3-Ethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-
-ylsulfanylmethyl)-[1,2,4]oxadiazole (28.1 mg, 27%, white solid)
was obtained from
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (59 mg, 0.30
mmol), 3-chloromethyl-5-(3-ethyl-phenyl)-[1,2,4]oxadiazole (60 mg,
0.27 mmol) and potassium carbonate (111 mg, 0.80 mmol) in
acetonitrile (1 ml) at room temperature. Purification was performed
by SPE (flash) chromatography using 50% ethyl acetate in hexane.
.sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.90 (t, 2H), 7.51 (m,
2H), 7.42 (t, 2H) 7.18 (m, 1H), 4.52 (s, 2H), 3.72 (s, 3H), 2.70
(m, 2H), 1.26 (t, 3H)
Example 79
2-[5-(2-Methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzo-
imidazole
[1396]
2-[5-(2-Methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]--
1H-benzoimidazole (46.0 mg, 59%, white solid) was obtained from
2-mercaptobenzimidazole (41 mg, 0.27 mmol),
4-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-2-methyl-pyridine (50 mg,
0.24 mmol), and potassium carbonate (100 mg, 0.72 mmol) in DMF (1
ml) at room temperature. Purification was performed by SPE (flash)
chromatography using 100% ethyl acetate and titurated with ether.
.sup.1H NMR (DMSO-d.sub.6), .delta. (ppm): 8.72 (d, 1H), 7.87 (s,
1H), 7.78 (d, 1H), 7.47 (t, 2H), 7.14 (m, 2H), 4.81 (s, 2H), 2.59
(s, 3H)
Example 80
2-[5-(3-Iodo-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazol-
e
[1397]
2-[5-(3-Iodo-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzo-
imidazole (36 mg, 51%, white solid) was obtained from
3-chloromethyl-5-(3-iodo-phenyl)-[1,2,4]oxadiazole (50 mg, 0.16
mmol), potassium carbonate (65 mg, 0.47 mmol),
1H-benzoimidazole-2-thiol (23 mg, 0.16 mmol) in DMF (1 ml) at room
temperature. Purification was performed by SPE (flash)
chromatography using 50-100% ethyl acetate in hexanes followed by
trituration with ethyl acetate. .sup.1H NMR (DMSO), .delta. (ppm):
12.73 (bs, 1H), 8.30 (s, 1H), 8.09 (d, 2H), 7.45 (m, 3H), 7.18 (m,
2H), 4.78 (s, 2H).
Example 81
3-(4-Methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-to-
lyl-[1,2,4]oxadiazole
[1398]
3-(4-Methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl-
)-5-m-tolyl-[1,2,4]oxadiazole (54.3 mg, 80%, clear oil) was
obtained from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (40 mg,
0.19 mmol), potassium carbonate (79 mg, 0.58 mmol),
4-methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol (35.1 mg,
0.19 mmol) in acetonitrile (2 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 50% ethyl acetate in
hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.87 (m, 2H),
7.41 (m, 2H), 4.59 (s, 2H), 3.69 (s, 3H), 2.43 (s, 3H).
Example 82
2,6-Dichloro-4-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-
-4H-[1,2,4]triazol-3-yl]-pyridine
[1399]
2,6-Dichloro-4-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethyls-
ulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine (51.4 mg, 62%, off-white
solid) was obtained from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole
(40 mg, 0.19 mmol), potassium carbonate (79 mg, 0.58 mmol),
5-(2,6-dichloro-pyridin-4-yl)-4-methyl-4H-[1,2,4]triazole-3-thiol
(50.1 mg, 0.19 mmol) in acetonitrile (2 ml) at 60.degree. C.
overnight. Purification was performed on silica gel using 80% ethyl
acetate in hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.87
(m, 2H), 7.61 (s, 2H), 7.40 (m, 2H), 4.60 (s, 2H), 3.71 (s, 3H),
2.42 (s, 3H).
Example 83
3-(4-Methyl-5-p-tolyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2-
,4]oxadiazole
[1400]
3-(4-Methyl-5-p-tolyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-to-
lyl-[1,2,4]oxadiazole (57.8 mg, 81%, off-white solid) was obtained
from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (40 mg, 0.19 mmol),
potassium carbonate (79 mg, 0.58 mmol),
4-methyl-5-p-tolyl-4H-[1,2,4]triazole-3-thiol (39.4 mg, 0.19 mmol)
in acetonitrile (2 ml) at 60.degree. C. overnight. Purification was
performed on silica gel using 80% ethyl acetate in hexanes. .sup.1H
NMR (CDCl.sub.3), .delta. (ppm): 7.88 (m, 2H), 7.53 (d, 2H), 7.39
(m, 2H), 7.30 (d, 2H), 4.55 (s, 2H), 3.59 (s, 3H), 2.42 (d,
6H).
Example 84
Dimethyl-{3-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmet-
hyl)-[1,2,4]oxadiazol-5-yl]phenyl}-amine
[1401]
Dimethyl-{3-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazol-5-yl]phenyl}-amine (28.0 mg, 85%,
white solid) was obtained from
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (18 mg, 0.093
mmol),
3-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-dimethyl-amine (20
mg, 0.084 mmol), and potassium carbonate (35 mg, 0.25 mmol) in
acetonitrile (1 ml) at room temperature. Purification was performed
by SPE (flash) chromatography using 70% ethyl acetate in hexane.
.sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.49 (m, 2H), 7.36 (m,
3H), 7.17 (t, 1H), 6.91 (d, 1H), 4.51 (s, 2H), 3.72 (s, 3H), 3.00
(s, 6H)
Example 85
5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulf-
anylmethyl)-[1,2,4]oxadiazole
[1402]
5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol--
3-ylsulfanylmethyl)-[1,2,4]oxadiazole (76.8 mg, 90%, white solid)
was obtained from
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (47 mg, 0.24
mmol), 3-chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole (50 mg,
0.22 mmol), and potassium carbonate (91 mg, 0.66 mmol) in
acetonitrile (1 ml) at room temperature. Purification was performed
by SPE (flash) chromatography using 70% ethyl acetate in hexane.
.sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.09 (s, 1H), 7.98 (d,
1H), 7.49 (m, 4H), 7.18 (m, 1H), 4.55 (s, 2H), 3.73 (s, 3H)
Example 86
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-tri-
fluoromethoxy-phenyl) [1,2,4]oxadiazole
[1403]
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)--
5-(3-trifluoromethoxy-phenyl)[1,2,4]oxadiazole (144.0 mg, 91%,
white solid) was obtained from
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (78 mg, 0.39
mmol),
3-chloromethyl-5-(3-trifluoromethoxy-phenyl)-[1,2,4]oxadiazole (100
mg, 0.36 mmol) and potassium carbonate (149 mg, 1.08 mmol) in
acetonitrile (2 ml) at room temperature. Purification was performed
by SPE (flash) chromatography using 55% ethyl acetate in hexane.
.sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.04 (d, 1H), 7.95 (s,
1H), 7.51 (m, 4H), 7.18 (m, 1H), 4.56 (s, 2H), 3.74 (s, 3H)
Example 87
3-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[-
1,2,4]oxadiazole
[1404]
3-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-
-tolyl-[1,2,4]oxadiazole (10.5 mg, clear oil) was obtained from
3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol),
potassium carbonate (165 mg, 1.20 mmol),
5-cyclohexyl-4-methyl-4H-[1,2,4]triazole-3-thiol (94.6 mg, 0.48
mmol) in acetonitrile (3 ml) at 60.degree. C. overnight.
Purification was performed on silica gel using 2% ammonia (2 N
methanol) in dichloromethane. .sup.1H NMR (CDCl.sub.3), .delta.
(ppm): 7.88 (m, 2H), 7.39 (m, 2H), 4.42 (s, 2H), 3.46 (s, 3H), 2.60
(m, 1H), 2.42 (d, 3H), 1.74 (m, 7H), 1.34 (m, 3H).
Example 88
3-(5-tert-Butyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[-
1,2,4]oxadiazole
[1405]
3-(5-tert-Butyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-
-tolyl-[1,2,4]oxadiazole (56.8 mg, white solid) was obtained from
3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol),
potassium carbonate (100 mg, 0.72 mmol),
5-tert-butyl-4-methyl-4H-[1,2,4]triazole-3-thiol (41 mg, 0.24 mmol)
in acetonitrile (2 ml) at 60.degree. C. overnight. Purification was
performed on silica gel using 80% ethyl acetate in hexanes. .sup.1H
NMR (CDCl.sub.3), .delta. (ppm): 7.89 (m, 2H), 7.40 (m, 2H), 4.46
(s, 2H), 3.63 (s, 3H), 2.43 (m, 3H), 1.45 (s, 9H).
Example 89
5-(3-Bromo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfa-
nylmethyl)-[1,2,4]oxadiazole
[1406]
5-(3-Bromo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-
-ylsulfanylmethyl)-[1,2,4]oxadiazole (83.4 mg, 86%, white solid)
was obtained from
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (47 mg, 0.24
mmol), 5-(3-bromo-phenyl)-3-chloromethyl-[1,2,4]oxadiazole (60 mg,
0.22 mmol), and potassium carbonate (91 mg, 0.66 mmol) in
acetonitrile (2 ml) at room temperature. Purification was performed
by SPE (flash) chromatography using 60% ethyl acetate in hexane.
.sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.25 (t, 1H), 8.02 (d,
1H), 7.73 (d, 1H), 7.50 (m, 2H), 7.40 (t, 1H), 7.19 (m, 1H), 4.55
(s, 2H), 3.73 (s, 3H)
Example 90
2-[5-(3-Bromo-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazo-
le
[1407]
2-[5-(3-Bromo-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benz-
oimidazole (71.1 mg, 84%, white solid) was obtained from
2-mercaptobenzimidazole (35 mg, 0.23 mmol),
5-(3-Bromo-phenyl)-3-chloromethyl-[1,2,4]oxadiazole (60 mg, 0.22
mmol) and potassium carbonate (91 mg, 0.66 mmol) in DMF (2 ml) at
room temperature. Purification was performed by SPE (flash)
chromatography using 35% ethyl acetate in hexane and titurated with
ether. .sup.1H NMR (DMSO-d.sub.6), .delta. (ppm): 12.78 (broad s,
1H), 8.18 (s, 1H), 8.07 (d, 1H), 7.93 (d, 1H), 7.59 (t, 1H), 7.46
(s, 2H), 7.14 (m, 2H), 4.77 (s, 2H)
Example 91
5-(3-Methoxymethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-
-ylsulfanylmethyl)-[1,2,4]oxadiazole
[1408]
5-(3-Methoxymethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]t-
riazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole (76 mg, 90%, white
solid) was obtained from
3-chloromethyl-5-(3-methoxymethyl-phenyl)-[1,2,4]oxadiazole (50 mg,
0.21 mmol), potassium carbonate (87 mg, 0.63 mmol),
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (50 mg, 0.25
mmol) in acetonitrile (2 ml) at room temperature. Purification was
performed by SPE (flash) chromatography using 40-70% ethyl acetate
in hexanes. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.06 (s, 1H),
8.01 (d, 1H), 7.59 (d, 1H), 7.50 (m, 3H), 7.18 (t, 1H), 4.54 (s,
2H), 4.50 (s, 2H), 3.72 (s, 3H), 3.43 (s, 3H).
Example 92
2-[5-(3-Methoxymethyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benz-
oimidazole
[1409]
2-[5-(3-Methoxymethyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-
-1H-benzoimidazole (62 mg, 84%, white solid) was obtained from
3-chloromethyl-5-(3-methoxymethyl-phenyl)-[1,2,4]oxadiazole (50 mg,
0.21 mmol), potassium carbonate (87 mg, 0.63 mmol),
1H-benzoimidazole-2-thiol (32 mg, 0.21 mmol) in DMF (2 ml) at room
temperature. Purification was performed by SPE (flash)
chromatography using 40-100% ethyl acetate in hexanes. .sup.1H NMR
(DMSO), .delta. (ppm): 8.09 (d, 2H), 7.59 (m, 2H), 7.46 (bs, 2H),
7.14 (m, 2H), 4.77 (s, 2H), 4.51 (s, 2H), 3.35 (s, 3H).
Example 93
4-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,-
4]oxadiazol-5-yl]-pyridine
[1410] A solution of isonicotinoyl chloride (2.0 g, 11.2 mmol) in
dichloromethane was treated with 2-chloro-N-hydroxy-acetamidine
(1.58 g, 14.6 mmol), followed by addition of triethylamine (4.67
ml, 33.6 mmol) in a dropwise manner. After stirring at room
temperature 1 h, extraction with ethyl acetate using water and
brine washes afforded the oxy-acyl intermediate (used without
further purification, 150 mg, 0.7 mmol). A solution of the crude
product in acetonitrile (2 ml) and DMSO (2 ml) with K.sub.2CO.sub.3
(292 mg, 2.1 mmol) and
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (140 mg, 0.7
mmol) was stirred at room temperature for 24 h followed by 1.5 h at
120.degree. C. (sealed tube). Standard aqueous work-up with ethyl
acetate using water and brine washes followed by silica gel
chromatography afforded the title compound (110 mg, 44%). .sup.1H
NMR (CDCl.sub.3), .delta. (ppm): 8.41 dd, 2H), 7.92 dd, 2H), 7.50
dd, 1H), 7.47 dd, 1H), 7.18 dd, 1H), 4.58 (s, 2H), 3.74 (s, 3H);
LC-MS (M+H).sup.+: 357.
[1411] Example 94 was prepared in an analogous method to the
procedure given in Example 93.
Example 94
4-[5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,-
4]oxadiazol-3-yl]-pyridine
[1412]
4-[5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethy-
l)-[1,2,4]oxadiazol-3-yl]-pyridine (12 mg, 5%) was obtained from
N-hydroxy-isonicotinamidine (200 mg, 1.4 mmol) with chloroacetyl
chloride (0.11 ml, 1.4 mmol) and triethylamine (0.5 ml, 3.5 mmol);
aqueous work-up gave intermediate (150 mg, 0.7 mmol); treated with
K.sub.2CO.sub.3 (292 mg, 2.1 mmol), and
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (140 mg, 0.7
mmol). Purification was performed by silica gel chromatography and
recrystallization. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.76
(dd, 2H), 7.89 (dd, 2H), 7.53 (dd, 1H), 7.48 (dd, 1H), 7.18 (dd,
1H), 4.71 (s, 2H), 3.73 (s, 3H); LC-MS (M+H)+: 357.
Example 95
2-{1-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-1-methyl--
1H-imidazo[4,5-b]pyridine and
2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1-methyl-1H--
imidazo[4,5-b]pyridine
[1413] THF (3 ml) was added to a mixture of sodium hydride (60%, 8
mg, 0.2 mmol) and
2-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]1-H-imidazo[4-
,5-b]pyridine (24.6 mg, 0.072 mmol) and the resulting mixture was
stirred at 0.degree. C. for about 15 min. Methyl iodide (20 .mu.L,
0.32 mmol) was added the resulting mixture was stirred at 0.degree.
C. for 2 h. The reaction was quenched by the addition of
dichloromethane (10 ml) and water (2 ml). After vigorous stirring,
the organic extracts (10 ml, plus 3.times.5 ml) were eluted through
a Chem Elut Extraction Column (Varian, cat #1219-8002).
Purification using SPE chromatography (5 g silica) using 25/25/50
to 50/25/25 ethyl acetate/dichloromethane/hexane yielded two
products. The first product to elute was
2-{1-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-1-methyl-
-1H-imidazo[4,5-b]pyridine (6 mg, 23%). .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 8.46 (d, 1H), 7.72 (d, 1H), 7.62 (d, 1H), 7.55 (d,
1H), 7.42 (t, 1H), 7.14 (m, 2H), 5.67 (q, 1H), 3.88 (s, 3H), 3.71
(s, 3H), 2.01 (d, 3H).
[1414] The second product to elute was
2-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1-methyl-1H--
imidazo[4,5-b]pyridine (12 mg, 47%). .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 8.44 (d, 1H), 7.69 (d, 1H), 7.60 (d, 1H), 7.55 (d,
1H), 7.41 (t, 1H), 7.13 (m, 1H), 4.90 (s, 2H), 3.87 (s, 3H), 3.70
(s, 3H).
[1415] Example 96-97 was prepared in an analogous method to the
procedure given in Example 95.
Example 96
3-[1-Methyl-1-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-et-
hyl]-5-m-tolyl-[1,2,4]oxadiazole
[1416]
3-[1-Methyl-1-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulf-
anyl)-ethyl]-5-m-tolyl-[1,2,4]oxadiazole (13 mg, 47%) was obtained
from
3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tol-
yl-[1,2,4]oxadiazole (25.5 mg, 0.069 mmol) with 60% sodium hydride
(37 mg, 0.92 mmol) and methyl iodide (0.10 ml, 1.6 mmol) in THF (3
ml) at room temperature for 2 h. The product was extracted with
ethyl acetate and purified by SPE 20-40% ethyl acetate in 1:1
dichloromethane:hexane. .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
7.83 (br s, 2H), 7.48 (d, 1H), 7.42 (d, 1H), 7.36 (m, 2H), 7.13 (m,
1H), 3.50 (s, 3H), 2.35 (s, 3H), 1.95 (s, 6H).
Example 97
3-[1-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m--
tolyl-[1,2,4]oxadiazole
[1417]
3-[1-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-eth-
yl]-5-m-tolyl-[1,2,4]oxadiazole (6.1 mg, 17%) was obtained from
3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tol-
yl-[1,2,4]oxadiazole (33.8 mg, 0.091 mmol) with 60% sodium hydride
(17 mg, 0.42 mmol) and methyl iodide (20 .mu.L, 0.32 mmol) in THF
(2.5 ml) at room temperature for 1 h. The product was extracted
with dichloromethane and purified by SPE 25-40% ethyl acetate in
1:1 chloroform:hexane. .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
7.89 (br s, 2H), 7.50 (d, 1H), 7.46 (d, 1H), 7.38 (m, 2H), 7.16 (m,
1H), 4.89 (q, 1H), 3.64 (s, 3H), 2.37 (s, 3H), 1.90 (d, 3H).
Example 98
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulfonylmethyl)-5-m-tolyl-
-[1,2,4]oxadiazole and
3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulfinylmethyl)-5-m-toly-
l-[1,2,4]oxadiazole
[1418] Dichloromethane (2.5 ml) was added to a mixture of
3-chloro-benzenecarboperoxoic acid (57-85%, 49.5 mg, 0.16-0.25
mmol) and
3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tol-
yl-[1,2,4]oxadiazole (45 mg, 0.12 mmol) and the resulting mixture
was stirred at room temperature overnight. The reaction was
quenched by the addition of dichloromethane (10 ml) and 1 M sodium
hydroxide (3 ml). After vigorous stirring, the organic extracts (10
ml, plus 3.times.5 ml) were eluted through a Chem Elut Extraction
Column (Varian, cat #1219-8002). Purification was performed by SPE
chromatography (5 g silica) using 10-30% ethyl acetate in 1:1
dichloromethane:hexane yielded two products. The first product to
elute was
3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulfonylmethyl)-5-m-toly-
l-[1,2,4]oxadiazole (12.3 mg, 25%). .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 7.83 (br s, 2H), 7.63 (d, 1H), 7.56 (d, 1H), 7.36
(m, 2H), 7.24 (m, 1H), 5.12 (s, 2H), 3.94 (s, 3H), 2.36 (d,
3H).
[1419] The second product to elute was
3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulfinylmethyl)-5-m-toly-
l-[1,2,4]oxadiazole (33.2 mg, 71%). .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 7.87 (br s, 2H), 7.59 (d, 1H), 7.54 (d, 1H), 7.38
(m, 2H), 7.22 (m, 1H), 5.05 (d.sub.AB, 1H), 4.90 (d.sub.AB, 1H),
4.03 (s, 3H), 2.39 (d, 3H).
Example 99
5-(3-Furan-3-yl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl-
sulfanylmethyl)-[1,2,4]oxadiazole
[1420] To
5-(3-Iodo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-
-3-ylsulfanylmethyl)-[1,2,4]oxadiazole (50 mg, 0.10 mmol) in a vial
was added 3-furan boronic acid (17 mg, 0.16 mmol),
tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.0052 mmol),
ethylene glycol dimethyl ether (1 ml) and 2 M sodium carbonate (1
ml). The vial was then sealed and heated at 90.degree. C. for 1 h
with vigorous stirring. The reaction was cooled, diluted with ethyl
acetate, washed with water and saturated brine, filtered and
concentrated. The residue was purified by flash column
chromatography using 70% ethyl acetate in hexanes. Additional
purification by trituration with a mixture of diethyl ether and
hexanes and then filtration afforded the title compound as a beige
solid 25 mg (57%). .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.18
(s, 1H), 7.98 (d, 1H), 7.79 (s, 1H), 7.71 (d, 1H), 7.51 (m, 4H),
7.17 (m, 1H), 6.74 (s, 1H), 4.55 (s, 2H), 3.73 (s, 3H).
[1421] Intermediates
Example 100
Pyrimidine-4-carboxylic acid
[1422] 3-Methyl-pyrimidine (9.41 g, 100 mmol), potassium
permanganate (26.9 g) and sodium carbonate (10.6 g) was refluxed in
water (100 ml) for 72 h followed by filtration through celite. The
filtrate was washed with several portions of DCM and EtOAc before
acidification with conc. HCl. The formed precipitate was collected
and washed with water to yield 1.37 g of the title compound as a
white solid. 1H NMR (DMSO-d6) d (ppm): 13.94 (br. s, 1H), 9.37 (d,
1H), 9.07 (d, 1H), 8.01 (dd, 1H).
Example 101
5-Chloro-thiophene-3-carboxylic acid
[1423] Thiophene-3-carboxylic acid (17.51 g, 136.6 mmol) and
1-chloro-pyrrolidine-2,5-dione (23.7 g) was refluxed in acetic acid
(200 ml) for 4 h under argon before pouring onto water (700 ml).
Repeated extraction with several small portions of DCM, followed by
back extraction from the combined organics with several small
portions of 2 M aqueous sodium hydroxide, gave a combined alkaline
aqueous solution that was washed with DCM before acidified with
conc. HCl to precipitate the crude material. This precipitate was
recrystallized from water to yield 14.98 g of the title compound as
a grey solid contaminated with approximately 20 mol % of a
dichlorinated byproduct as judged from MS and 1H-NMR. 1H NMR
(DMSO-d6) d (ppm): 8.15 (d, 1H), 7.37 (d, 1H).
Example 102
3-Methylsulfanyl-benzoic acid
[1424] Methyl iodide (0.972 mL) was added to a mixture of
3-mercapto-benzoic acid (601 mg, 3.9 mmol) and potassium carbonate
(2.7 g, 19.5 mmol) in DMF (8 mL) in an ice-bath. After the reaction
was warmed to room temperature and stirred for 1 hour, the reaction
mixture was diluted with ethyl acetate, washed with water
(3.times.), dried over anhydrous sodium sulfate, filtered, and
concentrated to afford 3-methylsulfanyl-benzoic acid methyl ester
(684 mg, 96%, yellow oil). .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
7.90 (s, 1H), 7.80 (d, 1H), 7.44 (d, 1H), 7.35 (t, 1H), 3.92 (s,
3H), 2.53 (s, 3H).
[1425] 3-Methylsulfanyl-benzoic acid methyl ester (684 mg, 3.8
mmol) and 1N NaOH (5.6 mL, 5.6 mmol) in methanol (8 mL) and THF (8
mL) were heated at 70.degree. C. for 1 hour. The reaction mixture
was concentrated and then the residue was diluted with water. After
acidification with 1N HCl to pH.about.2, the aqueous layer was
extracted with ethyl acetate and then washed with water and
saturated brine, dried over anhydrous sodium sulfate, filtered, and
concentrated to afford 3-methylsulfanyl-benzoic acid (616 mg, 97%,
white solid). .sup.1H NMR (DMSO), .delta. (ppm): 13.1 (bs, 1H),
7.76 (s, 1H), 7.70 (d, 1H), 7.51 (d, 1H), 7.44 (t, 1H), 2.52 (s,
3H).
Example 103
3-Cyclopropyl-benzoic acid
[1426] 1.0 M Diethyl zinc in hexanes (27.3 ml, 27.3 mmol) was added
to a solution of 2,4,6-trichlorophenol (5.4 g, 27.3 mmol) in
dichloromethane (100 ml) at -40.degree. C. After stirring for 15
minutes, diiodo-methane (2.2 mL, 27.3 mmol) was added at
-40.degree. C. and stirred for an additional 15 minutes.
1-Bromo-3-vinyl-benzene (2.5 g, 13.7 mmol) was then added to the
reaction mixture, allowed to warm to room temperature, and left
stirring overnight. The reaction mixture was diluted with
dichloromethane, washed with 1N HCl (2.times.), saturated sodium
bicarbonate (2.times.), saturated sodium sulfite, 1N sodium
hydroxide, and saturated brine, dried over magnesium sulfate,
filtered and concentrated. GC-MS revealed that the reaction mixture
contained 1-Bromo-3-cyclopropyl-benzene and
1-bromo-3-vinyl-benzene.
[1427] To remove the bromo-3-vinyl-benzene, the crude mixture was
reacted with potassium permanganate. A solution of potassium
permanganate/water (1.5 g/20 mL) was added drop-wise to a solution
of the crude mixture (-3.5 g) in THF (40 mL) at 0.degree. C. and
then allowed to warm to room temperature. After 1 hour, the
reaction was diluted with diethyl ether, washed with water and
saturated brine, dried over anhydrous sodium sulfate filtered and
concentrated. Purification by flash column chromatography eluted
with 100 hexanes afforded 1-bromo-3-cyclopropyl-benzene (2.20 g,
81%).
[1428] 1.6 M n-Butyllithium in hexanes (3.2 mL, 5.1 mmol) was added
drop-wise to a solution of 1-bromo-3-cyclopropyl-benzene at
-78.degree. C. and stirred for 1 hour. This reaction mixture was
then transferred via canula to a 250 mL round bottom flask equipped
with a stirrer bar approximately 1/4 full of solid carbon dioxide
and stirred and for 1 hour. The reaction mixture was concentrated
and then the residue was diluted with water. The aqueous layer was
washed with dichloromethane (3.times.), acidified with 1 N HCl to
pH.about.2, and extracted with ethyl acetate. The organic phase was
washed with water and saturated brine, dried over anhydrous sodium
sulfate, filtered and concentrated to afford 3-cyclopropyl-benzoic
(356 mg, 43%, white solid). .sup.1H NMR (DMSO), .delta. (ppm):
12.90 (bs, 1H), 7.71 (d, 1H), 7.64 (s, 1H), 7.34 (m, 2H), 2.01 (m,
1H), 0.99 (m, 2H), 0.70 (m, 2H).
Example 104
3-tert-Butoxycarbonylamino-benzoic acid
[1429] To a flask containing ethyl-3-aminobenzoate (1 g, 6.05 mmol)
added di-tert-butyl dicarbonate (3.16 g, 14.5 mmol), triethyl amine
(500 mg, 4.94 mmol), and THF (10 mL) and allowed to stir at
60.degree. C. for two hours and then overnight at room temperature.
The THF was removed in vacuo, and the crude ester was partitioned
between ethyl acetate and water, washed with saturated brine, dried
over anhydrous sodium sulfate and the solvent was removed in vacuo.
The product was then purified by flash column chromatography using
15% ethyl acetate in hexane affording 2 g of
3-tert-butoxycarbonylamino-benzoic aid ethyl ester (white
slurry).
[1430] To the crude 3-tert-butoxycarbonylamino-benzoic acid ethyl
ester (.about.2.0 g, 0.00754 mmol) added THF (15 mL), and 0.5M LiOH
(15 mL). The mixture was heated for two hours at 75.degree. C. and
the THF was removed in vacuo after cooling. The precipitate was
filtered from the remaining mixture and the filtrate was
transferred to a separatory funnel. The aqueous layer was washed
with dichloromethane (3.times.) and was acidified to pH.about.5
using 1M HCl. The product was then extracted with ethyl acetate,
washed with water, saturated brine, dried over anhydrous sodium
sulfate, filtered and concentrated. 730 mg of
3-tert-Butoxycarbonylamino-benzoic acid (white solid) was isolated.
1H NMR (DMSO-d.sub.6) .delta. (ppm): 9.58 (s, 1H), 8.16 (s, 1H),
7.63 (d, 1H), 7.54 (d, 1H), 7.37 (t, 1H), 1.49 (s, 9H)
Example 105
3-Acetyl-benzoic acid
[1431] 6M Sodium hydroxide (25 mL) was added to
3-acetylbenzonitrile (850 mg, 5.82 mmol) in methanol (25 mL) and
then heated at 90.degree. C. overnight. After concentrating the
reaction mixture, the aqueous layer was washed with dichloromethane
(2.times.), then acidified pH.about.3 with 12M HCl. The precipitate
was extracted with ethyl acetate then washed with water and
saturated brine, dried over anhydrous sodium sulfate filtered and
concentrated to afford 3-ethylbenzoic acid as a colorless oil;
0.800 g (92%). 1H NMR (CDCl.sub.3) .delta. (ppm): 8.70 (s, 2H),
8.33 (d, 2H), 8.24 (d, 2H), 7.64 (t, 1H), 2.70 (s, 3H).
Example 106
2-Methyl-isonicotinic acid hydrazide
[1432] Dichloromethane (10 mL) was added to 2-methyl nicotinic acid
hydrochloride salt (1.1 g, 6.34 mmol) and oxalyl chloride (6.95 mL,
13.9 mmol) was added slowly under Argon while the flask was cooled
in ice. Dimethylformamide (2 drops) was added and the reaction was
allowed to stir overnight during which time it warmed to room
temperature. The reaction was concentrated and THF (10 mL) was
added to the flask and it was placed in an ice bath. Methanol (5
mL) was added and the reaction was allowed to stir for one hour.
The reaction was concentrated and the residue was partitioned
between NaHCO.sub.3 (sat) and EtOAc. The product was extracted with
EtOAc three times. The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated.
Purification was performed by solid phase extraction tube (20%
EtOAc/hexanes) gave the title compound as a clear oil. .sup.1H NMR
CDCl.sub.3 (ppm): 8.51 (d, 1H), 7.57 (d, 1H), 7.51 (d, 1H), 3.82
(s, 3H), 2.50 (s, 3H).
[1433] 2-Methyl-isonicotinic acid methyl ester (316.5 mg, 2.093
mmol) was dissolved in MeOH (7 mL) under Argon and hydrazine
monohydrate 98% (1 mL, 20.93 mmol) was added. The reaction was
allowed to stir under Argon at room temperature for eighteen hours.
The reaction was concentrated to give the title compound (271.9 mg,
86%) as a white solid. .sup.1H NMR CDCl.sub.3 (ppm): 8.59 (d, 1H),
7.50 (s, 1H), 7.38 (d, 1H), 3.09 (br. s, 3H), 2.60 (s, 3H).
Example 107
5-Chloro-2-fluoro-benzoic acid hydrazide
[1434] Step 1: 5-Chloro-2-fluoro-benzoic acid methyl ester:
Methanol (20 ml) was added to a solution 5-chloro-2-fluoro-benzoyl
chloride (1.2 g, 6.2 mmol) in dichloromethane (10 ml) in an
ice-bath. The reaction mixture was warmed to room temperature,
stirred for 3 h and then concentrated to afford
5-chloro-2-fluoro-benzoic acid methyl ester (0.17 g, 100%). 1H NMR
(CDCl.sub.3), .delta. (ppm): 7.93 (m, 1H), 7.48 (m, 1H), 7.12 (m,
1H), 3.96 (s, 3H). Step 2: 5-Chloro-2-fluoro-benzoic acid
hydrazide: A mixture of 5-chloro-2-fluoro-benzoic acid methyl ester
(0.17 g, 6.2 mmol) and hydrazine monohydrate (0.451 ml, 9.3 mmol)
in ethanol (20 ml) was stirred at room temperature overnight. The
reaction mixture was concentrated and then the residue was
triturated with diethyl ether to afford 5-chloro-2-fluoro-benzoic
acid hydrazide (497 mg, 42%, white solid). 1H NMR (DMSO), .delta.
(ppm): 9.66 (bs, 1H), 7.58 (m, 2H), 7.36 (m, 1H), 4.58 (bs,
2H).
[1435] Example 108 was prepared analogously to example 107.
Example 108
3-Cyano-benzoic acid hydrazide
[1436] 3-cyano-benzoyl chloride (3 g, 18.12 mmol) in dichlormethane
(5 mL) and methanol (20 mL) was stirred at room temperature and
overnight. The solvent was removed using a rotevaporator to afford
a white solid (3.76 g). .sup.1H NMR (DMSO) .quadrature. (ppm): 8.33
(m, 1H), 8.24 (m, 1H), 8.14 (m, 1H), 7.76 (m, 1H), 3.89 (d,
3H).
[1437] A mixture of 3-cyano-benzoic acid methyl ester (2 g, 12
mmol) and hydrazine monohydrate (0.60 mL, 12 mmol) in ethanol (10
mL) was stirred at room temperature overnight. The reaction mixture
was concentrated and then the residue was triturated with diethyl
ether to afford 3-cyano-benzoic acid hydrazide (1.02 g, 51%, pink
solid). .sup.1H NMR (DMSO) (ppm): 10.31 (s, 1H), 8.21 (m, 1H), 8.11
(m, 1H), 7.99 (m, 1H), 7.70 (m, 1H), 4.50 (s, 1H).
Example 109
2-Chloro-isonicotinic acid hydrazide
[1438] HOBt (823 mg, 6.09 mmol), and EDCI (1.2 g, 6.09 mmol) were
added to a suspension of 2-chloro-isonicotinic acid (800 mg, 5.08
mmol) in acetonitrile (10.3 ml) at room temperature. After two h a
solution of hydrazine monohydrate (0.493 ml, 10.2 mmol) in
acetonitrile (5.0 ml) was added drop-wise at 0.degree. C. After 30
min, the solvent was removed using a roto-evaporator and the
residue was diluted with ethyl acetate, quenched with water, dried
over sodium sulfate, filtered and concentrated to afford
2-chloro-isonicotinic acid hydrazide (493 mg, 57%, yellow solid).
1H NMR (DMSO) d (ppm): 10.21 (bs, 1H), 8.55 (d, 1H), 7.82 (s, 1H),
7.75 (d, 1H), 4.69 (bs, 2H).
[1439] The following compounds were prepared analogously to example
109: TABLE-US-00001 Example No. 1) Name 110
2-Fluoro-5-methyl-benzoic acid hydrazide 111
Pyrimidine-4-carboxylic acid hydrazide
[1440] The following compounds were prepared analogously to Example
6: TABLE-US-00002 Example No. Name 112
3-Fluoro-N-hydroxy-benzamidine 113
N-Hydroxy-thiophene-3-carboxamidine 114
2-Chloro-N-hydroxy-propionamidine 115 3,N-Dihydroxy-benzamidine 116
N-Hydroxy-2-methyl-benzamidine 117
N-Hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-
3-ylsulfanyl)-acetamidine 118 3-Chloro-N-hydroxy-benzamidine 119
N-Hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-
3-ylsulfanyl)-acetamidine 120
2,5-Difluoro-N-hydroxy-benzamidine
[1441] The following compounds were prepared analogously to Example
31: TABLE-US-00003 Example No. Name 121
4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol 122
4-Butyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol 123
4-(3-Methoxy-propyl)-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol 124
4-Benzyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol 125
4-Furan-2-ylmethyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol 126
5-Thiophen-2-yl-4-thiophen-2-ylmethyl-4H-[1,2,4]triazole-3-thiol
127 4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol 128
4-Furan-2-ylmethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol 129
4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol 130
4-Ethyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol 131
4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol 132
4-Furan-2-ylmethyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol 133
4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazole-3-thiol 134
4-Ethyl-5-(3-fluoro-phenyl)-4H-[1,2,4]triazole-3-thiol 135
4-Ethyl-5-(4-fluoro-phenyl)-4H-[1,2,4]triazole-3-thiol 136
5-(2-Fluoro-5-methyl-phenyl)-4-furan-2-ylmethyl-4H-[1,2,4]triazole-3-t-
hiol 137
4-Ethyl-5-(3-methyl-thiophen-2-yl)-4H-[1,2,4]triazole-3-thiol 138
4-Ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1,2,4]triazole-3-thiol 139
5-(2-Chloro-6-methyl-pyridin-4-yl)-4-ethyl-4H-[1,2,4]triazole-3-thiol
140 5-(5-Bromo-furan-2-yl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 141
4-Ethyl-5-(3-methoxy-thiophen-2-yl)-4H-[1,2,4]triazole-3-thiol 142
4-Ethyl-5-(tetrahydro-furan-2-yl)-2,4-dihydro-[1,2,4]triazole-3-thione
143 4-Ethyl-5-thioxo-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylic
acid methyl ester
[1442] The following compounds were prepared analogously to Example
36: TABLE-US-00004 Exam- ple No. Name 144
5-(2-Chloro-pyridin-4-yl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 145
5-(2-Chloro-6-methoxy-pyridin-4-yl)-4-ethyl-4H-
[1,2,4]triazole-3-thiol 146
4-Ethyl-5-(3-methyl-3H-imidazol-4-yl)-4H-[1,2,4]triazole-3-thiol
147 4-Propyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol 148
4-Ethyl-5-(1-methyl-1H-imidazol-2-yl)-4H-[1,2,4]triazole-3-thiol
149
4-Ethyl-5-(1-methyl-1H-imidazol-4-yl)-4H-[1,2,4]triazole-3-thiol
150 3-(5-Mercapto-4-methyl-4H-[1,2,4]triazol-3-yl)-benzonitrile 151
5-(3-Chloro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol 152
5-(4-Chloro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol 153
5-(2-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol 154
5-(3-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol 155
5-(4-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol 156
5-Benzo[b]thiophen-2-yl-4-methyl-4H-[1,2,4]triazole-3-thiol 157
5-(3-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol 158
5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol 159
4-Ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazole-3-thiol 160
5-(3,5-Difluoro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 161
5-(2,6-Difluoro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 162
5-(4-Butoxy-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 163
5-Benzo[1,3]dioxol-5-yl-4-ethyl-4H-[1,2,4]triazole-3-thiol 164
4-Ethyl-5-pyrimidin-5-yl-2,4-dihydro-[1,2,4]triazole-3-thione 165
4-Ethyl-5-furan-3-yl-2,4-dihydro-[1,2,4]triazole-3-thione 166
4-(Tetrahydrofuran-2-ylmethyl)-5-thiophene-2-yl-2,4-dihydro-
[1,2,4]triazole-3-thione 167
5-Cyclopentyl-4-ethyl-2,4-dihydro-[1,2,4]triazole-3-thione 168
4-Ethyl-5-[2-(4-methoxy-phenyl)-ethyl]-2,4-dihydro-
[1,2,4]triazole-3-thione
Example 169
5-(3,5-Dichloro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol
[1443] 3,5-Dichloro-benzoic acid (382 mg, 2 mmol) was mixed with
triethylamine (606 mg, 3 mmol) in THF (6 ml) at 10.degree. C. Then
isobutyl chloroformate (300 mg, 2.2 mmol) was added dropwise and
stirred for 45 min. To the reaction mixture,
4-methyl-3-thiosemicarbazide (238.4 mg, 2 mmol) was added. After
being stirred at room temperature for 10 min, the reaction mixture
was heated to 70.degree. C. overnight. Standard work-up. The
product was purified by column chromatography with 25.about.30%
ethyl acetate in hexanes to give 46.4 mg (8.5%) of
5-(3,5-dichloro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol.
[1444] The following compounds were prepared analogously to Example
169: TABLE-US-00005 Example No. Name 170
5-(3-Methylphenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 171
5-(4-Methylphenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 172
4-Ethyl-5-(3-nitrophenyl)-4H-[1,2,4]triazole-3-thiol 173
5-(2,5-Difluorophenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 174
5-(3-Chlorophenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 175
5-(4-Chlorophenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol
Example 176
4-Ethyl-5-methoxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione
[1445] Step 1: N-Ethyl-2-(methoxyacetyl)hydrazinecarbothioamide:
Methoxyacetic acid (360 mg, 3.99 mmol), 4-ethyl-3-thiosemicarbazide
(581 mg, 4.87 mmol), diisopropylcarbodiimide (615 mg, 4.87 mmol)
and hydroxybenzotriazole (69.6 mg, 0.51 mmol) were mixed in
dimethylformamide (10 ml) and stirred under argon at ambient
temperatures for 19 h. After evaporation to dryness the crude was
used directly in the next step. MS (ESI) m/z 192 (M+1). Step 2:
4-Ethyl-5-methoxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione:
N-Ethyl-2-(methoxyacetyl)hydrazinecarbothioamide (760 mg crude, 4
mmol) and sodium bicarbonate (560 mg, 6.6 mmol) were suspended in
water (15 ml) and refluxed for 5 h. After cooling and filtration
the filtrate was acidified with concentrated hydrochloric acid,
followed by extraction with ethyl acetate. After evaporation to
dryness the crude was recrystallized in ethyl acetate/heptane.
Filtration and recrystallization of the mother liquor gave a
combined yield of 325 mg (47%) of the title compound. 1H NMR
(CDCl.sub.3), .delta. (ppm): 4.47 (s, 2H), 4.13 (q, 2H), 3.37 (s,
3H), 1.38 (t, 3H).
[1446] The following compounds were prepared analogously to Example
176: TABLE-US-00006 Example No. Name 177
4-Methyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione 178
4-Allyl-5-furan-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione 179
4-Ethyl-5-(4-methoxy-phenoxymethyl)-2,4-dihydro-[1,2,4]triazole-3-thio-
ne 180 4-Ethyl-5-phenoxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione
181 4-Ethyl-5-hydroxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione
182
4-Ethyl-5-(2-methoxy-ethyl)-2,4-dihydro-[1,2,4]triazole-3-thione
183
4-Ethyl-5-methylsulfanylmethyl-2,4-dihydro-[1,2,4]triazole-3-thione
184 5-Ethoxymethyl-4-ethyl-2,4-dihydro-[1,2,4]triazole-3-thione 185
5-Furan-3-yl-4-methyl-2,4-dihydro-[1,2,4]triazole-3-thione 186
4-Methyl-5-pyrimidin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione 187
4-Ethyl-5-pyridazin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione 188
4-Ethyl-5-pyridin-4-ylmethyl-2,4-dihydro-[1,2,4]triazole-3-thione
189
4-Ethyl-5-(6-hydroxy-pyridin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thion-
e 190
4-Ethyl-5-(4-hydroxy-phenyl)-2,4-dihydro-[1,2,4]triazole-3-thione
191 4-Ethyl-5-p-tolyloxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione
192
4-Ethyl-5-(6-methoxy-pyridin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thion-
e 193
4-Ethyl-5-(2-methoxy-pyridin-4-yl)-2,4-dihydro-[1,2,4]triazole-3-thion-
e 194 4-Ethyl-5-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione
195
4-Ethyl-5-(5-methoxy-pyrimidin-2-yl)-2,4-dihydro-[1,2,4]triazole-3-thi-
one
Example 196
4-Furan-2-ylmethyl-4H-[1,2,4]triazole-3-thiol
[1447] A solution of formic acid hydrazide (439 mg, 7.809 mmol) in
pyridine (20 ml) was added to a solution of
2-isothiocyanatomethyl-furan (1 g, 7.185 mmol) in pyridine (20 ml).
Reaction took place at room temperature overnight, and ethanol (20
ml) was added directly to the reaction and placed in 80 C bath
overnight. Solvent was evaporated and the title compound (1.09 g,
83%) was obtained from purification by SPE chromatography on silica
gel with 500 ml 20%, 250 ml 25%, 250 ml 30%, 250 ml 35%, 250 ml
40%, and 250 ml 50% ethyl acetate in hexanes. 1H NMR (CD3OD),
.delta.(ppm): 14.0 (bs, 1H), 8.19 (s, 1H), 7.52 (q, 1H), 6.52 (m,
1H), 6.42 (m, 1H), 4.90 (s, 2H).
[1448] The following compounds were prepared analogously to Example
196: TABLE-US-00007 Example No. Name 197
4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol 198
4-Cyclopropylmethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol
Example 199
4-Cyclopropyl-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione
[1449] To a slurry of thiophene-2-carboxylic acid hydrazide (866
mg, 6.09 mmol) in iPrOH (25 ml) was added
isothiocyanato-cyclopropane (602 mg, 6.08 mmol). The mixture was
stirred at 70.degree. C. for 72 h and then cooled to room
temperature. The white precipitate was filtered off and suspended
in a MeOH:H.sub.2O (9:1, 40 ml) together with aq. NaOH (2%, 5 ml).
The reaction mixture was stirred at 70.degree. C. overnight and
then cooled to room temperature. The pH was adjusted to around 4
with aq. HCl (1N). The formed white precipitate was filtered off,
washed with water and dried under vacuum (829 mg, 61%). 1H NMR
(CD3OD), .delta. (ppm): 7.67 (dd, 1H), 7.63 (dd, 1H), 7.17 (dd,
1H), 3.15 (m, 1H), 1.14 (m, 2H), 0.86 (m, 2H).
[1450] The following compounds were prepared analogously to Example
199: TABLE-US-00008 Example No. Name 200
5-Furan-2-yl-4-(2-methoxy-ethyl)-2,4-dihydro-[1,2,4]triazole-3-thione
201 4-Cyclopropyl-5-furan-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione
202
(3-Thiophen-2-yl-5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-acetic
acid methyl ester 203
4-Cyclopropylmethyl-5-thiophene-2-yl-2,4-dihydro-[1,2,4]triazole-3-thi-
one 204
4-(2-Methoxy-ethyl)-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thio-
ne 205
Thiophen-2-yl-4-(2,2,2-trifluoroethyl)-2,4-dihydro-[1,2,4]triazole-3-t-
hione 206
4-Cyclopropyl-5-pyrimidin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione
207
4-Cyclopropyl-5-pyridin-3-yl-2,4-dihydro-[1,2,4]triazole-3-thione
Example 208
4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol
[1451] To a solution of 4-ethyl-3-thiosemicarbazide (2.38 g, 20
mmol) and triethylamine (6.06 g, 60 mmol) in THF (30 ml),
trifluoroacetic anhydride (5.04 g, 24 mmol) was added. The reaction
mixture was stirred at room temperature for an h and heated at
60.degree. C. overnight. Standard work-up, the product was
triturated with hexanes to give 564 g of as
4-ethyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol pale-brown
solid. 1H-NMR (CDCl.sub.3) d (ppm): 12.64 (w, 1H), 4.22 (q, 2H) and
1.44 (t, 3H).
Example 209
4-Ethyl-3-methanesulfonyl-5-thiophen-2-yl-4H-[1,2,4]triazole
[1452] The title compound was synthesized according to the method
described in .ANG.kerblom et al. J. Med. Chem. 16, 312 (1973).
4-Ethyl-3-methylsulfanyl-5-thiophen-2-yl-4H-[1,2,4]triazole (1.14
g, 5.06 mmol) was dissolved in glacial acetic acid (20 ml) followed
by the addition of 30% hydrogen peroxide (5 ml). After stirring at
ambient temperatures for 16 h additional 30% hydrogen peroxide (5
ml) was added. The mixture was stirred for 3 h at ambient
temperature, then heated to 100.degree. C. for 2.5 h. After cooling
in an ice/water bath the reaction was neutralized with sodium
hydroxide and extracted twice with dichloromethane. The organic
layers were combined, evaporated to dryness and dried in vacuo
yielding the title compound (0.78 g, 60%). 1H NMR (CDCl.sub.3),
.delta. (ppm): 7.60 (d, 1H), 7.56 (d, 1H), 7.22 (m, 1H), 4.51 (q,
2H), 3.58 (s, 3H), 1.55 (t, 3H).
[1453] The following compound was prepared analogously to Example
209: TABLE-US-00009 Exam- ple No. Name 210
4-(5-Methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine
Example 211
4-(2-Hydroxy-ethyl)-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione
[1454] To a slurry of LAH (38.1 mg, 1.00 mmol) in anhydrous THF (8
ml) was drop wise added
(3-thiophen-2-yl-5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-acetic
acid (101 mg, 0.42 mmol) in anhydrous THF (4 ml). The mixture was
reacted for 2 h and then quenched with saturated aq.
Na.sub.2SO.sub.4 (10 ml). THF was removed under reduced pressure
and the residue was made acidic with aq. HCl (3N) and partitioned
between EtOAc and water. The aqueous layer was extracted with EtOAc
(3.times.20 ml). The combined organic layers were washed with brine
(15 ml), dried (MgSO.sub.4) and concentrated under reduced
pressure. The crude product was used without purification in the
next step. 1H NMR (DMSO-d6), .delta. (ppm): 13.94 (s, 1H), 7.86 (d,
1H); 7.81 (d, 1H), 7.24 (dd, 1H), 5.09 (t, 1H), 4.16 (t, 2H), 3.76
(app. q, 2H).
Example 212
4-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-pyridine
[1455] 860 .mu.l (10 mmol) oxalyl chloride was slowly added to a
solution of 731 mg (10 mmol) N-methyl-acetamide and 2.33 ml (20
mmol) 2,6-lutidine in 20 ml CH.sub.2Cl.sub.2 at 0.degree. C. After
15 min 1.37 g (10 mmol) isonicotinic acid hydrazide was added in
one portion. The resulting mixture was stirred at room temperature
for 1 h and the neutralized with NaHCO.sub.3(sat). The phases were
separated and the water phase was extracted with CH.sub.2Cl.sub.2.
The combined organic phases were dried and concentrated. The
residue was dissolve in 20 ml acetic acid and heated at 120.degree.
C. for 2 h. After cooling the solvent was removed.
Flashchromatography (CH2Cl2/MeOH 10:1) afforded 765 mg (44%) of a
grey/white solid. 1H NMR (CDCl.sub.3), d (ppm): 2.52 (s, 3H) 3.66
(s, 3H) 7.58 (d, 2H) 8.76 (d, 2H).
Example 213
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine
[1456] A mixture of 1000 mg (4.35 mmol)
N-amino-N',N''-dimethyl-guanidine hydriodide (Henry; Smith; J.
Amer. Chem. Soc.; 73; 1951; 1858) and 774 mg (4.35 mmol)
isonicotinoyl chloride hydrochloride in 3 ml of pyridine was heated
with microwaves for 5 min at 160.degree. C. K.sub.2CO.sub.3(sat)
was added and the mixture was extracted 4 times with CHCl.sub.3.
The organic phase was dried and concentrated. Recrystallization
from ethanol, water and EtOAc gave 216 mg (26%) of a yellow white
solid. 1H NMR (DMSO), d (ppm): 2.85 (d, 3H) 3.45 (s, 3H) 6.25 (d,
1H) 7.65 (m, 2H) 8.67 (m, 2H).
Example 214
3-Pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
[1457] A solution of 750 mg (3.1 mmol)
(1,4,5,6-tetrahydro-pyrimidin-2-yl)-hydrazine hydroiodide (ref.
Krezel, Izabella; Pharmazie; EN; 49; 1; 1994; 27-31) and 552 mg
(3.1 mmol) isonicotinoyl chloride hydrochloride in 3 ml pyridine
was heated at 120.degree. C. over night. The reaction mixture was
cooled and diluted with K.sub.2CO.sub.3(sat) and extracted with
3.times.10 ml chloroform. The combined organic extracts were dried
and concentrated. Flashchromatography (CH.sub.2Cl.sub.2/MeOH 10:1)
afforded 83 mg (18%) of a white solid. 1H NMR (CDCl.sub.3), d
(ppm): 1.91 (m, 2H) 3.24 (m, 2H) 4.13 (m, 2H) 7.67 (m, 2H) 8.65 (m,
2H).
[1458] The following compound was prepared analogously to Example
214: TABLE-US-00010 Example No. Name 215
3-Furan-2-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-
a]pyrimidine
Example 216
4-Ethyl-5-(6-methoxy-pyridazin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thione
[1459] Step 1: 6-Chloro-pyridazine-3-carboxylic acid: Potassium
dichromate (3.3 g, 11.2 mmol) was added in portions to a solution
of 3-Chloro-6-methyl-pyridazine (1.2 g, 9.3 mmol) in
H.sub.2SO.sub.4 (10 ml). After addition the mixture is stirred at
50.degree. C. on. The reaction was pored on ice and the mixture was
extracted three times with diethyl ether. The combined organic
phases were dried and concentrated to give the title compound (840
mg, 57%). LC-MS (M++1): 159 and 161 (3:1). Step 2:
6-Chloro-pyridazine-3-carboxylic acid methyl ester: A solution of
6-chloro-pyridazine-3-carboxylic acid (700 mg, 4.53 mmol) in
thionyl chloride (15 ml) was refluxed for 3 h. The reaction was
cooled to ambient temperature and evaporated to dryness. Sodium
methoxide (244 mg, 4.53 mmol) in MeOH (20 ml) was added to the
residue and the solution was stirred on at room temperature (rt).
H.sub.2O was added and the mixture was extracted three times with
DCM. The combined organic phases were dried and concentrated.
Flashchromatography (SiO.sub.2, Heptane/EtOAc 1:1) afforded 560 mg
(72%) of the title compound. 1H NMR (CDCl.sub.3), .delta. (ppm):
4.09 (s, 3H), 7.69 (d, 1H), 8.18 (d, 1H). LC-MS (M.sup.++1): 173
and 175 (3:1). Step 3: 6-Methoxy-pyridazine-3-carboxylic acid
methyl ester: A solution of 6-chloro-pyridazine-3-carboxylic acid
methyl ester in NaOMe in MeOH (1M, 10 ml) was refluxed on. H.sub.2O
was added and the mixture was extracted three times with DCM to
give organic phase I. The combined organic phases I were dried and
concentrated to give the title compound (40 mg, 10%). The water
phase was acidified with concentrated hydrochloric acid and
extracted three times with DCM to give organic phase II. The
combined organic phases II were dried and concentrated to give
6-methoxy-pyridazine-3-carboxylic acid (LC-MS (M++1): 155) (230 mg,
65%). A solution of 6-methoxy-pyridazine-3-carboxylic acid in
thionyl chloride (6 ml) was refluxed for 3 h. The reaction was
cooled to ambient temperature and evaporated to dryness. MeOH (10
ml) was added to the residue and the solution was stirred on at rt.
Saturated NaHCO.sub.3 (aq) was added and the mixture was extracted
three times with DCM. The combined organic phases were dried and
concentrated to give the title compound (253 mg, 100%). LC-MS
(M++1): 169. Step 4:
4-Ethyl-5-(6-methoxy-pyridazin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thione-
: NaOMe (86 mg, 1.6 mmol) was added to a solution of
6-methoxy-pyridazine-3-carboxylic acid methyl ester (210 mg, 1.25
mmol) and 4-ethyl-3-thiosemicarbazide (190 mg, 1.6 mmol) in MeOH (6
ml) and the mixture was heated to 70.degree. C. at 72 h. The
reaction was cooled to ambient temperature and evaporated to
dryness. H.sub.2O (10 ml) was added to the residue and the mixture
was acidified with concentrated hydrochloric acid and the title
compound 35 mg (12%) was collected by filtration. LC-MS (M++1):
238.
Example 217
4-Ethyl-5-(5-methoxy-pyridin-2-yl)-2,4-dihydro-[1,2,4]triazole-3-thione
[1460] Step 1: 5-Methoxy-pyridine-2-carboxylic acid methyl ester:
5-Methoxy-2-methyl-pyridine (700 mg, 5.69 mmol) was dissolved in
H.sub.2O (20 ml) and heated to 80.degree. C. KMnO.sub.4 (4 g, 25.3
mmol) was added in portion to the solution over 1 h. After stirring
at 80.degree. C. for 5 h the mixture was filtrated and the filtrate
was washed with H.sub.2O (60.degree. C.). The combined water phase
was concentrated. DMF (20 ml), K.sub.2CO.sub.3 (785 mg, 5.7 mmol)
followed by MeI (540 ml, 8.6 mmol) was added to the remaining
residue and the mixture was heated to 80.degree. C. on. The
reaction was cooled to ambient temperature and H.sub.2O was added
and the mixture was extracted three times with toluene. The
combined organic phases were dried and concentrated.
Flashchromatography (SiO.sub.2, Heptane/EtOAc 1:1) afforded 210 mg
(22%) of the title compound. 1H NMR (CDCl.sub.3): d ppm 3.93 (s,
3H) 4.00 (s, 3H) 7.23 (m, 1H) 8.13 (d, 1H) 8.40 (d, 1H). Step 2:
4-Ethyl-5-(5-methoxy-pyridin-2-yl)-2,4-dihydro-[1,2,4]triazole-3-thione:
NaOMe (4 ml, 4.0 mmol, 1M) was added to a solution of
5-Methoxy-pyridine-2-carboxylic acid methyl ester (200 mg, 1.2
mmol), 4-ethyl-3-thiosemicarbazide (145 mg, 1.2 mmol) in MeOH (10
ml) and the mixture was heated to 70.degree. C. on. The reaction
was cooled to ambient temperature and evaporated to dryness.
H.sub.2O (10 ml) was added to the residue and the mixture was
acidified with concentrated hydrochloric acid and the title
compound 50 mg (18%) was collected by filtration. LC-MS (M++1):
237.
[1461] The following compounds were prepared analogously to example
10: TABLE-US-00011 Example No. Name 218
5-Chloromethyl-3-phenyl-[1,2,4]oxadiazole 219
5-Chloromethyl-3-(3-fluoro-phenyl)-[1,2,4]oxadiazole 220
5-Chloromethyl-3-(2-fluoro-5-methyl-phenyl)- [1,2,4]oxadiazole 221
5-Chloromethyl-3-thiophen-2-yl-[1,2,4]oxadiazole 222
5-Chloromethyl-3-thiophen-3-yl-[1,2,4]oxadiazole 223
3-(5-Chloromethyl-[1,2,4]oxadiazol-3-yl)-phenol 224
5-Chloromethyl-3-o-tolyl-[1,2,4]oxadiazole 225
5-Chloromethyl-3-(3-chloro-phenyl)-[1,2,4]oxadiazole 226
5-Chloromethyl-3-(2,5-difluoro-phenyl)-[1,2,4]oxadiazole
[1462] The following compounds were prepared analogously to example
16: TABLE-US-00012 Example No. Name 227
3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile 228
2-Chloro-4-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-pyridine 229
3-Chloromethyl-5-(2,5-dimethyl-phenyl)-[1,2,4]oxadiazole 230
3-Chloromethyl-5-(2-fluoro-5-methyl-phenyl)- [1,2,4]oxadiazole 231
3-Chloromethyl-5-(2,5-dichloro-phenyl)-[1,2,4]oxadiazole 232
3-Chloromethyl-5-(2-fluoro-5-bromo-phenyl)- [1,2,4]oxadiazole 233
3-Chloromethyl-5-(3-methyl-phenyl)-[1,2,4]oxadiazole 234
3-Chloromethyl-5-(2,5-difluoro-phenyl)-[1,2,4]oxadiazole 235
3-Chloromethyl-5-(3-methylsulfanyl-phenyl)- [1,2,4]oxadiazole 236
3-Chloromethyl-5-(3-cyclopropyl-phenyl)-[1,2,4]oxadiazole 237
3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-carbamic acid
tert-butyl ester 238
1-[3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]- ethanone 239
5-(5-Chloro-2-fluoro-phenyl)-3-chloromethyl- [1,2,4]oxadiazole 240
2-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-4-methyl-phenol
Example 241
3-Chloromethyl-5-(2-chloro-5-methyl-phenyl)-[1,2,4]oxadiazole
[1463] 2-Chloro-5-methyl-benzoic acid (1 g, 5.8 mmol) was treated
with 5 ml thionyl chloride at reflux for two h. Excess thionyl
chloride was removed under reduced pressure. The residue was added
to a suspension of 2-chloro-N-hydroxy-acetamidine (638 mg, 5.8
mmol) in dichloromethane (10 ml) at room temperature. After
stirring for 30 min, triethylamine (2.04 ml, 14.6 mmol) was added
and stirred for an additional h. The reaction mixture was diluted
with ethyl acetate, washed with water and brine, dried over
anhydrous sodium sulfate, filtered and concentrated. Flash column
chromatography using 10-20% ethyl acetate in hexanes afforded 460
mg of the acyclic ester intermediate. DMF was added to this
intermediate and then heated at 135.degree. C. for 4 h to effect
cyclization to oxadiazole. After cooling the reaction mixture was
washed with water (3 times) and brine, dried over anhydrous sodium
sulfate, filtered, and concentrated. Purification by flash column
chromatography on silica gel using 5% ethyl acetate in hexanes
afforded the title compound 160 mg (12% over 2 steps) as a white
solid. m/z 244 (GCMS).
[1464] The following compounds were prepared analogously to Example
241: TABLE-US-00013 Example No. Name 242
3-Chloromethyl-5-(2,5-dichloro-thiophen-3-yl)- [1,2,4]oxadiazole
243 3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile 244
3-Chloromethyl-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole 245
3-Chloromethyl-5-(2-methyl-thiazol-4-yl)- [1,2,4]oxadiazole 246
3-Chloromethyl-5-(4-fluoro-phenyl)-[1,2,4]oxadiazole 247
5-(5-Bromo-2-fluoro-phenyl)-3-chloromethyl- [1,2,4]oxadiazole 248
3-Chloromethyl-5-(4-methyl-thiophen-2-yl)- [1,2,4]oxadiazole 249
5-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-thiophene-3- carbonitrile
250 2-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-4-methyl- benzonitrile
251 3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-5-fluoro- benzonitrile
252 3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-4-fluoro- benzonitrile
253 4-Chloro-2-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-phenol 254
3-(1-Chloro-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole 255
3-(1-Chloro-ethyl)-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole 256
3-(1-Chloro-ethyl)-5-(5-chloro-2-fluoro-phenyl)-
[1,2,4]oxadiazole
Example 257
[3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanol
[1465] 3-Hydroxymethylbenzoic acid, described in Reed, G. A.;
Dimmel, D. R.; Malcolm, E. W. J. Org. Chem. 1993, 58 (23),
6372-6376, (175 mg, 1.15 mmol), 2-chloro-N-hydroxy-acetamidine (125
mg, 1.15 mmol) and HBTU was dissolved in anhydrous DMF (4 ml).
Triethylamine (0.48 ml, 3.5 mmol) was added and the reaction was
stirred at ambient temperature over night. The crude product was
partitioned between dichloromethane and NaHCO.sub.3 (aq), the
organic phase was dried (MgSO.sub.4) and the dichloromethane was
removed in vacuo. The resulting DMF-solution was heated at
120.degree. C. over night. The reaction mixture was concentrated in
vacuo and the title compound (64 mg, 25%) was isolated by flash
chromatography using 25-50% ethyl acetate in heptane. 1H NMR
(CDCl.sub.3), .delta. (ppm): 8.15 (s, 1H), 8.06 (d, 1H), 7.62 (d,
1H), 7.53 (t, 1H); 4.80 (d, 2H), 4.66 (s, 1H); 1.99 (br. t,
1H).
[1466] The following compounds were prepared analogously to Example
257: TABLE-US-00014 Example No. Name 258
3-Chloromethyl-5-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-
[1,2,4]oxadiazole 259 3-Chloromethyl-5-furan-3-yl-[1,2,4]oxadiazole
260 3-Chloromethyl-5-(5-chloro-thiophen-2-yl)-
[1,2,4]oxadiazole
Example 261
1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethanol
[1467] Step 1:
1-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethoxy}-1H-benzotriazole-
: 2-(1-Chloro-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole (109 mg,
0.45 mmol), hydroxybenzotriazole (76.4 mg, 0.56 mmol) and potassium
iodide (23.0 mg, 0.14 mmol) were dissolved in DMF (2.5 ml),
followed by the addition of potassium carbonate (74.0 mg, 0.53
mmol). After stirring under argon at ambient temperatures for 24 h
the reaction mixture was diluted with ethyl acetate and washed with
2N ammonium chloride solution. After reextraction of the aqueous
layer with ethyl acetate, the combined organic layers were washed
with brine and evaporated to dryness. Column chromatography over 12
g silica using heptane/ethyl acetate=4/1 gave after drying in vacuo
the title compound (129 mg, 84%). 1H NMR (CDCl.sub.3), .delta.
(ppm): 7.94 (d, 1H), 7.82 (m, 1H), 7.76 (m, 1H), 7.46 (m, 1H),
7.39-7.27 (m, 4H), 5.98 (q, 1H), 2.04 (d, 3H). Step 2:
1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethanol:
1-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethoxy}-1H-benzotriazole
(58.4 mg, 0.17 mmol) was dissolved under argon in dry THF (3 ml).
To this mixture a 0.1 molar solution of samarium diiodide in THF (5
ml, 0.5 mmol) was slowly added over 20 min. After stirring for 80
min additional samarium diode solution (4 ml, 0.4 mmol) was added
during 5 min. The reaction mixture was quenched after further 15
min of stirring with aqueous Na.sub.2S.sub.2O.sub.3, diluted with
diethyl ether and washed with 1 molare aqueous hydrochloric acid,
dried over sodium sulfate and evaporated to dryness. After drying
in vacuo crude title compound was obtained (36.0 mg, 92%) which was
used in the next step without further purification. 1H NMR
(CDCl.sub.3), .delta. (ppm): 7.98-7.75 (m, 2H), 7.50-7.38 (m, 2H),
5.25 (q, 1H), 1.74 (d, 3H).
[1468] The following compounds were prepared analogously to Example
261: TABLE-US-00015 Example No. Name 262
[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]- methanol
Example 263
1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethanol
[1469] To a solution of 3.19 g (30.6 mmol)
2,N-dihydroxy-propionamidine in 25 ml pyridine was added 4.3 ml
(33.7 mmol) 3-chloro-benzoyl chloride at 0.degree. C. Cooling was
removed and the mixture was stirred at room temperature for 25 min
and at reflux for 25 min. After cooling the mixture was poured into
water and extracted twice with CH.sub.2Cl.sub.2. The organic phase
was dried and concentrated. Recrystallization from heptane/EtOAc
afforded 4.12 g (60%) of a white solid. 1H NMR (CDCl.sub.3), d
(ppm): 1.68 (d, 3H) 2.67 (m, 1H) 5.09 (m, 1H) 7.46 (t, 1H) 7.56 (d,
1H) 8.01 (d, 1H) 8.13 (s, 1H).
Example 264
[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanol
[1470] Step 1:
N-{4-[(Z)-{[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]methylene}(oxido)amin-
o]phenyl}-N,N-dimethylamine: The title compound was synthesized
according to the method described in Palazzo et al. J. Heterocycl.
Chem. (1979) 16:1469.
1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-pyridinium
chloride (1.81 g, 5.87 mmol) was dissolved in water (20 ml). To
this solution, 4-nitroso-N,N-dimethylanilin (0.88 g, 5.86 mmol)
dissolved in ethanol (50 ml) was added, followed by slow addition
of 1 molar aq. sodium hydroxide (5.9 ml, 5.9 mmol) over a 3 min
period. After 1 h the formed precipitate was filtered, washed with
water and air-dried to give the title compound (2.08 g, wet) which
was used immediately in the next step MS (ESI) m/z 344 (M+1). Step
2: [5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanediol:
N-{4-[(Z)-{[5-(3-Chlorophenyl)-1,2,4-oxadiazol-3-yl]methylene}(oxido)amin-
o]phenyl}-N,N-dimethylamine (2.08 g wet) was suspended in diethyl
ether (30 ml), followed by the addition of 1 molar aqueous
hydrochloric acid. The mixture was stirred vigorously for 20 min,
transferred to a separation funnel and diluted with diethyl ether
and 1 molar aqueous hydrochloric acid. After extraction, the
aqueous layer was extracted two more times with diethyl ether.
Combining the organic layers, drying over magnesium sulfate,
followed by evaporation to dryness and drying in vacuo gave the
title compound as crude (0.56 g, 42% from
1-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-pyridinium
chloride). MS (ESI) m/z 227 (M+1). Step 3:
[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanol: Step 3:
[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanol:
1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-pyridinium
chloride (99.3 mg, 0.44 mmol) was dissolved in methanol (4 ml)
followed by the addition of sodium borohydride (32 mg, 0.84 mmol).
More sodium borohydride was added after 2 h and the reaction was
allowed to run over night. The reaction mixture was diluted with
dichloromethane and aq. ammonium chloride and stirred vigorously.
After separation of the layers and washing of the organic layer
with brine, followed by evaporation to dryness, crude product was
obtained. This was purified by flash chromatography using
heptane/ethyl acetate which gave the title compound (32.0 mg, 32%).
1H NMR (CDCl.sub.3), .delta. (ppm): 8.11 (s, 1H), 8.00 (apparent d,
1H), 7.56 (apparent d, 1H), 7.46 (apparent t, 1H), 4.87 (d, 2H),
2.91 (t, 1H).
Example 265
2-Chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole
[1471] 2-Fluoro-5-methyl-benzoic acid hydrazide (320 mg, 1.9 mmol)
and 2-chloro-1,1,1-triethoxy-ethane (1.9 ml) were heated in a
sealed vial at 120.degree. C. for 30 min. The reaction mixture was
place directly onto a flash column (silica gel) and purified by
using 0-5% ethyl acetate in hexanes to afford
2-chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole
(284.5 mg, 66%). 1H NMR (CDCl.sub.3) (ppm): 7.89 (q, 1H), 7.36 (m,
1H), 7.16 (t, 1H), 4.81 (s, 2H), 2.43 (s, 3H).
[1472] The following compounds were prepared analogously to Example
265: TABLE-US-00016 Example No. Name 266
2-Chloromethyl-5-(3-chloro-phenyl)-[1,3,4]oxadiazole 267
4-(5-Chloromethyl-[1,3,4]oxadiazol-2-yl)-2-methyl- pyridine 268
2-Chloromethyl-5-m-tolyl-[1,3,4]oxadiazole 269
3-(5-Chloromethyl-[1,3,4]oxadiazol-2-yl)-benzonitrile 270
2-Chloro-4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)- pyridine 271
2-(5-Chloro-2-fluoro-phenyl)-5-chloromethyl- [1,3,4]oxadiazole
Example 272
2-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole
[1473] 3-Chloro-benzoic acid hydrazide (170 mg, 1 mmol) and
2-bromo-1,1,1-triethoxypropane (1 ml) were heated in a sealed vial
at 120.degree. C. for 10 min. The reaction mixture was place
directly onto a flash column (silica gel) and purified using 0-50%
dichloromethane in hexanes. The product was re-purified by flash
column chromatography using a mixture of ethyl
acetate:hexanes:dichloromethane (1:19:20) to afford
2-(1-bromo-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole (93 mg,
32%, colorless oil). 1H NMR (CDCl.sub.3) (ppm): 8.09 (t, 1H), 7.99
(t, 1H), 7.55 (m, 3H), 5.30 (m, 1H), 2.21 (q, 3H).
[1474] The following compounds were prepared analogously to Example
272: TABLE-US-00017 Example No. Name 273
2-(1-Bromo-ethyl)-5-(5-chloro-2-fluoro-phenyl)- [1,3,4]oxadiazole
274 4-[5-(1-Bromo-ethyl)-[1,3,4]oxadiazol-2-yl]-2-methyl- pyridine
275 2-(1-Bromo-ethyl)-5-(2-fluoro-5-methyl-phenyl)-
[1,3,4]oxadiazole 276
2-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole
Example 277
3-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole
[1475] A solution of 396 mg (2.22 mmol) N-bromosuccinimid in 2 ml
THF was added dropwise to a solution of 583 mg (2.22 mmol)
triphenylphosphine in 2 ml THF at 0.degree. C. After stirring for
20 min 416 mg (1.85 mmol)
1-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethanol in 2 ml THF
was added. Stirring was continued overnight at room temperature
before the solvent was removed under reduced pressure. Flash
chromatography (heptane/EtOAc 6:1) afforded 168 mg (32%). 1H NMR
(CDCl.sub.3), d (ppm): 2.12 (d, 3H) 5.21 (q, 1H) 7.47 (t, 1H) 7.57
(m, 1H) 8.03 (d, 1H) 8.15 (s, 1H).
Example 278
1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol
[1476] Step 14-(3-Chloro-phenyl)-2,4-dioxo-butyric acid ethyl
ester: Sodium hydride (60% oil dispersion, 1.24 g, 31.1 mmol) was
added in portions to a solution of 3-chloroacetophenone (4.0 g,
25.9 mmol) and diethyl oxalate (4.54 g, 31.1 mmol) in DMF (32 ml)
at 0.degree. C. The mixture stirred at room temperature for 1 h and
was then heated at 80.degree. C. for a half an h. After cooling,
the mixture was treated with 3N HCl and then diluted with ethyl
acetate. The organic layer was washed with water (3.times.) and
saturated brine, dried over anhydrous sodium sulfate, filtered and
concentrated. The resulting residue was then purified by flash
column chromatography on silica using 0-10% ethyl acetate in
hexanes to afford of 4-(3-chloro-phenyl)-2,4-dioxo-butyric acid
ethyl ester (4.43 g, 67%, yellow solid). 1H NMR (CDCl.sub.3) d
(ppm): 15.12 (br s, 1H), 7.98 (s, 1H), 7.88 (d, 1H), 7.58 (d, 1H),
7.47 (t, 1H), 7.05 (s, 1H), 4.39 (m, 2H), 1.41 (m, 3H). Step 2:
5-(3-Chloro-phenyl)-isoxazole-3-carboxylic acid ethyl ester: A
solution of 4-(3-chloro-phenyl)-2,4-dioxo-butyric acid ethyl ester
(3.0 g, 11.8 mmol) and hydroxylamine hydrochloride (2.46 g, 35.4
mmol) in methanol (60 ml) was heated at 80.degree. C. for 4 h.
After cooling, the mixture was filtered and washed with cold
methanol to afford 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid
ethyl ester (2.0 g, 71%, white solid). 1H NMR (CDCl.sub.3) d (ppm):
7.82 (s, 1H), 7.72 (m, 1H), 7.47 (m, 2H), 4.03 (s, 3H). Mixture of
both methyl and ethyl ester (mostly methyl). Step 3:
1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanone: In a screw cap vial
equipped with stir bar added methyl magnesium iodide (3M in diethyl
ether) (0.79 ml, 2.38 mmol), toluene (1 ml), tetrahydrofuran (0.39
ml, 4.77 mmol) and triethylamine (1 ml, 7.15 mmol). Cooled the
solution down to 0.degree. C. and to it added solution of
5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid ethyl ester (300
mg, 1.19 mmol) in toluene (5 ml). Left the resulting mixture
stirring at 0.degree. C. for 5 h. Reaction mixture was quenched
with 1N hydrochloric acid (aqueous, 6.5 ml, 6.5 mmol), diluted with
toluene (35 ml), sequentially washed with water (50 ml), saturated
sodium bicarbonate (aqueous, 30 ml), water (50 ml) and brine (30
ml). The organic phase was concentrated, in-vacuo. The isolated
residue was dissolved in methanol (8 ml) and 20% potassium
hydroxide (aqueous, 1 ml). The mixture was stirred at 45.degree. C.
for 30 min. At this point the mixture was concentrated, in-vacuo.
The isolated residue was dissolved in toluene (60 ml), sequentially
washed with water (50 ml), saturated sodium bicarbonate (aqueous,
50 ml) and water (50 ml). The organic phase was concentrated,
in-vacuo. The crude residue was purified on silica gel using 2%
ethyl acetate in hexanes to isolate the desired compound as a white
solid (156 mg, 60%). 1H-NMR (CDCl.sub.3), d (ppm): 7.77 (m 1H),
7.66 (m, 1H), 7.42 (m, 2H), 6.90 (s, 1H), 2.69 (s, 3H). Step 4:
1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol: In a screw cap vial
equipped with stir bar added
1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanone (100 mg, 0.45 mmol),
sodium borohydride (34 mg, 0.90 mmol) and methanol (3 ml). Left the
resulting mixture stirring at room temperature for 3 h. Reaction
was quenched with water (30 ml) and brine (30 ml), extracted with
dichloromethane (3.times.30 ml). Combined organic phase was dried
(sodium sulfate), filtered and concentrated, in-vacuo to isolate
1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol as a white solid (110
mg). 1H-NMR (CDCl.sub.3), d (ppm): 7.69 (m, 1H), 7.59 (m, 1H), 7.37
(m, 2H), 6.59 (s, 1H), 5.07 (q, 1H), 3.45 (bs, 1H), 1.58 (d,
3H).
[1477] The following compound was prepared analogously to Example
278: TABLE-US-00018 Example No. Name 279
1-[5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethanol
[1478] The following compounds were prepared analogously to
5-(3-Chloro-phenyl)-isoxazole-3-carboxylic acid ethyl ester (step 2
in the synthesis of Example 279): TABLE-US-00019 Example No. Name
280 5-(2-Fluoro-5-methyl-phenyl)-isoxazole-3-carboxylic acid methyl
ester 281 5-Thiophen-3-yl-isoxazole-3-carboxylic acid methyl ester
282 5-Phenyl-isoxazole-3-carboxylic acid methyl ester 283
5-(3-Chloro-phenyl)-4-methyl-isoxazole-3-carboxylic acid ethyl
ester 284 5-(5-Chloro-thiophen-3-yl)-isoxazole-3-carboxylic acid
methyl ester
Example 285
[5-(3-Chloro-phenyl)-isoxazol-3-yl]-methanol
[1479] Lithium aluminum hydride (320 mg, 8.4 mmol) was slowly added
to a solution of 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid
ethyl ester (2.0 g, 8.4) in THF (100 ml) at room temperature. After
1 h, the reaction mixture was quenched with water and then
extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, dried over anhydrous sodium sulfate,
filtered, and concentrated. The resulting residue was then purified
by flash column chromatography using 15-40% ethyl acetate in hexane
to afford [5-(3-chloro-phenyl)-isoxazol-3-yl]-methanol (1.32 g,
75%, yellow solid). 1H NMR (CDCl.sub.3) d (ppm): 7.78 (s, 1H), 7.68
(m, 1H), 7.43 (m, 2H), 6.63 (s, 1H), 4.84 (d, 2H), 2.23 (t,
1H).
[1480] The following compounds were prepared analogously to Example
285: TABLE-US-00020 Example No. Name 286
[2-(3-Chloro-phenyl)-oxazol-4-yl]-methanol 287
[3-(3-Chloro-phenyl)-isoxazol-5-yl]-methanol 288
5-(Thiophen-3-yl-isoxazol-3-yl)methanol 289
[5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-yl]-methanol 290
(5-Phenyl-isoxazol-3-yl)-methanol 291
[5-(3-Chloro-phenyl)-4-methyl-isoxazol-3-yl]-methanol 292
[5-(5-Chloro-thiophen-3-yl)-isoxazol-3-yl)]-methanol
Example 293
Methanesulfonic acid 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethyl
ester
[1481] In a screw cap vial equipped with stir bar was added
1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol (110 mg, 0.49 mmol),
dichloromethane (3 ml) and triethylamine (0.34 ml, 2.46 mmol).
Cooled the mixture down to 0.degree. C. and to it added methane
sulfonyl chloride (0.08 ml, 0.98 mmol). Left the reaction mixture
stirring at room temperature for 30 min. Reaction was quenched with
saturated sodium bicarbonate (aqueous, 40 ml) and extracted with
dichloromethane (3.times.30 ml). Combined organic phase was washed
with brine (40 ml), dried (sodium sulfate), filtered and
concentrated, in-vacuo to isolate the desired compound as brown
oil.
[1482] The following compounds were prepared analogously to Example
293: TABLE-US-00021 Example No. Name 294 Methanesulfonic acid
2-(3-chloro-phenyl)-oxazol-4- ylmethyl ester 295 Methanesulfonic
acid 3-(3-chloro-phenyl)-isoazol-5- ylmethyl ester 296
Methanesulfonic acid 5-(2-fluoro-5-methyl-phenyl)-
isoxazol-3-ylmethyl ester 297 Methanesulfonic
acid-phenyl)-isoxazol-5-yl]-ethyl ester 298 Methanesulfonic acid
5-(5-chloro-2-fluoro-phenyl)- isoxazol-3-ylmethyl ester 299
Methanesulfonic acid 5-(3-chloro-phenyl)-isoxazol- 3-ylmethyl ester
300 Methanesulfonic acid 5-thiophen-3-yl-isoxazol-3-ylmethyl ester
301 Methanesulfonic acid 5-(2-fluoro-5-methyl-phenyl)-
isoxazol-3-ylmethyl ester 302 Methanesulfonic acid
5-phenyl-isoxazol-3-ylmethyl ester 303 Methanesulfonic acid
5-(3-chloro-phenyl)-4-methyl- isoxazol-3-ylmethyl ester 304
Methanesulfonic acid 5-(5-chloro-thiophen-3-yl)-isoxazol-
3-ylmethyl ester 305 Methanesulfonic acid
1-[5-(2-fluoro-5-methyl-phenyl)- isoxazol-3-yl]-ethyl ester 306
Methanesulfonic acid 1-[5-(5-chloro-2-fluoro-phenyl)-
isoxazol-3-yl]-ethyl ester
Example 307
Methanesulfonic acid
4-chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester
[1483] Sulfuryl chloride (1 ml) was added to methanesulfonic acid
5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester (200 mg, 0.70 mmol)
and then stirred at 60.degree. C. overnight. The reaction mixture
was diluted with dichloromethane, washed saturated sodium
bicarbonate, dried over anhydrous sodium sulfate, filtered and
concentrated to afford methanesulfonic acid
4-chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester (219 mg,
97%, light brown solid). 1H NMR (CDCl.sub.3) d (ppm): 8.07 (m, 1H),
7.92 (m, 1H), 7.50 (m, 2H), 5.38 (s, 2H), 3.16 (s, 3H).
Example 308
3-(3-Chloro-phenyl)-isoxazole-5-carboxylic acid methyl ester
[1484] Step 1: 3-Chloro-N-hydroxy-benzamidine: A solution of
3-chlorobenzaldehyde (3.35 ml, 0.030 mmol) in ethanol (40 ml) was
added to a solution of hydroxylamine hydrochloride (2.47 g, 0.036
mmol) and sodium hydroxide (1.42 g, 0.036) in water (20 ml) at room
temperature and then heated at 90.degree. C. for 24 h. After
cooling, the reaction mixture was concentrated, the residue diluted
with water and then the precipitate was filtered and dried to
afford 3-chloro-N-hydroxy-benzamidine (1.13 g, 93%). 1H NMR
(CDCl.sub.3) d (ppm): 8.11 (s, 1H), 7.72 (s, 1H), 7.61 (m, 1H),
7.46 (m, 1H), 7.36 (m, 1H). Step 2: 3-Chloro-N-hydroxy-benzimidoyl
chloride: N-chlorosuccinimide (858 mg, 6.4 mmol) was added to a
solution of 3-chloro-N-hydroxy-benzamidine (1 g, 6.4 mmol) at room
temperature and stirred for 1 h. The reaction mixture was diluted
with diethyl ether and then washed with water (3.times.), dried
over anhydrous magnesium sulfate, filtered, and concentrated to
afford the titled compound (1.13 g, 93%). 1H NMR (CDCl.sub.3) d
(ppm): 8.03 (s, 1H), 7.87 (m, 1H), 7.76 (m, 1H), 7.43 (m, 1H): Step
3: 3-(3-Chloro-phenyl)-isoxazole-5-carboxylic acid methyl ester:
Triethyl amine (0.73 ml, 5.3 mmol) was added drop-wise to a
solution of 3-chloro-N-hydroxy-benzimidoyl chloride (1.0 g, 5.3
mmol) and methyl propiolate (2.2 ml, 25.3 mmol) in an ice-bath. The
reaction mixture was warmed to room temperature and left to stir
overnight. After diluting the reaction with dichloromethane, the
organic layer was washed with water and saturated brine, dried over
anhydrous sodium sulfate, filtered, and concentrated. Purification
by flash column chromatography eluted with 50% hexanes in ethyl
acetate and then recrystallization with methanol afforded
3-(3-chloro-phenyl)-isoxazole-5-carboxylic acid methyl ester (635
mg, 51%, white solid). 1H NMR (CDCl.sub.3) d (ppm): 7.86 (m, 1H),
7.74 (m, 1H), 7.46 (2H), 7.2 (s, 1H), 4.05 (s, 3H).
Example 309
2-Bromomethyl-5-(3-chloro-phenyl)-oxazole
[1485] Step 1 5-(3-Chloro-phenyl)-2-methyl-oxazole: To a solution
of T1(OAc)3 (4.2 g, 11.1 mmol) in acetonitrile (80 ml),
trifluoromethanesulfuric acid (5 g, 33.3 mmol) was added dropwise
at room temperature and stirred for 15 min. The reaction mixture
was then heated to 80.degree. C. and 1-(3-chloro-phenyl)-ethanone
(1.14 g, 7.4 mmol) in acetonitrile (40 ml) was added. After one h,
the reaction was quenched with dichloromethane and saturated sodium
bicarbonate. The organic layer was dried, purified by column
chromatography with 5.about.19% ethyl acetate in hexanes to give
1.2 (83.9%) g of 5-(3-chloro-phenyl)-2-methyl-oxazole as yellow
oil. 1H-NMR (CDCl.sub.3) d (ppm): 7.60 (s, 1H), 7.48 (d, 1H), 7.29
(m, 2H), 7.23 (s, 1H) and 2.34 (s, 3H). Step 2:
2-Bromomethyl-5-(3-chloro-phenyl)-oxazole:
5-(3-chloro-phenyl)-2-methyl-oxazole (580 mg, 3 mmol) was mixed
with NBS (531 mg, 3 mmol) and BPOA (36.3 mg, 0.15 mmol) in
CCl.sub.4 at room temperature. The reaction mixture was heated at
75.degree. C. for 2 h and then quenched with water and
dichloromethane. The organic layer was dried, concentrated,
purified by column chromatography with 2.about.5% ethyl acetate in
hexanes to give 562 mg (68.3%) of
2-bromomethyl-5-(3-chloro-phenyl)-oxazole as yellow oil. 1H-NMR
(CDCl.sub.3) d (ppm): 7.67 (s, 1H), 7.54 (d, 1H), 7.35 (m, 3H) and
4.56 (s, 2H).
Example 310
2-(3-Chloro-phenyl)-oxazole-4-carboxylic acid methyl ester
[1486] To a mixture of 3-Chlorobenzoic acid (5.0 g, 31.9 mmol),
serine methylester hydrochloride (6.1 g, 31.9 mmol) and HOBt (4.31
g, 31.9 mmol) in DMF (100 ml) was added N-methylmorpholine (NMM)
(7.0 ml, 63.8 mmol) and EDCI (4.97 g, 31.9 mmol) at 0.degree. C.
The mixture was allowed to warm to room temperature and stirred for
18 h. The mixture was diluted with ethyl acetate (300 ml) and then
washed with water (3.times.250 ml) followed by brine. The organic
extract was dried over Na.sub.2SO.sub.4 (anhydrous) and then
concentrated in vacuo giving
2-(3-Chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester
(7.2 g, 93%) of a pale yellow solid. 1H NMR (CDCl.sub.3) d (ppm):
7.78 (s, 1H), 7.66 (d, 1H), 7.45, (dd, 1H), 7.34 (t, 1H), 7.25 (br,
d, 1H), 4.82 (m, 1H), 4.08 (m, 2H), 3.79 (s, 3H), 3.19 (br, t,
1H).
[1487] To a solution of
2-(3-chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester
(7.2 g, 29.6 mmol) in CH.sub.2Cl.sub.2 at -20.degree. C. was added
dropwise De-oxofluor (7.2 g, 32.6 mmol). After stirring at this
temperature for 30 min, BrCCl.sub.3 (3.6 g, 18.1 mmol) was added
dropwise followed by DBU (2.79 g, 18.1 mmol). The mixture was then
stirred at 2-3.degree. C. for 8 h ad then quenched with saturated
NaHCO.sub.3 followed by extraction with ethyl acetate. The organic
extract as then washed with brine and dried over Na.sub.2SO.sub.4
(anhydrous). Purification was performed by flash column
chromatography on silica gel using ethyl acetate in hexanes as
eluant to afford 2-(3-chloro-phenyl)-oxazole-4-carboxylic acid
methyl ester (4.1 g, 59%) as a yellow solid. 1H NMR (CDCl.sub.3) d
(ppm): 8.30 (s, 1H), 8.12 (d, 1H), 7.98 (dd, 1H), 7.45 (m, 2H),
3.96 (s, 3H).
Example 311
2-(3-Chloro-phenyl)-oxazole-4-carboxylic acid methyl ester
[1488] To a mixture of 3-Chlorobenzoic acid (5.0 g, 31.9 mmol),
serine methylester hydrochloride (6.1 g, 31.9 mmol) and HOBt (4.31
g, 31.9 mmol) in DMF (100 ml) was added N-methylmorpholine (NMM)
(7.0 ml, 63.8 mmol) and EDCI (4.97 g, 31.9 mmol) at 0.degree. C.
The mixture was allowed to warm to room temperature and stirred for
18 h. The mixture was diluted with ethyl acetate (300 ml) and then
washed with water (3.times.250 ml) followed by brine. The organic
extract was dried over Na.sub.2SO.sub.4 (anhydrous) and then
concentrated in vacuo giving
2-(3-Chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester
(7.2 g, 93%) of a pale yellow solid. 1H NMR (CDCl.sub.3) d (ppm):
7.78 (s, 1H), 7.66 (d, 1H), 7.45, (dd, 1H), 7.34 (t, 1H), 7.25 (br,
d, 1H), 4.82 (m, 1H), 4.08 (m, 2H), 3.79 (s, 3H), 3.19 (br, t,
1H).
[1489] To a solution of
2-(3-chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester
(7.2 g, 29.6 mmol) in CH.sub.2Cl.sub.2 at -20.degree. C. was added
dropwise De-oxofluor (7.2 g, 32.6 mmol). After stirring at this
temperature for 30 min, BrCCl.sub.3 (3.6 g, 18.1 mmol) was added
dropwise followed by DBU (2.79 g, 18.1 mmol). The mixture was then
stirred at 2-3.degree. C. for 8 h ad then quenched with saturated
NaHCO.sub.3 followed by extraction with ethyl acetate. The organic
extract as then washed with brine and dried over Na.sub.2SO.sub.4
(anhydrous). Purification was performed by flash column
chromatography on silica gel using ethyl acetate in hexanes as
eluant to afford 2-(3-chloro-phenyl)-oxazole-4-carboxylic acid
methyl ester (4.1 g, 59%) as a yellow solid. 1H NMR (CDCl.sub.3) d
(ppm): 8.30 (s, 1H), 8.12 (d, 1H), 7.98 (dd, 1H), 7.45 (m, 2H),
3.96 (s, 3H).
Example 312
1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethanol
[1490] Step 1:
5-(5-Chloro-2-fluoro-phenyl)-isoxazole-3-carbaldehyde: In a 50 ml
round bottom flask equipped with stir bar and drying tube added
5-(5-chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl
ester (0.78 g, 2.89 mmol) and dichloromethane (10 ml). Cooled the
solution down to -78.degree. C. and to this stirred solution added
diisobutylaluminum hydride (1M hexanes, 5.3 ml, 5.3 mmol). The
resulting mixture was left stirring at -78.degree. C. for 3 h.
Reaction was quenched using sodium sulfate decahydrate. The
resulting mixture was stirred at 63.degree. C. for 15 min after
which it was filtered through a celite pad. The filterate was
concentrated in-vacuo to isolate an off-white solid, which was
triturated with hexanes to isolate the title compound as a white
solid (0.55 g, 84%). 1H-NMR (CDCl.sub.3), d (ppm): 10.2 (s, 1H),
7.99 (m, 1H), 7.44 (m, 1H), 7.20 (m, 1H), 7.10 (d, 1H). Step 2:
1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethanol: In a 50 ml
round bottom flask equipped with stir bar added
5-(5-chloro-2-fluoro-phenyl)-isoxazole-3-carbaldehyde (0.55 g, 2.42
mmol) and tetrahydrofuran (6 ml). Cooled the mixture down to
0.degree. C. and to it added methyl magnesium iodide (3M in diethyl
ether, 3.23 ml, 9.67 mmol). The resulting mixture was left stirring
at 0.degree. C. for 3 h. Reaction mixture was quenched with
hydrochloric acid (1N, aqueous, 10 ml), extracted with diethyl
ether (3.times.50 ml). Combined organic phase was washed with water
(50 ml), brine (50 ml), dried (sodium sulfate), filtered and
concentrated in-vacuo. The crude residue was purified on silica gel
using 10% ethyl acetate in hexanes to isolate the desired compound
as clear oil (179 mg, 31%).
Example 313
1-[3-(3-Chloro-phenyl)-isoxazol-5-yl]-ethanol
[1491] 3-Chloro-benzohydroximoyl chloride (e.g. Kim, Jae Nyoung;
Ryu, Eung K; J. Org. Chem. (1992), 57(24), 6649-50) (2.84 g, 14.8
mmol) was suspended in benzene (50 ml) and cooled to 0.degree. C.
3-Butyn-2-ol (2.10 g, 29.9 mmol) and triethylamine (1.89 ml, 26.7
mmol) were added. The mixture was heated to 60.degree. C. for 1.5
hours, cooled and diluted with benzene and 1N aqueous hydrochloric
acid. After stirring, the separated benzene layer was evaporated to
dryness and the crude purified via flash chromatography over silica
using heptane/ethyl acetate=5/1 giving after drying in vacuo the
title compound (0.49 g, 15%). 1H NMR (CDCl.sub.3), .delta. (ppm):
1.64 (d, 3H), 5.07 (dq, 1H), 6.50 (s, 1H), 7.40 (m, 2H), 7.68 (m,
1H), 7.79 (m, 1H)
Example 314
[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-methanol
[1492] Step 1: (5-Chloro-2-fluoro-phenylethynyl)-trimethyl-silane:
In a 250 ml round bottom flask equipped with a stir bar and reflux
condenser added 4-chloro-2-bromo-1-fluoro-benzene (5 g, 23.9 mmol),
triphenylphosphine (250 mg, 0.10 mmol), (trimethylsilyl)acetylene
(5.2 ml, 36.5 mmol) and triethylamine (60 ml). The reaction mixture
was purged with argon, followed by addition of palladium (II)
acetate (108 mg, 0.05 mmol). The resulting mixture was left
stirring at reflux under argon, overnight. The reaction mixture was
filtered through a pad of celite using ethyl acetate and the
filterate was concentrated in-vacuo. The isolated residue was
absorbed on silica gel and filtered using hexanes. The filterate
was concentrated in-vacuo to isolate the title compound as brown
oil (5.42 g). Step 2: 4-Chloro-2-ethynyl-1-fluoro-benzene: In a 250
ml round bottom flask equipped with stir bar added
(5-chloro-2-fluoro-phenylethynyl)-trimethyl-silane (5.42 g, 23.9
mmol), potassium carbonate (16.5 g, 120 mmol) and methanol (60 ml).
The reaction mixture was left stirring at room temperature for 1 h.
Diluted the reaction mixture with hexanes (200 ml) and washed with
water (250 ml). The aqueous phase was extracted with hexanes
(2.times.100 ml). Combined organic phase was washed with brine (200
ml), dried (sodium sulfate), filtered and concentrated in-vacuo to
isolate the desired compound as brown oil (3.56 g). 1H-NMR
(CDCl.sub.3), d (ppm): 7.47 (dd, 1H), 7.30 (m, 1H), 7.05 (t, 1H),
3.36 (s, 1H). Step 3: Chloro-hydroxyimino-acetic acid ethyl ester:
In 1 L round bottom flask equipped with stir bar added amino-acetic
acid ethyl ester hydrochloride (20 g, 143 mmol) and water (30 ml).
The solution was cooled down to 0.degree. C. followed by sequential
addition of concentrated hydrochloric acid (11.8 ml, 143 mmol) and
dropwise addition of sodium nitrite (9.89 g, 143 mmol) solution in
water (15 ml). After 10 min added another equivalent each of
concentrated hydrochloric acid and sodium nitrite solution in
water. The reaction mixture was left stirring at 0.degree. C. for 1
h. Reaction mixture was extracted with ether (4.times.100 ml).
Combined organic phase was dried (sodium sulfate), filtered and
concentrated in-vacuo to isolate a lemon yellow solid. The solid
was recrystallized from hexanes to isolate a white solid (11 g,
51%). 1H-NMR (CDCl.sub.3), d (ppm): 9.98 (bs, 1H), 4.40 (q, 2H),
1.38 (t, 3H). Step 4:
5-(5-Chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl
ester: In a 250 ml round bottom flask equipped with stir bar added
4-chloro-2-ethynyl-1-fluoro-benzene (2 g, 12.9 mmol),
chloro-hydroxyimino-acetic acid ethyl ester (3.92 g, 25.9 mmol),
sodium bicarbonate (7.07 g, 84.1 mmol) and toluene (50 ml).
Reaction mixture was left stirring at room temperature for 48 h,
after which it was concentrated in-vacuo. Residue was taken up in
ethyl acetate (200 ml), sequentially washed with water (150 ml),
brine (150 ml), dried (sodium sulfate), filtered and concentrated
in-vacuo. The crude residue was purified on silica gel using 3%
acetone in hexanes to isolate the title compound as an off-white
solid (1.56 g). 1H-NMR (CDCl.sub.3), d (ppm): 8.00 (dd, 1H), 7.43
(m, 1H), 7.18 (m, 2H), 4.51 (q, 2H), 1.47 (t, 3H). Step 5:
[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-methanol: In a 50 ml
round bottom flask equipped with stir bar and drying tube added
5-(5-chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl
ester (0.78 g, 2.89 mmol) and tetrahydrofuran (10 ml). To this
stirred solution added solution of lithium aluminum hydride (0.12
g, 2.89 mmol) in tetrahydrofuran (2 ml). The resulting mixture was
left stirring at room temperature for 1 h. Reaction was quenched
using sodium sulfate decahydrate. The resulting mixture was stirred
at 63.degree. C. for 15 min after which it was filtered through a
celite pad. The filterate was concentrated in-vacuo to isolate the
title compound as yellow solid (0.65 g, 99%). 1H-NMR (CDCl.sub.3),
d (ppm): 7.73 (dd, 1H), 7.27 (m, 1H), 7.24 (t, 1H), 6.73 (d, 1H),
4.77 (s, 2H), 4.45 (bs, 1H).
Example 315
3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid
hydrazide
[1493] Step 1:
3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid:
3-Chloro-benzoic acid hydrazide (3.4 g, 20 mmol) and succinic
anhydride (2. g, 20 mmol) was mixed in ethyl acetate (50 ml) at
room temperature for 15 min. The reaction mixture was diluted with
ether and the precipitate was filtered to give 5.1 g of
4-[N'-(3-chloro-benzoyl)-hydrazino]-4-oxo-butyric acid. 1H-NMR
(CDCl.sub.3+DMSO-d6) d (ppm): 10.01 (s, 1H), 9.53 (s, 1H), 7.68 (s,
1H), 7.55 (d, 1H), 7.21 (d, 1H), 7.12 (t, 1H) and 2.35 (m, 4H).
This solid was mixed with conc. H.sub.2SO.sub.4 and stirred at room
temperature for 45 min and the reaction mixture was carefully added
to crashed ice (400 g). The precipitate was filtered to give 4.07 g
(80.6%) of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic
acid as white solid. 1H-NMR (DMSO-d6) d (ppm): 12.4 (w, 1H), 7.96
(s, 1H), 7.91 (d, 1H), 7.71 (d, 1H), 7.63 (t, 1H), 3.15 (t, 2H) and
2.82 (t, 2H). Step 2:
3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid
hydrazide: 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic
acid (2.52 g, 10 mmol) was mixed with iodomethane (5.68 g, 40 mmol)
and K.sub.2CO.sub.3 (5.52 g, 40 mmol) in DMF (25 ml) at room
temperature overnight. The reaction mixture was diluted with ethyl
acetate and washed with water 3 times, dried with MgSO.sub.4 and
concentrated to give 2.57 g of
3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid methyl
ester. The methyl ester (2.54 g, 9.52 mmol) was mixed with 98%
hydrazine hydrate (4.76 g, 95.2 mmol) in methanol (10 ml) for an h.
The reaction mixture was concentrated, diluted with water, filtered
to give 2.17 g (81.4%) of
3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid
hydrazide as white solid. 1H-NMR (CDCl.sub.3+DMSO-d6) d (ppm): 8.75
(w, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.42 (m, 2H), 3.45 (w, 2H),
3.19 (t, 2H) and 2.68 (t, 2H).
Example 316
3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid
hydrazide
[1494] Step 1:
2-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethyl}-malonic
acid dimethyl ester:
2-(1-Chloro-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole (331 mg,
1.36 mmol) was mixed with dimethyl malonate (360 mg, 2/76 mmol) and
DBU (207 mg, 1.36 mmol) in acetonitrile (3 ml) at 70.degree. C.
overnight. The reaction mixture was dilute with dichloromethane and
washed with water. The organic layer was dried and concentrated.
The residue was purified with 5.about.20% ethyl acetate in hexanes
to give 357 mg (74.3%)
2-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethyl}-malonic
acid dimethyl ester as white solid. 1H-NMR (CDCl.sub.3) d (ppm):
8.03 (s, 1H), 7.95 (d, 1H), 7.53 (d, 1H), 7.47 (t, 1H), 4.06 (d,
1H), 3.95 (m, 1H), 3.84 (s, 3H), 3.74 (s, 3H) and 1.51 (d, 3H).
Step 2: 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid
methyl ester:
2-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethyl}-malonic
acid dimethyl ester (352.8 mg, 1.0 mmol) was mixed with sodium
chloride (76.3 mg, 1.3 mmol) and a drop of water in DMSO (1.5 ml)
at 175.degree. C. for an h. The reaction mixture was diluted with
water and extracted with dichloromethane. The organic layer was
washed with water and concentrated. The residue was purified with
column chromatography with 10.about.20% ethyl acetate in hexanes to
give 215 mg
(76.8%)3-[5-(3-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid
methyl ester as clear oil. 1H-NMR (CDCl.sub.3) d (ppm): 8.03 (s,
1H), 7.94 (d, 1H), 7.53 (d, 1H), 7.45 (t, 1H), 3.73 (s, 3H), 3.67
(m, 1H), 3.05 (dd, 1H), 2.73 (dd, 1H) and 1.50 (d, 3H). Step 3:
3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid
hydrazide: 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric
acid hydrazide (146 mg, %) was obtained from
3-[5-(3-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid methyl
ester (215 mg, 0.766 mmol) reacted with hydrazine hydrate (0.74 ml)
in methanol (3 ml) at room temperature for 2.5 h. 1H-NMR
(CDCl.sub.3) d (ppm): 8.03 (s, 1H), 7.94 (d, 1H), 7.53 (d, 1H),
7.46 (t, 1H), 7.23 (w, 1H), 3.93 (w, 2H), 3.71 (m, 1H), 2.90 (dd,
1H), 2.57 (dd, 1H) and 1.50 (d, 3H).
Example 317
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionimidic acid
ethyl ester hydrochloride
[1495] Step 1:
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionamide:
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid (1.6
g, 6.33 mmol) was reacted with SOCl.sub.2 (10 ml) at room
temperature overnight. The reaction mixture was concentrated by
vacuum. The residue was mixed with THF (20 ml) and quenched with
28% NH.sub.3.H.sub.2O (5 ml) at 0.degree. C. After being stirred
for 2 h, the reaction mixture was dilute with dichloromethane and
washed with water and brine. The organic layer was dried,
concentrate and triturated with hexanes to give 1.21 g (76%) of
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionamide. 1H-NMR
(CDCl.sub.3) d (ppm): 8.07 (s, 1H), 7.96 (d, 1H), 7.45 (m, 2H),
5.60 (dw, 2H), 3.32 (t, 2H) and 2.87 (t, 2H). Step 2:
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionitrile:
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionamide (1.2 g,
4.77 mmol) was mixed with pyridine (0.829 g, 10.5 mmol) and
trifluoroacetic anhydride (1.2 g, 5.72 mmol) in dichloromethane (25
ml) at room temperature for 2 h. The reaction mixture was diluted
with dichloromethane and washed with water and brine. The organic
layer was dried to give 1.1 g (98%) of
3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionitrile as
pale-brown oil. 1H-NMR (CDCl.sub.3) d (ppm): 8.09 (s, 1H), 7.98 (d,
1H), 7.45 (m, 2H), 5.60 (dw, 2H), 3.35 (t, 2H) and 3.01 (t, 2H).
Step 3: 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionimidic
acid ethyl ester hydrochloride:
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionitrile (1.1 g,
4.71 mmol) was mixed with 24% HCl in ethanol (8 ml) overnight. The
precipitate was filtered and washed with ether to give 0.99 g (66%)
of 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionimidic acid
ethyl ester hydrochloride as white solid. 1H-NMR (DMSO-d6) d (ppm):
11.70 (w, 2H), 7.78 (m, 2H), 7.64 (m, 2H), 4.41 (q, 2H), 3.45 (t,
2H), 3.22 (t, 2H) and 1.28 (t, 3H).
Example 318
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid
hydrazide
[1496] Step 1:
3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid:
3-Chloro-N-hydroxy-benzamidine 4.52 g, 26.5 mmol) was heated with
succinic anhydride (2.65 mg, 26.5 mmol) in DMF (5 ml) at
150.degree. C. for an h. The reaction mixture was cooled down and
diluted with ethyl acetate. The organic solution was washed with
water and brine, concentrated by vacuum. The residue was triturated
with 20% ethyl acetate in hexanes to give 4.0 g (60%) of
3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid as
white solid.). 1H-NMR (CDCl.sub.3) d (ppm): 8.08 (s, 1H), 7.96 (d,
1H), 7.49 (d, 1H), 7.42 (t, 1H), 3.28 (t, 2H) and 3.04 (t, 2H).
Step 2: 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic
acid hydrazide: This acid was reacted with iodoethane (1.6 g, 10.5
mmol) and K.sub.2CO.sub.3 (1.46 10.5 mmol) in DMF (5 ml) for 5 min
to form 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic
acid ethyl ester. The ethyl ester was then treated with 37%
hydrazine (2 ml) in ethanol (5 ml) at 80.degree. C. for 2 h to give
595 mg (65% in 3 steps) of
3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid
hydrazide as off-white solid 1H-NMR (CDCl.sub.3) d (ppm): 8.07 (s,
1H), 7.96 (d, 1H), 7.49 (d, 1H), 7.43 (t, 1H), 7.00 (w, 1H), 3.95
(w, 2H), 3.34 (t, 2H) and 2.79 (t, 2H).
Example 319
[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid
hydrazide
[1497] Step 1: (N-Hydroxycarbamimidoyl)-acetic acid ethyl ester: To
a ethanol solution (40 ml) of cyano-acetic acid ethyl ester (9.9 g,
0.1 mol), the mixture solution of sodium hydroxide (4 g, 0.1 mol)
in water (40 ml) and 5 M hydroxylamine hydrochloride (20 ml) was
added and the reaction mixture was stirred at 50.degree. C.
overnight. After being concentrated, the reaction mixture was
diluted with water and extrated with ethyl acetate. The organic
layer was dried, concentrated again. The residue was purified by
column chromatography with 30.about.70% ethyl acetate in hexanes to
give 3.32 g (22.7%) of (N-Hydroxycarbamimidoyl)-acetic acid ethyl
ester as white solid. 1H-NMR (CDCl.sub.3) d (ppm): 5.04 (ws, 2H),
4.20 (q, 2H), 3.19 (s, 2H) and 1.30 (t, 3H). Step 2:
[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid ethyl
ester: To a dichloromethane solution (10 ml) of
(N-hydroxycarbamimidoyl)-acetic acid ethyl ester (1.46 g, 10 mmol)
and triethylamine, 3-chlorobenzoyl chloride (1.75 g, 10 mmol) was
added slowly at 5.degree. C. and the reaction mixture was stirred
for 10 min. DMF (8 ml) was added to the reaction mixture was heated
to 135.degree. C. for 2 h. Standard work-up, the product was passed
column with dichloromethane to give 1.2 g (45%) of
[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid ethyl ester
as pale-yellow oil. 1H-NMR (CDCl.sub.3) d (ppm): 8.168 (s, 1H),
8.04 (d, 1H), 7.59 (d, 1H), 7.49 (t, 1H), 4.26 (q, 2H), 3.91 (s,
2H) and 1.31 (t, 3H). Step 3:
[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid hydrazide:
5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid ethyl ester
(0.64 g, 2.4 mmol) was mixed with 37% hydrazine (1.6 ml) in ethanol
(10 ml) at 80.degree. C. for 4 h. The reaction mixture was
concentrated and diluted with water. The precipitate was filtered,
washed with water to give 0.51 g (83.3%) of
[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid
hydrazide.
Example 320
(R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid
hydrazide
[1498] Step 1:
(R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid
methyl ester: To a solution of (R)-2-methylsuccinic acid 4-methyl
ester (2.2 g, 15 mmol) and triethylamine (4.54 g, 45 mmol) in THF
(30 ml), isobutylchloroformate (2.16 g, 15.8 mmol) was added
dropwise at 0.degree. C. After being stirred for 30 min, the
3-chloro-N-hydroxy-benzamidine (2.56 g, 15 mmol) was added. The
reaction mixture was stirred at room temperature for another 30 min
and then heated to 135.degree. C. with DMF for 45 min. The reaction
mixture was diluted with ethyl acetate and washed with water and
brine. The organic layer was dried and concentrated to give 4.0 g
(95%) of (R)-3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric
acid methyl ester as pale-yellow oil. Step 2:
(R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid
hydrazide:
(R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid
hydrazide (430 mg, 77%) was obtained from
(R)-3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid
methyl ester (461.4 mg, 2.0 mmol) reacted with hydrazine hydrate (2
mL) in methanol (2 mL) at 65.degree. C. for 1 h. 1H-NMR
(CDCl.sub.3) d (ppm): 8.07 (s, 1H), 7.96 (d, 1H), 7.46 (m, 2H),
6.98 (w, 1H), 3.93 (w, 2H), 3.78 (m, 1H), 2.86 (dd, 1H), 2.55 (dd,
1H) and 1.59 (d, 3H).
[1499] The following compounds were prepared analogously to Example
320: TABLE-US-00022 Example No. Name 321
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-3- methyl-butyric
acid hydrazide
Example 322
3-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidin-2-one
[1500] 1.33 ml (3.32 mmol) n-BuLi (2.5 M in hexanes) was added
dropwise to a solution of 157 mg (1.58 mmol) d-valerolactone in 5,3
ml THF at 0.degree. C. After stirring for 2 h at 0.degree. C., 400
mg (1.58 mmol) 3-chloromethyl-5-[3-chloro-phenyl)-[1,2,4]oxadiazole
was added in one portion and stirring was continued for 3 h.
NH.sub.4Cl(sat) was added to quench the reaction and the mixture
was extracted twice with CH.sub.2Cl.sub.2. The combined organic
phases were dried and concentrated. Flashchromatography (SiO.sub.2,
Heptane/EtOAc 1:8) afforded 113 mg (25%) of a yellow-white solid.
1H NMR (CDCl.sub.3): d ppm 1.80 (m, 1H) 1.89 (m, 1H) 2.00 (m, 1H)
2.91 (m, 1H) 2.98 (m, 1H) 3.35 (m, 1H) 3.52 (m, 1H) 5.83 (s, 1H)
7.46 (t, 1H) 7.55 (d, J=8.08 Hz, 1H) 8.00 (d, 1H) 8.11 (s, 1H).
[1501] The following compounds were prepared analogously to Example
322: TABLE-US-00023 Example No. Name 323
3-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-
3-ylmethyl]-piperidin-2-one
Example 324
3-Chloromethyl-5-(5-chloro-thiophen-3-yl)-[1,2,4]oxadiazole and
1-[5-(5-Chloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethoxy]-1H-benzotriaz-
ole
[1502] A solution of 2-chloro-N-hydroxy-acetamidine (781 mg, 7.2
mmol), 5-chloro-thiophene-3-carboxylic acid (1.4 g), HBTU (3.55 g)
and DIPEA (1.3 g) in DMF (20 ml) was stirred at ambient temperature
for 1 h before heated at 120.degree. C. for 4 h under argon.
Removal of the solvent in vacuo followed by silica gel
chromatography of the obtained residue using 0-20% EtOAc in
n-heptane yielded 38.5 mg of the faster eluting
3-chloromethyl-5-(5-chloro-thiophen-3-yl)-[1,2,4]oxadiazole as a
syrup, followed by 65 mg of the slower eluting
1-[5-(5-chloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethoxy]-1H-benzotriaz-
ole as a white solid.
3-Chloromethyl-5-(5-chloro-thiophen-3-yl)-[1,2,4]oxadiazole: 1H NMR
(CDCl.sub.3) d (ppm): 8.01 (d, 1H), 7.50 (d, 1H), 4.63 (s, 2H).
1-[5-(5-Chloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethoxy]-1H-benzotriaz-
ole: 1H NMR (CDCl.sub.3) d (ppm): 7.97 (m, 2H), 7.52 (dt, 1H), 7.44
(m, 2H), 7.34 (m, 1H), 5.70 (s, 2H).
Example 325
(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetonitrile
[1503] 4-Methyl-5-thiophene-3-yl-4H-[1,2,4]triazole-3-thiol (197
mg, 1.0 mmol), chloroacetonitile (95 ml, 1.5 mmol), sodium
carbonate (424 mg, 4 mmol) and potassium iodide (332 mg, 2.0 mmol)
were stirred together at 100.degree. C. for 3 h with an additional
addition of chloroacetonitrile (60 ml, 0.5 mmol) after 2 h. The
reaction was cooled, diluted with ethyl acetate and washed with
water. The organic solution was dried, filtered and evaporated.
Silica gel chromatography (dichloromethane:methanol 19:1) yielded
150 mg of the desired compound.
Example 326
2-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-propionic
acid
[1504] (R)-2-chloro-propionic acid (500 mg, 4.6 mmol),
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (1.09 g, 5.58
mmol) and potassium carbonate (1.94 g, 14.03 mmol) were dissolved
in acetonitrile (15 ml) at room temperature. Reaction proceeded for
2.5 h and was partitioned between ethyl acetate (350 ml) and water
3 times, washed with 1 M HCl, once with saturated brine, dried over
anhydrous sodium sulphate, filtered and concentrated in vacuo.
Reaction was not completed at this stage and the crude was stirred
in DMF (10 ml) overnight. Extraction was repeated and purification
was performed by SPE (solid phase extraction) chromatography on
silica gel using 300 ml ethyl acetate, 100 ml 1%, and 100 ml 3%
formic acid in ethyl acetate, yielding title compound (150.7 mg,
12%) 1H-NMR (CDCl.sub.3), d (ppm): 7.52 (dd, 2H), 7.19 (m, 1H),
4.21 (q, 1H), 3.78 (s, 3H), 1.64 (d, 3H).
[1505] The following compounds were prepared analogously to Example
326: TABLE-US-00024 Example No. Name 327
2-(4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-
ylsulfanyl)-propionic acid
Example 328
3-(3-Chloro-phenyl)-5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2-
,4]oxadiazole
[1506] The title compound (2.08 g, 81.5%) was obtained form
5-chloromethyl-3-(3-chloro-phenyl)-[1,2,4]oxadiazole (1.9 g, 8.29
mmol) reacted with 4-methyl-4H-[1,2,4]triazole-3-thiol (1.0 g, 8.71
mmol) and K.sub.2CO.sub.3 (4.58 g, 33.2 mmol) in DMF (19 ml) at
room temperature overnight. 1H-NMR (CDCl.sub.3) d (ppm): 8.21 (s,
1H), 8.05 (s, 1H), 7.94 (d, 1H), 7.49 (d, 1H), 7.43 (t, 1H), 4.69
(s, 2H) and 3.64 (s, 3H).
Example 329
{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2-
,4]oxadiazol-5-yl-phenyl}-carbamic acid tert-butyl ester
[1507] The title compound was prepared from
4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (53 mg, 0.27
mmol), 3-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-carbamic
acid tert-butyl ester (75 mg, 0.24 mmol), and potassium carbonate
(101 mg, 0.73 mmol) in acetonitrile (2.5 ml). The product was
purified by SPE (flash) chromatography using 65% ethyl acetate in
hexane (88.0 mg, 79%, white solid). .sup.1H NMR (CDCl.sub.3) d
(ppm): 8.06 (s, 1H), 7.73 (d, 1H), 7.66 (d, 1H), 7.51 (t, 2H), 7.42
(t, 1H), 7.18 (m, 1H), 6.68 (s, 1H), 4.51 (s, 2H), 3.73 (s, 3H),
1.53 (s, 9H).
[1508] The following compounds were prepared analogously to Example
41: TABLE-US-00025 Example No. Name 1H NMR MS 330
4-(4-Cyclopropyl-5-{1-[5-(2,5- 8.88 (d, 2H), 7.81 (m,
difluoro-phenyl)-[1,2,4]oxadiazol-3- 1H), 7.75 (m, 2H),
yl]-ethylsulfanyl}-4H-[1,2,4]triazol- 7.22 (m, 2H), 5.42 (q, 1H),
3-yl)-pyridine 3.22 (m, 1H), 1.98 (d, 3H), 1.17 (m, 2H), 0.79 (m,
2H) 331 4-(5-{1-[5-(3-Methoxy-phenyl)- 8.69 (m, 2H), 7.6 (m,
[1,2,4]oxadiazol-3-yl]- 1H), 7.52 (m, 3H),
ethylsulfanyl}-4-methyl-4H- 7.35 (t, 1H), 7.04 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 4.93 (q, 1H), 3.78 (t, 3H), 3.55 (s,
3H), 1.86 (d, 3H) 332 4-{4-Methyl-5-[1-(5-m-tolyl- 8.71 (m, 2H),
7.82 (m, [1,2,4]oxadiazol-3-yl)- 2H), 7.53 (m, 2H),
ethylsulfanyl]-4H-[1,2,4]triazol-3- 7.32 (m, 2H), 4.94 (q, 1H),
yl}-pyridine 3.54 (s, 3H), 2.33 (s, 3H), 1.87 (d, 3H) 333
5-(4-Methyl-5-thiophen-2-yl-4H- 2.58 (s, 3H) 3.70 (s, 3H) 370.0
[1,2,4]triazol-3-ylsulfanylmethyl)-3- 4.65 (s, 2H) 7.17 (s,
o-tolyl-[1,2,4]oxadiazole 1H) 7.29 (s, 2H) 7.36 (s, 1H) 7.46 (s,
1H) 7.51 (s, 1H) 7.90 (s, 1H) 334 5-(3-Chloro-phenyl)-3-(4- 0.87
(m, 2H) 1.18 (m, 2H) 415.9 cyclopropyl-5-thiophen-2-yl-4H- 3.47
(ddd, J = 6.95, [1,2,4]triazol-3-ylsulfanylmethyl)- 3.41, 3.28 Hz,
1H) [1,2,4]oxadiazole 4.70 (s, 2H) 7.23 (m, 1H) 7.67 (m, 2H) 7.77
(m, 2H) 8.04 (d, 2H) 335 2-{3-[5-(2-Fluoro-5-methyl- 2.36 (s, 3H)
4.03 (t, 2H) 417.9 phenyl)-[1,2,4]oxadiazol-3- 4.30 (t, 2H) 4.57
(s, ylmethylsulfanyl]-5-thiophen-2-yl- 2H) 7.11 (m, 2H)
[1,2,4]triazol-4-yl}-ethanol 7.35 (s, 1H) 7.47 (d, 1H) 7.64 (d, 1H)
7.81 (d, 1H) 336 4-{4-Ethyl-5-[5-(2-fluoro-5-methyl- 1.38 (t, 3H)
2.34 (s, 3H) 398.0 phenyl)-[1,2,4]oxadiazol-3- 4.66 (m, 4H)
ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.19 (m, 1H) 7.47 (m, 1H)
3-yl}-pyrimidine 7.83 (d, 1H) 8.23 (d, 1H) 8.94 (d, 1H) 9.28 (s,
1H) 337 3-(4-Ethyl-5-furan-3-yl-4H- 1.34 (t, 3H) 2.37 (s, 3H) 386.0
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 4.06 (q, 2H) 4.61 (s,
(2-fluoro-5-methyl-phenyl)- 2H) 6.82 (s, 1H) [1,2,4]oxadiazole 7.12
(m, 1H) 7.36 (ddd, 1H) 7.55 (s, 1H) 7.85 (d, 2H). 338
{3-[5-(2-Fluoro-5-methyl-phenyl)- 2.36 (s, 3H) 3.70 (s, 3H) 445.9
[1,2,4]oxadiazol-3- 4.46 (s, 2H) 5.10 (s,
ylmethylsulfanyl]-5-thiophen-2-yl- 2H) 7.21 (m, 2H)
[1,2,4]triazol-4-yl}-acetic acid 7.47 (m, 2H) 7.73 (d, 1H) methyl
ester 7.86 (m, 1H) 339 5-(2-Fluoro-5-methyl-phenyl)-3-[5- 2.26 (s,
3H) 3.16 (s, 3H) 416.0 furan-2-yl-4-(2-methoxy-ethyl)-4H- 3.57 (t,
2H) 4.42 (t, [1,2,4]triazol-3-ylsulfanylmethyl]- 2H) 4.44 (s, 2H)
[1,2,4]oxadiazole 6.60 (s, 1H) 7.10 (m, 2H) 7.37 (m, 1H) 7.70 (s,
1H) 7.73 (d, 1H) 340 3-(4-Cyclopropyl-5-furan-2-yl-4H- 0.87 (m, 2H)
1.14 (m, 2H) 398.0 [1,2,4]triazol-3-ylsulfanylmethyl)-5- 2.35 (s,
3H) 3.39 (dt, (2-fluoro-5-methyl-phenyl)- 1H) 4.71 (s, 2H)
[1,2,4]oxadiazole 6.72 (s, 1H) 7.09 (d, 1H) 7.39 (m, 1H) 7.56 (m,
1H) 7.87 (d, 1H) 7.93 (s, 1H) 341
3-(5-Chloro-2-fluoro-phenyl)-5-(4- 0.32 (m, 2H) 0.56 (m, 2H) 448.1
cyclopropylmethyl-5-thiophen-2-yl- 1.14 (d, 1H) 4.00 (d,
4H-[1,2,4]triazol-3- 2H) 4.76 (s, 2H)
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.16 (ddd, 2H) 7.43 (m, 1H)
7.50 (t, 2H) 7.99 (dd, 1H) 342 4-{5-[3-(5-Chloro-2-fluoro-phenyl)-
1.40 (t, 3H) 4.63 (q, 2H) 417.8 [1,2,4]oxadiazol-5- 4.72 (s, 2H)
7.20 (m, ylmethylsulfanyl]-4-ethyl-4H- 1H) 7.53 (m, 1H)
[1,2,4]triazol-3-yl}-pyrimidine 8.06 (dd, 1H) 8.29 (d, 1H) 8.86 (d,
1H) 9.26 (s, 1H). 343 3-(5-Cyclopentyl-4-ethyl-4H- 1.29 (t, 3H)
1.66 (m, 3H) 370.2 [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1.87 (m,
2H) m-tolyl-[1,2,4]oxadiazole 2.02 (m, 3H) 2.42 (s, 3H) 3.01 (s,
2H) 3.90 (d, 2H) 4.52 (s, 2H) 7.39 (d, 2H) 7.90 (d, 2H) 344
3-(3-Chloro-phenyl)-5-{4-ethyl-5- 1.18 (t, 3H) 2.95 (t, 2H) 456.1
[2-(4-methoxy-phenyl)-ethyl]-4H- 3.09 (t, 2H) 3.72 (q,
[1,2,4]triazol-3-ylsulfanylmethyl}- 2H) 3.76 (s, 3H)
[1,2,4]oxadiazole 4.66 (s, 2H) 6.81 (d, 2H) 7.09 (d, 2H) 7.40 (t,
1H) 7.47 (m, 1H) 7.92 (d, 1H) 8.03 (s, 1H) 345
5-(3-Chloro-phenyl)-3-(4-ethyl-5-p- 1.23 (t, 3H) 2.22 (s, 3H) 442.1
tolyloxymethyl-4H-[1,2,4]triazol-3- 4.02 (d, 2H) 4.60 (s,
ylsulfanylmethyl)-[1,2,4]oxadiazole 2H) 5.22 (s, 2H) 6.92 (d, 2H)
7.09 (d, 2H) 7.65 (t, 1H) 7.79 (d, 1H) 8.04 (m, 2H) 346
5-(3-Chloro-phenyl)-3-[4-(2- 3.14 (s, 3H) 3.57 (t, 2H) 433.9
methoxy-ethyl)-5-thiophen-2-yl-4H- 4.30 (t, 2H) 4.58 (s,
[1,2,4]triazol-3-ylsulfanylmethyl]- 2H) 7.23 (m, 1H)
[1,2,4]oxadiazole 7.64 (m, 2H) 7.78 (m, 2H) 8.03 (d, 2H) 347
3-(5-Chloro-2-fluoro-phenyl)-5-(4- 7.98 (m, 1H), 7.43 (m, 384.9
ethyl-5-methoxymethyl-4H- 1H), 7.16 (apparent t,
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 4.73 (s, 2H),
[1,2,4]oxadiazole 4.62 (s, 2H), 4.01 (q, 2H), 3.33 (s, 3H), 1.34
(t, 3H). 348 5-(5-Chloro-2-fluoro-phenyl)-3-(4- 8.05 (m, 1H), 7.53
(m, 384.9 ethyl-5-methoxymethyl-4H- 1H), 7.21 (apparent t,
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H); 4.62 (s, 2H),
[1,2,4]oxadiazole 4.61 (s, 2H), 4.02 (q, 2H), 3.34 (s, 3H), 1.32
(t, 3H). 349 5-(3-Chloro-phenyl)-3-(4-ethyl-5- 8.07 (apparent s,
1H), 366.9 methoxymethyl-4H-[1,2,4]triazol-3- 7.97 (m, 1H), 7.55
(m, ylsulfanylmethyl)-[1,2,4]oxadiazole 1H), 7.45 (apparent t, 1H),
4.62 (s, 2H), 4.59 (s, 2H), 4.01 (q, 2H), 3.34 (s, 3H), 1.32 (t,
3H). 350 3-(3-Chloro-phenyl)-5-(4-ethyl-5- 8.02 (m, 1H), 7.92 (m,
366.9 methoxymethyl-4H-[1,2,4]triazol-3- 1H), 7.46 (m, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.39 (apparent t, 1H), 4.71 (s,
2H), 4.62 (s, 2H), 4.01 (q, 2H), 3.34 (s, 3H), 1.34 (t, 3H). 351
4-(5-{1-[3-(3-Chloro-phenyl)- 1.82 (d, 3H), 3.46 (s, 3H), 399.1
isoxazol-5-yl]-ethylsulfanyl}-4- 4.93 (q, 1H),
methyl-4H-[1,2,4]triazol-3-yl)- 6.33 (s, 1H), 7.23-7.31 (m, 2H),
pyridine 7.44 (d, 2H), 7.49 (m, 1H), 7.61 (s, 1H), 8.63 (d, 2H).
352 3-(4-Allyl-5-furan-2-yl-4H- 4.6 (s, 2H), 4.8 (d, 2H), 399.95
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 5.0 (d, 1H), 5.2 (d, 1H),
(3-chloro-phenyl)-[1,2,4]oxadiazole 5.9 (m, 1H), 6.5 (m, 1H), 7.1
(d, 1H), 7.4 (t, 1H), 7.5 (m, 2H), 8.0 (d, 1H), 8.1 (s, 1H) 353
3-(4-Allyl-5-furan-2-yl-4H- 4.5 (s, 2H) 4.8 (d, 2H) 371.98
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 5.0 (d, 1H) 5.2 (d, 1H)
thiophen-3-yl-[1,2,4]oxadiazole 5.9 (m, 1H) 6.5 (m, 1H) 7.0 (d, 1H)
7.4 (m, 1H) 7.5 (s, 1H) 7.6 (d, 1H) 8.2 (m, 1H) 354
5-(4-Allyl-5-furan-2-yl-4H- 4.7 (s, 2H) 4.8 (m, 2H) 356.01
[1,2,4]triazol-3-ylsulfanylmethyl)-3- 5.0 (d, 1H) 5.2 (d, 1H)
furan-2-yl-[1,2,4]oxadiazole 5.9 (m, 1H) 6.5 (dt, 2H) 7.1 (dd, 2H)
7.6 (dd, 2H) 355 5-(3-Chloro-phenyl)-3-[4-ethyl-5- 1.4 (t, 3H) 3.7
(s, 3H) 457.91 (4-methoxy-phenoxymethyl)-4H- 4.1 (q, 2H) 4.6 (s,
2H) [1,2,4]triazol-3-ylsulfanylmethyl]- 5.2 (s, 2H) 6.8 (d, 2H)
[1,2,4]oxadiazole 6.9 (d, 2H) 7.4 (t, 1H) 7.6 (d, 1H) 8.0 (d, 1H)
8.1 (s, 1H) 356 3-(3-Chloro-phenyl)-5-[4-ethyl-5- 1.4 (t, 3H) 3.7
(s, 3H) 457.97 (4-methoxy-phenoxymethyl)-4H- 4.1 (q, 2H) 4.8 (s,
2H) [1,2,4]triazol-3-ylsulfanylmethyl]- 5.2 (s, 2H) 6.8 (d, 2H)
[1,2,4]oxadiazole 6.9 (d, 2H) 7.4 (t, 1H) 7.5 (m, 1H) 7.9 (d, 1H)
8.0 (s, 1H) 357 {5-[3-(3-Chloro-phenyl)- 1.4 (t, 3H) 4.2 (d, 2H)
352.09 [1,2,4]oxadiazol-5- 4.7 (s, 2H) 4.9 (s, 2H)
ylmethylsulfanyl]-4-ethyl-4H- 7.4 (t, 1H) 7.5 (m, 1H)
[1,2,4]triazol-3-yl}-methanol 7.9 (d, 1H) 8.0 (s, 1H) 358
3-(3-Chloro-phenyl)-5-[4-ethyl-5- 1.3 (t, 3H) 3.0 (t, 2H) 380.12
(2-methoxy-ethyl)-4H- 3.3 (s, 3H) 3.8 (t, 2H)
[1,2,4]triazol-3-ylsulfanylmethyl]- 3.9 (q, 2H) 4.7 (s, 2H)
[1,2,4]oxadiazole 7.4 (t, 1H) 7.5 (ddd, 1H) 7.9 (dt, 1H) 8.0 (t,
1H) 359 3-(3-Chloro-phenyl)-5-(4-ethyl-5- 1.4 (t, 3H) 2.1 (s, 3H)
382.07 methylsulfanylmethyl-4H- 3.8 (s, 2H) 4.0 (q, 2H)
[1,2,4]triazol-3-ylsulfanylmethyl)- 4.7 (s, 2H) 7.4 (t, 1H)
[1,2,4]oxadiazole 7.5 (ddd, 1H) 7.9 (dt, 1H) 8.0 (t, 1H) 360
3-(3-Chloro-phenyl)-5-(5- .2 (t, 3H) 1.3 (t, 3H) 379.13
ethoxymethyl-4-ethyl-4H- 3.5 (q, 2H) 4.0 (q, 2H)
[1,2,4]triazol-3-ylsulfanylmethyl)- 4.7 (s, 2H) 4.7 (s, 2H)
[1,2,4]oxadiazole 7.4 (t, 1H) 7.5 (ddd, 1H) 7.9 (dt, 1H) 8.0 (t,
1H) 361 5-[3-(3-Chloro-phenyl)- [1,2,4]oxadiazol-5-
ylmethylsulfanyl]-4-ethyl-4H- [1,2,4]triazole-3-carboxylic acid
methyl ester 362 2-(5-Chloro-2-fluoro-phenyl)-5-(4- 1.4 (t 3H) 4.2
(q, 2H) 406.07 ethyl-5-furan-2-yl-4H-[1,2,4]triazol- 4.7 (s, 2H)
6.6 (dd, 1H) 3-ylsulfanylmethyl)- 7.1 (d, 1H) 7.2 (m, 1H)
[1,3,4]oxadiazole 7.5 (ddd, 1H) 7.6 (d, 1H) 8.0 (dd, 1H) 363
2-(3-Chloro-phenyl)-5-(4- 0.9 (m, 2H) 1.2 (m, 2H) 399.86
cyclopropyl-5-furan-2-yl-4H- 3.2 (m, 1H) 4.8 (s, 2H)
[1,2,4]triazol-3-ylsulfanylmethyl)- 6.6 (m, 1H) 7.0 (d, 1H)
[1,3,4]oxadiazole 7.4 (t, 1H) 7.5 (m, 1H) 7.6 (m, 1H) 7.9 (m, 1H)
8.0 (m, 1H) 364 5-(3-Chloro-phenyl)-3-{1-[4-ethyl- 1.3 (t, 3H) 1.9
(d, 3H) 406.04 5-(tetrahydro-furan-2-yl)-4H- 2.0 (m, 1H) 2.1 (m,
1H) [1,2,4]triazol-3-ylsulfanyl]-ethyl}- 2.3 (m, 1H) 2.8 (m,
[1,2,4]oxadiazole 1H) 3.8 (m, 2H) 4.0 (m, 1H) 4.1 (m, 1H) 5.0 (m,
1H) 5.1 (m, 1H) 7.4 (t, 1H) 7.6 (m, 1H) 8.0 (m, 1H) 8.1 (s, 1H) 365
4-(5-{1-[5-(3-Chloro-phenyl)- 1.4 (t, 3H) 1.9 (d, 3H) 414.12
[1,2,4]oxadiazol-3-yl]- 4.1 (m, 2H) 5.2 (q, 1H)
ethylsulfanyl}-4-ethyl-4H- 7.4 (t, 1H) 7.5 (m, 1H)
[1,2,4]triazol-3-yl)-pyridazine 7.8 (m, 1H) 8.0 (m, 1H) 8.1 (m, 1H)
9.4 (m, 1H) 9.5 (s, 1H) 366 4-(5-{1-[5-(3-Chloro-phenyl)- 1.0 (t,
3H) 1.9 (d, 3H) 427.06 [1,2,4]oxadiazol-3-yl]- 3.7 (m, 2H) 4.2 (m,
2H) ethylsulfanyl}-4-ethyl-4H- 5.0 (q, 1H) 7.1 (m, 2H)
[1,2,4]triazol-3-ylmethyl)-pyridine 7.4 (t, 1H) 7.5 (m, 1H) 7.9 (d,
1H) 8.1 (s, 1H) 8.5 (m, 2H) 367 5-(5-{1-[5-(3-Chloro-phenyl)- 1.3
(t, 3H) 1.9 (d, 3H) 429.1 [1,2,4]oxadiazol-3-yl]- 3.9 (m, 2H) 5.1
(q, 1H) ethylsulfanyl}-4-ethyl-4H- 6.7 (d, 1H) 7.5 (t, 1H)
[1,2,4]triazol-3-yl)-pyridin-2-ol 7.6 (m, 1H) 7.7 (m, 1H) 7.7 (s,
1H) 8.0 (d, 1H) 8.1 (s, 1H) 13.1 (s, 1H) 368
4-(5-{1-[5-(3-Chloro-phenyl)- 1.2 (t, 3H) 1.9 (d, 3H) 428.08
[1,2,4]oxadiazol-3-yl]- 3.9 (q, 2H) 5.1 (q, 1H)
ethylsulfanyl}-4-ethyl-4H- 6.9 (d, 2H) 7.3 (d, 2H)
[1,2,4]triazol-3-yl)-phenol 7.4 (t, 1H) 7.5 (m, 1H) 7.9 (m, 1H) 8.1
(m, 1H) 10.2 (s, 1H) 369 5-(3-Chloro-phenyl)-3-[5-(4- 1.54 (m, 1H)
1.86 (m, 2H) methoxy-phenoxymethyl)-4- 2.02 (m, 1H)
(tetrahydro-furan-2-ylmethyl)-4H- 3.71 (m, 4H) 3.79 (m, 1H)
[1,2,4]triazol-3-ylsulfanylmethyl]- 4.13 (m, 3H) 4.60 (m, 2H)
[1,2,4]oxadiazole 5.30 (s, 2H) 6.82 (m, 2H) 6.92 (m, 2H) 7.44 (t,
1H) 7.55 (d, 1H) 7.95 (d, 1H) 8.07 (s, 1H) 370
5-(3-Chloro-phenyl)-3-[4- 1.14 (m, 4H) 3.10 (s, 1H)
cyclopropyl-5-(4-methoxy- 3.75 (s, 3H) 4.70 (s,
phenoxymethyl)-4H-[1,2,4]triazol- 2H) 5.21 (s, 2H)
3-ylsulfanylmethyl]- 6.82 (d, 2H) 6.95 (d, 2H) [1,2,4]oxadiazole
7.45 (t, 1H) 7.56 (m, 1H) 7.99 (d, 1H) 8.10 (s, 1H) 371
5-(5-Chloro-2-fluoro-phenyl)-3-(4- 1.38 (t, 3H) 4.27 (q, 2H)
ethyl-5-furan-2-yl-4H-[1,2,4]triazol- 4.64 (s, 2H) 6.58 (m,
3-ylsulfanylmethyl)- 1H) 7.21 (m, 2H) [1,2,4]oxadiazole 7.53 (m,
1H) 7.59 (m, 1H) 8.06 (m, 1H) 372 3-(4-Ethyl-5-methoxymethyl-4H-
1.29 (t, 3H) 2.40 (s, 3H) 346
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 3.31 (s, 3H) 3.99 (m,
m-tolyl-[1,2,4]oxadiazole 2H) 4.56 (s, 2H) 4.60 (s, 2H) 7.37 (m,
2H) 7.87 (m, 2H) 373 3-[4-Ethyl-5-(tetrahydro-furan-2- 1.30 (t, 3H)
1.97 (m, 1H) 372 yl)-4H-[1,2,4]triazol-3- 2.10 (m, 1H)
ylsulfanylmethyl]-5-m-tolyl- 2.24 (m, 1H) 2.39 (s, 3H)
[1,2,4]oxadiazole 2.80 (m, 1H) 3.79 (m, 1H) 3.86 (m, 1H) 3.99 (m,
1H) 4.08 (m, 1H) 4.54 (m, 2H) 4.98 (m, 1H) 7.36 (m, 2H) 7.86 (m,
1H) 7.88 (s, 1H) 374 2-(3-Chloro-phenyl)-5-{1-[4-ethyl- 1.18 (m,
3H) 1.95 (d, 3H) 5-(4-methoxy-phenyl)-4H- 3.81 (s, 3H) 3.90 (q,
[1,2,4]triazol-3-ylsulfanyl]-ethyl}- 2H) 5.15 (q, 1H)
[1,3,4]oxadiazole 6.94 (m, 2H) 7.35 (m, 1H) 7.45 (m, 3H) 7.81 (m,
1H) 7.92 (m, 1H) 375 4-{5-[3-(2,5-Difluoro-phenyl)- 1.43 (t, 3H),
4.64 (q, 2H), 402.1 [1,2,4]oxadiazol-5- 4.87 (s, 2H),
ylmethylsulfanyl]-4-ethyl-4H- 7.18 (m, 2H), 7.72 (m, 1H),
[1,2,4]triazol-3-yl}-pyrimidine 8.29 (dd, 1H), 8.89 (d, 1H), 9.30
(d, 1H) 376 4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 4.12 (s, 3H), 4.64
(s, 2H), 404.1 [1,2,4]oxadiazol-3- 7.21 (t, 1H),
ylmethylsulfanyl]-4-methyl-4H- 7.57 (m, 1H), 8.06 (dd, 1H),
[1,2,4]triazol-3-yl}-pyrimidine 8.28 (dd, 1H), 8.92 (d, 1H), 9.30
(d, 1H) 377 3-(3-Chloro-phenyl)-5-(4-methyl-5- 8.03 (s, 1H), 7.92
(d, 390.96 thiophen-2-yl-4H-[1,2,4]triazol-3- 1H), 7.53 (d, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.48 (m, 2H), 7.40 (t, 1H),
7.18 (t, 1H), 4.87 (s, 2H), 3.72 (s, 3H). 378
5-(3-Methylsulfanyl-phenyl)-3-(4- 7.92 (s, 1H), 7.84 (d,
methyl-5-thiophen-2-yl-4H- 1H), 7.53 (m, 2H),
[1,2,4]triazol-3-ylsulfanylmethyl)- 7.43 (m, 2H), 7.18 (m, 1H),
[1,2,4]oxadiazole 4.53 (s, 2H), 3.73 (s, 3H), 2.52 (s, 3H). 379
2-[5-(3-Methylsulfanyl-phenyl)- [1,2,4]oxadiazol-3-
ylmethylsulfanyl]-1H- benzoimidazole 380
5-(2,5-Dimethyl-phenyl)-3-(4- 7.87 (s, 1H), 7.49 (m,
methyl-5-thiophen-2-yl-4H- 2H), 7.22 (m, 3H),
[1,2,4]triazol-3-ylsulfanylmethyl)- 4.56 (d, 2H), 3.74 (s, 3H),
[1,2,4]oxadiazole 2.61 (s, 3H), 2.37 (s, 3H). 381
5-(2-Fluoro-5-methyl-phenyl)-3-(4- 7.83 (dd, 1H), 7.49 (m, 388.10
methyl-5-thiophen-2-yl-4H- 2H), 7.35 (m, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl)- 7.16 (m, 2H), 4.53 (s, 2H),
[1,2,4]oxadiazole 3.73 (s, 3H), 2.35 (s, 3H). 382
5-(3-Cyclopropyl-phenyl)-3-(4- 7.87 (d, 1H), 7.79 (s,
methyl-5-thiophen-2-yl-4H- 1H), 7.51 (m, 2H),
[1,2,4]triazol-3-ylsulfanylmethyl)- 7.40 (t, 1H), 7.30 (m, 1H),
[1,2,4]oxadiazole 7.20 (m, 1H), 4.53 (s, 2H), 3.73 (s, 3H), 1.96
(m, 1H), 1.04 (m, 2H), 0.77 (m, 2H). 383
4-{5-[2-(3-Chloro-phenyl)-oxazol- 8.80 (d, 2H), 8.02 (dd,
4-ylmethylsulfanyl]-4-methyl-4H- 1H), 7.88 (dd, 1H),
[1,2,4]triazol-3-yl}-pyridine 7.80 (s, 1H), 7.60 (d, 2H), 7.42 (m,
2H), 4.51 (s, 2H), 3.64 (s, 3H). 384
4-[4-Methyl-5-(5-thiophen-2-yl- 8.82 (bs, 2H), 7.90 (m,
[1,2,4]oxadiazol-3- 1H), 7.66 (m, 3H),
ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.22 (m, 1H), 4.58 (s, 2H),
3-yl]-pyridine 3.73 (s, 3H). 385 4-{4-Methyl-5-[5-(3- 8.81 (m, 2H),
7.95 (s, methylsulfanyl-phenyl)- 1H), 7.86 (m, 1H),
[1,2,4]oxadiazol-3- 7.64 (m, 2H), 7.45 (m, 2H),
ylmethylsulfanyl]-4H-[1,2,4]triazol- 4.63 (s, 2H), 3.72 (s,
3-yl}-pyridine 3H), 2.55 (3H). 386 4-{5-[5-(3-Chloro-phenyl)- 8.83
(d, 2H), 8.11 (s, [1,2,4]oxadiazol-3- 1H), 8.00 (d, 1H),
ylmethylsulfanyl]-4-methyl-4H- 7.64 (m, 2H), 7.60 (m, 1H),
[1,2,4]triazol-3-yl}-pyridine 7.49 (t, 1H), 4.64 (s, 2H), 3.73 (s,
3H). 387 2-Methyl-4-[3-(4-methyl-5-pyridin- 8.82 (d, 2H), 8.74 (d,
4-yl-4H-[1,2,4]triazol-3- 1H), 7.82 (s, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.76 (d, 1H), 7.64 (d, 2H),
5-yl]-pyridine 4.68 (s, 2H), 3.74 (s, 3H), 2.68 (s, 3H). 388
1-{3-[3-(4-Methyl-5-thiophen-2-yl- 8.67 (s, 1H), 8.29 (d,
4H-[1,2,4]triazol-3- 1H) 8.20 (d, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.68 (t, 1H), 7.52 (m, 2H),
5-yl]-phenyl}-ethanone 7.20 (m, 1H), 4.58 (s, 2H), 3.76 (s, 3H),
2.68 (s, 3H). 389 4-{5-[5-(2-Fluoro-5-methyl- 8.81 (dd, 2H), 7.86
(d, 383.09 phenyl)-[1,2,4]oxadiazol-3- 1H), 7.64 (m, 2H),
ylmethylsulfanyl]-4-methyl-4H- 7.39 (m, 1H), 7.14 (dd, 1H),
[1,2,4]triazol-3-yl}-pyridine 4.63 (s, 2H), 3.73 (s, 3H), 2.39 (s,
3H). 390 2-Methyl-4-[4-methyl-5-(5-m-tolyl- 8.68 (dd, 1H), 7.92 (m,
[1,2,4]oxadiazol-3- 2H), 7.52 (bs, 1H),
ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.4 (m, 3H), 4.61 (s, 2H),
3-yl]-pyridine 3.7 (s, 3H), 2.67 (s, 3H), 2.44 (s, 3913H). 391
3-[5-(3-Chloro-phenyl)-isoxazol-3- 7.76 (s, 1H), 7.68 (m,
ylmethylsulfanyl]-4-methyl-5- 1H), 7.54 (m, 1H),
thiophen-2-yl-4H-[1,2,4]triazole 7.48 (m, 1H), 7.40 (m, 2H), 7.20
(m, 1H), 6.76 (s, 1H), 4.56 (s, 2H), 3.70 (s, 3H). 392
4-{5-[5-(3-Chloro-phenyl)-isoxazol- 8.82 (m, 2H), 7.76 (m,
3-ylmethylsulfanyl]-4-methyl-4H- 1H), 7.65 (m, 3H),
[1,2,4]triazol-3-yl}-pyridine 7.41 (m, 2H), 6.77 (s, 1H), 4.61 (s,
2H), 3.69 (s, 3H). 393 3-(4-Butyl-5-thiophen-2-yl-4H- 8.07 (s, 1H),
7.95 (dd, [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.48 (m, 4H),
(3-chloro-phenyl)-[1,2,4]oxadiazole 7.17 (dd, 1H), 4.59 (s, 2H),
4.05 (t, 2H), 1.67 (m, 2H), 1.30 (m, 2H), 0.88 (t, 3H). 394
5-(3-Chloro-phenyl)-3-[4-(3- 8.01 (d, 1H), 7.91 (dd,
methoxy-propyl)-5-thiophen-2-yl- 1H), 7.48 (m, 4H),
4H-[1,2,4]triazol-3- 7.12 (m, 1H), 4.51 (s, 2H),
ylsulfanylmethyl]-[1,2,4]oxadiazole 4.17 (t, 2H), 3.34 (t, 2H),
3.18 (s, 3H), 1.90 (m, 2H). 395 3-(4-Benzyl-5-thiophen-2-yl-4H-
8.09 (s, 1H), 7.97 (dd, [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H),
7.57 (m, 1H), (3-chloro-phenyl)-[1,2,4]oxadiazole 7.47 (m, 2H),
7.24 (m, 4H), 7.06 (m, 3H), 5.37 (s, 2H), 4.57 (s, 2H). 396
5-(3-Chloro-phenyl)-3-(4-furan-2- 8.10 (d, 1H), 8.03 (dd, 457.02
ylmethyl-5-thiophen-2-yl-4H- 1H), 7.55 (m, 4H),
[1,2,4]triazol-3-ylsulfanylmethyl)- 7.38 (s, 1H), 7.20 (dd, 1H),
[1,2,4]oxadiazole 6.32 (m, 2H), 5.30 (s, 2H), 4.60 (s, 2H). 397
3-{5-[5-(3-Chloro-phenyl)- 8.93 (m, 1H), 8.78 (m,
[1,2,4]oxadiazol-3- 1H), 8.03 (m, 3H),
ylmethylsulfanyl]-4-methyl-4H- 7.59 (m, 1H), 7.51 (m, 2H),
[1,2,4]triazol-3-yl}-pyridine 4.63 (s, 2H), 3.69 (s, 3H). 398
5-(3-Chloro-phenyl)-3-(4-methyl-5- 8.11 (m, 1H), 8.05 (m,
thiophen-3-yl-4H-[1,2,4]triazol-3- 1H), 7.74 (m, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.59 (m, 1H), 7.51 (m, 3H),
4.57 (s, 2H), 3.71 (s, 3H). 399 4-{5-[5-(3-Chloro-phenyl)- 8.69 (d,
1H), 8.10 (s, [1,2,4]oxadiazol-3- 1H), 8.00 (m, 1H),
ylmethylsulfanyl]-4-methyl-4H- 7.49 (m, 4H), 4.63 (s, 2H),
[1,2,4]triazol-3-yl}-2-methyl- 3.71 (s, 3H), 2.67 (s, pyridine 3H).
400 5-(5-Chloro-2-fluoro-phenyl)-3-(4- 8.08 (m, 1H), 7.51 (m,
409.00 methyl-5-thiophen-2-yl-4H- 1H) 7.21 (m, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl)- 4.59 (s, 2H), 3.77 (s, 3H).
[1,2,4]oxadiazole 401 4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.82 (d,
2H), 8.08 (m, 404.07 [1,2,4]oxadiazol-3- 1H) 8.29 (d, 1H),
ylmethylsulfanyl]-4-methyl-4H- 7.64 (d, 2H), 7.56 (m, 1H),
[1,2,4]triazol-3-yl}-pyridine 7.24 (t, 1H), 4.66 (s, 2H), 3.75 (s,
3H). 402 3-{5-[5-(2-Fluoro-5-methyl- 8.92 (s, 1H), 8.76 (d,
phenyl)-[1,2,4]oxadiazol-3- 1H), 8.07 (d, 1H),
ylmethylsulfanyl]-4-methyl-4H- 7.87 (d, 1H), 7.36 (m, 3H),
[1,2,4]triazol-3-yl}-pyridine 4.59 (s, 2H), 3.69 (s, 3H), 2.39 (s,
3H). 403 5-(3-Chloro-phenyl)-3-(5-thiophen- (CD3OD as solvent):
2-yl-4-thiophen-2-ylmethyl-4H- 8.05 (m, 1H), 8.00 (dd,
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.75 (dd, 1H),
[1,2,4]oxadiazole 7.58 (m, 1H), 7.54 (m, 1H), 7.53 (m, 1H), 7.26
(m, 1H), 7.22 (m, 1H), 6.86 (m, 2H), 5.63 (s, 2H), 4.51 (s, 2H).
404 5-(3-Chloro-phenyl)-3-(4-ethyl-5- (CD3OD as 405.10
thiophen-2-yl-4H-[1,2,4]triazol-3- solvent): 8.08 (m, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 8.07 (dd, 1H), 7.75 (m, 1H),
7.67 (m, 1H), 7.60 (m, 2H), 7.28 (dd, 1H), 4.57 (s, 2H), 4.27 (m,
2H), 1.29 (m, 3H). 405 3-{5-[3-(2-Fluoro-5-methyl- 8.90 (m, 1H),
8.77 (dd, phenyl)-[1,2,4]oxadiazol-5- 1H), 8.03 (m, 1H),
ylmethylsulfanyl]-4-methyl-4H- 7.78 (m, 1H), 7.48 (m, 1H),
[1,2,4]triazol-3-yl}-pyridine 7.28 (m, 1H), 7.12 (m, 1H), 4.73 (s,
2H), 3.68 (s, 3H), 2.36 (s, 3H). 406 4-{5-[3-(2-Fluoro-5-methyl-
8.81 (m, 2H), 7.77 (m, phenyl)-[1,2,4]oxadiazol-5- 1H), 7.62 (m,
2H), ylmethylsulfanyl]-4-methyl-4H- 7.31 (m, 1H), 7.11 (dd, 1H),
[1,2,4]triazol-3-yl}-pyridine 4.75 (s, 2H), 3.72 (s, 3H), 2.37 (s,
3H). 407 4-{5-[5-(5-Bromo-2-fluoro-phenyl)- 8.82 (m, 2H), 8.23 (m,
448.02 [1,2,4]oxadiazol-3- 1H), 7.71 (m, 2H),
ylmethylsulfanyl]-4-methyl-4H- 7.65 (m, 1H), 7.18 (d, 1H),
[1,2,4]triazol-3-yl}-pyridine 4.66 (s, 2H), 3.75 (s, 3H). 408
3-{5-[5-(5-Bromo-2-fluoro-phenyl)- 8.92 (m, 1H), 8.76 (m,
[1,2,4]oxadiazol-3- 1H), 8.22 (m, 1H),
ylmethylsulfanyl]-4-methyl-4H- 8.05 (m, 1H), 7.50 (m, 1H),
[1,2,4]triazol-3-yl}-pyridine 7.48 (m, 1H), 7.17 (dd, 1H), 4.63 (s,
2H), 3.70 (s, 3H). 409 5-(5-Bromo-2-fluoro-phenyl)-3-(4- 8.23 (dd,
1H), 7.70 (m, 452.90 methyl-5-thiophen-2-yl-4H- 1H), 7.52 (m, 2H),
[1,2,4]triazol-3-ylsulfanylmethyl)- 7.19 (m, 2H), 4.49 (s, 2H),
[1,2,4]oxadiazole 3.77 (s, 3H). 410 5-(4-Methyl-5-thiophen-3-yl-4H-
8.06 (d, 2H) 7.34 (d, [1,2,4]triazol-3-ylsulfanylmethyl)-3- 1H),
7.51 (m, 5H), phenyl-[1,2,4]oxadiazole 4.68 (s, 2H), 3.68 (s, 3H).
411 3-{5-[5-(3-Fluoro-phenyl)- 8.92 (s, 1H), 8.78 (d,
[1,2,4]oxadiazol-3- 1H) 8.05 (d, 1H),
ylmethylsulfanyl]-4-methyl-4H- 7.93 (d, 1H), 7.91 (d, 1H),
[1,2,4]triazol-3-yl}-pyridine 7.50 (m, 2H), 7.28 (t, 1H), 4.64 (s,
2H), 3.70 (s, 3H). 412 4-{5-[5-(3-Fluoro-phenyl)- 8.82 (d, 2H),
7.93 (d, [1,2,4]oxadiazol-3- 1H) 7.90 (d, 1H),
ylmethylsulfanyl]-4-methyl-4H- 7.64 (d, 2H), 7.52 (m, 1H),
[1,2,4]triazol-3-yl}-pyridine 7.33 (m, 1H), 4.64 (s, 2H), 3.73 (s,
3H). 413 5-(3-Fluoro-phenyl)-3-(4-methyl-5- 7.90 (d, 1H) 7.82 (d,
thiophen-3-yl-4H-[1,2,4]triazol-3- 1H), 7.74 (d, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.51 (m, 3H), 4.58 (s, 2H),
3.71 (s, 3H). 414 3-[4-Methyl-5-(5-thiophen-3-yl- 8.91 (s, 1H),
8.78 (d, [1,2,4]oxadiazol-3- 1H) 8.23 (d, 1H),
ylmethylsulfanyl)-4H-[1,2,4]triazol- 8.04 (d, 1H), 7.66 (d, 1H),
3-yl]-pyridine 7.49 (m, 2H), 4.60 (s, 2H), 3.69 (s, 3H). 415
3-(4-Methyl-5-thiophen-3-yl-4H- 8.22 (d, 1H) 7.74 (d,
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.63 (d, 1H),
thiophen-3-yl-[1,2,4]oxadiazole 7.49 (m, 3H), 4.54 (s, 2H), 3.70
(s, 3H). 416 2-Chloro-4-[3-(4-methyl-5-pyridin- 8.92 (s, 1H), 8.78
(d, 3-yl-4H-[1,2,4]triazol-3- 1H) 8.65 (d, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazol- 8.04 (t, 2H), 7.89 (d, 1H),
5-yl]-pyridine 7.51 (m, 1H), 4.69 (s, 2H), 3.71 (s, 3H). 417
2-Chloro-4-[3-(4-methyl-5-pyridin- 8.82 (d, 2H), 8.65 (d,
4-yl-4H-[1,2,4]triazol-3- 1H) 8.02 (s, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.89 (d, 1H), 7.64 (d, 2H),
5-yl]-pyridine 4.70 (s, 2H), 3.74 (s, 3H). 418
2-Chloro-4-[3-(4-methyl-5- 8.64 (d, 1H) 8.01 (s,
thiophen-3-yl-4H-[1,2,4]triazol-3- 1H), 7.88 (d, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.75 (d, 1H), 7.52 (m, 2H),
5-yl]-pyridine 4.62 (s, 2H), 3.72 (s, 3H). 419
4-[4-Methyl-5-(5-phenyl- 8.82 (d, 2H), 8.12 (d, [1,2,4]oxadiazol-3-
2H) 7.63 (m, 3H), ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.55 (m,
2H), 4.63 (s, 2H), 3-yl]-pyridine 3.72 (s, 3H). 420
3-(4-Methyl-5-thiophen-3-yl-4H- 8.11 (d, 2H) 7.74 (d,
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.57 (m, 1H),
phenyl-[1,2,4]oxadiazole 7.52 (m, 4H), 4.56 (s, 2H), 3.70 (s, 3H).
421 5-(5-Bromo-2-fluoro-phenyl)-3-(4- (CD3OD as
methyl-5-thiophen-3-yl-4H- solvent): 8.21 (m, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl)- 8.02 (m, 1H), 7.82 (m,
[1,2,4]oxadiazole 1H), 7.68 (m, 1H), 7.56 (m, 1H), 7.33 (t, 1H),
4.50 (s, 2H), 3.82 (s, 3H). 422 3-[5-(3-Chloro-phenyl)-isoxazol-3-
(CD3OD as solvent): 404.05 ylmethylsulfanyl]-4-ethyl-5- 7.84 (s,
1H), 7.75 (m, thiophen-2-yl-4H-[1,2,4]triazole 2H), 7.60 (m, 1H)
7.50 (m, 2H), 7.27 (m, 1H), 6.92 (s, 1H), 4.51 (s, 2H), 4.23 (q,
2H), 1.33 (t, 3H). 423 2-Chloro-4-[3-(4-methyl-5- 8.64 (d, 1H),
8.01 (s, 392.00 thiophen-2-yl-4H-[1,2,4]triazol-3- 1H) 7.98 (d,
1H), ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.54 (d, 1H), 7.50 (d,
1H), 5-yl]-pyridine 7.20 (m, 1H), 4.61 (s, 2H), 3.76 (s, 3H). 424
4-{5-[3-(3-Fluoro-phenyl)- 8.83 (d, 2H), 7.85 (d,
[1,2,4]oxadiazol-5- 1H) 7.78 (d, 1H),
ylmethylsulfanyl]-4-methyl-4H- 7.62 (d, 2H), 7.46 (m, 1H),
[1,2,4]triazol-3-yl}-pyridine 7.22 (m, 1H), 4.76 (s, 2H), 3.72 (s,
3H). 425 3-(3-Fluoro-phenyl)-5-(4-methyl-5- 7.84 (d, 1H) 7.74 (m,
thiophen-3-yl-4H-[1,2,4]triazol-3- 1H), 7.51 (m, 3H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.24 (m, 1H), 4.70 (s, 2H),
3.70 (s, 3H). 426 3-(4-Ethyl-5-thiophen-2-yl-4H- (CD3OD as 384.13
[1,2,4]triazol-3-ylsulfanylmethyl)-5- solvent): 7.89 (m, 2H),
m-tolyl-[1,2,4]oxadiazole 7.76 (m, 1H), 7.60 (m, 1H), 7.47 (m, 2H),
7.27 (m, 1H), 4.55 (s, 2H), 4.25 (q, 2H), 2.41 (s, 3H), 1.32 (s,
3H) 427 3-(4-Ethyl-5-thiophen-2-yl-4H- (CD3OD as 402.09
[1,2,4]triazol-3-ylsulfanylmethyl)-5- solvent): 7.85 (m, 1H),
(2-fluoro-5-methyl-phenyl)- 7.75 (m, 1H), 7.60 (m,
[1,2,4]oxadiazole 1H), 7.55 (m, 1H), 7.27 (m, 1H), 7.22 (m, 1H),
4.57 (s, 2H), 4.27 (q, 2H), 2.36 (s, 3H), 1.33 (s, 3H). 428
4-{5-[5-(3-Chloro-phenyl)- (CD3OD as 452.10 [1,2,4]oxadiazol-3-
solvent): 8.75 (m, 2H), ylmethylsulfanyl]-4-furan-2- 8.04 (m, 2H),
7.78 (m, ylmethyl-4H-[1,2,4]triazol-3-yl}- 2H), 7.66 (m, 1H),
pyridine 7.60 (m, 1H), 7.37 (m, 1H), 6.30 (m, 2H), 5.42 (s, 2H),
4.56 (s, 2H). 429 4-{5-[5-(3-Chloro-phenyl)- 8.80 (m, 2H), 8.09 (m,
[1,2,4]oxadiazol-3- 1H), 7.98 (m, 1H),
ylmethylsulfanyl]-4-ethyl-4H- 7.58 (m, 3H), 7.50 (dd, 1H),
[1,2,4]triazol-3-yl}-pyridine 4.69 (s, 2H), 4.12 (m, 2H), 1.36 (m,
3H). 430 3-{5-[5-(3-Chloro-phenyl)- (CD3OD as 400.12
[1,2,4]oxadiazol-3- solvent): 8.87 (s, 1H),
ylmethylsulfanyl]-4-ethyl-4H- 8.77 (d, 1H), 8.07 (m,
[1,2,4]triazol-3-yl}-pyridine 3H), 7.67 (m, 2H), 7.61 (dd, 1H),
4.62 (s, 2H), 4.13 (m, 2H), 1.26 (m, 3H). 431
5-(3-Chloro-phenyl)-3-(4-ethyl-5- (CD3OD as 405.07
thiophen-3-yl-4H-[1,2,4]triazol-3- solvent): 7.79 (m, 3H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.67 (m, 2H), 7.51 (m, 2H),
4.56 (s, 2H), 4.22 (q, 2H), 1.30 (t, 3H). 432
3-{5-[5-(3-Chloro-phenyl)- (CD3OD as 452.12 [1,2,4]oxadiazol-3-
solvent): 8.86 (s, 1H), ylmethylsulfanyl]-4-furan-2- 8.76 (d, 1H),
8.07 (m, ylmethyl-4H-[1,2,4]triazol-3-yl}- 1H), 8.01 (m, 2H),
pyridine 7.64 (m, 3H), 7.36 (s, 1H), 6.29 (s, 2H), 5.37 (s, 2H),
4.55 (s, 2H). 433 3-(4-Furan-2-ylmethyl-5-thiophen- (CD3OD as
436.16 2-yl-4H-[1,2,4]triazol-3- solvent): 7.87 (m, 2H),
ylsulfanylmethyl)-5-m-tolyl- 7.73 (m, 1H), 7.63 (m,
[1,2,4]oxadiazole 1H), 7.45 (m, 3H), 7.25 (m, 1H), 6.31 (m, 2H),
5.42 (s, 2H), 4.49 (s, 2H), 2.40 (s, 3H). 434
5-(5-Fluoro-2-methyl-phenyl)-3-(4- (CD3OD as 454.12
furan-2-ylmethyl-5-thiophen-2-yl- solvent): 7.75 (dd, 1H),
4H-[1,2,4]triazol-3- 7.69 (m, 1H), 7.66 (m,
ylsulfanylmethyl)-[1,2,4]oxadiazole 1H), 7.41 (m, 1H), 7.38 (m,
1H), 7.25 (m, 2H), 6.32 (s, 2H), 5.44 (s, 2H), 4.51 (s, 2H), 2.36
(s, 3H). 435 5-(3-Chloro-phenyl)-3-(4-furan-2- 8.23 (s, 1H), 8.09
(m, 375.09 ylmethyl-4H-[1,2,4]triazol-3- 1H), 7.97 (m, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.48 (m, 1H), 7.45 (m, 1H),
7.37 (s, 1H), 6.39 (m, 1H), 6.34 (m, 1H), 5.12 (s, 2H), 4.55 (s,
2H). 436 3-[3-(4-Methyl-5-pyridin-3-yl-4H- 8.92 (s, 1H), 8.78 (d,
376.20 [1,2,4]triazol-3-ylsulfanylmethyl)- 1H) 8.43 (s, 1H),
[1,2,4]oxadiazol-5-yl]-benzonitrile 8.35 (d, 1H), 8.05 (d, 1H),
7.91 (d, 1H), 7.72 (t, 1H), 7.52 (m, 1H), 4.67 (s, 2H), 3.71 (s,
3H). 437 3-[3-(4-Methyl-5-pyridin-4-yl-4H- 8.82 (d, 2H), 8.43 (s,
376.10 [1,2,4]triazol-3-ylsulfanylmethyl)- 1H) 8.35 (d, 1H),
[1,2,4]oxadiazol-5-yl]-benzonitrile 7.90 (t, 1H), 7.64 (d, 2H),
4.68 (s, 2H), 3.74 (s, 3H). 438 3-[3-(4-Methyl-5-thiophen-3-yl-4H-
8.42 (s, 1H), 8.35 (d, [1,2,4]triazol-3-ylsulfanylmethyl)- 1H) 7.89
(d, 1H), [1,2,4]oxadiazol-5-yl]-benzonitrile 7.72 (m, 2H), 7.52 (s,
1H), 4.61 (s, 2H), 3.73 (s, 3H). 439
5-(5-Chloro-2-fluoro-phenyl)-3-(4- 8.08 (m, 1H), 7.54 (m, 423.12
ethyl-5-thiophen-2-yl-4H- 2H), 7.48 (d, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl)- 7.20 (m, 2H), 4.69 (s, 2H),
[1,2,4]oxadiazole 4.18 (m, 2H), 1.39 (t, 3H). 440
2-Chloro-4-[3-(4-ethyl-5-thiophen- 8.64 (d, 1H), 8.02 (s, 406.00
2-yl-4H-[1,2,4]triazol-3- 1H), 7.89 (d, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.53 (d, 1H), 7.48 (d, 1H),
5-yl]-pyridine 7.20 (t, 1H), 4.69 (s, 2H), 4.17 (m, 2H), 1.40 (t,
3H). 441 3-(4-Ethyl-5-thiophen-2-yl-4H- 8.23 (s, 1H), 7.66 (d,
376.10 [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.53 (d, 1H),
thiophen-3-yl-[1,2,4]oxadiazole 7.48 (m, 2H), 7.19 (t, 1H), 4.63
(s, 2H), 4.17 (m, 2H), 1.40 (t, 3H). 442
3-(4-Ethyl-5-thiophen-3-yl-4H- 7.93 (m, 2H), 7.71 (m, 384.10
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.49 (m, 2H),
m-tolyl-[1,2,4]oxadiazole 7.42 (m, 2H), 4.63 (s, 2H), 4.10 (q, 2H),
2.43 (s, 3H), 1.36 (t, 3H). 443 4-[4-Ethyl-5-(5-m-tolyl- 8.80 (m,
2H), 7.91 (m, 379.20 [1,2,4]oxadiazol-3- 2H), 7.60 (m, 2H),
ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.41 (m, 2H), 4.68 (s, 2H),
3-yl]-pyridine 4.09 (m, 2H), 2.43 (s, 3H), 1.29 (s, 3H). 444
3-[4-Ethyl-5-(5-m-tolyl- (CD3OD as 379.20 [1,2,4]oxadiazol-3-
solvent): 8.87 (s, 1H), ylmethylsulfanyl)-4H-[1,2,4]triazol- 8.77
(d, 1H), 8.02 (m, 3-yl]-pyridine 1H), 7.92 (m, 2H), 7.49 (m, 1H),
7.42 (m, 2H), 4.67 (s, 2H), 4.05 (q, 2H), 2.43 (s, 3H), 1.35 (t,
3H). 445 3-(4-Ethyl-5-thiophen-3-yl-4H- 7.88 (dd, 1H), 7.71 (m,
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.49 (m, 2H),
(2-fluoro-5-methyl-phenyl)- 7.28 (m, 1H), 7.14 (dd, 1H),
[1,2,4]oxadiazole 4.66 (s, 2H), 4.11 (q, 2H), 2.39 (s, 3H), 1.34
(t, 3H). 446 4-{4-Ethyl-5-[5-(2-fluoro-5-methyl- 8.80 (m, 2H), 7.86
(m, 398.20 phenyl)-[1,2,4]oxadiazol-3- 1H), 7.60 (m, 2H),
ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.38 (m, 1H), 7.14 (dd, 1H),
3-yl}-pyridine 4.70 (s, 2H), 4.11 (q, 2H), 2.39 (s, 3H), 1.36 (t,
3H). 447 3-{4-Ethyl-5-[5-(2-fluoro-5-methyl- 8.87 (s, 1H), 8.76 (d,
phenyl)-[1,2,4]oxadiazol-3- 1H), 8.01 (m, 1H),
ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.88 (m, 1H), 7.49 (m, 1H),
3-yl}-pyridine 7.28 (m, 1H), 7.14 (dd, 1H), 4.69 (s, 2H), 4.07 (q,
2H), 2.39 (q, 2H), 1.35 (t, 3H). 448 3-[5-(3-Chloro-phenyl)-
(DMSO-D6 as solvent): 387.05 [1,2,4]oxadiazol-3- 8.75 (dd, 2H),
8.05 (m, ylmethylsulfanyl]-5-pyridin-4-yl- 4H), 7.79 (m, 1H),
[1,2,4]triazol-4-ylamine 7.66 (dd, 1H), 6.33 (s, 2H), 4.65 (s, 2H).
449 4-{5-[5-(5-Bromo-2-fluoro-phenyl)- 8.81 (dd, 2H), 8.24 (m,
464.02 [1,2,4]oxadiazol-3- 1H), 7.71 (m, 1H),
ylmethylsulfanyl]-4-ethyl-4H- 7.61 (m, 2H), 7.18 (dd, 1H),
[1,2,4]triazol-3-yl}-pyridine 4.72 (s, 2H), 4.13 (m, 2H), 1.29 (m,
3H). 450 5-(4-Methyl-5-thiophen-3-yl-4H- 7.75 (m, 2H), 7.51 (m,
[1,2,4]triazol-3-ylsulfanylmethyl)-3- 3H), 7.16 (m, 1H),
thiophen-2-yl-[1,2,4]oxadiazole 4.64 (s, 2H), 3.70 (s, 3H). 451
3-[3-(4-Ethyl-5-thiophen-2-yl-4H- 8.42 (s, 1H), 8.35 (d, 395.10
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.89 (d, 1H),
[1,2,4]oxadiazol-5-yl]-benzonitrile 7.71 (t, 1H), 7.54 (d, 1H),
7.48 (d, 1H), 7.20 (t, 1H), 4.68 (s, 2H), 4.16 (m, 2H), 1.40 (t,
3H). 452 3-(4-Ethyl-5-thiophen-2-yl-4H- 8.13 (d, 2H), 7.49 (br
370.09 [1,2,4]triazol-3-ylsulfanylmethyl)-5- m, 5H), 7.20 (m, 1H),
phenyl-[1,2,4]oxadiazole 4.65 (s, 2H), 4.16 (m, 2H), 1.40 (t, 3H).
453 4-[3-(4-Ethyl-5-thiophen-2-yl-4H- 8.36 (d, 1H), 7.51 (br
[1,2,4]triazol-3-ylsulfanylmethyl)- m, 3H), 7.42 (s, 1H),
[1,2,4]oxadiazol-5-yl]-2-methoxy- 7.19 (m, 1H), 4.68 (s, pyridine
2H), 4.16 (m, 2H), 1.42 (t, 3H). 454
3-(3-Chloro-phenyl)-5-(4-ethyl-5- 8.06 (s, 1H), 7.95 (d,
thiophen-2-yl-4H-[1,2,4]triazol-3- 1H), 7.54 (m, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.49 (m, 1H), 7.42 (m, 2H),
7.20 (m, 1H), 4.78 (s, 2H), 4.17 (q, 2H), 1.41 (t, 3H). 455
4-{5-[5-(3-Chloro-phenyl)-isoxazol- 8.82 (m, 2H), 7.76 (m, 399.10
3-ylmethylsulfanyl]-4-ethyl-4H- 1H), 7.66 (m, 1H),
[1,2,4]triazol-3-yl}-pyridine 7.60 (m, 2H), 7.41 (m, 2H), 6.78 (s,
1H), 4.65 (s, 2H), 4.07 (q, 2H), 1.40 (t, 3H). 456
2-Methyl-4-[3-(4-methyl-5- 8.73 (d, 1H), 7.81 (s,
thiophen-3-yl-4H-[1,2,4]triazol-3- 1H), 7.75 (s, 2H),
ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.51 (m, 2H), 4.60 (s, 2H),
5-yl]-pyridine 3.71 (s, 3H) 2.68 (s, 3H). 457
4-[3-(4-Ethyl-5-thiophen-2-yl-4H- 8.73 (d, 1H), 7.82 (s,
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.76 (d, 1H),
[1,2,4]oxadiazol-5-yl]-2-methyl- 7.54 (d, 1H), 7.48 (d, 1H),
pyridine 7.29 (m, 1H), 4.68 (s, 2H), 4.16 (m, 2H), 2.68 (s, 3H),
1.41 (t, 3H). 458 5-(4-Ethyl-5-thiophen-2-yl-4H- 7.78 (d, 1H), 7.53
(t, 376.00 [1,2,4]triazol-3-ylsulfanylmethyl)-3- 2H), 7.48 (d, 1H),
thiophen-2-yl-[1,2,4]oxadiazole 7.18 (m, 2H), 4.74 (s, 2H), 4.17
(m, 2H), 1.41 (t, 3H). 459 4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.82
(d, 2H), 8.09 (m, 418.10 [1,2,4]oxadiazol-3- 1H), 7.58 (m, 3H),
ylmethylsulfanyl]-4-ethyl-4H- 7.24 (m, 1H), 4.73 (s, 2H),
[1,2,4]triazol-3-yl}-pyridine 4.13 (m, 2H), 1.41 (t, 3H). 460
4-[3-(4-Ethyl-5-pyridin-4-yl-4H- 8.82 (d, 2H), 8.75 (d,
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.84 (s, 1H),
[1,2,4]oxadiazol-5-yl]-2-methyl- 7.76 (d, 1H), 7.60 (d, 2H),
pyridine 4.74 (s, 2H), 4.13 (m, 2H), 1.41 (t, 3H). 461
3-{5-[5-(3-Chloro-phenyl)- 8.11 (s, 1H), 7.97 (m,
[1,2,4]oxadiazol-3- 3H), 7.83 (d, 1H),
ylmethylsulfanyl]-4-methyl-4H- 7.63 (m, 3H), 7.50 (t,
[1,2,4]triazol-3-yl}-benzonitrile 1H), 4.63 (s, 2H) and 3.68 (s,
3H) 462 5-(3-Chloro-phenyl)-3-[5-(3-chloro- 8.11 (s, 1H), 8.00 (d,
phenyl)-4-methyl-4H-[1,2,4]triazol- 1H), 7.67 (m, 1H),
3-ylsulfanylmethyl]- 7.50 (m, 5H), 4.61 (s, 2H) [1,2,4]oxadiazole
and 3.66 (s, 3H). 463 5-(3-Chloro-phenyl)-3-[5-(4-chloro- 8.11 (s,
1H), 8.01 (d, phenyl)-4-methyl-4H-[1,2,4]triazol- 1H), 7.55 (m,
6H), 3-ylsulfanylmethyl]- 4.61 (s, 2H) and 3.64 (s, 3H).
[1,2,4]oxadiazole 464 4-{5-[5-(2,5-Dichloro-phenyl)- 8.80 (dd, 2H),
8.05 (m, [1,2,4]oxadiazol-3- 1H), 7.59 (m, 2H),
ylmethylsulfanyl]-4-ethyl-4H- 7.47 (s, 2H), 4.73 (s, 2H),
[1,2,4]triazol-3-yl}-pyridine 4.11 (m, 2H), 1.32 (m, 3H). 465
5-(2,5-Dichloro-phenyl)-3-(4-ethyl- 8.06 (dd, 1H), 7.50 (m,
5-thiophen-2-yl-4H-[1,2,4]triazol-3- 4H), 7.19 (dd, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 4.68 (s, 2H), 4.17 (q, 2H),
1.39 (t, 3H). 466 5-(2,5-Difluoro-phenyl)-3-(4-ethyl- 8.80 (dd,
2H), 7.79 (m, 406.10 5-thiophen-2-yl-4H-[1,2,4]triazol-3- 1H), 7.60
(m, 2H), ylsulfanylmethyl)-[1,2,4]oxadiazole 7.28 (m, 1H), 4.68 (s,
2H), 4.11 (q, 2H), 1.39 (t, 3H). 467 4-{5-[5-(2,5-Difluoro-phenyl)-
7.80 (m, 1H), 7.52 (m, [1,2,4]oxadiazol-3- 1H), 7.48 (m, 1H),
ylmethylsulfanyl]-4-ethyl-4H- 7.20 (m, 4H), 4.68 (s, 2H),
[1,2,4]triazol-3-yl}-pyridine 4.17 (m, 2H), 1.40 (t, 3H). 468
5-(2,5-Dichloro-phenyl)-3-(4-ethyl- 8.07 (dd, 1H), 7.71 (dd,
5-thiophen-3-yl-4H-[1,2,4]triazol-3- 1H), 7.49 (m, 4H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 4.69 (s, 2H), 4.12 (m, 2H),
1.38 (t, 3H). 469 5-(2,5-Difluoro-phenyl)-3-(4-ethyl- 7.80 (m, 1H),
7.72 (m, 406.10 5-thiophen-3-yl-4H-[1,2,4]triazol-3- 1H), 7.49 (m,
2H), ylsulfanylmethyl)-[1,2,4]oxadiazole 7.28 (m, 2H), 4.68 (s,
2H), 4.12 (q, 2H), 1.37 (t, 3H). 470 4-{5-[5-(3-Chloro-phenyl)-
8.80 (dd, 2H), 8.11 (m, [1,2,4]oxadiazol-3- 1H), 7.99 (m, 1H),
ylmethylsulfanyl]-4-propyl-4H- 7.57 (m, 3H), 7.48 (t, 1H),
[1,2,4]triazol-3-yl}-pyridine 4.70 (s, 2H), 3.99 (q, 2H), 1.72 (m,
2H), 0.91 (t, 3H). 471 4-{5-[5-(2-Fluoro-5-methyl- 8.80 (dd, 2H),
7.87 (dd, phenyl)-[1,2,4]oxadiazol-3- 1H), 7.58 (m, 2H),
ylmethylsulfanyl]-4-propyl-4H- 7.39 (m, 1H), 7.15 (q, 1H),
[1,2,4]triazol-3-yl}-pyridine 4.70 (s, 2H), 4.01 (m, 2H), 2.40 (s,
3H), 1.70 (m, 2H), 0.87 (t, 3H). 472 3-(4-Ethyl-5-thiophen-2-yl-4H-
7.91 (d, 1H), 7.67 (d, 376.10 [1,2,4]triazol-3-ylsulfanylmethyl)-5-
1H), 7.52 (d, 1H), thiophen-2-yl-[1,2,4]oxadiazole 7.48 (d, 1H),
7.20 (m, 2H), 4.62 (s, 2H), 4.18 (m, 2H), 1.38 (t, 3H). 473
3-(4-Methyl-5-thiophen-3-yl-4H- 7.90 (s, 1H), 7.74 (d,
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.67 (d, 1H),
thiophen-2-yl-[1,2,4]oxadiazole 7.52 (m, 2H), 7.21 (m, 1H), 4.60
(s, 2H), 3.71 (s, 3H) 2.68 (s, 3H). 474
4-[4-Methyl-5-(3-thiophen-3-yl- 8.82 (d, 2H), 8.05 (s,
[1,2,4]oxadiazol-5- 1H), 7.61 (m, 3H),
ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.44 (m, 1H), 4.73 (s, 2H),
3-yl]-pyridine 3.70 (s, 3H). 475 5-(4-Methyl-5-thiophen-3-yl-4H-
8.05 (s, 1H), 7.73 (d, [1,2,4]triazol-3-ylsulfanylmethyl)-3- 1H),
7.62 (d, 1H), thiophen-3-yl-[1,2,4]oxadiazole 7.51 (s, 2H), 7.44
(m, 1H), 4.66 (s, 2H), 3.68 (s, 3H). 476
5-(4-Ethyl-5-thiophen-2-yl-4H- 8.05 (d, 1H), 7.62 (d, 376.10
[1,2,4]triazol-3-ylsulfanylmethyl)-3- 1H), 7.53 (d, 1H),
thiophen-3-yl-[1,2,4]oxadiazole 7.47 (d, 1H), 7.44 (m, 1H), 7.19
(m, 1H), 4.75 (s, 2H), 4.15 (m, 2H), 1.40 (t, 3H). 477
5-[3-(4-Ethyl-5-thiophen-2-yl-4H- 8.18 (d, 1H), 8.03 (d, 401.00
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.51 (m, 1H),
[1,2,4]oxadiazol-5-yl]-thiophene-3- 7.46 (m, 1H), 7.18 (m, 1H),
carbonitrile 4.63 (s, 2H), 4.16 (q, 2H), 1.40 (t, 3H). 478
5-(3-Chloro-phenyl)-3-[5-(2-fluoro- 8.13 (s, 1H), 8.01 (d,
phenyl)-4-methyl-4H-[1,2,4]triazol- 1H), 7.52 (m, 4H),
3-ylsulfanylmethyl]- 7.34 (t, 1H), 7.27 (m, 1H), [1,2,4]oxadiazole
4.63 (s, 2H) and 3.54 (s, 3H). 479
5-(3-Chloro-phenyl)-3-[5-(3-fluoro- 8.11 (s, 1H), 8.00 (d, 403.00
phenyl)-4-methyl-4H-[1,2,4]triazol- 1H), 7.52 (m, 5H),
3-ylsulfanylmethyl]- 7.27 (m, 1H), 4.62 (s, 2H) [1,2,4]oxadiazole
and 3.66 (s, 3H). 480 5-(3-Chloro-phenyl)-3-[5-(4-fluoro- 8.11 (s,
1H), 8.00 (d, 403.10 phenyl)-4-methyl-4H-[1,2,4]triazol- 1H), 7.59
(m, 4H), 3-ylsulfanylmethyl]- 7.49 (t, 1H), 7.22 (m, H),
[1,2,4]oxadiazole 4.61 (s, 2H) and 3.64 (s, 3H). 481
3-(5-Benzo[b]thiophen-2-yl-4- 8.11 (s, 1H), 8.01 (d,
methyl-4H-[1,2,4]triazol-3- 1H), 7.87 (m, 2H),
ylsulfanylmethyl)-5-(3-chloro- 7.72 (s, 1H), 7.58 (d, 1H),
phenyl)-[1,2,4]oxadiazole 7.45 (m, 3H), 4.60 (s, 2H) and 3.85 (s,
3H). 482 5-(3-Chloro-phenyl)-3-[5-(3- 8.12 (s, 1H), 8.01 (d,
methoxy-phenyl)-4-methyl-4H- 1H), 7.59 (dd, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl]- 7.49 (t, 1H), 7.44 (t, 1H),
[1,2,4]oxadiazole 7.2 (m, 2H), 7.05 (dd, 1H), 4.60 (s, 2H), 3.88
(s, 3H) and 3.65 (s, 3H). 483 5-(3-Chloro-phenyl)-3-[5-(4- 8.12 (s,
1H), 8.01 (d, 415.00 methoxy-phenyl)-4-methyl-4H- 1H), 7.59 (m,
3H), [1,2,4]triazol-3-ylsulfanylmethyl]- 7.49 (t, 1H), 7.03 (d,
2H), [1,2,4]oxadiazole 4.59 (s, 2H), 3.89 (s, 3H) and 3.63 (s, 3H).
484 3-(4-Ethyl-5-furan-2-yl-4H- 7.86 (dd, 1H), 7.59 (m, 386.10
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.37 (m, 1H),
(2-fluoro-5-methyl-phenyl)- 7.14 (m, 2H), 6.58 (q, 1H),
[1,2,4]oxadiazole 4.63 (s, 2H), 4.26 (q, 2H), 2.39 (s, 3H), 1.37
(t, 3H). 485 3-(4-Ethyl-5-furan-2-yl-4H- 7.91 (m, 2H), 7.59 (m,
368.20 [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.40 (m, 2H),
m-tolyl-[1,2,4]oxadiazole 7.10 (q, 1H), 6.58 (q, 1H), 4.61 (s, 2H),
4.24 (q, 2H), 2.43 (s, 3H), 1.36 (t, 3H). 486
3-(4-Ethyl-5-trifluoromethyl-4H- 7.97 (m, 1H), 7.47 (m,
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.16 (t, 1H),
(2-fluoro-5-methyl-phenyl)- 4.72 (d, 2H), 4.16 (m, 2H),
[1,2,4]oxadiazole 2.41 (d, 3H), 1.37 (m, 3H). 487
3-[5-(2-Fluoro-5-methyl-phenyl)- (CD3OD as [1,2,4]oxadiazol-3-
solvent): 8.72 (m, 2H), ylmethylsulfanyl]-5-pyridin-4-yl- 8.17 (m,
2H), 7.86 (dd, [1,2,4]triazol-4-ylamine 1H), 7.49 (m, 1H), 7.23
(dd, 1H), 4.59 (s, 2H), 2.35 (s, 3H). 488
3-[5-(2-Fluoro-5-methyl-phenyl)- (CD3OD as [1,2,4]oxadiazol-3-
solvent): 8.05 (s, 1H), ylmethylsulfanyl]-5-thiophen-2-yl- 7.84
(dd, 1H), 7.69 (m, [1,2,4]triazol-4-ylamine 1H), 7.47 (m, 1H), 7.22
(m, 2H), 4.52 (s, 2H), 2.33 (s, 3H). 489
3-Pyridin-4-yl-5-(5-m-tolyl- (CD3OD as [1,2,4]oxadiazol-3-
solvent): 8.73 (dd, 2H), ylmethylsulfanyl)-[1,2,4]triazol-4- 8.17
(dd, 2H), 7.89 (m, ylamine 2H), 7.46 (m, 2H), 4.58 (s, 2H), 2.389
(s, 3H). 490 3-Thiophen-2-yl-5-(5-m-tolyl- (CD3OD as
[1,2,4]oxadiazol-3- solvent): 8.05 (dd, 1H),
ylmethylsulfanyl)-[1,2,4]triazol-4- 7.87 (d, 2H), 7.70 (dd, ylamine
1H), 7.45 (m, 2H), 7.23 (q, 1H), 4.50 (s, 2H), 2.39 (s, 3H). 491
3-(4-Ethyl-5-furan-2-yl-4H- 8.23 (m, 1H), 7.66 (m, 360.10
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.60 (m, 1H),
thiophen-3-yl-[1,2,4]oxadiazole 7.47 (m, 1H), 7.11 (m, 1H), 6.60
(m, 1H), 4.61 (s, 2H), 4.26 (q, 2H), 1.38 (t, 3H). 492
5-(3-Chloro-phenyl)-3-(4-ethyl-5- 8.11 (m, 1H), 8.00 (m, 389.00
furan-2-yl-4H-[1,2,4]triazol-3- 1H), 7.59 (m, 2H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.51 (t, 1H), 7.12 (m, 1H),
6.60 (m, 1H), 4.63 (s, 2H), 4.26 (q, 2H), 1.38 (t, 3H). 493
4-[3-(4-Ethyl-5-furan-2-yl-4H- 8.73 (d, 1H), 7.82 (s,
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.75 (m, 1H),
[1,2,4]oxadiazol-5-yl]-2-methyl- 7.60 (m, 1H), 7.12 (m, 1H),
pyridine 6.60 (m, 1H), 4.65 (s, 2H), 4.26 (q, 2H), 2.68 (s, 3H),
1.39 (t, 3H). 494 5-(2,5-Difluoro-phenyl)-3-(4-ethyl- 7.80 (m, 1H),
7.61 (m, 390.09 5-furan-2-yl-4H-[1,2,4]triazol-3- 1H), 7.29 (m,
2H), ylsulfanylmethyl)-[1,2,4]oxadiazole 7.12 (m, 1H), 6.60 (m,
1H), 4.65 (s, 2H), 4.28 (q, 2H), 1.39 (t, 3H). 495
4-[4-Ethyl-5-(5-thiophen-3-yl- 8.81 (m, 2H), 7.63 (m, 371.00
isoxazol-3-ylmethylsulfanyl)-4H- 1H), 7.59 (m, 2H),
[1,2,4]triazol-3-yl]-pyridine 7.41 (m, 2H), 6.58 (s, 1H), 4.63 (s,
2H), 4.06 (q, 2H), 1.38 (t, 3H). 496
4-Ethyl-3-furan-2-yl-5-(5-thiophen- 7.77 (m, 1H), 7.60 (m, 359.10
3-yl-isoxazol-3-ylmethylsulfanyl)- 1H) 7.40 (m, 2H),
4H-[1,2,4]triazole 7.10 (m, 1H), 6.60 (m, 1H), 6.55 (s, 1H), 4.58
(s, 2H), 4.21 (q, 2H), 1.38 (t, 3H). 497
5-(3-Chloro-phenyl)-3-[5-(3,5- 8.12 (s, 1H), 8.01 (d,
dichloro-phenyl)-4-ethyl-4H- 1H), 7.60 (d, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl]- 7.54 (s, 3H), 7.47 (t, 1H),
[1,2,4]oxadiazole 4.69 (s, 2H), 4.06 (q, 2H) and 1.36 (t, 3H). 498
5-(3-Chloro-phenyl)-3-(4-ethyl-5-p- 8.13 (s, 1H), 8.01 (d,
tolyl-4H-[1,2,4]triazol-3- 1H), 7.53 (m, 4H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.20 (d, 2H), 4.68 (s, 2H),
4.03 (q, 3H), 2.45 (s, 1H) and 1.32 (t, 3H). 499
5-(3-Chloro-phenyl)-3-(4-ethyl-5- 8.11 (s, 1H), 8.00 (d,
m-tolyl-4H-[1,2,4]triazol-3- 1H), 7.58 (d, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.29-7.50 (m, 5H), 4.66 (s,
2H), 4.02 (q, 2H), 2.45 (s, 1H) and 1.32 (t, 3H). 500
5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.52 (s, 1H), 8.40 (d,
(3-nitro-phenyl)-4H-[1,2,4]triazol- 1H), 8.12 (s, 1H),
3-ylsulfanylmethyl]- 8.05 (dd, 2H), 7.76 (t, [1,2,4]oxadiazole 1H),
7.60 (d, 1H), 7.50 (t, 1H), 4.72 (s, 2H), 4.10 (q, 2H) and 1.41 (t,
3H). 501 4-{5-[3-(3-Chloro-phenyl)-isoxazol- 7.80 (m, 2H), 7.78 (m,
5-ylmethylsulfanyl]-4-methyl-4H- 1H), 7.65 (m, 1H),
[1,2,4]triazol-3-yl}-pyridine 7.59 (m, 2H), 7.40 (m, 2H), 6.65 (s,
1H), 4.67 (s, 2H), 3.64 (s, 3H). 502 5-(3-Chloro-phenyl)-3-[5-(2,5-
8.14 (s, 1H), 8.02 (d, difluoro-phenyl)-4-ethyl-4H- 1H), 7.60 (d,
1H), [1,2,4]triazol-3-ylsulfanylmethyl]- 7.52 (t, 1H), 7.32 (m,
1H), [1,2,4]oxadiazole 7.23 (m, 2H), 4.70 (s, 2H), 3.96 (q, 2H) and
1.27 (t, 3H). 503 5-(3-Chloro-phenyl)-3-[5-(3-chloro- 8.11 (s, 1H),
8.06 (d, phenyl)-4-ethyl-4H-[1,2,4]triazol-3- 1H), 7.63 (s, 1H),
ylsulfanylmethyl]-[1,2,4]oxadiazole 7.58 (d, 1H), 7.49 (m, 4H),
7.23 (m, 2H), 4.68 (s, 2H), 4.04 (q, 2H) and 1.34 (t, 3H). 504
5-(3-Chloro-phenyl)-3-[5-(4-chloro- 8.13 (s, 1H), 8.01 (d,
phenyl)-4-ethyl-4H-[1,2,4]triazol-3- 1H), 7.3 (m, 6H), 4.68 (s,
ylsulfanylmethyl]-[1,2,4]oxadiazole 2H), 4.03 (q, 2H) and 1.34 (t,
3H). 505 4-{5-[5-(3-Chloro-phenyl)-oxazol- 8.78 (d, 2H), 7.55 (m,
2-ylmethylsulfanyl]-4-ethyl-4H- 3H), 7.44 (m, 1H),
[1,2,4]triazol-3-yl}-pyridine 7.29 (m, 3H), 4.69 (s, 2H), 4.04 (q,
2H) and 1.34 (t, 3H). 506 3-[5-(3-Chloro-phenyl)-oxazol-2- 7.55 (s,
1H), 7.50 (d, 404.00 ylmethylsulfanyl]-4-ethyl-5- 1H), 7.44 (m,
2H), thiophen-2-yl-4H-[1,2,4]triazole 7.28 (m, 3H), 7.18 (dd, 1H),
4.64 (s, 2H), 4.10 (q, 2H) and 1.35 (t, 3H). 507
3-[5-(3-Chloro-phenyl)-oxazol-2- 7.58 (s, 1H), 7.53 (s, 388.00
ylmethylsulfanyl]-4-ethyl-5-furan- 1H), 7.40 (m, 1H),
2-yl-4H-[1,2,4]triazole 7.27 (m, 3H), 7.10 (d, 1H), 6.68 (d, 1H),
4.62 (s, 2H), 4.19 (q, 2H) and 1.33 (t, 3H). 508
5-(2-Chloro-5-methyl-phenyl)-3-(4- 7.83 (s, 1H), 7.53 (d,
ethyl-5-thiophen-2-yl-4H- 1H), 7.44 (m, 2H),
[1,2,4]triazol-3-ylsulfanylmethyl)- 7.32 (d, 1H), 7.18 (t, 2H),
[1,2,4]oxadiazole 4.63 (s, 2H), 4.17 (q, 2H), 2.37 (s, 3H), 1.38
(t, 3H). 509 4-{5-[3-(3-Chloro-phenyl)-isoxazol- 8.80 (m, 2H), 7.78
(m, 5-ylmethylsulfanyl]-4-ethyl-4H- 1H), 7.66 (m, 1H),
[1,2,4]triazol-3-yl}-pyridine 7.57 (m, 2H), 7.41 (m, 2H), 6.67 (s,
1H), 4.71 (s, 2H), 4.03 (q, 2H), 1.36 (t, 3H). 510
3-[3-(3-Chloro-phenyl)-isoxazol-5- 7.78 (s, 1H), 7.64 (m, 404.00
ylmethylsulfanyl]-4-ethyl-5- 1H) 7.52 (m, 1H),
thiophen-2-yl-4H-[1,2,4]triazole 7.41 (m, 3H), 7.18 (m, 1H), 6.65
(s, 1H), 4.66 (s, 2H), 4.08 (q, 2H), 1.36 (t, 3H). 511
3-[3-(3-Chloro-phenyl)-isoxazol-5- 7.77 (s, 1H), 7.64 (d, 388.10
ylmethylsulfanyl]-4-ethyl-5-furan- 1H), 7.59 (m, 1H),
2-yl-4H-[1,2,4]triazole 7.39 (m, 2H), 7.10 (m, 1H), 6.62 (s, 1H),
6.59 (m, 1H), 4.65 (s, 2H), 4.17 (q, 2H), 1.35 (t, 3H).
512 4-{5-[5-(2-Fluoro-5-methyl- phenyl)-isoxazol-3-
ylmethylsulfanyl]-4-methyl-4H- [1,2,4]triazol-3-yl}-pyridine 513
5-(2,5-Dichloro-thiophen-3-yl)-3- (DMSO-D6 as solvent):
(4-ethyl-5-thiophen-2-yl-4H- 7.82 (dd, 1H), 7.65 (d,
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.58 (m, 1H),
[1,2,4]oxadiazole 7.25 (m, 1H), 4.60 (s, 2H), 4.16 (q, 2H), 1.24
(t, 3H). 514 4-{5-[5-(2,5-Dichloro-thiophen-3- 8.78 (d, 2H), 7.71
(d, yl)-[1,2,4]oxadiazol-3- 2H), 7.68 (m, 1H),
ylmethylsulfanyl]-4-ethyl-4H- 4.67 (s, 2H), 4.10 (q, 2H),
[1,2,4]triazol-3-yl}-pyridine 1.21 (t, 3H). 515
4-{4-Ethyl-5-[5-(2-fluoro-5-methyl- 8.81 (m, 2H), 7.73 (m,
phenyl)-isoxazol-3- 1H), 7.60 (m, 2H),
ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.21 (m, 1H), 7.07 (m, 1H),
3-yl}-pyridine 6.76 (m, 1H), 4.63 (s, 2H), 4.02 (q, 2H), 2.40 (s,
3H), 1.38 (t, 3H). 516 4-Ethyl-3-[5-(2-fluoro-5-methyl- 7.71 (d,
1H), 7.53 (m, phenyl)-isoxazol-3- 1H), 7.47 (m, 1H),
ylmethylsulfanyl]-5-thiophen-2-yl- 7.46 (m, 2H), 7.07 (m, 1H),
4H-[1,2,4]triazole 6.77 (d, 1H), 4.63 (s, 2H), 4.12 (q, 2H), 2.40
(s, 3H), 1.39 (t, 3H). 517 4-Ethyl-3-[5-(2-fluoro-5-methyl- 7.72
(d, 1H), 7.60 (m, phenyl)-isoxazol-3- 1H), 7.10 (m, 1H),
ylmethylsulfanyl]-5-furan-2-yl-4H- 7.05 (m, 2H), 6.77 (d, 1H),
[1,2,4]triazole 6.60 (m, 1H), 4.61 (s, 2H), 4.21 (q, 2H), 2.39 (s,
3H), 1.38 (t, 3H). 518 5-(3-Chloro-phenyl)-3-(4-ethyl-5- 8.11 (s,
1H), 8.01 (d, 391.00 trifluoromethyl-4H-[1,2,4]triazol-3- 1H), 7.60
(d, 1H), ylsulfanylmethyl)-[1,2,4]oxadiazole 7.50 (t, 1H), 4.72 (s,
2H), 4.12 (q, 2H) and 1.42 (t, 3H). 519
3-(3-Chloro-phenyl)-5-(4-ethyl-5- 8.05 (s, 1H), 7.94 (d,
trifluoromethyl-4H-[1,2,4]triazol-3- 1H), 7.50 (d, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.43 (t, 1H), 4.83 (s, 2H),
4.13 (q, 2H) and 1.44 (t, 3H). 520 3-(4-Ethyl-5-trifluoromethyl-4H-
8.23 (s, 1H), 7.65 (d, [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H),
7.48 (m, 1H), thiophen-3-yl-[1,2,4]oxadiazole 4.69 (s, 2H), 4.12
(q, 2H) and 1.41 (t, 3H). 521 5-(4-Ethyl-5-trifluoromethyl-4H- 8.05
(s, 1H), 7.61 (d, [1,2,4]triazol-3-ylsulfanylmethyl)-3- 1H), 7.43
(m, 1H), thiophen-3-yl-[1,2,4]oxadiazole 4.81 (s, 2H), 4.12 (q, 2H)
and 1.43 (t, 3H). 522 5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.12 (d,
1H), 8.00 (d, (3-fluoro-phenyl)-4H-[1,2,4]triazol- 1H), 7.52 (m,
4H), 3-ylsulfanylmethyl]- 7.25 (m, 2H), 4.67 (s, 2H),
[1,2,4]oxadiazole 4.06 (q, 2H), 1.31 (t, 3H). 523
5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.10 (s, 1H), 7.99 (d,
(4-fluoro-phenyl)-4H-[1,2,4]triazol- 1H), 7.59 (m, 4H),
3-ylsulfanylmethyl]- 7.48 (t, 1H), 7.22 (d, 1H), [1,2,4]oxadiazole
4.67 (s, 2H), 4.01 (q, 2H), 1.30 (t, 3H). 524
3-(4-Ethyl-5-trifluoromethyl-4H- 7.91 (s, 1H), 7.68 (d,
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.21 (m, 1H),
thiophen-2-yl-[1,2,4]oxadiazole 4.67 (s, 2H), 4.13 (q, 2H) and 1.41
(t, 3H). 525 3-{3-[5-(3-Chloro-thiophen-2-yl)-4- 8.35 (m, 2H), 7.89
(d, ethyl-4H-[1,2,4]triazol-3- 1H), 7.87 (t, 1H),
ylsulfanylmethyl]-[1,2,4]oxadiazol- 7.58 (d, 1H), 7.09 (d, 1H),
5-yl}-benzonitrile 4.70 (s, 2H), 4.00 (q, 2H), 1.27 (t, 3H). 526
4-{5-[5-(3-Chloro-phenyl)- 8.82 (d, 2H), 8.01 (d, 400.10
[1,3,4]oxadiazol-2- 1H), 9.93 (m, 1H),
ylmethylsulfanyl]-4-ethyl-4H- 7.59 (m, 2H), 7.52 (m, 1H),
[1,2,4]triazol-3-yl}-pyridine 7.47 (m, 1H), 4.83 (s, 2H), 4.11 (q,
2H), 1.40 (t, 3H). 527 2-(3-Chloro-phenyl)-5-(4-ethyl-5- 8.00 (s,
1H), 7.89 (d, 389.00 furan-2-yl-4H-[1,2,4]triazol-3- 1H), 7.60 (m,
1H), ylsulfanylmethyl)-[1,3,4]oxadiazole 7.50 (m, 1H), 7.44 (m,
1H), 7.13 (m, 1H), 6.60 (m, 1H), 4.76 (s, 2H), 4.25 (q, 2H), 1.38
(t, 3H). 528 5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.12 (s, 1H), 8.01
(d, (4-methoxy-phenyl)-4H- 1H), 7.57 (m, 3H),
[1,2,4]triazol-3-ylsulfanylmethyl]- 7.51 (t, 1H), 7.05 (d, 2H),
[1,2,4]oxadiazole 4.67 (s, 2H), 4.02 (q, 2H), 3.89 (s, 3H), 1.31
(t, 3H). 529 5-(3-Chloro-phenyl)-3-[5-(2-fluoro- 8.12 (s, 1H), 8.02
(d, 5-methyl-phenyl)-4-furan-2- 1H), 7.58 (d, 1H),
ylmethyl-4H-[1,2,4]triazol-3- 7.52 (d, 1H), 7.35 (d, 2H),
ylsulfanylmethyl]-[1,2,4]oxadiazole 7.23 (s, 1H), 7.22 (d, 1H),
6.19 (s, 1H), 6.04 (s, 1H), 5.13 (s, 2H), 4.61 (s, 2H), 2.37 (s,
3H). 530 4-[3-(4-Ethyl-5-trifluoromethyl-4H- 8.74 (d, 1H), 7.81 (s,
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.74 (d, 1H),
[1,2,4]oxadiazol-5-yl]-2-methyl- 4.74 (s, 2H), 4.12 (q, 2H)
pyridine 2.69 (s, 1H) and 1.42 (t, 3H). 531
3-(4-Ethyl-5-trifluoromethyl-4H- 7.70 (d, 1H), 7.60 (s,
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.44 (t, 1H),
(3-methoxy-phenyl)- 7.16 (d, 1H), 4.70 (s, 2H), [1,2,4]oxadiazole
4.12 (q, 2H), 3.90 (s, 3H) and 1.41 (t, 3H). 532
5-(4-Ethyl-5-trifluoromethyl-4H- 7.63 (d, 1H), 7.56 (s,
[1,2,4]triazol-3-ylsulfanylmethyl)-3- 1H), 7.39 (t, 1H),
(3-methoxy-phenyl)- 7.07 (d, 1H), 4.82 (s, 2H), [1,2,4]oxadiazole
4.12 (q, 2H) and 1.42 (t, 3H). 533 5-(4-Ethyl-5-trifluoromethyl-4H-
7.77 (s, 1H), 7.52 (d, [1,2,4]triazol-3-ylsulfanylmethyl)-3- 1H),
7.16 (m, 1H), thiophen-2-yl-[1,2,4]oxadiazole 4.79 (s, 2H), 4.13
(q, 2H) and 1.42 (t, 3H). 534 5-(5-Chloro-2-fluoro-phenyl)-3-(4-
8.07 (dd, 1H), 7.56 (m, ethyl-5-trifluoromethyl-4H- 1H), 7.24 (dd,
1H), [1,2,4]triazol-3-ylsulfanylmethyl)- 4.73 (s, 2H), 4.13 (q, 2H)
and [1,2,4]oxadiazole 1.42 (t, 3H). 535
3-[3-(4-Ethyl-5-trifluoromethyl-4H- 8.40 (s, 1H), 8.34 (d, 381.10
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.91 (d, 1H),
[1,2,4]oxadiazol-5-yl]-benzonitrile 7.01 (t, 1H), 4.73 (s, 2H),
4.12 (q, 2H) and 1.42 (t, 3H). 536
3-[5-(3-Chloro-phenyl)-isoxazol-3- 7.75 (s, 1H), 7.63 (m,
ylmethylsulfanyl]-4-ethyl-5- 1H), 7.40 (m, 2H),
trifluoromethyl-4H-[1,2,4]triazole 6.73 (s, 1H), 4.65 (s, 2H), 4.07
(q, 2H) and 1.40 (t, 3H). 537 3-[5-(3-Chloro-phenyl)-oxazol-2- 7.58
(s, 1H), 7.46 (d, ylmethylsulfanyl]-4-ethyl-5- 1H), 7.32 (d, 3H),
trifluoromethyl-4H-[1,2,4]triazole 4.74 (s, 2H), 4.09 (q, 2H) and
1.39 (t, 3H). 538 4-Ethyl-3-(5-thiophen-3-yl- 7.78 (s, 1H), 7.39
(m, isoxazol-3-ylmethylsulfanyl)-5- 1H), 6.53 (d, 1H),
trifluoromethyl-4H-[1,2,4]triazole 4.63 (s, 2H), 4.07 (q, 2H) and
1.39 (t, 3H). 539 4-{3-[5-(3-Fluoro-phenyl)-4- 8.73 (d, 1H), 7.83
(s, methyl-4H-[1,2,4]triazol-3- 1H), 7.76 (d, 1H),
ylsulfanylmethyl]-[1,2,4]oxadiazol- 7.47 (m, 3H), 7.27 (s, 1H),
5-yl}-2-methyl-pyridine 4.65 (s, 2H), 3.67 (s, 3H), 2.69 (s, 3H).
540 4-{3-[5-(3-Chloro-phenyl)-4- 8.74 (d, 1H), 7.82 (s,
methyl-4H-[1,2,4]triazol-3- 1H), 7.67 (d, 1H),
ylsulfanylmethyl]-[1,2,4]oxadiazol- 7.56 (d, 1H), 7.51 (m, 1H),
5-yl}-2-methyl-pyridine 7.48 (m, 1H), 7.46 (s, 1H), 4.65 (s, 2H),
3.67 (s, 3H), 2.69 (s, 3H). 541 4-{3-[5-(4-Chloro-phenyl)-4- 8.73
(d, 1H), 7.82 (s, methyl-4H-[1,2,4]triazol-3- 1H), 7.75 (d, 1H),
ylsulfanylmethyl]-[1,2,4]oxadiazol- 7.63 (d, 2H), 7.51 (d, 2H),
5-yl}-2-methyl-pyridine 4.65 (s, 2H), 3.65 (s, 3H), 2.69 (s, 3H).
542 4-{3-[5-(4-Methoxy-phenyl)-4- 8.73 (d, 1H), 7.83 (s,
methyl-4H-[1,2,4]triazol-3- 1H), 7.45 (d, 1H),
ylsulfanylmethyl]-[1,2,4]oxadiazol- 7.61 (d, 2H), 7.04 (d, 2H),
5-yl}-2-methyl-pyridine 4.62 (s, 2H), 3.89 (s, 3H), 3.64 (s, 3H),
2.69 (s, 3H). 543 4-[3-(4-Ethyl-5-p-tolyl-4H- 8.74 (d, 1H), 7.85
(s, [1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.77 (d, 1H),
[1,2,4]oxadiazol-5-yl]-2-methyl- 7.51 (d, 2H), 7.32 (d, 2H),
pyridine 4.70 (s, 2H), 4.03 (q, 2H), 2.70 (s, 3H), 2.45 (s, 3H),
1.31 (t, 3H). 544 3-(4-Ethyl-5-thiophen-2-yl-4H- (DMSO-D6 as
solvent): 388.10 [1,2,4]triazol-3-ylsulfanylmethyl)-5- 7.93 (m,
1H), 7.86 (m, (3-fluoro-phenyl)-[1,2,4]oxadiazole 2H), 7.80 (m,
1H), 7.67 (m, 2H), 7.25 (m, 1H), 4.61 (s, 2H), 4.16 (q, 2H), 1.24
(t, 3H). 545 4-{4-Ethyl-5-[5-(3-fluoro-phenyl)- 8.78 (bs, 2H), 7.92
(m, 383.10 [1,2,4]oxadiazol-3- 2H), 7.71 (d, 2H),
ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.68 (m, 1H), 7.27 (m, 1H),
3-yl}-pyridine 4.70 (s, 2H), 4.10 (q, 2H), 1.39 (t, 3H). 546
5-(3-Chloro-phenyl)-3-[5-(3,5- 8.11 (s, 1H), 8.01 (d,
difluoro-phenyl)-4-ethyl-4H- 1H), 7.58 (d, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl]- 7.50 (t, 1H), 7.21 (m, 2H),
[1,2,4]oxadiazole 7.00 (t, 1H), 4.68 (s, 2H), 4.07 (q, 2H), 1.35
(t, 3H). 547 5-(3-Chloro-phenyl)-3-[5-(2,6- 8.12 (s, 1H), 8.02 (d,
difluoro-phenyl)-4-ethyl-4H- 1H), 7.59 (m, 2H),
[1,2,4]triazol-3-ylsulfanylmethyl]- 7.52 (d, 1H), 7.41 (d, 1H),
[1,2,4]oxadiazole 7.04 (d, 1H), 4.73 (s, 2H), 4.21 (q, 2H), 1.42
(t, 3H). 548 2-[3-(4-Ethyl-5-thiophen-2-yl-4H- 9.89 (s, 1H), 7.70
(s, 399.90 [1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.56 (d, 1H),
[1,2,4]oxadiazol-5-yl]-4-methyl- 7.54 (d, 1H), 7.30 (m, 1H), phenol
7.18 (m, 1H), 6.98 (d, 1H), 4.66 (s, 2H), 4.12 (q, 2H), 2.34 (s,
3H), 1.37 (t, 3H). 549 3-{1-[5-(3-Chloro-phenyl)-isoxazol- 7.73
(bs, 1H), 7.59 (m, 401.10 3-yl]-ethylsulfanyl}-4-ethyl-5- 2H), 7.41
(m, 2H), furan-2-yl-4H-[1,2,4]triazole 7.10 (dd, 1H), 6.59 (m, 2H),
5.05 (q, 1H), 4.13 (q, 2H), 1.91 (d, 3H), 1.27 (t, 3H). 550
4-(5-{1-[5-(3-Chloro-phenyl)- 8.8 (dd, 2H), 7.74 (bs,
isoxazol-3-yl]-ethylsulfanyl}-4- 1H), 7.63 (m, 1H),
ethyl-4H-[1,2,4]triazol-3-yl)- 7.57 (dd, 2H), 7.40 (m, 2H),
pyridine 6.62 (s, 2H), 5.15 (q, 1H), 4.05 (q, 2H), 1.95 (d, 3H),
1.34 (t, 3H). 551 3-[5-(4-Butoxy-phenyl)-4-ethyl-4H- 8.12 (s, 1H),
8.01 (d, [1,2,4]triazol-3-ylsulfanylmethyl]-5- 1H), 7.58 (d, 1H),
(3-chloro-phenyl)-[1,2,4]oxadiazole 7.52 (d, 2H), 7.49 (d, 1H),
7.01 (d, 2H), 4.69 (s, 2H), 4.02 (q, 4H), 1.82 (m, 2H), 1.51 (q,
2H), 1.32 (t, 3H), 1.01 (t, 3H). 552
3-(5-Benzo[1,3]dioxol-5-yl-4-ethyl- 8.12 (s, 1H), 8.00 (d,
4H-[1,2,4]triazol-3- 1H), 7.58 (d, 1H),
ylsulfanylmethyl)-5-(3-chloro- 7.51 (d, 1H), 7.09 (d, 2H),
phenyl)-[1,2,4]oxadiazole 6.96 (s, 1H), 6.08 (s, 2H), 4.67 (s, 2H),
4.02 (q, 2H), 1.31 (t, 3H). 553 3-(4-Ethyl-5-thiophen-2-yl-4H- 8.11
(s, 1H), 7.48 (m, 391.90 [1,2,4]triazol-3-ylsulfanylmethyl)-5- 2H),
7.16 (t, 1H), (2-methyl-thiazol-4-yl)- 4.63 (s, 2H), 4.13 (q, 2H),
[1,2,4]oxadiazole 2.82 (s, 3H), 1.37 (t, 3H). 554
3-(4-Ethyl-5-thiophen-2-yl-4H- (DMSO-D6 as solvent):
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 8.21 (m, 2H), 7.51 (m,
(4-fluoro-phenyl)-[1,2,4]oxadiazole 2H), 7.21 (m, 3H), 4.63 (s,
2H), 4.16 (q, 2H), 1.38 (t, 3H). 555
4-Ethyl-3-{1-[5-(2-fluoro-5-methyl- 7.71 (dd, 1H), 7.59 (dd,
phenyl)-isoxazol-3-yl]- 1H), 7.26 (m, 1H),
ethylsulfanyl}-5-furan-2-yl-4H- 7.06 (m, 2H), 6.66 (d, 1H),
[1,2,4]triazole 6.58 (dd, 1H), 5.06 (q, 1H), 4.13 (q, 2H), 2.39 (s,
3H), 1.91 (d, 3H), 1.28 (t, 3H). 556
4-(4-Ethyl-5-{1-[5-(2-fluoro-5- 8.79 (dd, 2H), 7.71 (dd, 410.10
methyl-phenyl)-isoxazol-3-yl]- 1H), 7.59 (dd, 2H),
ethylsulfanyl}-4H-[1,2,4]triazol-3- 7.23 (m, 1H), 7.06 (m, 1H),
yl)-pyridine 6.64 (d, 1H), 5.15 (q, 1H), 4.01 (q, 2H), 2.39 (s,
3H), 1.94 (d, 3H), 1.30 (t, 3H). 557
5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.11 (s, 1H), 8.00 (d,
(3-methyl-3H-imidazol-4-yl)-4H- 1H), 7.66 (s, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl]- 7.58 (d, 1H), 7.52 (t, 1H),
[1,2,4]oxadiazole 7.37 (s, 1H), 4.69 (s, 2H), 4.09 (q, 2H), 3.93
(s, 3H), 1.37 (t, 3H). 558 5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.12
(s, 1H), 8.01 (d, (1-methyl-1H-imidazol-2-yl)-4H- 1H), 7.57 (d,
1H), [1,2,4]triazol-3-ylsulfanylmethyl]- 7.51 (t, 1H), 7.17 (s,
1H),
[1,2,4]oxadiazole 7.04 (s, 1H), 4.69 (s, 2H), 4.56 (q, 2H), 4.12
(s, 3H), 1.40 (t, 3H). 559 5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.12
(s, 1H), 8.01 (d, (1-methyl-1H-imidazol-4-yl)-4H- 1H), 7.65 (s,
1H), [1,2,4]triazol-3-ylsulfanylmethyl]- 7.57 (d, 1H), 7.48 (d,
2H), [1,2,4]oxadiazole 4.60 (s, 2H), 4.50 (q, 2H), 3.79 (s, 3H),
1.36 (t, 3H). 560 4-{5-[5-(3-Chloro-phenyl)-4- 8.81 (bs, 2H), 7.70
(m, methyl-isoxazol-3- 1H), 7.61 (m, 3H),
ylmethylsulfanyl]-4-ethyl-4H- 7.44 (m, 2H), 4.65 (s, 2H),
[1,2,4]triazol-3-yl}-pyridine 4.09 (q, 2H), 2.31 (s, 3H), 1.40 (t,
3H). 561 3-[5-(3-Chloro-phenyl)-4-methyl- 7.70 (s, 1H), 7.60 (m,
isoxazol-3-ylmethylsulfanyl]-4- 2H), 7.43 (m, 2H),
ethyl-5-furan-2-yl-4H- 7.10 (m, 1H), 6.59 (m, 1H), [1,2,4]triazole
4.59 (s, 2H), 4.23 (q, 2H), 2.28 (s, 3H), 1.38 (t, 3H). 562
3-(4-Ethyl-5-thiophen-2-yl-4H- 7.61 (d, 1H), 7.49 (m,
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 2H), 7.22 (m, 2H),
(4-methyl-thiophen-2-yl)- 4.59 (s, 2H), 4.16 (q, [1,2,4]oxadiazole
2H), 2.32 (s, 3H), 1.38 (t, 3H). 563
5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.13 (s, 1H), 8.01 (d,
(3-methyl-thiophen-2-yl)-4H- 1H), 7.58 (d, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl]- 7.52 (d, 1H), 7.45 (d, 1H),
[1,2,4]oxadiazole 7.02 (d, 1H), 4.69 (s, 2H), 3.97 (q, 2H), 2.32
(s, 3H), 1.28 (t, 3H). 564 5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.11
(s, 1H), 8.01 (d, (5-methyl-thiophen-2-yl)-4H- 1H), 7.58 (d, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl]- 7.51 (t, 1H), 7.28 (s, 1H),
[1,2,4]oxadiazole 6.83 (d, 1H), 4.64 (s, 2H), 4.14 (q, 2H), 2.56
(s, 3H), 1.39 (t, 3H). 565 4-{5-[4-Chloro-5-(3-chloro-phenyl)- 8.81
(d, 2H), 7.99 (m, isoxazol-3-ylmethylsulfanyl]-4- 1H), 7.90 (m,
1H), ethyl-4H-[1,2,4]triazol-3-yl}- 7.60 (m, 2H), 7.48 (m, 2H),
pyridine 4.65 (s, 2H), 4.10 (q, 2H), 1.39 (t, 3H). 566
3-[4-Chloro-5-(3-chloro-phenyl)- 7.99 (s, 1H), 7.90 (m,
isoxazol-3-ylmethylsulfanyl]-4- 1H), 7.60 (m, 1H),
ethyl-5-furan-2-yl-4H- 7.47 (m, 2H), 7.12 (m, 1H), [1,2,4]triazole
6.60 (m, 1H), 4.59 (s, 2H), 4.25 (q, 2H), 1.38 (t, 3H). 567
2-Chloro-4-{5-[5-(3-chloro-phenyl)- 8.11 (s, 1H), 8.00 (d,
[1,2,4]oxadiazol-3- 1H), 7.58 (d, 1H),
ylmethylsulfanyl]-4-ethyl-4H- 7.52 (d, 1H), 7.40 (d, 2H),
[1,2,4]triazol-3-yl}-6-methyl- 4.71 (s, 2H), 4.10 (q, pyridine 2H),
2.64 (s, 3H), 1.40 (t, 3H). 568 3-[5-(5-Bromo-furan-2-yl)-4-ethyl-
8.11 (s, 1H), 7.99 (d, 4H-[1,2,4]triazol-3- 1H), 7.58 (d, 1H),
ylsulfanylmethyl]-5-(3-chloro- 7.51 (t, 1H), 7.07 (d, 1H),
phenyl)-[1,2,4]oxadiazole 6.52 (d, 1H), 4.64 (s, 2H), 4.23 (q, 2H),
1.40 (t, 3H). 569 2-Chloro-4-{5-[5-(3-chloro-phenyl)- 8.59 (d, 1H),
8.10 (s, [1,2,4]oxadiazol-3- 1H), 8.00 (d, 1H),
ylmethylsulfanyl]-4-ethyl-4H- 7.66 (s, 1H), 7.59 (d, 1H),
[1,2,4]triazol-3-yl}-pyridine 7.54 (d, 1H), 7.50 (d, 1H), 4.72 (s,
2H), 4.11 (q, 2H), 1.42 (t, 3H). 570
2-Chloro-4-{5-[5-(3-chloro-phenyl)- 8.11 (s, 1H), 8.00 (d, 464.10
[1,2,4]oxadiazol-3- 1H), 7.58 (d, 1H),
ylmethylsulfanyl]-4-ethyl-4H- 7.50 (t, 1H), 7.24 (s, 1H),
[1,2,4]triazol-3-yl}-6-methoxy- 6.91 (s, 1H), 4.70 (s, pyridine
2H), 4.08 (q, 2H), 4.02 (s, 3H), 1.39 (t, 3H). 571
2-[3-(4-Ethyl-5-thiophen-2-yl-4H- 8.02 (s, 1H), 7.76 (d,
[1,2,4]triazol-3-ylsulfanylmethyl)- 2H), 7.47 (m, 3H),
[1,2,4]oxadiazol-5-yl]-4-methyl- 7.17 (t, 1H), 4.68 (s, 2H),
benzonitrile 4.19 (q, 2H), 2.51 (s, 3H), 1.39 (t, 3H). 572
5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.14 (s, 1H), 8.03 (d,
(3-methoxy-thiophen-2-yl)-4H- 1H), 7.58 (d, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl]- 7.50 (d, 1H), 7.44 (d, 1H),
[1,2,4]oxadiazole 6.94 (1H), 4.67 (s, 2H), 4.03 (q, 2H), 3.88 (s,
3H), 1.29 (t, 3H). 573 3-[5-(5-Chloro-thiophen-3-yl)- 7.61 (m, 1H),
7.52 (d, 393.10 isoxazol-3-ylmethylsulfanyl]-4- 1H), 7.21 (d, 1H),
ethyl-5-furan-2-yl-4H- 7.11 (m, 1H), 7.61 (m, 1H), [1,2,4]triazole
6.55 (s, 1H), 4.57 (s, 2H), 4.21 (q, 2H), 1.38 (t, 3H). 574
3-[3-(4-Ethyl-5-furan-2-yl-4H- 8.21 (m, 1H), 8.04 (dd,
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.59 (m, 2H),
[1,2,4]oxadiazol-5-yl]-5-fluoro- 7.10 (dd, 1H), 6.59 (dd, 1H),
benzonitrile 4.64 (s, 2H), 4.25 (q, 2H), 1.38 (t, 3H). 575
4-Ethyl-3-(5-phenyl-isoxazol-3- 7.77 (m, 2H), 7.53 (d,
ylmethylsulfanyl)-5-thiophen-2-yl- 1H), 7.47 (m, 4H),
4H-[1,2,4]triazole 7.19 (dd, 1H), 6.71 (s, 1H), 4.61 (s, 2H), 4.12
(q, 2H) and 1.39 (t, 3H). 576 4-Methyl-3-(5-phenyl-isoxazol-3- 7.77
(m, 3H), 7.50 (m, ylmethylsulfanyl)-5-thiophen-3-yl- 5H), 6.69 (s,
1H), 4H-[1,2,4]triazole 4.56 (s, 2H) and 3.67 (s, 3H) 577
4-Ethyl-3-furan-2-yl-5-(5-phenyl- 7.77 (m, 2H), 7.61 (s,
isoxazol-3-ylmethylsulfanyl)-4H- 1H), 7.46 (m, 3H), [1,2,4]triazole
7.14 (d, 1H), 6.69 (s, 1H), 6.60 (d, 1H), 4.60 (s, 2H), 4.22 (q,
2H) and 1.38 (t, 3H). 578 4-[4-Ethyl-5-(5-phenyl-isoxazol-3- 8.82
(w, 2H), 7.77 (m, ylmethylsulfanyl)-4H-[1,2,4]triazol- 2H), 7.61
(d, 2H), 3-yl]-pyridine 7.45 (m, 3H), 6.71 (s, 1H), 4.65 (s, 2H),
4.06 (q, 2H) and 1.39 (t, 3H). 579
4-[4-Methyl-5-(5-phenyl-isoxazol- 8.81 (w, 2H), 7.77 (m,
3-ylmethylsulfanyl)-4H- 2H), 7.63 (d, 2H),
[1,2,4]triazol-3-yl]-pyridine 7.46 (m, 3H), 6.70 (s, 1H), 4.60 (s,
2H) and 3.68 (s, 3H). 580 2-(4-Ethyl-5-furan-2-yl-4H- 7.80 (m, 2H),
7.70 (m, 368.10 [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.35 (m,
2H), m-tolyl-[1,3,4]oxadiazole 7.13 (m, 2H), 6.60 (m, 1H), 4.74 (s,
2H), 4.23 (q, 2H), 2.40 (s, 3H), 1.36 (t, 3H). 581
4-[4-Methyl-5-(5-m-tolyl- 8.81 (m, 2H), 7.80 (m, 365.10
[1,3,4]oxadiazol-2- 2H), 7.61 (d, 2H),
ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.39 (m, 2H), 4.74 (s, 2H),
3-yl]-pyridine 3.71 (s, 3H), 2.4 (s, 3H). 582
4-[4-Ethyl-5-(5-m-tolyl- 8.81 (d, 2H), 7.81 (m, 379.10
[1,3,4]oxadiazol-2- 2H), 7.58 (m, 2H),
ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.37 (m, 2H), 4.81 (s, 2H),
3-yl]-pyridine 4.41 (q, 2H), 2.42 (s, 3H), 1.33 (t, 3H). 583
4-{5-[5-(5-Chloro-thiophen-3-yl)- 8.80 (d, 2H), 7.98 (m, 405.90
[1,2,4]oxadiazol-3- 1H), 7.58 (d, 2H),
ylmethylsulfanyl]-4-ethyl-4H- 7.46 (d, 1H), 4.66 (s, 2H),
[1,2,4]triazol-3-yl}-pyridine 4.10 (q, 2H), 1.38 (t, 3H). 584
3-[3-(4-Ethyl-5-pyridin-4-yl-4H- 8.79 (bs, 2H), 8.46 (m,
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.91 (m, 1H),
[1,2,4]oxadiazol-5-yl]-4-fluoro- 7.59 (d, 2H), 7.43 (t, 1H),
benzonitrile 4.74 (s, 2H), 4.12 (q, 2H), 1.41 (t, 3H). 585
3-[3-(4-Ethyl-5-furan-2-yl-4H- 8.45 (dd, 1H), 7.91 (m, 397.10
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.59 (d, 1H),
[1,2,4]oxadiazol-5-yl]-4-fluoro- 7.43 (t, 1H), 7.10 (d, 1H),
benzonitrile 6.58 (dd, 1H), 4.65 (s, 2H), 4.27 (q, 2H), 1.39 (t,
3H). 586 3-[3-(4-Ethyl-5-thiophen-2-yl-4H- 8.45 (dd, 1H), 7.90 (m,
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.47 (m, 3H),
[1,2,4]oxadiazol-5-yl]-4-fluoro- 7.18 (t, 1H), 4.68 (s, 2H),
benzonitrile 4.17 (q, 2H), 1.41 (t, 3H). 587
3-[3-(4-Ethyl-5-furan-2-yl-4H- 8.41 (m, 2H), 7.89 (d, 379.10
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.69 (d, 1H),
[1,2,4]oxadiazol-5-yl]-benzonitrile 7.13 (m, 1H), 6.60 (m, 1H),
4.65 (s, 2H), 4.27 (q, 2H), 1.40 (t, 3H). 588
3-[5-(4-Ethyl-5-furan-2-yl-4H- 8.36 (m, 2H), 7.80 (t, 379.10
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.62 (m, 2H),
[1,2,4]oxadiazol-3-yl]-benzonitrile 7.15 (m, 1H), 6.61 (m, 1H),
4.78 (s, 2H), 4.2 (q, 2H), 1.40 (t, 3H). 589
3-[3-(4-Methyl-5-trifluoromethyl- 8.41 (m, 2H), 7.90 (m,
4H-[1,2,4]triazol-3- 1H), 7.72 (t, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazol- 4.68 (s, 2H), 3.73 (s, 3H).
5-yl]-benzonitrile 590 5-(5-Chloro-2-fluoro-phenyl)-3-(4- 8.08 (m,
1H), 7.58 (m, 394.90 methyl-5-trifluoromethyl-4H- 1H), 7.25 (m,
1H), [1,2,4]triazol-3-ylsulfanylmethyl)- 4.67 (s, 2H), 3.74 (s,
3H). [1,2,4]oxadiazole 591 2-Chloro-4-[3-(4-ethyl-5-furan-2-yl-
8.63 (m, 1H), 8.02 (m, 390.00 4H-[1,2,4]triazol-3- 1H), 7.89 (m,
1H), ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.61 (m, 1H), 7.14 (m,
1H), 5-yl]-pyridine 6.61 (m, 1H), 4.67 (s, 2H), 4.27 (q, 2H), 1.40
(t, 3H). 592 2-Chloro-4-[3-(5-furan-2-yl-4- 8.63 (d, 1H), 8.00 (d,
methyl-4H-[1,2,4]triazol-3- 1H), 7.88 (m, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.62 (d, 1H), 7.14 (d, 1H),
5-yl]-pyridine 6.61 (m, 1H), 4.60 (s, 2H), 3.82 (s, 3H). 593
2-(3-Chloro-phenyl)-5-[4-methyl-5- 7.98 (m, 2H), 7.89 (d,
(2-methyl-thiazol-4-yl)-4H- 1H), 7.49 (m, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl]- 7.44 (m, 1H), 4.69 (s, 2H),
[1,3,4]oxadiazole 3.92 (s, 3H), 2.77 (s, 3H). 594
2-(3-Chloro-phenyl)-5-(4-methyl-5- 8.91 (s, 1H), 8.24 (s,
thiazol-4-yl-4H-[1,2,4]triazol-3- 1H), 7.98 (s, 1H),
ylsulfanylmethyl)-[1,3,4]oxadiazole 7.91 (d, 1H), 7.49 (m, 1H),
7.43 (m, 1H), 4.72 (s, 2H), 3.96 (s, 3H). 595
2-(3-Chloro-phenyl)-5-(5-furan-2- 8.00 (s, 1H), 7.89 (d,
yl-4-methyl-4H-[1,2,4]triazol-3- 1H), 7.60 (s, 1H),
ylsulfanylmethyl)-[1,3,4]oxadiazole 7.53 (m, 1H), 7.43 (m, 1H),
7.12 (d, 1H), 6.60 (d of d, 1H), 4.68 (s, 2H), 3.80 (s, 3H). 596
2-(3-Chloro-phenyl)-5-(4-ethyl-5- 8.00 (s, 1H), 7.90 (d,
trifluoromethyl-4H-[1,2,4]triazol-3- 1H), 7.52 (m, 2H),
ylsulfanylmethyl)-[1,3,4]oxadiazole 4.86 (s, 2H), 4.13 (q, 2H),
1.42 (t, 3H). 597 4-{4-Ethyl-5-[5-(4-methyl- 8.79 (d, 2H), 7.68 (s,
thiophen-2-yl)-[1,2,4]oxadiazol-3- 1H), 7.59 (d, 2H),
ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.23 (m, 1H), 4.63 (s, 2H),
3-yl}-pyridine 4.10 (q, 2H), 2.32 (d, 3H), 1.37 (t, 3H). 598
3-(4-Ethyl-5-furan-2-yl-4H- 7.67 (d, 1H), 7.59 (m, 374.00
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.2 (s, 1H), 7.09 (d,
(4-methyl-thiophen-2-yl)- 1H), 6.58 (dd, 1H), [1,2,4]oxadiazole
4.56 (s, 2H), 4.24 (q, 2H), 2.32 (s, 3H), 1.36 (t, 3H). 599
3-(3-Chloro-phenyl)-5-(4-ethyl-5- 8.02 (m, 1H), 7.91 (m,
furan-2-yl-4H-[1,2,4]triazol-3- 1H), 7.57 (d, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.35 (m, 2H), 7.08 (d, 1H),
6.56 (dd, 1H), 4.72 (s, 2H), 4.22 (q, 2H), 2.32 (s, 3H), 1.36 (t,
3H). 600 4-{5-[3-(3-Chloro-phenyl)- 8.79 (dd, 2H),
[1,2,4]oxadiazol-5- 8.02 (m, 1H), 7.92 (m, 1H),
ylmethylsulfanyl]-4-ethyl-4H- 7.57 (dd, 2H),
[1,2,4]triazol-3-yl}-pyridine 7.42 (m, 2H), 4.80 (s, 2H), 4.08 (q,
2H), 1.38 (t, 3H). 601 4-{4-Ethyl-5-[5-(3-nitro-phenyl)- 8.87 (m,
3H), 8.42 (m, [1,3,4]oxadiazol-2- 2H), 7.75 (t, 1H),
ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.66 (d, 2H), 4.88 (s, 2H),
3-yl}-pyridine 4.15 (q, 2H), 1.45 (t, 3H). 602
2-(4-Ethyl-5-furan-2-yl-4H- 8.87 (t, 1H), 8.39 (m,
[1,2,4]triazol-3-ylsulfanylmethyl)-5- 2H), 7.73 (t, 1H),
(3-nitro-phenyl)-[1,3,4]oxadiazole 7.61 (m, 1H), 7.15 (m, 1H), 6.61
(m, 1H), 4.28 (q, 2H), 1.78 (s, 2H), 1.41 (t, 3H). 603
4-{5-[5-(3-Chloro-phenyl)-isoxazol- 8.79 (d, 2H), 7.78 (m, 411.00
3-ylmethylsulfanyl]-4-cyclopropyl- 3H), 7.66 (m, 1H),
4H-[1,2,4]triazol-3-yl}-pyridine 7.39 (m, 2H), 6.84 (s, 1H), 4.69
(s, 2H), 3.27 (m, 1H), 1.20 (q, 2H), 0.83 (m, 2H). 604
3-[5-(3-Chloro-phenyl)-isoxazol-3- 7.77 (m, 1H), 7.65 (m, 428.20
ylmethylsulfanyl]-4-ethyl-5-(4- 1H), 7.56 (m, 2H),
methoxy-phenyl)-4H-[1,2,4]triazole 7.41 (m, 2H), 7.04 (m, 2H), 6.79
(s, 1H), 4.61 (s, 2H), 3.97 (q, 2H), 3.89 (s, 3H), 1.32 (t, 3H).
605 5-(3-Chloro-phenyl)-3-[1-(4- 8.08 (m, 1H), 7.96 (dd, 404.92
methyl-5-thiophen-2-yl-4H- 1H), 7.45 (m, 4H),
[1,2,4]triazol-3-ylsulfanyl)-ethyl]- 7.17 (m, 1H), 4.93 (q, 1H),
[1,2,4]oxadiazole 3.67 (s, 3H), 1.91 (d, 3H). 606
5-(3-Chloro-phenyl)-3-[1-(4-ethyl- 8.1 (d, 1H), 7.98 (d, 1H),
418.90 5-thiophen-2-yl-4H-[1,2,4]triazol-3- 7.51 (m, 4H), 7.17 (t,
ylsulfanyl)-ethyl]-[1,2,4]oxadiazole 1H), 5.11 (q, 1H), 4.11 (q,
2H), 1.93 (d, 3H), 1.34 (t, 3H). 607 4-(5-{1-[5-(3-Chloro-phenyl)-
8.79 (dd, 2H), 400.07 [1,2,4]oxadiazol-3-yl]- 8.08 (m, 1H), 7.98
(dd, 1H), ethylsulfanyl}-4-methyl-4H- 7.59 (m, 3H), 7.46 (t,
[1,2,4]triazol-3-yl)-pyridine 1H), 5.05 (q, 1H), 3.66 (s, 3H), 1.94
(d, 3H). 608 4-(5-{1-[5-(3-Chloro-phenyl)- 8.79 (dd, 2H), 414.05
[1,2,4]oxadiazol-3-yl]- 8.10 (m, 1H), 7.99 (dd, 1H),
ethylsulfanyl}-4-ethyl-4H- 7.58 (m, 3H), 7.47 (t,
[1,2,4]triazol-3-yl)-pyridine 1H), 5.20 (q, 1H), 4.06 (q, 2H), 1.96
(d, 3H), 1.33 (t, 3H). 609 3-[5-(4-Ethyl-5-pyridin-4-yl-4H- 8.84
(s, 2H), 8.30 (m, [1,2,4]triazol-3-ylsulfanylmethyl)- 2H), 7.85 (m,
1H), [1,3,4]oxadiazol-2-yl]-benzonitrile 7.66 (m, 3H), 4.84 (s,
2H), 4.14 (q, 2H), 1.43 (t, 3H). 610 3-[5-(4-Ethyl-5-furan-2-yl-4H-
8.27 (m, 2H), 7.82 (m, [1,2,4]triazol-3-ylsulfanylmethyl)- 1H),
7.62 (m, 2H), [1,3,4]oxadiazol-2-yl]-benzonitrile 7.18 (t, 1H),
6.62 (m, 1H), 4.79 (s, 2H), 4.27 (q, 2H), 1.40 (t, 3H). 611
3-[5-(4-Methyl-5-pyridin-4-yl-4H- 8.83 (d, 2H), 8.31 (m,
[1,2,4]triazol-3-ylsulfanylmethyl)- 2H), 7.84 (m, 4H),
[1,3,4]oxadiazol-2-yl]-benzonitrile 4.81 (s, 2H), 3.77 (s, 3H). 612
3-[5-(4-Cyclopropyl-5-pyridin-4-yl- 8.82 (s, 2H), 8.33 (m, 402.20
4H-[1,2,4]triazol-3- 2H), 7.86 (t, 3H),
ylsulfanylmethyl)-[1,3,4]oxadiazol- 7.67 (t, 1H), 4.91 (d, 2H),
2-yl]-benzonitrile 1.24 (m, 3H), 0.88 (m, 2H). 613
4-{5-[5-(3-Chloro-phenyl)- (CD3OD as solvent): [1,3,4]oxadiazol-2-
8.80 (s (br), 2H), ylmethylsulfanyl]-4-methyl-4H- 7.96 (m, 2H),
7.81 (d, 2H), [1,2,4]triazol-3-yl}-pyridine 7.61 (m, 2H), 4.73 (s,
2H), 3.84 (s, 3H). 614 4-{5-[5-(3-Chloro-phenyl)- (CD3OD as
solvent): 412.16 [1,3,4]oxadiazol-2- 8.75 (d, 2H), 8.02 (s,
ylmethylsulfanyl]-4-cyclopropyl- 1H), 7.96 (d, 1H),
4H-[1,2,4]triazol-3-yl}-pyridine 7.89 (d, 2H), 7.60 (m, 2H), 4.89
(s, 2H), 3.59 (m, 1H), 1.21 (m, 2H), 0.84 (m, 2H). 615
4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 7.80 (m, 2H), 8.04 (m, 430.11
[1,3,4]oxadiazol-2- 1H), 7.77 (d, 2H),
ylmethylsulfanyl]-4-cyclopropyl- 7.51 (m, 1H), 7.21 (t, 1H),
4H-[1,2,4]triazol-3-yl}-pyridine 4.92 (s, 2H), 3.32 (m, 1H), 1.21
(m, 2H), 0.85 (m, 2H). 616 2-(5-Chloro-2-fluoro-phenyl)-5-[4- 8.02
(m, 1H), 7.52 (m, ethyl-5-(4-methoxy-phenyl)-4H- 3H), 7.20 (t, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl]- 7.04 (m, 2H), 4.81 (s, 2H),
[1,3,4]oxadiazole 4.03 (q, 2H), 3.89 (s, 3H), 1.33 (t, 3H). 617
4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.83 (d, 2H), 8.03 (m,
[1,3,4]oxadiazol-2- 1H), 7.65 (m, 2H),
ylmethylsulfanyl]-4-methyl-4H- 7.51 (m, 1H), 7.20 (t, 1H),
[1,2,4]triazol-3-yl}-pyridine 4.78 (s, 2H), 3.75 (s, 3H). 618
4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.82 (bs, 2H), 8.02 (m,
[1,3,4]oxadiazol-2- 1H), 7.61 (m, 2H),
ylmethylsulfanyl]-4-ethyl-4H- 7.51 (m, 1H), 7.20 (t, 1H),
[1,2,4]triazol-3-yl}-pyridine 4.85 (s, 2H), 4.13 (q, 2H), 1.41 (t,
3H). 619 2-(3-Chloro-phenyl)-5-[4-ethyl-5- 8.01 (d of d collapsed,
(4-methoxy-phenyl)-4H- 1H), 7.85 (d, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl]- 7.51 (m, 4H), 7.00 (d,
[1,3,4]oxadiazole 2H), 4.79 (s, 2H), 4.00 (q, 2H), 3.88 (s, 3H),
1.30 (t, 3H). 620 2-(3-Chloro-phenyl)-5-[1-(4-ethyl- 7.97 (s, 1H),
7.84 (d, 5-furan-2-yl-4H-[1,2,4]triazol-3- 1H), 7.58 (d, 1H),
ylsulfanyl)-ethyl]-[1,3,4]oxadiazole 7.49 (m, 1H), 7.40 (m, 1H),
7.12 (d, 1H), 6.59 (d of d, 1H), 5.16 (q, 1H), 4.17 (q, 2H), 2.02
(d, 3H), 1.28 (t, 3H). 621 5-(5-Chloro-2-fluoro-phenyl)-3-[1- 8.06
(m, 1H), 7.54 (m, (4-methyl-5-thiophen-2-yl-4H- 3H), 7.23 (m, 2H),
[1,2,4]triazol-3-ylsulfanyl)-ethyl]- 4.93 (q, 1H), 3.72 (s, 3H),
[1,2,4]oxadiazole 1.91 (d, 3H). 622 4-(5-{1-[5-(5-Chloro-2-fluoro-
8.79 (dd, 2H), 418.10 phenyl)-[1,2,4]oxadiazol-3-yl]- 8.07 (dd,
1H), 7.62 (dd, 2H), ethylsulfanyl}-4-methyl-4H- 7.54 (m, 1H), 7.21
(t, [1,2,4]triazol-3-yl)-pyridine 1H), 5.07 (q, 1H), 3.69 (s, 3H),
1.95 (d, 3H). 623 4-(5-{1-[5-(5-Chloro-2-fluoro- 8.79 (dd, 2H),
phenyl)-[1,2,4]oxadiazol-3-yl]- 8.08 (m, 1H), 7.57 (m, 3H),
ethylsulfanyl}-4-ethyl-4H- 7.22 (t, 1H), 5.21 (q,
[1,2,4]triazol-3-yl)-pyridine 1H), 4.08 (q, 2H), 1.97 (d, 3H), 1.35
(t, 3H). 624 2-Chloro-4-[3-(4-cyclopropyl-5- 8.83 (m, 2H), 8.65 (m,
pyridin-4-yl-4H-[1,2,4]triazol-3- 1H), 8.05 (t, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.92 (t, 1H), 7.76 (t, 2H),
5-yl]-pyridine 4.82 (2H), 3.31 (m, 1H), 1.23 (m, 2H), 0.86 (m, 2H).
625 4-{5-[5-(2-Fluoro-5-methyl- 8.83 (t, 2H), 7.82 (m,
phenyl)-[1,3,4]oxadiazol-2- 1H), 7.63 (m, 2H),
ylmethylsulfanyl]-4-methyl-4H- 7.32 (m, 1H), 7.10 (m, 1H),
[1,2,4]triazol-3-yl}-pyridine 4.75 (s, 2H), 3.73 (s, 3H), 2.39 (s,
3H), 1.61 (d, 1H). 626 4-{4-Ethyl-5-[5-(2-fluoro-5-methyl- 8.82 (d,
2H), 7.82 (m, 397.08 phenyl)-[1,3,4]oxadiazol-2- 1H), 7.59 (t, 2H),
ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.33 (m, 1H), 7.11 (m, 1H),
3-yl}-pyridine 4.82 (s, 2H), 4.10 (m, 2H), 2.39 (s, 3H), 1.38 (t,
3H). 627 4-{4-Cyclopropyl-5-[5-(2-fluoro-5- 8.80 (s, 2H), 7.84 (m,
409.15 methyl-phenyl)-[1,3,4]oxadiazol-2- 1H), 7.76 (d, 2H),
ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.32 (m, 1H), 7.12 (q, 1H),
3-yl}-pyridine 4.91 (s, 2H), 3.31 (m, 1H), 2.39 (d, 3H), 1.21 (m,
2H), 0.84 (m, 2H). 628 2-(4-Ethyl-5-furan-2-yl-4H- 7.77 (m, 1H),
7.61 (m, [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.32 (d, 1H),
(2-fluoro-5-methyl-phenyl)- 7.12 (m, 2H), 6.61 (m, 1H),
[1,3,4]oxadiazole 4.76 (s, 2H), 4.26 (q, 2H), 2.37 (d, 3H), 1.23
(t, 3H). 629 2-[4-Ethyl-5-(4-methoxy-phenyl)- 7.81 (m, 1H), 7.54
(m, 426.15 4H-[1,2,4]triazol-3- 2H), 7.32 (d, 1H),
ylsulfanylmethyl]-5-(2-fluoro-5- 7.11 (m, 1H), 7.03 (m, 2H),
methyl-phenyl)-[1,3,4]oxadiazole 4.79 (s, 2H), 4.02 (q, 2H), 3.89
(s, 3H), 2.37 (d, 3H), 1.31 (t, 3H). 630
4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.82 (dd, 2H), 7.91 (dd, 417.02
isoxazol-3-ylmethylsulfanyl]-4- 1H), 7.60 (dd, 2H),
ethyl-4H-[1,2,4]triazol-3-yl}- 7.38 (m, 1H), 7.15 (m, 1H), pyridine
6.86 (d, 1H), 4.67 (s, 2H), 4.05 (q, 2H), 1.37 (t, 3H). 631
4-(5-{1-[5-(5-Chloro-2-fluoro- 8.81 (dd, 2H), 7.91 (dd, 431.10
phenyl)-isoxazol-3-yl]- 1H), 7.59 (dd, 2H),
ethylsulfanyl}-4-ethyl-4H- 7.38 (m, 1H), 7.15 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 6.74 (d, 1H), 5.20 (q, 1H), 4.05 (q,
2H), 1.95 (d, 3H), 1.34 (t, 3H). 632
4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.82 (dd, 2H), 7.91 (dd, 403.10
isoxazol-3-ylmethylsulfanyl]-4- 1H), 7.63 (dd, 2H),
methyl-4H-[1,2,4]triazol-3-yl}- 7.39 (m, 1H), 7.15 (m, 1H),
pyridine 6.85 (d, 1H), 4.62 (s, 2H), 3.69 (s, 3H). 633
4-(5-{1-[5-(5-Chloro-2-fluoro- 8.81 (dd, 2H), 7.91 (dd, 417.10
phenyl)-isoxazol-3-yl]- 1H), 7.60 (dd, 2H),
ethylsulfanyl}-4-methyl-4H- 7.38 (m, 1H), 7.15 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 6.72 (d, 1H), 5.06 (q, 1H), 3.64 (s,
3H), 1.93 (d, 3H). 634 4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.80
(dd, 2H), 7.92 (dd, 429.10 isoxazol-3-ylmethylsulfanyl]-4- 1H),
7.76 (dd, 2H), cyclopropyl-4H-[1,2,4]triazol-3-yl}- 7.38 (m, 1H),
7.15 (m, 1H), pyridine 6.95 (d, 1H), 4.71 (s, 2H), 3.27 (m, 1H),
1.18 (m, 2H), 0.82 (m, 2H). 635 4-(5-{1-[5-(5-Chloro-2-fluoro- 8.78
(dd, 2H), 7.92 (dd, 443.20 phenyl)-isoxazol-3-yl]- 1H), 7.76 (dd,
2H), ethylsulfanyl}-4-cyclopropyl-4H- 7.38 (m, 1H), 7.15 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 6.85 (d, 1H), 5.40 (q, 1H), 3.24 (m,
1H), 1.98 (d, 3H), 1.88 (m, 2H), 0.80 (m, 2H). 636
3-[5-(5-Chloro-2-fluoro-phenyl)- 7.90 (dd, 1H), 7.60 (dd,
isoxazol-3-ylmethylsulfanyl]-4- 1H), 7.39 (m, 1H),
ethyl-5-furan-2-yl-4H- 7.11 (m, 2H), 6.85 (d, 1H), [1,2,4]triazole
6.59 (dd, 1H), 4.62 (s, 2H), 4.20 (q, 2H), 1.38 (t, 3H). 637
3-{1-[5-(5-Chloro-2-fluoro-phenyl)- 7.88 (dd, 1H), 7.59 (dd,
isoxazol-3-yl]-ethylsulfanyl}-4- 1H), 7.39 (m, 1H),
ethyl-5-furan-2-yl-4H- 7.11 (m, 2H), 6.74 (d, 1H), [1,2,4]triazole
6.58 (dd, 1H), 5.08 (q, 1H), 4.20 (q, 2H), 1.92 (d, 3H), 1.34 (t,
3H). 638 4-(5-{1-[5-(3-Chloro-phenyl)- 1.96 (d, 3H) 3.61 (s, 3H)
[1,3,4]oxadiazol-2-yl]- 5.10 (q, 1H) 7.38 (t,
ethylsulfanyl}-4-methyl-4H- 1H) 7.47 (m, 1H)
[1,2,4]triazol-3-yl)-pyridine 7.54 (m, 2H) 7.84 (m, 1H) 7.93 (m,
1H) 8.74 (d, 2H) 639 4-(5-{1-[5-(3-Chloro-phenyl)- 8.80 (bs, 2H),
7.99 (m, 414.10 [1,3,4]oxadiazol-2-yl]- 1H), 7.90 (m, 1H),
ethylsulfanyl}-4-ethyl-4H- 7.58 (d, 2H), 7.51 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 7.46 (t, 1H), 5.31 (q, 1H), 4.06 (q,
2H), 2.04 (d, 3H), 1.31 (t, 3H). 640 4-(5-{1-[5-(3-Chloro-phenyl)-
8.79 (bs, 2H), 8.03 (m, 426.07 [1,3,4]oxadiazol-2-yl]- 1H), 7.94
(d, 1H), ethylsulfanyl}-4-cyclopropyl-4H- 7.76 (d, 2H), 7.51 (m,
1H), [1,2,4]triazol-3-yl)-pyridine 7.45 (t, 1H), 7.54 (q, 1H), 3.25
(m, 1H), 2.06 (d, 3H), 1.19 (m, 2H), 0.81 (m, 2H). 641
5-(5-Chloro-2-fluoro-phenyl)-3-(5- 8.06 (dd, 1H), 7.60 (d,
furan-2-yl-4-methyl-4H- 1H), 7.55 (m, 1H),
[1,2,4]triazol-3-ylsulfanylmethyl)- 7.22 (t, 1H), 7.09 (d, 1H),
[1,2,4]oxadiazole 6.58 (m, 1H), 4.55 (s, 2H), 3.81 (s, 3H). 642
5-(5-Chloro-2-fluoro-phenyl)-3-(5- 8.06 (dd, 1H), 7.89 (d,
furan-3-yl-4-methyl-4H- 1H), 7.55 (m, 2H),
[1,2,4]triazol-3-ylsulfanylmethyl)- 7.22 (t, 1H), 6.88 (dd, 1H),
[1,2,4]oxadiazole 4.55 (s, 2H), 3.67 (s, 3H). 643
4-Chloro-2-[3-(4-ethyl-5-thiophen- 10.08 (s, 1H), 7.88 (d,
2-yl-4H-[1,2,4]triazol-3- 1H), 7.47 (m, 3H),
ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.17 (t, 1H), 7.06 (d, 1H),
5-yl]-phenol 4.68 (s, 2H), 4.14 (q, 2H), 1.38 (t, 3H). 644
2-Chloro-4-[5-(4-methyl-5-pyridin- 8.83 (d, 2H), 8.60 (m,
4-yl-4H-[1,2,4]triazol-3- 1H), 7.94 (m, 1H),
ylsulfanylmethyl)-[1,3,4]oxadiazol- 7.85 (m, 1H), 7.62 (m, 2H),
2-yl]-pyridine 4.82 (s, 2H), 3.75 (s, 3H). 645
2-Chloro-4-[5-(4-ethyl-5-pyridin-4- 8.82 (d, 2H), 8.60 (m,
yl-4H-[1,2,4]triazol-3- 1H), 7.94 (m, 1H),
ylsulfanylmethyl)-[1,3,4]oxadiazol- 7.86 (m, 1H), 7.59 (m, 2H),
2-yl]-pyridine 4.87 (s, 2H), 4.12 (q, 2H), 1.43 (t, 3H). 646
2-Chloro-4-[5-(4-cyclopropyl-5- 8.81 (d, 2H), 8.60 (m,
pyridin-4-yl-4H-[1,2,4]triazol-3- 1H), 7.96 (m, 1H),
ylsulfanylmethyl)-[1,3,4]oxadiazol- 7.86 (m, 1H), 7.75 (m, 2H),
2-yl]-pyridine 4.92 (s, 2H), 3.32 (m, 1H), 1.21 (m, 2H), 0.87 (q,
2H). 647 2-Chloro-4-[5-(4-ethyl-5-furan-2-yl- 8.57 (m, 1H), 7.92
(m, 4H-[1,2,4]triazol-3- 1H), 7.81 (m, 1H),
ylsulfanylmethyl)-[1,3,4]oxadiazol- 7.61 (m, 1H), 7.12 (m, 1H),
2-yl]-pyridine 6.61 (m, 1H), 4.79 (s, 2H), 4.26 (q, 2H), 1.40 (t,
3H). 648 2-Chloro-4-{5-[4-ethyl-5-(4- 8.59 (m, 1H), 7.94 (m,
methoxy-phenyl)-4H-[1,2,4]triazol- 1H), 7.84 (m, 1H),
3-ylsulfanylmethyl]- 7.55 (m, 2H), 7.05 (m, 2H),
[1,3,4]oxadiazol-2-yl}-pyridine 4.83 (s, 2H), 4.02 (q, 2H), 1.34
(t, 3H). 649 2-(3-Chloro-phenyl)-5-{1-[5-(4- 8.00 (m, 1H), 7.87 (d,
methoxy-phenyl)-4-methyl-4H- 1H), 7.53 (m, 3H),
[1,2,4]triazol-3-ylsulfanyl]-ethyl}- 7.42 (t, 1H), 7.01 (m, 2H),
[1,3,4]oxadiazole 5.07 (q, 1H), 3.88 (s, 3H), 3.54 (s, 3H), 2.00
(d, 3H). 650 4-(5-{1-[5-(5-Chloro-2-fluoro- 8.81 (bs, 2H), 8.01 (m,
phenyl)-[1,3,4]oxadiazol-2-yl]- 1H), 7.63 (d, 2H),
ethylsulfanyl}-4-methyl-4H- 7.50 (m, 1H), 7.18 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 5.17 (q, 1H), 3.69 (s,
3H), 2.02 (d, 3H). 651 5-(5-Bromo-2-fluoro-phenyl)-3-(4- 8.20 (m,
1H), 7.65 (m, ethyl-5-furan-2-yl-4H-[1,2,4]triazol- 1H), 7.60 (s,
1H), 3-ylsulfanylmethyl)- 7.13 (m, 2H), 6.56 (m, 1H),
[1,2,4]oxadiazole 4.64 (s, 2H), 4.25 (q, 2H), 1.38 (t, 3H). 652
2-(3-Chloro-phenyl)-5-[5-(4- 8.02 (d, 1H), 7.90 (d,
methoxy-phenyl)-4-methyl-4H- 1H), 7.50 (m, 4H),
[1,2,4]triazol-3-ylsulfanylmethyl]- 7.03 (d, 2H), 4.71 (s, 2H),
[1,3,4]oxadiazole 3.88 (s, 3H), 3.61 (s, 3H). 653
4-{5-[3-(3-Chloro-phenyl)- 8.79 (d, 2H), 8.09 (t, 412.07
[1,2,4]oxadiazol-5- 1H), 7.97 (m, 1H),
ylmethylsulfanyl]-4-cyclopropyl- 7.76 (d, 2H), 7.45 (m, 2H),
4H-[1,2,4]triazol-3-yl}-pyridine 4.89 (s, 2H), 3.30 (m, 1H), 1.22
(m, 2H), 0.86 (m, 2H). 654 4-{5-[5-(3-Chloro-phenyl)- 8.78 (s, 2H),
8.14 (m, [1,2,4]oxadiazol-3- 1H), 8.04 (m, 1H),
ylmethylsulfanyl]-4-cyclopropyl- 7.77 (t, 2H), 7.54 (m, 2H),
4H-[1,2,4]triazol-3-yl}-pyridine 4.79 (s, 2H), 3.29 (m, 1H), 1.21
(m, 2H), 0.85 (d, 2H). 655 4-(5-{1-[5-(2-Fluoro-5-methyl- 8.79 (s,
2H), 7.79 (t, phenyl)-[1,3,4]oxadiazol-2-yl]- 1H), 7.61 (t, 2H),
ethylsulfanyl}-4-methyl-4H- 7.33 (m, 1H), 7.08 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 5.09 (m, 1H), 3.65 (s, 3H), 2.37 (s,
3H), 2.02 (d, 3H). 656 4-(4-Ethyl-5-{1-[5-(2-fluoro-5- 8.81 (m,
2H), 8.23 (m, methyl-phenyl)-[1,3,4]oxadiazol-2- 1H), 7.79 (d, 2H),
yl]-ethylsulfanyl}-4H-[1,2,4]triazol- 7.32 (m, 1H), 7.09 (m, 1H),
3-yl)-pyridine 5.28 (m, 1H), 4.07 (m, 2H), 2.37 (s, 3H), 2.04 (d,
3H), 1.24 (m, 3H). 657 4-(4-Cyclopropyl-5-{1-[5-(2-fluoro- 8.78 (m,
2H), 7.82 (d, 5-methyl-phenyl)-[1,3,4]oxadiazol- 1H), 7.74 (d, 2H),
2-yl]-ethylsulfanyl}-4H- 7.31 (m, 1H), 7.11 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 5.51 (m, 1H), 3.23 (m, 1H), 2.38 (s,
3H), 2.06 (d, 3H), 1.16 (m, 2H), 0.78 (m, 2H). 658
4-(4-Cyclopropylmethyl-5-{1-[5-(2- 8.83 (m, 2H), 7.78 (m,
fluoro-5-methyl-phenyl)- 1H), 7.59 (m, 2H), [1,3,4]oxadiazol-2-yl]-
7.33 (m, 1H), 7.10 (m, 1H), ethylsulfanyl}-4H-[1,2,4]triazol-3-
5.26 (m, 1H), 3.90 (m, yl)-pyridine 2H), 2.37 (s, 3H), 2.03 (d,
3H), 0.92 (m, 1H), 0.48 (m, 2H), 0.21 (m, 2H). 659
2-(2-Fluoro-5-methyl-phenyl)-5-{1- 7.98 (s, 1H), 7.75 (m,
[4-methyl-5-(2-methyl-thiazol-4- 1H), 7.31 (m, 1H),
yl)-4H-[1,2,4]triazol-3-ylsulfanyl]- 7.08 (m, 1H), 5.03 (q, 1H),
ethyl}-[1,3,4]oxadiazole 3.85 (s, 3H), 2.75 (s, 3H), 2.35 (s, 3H),
1.98 (d, 3H). 660 4-(5-{1-[5-(5-Chloro-2-fluoro- 8.80 (m, 2H), 8.01
(m, phenyl)-[1,3,4]oxadiazol-2-yl]- 1H), 7.58 (m, 2H),
ethylsulfanyl}-4-ethyl-4H- 7.49 (m, 1H), 7.19 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 5.32 (q, 1H), 4.08 (q, 2H), 2.04 (d,
3H), 1.35 (t, 3H). 661 4-(5-{1-[5-(5-Chloro-2-fluoro- 8.79 (d, 2H),
8.03 (m, phenyl)-[1,3,4]oxadiazol-2-yl]- 1H), 7.75 (m, 2H),
ethylsulfanyl}-4-cyclopropyl-4H- 7.50 (m, 1H), 7.20 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 5.55 (q, 1H), 3.26 (s, 1H), 2.06 (d,
3H), 1.18 (m, 2H), 0.81 (m, 2H). 662
2-(5-Chloro-2-fluoro-phenyl)-5-[1- 8.97 (m, 1H), 7.59 (m,
(4-ethyl-5-furan-2-yl-4H- 1H), 7.47 (m, 1H),
[1,2,4]triazol-3-ylsulfanyl)-ethyl]- 7.17 (m, 1H), 7.12 (m, 1H),
[1,3,4]oxadiazole 6.59 (m, 1H), 5.18 (q, 1H), 4.21 (q, 2H), 2.00
(d, 3H), 1.33 (t, 3H). 663 2-(5-Chloro-2-fluoro-phenyl)-5-{1- 7.99
(s, 1H), 7.96 (m, [4-methyl-5-(2-methyl-thiazol-4- 1H), 7.48 (m,
1H), yl)-4H-[1,2,4]triazol-3-ylsulfanyl]- 7.17 (t, 1H), 7.06 (q,
1H), ethyl}-[1,3,4]oxadiazole 3.86 (s, 3H), 2.75 (s, 3H), 1.98 (d,
3H). 664 4-(4-Cyclopropylmethyl-5-{1-[5-(2- 8.78 (dd, 2H), 7.71
(dd, fluoro-5-methyl-phenyl)-isoxazol-3- 1H), 7.58 (dd, 2H),
yl]-ethylsulfanyl}-4H-[1,2,4]triazol- 7.25 (m, 1H), 7.08 (m, 1H),
3-yl)-pyridine 6.62 (d, 1H), 5.12 (q, 1H), 3.87 (dd, 2H), 2.40 (s,
3H), 1.94 (d, 3H), 0.90 (m, 1H), 0.49 (m, 2H), 0.19 (m, 2H). 665
4-(5-{1-[5-(3-Fluoro-phenyl)- 8.78 (bs, 2H), 7.92 (d,
[1,2,4]oxadiazol-3-yl]- 1H), 7.80 (dd, 1H),
ethylsulfanyl}-4-methyl-4H- 7.60 (d, 2H), 7.50 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 7.25 (m, 1H), 5.05 (q, 2H), 3.65 (s,
3H), 1.94 (d, 3H). 666 4-(4-Cyclopropyl-5-{1-[5-(3-fluoro- 8.76 (d,
2H), 7.95 (d, phenyl)-[1,2,4]oxadiazol-3-yl]- 1H), 7.85 (dd, 1H),
ethylsulfanyl}-4H-[1,2,4]triazol-3- 7.75 (d, 2H), 7.50 (m, 1H),
yl)-pyridine 7.25 (m, 1H), 5.45 (q, 2H), 3.20 (m, 1H), 1.98 (d, 3H)
1.22 (m, 2H), 0.88 (m, 2H). 667 4-(5-{1-[5-(4-Methoxy-phenyl)-4-
8.65 (d, 1H), 7.71 (s, methyl-4H-[1,2,4]triazol-3- 1H), 7.63 (d,
1H), ylsulfanyl]-ethyl}-[1,3,4]oxadiazol- 7.54 (d, 2H), 7.00 (d,
2H), 2-yl)-2-methyl-pyridine 5.10 (q, 1H), 3.87 (s, 3H), 3.53 (s,
3H), 2.58 (s, 3H), 2.00 (d, 3H). 668 4-(5-{1-[4-Ethyl-5-(4-methoxy-
8.65 (d, 1H), 7.71 (s, phenyl)-4H-[1,2,4]triazol-3- 1H), 7.63 (d,
1H), ylsulfanyl]-ethyl}-[1,3,4]oxadiazol- 7.49 (d, 2H), 7.01 (d,
2H), 2-yl)-2-methyl-pyridine 5.26 (q, 1H), 3.96 (q, 2H), 3.88 (s,
3H), 2.62 (s, 3H), 2.02 (d, 3H), 1.24 (t, 3H). 669
4-{5-[1-(4-Ethyl-5-pyridin-4-yl-4H- 8.79 (d, 2H), 8.67 (d,
[1,2,4]triazol-3-ylsulfanyl)-ethyl]- 1H), 7.73 (s, 1H),
[1,3,4]oxadiazol-2-yl}-2-methyl- 7.65 (d, 1H), 7.55 (d, 2H),
pyridine 5.33 (q, 1H), 4.08 (q, 2H), 2.64 (s, 3H), 2.03 (d, 3H),
1.30 (t, 3H). 670 4-{5-[1-(4-Cyclopropyl-5-pyridin-4- 8.77 (d, 2H),
8.68 (d, yl-4H-[1,2,4]triazol-3-ylsulfanyl)- 1H), 7.72 (m, 4H),
ethyl]-[1,3,4]oxadiazol-2-yl}-2- 5.55 (q, 1H), 3.24 (m, 1H),
methyl-pyridine 2.64 (s, 3H), 2.04 (d, 3H), 1.16 (m, 2H), 0.81 (m,
2H). 671 4-{5-[1-(5-Furan-2-yl-4-methyl-4H- 8.61 (d, 1H), 7.57 (m,
[1,2,4]triazol-3-ylsulfanyl)-ethyl]- 3H), 7.08 (d, 1H),
[1,3,4]oxadiazol-2-yl}-2-methyl- 6.57 (d, 1H), 5.02 (q, 1H),
pyridine 3.70 (s, 3H), 1.96 (d, 3H). 672
2-(3-Chloro-phenyl)-5-{1-[4- 7.99 (s, 1H),
methyl-5-(2-methyl-thiazol-4-yl)- 7.94 (m, 1H), 7.86 (m, 1H),
4H-[1,2,4]triazol-3-ylsulfanyl]- 7.48 (m, 1H), 7.39 (m,
ethyl}-[1,3,4]oxadiazole 1H), 5.03 (q, 1H), 3.82 (t, 3H), 2.73 (d,
3H), 1.98 (d, 3H). 673 3-(5-{1-[5-(3-Chloro-phenyl)- 8.88 (s, 1H),
8.76 (d, [1,3,4]oxadiazol-2-yl]- 1H), 8.00 (m, 2H),
ethylsulfanyl}-4-methyl-4H- 7.90 (d, 1H), 7.48 (m, 3H),
[1,2,4]triazol-3-yl)-pyridine 5.14 (q, 1H), 3.60 (s, 3H), 2.02 (d,
3H). 674 4-(5-{1-[5-(3-Chloro-phenyl)- 8.66 (d, 1H), 7.99 (m,
[1,3,4]oxadiazol-2-yl]- 1H), 7.88 (m, 1H),
ethylsulfanyl}-4-methyl-4H- 7.51 (m, 1H), 7.43 (m, 2H),
[1,2,4]triazol-3-yl)-2-methyl- 7.34 (d, 1H), 5.13 (q, pyridine 1H),
3.61 (s, 3H), 2.63 (s, 3H), 2.00 (d, 3H). 675
4-(5-{1-[5-(3-Chloro-phenyl)- 8.68 (dd, 2H), 8.05 (d,
[1,2,4]oxadiazol-3-yl]- 1H), 7.92 (d, 1H),
ethylsulfanyl}-4-cyclopropyl-4H- 7.67 (dd, 2H), 7.51 (d, 1H),
[1,2,4]triazol-3-yl)-pyridine 7.37 (t, 1H) 5.37 (q, 1H), 3.18 (m,
1H), 1.90 (d, 3H), 1.08 (m, 2H), 0.74 (m, 2H). 676
5-(3-Chloro-phenyl)-3-{1-[5-(4- 8.01 (s, 1H), 7.90 (d,
methoxy-phenyl)-4-methyl-4H- 1H), 7.50 (m, 3H),
[1,2,4]triazol-3-ylsulfanyl]-ethyl}- 7.38 (t, 1H), 6.92 (d, 2H),
[1,2,4]oxadiazole 4.88 (q, 1H) 3.78 (s, 3H), 3.47 (s, 3H), 1.83 (d,
3H). 677 4-(5-{1-[5-(5-Chloro-2-fluoro- 8.70 (dd, 2H), 8.05 (m,
phenyl)-[1,2,4]oxadiazol-3-yl]- 1H), 7.67 (m, 2H),
ethylsulfanyl}-4-cyclopropyl-4H- 7.46 (m, 1H), 7.18 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 5.41 (q, 1H), 3.18 (m, 1H), 1.90 (d,
3H), 1.08 (m, 2H), 0.74 (m, 2H). 678
5-(5-Chloro-2-fluoro-phenyl)-3-{1- 8.05 (m, 1H), 7.56 (m,
[5-(4-methoxy-phenyl)-4-methyl- 3H), 7.21 (t, 1H),
4H-[1,2,4]triazol-3-ylsulfanyl]- 7.00 (m, 3H), 5.01 (q, 1H),
ethyl}-[1,2,4]oxadiazole 3.85 (s, 3H), 3.56 (s, 3H), 1.90 (d, 3H).
679 4-[5-(4-Ethyl-5-pyridin-4-yl-4H- 8.79 (d, 2H), 8.67 (d,
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.75 (s, 1H),
[1,3,4]oxadiazol-2-yl]-2-methyl- 7.67 (d, 1H), 7.56 (d, 2H),
pyridine 4.82 (s, 2H), 4.10 (q, 2H), 2.64 (s, 3H), 1.39 (t, 3H).
680 4-[5-(4-Cyclopropyl-5-pyridin-4-yl- 8.78 (d, 3H), 8.68 (d,
4H-[1,2,4]triazol-3- 1H), 7.74 (m, 4H),
ylsulfanylmethyl)-[1,3,4]oxadiazol- 4.90 (s, 2H), 3.30 (m, 1H),
2-yl]-2-methyl-pyridine 2.65 (s, 3H), 1.21 (m, 2H), 0.84 (m, 2H).
681 4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.79 (d, 2H), 8.12 (m,
[1,2,4]oxadiazol-3- 1H), 7.76 (m, 2H),
ylmethylsulfanyl]-4-cyclopropyl- 7.57 (m, 1H), 7.25 (m, 1H),
4H-[1,2,4]triazol-3-yl}-pyridine 4.81 (s, 2H), 3.31 (m, 1H), 1.20
(m, 2H), 0.85 (m, 2H). 682 4-[5-(5-Furan-2-yl-4-methyl-4H- 8.66 (d,
1H), 7.72 (s, [1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.65 (d,
1H), [1,3,4]oxadiazol-2-yl]-2-methyl- 7.60 (d, 1H), 7.11 (d, 1H),
pyridine 6.60 (d of d, 1H), 4.70 (s, 2H), 3.80 (s, 3H), 2.64 (s,
3H). 683 4-(5-{1-[5-(3-Chloro-phenyl)- 8.79 (bs, 2H), 7.98 (m,
[1,3,4]oxadiazol-2-yl]- 1H), 7.88 (m, 1H), ethylsulfanyl}-4- 7.51
(m, 4H), 5.30 (q, 1H), cyclopropylmethyl-4H- 3.90 (m, 2H), 2.05 (t,
[1,2,4]triazol-3-yl)-pyridine 3H), 0.94 (ms, 1H), 0.50 (m, 2H),
0.19 (m, 2H). 684 4-(5-{1-[5-(4-Fluoro-phenyl)-4- 8.66 (d, 1H),
7.72 (s, methyl-4H-[1,2,4]triazol-3- 1H), 7.60 (m, 3H),
ylsulfanyl]-ethyl}-[1,3,4]oxadiazol- 7.17 (m, 3H), 5.13 (q, 1H),
2-yl)-2-methyl-pyridine 3.57 (s, 3H), 2.63 (s, 3H), 2.00 (d, 3H).
685 4-(5-{1-[5-(3-Fluoro-phenyl)-4- 8.65 (d, 1H), 7.72 (s,
methyl-4H-[1,2,4]triazol-3- 1H), 7.66 (d, 1H),
ylsulfanyl]-ethyl}-[1,3,4]oxadiazol- 7.48-7.20 (m, 4H), 5.15 (q,
2-yl)-2-methyl-pyridine 1H), 3.60 (s, 3H), 2.63 (s, 3H), 2.01 (d,
3H). 686 3-[3-(4-Cyclopropyl-5-pyridin-4-yl- 8.77 (dd, 2H),
4H-[1,2,4]triazol-3- 8.49 (dd, 1H), 7.90 (m, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.74 (dd, 2H), 7.43 (t,
5-yl]-4-fluoro-benzonitrile 1H), 4.81 (s, 2H), 3.31 (m, 1H), 1.21
(m, 2H), 0.83 (m, 2H). 687 4-Chloro-2-[3-(4-cyclopropyl-5- 10.15
(bs, 1H), 8.77 (dd, pyridin-4-yl-4H-[1,2,4]triazol-3- 2H), 7.89 (d,
1H), ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.75 (dd, 2H), 7.45 (dd,
1H), 5-yl]-phenol 7.06 (d, 1H), 4.79 (s, 2H), 3.29 (m, 1H), 1.21
(m, 2H), 0.83 (m, 2H). 688 4-{4-Cyclopropyl-5-[5-(3-methoxy- 8.77
(dd, 2H), 7.72 (m, phenyl)-[1,2,4]oxadiazol-3- 3H), 7.62 (dd, 1H),
ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.43 (t, 1H), 7.14 (m, 1H),
3-yl}-pyridine 4.77 (s, 2H), 3.88 (s, 3H), 3.28 (m, 1H), 1.17 (m,
2H), 0.84 (m, 2H). 689 4-{4-Cyclopropyl-5-[5-(2-fluoro-5- 8.7 (q,
2H), 7.81 (d, methyl-phenyl)-[1,2,4]oxadiazol-3- 1H), 7.7 (q, 2H),
ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.29 (m, 1H), 7.1 (t, 1H),
3-yl}-pyridine 4.71 (s, 2H), 3.23 (m, 1H), 2.32 (s, 3H), 1.11 (m,
2H), 0.76 (m, 2H) 690 4-{4-Cyclopropyl-5-[5-(3-fluoro- 8.67 (m,
2H), 7.82 (m, phenyl)-[1,2,4]oxadiazol-3- 1H), 7.72 (m, 1H),
ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.66 (m, 1H), 7.42 (m, 1H),
3-yl}-pyridine 7.21 (m, 1H), 4.68 (s, 1H), 3.23 (m, 1H), 1.11 (m,
2H), 0.75 (m, 2H) 691 4-[4-Cyclopropyl-5-(5-m-tolyl- 8.69 (q, 2H),
7.85 (m, [1,2,4]oxadiazol-3- 2H), 7.67 (q, 2H),
ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.32 (m, 2H), 4.69 (s, 2H),
3-yl]-pyridine 3.2 (m, 1H), 2.35 (s, 3H), 1.11 (m, 2H), 0.76 (m,
2H) 692 3-[3-(4-Cyclopropyl-5-pyridin-4-yl- 8.71 (b s, 2H), 8.36
(m, 4H-[1,2,4]triazol-3- 1H), 8.28 (d, 1H),
ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.83 (d d, 1H), 7.67 (m, 3H),
5-yl]-benzonitrile 4.72 (s, 2H), 3.23 (m, 1H), 1.14 (m, 2H),
0.77 (m, 2H) 693 4-{4-Cyclopropyl-5-[5-(2,5- 8.75 (t, 2H), 7.79 (m,
difluoro-phenyl)-[1,2,4]oxadiazol-3- 2H), 7.26 (m, 2H),
ylmethylsulfanyl]-4H-[1,2,4]triazol- 4.78 (s, 2H), 3.28 (m, 1H),
3-yl}-pyridine 1.14 (m, 2H), 0.82 (m, 2H) 694
4-{4-Cyclopropyl-5-[1-(5-m-tolyl- 8.67 (d d, 2H), 7.87 (m,
[1,2,4]oxadiazol-3-yl)- 2H), 7.67 (d d, 2H),
ethylsulfanyl]-4H-[1,2,4]triazol-3- 7.33 (m, 2H), 5.36 (q, 1H),
yl}-pyridine 3.15 (m, 1H), 2.36 (s, 3H), 1.92 (d, 3H), 1.07 (m,
2H), 0.72 (m, 2H) 695 4-(4-Cyclopropyl-5-{1-[5-(3- 8.69 (m, 2H),
7.6 (m, methoxy-phenyl)-[1,2,4]oxadiazol- 3H), 7.52 (m, 1H),
3-yl]-ethylsulfanyl}-4H- 7.35 (t, 1H), 7.04 (d d, 1H),
[1,2,4]triazol-3-yl)-pyridine 5.35 (q, 1H), 3.81 (s, 3H), 3.15 (m,
1H), 1.91 (d, 3H), 1.11 (m, 2H), 0.7 (m, 2H) 696
4-{5-[5-(2-Chloro-5-methyl- 8.69 (d, 2H), 7.78 (m,
phenyl)-[1,2,4]oxadiazol-3- 1H), 7.67 (m, 2H),
ylmethylsulfanyl]-4-cyclopropyl- 7.35 (d, 1H), 7.24 (m, 1H),
4H-[1,2,4]triazol-3-yl}-pyridine 4.72 (s, 2H), 3.22 (m, 1H), 2.31
(s, 3H), 1 (m, 2H), 0.76 (m, 2H) 697
2-[3-(4-Cyclopropyl-5-pyridin-4-yl- 9.89 (s, 1H), 8.7 (m,
4H-[1,2,4]triazol-3- 2H), 7.68 (m, 3H),
ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.2 (m, 1H), 6.92 (d, 1H),
5-yl]-4-methyl-phenol 4.72 (s, 2H), 3.22 (m, 1H), 2.26 (s, 3H),
1.01 (m, 2H), 0.74 (m, 2H) 698 4-(5-{1-[5-(2-Chloro-5-methyl- 8.69
(d d, 2H), 7.8 (q, phenyl)-[1,2,4]oxadiazol-3-yl]- 1H), 7.67 (m,
2H), ethylsulfanyl}-4-cyclopropyl-4H- 7.35 (d, 1H), 7.22 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 5.4 (q, 1H), 3.16 (m, 1H), 2.32 (s,
3H), 1.93 (d, 3H), 1.09 (m, 2H), 0.73 (m, 2H)
Example 699
{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2-
,4]oxadiazol-5-yl]-phenyl}-methanol
[1509] [3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanol
(32 mg, 0.14 mmol),
4-methyl-5-thiophene-3-yl-4H-[1,2,4]triazole-3-thiol (41 mg, 0.21
mmol) and potassium carbonate (29 mg, 0.21 mmol) was dissolved in
anhydrous acetonitrile and refluxed under nitrogen atmosphere for 1
h. The solvent was removed in vacuo and the residue was dissolved
in NaHCO3 (aq) and extracted with dichloromethane ('3). The organic
phase was dried (MgSO4), filtered and concentrated. The title
compound was isolated as an colorless oil (43 mg, 80%) by flash
chromatography using 3% methanol in dichloromethane. 1H NMR
(CDCl.sub.3), .delta. (ppm): 8.07 (s, 1H), 7.98 (d, 1H), 7.60 (d,
1H), 7.52-7.45 (m, 3H), 7.16 (dd, 1H), 5.29 (s, 2H), 4.75 (s, 2H),
4.50 (s, 2H), 3.71 (s, 1H).
[1510] The following compounds were prepared analogously to Example
699: TABLE-US-00026 Example No. Name 1H NMR MS 700
3-[5-(4-Methyl-5-thiophen-2-yl-4H-
[1,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4]oxadiazol-3-yl]-phenol
701 5-(3-Chloro-phenyl)-3-[4- 1.5 (m, 1H) 1.8 (m, 2H) 460
(tetrahydro-furan-2-ylmethyl)-5- 2.0 (m, 1H) 3.7 (m,
thiophen-2-yl-4H-[1,2,4]triazol-3- 1H) 3.8 (m, 1H)
ylsulfanylmethyl]-[1,2,4]oxadiazole 4.1 (s, m, 3H) 4.5 (dd, 2H) 7.1
(dd, 1H) 7.4 (t, 2H) 7.5 (m, 2H) 7.9 (dd, 1H) 8.0 (m, 1H 702
(2-Chloro-phenyl)-{5-[5-(3-chloro- 0.8 (2d, 6H) 2.0 (m, 1H) 490
phenyl)-[1,2,4]oxadiazol-3- 3.5 (dd, 1H) 3.6 (dd,
ylmethylsulfanyl]-4-isobutyl-4H- 1H) 4.5 (s, 2H) 6.3 (d,
[1,2,4]triazol-3-yl}-methanol 1H) 7.3 (m, 3H) 7.5 (apparent
triplett, 1H) 7.6 (m, 2H) 8.0 (apparent d, 1H) 8.1 (m, 1H) 703
5-(2-Fluoro-5-methyl-phenyl)-3-[5- 2.4 (s, 3H) 4.6 (s, 2H) 455.9
thiophen-2-yl-4-(2,2,2-trifluoro- 4.8 (q, J = 7.7 Hz, 2H)
ethyl)-4H-[1,2,4]triazol-3- 7.1 (m, 1H) 7.2 (m, 1H)
ylsulfanylmethyl]-[1,2,4]oxadiazole 7.4 (m, 1H) 7.5 (m, 1H) 7.6 (m,
1H) 7.8 (m, 1H)
Example 704
3-(2,5-Difluoro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yls-
ulfanylmethyl)-[1,2,4]oxadiazole
[1511] 5-Chloromethyl-3-(2,5-difluoro-phenyl)-[1,2,4]oxadiazole (23
mg, 0.10 mmol) and
4-ethyl-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione (23
mg, 0.1 mmol) was dissolved in anhydrous DMF (1 ml) and potassium
carbonate (21 mg, 0.15 mmol) was added. After stirring for 22 h
ethyl acetate was added, the resulting mixture was washed twice
with water and once with brine, dried over MgSO4 and evaporated.
Flash chromatography using heptane:ethyl acetate 1:1 yielded the
title compound (20 mg, 50%). 1H NMR (CDCl.sub.3) d (ppm): 7.64 (m,
1H), 7.45 (d, 1H), 7.39 (d, 1H), 7.10 (m, 3H), 4.70 (s, 2H), 4.08
(q, 2H), 1.32 (t, 3H).
[1512] The following compounds were prepared analogously to
Examples 704: TABLE-US-00027 Example No. Name 1H NMR MS 705
5-Furan-3-yl-3-(4-methyl-5- 3.71 (s, 3H) 4.51 (s, 2H) 345.92
thiophen-2-yl-4H-[1,2,4]triazol-3- 6.88 (dd, 1H)
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.17 (dd, 1H) 7.48 (dd, 1H)
7.51 (dd, 1H) 7.54 (t, 1H) 8.18 (m, 1H) 706
3-(3-Chloro-phenyl)-5-(5-furan-2- 3.78 (s, 3H) 4.64 (s, 2H) 373.96
yl-4-methyl-4H-[1,2,4]triazol-3- 6.57 (dd, 1H)
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.09 (d, 1H) 7.38 (t, 1H) 7.46
(m, 1H) 7.58 (d, 1H) 7.91 (d, 1H) 8.01 (m, 1H) 707
3-(3-Chloro-phenyl)-5-(5-furan-3- 3.63 (s, 3H) 4.64 (s, 2H) 373.96
yl-4-methyl-4H-[1,2,4]triazol-3- 6.85 (d, 1H) 7.39 (t,
ylsulfanylmethyl)-[1,2,4]oxadiazole 1H) 7.47 (dt, 1H) 7.56 (t, 1H)
7.87 (br. s, 1H) 7.91 (dt, 1H) 8.01 (t, 1H) 708
5-(3-Chloro-phenyl)-3-(5-furan-2- 3.77 (s, 3H) 4.50 (s, 2H) 373.96
yl-4-methyl-4H-[1,2,4]triazol-3- 6.55 (dd, 1H)
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.07 (d, 1H) 7.43 (t, 1H) 7.55
(m, 2H) 7.95 (dt, 1H) 8.05 (t, 1H) 709
5-(3-Chloro-phenyl)-3-(5-furan-3- 3.63 (s, 3H) 4.49 (s, 2H) 373.97
yl-4-methyl-4H-[1,2,4]triazol-3- 6.84 (br. s, 1H)
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.43 (t, 1H) 7.54 (m, 2H) 7.87
(s, 1H) 7.94 (d, 1H) 8.04 (m, 1H) 710 4-{5-[5-(3-Chloro-phenyl)-
4.06 (s, 3H) 4.63 (s, 2H) 385.97 [1,2,4]oxadiazol-3- 7.43 (t, 1H)
7.53 (m, ylmethylsulfanyl]-4-methyl-4H- 1H) 7.95 (d, 1H)
[1,2,4]triazol-3-yl}-pyrimidine 8.05 (t, 1H) 8.27 (dd, 1H) 8.85 (d,
1H) 9.25 (d, 1H) 711 4-{5-[3-(3-Chloro-phenyl)- 4.06 (s, 3H) 4.75
(s, 2H) 385.97 [1,2,4]oxadiazol-5- 7.35 (t, 1H)
ylmethylsulfanyl]-4-methyl-4H- 7.42 (ddd, 1H) 7.88 (dt, 1H)
[1,2,4]triazol-3-yl}-pyrimidine 7.97 (t, 1H) 8.24 (dd, 1H) 8.84 (d,
1H) 9.23 (d, 1H) 712 3-(5-Chloro-2-fluoro-phenyl)-5-(4- 1.29 (t,
3H) 4.07 (q, 2H) 421.99 ethyl-5-thiophen-2-yl-4H- 4.68 (s, 2H) 7.08
(m, [1,2,4]triazol-3-ylsulfanylmethyl)- 2H) 7.35 (m, 2H)
[1,2,4]oxadiazole 7.44 (dd, 1H) 7.87 (dd, 1H) 713
3-(5-Chloro-2-fluoro-phenyl)-5-(4- 1.32 (t, 3H) 4.18 (q, 2H) 406.02
ethyl-5-furan-2-yl-4H-[1,2,4]triazol- 4.71 (s, 2H)
3-ylsulfanylmethyl)- 6.51 (dd, 1H) 7.02 (dd, 1H) [1,2,4]oxadiazole
7.10 (dd, 1H) 7.37 (ddd, 1H) 7.53 (dd, 1H) 7.91 (dd, 1H) 714
5-(5-Chloro-thiophen-2-yl)-3-(4- 1.30 (t, 3H) 4.09 (q, 2H) 409.92
ethyl-5-thiophen-2-yl-4H- 4.47 (s, 2H) 6.96 (d,
[1,2,4]triazol-3-ylsulfanylmethyl)- 1H) 7.11 (dd, 1H)
[1,2,4]oxadiazole 7.40 (dd, 1H) 7.47 (dd, 1H) 7.60 (d, 1H) 715
5-(5-Chloro-thiophen-2-yl)-3-(4- 1.33 (t, 3H) 4.21 (q, 2H) 393.96
ethyl-5-furan-2-yl-4H-[1,2,4]triazol- 4.52 (s, 2H)
3-ylsulfanylmethyl)- 6.54 (dd, 1H) 6.98 (d, 1H) [1,2,4]oxadiazole
7.05 (dd, 1H) 7.55 (dd, 1H) 7.62 (d, 1H) 716
5-(5-Chloro-thiophen-3-yl)-3-(4- 1.36 (t, 3H) 4.12 (q, 2H) 409.92
ethyl-5-thiophen-2-yl-4H- 4.58 (s, 2H)
[1,2,4]triazol-3-ylsulfanylmethyl)- 7.15 (dd, 1H) 7.43 (m, 2H)
[1,2,4]oxadiazole 7.48 (dd, 1H) 7.94 (d, 1H) 717
4-{5-[5-(3-Chloro-phenyl)- 1.30 (t, 3H) 4.02 (q, 2H) 443.9
[1,2,4]oxadiazol-3- 4.51 (s, 2H) 5.07 (s,
ylmethylsulfanyl]-4-ethyl-4H- 2H) 6.72 (m, 4H)
[1,2,4]triazol-3-ylmethoxy}-phenol 7.39 (t, 1H) 7.49 (m, 1H) 7.89
(m, 1H) 7.99 (t, 1H) 718 4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 1.33
(t, 3H) 4.05 (q, 2H) 461.9 [1,3,4]oxadiazol-2- 4.70 (s, 2H) 5.11
(s, ylmethylsulfanyl]-4-ethyl-4H- 2H) 6.74 (m, 4H)
[1,2,4]triazol-3-ylmethoxy}-phenol 7.13 (t, 1H) 7.44 (m, 1H) 7.93
(dd, 1H) 719 3-(2,5-Difluoro-phenyl)-5-(4-ethyl- 7.75 (m, 1H), 7.64
(d, 389.9 5-furan-2-yl-4H-[1,2,4]triazol-3- 1H), 7.23 (m, 2H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.16 (d, 1H), 6.63 (dd, 1H),
4.80 (s, 2H), 4.29 (q, 2H), 1.43 (t, 3H) 720
3-(2,5-Difluoro-phenyl)-5-(5-furan- 8.17 (dd, 1H), 7.87 (m, 375.8
2-yl-4-methyl-4H-[1,2,4]triazol-3- 1H), 7.74 (m, 2H),
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.33 (dd, 1H), 6.95 (dd, 1H),
5.01 (s, 2H), 3.96 (s, 3H) 721 4-(5-{1-[3-(3-Chloro-phenyl)- 8.74
(d, 2H), 7.97 (s, 1H), 400 [1,2,4]oxadiazol-5-yl]- 7.87 (m, 1H),
ethylsulfanyl}-4-methyl-4H- 7.56 (d, 2H), 7.44 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 7.36 (apparent t, 1H), 5.06 (q, 1H),
3.58 (s, 3H), 1.96 (d, 3H). 722 4-{5-[5-(5-Chloro-2-fluoro-phenyl)-
0.90 (m, 2H), 1.22 (m, 430.1 [1,2,4]oxadiazol-3- 2H), 3.49 (m, 1H),
ylmethylsulfanyl]-4-cyclopropyl- 4.81 (s, 2H), 7.26 (t, 1H),
4H-[1,2,4]triazol-3-yl}-pyrimidine 7.53 (m, 1H), 8.11 (m, 2H), 8.88
(d, 1H) 9.33 (s, 1H) 723 2-(5-{1-[5-(3-Chloro-phenyl)- 1.32 (t,
3H), 1.94 (d, 3H), 444.1 [1,2,4]oxadiazol-3-yl]- 4.00 (s, 3H),
ethylsulfanyl}-4-ethyl-4H- 4.50 (m, 2H), 5.20 (q, 1H),
[1,2,4]triazol-3-yl)-5-methoxy- 7.46 (t, 1H), 7.56 (m, 1H),
pyrimidine 7.99 (d, 1H), 8.10 (t, 1H), 8.56 (d, 2H). 724
2-(5-{1-[5-(3-Chloro-phenyl)- 1.34 (t, 3H), 1.94 (d, 3H), 414
[1,2,4]oxadiazol-3-yl]- 4.50 (m, 2H), ethylsulfanyl}-4-ethyl-4H-
5.26 (q, 1H), 7.36 (t, 1H), [1,2,4]triazol-3-yl)-pyrimidine 7.46
(t, 1H), 7.57 (d, 1H), 7.99 (m, 1H), 8.10 (m, 1H), 8.92 (d, 2H).
725 4-(5-{1-[5-(3-Chloro-phenyl)- 1.32 (t, 3H), 1.97 (d, 3H), 443.1
[1,2,4]oxadiazol-3-yl]- 3.99 (s, 3H), ethylsulfanyl}-4-ethyl-4H-
4.06 (m, 2H), 5.19 (q, 1H), [1,2,4]triazol-3-yl)-2-methoxy- 6.98
(bs, 1H), 7.16 (m, pyridine 1H), 7.47 (t, 1H), 7.58 (m, 1H), 7.98
(dt, 1H), 8.10 (m, 1H) 8.31 (d, 1H). 726
5-(5-{1-[5-(3-Chloro-phenyl)- 1.30 (t, 3H), 1.96 (d, 3H), 443
[1,2,4]oxadiazol-3-yl]- 3.99 (m, 2H), 4.00 (s,
ethylsulfanyl}-4-ethyl-4H- 3H), 5.16 (q, 1H),
[1,2,4]triazol-3-yl)-2-methoxy- 6.87 (d, 1H), 7.47 (t, 1H),
pyridine 7.58 (m, 1H), 7.86 (dd, 1H), 8.00 (d, 1H), 8.11 (t, 1H)
8.40 (d, 1H). 727 2-(5-{1-[5-(3-Chloro-phenyl)- 1.30 (t, 3H), 1.93
(d, 3H), 443.1 [1,2,4]oxadiazol-3-yl]- 3.92 (s, 3H),
ethylsulfanyl}-4-ethyl-4H- 4.52 (m, 2H), 5.13 (q, 1H),
[1,2,4]triazol-3-yl)-5-methoxy- 7.32 (dd, 1H), 7.46 (t, 1H),
pyridine 7.56 (m, 1H), 7.99 (dt, 1H), 8.10 (t, 1H), 8.25 (d, 1H)
8.30 (d, 1H). 728 3-(5-{1-[5-(3-Chloro-phenyl)- 1.38 (t, 3H), 1.96
(d, 3H), 444 [1,2,4]oxadiazol-3-yl]- 4.20 (s, 3H),
ethylsulfanyl}-4-ethyl-4H- 4.61 (m, 2H), 5.20 (q, 1H),
[1,2,4]triazol-3-yl)-6-methoxy- 7.12 (d, 1H), 7.46 (t, 1H),
pyridazine 7.56 (t, 1H), 8.00 (d, 1H), 8.10 (s, 1H), 8.40 (d, 1H)
729 3-(5-{1-[5-(3-Chloro-phenyl)- 0.77 (m, 2H), 1.14 (m,
[1,2,4]oxadiazol-3-yl]- 2H), 1.99 (d, 3H),
ethylsulfanyl}-4-cyclopropyl-4H- 3.22 (m, 1H), 5.44 (q, 1H),
[1,2,4]triazol-3-yl)-pyridine 7.45 (m, 2H), 7.58 (d, 1H), 8.02 (d,
1H), 8.15 (m, 2H), 8.72 (d, 1H) 9.05 (s, 1H). 730
4-{5-[3-(3-Chloro-phenyl)- 3.69 (s, 3H) 4.73 (s, 2H) 384.91
[1,2,4]oxadiazol-5- 7.39 (t, 1H) 7.47 (m,
ylmethylsulfanyl]-4-methyl-4H- 1H) 7.60 (m, 2H)
[1,2,4]triazol-3-yl}-pyridine 7.92 (m, 1H) 8.02 (t, 1H) 8.79 (m,
2H)
Example 731
5-(3-Chloro-phenyl)-3-(5-furan-2-yl-4-isobutyl-4H-[1,2,4]triazol-3-ylsulfa-
nylmethyl)-[1,2,4]oxadiazole
[1513] The title compound was synthesized according to the method
described by Graybill et al. Tetrahedron lett. 2002 43, 5305-5309
from furan-2-carboxylic acid hydrazide (55.2 mg, 0.44 mmol),
1-isothiocyanato-2-methyl-propane (47 ml, 0.38 mmol) and
3-chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole (45.0 mg, 0.20
mmol) with P-BEMP (136 mg, 0.30 mmol) as base. Purification by
flash chromatography (33-66% EtOAc in heptane) gave the product as
an oil (12.7 mg, 15.6%). 1H NMR (CDCl.sub.3) d (ppm): 8.08 (s, 1H),
7.97 (d, 1H), 7.55 (d, 2H), 7.45 (t, 1H), 7.10 (d, 1H), 6.56 (d,
1H), 4.62 (s, 2H), 4.01 (d, 2H), 2.03 (m, 1H), 0.86 (d, 6H).
[1514] General: Thiophene-2-carbohydrazide (1.5 equiv) and an
isothiocyanate (1.3 equiv) were dissolved in DMF (1 ml).
2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphospho-
rine (1 equiv) on polystyrene was added and the reactions were
shaken on a Bohdan miniblock at ambient temperature for 1 h and
then for one additional h at 45.degree. C. The resin was washed
with dioxane:water 1:1 several times. The ring closure was carried
out at 85.degree. C. for 48 h in dioxane:water 1:1 on the
miniblock. The resin was washed with acetonitrile (2' 2 ml). The
3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole was added to
the reaction and shaken in acetonitrile at 50.degree. C. for 2 h.
The product was filtrated and purified on MS-directed prep-HPLC,
gradient 0-100% acetonitrile over 15 min.
[1515] The following compounds were prepared analogously to Example
731: TABLE-US-00028 Example No. Name 1H NMR MS 732
5-(3-Chloro-phenyl)-3-[4-(3- 464.0
methylsulfanyl-propyl)-5-thiophen- 2-yl-4H-[1,2,4]triazol-3-
ylsulfanylmethyl]-[1,2,4]oxadiazole 733
5-(3-Chloro-phenyl)-3-(4-hexyl-5- 460.0
thiophen-2-yl-4H-[1,2,4]triazol-3-
ylsulfanylmethyl)-[1,2,4]oxadiazole 734 5-(3-Chloro-phenyl)-3-(4-
430.0 cyclopropylmethyl-5-thiophen-2-yl- 4H-[1,2,4]triazol-3-
ylsulfanylmethyl)-[1,2,4]oxadiazole 735
5-(3-Chloro-phenyl)-3-[4-(3-fluoro- 484.0
benzyl)-5-thiophen-2-yl-4H- [1,2,4]triazol-3-ylsulfanylmethyl]-
[1,2,4]oxadiazole 736 5-(3-Chloro-phenyl)-3-[4-(3- 480.0
methyl-benzyl)-5-thiophen-2-yl-4H-
[1,2,4]triazol-3-ylsulfanylmethyl]- [1,2,4]oxadiazole 737
5-(3-Chloro-phenyl)-3-[4-(2- 446.0
methyl-butyl)-5-thiophen-2-yl-4H-
[1,2,4]triazol-3-ylsulfanylmethyl]- [1,2,4]oxadiazole 738
5-(3-Chloro-phenyl)-3-[4-(3- 446.0
methyl-butyl)-5-thiophen-2-yl-4H-
[1,2,4]triazol-3-ylsulfanylmethyl]- [1,2,4]oxadiazole 739
5-(3-Chloro-phenyl)-3-[4-(2-fluoro- 484.0
benzyl)-5-thiophen-2-yl-4H- [1,2,4]triazol-3-ylsulfanylmethyl]-
[1,2,4]oxadiazole
Example 740
5-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yloxyme-
thyl)-[1,2,4]oxadiazole
[1516] [5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanol (28.0
mg, 0.13 mmol),
4-ethyl-3-methanesulfonyl-5-thiophen-2-yl-4H-[1,2,4]triazole (35.2
mg, 0.13 mmol) and cesium carbonate (130 mg) were dissolved in
dimethylformamide and stirred under argon at ambient temperatures
for 46 h. After evaporation to dryness the crude was
chromatographed on 12 g silica, heptane/ethyl acetate 4/1 to 2/1.
Collection of the appropriate fractions gave after evaporation to
dryness and drying in vacuo the title compound (17.0 mg, 33%). 1H
NMR (CDCl.sub.3), .delta. (ppm): 8.13 (m, 1H), 8.02 (m, 1H), 7.58
(m, 1H), 7.47 (m, 2H), 7.40 (dd, 1H), 7.14 (dd, 1H), 5.74 (s, 2H),
4.04 (q, 2H), 1.38 (t, 3H).
[1517] The following compounds were prepared analogously to Example
740: TABLE-US-00029 Example No. Name 1H NMR MS The following
compounds were prepared analogously to Example 740: 741
4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.92 (s broad, 2 H), 8.12 388
[1,2,4]oxadiazol-3-ylmethoxy]-4- (apparent dd, 1 H), 7.78
methyl-4H-[1,2,4]triazol-3-yl}- (s, 1 H), 7.56 (s broad, 2 pyridine
H), 7.25 (apparent t, 1 H), 5.79 (s, 2 H), 3.66 (s, 3 H). 742
4-(5-{1-[5-(3-Chloro-phenyl)- 8.82 (s broad, 2 H), 384.1
[1,3,4]oxadiazol-2-yl]-ethoxy}-4- 8.07-7.94 (m, 2 H), 7.69
methyl-4H-[1,2,4]triazol-3-yl)- (s broad, 2 H), 7.47 (m, pyridine 2
H), 6.47 (q, 1 H), 3.63 (s, 3 H), 2.02 (d, 3 H). 743
4-(5-{1-[3-(3-Chloro-phenyl)- 1.92 (d, 3 H), 3.57 (s, 3 383.1
isoxazol-5-yl]-ethoxy}-4-methyl- H), 6.36 (q, 1 H), 6.74
4H-[1,2,4]triazol-3-yl)-pyridine (s, 1 H), 7.39 (m, 2 H), 7.60 (m,
2 H), 7.66 (m, 1 H), 7.78 (m, 1 H), 8.75 (m, 2 H) 744
3-(5-{1-[5-(3-Chloro-phenyl)- [1,2,4]oxadiazol-3-yl]-ethoxy}-4-
cyclopropyl-4H-[1,2,4]triazol-3-yl)- pyridine The following
compounds were prepared analogously to Example 740 with the
exception that sodium hydride was employed as the base and the
reaction was heated at 80.degree. C.: 745
4-{5-[5-(3-Chloro-phenyl)- 8.77 (d, 2H), 8.17 (s,
[1,2,4]oxadiazol-3-ylmethoxy]-4- 1H), 8.05 (d, 1H), 7.79
cyclopropyl-4H-[1,2,4]triazol-3-yl}- (d, 2H), 7.62 (dd, 1H),
pyridine 7.52 (t, 1 H), 5.79 (s, 2H), 3.25 (m, 1H), 1.14 (d, 2H),
0.89 (m, 2H) 746 4-{5-[5-(3-Chloro-phenyl)-isoxazol- 8.77 (d, 2H),
7.79 (m, 3-ylmethoxy]-4-cyclopropyl-4H- 3H), 7.7 (m, 1H), 7.44
[1,2,4]triazol-3-yl}-pyridine (m, 2H), 6.84 (s, 1H), 5.71 (s, 2H),
3.21 (m, 1H), 1.13 (d, 2H), 0.82 (m, 2H)
[1518] The following compounds were prepared analogously to Example
740 with the exception that sodium hydride was employed as the base
and the reaction was heated at 80.degree. C.:
Example 747
5-(2-Methoxy-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsul-
fanylmethyl)-[1,2,4]oxadiazole
[1519] HBTU (171 mg, 0.45 mmol) and HOBT (8 mg, 0.06 mmol) were
added to a solution of 2-methoxy benzoic acid (68 mg, 0.45 mmol)
and DIPEA (192 ml, 1.11 mmol) in DMF (3 ml). After 10 min
N-hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ace-
tamidine (100 mg, 0.37 mmol) was added. The reaction mixture was
stirred at RT for 7 h and then at 110.degree. C. over night. After
cooling the reaction mixture was diluted with water and extracted
with CH.sub.2Cl.sub.2. The organic phase was dried and
concentrated. Flash chromatography (heptane/EtOAc 1:2) afforded 1.9
mg (11%) of the desired product.
[1520] 1H NMR (CDCl.sub.3), d (ppm): 7.99 (m, 1H), 7.53 (m, 1H),
7.50 (m, 1H), 7.47 (m, 1H), 7.16 (m, 1H), 7.04 (m, 2H), 4.52 (s,
2H), 3.94 (s, 3H), 3.71 (s, 3H).
[1521] The following compounds were prepared analogously to Example
747: TABLE-US-00030 Example No. Name 1H NMR MS 748
5-Furan-2-yl-3-(4-methyl-5- 3.72 (s, 3H) 4.52 (s, 2H) 345.92
thiophen-2-yl-4H-[1,2,4]triazol-3- 6.61 (dd, 1H)
ylsulfanylmethyl)-[1,2,4]oxadiazole 7.16 (dd, 1H) 7.30 (dd, 1H)
7.47 (dd, 1H) 7.50 (dd, 1H) 7.67 (dd, 1H) 749
3-[3-(4-Methyl-5-thiophen-2-yl-4H- 414.0
[1,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4]oxadiazol-5-yl]-benzoic
acid methyl ester 750 5-(2-Fluoro-phenyl)-3-(4-methyl-5- 374.0
thiophen-2-yl-4H-[1,2,4]triazol-3-
ylsulfanylmethyl)-[1,2,4]oxadiazole 751
5-(2,5-Difluoro-phenyl)-3-(4- 392.0 methyl-5-thiophen-2-yl-4H-
[1,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4]oxadiazole 752
3-(4-Methyl-5-thiophen-2-yl-4H- 382.1
[1,2,4]triazol-3-ylsulfanylmethyl)-5-
(3-vinyl-phenyl)-[1,2,4]oxadiazole 753
5-(3-Difluoromethoxy-phenyl)-3-(4- 422.0 methyl-5-thiophen-2-yl-4H-
[1,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4]oxadiazole 754
5-(4-Methoxy-thiophen-3-yl)-3-(4- 392.0 methyl-5-thiophen-2-yl-4H-
[1,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4]oxadiazole 755
5-(2-Chloro-phenyl)-3-(4-methyl-5- 390.0
thiophen-2-yl-4H-[1,2,4]triazol-3-
ylsulfanylmethyl)-[1,2,4]oxadiazole 756
5-(4-Fluoro-phenyl)-3-(4-methyl-5- 374.0
thiophen-2-yl-4H-[1,2,4]triazol-3-
ylsulfanylmethyl)-[1,2,4]oxadiazole
Example 757
3-(3-Chloro-phenyl)-5-[1-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yls-
ulfanyl)-ethyl]-[1,2,4]oxadiazole
[1522] DMF was added to a mixture of
2-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-propionic
acid (50 mg, 0.186 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)
(35.7 mg, 0.186 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (28.5
mg, 0.186 mmol) and 3-chloro-N-hydroxy-benzamidine (29.3 mg, 0.172
mmol) at room temperature and stirred overnight. The reaction
mixture was diluted with ethyl acetate (75 ml), washed with water 3
times, once with 1.0 M HCl (30 ml), saturated NaHCO.sub.3 (30 ml)
and saturated brine (30 ml), dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo. DMF (1 ml) was added to the
residue and the resulting solution was heated at 135.degree. C. for
3 h to effect cyclization to oxadiazole. After cooling the reaction
mixture was diluted with ethyl acetate (75 ml), washed with water 3
times, once with 1.0 M HCl (30 ml), saturated NaHCO.sub.3 (30 ml)
and saturated brine (30 ml), dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo. The title compound (46.5 mg,
66.9%) was purified by SPE chromatography on silica gel using 50 ml
40%, 150 ml 50% ethyl acetate in hexanes. 1H NMR (CDCl.sub.3),
.delta. (ppm): 8.03 (s, 1H), 7.92 (m, 1H), 7.47 (m, 4H), 7.18 (dd,
1H), 4.99 (q, 1H), 3.64 (s, 3H), 1.97 (d, 3H).
[1523] The following compounds were prepared analogously to Example
757: TABLE-US-00031 Exam- ple No. Name 1H NMR MS 758
3-(5-{1-[3-(3-Chloro-phenyl)- 8.88 (d, 1H), 8.76 (dd,
[1,2,4]oxadiazol-5-yl]- 1H), 8.03 (m, 2H),
ethylsulfanyl}-4-methyl-4H- 7.93 (d, 1H), 7.74 (m,
[1,2,4]triazol-3-yl)-pyridine 3H), 5.09 (m, 1H), 3.58 (s, 3H), 2.00
(d, 3H)
[1524] The following compounds were prepared analogously to Example
10: TABLE-US-00032 Example No. Name 759
5-(1-Chloro-ethyl)-3-(3-chloro-phenyl)- [1,2,4]oxadiazole
3-(1-Chloro-ethyl)-5-m-tolyl-[1,2,4]oxadiazole 761
3-(1-Chloro-ethyl)-5-(3-methoxy-phenyl)- [1,2,4]oxadiazole 762
3-(1-Chloro-ethyl)-5-(2-chloro-5-methyl-phenyl)- [1,2,4]oxadiazole
763 3-(1-Chloro-ethyl)-5-(2,5-difluoro-phenyl)- [1,2,4]oxadiazole
764 3-(1-Chloro-ethyl)-5-(2-fluoro-5-methyl-phenyl)-
[1,2,4]oxadiazole 765 3-[3-(1-Chloro-ethyl)-[1,2,4]oxadiazol-5-yl]-
benzonitrile
[1525] The following compounds were prepared analogously to Example
40: TABLE-US-00033 Example No. Name 1H NMR MS 766
4-(5-{1-[5-(2-Chloro-5-methyl- 8.74 (d, 2H), 7.79 (s,
phenyl)-[1,2,4]oxadiazol-3-yl]- 1H), 7.57 (d d, 2H),
ethylsulfanyl}-4-methyl-4H- 7.38 (d, 1H), 7.25 (d,
[1,2,4]triazol-3-yl)-pyridine 1H), 5 (q, 1H), 3.62 (s, 3H), 2.33
(s, 3H), 1.92 (d, 3H) 767 4-(5-{1-[5-(2,5-Difluoro-phenyl)- 8.67
(d, 2H), 7.7 (m, [1,2,4]oxadiazol-3-yl]- 1H), 7.57 (d d, 2H),
ethylsulfanyl}-4-methyl-4H- 7.2 (m, 2H), 5 (q, 1H),
[1,2,4]triazol-3-yl)-pyridine 3.61 (s, 3H), 1.87 (d, 3H) 768
4-(5-{1-[5-(2-Fluoro-5-methyl- 8.77 (d, 2H), 7.85 (m,
phenyl)-[1,2,4]oxadiazol-3-yl]- 1H), 7.61 (m, 2H),
ethylsulfanyl}-4-methyl-4H- 7.38 (m, 1H), 7.06 (t, 1H),
[1,2,4]triazol-3-yl)-pyridine 5.02 (q, 1H), 3.66 (s, 3H), 2.37 (s,
3H), 1.94 (d, 3H) 769 4-(4-Cyclopropyl-5-{1-[5-(2-fluoro- 8.75 (d,
2H), 7.9 (m, 5-methyl-phenyl)-[1,2,4]oxadiazol- 1H), 7.74 (m, 2H),
3-yl]-ethylsulfanyl}-4H- 7.38 (m, 1H), 7.13 (m, 1H),
[1,2,4]triazol-3-yl)-pyridine 5.45 (q, 1H), 3.24 (m, 1H), 2.39 (s,
3H), 2 (d, 3H), 1.15 (m, 2H), 0.79 (m, 2H) 770
3-{3-[1-(4-Methyl-5-pyridin-4-yl- 8.76 (d d, 2H), 8.4 (s,
4H-[1,2,4]triazol-3-ylsulfanyl)- 1H), 8.32 (d, 1H),
ethyl]-[1,2,4]oxadiazol-5-yl}- 7.87 (d, 1H), 7.65 (t, 1H),
benzonitrile 7.59 (m, 2H), 5.07 (q, 1H), 3.67 (s, 3H), 2.59 (s,
2H), 1.91 (d, 3H) 771 3-{3-[1-(4-Cyclopropyl-5-pyridin- 8.77 (m,
2H), 8.42 (d, 4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)- 1H), 8.38 (m,
1H), ethyl]-[1,2,4]oxadiazol-5-yl}- 7.9 (m, 1H), 7.71 (m, 3H),
benzonitrile 5.49 (q, 1H), 3.25 (m, 1H), 2 (d, 3H), 1.17 (m, 2H),
0.81 (m, 2H) 772 3-{1-[5-(3-Chloro-phenyl)- 8.77 (br s, 2H), 8.18
(d, [1,3,4]oxadiazol-2-yl]- 2H), 7.98 (s, 1H),
ethylsulfanyl}-5-pyridin-4-yl- 7.87 (d, 1H), 7.52 (d, 1H),
[1,2,4]triazol-4-ylamine 7.44 (t, 1H), 5.66 (s, 2H), 4.88 (q, 1H),
1.98 (d, 3H)
[1526] The following compounds were prepared analogously to Example
316: TABLE-US-00034 Example No. Name 773
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-methyl- propionic
acid hydrazide 774
Rac-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid
hydrazide
[1527] The following compounds were prepared analogously to Example
318: TABLE-US-00035 Example No. Name 775
2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-
cyclopropanecarboxylic acid hydrazide
Example 776
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic
acid hydrazide
[1528] 3,3-Dimethyl-dihydro-furan-2,5-dione (6.4 g) was heated at
50.degree. C. in ethanol (150 mL) overnight. The solvent was
removed in vacuo and the residue triturated with hexane to yield
2,2-Dimethyl-succinic acid 4-ethyl ester (4.66 g) which was used
without further purification. t-Butanol (7.5 mL) was added to a
mixture of 2,2-Dimethyl-succinic acid 4-ethyl ester (2.74 g, 15.7
mmol) in dichloromethane (62 mL) containing magnesium sulfate (7.5
g) and conc. sulfuric acid (0.85 mL) and the mixture was stirred at
room temperature overnight. Saturated sodium bicarbonate solution
was added and the product was extracted into dichloromethane,
washed with brine solution, dried and concentrated to yield the
diested as a colorless oil (1.89 g). The ethyl ester was hydrolyzed
by trating the crude sample with potassium hydroxide (2.75 g) in a
mixture of ethanol (50 mL) and water (25 mL) at room temperature
for 2 h. The reaction was acidified using 1N HCl (aq) and extracted
into ether, dried and concentrated to yield 2,2-Dimethyl-succinic
acid 1-tert-butyl ester (1.4 g). This acid was treated under the
conditions of Example 320 (step 1) to yield
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic
acid tert-butyl ester (1.9 g). This t-Bu ester was deprotected
using formic acid (19 mL) at 50.degree. C. for 20 min. The crude
product was concentrated and triturated with a mixture of ether and
hexane to yield
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic
acid (1.12 g). To a solution of
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic
acid (561 mg, 2 mmol) and triethylamine (1.1 mL, 8 mmol) in THF (9
ml), isobutyl chloroformate (0.31 mL, 2.4 mmol) was added dropwise
at -78.degree. C. After being stirred for 1 h, hydrazine hydrate (1
mL, 11 mmol) was added. The reaction mixture was stirred at room
temperature for 1 h and concentrated. A small amount of ice was
added to quence any excess reagent and precipitate the product,
which was collected by filtration to give 482 mg of the title
compound.
[1529] The following compounds were prepared analogously to Example
320: TABLE-US-00036 Example No. Name 777
(S)-{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-
hydrazinocarbonyl-ethyl}-carbamic acid tert-butyl ester
Example 778
3-(3-Chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl)-
-ethyl]-[1,2,4]oxadiazole
[1530] Step 1:
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid
(ethoxy-thiophen-2-yl-methylene)-hydrazide:
3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid
hydrazide (266.69 mg, 1 mmol) was mixed with
thiophene-2-carboximidic acid ethyl ester (191.6 mg, 1 mmol) in
ethanol (6 ml) and stirred at room temperature overnight. The
reaction was quenched with water, extracted with ethyl acetate,
dried and concentrated in vacuo. The crude product was triturated
with hexane to yield
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid
(ethoxy-thiophen-2-yl-methylene)-hydrazide as a white solid (305
mg, 75%). 1H-NMR (CDCl.sub.3) d (ppm): 8.99 (ws, 1H), 8.09 (s, 1H),
7.98 (d, 1H), 7.41 (m, 4H), 7.08 (dd, 1H), 4.27 (q, 2H), 3.34 (m,
4H) and 1.41 (t, 3H). Step 2:
3-(3-Chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl-
)-ethyl]-[1,2,4]oxadiazole:
3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid
(ethoxy-thiophen-2-yl-methylene)-hydrazide (81 mg, 0.2 mmol) was
mixed with 2M methylamine (0.3 ml in THF) in ethanol (2 ml) at
70.about.80.degree. C. overnight. The reaction mixture was
concentrated with silica gel and purified by column chromatography
with 0.5.about.2.0% methanol in ethyl acetate to give 54 mg (72.5%)
of
3-(3-chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl-
)-ethyl]-[1,2,4]oxadiazole. 1H-NMR (CDCl.sub.3) d (ppm): 8.08 (s,
1H), 7.97 (d, 1H), 7.41 (m, 4H), 7.20 (dd, 1H), 3.80 (s, 3H), 3.68
(dd, 2H), 3.38 (dd, 2H).
[1531] The following compounds were prepared analogously to Example
778: TABLE-US-00037 Example No. Name 1H NMR MS 779
3-(3-Chloro-phenyl)-5-[2-(4-ethyl- 8.08 (s, 1H), 7.97 (d,
5-thiophen-2-yl-4H-[1,2,4]triazol-3- 1H), 7.47 (m, 4H),
yl)-ethyl]-[1,2,4]oxadiazole 7.20 (dd, 1H), 4.20 (q, 2H), 3.72 (dd,
2H), 3.38 (dd, 2H) and 1.47 (t, 3H) 780
5-(3-Chloro-phenyl)-3-(5-furan-2- 8.11 (s, 1H), 8.01 (d,
yl-4-methyl-4H-[1,2,4]triazol-3- 1H), 7.61 (s, 1H),
ylmethyl)-[1,2,4]oxadiazole 7.58 (d, 1H), 7.48 (t, 1H), 7.11 (d,
1H), 6.59 (m, 1H), 4.48 (s, 2H) and 3.92 (s, 3H) 781
2-(3-Chloro-phenyl)-5-[2-(5-furan- 8.04 (s, 1H), 7.93 (d,
2-yl-4-methyl-4H-[1,2,4]triazol-3- 1H), 7.60 (s, 1H),
yl)-ethyl]-[1,3,4]oxadiazole 7.52 (d, 1H), 7.46 (t, 1H), 7.06 (d,
1H), 6.59 (m, 1H), 3.87 (s, 3H), 3.65 (t, 2H) and 3.38 (t, 2H) 782
2-(3-Chloro-phenyl)-5-[2-(4-ethyl- 8.05 (s, 1H), 7.94 (d,
5-furan-2-yl-4H-[1,2,4]triazol-3-yl)- 1H), 7.60 (s, 1H),
ethyl]-[1,3,4]oxadiazole 7.52 (d, 1H), 7.47 (t, 1H), 7.10 (d, 1H),
6.59 (m, 1H), 4.30 (q, 2H), 3.67 (t, 2H), 3.39 (t, 2H) and 1.43 (t,
3H) 783 2-(3-Chloro-phenyl)-5-[2-(4- 8.05 (s, 1H), 7.94 (d, 383.12
cyclopropyl-5-furan-2-yl-4H- 1H), 7.63 (s, 1H),
[1,2,4]triazol-3-yl)-ethyl]- 7.52 (d, 1H), 7.46 (t, 1H),
[1,3,4]oxadiazole 7.01 (d, 1H), 6.58 (m, 1H), 3.67 (dd, 2H), 3.51
(t, 2H), 3.33 (m, 1H) 1.25 (m, 2H) and 0.93 (m, 2H)
Example 784
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-4-methyl-4H-[1,-
2,4]triazol-3-yl)-pyridine
[1532] Step 1: Isonicotinic acid
{4-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-ethoxy-butylidene}-hydra-
zide: 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionimidic
acid ethyl ester hydrochloride (473.3, 1.5 mmol) was mixed with
isonicotinic acid hydrazide (205.7 mg, 1.5 mmol) in ethanol (8 ml)
at 60.degree. C. for an h and then at room temperature for 2 h. The
reaction mixture was diluted with dichloromethane and washed with
water. The organic layer was dried, concentrated with vacuum and
the residue was triturated with ether to give 490 mg (78.9%) of
isonicotinic acid
{4-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-ethoxy-butylidene}-hydra-
zide as white solid.
[1533] Step 2:
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-4-methyl-4H-[1-
,2,4]triazol-3-yl)-pyridine (47.1 mg, 82%) as white solid was
obtained from isonicotinic acid
{4-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-ethoxy-butylidene}-hydra-
zide (60 mg, 0.15 mmol) reacted with 2M methylamine (0.45 ml, 0.9
mmol) in ethanol (1 ml) at 60.degree. C. overnight. 1H-NMR
(CDCl.sub.3) d (ppm): 8.77 (d, 2H), 8.02 (s, 1H), 7.91 (d, 1H),
7.58 (d, 2H), 7.42 (m, 2H), 3.76 (s, 3H), 3.66 (t, 2H) and 3.38 (t,
2H).
[1534] The following compounds were prepared analogously to Example
784: TABLE-US-00038 Exam- ple No. Name 1H NMR MS 785
4-(5-{2-[3-(3-Chloro-phenyl)- 8.79 (d, 2H), 8.05 (s,
[1,2,4]oxadiazol-5-yl]-ethyl}-4- 1H), 7.94 (d, 1H),
ethyl-4H-[1,2,4]triazol-3-yl)- 7.58 (d, 2H), 7.43 (m, pyridine 2H),
4.16 (q, 2H), 3.72 (t, 2H), 3.40 (t, 2H) and 1.44 (t, 3H) 786
4-(5-{2-[3-(3-Chloro-phenyl)- 8.77 (d, 2H), 8.05 (s,
[1,2,4]oxadiazol-5-yl]-ethyl}-4- 1H), 7.93 (d, 1H),
cyclopropyl-4H-[1,2,4]triazol- 7.73 (d, 2H), 7.44 (m,
3-yl)-pyridine 2H), 3.72 (t, 3H), 3.51 (t, 2H), 3.38 (m, 1H), 1.23
(m, 2H) and 0.79 (m, 2H)
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl--
4H-[1,2,4]triazol-3-yl)-pyridine
[1535] Step 1: N-Cyclopropyl-isonicotinamide: Isonicotinic acid
ethyl ester (3.0 g, 20 mmol) was mixed with cyclopropylamine (2 ml)
at 120.degree. C. in a sealed vial for 40 h. The reaction mixture
was triturated with ether to give 1.62 g (50%) of
N-cyclopropyl-isonicotinamide as off-white solid. 1H-NMR
(CDCl.sub.3) d (ppm): 8.73 (d, 2H), 7.60 (d, 2H) and 6.55 (w, 1H),
2.92 (m, 1H), 0.90 (m, 2H) and 0.66 (m, 2H). Step 2:
N-Cyclopropyl-isonicotinimidoyl chloride hydrochloride:
N-Cyclopropyl-isonicotinamide (1.62 g, 10 mmol) was reacted with
SOCl2 (12 g, 100 mol) at 80.degree. C. overnight. The reaction
mixture was concentrated and triturated with dichloromethane to
give 1.3 g (64%) of N-cyclopropyl-isonicotinimidoyl chloride
hydrochloride as yellow solid. Step 3:
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-
-4H-[1,2,4]triazol-3-yl)-pyridine:
(R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid
hydrazide (56 mg, 0.2 mmol) was mixed with
N-cyclopropyl-isonicotinimidoyl chloride hydrochloride (40.6 mg,
0.2 mmol) and K.sub.2CO.sub.3 (60 mg, 0.43 mmol) in DMF (1 ml) at
100.degree. C. for 3 h. The reaction mixture was dilute with
dichloromethane and then washed with water. The organic layer was
concentrated and purified with 5.about.6% methanol in ethyl acetate
to give 32 mg (39%) of the title compound. 1H-NMR (CDCl.sub.3) d
(ppm): 8.78 (d, 2H), 8.05 (s, 1H), 7.96 (d, 1H), 7.73 (d, 2H), 7.45
(m, 2H), 4.15 (q, 1H), 3.64 (dd, 1H), 3.31 (m, 2H), 1.68 (d, 3H),
1.25 (m, 2H) and 0.79 (m, 2H).
[1536] The following compounds were prepared analogously to Example
787: It should be noted that some reactions provided
1,3,4-oxadiazole cyclization products with loss of the methylamino
or cyclopropylamino group instead of or as well as the triazole
product. TABLE-US-00039 Example No. Name 1H NMR MS 788
4-(5-{2-[3-(3-Chloro-phenyl)- 8.74 (d, 2H), 8.04 (s,
[1,2,4]oxadiazol-5-yl]-2-methyl- 1H), 7.94 (d, 1H),
propyl}-4-cyclopropyl-4H- 7.67 (d, 2H), 7.43 (m, 2H),
[1,2,4]triazol-3-yl)-pyridine 3.48 (s, 2H), 3.09 (m, 1H), 1.75 (s,
6H), 1.16 (m, 2H) and 0.68 (m, 2H) 789
4-(5-{2-[5-(3-Chloro-phenyl)- 8.76 (w, 2H), 8.03 (s,
[1,3,4]oxadiazol-2-yl]-propyl}-4- 1H), 7.92 (d, 1H),
cyclopropyl-4H-[1,2,4]triazol-3-yl)- 7.72 (d, 2H), 7.44 (m,
pyridine 2H), 4.13 (m, 1H), 3.72 (dd, 1H), 3.43 (m, 1H), 3.27 (dd,
1H), 1.66 (d, 3H), 1.25 (m, 2H) and 0.79 (m, 2H) 790
4-(5-{2-[3-(3-Chloro-phenyl)- 8.78 (d, 2H), 8.01 (s,
[1,2,4]oxadiazol-5-yl]-1-methyl- 1H), 7.91 (d, 1H),
ethyl}-4-cyclopropyl-4H- 7.73 (d, 2H), 7.49 (d, 1H),
[1,2,4]triazol-3-yl)-pyridine 7.42 (t, 1H), 3.99 (m, 1H), 3.83 (dd,
1H), 3.48 (m, 1H), 3.39 (m, 1H), 1.61 (d, 3H), 1.25 (m, 2H), 0.98
(m, 1H), 0.74 (m, 1H) 791 cis-4-(5-{2-[3-(3-Chloro-phenyl)- 8.73
(d, 2H), 7.88 (s, [1,2,4]oxadiazol-5-yl]- 1H), 7.78 (d, 1H),
cyclopropyl}-4-cyclopropyl-4H- 7.65 (d, 2H), 7.41 (d, 1H),
[1,2,4]triazol-3-yl)-pyridine 7.34 (t, 1H), 3.20 (m, 1H), 2.89 (m,
2H), 2.54 (dd, 1H), 2.00 (td, 1H), 1.20 (m, 2H), 0.83 (m, 2H) 792
4-(5-{2-[3-(3-Chloro-phenyl)- 8.82 (m, 2H), 7.98 (s,
[1,2,4]oxadiazol-5-yl]-1,1-dimethyl- 1H), 7.90 (m, 3H),
ethyl}-[1,3,4]oxadiazol-2-yl)- 7.47 (d, 1H), 7.39 (t, 1H), pyridine
3.51 (s, 2H), 1.70 (s, 6H) 793 4-(5-{2-[3-(3-Chloro-phenyl)- 8.76
(d, 2H), 8.07 (s, [1,2,4]oxadiazol-5-yl]-2-methyl- 1H), 7.97 (d,
1H), propyl}-[1,3,4]oxadiazol-2-yl)- 7.77 (d, 2H), 7.49 (dd, 1H),
pyridine 7.43 (t, 1H), 3.53 (s, 2H), 1.69 (s, 6H) 794
4-(5-{2-[3-(3-Chloro-phenyl)- 8.82 (d, 2H), 8.05 (m,
[1,2,4]oxadiazol-5-yl]-1-methyl- 1H), 7.95 (d, 1H),
ethyl}-[1,3,4]oxadiazol-2-yl)- 7.91 (d, 2H), 7.50 (dd, 1H),
pyridine 7.42 (t, 1H), 3.94 (dd, 1H), 3.67 (dd, 1H), 3.41 (dd, 1H),
1.66 (d, 3H) 795 4-(5-{2-[3-(3-Chloro-phenyl)- 8.77 (d, 2H), 7.81
(m, [1,2,4]oxadiazol-5-yl]- 4H), 7.42 (d, 1H),
cyclopropyl}-[1,3,4]oxadiazol-2- 7.32 (t, 1H), 3.07 (q, 1H),
yl)-pyridine 2.99 (q, 1H), 2.41 (q, 1H), 2.08 (td, 1H) 796
4-(5-{2-[3-(3-Chloro-phenyl)- 8.76 (d, 2H), 7.85 (m,
[1,2,4]oxadiazol-5-yl]- 1H), 7.77 (d, 1H),
cyclopropyl}-4-methyl-4H- 7.55 (d, 2H), 7.44 (dd, 1H),
[1,2,4]triazol-3-yl)-pyridine 7.34 (t, 1H), 3.70 (s, 3H), 2.89 (m,
1H), 2.72 (m, 1H), 2.51 (q, 1H), 2.02 (dt, 1H) 797
4-(5-{2-[5-(3-Chloro-phenyl)- 8.79 (d, 2H), 8.02 (s,
[1,3,4]oxadiazol-2-yl]-propyl}-4- 1H), 7.93 (d, 1H),
methyl-4H-[1,2,4]triazol-3-yl)- 7.59 (d, 2H), 7.53 (d, 1H),
pyridine 7.46 (t, 1H), 4.03 (m, 1H), 3.80 (s, 3H), 3.52 (m, 1H),
3.23 (dd, 1H), 1.66 (d, 3H) 798 4-(5-{2-[3-(3-Chloro-phenyl)- 8.81
(d, 2H), 8.07 (s, [1,2,4]oxadiazol-5-yl]-propyl}- 1H), 7.97 (d,
1H), [1,3,4]oxadiazol-2-yl)-pyridine 7.87 (d, 2H), 7.50 (d, 1H),
7.43 (t, 1H), 3.91 (q, 1H), 3.66 (dd, 1H), 3.44 (dd, 1H), 1.65 (d,
3H) 799 4-(5-{2-[3-(3-Chloro-phenyl)- 8.80 (d, 2H), 8.05 (s,
[1,2,4]oxadiazol-5-yl]-propyl}-4- 1H), 7.95 (d, 1H),
methyl-4H-[1,2,4]triazol-3-yl)- 7.61 (d, 2H), 7.51 (d, 1H),
pyridine 7.45 (t, 1H), 4.07 (q, 1H), 3.75 (s, 3H), 3.48 (dd, 1H),
3.23 (dd, 1H), 1.68 (d, 3H) 800 4-(5-{2-[3-(3-Chloro-phenyl)- 8.78
(d, 2H), 8.05 (s, [1,2,4]oxadiazol-5-yl]-propyl}-4- 1H), 7.96 (d,
1H), cyclopropyl-4H-[1,2,4]triazol-3-yl)- 7.74 (d, 2H), 7.50 (dd,
1H), pyridine 7.46 (t, 1H), 4.15 (q, 1H), 3.64 (dd, 1H), 3.31 (m,
2H), 1.67 (d, 3H), 1.25 (m, 2H), 0.81 (m, 2H) 801
(S)-[1-[3-(3-Chloro-phenyl)- [1,2,4]oxadiazol-5-yl]-2-(4-
cyclopropyl-5-pyridin-4-yl-4H- [1,2,4]triazol-3-yl)-ethyl]-carbamic
acid tert-butyl ester
Example 802
(S)--1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyri-
din-4-yl-4H-[1,2,4]triazol-3-yl)-ethylamine
[1537]
(S)-[1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropy-
l-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-carbamic acid
tert-butyl ester (135 mg) was mixed with 96% formic acid (1.3 mL)
and heated at 50.degree. C. for 1 h. The reaction mixture was
concentrated in vacuo. The residue was quenched with saturated
sodium bicarbonate and extracted with ethyl acetate. The organic
layer was dried with sodium sulfate and concentrated. Purification
was performed by flash column silica gel chromatography with 2-3%
(2 M ammonia methanol) in dichloromethane to give 106 mg of the
title compound as an off-white solid. 1H NMR (CDCl.sub.3): d ppm
8.73 (d, 2H), 8.03 (s, 1H), 7.93 (d, 1H), 7.69 (d, 2H), 7.46 (d,
1H), 7.42 (t, 1H), 5.02 (dd, 1H), 3.61 (dd, 1H), 3.49 (dd, 1H),
3.35 (m, 1H), 2.47 (br s, 2H), 1.20 (m, 2H), 0.75 (m, 2H)
Example 803
(S)-[1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyri-
din-4-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-dimethyl-amine
[1538] Sodium cyanoborohydride (0.1 mL, 1M in THF) was added to a
solution of
(S)-1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyri-
din-4-yl-4H-[1,2,4]triazol-3-yl)-ethylamine (30 mg) in methanol
(0.8 mL) containing 96% formic acid (0.1 mL) and 37% formalin
solution (0.1 mL). The residue was quenched with water and
extracted with ethyl acetate. The organic layer was dried with
sodium sulfate and concentrated. Purification was performed by
flash column silica gel chromatography with 3% (2 M ammonia
methanol) in dichloromethane to give 22 mg of the title
compound.
[1539] 1H NMR (CDCl.sub.3): d ppm 8.76 (d, 2H), 8.06 (s, 1H), 7.97
(d, 1H), 7.73 (d, 2H), 7.47 (d, 1H), 7.45 (t, 1H), 5.00 (dd, 1H),
3.76 (dd, 1H), 3.51 (dd, 1H), 3.42 (m, 1H), 2.45 (br s, 6H), 1.26
(m, 2H), 0.88 (m, 1H), 0.79 (m, 1H)
Example 804
8-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8-
-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine
[1540] 37 mg (0.25 mmol) Me3OBF4 was added to a solution of 60 mg
(0.21 mmol)
3-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidin-2-one
in 2 ml CH.sub.2Cl.sub.2. The mixture was stirred overnight at room
temperature. The reaction mixture was diluted with
CH.sub.2Cl.sub.2, washed with NaHCO3 (sat), dried and concentrated.
The residue was dissolved in 3 ml EtOH and 22 mg (0.16 mmol)
isonicotinic hydrazide was added. The solution was heated with
microwaves at 120.degree. C. for 10 min. The reaction mixture was
cooled and the volatiles were removed under reduced pressure. The
crude product was purified by preparative HPLC to afford 17 mg
(20%) of the desired product. 1H NMR (CDCl.sub.3): d ppm 1.75 (m,
1H) 1.99 (m, 1H) 2.21 (m, 2H) 3.16 (dd, 1H) 3.73 (m, 1H) 3.85 (dd,
1H) 4.07 (m, 1H) 4.19 (m, 1H) 7.47 (t, 1H) 7.56 (m, 1H) 7.67 (m,
2H) 8.01 (m, 1H) 8.11 m, 1H) 8.76 (d, 2H).
[1541] The following compounds were prepared analogously to Example
804: TABLE-US-00040 Exam- ple No. Name 1H NMR MS 805
8-[5-(3-Chloro- 1.69 (m, 1H) 1.99 (m, 1H)
phenyl)-[1,2,4]oxadiazol-3- 2.18 (m, 2H) ylmethyl]-3-thiophen-2-yl-
3.11 (m, 1H) 3.67 (m, 1H) 5,6,7,8-tetrahydro- 3.87 (m, 1H) 4.02 (m,
1H) [1,2,4]triazolo[4,3- 4.24 (m, 1H) a]pyridine 7.15 (m, 1H) 7.47
(m, 3H) 7.56 (m, 1H) 8.01 (d, J = 7.83 Hz, 1H) 8.12 (d, J = 1.77
Hz, 1H) 806 8-[5-(5-Chloro-2-fluoro- 1.76 (m, 1H) 2.00 (m, 1H)
phenyl)-[1,2,4]oxadiazol-3- 2.21 (m, 2H) ylmethyl]-3-pyridin-4-yl-
3.22 (dd,, 1H) 3.74 (m, 1H) 5,6,7,8-tetrahydro- 3.87 (dd, 1H) 4.09
(m, [1,2,4]triazolo[4,3- 1H) 4.19 (m, 1H) a]pyridine 7.23 (m, 1H)
7.53 (m, 1H) 7.68 (m, 2H) 8.10 (dd, 1H) 8.77 (m, 2H)
Example 807
5-(5-Bromo-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-(3-chloro-phen-
yl)-[1,2,4]oxadiazole
[1542]
3-(3-Chloro-phenyl)-5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmeth-
yl)-[1,2,4]oxadiazole was mixed with 30 ml of chloroform/pyridine
(25/1) at room temperature. Then bromine in chloroform (0.5 ml) was
added dropwise and the reaction mixture was heated at 70.degree. C.
overnight. The reaction mixture was diluted with chloroform and
washed with saturated NH.sub.4Cl twice and the organic layer was
dried with sodium sulfate, concentrated, the residue was triturated
with diethyl ether to give the title compound (1.5 g, 57.5%, yellow
solid). 1H-NMR (CDCl.sub.3) d (ppm): 8.05 (s, 1H), 7.94 (d, 1H),
7.47 (d, 1H), 7.43 (t, 1H), 4.66 (s, 2H) and 3.59 (s, 3H).
Example 808
3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,-
4]oxadiazol-5-yl]-phenylamine
[1543] To
{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylm-
ethyl)[1,2,4]oxadiazole 5-yl-phenyl}-carbamic acid tert-butyl ester
(88.0 mg, 0.19 mmol) in dichloromethane (3 ml) at 0.degree. C.
added TFA (1.5 ml) and allowed to stir for 1 h. The reaction
mixture was warmed to room temperature and the solvent was removed
under vacuum. Dichloromethane was added to the resulting residue
and the mixture was cooled to 0.degree. C. and saturated sodium
bicarbonate was added to the stirring solution until turning basic
(pH.about.8). The mixture was then transferred to a separatory
funnel and the product was extracted with dichloromethane, dried
using anhydrous sodium sulfate, and concentrated in vacuo. The
resulting residue was titurated with ether and 61.1 mg (87%) of
3-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2-
,4]oxadiazol-5-yl]-phenylamine was isolated (light yellow solid).
1H NMR (DMSO-d6) d (ppm): 7.81 (d, 1H), 7.64 (d, 1H), 7.23 (m, 4H),
6.84 (d, 1H), 5.57 (s, 2H), 4.50 (s, 2H), 3.72 (s, 3H).
[1544] The following compounds were prepared analogously to Example
98: TABLE-US-00041 Example No. Name 1H NMR MS 809
5-(3-Chloro-phenyl)-3-(4-methyl-5- 423.01
thiophen-2-yl-4H-[1,2,4]triazole-3-
sulfonylmethyl)-[1,2,4]oxadiazole 810
5-(3-Chloro-phenyl)-3-(4-methyl-5-
thiophen-2-yl-4H-[1,2,4]triazole-3-
sulfinylmethyl)-[1,2,4]oxadiazole
[1545] The following compounds were prepared analogously to Example
93: TABLE-US-00042 Example No. Name 1H NMR MS 811
2-Methyl-6-[3-(4-methyl-5- thiophen-2-yl-4H-[1,2,4]triazol-3-
ylsulfanylmethyl)-[1,2,4]oxadiazol- 5-yl]-pyridine
Example 812
4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-
-4H-[1,2,4]triazol-3-yl)-pyridin-2-ol
[1546] HBr (1 ml) and HOAc (1 ml) were added to
4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethy-
l-4H-[1,2,4]triazol-3-yl)-2-methoxy-pyridine (9 mg, 0.02 mmol) and
the reaction was stirred at 80.degree. C. on. Saturated NaHCO.sub.3
(aq) was added to the reaction and the mixture was extracted three
times with dichloromethane. The combined organic phases were dried
and concentrated to give the title compound (8.5 mg, 99%). 1H NMR
(CDCl.sub.3), .delta. (ppm): 1.37 (t, 3H), 1.96 (d, 3H), 4.10 (q,
2H), 5.23 (q, 1H), 6.80 (m, 2H), 7.49 (t, 2H), 7.59 (m, 1H), 7.99
(d, 1H), 8.11 (s, 1H).
Example 813
4-(5-{2-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-propyl}-4-methyl-4H-[1-
,2,4]triazol-3-yl)-pyridine
[1547] 84 microl (0.21 mmol, 2.5 M) n-BuLi was added dropwise to a
solution of 37 mg (0.21 mmol)
4-(4,5-dimethyl-4H-[1,2,4]triazol-3-yl)-pyridine in 2.1 ml THF at
0.degree. C. After 20 min a solution of 60 mg (0.21 mmol)
3-(1-bromo-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole was added
dropwise. The reaction mixture was allowed to reach room
temperature and stirred over night. NH.sub.4Cl(sat) was added and
the mixture was extracted twice with EtOAc. The organic phase was
dried and concentrated. Flashchromatography (CH.sub.2Cl.sub.2/MeOH
20:1) afforded 7.7 mg (10%) of the desired product. 1H NMR
(CDCl.sub.3), d (ppm): 1.57 (d, 3H) 3.16 (m, 1H) 3.38 (m, 1H) 3.71
(s, 3H) 3.84 (d, 1H) 7.46 (t, 1H) 7.55 (m, 1H) 7.58 (m, 2H) 7.98
(m, 1H) 8.10 (t, 1H) 8.77 (d, 2H)
Example 814
[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-methyl-(4-methyl-5-pyrid-
in-4-yl-4H-[1,2,4]triazol-3-yl)-amine
[1548] 10 mg (0.4 mmol) NaH was added to a solution of 38 mg (0.2
mmol) methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine
in 3 ml DMF under an atmosphere of nitrogen. After 10 min a
solution of 50 mg (0.22 mmol)
3-chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole in 2 ml DMF
was added. After stirring for 45 min NH.sub.4Cl(sat) was added and
the mixture was extracted twice with CHCl.sub.3. The organic phase
was dried and concentrated. Flashchromatography
(CH.sub.2Cl.sub.2/MeOH 20:1) afforded 41 mg (54%) of the desired
product. 1H NMR (CDCl.sub.3), d (ppm): 3.07 (s, 3H) 3.71 (s, 3H)
4.56 (s, 2H) 7.45 (m, 1H) 7.55 (m, 1H) 7.62 (d, 2H) 7.98 (d, 1H)
8.09 (m, 1H) 8.73 (d, 2H).
Example 815
8-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8-
-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
[1549] 32 mg (1.31 mmol) NaH was added to a solution of 193 mg
(0.96 mmol)
3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
in 10 ml DMF at room temperature. After 10 min 200 mg (0.87 mmol)
5-(3-chloro-phenyl)-3-chloromethyl-[1,2,4]oxadiazole was added to
the reaction mixture. The reaction mixture was stirred at room
temperature over night. The reaction mixture was diluted with
NH.sub.4Cl(sat) and extracted twice with EtOAc. The combined
organic phases were washed with water, dried and concentrated.
Flashchromatography (CH.sub.2Cl.sub.2/MeOH 20:1) afforded 111 mg
(32%) of a white solid. 1H NMR (CDCl.sub.3), d (ppm): 2.24 (m, 2H)
3.57 (m, 2H) 4.15 (m, 2H) 5.01 (s, 2H) 7.46 (t, 1H) 7.56 (d, 1H)
7.62 (d, 2H) 7.99 (d, 1H) 8.10 (s, 1H) 8.70 (d, 2H).
[1550] The following compounds were prepared analogously to Example
815: TABLE-US-00043 Example No. Name 1H NMR MS 816
8-[5-(5-Chloro-2-fluoro-phenyl)- [1,2,4]oxadiazol-3-ylmethyl]-3-
pyridin-4-yl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrimidine
817 8-[5-(3-Chloro-phenyl)- [1,3,4]oxadiazol-2-ylmethyl]-3-
pyridin-4-yl-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrimidine
818 8-{1-[5-(3-Chloro-phenyl)- 1.81 (d, 3H) 2.19 (m, 2H)
[1,3,4]oxadiazol-2-yl]-ethyl}-3- 3.47 (m, 2H)
pyridin-4-yl-5,6,7,8-tetrahydro- 4.12 (m, 2H) 6.07 (q, 1H)
[1,2,4]triazolo[4,3-a]pyrimidine 7.42 (m, 1H) 7.49 (m, 1H) 7.61 (m,
2H) 7.91 (m, 1H) 8.00 (m, 1H) 8.70 (m, 2H) 819
8-[5-(5-Chloro-2-fluoro-phenyl)- 2.23 (m, 2H) 3.50 (m, 2H)
[1,2,4]oxadiazol-3-ylmethyl]-3-furan- 4.20 (m, 2H) 4.97 (s,
2-yl-5,6,7,8-tetrahydro- 2H) 6.49 (m, 1H)
[1,2,4]triazolo[4,3-a]pyrimidine 6.89 (d, 1H) 7.19 (t, 1H) 7.48 (m,
1H) 7.51/m, 1H) 8.06 (m, 1H) 820 8-{1-[5-(3-Chloro-phenyl)- 1.74
(d, 3H) 2.17 (m, 2H) [1,2,4]oxadiazol-3-yl]-ethyl}-3- 3.45 (m, 2H)
pyridin-4-yl-5,6,7,8-tetrahydro- 4.10 (m, 2H) 5.96 (m, 1H)
[1,2,4]triazolo[4,3-a]pyrimidine 7.44 (t, 1H) 7.53 (m, 1H) 7.59 (m,
2H) 7.97 (m, 1H) 8.08 (m, 1H) 8.67 (d, 2H)
Example 821
3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(1H-pyr-
rol-3-yl)-[1,2,4]oxadiazole
[1551]
3-Chloromethyl-5-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-[1,2,4]ox-
adiazole (50 mg) and potassium hydroxide (50 mg) was heated for two
h in methanol (5 ml). The mixture was diluted with ethyl acetate
(10 ml), washed with water and brine, dried over MgSO.sub.4,
filtered and concentrated. The title compound was isolated in 57%
yield by flash chromatography on silica gel using 40% ethyl acetate
in heptane. 1H NMR (CDCl.sub.3) d (ppm): 9.8 (s, 1H), 7.5 (m, 2H),
7.4 (d, 1H), 7.2 (dd, 1H), 6.8 (m, 1H), 6.7 (d, 1H), 4.5 (s, 2H),
4.1 (q, 2H), 1.4 (t, 3H).
Example 822
4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
-[1,2,4]triazol-3-yl}-pyridine 1-oxide
[1552]
4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-m-
ethyl-4H-[1,2,4]triazol-3-yl}-pyridine and wet 57%-86% MCPBA (52.4
mg, 0.20-0.30 mmol) were dissolved in dichloromethane (4 ml) and
stirred for 16 h. The reaction mixture was purified via reversed
phase preparative LC to give the title compound (7.5 mg, 8%). 1H
NMR (CDCl.sub.3), .delta. (ppm): 8.33 (d, 2H), 8.06 (m, 1H), 7.96
(m, 1H), 7.67 (d, 2H), 7.57 (m, 1H), 7.46 (apparent t, 1H), 4.60
(s, 2H), 3.71 (s, 3H).
Example 823
5-(3-Chloro-phenyl)-3-(2-furan-2-yl-3-methyl-3H-imidazol-4-ylsulfanylmethy-
l)-[1,2,4]oxadiazole
[1553] 2-Furan-2-yl-3-methyl-3,5-dihydro-imidazol-4-one (described
in Takeuchi, H., Hagiwara, S., Eguchi, S., Tetrahedron (1989)
6375-6386) (50 mg, 0.30 mmol) was dissolved in dioxane (3 ml) and
Lawesson reagent (136 mg, 0.34 mmol) was added. The reaction
mixture was heated to reflux over night and then allowed to room
temperature at which time DIPEA (212 ml, 1.22 mmol) and
3-chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole (140 mg, 0.61
mmol) was added. The resulting mixture was heated to reflux for 5 h
and then kept at room temperature over night. Ethyl acetate was
added and the reaction mixture was washed with water followed by
brine. The organic phase was dried over MgSO.sub.4 and evaporated.
The title compound (13 mg, 11%) was obtained by flash
chromatography using 1% methanol in chloroform. 1H NMR (CD.sub.3OD)
d (ppm): 7.96 (m, 1H), 7.90 (m, 1H), 7.60 (dd, 1H), 7.57 (ddd, 1H),
7.46 (t, 1H), 7.09 (s, 1H), 6.86 (dd, 1H), 6.52 (dd, 1H), 3.95 (s,
2H), 3.74 (s, 3H).
Example 824
5-(5-Chloro-2-fluoro-phenyl)-3-[4-(2-fluoro-ethyl)-5-thiophen-2-yl-4H-[1,2-
,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole
[1554] To a cooled (-15.degree. C.) solution of
2-{3-[5-(5-chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-
-thiophen-2-yl-[1,2,4]triazol-4-yl}-ethanol (46 mg, 0.11 mmol) in
anhydrous THF (15 ml) was dropwise added DAST (32 ml, 0.24 mmol).
The mixture was stirred at room temperature for 1.5 h and was then
quenched with MeOH (1 ml). The solvent was removed under reduced
pressure and the residue was partitioned between brine and EtOAc.
The aqueous layer was extracted with EtOAc (2.times.20 ml). The
combined organic layers were washed with brine (10 ml), dried
(MgSO.sub.4) and concentrated under reduced pressure. Purification
by flash chromatography (EtOAc:heptane 2:1) and preparative HPLC
afforded the title compound as a white solid (11 mg, 22%). 1H NMR
(CDCl.sub.3) d (ppm): 8.05 (dd, 1H), 7.52 (m, 3H), 7.20 (m, 1H),
7.16 (m, 1H), 4.75 (t, 1H), 4.63 (m, 3H), 4.45 (m, 2H).
Example 825
5-(5-Chloro-thiophen-3-yl)-3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-yls-
ulfanylmethyl)-[1,2,4]oxadiazole
[1555] The title compound was prepared according to method for
2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimid-
azole, with the exception of using molar equivalent cesium
carbonate instead of potassium carbonate as the base, from
1-[5-(5-chloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethoxy]-1H-benzotriaz-
ole (32.3 mg, 0.097 mmol) and
4-ethyl-5-furan-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione (23 mg)
by using 50% EtOAc in n-heptane as chromatography eluent to yield
21 mg. 1H NMR (CDCl.sub.3) d (ppm): 7.95 (d, 1H), 7.57 (dd, 1H),
7.44 (d, 1H), 7.07 (dd, 1H), 6.56 (dd, 1H), 4.56 (s, 2H), 4.22 (q,
2H), 1.35 (t, 3H).
Example 826
3-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]ox-
adiazol-5-yl]-4-hydroxy-benzonitrile
[1556] The title compound was prepared using the general procedure
of Rogers et al., Tetrahedron Letters (2002) 43: 3585-3587. To a
stirring solution of
3-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]o-
xadiazol-5-yl]-4-fluoro-benzonitrile (20 mg, 0.050 mmol),
2-(methylsulfonyl-ethanol) (9.38 mg, 0.075 mmol), and DMF (0.05 M)
at 0.degree. C. was added NaH (5.8 mg, 0.150 mmol). Stirred for 20
min and removed the ice bath. Stirred an additional 20 min while
warming to room temperature. The reaction mixture was quenched with
1 N HCl solution and partitioned between ethyl acetate and brine.
The organic layer was dried (Na.sub.2SO.sub.4), filtered and
concentrated to dryness. The crude organics were purified by flash
column chromatography using ethyl acetate followed by 5% methanol
in ethyl acetate to give the title compound (8.1 mg, 41%, white
solid). 1H NMR (CDCl.sub.3), .delta. (ppm): 8.25 (m, 1H), 7.75 (m,
1H), 7.60 (s, 1H), 7.18 (m, 2H), 6.60 (m, 1H), 4.64 (s, 2H), 4.25
(q, 2H), 1.38 (t, 3H).
Example 827
3-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine
[1557] ##STR46##
[1558] KMnO.sub.4 (5 g, 32 mmol) was added to a solution of
3-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]pyridine (6.0 g,
29 mmol) in H.sub.2O (40 mL) and acetic acid (100 mL). After 1 h
stirring at rt the reaction was basified with aq. NaOH (4M).
CHCl.sub.3 was added and the mixture was filtrated through celite.
The layers were separated and the water phase was washed with
CHCl.sub.3. The combined organic phase was dried and concentrated
to give 3.67 g (53%) of the title compound. .sup.1H NMR: 3.59 (s,
3H) 3.99 (s, 3H) 7.52 (m, 1H) 8.02 (dt, 1H) 8.83 (dd, 1H) 8.91 (m,
1H)
[1559] The following examples were synthesized in a manner
analogous to that for
3-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine.
TABLE-US-00044 Structure Name .sup.1H-NMR Example No. ##STR47##
3-[4-cyclopropyl-5- (methylsulfonyl)-4H- 1,2,4-triazol-3-
yl]pyridine 0.98 (m, 2 H) 1.26 (m, 2 H) 3.61 (s, 3 H) 3.68 (m, 1 H)
828 ##STR48## 4-[4-methyl-5- (methylsulfonyl)-4H- 1,2,4-triazol-3-
yl]pyridine (DMSO-D6): 3.6 (s, 3 H) 3.9 (s, 3 H) 7.8 (s, 2 H) 8.8
(s, 2 H) 829 ##STR49## 4-(4-Cyclopropyl-5- methanesulfonyl-4H-
1,2,4-triazol-3-yl)- pyridine 8.86 (d, 2 H), 7.77 (d, 2 H), 3.64
(m, 1 H), 3.63 (s, 3 H), 1.25 (m, 2 H), 1.01 (m, 2 H). 830
Example 831
4-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)-4H-1,2,4-triazole
[1560] ##STR50##
[1561] To
4-methyl-3-(methylthio)-5-(trifluoromethyl)-4H-1,2,4-triazole (4.15
g, 21.0 mmol) in DCM (150 ml) at 0.degree. C. was added mCPBA
(57-86%, 15.1 g, 52.6 mmol) in portions. After stirring at r.t.
o.n. DCM (150 ml) was added. The resulting mixture was washed with
sat. aq. NaHCO.sub.3, sat. aq. Na.sub.2S.sub.2O.sub.3 and brine,
dried and evaporated to afford 4.4 g (91%) of the title compound.
MS (M.sup.+-1)=228.
[1562] The following examples were synthesized in a manner
analogous to that for
4-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)-4H-1,2,4-triazol-
e. TABLE-US-00045 Structure Name Analytical data Example No.
##STR51## 3-(3,5- difluorophenyl)-4- methyl-5- (methylsulfonyl)-4H-
1,2,4-triazole .sup.1H-NMR (DMSO-D6): 3.60 (s, 3 H) 3.89 (s, 3 H)
7.56 (s, 3 H) MS (M + 1) 242 832 ##STR52## 3-(4-fluorophenyl)-4-
methyl-5- (methylsulfonyl)-4H- 1,2,4-triazole MS (M.sup.+ + 1) 256
833
[1563] Preparation of Intermediate Compounds
Example 834
3-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]pyridine
[1564] ##STR53##
[1565] MeI (2 mL, 32 mmol) in EtOH (10 mL) was added to a mixture
of 4-methyl-5-pyridin-3-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione
in 1 M NaOH (70 mL, 70 mmol). After 1 h stirring at rt, DCM was
added and the layers were separated. The water phase was washed
with DCM and the combined organic phases were dried and
concentrated to give 6.5 g (98%) of the title compound. .sup.1H
NMR: 2.76 (s, 3H) 3.59 (s, 3H) 7.43 (m, 1H) 7.99 (m, 1H) 8.71 (m,
1H) 8.86 (m, 1H)
[1566] The following examples were synthesized in a manner
analogous to that for
3-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]pyridine
TABLE-US-00046 Structure Name Analytical data Example No. ##STR54##
3-[4-cyclopropyl-5- (methylthio)-4H- 1,2,4-triazol-3- yl]pyridine
LC-MS (M.sup.+ + 1): 233 835 ##STR55## 4-(4-Cyclopropyl-5-
methylsulfanyl-4H- 1,2,4-triazol-3-yl)- pyridine .sup.1H NMR: 8.77
(d, 2 H), 7.75 (m, 2 H), 3.23 (m, 1 H), 2.82 (s, 3 H), 1.17 (m, 2
H), 0.80 (m, 2 H). 836 ##STR56## 4-[4-methyl-5- (methylthio)-4H-
1,2,4-triazol-3- yl]-pyridine .sup.1H NMR: (DMSO-D6): 2.7 (s, 3 H)
3.6 (s, 3 H) 7.7 (m, 2 H) 8.8 (d, 2 H) 837 ##STR57##
3-(4-fluorophenyl)-4- methyl-5- (methylthio)-4H- 1,2,4-triazole
Used directly in the next step towards 3-(4-
fluorophenyl)-4-methyl-5- (methylsulfonyl)-4H-1,2,4- triazole.
838
Example 839
4-methyl-3-(methylthio)-5-(trifluoromethyl)-4H-1,2,4-triazole
[1567] ##STR58##
[1568] 4-Methylthiosemicarbazid (10.0 g, 95.09 mmol) in TFA (46.7
ml) was heated to reflux o.n. Excess TFA was removed via
evaporation. The residue was dissolved in aq. 1M NaOH (100 ml),
followed by dropwise addition of CH.sub.3I (4.47 ml, 71.17 mmol) in
EtOH (22 ml). The resulting mixture was stirred o.n. Partial
evaporation of the solvent induced crystallization. After dilution
with H.sub.2O the solid was collected via filtration and gave after
drying the title compound (5.2 g, 28%). MS (M.sup.++1) 198
Example 840
3-(3,5-difluorophenyl)-4-methyl-5-(methylthio)-4H-1,2,4-triazole
[1569] ##STR59##
[1570] The title compound was obtained as a byproduct in the
synthesis of
5-(3,5-difluorophenyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine.
.sup.1H NMR (DMSO-D6): 2.66 (s, 3H) 3.60 (s, 3H) 7.43-7.52 (m, 3H).
MS (M.sup.++1) 242.
Example 841
4-methyl-5-pyridin-3-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione
[1571] ##STR60##
[1572] Nicotinohydrazide (10 g, 73 mmol) and methyl isothiocyanate
(5.6 g, 76 mmol) were mixed in 2-propanol (150 ml) and heated to
70.degree. C. o.n. The reaction was cooled to r.t. and evaporated
to dryness. H.sub.2O (180 mL) and NaHCO.sub.3 (12.8 g, 152 mmol)
were added to the residue and the mixture was refluxed o.n. The
reaction mixture was cooled to rt, acidified with concentrated
hydrochloric acid and the title compound, 13.1 g (93%), was
collected by filtration. LC-MS (M.sup.++1): 193
[1573] The following examples were synthesized in a manner
analogous to that for
4-methyl-5-pyridin-3-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione
TABLE-US-00047 Structure Name Analytical data Example No. ##STR61##
4-cyclopropyl-5- pyridin-4-yl-2,4- dihydro-3H-1,2,4-
triazole-3-thione .sup.1H-NMR: 0.63 (m, 2 H) 1.00 (m, 2 H) 3.25 (m,
1 H) 7.75 (d, 2 H) 8.74 (m, 2 H) 842 ##STR62## 4-cyclopropyl-5-
pyridin-3-yl-2,4- dihydro-3H-1,2,4- triazole-3-thione LC-MS
(M.sup.+ + 1): 219 843
Example 844
5-(4-fluorophenyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione
[1574] ##STR63##
[1575] To 4-methylthiosemicarbazid (4.24 g, 40.30 mmol) in pyridine
(50 ml) was added dropwise 4-fluorobenzoyl chloride (4.9 ml, 40.00
mmol) and the resulting mixture was stirred at r.t. o.n. The
pyridine was removed by evaporation and the residue was heated in
aq. sat. NaHCO.sub.3 at reflux o.n. After cooling to r.t., the
product was collected by filtration, washed with water and dried
under vacuum to give 3.22 g (38%) which was used in the next step
without further purification. .sup.1H NMR: 3.9 (m, 3H) 6.98 (t, 2H)
7.92 (m, 2H).
Example 845
N'-[(3-chlorobenzoyl)oxy]-2-hydroxypropanimidamide
[1576] ##STR64##
[1577] 6.45 g crude N',2-dihydroxypropanimidamide was cooled on an
ice-bath with 23.5 mL DEA in THF (200 mL). To this slurry 21.94 g
3-chlorobenzoyl chloride was added. The mixture was warmed to r.t.
and stirred for 2 h. Addition of Et.sub.2O (200 mL), washing with
sat. aq. NH.sub.4Cl and re-extraction of the aq. layer gave after
combining and concentration of the org. layers followed by drying
in vacuo 27.24 g of crude title compound, which was used directly
in the next step for
1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol. LC-MS
(M.sup.++1): 243
Example 846
3-chloro-N'-{[(2R)-2-hydroxypropanoyl]oxy}benzenecarboximidamide
[1578] ##STR65##
[1579] 3.82 g (22.4 mmol) of
3-chloro-N'-hydroxybenzenecarboximidamide and 2.00 g (22.2 mmol) of
(R)-lactic acid were dissolved under Ar at 0.degree. C. in DCM (50
mL) and DMF (15 mL). After 5 min 3.4 mL (33.2 mmol) DIC and 3.50 g
(25.9 mmol) HOBt were added. After 15 min the mixture was warmed to
r.t. and stirred for additional 3 h, followed by filtration and
washing with DCM. The filtrate was evaporated in vacuo to near
dryness, taken up in EA and washed with aq. NaHCO.sub.3, followed
by water and finally 2 M aq. citric acid. The EA layer was filtered
over a mixture of Na.sub.2SO.sub.4 and silica. Flash chromatography
(Hep/EA=4/1 to 2/1 to 1/2) gave an oil which was triturated with
Et.sub.2O to yield after drying 4 g (75%) of the title compound.
.sup.1H NMR: 7.69 (t, 1H), 7.55-7.59 (m, 1H), 7.44-7.49 (m, 1H),
7.36 (t, 1H), 5.10 (s, 2H), 4.50 (q, 1H), 1.54 (d, 3H)
Example 847
N',2-dihydroxypropanimidamide
[1580] ##STR66##
[1581] 44.2 g (0.64 mol) of hydroxylamine hydrochloride and 25.5 g
(0.64 mol) sodium hydroxide were dissolved in ethanol (500 mL) at
r.t. and stirred for 3 h. After filtration, 8.11 g (0.11 mol)
2-hydroxypropanenitrile were added to the filtrate, followed by
stirring for 4 h. After concentration to dryness the title compound
was obtained which was directly used in the next step. .sup.1H NMR
(DMSO-D6): 8.88 (s, 1H), 5.15 (s, 1H), 5.02 (s, 1H), 4.00 (q, 1H),
1.19 (d, 3H).
Example 848
1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]-N-methylmethanamine
[1582] ##STR67##
[1583] MeNH.sub.2 in EtOH (6 mL, 8 M, 48 mmol) was added to
3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (1.5 g, 6.5
mmol) in EtOH (20 mL). After 20 h the solvent was evaporated and
the residue was dried in vacuum to give 1.47 g (100%) of the title
compound. LC-MS (M.sup.++1): 224
[1584] The following examples were synthesized in a manner
analogous to that for
1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]-N-methylmethanamine- .
TABLE-US-00048 Example Structure Name .sup.1H-NMR No. ##STR68##
[3-(3-Chloro-phenyl)- [1,2,4]oxadiazol-5-ylmethyl]-
cyclopropyl-amine 8.05 (s, 1 H), 7.95 (d, 1 H), 7.42 (d, 1 H), 7.39
(t, 1 H), 4.08 (s, 2 H), 2.89 (m, 1 H), 1.75 (brs, 1 H), 1.09 (d, 6
H). 849 ##STR69## {1-[3-(3-Chloro-phenyl)-
[1,2,4]oxadiazol-5-yl]-ethyl}- cyclopropyl-amine 8.12 (s, 1 H), 8
(d, 1 H), 7.45 (d, 1 H), 7.4 (t, 1 H), 4.2 (q, 1 H), 2.14 (brs, 1
H), 2.04 (m, 1 H), 1.54 (d, 3 H), 0.43 (brm, 4 H). 850 ##STR70##
[5-(3-Chloro-phenyl)- isoxazol-3-ylmethyl]-methyl- amine 7.78 (m, 1
H), 7.67 (m, 1 H), 7.42 (m, 2 H), 6.58 (s, 2 H), 3.90 (s, 2 H),
2.53 (s, 3 H). 851 ##STR71## {1-[3-(3-Chloro-phenyl)-
[1,2,4]oxadiazol-5-yl]-ethyl}- methyl-amine 8.03 (s, 1 H), 7.9 (d,
1 H), 7.41 (d, 1 H), 7.37 (t, 1 H), 1.04 (q, 1 H), 2.4 (s, 3 H),
1.6 (br, 1 H), 1.51 (d, 3 H). 852 ##STR72## [3-(3-Chloro-phenyl)-
[1,2,4]oxadiazol-5-ylmethyl]- ethyl-amine 8.02 (s, 1 H), 7.9 (d, 1
H), 7.42 (d, 1 H), 7.35 (t, 1 H), 4.06 (s, 2 H), 2.72 (q, 2 H),
1.73 (br. m, 1 H), 1.11 (t, 3 H). 853 ##STR73##
[3-(3-Chloro-phenyl)- [1,2,4]oxadiazol-5-ylmethyl]- isopropyl-amine
7.98 (s, 1 H), 7.87 (d, 1 H), 7.35 (d, 1 H), 7.31 (t, 1 H), 4.04
(s, 2 H), 2.23 (brs, 1 H), 2.2 (m, 1 H), 0.37 (m, 4 H). 854
##STR74## 3-(3-Chloro-phenyl)- [1,2,4]oxadiazol-5-ylmethyl]-
methyl-amine 8.13 (S, 1 H), 8.00 (d, 1 H), 7.52 (dm, 1 H), 7.47 (t,
1 H), 4.11 (s, 2 H), 2.58 (s, 3 H). 855
Example 856
N-{[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]methyl}-N'-cyclopropyl-N-meth-
ylthiourea
[1585] ##STR75##
[1586] Cyclopropyl isothiocyanate (650 mg, 6.6 mmol) was added to
1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]-N-methylmethanamine
(1.47 g, 6.5 mmol) in EtOH (20 mL). After 3 h the formed
precipitate was filtrated off and washed with cold EtOH to give
1.63 g (78%) of the title compound. LC-MS (M.sup.++1): 323.
[1587] The following examples were synthesized in a manner
analogous to that for
N-{[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]methyl}-N'-cyclopro-
pyl-N-methylthiourea. TABLE-US-00049 Structure Name .sup.1H-NMR
Example No. ##STR76## 1-[3-(3-Chloro- phenyl)- [1,2,4]oxadiazol-
5-ylmethyl]- 1-cyclopropyl- 3-methyl- thiourea 8.07 (s, 1 H), 7.96
(d, 1 H),7.48 (d, 1 H), 7.41 (t, 1 H), 6.82 (br, 1 H), 5.48 (s, 2
H), 3.25 (d, 3 H), 2.91 (br, 1 H), 1.05 (br, 4 H). 857 ##STR77##
1-[3-(3-Chloro- phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]- 1-ethyl-3-
methyl-thiourea 8.08 (s, 1 H), 7.96 (d, 1 H), 7.48 (d, 1 H), 7.45
(t, 1 H), 6.1 (br, 1 H), 5.38 (s, 2 H), 3.73 (q, 2 H), 3.21 (d, 3
H), 1.33 (t, 3 H). 858 ##STR78## 1-[3-(3-Chloro- phenyl)-
[1,2,4]oxadiazol- 5-ylmethyl]- 1-isopropyl-3- methyl-thiourea 8.05
(s, 1 H), 7.93 (d, 1 H), 7.48 (d, 1 H), 7.42 (t, 1 H), 6.45 (br, 1
H), 5.04 (s, 2 H), 4.96 (m, 1 H), 3.21 (d, 3 H), 1.26 (m, 4 H). 859
##STR79## 1-[5-(3-Chloro- phenyl)- isoxazol-3- ylmethyl]-1,3-
dimethyl- thiourea .sup.1H NMR (DMSO-d6): 7.98 (m, 1 H), 7.84 (m, 1
H), 7.72 (m, 1 H), 7.56 (m, 2 H), 7.06 (s, 1 H), 5.19 (s, 2 H),
3.08 (s, 3 H), 2.94 (s, 3 H). 860 ##STR80## 1-{1-[3-(3- Chloro-
phenyl)- [1,2,4]oxadiazol- 5-yl]-ethyl}- 1-cyclopropyl- 3-methyl-
thiourea 8.00 (s, 1 H), 7.98 (d, 1 H), 7.47 (d, 1 H), 7.44 (t, 1
H), 7.25 (m, 1 H), 6.84 (br, 1 H), 3.26 (d, 3 H), 2.55 (br, 1 H),
1.9 (d, 3 H), 0.91 (br, 2 H), 0.76 (br, 2 H). 861 ##STR81##
1-{1-[3-(3- Chloro- phenyl)- [1,2,4]oxadiazol- 5-yl]-ethyl}-
1,3-dimethyl- thiourea 8.05 (s, 1 H), 7.95 (d, 1 H), 7.46 (d, 1 H),
7.4 (t, 1 H), 5.99 (br, 1 H), 3.21 (d, 3 H), 3.15 (s, 3 H), 1.72
(d, 3 H), 1.4 (q, 1 H). 862 ##STR82## 1-[3-(3-Chloro- phenyl)-
[1,2,4]oxadiazol- 5-ylmethyl]- 1,3-dimethyl- thiourea 8.09 (s, 1
H), 7.98 (d, 1 H), 7.51 (d, 1 H), 7.46 (t, 1 H), 5.91 (w, 1 H),
5.55 (s, 2 H), 3.32 (s, 3 H) and 3.23 (d, 3 H). 863
Example 864
1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-3-cyclopropyl-1-methyl-
-thiourea
[1588] ##STR83##
[1589]
3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-methyl-amine (415
mg, 1.85 mmol) was mixed with cyclopropylisothiocyanate (220 mg,
2.22 mmol) in chloroform (5 mL) at r.t. for 2 hours. The reaction
mixture was concentrated and the residue was triturated with
Et.sub.2O to yield the title compound (406 mg, 67.9%). .sup.1H-NMR:
8.09 (s, 1H), 7.98 (d, 1H), 7.51 (d, 1H), 7.46 (t, 1H), 6.00 (w,
1H), 5.53 (s, 2H), 3.28 (s, 3H), 3.11 (m, 1H), 2.45 (s, 3H), 0.94
(m, 2H) and 0.69 (m, 2H).
Example 865
Methyl
N-{[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]methyl}-N'-cyclopropyl-
-N-methylimidothiocarbamate
[1590] ##STR84##
[1591] MeI (320 .mu.L, 5.1 mmol) and
N-{[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]methyl}-N'-cyclopropyl-N-met-
hylthiourea (1.59 g, 4.9 mmol) were mixed in EtOH (20 mL) and
heated to 70.degree. C. for 2 h. The reaction was cooled to r.t.
and NaOH (1M) was added until pH=10. EA was added and the mixture
was stirred for 5 min. The layers were separated and the water
phase was extracted with EA. The organic phase was dried and
concentrated. The product was purified by column chromatography
(Hep-EA 1:1) to afford 960 mg (59%) of the title compound. LC-MS
(M.sup.++1): 337
[1592] The following examples were synthesized in a manner
analogous to that for methyl
N-{[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]methyl}-N'-cyclopropyl-N-met-
hylimidothiocarbamate. TABLE-US-00050 Structure Name .sup.1H-NMR
Example No. ##STR85## 1-[3-(3-Chloro- phenyl)- [1,2,4]oxadiazol-
5-ylmethyl]- 1,2,3-trimethyl- isothiourea 8.09 (s, 1 H), 7.98 (d, 1
H), 7.50 (d, 1 H), 7.45 (t, 1 H), 4.85 (s, 2 H), 3.23 (s, 3 H),
3.11 (d, 3 H) and 2.37 (s, 3 H). 866 ##STR86## 1-[3-(3-Chloro-
phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]- 1-cyclopropyl-
2,3-dimethyl- isothiourea 8.07 (s, 1 H), 7.96 (d, 1 H), 7.47 (d, 1
H), 7.44 (t, 1 H), 4.84 (s, 2 H), 3.23 (s, 3 H), 2.85 (m, 1 H),
2.37 (s, 3 H), 0.83 (m, 2 H), 0.68 (m, 2 H). 867 ##STR87##
1-[3-(3-Chloro- phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]-
1-ethyl-2,3- dimethyl- isothiourea 8.08 (s, 1 H), 7.96 (d, 1 H),
7.46 (d, 1 H), 7.44 (t, 1 H), 4.79 (s, 2 H), 3.58 (q, 2 H), 3.2 (s,
3 H), 2.38 (s, 3 H), 1.2 (t, 3 H). 868 ##STR88## 1-[3-(3-Chloro-
phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]- 3-cyclopropyl-
1,2-dimethyl- isothiourea 8.09 (s, 1 H), 7.98 (d, 1 H), 7.51 (d, 1
H), 7.44 (t, 1 H), 4.78 (s, 2 H), 3.17 (m, 1 H), 3.13 (s, 3 H),
2.43 (s, 3 H), 0.72 (m, 2 H) and 0.56 (m, 2 H). 869 ##STR89##
1-[5-(3-Chloro- phenyl)- isoxazol-3- ylmethyl]- 1,2,3-trimethyl-
isothiourea 7.70 (m, 1 H), 7.67 (m, 1 H), 7.42 (m, 2 H), 6.51 (s, 1
H), 4.67 (s, 2 H), 3.31 (s, 3 H), 2.94 (s, 3 H), 2.37 (s, 3 H). 870
##STR90## 1-{1-[3-(3- Chloro- phenyl)- [1,2,4]oxadiazol-
5-yl]-ethyl}- 1,2,3-trimethyl- isothiourea 8.09 (s, 1 H), 7.98 (d,
1 H), 7.47 (d, 1 H), 7.45 (t, 1 H), 5.75 (br, 1 H), 3.26 (s, 3 H),
2.91 (s, 3 H), 2.39 (s, 3 H), 1.7 (d, 3 H). 871
Example 872
1-{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-1-cyclopropyl-2-et-
hyl-3-methyl-isothiourea
[1593] ##STR91##
[1594]
1-{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-1-cyclopro-
pyl-3-methyl-thiourea (287 mg, 0.85 mmol) was mixed with iodoethane
(484 mg, 3.4 mmol) in MeOH (5 mL) at 60.degree. C. overnight. The
reaction mixture was concentrated and basified with saturated
sodium carbonate, then extracted with DCM. The organic layer was
dried, concentrated to give the title compound (298 mg, 96%).
.sup.1H-NMR: 8.11 (s, 1H), 8.01 (d, 1H), 7.51 (d, 1H), 7.46 (t,
1H), 5.51 (m, 1H), 3.27 (s, 3H), 2.85-3.00 (m, 2H), 2.60 (m, 1H),
1.79 (d, 3H), 1.30 (t, 3H), 0.83 (m)
Example 873
1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-2-ethyl-1-isopropyl-3--
methyl-isothiourea
[1595] ##STR92##
[1596] The title compound was synthesized analogous to
1-{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-1-cyclopropyl-2-e-
thyl-3-methyl-isothiourea. .sup.1H-NMR: 8.09 (s, 1H), 7.97 (d, 1H),
7.50 (d, 1H), 7.44 (t, 1H), 4.87 (m, 1H), 4.66 (s, 2H), 3.15 (s,
3H), 2.88 (q, 2H), 1.35 (t, 3H) and 1.23 (s, 6H)
Example 874
methyl N-cyclopropyl-N'-methylimidothiocarbamate hydroiodide
[1597] ##STR93##
[1598] MeI (265 ml, 4.2 mmol) was added to
N-cyclopropyl-N'-methylthiourea (500 mg 3.8 mmol) in acetone (10
ml) and the mixture was heated to reflux. After stirring for 20 min
heating was stopped and the solvent was removed under reduced
pressure giving the crude title compound in 960 mg yield that was
used directly in the next step.
Example 875
N-cyclopropyl-N'-methylcarbonohydrazonic diamide hydroiodide
[1599] ##STR94##
[1600] Crude methyl N-cyclopropyl-N'-methylimidothiocarbamate
hydroiodide (960 mg, 3.5 mmol) was mixed with hydrazine hydrate
(240 ml, 3.9 mmol) in ethanol and heated to reflux for 3 h. The
mixture was kept at 7.degree. C. for 12 h, yielding crude title
compound (0.9 g) which was used directly in the next step.
Example 876
5-(3,5-difluorophenyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine
[1601] ##STR95##
[1602] To a solution of methyl N,N'-dimethylimidothiocarbamate
hydroiodide (5.0 g, 20.3 mmol) in pyridine (30 ml) was added
3,5-difluorobenzohydrazide (3.5 g, 20.3 mmol) and the mixture was
heated to reflux for 24 h. After cooling to r.t. the reaction
mixture was poured into ice/H.sub.2O, the formed precipitate was
removed via filtration. The filtrate was extracted with CHCl.sub.3,
the organic phase was dried and concentrated. The residue was
washed with Et.sub.2O and then purified by column chromatography
using CHCl.sub.3:MeOH=99:1 to 10:1. The title compound was obtained
(0.83 g, 18%) together with
3-(3,5-difluorophenyl)-4-methyl-5-(methylthio)-4H-1,2,4-triazole
(0.44 g, 9%) as a byproduct. .sup.1H NMR (DMSO-D6): 2.83 (d, 3H)
3.41 (s, 3H) 6.20 (d, 1H) 7.35 (m, 3H), MS (M.sup.++1) 225.
Example 877
Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine
[1603] ##STR96##
[1604] A mixture of 1000 mg (4.35 mmol)
N-amino-N',N''-dimethyl-guanidine hydriodide (Henry; Smith; J.
Amer. Chem. Soc.; 73; 1951; 1858) and 774 mg (4.35 mmol)
isonicotinoyl chloride hydrochloride in pyridine (3 mL) was heated
under microwave irradiation for 5 min at 160.degree. C. Aq. sat.
K.sub.2CO.sub.3 was added and the mixture was extracted with
CHCl.sub.3. The organic phase was dried and concentrated.
Recrystallization from EtOH, water and EA gave 216 mg (26%) of the
title compound. .sup.1H NMR (DMSO-d6): 2.85 (d, 3H) 3.45 (s, 3H)
6.25 (d, 1H) 7.65 (m, 2H) 8.67 (m, 2H).
Example 878
3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine
[1605] ##STR97##
[1606] A solution of 750 mg (3.1 mmol)
(1,4,5,6-tetrahydro-pyrimidin-2-yl)-hydrazine hydroiodide (Krezel,
Izabella; Pharmazie; 1994; p. 27-31) and 552 mg (3.1 mmol)
isonicotinoyl chloride hydrochloride in 3 ml pyridine was heated at
120.degree. C. o.n. The reaction mixture was cooled and diluted
with aq. sat. K.sub.2CO.sub.3 and extracted with chloroform. The
combined organic extracts were dried and concentrated. Flash
chromatography (DCM/MeOH 10:1) afforded 83 mg (18%) of the title
compound. .sup.1H NMR: 1.91 (m, 2H) 3.24 (m, 2H) 4.13 (m, 2H) 7.67
(m, 2H) 8.65 (m, 2H)
Example 879
N,4-dimethyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-amine
[1607] ##STR98##
[1608] A mixture of N-amino-N',N''-dimethyl-guanidine (500 mg, 2.17
mmol) [J. Amer. Chem. Soc.; 1951; p. 1858] and nicotinoyl chloride
hydrochloride (385 mg, 2.17 mmol) in pyridine (10 mL) was refluxed
o.n. Aq. sat. K.sub.2CO.sub.3 was added and the mixture extracted
with CHCl.sub.3. The organic phase was dried and concentrated. The
crude product 240 mg (61%) was used in the next step without
further purifications. LC-MS (M.sup.++1): 190
Example 880
N-cyclopropyl-4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine
[1609] ##STR99##
[1610] Isonicotinoyl chloride hydrochloride (630 mg, 3.5 mmol) was
added to N-cyclopropyl-N'-methylcarbonohydrazonic diamide
hydroiodide (900 mg 3.5 mmol) in pyridine (10 ml) and the mixture
was stirred at r.t. for 2 h. The mixture was the heated to
160.degree. C. under microwave irradiation for 10 min. Water (50
ml) was added and the mixture was extracted with DCM. The pooled
organic phases were dried and concentrated and the desired product
was obtained by prep. HPLC. LCMS (M.sup.++1) 216
Example 881
5-(2-methoxypyridin-4-yl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine
[1611] ##STR100##
[1612] 2-Chloroisonicotinic acid (2.2 g, 13.8 mmol) was refluxed in
thionyl chloride (50 ml) for 5 h. The solvent was evaporated
(coevaporation with toluene) and the residue was dissolved in
pyridine (25 ml) and added in portions to
N,N'-dimethylcarbonohydrazonic diamide hydroiodide (3.0 g, 13.0
mmol) dissolved in pyridine (25 ml). The reaction mixture was
heated at 120.degree. C. overnight and the solvent was evaporated,
followed by addition of water (10 ml) and filtration. The remaining
aq. solution was purified by prep HPLC to give 0.54 g (19%) of the
intermediate
5-(2-chloropyridin-4-yl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine.
.sup.1H-NMR (DMSO-d6): 8.51 (dd, 1H), 7.76 (m, 1H), 7.71 (dd, 1H),
6.37 (m, 1H), 3.49 (s, 3H), 2.86 (d, 3H). This intermediate (0.52
g, 2.3 mmol) was dissolved in MeOH (35 ml) and sodium methoxide
(4.4 ml of a 30% solution in MeOH, 23.3 mmol) was added. The
mixture was refluxed o.n., added to brine and extracted with
CHCl.sub.3. The combined organic layers were dried (MgSO.sub.4) and
concentrated to give the title compound (0.28 g, 55%). .sup.1H NMR
(DMSO-d6): 8.26 (d, 1H), 7.27 (dd, 1H), 7.05 (m, 1H), 6.26 (q, 1H),
3.90 (s, 3H), 3.44 (s, 3H), 2.85 (d, 3H).
Example 882
4-(4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridine
[1613] ##STR101##
[1614] Oxalyl chloride (860 ml, 10 mmol) was slowly added to a
solution of N-cyclopropylacetamide (1 g, 10 mmol) [Bouzoubaa,
Mohamed, J. Med. Chem.; 28; 7; 1985; 896-900]. and 2,6-lutidine
(2.33 ml, 20 mmol) in DCM (30 ml) at r.t. After stirring for 30 min
isonicotinic acid hydrazide (1.37 g, 10 mmol) was added. The
mixture was stirred at r.t. for 3 hours. The solvent was then
removed under reduced pressure. Aq. sat. sodium carbonate (15 ml)
was added and the mixture was heated to reflux for 2 h, then
extracted with EA. The combined organic phases were dried and
concentrated. The resulting solid was recrystallized from EA giving
the title compound in 1.1 g yield. .sup.1H NMR: 0.7 (m, 2H) 1.2 (m,
2H) 2.6 (s, 3H) 3.3 (ddd, 1H) 7.7 (m, 2H) 8.7 (d, 2H)
[1615] The following examples were synthesized in a manner
analogous to that for
4-(4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridine.
TABLE-US-00051 Structure Name .sup.1H-NMR Example No. ##STR102##
4-(4- cyclopropyl-5- ethyl-4H-1,2,4- triazol-3- yl)pyridine 0.69
(m, 2 H) 1.15 (d, 2 H) 1.48 (t, 3 H) 1.66 (s, 2 H) 2.95 (q, 2 H)
3.28 (s, 1 H) 7.71 (d, 2 H) 8.75 (d, 2 H) 883 ##STR103## 4-(4,5-
dimethyl-4H- 1,2,4-triazol-3- yl)pyridine 8.76 (dd, 2 H), 7.52-7.63
(m, 2 H), 3.66 (s, 3 H), 2.52 (s, 3 H) 884
Example 885
3-[3-Cyclopropyl-2-(2,6-dichloro-pyridin-4-yl)-3H-imidazol-4-yl]-2-methyl--
acrylic acid ethyl ester
[1616] ##STR104##
[1617]
3-cyclopropyl-2-(2,6-dichloro-pyridin-4-yl)-3H-imidazole-4-carbald-
ehyde (1.48 g, 5.25 mmol), triethyl-2-phosphonopropionate (1.46 ml,
6.83 mmol) and DBU (1.02 ml, 6.83 mmol) were dissolved in
acetonitrile (20 ml). After stirring at 78.degree. C. o.n. the
reaction mixture was cooled to r.t, diluted with water and
extracted with DCM. The combined organic phase was dried
(Na.sub.2SO.sub.4), filtered and concentrated in-vacuo. The crude
was purified on silica gel using 6% EA in DCM, and the isolated
residue was triturated with hex. to isolate the title compound
(1.66 g, 86%). .sup.1H-NMR: 7.86 (m, 1H), 7.75 (d, 2H), 7.43 (s,
1H), 4.34 (q, 2H), 3.45 (m, 1H), 2.19 (s, 3H), 1.39 (t, 3H), 1.29
(m, 2H), 0.78 (m, 2H).
Example 886
3-[3-Cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-acrylic
acid ethyl ester
[1618] ##STR105##
[1619]
3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazole-4-carbaldehyde (500
mg, 2.06 mmol), triethyl phosphonoacetate (0.53 ml, 2.68 mmol) and
DBU (0.40 ml, 2.68 mmol) were dissolved in acetonitrile (5 ml).
After stirring at 78.degree. C. o.n. the reaction mixture was
cooled to r.t., diluted with water (50 ml), extracted with DCM. The
combined organic phase was dried (Na.sub.2SO.sub.4), filtered and
concentrated in-vacuo. Purification of the crude on silica gel
using 50% EA in hex. gave the title compound (471 mg, 73%).
.sup.1H-NMR: 7.85 (d, 1H), 7.79 (d, 2H), 7.49 (s, 1H), 7.00 (d,
2H), 6.36 (d, 1H), 4.31 (q, 2H), 3.89 (s, 3H), 3.39 (m, 1H), 1.36
(t, 3H), 1.14 (m, 2H), 0.69 (m, 2H).
Example 887
3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-acrylic
acid ethyl ester
[1620] ##STR106##
[1621]
(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol (6.8
g, 31.4 mmol) was mixed with MnO.sub.2 (40 g, 0.46 mol) in
acetonitrile at r.t. for 2 hours and then heated at 80.degree. C.
for another 30 min. The reaction mixture was filtered through
celite. The filtrate was mixed with
2-(diethoxy-phosphoryl)-propionic acid ethyl ester (12.35 g, 51.8
mmol) and DBU (7.17 g, 47 mmol) at 80 to 90.degree. C. for 4 h. The
reaction mixture was concentrated, dissolved in EA and washed with
water and brine. The organic layer was dried, concentrated and
triturated with hex. to give the title compound in 5.76 g (61%)
yield. .sup.1H-NMR: 8.78 (d, 2H), 7.78 (d, 2H), 7.67 (s, 1H), 4.32
(q, 2H), 3.43 (m, 1H), 2.53 (s, 3H), 1.38 (t, 3H), 1.24 (m, 2H) and
0.73 (m, 2H).
Example 888
3-[3-Cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-2-methyl-propionic
acid ethyl ester
[1622] ##STR107##
[1623]
3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazole-4-carbaldehyde (475
mg, 1.96 mmol), triethyl-2-phosphonopropionate (0.63 ml, 2.94 mmol)
and DBU (0.44 ml, 2.94 mmol) were dissolved in acetonitrile (5 ml).
After stirring at 78.degree. C. o.n. the reaction mixture was
cooled to r.t., diluted with water (50 ml) and extracted with DCM.
The combined organic phase was dried (Na.sub.2SO.sub.4), filtered
and concentrated, to yield
3-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-2-methyl-acrylic
acid ethyl ester, which was dissolved in ethanol and hydrogenated
at atmospheric pressure over 10% Pd/C (0.5 g) for 24 h. The
reaction mixture was filtered through a celite pad and
concentrated. After purification on silica gel (EA/DCM=1/1) the
isolated product was dissolved in Et.sub.2O (10 ml) and treated
with HCl (1N in Et.sub.2O, 4 ml). The resulting mixture was
concentrated and the isolated residue was triturated with Et.sub.2O
to isolate the title compound solid (466 mg). .sup.1H-NMR: 7.90 (d,
2H), 7.10 (m, 3H), 4.16 (m, 2H), 3.90 (s, 3H), 3.47 (m, 1H), 3.24
(m, 1H), 2.85 (m, 2H), 1.37 (d, 3H), 1.27 (m, 5H), 0.75 (m,
2H).
Example 889
3-[2-(4-Methoxy-phenyl)-3-methyl-3H-imidazol-4-yl]-2-methyl-propionic
acid ethyl ester
[1624] ##STR108##
[1625] The title compound was synthesized analogous to
3-[3-Cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-2-methyl-propioni-
c acid ethyl ester. .sup.1H-NMR: 7.52 (dd, 2H), 6.99 (dd, 2H), 6.88
(s, 1H), 4.15 (q, 2H), 3.87 (s, 3H), 3.59 (s, 3H) 3.00 (m, 1H),
2.80 (m, 1H), 2.67 (m, 1H), 1.27 (m, 6H).
Example 890
3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propionic
acid ethyl ester
[1626] ##STR109##
[1627]
3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-a-
crylic acid ethyl ester (5.76 g, 19.3 mmol) was hydrogenated with
10% Pd/C (3.0 g) in EtOH (100 ml) o.n. The reaction mixture was
filtered and concentrated. The residue was triturated with hex. to
give the title compound in 3.1 g (53%) yield. .sup.1H-NMR: 8.76 (d,
2H), 7.73 (d, 2H), 4.14 (m, 2H), 3.35 (m, 3H), 2.88 (q, 1H), 1.39
(d, 3H), 1.25 (t, 3H), 1.18 (m, 2H) and 0.73 (m, 2H).
[1628] The following examples were synthesized analogous to
3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propioni-
c acid ethyl ester TABLE-US-00052 Structure Name .sup.1H-NMR
Example No. ##STR110## 3-(3- Cuclopropyl-2- pyridin-4-yl-
3H-imidazol-4- yl)-2-methyl- propionic acid ethyl ester 8.69 (dd, 2
H), 7.68 (dd, 2 H), 6.91 (s, 1 H), 4.16 (q, 2 H), 3.33 (m, 1 H),
3.19 (m, 1 H), 2.85 (m, 2 H), 1.33 (d, 3 H), 1.25 (t, 3 H), 1.14
(m, 2 H), 0.69 (m, 2 H). 891 ##STR111## 3-[3- Cyclopropyl-2-
(4-methoxy- phenyl)-3H- imidazol-4-yl]- propionic acidethyl ester
7.66 (d, 2 H), 6.95 (d, 2 H), 6.80 (br. s, 1 H), 4.20 (q, 2 H),
3.88 (s, 3 H), 3.23 (m, 1 H), 3.05 (m, 2 H), 2.76 (m, 2 H), 1.30
(t, 3 H), 1.03 (m, 2 H), 0.65 (m, 2 H). 892
Example 893
3-(3-Cyclopropyl-2-pyridin-4-yl-3H-imidazol-4-yl)-2-methyl-propionic
acid
[1629] ##STR112##
[1630]
3-(3-cyclopropyl-2-pyridin-4-yl-3H-imidazol-4-yl)-2-methyl-propion-
ic acid ethyl ester (1.02 g, 3.40 mmol) was mixed with MeOH (8 ml)
and sodium hydroxide (1N in water, 5.1 ml, 5.10 mmol). This mixture
was left stirring at r.t. for 5 h, followed by concentration
in-vacuo. The isolated residue was treated with aq. HCl (2N, 6 ml)
to isolate the title compound (702 mg, 76%). .sup.1H-NMR (DMSO-d6):
8.63 (dd, 2H), 7.74 (dd, 2H), 6.82 (s, 1H), 3.55 (m, 1H), 3.09 (m,
1H), 2.82 (m, 2H), 1.19 (d, 3H), 1.08 (m, 2H), 0.56 (m, 2H).
Example 894
3-[2-(4-Methoxy-phenyl)-3-methyl-3H-midazol-4-yl]-2-methyl-propionic
acid
[1631] ##STR113##
[1632] The title compound was synthesized analogous to
3-(3-Cyclopropyl-2-pyridin-4-yl-3H-imidazol-4-yl)-2-methyl-propionic
acid. .sup.1H-NMR (DMSO-d6): 7.52 (d, 2H), 7.02 (d, 2H), 6.71 (s,
1H), 3.80 (s, 3H), 3.55 (s, 3H) 2.89 (m, 1H), 2.67 (m, 2H), 1.15
(d, 3H).
Example 895
3-Cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazole-4-carbaldehyde
[1633] ##STR114##
[1634] N-cyclopropyl-4-methoxy-benzamidine (0.90 g, 4.75 mmol),
2-bromo-3-isopropoxy-propenal (1.37 g, 7.12 mmol) and
K.sub.2CO.sub.3 (0.98 g, 7.12 mmol) were mixed with chloroform (10
ml) and water (1.2 ml), followed by stirring at r.t. for 24 h.
After drying of the reaction mixture (Na.sub.2SO.sub.4), filtration
and concentration of the filterate in-vacuo, the crude residue was
purified via flash chromatography (40% EA in hex.) to isolate the
title compound (973 mg, 85%). .sup.1H-NMR: 9.83 (s, 1H), 7.82 (m,
3H), 7.02 (d, 2H), 3.89 (s, 3H), 3.58 (m, 1H), 1.13 (m, 2H), 0.64
(m, 2H).
[1635] The following examples were synthesized in a manner
analogous to that for
3-Cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazole-4-carbaldehyde.
TABLE-US-00053 Structure Name .sup.1H-NMR Example No. ##STR115##
3-Cyclopropyl- 2-(2,6- dichloro- pyridin-4-yl)- 3H-imidazole-
4-carbaldehyde 9.92 (s, 1 H), 7.88 (s, 1 H), 7.79 (s, 2 H), 3.65
(m, 1 H), 1.33 (m, 2 H), 0.72 (m, 2 H). 896 ##STR116##
2-(4-methoxy- phenyl)-3- methyl-3H- imidazole-4- carbaldehyde 9.77
(s, 1 H), 7.87 (s, 1 H), 7.63 (dd, 2 H), 7.04 (dd, 2 H), 4.02 (s, 3
H), 3.89 (s, 3 H). 897
Example 898
(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol
[1636] ##STR117##
[1637] 4-(4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine (6.85 g,
36.8 mmol) was mixed with 37% formaldehyde (30 mL) in a sealed vial
and heated at 135.degree. C. o.n. The reaction mixture was
concentrated with silica gel and then mixed with MeOH. The mixture
was filtered and washed with MeOH. The filtrate was concentrated
with silica gel again and loaded on a flash column and eluted with
10% MeOH (2 M NH.sub.3) in DCM to give the title compound (6.8 g,
85%). .sup.1H-NMR (DMSO-d.sub.6): 8.75 (d, 2H), 7.84 (d, 2H), 5.63
(t, 1H), 4.72 (d, 2H), 3.66 (m, 1H), 1.04 (m, 2H), 0.73 (m,
2H).
Example 899
3-chloro-N'-hydroxybenzenecarboximidamide
[1638] ##STR118##
[1639] A solution of 3.35 mL (30.0 mmol) 3-chlorobenzonitrile in
ethanol (40 mL) was added to a solution of 2.47 g (35.5 mmol)
hydroxylamine hydrochloride and 1.42 g (35.5 mmol) NaOH in water
(20 mL) at r.t. and then heated at 90.degree. C. for 24 h. After
cooling, the reaction mixture was concentrated, the residue diluted
with water, followed by filtration and drying to afford 1.13 g
(93%) of the title compound. .sup.1H NMR: 8.11 (s, 1H), 7.72 (s,
1H), 7.61 (m, 1H), 7.46 (m, 1H), 7.36 (m, 1H).
Example 900
N-Cyclopropyl-4-methoxy-benzamidine
[1640] ##STR119##
[1641] 4-methoxy-benzimidic acid ethyl ester hydrochloride (1.25 g,
5.8 mmol), DCM (5 ml) and cyclopropylamine (0.92 ml, 13.3 mmol)
were mixed. After stirring at r.t for 3 h, the reaction mixture was
concentrated in-vacuo. The residue was treated with cold aq. sodium
hydroxide (IM) and extracted with EA. The combined organic phase
was washed with water and brine, dried (Na.sub.2SO.sub.4), filtered
and concentrated in-vacuo, to isolate the title compound (0.90 g,
82%). .sup.1H-NMR: 7.64 (d, 2H), 6.90 (d, 2H), 5.3 (bs, 2H), 3.85
(s, 3H), 2.59 (m, 1H), 0.84 (m, 2H), 0.62 (m, 2H).
Example 901
4-Methoxy-N-methyl-benzamidine
[1642] ##STR120##
[1643] Methylamine hydrochloride (2.28 g, 33.8 mmol) was suspended
in toluene (16 ml). After cooling the resulting mixture to
0.degree. C., trimethylaluminum (2M in toluene) was added drop-wise
under Ar, followed by warming the mixture to r.t and stirring for 2
h. To this mixture was then added a solution of
4-methoxybenzonitrile in toluene (16 ml), followed by stirring at
80.degree. C. for 24 h. The reaction mixture was cooled to r.t. and
slowly poured in to a slurry of silica gel (10 g) in CHCl.sub.3 (75
ml). The slurry was stirred at r.t for 15 minutes and filtered
using MeOH. The filtrate was concentrated. The isolated residue was
dissolved in water (50 ml) and extracted with CHCl.sub.3. The
combined organic phase was washed with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated in-vacuo, to isolate
the title compound (1.25 g). .sup.1H-NMR (DMSO-d6): 7.68 (d, 2H),
6.91 (dd, 2H), 6.33 (br. s, 2H), 3.77 (s, 3H), 2.77 (s, 3H)
Example 902
2,6-Dichloro-N-cyclopropyl-isonicotinamidine
[1644] ##STR121##
[1645] 2,6-dichloropyridine-4-carbonitrile (5 g, 28.9 mmol),
methanol (50 ml) and sodium methoxide (0.66 ml, 2.89 mmol) were
mixed and stirred at r.t. for 3 h. HCl in EtOH (24% w/w, 10 ml) and
cyclopropylamine (3 mL, 43.4 mmol) were added at 0.degree. C.,
followed by stirring at r.t. o.n. The reaction mixture was
concentrated in-vacuo. The isolated residue was treated with cold
aq. NaOH (1N, 75 ml) and extracted with EA. The combined organic
phase was washed sequentially with aq. NaOH and brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated in-vacuo. The
isolated residue was triturated with Et.sub.2O to isolate the title
compound (3.82 g). .sup.1H-NMR: 7.59 (br. s, 2H), 4.96 (br. s, 2H),
2.60 (m, 1H), 0.90 (m, 2H), 0.69 (m, 2H).
Example 903
4-Methoxy-benzimidic acid ethyl ester hydrochloride
[1646] ##STR122##
[1647] 4-Methoxybenzonitrile and 24% hydrochloric acid in EtOH were
mixed at 0.degree. C. This mixture was left stirring at r.t. o.n.,
followed by concentration in-vacuo. The isolated residue was
triturated with Et.sub.2O to isolate the title compound (1.25 g).
.sup.1H-NMR: 12.3 (br. s, 1H), 11.6 (br. s, 1H), 8.43 (d, 2H), 7.04
(d, 2H), 4.91 (t, 3H), 3.90 (s, 3H), 1.61 (t, 3H).
Example 904
2-Bromo-3-isopropoxy-propenal
[1648] ##STR123##
[1649] A mixture of 2-bromomalonaldehyde, para-toluenesulfonic acid
monohydrate, 2-propanol and cyclohexane were stirred at 86.degree.
C. in flask with a dean-stark trap under azeotropic conditions.
Further distillation removed another 40% of the original solvent
volume. The mixture was cooled to 0.degree. C., then concentrated
in-vacuo, to isolate the title compound (13.2 g). .sup.1H-NMR: 9.16
(s, 1H), 7.65 (s, 1H), 4.51 (m, 1H), 1.47 (d, 6H).
Example 905
5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid ethyl ester
[1650] ##STR124##
[1651] A solution of 4-(3-chloro-phenyl)-2,4-dioxo-butyric acid
ethyl ester (3.0 g, 11.8 mmol) and hydroxylamine hydrochloride
(2.46 g, 35.4 mmol) in MeOH (60 mL) was heated at 80.degree. C. for
4 h. After cooling, the mixture was filtered and washed with cold
MeOH to afford the title compound (2.0 g, 71%). .sup.1H NMR: 7.82
(s, 1H), 7.72 (m, 1H), 7.47 (m, 2H), 4.03 (s, 3H).
Example 906
4-(4-Cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine
[1652] ##STR125##
[1653]
4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-3H-1,2,4-triazole-3-thion-
e (11.11 g, 51 mmol) was slowly added to wet Raney nickel (90 g) in
EtOH (200 mL) in portions. The reaction mixture was heated at
60.degree. C. for 3.5 h and then filtered through celite. The
filtrate was concentrated to give the title compound (6.85 g,
72.3%). .sup.1H-NMR: 8.76 (d, 2H), 8.71 (s, 1H), 7.95 (d, 2H), 3.75
(m, 1H), 1.08 (m, 2H) and 0.94 (m, 2H).
Example 907
N-cyclopropylpropanamide
[1654] ##STR126##
[1655] A solution of propionic anhydride (6.41 ml, 50.0 mmol) and
cyclopropylamine (3.48 ml, 50.0 mmol) in benzene (50 ml) was heated
to reflux for 6 h and then the solvent was evaporated.
Recrystallization from EA/hex. afforded the title compound (1.45 g,
26%). .sup.1H NMR: 0.48 (m, 2H) 0.76 (m, 2H) 1.13 (t, 3H) 2.14 (q,
2H) 2.69 (m, 1H)
Example 908
4-(3-Chloro-phenyl)-2,4-dioxo-butyric acid ethyl ester
[1656] ##STR127##
[1657] Sodium hydride (60% oil dispersion, 1.24 g, 31.1 mmol) was
added in portions to a solution of 3-chloroacetophenone (4.0 g,
25.9 mmol) and diethyl oxalate (4.54 g, 31.1 mmol) in DMF (32 mL)
at 0.degree. C. The mixture was stirred at r.t for 1 h and was then
heated at 80.degree. C. for 0.5 h. After cooling, the mixture was
treated with 3N HCl and then diluted with EA. The organic layer was
washed with water and saturated brine, dried (Na.sub.2SO.sub.4),
filtered and concentrated. The resulting residue was then purified
by column chromatography using 0-10% EA in hex to afford the title
compound (4.43 g, 67%). .sup.1H NMR: 15.12 (br s, 1H), 7.98 (s,
1H), 7.88 (d, 1H), 7.58 (d, 1H), 7.47 (t, 1H), 7.05 (s, 1H), 4.39
(m, 2H), 1.41 (m, 3H).
Example 909
1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol
[1658] ##STR128##
[1659] 27.2 g crude
N'-[(3-chlorobenzoyl)oxy]-2-hydroxypropanimidamide was dissolved in
ethanol (250 mL) and refluxed for 1 h, followed by addition of 14.0
g (170 mmol) sodium acetate in water (40 mL). After refluxing o.n.,
cooling to r.t. and addition of water (250 mL) the mixture was
concentrated in vacuo to about 1/2 of its volume, resulting in a
precipitate which was filtered off and recrystallized from EA/Hep
to yield 6.45 g (25%) of the title compound. .sup.1H NMR: 8.14 (s,
1H), 8.02 (d, 1H), 7.57 (d, 1H), 7.47 (t, 1H), 5.04-5.14 (m, 1H),
2.51 (d, 1H), 1.67 (d, 3H)
Example 910
1-[5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazol-3-yl]ethanol
[1660] ##STR129##
[1661] The title compound was synthesized analogous to
1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol. .sup.1H-NMR:
8.12 (dd, 1H), 7.49-7.58 (m, 1H), 7.18-7.27 (m, 1H), 5.12 (q, 1H),
1.68 (d, 3H)
Example 911
1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]propan-1-ol
[1662] ##STR130##
[1663] Propionaldehyde cyanohydrin (9.62 g, 113 mmol) was added
slowly to hydroxylamine (100 ml, 1.27 M in EtOH) at 0.degree. C.
Stirring was continued at r.t. for 3 h and then the reaction
mixture was concentrated to dryness under reduced pressure to give
crude (E/Z)-N',2-dihydroxybutanimidamide (9.1 g, 68%). Crude
(E/Z)-N',2-dihydroxybutanimidamide (8.0 g, 67.7 mmol) was dissolved
in pyridine (350 ml) and 3-chlorobenzoyl chloride (8.72 ml, 67.7
mmol) was added slowly at 0.degree. C. After stirring at r.t. for 1
h the mixture was heated at reflux o.n. After cooling to r.t. sat.
aq. NaHCO.sub.3 was added and the mixture was extracted with DCM.
The organic phase was washed with water and brine, dried and
concentrated. Column chromatography (hep/EA 4:1) gave 7.15 g (44%)
of the title compound. .sup.1H NMR: 1.04 (t, 3H) 2.00 (m, 2H) 2.35
(m, 1H) 4.87 (m, 1H) 7.47 (t, 1H) 7.57 (m, 1H) 8.02 (m, 1H) 8.14
(m, 1H)
Example 912
(+)-(1R)-1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethanol
[1664] ##STR131##
[1665] A solution of 1.53 g (18.6 mmol) sodium acetate in water (12
mL) was added to 3.88 g (16.0 mmol)
3-chloro-N'-{[(2R)-2-hydroxypropanoyl]oxy}benzenecarboximidamide
dissolved in ethanol (50 mL). The mixture was heated to 90.degree.
C. for 5.5 h and then evaporated to dryness and purified via flash
chromatography (Hep/EA=9/1) to give after drying 2.3 g (65%) of the
title compound. .sup.1H NMR: 8.09 (t, 1H), 7.97 (td, 1H), 7.45-7.51
(m, 1H), 7.42 (t, 1H), 5.15 (qd, 1H), 2.57 (d, 1H), 1.72 (d,
3H)
Example 913
3-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]benzonitrile
[1666] ##STR132##
[1667] Hydroxylamine (50% aq., 5.7 g, 172 mmol) was added drop-wise
to a solution of hydroxyacetonitrile (55% aq., 8.9 g, 156 mmol) in
water (100 ml) and stirred at rt for 4 h. Water was evaporated and
the residue was dissolved in EtOH and dried (Na.sub.2SO.sub.4).
3-Cyanobenzoyl chloride (9.5 g, 57.1 mmol) in THF (10 ml) was added
drop-wise to a slurry of the obtained crude
(1E)-N',2-dihydroxyethanimidamide (4.7 g, 51.9 mmol) and DEA (8.0
g, 62.3 mmol) in THF (10 ml) at 0.degree. C. The reaction mixture
was stirred at 0.degree. C. for 2 h, diluted with Et.sub.2O (100
ml) and washed (NH.sub.4Cl aq.). The water phase was extracted with
Et.sub.2O and the organic layers were dried (Na2.sub.SO.sub.4). The
obtained crude
(1E)-N'-[(3-cyanobenzoyl)oxy]-2-hydroxyethanimidamide (5.0 g, 22.8
mmol) was dissolved in EtOH (50 ml). NaOAc (2.8 g, 34.2 mmol) was
added and the mixture was refluxed o.n. The reaction mixture was
concentrated and the precipitate recrystallized from EtOH (10 ml)
to give the title compound (1.4 g). .sup.1H NMR (DMSO-d6): 8.51 (m,
1H), 8.39 (m, 1H), 8.16 (m, 1H), 7.84 (t, 1H), 5.78 (t, 1H), 4.63
(t, 2H).
Example 914
(+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol
[1668] ##STR133##
[1669] 7.13 g (26.7 mmol)
(+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethyl acetate
and 2.33 g (56.7 mmol) lithium hydroxide monohydrate were mixed
with 1:1 THF/Water (100 mL) and stirred for 18 h. Reducing the
volume of the mixture in vacuo to about 1/2, followed by dilution
with brine and extraction with ethyl acetate. 5.8 g (97%) of the
title compound was obtained after evaporation and drying. .sup.1H
NMR: 8.14 (s, 1H), 8.02 (d, 1H), 7.57 (d, 1H), 7.47 (t, 1H),
5.04-5.14 (m, 1H), 2.42 (br s, 1H), 1.67 (d, 3H)
Example 915
(+)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]propan-1-ol
[1670] ##STR134##
[1671] The title compound was synthesized analogous to
(+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol and
was used directly in the next step for
(+)-4-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propoxy}-4-methyl-4H-
-1,2,4-triazol-3-yl)pyridine.
Example 916
(-)-(1S)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol
[1672] ##STR135##
[1673] The title compound was isolated from the reaction as
described for the synthesis of
(+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethyl acetate.
Isolation took place during DCM elution of the column
chromatography, yielding 5 g (50%) of the title compound. .sup.1H
NMR: 8.14 (s, 1H), 8.02 (d, 1H), 7.57 (d, 1H), 7.47 (t, 1H),
5.04-5.14 (m, 1H), 2.51 (d, 1H), 1.67 (d, 3H).
Example 917
[5-(3-Chloro-phenyl)-isoxazol-3-yl]-methanol
[1674] ##STR136##
[1675] Lithium aluminum hydride (320 mg, 8.4 mmol) was slowly added
to a solution of 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid
ethyl ester (2.0 g, 8.4) in THF (100 ml) at r.t After 1 h, the
reaction mixture was quenched with water and then extracted with
EA. The organic layer was washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The resulting
residue was then purified by column chromatography using 15-40% EA
in hex. to afford the title compound (1.32 g, 75%,). .sup.1H NMR:
7.78 (s, 1H), 7.68 (m, 1H), 7.43 (m, 2H), 6.63 (s, 1H), 4.84 (d,
2H), 2.23 (t, 1H).
Example 918
1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol
[1676] ##STR137##
[1677] Step 1: 5-(3-Chloro-phenyl)-isoxazole-3-carboxylic acid
methyl ester: A solution of 4-(3-chloro-phenyl)-2,4-dioxo-butyric
acid ethyl ester (3.0 g, 11.8 mmol) and hydroxylamine hydrochloride
(2.46 g, 35.4 mmol) in MeOH (60 ml) was heated at 80.degree. C. for
4 h. After cooling, the mixture was filtered and washed with cold
methanol to afford 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid
methyl ester (2.0 g, 71%). .sup.1H NMR: 7.82 (s, 1H), 7.72 (m, 1H),
7.47 (m, 2H), 4.03 (s, 3H). Step 2:
1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanone: In a screw cap vial
equipped with stir bar was mixed methyl magnesium iodide (3M in
Et.sub.2O) (0.79 ml, 2.38 mmol), toluene (1 ml), tetrahydrofuran
(0.39 ml, 4.77 mmol) and TEA (1 ml, 7.15 mmol). After cooling to
0.degree. C. a solution of
5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid methyl ester (300
mg, 1.19 mmol) in toluene (5 ml) was added, followed by stirring at
0.degree. C. for 5 h. The mixture was then quenched with aq 1N HCl
(6.5 ml, 6.5 mmol), diluted with toluene (35 ml), sequentially
washed with water, sat. aq. sodium bicarbonate, water and brine.
The organic phase was concentrated in-vacuo. The isolated residue
was dissolved in MeOH (8 ml) and 20% aq. KOH (1 ml) was added,
followed by stirring at 45.degree. C. for 30 min and then
concentrated in-vacuo. The residue was dissolved in toluene (60
ml), sequentially washed with water, sat. aq. sodium bicarbonate
and water. The organic phase was concentrated in-vacuo. The crude
residue was purified on silica gel using 2% EA in hex. to isolate
the desired compound (156 mg, 60%). .sup.1H-NMR: 7.77 (m, 1H), 7.66
(m, 1H), 7.42 (m, 2H), 6.90 (s, 1H), 2.69 (s, 3H). Step 3:
1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol: In a screw cap vial
equipped with stir bar was mixed
1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanone (100 mg, 0.45 mmol),
sodium borohydride (34 mg, 0.90 mmol) and MeOH (3 ml), followed by
stirring at r.t for 3 h and the quenched with water and brine,
extracted with DCM. The combined organic phase was dried
(Na.sub.2SO.sub.4), filtered and concentrated in-vacuo to isolate
the title compound. .sup.1H-NMR: 7.69 (m, 1H), 7.59 (m, 1H), 7.37
(m, 2H), 6.59 (s, 1H), 5.07 (q, 1H), 3.45 (br. s, 1H), 1.58 (d,
3H).
Example 919
(+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethyl
acetate
[1678] ##STR138##
[1679] 12.1 g (53.9 mmol)
1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol and 1.60 g
Novozyme 435.RTM. are taken up under Ar in toluene (750 mL). After
addition of 5.0 mL (54.2 mmol) vinyl acetate the reaction was run
at r.t. o.n., followed by filtration over celite and washing with
DCM. The filtrate was purified over silica using DCM neat, followed
by EA/Hep=1/1, yielding 7.1 g (49%) of the title compound. .sup.1H
NMR: 8.13 (t, 1H), 8.01 (d, 1H), 7.55 (d, 1H), 7.47 (t, 1H), 6.07
(q, 1H), 2.15 (s, 3H), 1.69 (d, 3H)
Example 920
(+)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]propyl acetate
[1680] ##STR139##
[1681] The title compound was prepared analogous to
(+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethyl acetate
with stirring at 70.degree. C. for 6 h. .sup.1H NMR: 1.00 (t, 3H)
2.07 (m, 2H) 2.16 (s, 3H) 5.90 (t, 1H) 7.46 (t, 1H) 7.52-7.59 (m,
1H) 7.98-8.06 (m, 1H) 8.13 (t, 1H)
Example 921
3-(1-chloroethyl)-5-(3-chlorophenyl)-[1,2,4]oxadiazole
[1682] ##STR140##
[1683] 5 drops of DMF were added to
1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol (12.3 g, 54.9
mmol) in SOCl.sub.2 (150 mL) and the reaction was heated at
70.degree. C. for 5 h. The excess SOCl.sub.2 was evaporated and the
residue was purified by column chromatography (Hep 100% to
Hep/EA=5/1) to give 12.4 g (93%) of the title compound. .sup.1H
NMR: 1.96 (d, 3H) 5.20 (q, 1H) 7.46 (t, 1H) 7.59 (m, 1H) 8.04 (m,
1H) 8.17 (t, 1H)
[1684] The following examples were synthesized in a manner
analogous to that for
3-(1-chloroethyl)-5-(3-chlorophenyl)-[1,2,4]oxadiazole.
TABLE-US-00054 Structure Name .sup.1H-NMR Example No. ##STR141##
5-(5-Chloro-2- fluoro-phenyl)- 3-chloromethyl- [1,2,4]oxadiazole
8.16 (m, 1 H), 7.58 (m, 1 H), 7.29 (m, 1 H), 4.72 (s, 3 H). 922
##STR142## 3-Chloromethyl- 5-(3-methyl- phenyl)-
[1,2,4]oxadiazole
Example 924
5-(1-chloroethyl)-3-(3-chlorophenyl)-[1,2,4]oxadiazole
[1685] ##STR143##
[1686] 1.80 g 3-chloro-N'-hydroxybenzenecarboximidamide and 3.7 mL
DEA were dissolved under Ar in DCM (100 mL) and cooled on an
ice/water bath, followed by addition of 2-chloropropanoyl chloride.
After 1 h at r.t. the mixture was concentrated and the crude taken
up in DMF (120 mL), followed by heating for at 120.degree. C. for 2
h. The mixture was concentrated onto celite and purified via column
chromatography (hep 100% to hep/EA=7/3) yielding the title compound
(1.72 g, 67%). .sup.1H NMR: 8.09 (t, 1H), 7.93-8.02 (m, 1H),
7.38-7.54 (m, 2H), 5.22 (q, 1H), 2.02 (d, 3H)
Example 925
5-Chloromethyl-3-(3-chloro-phenyl)-[1,2,4]oxadiazole
[1687] ##STR144##
[1688] The title compound was prepared analogous to
5-(1-chloroethyl)-3-(3-chlorophenyl)-[1,2,4]oxadiazole. .sup.1H
NMR: 8.07 (t, 1H), 7.93-7.98 (m, 1H), 7.46-7.52 (m, 1H), 7.42 (t,
1H), 4.74 (s, 2H)
Example 926
3-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]benzonitrile
[1689] ##STR145##
[1690] The title compound was prepared analogous to
5-(1-chloroethyl)-3-(3-chlorophenyl)-[1,2,4]oxadiazole. .sup.1H
NMR: 8.40 (s, 1H), 8.32 (d, 1H), 7.82 (d, 1H), 7.64 (t, 1H), 4.77
(s, 2H).
Example 927
3-(1-chloro-ethyl)-5-m-tolyl-[1,2,4]oxadiazole
[1691] ##STR146##
[1692] 2-Chloro-N-hydroxy-propionamidine (218 mg, 1.78 mmol) and
triethylamine (0.677 ml, 4.86 mmol) were added to 3-methyl-benzoyl
chloride (250 mg, 1.62 mmol) in DCM (10.0 ml) at 0.degree. C. and
the resulting mixture was stirred for 20 min. The solution was
concentrated and DMF (20 ml) was added to the residue and heated at
120.degree. C. for 20 min. The product was purified by flash
chromatography using 10-20% EA in hex. affording 0.250 g (59% yield
over 2 steps) of the title compound. GCMS (M/Z)=222.
Example 928
3-Chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole
[1693] ##STR147##
[1694] Step A. The acyclic intermediate was obtained from
3-chlorobenzoic acid (2.82 g, 18 mmol), EDCI (3.46 g, 18 mmol),
HOBt (2.76 g, 18 mmol) and 2-chloro-N-hydroxy-acetamidine (1.75 g,
16.2 mmol) [Chem. Ber. 1907, 40, 1639] in DMF (40 mL). Step B: The
cyclic compound was obtained from heating in DMF (40 mL) and
purified by SPE chromatography on silica gel using 2% acetone in
hex. yielding the title compound (1.46 g, 39% yield over 2 steps).
.sup.1H NMR: 8.17 (m, 1H), 8.07 (dd, 1H), 7.60 (m, 1H), 7.55 (t,
1H), 4.69 (s, 2H).
Example 929
3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]benzonitrile
[1695] ##STR148##
[1696] N'-(chloroacetyl)-3-cyanobenzohydrazide (795 mg, 3.34 mmol)
and P.sub.2O.sub.5 (4.7 g, 33.4 mmol) were added to DMF (6 ml) and
toluene (4 ml). The reaction mixture was refluxed for 2 h.
K.sub.2CO.sub.3 (aq., sat.) was added until pH was basic and the
mixture was extracted with DCM. The combined organic layers were
dried (Na.sub.2SO.sub.4) and purified with flash chromatography
using 0 to 100% EA in hep. to give the title compound (209 mg,
29%). .sup.1H NMR: 8.29 (m, 2H), 7.82 (m, 1H), 7.66 (t, 1H), 4.78
(s, 2H).
Example 930
3-cyanobenzohydrazide
[1697] ##STR149##
[1698] 3-cyanobenzoyl chloride (4.8 g, 29.0 mmol) was dissolved in
DCM (20 ml) and MeOH (40 ml) was added in portions at 0.degree. C.
The mixture was stirred at 0.degree. C. for 1 h and at rt for 2 h.
The solvents were evaporated and the crude methyl ester was
dissolved in EtOH (50 ml) and hydrazine (24% aq., 9 ml, 45 mmol)
was added. The reaction mixture was refluxed for 48 h and the
solvents were evaporated (coevaporation with water). The residue
was purified with prep. HPLC to give the title compound (1.8 g,
39%). .sup.1H NMR (DMSO-d6): 9.98 (br s, 1H), 8.21 (m, 1H), 8.13
(m, 1H), 7.99 (m, 1H), 7.69 (t, 1H), 4.61 (br s, 2H).
Example 931
N'-(chloroacetyl)-3-cyanobenzohydrazide
[1699] ##STR150##
[1700] 3-cyanobenzohydrazide (1.6 g, 10.0 mmol) was added to THF
(40 ml) and DMF (10 ml). TEA (1.4 ml, 10.0 mmol) was added at
0.degree. C. followed by chloroacetyl chloride (1.0 ml, 12.6 mmol)
and the reaction mixture was stirred at 0.degree. C. for 1 h and at
rt for 2 h. The THF was evaporated, water was added to the
remaining mixture, followed by filtration over celite and
purification with prep. HPLC to give the title compound (1.6 g,
69%). .sup.1H NMR (DMSO-d6): 10.62 (br s, 2H), 8.28 (m, 1H), 8.18
(m, 1H), 8.08 (m, 1H), 7.75 (t, 1H), 4.22 (s, 2H).
Example 932
3-(bromomethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole
[1701] ##STR151##
[1702] 3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (1.38
g, 6.0 mmol) and LiBr (0.90 g, 10.3 mmol) in THF (50 ml) were
heated to reflux under a nitrogen atm. o.n. After cooling to r.t.
EA was added and the organic phase was washed with H.sub.2O and
brine, dried and evaporated to give the title compound (1.40 g,
85%). MS (M.sup.++1) 275.
Example 933
3-(bromomethyl)-5-(3-methylphenyl)-1,2,4-oxadiazole
[1703] ##STR152##
[1704] The title compound was prepared analogous to
3-(bromomethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole MS (M.sup.++1)
253.
Example 934
3-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole
[1705] ##STR153##
[1706] A solution of NBS (396 mg, 2.22 mmol) in THF (2 ml) was
added dropwise to a solution of triphenylphosphine (583 mg, 2.22
mmol) in THF (2 ml) at 0.degree. C. After stirring for 20 min
1-[5-(3-chloro-phenyl)-1,2,4-oxadiazol-3-yl]-ethanol (416 mg, 1.85
mmol) in THF (2 ml) was added. Stirring was continued o.n. at r.t.
before the solvent was removed under reduced pressure. Flash
chromatography (hep/EA 6:1) afforded 168 mg (32%) of the title
compound. .sup.1H NMR: 2.12 (d, 3H) 5.21 (q, 1H) 7.47 (t, 1H) 7.57
(m, 1H) 8.03 (d, 1H) 8.15 (s, 1H)
Example 936
3-(1-bromoethyl)-5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazole
[1707] ##STR154##
[1708] 1.6 g
1-[5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazol-3-yl]ethanol was
dissolved in benzene (30 mL), followed by addition of 0.6 mL
phosphorous tribromide. After heating to reflux for 90 min water
(15 mL) was added. Solid NaHCO.sub.3 was added, followed by
extraction with CHCl.sub.3. After drying over Na.sub.2SO.sub.4 and
removal of solvent, purification was done on 2 mm chromatotron
plate (hep 100% to hep/EA=99/1) to yield 0.60 g (32%) of the title
compound. .sup.1H NMR: 8.15 (dd, 1H), 7.49-7.59 (m, 1H), 7.19-7.26
(m, 1H), 5.23 (q, 1H), 2.13 (d, 3H)
Example 937
1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethyl
methanesulfonate
[1709] ##STR155##
[1710] Methane sulfonyl chloride (40 ml, 0.49 mmol) was added to a
mixture of TEA (95 ml, 0.67 mmol) and
1-[5-(3-Chloro-phenyl)-1,2,4-oxadiazol-3-yl]-ethanol (100 mg, 0.45
mmol) in DCM (5 ml). After stirring for 15 min the mixture was
washed with water and brine, dried and concentrated to yield the
title compound (135 mg). .sup.1H NMR: 1.9 (d, 3H) 3.1 (s, 3H) 5.9
(q, 1H) 7.5 (t, 1H) 7.6 (m, 1H) 8.0 (m, 1H) 8.1 (t, 1H)
[1711] The following examples were synthesized in a manner
analogous to that for
1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethyl methanesulfonate.
TABLE-US-00055 Structure Name .sup.1H-NMR Example No. ##STR156##
[5-(3- chlorophenyl)- isoxazol-3- yl]methyl methanesulfonate 7.80
(s, 1 H), 7.70 (m, 1 H) 7.45 (m, 2 H), 6.73 (s, 1 H), 5.37 (s, 2
H), 3.16 (s, 3 H). 938 ##STR157## [5-(3- cyanophenyl)- 1,2,4-
oxadiazol-3- yl]methyl methanesulfonate
Example 940
5-(3-chlorophenyl)-N-methyl-1,2,4-oxadiazol-3-amine
[1712] ##STR158##
[1713] Hydroxycarbonimidic dibromide (2.21 g, 10.89 mmol) was added
portionwise over 1 h 20 min to a mixture of 3-chlorobenzonitrile
(3.00 g, 21.29 mmol) and NaHCO.sub.3 (2.9 g, 34.87 mmol) in toluene
(3 ml) at 90.degree. C. Stirring was continued for 3 h and then the
reaction mixture was cooled to r.t., diluted with EA and washed
with water. The organic phase was dried and concentrated. A mixture
of 3-chlorobenzonitrile and
3-bromo-5-(3-chlorophenyl)-1,2,4-oxadiazole was obtained after
flash chromatography (hex/EA 10:1). 1.0 g of the mixture was
dissolved in MeNH.sub.2 (4 ml, 8.5 M in EtOH) and heated in a
microwave reactor for 30 min at 60.degree. C. The volatiles were
removed under reduced pressure and the residue was dissolved in
water and extracted with CHCl.sub.3. The organic phase was dried
and concentrated. Recrystallization from EA gave 137 mg of the
title compound. .sup.1H NMR: 3.00 (d, 3H) 4.35 (bs, 1H) 7.43 (t,
1H) 7.50-7.55 (m, 1H) 7.92 (d, 1H) 8.03 (s, 1H)
Example 941
5-(3-chlorophenyl)-N-ethyl-1,2,4-oxadiazol-3-amine
[1714] ##STR159##
[1715] The title compound was prepared analogous to
5-(3-chlorophenyl)-N-methyl-1,2,4-oxadiazol-3-amine. .sup.1H NMR:
1.28 (t, 3H) 3.36 (q, 2H) 7.43 (t, 1H) 7.49-7.55 (m, 1H) 7.92 (m,
1H) 8.03 (s, 1H)
Example 942
4-[5-(chloromethyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine
[1716] ##STR160##
[1717] Sulfuryl dichloride (0.58 ml, 8.34 mmol) in DCM (8 ml) was
slowly added to a cooled (-10.degree. C.) solution of
4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)pyridine (454 mg, 2.61 mmol)
in DCM (25 ml) and DMF (8 ml) and then the solution was stirred for
2 h. NaHCO3 (sat.) was added and the mixture was extracted with EA.
The organic phase was dried and concentrated. Recrystallization
from EA afforded 124 mg (23%) of the title compound. .sup.1H NMR:
3.83 (s, 3H) 4.84 (s, 2H) 7.62 (d, 2H) 8.82 (d, 2H).
[1718] Preparation of Final Compounds
Example 943
4-(5-{2-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propyl}-4-cyclopropyl-4H--
1,2,4-triazol-3-yl)pyridine
[1719] ##STR161##
[1720] n-BuLi (210 ml, 2.5 M in hex., 0.52 mmol) was added dropwise
to a solution of
4-(4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridine (80 mg,
0.4 mmol) in THF (10 ml) at -78.degree. C. under an atm. of
nitrogen. After stirring for 15 min
3-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole (115 mg,
0.4 mmol) in THF (2 ml) was added. The mixture was stirred for 2 h
at -78.degree. C. and then at r.t. for 1 h. The solvent was removed
under reduced pressure and the desired product was obtained by
prep. HPLC in 20 mg yield. .sup.1H NMR: 0.7 (m, 2H) 1.2 (ddd, 2H)
1.6 (d, 3H) 3.2 (dd, 1H) 3.3 (ddd, 1H) 3.6 (dd, 1H) 3.9 (m, 1H) 7.5
(t, 1H) 7.6 (m, 1H) 7.7 (m, 2H) 8.0 (m, 1H) 8.1 (t, 1H) 8.7 (m,
2H)
[1721] The following examples were synthesized in a manner
analogous to that for
4-(5-{2-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propyl}-4-cyclo-
propyl-4H-1,2,4-triazol-3-yl)pyridine. TABLE-US-00056 Example
Structure No. Name .sup.1H-NMR ##STR162## 944 4-(5-{2-[5-(3-
chlorophenyl)- 1,2,4-oxadiazol- 3-yl]ethyl}-4- cyclopropyl-4 H-
1,2,4-triazol-3- yl)pyridine 0.72-0.78 (m, 2 H) 1.21 (m, 2 H) 3.35
(m, 1 H) 3.41-3.48 (m, 2 H) 3.49-3.57 (m, 2 H) 7.47 (m, 1 H) 7.53-
7.59 (m, 1 H) 7.73 (m, 2 H) 7.95-8.03 (m, 1 H) 8.11 (tm, 1 H) 8.76
(d, 2 H). ##STR163## 945 4-(5-{2-[5-(3- chlorophenyl)-
1,2,4-oxadiazol- 3-yl]-1- methylethyl}-4- cyclopropyl-4 H-
1,2,4-triazol-3- yl)pyridine 0.62-0.72 (m, 1 H) 0.81-0.92 (m, 1 H)
1.14-1.21 (m, 2 H) 1.52 (d, 3 H) 3.24 (m, 1 H) 3.35 (m, 1 H) 3.56
(m, 1 H) 3.83-3.93 (m, 1 H) 7.41 (t, 1 H) 7.50 (m, 1 H) 7.68 # (d,
2 H) 7.91 (d, 1 H) 8.01 (t, 1 H) 8.70 (d, 2 H) ##STR164## 946
4-(5-{2-[5-(5- chloro-2- fluorophenyl)- 1,2,4-oxadiazol-
3-yl]propyl}-4- methyl-4 H- 1,2,4-triazol-3- yl)pyridine 1.58 (d, 3
H) 3.17 (m, 1 H) 3.8 (m, 1 H) 3.72 (s, 3 H) 3.82-3.93 (m, 1 H) 7.20
(t, 1 H) 7.52 (m, 1 H) 7.59 (d, 2 H) 8.07 (m, 1 H) 8.77 (s, 2 H)
##STR165## 947 4-(5-{2-[5-(5- chloro-2- fluorophenyl)-
1,2,4-oxadiazol- 3-yl]propyl}-4- cyclopropyl-4 H- 1,2,4-triazol-3-
yl)pyridine 0.69-0.81 (m, 2 H) 1.15-1.27 (m, 2 H) 1.59 (d, 3 H)
3.23 (m, 1 H) 3.38 (m, 1 H) 3.57 (m, 1 H) 3.92-4.03 (m, 1 H) 7.20
(t, J = 9.35 Hz, 1 H) 7.52 (m, 1 H) # 7.77 (d, 2 H) 8.07 (m, 1 H)
8.76 (d, 2 H) ##STR166## 948 4-(4-methyl-5- {2-[5-(3-
methylphenyl)- 1,2,4-oxadiazol- 3-yl]ethyl}-4 H- 1,2,4-triazol-3-
yl)pyridine 2.41 (s, 3 H) 3.28 3.37 (m, 2 H) 3.44- 3.52 (m, 2 H)
3.72 (s, 3 H) 7.38 (m, 2 H) 7.61 (d, 2 H) 7.85-7.90 (m, 1 H) 7.90
(s, 1 H) 8.78 (bs, 2 H) ##STR167## 949 4-(4- cyclopropyl-5-
{1-methyl-2-[5- (3- methylphenyl)- 1,2,4-oxadiazol- 3-yl]ethyl}-4
H- 1,2,4-triazol-3- yl)pyridine 0.69 (m, 1 H) 0.87 (m, 1 H)
1.14-1.24 (m, 2 H) 1.55 (d, 3 H) 2.40 H) 1.55 (d, 3 H) 2.40 (s, 3
H) 3.26 (m, 1 H) 3.35 (m, 1 H) 3.57 (m, 1 H) 3.85-3.95 # (m, 1 H)
3.85-3.95 (m, 1 H) 7.37 (d, 2 H) 7.73 (m, 2 H) 7.81-7.89 (m, 2 H)
8.73 (bs, 2 H)
Example 950
3-(3-Chloro-phenyl)-5-{2-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-
-yl]-ethyl}-[1,2,4]oxadiazole
[1722] ##STR168##
[1723] 3-chloro-N'-hydroxybenzenecarboximidamide (54.3 mg, 0.32
mmol),
3-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-propionic
acidethyl ester (100 mg, 0.32 mmol) and sodium-tert-butoxide (30.6
mg, 0.32 mmol) were mixed with EtOH (1 ml) and toluene (1 ml),
followed by stirring at 100.degree. C. for 24 h. The mixture was
then concentrated, in-vacuo, and the residue was purified via
column chromatography using 50% EA in hex. and then triturated with
Et.sub.2O to isolate the title compound (27 mg). .sup.1H-NMR: 8.1
(m, 1H), 7.97 (dd, 1H), 7.64 (d, 2H), 7.47 (m, 2H), 6.96 (d, 2H),
6.88 (s, 1H), 3.87 (s, 3H), 3.37 (m, 4H), 3.24 (m, 1H), 1.06 (m,
2H), 0.68 (m, 2H).
Example 951
3-(3-Chloro-phenyl)-5-{2-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-
-yl]-1-methyl-ethyl}-[1,2,4]oxadiazole
[1724] ##STR169##
[1725] The title compound was synthesized analogous to
3-(3-Chloro-phenyl)-5-{2-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol--
4-yl]-ethyl}-[1,2,4]oxadiazole. .sup.1H-NMR: 8.1 (m, 1H), 7.98 (dd,
1H), 7.63 (d, 2H), 7.46 (m, 2H), 6.97 (d, 2H), 6.85 (s, 1H), 3.88
(s, 3H), 3.65 (m, 1H), 3.42 (m, 1H), 3.15 (m, 2H), 1.58 (d, 3H),
1.06 (m, 2H), 0.67 (m, 2H).
Example 952
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-1-cyclopropyl--
1H-imidazol-2-yl)-pyridine
[1726] ##STR170##
[1727] 3-chloro-N-hydroxy-benzamidine (486 mg, 2.85 mmol),
3-(3-cyclopropyl-2-pyridin-4-yl-3H-imidazol-4-yl)-2-methyl-propionic
acid (702 mg, 2.59 mmol), EDCI (546 mg, 2.85 mmol) and HOBt hydrate
(385 mg, 2.85 mmol) were mixed with DMF (20 ml) and stirred o.n. at
r.t. The reaction was diluted with water and extracted with EA. The
combined organic phase was successively washed with sat. aq. sodium
bicarbonate, brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated in-vacuo. The residue was heated in DMF (10 ml) at
120.degree. C. for 2 h. The reaction mixture was cooled to r.t.,
diluted with EA (50 ml), successively washed with water and brine,
dried (Na.sub.2SO.sub.4), filtered and concentrated in-vacuo. The
crude was purified via column chromatography using 2% MeOH in DCM
to isolate the title compound (404 mg). .sup.1H-NMR: 8.69 (dd, 2H),
8.09 (m, 1H), 7.96 (d, 1H), 7.67 (dd, 2H), 7.46 (m, 2H), 6.94 (s,
1H), 3.66 (m, 1H), 3.48 (m, 1H), 3.31 (m, 1H), 3.16 (m, 1H), 1.59
(d, 3H), 1.19 (m, 2H), 0.72 (m, 2H).
Example 953
3-(3-Chloro-phenyl)-5-{2-[2-(4-methoxy-phenyl)-3-methyl-3H-imidazol-4-yl]--
1-methyl-ethyl}-[1,2,4]oxadiazole
[1728] ##STR171##
[1729] The title compound was synthesized analogous to
4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-1-cyclopropyl-
-1H-imidazol-2-yl)-pyridine. .sup.1H-NMR: 8.1 (m, 1H), 7.98 (dd,
1H), 7.50 (m, 4H), 6.97 (d, 2H), 6.92 (s, 1H), 3.87 (s, 3H), 3.62
(s, 3H) 3.54 (m, 1H), 3.30 (m, 1H), 3.00 (m, 1H), 1.57 (d, 3H).
Example 954
(S)-4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopro-
pyl-4H-[1,2,4]triazol-3-yl)-pyridine
[1730] ##STR172##
[1731] After 3-chloro-N-hydroxy-benzamidine (0.7 g, 4.1 mmol) was
mixed with potassium-tert-butoxide (0.373 g, 3.33 mmol) in
n-propanol at 80.degree. C. for 10 min,
3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propioni-
c acid ethyl ester (1.0 g, 3.33 mmol) was added to the reaction
mixture and heated at 100.degree. C. for 3 h. The reaction mixture
was concentrated, quenched with sat. ammonium chloride and
extracted with DCM. The organic layer was dried with MgSO.sub.4,
purified by column chromatography and triturated with Et.sub.2O to
give racemic
4-(5-{2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-
-4H-[1,2,4]triazol-3-yl)-pyridine (0.8 g, 59%). The title product
(10 mg) was obtained by separation on Chiracel OJ with EtOH:hex.
(1:4). .sup.1H-NMR: 8.78 (d, 2H), 8.05 (s, 1H), 7.96 (d, 1H), 7.74
(d, 2H), 7.50 (d, 1H), 7.43 (t, 1H), 4.15 (m, 1H), 3.64 (dd, 1H),
3.31 (m, 2H), 1.67 (d, 3H), 1.25 (m, 2H) and 0.78 (m, 2H).
Example 955
4-(5-{(2S)-2-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]propyl}-4-cyclopropy-
l-4H-1,2,4-triazol-3-yl)pyridine
[1732] ##STR173##
[1733]
3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-p-
ropionic acid ethyl ester (2.14 g, 7.1 mmol) was mixed with
hydrazine monohydrate in ethanol at 120.degree. C. in a sealed
flask for 2 hours. The reaction mixture was concentrated and
triturated with ether to give
3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propioni-
c acid hydrazide. This compound was mixed with 3-Chloro-benzimidic
acid ethyl ester hydrochloride (0.722 g, 7.8 mmol) in ethanol at
130.degree. C. o.n. The reaction mixture was concentrated, quenched
with saturated sodium carbonate, extracted with DCM. The organic
layer was dried and purified by column chromatograph with 5%
methanol (2M NH.sub.3) in DCM to racemic
4-(5-{2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyc-
lopropyl-4H[1,2,4]triazol-3-yl)-pyridine 1.19 g (41.1%). This
material (70 mg) was separated on Chiralpak AD using ethanol as
eluent to give the title compound. .sup.1H-NMR: 8.77 (d, 2H), 8.02
(s, 1H), 7.92 (d, 1H), 7.72 (d, 2H), 7.51 (d, 1H), 7.47 (t, 1H),
4.12 (m, 1H), 3.69 (dd, 1H), 3.44 (m, 1H), 3.26 (dd, 1H), 1.66 (d,
3H), 1.24 (m, 2H) and 0.79 (m, 2H).
Example 956
4-(5-{(2R)-2-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]propyl}-4-cyclopropy-
l-4H-1,2,4-triazol-3-yl)pyridine
[1734] ##STR174##
[1735] The title compound was obtained from chiral LC separation in
example
4-(5-{(2S)-2-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]propyl}-4-c-
yclopropyl-4H-1,2,4-triazol-3-yl)pyridine.
Example 957
4-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methyl-4H-1,2,4-
-triazol-3-yl)pyridine
[1736] ##STR175##
[1737] 1.45 g (6.08 mmol)
4-[4-Methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine, 1.73
g (7.70 mmol) 1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethanol
and 4.03 g (12.3 mmol) cesium carbonate were dissolved under
Ar-atmosphere in DMF (25 mL) and stirred at 30.degree. C. for 3 d.
After filtration and evaporation to dryness the crude was purified
on 4 mm silica chromatotron plate (DCM/MeOH=100/0 to 90/10).
Further purification on 2 mm silica chromatotron plate
(Hep/EA/MeOH=15/15/1) gave 0.36 g (15%) of the title compound.
.sup.1H NMR: 8.75 (br s, 2H), 8.12 (s, 1H), 8.00 (d, 1H), 7.64 (d,
2H), 7.56 (d, 1H), 7.46 (t, 1H), 6.39 (q, 1H), 3.63 (s, 3H), 1.94
(d, 3H).
[1738] The following examples were synthesized analogous to
4-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methyl-4H-1,2,-
4-triazol-3-yl)pyridine. TABLE-US-00057 Example Structure No. Name
.sup.1H-NMR ##STR176## 958 5-(3- chlorophenyl)-3- ((1R)-1-{[4-
methyl-5- (trifluoromethyl)- 4 H-1,2,4-triazol- 3-yl]oxy}ethyl)-
1,2,4-oxadiazole 8.13 (m, 1 H) 8.01 (m, 1 H) 7.58 (m, 1 H) 7.48 (m,
1 H) 6.24 (q, 1 H) 3.74 (s, 3 H) 1.90 (d, 3 H). ##STR177## 959
3-(5-{1-[5-(3- chlorophenyl)- 1,2,4-oxadiazol- 3-yl]ethoxy}-4-
cylcopropyl-4 H- 1,2,4-triazol-3- yl)pyridine 1.04 (m, 4 H) 1.96
(d, 3 H) 3.21 (m, 1 H) 6.41 (q, 1 H) 7.45 (m, 2 H) 7.58 (m, 1 H)
8.03 (d, 1 H) 8.15 (m, 2 H) 8.70 (bd, 1 H) 9.08 (bs, 1 H)
##STR178## 960 3-(5-{(1R)-1-[5- (3-chlrophenyl)- 1,2,4-oxadiazol-
3-yl]ethoxy}-4- methyl-4 H-1,2,4- triazol-3- yl)pyridine 1.95 (d, 3
H) 3.59 (s, 3 H) 6.39 (q, 1 H) 7.46 (m, 1 H) 7.49 (t, 1 H) 7.58 (m,
1 H) 8.02 (m, 2 H) 8.14 (t, 1 H) 8.72 (bd, 1 H) 8.89 (bs, 1 H)
##STR179## 961 5-(3- chlorophenyl)-3- ((1R)-1-}[5-(4-
fluorophenyl)-4- methyl-4 H-1,2,4- triazol-3- yl]oxy}ethyl)-
1,2,4-oxadiazole 8.14 (m, 1 H) 8.02 (m, 1 H) 7.93-7.99 (m, 2 H)
7.57 (m, 1 H) 7.47 (m, 1 H) 7.06 (m, 2 H) 6.30 (q, 1 H) 3.71 (s, 3
H) 1.90 (d, 3 H). ##STR180## 962 5-(3- chlorophenyl)-3-
((1R)-1-}[5-(3,5- difluorophenyl)- 4-methyl-4 H- 1,2,4-triazol-3-
yl]oxy}ethyl)- 1,2,4-oxadiazole 1.93 (d, 3 H) 3.57 (s, 3 H) 6.37
(m, 1 H) 6.86-6.97 (m, 1 H) 7.20 (d, 2 H) 7.46 (t, 1 H) 7.56 (d, 1
H) 8.00 (d, 1 H) 8.12 (s, 1 H) ##STR181## 963 (+)-4-(5-{1-[5-(3-
chlorophenyl)- 1,2,4-oxadiazol- 3-yl]propoxy}-4- methyl-4 H-1,2,4-
triazol-3- yl)pyridine 1.12 (t, 3 H) 2.25-2.36 (m, 2 H) 3.64 (s, 3
H) 6.22 (t, J = 6.57 Hz, 1 H) 7.46 (t, 1 H) 7.54-7.63 (m, 3 H)
7.97- 8.05 (m, 1 H) 8.12 (t, 1 H) 8.70- # 8.78 (m, 2 H). ##STR182##
964 (-)-4-(5-{(1 R)-1- [5-(3- chlorophenyl)- 1,2,4-oxadiazol-
3-yl]ethoxy}-4- methyl-4 H-1,2,4- triazol-3- yl)pyridine 8.74 (d, 2
H), 8.13 (t, 1 H), 8.01 (d, 1 H), 7.60 (dd, 2 H), 7.57 (d, 1 H),
7.47 (t, 1 H), 6.39 (q, 1 H), 3.63 (s, 3 H), 1.94 (d, 3 H).
##STR183## 965 (+)-4-(5-{(1S)-1- [5-(3- chlorophenyl)-
1,2,4-oxadiazol- 3-yl]ethoxy}-4- methyl-4 H-1,2,4- triazol-3-
yl)pyridine 8.71 (d, 2 H), 8.09 (s, 1 H), 7.97 (d, 1 H), 7.57 (d, 2
H), 7.54 (d, 1 H), 7.44 (t, 1 H), 6.36 (q, 1 H), 3.60 (s, 3 H),
1.91 (d, 3 H).
Example 966
(-)-4-(5-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}-4-methyl-4H-1-
,2,4-triazol-3-yl)pyridine
[1739] ##STR184##
[1740] 0.57 g (2.54 mmol)
(+)-(1R)-1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethanol, 0.64 g
(2.68 mmol)
4-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine and
0.90 g (2.76 mmol) cesium carbonate were stirred at 65.degree. C.
for 6 h, followed by dilution with water. Extraction with EA,
washing with aq. citric acid, drying over Na.sub.2SO.sub.4,
followed by purification via chromatotron 2 mm
(Hep/EA/MeOH=10/10/1) gave 0.81 g (83%) racemic
4-(5-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}-4-methyl-4H-1,2,-
4-triazol-3-yl)pyridine. Prep. chiral separation on Chiralpak AD
using 100% 2-propanol yielded 0.25 g of the title compound as the
second eluting enantiomer. .sup.1H NMR: 8.76 (d, 2H), 8.07 (t, 1H),
7.92-7.99 (m, 1H), 7.60-7.68 (m, 2H), 7.45-7.51 (m, 1H), 7.41 (t,
1H), 6.45 (q, 1H), 3.66 (s, 3H), 1.99 (d, 3H)
Example 967
(+)-4-(5-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}-4-methyl-4H-1-
,2,4-triazol-3-yl)pyridine
[1741] ##STR185##
[1742] 0.2 g of the title compound was isolated as the first
eluting enantiomer during preparative chiral HPLC separation in the
example of
(-)-4-(5-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}-4-methyl-4H--
1,2,4-triazol-3-yl)pyridine. .sup.1H NMR: 8.77 (d, 2H), 8.07 (t,
1H), 7.93-8.00 (m, 1H), 7.68 (dd, 2H), 7.45-7.52 (m, 1H), 7.41 (t,
1H), 6.45 (q, 1H), 3.67 (s, 3H), 1.99 (d, 3H)
Example 968
4-(5-{1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethoxy}-4-methyl-4H-[1,2,4]tri-
azol-3-yl)-pyridine
[1743] ##STR186##
[1744] 1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol (63.4 mg, 0.28
mmol), DMF and sodium hydride (60% dispersion in oil, 15.1 mg, 0.38
mmol) were mixed under inert atm. and stirred at r.t for 1 h,
followed by addition of
4-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine (45
mg, 0.19 mmol). After stirring at 80.degree. C. for 24 h, the
mixture was cooled to r.t., diluted with EA, sequentially washed
with water and brine. The organic phase was dried
(Na.sub.2SO.sub.4), filtered and concentrated, in-vacuo. The crude
residue was purified via column chromatography using 5% MeOH in EA
to isolate the title compound (11.7 mg). .sup.1H-NMR: 8.81 (bs,
2H), 7.77 (s, 1H), 7.67 (m, 3H), 7.42 (m, 2H), 6.73 (s, 1H), 6.36
(q, 1H), 3.62 (s, 3H), 1.94 (d, 3H).
Example 969
N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridi-
n-3-yl-4H-1,2,4-triazol-3-amine
[1745] ##STR187##
[1746] NaH (14 mg, 0.35 mmol) was added to
N,4-dimethyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-amine (33 mg, 0.18
mmol) in DMF (3 mL). After 30 min
3-(1-chloroethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (80 mg, 0.18
mmol) in DMF (1 mL) was added to the mixture and the reaction was
stirred at 60.degree. C. o.n. Brine was added and the mixture was
extracted with EA. The organic phase was dried and concentrated.
The product was purified by column chromatography (DCM to DCM-MeOH
30:1) to give 31 mg (43%) of the title compound. .sup.1H NMR: 1.71
(d, 3H) 2.97 (s, 3H) 3.67 (s, 3H) 4.88 (q, 1H) 7.46 (m, 2H) 7.56
(d, 1H) 8.00 (d, 1H) 8.10 (d, 2H) 8.71 (bs, 1H) 8.92 (bs, 1H)
[1747] The following examples were made in a manner analogous to
that for
N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyrid-
in-3-yl-4H-1,2,4-triazol-3-amine. TABLE-US-00058 Example Structure
No. Name .sup.1H-NMR ##STR188## 970 3-Pyridin-4-yl-8-[1-(5-m-
tolyl-[1,2,4]oxadiazol-3- yl)-ethyl]-5,6,7,8- tetrahydro-
[1,2,4]triazol[4,3- a]pyrimidine 1.76 (d, 3 H) 2.18 (m, 2 H) 2.44
(s, 3 H) 3.46 (t, 2 H) 4.15 (m, 2 H) 5.99 (q, 2 H) 7.40 (d, 2 H)
7.62 (d, 2 H) 7.89 (d, 1 H) 7.90 (s, 1 H) 8.70 (d, 2 H). ##STR189##
971 N,4-dimethyl-N-{[5-(3- methylphenyl)-1,2,4-
oxadiazol-3-yl]methyl}-5- pyridin-4-yl-4 H-1,2,4- triazol-3-amine
2.43 (s, 3 H) 3.08 (s, 3 H) 3.71 (s, 3 H) 4.56 (s, 2 H) 7.40 (d, 2
H) 7.66 (d, 2 H) 7.92 (m, 2 H) 8.77 (bs, 2 H) ##STR190## 972
N-{[5-(5-chloro-2- fluorophenyl)-1,2,4- oxadiazol-3-yl]methyl}-
N,4-dimethyl-5-pyridin-4- yl-4 H-1,2,4-triazol-3- amine 3.04 (s, 3
H) 3.66 (s, 3 H) 4.56 (s, 2 H) 7.19 (m, 1 H) 7.49 (m, 1 H) 7.64
(bs, 2 H) 8.03 (m, 1 H) 8.72 (bs, 2 H) ##STR191## 973
N-{[5-(4-chlorophenyl)- 1,2,4-oxadiazol-3-
yl]methyl}-N-cyclopropyl- 4-methyl-5-pyridin-4-yl- 4
H-1,2,4-triazol-3-amine 1H NMR: 0.6 (s, 2 H) 0.8 (d, 2 H) 3.1 (s, 1
H) 3.7 (s, 3 H) 4.7 (s, 2 H) 7.4 (t, 1 H) 7.5 (d, 1 H) 7.6 (d, 2 H)
7.9 (d, 1 H) 8.1 (s, 1 H) 8.7 (s, 2 H)
Example 974
(+)-N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-5-(3,5-difluoroph-
enyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine
[1748] ##STR192##
[1749] To a solution of
5-(3,5-difluorophenyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine (0.47
g, 2.10 mmol) in DMF (10 ml) at r.t. under nitrogen was added NaH
(77 mg, 3.20 mmol). After stirring for 15 min. a solution of
1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl methanesulfonate
(0.70 g, 2.30 mmol) in DMF 10 ml was added. After 3 h the mixture
was diluted with sat. NH.sub.4Cl solution and then extracted with
EA. The organic phase was washed with H.sub.2O and brine, dried and
evaporated. Purification by silica gel chromatography using
hex.:EA=1:1 afforded 400 mg of the racemic
N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-5-(3,5-difluoropheny-
l)-N,4-dimethyl-4H-1,2,4-triazol-3-amine, which was separated using
prep. chiral HPLC on a Chiralpak AD column (hex./2-propanol 80/20
to 100% 2-propanol) to give 183 mg (21%) of the title compound
which eluted last. .sup.1H NMR: 1.68 (d, 3H) 2.89 (s, 3H) 3.62 (s,
3H) 4.79 (q, 1H) 6.80-6.90 (m, 1H) 7.19 (d, 2H) 7.40 (t, 1H) 7.49
(d, 1H) 7.94 (d, 1H) 8.04 (s, 1H)
Example 975
(-)-N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-5-(3,5-difluoroph-
enyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine
[1750] ##STR193##
[1751] 186 mg of the title compound was isolated as the first
eluting enantiomer during preparative chiral HPLC separation in
example of
(+)-N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-5-(3,5-difluorop-
henyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine. .sup.1H NMR: 1.68 (d,
3H) 2.89 (s, 3H) 3.62 (s, 3H) 4.79 (q, 1H) 6.80-6.90 (m, 1H) 7.19
(d, 2H) 7.40 (t, 1H) 7.49 (d, 1H) 7.94 (d, 1H) 8.04 (s, 1H).
Example 976
(+)-8-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4--
yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine
[1752] ##STR194##
[1753] NaH (716 mg, 29.8 mmol) was added slowly to a solution of
3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine
(5.0 g, 24.8 mmol) in DMF (250 ml) under nitrogen. After 10 min a
solution of 3-(1-chloroethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole
(6.0 g, 24.8 mmol) in DMF (200 ml) was added, followed by stirring
o.n. at r.t. A sat NH.sub.4Cl solution was added followed by water.
The mixture was extracted with EA and DCM. The combined organic
extracts were washed with water and brine, dried and concentrated.
Recrystallization from EA gave 2.24 g (22%) of the racemic product
8-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-yl-5,6,7-
,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine. Separation on a
Chiralpak AD column (100% 2-propanol) gave the title compound which
eluted as second enantiomer. .sup.1H NMR: 1.74 (d, 3H) 2.17 (m, 2H)
3.45 (m, 2H) 4.10 (m, 2H) 5.96 (m, 1H) 7.44 (t, 1H) 7.53 (m, 1H)
7.59 (m, 2H) 7.97 (m, 1H) 8.08 (m, 1H) 8.67 (d, 2H)
Example 977
(-)-8-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4--
yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine
[1754] ##STR195##
[1755] The title compound was isolated as the first eluting
enantiomer during preparative chiral HPLC separation in example of
(+)-8-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-
-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine. .sup.1H
NMR: 1.74 (d, 3H) 2.17 (m, 2H) 3.45 (m, 2H) 4.10 (m, 2H) 5.96 (m,
1H) 7.44 (t, 1H) 7.53 (m, 1H) 7.59 (m, 2H) 7.97 (m, 1H) 8.08 (m,
1H) 8.67 (d, 2H)
Example 978
(-)-N-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}-N,4-dimethyl-5-py-
ridin-4-yl-4H-1,2,4-triazol-3-amine
[1756] ##STR196##
[1757] Prep. chiral HPLC separation on Chiralpak AD (100%
2-propanol) yielded the title compound as the last eluting isomer.
.sup.1H NMR: 8.74 (s, 2H), 8.05 (t, 1H), 7.87-8.00 (m, 1H),
7.56-7.69 (m, 2H), 7.32-7.53 (m, 2H), 5.03 (q, 1H), 3.68 (s, 3H),
2.98 (s, 3H), 1.81 (d, 3H)
Example 979
(+)-N-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}-N,4-dimethyl-5-py-
ridin-4-yl-4H-1,2,4-triazol-3-amine
[1758] ##STR197##
[1759] Prep. chiral HPLC separation on Chiralpak AD (100%
2-propanol) yielded the title compound as the first eluting isomer.
.sup.1H NMR: 8.74 (s, 2H), 8.05 (t, 1H), 7.87-8.00 (m, 1H),
7.56-7.69 (m, 2H), 7.32-7.53 (m, 2H), 5.03 (q, 1H), 3.68 (s, 3H),
2.98 (s, 3H), 1.81 (d, 3H)
Example 980
(-)-N-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-
-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine
[1760] ##STR198##
[1761] Prep. chiral HPLC separation on Chiralpak AD (100%
2-propanol) of racemic
N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-
-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine yielded the title compound
which eluted last.
Example 981
(+)-N-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-
-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine
[1762] ##STR199##
[1763] The title compound was isolated as the first eluting
enantiomer during prep. chiral HPLC separation in example of
(-)-N-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethy-
l-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine.
Example 982
3-[5-(3-Pyridin-4-yl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylme-
thyl) [1,3,4]oxadiazol-2-yl]benzonitrile
[1764] ##STR200##
[1765]
3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine
(172 mg, 0.85 mmol) and
3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]benzonitrile (94 mg, 0.43
mmol) were dissolved in butanone (5 ml) and K.sub.2CO.sub.3 (118
mg, 0.85 mmol) and KI (35 mg, 0.21 mmol) were added. The reaction
mixture was refluxed for 1 h and the solvent was evaporated. The
residue was dissolved in K.sub.2CO.sub.3 (aq., 1M, 25 ml) and was
extracted with DCM. The combined organic layers were dried
(Na.sub.2SO.sub.4) and purified with prep. HPLC to give the title
compound (27 mg, 16%). .sup.1H NMR: 8.75 (d, 2H), 8.30 (m, 2H),
7.79 (d, 1H), 7.63 (m, 1H), 7.53 (dd, 2H), 5.57 (d, 2H), 4.06 (t,
2H), 3.58 (t, 2H), 1.99 (m, 2H).
[1766] The following compounds were prepared analogous to
3-[5-(3-Pyridin-4-yl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylm-
ethyl) [1,3,4]oxadiazol-2-yl]benzonitrile TABLE-US-00059 Example
Structure No. Name .sup.1H-NMR ##STR201## 983
3-{5-[3-(2-Methoxypyridin- 4-yl)-6,7-dihydro-5 H-
[1,2,4]triazolo[4,3- a]pyrimidin-8- ylmethyl][1,3,4]oxadiazol-
2-yl}benzonitrile 8.31 (s, 1 H), 8.26 (t, 2 H), 7.80 (d, 1 H), 7.63
(t, 1 H), 7.11 (d, 1 H), 6.93 (s, 1 H), 5.48 (d, 2 H), 4.01 (t, 2
H), 3.96 (s, 3 H), 3.56 (s, 2 H), 1.96 (s, 2 H). ##STR202## 984
3-(5-{[Methyl-(4-methyl-5- pyridin-4-yl-4 H-
[1,2,4]triazol-3-yl)-amino]- methyl}[1,3,4]oxadiazol-2-
yl)benzonitrile 8.77 (s, 2 H), 8.30 (m, 2 H), 7.82 (d, 1 H), 7.65
(m, 3 H), 4.79 (s, 2 H), 3.71 (s, 3 H), 3.11 (s, 3 H). ##STR203##
985 3-{5-[3-(2-Methoxy- pyridin-4-yl)-6,7-dihydro- 5
H-[1,2,4]triazolo[4,3- a]pyrimidin-8-ylmethyl]-
[1,2,4]oxadiazol-3-yl}- benzonitrile
Example 986
3-{3-[(3-pyridin-4-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl)-
methyl]-1,2,4-oxadiazol-5-yl}benzonitrile
[1767] ##STR204##
[1768] [5-(3-cyanophenyl)-1,2,4-oxadiazol-3-yl]methyl
methanesulfonate (0.278 g; 0.99 mmol) and
3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine
(0.220 g; 1.09 mmol) were dissolved in butanone (20 ml) and
potassium carbonate (0.275 g; 1.99 mmol) was added portionwise. The
mixture was heated at reflux for 18 h before cooling to r.t. This
mixture was concentrated in vacuo and DCM (20 ml) was added. The
mixture was washed with water, dried (Na.sub.2SO.sub.4), evaporated
and purified using prep. HPLC chromatography to give the title
compound (5.4 mg). .sup.1H NMR: 8.77 (m, 2H), 8.41 (s, 1H), 8.34
(d, 1H), 7.87 (d, 1H), 7.68 (t, 1H), 7.56 (m, 2H) 5.51 (s, 2H),
4.09 (m, 2H), 3.62 (m, 2H), 2.19 (m, 2H).
Example 987
3-(3-{[[5-(2-methoxypyridin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]
(methyl)amino]methyl}-1,2,4-oxadiazol-5-yl)benzonitrile
[1769] ##STR205##
[1770] Sodium hydride (0.013 g, 0.53 mmol) was added portionwise to
a stirred solution of
5-(2-methoxypyridin-4-yl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine
(0.086 g; 0.39 mmol) in DMF (10 ml) at 0.degree. C. The mixture was
stirred for 30 minutes before
[5-(3-cyanophenyl)-1,2,4-oxadiazol-3-yl]methyl methanesulfonate
(0.1 g; 0.36 mmol) in DMF (1 ml) was added dropwise. The mixture
was stirred at r.t. for 3 h before quenching with water (30 ml).
The resulting mixture was extracted with EA (3.times.40 ml). The
organics were combined, dried (Na.sub.2SO.sub.4) and evaporated to
give a crude material, which was purified by prep. HPLC to give the
title compound (0.061 g; 42.3%). .sup.1H NMR: 8.49 (s, 1H), 8.33
(dd, 1H), 8.28 (d, 1H), 7.86 (dd, 1H), 7.67 (t, 1H), 7.24 (d, 1H),
7.02 (s, 1H), 4.60 (s, 2H), 3.97 (s, 3H), 3.70 (s, 3H), 3.08 (s,
3H).
[1771] The following examples were prepared in a manner analogous
to that for
3-(3-{[[5-(2-methoxypyridin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]
(methyl)amino]methyl}-1,2,4-oxadiazol-5-yl)benzonitrile
TABLE-US-00060 Example Structure No. Name .sup.1H-NMR ##STR206##
988 3-(3-{[methyl(4-methyl-5- pyridin-4-yl-4 H-1,2,4- triazol-3-
yl)amino]methyl}-1,2,4- oxadiazol-5-yl)benzonitrile 8.41 (s, 1 H),
8.33 (d, 2 H), 7.88 (d, 2 H), 7.71- 7.65 (m, 3 H), 4.61 (s, 2 H),
3.73 (s, 3 H), 3.09 (s, 3 H). ##STR207## 989 3-(3-{[3-(2-
methoxypyridin-4-yl)-6,7- dihydro[1,2,4]triazolo[4,3-
a]pyrimidin-8(5 H)- yl]methyl}-1,2,4- oxadiazol-5-yl)benzonitrile
8.40 (s, 1 H), 8.32 (d, 1 H), 8.24 (d, 1 H), 7.86 (d, 1 H), 7.68
(t, 1 H), 7.24 (d, 1 H), 6.97 (s, 1 H), 5.05 (s, 2 H), 4.13 (t, 2
H), 3.96 (s, 3 H), 3.57 (t, 2 H), # 2.23 (m, 2 H). ##STR208## 990
N-{1-[5-(3-chlorophenyl)- 1,2,4-oxadiazol-3-
yl]ethyl}-N,4-dimethyl-5- pyridin-4-yl-4 H-1,2,4- triazol-3-amine
8.72 (d, 2 H) 8.09 (s, 1 H) 7.98 (d, 1 H) 7.62 (d, 2 H) 7.54 (d, 1
H) 7.44 (t, 1 H) 4.85 (d, 1 H) 3.70 (s, 3 H) 2.95 (s, 3 H) 1.73 (d,
3 H)
Example 991
3-{5-[(3-pyridin-4-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl)-
methyl]-1,2,4-oxadiazol-3yl}benzonitrile
[1772] ##STR209##
[1773] 3-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]benzonitrile (98.2
mg, 0.447 mmol), and
3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine
(62.2 mg, 0.309 mmol) were suspended in acetonitrile (2 ml) and
isopropanol (2.4 ml). After stirring for 45 min. potassium
carbonate (88.1 mg, 0.637 mmole) was added. The mixture was heated
in a microwave oven (130.degree. C.) for 30 min. The product was
filtered and then purified on prep. HPLC to give 29 mg of the title
compound. .sup.1H NMR (DMSO-d6): 8.72 (dd, 2H), 8.36 (br t, 1H),
8.30 (dt, 1H), 8.08 (dt, 1H), 7.79 (t, 1H), 7.68 (dd, 2H), 5.49 (s,
2H), 4.02 (t, 2H), 3.3 (m, 1H), 2.36 (s, 3H), 1.71 (t, 2H).
Example 992
3-{5-[3-(2-Hydroxy-pyridin-4-yl)-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyri-
midin-8-ylmethyl]-[1,2,4]oxadiazol-3-yl}-benzonitrile
[1774] ##STR210##
[1775] The title compound was synthesized analogous to
3-{5-[(3-pyridin-4-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl-
)methyl]-1,2,4-oxadiazol-3-yl}benzonitrile. .sup.1H NMR: 8.34 (s,
1H), 8.29 (d, 1H), 7.79 (d, 1H), 7.67 (t, 1H), 7.38 (d, 1H), 6.97
(m, 1H), 6.72 (s, 1H), 5.13 (s, 2H), 4.22 (m, 2H), 3.64 (m, 2H),
2.27 (m, 2H).
Example 993
N-{[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-N,4-dimethyl-5-pyridin-
-4-yl-4H-1,2,4-triazol-3-amine
[1776] ##STR211##
[1777]
1-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-1,2,3-trimethy-
l-isothiourea (55 mg, 0.177 mmol) was mixed with isonicotinic
hydrazide (29.1 mg, 0.212 mmol) in ethanol (1 mL) at 85.degree. C.
o.n. The reaction mixture was diluted with DCM and washed with
water. The product was purified by column chromatography with
5.about.7% MeOH in EA and triturated with Et.sub.2O to give the
title compound (22.5 mg, 40%). .sup.1H-NMR: 8.80 (d, 2H), 8.10 (s,
1H), 8.00 (d, 1H), 7.66 (d, 2H), 7.51 (d, 1H), 7.47 (t, 1H), 4.80
(s, 2H), 3.74 (s, 3H), 3.15 (s, 3H).
[1778] The following examples were synthesized in a manner
analogous to that for
N-{[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-N,4-dimethyl-
-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine TABLE-US-00061 Example
Structure No. Name .sup.1H-NMR ##STR212## 994 N-{[3-(3-
Chlorophenyl)- 1,2,4-oxadiazol- 5-yl]methyl}-4- cyclopropyl-N-
methyl-5- pyridin-4-yl-4 H- 1,2,4-triazol-3- amine 8.75 (d, 2 H),
8.09 (s, 1 H), 7.98 (d, 1 H), 7.77 (d, 2 H), 7.52 (d, 1 H), 7.46
(t, 1 H), 4.95 (s, 2 H), 3.34 (m, 1 H), 3.32 (s, 3 H) 1.12 (m, 2 H)
# and 0.95 (m, 2 H). ##STR213## 995 [3-(3-Chloro- phenyl)-
[1,2,4]oxadiazol- 5-ylmethyl]- ethyl-(4-methyl- 5-pyridin-4-yl- 4
H- [1,2,4]triazol-3- yl)-amine 8.74 (d, 2 H), 8.01 (s, 1 H), 7.92
(d, 1 H), 7.62 (d, 2 H), 7.42 (d, 1 H), 7.38 (t, 1 H), 4.78 (d, 2
H), 3.74 (d, 3 H), 3.41 (q, 2 H), 1.24 (t, 3 H). ##STR214## 996
[3-(3-Chloro- phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]-
ethyl-(4-methyl- 5-pyridin-4-yl- 4 H- [1,2,4]triazol-3- yl)-amine
8.74 (d, 2 H), 8 (s, 1 H), 7.89 (d, 1 H), 7.62 (d, 2 H), 7.44 (d, 1
H), 7.41 (t, 1 H), 4.87 (s, 2 H), 3.76 (s, 3 H), 3.12 (m, 1 H),
0.82 (br, 2 H), # 0.7 (br, 2 H). ##STR215## 997 N-{[3-(3-
Chlorophenyl)- 1,2,4-oxadiazol- 5-yl]methyl}-N- isopropyl-4-
methyl-5- pyridin-4-yl-4 H- 1,2,4-triazol-3- amine 8.79 (d, 2 H),
8.01 (s, 1 H), 8.91 (d, 1 H), 7.68 (d, 2 H), 7.49 (d, 1 H), 7.44
(t, 1 H), 4.82 (s, 2 H), 3.76 (s, 3 H), 3.60 (m, 1 H) and 1.35 (d,
6 H). ##STR216## 998 N-{1-[3-(3- Chlorophenyl)- 1,2,4-oxadiazol-
5-yl]-ethyl}-N- cyclopropyl-4- methyl-5- pyridin-4-yl-4 H-
1,2,4-triazol-3- amine 8.80 (d, 2 H), 8.09 (s, 1 H), 7.99 (d, 1 H),
7.68 (d, 2 H), 7.52 (d, 1 H), 7.47 (t, 1 H), 4.92 (q, 1 H), 3.71
(s, 3 H), 3.07 (m, 1 H), 1.87 # (d, 3 H), 0.73 (m, 2 H), 0.55 (m, 1
H) and 0.42 (m, 1 H). ##STR217## 999 {1-[3-(3-Chloro- phenyl)-
[1,2,4]oxadiazol- 5-yl]ethyl}- methyl-(4- methyl-5- pyridin-4-yl- 4
H- [1,2,4]triazol-3- yl)-amine 8.79 (d, 2 H), 8.12 (s, 1 H), 8.02
(d, 1 H), 7.67 (d, 2 H), 7.5 (d, 1 H), 7.4 (t, 1 H), 5.06 (q, 1 H),
3.73 (s, 3 H), 3.04 (s, 3 H), 1.87 (d, 3 H). ##STR218## 1000
[5-(3-Chloro- phenyl)- isoxazol-3- ylmethyl]- methyl-(4- methyl-5-
pyridin-4-yl-4 H- [1,2,4]triazol-3- yl)-amine .sup.1H NMR
(CDCl.sub.3) d (ppm): 8.79 (d, 2 H), 7.79 (m, 1 H), 7.66 (m, 3 H),
7.42 (m, 2 H), 6.83 (s, 1 H), 4.59 (s, 2 H), 3.69 (s, 3 H), 3.00
(s, 3 H). ##STR219## 1001 N-{[5-(3- chlorophenyl)- 1,2,4-oxadiazol-
3-yl]methyl}-4- cyclopropyl-N- methyl-5- pyridin-4-yl-4 H-
1,2,4-triazol-3- amine
Example 1002
N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]-1-methylethyl}-N,4-dimethyl-
-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine
[1779] ##STR220##
[1780] n-BuLi (132 ml 2.5 M in hex., 0.33 mmol) was added to
diisopropyl amine (55 ml, 0.39 mmol). After stirring for 20 minutes
at 0.degree. C. the mixture was cooled to -78.degree. C. and
N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyrid-
in-4-yl-4H-1,2,4-triazol-3-amine (110 mg, 0.28 mmol) was added.
After 15 min. methyl iodide (20 VI, 0.33 mmol) was added and the
temperature was raised to r.t. After stirring for 2 h five drops of
water were added. After solvent removal in vacuo, the crude was
taken up in DCM, washed with water and brine, dried and
concentrated. The desired product was obtained by prep. HPLC in 20
mg yield. .sup.1H NMR: 1.7 (s, 6H) 2.8 (s, 3H) 3.8 (s, 3H) 7.5 (t,
1H) 7.6 (d, 1H) 7.7 (s, 2H) 8.0 (d, 1H) 8.1 (s, 1H) 8.8 (s, 2H)
Example 1003
4-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]-1-methylethoxy}-4-methyl-
-4H-1,2,4-triazol-3-yl)pyridine
[1781] ##STR221##
[1782] To a solution of diisopropylamine (55.0 ml, 0.39 mmol) in
THF (3 ml) at 0.degree. C. was added nBuLi (2.5M, hex., 135 ml)
slowly. After 20 minutes the mixture was cooled to -78.degree. C.
and
(-)-4-(5-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methy-
l-4H-1,2,4-triazol-3-yl)pyridine (107 mg, 0.28 mmol) in THF (2 ml)
was added. The resulting mixture was stirred for 45 minutes before
CH.sub.3I (22 ml, 0.34 mmol) was added and the reaction mixture was
stirred for 1 h at r.t. Sat. NH.sub.4Cl solution was added and the
mixture was extracted with EA. The organic phase was washed with
H.sub.2O and brine, dried and evaporated. Purification of the
residue by silica gel chromatography using CHCl.sub.3:MeOH 50:1
followed by prep. HPLC gave the title compound (22 mg, 20%).
.sup.1H-NMR: 2.11 (s, 6H) 3.63 (s, 3H) 7.45 (d, 1H) 7.52-7.57 (m,
1H) 7.59 (d, 2H) 7.98 (d, 1H) 8.09 (s, 1H) 8.72 (d, 2H)
Example 1004
N-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-4-methyl-5-pyrid-
in-4-yl-4H-1,2,4-triazol-3-amine
[1783] ##STR222##
[1784]
N-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dime-
thyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine (3.1 mg, 7.8 mmol) was
incubated with human microsome protein (from individual with 70%
3A4) in 50% acetonitrile phosphate buffered at pH 7.4 for 3 h and
then concentrated under reduced pressure. The mixture was extracted
CHCl.sub.3. The organic extract was dried and concentrated.
Purification by prep. HPLC afforded 0.5 mg (16%) of the title
compound. .sup.1H NMR: 1.77-1.83 (d, 3H) 3.60 (s, 3H) 5.38-5.48 (m,
1H) 7.48 (m, 1H) 7.54-7.62 (m, 2H) 8.01 (m, 1H) 8.12 (m, 1H) 8.74
(s, 2H).
Example 1005
5-(3-chlorophenyl)-N-methyl-N-[(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-
-yl)methyl]-1,2,4-oxadiazol-3-amine
[1785] ##STR223##
[1786] NaH (7.0 mg, 0.35 mmol) was added to a solution of
5-(3-chlorophenyl)-N-methyl-1,2,4-oxadiazol-3-amine (60 mg, 0.29
mmol) in DMF (3 ml) at r.t. After 5 min
4-[5-(chloromethyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (60 mg,
0.29 mmol) dissolved in DMF (3 ml) was added. The reaction mixture
was stirred for 4 h at r.t. Aq. sat. NH.sub.4Cl was added and the
mixture was extracted with EA. The organic phase was washed with
water and brine, dried and concentrated. Flash chromatography
(DCM/MeOH 20:1) afforded 60 mg (54%) of the title compound. .sup.1H
NMR: 3.12 (s, 3H) 3.80 (s, 3H) 4.94 (s, 2H) 7.46 (t, 1H) 7.56 (m,
1H) 7.58-7.63 (m, 2H) 7.95 (m, 1H) 8.06 (t, 1H) 8.79 (m, 2H).
Example 1006
5-(3-chlorophenyl)-N-ethyl-N-[(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3--
yl)methyl]-1,2,4-oxadiazol-3-amine
[1787] ##STR224##
[1788] The title compound was prepared analogous to
5-(3-chlorophenyl)-N-methyl-N-[(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol--
3-yl)methyl]-1,2,4-oxadiazol-3-amine. .sup.1H NMR: 1.21 (t, 3H)
3.53 (q, 2H) 3.78 (s, 3H) 4.95 (s, 2H) 7.46 (d, 1H) 7.53 (d, 1H)
7.59 (m, 2H) 7.95 (m, 1H) 8.05 (m, 1H) 8.77 (d, 2H).
Example 1007
Ethyl
3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-ca-
rboxylate
[1789] ##STR225##
[1790] The title compound was prepared analogous to
3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole from
ethyl 2-oxopiperidine-3-carboxylate (2.57 g, 15 mmol),
Me.sub.3OBF.sub.4 (2.66 g, 18 mmol) and isonicotinic hydrazide
(2.06 g, 15 mmol) in DCM (150 ml) and EtOH (16 ml).
Recrystallization from EA afforded 1.67 g (41%). .sup.1H NMR: 1.29
(t, 3H), 2.03 (m, 1H), 2.14-2.25 (m, 2H), 2.32 (m, 1H), 4.01-4.12
(m, 1H), 4.16-4.27 (m, 4H), 7.64 (d, 2H), 8.74 (d, 2H)
Example 1008
3-(1-chloroethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole
[1791] ##STR226##
[1792] 5 drops of DMF was added to
1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethanol (12.3 g, 54.9
mmol) in SOCl.sub.2 (150 mL) and the reaction was heated at
70.degree. C. for 5 h. The excess SOCl.sub.2 was evaporated and the
residue was purified by column chromatography (Hep to Hep-EA 5:1)
to give 12.4 g (93%) of the title compound. .sup.1H NMR: 1.96 (d,
3H) 5.20 (q, 1H) 7.46 (t, 1H) 7.59 (m, 1H) 8.04 (m, 1H) 8.17 (t,
1H)
Example 1009
Ethyl
8-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-yl--
5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate
[1793] ##STR227##
[1794] A solution of ethyl
3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-.alpha.]pyridine-8-c-
arboxylate (182 mg, 0.67 mmol) in DMF (2 ml) was added to a stirred
mixture of NaH (20 mg, 0.81 mmol) in DMF (2 ml). After 45 min a
solution of 3-(1-chloroethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole
(180 mg, 0.74 mmol) in DMF (1 ml) was added and the resulting
solution was stirred at 65.degree. C. for 3 h and then cooled to
r.t. Aq. sat. NH.sub.4Cl solution was added and the mixture was
extracted with EA. The organic phase was washed with water and
brine, dried and concentrated. Column chromatography (DCM/MeOH
20:1) gave 207 mg (65%) of the title compound as a diastereomeric
mixture. .sup.1H NMR: 1.27 (t, 3H), 1.34 (t, 3H), 1.48 (d, 3H),
1.55 (d, 3H), 2.15 (m, 2H), 2.18 (m, 4H), 2.61 (m, 2H), 4.00 (m,
2H), 4.18-4.29 (m, 4H), 4.30-4.40 (m, 2H), 4.55 (q, 1H), 4.65 (q,
1H), 7.37 (t, 1H), 7.44 (t, 1H), 7.50 (m, 1H), 7.55 (m, 1H), 7.63
(d, 2H), 7.69 (d, 2H), 7.83 (m, 1H), 7.92 (m, 1H), 7.95 (m, 1H),
8.05 (m, 1H), 8.75 (d, 2H), 8.76 (d, 2H)
Pharmaceutical Examples
[1795] FLIPR Assay of Group I Receptor Antagonist Activity
[1796] For FLIPR analysis, cells were seeded on collagen coated
clear bottom 96-well plates with black sides and analysis of
[Ca.sup.2+].sub.i mobilization was performed 24 hours following
seeding. Cell cultures in the 96-well plates were loaded with a 4
.mu.M solution of acetoxymethyl ester form of the fluorescent
calcium indicator fluor-3 (Molecular Probes, Eugene, Oreg.) in
0.01% pluronic. All assays were performed in a buffer containing
127 mM NaCl, 5 mM KCl, 2 mM MgCl.sub.2, 0.7 mM NaH.sub.2PO.sub.4, 2
mM CaCl.sub.2, 0.422 mg/ml NaHCO.sub.3, 2.4 mg/ml HEPES, 1.8 mg/ml
glucose and 1 mg/ml BSA Fraction IV (pH 7.4).
[1797] FLIPR experiments were done using a laser setting of 0.800 W
and a 0.4 second CCD camera shutter speed with excitation and
emission wavelengths of 488 nm and 562 nm, respectively. Each FLIPR
experiment was initiated with 160 .mu.L of buffer present in each
well of the cell plate. A 40 .mu.L addition from the antagonist
plate was followed by a 50 .mu.L addition from the agonist plate.
After each addition the fluorescence signal was sampled 50 times at
1 second intervals followed by 3 samples at 5 second intervals.
Responses were measured as the peak height of the response within
the sample period.
[1798] EC.sub.50/IC.sub.50 determinations were made from data
obtained from 8 point concentration response curves (CRC) performed
in duplicate. Agonist CRC were generated by scaling all responses
to the maximal response observed for the plate. Antagonist block of
the agonist challenge was normalized to the average response of the
agonist challenge in 14 control wells on the same plate.
[1799] Measurement of Inositol Phosphate (IP3) Turnover in Intact
Whole Cells
[1800] GHEK stably expressing the human mGluR5d receptor were
seeded onto 24 well poly-L-lysine coated plates at
40.times.10.sup.4 cells/well in media containing 1 .mu.Ci/well [3H]
myo-inositol. Cells were incubated overnight (16 h), then washed
three times and incubated for 1 hour at 37.degree. C. in HEPES
buffered saline (146 mM NaCl, 4.2 mM KCl, 0.5 mM MgCl.sub.2, 0.1%
glucose, 20 mM HEPES, pH 7.4) supplemented with 1 unit/ml glutamate
pyruvate transaminase and 2 mM pyruvate. Cells were washed once in
HEPES buffered saline and pre-incubated for 10 minutes in HEPES
buffered saline containing 10 mM LiCl. Compounds (agonists) were
added and incubated at 37.degree. C. for 30 minutes. Antagonist
activity was determined by pre-incubating test compounds for 15
minutes, then incubating in the presence of glutamate (80 .mu.M) or
DHPG (30 .mu.M) for 30 minutes. The reaction was terminated by the
addition of 0.5 ml perchloric acid (5%) on ice, with incubation at
4.degree. C. for at least 30 minutes. Samples were collected in 15
ml Falcon tubes and inositol phosphates were separated using Dowex
columns, as described below.
[1801] Assay for Inositol Phosphates Using Gravity-Fed Ion-Exchange
Columns
[1802] Preparation of Ion-Exchange Columns
[1803] Ion-exchange resin (Dowex AG1-X8 formate form, 200-400 mesh,
BIORAD) was washed three times with distilled water and stored at
4.degree. C. 1.6 ml resin was added to each column and washed with
3 ml 2.5 mM HEPES, 0.5 mM EDTA, pH 7.4.
[1804] Sample Treatment
[1805] Samples were collected in 15 ml Falcon tubes and neutralized
with 0.375 M HEPES, 0.75 M KOH. 4 ml of HEPES/EDTA (2.5/0.5 mM, pH
7.4) were added to precipitate the potassium perchlorate.
Supernatant was added to the prepared Dowex columns.
[1806] Inositol Phosphate Separation
[1807] Elute glycero phosphatidyl inositols with 8 ml 30 mM
ammonium formate.
[1808] Elute total inositol phosphates with 8 ml 700 mM ammonium
formate/100 mM formic acid and collect eluate in scintillation
vials. Count eluate mixed with 8 ml scintillant.
[1809] Screening for Compounds Active Against TLESR
[1810] Adult Labrador retrievers of both genders, trained to stand
in a Pavlov sling, are used. Mucosa-to-skin esophagostomies are
formed and the dogs are allowed to recover completely before any
experiments are done.
[1811] Motility Measurement
[1812] In brief, after fasting for approximately 17 h with free
supply of water, a multilumen sleeve/sidehole assembly (Dentsleeve,
Adelaide, South Australia) is introduced through the esophagostomy
to measure gastric, lower esophageal sphincter (LES) and esophageal
pressures. The assembly is perfused with water using a
low-compliance manometric perfusion pump (Dentsleeve, Adelaide,
South Australia). An air-perfused tube is passed in the oral
direction to measure swallows, and an antimony electrode monitored
pH, 3 cm above the LES. All signals are amplified and acquired on a
personal computer at 10 Hz.
[1813] When a baseline measurement free from fasting gastric/LES
phase III motor activity has been obtained, placebo (0.9% NaCl) or
test compound is administered intravenously (i.v., 0.5 ml/kg) in a
foreleg vein. Ten min after i.v. administration, a nutrient meal
(10% peptone, 5% D-glucose, 5% Intralipid, pH 3.0) is infused into
the stomach through the central lumen of the assembly at 100 ml/min
to a final volume of 30 ml/kg. The infusion of the nutrient meal is
followed by air infusion at a rate of 500 ml/min until an
intragastric pressure of 10.+-.1 mmHg is obtained. The pressure is
then maintained at this level throughout the experiment using the
infusion pump for further air infusion or for venting air from the
stomach. The experimental time from start of nutrient infusion to
end of air insufflation is 45 min. The procedure has been validated
as a reliable means of triggering TLESRs.
[1814] TLESRs is defined as a decrease in lower esophageal
sphincter pressure (with reference to intragastric pressure) at a
rate of >1 mmHg/s. The relaxation should not be preceded by a
pharyngeal signal .ltoreq.2s before its onset in which case the
relaxation is classified as swallow-induced. The pressure
difference between the LES and the stomach should be less than 2
mmHg, and the duration of the complete relaxation longer than 1
s.
[1815] Abbreviations
[1816] BSA Bovine Serum Albumin
[1817] CCD Charge Coupled Device
[1818] CRC Concentration Response Curve
[1819] DHPG 3,5-dihydroxyphenylglycine;
[1820] EDTA Ethylene Diamine Tetraacetic Acid
[1821] FLIPR Fluorometric Imaging Plate reader
[1822] GHEK GLAST-containing Human Embrionic Kidney
[1823] GLAST glutamate/aspartate transporter
[1824] HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
(buffer)
[1825] IP.sub.3 inositol triphosphate
[1826] Results
[1827] Typical IC.sub.50 values as measured in the assays described
above are 10 .mu.M or less. In one aspect of the invention the
IC.sub.50 is below 2 .mu.M. In another aspect of the invention the
IC.sub.50 is below 0.2 .mu.M. In a further aspect of the invention
the IC.sub.50 is below 0.05 .mu.M.
* * * * *