WO2004014881A2 - '1,2,4'oxadiazoles as modulators of metabotropic glutamate receptor-5 - Google Patents

'1,2,4'oxadiazoles as modulators of metabotropic glutamate receptor-5 Download PDF

Info

Publication number
WO2004014881A2
WO2004014881A2 PCT/US2003/024846 US0324846W WO2004014881A2 WO 2004014881 A2 WO2004014881 A2 WO 2004014881A2 US 0324846 W US0324846 W US 0324846W WO 2004014881 A2 WO2004014881 A2 WO 2004014881A2
Authority
WO
WIPO (PCT)
Prior art keywords
triazol
phenyl
methyl
chloro
oxadiazol
Prior art date
Application number
PCT/US2003/024846
Other languages
French (fr)
Other versions
WO2004014881A3 (en
WO2004014881B1 (en
Inventor
David Wensbo
Tao Xin
Tomislav Stefanac
Jalaj Arora
Louise Edwards
Methvin Isaac
Abdelmalik Slassi
Thomas M. Stormann
Donald A. Mcleod
Annika Kers
Johan Malmberg
Karin Oscarsson
Helena Gyback
Martin Johansson
Alexander Minidis
Magnus Waldman
Ulrika Yngve
Christoffer Osterwall
Original Assignee
Astra Zeneca Ab
Nps Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to MXPA05001594A priority Critical patent/MXPA05001594A/en
Application filed by Astra Zeneca Ab, Nps Pharmaceuticals, Inc. filed Critical Astra Zeneca Ab
Priority to BR0313265-0A priority patent/BR0313265A/en
Priority to NZ538225A priority patent/NZ538225A/en
Priority to IL16651003A priority patent/IL166510A0/en
Priority to EP03785036A priority patent/EP1529045A2/en
Priority to CA2494987A priority patent/CA2494987C/en
Priority to AU2003259068A priority patent/AU2003259068B2/en
Priority to JP2004527872A priority patent/JP4637578B2/en
Publication of WO2004014881A2 publication Critical patent/WO2004014881A2/en
Publication of WO2004014881A3 publication Critical patent/WO2004014881A3/en
Publication of WO2004014881B1 publication Critical patent/WO2004014881B1/en
Priority to NO20051225A priority patent/NO20051225L/en
Priority to IS7733A priority patent/IS7733A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • 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.
  • 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 ionofropic and metabofropic glutamate receptors, based on the stractural features ofthe receptor proteins, the means by which the receptors transduce signals into the cell, and pharmacological profiles.
  • the metabofropic glutamate receptors 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 ofthe 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 2 ; increases in arachidonic acid release; and increases or decreases in the activity of voltage- and ligand- gated ion channels.
  • PI phosphoinositide
  • mGluRl through n ⁇ GluR8.
  • Nakanishi Neuron 13:1031 (1994)
  • Pin et al Neuropharmacology 34:1 (1995)
  • Knopfel et al J. Med. Chem. 38:1411 (1995).
  • Further receptor diversity occurs via expression of alternatively spliced forms of certain mGluR subtypes. Pin et al, PNAS ⁇ °P:10331 (1992), Minakami et al, BBRC 199:1136 (1994), Joly et al, J. Neurosci. 15:3910 (1995).
  • Metabofropic glutamate receptor subtypes may be subdivided into three groups, Group I, Group II, and Group ILT mGluRs, based on amino acid sequence homology, the second messenger systems utilized by the receptors, and by their pharmacological characteristics.
  • Group I mGluR comprises mGluRl, 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.
  • Group I mGluRs 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.
  • mGluR activation has been demonsfrated, Meller et al, Neuroreport 4: 879 (1993), Bordi and Ugolini, Brain Res. 871:223 (1999).
  • 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 ofthe vestibulo-ocular reflex. Nakanishi, Neuron 13: 1031 (1994), Pin et al, Neuropharmacology 34:1, Knopfel et al, J. Med. Chem.
  • Group I metabofropic 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), Holhnan et al, Ann. Rev. Neurosci. 17:31 (1994), Pin et al, Neuropharmacology 34:1 (1995), Knopfel et al, J. Med. Chem.
  • 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.
  • the object ofthe present invention is to provide compounds exliibiting an activity at metabofropic glutamate receptors (mGluRs), especially at the mGluR5 receptor.
  • mGluRs metabofropic glutamate receptors
  • the present invention provides a compound of formula la
  • P is selected from the group consisting of hydrogen, C 3 . 7 alkyl 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;
  • R 1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, OC 2-6 alkenyl, C -6 alkynyl, OC 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, OCo -6 alkylC 3-6 cycloalkyl, Co -6 alkylaryl, OC 0-6 alkylaryl, CHO,
  • M 1 is selected from the group consisting of a bond, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 0- 4 alkyl(CO)C 0- 4alkyl, Co-salkylOCo-salkyl, C 0-3 alkyl(CO)NR 5 , Co-3alkyl(CO)NR 5 C 0-3 alkyl, C 0 -4alkylNR 5 , Co -3 alkylSCo -3 alkyl, C 0-3 alkyl(SO)C 0-3 alkyl or Co -3 alkyl(SO 2 )C 0 - 3 alkyl;
  • X 1 , X 2 and X 3 are independently selected from the group consisting of CR, CO, N, NR, O and S;
  • R is selected from the group consisting of hydrogen, C 0 - 3 alkyl, halo, C 0-3 alkylOR , C 0- 3 alkylNR 5 R 6 , C 0-3 alkyl(CO)OR 5 , C 0-3 all ylNR 5 R 6 and C 0-3 alkylaryl;
  • M 2 is selected from a group consisting of a bond, C1. 3 alkyl, C -7 cycloalkyl, C 2-3 alkenyl, C 2- 3 alkynyl, C 0-4 alkyl(CO)C 0-4 alkyl, QwalkylOQwalkyl, C 0-3 alkylNR 5 C 1-3 alkyl, C 0 .
  • 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;
  • R and R are independently selected from the group consisting of hydrogen, hydroxy, Ci. 6 alkyl, Co -6 allcylC 3-6 cycloalkyl, C 0-6 alkylaryl, Co -6 alkylheteroaryl and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S, and wherein R 5 and R 6 may together form a 5- or 6-membered ring containing one or more atoms independently selected from the goup consisting of C, N, O and S; wherein any C 1-6 alkyl, C 2-6 alkenyl, C -6 alkynyl, Co -6 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl and C 0 . 6 alkylheteroaryl defined under R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be substituted by one or more A;
  • A is selected from the group consisting of hydrogen, hydroxy, oxo, halo, nitro, Co- 6 alkylcyano, C 1-4 alkyl, C 0- alkylC 3-6 cycloalkyl, C ⁇ . 6 alkylhalo, OC 1-6 alkylhalo, C 2-6 alkenyl, OC 1-6 alkyl, Co- 3 a ⁇ kylaryl, C 0-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 1-6 alkylSR 5 , OC 2-6 alkylSR 5 , (CO)R 5 , O(CO)R 5 , OC 2-6 alkylcyano, C 0-6 alkylCO 2 R 5 , OC 1-6 alkylCO 2 R 5 , O(CO)OR 5 , O . 6 alkyl(CO)R 5 , C 1-6 alkyl(CO)R 5 , NR 5 OR 6 , C 0-6 alkylNR 5 R 6 ,
  • OC 2-6 alkyl(SO 2 )NR 5 R 6 C 0-6 alkylNR 5 (SO 2 )R 6 , OC 2-6 alkylNR 5 (SO 2 )R 6 , SO 3 R 5 , C 1-6 alkylNR 5 (SO 2 )NR 5 R 6 , OC 2-6 alkyl(SO 2 )R 5 , C 0-6 alkyl(SO 2 )R 5 , C 0-6 alkyl(SO)R 5 , OC 2-6 alkyl(SO)R 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; m is selected from 0, 1, 2, 3 and 4; and n is selected from 0, 1, 2 and 3, or salt thereof.
  • the present invention provides a compound of formula I
  • P is selected from the group consisting of thiophene, pyridyl, thiazolyl, fxrryl, pyrrolyl and phenyl, whereby the phenyl ring is substituted on position 3 or disubstituted on positions 2 and 5;
  • R 1 is attached to P via a carbon atom on ring P and is selected from the group consisting of hydrogen, hydroxy, halo, nitro, Cj . .
  • R is selected from the group consisting of hydrogen, C 0-3 alkyl, halo, Co- 3 alkylOR 5 , C 0- 3 alkylNR 5 R 6 , C 0-3 alkyl(CO)OR 5 and Co -3 alkylaryl;
  • M 2 is selected from a group consisting of a bond, C 1-3 alkyl, C 2-3 alkynyl, C 0- alkyl(CO)Co- 4 alkyl, C 0-3 alkylOC 0- 3alkyl, C 0 . 3 alkylNR 5 C 1-3 alkyl, Co-3alkyl(CO)NR 5 , Co ⁇ alkylNR 5 , C 0- 3 alkyl(SO)C 0-3 alkyl and Co -3 alkyl(SO 2 )C 0-3 alkyl;
  • X 4 is selected from the group consisting of C 0-4 alkylR 5 R 6 , C 3-7 cycloalkyl, Ci.
  • R 4 alkylOR 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; or ii) selected from the group consisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tefrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl; and R 4 is selected from
  • R 5 and R 6 are independently selected from the group consisting of hydrogen and C 1-6 alkyl; wherein any C 1-6 alkyl defined under R 1 , R 2 and R 4 may be substituted by one or more A ;
  • A is selected from the group consisting of hydrogen, hydroxy, halo, nitro, oxo, C 0-
  • C 0-3 alkylaryl C 0-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 1-6 alkylSR 5 , OC 2-6 alkylSR 5 , (CO)R 5 , O(CO)R 5 , OC 2-6 alkylcyano, OC 1-6 alkylCO 2 R 5 , O(CO)OR 5 , OC 1-6 alkyl(CO)R 5 , d
  • the present invention provides a compound of formula lb
  • 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;
  • R 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 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2- ⁇ alkenyl, OC 2-6 alkenyl, C 2-6 alkynyl, OC 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, OC 0-6 alkylC 3- ecycloall yl, C 0 .
  • M 1 is a bond;
  • X 1 selected from the group consisting of C, CO, N, O and S;
  • X 2 is selected from the group consisting of C, N, O and S;
  • X 3 is selected from the group consisting of N, O and S, or X 3 is CH when X 2 is N, O or S;
  • R is selected from the group consisting of hydrogen, Co- 3 alkyl, halo, Co- 3 alkylOR 5 , C 0-
  • M 2 is selected from a group consisting of a bond, d ⁇ alkyl, C 2-3 alkynyl, Co -4 alkyl(CO)C 0-
  • X 4 is selected from the group consisting of Co- alkylR 5 R 6 , C 3-7 cycloalkyl, Cj . .
  • R 5 and R 6 are independently selected from the group consisting of hydrogen and C 1-6 alkyl; wherein any C 1-6 alkyl defined under R 1 , R 2 and R 4 may be substituted by one or more A ;
  • A is selected from the group consisting of hydrogen, hydroxy, halo, nitro, oxo, C 0-
  • compositions comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • alkyl includes both sfraight and branched chain alkyl groups and may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl, t-hexyl.
  • Ci ⁇ alkyl refers to an alkyl group having 1, 2 or 3 carbon atoms, and may be methyl, ethyl, n-propyl and i-propyl.
  • cycloalkyl refers to an optionally substituted, saturated cyclic hydrocarbon ring system.
  • C 3-7 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • alkenyl includes both straight and branched chain alkenyl groups.
  • C 2 - 6 alkenyl 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.
  • alkynyl includes both sfraight and branched chain alkynyl groups.
  • 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.
  • heteroaryl refers to an optionally substituted monocyclic or bicyclic unsaturated, aromatic ring system containing at least one heteroatom selected independently from N, O or S.
  • heteroaryl may be, but are not limited to thiophene, thienyl, pyridyl, thiazolyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tefrazolyl and thiadiazolyl, benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, benzofuryl, indolyl, isoindolyl, pyr
  • alkylaryl refers to a substituent that is attached via the alkyl group to an aryl, heteroaryl and cycloalkyl group.
  • 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.
  • 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.
  • 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.
  • rings may be, but are not limited to imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tefrahydropyranyl or thiomorpholinyl, tetrahydrothiopyranyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, oxazolyl, oxazolidinonyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, triazolyl, phenyl, cyclopropyl, aziridinyl, cyclobutyl, azetidinyl, cyclobut
  • 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.
  • 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.
  • 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.
  • halo may be fluoro, chloro, bromo or iodo.
  • alkylhalo means an alkyl group as defined above, substituted with one or more halo.
  • C 1-6 alkylhalo may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyi, fluoroethyl, difluoroethyl and bromopropyl.
  • OC 1-6 alkylhalo may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy and difluoroethoxy.
  • P may be hydrogen or C 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.
  • P is selected from 5 and 6 membered aromatic and heteroaromatic rings.
  • 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.
  • P is phenyl substituted on position 3 or disubstituted on positions 2 and 5.
  • P is optionally substituted via a carbon atom with 0, 1, 2, 3 or 4 groups R 1 , wherein the number of R 1 substituents on the P ring is designated by the term ml.
  • ml is 1 or 2. In further preferred embodiments ofthe invention ml is 1.
  • R 1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, OC 2- 6 alkenyl, C 2-6 alkynyl, OC 2-6 alkynyl, C 0-6 alkylC 3-6 cycloalkyl, OC 0-6 alkylC 3-6 cycloalkyl, C 0- 6 alkylaryl, OCo-ealkylaryl, CHO, (CO)R 5 , O(CO)R 5 , O(CO)OR 5 , O(CN)OR 5 , C 1-6 alkylOR 5 , OC 2-6 alkylOR 5 , C 1-6 alkyl(CO)R 5 , OC 1-6 alkyl(CO)R 5 , C 0-6 alkylCO 2 R 5 , OC 1-6 alkylCO 2 R 5 ,
  • R 1 is selected from hydrogen, hydroxy, halo, nitro, C ⁇ -6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, Co- 6 alkylC 3- ⁇ cycloalkyl, C 1-6 alkylOR 5 , C 1-6 alkyl(CO)R 5 , C 0-6 alkylCO 2 R 5 , C 0-6 alkylcyano, C 0-
  • R 1 is ethyl and A is hydroxyl.
  • R 1 is selected from hydrogen, methyl, ethyl, cyclopropyl, hydroxy, methoxy, cyano, flouro, chloro, bromo, iodo, trifluoromethyi, difluoromethoxy, trifluoromethoxy, amino, nitro, dirnethylamino, methylsulfanyl, vinyl, acetyl, formic acid methyl ester, methoxymethyl, ethanol and furyl.
  • 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 1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl,
  • OC 1-6 alkyl C 2-6 alkenyl, C 0-6 alkylC 3-6 cycloalkyl, C 1-6 alkylOR 5 , C 1-6 alkyl(CO)R 5 , C 0- 6 alkylCO 2 R 5 , Co-ealkylcyano, C 0-6 alkylNR 5 R 6 , C 0-6 alkylSR 5 and a 5-membered ring containing one or more atoms independently selected from the group consisting of C and O.
  • P is phenyl substituted on position 3 or disubstituted on positions 2 and 5 and R 1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2- 6 alkenyl, C 0-6 alkylC 3-6 cycloalkyl, C 1-6 alkylOR 5 , C 1-6 alkyl(CO)R 5 , Co -6 alkylCO 2 R 5 , C 0- 6 alkylcyano, Co -6 alkylNR 5 R 6 , Co- ⁇ alkylSR 5 and a 5-membered ring containing one or more atoms independently selected from the group consisting of C and O.
  • the ring P is connected to the core ring by M 1 , wherein M 1 can be a bond directly joining P to the core ring.
  • M 1 can also be a linker Ci. 3 alkyl.
  • M 1 is a bond.
  • M 1 can be further substituted with 0, 1, 2 or 3 substituents R 2 wherein the number of substituents R is designated by the term n.
  • the substituents R may be selected from hydrogen, hydroxy, oxo, C 1-4 alkylhalo, halo and C 1- alkyl.
  • n is 0.
  • X 1 is selected from the group consisting of C, CO, N, O and S.
  • X 2 is selected from the group consisting of C, N, O and S.
  • X 3 is selected from the group consisting of N, O and S, or X 3 is selected from N, O, S, and C when X 2 is selected from N, O, or S, and when X 3 is C the substituent R on X 3 is H.
  • X 1 , X 2 and X 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 0-3 alkyl, halo, Co- 3 alkylOR , Co- 3 alkylNR R , C 0-
  • R is selected from the group consisting of hydrogen, C 0-3 alkyl and halo.
  • X 1 is C, N or O and R is selected from hydrogen, Co- 3 alkyl and halo.
  • R is selected from hydrogen, chloro or methyl.
  • X 1 is N.
  • X 2 is selected from N, O and S, and R is hydrogen.
  • X is N, O or S.
  • X 1 is O and one of X 2 and X 3 is O and the other is N.
  • X 1 is N and one of X 2 and X 3 is O and the other is N.
  • X 1 is C or CR and one of X 2 and X 3 is O and the other is N.
  • X 2 is O and X 3 is N
  • X 2 is N and X 3 is O
  • X 1 is O and X 2 and X 3 are N.
  • the ring containing X , X 2 and X 3 forms an oxadiazole, isoxazole, oxazole, chloro-isoxazole or a methyl-isoxazole.
  • the ring containing X , X and X forms an oxadiazole.
  • the ring contaimng X , X and X 3 forms an isoxazole.
  • the ring containing X 1 , X 2 and X 3 should not be further annulated onto any other ring.
  • M 2 may be a direct bond from the core ring to the variable X 4 or M 2 may be selected from the group consisting of bond, C ⁇ -3 alkyl, C 2- 3 alkynyl, C 0-4 alkyl(CO)C 0- 4all yl C 0- 3alkylOC 0- 3 alkyl, C 0-3 alkylNR 5 C 1-3 alkyl, C 0- 3 alkyl(CO)NR 5 , C 0-4 alkylNR 5 , C 0-3 alkyl(SO)Co -3 alkyl and Co -3 alkyl(SO 2 )C 0-3 alkyl.
  • M is a bond or C ⁇ aUcyl.
  • M 2 is C 1-3 alkyl, preferably methyl or ethyl.
  • M 2 When M 2 is not a direct bond M 2 may be further substituted with 0, 1 or 2 R 3 groups wherein the number of substituents R 3 is designated by the term n. In one embodiment of the invention n is 1 or 2. In another embodiment ofthe invention n is 0.
  • R 3 is selected from hydrogen and C 1-4 alkyl, preferably methyl or dimethyl.
  • M 2 may be selected from the group consisting of a bond, C 1-3 alkyl, C 2-3 alkynyl, C 0-4 alkyl(CO)C 0- alkyl, Co -3 alkylOCo -3 alkyl, C 0-3 alkylNR 5 C 1 _ 3 alkyl,
  • R 3 is selected from hydrogen and C 1-4 alkyl.
  • M 2 is a bond or C 1-3 alkyl and R 3 is hydrogen, methyl or dimethyl.
  • M 2 may be selected from the group consisting of a bond, methyl and ethyl and R 3 is hydrogen, methyl or dimethyl.
  • M 2 is nifrogen.
  • M 2 is oxygen.
  • X A is selected from the group consisting of C 0- 4 alkylR 5 R 6 , C 3-7 cycloalkyl, NR 5 , O, SO, SO 2 and S and R 5 and R 6 are independently selected from hydrogen and C 1-6 alkyl.
  • X 4 is selected from the group consisting of CH 2 , CHCH 3 , CH(CH 3 ) 2 and NR 5 .
  • X 4 is NR 5 and R 5 is selected from hydrogen and C 1-6 alkyl.
  • R is methyl or hydrogen and R is hydrogen.
  • X 4 is O.
  • X is S.
  • Embodiments ofthe present invention include those wherein Q is a 5- or 6-membered ring.
  • Q is selected from the group consisting ofthe 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 4 on such nitrogen atom.
  • 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.
  • Q is selected from the group consisting of benzoimidazolyl, benzooxazolyl, tefrahydrotriazolopyridyl, tetrahydrofriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl.
  • the 6 membered ring Q is selected from the group consisting of pyridonyl, tetrahydrotriazolopyridyl and tetrahydrotriazolopyrimidinyl.
  • the 6 membered ring Q is pyridazinyl.
  • the 6 membered ring Q is selected from the group consisting of benzoimidazolyl, benzooxazolyl and imidazopyridyl.
  • Q can be further substituted with 0, 1, 2 or 3 substituents R 4 , wherein the number of R 4 substituents is designated by the term m2.
  • m2 is 1 or 2.
  • R 4 on the 5 membered Q ring is selected from the group consisting of C 1-4 alkylhalo, C 1-6 alkyl, C 2-4 alkenyl, C 0-2 alkylC 3-6 cycloalkyl, C 0- 6 alkylaryl, Co -6 alkylheteroaryl, OC 0-6 alkylaryl, OC 0-6 alkylheteroaryl, NCo -6 alkylaryl, NC 0- 6 alkylheteroaryl, Co -6 alkylOaryl, Co- 6 alkylOheteroaryl, C 0-6 alkylNaryl, C 0- 6 alkylNheteroaryl, OC 0-6 alkylOaryl, OCo -6 alkylOheteroaryl, OC 0-6 alkylNaryl, OC 0- 6 alkylNheteroaryl, NC 0-6 alkylOaryl, NC 0-6 alkylNaryl, OC
  • 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 4 on such nitrogen atom and R is selected from the group consisting of C 1-4 alkylhalo, C 1- alkyl, C 2- alkenyl, C 0-2 alkylC 3-6 cycloalkyl, C 0-6 alkylaryl, C 0-6 alkylheteroaryl, OCo- 6 alkylaryl, OC 0- 6 alkylheteroaryl, NCo- 6 alkylaryl, NCo -6 alkylheteroaryl,Co -6 alkylOaryl, C 0-
  • 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 4 on such nitrogen atom and R 4 is selected from the group consisting of C 1- alkylhalo, C 1-6 alkyl, C 2-4 alkenyl, Co- alkylC 3-6 cycloalkyl, C 0- 6 alkylaryl, Co-ealkylheteroaryl, OCo- ⁇ alkylaryl, OCo -6 alkylheteroaryl, NC 0-6 alkylaryl, NC 0- 6 alkylheteroaryl,C 0-6 alkylOaryl, C 0-6 alkylOheteroaryl, Co -6 alkylNaryl, C 0 , 6 alkylNheteroaryl, OC 0-6 alkylOaryl, OCo
  • R on the 6 membered Q ring is selected from hydrogen and C 1-6 alkyl.
  • R 4 is hydrogen, methyl, ethyl, propyl, butyl or hexyl.
  • Q selected from the group consisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tefrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl and R 4 is hydrogen or C 1-6 alkyl.
  • Q selected from the group consisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tefrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl and imidazopyridyl, and R 4 is hydrogen or C 1-6 alkyl.
  • R 4 is selected from the group consisting of benzo[b]thiophenyl, benzodioxolyl, bromo, bromofuryl, butoxyphenyl, chloromethoxypyridyl, chlorophenyl, chlorophenyhnethanol, 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, niethoxyphenyl, methoxyphenylethyl, methoxypyridazinyl, methoxypyr
  • Ring Q may be substituted by one or more R 4 on a carbon and/or a nifrogen atom in the ring.
  • R 4 is selected from benzo[b]thiophenyl, benzodioxolyl, bromo, bromofuryl, butoxyphenyl, chloromethoxypyridyl, chlorophenyl, chlorophenyhnethanol, 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, methoxymethyl, methoxymethyl
  • R 4 is selected from acetic acid methylester, allyl, amino, benzyl, cyclopropyl, cyclopropylmethyl, ethyl, floxirobenzyl, fluoroethyl, furylmethyl, hydroxyethyl, isobutyl, methoxyethyl, methyl, methylbenzyl, methylbutyl, methylsulfanylpropyl, n-butyl, n-hexyl, n-propyl, tefrahydrofurylmethyl, thiophenylmethyl and trifluoroethyl.
  • R 4 can be substituted with one or more substituents A, wherein A is selected from hydrogen, hydroxy, halo, nitro, oxo, C 0-6 alkylcyano, Co ⁇ alkyld-ecycloalkyl, C 1-6 alkyl, C 1-6 alkylhalo, OC 1-6 alkylhalo, C 2-6 alkenyl, C 0-3 alkylaryl, Co-ealkylOR 5 , OC 2- 6 alkylOR 5 , d-galkylSR 5 , OC 2-6 alkylSR 5 , (CO)R 5 , O(CO)R 5 , OC 2-6 alkylcyano, Od. 6 alkylCO 2 R 5 , O(CO)OR 5 , OC 1-6 alkyl(CO)R 5 , C 1-6 alkyl(CO)R 5 , NR 5 OR 6 , OC 2-
  • A is selected from hydroxy, halo, nifro, oxo, C 0-6 alkylcyano, d_ 6 alkyl, C 2-6 alkenyl, Co ⁇ alkylaryl, C 0-6 alkylOR 5 and a 5-membered ring containing one or more atoms independently selected from the group consisting of C and O.
  • Specific embodiments ofthe invention include, 2-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole,
  • [ 1 ,2,4]triazol-3 -yl ⁇ -pyrimidine is 3-(4-Ethyl-5-fman-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl- phenyl)-[ 1 ,2,4] oxadiazole,
  • [l,2,4]triazole is 3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(4-methyl-thiophen-2- yl)-[ 1 ,2,4]oxadiazole,
  • [1,2,4] oxadiazole is 5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3-sulfinylmethyl)-
  • P is selected from the group consisting of hydrogen, C 3 - 7 alkyl 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;
  • R 1 is selected from the group consisting of hydrogen, hydroxy, halo, nifro, C ⁇ - 6 alkylhalo, OC 1-6 alkylhalo, C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, OC 2-6 alkenyl, C 2-6 alkynyl, OC 2-6 alkynyl, Co -6 alkylC 3-6 cycloalkyl, OCo-6alkylC 3-6 cycloalkyl, Co- 6 alkylaryl, OC 0 - 6 alkylaryl, CHO, (CO
  • M 1 is selected from the group consisting of a bond, C 2-3 alkenyl, C 2-3 alkynyl, Co- 4 a ⁇ kyl(CO)Co- 4 arkyl, QwalkylOCo-salkyl, Co -3 alkyl(CO)NR 5 , C 0-3 alkyl(CO)NR 5 C 0-3 alkyl, C 0- alkylNR 5 , C 0-3 alkylSC 0-3 alkyl, Co- 3 alkyl(SO)C 0-3 alkyl and Co-salky SO ⁇ Co-salkyl;
  • X 1 , X 2 and X 3 are independently selected from the group consisting of CR, CO, N, NR, O and S;
  • R is selected from the group consisting of hydrogen, Co- 3 alkyl, halo, Co- 3 alky 1OR 5 , Co- 3 alkylNR 5 R 6 , C 0-3 alkyl(CO)OR 5 , C 0-3 alkylNR 5 R 6 and C 0-3 alkylaryl;
  • M 2 is selected from the group consisting of a bond, Ci ⁇ alkyl, C 3- cycloalkyl, C 2-3 alkenyl, ' C 2-3 allcynyl, Co ⁇ alky CO ⁇ o ⁇ alkyl, Co ⁇ alkylOCo ⁇ alkyl, Co- 3 alkylNR 5 C 1 .
  • 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;
  • R 5 and R 6 are independently selected from the group consisting of hydrogen, hydroxy, d- 6 alkyl, Co -6 alkylC 3-6 cycloalkyl, Co -6 alkylaryl, Co -6 alkylheteroaryl and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S, and wherein R and R may together form a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S; wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Co -6 alkylC 3-6 cycloalkyl, Co -6 alkylaryl and Co -6 alkylheteroaryl defined under R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be substituted by one or more A; and A is selected from the group consisting of hydrogen, hydroxy, oxo, halo, nifro,
  • 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 ofthe compounds of formula I and la.
  • 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 th Edition, Mack Publishing Co.).
  • 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.
  • the invention relates to any and all tautomeric forms ofthe compounds of formula I.
  • the invention relates to the following compounds, which may be used as intermediates in the preparation of a compound of formula I; 6-Methylpyridine-4-carboxylic acid,
  • N-Hydroxy-2-methyl-benzamidine N-Hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetamidine,
  • Methanesulfonic acid 5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester Methanesulfonic acid 5-thiophen-3-yl-isoxazol-3-ylmethyl ester, Methanesulfonic acid 5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethyl ester, Methanesulfonic acid 5-phenyl-isoxazol-3-ylmethyl ester, Methanesulfonic acid 5-(3-chloro-phenyl)-4-methyl-isoxazol-3-ylmethyl ester, Methanesulfonic acid 5-(5-chloro-thiophen-3-yl)-isoxazol-3-ylmethyl ester,
  • a pharmaceutical formulation comprising a compound of formula I, or salt thereof, for use in the prevention and/or treatment of metabofropic glutamate receptor subtype 5 receptor (mGluR5) mediated disorders and any disorder listed below.
  • mGluR5 metabofropic glutamate receptor subtype 5 receptor
  • 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, mtravascular or infusion) as a sterile solution, suspension or emulsion, for topical adminisfration as an ointment, patch or cream or for rectal administration as a suppository.
  • parenteral injection including intravenous, subcutaneous, intramuscular, mtravascular or infusion
  • a sterile solution, suspension or emulsion for topical adminisfration as an ointment, patch or cream or for rectal administration as a suppository.
  • compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical diluents and/or inert carriers.
  • a phannaceutical 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.
  • Suitable daily doses ofthe compounds of formula I in the freatment of a mammal, including man are approximately 0.01 to 250 mg/kg bodyweight at peroral adminisfration and about 0.001 to 250 mg/kg bodyweight at parenteral adminisfration.
  • the typical daily dose ofthe active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of adminisfration, the age, weight and sex ofthe patient and may be determined by a physician.
  • the compounds according to the present invention exhibit a high degree of potency and selectivity for individual metabofropic glutamate receptor (mGluR) subtypes.
  • mGluR metabofropic glutamate receptor
  • the compounds according to the present invention that are potent and selective for the mGluR Group I receptor and more particularly for mGluR5.
  • the compounds ofthe 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 n ⁇ GluR5.
  • the compounds may be used to produce an inhibitory effect of mGlxxR Group I, especially mGluR5, in mammals, including man.
  • mGluR5 is highly expressed in the central and peripheral nervous system and in other tissues.
  • the compounds ofthe invention are well suited for the prevention and/or freatment of mGluR5 receptor-mediated disorders such as acute and chronic neurological and psychiatric disorders and chronic and acute pain disorders.
  • Alzheimer's disease senile dementia ALOS-induced dementia
  • Parkinson's disease amyotrophic lateral sclerosis
  • Huntington's Chorea migraine
  • epilepsy schizophrenia, depression, anxiety, acute anxiety, obsessive compulsive disorder
  • ophthalmological 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.
  • 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.
  • Other disorders are stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, cardiovascular diseases and epilepsy.
  • the dose required for the therapeutic or preventive freatment of a particular disorder will necessarily be varied depending on the host treated, the route of administration and the severity ofthe illness being freated.
  • the invention relates to compounds of formula I as defined hereinbefore, for use in therapy.
  • the invention relates to compounds of formula I as defined hereinbefore, for use in prevention and/or treatment of neurological disorders.
  • the invention relates to compounds of formula I as defined hereinbefore, for use in prevention and/or freatment of psychiatric disorders.
  • the invention relates to compounds of formula I as defined hereinbefore, , for use in prevention and/or freatment of chronic and acute pain disorders.
  • the invention relates to compounds of formula I as defined hereinbefore, for use in prevention and/or treatment of mGluR5 receptor-mediated disorders.
  • the invention relates to compounds of formula I as defined hereinbefore, for use in prevention and/or freatment of Alzheimer's disease senile dementia, AIDS-induced dementia, Parkinson's disease, amylofropic lateral sclerosis, Huntington's Chorea, migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, ophthalmological disorders such as retinopathies, diabetic retinopathies, glaucoma, auditory neuropathic disorders such as tinnitus, chemotherapy induced neuropathies, post-he ⁇ etic neuralgia and trigeminal neuralgia, tolerance, dependency, Fragile X, autism, mental retardation, schizophrenia and Down's Syndrome.
  • the invention relates to compounds of formula I as defined hereinbefore, for use in prevention and/or freatment 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.
  • the invention relates to compounds of formula I as defined hereinbefore, for use in prevention and/or freatment of stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, cardiovascular diseases and epilepsy.
  • 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.
  • the invention also provides a method of freatment 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.
  • 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.
  • 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.
  • disorder means any condition and disease associated with metabofropic glutamate receptor activity.
  • the compounds of formula I or salt thereof are also useful as pharmacological tools in the development and standardisation of tn vitro and in vivo test systems for the evaluation ofthe 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.
  • the pharmacological properties ofthe compounds ofthe invention can be analyzed using standard assays for functional activity.
  • 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 inco ⁇ orated herein by reference.
  • the compounds ofthe invention can be studied by means of an assay that measures the mobilization of intracellular calcium, [Ca 2+ ]i in cells expressing mGluR5.
  • 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.
  • FLIPR analysis cells expressing human mGluR5d were seeded on collagen coated clear bottom 96-well plates with black sides and analysis of [Ca 2+ ]j mobilization was done 24 hours after seeding.
  • 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 ⁇ L of buffer present in each well ofthe cell plate. After each addition ofthe 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 ofthe response within the sample period. EC50 and IC 5 o determinations were made from data obtained from 8-point concenfration response curves (CRC) performed in duplicate. Agonist CRC were generated by scaling all responses to the maximal response observed for the plate. Antagonist block ofthe agonist challenge was normalized to the average response ofthe agonist challenge in 14 confrol wells on the same plate.
  • IP 3 Inositol Phosphate
  • Antagonist activity was determined by pre- incubating test compoxmds for 15 minutes, then incubating in the presence of glutamate (80 ⁇ M) or DHPG (30 ⁇ 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Psychiatry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Psychology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Toxicology (AREA)
  • Hospice & Palliative Care (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The present invention relates to new compounds of formula (I), a process for their preparation and new intermediates prepared therein, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy. 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. 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.

Description

NEW COMPOUNDS
FIELD OF THE INVENTION
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
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 ionofropic and metabofropic glutamate receptors, based on the stractural features ofthe receptor proteins, the means by which the receptors transduce signals into the cell, and pharmacological profiles. The metabofropic 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 ofthe 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 A2; 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).
Molecular cloning has identified eight distinct mGluR subtypes, termed mGluRl through nιGluR8. Nakanishi, Neuron 13:1031 (1994), Pin et al, Neuropharmacology 34:1 (1995), Knopfel et al, J. Med. Chem. 38:1411 (1995). Further receptor diversity occurs via expression of alternatively spliced forms of certain mGluR subtypes. Pin et al, PNAS <°P:10331 (1992), Minakami et al, BBRC 199:1136 (1994), Joly et al, J. Neurosci. 15:3910 (1995). Metabofropic glutamate receptor subtypes may be subdivided into three groups, Group I, Group II, and Group ILT mGluRs, based on amino acid sequence homology, the second messenger systems utilized by the receptors, and by their pharmacological characteristics. Group I mGluR comprises mGluRl, 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.
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). Metabofropic 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 363:341 (1993), Bortolotto et al, Nature 368:140 (1994), Aiba et al, Cell 79:365 (1994), Aiba et al, Cell 79:311 (1994). A role for mGluR activation in nociception and analgesia also has been demonsfrated, 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 ofthe vestibulo-ocular reflex. Nakanishi, Neuron 13: 1031 (1994), Pin et al, Neuropharmacology 34:1, Knopfel et al, J. Med. Chem. 38:1417 (1995). Further, Group I metabofropic 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), Holhnan et al, Ann. Rev. Neurosci. 17:31 (1994), Pin et al, Neuropharmacology 34:1 (1995), Knopfel et al, J. Med. Chem. 5c?: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 ofthe 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.
Recent advances in the elucidation ofthe neurophysiological roles of metabofropic glutamate receptors generally and Group I in particular, have established these receptors as promising drag 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.
The object ofthe present invention is to provide compounds exliibiting an activity at metabofropic glutamate receptors (mGluRs), especially at the mGluR5 receptor.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula la
Figure imgf000005_0001
wherein:
P is selected from the group consisting of hydrogen, C3.7alkyl 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; R1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C -6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OCo-6alkylC3-6cycloalkyl, Co-6alkylaryl, OC0-6alkylaryl, CHO,
(CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OC1-6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0- 6alkylNR5R6, OC2-6alkylNR5R6, C1-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, C0- 6alkylNR5(CO)R6, OC2-6alkylNR5(CO)R6, C0-6alkylNR5(CO)NR5R6, Co-ealkylSR5, OC2- 6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0- 6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R^Co-6alkylNR5(SO2)R^ OC2-6aUiylNR5(SO2)R0, C0-6alkylNR5(SO2)NR5R6, OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6, C0-6alkylNR5(CO)OR6, OC2-6alkylNR5(CO)OR6, SO3R5 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;
M1 is selected from the group consisting of a bond, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, C0- 4alkyl(CO)C0-4alkyl, Co-salkylOCo-salkyl, C0-3alkyl(CO)NR5, Co-3alkyl(CO)NR5C0-3alkyl, C0-4alkylNR5, Co-3alkylSCo-3alkyl, C0-3alkyl(SO)C0-3alkyl or Co-3alkyl(SO2)C0-3alkyl; R2 is selected from the group consisting of hydrogen, hydroxy, C0-6alkylcyano, oxo, =NR5, =NOR5, CMalkylhalo, halo, C1-4alkyl, O(CO)Cι-4alkyl, C1-4alkyl(SO)C0-4alkyl, C . 4alkyl(SO2)C0- alkyl, (SO)C0- alkyl, (SO2)C0- alkyl, OCι-4alkyl, C1-4alkylOR5 and C0- 4alkylNR5R6; X1, X2 and X3 are independently selected from the group consisting of CR, CO, N, NR, O and S;
R is selected from the group consisting of hydrogen, C0-3 alkyl, halo, C0-3alkylOR , C0- 3alkylNR5R6, C0-3alkyl(CO)OR5, C0-3all ylNR5R6 and C0-3alkylaryl; M2 is selected from a group consisting of a bond, C1.3 alkyl, C -7cycloalkyl, C2-3 alkenyl, C2- 3alkynyl, C0-4alkyl(CO)C0-4alkyl, QwalkylOQwalkyl, C0-3alkylNR5C1-3alkyl, C0. 3alkyl(CO)NR5, C0-4alkylNR5, Co-3alkylSCo-3alkyl, Co-3alkyl(SO)C0-3alkyl and C0- 3alkyl(SO2)C0-3alkyl; R is selected from a group consisting of hydrogen, hydroxy, C0-6alkylcyano, oxo, =NR , =NOR5, C1-4alkylhalo, halo, C1-4alkyl, O(CO)C1-4alkyl, C1-4alkyl(SO)C0-4alkyl, Ci. 4alkyl(SO2)C0-4alkyl, (SO)C0-4alkyl, (SO2)C0-4alkyl, OC1-4alkyl, C1-4alkylOR5 and C0- 4alkylNR5R6;
X4 is selected from the group consisting of C0-4alkylR5, Co-4alkyl(NR5R6), C0- 4alkyl(NR5R6)=N, NR5C0-4alkyl(NR5R6)=N, NOCo-4alkyl, C1-4alkylhalo, C, O, SO, SO2 and S;
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; R is selected from the group consisting of hydrogen, hydroxy, Co-6alkylcyano, oxo, =NR5, =NOR5, C1-4alkylhalo, halo, C1-4alkyl, OC1-4alkyl, OC0-6alkylaryl, O(CO)C1-4alkyl, C0- 4alkyl(S)C0-4alkyl, Cι-4alkyl(SO)C0-4alkyl, C1-4alkyl(SO2)C0-4alkyl, (SO)C0- alkyl, (SO2)C0- 4alkyl, C1-4alkylOR , Co- alkylNR R 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;
R and R are independently selected from the group consisting of hydrogen, hydroxy, Ci. 6alkyl, Co-6allcylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S, and wherein R5 and R6 may together form a 5- or 6-membered ring containing one or more atoms independently selected from the goup consisting of C, N, O and S; wherein any C1-6alkyl, C2-6alkenyl, C -6alkynyl, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl and C0.6alkylheteroaryl defined under R1, R2, R3, R4, R5 and R6 may be substituted by one or more A;
A is selected from the group consisting of hydrogen, hydroxy, oxo, halo, nitro, Co- 6alkylcyano, C1-4alkyl, C0- alkylC3-6cycloalkyl, Cι.6alkylhalo, OC1-6alkylhalo, C2-6alkenyl, OC1-6alkyl, Co-3aιkylaryl, C0-6alkylOR5, OC2-6alkylOR5, C1-6alkylSR5, OC2-6alkylSR5, (CO)R5, O(CO)R5, OC2-6alkylcyano, C0-6alkylCO2R5, OC1-6alkylCO2R5, O(CO)OR5, O . 6alkyl(CO)R5, C1-6alkyl(CO)R5, NR5OR6, C0-6alkylNR5R6, OC2-6alkylNR5R6, C0-
6alkyl(CO)NR ,5°rR»60, OC1-6alkyl(CO)NR >5JτR»6°, OC2-6alkylNR:'(CO)R0, C0-6alkylNRD(CO)RD, C0-6alkylNR;'(CO)NR , 5DRn6o, O(CO)NR 5"Rr> 6D, NR:'(CO)ORD,
Figure imgf000007_0001
OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, SO3R5, C1-6alkylNR5(SO2)NR5R6, OC2-6alkyl(SO2)R5, C0-6alkyl(SO2)R5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5 and a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S; m is selected from 0, 1, 2, 3 and 4; and n is selected from 0, 1, 2 and 3, or salt thereof.
The present invention provides a compound of formula I
Figure imgf000007_0002
(I) wherein:
P is selected from the group consisting of thiophene, pyridyl, thiazolyl, fxrryl, pyrrolyl and phenyl, whereby the phenyl ring is substituted on position 3 or disubstituted on positions 2 and 5; R1 is attached to P via a carbon atom on ring P and is selected from the group consisting of hydrogen, hydroxy, halo, nitro, Cj..6alkylhalo, Od-βalkylhalo, C1-6alkyl, OCι-6alkyl, C2- 6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, Co-6alkylC3-6cycloalkyl, OC0-6alkylC3- 6cycloalkyl, C0-6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OCj. 6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, d_ 6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, Co-6alkylNR5(CO)R6, OC2-6alkylNR5(CO)R0, C0- 6alkylNR5(CO)NR5R6, C0-6alkylSR5, OC2-6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6,C0- 6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, C0-6allcylNR5(SO2)NR5R6, OC2-
6alkylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6, C0-6alkylNR5(CO)OR6, OC2- 6alkylNR5(CO)OR6, SO3R5 and a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S; M1 is a bond; X1 selected from the group consisting of C, CO, N, O and S; X2 is selected from the group consisting of C, N, O and S; X3 is i) selected from the group consisting of N, O and S, or ii) selected from N, O, S, and C when X2 is selected from N, O, or S, and when X3 is C the substituent R on X3 is H. ; R is selected from the group consisting of hydrogen, C0-3alkyl, halo, Co-3alkylOR5, C0- 3alkylNR5R6, C0-3alkyl(CO)OR5 and Co-3alkylaryl;
M2 is selected from a group consisting of a bond, C1-3alkyl, C2-3alkynyl, C0- alkyl(CO)Co- 4alkyl, C0-3alkylOC0-3alkyl, C0.3alkylNR5C1-3alkyl, Co-3alkyl(CO)NR5, Co^alkylNR5, C0- 3alkyl(SO)C0-3alkyl and Co-3alkyl(SO2)C0-3alkyl; R3 is selected from a group consisting of hydroxy, C0-6alkylcyano, oxo, =NR5, =NOR5, Ci. 4alkylhalo, halo, C1-4alkyl, O(CO)C1-4alkyl, C1-4alkyl(SO)C0-4alkyl, C1-4alkyl(SO2)C0- 4alkyl, (SO)C0-4alkyl, (SO2)C0-4alkyl, OC1-4afkyl, C1-4alkylOR5 and C0- aιkylNR5R6; X4 is selected from the group consisting of C0-4alkylR5R6 , C3-7cycloalkyl, Ci. 4alkyl(NR5R6), NR5, C0-4alkyl(NR5R6)=N, NR5Co-4alkyl(NR5R6)=N, NOC0-4alkyl, d. 4alkylhalo, O, SO, SO2 and S, and wherein the bond between M2 and X4 is a single bond ; 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 R4 on such nifrogen atom and any suitable carbon atom is optionally substituted with R4; and
R4 is selected from the group consisting of Co-6alkylcyano, =NC1-4alkyl, =NOR5, Ci- 4alkylhalo, halo, C1-6alkyl, OC1-4alkyl, C2-4alkenyl, Co-2alkylC3-6cycloalkyl, Co- 6alkylaryl, Cc-6alkylheteroaryl, OC0-6alkylaryl, OC0-6alkylheteroaryl, NC0-6alkylaryl,
NCo-6alkylheteroaryl,Co-6alkylOaryl, Co-6alkylOheteroaryl, C0-6alkylNaryl, C0- alkylNheteroaryl, OC0.6alkylOaryl, OC0-6alkylOheteroaryl, OCo-6alkylNaryl, OC0- 6alkylNheteroaryl, NC0,6alkylOaryl, NC0-6alkylOheteroaryl, NC0-6alkylNaryl, NC0- 6alkylNheteroaryl, O(CO)C1-4alkyl, C0-4alkyl(CO)OC1-4alkyl, C1-4alkyl(S)C0-4alkyl, d. 4alkyl(SO)C0-4alkyl, C1.4alkyl(SO2)C0-4alkyl, (SO)C0-4alkyl, (SO2)C0- alkyl, Ci-
4alkylOR5,
Figure imgf000009_0001
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 ii) selected from the group consisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tefrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl; and R4 is selected from the group consisting of hydrogen, hydroxy, C0-6alkylcyano, =NR5,
=NOR5, C1-4alkylhalo, halo, C1-6alkyl, OC1-4alkyl, OC0-6alkylaryl, O(CO)C1-4alkyl, C0- 4alkyl(S)C0-4alkyl, C1-4alkyl(SO)C0-4alkyl, C1-4alkyl(SO2)C0-4afkyl, (SO)C0-4alkyl, (SO2)Co-4alkyl, C1-4alkylOR5, Co-4alkylNR5R6 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;
R5 and R6 are independently selected from the group consisting of hydrogen and C1-6alkyl; wherein any C1-6alkyl defined under R1, R2 and R4 may be substituted by one or more A ; A is selected from the group consisting of hydrogen, hydroxy, halo, nitro, oxo, C0-
6alkylcyano, C0- alkylC3-6cycloalkyl, C1-6alkyl, Cι.6alkylhalo, OC1-6alkylhalo, C2-6alkenyl,
C0-3alkylaryl, C0-6alkylOR5, OC2-6alkylOR5, C1-6alkylSR5, OC2-6alkylSR5, (CO)R5, O(CO)R5, OC2-6alkylcyano, OC1-6alkylCO2R5, O(CO)OR5, OC1-6alkyl(CO)R5, d
6alkyl(CO)RD, NRDOR°, OC2-6alkylNR » 5D nR6°, C0-6alkyl(CO)NR 5°Rn 6°, OC1-6alkyl(CO)NR »5D nR6°,
OC2-6alkylNR:,(CO)R0, C0-6alkylNR:'(CO)R0, C0-6alkylNR:)(CO)NR 53TR6o, O(CO)NR »5:'Rτ 60, C0.
Figure imgf000010_0001
C0-6alkylNRD(SO2)Ro, OC2-6alkylNR;,(SO2)R0 : SO3R5, C1-6alkylNR5(SO2)NR5R6, OC2-6alkyl(SO2)R5, C0-6alkyl(SO2)R5, C0-6alkyl(SO)R5,
OC2-6alkyl(SO)R5 and a 5-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S; ml is selected from 0, 1, 2, 3 and 4; m2 is selected from 0, 1, 2 and 3; n is selected from 0, 1 and 2; and t is O or 1, and salts thereof, with the proviso that the compound is not 5-(4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-3-thiophen-3-yl-[l,2,4]oxadiazole, l,2-di{2-(3-amino-phenyl)- [l,3,4]oxadiazole-yl)ethane, l,2-di{5-[5-(4-nifro-phenyl)furan-2-yl]-[l,3,4]oxadiazol- yl)ethane, 1 ,2-di {5-[5-(4-bromo-phenyl)furan-2-yl]-[l ,3,4]oxadiazol-yl)ethane, 1 ,2-di {5- , [5-(4-chloro-phenyl)furan-2-yl]-[l,3,4]oxadiazol-yl)ethane and l,2-di{5-[5-(2,4-dibromo- phenyl)furan-2-yl]-[l,3,4]oxadiazol-yl)ethane.
The present invention provides a compound of formula lb
Figure imgf000010_0002
(lb) wherein: 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; R1 is attached to P via a carbon atom on ring P and; is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2- βalkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0-6alkylC3- ecycloall yl, C0.6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OCj. 6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, Ci. 6alkyl(CO)NR5R6, OCι-6alkyl(CO)NR5R6, C0-6alkylNR5(CO)R6, OC2-6alkylNR5(CO)R6, C0- 6alkylNR5(CO)NR5R6, C0-6alkylSR5, OC2-6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6,C0- 6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, C0-6alkylNR5(SO2)NR5R6, OC2-
Figure imgf000011_0001
OC2-
6alkylNR (CO)OR , SO3R and a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S;
M1 is a bond; X1 selected from the group consisting of C, CO, N, O and S;
X2 is selected from the group consisting of C, N, O and S;
X3 is selected from the group consisting of N, O and S, or X3 is CH when X2 is N, O or S;
R is selected from the group consisting of hydrogen, Co-3alkyl, halo, Co-3alkylOR5, C0-
3alkylNR5R6, C0-3alkyl(CO)OR5 and Co-3alkylaryl; M2 is selected from a group consisting of a bond, d^alkyl, C2-3alkynyl, Co-4alkyl(CO)C0-
4alkyl, C0-3alkylOC0-3alkyl,
Figure imgf000011_0002
C0-3alkyl(CO)NR5, C0-4alkylNR5, C0-
3alkyl(SO)C0-3alkyl and Co-3alkyl(SO2)C0-3alkyl;
R3 is selected from a group consisting of hydroxy, C0-6alkylcyano, oxo, =NR5, =NOR5, Ci-
4alkylhalo, halo, C1-4alkyl, O(CO)C1-4alkyl, C1-4alkyl(SO)C0-4alkyl, C1-4alkyl(SO2)C0- 4alkyl, (SO)C0-4alkyl, (SO2)C0-4alkyl, OC1-4alkyl, C1-4alkylOR5 and C0-4arkylNR5R6;
X4 is selected from the group consisting of Co- alkylR5R6 , C3-7cycloalkyl, Cj..
4alkyl(NR5R6), NR5, C0- alkyl(NR5R6)=N, NR5C0-4alkyl(NR5R6)=N, NOC0-4alkyl, d.
4alkylhalo, O, SO, SO2 and S, and wherein the bond between M2 and X4 is a single bond ;
Q is i) selected from the group consisting of triazolyl, imidazolyl, oxadiazolyl, irnidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl, and wherein any substitutable nitrogen atom in the ring is substituted with R4 on such nitrogen atom; and R4 is selected from the group consisting of C0-6alkylcyano, =NC1-4alkyl, =NOR5, d- 4alkylhalo, halo, C1-6alkyl, OC1-4alkyl, C2- alkenyl, Co-2alkylC3-6cycloalkyl, C0- 6alkylaryl, C0-6alkylheteroaryl, OCo-6alkylaryl, OC0-6alkylheteroaryl, NC0-6alkylaryl, NCo-6alkylheteroaryl,C0-6alkylOaryl, C0-6alkylOheteroaryl, Co-6alkylNaryl, C0- 6alkylNheteroaryl, OC0-6alkylOaryl, OCo-6alkylOheteroaryl, OC0-6alkylNaryl, OC0- όalkylNheteroaryl, NC0-6alkylOaryl, NCo-6alkylOheteroaryl, NC0-6alkylNaryl, NC0- 6alkylNheteroaryl, O(CO)C1-4alkyl, C0-4alkyl(CO)OC1-4alkyl, C1-4alkyl(S)C0-4alkyl, d. 4alkyl(SO)Co-4alkyl, C1-4alkyl(SO2)C0-4alkyl, (SO)C0- alkyl, (SO2)C0-4alkyl, d- 4alkylOR5, Co-4alkylN(C1-4alkyl) 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 ii) selected from the group consisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl; and
R4 is selected from the group consisting of hydrogen, hydroxy, C0-6alkylcyano, ^NR5, =NOR5, C1-4alkylhalo, halo, C1-6alkyl, OC1-4alkyl, OC0-6alkylaryl, O(CO)C1- alkyl, C0- 4alkyl(S)C0- alkyl, Cι-4alkyl(SO)Co-4alkyl, C1-4alkyl(SO2)C0-4alkyl, (SO)C0-4alkyl,
(SO2)C0- alkyl, C1-4alkylOR5, Co^alkylNR^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;
R5 and R6 are independently selected from the group consisting of hydrogen and C1-6alkyl; wherein any C1-6alkyl defined under R1, R2 and R4 may be substituted by one or more A ;
A is selected from the group consisting of hydrogen, hydroxy, halo, nitro, oxo, C0-
6alkylcyano, C0-4alkylC3.6cycloalkyl, C1-6alkyl, C1-6alkylhalo, OC1-6alkylhalo, C2-6alkenyl, C0-3alkylaryl, C0-6alkylOR5, OC2-6alkylOR5, C1-6alkylSR5, OC2-6alkylSR5, (CO)R5,
O(CO)R5, OC2-6alkylcyano, OC1-6alkylCO2R5, O(CO)OR5, OC1-6alkyl(CO)R5, Ci.
6alkyl(CO)R5, NR5OR6, OC2-6alkylNR5R6, C0-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, OC2.6alkylNR5(CO)R6, C0-6alkylNR5(CO)R6, C0-6alkylNR5(CO)NR5R6, O(CO)NR5R6, C0, 6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, SO3R5, C1-6alkylNR5(SO2)NR5R6, OC2-6alkyl(SO2)R5, C0-6alkyl(SO2)R5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5 and a 5-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S; ml is selected from 0, 1, 2, 3 and 4; m2 is selected from 0, 1, 2 and 3; n is selected from 0, 1 and 2; and t is 0 or 1, and salts thereof, with the proviso that the compound is not 5-(4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-3 -thiophen-3 -yl- [1,2,4] oxadiazole.
In a further aspect ofthe invention there is provided pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
In yet a further aspect ofthe 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.
In still a further aspect ofthe 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.
In another aspect ofthe invention there is provided a process for the preparation of compounds of formula I, and the intermediates provided therein.
These and other aspects ofthe present invention are described in greater detail herein below. DETAILED DESCRIPTION OF THE INVENTION
Listed below are definitions of various terms used in the specification and claims to describe the present invention.
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 ofthe other definitions for that group.
For the avoidance of doubt it is to be understood that in this specification 'C1-6' means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. In this specification "C" means 1 cabon atom.
In this specification, unless stated otherwise, the term "alkyl" includes both sfraight and branched chain alkyl groups and may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl, t-hexyl. The term "Ci^alkyl" refers to an alkyl group having 1, 2 or 3 carbon atoms, and may be methyl, ethyl, n-propyl and i-propyl.
In this specification, unless stated otherwise, the term "cycloalkyl" refers to an optionally substituted, saturated cyclic hydrocarbon ring system. The term "C3-7cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
In this specification, unless stated otherwise, the term "alkenyl" includes both straight and branched chain alkenyl groups. The term "C2-6alkenyl" 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.
In this specification, unless stated otherwise, the term "alkynyl" includes both sfraight and branched chain alkynyl groups. The term C2-6alkynyl 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.
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.
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, tefrazolyl and thiadiazolyl, benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, benzofuryl, indolyl, isoindolyl, pyridonyl, pyridazinyl, pyrimidinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, pyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl.
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.
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.
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, tefrahydropyranyl 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.
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.
In this specification, unless stated otherwise, the term "=NR5" and ' -NOR5" include imino- and oximogroups carrying an R5 substituent and may be, or be part of, groups including, but not limited to iminoalkyl, iminohydroxy, iminoalkoxy, amidine, hydroxyamidine and alkoxyamidine.
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.
In this specification, unless stated otherwise, the term "bond" is a saturated bond.
In this specification, unless stated otherwise, the term "halo" may be fluoro, chloro, bromo or iodo. In this specification, unless stated otherwise, the term "alkylhalo" means an alkyl group as defined above, substituted with one or more halo. The term "C1-6alkylhalo" may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyi, fluoroethyl, difluoroethyl and bromopropyl. The term "OC1-6alkylhalo" may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy and difluoroethoxy.
In one embodiments ofthe invention P may be hydrogen or C3-7 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 ofthe invention P is selected from 5 and 6 membered aromatic and heteroaromatic rings. 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. In yet a further preferred embodiment ofthe invention P is phenyl substituted on position 3 or disubstituted on positions 2 and 5.
P is optionally substituted via a carbon atom with 0, 1, 2, 3 or 4 groups R1, wherein the number of R1 substituents on the P ring is designated by the term ml. In preferred embodiments ofthe invention ml is 1 or 2. In further preferred embodiments ofthe invention ml is 1.
In suitable embodiments of invention R1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2- 6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0-6alkylC3-6cycloalkyl, C0- 6alkylaryl, OCo-ealkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OC1-6alkylCO2R5, C0- 6alkylcyano, OC2-6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, C1-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, C0-6alkylNR5(CO)R6, OC2-6alkylNR5(CO)R6, C0- 6alkylNR5(CO)NR5R6, C0.6alkylSR5, OC2-6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6,C0- 6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, C0-6alkylNR5(SO2)NR5R6, OC2- 6all ylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6, C0-6alkylNR5(CO)OR6, OC2- 6alkylNR5(CO)OR6, SO3R5 and a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S.
In a more suitable embodiment ofthe invention R1 is selected from hydrogen, hydroxy, halo, nitro, Cι-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, Co-6alkylC3- βcycloalkyl, C1-6alkylOR5, C1-6alkyl(CO)R5, C0-6alkylCO2R5, C0-6alkylcyano, C0-
6alkylNR5R6, Co-6alkylSR5 and a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C and O.
Any C1-6alkyl defined under R1 may be substituted by one or more A. In one embodiment ofthe invention R1 is ethyl and A is hydroxyl. In a further suitable embodiment ofthe invention R1 is selected from hydrogen, methyl, ethyl, cyclopropyl, hydroxy, methoxy, cyano, flouro, chloro, bromo, iodo, trifluoromethyi, difluoromethoxy, trifluoromethoxy, amino, nitro, dirnethylamino, methylsulfanyl, vinyl, acetyl, formic acid methyl ester, methoxymethyl, ethanol and furyl.
In a more suitable embodiment ofthe 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 R1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl,
OC1-6alkyl, C2-6alkenyl, C0-6alkylC3-6cycloalkyl, C1-6alkylOR5, C1-6alkyl(CO)R5, C0- 6alkylCO2R5, Co-ealkylcyano, C0-6alkylNR5R6, C0-6alkylSR5 and a 5-membered ring containing one or more atoms independently selected from the group consisting of C and O. In a further suitable embodiment ofthe invention P is phenyl substituted on position 3 or disubstituted on positions 2 and 5 and R1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2- 6alkenyl, C0-6alkylC3-6cycloalkyl, C1-6alkylOR5, C1-6alkyl(CO)R5, Co-6alkylCO2R5, C0- 6alkylcyano, Co-6alkylNR5R6, Co-βalkylSR5 and a 5-membered ring containing one or more atoms independently selected from the group consisting of C and O.
According to another aspect ofthe invention the ring P is connected to the core ring by M1, wherein M1 can be a bond directly joining P to the core ring. M1 can also be a linker Ci. 3alkyl.
In a preferred embodiment ofthe invention M1 is a bond. When M1 is not a direct bond M1 can be further substituted with 0, 1, 2 or 3 substituents R2 wherein the number of substituents R is designated by the term n. The substituents R may be selected from hydrogen, hydroxy, oxo, C1-4alkylhalo, halo and C1- alkyl. In a preferred embodiment ofthe invention n is 0.
In another aspect ofthe invention there is provided compounds of formula I wherein X1 is selected from the group consisting of C, CO, N, O and S. In a further aspect ofthe invention X2 is selected from the group consisting of C, N, O and S. In yet a further aspect ofthe invention X3 is selected from the group consisting of N, O and S, or X3 is selected from N, O, S, and C when X2 is selected from N, O, or S, and when X3 is C the substituent R on X3 is H.
X1, X2 and X3 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, C0-3alkyl, halo, Co-3alkylOR , Co-3alkylNR R , C0-
3alkyl(CO)OR5, Co-3alkylNR5R6 and C0-3alkylaryl. In one embodiment ofthe invention R is selected from the group consisting of hydrogen, C0-3 alkyl and halo. In a preferred embodiment ofthe invention X1 is C, N or O and R is selected from hydrogen, Co-3alkyl and halo. In one embodiment R is selected from hydrogen, chloro or methyl.
In another preferred embodiment ofthe invention X1 is N.
In a suitable embodiment X2 is selected from N, O and S, and R is hydrogen. In another embodiment ofthe invention X is N, O or S. In a further preferred embodiment ofthe invention X1 is O and one of X2 and X3 is O and the other is N. In yet a further preferred embodiment ofthe invention X1 is N and one of X2 and X3 is O and the other is N. In yet another preferred embodiment ofthe invention X1 is C or CR and one of X2 and X3 is O and the other is N.
In another preferred embodiment ofthe invention X2 is O and X3 is N, and in yet another preferred embodiment ofthe invention X2 is N and X3 is O. In a further preferred embodiment ofthe invention X1 is O and X2 and X3 are N.
In another suitable embodiment ofthe invention the ring containing X , X2 and X3 forms an oxadiazole, isoxazole, oxazole, chloro-isoxazole or a methyl-isoxazole. In a preferred embodiment ofthe invention the ring containing X , X and X forms an oxadiazole. In another preferred embodiment ofthe invention the ring contaimng X , X and X3 forms an isoxazole.
The ring containing X1, X2 and X3 should not be further annulated onto any other ring.
In a suitable embodiment ofthe invention M2 may be a direct bond from the core ring to the variable X4 or M2 may be selected from the group consisting of bond, Cι-3alkyl, C2- 3alkynyl, C0-4alkyl(CO)C0-4all yl C0-3alkylOC0-3 alkyl, C0-3alkylNR5C1-3 alkyl, C0- 3alkyl(CO)NR5, C0-4alkylNR5, C0-3alkyl(SO)Co-3alkyl and Co-3alkyl(SO2)C0-3alkyl.
In preferred embodiments ofthe invention M is a bond or C^aUcyl. In further preferred embodiments ofthe invention M2 is C1-3alkyl, preferably methyl or ethyl.
When M2 is not a direct bond M2 may be further substituted with 0, 1 or 2 R3 groups wherein the number of substituents R3 is designated by the term n. In one embodiment of the invention n is 1 or 2. In another embodiment ofthe invention n is 0.
In a suitable embodiment ofthe invention R is selected from the group consisting of R is selected from a group consisting of hydroxy, Co-6alkylcyano, oxo, =NR5, =NOR5, Cj.. 4alkylhalo, halo, C1-4alkyl, O(CO)C1-4alkyl, C1-4alkyl(SO)C0-4alkyl, C1-4alkyl(SO2)Co-
4alkyl, (SO)C0-4alkyl, (SO2)C0-4alkyl, OC1-4alkyl, C1-4alkylOR5 and Co- alkylNR5R6.
In a preferred embodiment R3 is selected from hydrogen and C1-4alkyl, preferably methyl or dimethyl.
In another preferred embodiment M2 may be selected from the group consisting of a bond, C1-3alkyl, C2-3alkynyl, C0-4alkyl(CO)C0- alkyl, Co-3alkylOCo-3alkyl, C0-3alkylNR5C1_3alkyl,
Co-3alkyl(CO)NR5, C0-4alkylNR5, C0-3alkyl(SO)C0-3alkyl and Co-3alkyl(SO2)C0-3alkyl and
R3 is selected from hydrogen and C1-4alkyl.
In yet another preferred embodiments ofthe invention M2 is a bond or C1-3 alkyl and R3 is hydrogen, methyl or dimethyl. In a further preferred embodiment M2 may be selected from the group consisting of a bond, methyl and ethyl and R3 is hydrogen, methyl or dimethyl. In a further embodiment ofthe invention M2 is nifrogen. In yet a further embodiment ofthe invention M2 is oxygen.
According to another aspect ofthe invention X4 is selected from the group consisting of C0- alkylR5R6 , C3-7cycloalkyl, C1-4alkyl(NR5R6), NR5, C0-4alkyl(NR5R6)=N, NR5C0- 4alkyl(NR5R6)=N, NOC0- alkyl, C1-4alkylhalo, O, SO, SO2 and S, and wherein the bond between M2 and X4 is a single bond.
In a preferred embodiment ofthe invention X A . is selected from the group consisting of C0- 4alkylR5R6, C3-7cycloalkyl, NR5, O, SO, SO2 and S and R5 and R6 are independently selected from hydrogen and C1-6alkyl.
In a further preferred embodiment ofthe invention X4 is selected from the group consisting of CH2, CHCH3, CH(CH3)2 and NR5. In a further preferred embodiment ofthe invention X4 is NR5 and R5 is selected from hydrogen and C1-6alkyl. In a preferred embodiment of the invention R is methyl or hydrogen and R is hydrogen. In still a further preferred embodiment ofthe invention X4 is O. In yet another preferred embodiment ofthe invention X is S.
9
It is to be understood that the bond between M and X is a single bond in all tautomeric forms.
Embodiments ofthe present invention include those wherein Q is a 5- or 6-membered ring. When Q is a 5-membered ring, Q is selected from the group consisting ofthe group consisting of triazolyl, imidazolyl, oxadiazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl, and wherein any substitutable nitrogen atom in the ring is substituted with R4 on such nitrogen atom.
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.
When Q is a 6-membered ring, Q is selected from the group consisting of benzoimidazolyl, benzooxazolyl, tefrahydrotriazolopyridyl, tetrahydrofriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl.
In a preferred embodiment ofthe 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.
Q can be further substituted with 0, 1, 2 or 3 substituents R4, wherein the number of R4 substituents is designated by the term m2. In a prefened embodiment m2 is 1 or 2.
When Q is a 5-membered ring the substituent R4 is selected from the group consisting of C0-6alkylcyano, =NC1-4alkyl, =NOR5, C1-4alkylhalo, halo, C1-6alkyl, OC1-4alkyl, C2- 4alkenyl, Co-2alkylC3-6cycloalkyl, Co-δalkylaryl, Co-6alkylheteroaryl, OC0- alkylaryl, OC0- gall y lheteroaryl, NCo-6alkylaryl, NCo-6alkylheteroaryl, Co-6alkylOaryl, C0.
6alkylOheteroaryl, Co-6alkylNaryl, C0-6alkylNheteroaryl, OCo-6alkylOaryl, OC0- 6alkylOheteroaryl, OCo-6alkylNaryl, OCo-6alkylNheteroaryl, NCo-6alkylOaryl, NC0- 6alkylOheteroaryl, NC0-6alkylNaryl, NCo-6alkylNheteroaryl, O(CO)C1-4alkyl, C0- 4alkyl(CO)OC1-4alkyl, C1-4alkyl(S)C0-4alkyl, C1-4alkyl(SO)C0- alkyl, d-4alkyl(SO2)C0- 4alkyl, (SO)C0-4alkyl, (SO2)C0-4alkyl, C1-4alkylOR5, Co- alkylN(C1-4alkyl)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. In a further embodiment ofthe invention R4 on the 5 membered Q ring is selected from the group consisting of C1-4alkylhalo, C1-6alkyl, C2-4alkenyl, C0-2alkylC3-6cycloalkyl, C0- 6alkylaryl, Co-6alkylheteroaryl, OC0-6alkylaryl, OC0-6alkylheteroaryl, NCo-6alkylaryl, NC0- 6alkylheteroaryl, Co-6alkylOaryl, Co-6alkylOheteroaryl, C0-6alkylNaryl, C0- 6alkylNheteroaryl, OC0-6alkylOaryl, OCo-6alkylOheteroaryl, OC0-6alkylNaryl, OC0- 6alkylNheteroaryl, NC0-6alkylOaryl, NC0.6alkylOheteroaryl, NC0-6alkylNaryl, NCo-
6alkylNheteroaryl, C0-4alkyl(CO)OC1-4alkyl, C1.4alkyl(S)C0-4alkyl, C1-4alkylOR5 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.
In one embodiment ofthe 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 R4 on such nitrogen atom and R is selected from the group consisting of C1-4alkylhalo, C1- alkyl, C2- alkenyl, C0-2alkylC3-6cycloalkyl, C0-6alkylaryl, C0-6alkylheteroaryl, OCo-6alkylaryl, OC0- 6alkylheteroaryl, NCo-6alkylaryl, NCo-6alkylheteroaryl,Co-6alkylOaryl, C0-
6alkylOheteroaryl, Co-ealkylNaryl, Co-6alkylNheteroaryl, OCo-6alkylOaryl, OC0- 6alkylOheteroaryl, OCo-ealkylNaryl, OCo-6alkylNheteroaryl, NCo-6alkylOaryl, NC0- βalkylOheteroaryl, NC0-6alkylNaryl, NCo-6alkylNheteroaryl, Co-4alkyl(CO)OC1-4alkyl, Ci. 4alkyl(S)Co-4alkyl, C1-4alkylOR5 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. In another embodiment ofthe 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 R4 on such nitrogen atom and R4 is selected from the group consisting of C1- alkylhalo, C1-6alkyl, C2-4alkenyl, Co- alkylC3-6cycloalkyl, C0- 6alkylaryl, Co-ealkylheteroaryl, OCo-όalkylaryl, OCo-6alkylheteroaryl, NC0-6alkylaryl, NC0- 6alkylheteroaryl,C0-6alkylOaryl, C0-6alkylOheteroaryl, Co-6alkylNaryl, C0, 6alkylNheteroaryl, OC0-6alkylOaryl, OCo-6alkylOheteroaryl, OCo-6alkylNaryl, OC0- 6alkylNheteroaryl, NCo-ealkylOaryl, NCo-6alkylOheteroaryl, NC0-6alkylNaryl, NC0- 6alkylNheteroaryl, C0-4alkyl(CO)OC1-4alkyl, d-4alkyl(S)C0-4alkyl, C1-4alkylOR5 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. When Q is a 6-membered ring the substituent R 4 . is selected from the group consisting of hydrogen, hydroxy, Co-6alkylcyano, =NR5, =NOR5, C1-4alkylhalo, halo, C1-6alkyl, OCι- 4alkyl, OCo-ealkylaryl, O(CO)C1-4alkyl, C0-4alkyl(S)C0-4aUcyl, C1-4alkyl(SO)C0-4alkyl, Cι_ 4alkyl(SO2)C0-4alkyl, (SO)C0-4alkyl, (SO2)C0-4alkyl, C1-4alkylOR5, C0-4alkylNR5R6 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. In a suitable embodiment ofthe invention R on the 6 membered Q ring is selected from hydrogen and C1-6alkyl. In a further embodiment ofthe invention R4 is hydrogen, methyl, ethyl, propyl, butyl or hexyl.
In a preferred embodiment ofthe invention Q selected from the group consisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tefrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl and R4 is hydrogen or C1-6alkyl.
In another preferred embodiment ofthe invention Q selected from the group consisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tefrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl and imidazopyridyl, and R4 is hydrogen or C1-6alkyl.
In a suitable embodiment ofthe invention R4 is selected from the group consisting of benzo[b]thiophenyl, benzodioxolyl, bromo, bromofuryl, butoxyphenyl, chloromethoxypyridyl, chlorophenyl, chlorophenyhnethanol, 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, niethoxyphenyl, methoxyphenylethyl, methoxypyridazinyl, methoxypyridyl, methoxypyrimidinyl, methoxythiophene, methylimidazolyl, methylpyridyl, methylsulfanylmethyl, methylthiazolyl, methylthiophene, nifroflxryl, nitrophenyl, phenyl, p-tolyloxymethyl, pyridazinyl, pyridine-oxidyl, benzyhnorpholinyl, pyridinolyl, pyridyl, pyridylmethyl, pyrimidinyl, tert-butylphenyl, tetrahydrofuryl, thiazolyl, thiophene, tolyl, trifluoromethyi, acetic acid methylester, allyl, amino, benzyl, cyclopropylmethyl, ethyl, fluorobenzyl, fluoroethyl, furyhnethyl, hydroxyethyl, isobutyl, methyl, methylbenzyl, methylbutyl, methylsulfanylpropyl, n-butyl, n-hexyl, n-propyl, tefrahycfrofurylmethyl, thiophenylmethyl and trifluoroethyl.
Ring Q may be substituted by one or more R4 on a carbon and/or a nifrogen atom in the ring. When Q is substituted on the carbon atom, R4 is selected from benzo[b]thiophenyl, benzodioxolyl, bromo, bromofuryl, butoxyphenyl, chloromethoxypyridyl, chlorophenyl, chlorophenyhnethanol, 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, benzylmo holinyl, pyridinolyl, pyridyl, pyridylmethyl, pyrimidinyl, tert- butylphenyl, tetrahydrofuryl, thiazolyl, thiophene, tolyl and trifluoromethyi.
When Q is substituted on the nitrogen atom, R4 is selected from acetic acid methylester, allyl, amino, benzyl, cyclopropyl, cyclopropylmethyl, ethyl, floxirobenzyl, fluoroethyl, furylmethyl, hydroxyethyl, isobutyl, methoxyethyl, methyl, methylbenzyl, methylbutyl, methylsulfanylpropyl, n-butyl, n-hexyl, n-propyl, tefrahydrofurylmethyl, thiophenylmethyl and trifluoroethyl.
When R is a ring R4 can be substituted with one or more substituents A, wherein A is selected from hydrogen, hydroxy, halo, nitro, oxo, C0-6alkylcyano, Co^alkyld-ecycloalkyl, C1-6alkyl, C1-6alkylhalo, OC1-6alkylhalo, C2-6alkenyl, C0-3alkylaryl, Co-ealkylOR5, OC2- 6alkylOR5, d-galkylSR5, OC2-6alkylSR5, (CO)R5, O(CO)R5, OC2-6alkylcyano, Od. 6alkylCO2R5, O(CO)OR5, OC1-6alkyl(CO)R5, C1-6alkyl(CO)R5, NR5OR6, OC2-
6alkylNR5R6, C0.6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, OC2-6alkylNR5(CO)R6, C0, 6alkylNR5(CO)R6, C0-6alkylNR5(CO)NR5R6, 0(CO)NR5R6, C0-6alkyl(SO2)NR5R6, OC2- 6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, SO3R5, Ci. 6alkylNR5(SO2)NR5R6, OC2-6alkyl(SO2)R5, C0-6alkyl(SO2)R5, C0-6alkyl(SO)R5, OC2- 6alkyl(SO)R5 and a 5-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S. In a prefened embodiment A is selected from hydroxy, halo, nifro, oxo, C0-6alkylcyano, d_ 6alkyl, C2-6alkenyl, Co^alkylaryl, C0-6alkylOR5 and a 5-membered ring containing one or more atoms independently selected from the group consisting of C and O.
Specific embodiments ofthe invention include, 2-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole,
5-(3-Methoxy-phenyl)-3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
3-[5-(l-Methyl-5-thiophen-2-yl-lH-imidazol-2-ylsulfanylmethyl)-[l,2,4]oxadiazol-3-yl]- benzonitrile, 3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]fraiazol-3-ylsulfanyhnethyl)-5-phenyl-
[l,2,4]oxadiazole,
2-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-5-methyl-lH- benzoimidazole,
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]friazol-3-ylsulfanylmethyl)-5-m-tolyl- [l,2,4]oxadiazole,
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-(3-trifluoromethyl- phenyl)-[l,2,4]oxadiazole,
3-(3-Methoxy-ρhenyl)-5-(4-methyl-5-thioρhen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole, 5-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-3-phenyl-
[l,2,4]oxadiazole,
5-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-3-m-tolyl-
[l,2,4]oxadiazole,
3-[3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-benzonitrile,
3-[4-Methyl-5-(2-methyl-thiazol-4-yl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-
[l,2,4]oxadiazole, 3-[5-(2-Methyl-thiazol-4-yl)-[l,3,4]oxadiazol-2-ylsulfanylmethyl]-5-m-tolyl-
[l,2,4]oxadiazole,
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl-
[l,2,4]oxadiazole, 3-[5-(2,4-Dimethyl-thiazol-5-yl)-4-methyl-4H-[ 1 ,2,4]triazol-3-ylsulfanyhnethyl]-5-m- tolyl- [ 1 ,2,4] oxadiazole,
3-[4-Methyl-5-(5-nitro-furan-2-yl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-
[l,2,4]oxadiazole,
4-[4-Methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine,
3-[5-(4-tert-Butyl-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-
[l,2,4]-oxadiazole,
2-Chloro-5-[4-methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-
3-yl]-pyridine, 2-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-benzooxazole,
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-
[l,2,4]oxadiazole,
3-(5-Furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[l,2,4]oxadiazole, 5-(3-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
2-(5-m-Tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-pyridine,
2-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-imidazo[4,5- b]pyridine, 5-(3-Fluoro-5-methyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]friazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole,
3-Methyl-5-[3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-pyridine,
3-(4-Methyl-5-phenyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[l,2,4]oxadiazole, 2-[4-Methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine, 4-Benzyl-2-[4-methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-
[ 1 ,2,4]triazol-3-yl]-morpholine,
4-[4-Methyl-5-(5-thiophen-3-yl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3- yl] -pyridine, 3-(4-Methyl-5-thioρhen-2-yl-4H-[ 1 ,2,4]triazol-3-ylsulfanylmethyl)-5-thiazol-4-yl-
[l,2,4]oxadiazole,
3-(4-Methyl-5-tWophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-(3-nitro-phenyl)-
[l,2,4]oxadiazole,
2-Methyl-4-[3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)- [l,2,4]oxadiazol-5-yl]-pyridine,
3-[4-Methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine,
3-(4-Methyl-5-thiophene-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[l,2,4]oxadiazole, 3-(4-Methyl-5-thiazol-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[l,2,4]oxadiazole,
5-(3-Iodo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
5-(3-Ethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazole,
2-[5-(2-Methyl-pyridin-4-yl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole,
2-[5-(3-Iodo-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole,
3-(4-Methyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[l,2,4]oxadiazole, 2,6-Dichloro-4-[4-methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-
[1 ,2,4]triazol-3-yl]-pyridine,
3-(4-Methyl-5-ρ-tolyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[l,2,4]oxadiazole,
Dimethyl-{3-[3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]phenyl}-amine, 5-(3-Chloro-phenyl)-3-(4-methyl-5-thioρhen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole, 3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-trifluoromethoxy- phenyl) [1,2,4] oxadiazole,
3-(5-Cyclohexyl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[ 1 ,2,4] oxadiazole, 3-(5-tert-Butyl-4-methyl-4H-[ 1 ,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[l,2,4]oxadiazole,
5-(3-Bromo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[l,2,4]oxadiazole,
2- [5 -(3 -Bromo-phenyl)- [1,2,4] oxadiazol-3 -ylmethylsulfanyl] - lH-benzoimidazole, 5-(3-Methoxymethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- lsulfanylmethyl)-[l,2,4]oxadiazole,
2-[5-(3-Methoxymethyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole,
4-[5-(4-Methyl-5-thiophen-2-yl-4Η-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-3- yl]-pyridine, 2- { 1 -[5-(3-Methoxy-phenyl)-[l ,2,4]oxadiazol-3-yl]-ethylsulfanyl}- 1 -methyl- 1H- imidazo [4,5 -b]pyridine,
2-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-l-methyl-lH-imidazo[4,5- b],
3-[l-Methyl-l-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m-tolyl- [l,2,4]oxadiazole,
3-[l-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m-tolyl-
[l,2,4]oxadiazole,
3-(4-Methyl-5-thioρhen-2-yl-4H-[l,2,4]triazole-3-sulfonyhnethyl)-5-m-tolyl-
[1,2,4] oxadiazole, 3-(4-Methyl-5-thioρhen-2-yl-4H-[ 1 ,2,4]triazole-3-sulfmyhnethyl)-5-m-tolyl-
[l,2,4]oxadiazole, or
5-(3-Furan-3-yl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole, or salt thereof.
Further specific embodiments ofthe invention include, 4-(4-Cycloρroρyl-5-{l-[5-(2,5-difluoro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4H-
[ 1 ,2,4]triazol-3 -yι)-pyridine,
4-(5- { 1 -[5-(3-Methoxy-phenyl)-[l ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine, 5 4-{4-Methyl-5-[l-(5-m-tolyl-[l,2,4]oxadiazol-3-yl)-ethylsulfanyl]-4H-[l,2,4]triazol-3-yl}- pyridine,
5-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-o-tolyl-
[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-cyclopropyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- l o ylsulfanylmethyl)- [ 1 ,2,4] oxadiazole,
2-{3-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-5-thiophen-2-yl-
[ 1 ,2,4]triazol-4-yl} -ethanol,
4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-
[ 1 ,2,4]triazol-3 -yl} -pyrimidine, is 3-(4-Ethyl-5-fman-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl- phenyl)-[ 1 ,2,4] oxadiazole,
(3-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-5-thiophen-2-yl-
[l,2,4]triazol-4-yl} -acetic acid methyl ester,
5-(2-Fluoro-5-methyl-phenyl)-3-[5-furan-2-yl-4-(2-methoxy-ethyl)-4H-[l,2,4]triazol-3- 0 ylsulfanylmethyl]-[l,2,4]oxadiazole,
3-(4-Cyclopropyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5- methyl-phenyl)-[l,2,4]oxadiazole,
3-(5-Chloro-2-fluoro-phenyl)-5-(4-cyclopropylmethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole, 5 4-{5-[3-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-5-yhnethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyrimidine,
3-(5-Cyclopentyl-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[1,2,4] oxadiazole,
3-(3-Chloro-phenyl)-5- {4-ethyl-5-[2-(4-methoxy-phenyl)-ethyl]-4H-[ 1 ,2,4]triazol-3- 0 ylsulfanyhnethyl}-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-p-tolyloxymethyl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[l,2,4]oxadiazole, 5-(3-Chloro-phenyl)-3-[4-(2-methoxy-ethyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[ 1 ,2,4]oxadiazole,
3-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-methoxymethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole, 5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-methoxymethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-methoxymethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
3 -(3 -Chloro-phenyl)-5 -(4-ethyl-5 -methoxymethyl-4H- [ 1 ,2,4] triazol-3 -ylsulfanylmethyl)- [1,2,4] oxadiazole,
4-(5-{l-[3-(3-Chloro-ρhenyl)-isoxazol-5-yl]-ethylsulfanyl}-4-methyl-4H-[l,2,4]triazol-3- yl)-pyridine,
3-(4-Allyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro-phenyl)-
[1,2,4] oxadiazole, 3-(4-Allyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-
[l,2,4]oxadiazole,
5-(4-Allyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-3-furan-2-yl-
[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(4-methoxy-phenoxymethyl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[ 1 ,2,4]oxadiazole,
3-(3-Chloro-ρhenyl)-5-[4-ethyl-5-(4-methoxy-phenoxymethyl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
{5-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol-3- yl} -methanol, 3-(3-Chloro-phenyl)-5-[4-ethyl-5-(2-methoxy-ethyl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]- [ 1,2,4] oxadiazole,
3-(3-Chloro-phenyl)-5-(4-ethyl-5-methylsulfanyhnethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole,
3-(3-Chloro-phenyl)-5-(5-ethoxymethyl-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4] oxadiazole,
5-[3-(3-Chloro-ρhenyl)-[l,2,4]oxadiazol-5-yhnethylsulfanyl]-4-ethyl-4H-[l,2,4]triazole-3- carboxylic acid methyl ester, 2-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,3,4]oxadiazole,
2-(3-Chloro-phenyl)-5-(4-cyclopropyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,3,4]oxadiazole, 5-(3-Chloro-phenyl)-3-{l-[4-ethyl-5-(tetrahydro-furan-2-yl)-4H-[l,2,4]triazol-3- ylsulfanyl] -ethyl} - [ 1 ,2,4] oxadiazole,
4-(5- { 1 -[5-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridazine,
4-(5- { 1 -[5-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H- [l,2,4]triazol-3-ylmethyl)-pyridine,
5-(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,
4-(5- { 1 -[5-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl)-phenol, 5-(3-Chloro-phenyl)-3-[5-(4-methoxy-phenoxymethyl)-4-(tefrahyα^o-furan-2-ylmethyl)-
4H- [ 1 ,2,4]triazol-3 -ylsulfanylmethyl] -[1,2,4] oxadiazole,
5 -(3 -Chloro-phenyl)-3 - [4-cy clopropyl-5-(4-methoxy-phenoxymethyl)-4H- [ 1 ,2,4] triazol-3 - ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)- [ 1 ,2,4]oxadiazole,
3-(4-Ethyl-5-methoxymethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[l,2,4]oxadiazole,
3-[4-Ethyl-5-(tefrahydro-lwan-2-yl)-4H-[l,2,4]friazol-3-ylsulfanyhnethyl]-5-m-tolyl-
[l,2,4]oxadiazole, 2-(3-Chloro-phenyl)-5-{l-[4-ethyl-5-(4-methoxy-phenyl)-4H-[l,2,4]triazol-3-ylsulfanyl]- ethyl}-[l,3,4]oxadiazole,
4- {5-[3-(2,5-Difluoro-phenyl)-[ 1 ,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyrimidine,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H- [l,2,4]triazol-3-yl} -pyrimidine,
3-(3-Chloro-phenyl)-5-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[1,2,4] oxadiazole, 5-(3-Methylsulfanyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
2-[5-(3-Methylsulfanyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole,
5-(2,5-Dimethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)- [ 1 ,2,4] oxadiazole,
5-(2-Fluoro-5-methyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
5-(3-Cyclopropyl-phenyl)-3-(4-methyl-5-thioρhen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole, 4- {5-[2-(3-Chloro-phenyl)-oxazol-4-ylmethylsulfanyl]-4-methyl-4H-[l ,2,4]triazol-3-yl}- pyridine,
4-[4-Methyl-5-(5-thiophen-2-yl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3- yl] -pyridine,
4-{4-Methyl-5-[5-(3-methylsulfanyl-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-4H- [l,2,4]triazol-3-yl} -pyridine,
4- (5-[5-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
2-Methyl-4-[3-(4-methyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazol-5-yl] -pyridine, l-{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-
5-yl]-phenyl} -ethanone,
4-{5-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
2-Methyl-4-[4-methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H- [l,2,4]friazol-3-yl]-pyridine,
3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl-5-thiophen-2-yl-4H-
[l,2,4]triazole,
4-{5-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl-4H-[l,2,4]triazol-3-yl}- pyridine, 3-(4-Butyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro-phenyl)-
[1,2,4] oxadiazole, 5-(3-Chloro-phenyl)-3-[4-(3-methoxy-propyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
3-(4-Benzyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro-phenyl)-
[1,2,4] oxadiazole, 5-(3-Chloro-phenyl)-3-(4-furan-2-ylmethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
3-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4] oxadiazole,
4- {5-[5-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -2-methyl-pyridine,
5-(5-Chloro-2-fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole, 4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
3-{5-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
5-(3-Chloro-phenyl)-3-(5-thiophen-2-yl-4-thiophen-2-ylmethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[1,2,4] oxadiazole,
3-{5-[3-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 4-{5-[3-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-5-yhnethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-{5-[5-(5-Bromo-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
3-{5-[5-(5-Bromo-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H- [l,2,4]triazol-3-yl} -pyridine,
5-(5-Bromo-2-fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanyhnethyl)-[l,2,4]oxadiazole, 5-(4-Methyl-5-thioρhen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-ρhenyl-
[l,2,4]oxadiazole,
3-{5-[5-(3-Fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 4-{5-[5-(3-Fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
5-(3-Fluoro-phenyl)-3-(4-methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[l,2,4]oxadiazole,
3-[4-Methyl-5-(5-thiophen-3-yl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3- yl] -pyridine,
3-(4-Methyl-5-thioρhen-3-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-thiophen-3-yl-
[1,2,4] oxadiazole,
2-Chloro-4-[3-(4-methyl-5-pyridin-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-pyridine, 2-Chloro-4-[3-(4-methyl-5-pyridin-4-yl-4H-[ 1 ,2,4]triazol-3-ylsulfanyhnethyl)-
[1 ,2,4]oxadiazol-5-yl]-pyridine,
2-Chloro-4-[3-(4-methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[ 1 ,2,4]oxadiazol-5-yl]-pyridine,
4-[4-Methyl-5-(5-phenyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine,
3-(4-Methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-phenyl-
[l,2,4]oxadiazole,
5-(5-Bromo-2-fluoro-phenyl)-3-(4-methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole, 3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-thiophen-2-yl-4H-
[l,2,4]triazole,
2-Chloro-4-[3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[l,2,4]oxadiazol-5-yl]-pyridine,
4-{5-[3-(3-Fluoro-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4H- [l,2,4]triazol-3-yl}-pyridine,
3-(3-Fluoro-phenyl)-5-(4-methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole, 3-(4-Ethyl-5-thioρhen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[l,2,4]oxadiazole,
3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl- phenyl)-[ 1 ,2,4] oxadiazole, 4-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-furan-2-yhnethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-{5-[5-(3-Chloro-ρhenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol-
3 -yl} -pyridine,
3-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol- 3 -yl} -pyridine,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
3-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-furan-2-ylmethyl-4H-
[1 ,2,4]triazol-3-yl} -pyridine, 3-(4-Furan-2-ylmethyl-5-thiophen-2-yl-4H-[ 1 ,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[1,2,4] oxadiazole,
5-(5-Fluoro-2-methyl-phenyl)-3-(4-furan-2-ylmethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanyhnethyl)-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-furan-2-ylmethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazole,
3-[3-(4-Methyl-5-ρyridin-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-benzonitrile,
3-[3-(4-Methyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-benzonitrile, 3-[3-(4-Methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-benzonitrile,
5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole,
2-Chloro-4-[3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [1 ,2,4]oxadiazol-5-yl]-pyridine,
3-(4-Ethyl-5-thioρhen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-
[l,2,4]oxadiazole, 3-(4-Ethyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[l,2,4]oxadiazole,
4-[4-Ethyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine, 3-[4-Ethyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine,
3-(4-Ethyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl- phenyl)- [ 1 ,2,4] oxadiazole,
4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4H- [l,2,4]triazol-3-yl}-pyridine,
3-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
3-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-5-pyridin-4-yl-[l,2,4]triazol-
4-ylamine, 4-{5-[5-(5-Bromo-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[l,2,4]triazol-3-yl}-pyridine,
5-(4-Methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-2-yl-
[l,2,4]oxadiazole,
3-[3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-[l,2,4]oxadiazol-5- yl] -benzonitrile,
3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-phenyl-
[l,2,4]oxadiazole,
4-[3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl] -2-methoxy-pyridine, 3-(3-Chloro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
4-{5-[5-(3-Chloro-phenyl)-isoxazol-3-yhnethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol-3-yl}- pyridine,
2-Methyl-4-[3-(4-methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)- [l,2,4]oxadiazol-5-yl]-pyridine,
4-[3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl] -2-methyl-pyridine, 5-(4-Ethyl-5-thioρhen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-thioρhen-2-yl-
[l,2,4]oxadiazole,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 4-[3-(4-Ethyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]-
2-methyl-pyridine,
3-{5-[5-(3-Chloro-ρhenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -benzonitrile,
5-(3-Chloro-phenyl)-3-[5-(3-chloro-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[5-(4-chloro-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl] -[ 1 ,2,4] oxadiazole,
4- {5-[5-(2,5-Dichloro-phenyl)-[ 1 ,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 5-(2,5-Dichloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
5-(2,5-Difluoro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[l,2,4]oxadiazole,
4-{5-[5-(2,5-Difluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H- [l,2,4]triazol-3-yl} -pyridine,
5-(2,5-Dichloro-phenyl)-3-(4-ethyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
5-(2,5-Difluoro-phenyl)-3-(4-ethyl-5-tWophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[l,2,4]oxadiazole, 4- {5-[5-(3-Chloro-phenyl)-[l ,2,4]oxadiazol-3-yhnethylsulfanyl]-4-propyl-4H-
[ 1 ,2,4]triazol-3-yl} -pyridine,
4- {5-[5-(2-Fluoro-5-methyl-phenyl)-[ 1 ,2,4]oxadiazol-3-ylmethylsulfanyl]-4-propyl-4H-
[l,2,4]triazol-3-yl}-pyridine,
3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl- [1,2,4] oxadiazole,
3-(4-Methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfaι ylmethyl)-5-thioρhen-2-yl-
[l,2,4]oxadiazole, 4-[4-Methyl-5-(3-thiophen-3-yl-[l,2,4]oxadiazol-5-yhnethylsulfanyl)-4H-[l,2,4]triazol-3- yl]-pyridine,
5-(4-Methyl-5-thioρhen-3-yl-4H-[l,2,4]friazol-3-ylsulfanylmethyl)-3-thiophen-3-yl-
[l,2,4]oxadiazole, 5-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-3-yl-
[1,2,4] oxadiazole,
5-[3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-[l,2,4]oxadiazol-5- yl]-thiophene-3-carbonitrile,
5-(3-Chloro-phenyl)-3-[5-(2-fluoro-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[ 1 ,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[5-(3-fluoro-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[ 1 ,2,4] oxadiazole,
5-(3-Chloro-phenyl)-3-[5-(4-fluoro-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole, 3-(5-Benzo[b]thiophen-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro- phenyl)-[ 1 ,2,4] oxadiazole,
5-(3-Chloro-phenyl)-3-[5-(3-methoxy-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[5-(4-methoxy-ρhenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl] - [ 1 ,2,4] oxadiazole,
3-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]friazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl- phenyl)- [ 1 ,2,4] oxadiazole,
3-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-m-tolyl-[l,2,4]oxadiazole,
3-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl- phenyl)- [1,2,4] oxadiazole,
3-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-5-pyridin-4-yl-
[ 1 ,2,4]triazol-4-ylamine,
3-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-5-thiophen-2-yl-
[ 1 ,2,4]triazol-4-ylamine, 3-Pyridin-4-yl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-[l,2,4]triazol-4-ylamine,
3-Thiophen-2-yl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-[l,2,4]triazol-4- ylamine, 3.9
3-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thioρhen-3-yl-
[1,2,4] oxadiazole,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[l,2,4]friazol-3-ylsulfanyhnethyl)-
[l,2,4]oxadiazole, 4-[3-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]-2- methyl-pyridine,
5-(2,5-Difluoro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[ 1 ,2,4] oxadiazole,
4-[4-Ethyl-5-(5-thiophen-3-yl-isoxazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine,
4-Ethyl-3-furan-2-yl-5-(5-thiophen-3-yl-isoxazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazole,
5-(3-Chloro-phenyl)-3-[5-(3,5-dichloro-phenyl)-4-ethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-ρ-tolyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-m-tolyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[ 1 ,2,4] oxadiazole,
5-(3-Chloro-ρhenyl)-3-[4-ethyl-5-(3-nitro-phenyl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[ 1 ,2,4]oxadiazole, 4-{5-[3-(3-Chloro-ρhenyl)-isoxazol-5-ylmethylsulfanyl]-4-methyl-4H-[l,2,4]triazol-3-yl}- pyridine,
5-(3-Chloro-phenyl)-3-[5-(2,5-difluoro-phenyl)-4-ethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl] - [ 1 ,2,4] oxadiazole,
5-(3-Chloro-phenyl)-3-[5-(3-chloro-phenyl)-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]- [l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[5-(4-chloro-phenyl)-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[l,2,4]oxadiazole,
4-{5-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol-3-yl}- pyridine, 3-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-5-thiophen-2-yl-4H-
[l,2,4]triazole, 3-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-5-furan-2-yl-4H-
[l,2,4]triazole,
5-(2-Chloro-5-methyl-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)- [ 1 ,2,4] oxadiazole, 4-{5-[3-(3-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol-3-yl}- pyridine,
3-[3-(3-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-4-ethyl-5-thiophen-2-yl-4H-
[l,2,4]triazole,
3 - [3 -(3 -Chloro-phenyl)-isoxazol-5-yhnethylsulfanyl] -4-ethyl-5-furan-2-yl-4H- [l,2,4]triazole,
4-{5-[5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
5-(2,5-Dichloro-thiophen-3-yl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole, 4-{5-[5-(2,5-Dichloro-thioρhen-3-yl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-Ethyl-3-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-thiophen-2-yl- 4H-[l,2,4]triazole,
4-Ethyl-3-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-furan-2-yl-4H-
[l,2,4]triazole,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-1rifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole, 3-(3-Chloro-phenyl)-5-(4-ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
3-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-thioρhen-3-yl-
[l,2,4]oxadiazole,
5-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-3-yl- [l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-fluoro-phenyl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[l,2,4]oxadiazole, 5-(3-Chloro-phenyl)-3-[4-ethyl-5-(4-fluoro-phenyl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[l,2,4]oxadiazole,
3-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl-
[l,2,4]oxadiazole, 3-{3-[5-(3-Chloro-thiophen-2-yl)-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[l,2,4]oxadiazol-5-yl}-benzonitrile,
4-{5-[5-(3-Chloro-ρhenyl)-[l,3,4]oxadiazol-2-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol-
3 -yl} -pyridine,
2-(3-Chloro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,3,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(4-methoxy-phenyl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
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, 4-[3-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl] -2-methyl-pyridine, 3-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-methoxy-phenyl)-
[l,2,4]oxadiazole,
5-(4-Ethyl-5-trifluoromethyl-4H-[ 1 ,2,4]triazol-3 -ylsulfanylmethyl)-3 -(3 -methoxy-phenyl)- [1,2,4] oxadiazole,
5-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]1riazol-3-ylsulfanylmethyl)-3-thioρhen-2-yl-
[1,2,4] oxadiazole,
5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-trifluoromethyi-4H-[l,2,4]triazol-3- ylsulfanylmethyl)- [1,2,4] oxadiazole, 3-[3-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-benzonitrile,
3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-trifluoromethyl-4H-
[l,2,4]triazole,
3-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-5-trifluoromethyl-4H- [l,2,4]triazole,
4-Ethyl-3-(5-thiophen-3-yl-isoxazol-3-yhnethylsulfanyl)-5-trifluoromethyl-4H-
[l,2,4]triazole, 4-{3-[5-(3-Fluoro-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[ 1 ,2,4]oxadiazol-5-yl} -2-methyl-pyridine,
4-{3-[5-(3-Chloro-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[l,2,4]oxadiazol-5-yl}-2-methyl-pyridine, 4-{3-[5-(4-Chloro-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[l,2,4]oxadiazol-5-yl}-2-methyl-pyridine,
4-{3-[5-(4-Methoxy-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[l,2,4]oxadiazol-5-yl}-2-methyl-pyridine,
4-[3-(4-Ethyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]-2- methyl-pyridine,
3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-fluoro-phenyl)-
[1,2,4] oxadiazole,
4-{4-Ethyl-5-[5-(3-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-[l,2,4]triazol-
3-yl} -pyridine, 5-(3-Chloro-phenyl)-3-[5-(3,5-difluoro-phenyl)-4-ethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[5-(2,6-difluoro-phenyl)-4-ethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl] - [ 1 ,2,4] oxadiazole,
2-[3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-4-methyl-phenol,
3-{l-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-ethyl-5-furan-2-yl-4H-
[l,2,4]triazole,
4-(5-{l-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[l,2,4]friazol-3- yl)-pyridine, 3-[5-(4-Butoxy-phenyl)-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-(3-chloro- phenyl)-[l,2,4]oxadiazole,
3-(5-Benzo[l,3]dioxol-5-yl-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro- phenyl)-[l,2,4]oxadiazole,
3-(4-Ethyl-5-tlnophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-(2-methyl-thiazol-4- yl)-[ 1,2,4] oxadiazole,
3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(4-fluoro-ρhenyl)-
[1,2,4] oxadiazole, 4-Ethyl-3- { 1 -[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethylsulfanyl} -5-furan-2-yl-
4H-[l,2,4]triazole,
4-(4-Ethyl-5-{l-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4H-
[l,2,4]triazol-3-yl)-pyridine, 5 5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-methyl-3H-imidazol-4-yl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(l-methyl-lH-imidazol-2-yl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(l -methyl- lH-imidazol-4-yl)-4H-[ 1 ,2,4]triazol-3- l o ylsulfanylmethyl] - [ 1 ,2,4] oxadiazole,
4-{5-[5-(3-Chloro-phenyl)-4-methyl-isoxazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
3 - [5 -(3 -Chloro-phenyl)-4-methyl-isoxazol-3 -ylmethylsulfanyl] -4-ethyl-5-furan-2-yl-4H-
[l,2,4]triazole, is 3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(4-methyl-thiophen-2- yl)-[ 1 ,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-methyl-thioρhen-2-yl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(5-methyl-thioρhen-2-yl)-4H-[l,2,4]triazol-3- 0 ylsulfanylmethyl]-[l,2,4]oxadiazole,
4-{5-[4-Chloro-5-(3-chloro-phenyl)-isoxazol-3-yhnethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
3-[4-Chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-furan-2-yl-4H-
[l,2,4]triazole, 5 2-Chloro-4-{5-[5-(3-chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -6-methyl-pyridine,
3-[5-(5-Bromo-furan-2-yl)-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-(3-chloro- phenyl)- [ 1 ,2,4] oxadiazole,
2-Chloro-4-{5-[5-(3-chloro-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-4-ethyl-4H- 0 [l,2,4]triazol-3-yl} -pyridine,
2-Chloro-4-{5-[5-(3-chloro-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-4-ethyl-4H-
[l,2,4]triazol-3-yl}-6-methoxy-pyridine, 2-[3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl] -4-methyl-benzonitrile,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-methoxy-thiophen-2-yl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[ 1 ,2,4]oxadiazole, 3-[5-(5-Chloro-thiophen-3-yl)-isoxazol-3-yhnethylsulfanyl]-4-ethyl-5-furan-2-yl-4H-
[l,2,4]triazole,
3-[3-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]-5- fluoro-benzonitrile,
4-Ethyl-3-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-5-thiophen-2-yl-4H-[l,2,4]triazole, 4-Methyl-3-(5-phenyl-isoxazol-3-yhnethylsulfanyl)-5-thiophen-3-yl-4H-[l,2,4]triazole,
4-Ethyl-3-furan-2-yl-5-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazole,
4-[4-Ethyl-5-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]-pyridine,
4-[4-Methyl-5-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]-pyridine,
2-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-m-tolyl-[l,3,4]oxadiazole, 4-[4-Methyl-5-(5-m-tolyl-[l,3,4]oxadiazol-2-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine,
4-[4-Ethyl-5-(5-m-tolyl-[l,3,4]oxadiazol-2-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine,
4-{5-[5-(5-Chloro-thiophen-3-yl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H- [l,2,4]triazol-3-yl} -pyridine,
3-[3-(4-Ethyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]-
4-fluoro-benzonitrile,
3-[3-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]-4- fluoro-benzonitrile, 3-[3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]friazol-3-ylsulfanyhnethyl)-[l,2,4]oxadiazol-5- yl]-4-fluoro-benzonitrile,
3-[3-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]- benzonitrile,
3-[5-(4-Ethyl-5-fxrran-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-3-yl]- benzonitrile,
3-[3-(4-Methyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-[l,2,4]oxadiazol-
5-yl]-benzonitrile, 5-(5-Chloro-2-fluoro-phenyl)-3-(4-methyl-5-trifluoromethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole,
2-Chloro-4-[3-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-pyridine, 2-Chloro-4-[3-(5-furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-pyridine,
2-(3-Chloro-phenyl)-5-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl] - [ 1 ,3 ,4] oxadiazole,
2-(3-Chloro-phenyl)-5-(4-methyl-5-thiazol-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,3,4]oxadiazole,
2-(3-Chloro-phenyl)-5-(5-fman-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,3,4]oxadiazole,
2-(3-Chloro-phenyl)-5-(4-ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,3,4]oxadiazole, 4- {4-Ethyl-5-[5-(4-methyl-thiophen-2-yl)-[l ,2,4]oxadiazol-3-yhnethylsulfanyl]-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
3-(4-Ethyl-5-furan-2-yl-4H-[ 1 ,2,4]triazol-3-ylsulfanylmethyl)-5-(4-methyl-thiophen-2-yl)-
[l,2,4]oxadiazole,
3-(3-Chloro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)- [l,2,4]oxadiazole,
4-{5-[3-(3-Chloro-ρhenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol-
3 -yl} -pyridine,
4-{4-Ethyl-5-[5-(3-nitro-phenyl)-[l,3,4]oxadiazol-2-yhnethylsulfanyl]-4H-[l,2,4]triazol-3- yl} -pyridine, 2-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]friazol-3-ylsulfanylmethyl)-5-(3-nitro-phenyl)-
[l,3,4]oxadiazole,
4-{5-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-cyclopropyl-4H-[l,2,4]triazol-
3-yl}-pyridine,
3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-(4-methoxy-phenyl)-4H- [l,2,4]triazole,
5-(3-Chloro-phenyl)-3-[l-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)- ethyl]-[ 1 ,2,4]oxadiazole, 5-(3-Chloro-phenyl)-3-[l-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-
[1,2,4] oxadiazole,
4-(5- { l-[5-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine, 4-(5- { l-[5-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
3-[5-(4-Ethyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,3,4]oxadiazol-2-yl]- benzonitrile,
3-[5-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,3,4]oxadiazol-2-yl]- benzonitrile,
3-[5-(4-Methyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,3,4]oxadiazol-2- yl]-benzonitrile,
3-[5-(4-Cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[l,3,4]oxadiazol-2-yl]-benzonitrile, 4- {5-[5-(3-Chloro-phenyl)-[l ,3,4]oxadiazol-2-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-{5-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-ylmethylsulfanyl]-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,3,4]oxadiazol-2-ylmethylsulfanyl]-4-cyclopropyl- 4H-[1 ,2,4]triazol-3-yl} -pyridine,
2-(5-Chloro-2-fluoro-phenyl)-5-[4-ethyl-5-(4-methoxy-phenyl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,3,4]oxadiazole,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,3,4]oxadiazol-2-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3-yl} -pyridine, 4-{5-[5-(5-Chloro-2-fluoro-ρhenyl)-[l,3,4]oxadiazol-2-yhnethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
2-(3-Chloro-phenyl)-5-[4-ethyl-5-(4-methoxy-phenyl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,3,4]oxadiazole,
2-(3-Chloro-phenyl)-5-[l-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]- [l,3,4]oxadiazole,
5-(5-Chloro-2-fluoro-phenyl)-3-[l-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanyl)-ethyl]-[l,2,4]oxadiazole, 4-(5- { 1 -[5-(5-Chloro-2-fluoro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-methyl-4H-
[1 ,2,4]triazol-3-yl)-pyridine,
4-(5-{l-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine, 2-Chloro-4-[3-(4-cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[ 1 ,2,4]oxadiazol-5-yl]-pyridine,
4-{5-[5-(2-Fluoro-5-methyl-phenyl)-[l,3,4]oxadiazol-2-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3-yl} -pyridine,
4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[l,3,4]oxadiazol-2-yhnethylsulfanyl]-4H- [l,2,4]triazol-3-yl} -pyridine,
4-{4-Cyclopropyl-5-[5-(2-fluoro-5-methyl-phenyl)-[l,3,4]oxadiazol-2-yhnethylsulfanyl]-
4H-[l,2,4]triazol-3-yl}-pyridine,
2-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl- phenyl)- [1,3,4] oxadiazole, 2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-(2-fluoro-5- methyl-phenyl)-[ 1 ,3,4]oxadiazole,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-(5- { 1 -[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl} -4-ethyl-4H- [l,2,4]triazol-3-yl)-pyridine,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3-yl} -pyridine,
4-(5- { 1 -[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl} -4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine, 4-{5-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-(5- { 1 -[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl)-ρyridine,
3-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yi^ethylsulfanyl]-4-ethyl-5-furan-2-yl-4H- [l,2,4]triazole,
3-{l-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-ethyl-5-furan-2-yl-4H-
[l,2,4]triazole, 4-(5- { 1 -[5-(3-Chloro-phenyl)-[ 1 ,3,4]oxadiazol-2-yl]-ethylsulfanyl} -4-methyl-4H-
[l,2,4]triazol-3-yl)-pyridine,
4-(5-{l-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine, 4-(5- { 1 -[5-(3-Chloro-phenyl)-[ 1 ,3,4]oxadiazol-2-yl]-ethylsulfanyl} -4-cyclopropyl-4H-
[l,2,4]triazol-3-yl)-pyridine,
5-(5-Chloro-2-fluoro-phenyl)-3-(5-furan-2-yl-4-methyl-4H-[l,2,4]friazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole,
5-(5-Chloro-2-fluoro-phenyl)-3-(5-furan-3-yl-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
4-Chloro-2-[3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1 ,2,4]oxadiazol-5-yl]-phenol,
2-Chloro-4-[5-(4-methyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[ 1 ,3 ,4] oxadiazol-2-yl] -pyridine, 2-Chloro-4-[5-(4-ethyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,3,4]oxadiazol-2-yl]-pyridine,
2-Chloro-4- [5 -(4-cyclopropyl-5 -pyridin-4-yl-4H- [ 1 ,2,4]triazol-3 -ylsulfanylmethyl)-
[ 1 ,3 ,4]oxadiazol-2-yl]-pyridine,
2-Chloro-4-[5-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [ 1 ,3,4]oxadiazol-2-yl]-pyridine,
2-Chloro-4-{5-[4-ethyl-5-(4-methoxy-phenyl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[ 1 ,3,4]oxadiazol-2-yl} -pyridine,
2-(3-Chloro-phenyl)-5-{l-[5-(4-methoxy-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanyl] -ethyl} - [1,3,4] oxadiazole, 4-(5- { 1 -[5-(5-Chloro-2-fluoro-phenyl)-[ 1 ,3,4]oxadiazol-2-yl]-ethylsulfanyl} -4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
5-(5-Bromo-2-fluoro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
2-(3-Chloro-phenyl)-5-[5-(4-methoxy-ρhenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanyhnethyl]-[l,3,4]oxadiazole,
4-{5-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 4-{5-[5-(3-Chloro-ρhenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-cycloproρyl-4H-
[1 ,2,4]triazol-3 -yl} -pyridine,
4-(5-{l-[5-(2-Fluoro-5-methyl-phenyl)-[l,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-methyl-
4H-[l,2,4]triazol-3-yl)-pyridine, 4-(4-Ethyl-5-{l-[5-(2-fluoro-5-methyl-phenyl)-[l,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4H-
[ 1 ,2,4]triazol-3 -yl)-p yridine,
4-(4-Cyclopropyl-5-{l-[5-(2-fluoro-5-methyl-phenyl)-[l,3,4]oxadiazol-2-yl]- ethylsulfanyl} -4H-[ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(4-Cyclopropylmethyl-5-{l-[5-(2-fluoro-5-methyl-phenyl)-[l,3,4]oxadiazol-2-yl]- ethylsulfanyl}-4H-[l,2,4]triazol-3-yl)-pyridine,
2-(2-Fluoro-5-methyl-phenyl)-5-{l-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[l,2,4]triazol-
3-ylsulfanyl]-ethyl} -[ 1 ,3,4]oxadiazole,
4-(5- { 1 -[5-(5-Chloro-2-fluoro-phenyl)-[l ,3,4]oxadiazol-2-yl]-ethylsulfanyl} -4-ethyl-4H-
[l,2,4]triazol-3-yl)-pyridine, 4-(5-{l-[5-(5-Chloro-2-fluoro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4- cyclopropyl-4H-[ 1 ,2,4]triazol-3-yl)-pyridine,
2-(5-Chloro-2-fluoro-phenyl)-5-[l-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)- ethyl]-[l,3,4]oxadiazole,
2-(5-Chloro-2-fluoro-phenyl)-5-{l-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[l,2,4]triazol- 3-ylsulfanyl]-ethyl}-[l,3,4]oxadiazole,
4-(4-Cyclopropylmethyl-5- { 1 -[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]- ethylsulfanyl}-4H-[l,2,4]triazol-3-yl)-pyridine,
4-(5-{l-[5-(3-Fluoro-ρhenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine, 4-(4-Cycloρroρyl-5-{l-[5-(3-fluoro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4H-
[l,2,4]triazol-3-yl)-pyridine,
4-(5-{l-[5-(4-Methoxy-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanyl]-ethyl}-
[l,3,4]oxadiazol-2-yl)-2-methyl-pyridine,
4-(5- { 1 -[4-Ethyl-5-(4-methoxy-phenyl)-4H-[ 1 ,2,4]triazol-3-ylsulfanyl]-ethyl}- [l,3,4]oxadiazol-2-yl)-2-methyl-pyridine,
4-{5-[l-(4-Ethyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-[l,3,4]oxadiazol-2- yl} -2-methyl-pyridine, 4-{5-[l-(4-Cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-
[ 1 ,3 ,4]oxadiazol-2-yl} -2-methyl-pyridine,
4-{5-[l-(5-Furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-[l,3,4]oxadiazol-2- yl} -2-methyl-pyridine, 2-(3-Chloro-phenyl)-5-{l-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[l,2,4]triazol-3- ylsulfanyl]-ethyl} -[ 1 ,3 ,4]oxadiazole,
3-(5- { 1 -[5-(3-Chloro-phenyl)-[ 1 ,3,4]oxadiazol-2-yl]-ethylsulfanyl} -4-methyl-4H-
[l,2,4]triazol-3-yl)-pyridine,
4-(5-{l-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-methyl-4H- [l,2,4]triazol-3-yl)-2-methyl-pyridine,
4-(5- { 1 -[5-(3-Chloro-phenyl)-[l ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-cyclopropyl-4H-
[1 ,2,4]triazol-3-yl)-pyridine,
5-(3-Chloro-phenyl)-3-{l-[5-(4-methoxy-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanyl]-ethyl} -[ 1 ,2,4] oxadiazole, 4-(5-{l-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4- cyclopropyl-4H-[l,2,4]triazol-3-yl)-pyridine,
5-(5-Chloro-2-fluoro-phenyl)-3-{l-[5-(4-methoxy-ρhenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanyl]-ethyl}-[l,2,4]oxadiazole,
4-[5-(4-Ethyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,3,4]oxadiazol-2-yl]- 2-methyl-pyridine,
4-[5-(4-Cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[l,3,4]oxadiazol-2-yl]-2-methyl-pyridine,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-cyclopropyl-
4H-[ 1 ,2,4]triazol-3-yl} -pyridine, 4-[5-(5-Furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,3,4]oxadiazol-2-yl]-
2-methyl-pyridine,
4-(5- { 1 -[5-(3-Chloro-phenyl)-[ 1 ,3,4]oxadiazol-2-yl]-ethylsulfanyl} -4-cyclopropylmethyl-
4H-[l,2,4]triazol-3-yl)-pyridine,
4-(5-{l-[5-(4-Fluoro-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanyl]-ethyl}- [ 1 ,3 ,4]oxadiazol-2-yl)-2-methyl-pyridine,
4-(5-{l-[5-(3-Fluoro-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanyl]-ethyl}-
[l,3,4]oxadiazol-2-yl)-2-methyl-pyridine, 3-[3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-4-fluoro-benzonitrile,
4-Chloro-2-[3-(4-cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazol-5 -yl] -phenol, 4-{4-Cyclopropyl-5-[5-(3-methoxy-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-4H-
[1 ,2,4]triazol-3-yl}-pyridine,
4- {4-Cyclopropyl-5- [5-(2-fluoro-5 -methyl-phenyl)- [1,2,4] oxadiazol-3 -ylmethylsulfanyl] -
4H-[l,2,4]triazol-3-yl}-pyridine,
4- {4-Cyclopropyl-5- [5-(3 -fluoro-phenyl)- [ 1 ,2,4] oxadiazol-3 -ylmethylsulfanyl] -4H- [l,2,4]triazol-3-yl}-pyridine,
4-[4-Cyclopropyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3- yl]-pyridine,
3-[3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-benzonitrile, 4-{4-Cyclopropyl-5-[5-(2,5-difluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-{4-Cyclopropyl-5-[l-(5-m-tolyl-[l,2,4]oxadiazol-3-yl)-ethylsulfanyl]-4H-[l,2,4]triazol-
3-yl} -pyridine,
4-(4-Cyclopropyl-5-{l-[5-(3-methoxy-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4H- [l,2,4]triazol-3-yl)-pyridine,
4-{5-[5-(2-Chloro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-4-cyclopropyl-
4H-[ 1 ,2,4]triazol-3-yl} -pyridine,
2-[3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]friazol-3-ylsulfanylmethyl)-
[ 1 ,2,4]oxadiazol-5-yl]-4-methyl-phenol, 4-(5- { 1 -[5-(2-Chloro-5-methyl-phenyl)-[l ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4- cyclopropyl-4H-[l,2,4]triazol-3-yl)-pyridine,
{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-phenyl} -methanol,
3-[5-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-3- yl] -phenol,
5-(3-Chloro-phenyl)-3-[4-(tefrahyαro-furan-2-ylmethyl)-5-tlnophen-2-yl-4H-[l,2,4]triazol-
3-ylsulfanyhnethyl]-[l,2,4]oxadiazole, (2-Chloro-phenyl)- {5-[5-(3-chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-ylmethylsulfanyl]-4- isobutyl-4H-[l,2,4]triazol-3-yl}-methanol,
5-(2-Fluoro-5-methyl-phenyl)-3-[5-thiophen-2-yl-4-(2,2,2-trifluoro-ethyl)-4H-
[l,2,4]triazol-3-ylsulfanylmethyl]-[l,2,4]oxadiazole, 3-(2,5-Difluoro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
5-Furan-3-yl-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
3-(3-Chloro-phenyl)-5-(5-furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4] oxadiazole,
3-(3-Chloro-phenyl)-5-(5-furan-3-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(5-furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole, 5-(3-Chloro-phenyl)-3-(5-furan-3-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
4-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[l,2,4]triazol-3-yl}-pyrimidine,
4-{5-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4H- [l,2,4]triazol-3-yl}-pyrimidine,
3-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole,
3-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole, 5-(5-Chloro-thiophen-2-yl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)- [1,2,4] oxadiazole,
5-(5-Chloro-thiophen-2-yl)-3-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
5-(5-Chloro-thioρhen-3-yl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole,
4-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol-
3-yhnethoxy} -phenol, 4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,3,4]oxadiazol-2-yhnethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -ylmethoxy} -phenol,
3-(2,5-Difluoro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole, 3-(2,5-Difluoro-phenyl)-5-(5-furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
4-(5-{l-[3-(3-Chloro-ρhenyl)-[l,2,4]oxadiazol-5-yl]-ethylsulfanyl}-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4- { 5- [5 -(5-Chloro-2-fluoro-phenyl)- [ 1 ,2,4] oxadiazol-3 -ylmethylsulfanyl] -4-cyclopropyl- 4H-[l,2,4]triazol-3-yl}-pyrimidine,
2-(5- { 1 -[5-(3-Chloro-ρhenyl)-[l ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl)-5-methoxy-pyrimidine,
2-(5-{l-[5-(3-Chloro-ρhenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-
[l,2,4]triazol-3-yl)-pyrimidine, 4-(5-{l-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl)-2-methoxy-pyridine,
5-(5-{l-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-
[l,2,4]triazol-3-yl)-2-methoxy-pyridine,
2-(5- { 1 -[5-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-ethyl-4H- [ 1 ,2,4]friazol-3 -yl)-5-methoxy-pyridine,
3-(5-{l-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-
[l,2,4]triazol-3-yl)-6-methoxy-pyridazine,
3-(5- { 1 -[5-(3-Chloro-phenyl)-[ l,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-cycloproρyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine, 4-{5-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3-yl} -pyridine,
5-(3-Chloro-ρhenyl)-3-(5-fman-2-yl-4-isobutyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
5-(3-Chloro-ρhenyl)-3-[4-(3-methylsulfanyl-propyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-hexyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[1,2,4] oxadiazole, 5-(3-Chloro-phenyl)-3-(4-cyclopropylmethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
5-(3-Chloro-ρhenyl)-3-[4-(3-fluoro-benzyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl] -[1,2,4] oxadiazole, 5-(3-Chloro-phenyl)-3-[4-(3-methyl-benzyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-(2-methyl-butyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-(3-methyl-butyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[ 1 ,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-(2-fluoro-benzyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[ 1 ,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-yloxymethyl)-
[l,2,4]oxadiazole, 4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-yhnethoxy]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-(5-{l-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethoxy}-4-methyl-4H-[l,2,4]triazol-
3-yl)-pyridine,
4-(5-{l-[3-(3-Chloro-phenyl)-isoxazol-5-yl]-ethoxy}-4-methyl-4H-[l,2,4]triazol-3-yl)- pyridine,
5-(2-Methoxy-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
5-Furan-2-yl-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole, 3-[3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl] -benzoic acid methyl ester,
5-(2-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[l,2,4]oxadiazole,
5-(2,5-Difluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanyhnethyl)-[l,2,4]oxadiazole,
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-vinyl-phenyl)-
[1,2,4] oxadiazole, 5-(3-Difluoromethoxy-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
5-(4-Methoxy-thiophen-3-yl)-3-(4-methyl-5-thioρhen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole, 5-(2-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
5 -(4-Fluoro-phenyl)-3 -(4-methyl-5 -thiophen-2-yl-4H- [ 1 ,2,4]triazol-3 -ylsulfanyhnethyl)-
[l,2,4]oxadiazole,
3-(3-Chloro-phenyl)-5-[l-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)- ethyl]-[l,2,4]oxadiazole,
-(5- { 1 -[3-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-ethylsulfanyl} -4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
3-(3-Chloro-phenyl)-5-[2-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-yl)-ethyl]-
[l,2,4]oxadiazole, 5-(3-Chloro-phenyl)-3-(5-furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylmethyl)-
[l,2,4]oxadiazole,
2-(3-Chloro-phenyl)-5-[2-(5-furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-yl)-ethyl]-
[l,3,4]oxadiazole,
2-(3-Chloro-phenyl)-5-[2-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-yl)-ethyl]- [l,3,4]oxadiazole,
2-(3-Chloro-phenyl)-5-[2-(4-cyclopropyl-5-furan-2-yl-4H-[l,2,4]triazol-3-yl)-ethyl]-
[l,3,4]oxadiazole,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-ethyl}-4-methyl-4H-[l,2,4]triazol-3- yl)-pyridine, 4-(5- {2-[3-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-ethyl} -4-ethyl-4H-[l ,2,4]triazol-3- yl)-ρyridine, 4-(5- {2-[3-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-ethyl} -4-cyclopropyl-4H-
[1 ,2,4]triazol-3-yl)-pyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H- [l,2,4]triazol-3-yl)-pyridine,
4-(5- {2-[3-(3-Chloro-ρhenyl)-[ 1 ,2,4]oxadiazol-5-yl]-2-methyl-ρropyl} -4-cyclopropyl-4H-
[1 ,2,4]triazol-3-yl)-pyridine, 4-(5-{2-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-propyl}-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3-yl)-pyridine,
8-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tefrahydiO-
[l,2,4]triazolo[4,3-a]pyridine, 5 8-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-3-thioρhen-2-yl-5,6,7,8-tefrahydro-
[l,2,4]triazolo[4,3-a]pyridine,
8-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8- tefrahydro-[l,2,4]triazolo[4,3-a]pyridine,
5-(5-Bromo-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-(3-chloro-phenyl)- ι0 [1,2,4] oxadiazole,
3-[3-(4-Methyl-5-thiophen-2-yl-4H-[ 1 ,2,4]triazol-3 -ylsulfanylmethyl)- [ 1 ,2,4]oxadiazol-5- yl] -phenylamine,
5-(3-Chloro-ρhenyl)-3-(4-methyl-5-thioρhen-2-yl-4H-[l,2,4]triazole-3-sulfonylmethyl)-
[1,2,4] oxadiazole, is 5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3-sulfinylmethyl)-
[1,2,4] oxadiazole,
2-Methyl-6-[3-(4-methyl-5-thioρhen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1 ,2,4]oxadiazol-5-yl]-pyridine,
4-(5- { 1 -[5-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-ethyl-4H- 0 [ 1 ,2,4]triazol-3 -yl)-pyridin-2-ol,
4-(5-{2-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-propyl}-4-methyl-4H-[l,2,4]triazol-3- yl)-pyridine,
[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-methyl-(4-methyl-5-pyridin-4-yl-4H-
[l,2,4]triazol-3-yl)-amine, 5 8-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tefrahydro-
[l,2,4]triazolo[4,3-a]pyrimidine,
8-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-3-ρyridin-4-yl-5,6,7,8- tetrahydro- [ 1 ,2,4]triazolo [4,3 -a]pyrimidine,
8-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yhnethyl]-3-pyridin-4-yl-5,6,7,8-tefrahydro- o [l,2,4]triazolo[4,3-a]pyrimidine,
8-{l-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-tefrahydro-
[ 1 ,2,4] triazolo [4,3 -ajpyrimidine, 8-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-3-furan-2-yl-5,6,7,8- tetrahydro-[ 1 ,2,4]triazolo[4,3-a]pyrimidine,
8-{l-[5-(3-Chloro-ρhenyl)-[l,2,4]oxadiazol-3-yl]-ethyl}-3-ρyridin-4-yl-5,6,7,8-tefrahydro-
[ 1 ,2,4]triazolo[4,3 -a]pyrimidine, 3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-(lH-pyrrol-3-yl)-
[1,2,4] oxadiazole,
4-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine 1 -oxide,
5-(3-Chloro-phenyl)-3-(2-furan-2-yl-3-methyl-3H-imidazol-4-ylsulfanylmethyl)- [1,2,4] oxadiazole,
5-(5-Chloro-2-fluoro-phenyl)-3-[4-(2-fluoro-ethyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[ 1 ,2,4]oxadiazole,
5-(5-Chloro-tWophen-3-yl)-3-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole, 3-[3-(4-Ethyl-5-fiιran-2-yl-4H-[l,2,4]triazol-3-y^ hydroxy-benzonitrile,
3-(3-Chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-yl)-ethyl]-
[l,2,4]oxadiazole,
4-(5- {2-[3-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-propyl} -[1 ,3,4]oxadiazol-2-yl)- pyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-l-methyl-ethyl}-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(5- {2-[3-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-cyclopropyl} -4-cyclopropyl-4H-
[l,2,4]triazol-3-yl)-pyridine, or 4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-l,l-dimethyl-ethyl}-[l,3,4]oxadiazol-
2-yl)-pyridine,
3-(5-{l-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethoxy}-4-cyclopropyl-4H- [ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(5- { 1 -[5-(2-Chloro-5-methyl-phenyl)-[l ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-methyl- 4H-[l,2,4]triazol-3-yl)-pyridine, 4-(5- { l-[5-(2,5-Difluoro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(5-{l-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-methyl-
4H-[l,2,4]triazol-3-yl)-pyridine, 4-(4-Cyclopropyl-5-{l-[5-(2-fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-yl]- ethylsulfanyl} -4H-[ 1 ,2,4]triazol-3 -yl)-pyridine,
3- {3-[ 1 -(4-Methyl-5-pyridin-4-yl-4H-[ 1 ,2,4]triazol-3-ylsulfanyl)-ethyl]-[l ,2,4]oxadiazol-
5 -yl} -benzonitrile,
3-{3-[l-(4-Cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]- [l,2,4]oxadiazol-5-yl}-benzonitrile,
3-{l-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethylsulfanyl}-5-pyridin-4-yl-
[ 1 ,2,4]triazol-4-ylamine,
3-(3-Chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-yl)-ethyl]-
[1,2,4] oxadiazole, 4-(5- {2-[3-(3-Chloro-ρhenyl)-[ 1 ,2,4]oxadiazol-5-yl]-l -methyl-ethyl} -4-cyclopropyl-4H-
[l,2,4]triazol-3-yl)-pyridine, cis-4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-cyclopropyl}-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(5- {2-[3-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-l , 1 -dimethyl-ethyl} -[1 ,3,4]oxadiazol- 2-yl)-pyridine,
4-(5- {2-[3-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-2-methyl-propyl} -[1 ,3,4]oxadiazol-2- yl)-pyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-l-methyl-ethyl}-[l,3,4]oxadiazol-2- yl)-pyridine, 4-(5- {2-[3-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-cyclopropyl} -[ 1 ,3,4]oxadiazol-2-yl)- pyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-cyclopropyl}-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(5-{2-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-propyl}-4-methyl-4H-[l,2,4]triazol-3- yl)-pyridine, 4-(5-{2-[3-(3-Chloro-ρhenyl)-[l,2,4]oxadiazol-5-yl]-proρyl}-[l,3,4]oxadiazol-2-yl)- pyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-propyl}-4-methyl-4H-[l,2,4]triazol-3- yl)-pyridine, 4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
(S)-[l-[3-(3-Chloro-ρhenyl)-[l,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-
[l,2,4]triazol-3-yl)-ethyl]-carbamic acid tert-butyl ester,
(S)rl-[3-(3-Chloro-ρhenyl)-[l,2,4]oxadiazol-5-yl]-2-(4-cycloproρyl-5-ρyridin-4-yl-4H- [l,2,4]triazol-3-yl)-ethylamine,
(S)-[l-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-
[l,2,4]triazol-3-yl)-ethyl]-dimethyl-amine,
or salt thereof. Further feasible examples of compounds of formula I are provided by compounds of formula la
Figure imgf000060_0001
wherein:
P is selected from the group consisting of hydrogen, C3-7alkyl 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; R1 is selected from the group consisting of hydrogen, hydroxy, halo, nifro, Cι-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, Co-6alkylC3-6cycloalkyl, OCo-6alkylC3-6cycloalkyl, Co-6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OC1-6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0- 6alkylNR5R6, OC2-6alkylNR5R6, C1-6alkyl(CO)NR5R6, OC1-6afkyl(CO)NR5R6, C0- 6alkylNR5(CO)R6, OC2-6alkylNR5(CO)R6, C0-6alkylNR5(CO)NR5R6, C0-6alkylSR5, OC2- 6alkylSR5, Co-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0- 6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R^C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R^ Co-6alkylNR5(SO2)NR5R6, OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6, C0-6alkylNR5(CO)OR6, OC2-6alkylNR5(CO)OR6, SO3R5 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;
M1 is selected from the group consisting of a bond,
Figure imgf000061_0001
C2-3alkenyl, C2-3alkynyl, Co- 4aιkyl(CO)Co-4arkyl, QwalkylOCo-salkyl, Co-3alkyl(CO)NR5, C0-3alkyl(CO)NR5C0-3alkyl, C0- alkylNR5, C0-3alkylSC0-3alkyl, Co-3alkyl(SO)C0-3alkyl and Co-salky SO^Co-salkyl; R2 is selected from the group consisting of hydrogen, hydroxy, Co-6alkylcyano, oxo, =NR5, =NOR5, C1-4alkylhalo, halo, C1-4alkyl, O(CO)C alkyl, C1-4alkyl(SO)C0-4alkyl, Ci. 4alkyl(SO2)C0-4alkyl, (SO)C0-4alkyl, (SO2)C0-4alkyl, OCι-4alkyl, , d-4alkylOR5 and C0- 4alkylNR5R6;
X1, X2 and X3 are independently selected from the group consisting of CR, CO, N, NR, O and S; R is selected from the group consisting of hydrogen, Co-3 alkyl, halo, Co-3 alky 1OR5, Co- 3alkylNR5R6, C0-3alkyl(CO)OR5, C0-3alkylNR5R6 and C0-3alkylaryl; M2 is selected from the group consisting of a bond, Ci^alkyl, C3- cycloalkyl, C2-3alkenyl, ' C2-3allcynyl, Co^alky CO^o^alkyl, Co^alkylOCo^alkyl, Co-3alkylNR5C1.3 alkyl, C0- 3alkyl(CO)NR5, C0-4alkylNR5, Co-3alkylSCo-3alkyl, Co-3alkyl(SO)Co-3alkyl and C0- 3alkyl(SO2)Co-3aUcyl;
R3 is selected from the group consisting of hydrogen, hydroxy, Co-6alkylcyano, oxo, =NR5,
NOR >5D, C1-4alkylhalo, halo, C1-4alkyl, O(CO)C1-4alkyl, C1-4alkyl(SO)C0-4alkyl, C
4alkyl(SO2)C0-4alkyl, (SO)C0-4alkyl, (SO2)C0-4alkyl, OC1-4alkyl, C1- alkylOR5 and C0- 4alkylNR5R6; X4 is selected from the group consisting of C0-4alkylR5, Co-4alkyl(NR5R6), C0- 4alkyl(NR5R6)=N, NR5C0-4alkyl(NR5RD)=N, NOC0-4alkyl, C1-4alkylhalo, C, O, SO, SO2 and S; 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; R4 is selected from the group consisting of hydrogen, hydroxy, Co-6alkylcyano, oxo, =NR5, =NOR5, C1-4alkylhalo, halo, C1-4alkyl, OC1-4alkyl, OC0-6alkylaryl, O(CO)C1-4alkyl, C0- 4alkyl(S)Co-4alkyl, Cι-4alkyl(SO)C0-4alkyl, C1-4alkyl(SO2)C0-4alkyl, (SO)C0-4alkyl, (SO2)C0- alkyl, C1-4alkylOR5, Co- alkylNR5R6 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;
R5 and R6 are independently selected from the group consisting of hydrogen, hydroxy, d- 6alkyl, Co-6alkylC3-6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S, and wherein R and R may together form a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S; wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, Co-6alkylaryl and Co-6alkylheteroaryl defined under R1, R2, R3, R4, R5 and R6 may be substituted by one or more A; and A is selected from the group consisting of hydrogen, hydroxy, oxo, halo, nifro, Co- 6alkylcyano, C1-4alkyl, Co- alkylC -6cycloalkyl, C1-6alkylhalo, OC1-6alkylhalo, C2-6alkenyl, OC1-6alkyl, C0-3alkylaryl, Co-6alkylOR5, OC2-6alkylOR5, Cι-6alkylSR5, OC2-6alkylSR5, (CO)R5, O(CO)R5, OC2-6alkylcyano, Co-6alkylCO2R5, OC1-6alkylCO2R5, O(CO)OR5, OCj. 6alkyl(CO)R5, C1-6alkyl(CO)R5, NR5OR6, C0-6alkylNR5R6, OC2-6alkylNR5R6, C0- 6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, OC2-6alkylNR5(CO)R6, C0-6alkylNR5(CO)R6, Co-6alkylNR5(CO)NR5R6, O(CO)NR5R6, NR5(CO)OR6, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, SO3R5, C1-6alkylNR5(SO2)NR5R6, OC2-6alkyl(SO2)R5, C0-6alkyl(SO2)R5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5 and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S; m is selected from 0, 1, 2, 3 and 4; and n is selected from 0, 1, 2 and 3, or salt thereof. 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 ofthe compounds of formula I and la.
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 (18th Edition, Mack Publishing Co.).
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.
The invention relates to any and all tautomeric forms ofthe compounds of formula I.
The invention relates to the following compounds, which may be used as intermediates in the preparation of a compound of formula I; 6-Methylpyridine-4-carboxylic acid,
1 -Cyano-3-ethylbenzene,
3-Ethylbenzoic acid,
3-Fluoro-5-methyl-benzoic acid,
3-Methoxymethyl-benzoic acid, N-Hydroxy-3 -methoxy-benzamidine,
N-Hydroxy-benzamidine,
N-Hydroxy-3-methyl-benzamidine,
5-Chloromethyl-3-(3-methoxy-phenyl)-[l,2,4]oxadiazole,
5-Chloromethyl-3-phenyl-[l,2,4]oxadiazole, 5-Chloromethyl-3-m-tolyl-[l,2,4]oxadiazole,
3-(3-Chloromethyl-[l,2,4]oxadiazol-5-yl)-benzonitrile,
3-(5-Chloromethyl-[l,2,4]oxadiazol-3-yl)-benzonitrile, -Chloromethyl-5-m-tolyl-[l,2,4]oxadiazole, -Chloromethyl-5-(3-fluoro-phenyl)-[l,2,4]oxadiazole, -Chloromethyl-5-thiophen-3-yl-[l,2,4]oxadiazole, -(3 -Chloromethyl- [1,2,4] oxadiazol-5 -yl)-5-methyl-pyridine, -Chloromethyl-5-(3-nitro-phenyl)-[l,2,4]oxadiazole, -(3 -Chloromethyl- [ 1 ,2,4]oxadiazol-5-yl)-2-methyl-pyridine, -Chloromethyl-5-(3-ethyl-phenyl)-[l,2,4]oxadiazole, -(3 -Chloromethyl- [ 1 ,2,4] oxadiazol-5 -yl)-phenyl] -dimethyl-amine, -Chloromethyl-5-(3-chloro-phenyl)-[l,2,4]oxadiazole, -Chloromethyl-5-(3-trifluoromethoxy-phenyl)-[ 1 ,2,4]oxadiazole, -(3-Bromo-phenyl)-3-chloromethyl-[l,2,4]oxadiazole, -Chloromethyl-5-thiophen-2-yl-[ 1 ,2,4] oxadiazole, -Chloromethyl-5-(3-fluoro-5-methyl-phenyl)-[l,2,4]oxadiazole, -Chloromethyl-5-thiazol-4-yl-[ 1 ,2,4] oxadiazole, -Chloromethyl-5-(3-iodo-phenyl)-[l,2,4]oxadiazole, -Chloromethyl-5-(3-methoxymethyl-phenyl)-[l,2,4]oxadiazole, -Furan-2-yl-4-methyl-4H-[ 1 ,2,4]triazole-3-thiol, -Methyl-5-phenyl-4H-[l,2,4]triazole-3-thiol, -Methyl-5-pyridin-2-yl-4Η-[ 1 ,2,4]triazole-3-thiol, -(4-Benzyl-morpholin-2-yl)-4-methyl-4H-[l,2,4]triazole-3-thiol, -tert-Butyl-4-methyl-4H-[ 1 ,2,4]triazole-3-thiol, -Methyl-5-pyridin-3-yl-4H-[l,2,4]triazole-3-thiol, -Methyl-5-thiophene-3-yl-4H-[ 1 ,2,4]triazole-3-thiol, -Methyl-5-thiazol-4-yl-4H-[ 1 ,2,4]triazole-3-thiol, -Cyclohexyl-4-methyl-4H-[ 1 ,2,4]triazole-3 -thiol, -Chloro-thiophene-3-carboxylic acid, -Methylsulfanyl-benzoic acid, -Cyclopropyl-benzoic acid, -tert-Butoxycarbonylamino-benzoic acid, -Acetyl-benzoic acid, -Methyl-isonicotinic acid hydrazide, -Chloro-2-fluoro-benzoic acid hydrazide., 3-Cyano-benzoic acid hydrazide,
2-Chloro-isonicotinic acid hydrazide,
2-Fluoro-5-methyl-benzoic acid hydrazide ,
Pyrimidine-4-carboxylic acid hydrazide, 3-Fluoro-N-hydroxy-benzamidine,
N-Hydroxy-thiophene-3-carboxamidine,
2-Chloro-N-hydroxy-propionamidine ,
3,N-Dihydroxy-benzamidine,
N-Hydroxy-2-methyl-benzamidine, N-Hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetamidine,
3-Chloro-N-hydroxy-benzamidine ,
N-Hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetamidine,
2,5-Difluoro-N-hydroxy-benzamidine,
4-Methyl-5-pyridin-3-yl-4H-[l,2,4]triazole-3-thiol, 4-Butyl-5-thiophen-2-yl-4H-[ 1 ,2,4]triazole-3-thiol,
4-(3-Methoxy-propyl)-5-thiophen-2-yl-4H-[l,2,4]triazole-3-thiol ,
4-Benzyl-5-thioρhen-2-yl-4H-[l,2,4]triazole-3-thiol ,
4-Furan-2-ylmethyl-5-thiophen-2-yl-4H-[ 1 ,2,4]triazole-3-thiol ,
5-Thiophen-2-yl-4-thiophen-2-ylmethyl-4H-[l,2,4]triazole-3-thiol , 4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3-thiol ,
4-Furan-2-ylmethyl-5-pyridin-4-yl-4H-[l,2,4]triazole-3-thiol ,
4-Ethyl-5-pyridin-4-yl-4H-[l,2,4]triazole-3-thiol ,
4-Ethyl-5-pyridin-3-yl-4H-[l,2,4]triazole-3-thiol ,
4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3-thiol , 4-Fxxran-2-ylmethyl-5-pyridin-3-yl-4H-[l,2,4]triazole-3-thiol ,
4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazole-3-thiol ,
4-Ethyl-5-(3-fluoro-phenyl)-4H-[l,2,4]triazole-3-thiol ,
4-Ethyl-5-(4-fluoro-phenyl)-4H-[ 1 ,2,4]triazole-3-thiol ,
5-(2-Fluoro-5-methyl-ρhenyl)-4-furan-2-ylmethyl-4H-[l,2,4]triazole-3-thiol , 4-Ethyl-5-(3-methyl-thiophen-2-yl)-4H-[l,2,4]triazole-3-thiol ,
4-Ethyl-5-(5-methyl-thiophen-2-yl)-4H-[l,2,4]triazole-3-thiol ,
5-(2-Chloro-6-methyl-pyridin-4-yl)-4-ethyl-4H-[ 1 ,2,4]triazole-3-thiol , -(5-Bromo-furan-2-yl)-4-ethyl-4H-[ 1 ,2,4]triazole-3-thiol , -Ethyl-5-(3-methoxy-thiophen-2-yl)-4H-[l,2,4]triazole-3-thiol , -Ethyl-5-(tetrahy(fro-furan-2-yl)-2,4-dihydro-[l,2,4]triazole-3-thione, -Ethyl-5-thioxo-4,5-dihydro-lH-[l,2,4]triazole-3-carboxylic acid methyl ester, -(2-Chloro-pyridin-4-yl)-4-ethyl-4H-[l,2,4]triazole-3-thiol , -(2-Chloro-6-methoxy-pyridin-4-yl)-4-ethyl-4H-[l,2,4]triazole-3-thiol , -Ethyl-5-(3-methyl-3H-imidazol-4-yl)-4H-[l,2,4]triazole-3-thiol, -Propyl-5-pyridin-4-yl-4H-[ 1 ,2,4]triazole-3-thiol , -Ethyl-5-(l-methyl-lH-imidazol-2-yl)-4H-[l,2,4]triazole-3-thiol , -Ethyl-5-(l -methyl- lH-imidazol-4-yl)-4H-[ 1 ,2,4]triazole-3-thiol, -(5-Mercapto-4-methyl-4H-[ 1 ,2,4]triazol-3-yl)-benzonifrile, -(3-Chloro-phenyl)-4-methyl-4H-[l,2,4]triazole-3-thiol, -(4-Chloro-phenyl)-4-methyl-4H-[l,2,4]triazole-3-thiol, -(2-fluoro-phenyl)-4-methyl-4H-[ 1 ,2,4]triazole-3-thiol, -(3-fluoro-phenyl)-4-methyl-4H-[l ,2,4]triazole-3-thiol, -(4-fluoro-phenyl)-4-methyl-4H-[ 1 ,2,4]triazole-3-thiol, -Benzo[b]thiophen-2-yl-4-methyl-4H-[l,2,4]triazole-3-thiol, -(3 -methoxy-phenyl)-4-methyl-4H- [ 1 ,2,4] triazole-3 -thiol, -(4-methoxy-phenyl)-4-methyl-4H-[l,2,4]triazole-3-thiol, -Ethyl-5-(4-methoxy-phenyl)-4H-[l,2,4]triazole-3-thiol , -(3,5-Difluoro-phenyl)-4-ethyl-4H-[l,2,4]friazole-3-thiol , -(2,6-Difluoro-phenyl)-4-ethyl-4H-[l,2,4]triazole-3-thiol, -(4-Butoxy-phenyl)-4-ethyl-4H-[l,2,4]triazole-3-thiol , -Benzo[l,3]dioxol-5-yl-4-ethyl-4H-[l,2,4]triazole-3-thiol , -Ethyl-5-pyrimidin-5-yl-2,4-dihydro-[ 1 ,2,4]triazole-3-thione, -Ethyl-5-furan-3-yl-2,4-dihydro-[l,2,4]triazole-3-thione, -(Tefrahydrofiιran-2-ylmethyl)-5-tMophene-2-yl-2,4-dihydro-[l,2,4]1riazole-3-thione, -Cyclopentyl-4-ethyl-2,4-dihydro-[l,2,4]triazole-3-thione, -Ethyl-5-[2-(4-methoxy-phenyl)-ethyl]-2,4-dihydro-[l,2,4]triazole-3-thione, -(3,5-Dichloro-phenyl)-4-ethyl-4H-[l,2,4]triazole-3-thiol, -(3-Methylphenyl)-4-ethyl-4H-[l,2,4]triazole-3-thiol, -(4-Methylphenyl)-4-ethyl-4H-[l,2,4]triazole-3-thiol, 4-Ethyl- 5-(3-nitrophenyl)-4H-[l,2,4]triazole-3-thiol, 5-(2,5-Difluorophenyl)-4-ethyl-4H-[ 1 ,2,4]triazole-3-thiol, 5-(3-Chlorophenyl)-4-ethyl-4H-[l,2,4]triazole-3-thiol, 5-(4-Chlorophenyl)-4-ethyl-4H-[l,2,4]triazole-3-thiol, 4-Ethyl-5-methoxymethyl-2,4-dihydro-[l,2,4]triazole-3-thione, 4-Methyl-5-pyridin-4-yl-2,4-dihydro-[l,2,4]triazole-3-thione, 4-Allyl-5-furan-2-yl-2,4-dihydro-[l,2,4]triazole-3-thione, 4-Ethyl-5-(4-methoxy-phenoxymethyl)-2,4-dihy(iro-[l,2,4]triazole-3-thione, 4-Ethyl-5-phenoxymethyl-2,4-dihydro-[l,2,4]triazole-3-thione, 4-Ethyl-5-hydroxymethyl-2,4-dihydro-[l,2,4]triazole-3-thione, 4-Ethyl-5-(2-methoxy-ethyl)-2,4-dihydro-[l,2,4]triazole-3-thione, 4-Ethyl-5-methylsulfanylmethyl-2,4-dihydro-[l,2,4]triazole-3-thione, 5-Ethoxymethyl-4-ethyl-2,4-dihydro-[l,2,4]triazole-3-thione, 5-Furan-3-yl-4-methyl-2,4-dihydro-[ 1 ,2,4]triazole-3-thione , 4-Methyl-5-pyrimidin-4-yl-2,4-dihydro-[l,2,4]triazole-3-thione, 4-Ethyl-5-pyridazin-4-yl-2,4-dihydro-[l,2,4]triazole-3-thione, 4-Ethyl-5-pyridin-4-ylmethyl-2,4-dihydro-[l,2,4]triazole-3-thione, 4-Ethyl-5-(6-hydroxy-pyridin-3-yl)-2,4-dihydro-[l,2,4]triazole-3-thione, 4-Ethyl-5-(4-hydroxy-phenyl)-2,4-dihydro-[l,2,4]triazole-3-thione, 4-Ethyl-5-p-tolyloxymethyl-2,4-dihydro-[l,2,4]triazole-3-thione,
4-Ethyl-5 -(6-methoxy-pyridin-3 -yl)-2,4-dihydro- [ 1 ,2,4]triazole-3 -thione, 4-Ethyl-5-(2-methoxy-pyridin-4-yl)-2,4-dihydro-[l,2,4]triazole-3-thione, 4-Ethyl-5-pyrimidin-2-yl-2,4-dihydro-[ 1 ,2,4]triazole-3-thione, 4-Ethyl-5-(5-methoxy-pyrimidin-2-yl)-2,4-dihydro-[l,2,4]triazole-3-thione, 4-Furan-2-ylmethyl-4H-[l,2,4]triazole-3-thiol,
4-Cyclopropyl-5-pyridin-4-yl-4H-[ 1 ,2,4]triazole-3-thiol, 4-Cyclopropylmethyl-5 -pyridin-4-yl-4H- [ 1 ,2,4]triazole-3 -thiol, 4-Cyclopropyl-5-thiophen-2-yl-2,4-dihydro-[l,2,4]triazole-3-thione, 5-Furan-2-yl-4-(2-methoxy-ethyl)-2,4-dihydro-[l,2,4]triazole-3-thione, 4-Cyclopropyl-5-furan-2-yl-2,4-dihydro-[l,2,4]triazole-3-thione,
(3-Thiophen-2-yl-5-thioxo-l,5-dihydro-[l,2,4]triazol-4-yl)-acetic acid methyl ester, 4-Cyclopropylmethyl-5-thiophene-2-yl-2,4-dihydro-[l,2,4]triazole-3-thione, 4-(2-Methoxy-ethyl)-5-thiophen-2-yl-2,4-dihydro-[l,2,4]triazole-3-thione,
Thiophen-2-yl-4-(2,2,2-trifluoroethyl)-2,4-dihydro-[l,2,4]triazole-3-thione,
4-Cyclopropyl-5-pyrimidin-4-yl-2,4-dihydro-[l,2,4]triazole-3-thione,
4-Cyclopropyl-5-pyridin-3-yl-2,4-dihydro-[l,2,4]friazole-3-thione, 4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazole-3-thiol,
4-Ethyl-3-methanesulfonyl-5-thiophen-2-yl-4H-[l,2,4]triazole,
4-(5 -Methanesulfonyl-4-methyl-4H- [ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(2-Hydroxy-ethyl)-5-thiophen-2-yl-2,4-dihydro-[l,2,4]triazole-3-thione,
4-(4,5-Dimethyl-4H-[l,2,4]triazol-3-yl)-pyridine, Methyl-(4-methyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-yl)-amine,
3-Pyridin-4-yl-5,6,7,8-tefrahydro-[l,2,4]triazolo[4,3-a]pyrimidine,
3 -Furan-2-yl-5 ,6,7,8 -tefrahydro- [ 1 ,2,4] triazolo [4,3 - a]pyrimidine,
4-Ethyl-5-(6-methoxy-pyridazin-3-yl)-2,4-dihydro-[l,2,4]triazole-3-thione,
4-Ethyl-5-(5-methoxy-pyridin-2-yl)-2,4-dihydro-[l,2,4]triazole-3-thione, 5 -Chloromethyl-3 -phenyl- [ 1 ,2,4]oxadiazole,
5-Chloromethyl-3 -(3 -fluoro-phenyl)- [1,2,4] oxadiazole,
5-Chloromethyl-3-(2-fluoro-5-methyl-phenyl)-[ 1 ,2,4]oxadiazole ,
5-Chloromethyl-3-thiophen-2-yl-[l,2,4]oxadiazole,
5 -Chloromethyl-3 -thiophen-3 -yl- [ 1 ,2,4] oxadiazole, 3 -(5 -Chloromethyl- [ 1 ,2,4] oxadiazol-3 -yl)-phenol,
5-Chloromethyl-3-o-tolyl-[l,2,4]oxadiazole,
5-Chloromethyl-3-(3-chloro-phenyl)-[l,2,4]oxadiazole,
5-Chloromethyl-3-(2,5-difluoro-phenyl)-[l,2,4]oxadiazole,
3 -(3 -Chloromethyl- [1,2,4] oxadiazol-5 -yl)-benzonitrile, 2-Chloro-4-(3-chloromethyl-[ 1 ,2,4]oxadiazol-5-yl)-pyridine,
3-Chloromethyl-5-(2,5-dimethyl-phenyl)-[l,2,4]oxadiazole ,
3-Chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[ 1 ,2,4] oxadiazole,
3-Chloromethyl-5-(2,5-dichloro-phenyl)-[ 1 ,2,4]oxadiazole,
3 -Chloromethyl-5 -(2-fluoro-5 -bromo-phenyl)- [ 1 ,2,4] oxadiazole, 3-Chloromethyl-5-(3-methyl-phenyl)-[l,2,4]oxadiazole ,
3-Chloromethyl-5-(2,5-difluoro-phenyl)-[ 1 ,2,4] oxadiazole ,
3-Chloromethyl-5-(3 -methylsulfanyl-phenyl)-[ 1 ,2,4]oxadiazole , 3-Chloromethyl-5-(3-cyclopropyl-phenyl)-[l,2,4]oxadiazole,
3-(3-Chloromethyl-[l,2,4]oxadiazol-5-yl)-phenyl]-carbamic acid tert-butyl ester, l-[3-(3-Chloromethyl-[l,2,4]oxadiazol-5-yl)-phenyl]-ethanone,
5-(5-Chloro-2-fluoro-phenyl)-3-chloromethyl-[l,2,4]oxadiazole, 2-(3 -Chloromethyl- [ 1 ,2,4] oxadiazol-5 -yl)-4-methyl-phenol,
3-Chloromethyl-5-(2-chloro-5-methyl-phenyl)-[l,2,4]oxadiazole,
3-Chloromethyl-5-(2,5-dichloro-thiophen-3-yl)-[l,2,4]oxadiazole,
3 -(3 -Chloromethyl- [ 1 ,2,4] oxadiazol-5 -yl)-benzonitrile,
3-Chloromethyl-5-(3-fluoro-phenyl)-[l,2,4]oxadiazole , 3-Chloromethyl-5-(2-methyl-thiazol-4-yl)-[l,2,4]oxadiazole,
3-Chloromethyl-5-(4-fluoro-phenyl)-[l,2,4]oxadiazole ,
5-(5-Bromo-2-fluoro-phenyl)-3-chloromethyl-[l,2,4]oxadiazole,
3-Chloromethyl-5 -(4-methyl-thiophen-2-yl)- [ 1 ,2,4] oxadiazole,
5-(3-chloromethyl-[l,2,4]oxadiazol-5-yl)-thiophene-3-carbonitrile, 2-(3-Chloromethyl-[l,2,4]oxadiazol-5-yl)-4-methyl-benzonitrile,
3 -(3 -Chloromethyl- [1,2,4] oxadiazol-5 -yl)-5 -fluoro-benzonitrile,
3 -(3 -Chloromethyl- [ 1 ,2,4]oxadiazol-5-yl)-4-fluoro-benzonitrile,
4-Chloro-2-(3-chloromethyl-[l,2,4]oxadiazol-5-yl)-phenol,
3 -( 1 -Chloro-ethyl)-5 -(3 -chloro-phenyl)- [1,2,4] oxadiazole, 3-(l -Chloro-ethyl)-5-(3-fluoro-phenyl)-[ 1 ,2,4]oxadiazole,
3-(l-Chloro-ethyl)-5-(5-chloro-2-fluoro-phenyl)-[l,2,4]oxadiazole,
[3 -(3 -Chloromethyl- [1,2,4] oxadiazol-5 -yl)-phenyl] -methanol,
3 -Chloromethyl-5 - [ 1 -(toluene-4-sulfonyl)- 1 H-pyr rol-3 -yl] - [ 1 ,2,4] oxadiazole,
3-Chloromethyl-5-furan-3-yl-[l,2,4]oxadiazole, 3 -Chloromethyl-5 -(5 -chloro-thiophen-2-yl)- [ 1 ,2,4] oxadiazole, l-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethanol,
[5-(5 -Chloro-2-fluoro-phenyl)- [ 1 ,2,4] oxadiazol-3 -yl] -methanol,
1 - [5 -(3 -Chloro-phenyl)- [1,2,4] oxadiazol-3 -yl]-ethanol,
[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-methanol, 2-Chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[l,3,4]oxadiazole,
2-Chloromethyl-5-(3-chloro-phenyl)-[l,3,4]oxadiazole,
4-(5 -Chloromethyl- [1,3,4] oxadiazol-2-yl)-2-methyl-pyridine, 2-Chloromethyl-5-m-tolyl-[ 1 ,3,4]oxadiazole,
3 -(5 -Chloromethyl- [1,3,4] oxadiazol-2-yl)-benzonitrile,
2-Chloro-4-(5-chloromethyl-[l,3,4]oxadiazol-2-yl)-pyridine,
2-(5 -Chloro-2-fluoro-phenyl)-5 -chloromethyl- [ 1 ,3 ,4] oxadiazole, 2-(l-Bromo-ethyl)-5-(3-chloro-phenyl)-[l,3,4]oxadiazole,
2-(l -Bromo-ethyl)-5-(5-chloro-2-fluoro-phenyl)-[ 1 ,3,4]oxadiazole,
4-[5-(l -Bromo-ethyl)-[l ,3,4]oxadiazol-2-yl]-2-methyl-pyridine,
2-(l-Bromo-ethyl)-5-(2-fluoro-5-methyl-phenyl)-[l,3,4]oxadiazole,
2-(l-Bromo-ethyl)-5-(3-chloro-phenyl)-[l,3,4]oxadiazole, 3-(l-Bromo-ethyl)-5-(3-chloro-phenyl)-[l,2,4]oxadiazole,
1 - [5 -(3 -Chloro-phenyl)-isoxazol-3 -yl] -ethanol, l-[5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethanol,
5-(2-Fluoro-5-methyl-phenyl)-isoxazole-3-carboxylic acid methyl ester,
5-Thiophen-3-yl-isoxazole-3-carboxylic acid methyl ester, 5-Phenyl-isoxazole-3-carboxylic acid methyl ester,
5-(3-Chloro-phenyl)-4-methyl-isoxazole-3-carboxylic acid ethyl ester,
5-(5-Chloro-thiophen-3-yl)-isoxazole-3-carboxylic acid methyl ester,
[5-(3-Chloro-phenyl)-isoxazol-3-yl]-methanol,
[2-(3-Chloro-phenyl)-oxazol-4-yl]-methanol, [3-(3-Chloro-phenyl)-isoxazol-5-yl]-methanol,
5-(Thiophen-3-yl-isoxazol-3-yl)methanol,
[5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-yl]-methanol,
(5-Phenyl-isoxazol-3-yl)-methanol,
[5-(3 -Chloro-phenyl)-4-methyl-isoxazol-3 -yl] -methanol, [5-(5-Chloro-thiophen-3-yl)-isoxazol-3-yl)]-methanol,
Methanesulfonic acid l-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethyl ester,
Methanesulfonic acid 2-(3-chloro-phenyl)-oxazol-4-ylmethyl ester,
Methanesulfonic acid 3-(3-chloro-phenyl)-isoazol-5-ylmethyl ester,
Methanesulfonic acid 5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethyl ester, Methanesulfonic acid -phenyl)-isoxazol-5-yl]-ethyl ester,
Methanesulfonic acid 5-(5-chloro-2-fluoro-phenyl)-isoxazol-3-ylmethyl ester,
Methanesulfonic acid 5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester, Methanesulfonic acid 5-thiophen-3-yl-isoxazol-3-ylmethyl ester, Methanesulfonic acid 5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethyl ester, Methanesulfonic acid 5-phenyl-isoxazol-3-ylmethyl ester, Methanesulfonic acid 5-(3-chloro-phenyl)-4-methyl-isoxazol-3-ylmethyl ester, Methanesulfonic acid 5-(5-chloro-thiophen-3-yl)-isoxazol-3-ylmethyl ester,
Methanesulfonic acid l-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethyl ester, Methanesulfonic acid l-[5-(5-chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethyl ester, Methanesulfonic acid 4-chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester, Pyrimidine-4-carboxylic acid, 3-(3-Chloro-phenyl)-isoxazole-5-carboxylic acid methyl ester, 2-Bromomethyl-5-(3-chloro-phenyl)-oxazole, 2-(3-Chloro-phenyl)-oxazole-4-carboxylic acid methyl ester, 2-(3-Chloro-phenyl)-oxazole-4-carboxylic acid methyl ester, l-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethanol, l-[3-(3-Chloro-phenyl)-isoxazol-5-yl]-ethanol,
[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-methanol, 3-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-propionic acid hydrazide, 3-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-butyric acid hydrazide, 3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-propionimidic acid ethyl ester hydrochloride,
3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-propionic acid hydrazide, [5-(3 -Chloro-phenyl)- [ 1 ,2,4] oxadiazol-3 -yl] -acetic acid hydrazide, (R)-3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-butyric acid hydrazide, 3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-3-methyl-butyric acid hydrazide, 3-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yhnethyl]-piperidin-2-one,
3-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-yhnethyl]-piperidin-2-one, 3-Chloromethyl-5-(5-chloro-thiophen-3-yl)-[l,2,4]oxadiazole, l-[5-(5-Chloro-thiophen-3-yl)-[l,2,4]oxadiazol-3-yhnethoxy]-lH-benzotriazole, (4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetonitrile, 2-(4-Methyl-5-thiophen-2-yl-4H-[ 1 ,2,4]triazol-3 -ylsulfanyl)-propionic acid, 2-(4-Methyl-5-pyridin-3-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-propionic acid, 3-(3-Chloro-ρhenyl)-5-(4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazole or, ,
{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl-phenyl}-carbamic acid tert-butyl ester.
Pharmaceutical formulations
According to one aspect ofthe 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 metabofropic glutamate receptor subtype 5 receptor (mGluR5) mediated disorders and any disorder listed below.
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, mtravascular or infusion) as a sterile solution, suspension or emulsion, for topical adminisfration as an ointment, patch or cream or for rectal administration as a suppository.
In general the above compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical diluents and/or inert carriers. According to another aspect ofthe invention thee is provided a phannaceutical 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. Suitable daily doses ofthe compounds of formula I in the freatment of a mammal, including man are approximately 0.01 to 250 mg/kg bodyweight at peroral adminisfration and about 0.001 to 250 mg/kg bodyweight at parenteral adminisfration. The typical daily dose ofthe active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of adminisfration, the age, weight and sex ofthe patient and may be determined by a physician.
Medical use 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 metabofropic 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 ofthe 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 nιGluR5. The compounds may be used to produce an inhibitory effect of mGlxxR Group I, especially mGluR5, in mammals, including man. mGluR5 is highly expressed in the central and peripheral nervous system and in other tissues. Thus, it is expected that the compounds ofthe invention are well suited for the prevention and/or freatment of mGluR5 receptor-mediated disorders such as acute and chronic neurological and psychiatric disorders and chronic and acute pain disorders.
Further disorders are Alzheimer's disease senile dementia, ALOS-induced dementia, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's Chorea, migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, obsessive compulsive disorder, ophthalmological 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. 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. Other disorders are stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, cardiovascular diseases and epilepsy. The dose required for the therapeutic or preventive freatment of a particular disorder will necessarily be varied depending on the host treated, the route of administration and the severity ofthe illness being freated.
The invention relates to compounds of formula I as defined hereinbefore, for use in therapy.
The invention relates to compounds of formula I as defined hereinbefore, for use in prevention and/or treatment of neurological disorders.
The invention relates to compounds of formula I as defined hereinbefore, for use in prevention and/or freatment of psychiatric disorders.
The invention relates to compounds of formula I as defined hereinbefore, , for use in prevention and/or freatment of chronic and acute pain disorders.
The invention relates to compounds of formula I as defined hereinbefore, for use in prevention and/or treatment of mGluR5 receptor-mediated disorders.
The invention relates to compounds of formula I as defined hereinbefore, for use in prevention and/or freatment of Alzheimer's disease senile dementia, AIDS-induced dementia, Parkinson's disease, amylofropic lateral sclerosis, Huntington's Chorea, migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, ophthalmological disorders such as retinopathies, diabetic retinopathies, glaucoma, auditory neuropathic disorders such as tinnitus, chemotherapy induced neuropathies, post-heφetic neuralgia and trigeminal neuralgia, tolerance, dependency, Fragile X, autism, mental retardation, schizophrenia and Down's Syndrome.
The invention relates to compounds of formula I as defined hereinbefore, for use in prevention and/or freatment 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.
The invention relates to compounds of formula I as defined hereinbefore, for use in prevention and/or freatment of stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, cardiovascular diseases and epilepsy.
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.
The invention also provides a method of freatment 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.
In the context ofthe 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.
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.
The term "disorder", unless stated otherwise, means any condition and disease associated with metabofropic glutamate receptor activity.
Non- Medical use
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 tn vitro and in vivo test systems for the evaluation ofthe 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
The pharmacological properties ofthe compounds ofthe 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 incoφorated herein by reference. Conveniently, the compounds ofthe invention can be studied by means of an assay that measures the mobilization of intracellular calcium, [Ca2+]i in cells expressing mGluR5. 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. For FLIPR analysis, cells expressing human mGluR5d were seeded on collagen coated clear bottom 96-well plates with black sides and analysis of [Ca2+]j mobilization was done 24 hours after seeding.
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 μL of buffer present in each well ofthe cell plate. After each addition ofthe 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 ofthe response within the sample period. EC50 and IC5o determinations were made from data obtained from 8-point concenfration response curves (CRC) performed in duplicate. Agonist CRC were generated by scaling all responses to the maximal response observed for the plate. Antagonist block ofthe agonist challenge was normalized to the average response ofthe agonist challenge in 14 confrol wells on the same plate. We have validated a secondary functional assay for mGluR5d based on Inositol Phosphate (IP3) turnover. IP3 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°C. Antagonist activity was determined by pre- incubating test compoxmds for 15 minutes, then incubating in the presence of glutamate (80μM) or DHPG (30 μM) 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.
A detailed protocol for testing the compoxmds ofthe invention is provided below in Pharmaceutical Examples.
Abbreviations
FLIPR Fluorometric Imaging Plate reader CCD Charge Coupled Device
CRC Concenfration Response Curve
GHEK Human Embrionic Kidney expressing Glutamate Transporter
HEPES 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid (buffer)
IP3 inositol triphosphate DHPG 3,5-dihydroxyphenylglycine;
BSA Bovine Serum Albumin
EDTA Ethylene Diamine Tefraacetic Acid
Methods of Preparation
Another aspect ofthe present invention provides a process for preparing a compound of formula I, or salt thereof.
Tliroughout 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-lnterscience, New York, 1999.
Unless specified otherwise, are P, Q, X1, X2, X3, X4, R, R1, R2, R3, R4, R5, R6, M1, M2, m and n, defined as in formula I.
All starting materials are commercially available or earlier described in the literature. The 1H and 13C NMR spectra were recorded either on Bruker 300, Braker DPX400 or Varian +400 spectrometers operating at 300, 400 and 400 MHz for 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 ofthe signals as appearing in the recordings (s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet).
Analytical in line liquid chromatography separations followed by mass specfra 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-Tena MS, Waters, C8, 2.1 x 50mm, 3.5 μm, was applied a linear gradient from 5 % to 100% acetonitrile inlO mM ammonium acetate (aq.), or in 0.1% TFA (aq.). Preparative reversed phase chromatography was run on a Gilson autopreparative HPLC with a diode anay detector using an XTena MS C8, 19x300mm, 7μm as column. MS-triggered preparative reversed phase chromatograpy was run on a Waters autopurification LC-MS system with a diode anay detector and a ZQ mass detector using an XTena MS C8, 19x100 mm, 5 μm as column. Purification by a chromatofron 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 chromatofron. Purification of products were also done using Chem Elut Exfraction 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. Microwave heating was performed in a Smith Synthesizer Single-mode microwave cavity producing continuous inadiation at 2450 MHz (Personal Chemistry AB, Uppsala, Sweden).
Abbreviations:
DMF NN-dimethylformamide
BOPA Benzoyl Peroxide
P-BEMP Polystyrene bound 2-tert-Butylimino-2-diethylamino-l,3-dimethyl-perhydro-
- 1 ,3 ,2-diazaphosporine Deoxofluor [Bis(2-methoxyethyl)amino]sulfur trifluoride
DAST (Diethylamino)sulfur trifluoride
EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HOBt 1-hydroxybenzotriazole hydrate
THF tetrahydrofuran
TFA trifluoroacetic acid
Et ethyl
Ac acetyl
DIB AL diisobutylaluminum hydride
M, Ν molar and nonnal
HBTU O-Benzotriazol-l-yl-NNN',N'-tetramethyluronium hexafluoroρhosphate
Boc tert-butoxycarbonyloxy
LDA Lithium diisopropylamine
LHA Lithium aluminium hydride
MCPBA meta-chloroperoxybenzoic acid
SPE solid phase exfraction
Lawesson's Reagent [2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane- -2,4-disulfιde General syntheses of compounds of formula V.
Figure imgf000080_0001
III IV
N-O
7
R7 /AR7
A compound of formula V, wherein R7 is independently selected from a group consisting of M1-(R2)„-P-(R1)ml, M2-(R3)n-X4-Q-(R4)m2, and M2-(R3)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. 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.
The ester formation may be accomplished using an appropriate aprotic solvent such as dichloromethane, tefrahydrofuran, NN-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. The cyclization ofthe ester to form an oxadiazole may be carried out on the crude ester, with evaporation and replacement ofthe 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 inadiation (100-180°C), in a suitable solvent such as pyridine or NN-dimethylformamide or using a lower temperature method employing reagents like tetrabutylammonium fluoride in tefrahydrofuran or by any other suitable known literature method.
Other compatible non-reacting functional groups suitably protected may also be present in the substrates.
Further examples ofthe 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.
Synthesis of Nitrites and Acids for use in preparation of compounds of formula II and III
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 NN-dimethylformamide. The conesponding 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 CO2 to give directly the acid. 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 frapping 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 ofthe amine functionality, including such carbamate protecting group as Boc.
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 NN- dimethylformamide at elevated temperatures (80-120°C) for extended periods of time. The bromo group may subsequently be elaborated into the acid or nitrile as above. 1,3-Disubsituted and 1,3,5-trisubstituted benzoic acids and benzonitriles may be prepared by taking advantage of readily available substituted isophthalic acid derivatives. Monohydrolysis ofthe diester allows selective reaction ofthe 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 nitrile 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 tefrahyάrofuran. 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 ofthe methyl derivative when not commercially available. Ethers obtained by alkylation ofthe 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 tefrahydrofuran or the alcohol. When other substituents are present, these may also be employed in standard fransformation 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 tefrafluoroboric acid. Phenols react in the presence of a suitable base such as potassium carbonate with alkylating agents to form aromatic ethers.
Formation of compounds of formula IX
Figure imgf000083_0001
PhNCO
Figure imgf000083_0002
Figure imgf000083_0003
VIII
VII IX
Figure imgf000083_0004
A compound of formula IX, wherein R7 is independently selected from a group consisting of M1-(R2)„-P-(R1)ml, M2-(R3)n-X4-Q-(R4)m2, and M2-(R3)„-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 compoxmds of formula VI and VII under basic conditions using a suitable base such as sodium bicarbonate or triethylamine at suitable temperatures (0°C - 100°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 nifromethanes 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 °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. Alternativley, 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 ofthe hydrochloric acid salt, at elevated temperatures (60-120°C).
It is understood that for both methods subsequent functional group fransformations 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 DLBAL 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. Formation of compounds of formula XIV
Figure imgf000084_0001
XII III
A compound of formula XIV, wherein R7 is independently selected from a group consisting of M1-(R2)n-P-(R1)ml, M2-(R3)n-X4-Q-(R4)m2, and M2-(R3)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 reanangement to the 1,3,4-oxadizaole. Jursic, B.S.; Zdravkovski, Z.; Synth.Commun.; (1994) 24; 1575-1582.
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°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 decribed for example by Kakefuda, Akio; et al.; Bioorg. Med. Chem. (2002), 10; 1905-1912.
Formation of compounds of formula XVI
Figure imgf000085_0001
XVa XVb XVIa
Figure imgf000085_0002
A compound of formula XVI, wherein R8 as defined above is independently selected from a group consisting of M1-(R2)„-P-(R1)mi, M2-(R3)n-X4-Q-(R4)m2, and M2-(R3)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 Tl(OTf)3 under acidic conditions according to the procedure of Lee and Hong; Tetrahedron Lett., (1997), 35, 8959-60.
Alternatively compounds of formula III and XVII are reacted as described above for formula V to give an inteπnediate of foπnula XVIII. Such an inteπnediate may give the required oxazole by cyclodehydration with to generate the oxazoline followed by dehydrogenation using BrCCl3 in the same reaction pot. Phillips, A.J.; Uto, Y.; Wipf, P.; Reno, MJ. and Williams, D.R., Organic Letters, (2000) 2, 1165-8.
Formation ofthe bond between X4 and M2 or Q and M2 through nucleophilic displacement of a leaving group:
Figure imgf000086_0001
A compound of fonnula XX, may be used to displace the leaving group LG in compounds of formula XIX (R7 is M'-CR^n-P-CR1)^ ). When X4 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 ofthe X4 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°C) to accelerate the reaction. 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.
Similarly these reaction conditions may be carried out for compounds of formula XX when X4 = bond and ring Q is a fused bicycle containing a heteroatom such as N as defined aboved. In either the latter or the above described case with X4=N, NaH in DMF is prefened as desribed in literature precedences, for example Murdoch, Robert; Tully, W. Roger; Westwood, Robert; J.Heterocycl.Chem.; (1986), 23; 833-841. For compounds of formula XX containing X4 = 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 apropriate aprotic solvents such as THF, hexane or toluene at temperatures generally below ambient temperatures, e.g.at -78°C or 0°C.
Figure imgf000087_0001
An alternative procedure for the synthesis of above described type of thiomethyl oxadiazole is to fonn an acyclic ester IVa and IVb from the combination of a suitably substituted hydroxyamidine and activated acid coupling partner also suitably substituted. Displacement ofthe chloride using the thiol nucleophile may occur immediately prior to cyclization using one ofthe 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.
Formation of 4-alkyl-triazoles thiols/thiones:
Figure imgf000088_0001
XXIII XXIV
Any suitable acylating agent such as an acid chloride or an activated acid or the conesponding acid under amide coupling conditions as mentioned above, is reacted with a suitable 4-alkyl-3-tbiosemicarbazide in the presence of a base such as pyridine or non- nucleophilic amines to form the acyclic intermediate compound of formula XXV, wherein R4 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 freatment 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.
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.
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 la.
The triazole thiones XXIX and XXXI alkylated on the other nifrogen atoms ofthe 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°C, followed by heating with aqueous bicarbonate. The same product may also be obtained through freatment ofthe 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.
Figure imgf000089_0001
XXX XXXb XXXI
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 l-acyl-l-alkyl-3-thiosemicarbazide intermediate which undergoes alkaline ring closure in a manner similar to the alkaline ring closure yielding compounds of formula XXVI above.
Formation of compounds of fonnula XXXIII
Figure imgf000090_0001
XXXIIa XXXIIb XXXIIc
Figure imgf000090_0002
XXXIII
Figure imgf000090_0003
A compound of foπnula 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-l,4,5,6-tefrahydropyrimidine in case of n=l. The alkylation with for example methyhodide as alkylating agent can be done in several solvents (DMF, acetone, CH2θ2 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 ofthe conesponding 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 inadiation 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.
Acyclic thioureas of formula XXXIId , wherein R8 is defined as in the scheme and R3 and R4 are as defined in Formula I, may also be employed using a similar method to obtain compounds of formula XXXIIIa, wherein the introduction ofthe hydrazine portion may be carried out using either hydrazine followed by acylation, or by using a preformed acyl hydrazine.
Formation of compounds of formula XXXV
Figure imgf000091_0001
XXXVIc
Figure imgf000091_0002
Compounds of formula XXXIVb may be prepared by using similar methods as above, e.g. by activation of XXXIVa to give the conesponding 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 frapping 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 inteπnediate used in the formation of compounds of Formula I, or may be the final bioactive compound of Formula I.
A compound of foπnula XXXV, wherem R 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°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.
Fonnation of compounds of formula XXXVIa and XXXVIb
Figure imgf000092_0001
A compound of formula XXXVIa, wherein R8 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 R8 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.
Formation of compounds of foπnula XXXVId and XXXVIf
X1=0
Figure imgf000093_0001
Compound of foπnula XXXVId & XXXVIf, wherein R7 is a group consisting of M1-
9 1
(R )n-P-(R )m, may be prepared by either ofthe non-limiting methods: a) reaction of acyl hydrazide compounds of formula XII with a cyclic anhydride or monoesterified diacid followed by the cyclization ofthe formed intermediate would lead to 1,3,4-oxadiazoles of type XXXVId and XXXVIf respectively (X1=O, X2 and X3=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 X1 and X2 =N, X3=O; c) reaction of a compound of type III with an hydroxamidine type compoxmd, with the exception ofthe succinyl derivative, may be used to provide the 1,2,4-oxaziazole analogs XXXVIf wherein X1 and X3 =N, X2=O. Compounds XXXVId and XXXVTf may be interconverted independent ofthe nature of X1, X2 or X3 as described above. Formation of compounds of foπnula lb
Figure imgf000094_0001
7 1 1
A compound of foπnula lb, wherein R is selected from a group M -(R )n-P-(R ) ι may be prepared from compounds of formula XXXVII, generated from XIV as described below, through selective O alkylation using Me3OBF4 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 inadiation, as has been previously described by for example Lawson, Edward C; Hoeksfra, William J.; Addo, Michael F.; Andrade-Gordon, Patricia; Damiano, Brace P.; Kauffman, Jack A.; Mitchell, John A.; Maryanoff, Bruce E.; Bioorg.Med.Chem.Lett.; (2001); 11; 2619 - 2622.
Compounds of type XXXVII may be prepared by the reaction of cyclic amides, lactams, which are readily alkylated in the α-position to the carbonyl by successive freatment 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. General synthesis of compounds of formula Ic
Figure imgf000095_0001
XXXVIII XXXIX Ic
A compound of formula Ic, wherein R7 is consisting of M1-(R2)n-P-(R1)ml, may be prepared tlirough 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. Compounds of formula XXXVIII, may be prepared from the conesponding alcohol by reacting it with phosgene or preferably a phosgene analog such as carbonyldumidazole followed by coupling to hydrazine.
Figure imgf000095_0002
Figure imgf000095_0003
XXVI XLI1 XLIa
Other means of synthesizing a compound of formula Ic or Id, wherein X4 = O and wherein R7 is M1-(R2)n-P-(R1)ml, 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. Compounds of type XLI may be synthesized as exemplified with triazole XXVI by alkylation or arylation ofthe sulfur group using an apropriate alkylating or arylating reagent followed by double oxidation ofthe thio group to the conesponding sulfone using oxidants such as MCPBA, hydrogen peroxide in acetic acid or potassium permanganate. Such a sequence has previously been described for example by Akerblom 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).
The alcohols may be prepared either directly upon synthesis ofthe 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.T469, followed by a standard reduction protocol ofthe resulting aldehyde (or hydrate thereof) using for example sodium borohydride in methanol.
Figure imgf000096_0001
Yet another method may involve the reaction of a compound of stracture 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 prefened solvent, at an appropriate temperature (-75°C - +75°C). The cleavage ofthe 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. Formation of compounds of type Ie
Figure imgf000097_0001
A compound of formula Ie, wherein R7 is M1-(R2)n-P-(R1)mi, 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 XLIIla using P2Sιo or Lawesson's reagent under thermal conditions. Synthesis of compounds of type XLIIla has been described by Takeuchi, H., Hagiwara, S., Eguchi,
S., Tetrahedron (1989); 45; 6375-6386.
Introduction of substitution in the Q ring:
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 (R7 is M1-(R2)n-P-(R1)ral ) may be substituted with R4 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 la.
Figure imgf000097_0002
Introduction ofthe M2 substituent(s) and of the X4 substituent(s):
When the most acidic protons are positioned on the atom adjacent to X4, or on X4 itself, substitution may be achieved by deprotonation of compound of Formual la 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 frapping ofthe resulting anion with a suitable elecfrophile such as alkyl halides, acid chlorides or anhydrides, chloroformates, carbamoyl chlorides, sulfonyl chlorides, isocyanates, isothiocyanates and the like. When an excess of base and elecfrophile are employed and the reaction is left for sufficient time, two hydrogens may be replaced by the elecfrophile as illustrated below for the introduction of two R3-substituents (M2 exemplified as carbon). Two or more, different or same substituents, might also be introduced accordingly by subsequent deprotonations and reactions with appropriate elecfrophiles to yield compounds of Formula Ig.
Figure imgf000098_0001
Oxidation of S atom of chain (when X 4 . is S) or N atoms on substituents:
Oxidation ofthe 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 ofthe reaction.
Figure imgf000098_0002
If one ofthe subsitutents, e.g. R4 contains one or more nifrogen atoms as for example a pyridine moiety or any other susbtituent as defined above, then oxidation of this nifrogen may occur in the above reaction of la with an oxidant such as MCPBA to give the conesponding 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 purifcation protocol even in the case of mixtures containing for example In 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.
Other miscellaneous reactions:
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-(R1)ml, 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. 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 triphenylphospl ine 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 la. hi 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.
Other funtionalities which may be further elaborated are depicted in the following, non- limiting example (R7 is M1-(R2)n-P-(R1)mi ), where halogenation may be undergone on a carbon-atom of an oxazole unit employing a chlorinating agent such as sulfuryl chloride.
Figure imgf000099_0001
Examples Suitable embodiments ofthe invention will now be illusfrated by the following non- limiting examples. NMR measurements were made on the delta scale (δ).
The compounds prepared according to Examples 1 to 39 and 100 to 328 are intermediates. The compounds prepared according to Examples 40 to 99 and 329 to 794 are end products.
Intermediates
Example 1
6-Methylpyridme-4-carboxylic acid
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 stined 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%). 1H NMR (MeOD) δ (ppm): 8.62 (d, IH), 7.68 (s, IH), 7.60 (d, IH), 2.55 (s, 3H).
Example 2 l-Cyano-3-ethylbenzene
Argon was bubbled into a solution of l-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°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 (3x), saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by flash colxrmn chromatography using 2% ethyl acetate in hexane affording a colorless liquid (1.42 g). GC-MS (M+): 131.18.
Example 3 3-EthyIbenzoic acid 6 M Sodium hydroxide (25 ml) was added to l-cyano-3-ethylbenzene (1 g, 7.62 mmol) in methanol (25 ml) and then heated at 100°c overnight. After concentrating the reaction mixture, the aqueous layer was washed with dichloromethane (2x), 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). !H NMR (CDC13), δ (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
Concentrated HCl (30 ml) was added to a cooled (-5°C) suspension of dimethyl 5-amino isophthalate (20 g, 95.6 mmol) in water (75 ml), followed by portionwise addition of NaNO2 (7.5 g, 109 mmol). The reaction mixture was then stined for 15 min., after which HBF4 (18 ml, 100 mmol, 48% aqueous solution) was added. The resulting mixture was stined at 0°C for 30 min. and the precipitate formed was collected by filfration and washed with cold methanol (60 ml) and ether (60 ml). The residue was then decomposed by heating in an oil bath (~110°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. 1H NMR (CDC13), δ (ppm): 8.57 (s, IH), 7.95 (d, 2H), 3.97 (s, 6H).
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 fransfened 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. 1H NMR (DMSO), δ (ppm): 8.31 (t, IH), 7.96 (m, 2H), 3.91 (s, 3H). 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 tefrahydrofuran (10 ml) and then sodium borohydride (1.1 g, 29.02 mmol) in water (3ml) 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. 1H NMR (CDC13), δ (ppm): 7.82 (s, IH), 7.63 (d, IH), 7.32 (d, IH), 4.76 (s, 2H), 3.93 (s, 3H). 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. 1H NMR (CDCI3), δ (ppm): 7.65 (s, IH), 7.51 (d, IH), 7.08 (d, IH), 3.91 (s, 3H), 2.40 (s, 3H).
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 tefrahydrofuran (7.4 ml). The reaction was stined at 75 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 ofthe 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. IH NMR (DMSO), d (ppm): 7.62 (s, IH), 7.45 (d, IH), 7.32 (d, IH), 2.38 (s, 3H).
Example 5 3-MethoxymethyI-benzoic acid
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 tefrathydrofuran (10 ml) was heated at 55°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. 1H NMR (CDC13), δ (ppm): 8.01 (s, IH), 7.98 (d, IH), 7.55 (d, IH), 7.43 (t, IH), 4.50 (s, 2H), 3.92 (s, 3H), 3.41 (s, 3H).
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 tefrahydrofuran (5 ml). The reaction was stined at 70 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 exfraction ofthe 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. 1HNMR (DMSO), δ (ppm): 7.90 (s, IH), 7.87 (d, IH), 7.56 (d, IH), 7.48 (t, IH), 4.48 (s, 2H), 3.31 (s, 3H).
Example 6 N-Hydroxy-3-methoxy-benzamidine
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°C) for 12 h. After the mixture was cooled, most ofthe 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
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). 1H ΝMR (CDC13), δ (ppm): 8.81 (broad peak, IH), 7.63 (m, 2H), 7.39 (m, 3H), 4.91 (s, 2H). Example 8 N-Hydroxy-3-methyl-benzamidine
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). 1H ΝMR (CDC13), δ (ppm): 8.25 (broad peak, IH), 7.36 (m, 2H), 7.25 (m, 2H), 4.88 (s, 2H), 2.38 (s, 3H).
Example 9 3-Cyano-N-hydroxy-benzamidine 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. 1H ΝMR (DMSO), δ (ppm): 9.91 (s, IH), 8.06 (s, IH), 8.01 (d, IH), 7.85 (d, IH), 7.59 (t, IH), 6.01 (bs, 2H).
Example 10 5-Chloromethyl-3-(3-methoxy-phenyl)-[l,2,4]oxadiazoIe
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 and the resulting mixture was stined 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 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) ofthe title compound (yellow oil). 1H ΝMR (CDC13), δ (ppm): 7.68 (m, IH), 7.60 (d, IH), 7.40 (t, IH), 7.07 (m, IH), 4.76 (s, 2H), 3.88 (s, 3H).
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 5-Chloromethyl-3-phenyl-[l,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, 14.7mmol) in dichloromethane (29.3 ml). Purification was performed by flash chromatography using 10% ethyl acetate in hexane. 1H ΝMR (CDC13), δ (ppm): 8.08 (m, 2H), 7.51 (m, 3H), 4.76 (s, 2H).
Example 12
5-Chloromethyl-3-m-tolyl- [1 ,2,4] oxadiazole
5-Chloromethyl-3-m-tolyl-[l,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. 1H ΝMR (CDC13), δ (ppm): 7.90 (s, IH), 7.87 (s, IH), 7.36 (m, 2H), 4.75 (s, 2H), 2.34 (s, 3H)
Example 13
3~(3-Chloromethyl- [1 ,2,4] oxadiazo!-5-yl)-benzonitrile
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. 1H ΝMR (CDCI3), δ (ppm): 8.47 (bs, IH), 8.41 (dd, IH), 7.91 (dd, IH), 7.72(t, IH), 4.70 (s, 2H); GC-MS (M+): 219.
Example 14 3-(5-ChloromethyI- [1 ,2,4] oxadiazol-3-yl)-benzonitri!e
3-(5-Chloromethyl-[l,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. IH ΝMR (CDC13), d (ppm): 8.40 (s, IH), 8.32 (d, IH), 7.82 (d, IH), 7.64 (t, IH), 4.77 (s, 2H).
Example 15 3-Chloromethyl-5-m-tolyl-[l,2,4]oxadiazole
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 stined for 30 min. Then triethylamine (0.62 ml, 4.5 mmol) was added and the resulting mixture was stined 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 ofthe 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°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 ofthe solvent and flash chromatography on silica (5% ethyl acetate in hexanes) yielded 3-chloromethyl-5-m-tolyl-[l,2,4]oxadiazole (469 mg, 54% over 2 steps, white solid). 1H ΝMR (CDC13), δ (ppm): 7.99 (s, IH), 7.97 (m, IH), 7.43 (d, 2H), 4.68 (s, 2H), 2.45 (s, 3H).
Example 16 3-ChloromethyI-5-(3-fluoro-phenyl)-[l,2,4]oxadiazole
DMF (10 ml) was added to a mixture of 3-fluorobenzoic acid (710 mg, 5.07 mmol), l-(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 stined 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°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. 1H ΝMR (CDC13), δ (ppm): 7.96 (d, IH), 7.86 (m, IH), 7.54 (m, IH), 7.33 (m, IH), 4.68 (s, 2H).
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
3-Chloromethyl-5-thiophen-3-yl-[l,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. 1H ΝMR (CDC13), δ (ppm): 8.28 (s, IH), 7.70 (d, IH), 7.48 (m, IH).
Example 18 3-(3-Chloromethyl-[l,2,4]oxadiazol-5-yl)-5-methyl-pyridine
3-(3-Chloromethyl-[l,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%) ofthe acyclic ester was also isolated as side product.
Example 19
3-ChIoromethyl-5-(3-nitro-phenyl)- [1,2,4] oxadiazole
3-Chloromethyl-5-(3-nitro-phenyl)-[l,2,4]oxadiazole (335 mg, 30% yield over 2 steps, yellow solid) was obtained from 3-nifrobenzoic 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. 1H ΝMR (CDCI3), δ (ppm): 9.03 (t, IH), 8.50 (t, 2H), 7.79 (t, IH), 4.71 (s, 2H)
Example 20 4-(3-ChIoromethyl-[l,2,4]oxadiazol-5-yI)-2-methyl-pyridine 4-(3-Chloromethyl-[l,2,4]oxadiazol-5-yl)-2-methyl-ρyridine (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. 1H MR (CDC13), δ (ppm): 8.75 (d, IH), 7.88 (s, IH), 7.79 (d, IH), 4.70 (s, 2H), 2.70 (s, 3H)
Example 21 3-Chloromethyl-5-(3-ethyl-phenyl)- [1 ,2,4] oxadiazole
3-Chloromethyl-5-(3-ethyl-phenyl)-[l,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. 1H ΝMR (CDC13), δ (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-[l,2,4]oxadiazol-5-yl)-phenyl]-dimethyl-amine 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. 1H ΝMR (CDC13), δ (ppm): 7.46 (t, 2H), 7.37 (t, IH), 6.94 (d, IH), 4.68 (s, 2H), 3.04 (s, 6H).
Example 23 3-Chloromethyl-5-(3-chloro-phenyϊ)-[l,2,4]oxadiazoϊe
3-Chloromethyl-5-(3-chloro-phenyl)-[l,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. 1H NMR (CDC13), δ (ppm): 8.17 (t, IH), 8.05 (d, IH), 7.59 (t, IH), 7.50 (t, IH), 4.68 (s, 2H).
Example 24 3-Chloromethyl-5-(3-trifluoromethoxy-phenyl)- [1,2,4] oxadiazole
3-Chloromethyl-5-(3-trifluoromethoxy-phenyl)-[l,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. 1H ΝMR (CDC13), δ (ppm): 8.10 (m, IH), 8.03 (s, IH), 7.61 (t, IH), 7.48 (d, IH), 4.69 (s, 2H).
Example 25 5-(3-Bromo-phenyl)-3-chIoromethyl-[l,2,4]oxadiazole 5-(3-Bromo-phenyl)-3-chloromethyl-[l,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. IH ΝMR (CDC13) d (ppm): 8.10 (m, IH), 8.03 (s, IH), 7.61 (t, IH), 7.48 (d, IH), 4.69 (s, 2H).
Example 26 3-Chloromethyl-5-thiophen-2-yl-[l,2,4]oxadiazole
3-Chloromethyl-5-thiophen-2-yl-[l,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. 1H ΝMR (CDC13), δ (ppm): 8.00 (s, IH), 7.83 (d, IH), 7.19 (t, , lH), 4.13 (s, 2H).
Example 27 3-Chloromethyl-5-(3-fluoro-5-methyl-phenyl)-[l,2,4]oxadiazole 3-Chloromethyl-5-(3-fluoro-5-methyl-phenyl)-[l,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. 1H ΝMR (CDC13), δ (ppm): 7.79 (s, IH), 7.65 (d, IH), 7.15 (d, IH), 4.67 (s, 2H), 2.46 (s, 3H).
Example 28 3-Chloromethyl-5-thiazol-4-yl-[l,2,4]oxadiazoIe 3-Chloromethyl-5-thiazol-4-yl-[l,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. 1H ΝMR (CDC13), δ (ppm): 9.02 (d, IH), 8.42 (d, IH), 4.70 (s, 2H).
Example 29 3-Chloromethyl-5-(3-iodo-phenyl)-[l,2,4]oxadiazole
3-Chloromethyl-5-(3-iodo-phenyl)-[l,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. 1H ΝMR (CDCI3), δ (ppm): 8.52 (s, IH), 8.13 (d, IH), 7.96 (d, IH), 7.29 (t, IH), 4.68 (s, 2H).
Example 30 3-Chloromethyl-5-(3-methoxymethyl-phenyl)-[l,2,4]oxadiazole
3-Chloromethyl-5-(3-methoxymethyl-phenyl)-[l,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; 1H NMR (CDCI3), δ (ppm): 8.14 (s, IH), 8.08 (d, IH), 7.61 (d, IH), 7.53 (t, IH), 4.68 (s, 2H), 4.54 (s, 2H), 3.44 (s, 3H).
Example 31 5-Furan-2-yl-4-methyI-4£T-[l,2,4]triazole-3-thiol
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 stined at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate (100 ml), successively washed with water (3x100 ml) and brine (100 ml). The organic phase was dried (sodium sulfate), filtered and concenfrated in-vacuo. The residue was suspended in sodium bicarbonate (70 ml, 69.6 mmol, 1 M water) and left stirring at 100°C overnight. The reaction mixture was cooled to 0°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. 1H NMR (CDC13), δ (ppm): 11.4 (bs, IH), 7.63 (d, IH), 7.02 (d, IH), 6.60 (dd, IH), 3.83 (s, 3H).
Examples 32-35 were prepared in an analogous method to the procedure given in Example 31.
Example 32
4-Methyl-5-phenyl-4iy-[l,2,4]triazole-3-thiol
4-Methyl-5-phenyl-4H-[l,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°C overnight and the title compound was collected by filfration. !Η NMR (CDC13), δ (ppm): 12.3(bs, IH), 7.55 (m, 5H), 3.65 (s, 3H).
Example 33 4-Methyl-5-pyridm-2-yl-4JH-[l,2,4]triazole-3-thiol 4-Methyl-5-pyridin-2-yl-4H-[l,2,4]friazole-3-thiol (44 mg, greenish solid) was obtained from 4-methy 1-3 -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°C overnight and the title compound was collected using exfraction and evaporation. 1H NMR (CDC13), δ (ppm): 11.1 (bs, IH), 8.70 (d, IH), 8.02 (d, IH), 7.84 (m, IH), 7.41 (dd, IH), 4.05 (s, 3H).
Example 34
5-(4-Benzyl-morpholin-2-yl)-4-methyl-4H-[l,2,4]triazole-3-thiol
(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-moφholinecarbonyl chloride hydrochloride (1.00 g, 3.62 mmol). Then sodium bicarbonate (33 ml, 1 M water) was added at 100°C overnight and the title compound was collected using extraction and evaporation. 1H NMR (CDC13), δ (ppm): 9.48 (bs, IH), 7.25 (m, 5H), 4.68 (dd, IH), 3.86 (dAb, IH), 3.68 (tAB, IH), 3.59-3.64 (m, 5H), 3.07 (d, IH), 2.88 (d, IH), 2.61 (t, IH), 2.37 (dt, IH).
Example 35
5-tert-Butyl-4-methyl-4iϊ-[l,2,4]triazole-3-tIπol
5-tert-Butyl-4-methyl-4H-[l,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°C overnight and the title compound was collected extraction and evaporation. 1H NMR (CDCI3), δ (ppm): 11.7 (bs, 1Η), 3.72 (s, 3Η) 1.40 (s, 9H).
Example 36 4-Methyl-5-pyridin-3-yl-4H-[l,2,4]triazole-3-thiol
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 stined 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 concenfrated in- vacuo. The residue was stined in sodium hydroxide (53.4 ml, 66.7 mmol, 5% aqueous) at 60°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 (4x50 ml). The combined organic phase was washed with brine (100 ml), dried (sodium sulfate), filtered and concentrated in- vacuo (180 mg, off-white solid). 1H NMR (CDC13), δ (ppm): 11.6 (bs, IH), 8.94 (s, IH), 8.83 (dd, IH), 7.98 (m, IH), 7.51 (dd, IH), 3.69 (s, 3H).
Examples 37-39 were prepared in an analogous method to the procedure given in Example 36.
Example 37 4-Methyl-5-thiophene-3-yl-4Hr-[l,2,4]triazole-3-thiol
4-Methyl-5-thiophene-3-yl-4H-[l,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), ΗOBt (1.16 g, 8.58 mmol) in DMF (10 ml). Then sodium hydroxide (88 ml, 110 mmol, 5% aqueous) at 60°C overnight and the title compound was product collected extraction and evaporation. 1H NMR (CDCI3), δ (ppm): 11.4 (bs, 1Η), 7.77 (dd, 1Η), 7.51 (dd, 1Η), 7.42 (dd, 1Η), 3.61 (s, 3Η).
Example 38
4-Methyl-5-thiazol-4-yl-4iI-[l,2,4]triazole-3-tlιioI
4-Methyl-5-thiazol-4-yl-4H-[l,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), ΗOBt (1.16 g, 8.58 mmol) in DMF (10 ml). Then sodium hydroxide (43 ml, 54 mmol, 5% aqueous) at 60°C overnight and the title compound was collected extraction and evaporation.
Example 39 5-CycIohexyl-4-methyI-4H-[l,2,4]triazole-3-thioI 5-Cyclohexyl-4-methyl-4H-[l,2,4]friazole-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°C overnight.
Example 40 2-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole lH-Benzoimidazole-2-thiol (150 mg, 1 mmol) was added to a solution ofthe 3- chloromethyl-5-(3-methoxy-phenyl)-[l,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. 1H NMR (CDC13), δ (ppm): 7.71 (d, 1Η), 7.62 (d, 1Η), 7.53 (m, 2Η), 7.42 (t, IH), 7.18 (overlapping , m, 3H), 4.52 (s, 2H), 3.87 (s, 3H).
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-4iϊ-[l,2,4]triazol-3- ylsulfanylmethyl)- [1 ,2,4] oxadiazole
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-[l,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%) ofthe title compound as a white solid. 1H NMR (CDC13), δ (ppm): 7.68 (d, 1Η), 7.57 (t, 1Η), 7.49 (m, 2Η), 7.41 (t, IH), 7.15 (m, 2H), 4.53 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H). LC-MS (M+l)+ 386.3.
Example 42
3-[5-(l -Methyl-5-thiophen-2-yl-lfl-imidazol-2-ylsulfanylmethyl)- [1 ,2,4] oxadiazol-3- yl]-benzonitrile 3-[5-(l-Methyl-5-thioρhen-2-yl-lH-imidazol-2-ylsulfanylmethyl)-[l,2,4]oxadiazol-3-yl]- benzonitrile (39 mg, 47%, white solid) was obtained from 3 -chloromethyl-3 -(5- chloromethyl-[l,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-[l,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. 1H NMR (CDC1 ), δ (ppm): 8.34 (s, IH), 8.28 (d, IH), 7.79 (d, IH), 7.60 (t, IH), 7.53 (d, IH), 7.49 (d, IH), 7.19 (m, IH), 4.70 (s, 2H), 3.74 (s, 3H). LS-MS (ES+full scan, C17H12N6OS2) M+ calc. 380.05, found (M+l)+ 381.04.
Example 43
3-(4-Methyl-5-thiophen-2-yl-4JΪ-[l,2,4]traiazol-3-ylsulfanylmethyl)-5-phenyl- [1,2,4] oxadiazole
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]traiazol-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-4Η-[l,2,4]triazole-3-thiol (60.8 mg, 0.31 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 50% ethyl acetate in hexanes. 1H NMR (CDC13), δ (ppm): 8.09 (m, 2H), 7.57 (m, 5H), 7.17 (dd, IH), 4.53 (s, 2H), 3.72 (s, 3H).
Example 44 2- [5-(3-Methoxy-phenyl)- [1 ,2,4] oxadiazol-3-ylmethylsulfanyl] -5-methyl-llϊ- benzoimidazole
2- [5 -(3 -Methoxy-phenyl)- [ 1 ,2,4] oxadiazol-3 -ylmethylsulfanyl] -5 -methyl- 1H- benzoimidazole (75.5 mg, 70.5%, white foam) was obtained from 3-chloromethyl-5-(3- methoxy-phenyl)-[l,2,4]oxadiazole (82 mg, 0.365 mmol), potassium carbonate (210 mg, 1.520 mmol), 2-thiol-5-methyl-lΗ-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. 1H NMR (CDC13), δ (ppm): 11.95 (bs, IH), 7.80 (d, IH), 7.70 (s, IH), 7.52 (m, 2H), 7.21 (dd, 2H), 7.17 (d, IH), 4.40 (s, 2H), 3.95 (s, 3H), 2.50 (s, 3H).
Example 45 3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazoI-3-ylsulfanylmethyl)-5-m-tolyl- [1,2,4] oxadiazole
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl- [l,2,4]oxadiazole (76 mg, 85%, white solid) was obtained from 3 -chloromethyl-5 -m-tolyl- [l,2,4]oxadiazole (50 mg, 0.24 mmol), potassium carbonate (99.4 mg, 0.72 mmol), 4- methyl-5-thiophen-2-yl-4Η-[l,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. 1H NMR (CDC13), δ (ppm): 7.89 (m, 2H), 7.50 (m, 2H), 7.40 (m, 2H), 7.18 (t, IH), 4.52 (s, 2H), 3.71 (s, 3H), 2.41 (s, 3H).
Example 46
3-(4-Methyl-5-thiophen-2-yl-4fi-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3- trifluoromethyl-phenyl)-[l,2,4]oxadiazole
3-(4-Methyl-5-tMoρhen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-(3-trifluoromethyl- phenyl)-[l,2,4]oxadiazole (84 mg, 86%, white solid) was obtained from 3-chloromethyl-5- (3-trifluoromethyl-phenyl)-[l,2,4]oxadiazole (60 mg, 0.23 mmol), potassium carbonate (95 mg, 0.69 mmol), 4-methyl-5-thiophen-2-yl-4Η-[l,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. 1H NMR (CDCI3), δ (ppm): 8.38 (s, IH), 7.29 (d, IH), 7.86 (d, IH), 7.68 (t, IH), 7.50 (t, 2H), 7.19 (m, IH), 4.57 (s, 2H), 3.75 (s, 3H). <
Example 47 3-(3-Methoxy-phenyl)-5-(4-methyl-5-thiophen-2-yl-4Hr-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole
3-(3-Methoxy-phenyl)-5-(4-methyl-5-tMophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)- [l,2,4]oxadiazole (74.3 mg, 88%, white solid) was obtained from 4-methyl-5-thiophen-2- yl-4Η-[l,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. 1H NMR (CDCI3), δ (ppm): 7.62 (d, IH), 7.52 (d, 2H), 7.48 (d, IH), 7.37 (t, IH), 7.18 (t, IH), 7.06 (m, IH), 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-4Jϊ-[l,2,4]triazol-3-ylsuIfanylmethyl)-3-phenyl- [1,2,4] oxadiazole
5-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]friazol-3-ylsulfanylmethyl)-3-phenyl- [l,2,4]oxadiazole (79.9 mg, 87%, white solid) was obtained from 4-methyl-5-thiophen-2- yl-4Η-[l,2,4]triazole-3-thiol (86.8 mg, 0.44 mmol), 5 -chloromethyl-3 -phenyl- [l,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. 1H NMR (CDCI3), δ (ppm): 8.02 (d, 2H), 7.47 (m, 5H), 7.18 (t, IH).
Example 49
5-(4-Methyl-5-thiophen-2-yl-4i3-[l,2,4]triazol-3-ylsulfanylmethyl)-3-m-tolyl- [1,2,4] oxadiazole
5-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-m-tolyl- [l,2,4]oxadiazole (71.8 mg, 91%, white solid) was obtained from 4-methyl-5-thiophen-2- yl-4H-[l,2,4]triazole-3-thiol (78.9 mg, 0.40 mmol), 5 -chloromethyl-3 -m-tolyl-
[l,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. 1H NMR (CDC13), δ (ppm): 7.82 (d, 2Η), 7.52 (d, IH), 7.47 (d, IH), 7.31 (m, 2H), 7.18 (m, IH), 4.64 (s, 2H), 3.70 (s, 3H), 2.39 (s, 3H). LC-MS (MH+): 370.06.
Example 50
3-[3-(4-Methyl-5-thiophen-2-yl-41?-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-
5-yl]-benzonitrile 3-[3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]friazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-benzonitrile (130 mg, 75%) was obtained from 3-(3-chloromethyl-[l,2,4]oxadiazol-5- yl)-benzonitrile (100 mg, 0.45 mmol) with K2CO3 ( 189 mg, 1.36 mmol) and 4-methyl-5- (2-thienyl)l,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. 1H NMR (CDC13), δ (ppm): 8.38 (bs,lH), 8.32 (d,lH), 7.88 (d,lH), 7.68 (t,lH), 7.51 (dd, 2H), 7.18 (dd,lH), 4.56 (s,2H), 3.75 (s,3H); LC-MS (M+H)+: 381.
Example 51
3-[4-Methyl-5-(2-methyl-thiazol-4-yl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl- [1,2,4] oxadiazole 3-[4-Methyl-5-(2-methyl-thiazol-4-yl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl- [l,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)-4Η-[l,2,4]triazole-3-thiol (61 mg, 0.29 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 80% ethyl acetate in hexanes. 1H NMR (CDC13), δ (ppm): 7.96 (s, IH), 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)-[l,3,4]oxadiazol-2-ylsulfanylmethyl]-5-m-tolyl- [1,2,4] oxadiazole 3-[5-(2-Methyl-thiazol-4-yl)-[l,3,4]oxadiazol-2-ylsulfanylmethyl]-5-m-tolyl-
[l,2,4]oxadiazole (89 mg, 99%, off-white solid) was obtained from 3-chloromethyl-5-m- tolyl-[l,2,4]oxadiazole (50 mg, 0.24 mmol), potassium carbonate (99 mg, 0.72 mmol), 5- (2-methyl-thiazol-4-yl)-[l,3,4]oxadiazole-2-thiol (57.3 mg, 0.29 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 80% ethyl acetate in hexanes. 1H NMR (CDC13), δ (ppm): 7.97 (s, IH), 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-4fl-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl- [1,2,4] oxadiazole
3-(4-Methyl-5-thioρhen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl- [l,2,4]oxadiazole (80 mg, 88%, white solid) was obtained from 3-chloromethyl-5- thiophen-2-yl-[l,2,4]oxadiazole (50 mg, 0.25 mmol), potassium carbonate (103 mg, 0.75 mmol), 4-methyl-5-thiophen-2-yl-4H-[l,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. !H NMR (CDCI3), δ (ppm): 7.89 (d, IH), 7.65 (m, IH), 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-[l,2,4]triazol-3-ylsulfanylmethyl]-5-m- tolyl- [1 ,2,4] oxadiazole 3-[5-(2,4-Dimethyl-thiazol-5-yl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-m- tolyl-[ 1,2,4] oxadiazole (54.2 mg, 57%, off-white solid) was obtained from 3-chloromethyl- 5-m-tolyl-[l,2,4]oxadiazole (50 mg, 0.24 mmol), potassium carbonate (99 mg, 0.72 mmol), 5-(2,4-dimethyl-thiazol-5-yl)-4-methyl-4Η-[l,2,4]triazole-3-thiol (65.1 mg, 0.29 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 80% ethyl acetate in hexanes. 1H NMR (CDC13), δ (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)-4JHr-[l,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl- [1,2,4] oxadiazole
3-[4-Methyl-5-(5-mfro-furan-2-yl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl- [l,2,4]oxadiazole (77.9 mg, 81%), yellow solid) was obtained from 3 -chloromethyl-5 -m- tolyl-[l,2,4]oxadiazole (50 mg, 0.24 mmol), potassium carbonate (99 mg, 0.72 mmol), 4- methyl-5-(5-nifro-fLxran-2-yl)-4Η-[l,2,4]friazole-3-thiol (65.1 mg, 0.29 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 80% ethyl acetate in. 1H NMR (CDCI3), δ (ppm): 7.90 (m, 2H), 7.46 (d, IH), 7.40 (m, 2H), 7.33 (d, IH), 4.59 (s, 2H), 3.91 (s, 3H), 2.42 (s, 3H).
Example 56 4-[4-Methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4iϊ-[l,2,4]triazol-3-yl]- pyridine 4-[4-Methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine (66 mg, 75%, white solid) was obtained from 3-chloromethyl-5-m-tolyl- [l,2,4]oxadiazole (50 mg, 0.24 mmol), potassium carbonate (99 mg, 0.72 mmol), 4- methyl-5-pyridin-4-yl-4Η-[l,2,4]triazole-3-thiol (55.3 mg, 0.29 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 80% ethyl acetate in hexanes. 1H NMR (CDC13), δ (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-methy l-4fl- [1 ,2,4] triazol-3-ylsulf anylmethyl] -5-m-tolyl- [1 ,2,4]-oxadiazole
3-[5-(4-tert-Butyl-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl- [1,2,4] -oxadiazole (100 mg, 99%), white waxy solid) was obtained from 3-chloromethyl-5- m-tolyl-[l,2,4]oxadiazole (50 mg, 0.24 mmol), potassium carbonate (99 mg, 0.72 mmol), 5-(4-tert-butyl-phenyl)-4-methyl-4H-[l ,2,4]triazole-3-thiol (71.1 mg, 0.29 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 80% ethyl acetate in hexanes. 1H NMR (CDC13), δ (ppm): 7.89 (m, 2Η), 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)-4£T- [1 ,2,4] triazol-3-yl] -pyridine
2-Chloro-5-[4-methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,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-4Η-[l,2,4]triazole-3-thiol (65.2 mg, 0.29 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 80% ethyl acetate in hexanes. 1H NMR (CDCI3), δ (ppm): 8.67 (d, IH), 8.02 (dd, IH), 7.88 (m, 2H), 7.49 (d, IH), 7.40 (m, 2H), 4.58 (s, 2H), 3.65 (s, 3H), 2.42 (s, 3H).
Example 59 2-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-benzooxazole 2-[5-(3-Methoxy-phenyl)-[ 1 ,2,4]oxadiazol-3-ylmethylsulfanyl]-benzooxazole (138 mg, 62%) was obtained from 3-chloromethyl-5-(3-methoxy-phenyl)-[l,2,4]oxadiazole (225.9 mg, 1.11 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. 1H NMR (CDCI3), δ
(ppm):: 7.67 (d, IH), 7.57 (m, 3H), 7.43 (t, IH), 7.21 (m, 2H), 7.14 (m, IH), 4.50 (s, 2H), 3.86 (s, 3H).
Example 60 3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl- [1,2,4] oxadiazole
3-(4-Methyl-5-thiophen-2-yl-4H-[l,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-4Η-[l,2,4]triazole-3-thiol (61 mg, 0.31 mmol), 3 -chloromethyl-5 -thiophen-3-yl- [l,2,4]oxadiazole (50 mg, 0.28 mmol), and potassium carbonate (115 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. 1H NMR (CDCI3), δ (ppm): 8.20 (d, IH), 7.64 (d, IH), 7,48 (m, 3H), 7.18 (m, IH), 4.52 (s, 2H), 3.72 (s, 3H)
Example 61
3-(5-Furan-2-yl-4-methyl-4JHr-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl- [1,2,4] oxadiazole
3-(5-Furan-2-yl-4-methyl-4H-[l,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-[l,2,4]oxadiazole (40.0 mg, 0.19 mmol), potassium carbonate (79 mg, 0.58 mmol), 5- furan-2-yl-4-methyl-4Η-[l,2,4]triazole-3-thiol (41.7 mg, 0.23 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 80% ethyl acetate in hexanes. 1H NMR (CDC13), δ (ppm): 7.88 (m, 2H), 7.58 (s, IH), 7.40 (m, 2H), 7.10 (d, IH), 6.58 (dd, IH), 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-4ET-[l,2,4]triazol-3- ylsulfanylmethyl)- [1 ,2,4] oxadiazole
5-(3-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4] oxadiazole (75.4 mg, 83%, white solid) was obtained from 4-methyl-5-thiophen-2- yl-4Η-[l,2,4]triazole-3-thiol (51 mg, 0.26 mmol), 3-chloromethyl-5-(3-fluoro-phenyl)- [l,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. 1H NMR (CDC13), δ (ppm): 7.89 (d, IH), 7.78 (m, IH), 7.51 (m, 3H), 7.32 (m, IH), 7.18 (m, IH), 4.55 (s, 2H), 3.74 (s, 3H)
Example 63 2-(5-m-Tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-pyridine
2-(5-m-Tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-pyridine (27.3 mg, 96.5%) was obtained from 3-chloromethyl-5-m-tolyl-[l,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. 1H NMR (CDC13), δ (ppm): 8.47 ( dd, IH), 7.94 (s, IH), 7.90 (t, IH), 7.51 (dt, IH), 7.38 (d, 2H), 7.26 (dd, IH), 7.02 (dd, IH), 4.61 (s, 2H), 2.42 (s, 3H).
Example 64
2-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-15-imidazo[4,5- b] pyridine 2-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-imidazo[4,5-b]pyridine (74.5 mg, 96%) was obtained from 3-chloromethyl-5-(3-methoxy-phenyl)-
[l,2,4]oxadiazole (51.2 mg, 0.25 mmol), lH-imidazo[4,5-b]ρyridine-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. 1H-NMR (DMSO-d6), δ (ppm): 8.24 (br s, 1Η), 7.88 br s, 1Η), 7.66 (d, 1Η), 7.55 (m, 3Η), 7.29 (d, IH), 7.19 (m, IH), 4.82 (s, 2H), 3.85 (s, 3H).
Example 65 5-(3-Fluoro-5-methyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4JHr-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole
5-(3-Fluoro-5-methyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole (58 mg, 68%, white solid) was obtained from 3- chloromethyl-5-(3-fluoro-5-methyl-phenyl)-[l,2,4]oxadiazole (50 mg, 0.22 mmol), potassium carbonate (91.5 mg, 0.66 mmol), 4-methyl-5-tl iophen-2-yl-4H-[l,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. 1H NMR (CDC13), δ (ppm): 7.70 (s, 1Η), 7.58 (d, 1Η), 7.52 (m, 1Η), 7.49 (m, 1Η), 7.18 (m, 1Η), 7.12 (d, 1Η), 4.53 (s, 2Η), 3.73 (s, 3H), 2.42 (s, 3H).
Example 66
3-Methyl-5-[3-(4-methyl-5-thiophen-2-yl-4fl-[l,2,4]triazol-3-ylsulfanylmethyl)- [1 ,2,4] oxadiazol-5-yl] -pyridine 3-Methyl-5-[3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[ 1,2,4] oxadiazol-5 -yl] -pyridine (19.0 mg, 43%, light yellow solid) was obtained from 4- methyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3-thiol (26 mg, 0.13 mmol), 3-(3-chloromethyl- [l,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. 1H NMR (CDC13), δ (ppm): 9.13 (s, 1Η), 8.65 (s, 1Η), 8.16 (s, 1Η), 7.50 (m, 2Η), 7.19 (t, IH) 4.57 (s, 2H), 3.74 (s, 3H), 2.43 (s, 3H)
Example 67 3-(4-Methyl-5-phenyl-4S-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl- [1,2,4] oxadiazole
3-(4-Methyl-5-phenyl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-m-tolyl-[l,2,4]oxadiazole (55.8 mg, 67%, white solid) was obtained from 3 -chloromethyl-5 -m-tolyl- [l,2,4]oxadiazole (48.4 mg, 0.23 mmol), potassium carbonate (96 mg, 0.70 mmol), 4- methyl-5-phenyl-4H-[l,2,4]triazole-3-thiol (44.4 mg, 0.23 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 50% ethyl acetate in hexanes. 1H NMR (CDC13), δ (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-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4iϊ-[l,2,4]triazol-3-yl]- pyridine
2-[4-Methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine (42.8 mg, 51%, off-white solid) was obtained from 3-chloromethyl-5-m-tolyl- [l,2,4]oxadiazole (48.4 mg, 0.23 mmol), potassium carbonate (96 mg, 0.70 mmol), 4- methyl-5-pyridin-2-yl-4H-[l,2,4]triazole-3-thiol (44.6 mg, 0.23 mmol) in acetonitrile (2 . ml) at 60°C overnight. Purification was performed on silica gel using 50% ethyl acetate in hexanes. 1H NMR (CDCI3), δ (ppm): 8.62 (d, 1Η), 8.30 (d, 1Η), 7.85 (m, 3Η), 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-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H- [l,2,4]triazol-3-yl]-morpholine
4-Benzyl-2-[4-methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H- [l,2,4]triazol-3-yl]-moφholine (95.8 mg, 83%, clear oil) was obtained from 3- chloromethyl-5-m-tolyl-[l,2,4]oxadiazole (59.9 mg, 0.29 mmol), potassium carbonate (119 mg, 0.86 mmol), 5-(4-benzyl-moφholin-2-yl)-4-methyl-4H-[l,2,4]triazole-3-thiol (83.3 mg, 0.29 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 10% methanol in ethyl acetate. 1H NMR (CDC13), δ (ppm): 7.88 (m, 2Η), 7.31 (m, 7H), 4.75 (dd, IH), 4.47 (dd, 2H), 3.84 (m, 2H), 3.59 (bs, 5H), 3.20 (d, IH), 2.72 (m, 2H), 2.43 (s, 3H), 2.30 (dt, IH).
Example 70
4-[4-Methyl-5-(5-thiophen-3-yl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4fl-[l,2,4]triazol- 3-yl] -pyridine 4-[4-Methyl-5-(5-thiophen-3-yl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3- yl]-pyridine (24 mg, 34%, white solid) was obtained from 3-chloromethyl-5-thiophen-3-yl- [l,2,4]oxadiazole (40 mg, 0.20 mmol), potassium carbonate (82.5 mg, 0.60 mmol), 4- methyl-5-pyridin-4-yl-4H-[l,2,4]triazole-3-thiol (38.3 mg, 0.20 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 10% methanol in ethyl acetate. 1H NMR (CDC13), δ (ppm): 8.80 (bs, 2Η), 8.20 (dd, IH), 7.62 (m, 3H), 7.45 (dd, IH), 4.59 (s, 2H), 3.70 (s, 3H).
Example 71
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazoI-3-ylsulfanylmethyl)-5-thiazol-4-yl- [1 ,2,4] oxadiazole
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiazol-4-yl- [l,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-[l,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. 1H NMR (DMSO), δ (ppm): 9.37 (d, 1Η), 8.86 (d, 1Η), 7.80 (d, 1Η), 7.65 (d, 1Η), 7.26 (t, 1Η), 4.54 (s, 2Η), 3.75 (s, 3H).
Example 72
3-(4-Methyl-5-thiophen-2-yl-4iϊ-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-nitro-phenyl)- [1,2,4] oxadiazole 3-(4-Methyl-5-tlιiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-(3-nifro-phenyl)- [1,2,4] oxadiazole (21.1 mg, 13%, white solid) was obtained from 4-methyl-5-thiophen-2- yl-4H-[l,2,4]triazole-3-thiol (91 mg, 0.46 mmol), 3-chloromethyl-5-(3-nifro-phenyl)- [l,2,4]oxadiazole (100 mg, 0.42 mmol) and 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. 1H NMR (CDC13), δ (ppm): 8.96 (s, 1Η), 8.44 (t, 2Η), 7.75 (t, IH), 7.51 (m, 2H), 7.19 (t, IH), 4.59 (s, 2H), 3.76 (s, 3H)
Example 73
2-Methyl-4-[3-(4-methyl-5-thiophen-2-yl-4iϊ-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazol-5-yl]-pyridine
2-Methyl-4-[3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazol-5-yl]-pyridine (59.2 mg, 66%, white solid) was obtained from 4-methyl- 5-thiophen-2-yl-4H-[l,2,4]triazole-3-thiol (51 mg, 0.26 mmol), 4-(3-chloromethyl- [l,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. 1H NMR (CDCI3), δ (ppm): 8.71 (d, 1Η), 7.79 (s, 1Η), 7.73 (d, 1Η), 7.49 (m, 2Η), 7.19 (t, IH), 4.58 (s, 2H), 3.73 (s, 3H), 2.65 (s, 3H)
Example 74
3-[4-Methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine
3-[4-Methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-yhnethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine (30 mg, off-white solid) was obtained from 3-chloromethyl-5-m-tolyl- [l,2,4]oxadiazole (50 mg, 0.24 mmol), potassium carbonate (100 mg, 0.72 mmol), 4- methyl-5-pyridin-3-yl-4H-[l,2,4]triazole-3-thiol (46.1 mg, 0.24 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 5% methanol in ethyl acetate. 1H NMR (CDCI3), δ (ppm): 8.90 (bs, IH), 8.76 (bs, IH), 8.03 (m, IH), 7.88 (m, 2H), 7.46 (dd, IH), 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-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl- [1,2,4] oxadiazole
3-(4-Methyl-5-thioρhene-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl- [1,2,4] oxadiazole (60 mg, white solid) was obtained from 3-chloromethyl-5-m-tolyl- [l,2,4]oxadiazole (50 mg, 0.24 mmol), potassium carbonate (100 mg, 0.72 mmol), 4- methyl-5-thiophene-3-yl-4H-[l,2,4]triazole-3-thiol (47.3 mg, 0.24 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 40% ethyl acetate in dichloromethane. 1H NMR (CDC13), δ (ppm): 7.87 (m, 2Η), 7.71 (dd, IH), 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-4Jr7- [1 ,2,4] triazol-3-ylsulfanylmethyl)-5-m-tolyl- [1,2,4] oxadiazole 3-(4-Methyl-5-thiazol-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl- [l,2,4]oxadiazole (30 mg, off-white solid) was obtained from 3-chloromethyl-5-m-tolyl- [l,2,4]oxadiazole (50 mg, 0.24 mmol), potassium carbonate (100 mg, 0.72 mmol), 4- methyl-5-thiazol-4-yl-4H-[l,2,4]triazole-3-thiol (47.5 mg, 0.24 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 60% ethyl acetate in dichloromethane. 1H NMR (CDC13), δ (ppm): 8.89 (d, 1Η), 8.22 (d, 1Η), 7.88 (m, 2Η), 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-4jr7-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazole
5-(3-Iodo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazole (725 mg, 97%, white solid) was obtained from 3-chloromethyl-5-(3- iodo-phenyl)-[l,2,4]oxadiazole (500 mg, 1.56 mmol), potassium carbonate (647 mg, 4.68 mmol), 4-methyl-5-thiophen-2-yl-4H-[l,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. 1H NMR (CDCI3), δ (ppm): 8.44 (d, 1Η), 8.06 (d, 1Η), 7.93 (d, 1Η), 7.51 (m, 2Η), 7.26 (t, IH), 7.19 (m, IH), 4.54 (s, 2H), 3.73 (s, 3H).
Example 78
5-(3-Ethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4fl-[l,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4] oxadiazole 5-(3-Ethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)- [l,2,4]oxadiazole (28.1 mg, 27%, white solid) was obtained from 4-methyl-5-thiophen-2- yl-4H-[l,2,4]triazole-3-thiol (59 mg, 0.30 mmol), 3-chloromethyl-5-(3-ethyl-phenyl)- [l,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. 1H NMR (CDCI3), δ (ppm): 7.90 (t, 2Η), 7.51 (m, 2H), 7.42 (t, 2H)7.18 (m, IH), 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)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lfir-benzoimidazole
2-[5-(2-Methyl-pyridin-4-yl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-lH-benzoimidazole (46.0 mg, 59%, white solid) was obtained from 2-mercaptobenzimidazole (41 mg, 0.27 mmol), 4-(3-chloromethyl-[l,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. 1H NMR (DMSO-d6), δ (ppm): 8.72 (d, 1Η), 7.87 (s, 1Η), 7.78 (d, 1Η), 7.47 (t, 2Η), 7.14 (m, 2H), 4.81 (s, 2H), 2.59 (s, 3H)
Example 80 2-[5-(3-Iodo-phenyl)-[l,2,4]oxadiazoI-3-ylmethylsuIfanyI]-l.H-benzoimidazoIe
2-[5-(3-Iodo-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole (36 mg, 51%, white solid) was obtained from 3-chloromethyl-5-(3-iodo-phenyl)-[l,2,4]oxadiazole (50 mg, 0.16 mmol), potassium carbonate (65 mg, 0.47 mmol), lH-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. 1H NMR (DMSO), δ (ppm): 12.73 (bs, 1Η), 8.30 (s, 1Η), 8.09 (d, 2Η), 7.45 (m, 3H), 7.18 (m, 2H), 4.78 (s, 2H).
Example 81
3-(4-Methyl-5-trifluoromethyl-4Jff-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl- [1,2,4] oxadiazole
3-(4-Methyl-5-trifluoromethyl-4H-[l,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- [l,2,4]oxadiazole (40 mg, 0.19 mmol), potassium carbonate (79 mg, 0.58 mmol), 4- methyl-5-trifluromethyl-4H-[l,2,4]triazole-3-thiol (35.1 mg, 0.19 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 50% ethyl acetate in hexanes. 1H NMR (CDC13), δ (ppm): 7.87 (m, 2Η), 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-[l,2,4]oxadiazol-3-yImethylsulfanyl)-4JΪ- [1 ,2,4] triazol-3-yl] -pyridine
2,6-Dichloro-4-[4-methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H- [1 ,2,4]triazol-3-yl]-pyridine (51.4 mg, 62%, off-white solid) was obtained from 3- chloromethyl-5-m-tolyl-[l,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-[l,2,4]triazole-3-thiol (50.1 mg, 0.19 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 80% ethyl acetate in hexanes. 1H NMR (CDC13), δ (ppm): 7.87 (m, 2Η), 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-4iϊ-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl- [1,2,4] oxadiazole 3-(4-Methyl-5-p-tolyl-4H-[l,2,4]friazol-3-ylsulfanylmethyl)-5-m-tolyl-[l,2,4]oxadiazole (57.8 mg, 81%), off-white solid) was obtained from 3 -chloromethyl-5 -m-toly 1- [1,2,4] oxadiazole (40 mg, 0.19 mmol), potassium carbonate (79 mg, 0.58 mmol), 4- methyl-5-p-tolyl-4H-[l,2,4]triazole-3-thiol (39.4 mg, 0.19 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 80% ethyl acetate in hexanes. 1H NMR (CDCI3), δ (ppm): 7.88 (m, 2Η), 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-yI-4iϊ-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazol-5-yl]phenyl}-amine
Dimethyl-{3-[3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazol-5-yl]phenyl}-amine (28.0 mg, 85%, white solid) was obtained from 4- methyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3-thiol (18 mg, 0.093 mmol), 3-(3- chloromethyl-[l,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. 1H NMR (CDC13), δ (ppm): 7.49 (m, 2H), 7.36 (m, 3H), 7.17 (t, IH), 6.91 (d, IH), 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-4JH-[l,2,4]triazol-3- ylsulf nylmethyl)- [1 ,2,4] oxadiazole
5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4] oxadiazole (76.8 mg, 90%, white solid) was obtained from 4-methyl-5-thiophen-2- yl-4Η-[l,2,4]triazole-3-thiol (47 mg, 0.24 mmol), 3-chloromethyl-5-(3-chloro-phenyl)- [l,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. 1H NMR (CDC13), δ (ppm): 8.09 (s, IH), 7.98 (d, IH), 7.49 (m, 4H), 7.18 (m, IH), 4.55 (s, 2H), 3.73 (s, 3H)
Example 86
3-(4-Methyl-5-thiophen-2-yl-4Hr-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3- trifluoromethoxy-phenyl) [1 ,2,4] oxadiazole
3-(4-Methyl-5-t ophen-2-yl-4H-[l,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-[l,2,4]triazole-3-thiol (78 mg, 0.39 mmol), 3 -chloromethyl-5 -(3- trifluoromethoxy-phenyl)-[l,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. 1H NMR (CDC13), δ (ppm): 8.04 (d, 1Η), 7.95 (s, 1Η), 7.51 (m, 4Η), 7.18 (m, IH), 4.56 (s, 2H), 3.74 (s, 3H)
Example 87
3-(5-Cyclohexyl-4-methyl-4JH-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl- [1,2,4] oxadiazole 3-(5-Cyclohexyl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[l,2,4]oxadiazole (10.5 mg, clear oil) was obtained from 3-chloromethyl-5-m-tolyl- [l,2,4]oxadiazole (50 mg, 0.24 mmol), potassium carbonate (165 mg, 1.20 mmol), 5- cyclohexyl-4-methyl-4H-[l,2,4]triazole-3-thiol (94.6 mg, 0.48 mmol) in acetonitrile (3 ml) at 60°C overnight. Purification was performed on silica gel using 2% ammonia (2 N methanol) in dichloromethane. 1H NMR (CDC13), δ (ppm): 7.88 (m, 2Η), 7.39 (m, 2H), 4.42 (s, 2H), 3.46 (s, 3H), 2.60 (m, IH), 2.42 (d, 3H), 1.74 (m, 7H), 1.34 (m, 3H).
Example 88
3-(5-tert-Butyl-4-methyl-4H-[l,2,4]triazoI-3-ylsulfanylmethyl)-5-m-tolyl- [1,2,4] oxadiazole
3-(5-tert-Butyl-4-methyl-4H-[l,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- [l,2,4]oxadiazole (50 mg, 0.24 mmol), potassium carbonate (100 mg, 0.72 mmol), 5-tert- butyl-4-methyl-4H-[l,2,4]triazole-3-thiol (41 mg, 0.24 mmol) in acetonitrile (2 ml) at 60°C overnight. Purification was performed on silica gel using 80% ethyl acetate in hexanes. 1H NMR (CDC13), δ (ppm): 7.89 (m, 2Η), 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-4 T-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole 5-(3 -Bromo-phenyl)-3 -(4-methyl-5 -thiophen-2-yl-4H- [ 1 ,2,4]triazol-3 -ylsulfanylmethyl)- [l,2,4]oxadiazole (83.4 mg, 86%, white solid) was obtained from 4-methyl-5-thiophen-2- yl-4H-[l,2,4]triazole-3-thiol (47 mg, 0.24 mmol), 5-(3-bromo-phenyl)-3-chloromethyl- [l,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. 1H NMR (CDC13), δ (ppm): 8.25 (t, 1Η), 8.02 (d, 1Η), 7.73 (d, 1Η), 7.50 (m, 2Η), 7.40 (t, IH), 7.19 (m, IH), 4.55 (s, 2H), 3.73 (s, 3H)
Example 90 2-[5-(3-Bromo-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lHr-benzoimidazole
2-[5-(3-Bromo-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole (71.1 mg, 84%, white solid) was obtained from 2-mercaptobenzimidazole (35 mg, 0.23 mmol), 5-(3-Bromo-phenyl)-3-chloromethyl-[l,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%ι ethyl acetate in hexane and titurated with ether. 1H NMR (DMSO-d6), δ (ppm): 12.78 (broad s, IH), 8.18 (s, IH), 8.07 (d, IH), 7.93 (d, IH), 7.59 (t, IH), 7.46 (s, 2H), 7.14 (m, 2H), 4.77 (s, 2H)
Example 91
5-(3-Methoxymethyl-phenyl)-3-(4-methyl-5-thiophen-2-yI-4JΪ-[l,2,4]triazol-3- Isulf anylmethyl)- [1 ,2,4] oxadiazole 5-(3-Methoxymethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- lsulfanylmethyl)-[l,2,4]oxadiazole (76 mg, 90%, white solid) was obtained from 3- chloromethyl-5-(3-methoxymethyl-phenyl)-[l,2,4]oxadiazole (50 mg, 0.21 mmol), potassium carbonate (87 mg, 0.63 mmol), 4-methyl-5-thiophen-2-yl-4H-[l,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. 1H NMR (CDC13), δ (ppm): 8.06 (s, 1Η), 8.01 (d, 1Η), 7.59 (d, 1Η), 7.50 (m, 3Η), 7.18 (t, IH), 4.54 (s, 2H), 4.50 (s, 2H), 3.72 (s, 3H), 3.43 (s, 3H).
Example 92 2-[5-(3-Methoxymethyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lET- benzoimidazole
2-[5-(3-Methoxymethyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole (62 mg, 84%, white solid) was obtained from 3 -chloromethyl-5 -(3 -methoxymethyl- phenyl)-[l,2,4]oxadiazole (50 mg, 0.21 mmol), potassium carbonate (87 mg, 0.63 mmol), lH-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. 1HNMR (DMSO), δ (ppm): 8.09 (d, 2Η), 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-4i3-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol- 5-yl]-pyridine A solution of isonicotinoyl chloride (2.0 g, 11.2 mmol) in dichloromethane was freated 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 K2CO3 (292 mg, 2.1 mmol) and 4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3-thiol (140 mg, 0.7 mmol) was stined at room temperature for 24 h followed by 1.5 h at 120°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%). 1H ΝMR (CDC13), δ (ppm): 8.41 dd,2Η), 7.92 dd,2H), 7.50 dd,lH), 7.47 dd,lH), 7.18 dd,lH), 4.58 (s,2H), 3.74 (s,3H); LC-MS (M+H)+: 357.
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-4ET-[l,2,4]triazol-3-yIsulfanylmethyl)-[l,2,4]oxadiazol-
3-yl]-pyridine
4-[5-(4-Methyl-5-thiophen-2-yl-4H-[ 1 ,2,4]triazol-3-ylsulfanylmethyl)-[ 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); freated with K2CO (292 mg, 2.1 mmol), and 4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3-thiol (140 mg, 0.7 mmol). Purification was performed by silica gel chromatography and recrystallization. 1H ΝMR (CDCI3), δ (ppm): 8.76 (dd,2Η), 7.89 (dd,2H), 7.53 (dd,lH), 7.48 (dd,lH), 7.18 (dd,lH), 4.71 (s,2H), 3.73 (s,3H); LC-MS (M+H)+: 357.
Example 95
2-{l-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-l-methyl-lfl- imidazo[4,5-b]pyridine and 2-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazoI-3-ylmethylsulfanyl]-l-methyl-l£T- imidazo [4,5-b] pyridine
THF (3 ml) was added to a mixture of sodium hydride (60%, 8 mg, 0.2 mmol) and 2-[5-(3- methoxy-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-imidazo[4,5-b]pyridine (24.6 5 mg, 0.072 mmol) and the resulting mixture was stined at 0°c for about 15 min.. Methyl iodide (20 μL, 0.32 mmol) was added the resulting mixture was stined at 0 c for 2h. The reaction was quenched by the addition of dichloromethane (10 ml) and water (2 ml). After vigorous stirring, the organic extracts (10 ml, plus 3x5 ml) were eluted through a Chem Elut Extraction Column (Varian, cat #1219-8002). Purification using SPE chromatography o (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-{l-[5-(3-methoxy-phenyl)-[l,2,4]oxadiazol- 3-yl]-ethylsulfanyl}-l-methyl-lH-imidazo[4,5-b]pyridine (6 mg, 23%). 1H NMR (CDC13), δ (ppm): 8.46 (d, 1Η), 7.72 (d, 1Η), 7.62 (d, 1Η), 7.55 (d,lΗ), 7.42 (t,lH), 7.14 (m, 2H), 5.67 (q, IH), 3.88 (s, 3H), 3.71 (s, 3H), 2.01 (d, 3H). 5 The second product to elute was 2- [5 -(3 -methoxy-phenyl)- [ 1 ,2,4] oxadiazol-3 - ylmethylsulfanyl]-l-methyl-lH-imidazo[4,5-b]pyridine (12 mg, 47%). 1H NMR (CDC13), δ (ppm): 8.44 (d, IH), 7.69 (d, IH), 7.60 (d, IH), 7.55 (d, IH), 7.41 (t, IH), 7.13 (m, IH), 4.90 (s, 2H), 3.87 (s, 3H), 3.70 (s, 3H).
0 Example 96-97 was prepared in an analogous method to the procedure given in Example 95.
Example 96
3-[l-Methyl-l-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m- 5 tolyl- [1,2,4] oxadiazole
3-[l-Methyl-l-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m-tolyl- [l,2,4]oxadiazole (13 mg, 47%) was obtained from 3-(4-methyl-5-thiophen-2-yl-4H- [l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[l,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 TΗF o (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. 1H NMR (CDC13), δ (ppm): 7.83 (br s, 2H), 7.48 (d, IH), 7.42 (d, IH), 7.36 (m, 2H), 7.13 (m, IH), 3.50 (s, 3H), 2.35 (s, 3H), 1.95 (s, 6H).
Example 97 3-[l-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m-tolyl- [1,2,4] oxadiazole
3-[l-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m-tolyl- [1,2,4] oxadiazole (6.1 mg, 17%) was obtained from 3-(4-methyl-5-thiophen-2-yl-4H- [l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[l,2,4]oxadiazole (33.8 mg, 0.091 mmol) with 60% sodium hydride (17 mg, 0.42 mmol) and methyl iodide (20 μL, 0.32 mmol) in TΗF (2.5 ml) at room temperature for lh. The product was extracted with dichloromethane and purified by SPE 25-40% ethyl acetate in 1:1 chloroform : hexane. 1H NMR (CDC13), δ (ppm): 7.89 (br s, 2Η), 7.50 (d, IH), 7.46 (d, IH), 7.38 (m, 2H), 7.16 (m, IH) , 4.89 (q, IH), 3.64 (s, 3H), 2.37 (s, 3H), 1.90 (d, 3H).
Example 98
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3-sulfonylmethyl)-5-m-tolyl- [1 ,2,4] oxadiazole and 3-(4-MethyI-5-thiophen-2-yI-4H- [1 ,2,4] triazole-3- sulfinylmethyl)-5-m-tolyl-[l,2,4]oxadiazole 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-[l,2,4]triazol-3- ylsulfanylmethyl)-5-m-tolyl-[l,2,4]oxadiazole (45 mg, 0.12 mmol) and the resulting mixture was stined 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 3x5 ml) were eluted through a Chem Elut Exfraction 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- [l,2,4]triazole-3-sulfonylmethyl)-5-m-tolyl-[l,2,4]oxadiazole (12.3 mg, 25%). 1H NMR (CDC13), δ (ppm): 7.83 (br s, 2Η), 7.63 (d, IH), 7.56 (d, IH), 7.36 (m, 2H), 7.24 (m, IH), 5.12 (s, 2H), 3.94 (s, 3H), 2.36 (d, 3H). The second product to elute was 3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3- sulfmylmethyl)-5-m-tolyl-[l,2,4]oxadiazole (33.2 mg, 71%). 1H NMR (CDC13), δ (ppm): 7.87 (br s, 2Η), 7.59 (d, IH), 7.54 (d, IH), 7.38 (m, 2H), 7.22 (m, IH) , 5.05 (dAB, IH) , 4.90 (dAB, IH), 4.03 (s, 3H), 2.39 (d, 3H).
Example 99
5-(3-Furan-3-yl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4fl-[l,2,4]triazol-3- ylsulf anylmethyl)- [1 ,2,4] oxadiazole
To 5-(3-Iodo-phenyl)-3-(4-methyl-5-thioρhen-2-yl-4H-[l ,2,4]triazol-3-ylsulfanylmethyl) - [l,2,4]oxadiazole (50 mg, 0.10 mmol) in a vial was added 3-furan boronic acid (17 mg, 0.16 mmol), tefrakis(triphenylphospliine)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°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%). 1H NMR (CDC13), δ (ppm): 8.18 (s, 1Η), 7.98 (d, 1Η), 7.79 (s, 1Η), 7.71 (d, 1Η), 7.51 (m, 4Η), 7.17 (m, IH), 6.74 (s, IH), 4.55 (s, 2H), 3.73 (s, 3H).
Intermediates
Example 100 Pyrimidine-4-carboxylic acid.
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 filfration through celite. The filtrate was washed with several portions of DCM and EtOAc before acidification with cone. HCl. The formed precipitate was collected and washed with water to yield 1.37 g ofthe title compound as a white solid. IH NMR (DMSO-d6) d (ppm): 13.94 (br. s, IH), 9.37 (d, IH), 9.07 (d, IH), 8.01 (dd, IH). Example 101 5-Chloro-thiophene-3-carboxylic acid.
Thiophene-3 -carboxylic acid (17.51 g, 136.6 mmol) and l-chloro-pynolidine-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 exfraction with several small portions of DCM, followed by back exfraction 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 cone. HCl to precipitate the crude material. This precipitate was recrystallized from water to yield 14.98 g ofthe title compound as a grey solid contaminated with approximately 20 mol% of a dichlorinated byproduct as judged from MS and 1H-NMR. IH NMR (DMSO-d6) d (ppm): 8.15 (d, IH), 7.37 (d, IH).
Example 102 3-Methylsulfanyl-benzoic acid 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 stined for 1 hour, the reaction mixture was diluted with ethyl acetate, washed with water (3X), dried over anhydrous sodium sulfate, filtered, and concenfrated to afford 3-methylsulfanyl-benzoic acid methyl ester (684 mg, 96%, yellow oil). 1H NMR (CDC13), δ (ppm): 7.90 (s, IH), 7.80 (d, IH), 7.44 (d, IH), 7.35 (t, IH), 3.92 (s, 3H), 2.53 (s, 3H).
3-Methylsulfanyl-benzoic acid methyl ester (684mg, 3.8 mmol) and IN NaOH (5.6 mL, 5.6 mmol) in methanol (8 mL) and THF (8 mL) were heated at 70°C for 1 hour. The reaction mixture was concenfrated and then the residue was diluted with water. After acidification with IN HCl to pH ~ 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). 1H NMR (DMSO), δ (ppm): 13.1 (bs, IH), 7.76 (s, IH), 7.70 (d, IH), 7.51 (d, IH), 7.44 (t, IH), 2.52 (s, 3H).
Example 103 3-Cyclopropyl-benzoic acid 1.0 M Diethyl zinc in hexanes (27.3 ml, 27.3 mmol) was added to a solution of 2,4,6- trichlorophenol (5.4g, 27.3 mmol) in dichloromethane (100 ml) at -40°C. After stirring for 15 minutes, diiodo-methane (2.2 mL, 27.3 mmol) was added at -40°C and stined for an additional 15 minutes. l-Bromo-3 -vinyl-benzene (2.5 g, 13.7 mmol) was then added to the 5 reaction mixture, allowed to warm to room temperature, and left stirring overnight. The reaction mixture was diluted with dichloromethane, washed with IN HCl (2X), saturated sodium bicarbonate (2X), saturated sodium sulfite, IN sodium hydroxide, and saturated brine, dried over magnesium sulfate, filtered and concentrated. GC-MS revealed that the reaction mixture contained l-Bromo-3 -cyclopropyl-benzene and l-bromo-3 -vinyl-benzene. o 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 ofthe crude mixture (~ 3.5 g) in THF (40 mL) at 0°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 s and concentrated. Purication by flash column chromatography eluted with 100 hexanes afforded l-bromo-3-cyclopropyl-benzene (2.20g, 81%).
1.6 M n-Butyllithixrm in hexanes (3.2 mL, 5.1 mmol) was added drop-wise to a solution of l-bromo-3-cyclopropyl-benzene at -78°C and stined for 1 hour. This reaction mixture was then fransfened via canula to a 250 mL round bottom flask equipped with a stiner bar 0 approximately lA full of solid carbon dioxide and stined and for 1 hour. The reaction mixture was concenfrated and then the residue was diluted with water. The aqueous layer was washed with dichloromethane (3X), acidified with 1 N HCl to pH ~ 2, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concenfrated to afford 3-cyclopropyl-benzoic 5 (356 mg, 43%, white solid). 1H NMR (DMSO), δ (ppm): 12.90 (bs, IH), 7.71 (d, IH), 7.64 (s, IH), 7.34 (m, 2H), 2.01 (m, IH), 0.99 (m, 2H), 0.70 (m, 2H).
Example 104 o 3-tert-Butoxycarbonylamino-benzoic acid To a flask containing ethyl-3-aminobenzoate (lg, 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°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 2g of 3-tert-butoxycarbonylamino-benzoic aid ethyl ester (white slurry). To the crude 3-tert-butoxycarbonylamino-benzoic acid ethyl ester (~2.0g, 0.00754 mmol) added THF (15 mL), and 0.5M LiOH (15 mL). The mixture was heated for two hours at 75°C and the THF was removed in vacuo after cooling. The precipitate was filtered from the remaining mixture and the filtrate was transfeπed to a separatory funnel. The aqueous layer was washed with dichloromethane (3x) and was acidified to pH ~5 using IM HCl. The product was then extracted with ethyl acetate, washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered and concenfrated. 730mg of 3-tert-
Butoxycarbonylamino-benzoic acid (white solid) was isolated. IH NMR (DMSO-d6) δ (ppm): 9.58 (s, IH), 8.16 (s, IH), 7.63 (d, IH), 7.54 (d, IH), 7.37 (t, IH), 1.49 (s, 9H)
Example 105 3-Acetyl-benzoic acid
6M Sodium hydroxide (25 mL) was added to 3-acetylbenzonitrile (850 mg, 5.82 mmol) in methanol (25 mL) and then heated at 90°C overnight. After concentrating the reaction mixture, the aqueous layer was washed with dichloromethane (2x), then acidified pH ~ 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 concenfrated to afford 3-ethylbenzoic acid as a colorless oil; 0.800g (92%). IH NMR (CDC13) δ (ppm): 8.70 (s, 2H), 8.33 (d, 2H), 8.24 (d, 2H), 7.64 (t, IH), 2.70 (s, 3H).
Example 106 2-Methyl-isonicotinic acid hydrazide Dichloromethane (lOmL) was added to 2-methyl nicotinic acid hydrochloride salt (l.lg, 6.34 mmol) and oxalyl chloride (6.95mL, 13.9mmol) 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 concenfrated and THF (lOmL) was added to the flask and it was placed in an ice bath. Methanol (5mL) was added and the reaction was allowed to stir for one hour. The reaction was concenfrated and the residue was partitioned between NaHCO3 (sat) and EtOAc. The product was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concenfrated. Purification was performed by solid phase extraction tube (20% EtOAc/hexanes) gave the title compound as a clear oil. 1H NMR CDC13 δ (ppm): 8.51 (d, IH), 7.57 (d, IH), 7.51 (d, IH), 3.82 (s, 3H), 2.50 (s, 3H).
2-Methyl-isonicotinic acid methyl ester (316.5mg, 2.093mmol) was dissolved in MeOH (7mL) under Argon and hydrazine monohydrate 98% (lniL, 20.93mmol) was added. The reaction was allowed to stir under Argon at room temperature for eighteen hours. The reaction was concenfrated to give the title compound (271.9mg, 86%) as a white solid. H NMR CDC13 δ (ppm): 8.59 (d, IH), 7.50 (s, IH), 7.38 (d, IH), 3.09 (br. s, 3H), 2.60 (s, 3H).
Example 107
5-Chloro-2-fluoro-benzoic acid hydrazide.
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, stined for 3 h and then concenfrated to afford 5-chloro-2-fluoro-benzoic acid methyl ester (1.17 g, 100%). IH NMR (CDCI3), δ (ppm): 7.93 (m, IH), 7.48 (m, IH), 7.12 (m, IH), 3.96 (s, 3H). Step 2: 5- Chloro-2-fluoro-benzoic acid hydrazide: A mixture of 5-chloro-2-fluoro-benzoic acid methyl ester (1.17 g, 6.2 mmol) and hydrazine monohydrate (0.451 ml, 9.3 mmol) in ethanol (20 ml) was stined at room temperature overnight. The reaction mixture was concenfrated and then the residue was triturated with diethyl ether to afford 5-chloro-2- fluoro-benzoic acid hydrazide (497 mg, 42%, white solid). IH NMR (DMSO), δ (ppm): 9.66 (bs, IH), 7.58 (m, 2H), 7.36 (m, IH), 4.58 (bs, 2H).
Example 108 was prepared analogously to example 107. Example 108
3-Cyano-benzoic acid hydrazide
3-cyano-benzoyl chloride (3g, 18.12 mmol) in dichlormethane (5 mL) and methanol (20 mL) was stined at room temperature and overnight. The solvent was removed using a rotevaporator to afford a white solid (3.76g). !H NMR (DMSO) δ (ppm): 8.33 (m, IH), 8.24 (m, IH), 8.14 (m, IH), 7.76 (m, IH), 3.89 (d, 3H).
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 stined 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). 1H NMR (DMSO) δ (ppm): 10.31 (s, IH), 8.21 (m, IH), 8.11 (m, IH), 7.99 (m, IH), 7.70 (m, IH), 4.50 (s, IH).
Example 109 2-Chloro-isonicotinic acid hydrazide 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°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). IH NMR (DMSO) d (ppm): 10.21 (bs, IH), 8.55 (d, IH), 7.82 (s, IH), 7.75 (d, IH), 4.69 (bs, 2H).
The following compounds were prepared analogously to example 109:
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Example 169 5-(3,5-Dichloro-phenyl)-4-ethyl-4H-[l,2,4]triazole-3-thiol
3,5-Dichloro-benzoic acid (382 mg, 2 mmol) was mixed with triethylamine (606 mg, 3 mmol) in THF (6 ml) at 10 °C. Then isobutyl chloroformate (300 mg, 2.2 mmol) was added dropwise and stined for 45 min. To the reaction mixture, 4-methyl-3- thiosemicarbazide (238.4 mg, 2 mmol) was added. After being stined at room temperature for 10 min, the reaction mixture was heated to 70 °C overnight. Standard work-up. The product was purified by column chromatography with 25-30 % ethyl acetate in hexanes to give 46.4 mg (8.5 %) of 5-(3,5-dichloro-phenyl)-4-ethyl-4H-[l,2,4]triazole-3-thiol.
The following compounds were prepared analogously to Example 169:
Figure imgf000144_0002
Example 176
4-Ethyl-5-methoxymethyl-2,4-dihy dro- [1 ,2,4] triazole-3-thione
Step 1: N-Ethyl-2-(methoxyacetyl)hydrazinecarbotbioamide: 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 stined 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+l). Step 2: 4-Ethyl-5-methoxymethyl-2,4-dihydro-[l,2,4]triazole-3-thione: N-Ethyl-2- (methoxyacetyl)hydrazinecarbothioamide (760 mg crade, 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 exfraction with ethyl acetate. After evaporation to dryness the crude was recrystallized in ethyl acetate/heptane. Filfration and recrystallization ofthe mother liquor gave a combined yield of 325 mg (47%) ofthe title compound. IH NMR (CDC13), δ (ppm): 4.47 (s, 2H), 4.13 (q, 2H), 3.37 (s, 3H), 1.38 (t, 3H).
The following compounds were prepared analogously to Example 176:
Figure imgf000145_0001
Figure imgf000146_0001
Example 196 4-Furan-2-ylmethyl-4H-[l,2,4]triazole-3-thiol
A solution of formic acid hydrazide (439 mg, 7.809 mmol) in pyridine (20 ml) was added to a solution of 2-isotlιiocyanatomethyl-furan (1 g, 7.185 mmol) in pyridine (20ml). Reaction took place at room temperature overnight, and ethanol (20 ml) was added directly to the reaction and placed in 80C 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. IH NMR (CD3OD), δ (ppm): 14.0 (bs, IH), 8.19 (s, IH), 7.52 (q, IH), 6.52 (m, IH), 6.42 (m, IH), 4.90 (s, 2H).
The following compounds were prepared analogously to Example 196:
Figure imgf000146_0002
Example 199 4-Cyclopropyl-5-thiophen-2-yl-2,4-dihydro-[l,2,4]triazole-3-thione
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 stined at 70 °C for 72 h and then cooled to room temperature. The white precipitate was filtered off and suspended in a MeOH:H2O (9:1, 40 ml) together with aq. NaOH (2%, 5 ml). The reaction mixture was stined at 70 °C overnight and then cooled to room temperature. The pH was adjusted to around 4 with aq. HCl (IN). The formed white precipitate was filtered off, washed with water and dried under vacuum (829 mg, 61%). IH NMR (CD3OD), δ (ppm): 7.67 (dd, IH), 7.63 (dd, IH), 7.17 (dd, IH), 3.15 (m, IH), 1.14 (m, 2H), 0.86 (m, 2H).
The following compounds were prepared analogously to Example 199:
Figure imgf000147_0001
Example 208 4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazole-3-thiol
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 stined at room temperature for an h and and heated at 60 °C overnight. Standard work-up, the product was triturated with hexanes to give 564g of as 4- ethyl-5-trifluoromethyl-4H-[l,2,4]triazole-3-thiol pale-brown solid. 1H-NMR(CDC13) d(ppm): 12.64 (w, IH), 4.22 (q, 2H) and 1.44 (t, 3H).
Example 209
4-Ethyl-3-methanesulfonyl-5-thiophen-2-yl-4H-[l,2,4]triazole
The title compound was synthesized according to the method described in Akerblom et al. J. Med. Chem. 16, 312 (1973). 4-Ethyl-3-methylsulfanyl-5-thiophen-2-yl-4H- [l,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 stined for 3 h at ambient temperature, then heated to 100 °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%). IH NMR (CDC13), δ (ppm): 7.60 (d, IH), 7.56 (d, IH), 7.22 (m, IH), 4.51 (q, 2H), 3.58 (s, 3H), 1.55 (t, 3H).
The following compound was prepared analogously to Example 209:
Figure imgf000148_0001
Example 211
4-(2-Hy droxy-ethyl)-5-thiophen-2-yl-2,4-dihydro- [1 ,2,4] triazole-3-thione 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-l,5-dihydro-[l,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. Na2SO4 (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 exfracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (15 ml), dried (MgSO4) and concenfrated under reduced pressure. The crude product was used without purification in the next step.lH NMR (DMSO-d6), δ (ppm): 13.94 (s, IH), 7.86 (d, IH); 7.81 (d, IH), 7.24 (dd, IH), 5.09 (t, IH), 4.16 (t, 2H), 3.76 (app. q, 2H).
Example 212 4-(4,5-Dimethyl-4H-[l,2,4]triazol-3-yl)-pyridine
860 μl (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 CH2C12 at 0°C. After 15 min 1.37 g (10 mmol) isonicotinic acid hydrazide was added in one portion. The resulting mixture was stined at room temperature for lh and the neutralized with NaHCO3(sat). The phases were separated and the water phase was exfracted with CH2C12. The combined organic phases were dried and concenfrated. The residue was dissolve in 20 ml acetic acid and heated at 120°C for 2h. After cooling the solvent was removed. Flashchromatography (CH2C12/MeOH 10:1) afforded 765 mg (44%) of a grey/white solid. IH NMR (CDC13), d (ppm): 2.52 (s, 3 H) 3.66 (s, 3 H) 7.58 (d, 2 H) 8.76 (d, 2 H).
Example 213 Methyl-(4-methyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-yl)-amine
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 3ml of pyridine was heated with microwaves for 5 min at 160°C.
K2CO3(sat) was added and the mixture was extracted 4 times with CHCI3. The organic phase was dried and concenfrated. Recrystalhzation from ethanol, water and EtOAc gave
216 mg (26%) of a yellow white solid. IH NMR (DMSO), d (ppm): 2.85 (d, 3 H) 3.45 (s, 3
H) 6.25 (d, 1 H) 7.65 (m, 2 H) 8.67 (m, 2 H).
Example 214
3-Pyridin-4-yl-5,6,7,8-tetr ahydro- [1 ,2,4] t iazolo [4,3-a] pyrimidine
A solution of 750 mg (3.1 mmol) (l,4,5,6-tefrahydro-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 °C over night. The reaction mixture was cooled and diluted with K2CO3(sat) and extracted with 3x10 ml chloroform. The combined organic extracts were dried and concenfrated. Flashchromatography (CH2Cl2/MeOH 10:1) afforded 83 mg (18%) of a white solid. IH NMR (CDCI3), d (ppm): 1.91 (m, 2 H) 3.24 (m, 2 H) 4.13 (m, 2 H) 7.67 (m, 2 H) 8.65 (m, 2 H).
The following compound was prepared analogously to Example 214:
Figure imgf000149_0001
Example 21 4-Ethyl-5-(6-methoxy-pyridazin-3-yl)-2,4-dihydro-[l,2,4]triazole-3-thione 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 H2SO4 (10 ml). After addition the mixture is stined at 50 °C on. The reaction was pored on ice and the mixture was exfracted 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, 4.53mmol) 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 stined on at room temperature (rt). H2O was added and the mixture was exfracted three times with DCM. The combined organic phases were dried and concenfrated. Flashchromatography (Siθ2, Heptane/EtOAc 1:1) afforded 560 mg (72%) ofthe title compound. IH NMR (CDC13), δ (ppm): 4.09 (s, 3 H), 7.69 (d, 1 H), 8.18 (d, 1 H).LC-MS (M++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 (IM, 10ml) was refluxed on. H2O was added and the mixture was exfracted 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 exfracted three times with DCM to give organic phase II. The combined organic phases II were dried and concenfrated 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 stined on at rt. Saturated NaHCO3 (aq) was added and the mixture was exfracted three times with DCM. The combined organic phases were dried and concenfrated 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-[l,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-ethy 1-3 -thiosemicarbazide (190 mg, 1.6 mmol) in MeOH (6 ml) and the mixture was heated to 70°C at 72 h. The reaction was cooled to ambient temperature and evaporated to dryness. H2O (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 filfration. LC-MS (M++1): 238.
Example 217 4-Ethyl-5-(5-methoxy-pyridin-2-yl)-2,4-dihydro-[l,2,4]triazole-3-thione
Step 1 : 5-Methoxy-pyridine-2-carboxylic acid methyl ester: 5-Methoxy-2-methyl-pyridine (700 mg, 5.69 mmol) was dissolved in H2O (20 ml) and heated to 80 °C. KMnO4 (4 g, 25.3 mmol) was added in portion to the solution over 1 h. After stirring at 80 °C for 5 h the mixture was filtrated and the filtrate was washed with H2O (60 °C). The combined water phase was concentrated. DMF (20 ml), K2CO3 (785 mg, 5.7 mmol) followed by Mel (540 ml, 8.6 mmol) was added to the remaining residue and the mixture was heated to 80 °C on. The reaction was cooled to ambient temperature and H2O was added and the mixture was exfracted three times with toluene. The combined organic phases were dried and concenfrated. Flashchromatography (Siθ2, Heptane/EtOAc 1:1) afforded 210 mg (22%) of the title compound.lH NMR (CDCl3):d ppm 3.93 (s, 3 H) 4.00 (s, 3 H) 7.23 (m, 1 H) 8.13 (d, 1 H) 8.40 (d, 1 H). Step 2: 4-Ethyl-5-(5-methoxy-pyridin-2-yl)-2,4-dihydro- [l,2,4]triazole-3-thione: NaOMe (4 ml, 4.0 mmol, IM) 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°C on. The reaction was cooled to ambient temperature and evaporated to dryness. H2O (10 ml) was added to the residue and the mixture was acidified with concenfrated hydrochloric acid and the title compound 50 mg (18%) was collected by filtration. LC-MS (M++1): 237.
The following compounds were prepared analogously to example 10:
Figure imgf000151_0001
Figure imgf000152_0001
The following compounds were prepared analogously to example 16:
Figure imgf000152_0002
Example 241
3-Chloromethyl-5-(2-chloro-5-methyl-phenyl)- [1 ,2,4] oxadiazole
2-Chloro-5-methyl-benzoic acid (lg, 5.8 mmol) was freated 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 stined 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 ofthe acyclic ester intermediate. DMF was added to this inteπnediate and then heated at 135°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).
The following compounds were prepared analogously to Example 241:
Figure imgf000153_0001
Figure imgf000154_0001
Example 257
[3-(3-Chloromethyl-[l ,2,4] oxadiazol-5-yl)-phenyl] -methanol
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 stined at ambient temperature over night. The crude product was partitioned between dichloromethane and NaHCθ3 (aq), the organic phase was dried (MgSO ) and the dichloromethane was removed in vacuo. The resulting DMF-solution was heated at 120 °C over night. The reaction mixture was concenfrated in vacuo and the title compound (64 mg, 25%) was isolated by flash chromatography using 25-50% ethyl acetate in heptane. IH NMR (CDC13), δ (ppm): 8.15 (s, IH), 8.06 (d, IH), 7.62 (d, IH), 7.53 (t, IH); 4.80 (d, 2H), 4.66 (s, lH); 1.99 (br. t, IH).
The following compounds were prepared analogously to Example 257:
Figure imgf000154_0002
Example 261 l-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethanoI Step 1: l-{l-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethoxy}-lH-benzotriazole: 2-(l- Chloro-ethyl)-5-(3-chloro-phenyl)-[l,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 reexfraction ofthe 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 (CDC13), δ (ppm): 7.94 (d, 1 H), 7.82 (m, 1 H), 7.76 (m, 1 H), 7.46 (m, 1 H), 7.39-7.27 (m, 4 H), 5.98 (q, 1 H), 2.04 (d, 3 H). Step 2: l-[5-(3-Chloro-phenyl> [1,3,4] oxadiazol-2-yl] -ethanol: l-{l-[5-(3 -Chloro-phenyl)- [ 1 ,3 ,4]oxadiazol-2-yl] -ethoxy} - IH-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 diioide solution (4 ml, 0.4 mmol) was added during 5 min. The reaction mixture was quenched after further 15 min of stirring with aqueous Na2S2O3, 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. IH NMR (CDC13), δ (ppm): 7.98-7.75 (m, 2 H), 7.50-7.38 (m, 2 H), 5.25 (q, 1 H), 1.74 (d, 3 H).
The following compounds were prepared analogously to Example 261 :
Figure imgf000155_0001
Example 263
1 - [5-(3-Chlor o-phenyl)- [1 ,2,4] oxadiazol-3-yl] -ethanol
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°C. Cooling was removed and the mixture was stined at room temperature for 25 min and at reflux for 25 min. After cooling the mixture was poured into water and exfracted twice with CH2CI2. The organic phase was dried and concenfrated. Recrystalhzation from heptane/EtOAc afforded 4.12 g (60%) of a white solid. IH NMR (CDC13), d (ppm): 1.68 (d, 3 H) 2.67 (m, 1 H) 5.09 (m, 1 H) 7.46 (t, 1 H) 7.56 (d, 1 H) 8.01 (d, 1 H) 8.13 (s, 1 H). Example 264 [5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-methanol
Step 1: N-{4-[(Z)-{[5-(3-chlorophenyl)-l,2,4-oxadiazol-3- yl]methylene} (oxido)amino]phenyl}-N,N-dimethylamine: The title compound was synthesized according to the method described in Palazzo et al. J. Heterocycl. Chem. (1979) 16:1469. l-[5-(3-Chloro-ρhenyl)-[l,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+l). Step 2: [5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-methanediol: N-{4-[(Z)- { [5 -(3 -Chlorophenyl)- 1 ,2,4-oxadiazol-3 -yl]methylene} (oxido)amino]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 stined 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 l-[5-(3-chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-pyridinium chloride). MS (ESI) m/z 227 (M+l). Step 3: [5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-methanol: Step 3: [5- (3 -Chloro-phenyl)- [ 1 ,2,4] oxadiazol-3-yl] -methanol : 1 - [5 -(3 -Chloro-phenyl)- [l,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 stined vigorously. After separation ofthe layers and washing ofthe 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 (CDC13), δ (ppm): 8.11 (s, IH), 8.00 (apparent d, IH), 7.56 (apparent d, IH), 7.46 (apparent t, IH), 4.87 (d, 2H), 2.91 (t, IH). Example 265 2-Chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[l,3,4]oxadiazole
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°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)- [l,3,4]oxadiazole (284.5 mg, 66%). 1H NMR (CDC13) d (ppm): 7.89 (q, IH), 7.36 (m, IH), 7.16 (t, IH), 4.81 (s, 2H), 2.43 (s, 3H).
The following compounds were prepared analogously to Example 265:
Figure imgf000157_0001
Example 272 2-(l-Bromo-ethyl)-5-(3-chloro-phenyl)-[l,3,4]oxadiazole 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°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-(l-bromo-ethyl)-5-(3-chloro- phenyl)-[l ,3,4]oxadiazole (93 mg, 32%, colorless oil). IH NMR (CDC13) d (ppm): 8.09 (t, IH), 7.99 (t, IH), 7.55 (m, 3H), 5.30 (m, IH), 2.21 (q, 3H). The following compounds were prepared analogously to Example 272:
Figure imgf000158_0001
Example 277
3-(l-Bromo-ethyl)-5-(3-chloro-phenyl)- [1 ,2,4] oxadiazole
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°C. After stirring for 20 min 416 mg (1.85 mmol) l-[5-(3-chloro-phenyl)-[l,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%). IH NMR (CDC13), d (ppm): 2.12 (d, 3 H) 5.21 (q, 1 H) 7.47 (t, 1 H) 7.57 (m, 1 H) 8.03 (d, 1 H) 8.15 (s, 1 H).
Example 278 l-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol
Step 1 4-(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°C. The mixture stined at room temperature for 1 h and was then heated at 80°C for a half an h. After cooling, the mixture was freated with 3N HCl and then diluted with ethyl acetate. The organic layer was washed with water (3X) and saturated brine, dried over anhydrous sodium sulfate, filtered and concenfrated. 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). IH NMR (CDC13) d (ppm): 15.12 (br s, IH), 7.98 (s, IH), 7.88 (d, IH), 7.58 (d, IH), 7.47 (t, IH), 7.05 (s, IH), 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°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). IH NMR (CDC13) d (ppm): 7.82 (s, IH), 7.72 (m, IH), 7.47 (m, 2H), 4.03 (s, 3H). Mixture of both methyl and ethyl ester (mostly methyl). Step 3: l-[5-(3-Chloro-phenyi)-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°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°C for 5 h. Reaction mixture was quenched with IN 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 stined at 45°C for 30 min. At this point the mixture was concenfrated, 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 concenfrated, in-vacuo. The crade residue was purified on silica gel using 2% ethyl acetate in hexanes to isolate the desired compound as a white solid (156 mg, 60%). lH-NMR (CDCI3), d (ppm): 7.77 (m, IH), 7.66 (m, IH), 7.42 (m, 2H), 6.90 (s, IH), 2.69 (s, 3H). Step 4: l-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol: In a screw cap vial equipped with stir bar added l-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanone (100 mg, 0.45 mmol), sodixxm 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), exfracted with dichloromethane (3X30 ml). Combined organic phase was dried (sodium sulfate), filtered and concenfrated, in-vacuo to isolate l-[5-(3-Chloro-phenyl)- isoxazol-3-yl]-ethanol as a white solid (110 mg). 1H-NMR (CDC13), d (ppm): 7.69 (m, IH), 7.59 (m, IH), 7.37 (m, 2H), 6.59 (s, IH), 5.07 (q, IH), 3.45 (bs, IH), 1.58 (d, 3H). The following compound was prepared analogously to Example 278:
Figure imgf000160_0001
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):
Figure imgf000160_0002
Example 285 [5-(3-Chloro-phenyl)-isoxazol-3-yl]-methanol
Lithium aluminum hydride (320 mg, 8.4 mmol) was slowly added to a solution of 5-(3- chloro-phenyl)-isoxazole-3-carcoxylic 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 concenfrated. 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 (1.32g, 75%, yellow solid). IH NMR
(CDC13) d (ppm): 7.78 (s, IH), 7.68 (m, IH), 7.43 (m, 2H), 6.63 (s, IH), 4.84 (d, 2H), 2.23 (t, IH).
The following compounds were prepared analogously to Example 285:
Figure imgf000160_0003
Figure imgf000161_0001
Example 293
Methanesulfonic acid l-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethyl ester
In a screw cap vial equipped with stir bar was added l-[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°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 exfracted with dichloromethane (3X30 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.
The following compounds were prepared analogously to Example 293:
Figure imgf000161_0002
Figure imgf000162_0001
Example 307
Methanesulfonic acid 4-chloro-5~(3-chloro-phenyl)-isoxazol-3-ylmethyl ester
Sulfuryl chloride (1 ml) was added to methanesulfonic acid 5-(3-chloro-phenyl)-isoxazol- 3-ylmethyl ester (200 mg, 0.70 mmol) and then stined at 60°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). IH NMR (CDC13) d (ppm): 8.07 (m, IH), 7.92 (m, IH), 7.50 (m, 2H), 5.38 (s, 2H), 3.16 (s, 3H).
Example 308
3-(3-Chloro-phenyl)-isoxazole-5-carboxylic acid methyl ester
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°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 %). IH NMR (CDC13) d (ppm): 8.11 (s, IH), 7.72 (s, IH), 7.61 (m, IH), 7.46 (m, IH), 7.36 (m, IH). 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 stined for 1 h. The reaction mixture was diluted with diethyl ether and then washed with water (3X), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the titled compound (1.13 g, 93 %). IH NMR (CDC13) d (ppm): 8.03 (s, IH), 7.87 (m, IH), 7.76 (m, IH), 7.43 (m,lH).: 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 concenfrated. Purification by flash column chromatography eluted with 50% hexanes in ethyl acetate and then recrystalhzation with methanol afforded 3-(3-chloro-phenyl)- isoxazole-5-carboxylic acid methyl ester (635 mg, 51%, white solid). IH NMR (CDC13) d (ppm): 7.86 (m, IH), 7.74 (m, IH), 7.46 (2H), 7.2 (s, IH), 4.05 (s, 3H).
Example 309 2-Bromomethyl-5-(3-chloro-phenyl)-oxazole
Step 1 5-(3-Chloro-phenyl)-2-methyl-oxazole: To a solution of Tl(OAc)3 (4.2 g, 11.1 mmol) in acetonitrile (80 ml), trifluoromethanesulfuric acid (5g, 33.3 mmol) was added dropwise at room temperature and stined for 15 min. The reaction mixture was then heated to 80°C and l-(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 5~19 % ethyl acetate in hexanes to give 1.2 (83.9 %) g of 5-(3-chloro-phenyl)-2-methyl-oxazole as yellow oil. 1H-NMR(CDC13) d(ppm): 7.60 (s, IH), 7.48 (d, IH), 7.29 (m, 2H), 7.23 (s, IH) and 2.34 (s, 3H). Step 2: 2-Bromomethyl-5-(3-chloro-ρhenyl)-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 CC14 at room temperature. The reaction mixture was heated at 75 °C for 2 h and then quenched with water and dichloromethane. The organic layer was dried, concenfrated, purified by column chromatography with 2~5 % ethyl acetate in hexanes to give 562 mg (68.3 %) of 2-bromomethyl-5-(3-chloro-phenyl)-oxazole as yellow oil. 1H-NMR(CDC13) d(ppm): 7.67 (s, IH), 7.54 (d, IH), 7.35(m, 3H) and 4.56 (s, 2H). Example 310
2-(3-Chloro-phenyl)-oxazole-4-carboxylic acid methyl ester
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- methylmoφholine (NMM) (7.0 ml, 63.8 mmol) and EDCI (4.97 g, 31.9 mmol) at 0°C. The mixture was allowed to warm to room temperature and stined for 18 h. The mixture was diluted with ethyl acetate (300 ml) and then washed with water (3 x 250 ml) followed by brine. The organic extract was dried over Na2SO4 (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. IH NMR (CDC13) d (ppm): 7.78 (s, 1 H), 7.66 (d, 1 H), 7.45, (dd, 1 H), 7.34 (t, 1 H), 7.25 (br, d, IH), 4.82 (m, 1 H), 4.08 (m, 2 H), 3.79 (s, 3 H), 3.19 (br, t, lH).
To a solution of 2-(3-chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester (7.2 g, 29.6 mmol) in CH2C12 at -20°C was added dropwise De-oxofluor (7.2 g, 32.6 mmol). After stirring at this temperature for 30 min, BrCCl3 (3.6 g, 18.1 mmol) was added dropwise followed by DBU (2.79g, 18.1 mmol). The mixture was then stined at 2-3°C for 8 h ad then quenched with saturated NaHCO3 followed by exfraction with ethyl acetate. The organic extract as then washed with brine and dried over Na2SO4 (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 (4.1g, 59%) as a yellow solid. IH NMR (CDC13) d (ppm): 8.30 (s, 1 H), 8.12 (d, 1 H), 7.98 (dd, 1 H), 7.45 (m, 2 H), 3.96 (s, 3 H).
Example 311 2-(3-Chloro-phenyl)-oxazole-4-carboxylic acid methyl ester
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- methylmoφholine (NMM) (7.0 ml, 63.8 mmol) and EDCI (4.97 g, 31.9 mmol) at 0°C. The mixture was allowed to warm to room temperature and stined for 18 h. The mixture was diluted with ethyl acetate (300 ml) and then washed with water (3 x 250 ml) followed by brine. The organic extract was dried over Na2SO (anhydrous) and then concenfrated in vacuo giving 2-(3-Chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester (7.2 g, 93%) of a pale yellow solid. IH NMR (CDC13) d (ppm): 7.78 (s, 1 H), 7.66 (d, 1 H), 7.45, (dd, 1 H), 7.34 (t, 1 H), 7.25 (br, d, IH), 4.82 (m, 1 H), 4.08 (m, 2 H), 3.79 (s, 3 H), 3.19 (br, t, lH).
To a solution of 2-(3-chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester (7.2 g, 29.6 mmol) in CH2C12 at -20°C was added dropwise De-oxofluor (7.2 g, 32.6 mmol). After stirring at this temperature for 30 min, BrCCl3 (3.6 g, 18.1 mmol) was added dropwise followed by DBU (2.79g, 18.1 mmol). The mixture was then stined at 2-3°C for 8 h ad then quenched with saturated NaHCO3 followed by extraction with ethyl acetate. The organic extract as then washed with brine and dried over Na2SO4 (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 (4.1g, 59%) as a yellow solid. IH NMR (CDC13) d (ppm): 8.30 (s, 1 H), 8.12 (d, 1 H), 7.98 (dd, 1 H), 7.45 (m, 2 H), 3.96 (s, 3 H).
Example 312 l-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethanol
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°C and to this stined solution added diisobutylaluminum hydride (IM hexanes, 5.3 ml, 5.3 mmol). The resulting mixture was left stirring at -78°C for 3 h. Reaction was quenched using sodium sulfate decahydrate. The resulting mixture was stined at 63 °C for 15 min after which it was filtered tlirough 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 (0.55g, 84%). IH-NMR (CDC13), d (ppm): 10.2 (s, IH), 7.99 (m, IH), 7.44 (m, IH), 7.20 (m, IH), 7.10 (d, IH). Step 2: l-[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 tefrahydrofuran (6 ml). Cooled the mixture down to 0°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°C for 3 h. Reaction mixture was quenched with hydrochloric acid (IN, aqueous, 10 ml), extracted with diethyl ether (3X50 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 l-[3-(3-Chloro-phenyl)-isoxazol-5-yl]-ethanol
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°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°C for 1.5 houes, cooled and diluted with benzene and IN aqueous hydrochloric acid. After stirring, the separated benzene layer was evaporated to dryness and the crade purified via flash chromatography over silica using heptane/ethyl acetate = 5/1 giving after drying in vacuo the title compound (0.49 g, 15%). IH NMR (CDC13), δ (ppm): 1.64 (d, 3 H), 5.07 (dq, 1 H), 6.50 (s, 1 H), 7.40 (m, 2 H), 7.68 (m, 1 H), 7.79 (m, 1 H)
Example 314 [5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-methanol
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-l-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 concenfrated in-vacuo to isolate the title compound as brown oil (5.42 g). Step 2: 4-Chloro-2-ethynyl-l-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 exfracted with hexanes (2X100 ml). Combined organic phase was washed with brine (200 ml), dried (sodium sulfate), filtered and concenfrated in-vacuo to isolate the desired compound as brown oil (3.56 g). IH-NMR (CDC13), d (ppm): 7.47 (dd, IH), 7.30 (m, IH), 7.05 (t, IH), 3.36 (s, IH). 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°C followed by sequential addition of concenfrated 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°C for 1 h. Reaction mixture was extracted with ether (4X100 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%). IH-NMR (CDC13), d (ppm): 9.98 (bs, IH), 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-l-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 concenfrated in-vacuo. The crade residue was purified on silica gel using 3% acetone in hexanes to isolate the title compound as an off-white solid (1.56 g). IH-NMR (CDCI3), d (ppm): 8.00 (dd, IH), 7.43 (m, IH), 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 stined solution added solution of lithium aluminum hydride (0.12 g, 2.89 mmol) in tetrahydrfuran (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 stined at 63°C for 15 min after which it was filtered tlirough a celite pad. The filterate was concenfrated in-vacuo to isolate the title compound as yellow solid (0.65 g, 99%). IH-NMR (CDCI3), d (ppm): 7.73 (dd, IH), 7.27 (m, IH), 7.24 (t, IH), 6.73 (d, IH), 4.77 (s, 2H), 4.45 (bs, IH). Example 315
3~[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-propionic acid hydrazide
Step 1: 3-[5-(3-Chloro-phenyl)-[l,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(CDC13 + DMSO-d6) d(ppm): 10.01 (s, IH), 9.53 (s, IH), 7.68 (s, IH), 7.55 (d, IH), 7.21 (d, IH), 7.12 (t, IH) and 2.35 (m, 4H). This solid was mixed with cone. H2SO4 and stined at room temperature for 45 min and the reaction mixture was carefully added to crashed ice (400g). The precipitate was filtered to give 4.07 g (80.6 %) of 3-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-propionic acid as white solid. lH-NMR(DMSO-d6) d(ppm): 12.4 (w, IH), 7.96 (s, IH), 7.91 (d, IH), 7.71 (d, IH), 7.63 (t, IH), 3.15 (t, 2H) and 2.82 (t, 2H). Step 2: 3-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2- yl]-propionic acid hydrazide: 3-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-propionic acid (2.52 g, 10 mmol) was mixed with iodomethane (5.68 g, 40 mmol) and K2CO3 (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 MgSO4 and concenfrated to give 2.57 g of 3-[5-(3-Chloro-phenyl)-[l,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 concenfrated, diluted with water, filtered to give 2.17 g (81.4 %) of 3-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]- propionic acid hydrazide as white solid. 1H-NMR(CDC13 + DMSO-d6) dψpm): 8.75 (w, IH), 7.91 (s, IH), 7.82 (d, IH), 7.42 (m, 2H), 3.45 (w, 2H), 3.19 (t, 2H) and 2.68 (t, 2H).
Example 316
3-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-butyric acid hydrazide
Step 1: 2-{l-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethyl}-malonic acid dimethyl ester: 2-(l-Chloro-ethyl)-5-(3-chloro-phenyl)-[l,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 °C overnight. The reaction mixture was dilute with dichloromethane and washed with water. The organic layer was dried and concenfrated. The residue was purified with 5-20 % ethyl acetate in hexanes to give 357 mg (74.3 %) 2- {l-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethyl}-malonic acid dimethyl ester as white solid. 1H-NMR(CDC13) d(ppm): 8.03 (s, IH), 7.95 (d, IH), 7.53 (d, IH), 7.47 (t, IH), 4.06 (d, IH), 3.95 (m, IH), 3.84 (s, 3H), 3.74 (s, 3H) and 1.51 (d, 3H). Step 2: 3-[5- (3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-butyric acid methyl ester: 2-{l-[5-(3-Chloro- phenyl)-[l,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 °C for an h. The reaction mixture was diluted with water and exfracted with dichloromethane. The organic layer was washed with water and concenfrated. The residue was purified with column chromatography with 10-20 % ethyl acetate in hexanes to give 215 mg (76.8 %)3-[5-(3-chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-butyric acid methyl ester as clear oil. 1H-NMR(CDC13) d(ppm): 8.03 (s, IH), 7.94 (d, IH), 7.53 (d, IH), 7.45 (t, IH), 3.73 (s, 3H), 3.67 (m, IH), 3.05 (dd, IH), 2.73 (dd, IH) and 1.50 (d, 3H). Step 3: 3-[5-(3- Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-butyric acid hydrazide: 3-[5-(3-Chloro-phenyl)- [l,3,4]oxadiazol-2-yl]-butyric acid hydrazide (146 mg, %) was obtained from 3-[5-(3- chloro-phenyl)-[l,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(CDC13) d(ppm): 8.03 (s, IH), 7.94 (d, IH), 7.53 (d, IH), 7.46 (t, IH), 7.23 (w, IH), 3.93 (w, 2H), 3.71 (m, IH), 2.90 (dd, IH), 2.57 (dd, IH) and 1.50 (d, 3H).
Example 317
3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-propionimidic acid ethyl ester hydrochloride
Step 1: 3-[3-(3-Chloro-ρhenyl)-[l,2,4]oxadiazol-5-yl]-ρropionamide: 3-[3-(3-Chloro- phenyl)-[l,2,4]oxadiazol-5-yl]-propionic acid (1.6 g, 6.33 mmol) was reacted with SOCl2 (10 ml) at room temperature overnight. The reaction mixture was concenfrated by vacuum. The residue was mixed with THF (20 ml) and quenched with 28 % NH3.H2O (5 ml) at 0 °C. After being stined 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)-[l,2,4]oxadiazol-5-yl]- propionamide. 1H-NMR(CDC13) d(ppm): 8.07 (s, IH), 7.96 (d, IH), 7.45 (m, 2H), 5.60 (dw, 2H), 3.32 (t, 2H) and 2.87 (t, 2H). Step 2: 3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5- yl]-propionitrile: 3-[3-(3-Chloro-phenyl)-[l,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)-[l,2,4]oxadiazol-5-yl]-propionitrile as pale-brown oil. 1H-NMR(CDC13) dψpm): 8.09 (s, IH), 7.98 (d, IH), 7.45 (m, 2H), 5.60 (dw, 2H), 3.35 (t, 2H) and 3.01 (t, 2H). Step 3: 3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5- yl]-propionimidic acid ethyl ester hydrochloride: 3-[3-(3-Chloro-phenyl)-[l,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)-[l,2,4]oxadiazol-5-yl]-propionimidic acid ethyl ester hydrochloride as white solid. lH-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)-[l ,2,4] oxadiazol-5-yl] -propionic acid hydrazide
Step 1: 3-[3-(3-chloro-phenyl)-[l,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°C for an h. The reaction mixture was cooled down and diluted with ethyl acetate. The organic solution was washed with water and brine, concenfrated by vacuum. The residue was triturated with 20 % ethyl acetate in hexanes to give 4.0 g (60 %) of 3-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-propionic acid as white solid. ). 1H- NMR(CDC13) d(ppm): 8.08 (s, IH), 7.96 (d, IH), 7.49 (d, IH), 7.42 (t, IH), 3.28 (t, 2H) and 3.04 (t, 2H). Step 2: 3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-propionic acid hydrazide: This acid was reacted with iodoethane (1.6g, 10.5 mmol) and K2CO3 (1.46 10.5 mmol) in DMF (5 ml) for 5 min to form 3-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]- propionic acid ethyl ester. The ethyl ester was then freated with 37% hydrazine (2ml) in ethanol (5 ml) at 80 °C for2 h to give 595 mg (65% in 3 steps) of 3-[3-(3-chloro-phenyl)- [l,2,4]oxadiazol-5-yl]-propionic acid hydrazide as off-white solidlH-NMR(CDCl3) d(ρρm): 8.07 (s, IH), 7.96 (d, IH), 7.49 (d, IH), 7.43 (t, IH), 7.00 (w, IH), 3.95 (w, 2H), 3.34 (t, 2H) and 2.79 (t, 2H). Example 319
[5-(3-Chloro-phenyl)- [1 ,2,4] oxadiazoI-3-yl] -acetic acid hydrazide
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 stined at 50 °C overnight. After being concenfrated, 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 30-70 % ethyl acetate in hexanes to give 3.32 g (22.7 %) of (N-Hydroxycarbamimidoyl)- acetic acid ethyl ester as white solid. 1H-NMR(CDC13) dψpm): 5.04 (ws, 2H), 4.20 (q, 2H), 3.19 (s, 2H) and 1.30 (t, 3H). Step 2: [5-(3-Chloro-phenyl)-[l,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 °C and the reaction mixture was stined for 10 min. DMF (8 ml) was added to the reaction mixture was heated to 135 °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)-[l,2,4]oxadiazol-3-yl]-acetic acid ethyl ester as pale-yellow oil. 1H-NMR(CDC13) dψpm): 8.168 (s, IH), 8.04 (d, IH), 7.59 (d, IH), 7.49 (t, IH), 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)-[l,2,4]oxadiazol-3-yl]- acetic acid ethyl ester (0.64 g, 2.4 mmol) was mixed with 37 % hydrazine (1.6 ml) in ethabol (10 ml) at 80 °C for 4 h. The reaction mixture was concenfrated and diluted with water. The precipitate was filtered, washed with water to give 0.51 g (83.3 %) of [5-(3- chloro-phenyl)-[l,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
Step 1: (R)-3-[3-(3-Chloro-phenyl)-[l,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 °C. After being stined for 30 min, the 3-chloro-N-hydroxy-benzamidine (2.56 g, 15 mmol) was added. The reaction mixture was stined at room temperature for another 30 min and then heated to 135 °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 concenfrated to give 4.0 g (95 %) of (R)-3-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5- yl]-butyric acid methyl ester as pale-yellow oil. Step 2: (R)-3-[3-(3-Chloro-phenyl)- [l,2,4]oxadiazol-5-yl]-butyric acid hydrazide: (R)-3-[3-(3-Chloro-phenyl)-
[l,2,4]oxadiazol-5-yl]-butyric acid hydrazide (430 mg, 77%) was obtained from (R)-3-[3- (3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-butyric acid methyl ester (461.4 mg, 2.0 mmol) reacted with hydrazine hydrate (2rnL) in methanol (2 mL) at 65 °C for 1 h. 1H- NMR(CDC13) d (ppm): 8.07 (s, IH), 7.96 (d, IH), 7.46 (m, 2H), 6.98 (w, IH), 3.93 (w, 2H), 3.78 (m, IH), 2.86 (dd, IH), 2.55 (dd, IH) and 1.59 (d, 3H).
The following compounds were prepared analogously to Example 320:
Figure imgf000172_0001
Example 322 3-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-piperidin-2-one
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 °C. After stirring for 2 h at 0 °C, 400 mg (1.58 mmol) 3-chloromethyl-5-[3-chloro-phenyl)-[l,2,4]oxadiazole was added in one portion and stining was continued for 3 h. NH4Cl(sat) was added to quench the reaction and the mixture was extracted twice with CH2C12. The combined organic phases were dried and concentrated. Flashchromatography (SiO2, Heptane/EtOAc 1:8) afforded 113 mg (25%) of a yellow-white solid. IH NMR (CDCl3):d ppm 1.80 (m, 1 H) 1.89 (m, 1 H) 2.00 (m, 1 H) 2.91 (m, 1 H) 2.98 (m, 1 H) 3.35 (m, 1 H) 3.52 (m, 1 H) 5.83 (s, 1 H) 7.46 (t, 1 H) 7.55 (d, J=8.08 Hz, 1 H) 8.00 (d, 1 H) 8.11 (s, 1 H).
The following compounds were prepared analogously to Example 322:
Figure imgf000173_0001
Example 324
3-Chloromethyl-5-(5-chloro-thiophen-3-yl)-[l,2,4]oxadiazole and l-[5-(5-Chloro- thiophen-3-yl)-[l,2,4]oxadiazol-3-ylmethoxy]-lH-benzotriazole 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 stined at ambient temperature for 1 h before heated at 120 °C for 4 h under argon. Removal ofthe solvent in vacuo followed by silica gel chromatography ofthe obtained residue using 0- 20% EtOAc in n-heptane yielded 38.5 mg ofthe faster eluting 3-chloromethyl-5-(5-chloro- thiophen-3-yl)-[l,2,4]oxadiazole as a syrap, followed by 65 mg ofthe slower eluting l-[5- (5-chloro-thiophen-3-yl)-[l,2,4]oxadiazol-3-ylmethoxy]-lH-benzotriazole as a white solid. 3-Chloromethyl-5-(5-chloro-thiophen-3-yl)-[l,2,4]oxadiazole: IH NMR (CDC13) d (ppm): 8.01 (d, IH), 7.50 (d, IH), 4.63 (s, 2H). l-[5-(5-Chloro-thiophen-3-yl)-[l,2,4]oxadiazol-3- ylmethoxy]-lH-benzotriazole: 1H NMR (CDC13) d (ppm): 7.97 (m, 2H), 7.52 (dt, IH), 7.44 (m, 2H), 7.34 (m, IH), 5.70 (s, 2H).
Example 325 (4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-acetonitrile
4-Methyl-5-thiophene-3-yl-4H-[l,2,4]triazole-3-thiol (197 mg, 1.0 mmol), chloroacetomtile (95 ml, 1.5 mmol), sodium carbonate (424 mg, 4 mmol) and potassium iodide (332mg, 2.0 mmol) were stined together at 100 °C for 3 h with an additional addition of chloroacetonitrile (60ml, 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 (dichloromethanemethanol 19:1) yielded 150 mg ofthe desired compound.
Example 326 2-(4-MethyI-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-propionic acid (R)-2-chloro-propionic acid (500 mg, 4.6 mmol), 4-methyl-5-thiophen-2-yl-4H- [l,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 crade was stined in DMF (10 ml) overnight. Extraction was repeated and purification was performed by SPE (solid phase exfraction) chromatography on silica gel using 300 ml ethyl acetate, 100 ml 1%, and 100 ml 3% fonnic acid in ethyl acetate, yielding title compound (150.7 mg, 12%) IH-NMR (CDC13), d (ppm): 7.52 (dd, 2H), 7.19 (m, IH), 4.21 (q, IH), 3.78 (s, 3H), 1.64 (d, 3H).
The following compounds were prepared analogously to Example 326:
Figure imgf000174_0001
Example 328
3-(3-Chloro-phenyl)-5-(4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4] oxadiazole The title compound (2.08 g, 81.5 %) was obtained form 5-chloromethyl-3-(3-chloro- phenyl)-[l,2,4]oxadiazole (1.9 g, 8.29 mmol) reacted with 4-methyl-4H-[l,2,4]triazole-3- thiol (1.0 g, 8.71 mmol) and K2CO3 (4.58 g, 33.2 mmol) in DMF (19 ml) at room temperature overnight. 1H-NMR(CDC13) d (ppm): 8.21 (s, IH), 8.05 (s, IH), 7.94 (d, IH), 7.49(d, IH), 7.43 (t, IH), 4.69 (s, 2H) and 3.64(s, 3H).
Example 329
{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazol-5-yl-phenyl}-carbamic acid tert-butyl ester The title compoxmd was prepared from 4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3-thiol (53 mg, 0.27 mmol), 3-(3-chloromethyl-[l,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 (88.0mg, 79%, white solid) . IH NMR (CDC13) d (ppm): 8.06 (s, IH), 7.73 (d, IH), 7.66 (d, IH), 7.51 (t, 2H), 7.42 (t, IH), 7.18 (m, IH), 6.68 (s, IH), 4.51 (s, 2H), 3.73 (s, 3H), 1.53 (s, 9H).
The following compounds were prepared analogously to Example 41:
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Example 699
{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [1 ,2,4] oxadiazol-5-yl] -phenylj-methanol
[3-(3-Chloromethyl-[l,2,4]oxadiazol-5-yl)-phenyl]-methanol (32 mg, 0.14 mmol), 4- methyl-5-thiophene-3-yl-4H-[l,2,4]triazole-3-tliiol (41 mg, 0.21 mmol) and potassium carbonate (29 mg, 0.21 mmol) was dissolved in anhydrous acetonitrile and refluxed under nifrogen atmosphere for 1 h. The solvent was removed in vacuo and the residue was dissolved in NaHCO3 (aq) and exfracted 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 (CDC13), δ (ppm): 8.07 (s, IH), 7.98 (d, IH), 7.60 (d, IH), 7.52-7.45 (m, 3H), 7.16 (dd, IH), 5.29 (s, 2H), 4.75 (s, 2H), 4.50 (s, 2H), 3.71 (s, IH).
The following compounds were prepared analogously to Example 699:
Figure imgf000242_0001
Example 704
3-(2,5-Difluoro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulf anylmethyl)- [1 ,2,4] oxadiazole
5-Chloromethyl-3-(2,5-difluoro-phenyl)-[l,2,4]oxadiazole (23 mg, 0.10 mmol) and 4- ethyl-5-thiophen-2-yl-2,4-dihydro-[l,2,4]triazole-3-thione (23 mg, 0.11 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%). IH NMR (CDC13) d (ppm): 7.64 (m, IH), 7.45 (d, IH), 7.39 (d, IH), 7.10 (m, 3H), 4.70 (s, 2H), 4.08 (q, 2H), 1.32 (t, 3H).
The following compounds were prepared analogously to Examples 704:
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Example 731
5-(3-Chloro-phenyl)-3-(5-furan-2-yl-4-isobutyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4] oxadiazole The title compound was synthesized according to the method described by Graybill et al. Tetrahedron left. 2002 43, 5305-5309 from furan-2-carboxylic acid hydrazide (55.2 mg, 0.44 mmol), l-isothiocyanato-2-methyl-propane (47ml, 0.38 mmol) and 3-chloromethyl-5- (3-chloro-phenyl)-[l,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 (CDC13) d ψpm): 8.08 (s, 1 H), 7.97 (d, IH), 7.55 (d, 2H), 7.45 (t, IH), 7.10 (d, IH), 6.56 (d, IH), 4.62 (s, 2H), 4.01 (d, 2H), 2.03 (m, IH), 0.86 (d, 6H).
General: Thiophene-2-carbohydrazide (1.5 equiv) and an isothiocyanate (1.3 equiv) were dissolved in DMF (1 ml). 2-tert-Butylimino-2-diethylamino-l,3-dimethyl-perhydro-l,3,2- diazaphosporine (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 °C. The resin was washed with dioxane:water 1:1 several times. The ring closure was carried out at 85 °C for 48 h in dioxane:water 1:1 on the miniblock. The resin was washed with acetonitrile (2 '2ml). The 3-(chloromethyl)-5-(3-chlorophenyl)-l,2,4-oxadiazole was added to the reaction and shaken in acetonitrile at 50 °C for 2h. The product was filtrated and purified on MS-directed prep-HPLC, gradient 0-100% acetonitrile over 15 min.
The following compounds were prepared analogously to Example 731 :
Figure imgf000248_0002
Figure imgf000249_0001
Example 740
5-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-yloxymethyl)- [1,2,4] oxadiazole [5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-methanol (28.0 mg, 0.13 mmol), 4-ethyl-3- methanesulfonyl-5-thiophen-2-yl-4H-[l,2,4]triazole (35.2 mg, 0.13 mmol) and cesium carbonate (130 mg) were dissolved in dimethylformamide and stined under argon at ambient temperatures for 46 h. After evaporation to dryness the crade was chromatographed on 12 g silica, heptane/ethyl acetate 4/1 to 2/1. Collection ofthe appropriate fractions gave after evaporation to dryness and drying in vacuo the title compound (17.0 mg, 33%). IH NMR (CDC13), δ (ppm): 8.13 (m, IH), 8.02 (m, IH), 7.58 (m, IH), 7.47 (m, 2H), 7.40 (dd, IH), 7.14 (dd, IH), 5.74 (s, 2H), 4.04 (q, 2H), 1.38 (t, 3H). The following compounds were prepared analogously to Example 740:
Figure imgf000250_0001
Figure imgf000251_0001
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°C:
Figure imgf000251_0002
Example 747
5-(2-Methoxy-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole
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-[l,2,4]triazol-3-ylsulfanyl)- acetamidine (100 mg, 0.37 mmol) was added. The reaction mixture was stined at RT for 7 h and then at 110 °C over night. After cooling the reaction mixture was diluted with water and exfracted with CH2C12. The organic phase was dried and concentrated. Flash chromatography (heptane/EtOAc 1:2) afforded 1.9 mg (11%) ofthe desired product. IH NMR (CDC13), d (ppm): 7.99 (m, IH), 7.53 (m, IH), 7.50 (m, IH), 7.47 (m, IH), 7.16 (m, IH), 7.04 (m, 2H), 4.52 (s, 2H), 3.94 (s, 3H), 3.71 (s, 3H).
The following compounds were prepared analogously to Example 747:
Figure imgf000252_0001
Figure imgf000253_0001
Example 757
3-(3-Chloro-phenyl)-5-[l-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsuIfanyl)- ethyl] - [1 ,2,4] oxadiazole
DMF was added to a mixture of 2-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanyl)-propionic acid (50 mg, 0.186 mmol), l-(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 stined 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 NaHCO3 (30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered and concenfrated in vacuo. DMF (1 ml) was added to the residue and the resulting solution was heated at 135°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 NaHCO3 (30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered and concenfrated 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. IH NMR (CDC13), δ (ppm): 8.03 (s, IH), 7.92 (m, IH), 7.47 (m, 4H), 7.18 (dd, IH), 4.99 (q, IH), 3.64 (s, 3H), 1.97 (d, 3H).
The following compounds were prepared analogously to Example 757:
Example No. Name IH NMR MS
758 8.88 (d, IH), 8.76 (dd,
3-(5- { 1 -[3-(3-Chloro-phenyl)-
IH), 8.03 (m, 2H), 7.93
[l,2,4]oxadiazol-5-yl]-
(d, IH), 7.74 (m, 3H), ethylsulfanyl} -4-methyl-4H-
5.09 (m, IH), 3.58 (s, [ 1 ,2,4]triazol-3 -yl)-pyridine
3H), 2.00 (d, 3H)
The following compounds were prepared analogously to Example 10:
Figure imgf000254_0001
The following compounds were prepared analogously to Example 40:
Figure imgf000254_0002
Figure imgf000255_0001
The following compounds were prepared analogously to Example 316:
Figure imgf000255_0002
Figure imgf000256_0001
Example 776 3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid hydrazide
3,3-Dimethyl-dihydro-furan-2,5-dione (6.4g) was heated at 50oC 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 (4.66g) 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 (2.74g, 15.7mmol) in dichloromethane (62 mL) containing magnesium sulfate (7.5 g) and cone, sulfuric acid (0.85 mL) and the mixture was stined at room temperature overnight. Saturated sodium bicarbonate solution was added and the product was exfracted into dichloromethane, washed with brine solution, dried and concentrated to yield the diested as a colorloess oil (1.89 g). The ethyl ester was hydrolyzed by trating the crade sample with potassium hydroxide (2.75g) in a mixture of ethanol (50 mL) and water (25 mL) at room temperatire for 2h. The reaction was acidified using IN HCl (aq) and exfracted into ether, dried and concentrated to yield 2,2-Dimethyl-succinic acid 1 -tert-butyl ester (1.4g). This acid was freated under the conditions of Example 320 (step 1) to yield 3- [3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid tert-butyl ester (1.9g). This t-Bu ester was deprotected using formic acid (19 mL) at 50°C for 20 min. The crade product was concentrated and triturated with a mixture of ether and hexane to yield 3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid (1.12g). To a solution of 3-[3-(3-Chloro-phenyl)-[l,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 °C. After being stined for lh, hydrazine hydrate (1 mL, 11 mmol) was added. The reaction mixture was stined at room temperature for 1 h and concenfrated. A small amount of ice was added to quence any excess reagent and precipitate the product, which was collected by filfration to give 482 mg ofthe title compound.
The following compounds were prepared analogously to Example 320:
Figure imgf000257_0001
Example 778
3-(3-Chloro-phenyI)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-yl)-ethyl]- [1,2,4] oxadiazole
Step 1: 3-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-propionic acid (ethoxy-thiophen-2- yl-methylene)-hydrazide: 3-[3-(3-chloro-phenyl)-[l,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, lmmol) in ethanol (6 ml) and stined 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)- [l,2,4]oxadiazol-5-yl]-propionic acid (ethoxy-thiophen-2-yl-methylene)-hydrazide as a white solid (305 mg, 75%). 1H-NMR(CDC13) dψpm): 8.99 (ws, IH), 8.09 (s, IH), 7.98 (d, IH), 7.41(m, 4H), 7.08 (dd, IH), 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-[l,2,4]triazol-3-yl)-ethyl]- [1,2,4] oxadiazole: 3-[3-(3-chloro-phenyl)-[l,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 70-80 °C overnight. The reaction mixture was concenfrated with silica gel and purified by column chromatography with 0.5-2.0%) methanol in ethyl acetate to give 54 mg (72.5 %) of 3-(3-chloro-phenyl)-5-[2-(4-methyl-5- thiophen-2-yl-4H-[l,2,4]triazol-3-yl)-ethyl]-[l,2,4]oxadiazole. 1H-NMR(CDC13) d (ppm): 8.08 (s, IH), 7.97 (d, IH), 7.41 (m, 4H), 7.20 (dd, IH), 3.80 (s, 3H), 3.68 (dd, 2H), 3.38 (dd, 2H).
The following compounds were prepared analogously to Example 778:
Figure imgf000258_0001
Figure imgf000259_0001
Example 784
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-ethyl}-4-methyl-4H-[l,2,4]triazol-
3-yI)-pyridine Step 1: Isonicotinic acid {4-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-l-ethoxy- butylidene} -hydrazide: 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 °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, concenfrated with vacuum and the residue was triturated with ether to give 490 mg (78.9 %) of isonicotinic acid {4-[3-(3-chloro-phenyl)- [l,2,4]oxadiazol-5-yl]-l-ethoxy-butylidene}-hydrazide as white solid. Step 2: 4-(5-{2-[3- (3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-ethyl}-4-methyl-4H-[l,2,4]triazol-3-yl)-pyridine (47.1 mg, 82 %) as white solid was obtained from isonicotinic acid {4- [3 -(3 -chloraphenyl)-[ 1 ,2,4]oxadiazol-5-yl]- 1 -ethoxy-butylidene} -hydrazide (60 mg, 0.15 mmol) reacted with 2M methylamine (0.45 ml, 0.9 mmol) in ethanol (1 ml) at 60 °C overnight. 1H-NMR(CDC13) dψpm): 8.77 (d, 2H), 8.02 (s, IH), 7.91 (d, IH), 7.58(d, 2H), 7.42 (m, 2H), 3.76 (s, 3H), 3.66 (t, 2H) and 3.38 (t, 2H).
The following compounds were prepared analogously to Example 784:
Figure imgf000259_0002
Figure imgf000260_0001
Example 787
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazoI-5-yl]-propyl}-4-cycIopropyl-4H- [1 ,2,4] triazol-3-yl)-pyridine Step 1 : N-Cyclopropyl-isonicotinamide: Isonicotinic acid ethyl ester (3.0 g, 20 mmol) was mixed with cyclopropylamine (2 ml) at 120 °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(CDC13) d (ppm): 8.73 (d, 2H), 7.60 (d, 2H) and 6.55 (w, IH), 2.92 (m, IH), 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 SOC12 (12 g, 100 mol) at 80 °C overnight. The reaction mixture was concenfrated 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-[l ,2,4]triazol-3-yl)-pyridine: (R)-3-[3-(3- Chloro-phenyl)-[l,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 K2CO3 (60 mg, 0.43 mmol) in DMF (1 ml) at 100 °C for 3 h. The reaction mixture was dilute with dichloromethane and then washed with water. The organic layer was concentrated and purified with 5-6 % methanol in ethyl acetate to give 32 mg (39%) ofthe title comound. 1H-NMR(CDC13) d (ppm): 8.78 (d, 2H), 8.05 (s, IH), 7.96(d, IH), 7.73(d, 2H), 7.45(m, 2H), 4.15 (q, IH), 3.64 (dd, IH), 3.31 (m, 2H), 1.68 (d, 3H), 1.25 (m, 2H) and 0.79 (m, 2H).
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 ofthe methylamino or cycopropylamino group instead of or as well as the triazole product.
Figure imgf000261_0001
(dd, IH), 2.00 (td, IH),
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- IH), 7.90 (m, 3H), 7.47 ethyl} -[1 ,3,4]oxadiazol-2-yl> (d, IH), 7.39 (t, IH), pyridine 3.51 (s, 2H), 1.70 (s,
6H)
793
4-(5- {2-[3-(3-Chloro-phenyl)- 8.76 (d, 2H), 8.07 (s,
[l,2,4]oxadiazol-5-yl]-2-methyl- IH), 7.97 (d, IH), 7.77 propyl}-[l,3,4]oxadiazol-2-yl)- (d, 2H), 7.49 (dd, IH), pyridine 7.43 (t, IH), 3.53 (s, 2H), 1.69 (s, 6H)
794
8.82 (d, 2H), 8.05 (m,
4-(5- {2-[3-(3-Chloro-phenyl)- IH), 7.95 (d, IH), 7.91
[ 1 ,2,4]oxadiazol-5-yl]- 1 -methyl- (d, 2H), 7.50 (dd, IH), ethyl}-[l,3,4]oxadiazol-2-yl)- 7.42 (t, IH), 3.94 (dd, pyridine IH), 3.67 (dd, IH), 3.41 (dd, IH), 1.66 (d, 3H)
795
4-(5- {2-[3-(3-Chloro-phenyl)- 8.77 (d, 2H), 7.81 (m,
[l,2,4]oxadiazol-5-yl]- 4H), 7.42 (d, IH), 7.32 cyclopropyl} -[ 1 ,3,4]oxadiazol-2- (t, IH), 3.07 (q, IH), yl)-pyridine 2.99 (q, IH), 2.41 (q,
IH), 2.08 (td, IH)
796
4-(5- {2-[3-(3-Chloro-phenyl)- 8.76 (d, 2H), 7.85 (m,
[l,2,4]oxadiazol-5-yl]- IH), 7.77 (d, IH), 7.55 cyclopropyl} -4-methyl-4H- (d, 2H), 7.44 (dd, IH),
[l,2,4]triazol-3-yl)-ρyridine 7.34 (t, IH), 3.70 (s,
3H), 2.89 (m, IH), 2.72
Figure imgf000263_0001
Figure imgf000264_0001
Example 802
(S)-l-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-
[l,2,4]triazol-3-yl)-ethylamine
(S)-[l-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H- [l,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 °C for 1 h. The reaction mixture was concenfrated in vacuo. The residue was quenched with saturated sodium bicarbonate and exfracted with ethyl acetate. The organic layer was dried with sodium sulfate and concenfrated. Purification was performed by flash column silica gel chromatography with 2-3% (2 M ammonia methanol) in dichloromethane to give 106 mg ofthe title compound as an off- white solid. IH NMR (CDCl3):d ppm 8.73 (d, 2H), 8.03 (s, IH), 7.93 (d, IH), 7.69 (d, 2H), 7.46 (d, IH), 7.42 (t, IH), 5.02 (dd, IH), 3.61 (dd, IH), 3.49 (dd, IH), 3.35 (m, IH), 2.47 (br s, 2H), 1.20 (m, 2H), 0.75 (m, 2H)
Example 803
(S)-[l-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-
[l,2,4]triazol-3-yl)-ethyl]-dimethyl-amine Sodium cyanoborohydride (0.1 mL, IM in THF) was added to a solution of (S)-l-[3-(3- Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-[l,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 concenfrated. Purification was performed by flash column silica gel chromatography with 3% (2 M ammonia methanol) in dichloromethane to give 22 mg ofthe title compound. IH NMR (CDCl3):d ppm 8.76 (d, 2H), 8.06 (s, IH), 7.97 (d, IH), 7.73 (d, 2H), 7.47 (d, IH), 7.45 (t, IH), 5.00 (dd, IH), 3.76 (dd, IH), 3.51 (dd, IH), 3.42 (m, IH), 2.45 (br s, 6H), 1.26 (m, 2H), 0.88 (m, IH), 0.79 (m, IH)
Example 804
8-[5-(3-ChIoro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8- tetrahydro-[l,2,4]triazolo[4,3-a]pyridine 37 mg (0.25 mmol) Me3OBF4 was added to a solution of 60 mg (0.21 mmol) 3-[5-(3- chloro -phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-piperidin-2-one in 2 ml CH2C1 . The mixture was stined overnight at room temperature. The reaction mixture was diluted with CH C12, washed with NaHCO3 (sat), dried and concenfrated. 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 °C for 10 min. The reaction mixture was cooled and the volatiles were removed under reduced pressure. The crade product was purified by preparative HPLC to afford 17 mg (20%) ofthe desired product. IH NMR (CDCl3):d ppm 1.75 (m, 1 H) 1.99 (m, 1 H) 2.21 (m, 2 H) 3.16 (dd, 1 H) 3.73 (m, 1 H) 3.85 (dd, 1 H) 4.07 (m, 1 H) 4.19 (m, 1 H) 7.47 (t, 1 H) 7.56 (m, 1 H) 7.67 (m, 2 H) 8.01 (m, 1 H) 8.11 m, 1 H) 8.76 (d, 2 H).
The following compounds were prepared analogously to Example 804:
Figure imgf000265_0001
Figure imgf000266_0001
Example 807
5-(5-Bromo-4-methyl-4H- [1 ,2,4] triazol-3-ylsu!fanylmethyl)-3-(3-chloro-phenyl)-
[l,2,4]oxadiazole
3-(3-Chloro-phenyl)-5-(4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazole was mixed with 30 ml of chloroform pyridine(25/l) at room temperature. Then bromine in chloroform (0.5 ml) was added dropwise and the reaction mixture was heated at 70 °C overnight. The reaction mixture was diluted with chloroform and washed with saturated NH4C1 twice and the organic layer was dried with sodium sulfate, concenfrated, the residue was triturated with diethyl ether to give the title compound (1.5 g, 57.5 %, yellow solid). 1H-NMR(CDC13) dψpm): 8.05 (s, IH), 7.94 (d, IH), 7.47(d, IH), 7.43 (t, IH), 4.66 (s, 2H) and 3.59 (s, 3H).
Example 808 3-[3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol- 5-yl] -phenylamine
To {3-[3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)[l,2,4] oxadiazole 5-yl-phenyl}-carbamic acid tert-butyl ester (88.0 mg, 0.19 mmol) in dichloromethane (3 ml) at 0°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°C and saturated sodium bicarbonate was added to the stirring solution until turning basic (pH - 8). The mixture was then fransfened 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 61.1mg (87%) of 3-[3-(4-methyl-5- thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]-phenylamine was isolated (light yellow solid). IH NMR (DMSO-d6) d (ppm): 7.81 (d, IH), 7.64 (d, IH), 7.23 (m, 4H), 6.84 (d, IH), 5.57 (s, 2H), 4.50 (s, 2H), 3.72 (s, 3H).
The following compounds were prepared analogously to Example 98:
Figure imgf000267_0001
The following compounds were prepared analogously to Example 93:
Figure imgf000267_0002
Example 812
4-(5-{l-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yI]-ethylsulfanyl}-4-ethyl-4H- [1 ,2,4] triazol-3-yϊ)-py ridin-2-ol
HBr (1 ml) and HOAc (1 ml) were added to 4-(5-{l-[5-(3-Chloro-phenyl)- [1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-ethyl-4H-[ 1 ,2,4]triazol-3-yl)-2-methoxy-pyridine (9 mg, 0.02 mmol) and the reaction was stined at 80 °C on. Saturated NaHCO3 (aq) was added to the reaction and the mixture was exfracted three times with dichloromethane. The combined organic phases were dried and concenfrated to give the title compound (8.5 mg, 99 %). IH NMR (CDC13), δ (ppm): 1.37 (t, 3 H), 1.96 (d, 3 H), 4.10 (q, 2 H), 5.23 (q, 1 H), 6.80 (m, 2 H), 7.49 (t, 2 H), 7.59 (m, 1 H), 7.99 (d, 1 H), 8.11 (s, 1 H). Example 813
4-(5-{2-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-propyl}-4-methyl-4H-
[l,2,4]triazol-3-yl)-pyridine 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-[l,2,4]friazol-3-yl)-pyridine in 2.1 ml THF at 0°C. After 20 min a solution of 60 mg (0.21 mmol) 3-(l-bromo-ethyl)-5-(3-chloro-phenyl)- [l,2,4]oxadiazole was added dropwise. The reaction mixture was allowed to reach room temperature and stined over night. NH4Cl(sat) was added and the mixtxxre was exfracted twice with EtOAc. The organic phase was dried and concentrated. Flashchromatography (CH2Cl2/MeOH 20:1) afforded 7.7 mg (10%) ofthe desired product. IH NMR (CDC13), d (ppm): 1.57 (d, 3 H) 3.16 (m, 1 H) 3.38 (m, 1 H) 3.71 (s, 3 H) 3.84 (d, 1 H) 7.46 (t, 1 H) 7.55 (m, 1 H) 7.58 (m, 2 H) 7.98 (m, 1 H) 8.10 (t, 1 H) 8.77 (d, 2 H)
Example 814
[5-(3-Chloro-phenyl)- [1 ,2,4] oxadiazol-3-ylmethyl] -methyl-(4-methyl-5-pyridin-4-yl- 4H-[l,2,4]triazol-3-yI)-amine
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-[l,2,4]triazol-3-yl)-amine in 3 ml DMF under an atmosphere of nifrogen. 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 NH4Cl(sat) was added and the mixtxxre was extracted twice with CHC13. The organic phase was dried and concentrated. Flashchromatography (CH2Cl2/MeOH 20:1) afforded 41 mg (54%) ofthe desired product. IH NMR (CDC13), d (ppm): 3.07 (s, 3 H) 3.71 (s, 3 H) 4.56 (s, 2 H) 7.45 (m, 1 H) 7.55 (m, 1 H) 7.62 (d, 2 H) 7.98 (d, 1 H) 8.09 (m, 1 H) 8.73 (d, 2 H).
Example 815
8-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8- tetrahydro-[l,2,4]triazolo[4,3-a]pyrimidine 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-tefrahydro-[l,2,4]triazolo[4,3-a]pyrimidine in 10 ml DMF at room temperature. After 10 min 200 mg (0.87mmol) 5-(3-chloro-ρhenyl)-3-chloromethyl-[l,2,4]oxadiazole was added to the reaction mixture. The reaction mixture was stined at room temperature over night. The reaction mixture was diluted with NH4Cl(sat) and exfracted twice with EtOAc. The combined organic phases were washed with water, dried and concenfrated. Flashchromatography (CH2Cl2/MeOH 20:1) afforded 111 mg (32%) of a white solid. IH NMR (CDC13), d (ppm): 2.24 (m, 2 H) 3.57 (m, 2 H) 4.15 (m, 2 H) 5.01 (s, 2 H) 7.46 (t, 1 H) 7.56 (d, 1 H) 7.62 (d, 2 H) 7.99 (d, 1 H) 8.10 (s, 1 H) 8.70 (d, 2 H).
The following compounds were prepared analogously to Example 815:
Figure imgf000269_0001
Figure imgf000270_0001
Example 821
3-(4-Ethyl-5-thiophen-2-yI-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(lH-pyrrol-3-yI)- [1,2,4] oxadiazole
3-Chloromethyl-5-[l-(toluene-4-sulfonyl)-lH-pynol-3-yl]-[l,2,4]oxadiazole (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 MgSO4 , filtered and concentrated. The title compound was isolated in 57%ι yield by flash chromatography on silica gel using 40% ethyl acetate in heptane. IH NMR (CDC1 ) d (ppm): 9.8 (s, IH), 7.5 (m, 2H), 7.4 (d, IH), 7.2 (dd, IH), 6.8 (m, IH), 6.7 (d, IH), 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-ylmethylsulf anyl] -4-methyl-4H- [l,2,4]triazol-3-yl}-pyridine 1-oxide
4-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H- [l,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 stined for 16 h. The reaction mixtxxre was purified via reversed phase preparative LC to give the title compound (7.5 mg, 8%). IH NMR (CDC13), δ (ppm): 8.33 (d, 2 H), 8.06 (m, 1 H), 7.96 (m, 1 H), 7.67 (d, 2 H), 7.57 (m, 1 H), 7.46 (apparent t, 1 H), 4.60 (s, 2 H), 3.71 (s, 3 H).
Example 823
5-(3-Chloro-phenyl)-3-(2-furan-2-yl-3-methyl-3H-imidazol-4-ylsulfanylmethyl)- [1,2,4] oxadiazole 2-Furan-2-yl-3-methyl-3,5-dihydro-imidazol-4-one (described in Takeuchi, H., Hagiwara, S., Egucl i, 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 5h 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 MgSO4 and evaporated. The title compound (13 mg, 11%) was obtained by flash chromatography using 1% methanol in chloroform.
IH NMR (CD3OD) d (ppm): 7.96 (m, 1 H), 7.90 (m, IH), 7.60 (dd, IH), 7.57 (ddd, IH), 7.46 (t, IH), 7.09 (s, IH), 6.86 (dd, IH), 6.52 (dd, IH), 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-[l,2,4]triazol- 3-ylsulf anylmethyl] - [1 ,2,4] oxadiazole
To a cooled (-15 °C) solution of 2-{3-[5-(5-chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3- ylmethylsulfanyl]-5-thiophen-2-yl-[l,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 mixtxxre was stined 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 x 20 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4) 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%). IH NMR (CDCI3) d (ppm): 8.05 (dd, IH), 7.52 (m, 3H), 7.20 (m, IH), 7.16 (m, IH), 4.75 (t, IH), 4.63 (m, 3H), 4.45 (m, 2H).
Example 825 5-(5-Chloro-thiophen-3-yl)-3-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole The title compound was prepared according to method for 2-[5-(3-Methoxy-phenyl)- [l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole, with the exception of using molar equivalent cesium carbonate instead of potassium carbonate as the base, from l-[5- (5-chloro-thiophen-3-yl)-[l,2,4]oxadiazol-3-ylmethoxy]-lH-benzotriazole (32.3 mg, 0.097 mmol) and 4-ethyl-5-furan-2-yl-2,4-dihydro-[l,2,4]triazole-3-thione (23 mg) by using 50% EtOAc in n-heptane as chromatography eluent to yield 21 mg. IH NMR (CDC13) d (ppm): 7.95 (d, IH), 7.57 (dd, IH), 7.44 (d, IH), 7.07 (dd, IH), 6.56 (dd, IH), 4.56 (s, 2H), 4.22 (q, 2H), 1.35 (t, 3H).
Example 826
3-[3-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-4-hydroxy-benzonitrile
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- [l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]-4-fluoro-benzonitrile (20mg, 0.050 mmol), 2-(methylsulfonyl-ethanol) (9.38 mg, 0.075 mmol), and DMF (0.05 M) at 0 °C was added NaH (5.8 mg, 0.150 mmol). Stirred for 20 min and removed the ice bath. Stined an additional 20 min while warming to room temperature. The reaction mixtxxre was quenched with 1 N HCl solution and partitioned between ethyl acetate and brine. The organic layer was dried (Na2SO4), filtered and concentrated to dryness. The crade 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). IH NMR (CDCI3), δ (ppm): 8.25 (m, IH), 7.75 (m, IH), 7.60 (s, IH), 7.18 (m, 2H), 6.60 (m, IH), 4.64 (s, 2H), 4.25 (q, 2H), 1.38 (t, 3H).
Pharmaceutical Examples
FLIPR Assay of Group I receptor antagonist activity
For FLIPR analysis, cells were seeded on collagen coated clear bottom 96-well plates with black sides and analysis of [Ca2+]; mobilization was performed 24 hours following seeding. Cell cultures in the 96-well plates were loaded with a 4 μM solution of acetoxymethyl ester fonn ofthe fluorescent calcium indicator fluor-3 (Molecular Probes, Eugene, Oregon) in 0.01% pluronic. All assays were performed in a buffer containing 127 mM NaCl, 5 mM KCl, 2 mM MgCl2, 0.7 mM NaH2PO4, 2 mM CaCl2, 0.422 mg/ml NaHCO3, 2.4 mg/ml HEPES, 1.8 mg/ml glucose and 1 mg/ml BSA Fraction IV (pH 7.4).
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 μL of buffer present in each well ofthe cell plate. A 40 μL addition from the antagonist plate was followed by a 50 μL 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 ofthe response within the sample period. EC50/IC50 determinations were made from data obtained from 8 point concenfration response curves (CRC) performed in duplicate. Agonist CRC were generated by scaling all responses to the maximal response observed for the plate. Antagonist block ofthe agonist challenge was normalized to the average response ofthe agonist challenge in 14 confrol wells on the same plate.
Measurement of Inositol Phosphate (IP3) Turnover in Intact Whole Cells
GHEK stably expressing the human mGluR5d receptor were seeded onto 24 well poly-L-lysine coated plates at 40 x 104 cells /well in media containing 1 μCi/well [3H] myo-inositol. Cells were incubated overnight (16 h), then washed three times and incubated for 1 hour at 37°C in HEPES buffered saline (146 mM NaCl, 4.2 mM KCl, 0.5 mM MgCl2, 0.1% glucose, 20 mM HEPES, pH 7.4) supplemented with 1 unit/ml glutamate pyruvate transaminase and 2 mM pyravate. 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°C for 30 minutes. Antagonist activity was determined by pre-incubating test compounds for 15 minutes, then incubating in the presence of glutamate (80μM) or DHPG (30 μM) for 30 minutes. The reaction was terminated by the addition of 0.5 ml perchloric acid (5%) on ice, with incubation at 4°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.
Assay For Inositol Phosphates Using Gravity-Fed Ion-Exchange Columns
a) Preparation of Ion- Exchange Columns
Ion-exchange resin (Dowex AG1-X8 formate form, 200-400 mesh, BIORAD) was washed three times with distilled water and stored at 4°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.
b) Sample Treatment
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.
c) Inositol Phosphate Separation
Elute glycero phosphatidyl inositols with 8 ml 30 mM ammonium formate.
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.
Results
Typical IC50 values as measured in the assays described above are 10 μM or less. In one aspect ofthe invention the IC5o is below 2 μM. In another aspect ofthe invention the IC5o is below 0.2 μM. In a further aspect ofthe invention the IC50 is below 0.05 μM.

Claims

1. A compound having the formula la
Figure imgf000275_0001
wherein:
P is selected from the group consisting of hydrogen, C3- alkyl 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;
R1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, Ci-ealkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, Co-6alkylC3-6cycloalkyl, OC0-6alkylC3-6cycloalkyl, Co-6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OC1-6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0- 6alkylNR5R6, OC2-6alkylNR5R6, C1-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, C0- 6alkylNR5(CO)R6, OC2-6alkylNR5(CO)R6, Co-6alkylNR5(CO)NR5R6, C0-6alkylSR5, OC2- 6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0- 6al l(SO2)NR , OC2-6alkyl(SO2)NR5R^ Co-6alkylNR5(SO2)NR5R6, OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6,
NR5OR6, C0-6alkylNR5(CO)OR6, OC2-6alkylNR5(CO)OR6, SO3R5 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; M1 is selected from the group consisting of a bond, d^alkyl, C2-3alkenyl, C2-3alkynyl, Co- 4alkyl(CO)C0-4alkyl, C0-3alkylOC0-3alkyl, C0-3alkyl(CO)NR5, Co-3alkyl(CO)NR5C0-3alkyl, C0-4alkylNR5, Co-3alkylSC0-3alkyl, Co-3alkyl(SO)C0-3alkyl or Co-3alkyl(SO2)Co-3 alkyl; R2 is selected from the group consisting of hydrogen, hydroxy, Co-6alkylcyano, oxo, =NR5, =NOR5, C1-4alkylhalo, halo, C1-4alkyl, O(CO)C1-4alkyl, C1-4alkyl(SO)Co- alkyl, Cj. 4alkyl(SO2)Co-4aιkyl, (SO)C0-4alkyl, (SO2)C0-4alkyl, OC1-4alkyl, C1-4alkylOR5 and C0-
4alkylNR5R6;
X , X and X are independently selected from the group consisting of CR, CO, N, NR, O and S; R is selected from the group consisting of hydrogen, Co-3alkyl, halo, Co-3alkylOR5, Co-
3alkylNR5R6, C0-3alkyl(CO)OR5, Co-3aιkylNR5R6 and Co-3aιkylaryl;
M2 is selected from a group consisting of a bond, C^an yl, C3-7cycloalkyl, C2-3al enyl, C2-
3alkynyl, C0-4alkyl(CO)C0- alkyl, C0-3alkylOC0-3alkyl, Co-3alkylNR5C1-3alkyl, C0- 3alkyl(CO)NR5, C0-4alkylNR5, Co-salkylSCo-salkyl, C0-3alkyl(SO)C0-3alkyl and C0- 3alkyl(SO2)Co-3alkyl;
R >3 i ■s se Ile„c„+te„dJ fr r- om a gr .oup consi -sJt.;ing o Jfi h,.y,djrogen, ι h„y.djr_o„x„y., Co-6a „1l1k„y.1lcyano, o «,xo, = τNvmR5 ,
=NOR5, C1-4alkylhalo, halo, C1-4alkyl, O(CO)C1-4alkyl, C1-4alkyl(SO)C0-4alkyl, Ci
4alkyl(SO2)C0-4alkyl, (SO)C0-4alkyl, (SO2)C0- alkyl, OC1-4alkyl, C1-4alkylOR .5D and C0-
4alkylNR5R6; X4 is selected from the group consisting of Co- alkylR5, Co-4alkyl(NR5R6), Co-
4alkyl(NR5R6)==N, NR5C0- alkyl(NR5R6)=N, NOC0-4alkyl, C1-4alkylhalo, C, O, SO, SO2 and S;
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, Q and S and which fused ring may be substituted by one or more A;
R is selected from the group consisting of hydrogen, hydroxy, Co-6alkylcyano, oxo, =NR5,
=NOR5, C1-4alkylhalo, halo, C1-4alkyl, OC1-4alkyl, OC0-6afkylaryl, O(CO)C1-4alkyl, C0-
4alkyl(S)C0-4alkyl, C1-4alkyl(SO)C0-4alkyl, C1-4alkyl(SO2)C0-4alkyl, (SO)C0-4alkyl, (SO2)C0- 4alkyl, C1-4alkylOR5, Co-4alkylNR5R6 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;
R5 and R are independently selected from the group consisting of hydrogen, hydroxy, Ci.
6alkyl, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl, Co-6alkylheteroaryl and a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S, and wherein R and R6 may together form a 5- or 6-membered ring containing one or more atoms independently selected from the goup consisting of C, N, O and S; wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Co-6alkylC3-6cycloalkyl, C0-6alkylaryl and Co-6alkylheteroaryl defined under R1, R2, R3, R4, R5 and R6 may be substituted by one or more A;
A is selected from the group consisting of hydrogen, hydroxy, oxo, halo, nitro, Co- 6alkylcyano, C1-4alkyl, Co-4alkylC3-6cycloalkyl, Ci-ealkylhalo, OC1-6alkylhalo, C2-6alkenyl, OC1-6alkyl, Co-3alkylaryl, C0-6alkylOR5, OC2-6alkylOR5, C1-6alkylSR5, OC2-6alkylSR5, (CO)R5, O(CO)R5, OC2-6alkylcyano, C0.6a]kylCO2R5, OC1-6alkylCO2R5, O(CO)OR5, OQ.
6alkyl(CO)R°, C1-6alkyl(CO)RD, NRDOR°, Co-6alkylNR » 5DτR>6°, OC2-6alkylNR > 5°-Rr> 60, C0- 6alkyl(CO)NR5R6, OCι-6alkyl(CO)NR5R6, OC2-6alkylNR5(CO)R6, C0-6alkylNR5(CO)R6,
C0-6alkylNR3(CO)NR > 5:,R,6o, O(CO)NR ) 5DrR>6°, NR:'(CO)OR0, C0-6alkyl(SO2)NR >5DRτ>6°, OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, SO3R5, C1-6alkylNR5(SO2)NR5R6, OC2-6alkyl(SO2)R5, C0-6alkyl(SO2)R5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5 and a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S; m is selected from 0, 1, 2, 3 and 4; and n is selected from 0, 1, 2 and 3, or salt thereof.
2. A compound having the formula I
Figure imgf000277_0001
(I) wherein: P is selected from the group consisting of thiophene, pyridyl, thiazolyl, furyl, pynolyl and phenyl, whereby the phenyl ring is substituted on position 3 or disubstituted on positions 2 and 5; R1 is attached to P via a carbon atom on ring P and is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-
6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, Co-6alkylC3-6cycloalkyl, OCo-6alkylC3. δcycloalkyl, C0-6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OCi-
6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, Co-6alkylNR5R6, OC2-6alkylNR5R6, Ci.
6alkyl(CO)NR5R6, OCι-6alkyl(CO)NR5R6, C0-6alkylNR5(CO)R6, OC2-6alkylNR5(CO)R6, C0-
6alkylNR5(CO)NR5R6, C0-6alkylSR5, OC2-6alkylSR5, Co-6alkyl(SO)R5, OC2-6alkyl(SO)R5,
C0-6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6,C0- 6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, C0-6alkylNR5(SO2)NR5R6, OC2-
6alkylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6, C0-6alkylNR5(CO)OR6, OC2-
6alkylNR5(CO)OR6, SO3R5 and a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S;
M1 is a bond; X1 selected from the group consisting of C, CO, N, O and S;
X2 is selected from the group consisting of C, N, O and S;
X3 is i) selected from the group consisting of N, O and S, or ii) selected from N, O, S, and C when X2 is selected from N, O, or S, and when X3 is C the substituent R on X3 is H. ; R is selected from the group consisting of hydrogen, Co-3alkyl, halo, Co-3alkylOR5, Co-
3alkylNR5R6, C0-3alkyl(CO)OR5 and Qwalkylaryl;
M2 is selected from a group consisting of a bond, Ci -3 alkyl, C2-3alkynyl, Co- alkyl(CO)Co-
4alkyl, Co-3alkylOCo-3alkyl, C0-3alkylNR5C1-3arkyl, Co-3alkyl(CO)NR5, Co- alkylNR5, C0-
3alkyl(SO)Co-3alkyl and Co-3alkyl(SO2)Co-3alkyl; R3 is selected from a group consisting of hydroxy, Co-6alkylcyano, oxo, =NR5, =NOR5, Ci.
4alkylhalo, halo, C1-4alkyl, O(CO)C1-4alkyl, C1-4alkyl(SO)C0-4alkyl, C1-4alkyl(SO2)C0-
4alkyl, (SO)C0-4alkyl, (SO2)C0-4alkyl, OC1-4alkyl, C1-4alkylOR5 and Co-4alkylNR5R6;
X4 is selected from the group consisting of Co-4alkylR5R6 , C3-7cycloalkyl, Ci.
4alkyl(NR5R6), NR5, C0-4alkyl(NR5R6)=N, NR5C0-4alkyl(NR5R6)=N, NOC0-4alkyl, Q. 4alkylhalo, O, SO, SO2 and S, and wherein the bond between M2 and X4 is a single bond ;
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 R4 on such mfrogen atom and any suitable carbon atom is optionally substituted with R4; and
R4 is selected from the group consisting of Co-6alkylcyano, =NC1-4alkyl, =NOR5, Ci. 4alkylhalo, halo, C1-6alkyl, OC1-4alkyl, C2-4alkenyl, Co- alkylC3-6cycloalkyl, Co- 6alkylaryl, Co-6alkylhetero'aryl, OCo-6alkylaryl, OCo-6alkylheteroaryl, NCo-6alkylaryl,
NCo-6alkylheteroaryl,Co-6alkylOaryl, Co-6alkylOheteroaryl, Co-6alkylNaryl, Co- 6alkylNheteroaryl, OCo-6alkylOaryl, OCo-6alkylOheteroaryl, OCo-6alkylNaryl, OC0- 6alkylNheteroaryl, NC0-6all ylOaryl, NCo-6alkylOheteroaryl, NCo-6alkylNaryl, NCo- 6alkylNheteroaryl, O(CO)C1-4alkyl, C0-4alkyl(CO)OC1-4alkyl, C1-4alkyl(S)C0-4alkyl, Ci- 4alkyl(SO)C0-4alkyl, C1-4aιkyl(SO2)C0-4aιkyl, (SO)C0-4alkyl, (SO2)Co-4alkyl, Q.
4alkylOR5, Co-4alkylN(C1- alkyl)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 ii) selected from the group consisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tefrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl; and R4 is selected from the group consisting of hydrogen, hydroxy, Co-6alkylcyano, =NR5,
=NOR5, C1-4alkylhalo, halo, C1-6alkyl, OC1-4alkyl, OC0-6alkylaryl, O(CO)C1-4alkyl, C0- 4alkyl(S)C0- alkyl, C1-4alkyl(SO)C0- alkyl, C1-4alkyl(SO2)Co-4alkyl, (SO)C0-4alkyl, (SO2)Co-4alkyl, C1-4alkylQR5, Co-4alkylNR5R6 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;
R5 and R6 are independently selected from the group consisting of hydrogen and C1-6alkyl; wherein any C1-6alkyl defined under R1, R2 and R4 may be substituted by one or more A ; A is selected from the group consisting of hydrogen, hydroxy, halo, nifro, oxo, Co- βalkylcyano, Co-4alkylC3-6cycloalkyl, C1-6alkyl, C1-6alkylhalo, OC1-6alkylhalo, C2-6alkenyl,
Co-3alkylaryl, C0-6alkylOR5, OC2-6alkylOR5, C1-6alkylSR5, OC2-6alkylSR5, (CO)R5, O(CO)R5, OC2-6alkylcyano, OC1-6alkylCO2R5, O(CO)OR5, OC1-6alkyl(CO)R5, Ci.
6alkyl(CO)R5, NR5OR6, OC2-6alkylNR5R6, C0-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6,
OC2-6alkylNR5(CO)R6, C0-6alkylNR5(CO)R6, C0-6alkylNR5(CO)NR5R6, O(CO)NR5R6, C0-
6alkyl(SO2)NR5R6, OC2-6allcyl(SO2)NR5R6, Co-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, SO3R5, C1-6alkylNR5(SO2)NR5R6, OC2-6alkyl(SO2)R5, C0-6alkyl(SO2)R5, C0-6alkyl(SO)R5,
OC2-6alkyl(SO)R5 and a 5-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S; ml is selected from 0, 1, 2, 3 and 4; m2 is selected from 0, 1, 2 and 3; n is selected from 0, 1 and 2; and t is O or 1, and salts thereof, with the proviso that the compound is not 5-(4-methyl-4H-[l,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, l,2-di{5-[5-(4-bromo-phenyl)furan-2-yl]-[l,3,4]oxadiazol-yl)ethane, l,2-di{5-
[5-(4-chloro-phenyl)furan-2-yl]-[l,3,4]oxadiazol-yl)ethane and 1 ,2-di {5-[5-(2,4-dibramo- phenyl)furan-2-yl]-[l,3,4]oxadiazol-yl)ethane.
3. A compound according to claim 2, wherein P is selected from the group consisting of thiophene, pyridyl, thiazolyl, furyl, pynolyl or phenyl, whereby the phenyl ring is substituted on position 3 or disubstituted on positions 2 and 5 and R1 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, C0-6alkylC3-6cycloalkyl, C1-6alkylOR5, C1-6alkyl(CO)R5, C0- 6alkylCO2R5, C0-6alkylcyano, Co-6alkylNR5R6, C0-6alkylSR5 and a 5-membered ring containing one or more atoms independently selected from the group consisting of C and O.
4. A compound according to claim 3, wherein P is phenyl substituted on position 3 or disubstituted on positions 2 and 5.
5. A compound according to claim 2, wherein X1 is N and one of X2 and X3 is O and the other is N. 1 "
6. A compound according to claim 2, wherein the ring containing X , X and X forms an oxadiazole, isoxazole, oxazole, chloro-isoxazole or a methyl-isoxazole. π
IJ 7. A compound according to claim 2, wherein M2 is a bond or d .3 alkyl and R3 is hydrogen, methyl or dimethyl.
8. A compound according to claim 2, wherein X4 is selected from the group consisting of C0-4alkylR5R6, C3-7cycloalkyl, NR5, O, SO, SO2 and S and R5 and R6 are independently selected from hydrogen and C1-6alkyl.
9. A compound according to claim 8, wherein X4 is selected from the group consisting of CH2, CHCH3, CH(CH3)2 and NR5.
10. A compound according to claim 8, wherein X4 is S.
11. A compound according to claim 2, wherein 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 R4 on such nifrogen atom, and any suitable carbon atom is optionally substituted with R4 and R4 is selected from the group consisting of C1-4alkylhalo, C1-6alkyl, C2-4alkenyl, Co- 2alkylC3-6cycloalkyl, Co-6alkylaryl, Co-6alkylheteroaryl, OCo-6alkylaryl, OCo- 6alkylheteroaryl, NC0-6alkylaryl, NCo-6alkylheteroaryl,Co-6alkylOaryl, Co- 6alkylOheteroaryl, Co-6alkylNaryl, Co-6alkylNheteroaryl, OCo-6alkylOaryl, OCo- 6alkylOheteroaryl, OC0-6alkylNaryl, OCo-6alkylNheteroaryl, NC0-6alkylOaryl, NC0-
6alkylOheteroaryl, NC0-6alkylNaryl, NCo-ealkylNheteroaryl, C0- alkyl(CO)OCMalkyl, Cι_ 4alkyl(S)Co-4alkyl, C1-4alkylOR5 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.
12. A compoxmd according to any one of claims 2 or 11, wherein Q is selected from the group consisting of triazolyl and thiadiazolyl.
13. A compound according to claim 2, wherein Q is selected from the group consisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl and R4 is hydrogen or C1-6alkyl.
14. A compound according to any one of claims 2 or 13, wherein Q is selected from the group consisting of pyridonyl, tetrahydrotriazolopyridyl and tetrahydrotriazolopyrimidinyl.
15. A compound according to claim 2, wherein R4 is selected from the group consisting of benzo[b]thiophenyl, benzodioxolyl, bromo, bromofuryl, butoxyphenyl, chloromethoxypyridyl, chlorophenyl, chlorophenyhnethanol, chloropyridyl, chlorotl iophene, 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, nifrofuryl, nitrophenyl, phenyl, p-tolyloxymethyl, pyridazinyl, pyridine-oxidyl, benzylmoφholinyl, pyridinolyl, pyridyl, pyridylmethyl, pyrimidinyl, tert-butylphenyl, tetrahydrofuryl, thiazolyl, thiophene, tolyl, trifluoromethyi, acetic acid methylester, allyl, amino, benzyl, cyclopropylmethyl, ethyl, fluorobenzyl, fluoroethyl, furyhnethyl, hydroxyethyl, isobutyl, methyl, methylbenzyl, methylbutyl, methylsulfanylpropyl, n-butyl, n-hexyl, rc-propyl, tefrahydrofurylmethyl, thiophenylmethyl and trifluoroethyl.
16. A compound which is selected from the group consisting of
2- [5 -(3 -Methoxy-phenyl)- [1,2,4] oxadiazol-3 -ylmethylsulfanyl] - lH-benzoimidazole, 5-(3-Methoxy-phenyl)-3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
3-[5-(l -Methyl-5-thiophen-2-yl- lH-imidazol-2-ylsulfanylmethyl)-[ 1 ,2,4]oxadiazol-3-yl]- benzonitrile, 3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]traiazol-3-ylsulfanylmethyl)-5-phenyl-
[1,2,4] oxadiazole,
2-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-5-methyl-lH- benzoimidazole,
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl- [1,2,4] oxadiazole,
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-trifluoromethyl- phenyl)-[ 1 ,2,4]oxadiazole,
3-(3-Methoxy-phenyl)-5-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole, 5-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-
[1,2,4] oxadiazole,
5-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-m-tolyl-
[l,2,4]oxadiazole,
3-[3-(4-Methyl-5-thiophen-2-yl-4H-[ 1 ,2,4]triazol-3-ylsulfanylmethyl)-[ 1 ,2,4] oxadiazol-5 - yl]-benzonitrile,
3-[4-Methyl-5-(2-methyl-thiazol-4-yl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-
[1,2,4] oxadiazole,
3-[5-(2-Methyl-thiazol-4-yl)-[l,3,4]oxadiazol-2-ylsulfanylmethyl]-5-m-tolyl-
[l,2,4]oxadiazole, 3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl-
[l,2,4]oxadiazole,
3-[5-(2,4-Dimethyl-thiazol-5-yl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-m- tolyl-[l ,2,4]oxadiazole,
3-[4-Methyl-5-(5-mfro-furan-2-yl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl- [l,2,4]oxadiazole,
4-[4-Methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine, 3-[5-(4-tert-Butyl-phenyl)-4-methyl-4H-[l,2,4]tiiazol-3-ylsulfanylmethyl]-5-m-tolyl-
[l,2,4]-oxadiazole,
2-Chloro-5-[4-methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-
3 -yl] -pyridine, 2-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-benzooxazole,
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-
[l,2,4]oxadiazole,
3-(5-Furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[1,2,4] oxadiazole, 5-(3-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[ 1 ,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
2-(5-m-Tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-pyridine,
2-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-imidazo[4,5- bjpyridine, 5-(3-Fluoro-5-methyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)- [ 1 ,2,4] oxadiazole,
3-Methyl-5-[3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1 ,2,4]oxadiazol-5-yl]-pyridine,
3-(4-Methyl-5-phenyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[l,2,4]oxadiazole, 2-[4-Methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine,
4-Benzyl-2-[4-methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-
[ 1 ,2,4] triazol-3 -yl] -moφholine,
4-[4-Methyl-5-(5-thiophen-3-yl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3- yl] -pyridine,
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiazol-4-yl-
[1,2,4] oxadiazole,
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-nifro-phenyl)-
[1,2,4] oxadiazole, 2-Methyl-4-[3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-pyridine, 3-[4-Methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine,
3-(4-Methyl-5-thiophene-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[l,2,4]oxadiazole, 3-(4-Methyl-5-thiazol-4-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-m-tolyl-
[l,2,4]oxadiazole,
5-(3-Iodo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
5-(3-Ethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4] oxadiazole,
2-[5-(2-Methyl-pyridin-4-yl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole,
2-[5-(3-Iodo-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole,
3 -(4-Methyl-5 -trifluoromethyl-4H- [ 1 ,2,4]triazol-3 -ylsulfanylmethyl)-5 -m-tolyl-
[1,2,4] oxadiazole, 2,6-Dichloro-4-[4-methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-
[ 1 ,2,4] triazol-3 -yl] -pyridine,
3-(4-Methyl-5-ρ-tolyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[l,2,4]oxadiazole,
Dimethyl-{3-[3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]phenyl}-amine, 5 -(3 -Chloro-phenyl)-3 -(4-methyl-5 -thiophen-2-yl-4H- [ 1 ,2,4]triazol-3 -ylsulfanylmethyl)-
[1 ,2,4]oxadiazole,
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]xτiazol-3-ylsulfanylmethyl)-5-(3-trifluoromethoxy- phenyl) [1,2,4] oxadiazole,
3-(5-Cyclohexyl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl- [l,2,4]oxadiazole,
3-(5-tert-Butyl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[1,2,4] oxadiazole,
5-(3-Bromo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole, 2-[5-(3-Bromo-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole,
5-(3-Methoxymethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- lsulfanylmethyl)-[l,2,4]oxadiazole, 2-[5-(3-Methoxymethyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-lH-benzoimidazole, 4-[5-(4-Methyl-5-thiophen-2-yl-4Η-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-3- yl]-pyridine,
2-{l-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-l-methyl-lH- imidazo[4,5-b]pyridine,
2- [5-(3 -Methoxy-phenyl)- [1,2,4] oxadiazol-3 -ylmethylsulfanyl] - 1 -methyl- IH-imidazo [4,5- b],
3-[l-Methyl-l-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m-tolyl-
[1,2,4] oxadiazole, 3-[l-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m-tolyl-
[l,2,4]oxadiazole,
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3-sulfonylmethyl)-5-m-tolyl-
[l,2,4]oxadiazole,
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3-sulfmylmethyl)-5-m-tolyl- [l,2,4]oxadiazole and
5-(3-Furan-3-yl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole or salt thereof.
17. A compound which is selected from the group consisting of
4-(4-Cyclopropyl-5- { 1 -[5-(2,5-difluoro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4Η-
[l,2,4]triazol-3-yl)-pyridine,
4-(5-{l-[5-(3-Methoxy-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-methyl-4H-
[ 1 ,2,4]triazol-3-yl)-pyridine, 4-{4-Methyl-5-[l-(5-m-tolyl-[l,2,4]oxadiazol-3-yl)-ethylsulfanyl]-4H-[l,2,4]triazol-3-yl}- pyridine,
5-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-o-tolyl-
[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-cyclopropyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
2-{3-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-5-thiophen-2-yl-
[ 1 ,2,4]triazol-4-yl} -ethanol, 4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-
[1 ,2,4]triazol-3 -yl} -pyrimidine,
3-(4-Ethyl-5-fmaιι-3-yl-4H-[l,2,4]Mazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl- phenyl)- [1,2,4] oxadiazole, 5 {3-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-5-thiophen-2-yl-
[l,2,4]triazol-4-yl} -acetic acid methyl ester,
5-(2-Fluoro-5-methyl-phenyl)-3-[5-furan-2-yl-4-(2-methoxy-ethyl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl] -[1,2,4] oxadiazole,
3-(4-Cyclopropyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-(2-fluoro-5- l o methyl-phenyl)- [1,2,4] oxadiazole,
3-(5-Chloro-2-fluoro-phenyl)-5-(4-cyclopropylmethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanyhnethyl)-[l,2,4]oxadiazole,
4-{5-[3-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyrimidine, is 3-(5-Cyclopentyl-4-ethyl-4H-[ 1 ,2,4]triazol-3-ylsulfanyhnethyl)-5-m-tolyl-
[1,2,4] oxadiazole,
3-(3-Chloro-phenyl)-5-{4-ethyl-5-[2-(4-methoxy-phenyl)-ethyl]-4H-[l,2,4]triazol-3- ylsulfanylmethyl}-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-p-tolyloxymethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- 0 [l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-(2-methoxy-ethyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
3-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-methoxymethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole, 5 5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-methoxymethyl-4H-[l,2,4]triazol-3- ylsulfanyhnethyl)-[ 1 ,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-methoxymethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
3-(3-Chloro-phenyl)-5-(4-ethyl-5-methoxymethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- 0 [l,2,4]oxadiazole,
4-(5-{l-[3-(3-Chloro-phenyl)-isoxazol-5-yl]-ethylsulfanyl}-4-methyl-4H-[l,2,4]triazol-3- yl)-pyridine, 3-(4-Allyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro-phenyl)-
[l,2,4]oxadiazole,
3-(4-Allyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thioρhen-3-yl-
[l,2,4]oxadiazole, 5 5-(4-Allyl-5-furan-2-yl-4H-[ 1 ,2,4]triazol-3-ylsulfanylmethyl)-3-furan-2-yl-
[1,2,4] oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(4-methoxy-phenoxymethyl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl] -[1,2,4] oxadiazole,
3-(3-Chloro-phenyl)-5-[4-ethyl-5-(4-methoxy-phenoxymethyl)-4H-[l,2,4]triazol-3- l o ylsulfanylmethyl] - [ 1 ,2,4] oxadiazole,
{5-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol-3- yl} -methanol,
3-(3-Chloro-phenyl)-5-[4-ethyl-5-(2-methoxy-ethyl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole, is 3-(3-Chloro-ρhenyl)-5-(4-ethyl-5-methylsulfanylmethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[ 1 ,2,4] oxadiazole,
3-(3-Chloro-phenyl)-5-(5-ethoxymethyl-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
5-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazole-3- 20 carboxylic acid methyl ester,
2-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,3,4]oxadiazole,
2-(3-Chloro-phenyl)-5-(4-cyclopropyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,3,4]oxadiazole, 5 5-(3-Chloro-phenyl)-3-{l-[4-ethyl-5-(tefrahydro-furan-2-yl)-4H-[l,2,4]triazol-3- ylsulfanyl] -ethyl} -[1,2,4] oxadiazole,
4-(5- { l-[5-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridazine,
4-(5-{l-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H- 0 [1 ,2,4]triazol-3 -ylmethyl)-ρyridine,
5-(5-{l-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-
[l,2,4]triazol-3-yl)-ρyridin-2-ol, 4-(5-{l-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-
[l,2,4]triazol-3-yl)-phenol,
5-(3-Chloro-phenyl)-3-[5-(4-methoxy-phenoxyιnethyl)-4-(tefrahydro-furan-2-ylmethyl)-
4H- [ 1 ,2,4]triazol-3 -ylsulfanylmethyl] -[ 1 ,2,4] oxadiazole, 5-(3 -Chloro-phenyl)-3 - [4-cy clopropyl-5-(4-methoxy-phenoxymethyl)-4H- [ 1 ,2,4]triazol-3 - ylsulfanylmethyl] - [ 1 ,2,4] oxadiazole,
5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
3-(4-Ethyl-5-methoxymethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl- [l,2,4]oxadiazole,
3-[4-Ethyl-5-(tetrahydro-furan-2-yl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-
[l,2,4]oxadiazole,
2-(3-Chloro-phenyl)-5- { 1 -[4-ethyl-5-(4-methoxy-phenyl)-4H-[ 1 ,2,4]triazol-3-ylsulfanyl]- ethyl} -[ 1 ,3 ,4]oxadiazole, 4-{5-[3-(2,5-Difluoro-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyrimidine,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3-yl} -pyrimidine,
3-(3-Chloro-phenyl)-5-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazole,
5-(3-Methylsulfanyl-ρhenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]friazol-3- ylsulfanylmethyl)- [1,2,4] oxadiazole,
2- [5 -(3 -Methylsulfanyl-phenyl)- [ 1 ,2,4] oxadiazol-3 -ylmethylsulfanyl] - 1 H-benzoimidazole,
5-(2,5-Dimethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)- [1,2,4] oxadiazole,
5-(2-Fluoro-5-methyl-ρhenyl)-3-(4-methyl-5-thioρhen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)- [1,2,4] oxadiazole,
5-(3-Cyclopropyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole, 4-{5-[2-(3-Chloro-phenyl)-oxazol-4-ylmethylsulfanyl]-4-methyl-4H-[l,2,4]triazol-3-yl}- pyridine, 4-[4-Methyl-5-(5-thiophen-2-yl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3- yl] -pyridine,
4-{4-Methyl-5-[5-(3-methylsulfanyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 4-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[l,2,4]triazol-3-yl}-pyridine,
2-Methyl-4-[3-(4-methyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-pyridine, l-{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol- 5-yl]-phenyl} -ethanone,
4-{5-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[l,2,4]triazol-3-yl}-pyridine,
2-Methyl-4-[4-methyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-
[ 1 ,2,4]triazol-3 -yl] -pyridine, 3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl-5-thiophen-2-yl-4H-
[l,2,4]triazole,
4- {5-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl-4H-[ 1 ,2,4]triazol-3-yl} - pyridine,
3-(4-Butyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro-phenyl)- [l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-(3-methoxy-propyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
3-(4-Benzyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-(3-chloro-phenyl)-
[l,2,4]oxadiazole, 5-(3-Chloro-phenyl)-3-(4-furan-2-ylmethyl-5-thiophen-2-yl-4H-[ 1 ,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
3-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4] oxadiazole,
4-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[l,2,4]triazol-3-yl}-2-methyl-pyridine, 5-(5-Chloro-2-fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3-yl} -pyridine, 3-{5-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
5-(3-Chloro-phenyl)-3-(5-thiophen-2-yl-4-thiophen-2-ylmethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [ 1 ,2,4] oxadiazole,
3-{5-[3-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-5-yhnethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3-yl} -pyridine,
4-{5-[3-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3-yl} -pyridine, 4-{5-[5-(5-Bromo-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
3-{5-[5-(5-Bromo-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
5-(5-Bromo-2-fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)- [ 1 ,2,4]oxadiazole,
5-(4-Methyl-5-thioρhen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-
[l,2,4]oxadiazole,
3 - {5- [5 -(3 -Fluoro-phenyl)- [1,2,4] oxadiazol-3 -ylmethylsulfanyl] -4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 4-{5-[5-(3-Fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
5-(3-Fluoro-phenyl)-3-(4-methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
3-[4-Methyl-5-(5-thiophen-3-yl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3- yl] -pyridine,
3-(4-Methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-
[l,2,4]oxadiazole, 2-Chloro-4-[3-(4-methyl-5-pyridin-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1 ,2,4]oxadiazol-5-yl]-pyridine,
2-Chloro-4-[3-(4-methyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-pyridine, 2-Chloro-4-[3-(4-methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-pyridine,
4-[4-Methyl-5-(5-phenyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine,
3-(4-Methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-phenyl- [l,2,4]oxadiazole,
5-(5-Bromo-2-fluoro-phenyl)-3-(4-methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3- ylsulfanyhnethyl)-[ 1 ,2,4]oxadiazole,
3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-thiophen-2-yl-4H-
[l,2,4]triazole, 2-Chloro-4-[3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-pyridine,
4-{5-[3-(3-Fluoro-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
3-(3-Fluoro-phenyl)-5-(4-methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4] oxadiazole,
3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[l,2,4]oxadiazole,
3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl- phenyl)-[ 1 ,2,4]oxadiazole, 4-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-furan-2-ylmethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol-
3 -yl} -pyridine,
3-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol- 3 -yl} -pyridine,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole, 3-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-furan-2-ylnιethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
3-(4-Furan-2-ylmethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[1,2,4] oxadiazole, 5-(5-Fluoro-2-methyl-phenyl)-3-(4-raran-2-ylmethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-fraan-2-yhnethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
3-[3-(4-Methyl-5-pyridin-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl] -benzonitrile,
3-[3-(4-Methyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-benzonitrile,
3-[3-(4-Methyl-5-thioρhen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-benzonitrile, 5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole,
2-Chloro-4-[3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1 ,2,4]oxadiazol-5-yl]-pyridine,
3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl- [1,2,4] oxadiazole,
3-(4-Ethyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-
[l,2,4]oxadiazole,
4-[4-Ethyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine, 3-[4-Ethyl-5-(5-m-tolyl-[l ,2,4] oxadiazol-3 -ylmethylsulfanyl)-4H-[l ,2,4]triazol-3-yl]- pyridine,
3-(4-Ethyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl- phenyl)-[l,2,4]oxadiazole,
4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4H- [l,2,4]triazol-3-yl}-pyridine,
3-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 3-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-5-pyridin-4-yl-[l,2,4]triazol-
4-ylamine,
4- {5 - [5 -(5-Bromo-2-fluoro-phenyl)- [ 1,2,4] oxadiazol-3 -ylmethylsulfanyl] -4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 5-(4-Methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-tlιioρhen-2-yl-
[l,2,4]oxadiazole,
3-[3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-benzonitrile,
3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-ρhenyl- [l,2,4]oxadiazole,
4-[3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl] -2-methoxy-pyridine,
3-(3-Chloro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[ 1 ,2,4] oxadiazole, 4-{5-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol-3-yl}- pyridine,
2-Methyl-4-[3-(4-methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-pyridine,
4-[3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl] -2-methyl-pyridine,
5-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-2-yl-
[ 1 ,2,4]oxadiazole,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 4-[3-(4-Ethyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]-
2-methyl-pyridine,
3-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3-yl} -benzonitrile,
5-(3-Chloro-phenyl)-3-[5-(3-chloro-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[5-(4-chloro-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole, 4- {5-[5-(2,5-Dichloro-phenyl)-[ 1 ,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
5-(2,5-Dichloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole, 5-(2,5-Difluoro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
4- {5-[5-(2,5-Difluoro-ρhenyl)-[ 1 ,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
5-(2,5-Dichloro-phenyl)-3-(4-ethyl-5-thioρhen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazole,
5-(2,5-Difluoro-phenyl)-3-(4-ethyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
4-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-propyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 4-{5-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-4-propyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl-
[1,2,4] oxadiazole,
3-(4-Methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl- [l,2,4]oxadiazole,
4-[4-Methyl-5-(3-thiophen-3-yl-[l,2,4]oxadiazol-5-ylmethylsulfanyl)-4H-[l,2,4]triazol-3- yl]-pyridine,
5-(4-Methyl-5-thiophen-3-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-3-yl-
[1,2,4] oxadiazole, 5-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-thioρhen-3-yl-
[l,2,4]oxadiazole,
5-[3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-thiophene-3-carbonitrile,
5-(3-Chloro-phenyl)-3-[5-(2-fluoro-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[5-(3-fluoro-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole, 5-(3-Chloro-phenyl)-3-[5-(4-fluoro-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl] -[1,2,4] oxadiazole,
3-(5-Benzo[b]thioρhen-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro- phenyl)-[ 1,2,4] oxadiazole, 5-(3-Chloro-phenyl)-3-[5-(3-methoxy-phenyl)-4-methyl-4H-[ 1 ,2,4]triazol-3- ylsulfanylmethyl]-[ 1 ,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[5-(4-methoxy-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl] -[1,2,4] oxadiazole,
3-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl- phenyl)- [1,2,4] oxadiazole,
3-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[l,2,4]oxadiazole,
3-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl- phenyl)-[l,2,4]oxadiazole,
3-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-5-pyridin-4-yl- [1 ,2,4]triazol-4-ylamine,
3-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-5-thiophen-2-yl-
[ 1 ,2,4]triazol-4-ylamine,
3-Pyridin-4-yl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-[l,2,4]triazol-4-ylamine,
3 -Thiophen-2-y 1-5 -(5-m-tolyl- [ 1 ,2,4] oxadiazol-3 -ylmethylsulfanyl)- [ 1 ,2,4]triazol-4- ylamine,
3-(4-Ethyl-5-lnran-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-
[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole, 4-[3-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]-2- methyl-pyridine,
5-(2,5-Difluoro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
4-[4-Ethyl-5-(5-thiophen-3-yl-isoxazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine,
4-Ethyl-3 -furan-2-yl-5-(5-thiophen-3-yl-isoxazol-3 -ylmethylsulfanyl)-4H-[ 1 ,2,4]triazole, 5-(3-Chloro-phenyl)-3-[5-(3,5-dichloro-phenyl)-4-ethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[ 1 ,2,4] oxadiazole, 5-(3-Chloro-phenyl)-3-(4-ethyl-5-m-tolyl-4H-[ 1 ,2,4]triazol-3-ylsulfanylmethyl)-
[ 1 ,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-nifro-phenyl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[1,2,4] oxadiazole,
4-{5-[3-(3-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-4-methyl-4H-[l,2,4]triazol-3-yl}- pyridine,
5-(3-Chloro-phenyl)-3-[5-(2,5-difluoro-phenyl)-4-ethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[5-(3-chloro-phenyl)-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[1,2,4] oxadiazole, 5-(3-Chloro-phenyl)-3-[5-(4-chloro-ρhenyl)-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[1,2,4] oxadiazole,
4-{5-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol-3-yl}- pyridine,
3-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-5-thiophen-2-yl-4H- [l,2,4]triazole,
3-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-5-furan-2-yl-4H-
[l,2,4]triazole,
5-(2-Chloro-5-methyl-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole, 4-{5-[3-(3-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol-3-yl}- pyridine,
3 - [3 -(3 -Chloro-phenyl)-isoxazol-5 -ylmethylsulfanyl] -4-ethyl-5-thiophen-2-yl-4H-
[l,2,4]triazole,
3 - [3 -(3 -Chloro-phenyl)-isoxazol-5 -ylmethylsulfanyl] -4-ethyl-5 -furan-2-yl-4H- [l,2,4]triazole,
4-{5-[5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 5-(2,5-Dichloro-thiophen-3-yl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)- [1,2,4] oxadiazole,
4-{5-[5-(2,5-Dichloro-thiophen-3-yl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazo 1-3 -yl} -pyridine, 4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-Ethyl-3-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-thiophen-2-yl-
4H-[l,2,4]triazole,
4-Ethyl-3-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-furan-2-yl-4H- [l,2,4]triazole,
5-(3-Chloro-phenyl)-3-(4-ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
3-(3-Chloro-phenyl)-5-(4-ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole, 3-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-
[ 1 ,2,4]oxadiazole,
5-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-3-yl-
[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-fluoro-phenyl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]- [1,2,4] oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(4-fluoro-phenyl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[ 1 ,2,4]oxadiazole,
3-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl-
[1,2,4] oxadiazole, 3-{3-[5-(3-Chloro-thiophen-2-yl)-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[l,2,4]oxadiazol-5-yl}-benzonitrile,
4-{5-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol-
3-yl} -pyridine,
2-(3-Chloro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)- [l,3,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(4-methoxy-phenyl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole, 5-(3-Chloro-phenyl)-3-[5-(2-fluoro-5-methyl-phenyl)-4-ιuran-2-ylmethyl-4H-
[ 1 ,2,4]triazol-3 -ylsulfanylmethyl] -[ 1 ,2,4]oxadiazole,
4-[3-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl] -2-methyl-pyridine, 3-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-methoxy-phenyl)-
[l,2,4]oxadiazole,
5 -(4-Ethyl-5 -trifluoromethyl-4H- [ 1 ,2,4]triazol-3 -ylsulfanylmethyl)-3 -(3 -methoxy-phenyl)-
[l,2,4]oxadiazole,
5-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-2-yl- [l,2,4]oxadiazole,
5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)- [1,2,4] oxadiazole,
3-[3-(4-Ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-benzonitrile, 3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-trifluoromethyl-4H-
[l,2,4]triazole,
3-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-5-trifluoromethyl-4H-
[l,2,4]triazole,
4-Ethyl-3 -(5 -thiophen-3 -yl-isoxazol-3 -ylmethylsulfanyl)-5 -trifluoromethyl-4H- [l,2,4]triazole,
4-{3-[5-(3-Fluoro-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl]-
[1,2,4] oxadiazol-5 -yl} -2-methyl-pyridine,
4-{3-[5-(3-Chloro-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[l,2,4]oxadiazol-5-yl}-2-methyl-pyridine, 4-{3-[5-(4-Chloro-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[1 ,2,4]oxadiazol-5-yl} -2-methyl-pyridine,
4-{3-[5-(4-Methoxy-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-
[l,2,4]oxadiazol-5-yl}-2-methyl-pyridine,
4-[3-(4-Ethyl-5-p-tolyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]-2- methyl-pyridine,
3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-(3-fluoro-phenyl)-
[l,2,4]oxadiazole, 4-{4-Ethyl-5-[5-(3-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-[l,2,4]triazol-
3 -yl} -pyridine,
5-(3-Chloro-phenyl)-3-[5-(3,5-difluoro-ρhenyl)-4-ethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole, 5-(3-Chloro-phenyl)-3-[5-(2,6-difluoro-phenyl)-4-ethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
2-[3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-4-methyl-phenol,
3-{l-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-ethyl-5-furan-2-yl-4H- [l,2,4]triazole,
4-(5-{l-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[l,2,4]triazol-3- yl)-pyridine,
3-[5-(4-Butoxy-phenyl)-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-(3-chloro- phenyl)-[l ,2,4]oxadiazole, 3-(5-Benzo[l,3]dioxol-5-yl-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro- phenyl)-[l ,2,4]oxadiazole,
3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(2-methyl-thiazol-4- yl)-[ 1 ,2,4]oxadiazole,
3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-5-(4-fluoro-ρhenyl)- [l,2,4]oxadiazole,
4-Ethyl-3- { 1 -[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethylsulfanyl} -5-furan-2-yl-
4H-[l,2,4]triazole,
4-(4-Ethyl-5- { 1 -[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethylsulfanyl} -4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine, 5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-methyl-3H-imidazol-4-yl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl] -[1,2,4] oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(l-methyl-lH-imidazol-2-yl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(l-methyl-lH-imidazol-4-yl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole,
4-{5-[5-(3-Chloro-phenyl)-4-methyl-isoxazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 3-[5-(3-Chloro-phenyl)-4-methyl-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-furan-2-yl-4H-
[l,2,4]triazole,
3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(4-methyl-thiophen-2- yl)-[l,2,4]oxadi azote, 5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-methyl-thiophen-2-yl)-4H-[ 1 ,2,4]triazol-3- ylsulfanylmethyl] - [ 1 ,2,4] oxadiazole,
5-(3-Chloro-phenyl)-3-[4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl] -[1,2,4] oxadiazole,
4-{5-[4-Chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-4H- [l,2,4]triazol-3-yl} -pyridine,
3-[4-Chloro-5-(3-chloro-phenyl)-isoxazol-3-yhnethylsulfanyl]-4-ethyl-5-furan-2-yl-4H-
[l,2,4]triazole,
2-Chloro-4-{5-[5-(3-chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -6-methyl-pyridine, 3-[5-(5-Bramo-furan-2-yl)-4-ethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-(3-chloro- phenyl)- [1,2,4] oxadiazole,
2-Chloro-4-{5-[5-(3-chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
2-Chloro-4-{5-[5-(3-chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H- [ 1 ,2,4]triazol-3-yl} -6-methoxy-pyridine,
2-[3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl] -4-methyl-benzonitrile,
5-(3-Chloro-ρhenyl)-3-[4-ethyl-5-(3-methoxy-thiophen-2-yl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl] -[1,2,4] oxadiazole, 3-[5-(5-Chloro-thiophen-3-yl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-furan-2-yl-4H-
[l,2,4]triazole,
3-[3-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]-5- fluoro-benzonitrile,
4-Ethyl-3-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-5-thiophen-2-yl-4H-[l,2,4]triazole, 4-Methyl-3-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-5-thiophen-3-yl-4H-[l,2,4]triazole,
4-Ethyl-3-fxxran-2-yl-5-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazole,
4-[4-Ethyl-5-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]-pyridine, 4-[4-Methyl-5-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]-pyridine,
2-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[l,3,4]oxadiazole,
4-[4-Methyl-5-(5-m-tolyl-[l,3,4]oxadiazol-2-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine, 4-[4-Ethyl-5-(5-m-tolyl-[l,3,4]oxadiazol-2-ylmethylsulfanyl)-4H-[l,2,4]triazol-3-yl]- pyridine,
4-{5-[5-(5-Chloro-thiophen-3-yl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
3-[3-(4-Ethyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]- 4-fluoro-benzonitrile,
3-[3-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]-4- fluoro-benzonitrile,
3-[3-(4-Ethyl-5-thioρhen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-4-fluoro-benzonitrile, 3-[3-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]- benzonitrile,
3-[5-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-3-yl]- benzonitrile,
3-[3-(4-Methyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol- 5-yl]-benzonitrile,
5-(5-Chloro-2-fluoro-phenyl)-3-(4-methyl-5-trifluoromethyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
2-Chloro-4-[3-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[ 1 ,2,4] oxadiazol-5 -yl] -pyridine, 2-Chloro-4-[3-(5-furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-pyridine,
2-(3-Chloro-phenyl)-5-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,3,4]oxadiazole,
2-(3-Chloro-ρhenyl)-5-(4-methyl-5-thiazol-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [1,3 ,4] oxadiazole,
2-(3-Chloro-phenyl)-5-(5-furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,3,4]oxadiazole, 2-(3-Chloro-phenyl)-5-(4-ethyl-5-trifluoromethyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,3,4]oxadiazole,
4- {4-Ethyl-5-[5-(4-methyl-thiophen-2-yl)-[ 1 ,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-
[ 1 ,2,4]triazol-3-yl} -pyridine, 3-(4-Ethyl-5-furan-2-yl-4H-[ 1 ,2,4]triazol-3-ylsulfanylmethyl)-5-(4-methyl-thiophen-2-yl)-
[l,2,4]oxadiazole,
3-(3-Chloro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-
[1,2,4] oxadiazole,
4-{5-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol- 3 -yl} -pyridine,
4-{4-Ethyl-5-[5-(3-nitro-phenyl)-[l,3,4]oxadiazol-2-ylmethylsulfanyl]-4H-[l,2,4]triazol-3- yl} -pyridine,
2-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-nifro-phenyl)-
[l,3,4]oxadiazole, 4-{5-[5-(3 -Chloro-phenyl)-isoxazol-3 -ylmethylsulfanyl] -4-cyclopropyl-4H- [ 1 ,2,4] triazol-
3-yl} -pyridine,
3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-(4-methoxy-phenyl)-4H-
[l,2,4]triazole,
5-(3-Chloro-ρhenyl)-3-[l-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)- ethyl]-[l,2,4]oxadiazole,
5-(3-Chloro-ρhenyl)-3-[l-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-
[1,2,4] oxadiazole,
4-(5- { 1 -[5-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-methyl-4H-
[ 1 ,2,4]triazol-3-yl)-pyridine, 4-(5- { 1 -[5-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-ethyl-4H-
[l,2,4]triazol-3-yl)-pyridine,
3-[5-(4-Ethyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,3,4]oxadiazol-2-yl]- benzonitrile,
3-[5-(4-Ethyl-5-fiiran-2-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-[l,3,4]oxadiazol-2-yl]- benzonitrile,
3-[5-(4-Methyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanyhnethyl)-[l,3,4]oxadiazol-2- yl] -benzonitrile, 3-[5-(4-Cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,3,4]oxadiazol-2-yl]-benzonitrile,
4-{5-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 4- {5 - [5 -(3 -Chloro-phenyl)- [ 1,3,4] oxadiazol-2-ylmethylsulfanyl] -4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3-yl} -pyridine,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,3,4]oxadiazol-2-ylmethylsulfanyl]-4-cyclopropyl-
4H-[ 1 ,2,4]triazol-3-yl} -pyridine,
2-(5-Chloro-2-fluoro-phenyl)-5-[4-ethyl-5-(4-methoxy-phenyl)-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l ,3,4]oxadiazole,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,3,4]oxadiazol-2-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,3,4]oxadiazol-2-yhnethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 2-(3-Chloro-phenyl)-5-[4-ethyl-5-(4-methoxy-phenyl)-4H-[ 1 ,2,4]triazol-3- ylsulfanylmethyl] -[1,3,4] oxadiazole,
2-(3-Chloro-phenyl)-5-[l-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-
[l,3,4]oxadiazole,
5-(5-Chloro-2-fluoro-phenyl)-3-[l-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanyl)-ethyl] -[1,2,4] oxadiazole,
4-(5- { 1 -[5-(5-Chloro-2-fluoro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(5- { 1 -[5-(5-Chloro-2-fluoro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-ethyl-4H-
[ 1 ,2,4] triazol-3 -yl)-pyridine, 2-Chloro-4-[3-(4-cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-pyridine,
4-{5-[5-(2-Fluoro-5-methyl-phenyl)-[l,3,4]oxadiazol-2-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[l,3,4]oxadiazol-2-ylmethylsulfanyl]-4H- [l,2,4]triazol-3-yl}-pyridine,
4-{4-Cyclopropyl-5-[5-(2-fluoro-5-methyl-phenyl)-[l,3,4]oxadiazol-2-ylmethylsulfanyl]-
4H-[ 1 ,2,4]triazol-3 -yl} -pyridine, 2-(4-Ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl- phenyl)-[l,3,4]oxadiazole,
2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]-5-(2-fluoro-5- methyl-phenyl)- [ 1 ,3 ,4] oxadiazole, 4-{5-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3-yl} -pyridine,
4-(5- { 1 -[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl} -4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4- { 5 - [5 -(5 -Chloro-2-fluoro-phenyl)-isoxazol-3 -ylmethylsulfanyl] -4-methyl-4H- [l,2,4]triazol-3-yl} -pyridine,
4-(5-{l-[5-(5 -Chloro-2-fluoro-phenyl)-isoxazol-3 -yl] -ethylsulfanyl} -4-methyl-4H-
[l,2,4]triazol-3-yl)-pyridine,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 4-(5-{l-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
3 - [5 -(5 -Chloro-2-fluoro-phenyl)-isoxazol-3 -ylmethylsulfanyl] -4-ethyl-5 -furan-2-yl-4H-
[l,2,4]triazole,
3-{l-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-ethyl-5-furan-2-yl-4H- [l,2,4]triazole,
4-(5-{l-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(5- { 1 -[5-(3-Chloro-phenyl)-[l ,3,4]oxadiazol-2-yl]-ethylsulfanyl} -4-ethyl-4H-
[ 1 ,2,4] triazol-3 -yl)-pyridine, 4-(5-{l-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
5-(5-Chloro-2-fluoro-phenyl)-3-(5-furan-2-yl-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
5-(5-Chloro-2-fluoro-phenyl)-3-(5-furan-3-yl-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
4-Chloro-2-[3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-phenol, 2-Chloro-4-[5-(4-methyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,3,4] oxadiazol-2-yl] -pyridine,
2-Chloro-4-[5-(4-ethyl-5-ρyridin-4-yl-4H-[l,2,4]xriazol-3-ylsulfanylmethyl)-
[ 1 ,3 ,4]oxadiazol-2-yl]-pyridine, 2-Chloro-4-[5-(4-cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,3,4] oxadiazol-2-yl] -pyridine,
2-Chloro-4-[5-(4-ethyl-5-fxxran-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[ 1 ,3 ,4]oxadiazol-2-yl]-pyridine,
2-Chloro-4-{5-[4-ethyl-5-(4-methoxy-phenyl)-4H-[l,2,4]triazol-3-ylsulfanylmethyl]- [l,3,4]oxadiazol-2-yl}-pyridine,
2-(3-Chloro-phenyl)-5-{l-[5-(4-methoxy-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanyl]-ethyl}-[l,3,4]oxadiazole,
4-(5- { 1 -[5-(5-Chloro-2-fluoro-phenyl)-[ 1 ,3,4]oxadiazol-2-yl]-ethylsulfanyl} -4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine, 5-(5-Bromo-2-fluoro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole,
2-(3-Chloro-phenyl)-5-[5-(4-methoxy-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanylmethyl] -[1,3,4] oxadiazole,
4-{5-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-cyclopropyl-4H- [l,2,4]triazol-3-yl} -pyridine,
4-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-(5-{l-[5-(2-Fluoro-5-methyl-phenyl)-[l,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-methyl-
4H-[l,2,4]triazol-3-yl)-pyridine, 4-(4-Ethyl-5-{l-[5-(2-fluoro-5-methyl-phenyl)-[l,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(4-Cyclopropyl-5-{l-[5-(2-fluoro-5-methyl-phenyl)-[l,3,4]oxadiazol-2-yl]- ethylsulfanyl} -4H- [ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(4-Cyclopropylmethyl-5-{l-[5-(2-fluoro-5-methyl-phenyl)-[l,3,4]oxadiazol-2-yl]- ethylsulfanyl}-4H-[l,2,4]triazol-3-yl)-pyridine,
2-(2-Fluoro-5-methyl-phenyl)-5-{l-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[l,2,4]triazol-
3-ylsulfanyl]-ethyl}-[l,3,4]oxadiazole, 4-(5- { 1 -[5-(5-Chloro-2-fluoro-ρhenyl)-[ 1 ,3,4]oxadiazol-2-yl]-ethylsulfanyl} -4-ethyl-4H-
[ 1 ,2,4]triazol-3-yl)-pyridine,
4-(5-{l-[5-(5-Chloro-2-fluoro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4- cyclopropyl-4H-[l,2,4]triazol-3-yl)-pyridine, 2-(5-Chloro-2-fluoro-phenyl)-5-[l-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)- ethyl]-[l,3,4]oxadiazole,
2-(5-Chloro-2-fluoro-phenyl)-5-{l-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[l,2,4]triazol-
3-ylsulfanyl]-ethyl}-[l,3,4]oxadiazole,
4-(4-Cyclopropylmethyl-5- { 1 -[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]- ethylsulfanyl}-4H-[l,2,4]triazol-3-yl)-pyridine,
4-(5- { 1 -[5-(3-Fluoro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(4-Cyclopropyl-5-{l-[5-(3-fluoro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine, 4-(5-{l-[5-(4-Methoxy-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanyl]-ethyl}-
[ 1 ,3 ,4]oxadiazol-2-yl)-2-methyl-pyridine,
4-(5-{l-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[l,2,4]triazol-3-ylsulfanyl]-ethyl}-
[l,3,4]oxadiazol-2-yl)-2-methyl-pyridine,
4-{5-[l-(4-Ethyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-[l,3,4]oxadiazol-2- yl} -2-methyl-pyridine,
4-{5-[l-(4-Cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-
[1,3,4] oxadiazol-2-yl} -2-methyl-pyridine,
4-{5-[l-(5-Furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-[l,3,4]oxadiazol-2- yl} -2-methyl-pyridine, 2-(3-Chloro-phenyl)-5-{l-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[l,2,4]triazol-3- ylsulfanyl]-ethyl}-[l,3,4]oxadiazole,
3-(5-{l-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(5- { 1 -[5-(3-Chloro-phenyl)-[ 1 ,3,4]oxadiazol-2-yl]-ethylsulfanyl} -4-methyl-4H- [ 1 ,2,4]triazol-3-yi)-2-methyl-pyridine,
4-(5- { 1 -[5-(3-Chloro-ρhenyl)-[l ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3-yl)-pyridine, 5-(3-Chloro-phenyl)-3-{l-[5-(4-methoxy-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanyl]-ethyl}-[l,2,4]oxadiazole,
4-(5- { 1 -[5-(5-Chloro-2-fluoro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4- cyclopropyl-4H-[l,2,4]triazol-3-yl)-pyridine, 5-(5-Chloro-2-fluoro-phenyl)-3-{l-[5-(4-methoxy-phenyl)-4-methyl-4H-[l,2,4]triazol-3- ylsulfanyl]-ethyl}-[l,2,4]oxadiazole,
4-[5-(4-Ethyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,3,4]oxadiazol-2-yl]-
2-methyl-pyridine,
4-[5-(4-Cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [1 ,3,4]oxadiazol-2-yl]-2-methyl-pyridine,
4-{5-[5-(5 -Chloro-2-fluoro-phenyl)- [ 1 ,2,4] oxadiazol-3 -ylmethylsulfanyl] -4-cyclopropyl-
4H-[l,2,4]triazol-3-yl}-pyridine,
4-[5-(5-Furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,3,4]oxadiazol-2-yl]-
2-methyl-pyridine, 4-(5-{l-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-cyclopropylmethyl-
4H-[l,2,4]triazol-3-yl)-pyridine,
4-(5- { 1 -[5-(4-Fluoro-phenyl)-4-methyl-4H-[l ,2,4]triazol-3-ylsulfanyl]-ethyl} -
[ 1 ,3 ,4]oxadiazol-2-yl)-2-methyl-pyridine,
4-(5-{l-[5-(3-Fluoro-phenyl)-4-methyl-4H-[l,2,4]triazol-3-ylsulfanyl]-ethyl}- [l,3,4]oxadiazol-2-yl)-2-methyl-pyridine,
3-[3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-4-fluoro-benzonitrile,
4-Chloro-2-[3-(4-cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-phenol, 4- {4-Cyclopropyl-5- [5 -(3 -methoxy-phenyl)- [ 1 ,2,4] oxadiazol-3 -ylmethylsulfanyl] -4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine,
4-{4-Cyclopropyl-5-[5-(2-fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-
4H-[1 ,2,4]triazol-3-yl}-pyridine,
4-{4-Cyclopropyl-5-[5-(3-fluoro-phenyl)-[l,2,4]oxadiazol-3-yhnethylsulfanyl]-4H- [l,2,4]triazol-3-yl}-pyridine,
4-[4-Cyclopropyl-5-(5-m-tolyl-[l,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[l,2,4]triazol-3- yl]-pyridine, 3-[3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-benzonitrile,
4- {4-Cyclopropyl-5 - [5 -(2, 5 -difluoro-phenyl)- [1,2,4] oxadiazol-3 -ylmethylsulfanyl] -4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 4-{4-Cycloρropyl-5-[l-(5-m-tolyl-[l,2,4]oxadiazol-3-yl)-ethylsulfanyl]-4H-[l,2,4]triazol-
3-yl} -pyridine,
4-(4-Cyclopropyl-5- { 1 -[5-(3-methoxy-phenyl)-[l ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4H-
[l,2,4]triazol-3-yl)-pyridine,
4- { 5 - [5-(2-Chloro-5 -methyl-phenyl)-[ 1 ,2,4] oxadiazol-3 -ylmethylsulfanyl] -4-cyclopropyl- 4H-[l,2,4]triazol-3-yl}-pyridine,
2-[3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazol-5-yl]-4-methyl-phenol,
4-(5- { 1 -[5-(2-Chloro-5-methyl-phenyl)-[l ,2,4] oxadiazol-3 -yl] -ethylsulfanyl} -4- cyclopropyl-4H-[l,2,4]triazol-3-yl)-pyridine, {3-[3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl] -phenyl} -methanol,
3-[5-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-3- yl] -phenol,
5-(3-Chloro-phenyl)-3-[4-(tefrahydro-furan-2-ylmethyl)-5-thiophen-2-yl-4H-[l,2,4]triazol- 3 -ylsulfanylmethyl] - [ 1 ,2,4] oxadiazole,
(2-Chloro-phenyl)-{5-[5-(3-chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4- isobutyl-4H-[ 1 ,2,4]triazol-3 -yl} -methanol,
5-(2-Fluoro-5-methyl-ρhenyl)-3-[5-thioρhen-2-yl-4-(2,2,2-trifluoro-ethyl)-4H-
[l,2,4]triazol-3-ylsulfanylmethyl]-[l,2,4]oxadiazole, 3-(2,5-Difluoro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
5-Furan-3-yl-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
3-(3-Chloro-phenyl)-5-(5-iraan-2-yl-4-methyl-4H-[l,2,4]xriazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazole,
3-(3-Chloro-phenyl)-5-(5-l an-3-yl-4-methyl-4H-[l,2,4]friazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole, 5-(3-Chloro-phenyl)-3-(5-furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(5-furan-3-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole, 4-{5-[5-(3 -Chloro-phenyl)- [1,2,4] oxadiazol-3 -ylmethylsulfanyl] -4-methyl-4H-
[ 1 ,2,4]triazol-3-yl} -pyrimidine,
4-{5-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyrimidine,
3-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
3-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
5-(5-Chloro-thiophen-2-yl)-3-(4-ethyl-5-thioρhen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)- [ 1 ,2,4] oxadiazole, 5-(5-Chloro-thiophen-2-yl)-3-(4-ethyl-5-fiiran-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
5-(5-Chloro-thiophen-3-yl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
4-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[l,2,4]triazol- 3 -ylmethoxy} -phenol,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,3,4]oxadiazol-2-ylmethylsulfanyl]-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -ylmethoxy} -phenol,
3-(2,5-Difluoro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole, 3-(2,5-Difluoro-phenyl)-5-(5-furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
4-(5- { l-[3-(3-Chloro-ρhenyl)-[ 1 ,2,4]oxadiazol-5-yl]-ethylsulfanyl} -4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-cyclopropyl- 4H-[l,2,4]triazol-3-yl}-pyrimidine,
2-(5- { 1 -[5-(3-Chloro-phenyl)-[l ,2,4] oxadiazol-3 -yl] -ethylsulfanyl} -4-ethyl-4H-
[l,2,4]triazol-3-yl)-5-methoxy-pyrimidine, 2-(5- { 1 -[5-(3-Chloro-phenyl)-[ 1 ,2,4] oxadiazol-3 -yl] -ethylsulfanyl} -4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyrimidine,
4-(5-{l-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl)-2-methoxy-pyridine, 5-(5-{l-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl)-2-methoxy-pyridine,
2-(5-{l-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-
[ 1 ,2,4]triazol-3-yl)-5-methoxy-pyridine,
3-(5- { l-[5-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-ethyl-4H- [l,2,4]triazol-3-yl)-6-methoxy-pyridazine,
3-(5- { 1 -[5-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3-yl)-pyridine,
4-{5-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine, 5-(3 -Chloro-phenyl)-3 -(5 -furan-2-yl-4-isobutyl-4H- [ 1 ,2,4] triazol-3 -ylsulfanylmethyl)-
[l,2,4]oxadiazole,
5 -(3 -Chloro-phenyl)-3 - [4-(3 -methylsulfanyl-propyl)-5-thiophen-2-yl-4H- [ 1 ,2,4]triazol-3 - ylsulfanylmethyl]-[l,2,4]oxadi azote,
5-(3-Chloro-ρhenyl)-3-(4-hexyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-(4-cyclopropylmethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-(3-fluoro-benzyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl] - [ 1 ,2,4] oxadiazole, 5-(3-Chloro-phenyl)-3-[4-(3-methyl-benzyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl] - [ 1 ,2,4] oxadiazole,
5-(3-Chloro-phenyl)-3-[4-(2-methyl-butyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[ 1 ,2,4]oxadiazole,
5-(3-Chloro-phenyl)-3-[4-(3-methyl-butyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl] -[1,2,4] oxadiazole,
5-(3-Chloro-phenyl)-3-[4-(2-fluoro-benzyl)-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[ 1 ,2,4]oxadiazole, 5-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-yloxymethyl)-
[1,2,4] oxadiazole,
4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethoxy]-4-methyl-4H-
[l,2,4]triazol-3-yl}-pyridine, 4-(5- { 1 -[5-(3-Chloro-ρhenyl)-[ 1 ,3,4]oxadiazol-2-yl]-ethoxy} -4-methyl-4H-[l ,2,4]triazol-
3-yl)-pyridine,
4-(5-{l-[3-(3-Chloro-ρhenyl)-isoxazol-5-yl]-ethoxy}-4-methyl-4H-[l,2,4]triazol-3-yl)- pyridine,
5-(2-Methoxy-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)- [l,2,4]oxadiazole,
5-Furan-2-yl-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
3-[3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl] -benzoic acid methyl ester, 5-(2-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
5-(2,5-Difluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole,
3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(3-vinyl-phenyl)- [1,2,4] oxadiazole,
5-(3-Difluoromethoxy-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[ 1 ,2,4]oxadiazole,
5-(4-Methoxy-thiophen-3-yl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl)-[l,2,4]oxadiazole, 5-(2-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[ 1 ,2,4]triazol-3-ylsulfanyhnethyl)-
[l,2,4]oxadiazole,
5-(4-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[1,2,4] oxadiazole,
3-(3-Chloro-phenyl)-5-[l-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanyl)- ethyl]-[l,2,4]oxadiazole,
-(5- { l-[3-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-ethylsulfanyl} -4-methyl-4H-
[1 ,2,4]triazol-3-yl)-ρyridine, 3-(3-Chloro-phenyl)-5-[2-(4-ethyl-5-thioρhen-2-yl-4H-[l,2,4]friazol-3-yl)-ethyl]-
[1,2,4] oxadiazole,
5-(3-Chloro-ρhenyl)-3-(5-furan-2-yl-4-methyl-4H-[l,2,4]triazol-3-ylmethyl)-
[l,2,4]oxadiazole, 2-(3-Chloro-phenyl)-5-[2-(5-furan-2-yl-4-methyl-4H-[ 1 ,2,4]triazol-3-yl)-ethyl]-
[l,3,4]oxadiazole,
2-(3-Chloro-phenyl)-5-[2-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-yl)-ethyl]-
[l,3,4]oxadiazole,
2-(3-Chloro-phenyl)-5-[2-(4-cyclopropyl-5-furan-2-yl-4H-[l,2,4]triazol-3-yl)-ethyl]- [l,3,4]oxadiazole,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-ethyl}-4-methyl-4H-[l,2,4]triazol-3- yl)-pyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-ethyl}-4-ethyl-4H-[l,2,4]triazol-3- yl)-pyridine, 4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-ethyl}-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-2-methyl-propyl}-4-cyclopropyl-4H- [l,2,4]triazol-3-yl)-pyridine,
4-(5-{2-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-propyl}-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
8-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tefrahy(hO-
[ 1 ,2,4]triazolo[4,3 -a]pyridine, 8-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-3-thiophen-2-yl-5,6,7,8-tefrahydro-
[ 1 ,2,4] triazolo [4,3 -a]pyridine,
8-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-yhnethyl]-3-pyridin-4-yl-5,6,7,8- tetrahydro- [ 1 ,2,4]triazolo [4,3-a]pyridine,
5-(5-Bromo-4-methyl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-3-(3-chloro-phenyl)- [1,2,4] oxadiazole,
3-[3-(4-Methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5- yl]-phenylamine, 5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3-sulfonylmethyl)-
[1,2,4] oxadiazole,
5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazole-3-sulfmylmethyl)-
[1,2,4] oxadiazole, 2-Methyl-6-[3-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[ 1 ,2,4] oxadiazol-5 -yl] -pyridine,
4-(5-{l-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridin-2-ol,
4-(5-{2-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-yl]-proρyl}-4-methyl-4H-[l,2,4]triazol-3- yl)-pyridine,
[5 -(3 -Chloro-phenyl)- [ 1,2,4] oxadiazol-3 -ylmethyl] -methyl-(4-methyl-5 -pyridin-4-yl-4H-
[ 1 ,2,4]triazol-3 -yl)-amine,
8-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tefrahydro-
[l,2,4]triazolo[4,3-a]pyrimidine, 8-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8- tetrahydro-[l,2,4]triazolo[4,3-a]pyrimidine,
8-[5-(3-Chloro-phenyl)-[l,3,4]oxadiazol-2-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetrahydro-
[ 1 ,2,4]triazolo[4,3 -a]pyrimidine,
8- { 1 -[5-(3-Chloro-phenyl)-[l ,3,4]oxadiazol-2-yl]-ethyl} -3-pyridin-4-yl-5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrimidine,
8-[5-(5-Chloro-2-fluoro-phenyl)-[l,2,4]oxadiazol-3-ylmethyl]-3-furan-2-yl-5,6,7,8- tetrahydro-[l,2,4]triazolo[4,3-a]pyrimidine,
8- { 1 -[5-(3-Chloro-phenyl)-[l ,2,4]oxadiazol-3-yl]-ethyl} -3-pyridin-4-yl-5,6,7,8-tetrahydro-
[ 1 ,2,4]triazolo[4,3 -a]pyrimidine, 3-(4-Ethyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-5-(lH-pynol-3-yl)-
[l,2,4]oxadiazole,
4-{5-[5-(3-Chloro-phenyl)-[l,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl} -pyridine 1 -oxide,
5-(3-Chloro-phenyl)-3-(2-furan-2-yl-3-methyl-3H-imidazol-4-ylsulfanylmethyl)- [1,2,4] oxadiazole,
5-(5-Chloro-2-fluoro-phenyl)-3-[4-(2-fluoro-ethyl)-5-thioρhen-2-yl-4H-[l,2,4]triazol-3- ylsulfanylmethyl]-[l,2,4]oxadiazole, 5-(5-Chloro-thiophen-3-yl)-3-(4-ethyl-5-furan-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-
[l,2,4]oxadiazole,
3-[3-(4-Ethyl-5-fiiran-2-yl-4H-[l,2,4]triazol-3-ylsulfanylmethyl)-[l,2,4]oxadiazol-5-yl]-4- hydroxy-benzonitrile, 3-(3-Chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-yl)-ethyl]-
[l,2,4]oxadiazole,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-propyl}-[l,3,4]oxadiazol-2-yl)- pyridine,
4-(5- {2-[3-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]- 1 -methyl-ethyl} -4-cyclopropyl-4H- [l,2,4]triazol-3-yl)-pyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-cyclopropyl}-4-cyclopropyl-4H-
[l,2,4]triazol-3-yl)-pyridine, or
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-l,l-dimethyl-ethyl}-[l,3,4]oxadiazol-
2-yl)-pyridine,
3-(5-{l-[5-(3 -Chloro-phenyl)- [ 1 ,2,4] oxadiazol-3 -yl] -ethoxy} -4-cyclopropyl-4H-
[1 ,2,4]triazol-3-yl)-pyridine,
4-(5- { 1 -[5-(2-Chloro-5-methyl-phenyl)-[l ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-methyl-
4H-[ 1 ,2,4]triazol-3-yl)-pyridine,
4-(5- { 1 -[5-(2,5-Difluoro-phenyl)-[l ,2,4]oxadiazol-3-yl]-ethylsulfanyl} -4-methyl-4H- [l,2,4]triazol-3-yl)-pyridine,
4-(5-{l-[5-(2-Fluoro-5-methyl-phenyl)-[l,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-methyl-
4H- [ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(4-Cyclopropyl-5- { 1 -[5-(2-fluoro-5-methyl-phenyl)-[ 1 ,2,4] oxadiazol-3 -yl]- ethylsulfanyl}-4H-[l,2,4]triazol-3-yl)-pyridine, 3-{3-[l-(4-Methyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-[l,2,4]oxadiazol-
5-yl} -benzonitrile,
3-{3-[l-(4-Cyclopropyl-5-pyridin-4-yl-4H-[l,2,4]triazol-3-ylsulfanyl)-ethyl]-
[l,2,4]oxadiazol-5-yl}-benzonitrile,
3- { 1 -[5-(3-Chloro-phenyl)-[l ,3,4]oxadiazol-2-yl]-ethylsulfanyl} -5-ρyridin-4-yl- [l,2,4]triazol-4-ylamine, 3-(3-Chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[l,2,4]triazol-3-yl)-ethyl]-
[l,2,4]oxadiazole,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-l-methyl-ethyl}-4-cycloproρyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine, cis-4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-cyclopropyl}-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3-yl)-pyridine,
4-(5- {2-[3-(3-Chloro-phenyl)-[ 1 ,2,4]oxadiazol-5-yl]-l , 1 -dimethyl-ethyl} -[1 ,3,4]oxadiazol-
2-yl)-ρyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-2-methyl-propyl}-[l,3,4]oxadiazol-2- yl)-pyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-l-methyl-ethyl}-[l,3,4]oxadiazol-2- yl)-pyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-cyclopropyl}-[l,3,4]oxadiazol-2-yl)- pyridine, 4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-cyclopropyl}-4-methyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine,
4-(5-{2-[5-(3-Chloro-ρhenyl)-[l,3,4]oxadiazol-2-yl]-propyl}-4-methyl-4H-[l,2,4]triazol-3- yl)-pyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-propyl}-[l,3,4]oxadiazol-2-yl)- pyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-propyl}-4-methyl-4H-[l,2,4]triazol-3- yl)-pyridine,
4-(5-{2-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H-
[ 1 ,2,4]triazol-3 -yl)-pyridine, (S)-[l-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-
[l,2,4]triazol-3-yl)-ethyl]-carbamic acid tert-butyl ester,
(S)-l-[3-(3-Chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-
[l,2,4]triazol-3-yl)-ethylamine,
(S)-[l-[3-(3-Chloro-ρhenyl)-[l,2,4]oxadiazol-5-yl]-2-(4-cycloρroρyl-5-ρyridin-4-yl-4H- [l,2,4]triazol-3-yl)-ethyl]-dimethyl-amine, or salt thereof.
18. A pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 17 in association with one or more pharmaceutically acceptable diluent, excipients and/or inert carrier.
19. The pharmaceutical formulation according to claim 18, for use in the prevention and/or treatment of mGlxxR5 receptor-mediated disorders.
20. A compound according to any one of claims 1 to 17 for use in therapy.
21. The compound according to claim 20, for use in prevention and/or treatment of mGluR5 receptor-mediated disorders.
22. The compound according to claim 20, for use in prevention and/or freatment of neurological disorders.
23. The compound according to claim 20, for use in prevention and/or treatment of psychiatric disorders.
24. The compound according to claim 20, for use in prevention and/or treatment of chronic and acute pain disorders.
25. The use of a compound according to any one of claims 1 to 17 in the manufacture of a medicament for the use in the prevention and/or freatment of mGluR5 receptor-mediated disorders.
26. A method of prevention and/or treatment of mGluR5 receptor-mediated disorders, comprising administrering to a mammal, including man in need of such prevention and/or freatment, a therapeutically effective amount of a compound according to any one of claims 1 to 17.
27. A method for inhibiting activation of mGluR5 receptors, comprising treating a cell containing said receptor with an effective amount of a compound according to any one of claims 1 to 17.
28. Processes for the preparation of a compound according to claim 2, comprising;
Figure imgf000318_0001
IX lb wherein R' and R" contains either a group represented in Formula I by M2-(R3)n-X4-Q- (R4)m2 or a leaving group such as (CH2)nX, wherein X is any suitable leaving group such as chloro or mesylate or a group which may subsequently be transformed into a leaving group and Q, X4, R3 R4, M2, m and n are as defined in claim 1.
PCT/US2003/024846 2002-08-09 2003-08-08 '1,2,4'oxadiazoles as modulators of metabotropic glutamate receptor-5 WO2004014881A2 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
CA2494987A CA2494987C (en) 2002-08-09 2003-08-08 Isoxazoles and their use as modulators of metabotropic glutamate receptor-5
BR0313265-0A BR0313265A (en) 2002-08-09 2003-08-08 Compounds and their processes for the preparation, use and pharmaceutical formulations and methods for preventing and / or treating mglur5 receptor mediated disorders and inhibiting mglu r5 receptor activation.
NZ538225A NZ538225A (en) 2002-08-09 2003-08-08 "1,2,4"Oxadiazoles as modulators of metabotropic glutamate receptor-5
IL16651003A IL166510A0 (en) 2002-08-09 2003-08-08 1,2,4"oxadiazole as modulators of metabotropic glutamate receptor-5
EP03785036A EP1529045A2 (en) 2002-08-09 2003-08-08 New compounds
MXPA05001594A MXPA05001594A (en) 2002-08-09 2003-08-08 "1,2,4"oxadiazoles as modulators of metabotropic glutamate receptor-5.
AU2003259068A AU2003259068B2 (en) 2002-08-09 2003-08-08 "1,2,4"oxadiazoles as modulators of metabotropic glutamate receptor-5
JP2004527872A JP4637578B2 (en) 2002-08-09 2003-08-08 1,2,4-oxadiazoles as regulators of metabotropic glutamate receptor-5
NO20051225A NO20051225L (en) 2002-08-09 2005-03-09 1,2,4-oxadiazoles as modulators of metabotropic glutamate receptor-5
IS7733A IS7733A (en) 2002-08-09 2005-03-09 1,2,4-Oxadiazole Direct for Catalytic Glutamate Receptor-5

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US40204002P 2002-08-09 2002-08-09
US60/402,040 2002-08-09

Publications (3)

Publication Number Publication Date
WO2004014881A2 true WO2004014881A2 (en) 2004-02-19
WO2004014881A3 WO2004014881A3 (en) 2004-05-27
WO2004014881B1 WO2004014881B1 (en) 2004-07-15

Family

ID=31715777

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/024846 WO2004014881A2 (en) 2002-08-09 2003-08-08 '1,2,4'oxadiazoles as modulators of metabotropic glutamate receptor-5

Country Status (20)

Country Link
US (2) US20040152699A1 (en)
EP (1) EP1529045A2 (en)
JP (2) JP4637578B2 (en)
KR (1) KR20050033070A (en)
CN (2) CN101723941A (en)
AR (1) AR040847A1 (en)
AU (1) AU2003259068B2 (en)
BR (1) BR0313265A (en)
CA (1) CA2494987C (en)
IL (1) IL166510A0 (en)
IS (1) IS7733A (en)
MX (1) MXPA05001594A (en)
NO (1) NO20051225L (en)
NZ (1) NZ538225A (en)
PL (1) PL375256A1 (en)
RU (1) RU2352568C9 (en)
TW (1) TWI341314B (en)
UA (1) UA87653C2 (en)
WO (1) WO2004014881A2 (en)
ZA (1) ZA200500886B (en)

Cited By (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005077345A1 (en) * 2004-02-03 2005-08-25 Astrazeneca Ab Compounds for the treatment of gastro-esophageal reflux disease
WO2005080379A1 (en) * 2004-02-18 2005-09-01 Astrazeneca Ab Triazole compounds and their use as metabotropic glutamate receptor antagonists
WO2006014185A1 (en) * 2004-02-18 2006-02-09 Astrazeneca Ab Additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
WO2006051944A1 (en) 2004-11-15 2006-05-18 Riken Fluorescent protein
WO2006080533A1 (en) * 2005-01-31 2006-08-03 Mochida Pharmaceutical Co., Ltd. 3-amino-1,2,4-triazole derivative
WO2006123249A2 (en) 2005-05-18 2006-11-23 Addex Pharma Sa Novel oxadiazole derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors
JP2008526909A (en) * 2005-01-14 2008-07-24 エフ．ホフマン−ラ ロシュ アーゲー Thiazole-4-carboxamide derivatives as mGluR5 antagonists
US7425553B2 (en) 2003-05-30 2008-09-16 Gemin X Pharmaceuticals Canada Inc. Triheterocyclic compounds, compositions, and methods for treating cancer or viral diseases
JP2008540636A (en) * 2005-05-18 2008-11-20 アデックス ファーマ ソシエテ アノニム Novel heterocyclic compounds as positive allosteric modulators of metabotropic glutamate receptors
US7476684B2 (en) 2005-09-29 2009-01-13 Astrazeneca Ab Compounds for the treatment of neurological, psychiatric or pain disorders
WO2009051556A1 (en) * 2007-10-19 2009-04-23 Astrazeneca Ab Tetrazole derivatives as modulators of metabotropic glutamate receptors (mglurs)
WO2009054785A1 (en) * 2007-10-26 2009-04-30 Astrazeneca Ab 1,2,4-triazole ether derivatives as modulators of mglur5
EP2070922A1 (en) * 2004-02-23 2009-06-17 Glaxo Group Limited Azabicyclo(3.1.0) hexane derivatives useful as modulators of dopamine D3 receptors
US7576077B2 (en) 2004-02-19 2009-08-18 Astrazeneca Ab Fused heterocyclic compounds and their use as metabotropic glutamate receptor antagonists
JP2010505809A (en) * 2006-10-05 2010-02-25 アストラゼネカ・アクチエボラーグ mGluR5 regulator
US7678796B2 (en) 2006-05-05 2010-03-16 Astrazeneca Ab MGluR5 modulators I
DE102008057364A1 (en) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft New pyridyl or phenyl ring containing compounds are hypoxia-inducible factor regulation pathway modulators, useful to treat and/or prevent e.g. cancer or tumor diseases, heart attack, arrhythmia, stroke, psoriasis and diabetic retinopathy
DE102008057343A1 (en) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft New phenyl or pyridyl ring containing compounds are hypoxia-inducible factor regulation pathway modulators, useful to treat and/or prevent e.g. cancer or tumor diseases, heart attack, arrhythmia, stroke, psoriasis and diabetic retinopathy
DE102008057344A1 (en) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Aminoalkyl-substituted aryl compounds and their use
US7732465B2 (en) 2005-08-30 2010-06-08 Novartis Vaccines And Diagnostics, Inc. Substituted benzimidazoles and methods of their use
WO2010071558A1 (en) * 2008-12-18 2010-06-24 Astrazeneca Ab New process for the preparation of 1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanone and (r) -1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanol
US7776897B2 (en) 2004-09-16 2010-08-17 Astellas Pharma Inc. Triazole derivative or salt thereof
WO2010139966A1 (en) * 2009-06-05 2010-12-09 Oslo University Hospital Hf Azole derivatives as wtn pathway inhibitors
EP2272509A1 (en) 2006-09-11 2011-01-12 Novartis AG New Uses of metabotropic glutamate receptors
CN102119159A (en) * 2008-04-28 2011-07-06 阿斯利康(瑞典)有限公司 Methods of preparing substituted heterocycles
DE102009041241A1 (en) 2009-09-11 2011-08-04 Bayer Schering Pharma Aktiengesellschaft, 13353 New heteroaromatic compounds are hypoxia-inducible factor inhibitors useful to treat and/or prevent e.g. cancer or tumor diseases, heart attack, arrhythmia, stroke, psoriasis, diabetic retinopathy, rheumatoid arthritis and polycythemia
WO2011137206A1 (en) 2010-04-30 2011-11-03 Novartis Ag Predictive markers useful in the treatment of fragile x syndrome (fxs)
WO2011107530A3 (en) * 2010-03-03 2011-11-10 Probiodrug Ag Inhibitors of glutaminyl cyclase
DE102009041242A1 (en) 2009-09-11 2011-12-15 Bayer Schering Pharma Aktiengesellschaft New heterocyclically substituted aryl compounds are hypoxia-inducible factor inhibitors useful to treat and/or prevent e.g. cancer or tumor diseases, ischemic cardiovascular diseases, heart attack, arrhythmia, stroke, and psoriasis
US8377923B2 (en) 2008-07-03 2013-02-19 Astellas Pharma Inc. Triazole derivative or salt thereof
JP2013514285A (en) * 2009-12-17 2013-04-25 ハー・ルンドベック・アクチエゼルスカベット 2-Arylimidazole derivatives as enzyme PDE10A inhibitors
US8524718B2 (en) 2007-07-13 2013-09-03 Addex Pharma S.A. Heteroaromatic derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors
US8524751B2 (en) 2009-03-09 2013-09-03 GlaxoSmithKline Intellecutual Property Development 4-oxadiazol-2-YL-indazoles as inhibitors of P13 kinases
WO2013131981A1 (en) 2012-03-08 2013-09-12 Novartis Ag Predictive markers useful in the diagnosis and treatment of fragile x syndrome (fxs)
US8536169B2 (en) 2008-06-05 2013-09-17 Glaxo Group Limited Compounds
US8575162B2 (en) 2009-04-30 2013-11-05 Glaxosmithkline Intellectual Property Development Limited Compounds
WO2013169578A1 (en) 2012-05-07 2013-11-14 Bristol-Myers Squibb Company C-17 bicyclic amines of triterpenoids with hiv maturation inhibitory activity
US8592590B2 (en) 2009-12-29 2013-11-26 Eli Lilly And Company Tetrahydrotriazolopyridine compounds as selective MGLU5 receptor potentiators useful for the treatment of schizophrenia
US8658635B2 (en) 2008-06-05 2014-02-25 Glaxosmithkline Intellectual Property Development Limited Benzpyrazol derivatives as inhibitors of PI3 kinases
US8716317B2 (en) 2008-06-09 2014-05-06 Sanofi Sulfonamides with heterocycle and oxadiazolone headgroup, processes for their preparation and their use as pharmaceuticals
US8729263B2 (en) 2012-08-13 2014-05-20 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
US8765743B2 (en) 2008-06-05 2014-07-01 Glaxosmithkline Intellectual Property Development Limited Compounds
EP2826478A1 (en) 2008-06-30 2015-01-21 Novartis AG Combinations comprising mglur modulators for the treatment of parkinson's disease
US8993576B2 (en) 2010-10-27 2015-03-31 Glaxo Group Limited 6-(1H-indol-4-yl)-4-(5-{[4-1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole hemi succinate salt, polymorphs and pharmaceutical compositions thereof
US9040712B2 (en) 2013-01-23 2015-05-26 Novartis Ag Thiadiazole analogs thereof and methods for treating SMN-deficiency-related-conditions
US9073875B2 (en) 2012-11-20 2015-07-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
US9096587B2 (en) 2010-12-08 2015-08-04 Oslo University Hospital Hf Triazole derivatives as Wnt signaling pathway inhibitors
US9125410B2 (en) 2007-08-13 2015-09-08 Monsanto Technology Llc Compositions and methods for controlling nematodes
EP3159332A1 (en) 2015-10-23 2017-04-26 Ludwig-Maximilians-Universität München 5,5'-bis(2,4,6-trinitrophenyl)-2,2'-bi(1,3,4-oxadiazole) and bis(2,4,6-trinitrobenzoyl)oxalohydrazide
US9765040B2 (en) 2010-09-07 2017-09-19 Astellas Pharma Inc. Therapeutic agent for pain
US10118920B2 (en) 2015-04-20 2018-11-06 Cellcentric Ltd Isoxazolyl substituted benzimidazoles
US10428065B2 (en) 2015-04-20 2019-10-01 Cellcentric Ltd Isoxazolyl substituted imidazopyridines
EP3771711A1 (en) 2019-07-29 2021-02-03 Bayer Animal Health GmbH Pyrazole derivatives for controlling arthropods
US11672799B2 (en) 2013-07-31 2023-06-13 Novartis Ag 1,4-disubstituted pyridazine quinolne analogs there of and methods for treating SMN-deficiency-related conditions

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101723941A (en) * 2002-08-09 2010-06-09 阿斯利康(瑞典)有限公司 “1,2,4” oxadiazole as a metabotropic glutamate receptor-5 modulator
US20050288347A1 (en) * 2004-03-26 2005-12-29 Hodge Carl N Certain triazole-based compounds, compositions, and uses thereof
TW200635587A (en) * 2004-12-01 2006-10-16 Kalypsys Inc Inducible nitric oxide synthase dimerization inhibitors
CA2628146A1 (en) * 2005-11-28 2007-05-31 Kalypsys, Inc. Salts of inducible nitric oxide synthase dimerization inhibitors
BRPI0720043A2 (en) * 2006-12-15 2014-01-07 Abbott Lab OXADIAZOL COMPOUND
US20110207704A1 (en) * 2006-12-15 2011-08-25 Abbott Laboratories Novel Oxadiazole Compounds
EP1958631A1 (en) * 2007-02-14 2008-08-20 AEterna Zentaris GmbH Novel triazole derivatives as ligands of G-protein coupled receptors
EP2211619A1 (en) * 2007-10-18 2010-08-04 Merck Sharp & Dohme Corp. Substituted 1,2,4-oxadiazoles and analogs thereof as cb2 receptor modulators, useful in the treatment of pain, respiratory and non-respiratory diseases
US20110144049A1 (en) * 2009-10-21 2011-06-16 Serebruany Victor L Treating Cardiac Arrhythmias, Heart Failure, Peripheral Artery Disease and Stroke with Cyclopentyl-Triazolo-Pyrimidine or Derivative Thereof
AR081626A1 (en) 2010-04-23 2012-10-10 Cytokinetics Inc AMINO-PYRIDAZINIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USE OF THE SAME TO TREAT CARDIAC AND SKELETIC MUSCULAR DISORDERS
AR081331A1 (en) 2010-04-23 2012-08-08 Cytokinetics Inc AMINO- PYRIMIDINES COMPOSITIONS OF THE SAME AND METHODS FOR THE USE OF THE SAME
WO2011133920A1 (en) 2010-04-23 2011-10-27 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
WO2012006760A1 (en) * 2010-07-14 2012-01-19 Merck Sharp & Dohme Corp. Tricyclic compounds as allosteric modulators of metabotropic glutamate receptors
US20130203735A1 (en) * 2010-10-28 2013-08-08 John T. Sisko Caprolactam mglur5 receptor modulators
US8759380B2 (en) 2011-04-22 2014-06-24 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
EP2704573A4 (en) 2011-05-03 2014-10-15 Merck Sharp & Dohme Aminomethyl biaryl benzotriazole derivatives
US8592423B2 (en) 2011-06-21 2013-11-26 Bristol-Myers Squibb Company Inhibitors of PDE10
EP2545964A1 (en) 2011-07-13 2013-01-16 Phenex Pharmaceuticals AG Novel FXR (NR1H4) binding and activity modulating compounds
JP6596090B2 (en) 2014-12-17 2019-10-23 キングス カレッジ ロンドン Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists
CA2968836A1 (en) 2016-06-13 2017-12-13 Gilead Sciences, Inc. Fxr (nr1h4) modulating compounds
EP3730487B1 (en) 2016-06-13 2022-04-27 Gilead Sciences, Inc. Azetidine derivatives as fxr (nr1h4) modulators
GB201610867D0 (en) 2016-06-22 2016-08-03 King S College London Crystalline forms of a therapeutic compound and processes for their preparation
PT3600309T (en) 2017-03-28 2022-10-03 Gilead Sciences Inc Therapeutic combinations for treating liver diseases
EP3682881A4 (en) * 2017-09-14 2021-08-11 Daiichi Sankyo Company, Limited Compound having cyclic structure
CN111372576A (en) 2017-11-17 2020-07-03 塞尔利克斯生物私人有限公司 Compositions and methods for treating ocular disorders
SI3911647T1 (en) 2019-01-15 2024-04-30 Gilead Sciences, Inc. Isoxazole compound as fxr agonist and pharmaceutical compositions comprising same
JP2022519906A (en) 2019-02-19 2022-03-25 ギリアード サイエンシーズ， インコーポレイテッド Solid form of FXR agonist
CN111362934A (en) * 2020-04-21 2020-07-03 南开大学 Isothiazole oxadiazole derivatives, and preparation method and application thereof

Family Cites Families (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3740434A (en) * 1966-12-23 1973-06-19 American Cyanamid Co Substituted nitroimidazolylthiadiazoles and oxadiazoles as antiprotozoal agents
US3816426A (en) * 1970-10-27 1974-06-11 Abbott Lab 1-(5-phenyl-4-oxo-2-oxazolin-2-yl)piperazines
JPS56127364A (en) 1980-03-01 1981-10-06 Mitsui Toatsu Chem Inc Novel piperazine compound, its preparation and utilization
JP3003148B2 (en) 1989-01-05 2000-01-24 藤沢薬品工業株式会社 Thiazole compound, process for producing the same, and pharmaceutical composition containing the same
US5140034A (en) * 1989-03-14 1992-08-18 Merck Sharp & Dohme Ltd. Five-membered ring systems with bonded imidazolyl ring substituents
US4914207A (en) * 1989-05-09 1990-04-03 Pfizer Inc. Arylthiazolylimidazoles
DE3929673A1 (en) * 1989-09-07 1991-03-14 Bayer Ag SUBSTITUTED CARBAMOYLTRIAZOLE
IL96891A0 (en) 1990-01-17 1992-03-29 Merck Sharp & Dohme Indole-substituted five-membered heteroaromatic compounds,their preparation and pharmaceutical compositions containing them
AU678186B2 (en) * 1992-10-23 1997-05-22 Merck Sharp & Dohme Limited Dopamine receptor subtype ligands
DE19725450A1 (en) 1997-06-16 1998-12-17 Hoechst Schering Agrevo Gmbh 4-Haloalkyl-3-heterocyclylpyridines and 4-haloalkyl-5-heterocyclylpyrimidines, processes for their preparation, compositions containing them and their use as pesticides
DE19858193A1 (en) * 1998-12-17 2000-06-21 Aventis Cropscience Gmbh 4-Trifluoromethyl-3-oxadiazolylpyridines, process for their preparation, compositions containing them and their use as pesticides
WO1999026927A2 (en) * 1997-11-21 1999-06-03 Nps Pharmaceuticals, Inc. Metabotropic glutamate receptor antagonists for treating central nervous system diseases
DE19858191A1 (en) 1998-12-17 2000-06-21 Aventis Cropscience Gmbh 4-haloalkyl-3-heterocyclylpyridines and 4-haloalkyl-5-heterocyclylpyrimidines and their use as repellents
DE19858192A1 (en) * 1998-12-17 2000-06-21 Aventis Cropscience Gmbh 4-Trifluoromethyl-3-oxazolylpyridines, process for their preparation, compositions containing them and their use as pesticides
CO5170501A1 (en) 1999-04-14 2002-06-27 Novartis Ag USEFUL REPLACED BLUES FOR THE TREATMENT OF DISEASES MEDIATED BY TNFa eIL-1 AND DISEASES OF THE OSEO METABOLISM
AU780191B2 (en) 1999-08-19 2005-03-03 Astrazeneca Ab Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
AU7989400A (en) * 1999-10-01 2001-05-10 Smithkline Beecham Corporation Compounds and methods
TWI283577B (en) 1999-10-11 2007-07-11 Sod Conseils Rech Applic Pharmaceutical composition of imidazole derivatives acting as modulators of sodium channels and the use thereof
DE19962901A1 (en) 1999-12-23 2001-07-05 Aventis Cropscience Gmbh Azolylalkalylazole derivatives, process for their preparation and their use as pesticides
PL361397A1 (en) 2000-09-21 2004-10-04 Smithkline Beecham P.L.C. Imidazole derivatives as raf kinase inhibitors
AU2956702A (en) 2000-12-04 2002-06-18 Hoffmann La Roche Phenylethenyl or phenylethinyl derivatives as glutamate receptor antagonists
DE60203623T2 (en) 2001-07-19 2006-01-19 CV Therapeutics, Inc., Palo Alto SUBSTITUTED PIPERAZINE DERIVATIVES AND THEIR USE AS FATTY-OXIDATION INHIBITORS
CN101723941A (en) * 2002-08-09 2010-06-09 阿斯利康(瑞典)有限公司 “1,2,4” oxadiazole as a metabotropic glutamate receptor-5 modulator
WO2005077345A1 (en) 2004-02-03 2005-08-25 Astrazeneca Ab Compounds for the treatment of gastro-esophageal reflux disease
PL1716152T3 (en) 2004-02-18 2009-01-30 Astrazeneca Ab Fused hetrocyclic compounds and their use as metabotropic receptor antagonists for the treatment of gastrointestinal disorders
US7585881B2 (en) * 2004-02-18 2009-09-08 Astrazeneca Ab Additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
AR058807A1 (en) * 2005-09-29 2008-02-27 Astrazeneca Ab 5- (PHENYLYSOXAZOLETOXI) -TRIAZOL-3-IL PIRIDINES REPLACED, FOR THE TREATMENT OF DISORDERS MEDIATED BY THE RECEIVER MGLUR5

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
CUNNINGHAM ET AL., LIFE SCI., vol. 54, 1994, pages 135
GASPARINI ET AL., CURR. OPIN. PHARMACOL., vol. 2, 2002, pages 43
HOLLMAN ET AL., ANN. REV. NEUROSCI., vol. 17, 1994, pages 31
KNOPFEL ET AL., J. MED. CHEM., vol. 38, 1995, pages 1417
NEUGEBAUER PAIN, vol. 98, 2002, pages 1
PIN ET AL., NEUROPHARMACOLOGY, vol. 34, 1995, pages 1
SCHOEPP ET AL., TRENDS PHARMACOL. SCI., vol. 14, 1993, pages 13
SPOOREN ET AL., TRENDS PHARMACOL. SCI., vol. 22, no. 331, 2001

Cited By (92)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8420638B2 (en) 2003-05-30 2013-04-16 Gemin X Pharmaceuticals Canada Inc. Triheterocyclic compounds and compositions thereof
US7709477B2 (en) 2003-05-30 2010-05-04 Gemin X Pharmaceuticals Canada Inc. Methods for treating cancer
US7425553B2 (en) 2003-05-30 2008-09-16 Gemin X Pharmaceuticals Canada Inc. Triheterocyclic compounds, compositions, and methods for treating cancer or viral diseases
WO2005077345A1 (en) * 2004-02-03 2005-08-25 Astrazeneca Ab Compounds for the treatment of gastro-esophageal reflux disease
WO2005080379A1 (en) * 2004-02-18 2005-09-01 Astrazeneca Ab Triazole compounds and their use as metabotropic glutamate receptor antagonists
WO2006014185A1 (en) * 2004-02-18 2006-02-09 Astrazeneca Ab Additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
US7585881B2 (en) 2004-02-18 2009-09-08 Astrazeneca Ab Additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
EP2311830A1 (en) * 2004-02-18 2011-04-20 AstraZeneca AB Additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
US7576077B2 (en) 2004-02-19 2009-08-18 Astrazeneca Ab Fused heterocyclic compounds and their use as metabotropic glutamate receptor antagonists
EP2070922A1 (en) * 2004-02-23 2009-06-17 Glaxo Group Limited Azabicyclo(3.1.0) hexane derivatives useful as modulators of dopamine D3 receptors
US7776897B2 (en) 2004-09-16 2010-08-17 Astellas Pharma Inc. Triazole derivative or salt thereof
WO2006051944A1 (en) 2004-11-15 2006-05-18 Riken Fluorescent protein
JP2008526909A (en) * 2005-01-14 2008-07-24 エフ．ホフマン−ラ ロシュ アーゲー Thiazole-4-carboxamide derivatives as mGluR5 antagonists
WO2006080533A1 (en) * 2005-01-31 2006-08-03 Mochida Pharmaceutical Co., Ltd. 3-amino-1,2,4-triazole derivative
JP2008540634A (en) * 2005-05-18 2008-11-20 アデックス ファーマ ソシエテ アノニム Novel oxadiazole derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors
EA015263B1 (en) * 2005-05-18 2011-06-30 Аддекс Фарма Са Novel oxadiazole derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors
JP2008540636A (en) * 2005-05-18 2008-11-20 アデックス ファーマ ソシエテ アノニム Novel heterocyclic compounds as positive allosteric modulators of metabotropic glutamate receptors
AU2006248649B2 (en) * 2005-05-18 2012-04-26 Addex Pharma Sa Novel oxadiazole derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors
WO2006123249A3 (en) * 2005-05-18 2007-02-08 Addex Pharmaceuticals Sa Novel oxadiazole derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors
WO2006123249A2 (en) 2005-05-18 2006-11-23 Addex Pharma Sa Novel oxadiazole derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors
CN101218232B (en) * 2005-05-18 2012-06-27 艾德斯药物股份有限公司 Novel oxadiazole derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors
US7767820B2 (en) 2005-08-30 2010-08-03 Novartis Vaccines And Diagnostics, Inc. Substituted benzimidazoles and methods of preparation
US8592459B2 (en) 2005-08-30 2013-11-26 Novartis Ag Substituted benzimidazoles and methods of their use
US7732465B2 (en) 2005-08-30 2010-06-08 Novartis Vaccines And Diagnostics, Inc. Substituted benzimidazoles and methods of their use
US7476684B2 (en) 2005-09-29 2009-01-13 Astrazeneca Ab Compounds for the treatment of neurological, psychiatric or pain disorders
JP2010013476A (en) * 2005-09-29 2010-01-21 Astrazeneca Ab New compound for treatment of neurological, psychiatric or pain disorder
JP2009510064A (en) * 2005-09-29 2009-03-12 アストラゼネカ アクチボラグ Novel compounds for the treatment of neurological, psychiatric or painful disorders
US7678796B2 (en) 2006-05-05 2010-03-16 Astrazeneca Ab MGluR5 modulators I
EP2272509A1 (en) 2006-09-11 2011-01-12 Novartis AG New Uses of metabotropic glutamate receptors
JP2010505809A (en) * 2006-10-05 2010-02-25 アストラゼネカ・アクチエボラーグ mGluR5 regulator
US8524718B2 (en) 2007-07-13 2013-09-03 Addex Pharma S.A. Heteroaromatic derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors
US10112930B2 (en) 2007-08-13 2018-10-30 Monsanto Technology Llc Compositions and methods for controlling nematodes
US9420788B2 (en) 2007-08-13 2016-08-23 Monsanto Technology Llc Compositions and methods for controlling nematodes
US10827753B2 (en) 2007-08-13 2020-11-10 Monsanto Technology Llc Compositions and methods for controlling nematodes
US9125410B2 (en) 2007-08-13 2015-09-08 Monsanto Technology Llc Compositions and methods for controlling nematodes
US10375958B2 (en) 2007-08-13 2019-08-13 Monsanto Technology Llc Compositions and methods for controlling nematodes
US9642364B2 (en) 2007-08-13 2017-05-09 Monsanto Technology Llc Compositions and methods for controlling nematodes
US7960422B2 (en) 2007-10-19 2011-06-14 Astrazeneca Ab Pharmaceutically active compounds containing tetrazolyl and triazolyl rings
WO2009051556A1 (en) * 2007-10-19 2009-04-23 Astrazeneca Ab Tetrazole derivatives as modulators of metabotropic glutamate receptors (mglurs)
WO2009054785A1 (en) * 2007-10-26 2009-04-30 Astrazeneca Ab 1,2,4-triazole ether derivatives as modulators of mglur5
CN102119159A (en) * 2008-04-28 2011-07-06 阿斯利康(瑞典)有限公司 Methods of preparing substituted heterocycles
US8658635B2 (en) 2008-06-05 2014-02-25 Glaxosmithkline Intellectual Property Development Limited Benzpyrazol derivatives as inhibitors of PI3 kinases
US8765743B2 (en) 2008-06-05 2014-07-01 Glaxosmithkline Intellectual Property Development Limited Compounds
US8536169B2 (en) 2008-06-05 2013-09-17 Glaxo Group Limited Compounds
US8716317B2 (en) 2008-06-09 2014-05-06 Sanofi Sulfonamides with heterocycle and oxadiazolone headgroup, processes for their preparation and their use as pharmaceuticals
EP2826478A1 (en) 2008-06-30 2015-01-21 Novartis AG Combinations comprising mglur modulators for the treatment of parkinson's disease
US8377923B2 (en) 2008-07-03 2013-02-19 Astellas Pharma Inc. Triazole derivative or salt thereof
DE102008057343A1 (en) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft New phenyl or pyridyl ring containing compounds are hypoxia-inducible factor regulation pathway modulators, useful to treat and/or prevent e.g. cancer or tumor diseases, heart attack, arrhythmia, stroke, psoriasis and diabetic retinopathy
DE102008057364A1 (en) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft New pyridyl or phenyl ring containing compounds are hypoxia-inducible factor regulation pathway modulators, useful to treat and/or prevent e.g. cancer or tumor diseases, heart attack, arrhythmia, stroke, psoriasis and diabetic retinopathy
DE102008057344A1 (en) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Aminoalkyl-substituted aryl compounds and their use
WO2010071558A1 (en) * 2008-12-18 2010-06-24 Astrazeneca Ab New process for the preparation of 1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanone and (r) -1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanol
US8524751B2 (en) 2009-03-09 2013-09-03 GlaxoSmithKline Intellecutual Property Development 4-oxadiazol-2-YL-indazoles as inhibitors of P13 kinases
US10383879B2 (en) 2009-04-30 2019-08-20 Glaxo Group Limited Compounds
US8586583B2 (en) 2009-04-30 2013-11-19 Glaxosmithkline Intellectual Property Development Limited Compounds
US8586590B2 (en) 2009-04-30 2013-11-19 Glaxosmithkline Intellectual Property Development Limited Compounds
US10946025B2 (en) 2009-04-30 2021-03-16 Glaxo Group Limited Compounds
US8609657B2 (en) 2009-04-30 2013-12-17 Glaxosmithkline Intellectual Property Development Limited Compounds
US8580797B2 (en) 2009-04-30 2013-11-12 Glaxo Smith Kline Intellectual Property Development Limited Compounds
US8575162B2 (en) 2009-04-30 2013-11-05 Glaxosmithkline Intellectual Property Development Limited Compounds
US10624898B2 (en) 2009-04-30 2020-04-21 Glaxo Group Limited Compounds
WO2010139966A1 (en) * 2009-06-05 2010-12-09 Oslo University Hospital Hf Azole derivatives as wtn pathway inhibitors
US8883827B2 (en) 2009-06-05 2014-11-11 Oslo University Hospital Hf Azole derivatives as WTN pathway inhibitors
JP2012528842A (en) * 2009-06-05 2012-11-15 オスロ ユニヴァーシティー ホスピタル エイチエフ Azole derivatives as WTN pathway inhibitors
DE102009041241A1 (en) 2009-09-11 2011-08-04 Bayer Schering Pharma Aktiengesellschaft, 13353 New heteroaromatic compounds are hypoxia-inducible factor inhibitors useful to treat and/or prevent e.g. cancer or tumor diseases, heart attack, arrhythmia, stroke, psoriasis, diabetic retinopathy, rheumatoid arthritis and polycythemia
DE102009041242A1 (en) 2009-09-11 2011-12-15 Bayer Schering Pharma Aktiengesellschaft New heterocyclically substituted aryl compounds are hypoxia-inducible factor inhibitors useful to treat and/or prevent e.g. cancer or tumor diseases, ischemic cardiovascular diseases, heart attack, arrhythmia, stroke, and psoriasis
US8927738B2 (en) 2009-12-17 2015-01-06 H. Lundbeck A/S 2-arylimidazole derivatives as PDE10A enzyme inhibitors
JP2013514285A (en) * 2009-12-17 2013-04-25 ハー・ルンドベック・アクチエゼルスカベット 2-Arylimidazole derivatives as enzyme PDE10A inhibitors
US8592590B2 (en) 2009-12-29 2013-11-26 Eli Lilly And Company Tetrahydrotriazolopyridine compounds as selective MGLU5 receptor potentiators useful for the treatment of schizophrenia
WO2011107530A3 (en) * 2010-03-03 2011-11-10 Probiodrug Ag Inhibitors of glutaminyl cyclase
US9181233B2 (en) 2010-03-03 2015-11-10 Probiodrug Ag Inhibitors of glutaminyl cyclase
WO2011137206A1 (en) 2010-04-30 2011-11-03 Novartis Ag Predictive markers useful in the treatment of fragile x syndrome (fxs)
US9765040B2 (en) 2010-09-07 2017-09-19 Astellas Pharma Inc. Therapeutic agent for pain
US8993576B2 (en) 2010-10-27 2015-03-31 Glaxo Group Limited 6-(1H-indol-4-yl)-4-(5-{[4-1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H-indazole hemi succinate salt, polymorphs and pharmaceutical compositions thereof
US9403812B2 (en) 2010-12-08 2016-08-02 Oslo University Hospital Hf Triazole derivatives as Wnt signaling pathway inhibitors
US9096587B2 (en) 2010-12-08 2015-08-04 Oslo University Hospital Hf Triazole derivatives as Wnt signaling pathway inhibitors
WO2013131981A1 (en) 2012-03-08 2013-09-12 Novartis Ag Predictive markers useful in the diagnosis and treatment of fragile x syndrome (fxs)
WO2013169578A1 (en) 2012-05-07 2013-11-14 Bristol-Myers Squibb Company C-17 bicyclic amines of triterpenoids with hiv maturation inhibitory activity
US8729263B2 (en) 2012-08-13 2014-05-20 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
US10758533B2 (en) 2012-08-13 2020-09-01 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
US10195196B2 (en) 2012-08-13 2019-02-05 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
US9545404B2 (en) 2012-08-13 2017-01-17 Novartis Ag 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
US11229648B2 (en) 2012-08-13 2022-01-25 Novartis Ag 1,4-disubstituted pyridazine analogs thereof and methods for treating SMN-deficiency-related conditions
US9499497B2 (en) 2012-11-20 2016-11-22 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
US9073875B2 (en) 2012-11-20 2015-07-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
US9040712B2 (en) 2013-01-23 2015-05-26 Novartis Ag Thiadiazole analogs thereof and methods for treating SMN-deficiency-related-conditions
US11672799B2 (en) 2013-07-31 2023-06-13 Novartis Ag 1,4-disubstituted pyridazine quinolne analogs there of and methods for treating SMN-deficiency-related conditions
US10428065B2 (en) 2015-04-20 2019-10-01 Cellcentric Ltd Isoxazolyl substituted imidazopyridines
US10118920B2 (en) 2015-04-20 2018-11-06 Cellcentric Ltd Isoxazolyl substituted benzimidazoles
US10752560B2 (en) 2015-10-23 2020-08-25 Ludwig-Maximilians-Universitaet Muenchen 5,5′-bis(2,4,6-Trinitrophenyl)-2,2′-bi(1,3,4-oxadiazole) and bis(2,4,6-trinitrobenzoyl)oxalohydrazide
EP3159332A1 (en) 2015-10-23 2017-04-26 Ludwig-Maximilians-Universität München 5,5'-bis(2,4,6-trinitrophenyl)-2,2'-bi(1,3,4-oxadiazole) and bis(2,4,6-trinitrobenzoyl)oxalohydrazide
EP3771711A1 (en) 2019-07-29 2021-02-03 Bayer Animal Health GmbH Pyrazole derivatives for controlling arthropods
WO2021018849A1 (en) 2019-07-29 2021-02-04 Bayer Animal Health Gmbh Pyrazole derivatives for controlling arthropods

Also Published As

Publication number Publication date
TW200413361A (en) 2004-08-01
CA2494987C (en) 2012-04-17
AU2003259068A1 (en) 2004-02-25
EP1529045A2 (en) 2005-05-11
BR0313265A (en) 2005-07-05
AU2003259068B2 (en) 2009-07-02
WO2004014881A3 (en) 2004-05-27
JP2006503009A (en) 2006-01-26
ZA200500886B (en) 2006-07-26
US20060122397A1 (en) 2006-06-08
JP2010248214A (en) 2010-11-04
AR040847A1 (en) 2005-04-20
WO2004014881B1 (en) 2004-07-15
TWI341314B (en) 2011-05-01
IS7733A (en) 2005-03-09
MXPA05001594A (en) 2005-09-20
RU2352568C2 (en) 2009-04-20
CA2494987A1 (en) 2004-02-19
US7456200B2 (en) 2008-11-25
PL375256A1 (en) 2005-11-28
IL166510A0 (en) 2006-01-15
CN1894241A (en) 2007-01-10
NZ538225A (en) 2008-05-30
US20040152699A1 (en) 2004-08-05
KR20050033070A (en) 2005-04-08
RU2352568C9 (en) 2009-06-27
NO20051225L (en) 2005-05-09
RU2005106844A (en) 2005-08-27
UA87653C2 (en) 2009-08-10
CN101723941A (en) 2010-06-09
JP4637578B2 (en) 2011-02-23

Similar Documents

Publication Publication Date Title
US7456200B2 (en) Compounds
US7585881B2 (en) Additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
EP1716152B1 (en) Fused hetrocyclic compounds and their use as metabotropic receptor antagonists for the treatment of gastrointestinal disorders
KR20050039846A (en) Oxadiazoles as modulators of metabotrophic glutamate receptor-5
WO2005080379A1 (en) Triazole compounds and their use as metabotropic glutamate receptor antagonists
US7576077B2 (en) Fused heterocyclic compounds and their use as metabotropic glutamate receptor antagonists
MXPA06009020A (en) Additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
KR20070018006A (en) Additional heteropolyheterocyclic compounds and their use as metabotropic glutamate receptor antagonists
MXPA06009018A (en) Fused hetrocyclic compounds and their use as metabotropic receptor antagonists for the treatment of gastrointestinal disorders

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
B Later publication of amended claims

Effective date: 20040318

WWE Wipo information: entry into national phase

Ref document number: 166510

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2005/00886

Country of ref document: ZA

Ref document number: 200500886

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 2003259068

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 1020057002101

Country of ref document: KR

ENP Entry into the national phase

Ref document number: 2494987

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 486/DELNP/2005

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 375256

Country of ref document: PL

Ref document number: PA/a/2005/001594

Country of ref document: MX

Ref document number: 2004527872

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 538225

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 05021462

Country of ref document: CO

ENP Entry into the national phase

Ref document number: 2005106844

Country of ref document: RU

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2003785036

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 20038238454

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 1020057002101

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2003785036

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 1-2005-500253

Country of ref document: PH