IS2564B

Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists

Abstract

The present invention provides compounds and pharmaceutical compositions that act as antagonists at metabotropic glutamate receptors, and that are useful for treating neurological diseases and disorders. Method of preparing the compounds also are disclosed.

Term

No projected expiry on record.

10 claims: 2 independent, 8 dependent

1
Claims Kröfur 1, Efnasamband, eða lyfjafræðilega hæft salt þess, valið úr hópnum sem samanstendur af efnasamböndunum sem fram koma í eftirfarandi töflu:1. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds as set forth in the following table:
6
Notkun á efnasambandi úr hverri sem er af kröfum 1-4 til framleiðslunnar á samsetningu [sem] meðhöndlar sjúkdóm tengdan mGluR virkjun. 6. Use of a compound of any of claims 1-4 for the preparation of a composition treating a disease associated with mGluR activation.

Independent claims2

1,250 paragraphs in 13 sections, as filed

Description

FIELD OFThe invention [0001] The present invention provides compounds that are active at metabotropic glutamate receptors, particularly compounds that are active as antagonists at metabotropic glutamate receptors, more particularly at the mGluR5 glutamate receptor.

BACKGROUND OF The invention [0002] Recent advances in the elucidation of the neurophysiological roles of metabotropic glutamate receptors have established these receptors as promising drug targets in the therapy of acute and chronic neurological and psychiatric disorders and diseases. However, the major challenge to the realization of this promise has been the development of metabotropic glutamate receptor subtypeselective compounds.

[0003] Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate produces its effects on central neurons by binding to and thereby activating cell surface receptors. These receptors have been divided into two major classes, the ionotropic and metabotropic glutamate receptors, based on the structural features of the receptor proteins, the means by which the receptors transduce signals into the cell, and pharmacological profiles.

[0004] The metabotropic glutamate receptors (mGluRs) are G proteín-coupled receptors that activate a variety of intracellular second messenger systems following the binding of glutamate. Activation of mGluRs in intact mammalian neurons elicits one or more of the following responses: activation of phospholipase C; increases in phosphoinositide (Pl) 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 Az; increases in arachidonic acid release; and increases or decreases in the activity of voltage- and ligand-gated íon channels. Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993); Schoepp, Neurochem. Int. 24:439 (1994); Pin et al., Neuropharmacology 34:1 (1995).

[0005] Eight distinct mGluR subtypes, termed mGluRI through mGluR8, have been identified by molecular cloning. See, forexample, Nakanishi, Neuron 13:1031 (1994); Pinetal., Neuropharmacology 34:1 (1995); Knopfel etal., J. Med. Chem. 38:1417 (1995). Further receptor diversity occurs via expression of alternatively spliced forms of certain mGluR subtypes. Pin et al., PNAS 89:10331 (1992); Minakami et al., BBRC 199:1136 (1994); Joly et al., J. Neurosci. 15:3970 (1995).

[0006] Metabotropic glutamate receptor subtypes may be subdivided into three groups, Group I, Group II, and Group III mGluRs, based on amino acid sequence homology, the second messenger systems utilized by the receptors, and bytheirpharmacologicalcharacteristics. Nakanishi, Neuron 13:1031 (1994); Pinetal., Neuropharmacology 34:1 (1995); Knopfel etal., J. Med. Chem. 38:1417 (1995).

[0007] Group I mGluRs comprise mGluRI, mGluR5, and their altematively splíced vanants. The binding of agonists to these receptors results in the activation of phospholipase C and the subsequent mobilization of intracel lular calcium. Electrophysiological measurements have been used to demonstrate these effects, for example, in Xenopus oocytes that express recombinant mGluRI receptors. See, forexample, Masu et al., Nature 349:760 (1991); Pin et al., PNAS 89:10331 (1992). Similar results have been achieved with oocytes expressing recombinant mGluR5 receptors. Abe et al„ J. Biol. Chem. 267:13361 (1992); Minakami et al, BBRC 199:1136 (1994); Joly etal., J. Neurosci. 15:3970 (1995). Alternatively, agonist activation of recombinant mGluRI receptors expressed in Chinese hamster ovary (CHO) cells stimulates Pl hydrolysis, cAMP formation, and arachidonlc acid release as measured by standard biochemical assays. Aramori et al., Neuron 8:757 (1992).

[0008] By comparison, the activation of mGluR5 receptors, expressed in CHO cells, stimulates Pl hydrolysis and subsequent intracellular calcium transients, but no stimulation of cAMP formation or arachidonic acid release is observed. Abe et al., J. Biol. Chem. 267:13361 (1992). However, activation of nnGluR5 receptors expressed in LLC-PK1 cells results in Pl hydrolysis and increased cAMP formation. Joly et al., J. Neurosci. 15:3970 (1995). The agonist potency profile for Group I mGluRs is quisqualate > glutamate = ibotenate > (2S, 1'S,2'S)-2-carboxycyclopropyl)glycine (L-CCG-I) > (!S,3fíj-l -aminocyclopentane-1,3-dicarboxyllc acid (ACPD). Qulsqualate Is relatively selective for Group I receptors, as compared to Group II and Group III mGluRs, but it also is a potent activator of ionotropic AMPA receptors. Pin et al., Neuropharmacology 34:1, Knopfel et al„ J. Med. Chem. 38:1417 (1995).

[0009] The lack of subtype-specific mGluR agonists and antagonists has impeded elucidation of the physiological roles of particular mGluRs, and the mGluR-associated pathophysiologlcal processes that affect the CNS have yet to be defined. However, work with the available non-specific agonists and antagonists has yielded some general insights about the Group I mGluRs as compared to the Group II and Group III mGluRs.

[0010] Attempts at elucidating the physiological roles of Group I mGluRs suggest that activation of these receptors elicits neuronal excitation. Various studies have demonstrated that ACPD can produce postsynaptic excitation upon application to neurons in the hippocampus, cerebral cortex, cerebellum, and thalamus, as well as other brain regions. Evidence indicates that this excitation is due to direct activation of postsynaptic mGluRs, but it also has been suggested thatactivationofpresynapticmGluRsoccurs, resulting inincreasedneurotransmitterrelease, Baskys.TrendsPharmacol. Sci. 15:92 (1992); Schoepp, Neurochem. Int. 24:439 (1994); Pin et al., Neuropharmacology 34:1 (1995).

[0011] Pharmacological experíments implicate Group I mGluRs as the mediators of this excitatory mechanism. Tlie effects of ACPD can be reproduced by low concentrations of quisqualate in the presence of ÍonotrophicGluR antagonists. Hu et al., Brain Res. 568:339 (1991); Greene et al., Eur. J. Pharmacol. 226:279 (1992). Two phenylglycine compounds knowntoactivatemGluR1,namely (S)-3-hydroxyphenylglycine(('S>3HPG)and(S)-3,5-dihydroxyphenylglycine((S/DH-PG), also produce excitation. Watkins et al., Trends Pharmacol. Sci. 15:33 (1994). In addition, the excitation can be blocked by (S>4-carboxyphenylglycine ((S/-4CPG), (S/4-carboxy-3-hydroxyphenylglycine ((SJ-4C3HPG), and (+)-al-pha-methyl-4-carboxyphenylglycine ((+)-MCPG), compounds known to be mGluRI antagonists. Eaton et al., Eur. J. Pharmacol. 244:195 (1993); Watkins et al., Trends Pharmacol. Sci. 15:333 (1994).

[0012] Metabotropic glutamate receptors have been Implicated in a number of normal processes in the mammalian CNS. Activation of mGluRs has been shown to be required for induction of hippocampal long-term potentiation and cerebellar long-term depression. Bashir et al., Nature 363:347 (1993); Bortolotto et al., Nature 368:740 (1994); Aiba et al., Cell 79:365 (1994); Aiba et al., Cell 79:377 (1994). A role for mGluR activation in nociception and analgesia also has been demonstrated. Melleret al., Neuroreport 4: 879 (1993). 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, olf actory memory, central control of cardiac activity, waking, motorcontrol, and control of the vestibulo-ocular reflex. Generally, see Nakanishi, Neuron 13:1031 (1994); Pin eí al., Neuropharmacology 34:1; Knopfel et al„ J. Med Chem. 38:1417 (1995).

[0013] Metabotropic glutamate receptors also have been suggested to play roles in a variety of pathophysiological processes and disease states affecting the CNS. These include stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, epilepsy, and neurodegenerative diseases such as Alzheimer’s disease. Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993); Cunningham etal., LifeSci. 54:135 (1994); Hollman etal., Ann. Rev. Neurosci. 17:31 (1994); Pin et al., Neuropharmacology 34:1 (1995); Knopfel et al., J. Med. Chem. 38:1417 (1995). Much of the pathology in these conditions is thought to be due to excessive glutamate-induced excitation of CNS neurons. Because Group I mGluRs appear to increase glutamate-mediated neuronal excitation via postsynaptic mechanisms and enhanced pre-synaptic 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.

[0014] Prelimlnary studies assessing therapeutic potentials with the available mGluR agonists and antagonists have yielded seemingly contradictory results. For example, it has been reported that application of ACPD onto hippocampal neurons leads to seizures and neuronal damage (Sacaan et al., Neuroscl. Lett. 139:77 (1992); Lipparti et al., Life Sci. 52:85 (1993). Other studies indicate, however, that ACPD inhibits epileptiform activity, and also can exhibit neuropro-tective properties. Taschenberger et al., Neuroreport 3:629 (1992); Sheardown, Neuroreport 3:916 (1992); Koh et al., Proc. Natl. Acad Sci. USA 88:9431 (1991); Chiamulera et al„ Eur. J. Pharmacol. 216:335 (1992); Siliprandi et al., Eur. J. Pharmacol. 219:173 (1992); Pizzi et al„ J. Neurochem. 61:683 (1993).

[0015] It ís líkely that these conflicting results are due to the lack of selectivity of ACPD, which causes activation af several dlfferent mGluR subtypes. In the studies finding neuronal damage it appears that Group I mGluRs were activated, thereby enhancing undesirable excitatory neurotransmission. In the studies showing neuroprolective effects it appears that activation of Group II and/or Group III mGluRs occurred, inhibiting presynaptic glutamate release, and diminishing excitatory neurotransmission.

[0016] This interpretation is consistent with the observation that [S)-4C3HPG, a Group I mGluR antagonist and Group II mGluR agonist, protects against audiogenic seizures in DBA/2 mice, while the Group II mGluR selective agonists DCG-IV and L-CCG-I protect neurons from NMDA- and KA-induced toxicity. Thomsen et al., J. Neurochem. 62:2492 (1994); Bruno et al., Eur. J. Pharmacol. 256:109 (1994); Pizzi et al., J. Neurochem. 61:683 (1993).

[0017] WO98/17652 discloses aseriesofoxadiazoleswhich have affinityfor all kinds of receptors, including histamine H1,5-HT1,5-HT2A, and which are useful in the treatment of neurodegenerative disorders and cerebral ischaemia.

[0018] Based on the foregoing, it Is clearthat a lack of potency and selectivity llmits the value of the mGluR agonists and antagonists now availabl e. I n addition, most currently available compounds are amino acids or amino-acid derivatives which have limited bioavailabilities, thereby hampering in vivo studies to assess mGluR physiology, pharmacology, and therapeutlc potentia I. On the other hand, compounds that select ive ly inhibit activation of metabotropic glutamate receptor Group I subtypes are indicated for treatment of neurological disorders and diseases sucb as senile dementia, Parkinson’s disease, Alzheimer's disease, Huntington’s Chorea, pain, epilepsy, head trauma, anoxic and ischemic injuries, and psychiatric disorders such as anxiety, schizophrenia and depression.

[0019] Accordingly, a need exists for potent mGluR agonists and antagonists that display a high selectivity for a mGluR subtype, particularly a Group I receptor subtype.

[0020] Thepresent invention, provides metabotopic glutamate receptor-active compounds, which exhibita high degree of potency and selectivity for individual metabotropic glutamate receptor subtypes, and processes of making these compounds.

[0021 ] Further, this invention providespharmaceutical compositions containing compounds which exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor subtypes, and to provide methods of making these pharmaceutical compositions.

[0022] Another object of The invention is to provide methods of inhibiting activation of an mGluR Group I receptor, specif ically mGluR5. In particular, a medical condition associated with metabotropic glutamate receptors includes: stroke; head; trauma; anoxic injury; ischemic injury; hypoglycernia; epilepsy; pain; migraine headaches; Parkinson's disease; senile dementia; Huntington's Chorea; and Alzheimebs disease.

[0023] The invention provides methods of treating a disease associated with excitatory activation of an mGluR Group I receptor and of inhibiting neuronal damage caused by excitatory activation of an mGluR Group I receptor, specifically wherein the mGluR Group I receptor is mGluR5 Finally, the present invention provides potent antagonists of Group I mGluRs, specifically mGluR5.

[0024] In a first aspect, The invention concerns a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds as set forth in the following table:

<img file="IS2564B_D0007.tif" /> [0025] In specific embodiments of The invention, the compounds of formula II indude:

4-(3-Cyanophenyl)-1 -(2-pyridyl)-1 H-imidazole (B151) 1-(3-Cyanophenyl)-4-(2-pyridyl)-1 H-imidazole (B152).

Testing of compounds for mGluR Group I antagonist activity [0026] The pharmacological properties of the compounds of The invention can be analyzed using standard assays for functional activity. Examples of glutamate receptor assays are well known in the art, for example, see Aramori et al., Neuron 8:757 (1992); Tanabe et al., Neuron 8:169 (1992); Miller et al„ J. Neuroscience 15: 6103 (1995); Balazs, etal., J. Neurochemistry 69:151 (1997). The methodology described In those publications is incorporated herein by reference. [0027] Conveniently, the compounds of The invention can be studied by means of an assay that measures the mobilization of intracellular calcium, (Ca2+]j in cells expressing mGluR5 that can bind the compounds. A well-known cell line which is suitable for this purpose is described in Miller et al., J. Neuroscience 15: 6103 (1995), the contents of which are hereby incorporated by reference. It has been shown that exposure to rat astrocytes to the growth factors, basic f ibroblast growth factor, EGF, or transforming growth factor-α markedly increased the protein expression and functional activity of endogenous mGluR5 (Míller et al., J. Neuroscience, 15(9): 6103-6109,1995).

[0028] In brief, primary astrocyte cultures were prepared f rom 3-5 day old Sprague-Dawley rat pups using a modification of Miller et al. were plated on poly-L lysine coated flasks in Dulbecco's modified Eagle's medium (DMEM) containing fetal calf serum (FCS). For cuvette analysis, cultures were up-regulated with growth factors in flasks for 3-5 days, then harvested and prepared for measurement of [Ca2+]. mobilization as previously described (Nemeth et al., 1998).

[0029] For FLIPR analysis, cells were seeded on poly-D lysine coated clear bottom 96-well plates with black sides and analysis of [Ca2+]j mobilization was performed 3 days followlng the growth factor up-regulation.

[0030] 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 180 μΙ. of buffer present in each well of the cell plate. After each addition of compound, the fluorescence signal was sampled 50 times at 1 second intervals followed by 3 samples at 5 second intervals. Responses were measured as the peak height of the response within the sample period.

[0031] ECso and IC50 determinations were made from data obtalned from 8 point concentration response curves (CRC) performed in duplicate. Agonist CRC were generated by scaling all responses to the maximal response observed for the plate. Antagoníst block of the agonist challenge was normalized to the average response of the agonist challenge in 14 control wells on the same plate. A detailed protocol for testing the compounds of The invention is provided below at Example 6.

Preparation of pharmaceutical compositions containing rnGluR antagonists, and their use in treating neurological disorders [0032] The compounds of the present invention may be useful for treating neurological disorders or diseases. While these compounds typically will be used in therapy for human patients, they also can be used in veterinary medicine, to treat simila r or identical diseases.

[0033] In therapeutic and/or diagnostic applications, the compounds of The invention can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in REMINGTON'S PHARMACEUTICAL SCIENCES (18th ed.), Mack Publishing Co. (1990).

[0034] The compounds accordingtoThe invention are effective overa widedosage range. Forexample, in Ihe treatment

ot adult humans, dosages from about 0.01 to about 1000 mg, preferably from about 0.5 to about 100 mg, per day may be used. A most preferable dosage is about 2 mg to about 70 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0035] Pharmaceutically acceptable salts are generally well known to those of ordinary skíll in the art, and may include, by way of example but not limitation, acetate, benzenesulfonate, besylate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycol lylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (em-bonate), pantothenate, phosphate/disphosphate, polygalacturonate, salicy late, stearate, subacetate, succinate, sulfate, tannate, tartrate, or teoclate. Other pharmaceutically acceptable salts may be found, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES (18th ed.), supra.

[0036] Preferred pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate, pamoate (embonate), phosphate, sali-cylate, succinate, sulfate, or tartrate.

[0037] Depending on the specific conditions being treated, such agents may be formulated into liquid or solid dosage fomns and administered systemically or locally. The agents may be delivered, for example, in a timed- or sustained-release form as is known to those skilled in the art. Techniques for formulation and administration may be found in REMINGTON’S PHARMACEUTICAL SCIENCES; (18th ed.), sapra. Suitable routes may include oral, buccal, sublingual, rectal.transdermal, vaginal,transmucosal,nasalorintestinal administration;parenteraldelivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, in-tranasal, or intraocular injections, interalia.

[0038] For injection, the agents of The invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0039] Use of pharmaceutically acceptable carríers to formulate the compounds hereín disclosed for the practice of The invention into dosages suitable for systemic administration is within the scope of The invention. With proper choice of carrier and suitable manufacturing practice, the compositions of the present invention, in particular, those formulated as solutions, may be administered parenterally, such as by intravenous Injection. The compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the compounds of The invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.

[0040] Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determinatíon of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0041 ] In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries whlch facilltate processing of the active compounds into preparations which can be used pharmaceutically. The preparations formiilated for oral administration may be in the form of tablets, dragees, capsules, or solutions.

[0042] Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulti ng mixture, and processing the mixture of granules, after adding s uitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl-cellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents may be added, such as the cross-linked polyvinyIpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0043] Dragee cores are provided with suitablecoatings. Forthis purpose, concentrated sugarsolutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glyco! (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments may be added to the tablets or dragee coatings for Identiflcation or to characterize different combinations of active compound doses.

[0044] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticízer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft xapsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added.

[0045] The present invention wlll be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.

[0046] In the examples, examples preparing compounds B57 - B152 are according to The invention, while the remaining examples are reference examples.

Preparation of mGluR Group I antagonists [0047] Many starting materials for preparing the compounds of the present invention are available from commercial sources, such as Aldrich Chemical Company (Milwaukee, Wl). Moreover, compounds of The invention are readily pre-pared, from available precursors, using straightforward transforniations which are well known in the art. The skilled artisan will recognize that mGluR Group I antagonists, according to The invention, can be prepared via methodology that is well known, using widely recognized techniques of organic chemistry. Suitable reactions are described in standard textbooks of organic chemistry. For example, see March, ADVANCED ORGANIC CHEMISTRY, 2d ed., McGraw Hill (1977).

[0048] More specifically, compounds of The invention generally can be prepared by formation of the G moiety between two precursor compounds containing suitable Ar1 and Ar2 moieties. When the linker contains a 1,2,4-oxadiazole, the heterocycle may be tormed using well known techniques, such as reaction between an amidoxime and an acid chloride, or by the reaction of an amidoxime and an acylimidazote. An illustration of such a transformation is provided in Examples 4 and 5, below.

[0049] Arrildoximes can be prepared using well known techniques by the reaction of an Ar1 substituted nitrile with hydroxylamine, An illustration of such a transformation is provided below in Example 1.

[0050] In most cases, the precursor Ar2 acid chlorides are readily available, or may be prepared using straightforward techniques of organic chemistry. For example, carboxylic acids may be converted into the corresponding acid chlorides by reaction with, for example, thionyl chloride or oxalyl chloride.

[0051] In the case where the linker contains a 1,3-oxazole, compounds were prepared using a procedure similar to that given by Kelly et al,, J. Org. Chem. 61,4623-4633 (1996). Thus, 3,5-disubstituted-1,3-oxazoles were prepared by mixing a haloketone with carboxamide in refluxing toluene for 3 days. The resulting mixture was allowed to cool to room temperature, the solvent was removed and the residue was purified.

[0052] Scheme 1 illustrates a method for synthesizing compounds of the present invention. In particular, the method il lustrated by scheme 1 is used for making the following exemplif ied compounds: B77-B81, B86, B89, B101, B108, B115, B120-B122, B124, B129-B141.

Scheme 1 ' <img file="IS2564B_D0009.tif" /> [0053] Scheme 2 illustrates another method for synthesizlng compounds of the present invention. In particular, the method of scheme 2 is used to make the exemplified compound B144.

Scheme 2 <img file="IS2564B_D0010.tif" /> [0054] Scheme 3 illustrates a further method for synthesizing compounds of the present invention. In particular, the method of scheme 3 is used to make the following exemplified compounds: B57-B76, B82-B85, B87, B88, B90, B91, B93-B100, B102-B107, B109-B114, B116-B119, B123, B125-B128, B142, B143.

Scheme3 <img file="IS2564B_D0013.tif" /> [0055] Other compounds of the present invention may readily be prepared by modiflcations to the reactions exemplified in the Schemes above, as will be appreciated by the skilled artisan.

EXAMPLES

General Experimental Methods [0056] Capillary gas chromatographic and mass spectral data were obtained using a Hewlett-Packard (HP) 5890 Series II Gas Chromatograph coupled to an HP 5971 Series Mass Selective Detector [Ultra-2 Ultra Performance Capillary Column (crosslinked 5% PhMe silicone); column length, 25 m; column i.d., 0.20 mm; helium flow rate, 60 mL/min; injector temp., 250 ’C; temperature program, 20 'C/min from 125 to 325 'C for 10 min, then held constant at 325 ’C for 6 min]. Thin-layer chromatography was performed using Analtech Uniplate 250-μΓΠ sillca gel HF TLC plates. UV light sometimes in conjunction with ninhyd rin and Dragendorlf’s spray reagents (Sigma Chemlcal Co.) were used for detecting compounds on the TLC plates. Most reagents used in reactions were purchased from the Aldrich Chemical Co. (Milwaukee, Wl), Sigma Chemical Co. (Saint Louis, MO), Fluka Chemical Corp. (Milwaukee, Wl), Fisher Scientific (Pittsburgh, PA), TCI America (Portland, OR), or Lancaster Synthesis (Windham, NH).

Example 1: Synthesis of Amidoxime Intermediates

Pyrid-2-ylamidoxíme [0057] <img file="IS2564B_D0014.tif" /> [0058] Using the general procedure of Shine et al., J. Heterocyclic Chem. (1989) 26:125-128, hydroxylamine hydrochloride (7.65 g, 110 mmol) in ethanol (100 mL) was treated with a 10N solution of sodium hydroxide (11 mL, 110 mmol). A precipitate quickly formed and the reactlon mlxture was stirred at room temperaturefor30 min. The inorganic precipitate was filtered and rinsed with ethanol (100 mL). The filtrate and ethanol washings were combined and treated with 2-cyanopyridine (10.4 g, 100 mmol). The reaction mixture was then heated at reflux for 20 hours. After cooling, the volatiles were removed in vacuo, to afford 13.3 g (97%) of pyrid-2-ylamidoxime.

5-M ethy l-pyrid-2-yla midoxime [0059]

<img file="IS2564B_D0017.tif" /> [0060] A mixture of 2-bromo-5-methylpyridine (2.001 g, 11.63 mmol), zinc cyanide (830 mg, 7 mmol), zinc (dust, 35 mg, 0.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropaJladiumfll), complex with dichloromethane (1:1) (192.5 mg, 0.24 mmol) in /V,/V-dimethylformarnide (10 mL) was heated at reflux for 16 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. The organic solution was filtered through a plug of silica gel, washing dichloromethane. Removal of the solvent in vacuo, afforded 7-70 mg (56%) of 5-methyl-2-cyano-pyridine.

[0061] Using the general procedure for the synthesis of amidoximes, 5-methyl-2-cyano-pyridine (770 mg, 6.5 mmol), 5M hydroxylamine hydrochloride (1.5 mL, 7.5 mmol) in ethanol (10mL), and 10/Vsodium hydroxide (0.75 mL, 7.5 mmol), were heated at reflux for 18 hours. Standard work up afforded 594 mg (60%) of 5-methylpyrid-2-ylamidoxime.

5-Cyanopyrid-2-ylamidoxime [0062]<img file="IS2564B_D0018.tif" /> [0063] In a símilar fashion, a mixture of 2,5-dicyanopyridine (740mg, 5.74 mmol), 5M hydroxyamine hydrochloride (1.15 mL, 5,75 mmol) and 1M sodium hydroxide (5.74 mL, 5.74 mmol) in ethanol (10 mL) was heated at 80 ’C for 5 minutes. The precipitate was collected by filtration to afford 555 mg (60%) of 5-cyanopyrid-2-ylamidoxime.

5-Fluoropyrid-2-ylamidoxime [0064]<img file="IS2564B_D0019.tif" /> [0065] A mixture of 2-cyano-5-chloropyridine (1 g, 7.22 mmol) and potassium fluoride (1.26 g, 21.68 mmol) in 1 -methyl-2-pyrrolidinone (25 mL) was heated at reflux for 18 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. The organic solvents were then removed in vacuo. Silica gel chromatography of the residue aflorded 425 mg (48%) of 2-cyano-5-fluoropyridine.

[0066] Using the general procedure for the synthesis of amidoximes, 2-cyano-5-fluoropyridine (425 mg, 3.48 mmol), 5M hydroxylamine hydrochloride (0.79 ml, 3.95 mmol) in ethanol (5 mL), and 10N sodium hydroxide (0.398 mL, 3.98 mmol) were heated at reflux for 24 hours. Standard work up afforded 330 mg (61 %) of 5-fluoropyrid-2-ylamidoxime.

5-Tert-Butoxycarbonyl-pyrid-2-ylamidoxime [0067]

<img file="IS2564B_D0023.tif" /> [0068] A suspension of 6-cyanonicotinic acid (535 mg, 3.6 mmol) in dichloromethane (8 mL) at 0 ’C was treated with 2M oxalyl chloride (3.6 mL, 7.2 mmol, dichloromethane) and a catalytic amount of N,W-dimethylformamide. The reaction was then stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue dissolved in dichloromethane (10 mL). The resulting solution was treated with pyridine (2 mL) and tert-butanol (0.8 mL) and the reaction mixture stirred overnight at room temperature. The reaction mixture was diluted with dlchloromethane (200 mL) and washed sequentially wiffi saturated sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. Silica gel chromatography, using a gradient of 5% to 10% ethyl acetate in hexane, afforded 623 mg (84%) of 5-tert-butoxycarbonyl-2-cyano-pyridine, as ayellow solid. [0069] Usingthe general procedureforthesynthesisof amidoximes, 5-tert-butoxycarbonyl-2-cyano-pyridíne (623 mg, 3.05 mmol) and 5M hydroxylamine hydrochloride (0.69 mL, 3.4 mmol) in ethanol (7 mL) and 10/V sodium hydroxide (0.34 mL, 3.4 mmol), were heated at reflux for 18 bours. Standard work up afforded 570 mg (79%) of 5-tert-butoxycar-bonylpyrid-2-ylamidoxime.

3-Cyano-5-methoxypyrid-2-ylamidoxime [0070] <img file="IS2564B_D0024.tif" /> [0071] A solution of dimethyl-5-hydroxyisophthalate (6 g, 28.6 mmol) and potassium carbonate (9 g, 65.4 mmol) in acetone (120 mL) was prepared. To this, methyl iodide (4 mL, 63.7 mmol) was added and the reactlon was left stirring overnight at ambient temperature. The reaction mixture was filtered and then concentrated. The residue was dissolved in ethyl acetate and washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. 6.4 g (quantitative) of dimethyl-5-methoxy-isophthalate was isolated as an off-white solid.

[0072] A solution of dimethyl-5-methoxy-isophthalate (2.5 g, 11.1 mmol) in tetrahydrofuran/methanol (56 mU20 mL) was treated with 2.0 N sodium hydroxide (12 mL, 25 mmol). The reaction was left stirring for 15 hours at room temperature. After the solution was concentrated, the solid was dissolved in water and acidified with 2.0 N hydrogen chloride. Ethyl acetate was used to extract the p recip itate, which was then washed with brine and dried over anhydrous sodium sulphate. Afier removal of solvent in vacuo, a total of 2.5 g (quantitative) of 5-methoxyisophthalic acid was isolated.

[0073] A solution of 5-methoxyisophthalic acid (2.5g, 13.8 mmol) in dichloromethane (20 mL) was treated with 2M oxalyl chloride (38 ml, 76.6mmol) and a few draps of DMF. After stirring for 17 hours, the reaction was concentrated in vacuo and then the resulting brown oil was transferred into a cold, stirred solution of ammonium hydroxide ín ethyl acetate (70ml7200mL) with a small amount of dichloromethane. The reaction was allowed to proceed for 1 hour, after which a precipitate formed. Water (100 mL) and ethyl acetate (1500 mL) were combined with the reaction in a separatory funnel, and the organic layer was collected, washed with brine and dried over sodium sulphate. The remaining solid in the aqueous layer was i solated by filtration, washed wlth water, and dried. The organic layer was f iltered and concentrated and then triturated with hexanes. A total of 2.5g (quantitative) of the 5-methoxyisophthalamide was isolated.

[0074] A suspension of the 5-methoxyisophthalamide (3.1 g, 16 mmol) in a dichloromethane (27 ml) at 0 'C was treated with pyridine (5.2 mL, 65 mol) and then trifluoroacetic anhydride drop-wise (5.4 mL, 39 mmol). The reaction was stirred at 0 'C for 20 minutes and then stirred overnight at ambient temperature. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, íiltered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane afforded 940 mg (46%) of the 5-methoxy isophthalon itrile as a white solid.

[0075] Using the general procedure for the synthesis of amidoximes, 5-methoxyisophthalonitrile (600 mg, 3.8 mmol), 5M hydroxylamine hydrochloride (0.76 ml, 3.8 mmol) in ethanol (6 mL), and INsodium hydroxide (3.8 mL, 3.8 mmol) were heated at reflux for 3 hours. Standard work up and column chromatography using 30-40 % ethyl acetate/hexanes afforded 329 mg (45%) of 3-cyano-5-methoxyphenyl-amidoxime.

3-Cyano-5-fluorophenylamidoxime [0076] <img file="IS2564B_D0027.tif" /> [0077] 5-Fluoro-isophthalonítrile (730 mg, 5 mmol) and 5M hydroxylamine hydrochloride (1 mL, 5 mmol) in ethanol (10 mL) and 1 /Vsodium hydroxide (5 mL, 5mmol), wereheated at reflux for30 minutes. Standard work up followed by column chromatography afforded 473 mg (52.8%) of 3-cyano-5-fluorophenylamidoxime

5-Bromopyrid-3-yl-amidoxime [0078] <img file="IS2564B_D0028.tif" /> [0079] 5-Bromonicotinonitrile (982 mg, 5.4 mmol) and 5M hydroxylamine hydrochloride (1.098 mL, 5.4 mmol) in ethanol (5 mL) and 1 N sodium hydroxide (5.4 mL, 5.4 mmol), were heated at reflux for 5 minutes. Standard work up afforded 925 mg (79.3%) of 5-bromopyrid-3-yl-arriidoxime.

3-Cyano-5-methylphenylamidoxime [0080] <img file="IS2564B_D0029.tif" /> [0081] 3,5-Dicyanotoluene (1000 mg, 7.04 mmol) and 5M hydroxylamine hydrochloride (1.4 mL, 7.04 mmol) in ethanol (5 mL) and 1 Nsodium hydroxide (7.04 mL, 7.04 mmol), were heated at reflux for 12 minutes. Standard work up tollowed by column chromatography afforded 215 mg (17.4%) of 3-cyano-5-methylphenylamidoxime.

3-Cyanophenylamidoxime [0082] <img file="IS2564B_D0033.tif" /> [0083] Isophthalonitrile (640 mg, 5 mmol) and 5M hydroxylamine hydrochloride (1 mL, 5 mmol) in ethanol (5 mL) and 1 N sodium hydroxide (5 mL, 5 mmol), were heated at reflux for 2.5 hours. Standard work up followed by column chromatography afforded 650 mg (80.7%) of 3-cyanophenylamidoxime.

3-lodophenylamidoxime [0084] <img file="IS2564B_D0034.tif" /> [0085] 3-lodobenzonitrile (1145 mg, 5 mmol) and 5M hydroxylamine hydrochloride (1 mL, 5 mmol) in ethanol (5 mL) and 1 N sodium hydroxide (5 mL, 5 mmol), were heated at reflux for 2.5 hours. Standard work up followed by column chromatography afforded 920 mg (70.2%) of 3-iodophenylamidoxime.

3-Cyano-5-dimethylaminophenylamidoxime [0086] <img file="IS2564B_D0035.tif" /> [0087] 5-Dlmethylaminoisophthalonitrile (856 mg, 5 mmol) and 5M hydroxylamine hydrochloride (1 mL, 5 mmol) in ethanol (10 mL) and 1 /Vsodium hydroxide (5 mL, 5 mmol), were heated at reflux for 30 minutes. Standard work up followed by column chromatography afforded 280 mg (27.4%) of 3-cyano-5-dimethylaminophenylamidoxime.

6-Cyano-pyrid-2-yl-a midoxime [0088]

<img file="IS2564B_D0039.tif" /> [0089] 2,6-Dictanopyridine (3.87 g, 30 mmol) and 5M hydroxylamine hydrochloride (6 mL, 30 mmol) in ethanol (50 mL) and 1 N sodium hydroxide (30 mL, 30 mmol), were heated at reflux for 10 minutes. Standard work up followed by column chromatography afforded 2.87 g (59%) of 6-cyano-pyrid-2-yl-amidoxime.

3-Bromo-5-fluorophenylamidoxlme [0090] <img file="IS2564B_D0040.tif" /> [0091 ] 3-Bromo-5-fluorobenzonitrile (1.9 g, 9.5 mmol) and 5M hydroxylamine hydrochlo ride (4 mL, 20 nninol) in ethanol (20 mL) and 1 /Vsodium hydroxide (20 mL, 20 mmol), were heated at reflux for 1 hour. Standard work up followed by column chromatography afforded 721 mg (32.6%) of 3-bromo-5-fluorophenylamidoxime.

3-Fluoro-5-methoxyphenylamidoxime [0092] <img file="IS2564B_D0041.tif" /> [0093] 3-Fluoro-5-methoxybenzonitrile (379 mg, 2.5 mmol) and 5M hydroxylamine hydrochloride (0.5 mL, 2.5 mmol) in ethanol (2.5 mL) and 1 N sodium hydroxide (2.5 mL, 2.5 mmol), were heated at reflux for 1 hour. Standard work up afforded 431 mg (93.4%) of 3-fluoro-5-methoxyphenylamidoxime.

5-fluoro-3-(thiomethyl)benzoic acid [0094]

<img file="IS2564B_D0045.tif" /> [0095] 1 -Bromo-3,5-diíluorobenzene (1.00 g, 5.18 mmol) was dissolved in anhydrous DMF (10 ml). The solutlon was chilled in an ice bath, and NaSMe (0.36 g, 5.18 mmol) was added. After 30 minutes the reaction mixture was poured into water (100 mL) and extracted with hexanes. The organic phase was washed with waterand brine, dried (MgSO4), filtered, and concentrated to provide the title compound as a colourless oil. The crude product was used directly in the next step. Using the standard cyanation procedure, 5-cyano-3-fluoro-1-(thiomethyl)benzene was prepared as a yellow oil. The crude product was used directly in the next step. Using the standard saponification procedure, the title compound was prepared in 0.60 g yield (63% over 3 steps) as a colourless solid.

3-FI uoro-5-(1 H-imidazol-1 -yl)benzoic acid [0096]<img file="IS2564B_D0046.tif" /> [0097] 1 -Bromo-3,5-difluorobenzene (1.00 g, 5.18 mmol) wasdissolved ir. anhydraus DMF (10 mL). The solution was chilled in an ice bath. Imidazole (0.36 g, 5,18 mmol) and K2CO3 (0.72 g, 5.18 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours, and at 80 'C for 24 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filte red, and concentrated. The intermediate 3-Fluoro-5-Bromo-(1 H-imidazol-1-yl)-benzene was used directly in the next step. Using the standard cyanation procedure, 3-Fluoro-5-cyano-(1 H-imidazol-1-yl)-benzene was prepared as a colourless solid. The crude product was used directly in the next step. Using the standard saponification procedure, the title compound was prepared as a colourless solid. The crude product was used directly in the next step,

3-lodo-5-T rifluoromethylbenzoic acid [0098] <img file="IS2564B_D0047.tif" /> [0099] The title product was prepared according to the literature procedure (Fujikí, Kanji; Kashiwagi, Mitsuyoshi; Miyamoto, Hideyuki; Sonoda, Akinari; lchikawa, Junji; et al J.FIuorine Chem. 1992, 57, 307-321) from 3,5-bis(trifluor-omethyl)benzene (7.3 mL, 47 mmol) and iodine (11.95 g, 47 mmol) in 30% oleum (30 mL) at 55 degrees for 15h. Quenching with ice was followed by extraction of the crude product into ether, sequential washing of the aqueous layer with sodium sulfite (1M) and water. Sodium hydroxide (1N, ~ 150 mL) was added to the crude ether solution until pH basic, the layers were separated and the aqueous layer was then acidified using HCI (12N, -10 mL, pH acidic). Extraction

into ether followed by drying over magnesium sulfate yielded the crude acid (4.3 g, 29%). The material was insuff icient ly pure for use, so the product was esterified using acetyl chloride in methanol, purified using flash chromatography (silica gel, 20% dichloromethane in hexane) and hydrolyzed with sodium hydroxide in methanol yielding 2.95 g (69%) of pure

3-iodo-5-T rifluoromethylbenzoic acid.

3-Allyloxy-5-cyanobenzoic acid [0100]<img file="IS2564B_D0051.tif" /> [0101 ] A suspension of 3-allyloxy-5-(methoxycarbonyl)benzoic acid (5.5 mg, 23 mmol) in thionyl chloride (30 mL) was heated at reflux for 2 hours. The excess thionyl chloride was then removed in vacuo and the intermediate acid chloride dissolved in dichloromethane (25 mL). After cooling to 0 'C the solution was treated with 0.5 M ammonia in 1,4-dioxane (100 mL) and then allowed to warm to room temperature. After 2 hours of stirring the solvent was removed in vacuo and the residue was titurated with water. The precipitate was collected, washed with water, and dried in vacuo to afford the 5.0 g (92 %) of methyl 3-(allyloxy)-(5-aminocarbonyl)benzoate as a white solid.

[0102] Asuspension of methyl 3-(allyloxy)-(5-aminocarbonyl)benzoate (5.0 g, 21 mmol) in a dlchloromethane (70 mL) at 0 ‘C was treated with pyridine (3.5 mL, 43 mmol) and then trifluoroacetic anhydnde drop-wise (3.6 mL, 25 mmol). The reaction was stirred at 0 ‘C for 20 minutes and then stirred overnight at ambient temperature. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography using a 10 % ethyl acetate/hexanes afforded 3.8 g (81 %) of methyl 3-(allyloxy)-5-cyanobenzoate as a white solid.

[0103] A solution of methyl 3-(allyloxy)-5-cyanobenzoate (1.5 g, 6.9 mmol) in methanol-tetrahydrofuran (1:2, 30 mL) was treated with 0.5 N lithium hydroxide (17 mL, 8.3 mmol). The reaction was stirred at 70'C for 30 minutes and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH ~ 4) by the addition of 2N hydrogen chloride. The precipitate was collected and dried to afford 1.0 g (74%) of 3-allyloxy-5-cyanobenzoic acid as a whlte solid.

3-Cyano-5-propoxybenzoic acid [0104] <img file="IS2564B_D0052.tif" /> [0105] A suspension of 3-allyloxy-5-(methoxycarbonyl)benzoic acid (5.5 mg, 23 mmol) in thionyl chloride (30 mL) was heated at reflux for 2 hours. The excess thionyl chloride was then removed in vacuo and the intermediate acid chloride dissolved in dichloromethane (25 mL). After cooling to 0 ‘C the solution was treated with 0.5 M ammonia in 1,4-dioxane (100 mL) and then allowed to warm to room temperature. After 2 hours of stirring the solvent was removed in vacuo and the residue was titurated with water. The precipitate was collected, washed with water, and dried in vacuolo afford the 5.0 g (92 %) of methyl 3-(allyloxy)-(5-aminocarbonyl)benzoate as a white solid.

[0106] Methanol (20 mL) and dichloromethane (20 mL) were added to round bottom flask that contained methyl 3-(allyloxy)-(5-aminocarbonyl)benzoate (2.0 g, 8.5 mmol) and palladium(10 wt.% on activated carbon, 200 mg) under argon. The flask was evacuated using a water aspirator and then filled with hydrogen from a balloon. The balloon filled was hydrogen was attached to the flask as the reaction stirred for 2 hours. The palladium on carbon was remove by filtration through celite. The solvent was removed using a roto-evaporator and then the sample was dded under vacuum

to afford 2.0 (97%) of methyl 3-(aminocarbonyl)-5-propoxybenzoate as a white solid.

[0107] A suspension of methyl 3-(aminocarbonyl)-5-propoxybenzoate (2.0 g, 8.2 mmol) in a dichloromethane (25 mL) at 0 'C was treated with pyridine (1.3 mL, 17 mmol) and then trif luoroacetic anhydride dropwise (1.4 mL, 9.9 mmol). The reaction was stirred at 0 'C for 20 minutes and then stirred overnight at ambient temperature. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodíum sulfate, filtered and concentrated. Silica gel chromatography using a 40 % dichloromethane/hexanes afforded 1.5 g (84%) of methyl 3-cyano-5-propoxybenzoate as a white solid.

[0108] A solution of methyl 3-cyano-5-propoxybenzoate (1.5 g, 6.8 mmol) in methanol-tetrahydrofuran (1:2, 30 mL) was treated with 0.5 M lithium hydroxide (16 mL, 8.2 mmol). The reaction was stirred at 70'0 for 30 minutes and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH - 4) by the addition of 2/Vhydrogen chloride. The precipitate was collected and dried to afíord 1.2 g (86%) of 3-cyano-5-propoxybenzolc acid.

3-Cyano-5-nitrobenzoic acid [0109]<img file="IS2564B_D0055.tif" /> [0110] Using the same procedure as for 3-allyloxy-5-cyanobenzolc acid,

3-cyano-5-nitrobenzoic acid (2.0 g, 10.7 mmol) was prepared from monomethyl 5-nitroisophthalate (5.0 g, 22 mmol).

3-Cyano-5-dimethylaminobenzoic acid [0111] <img file="IS2564B_D0056.tif" /> [0112] Methyl 3-cyano-2-nitrobenzoate (6.0g, 29 mmol) and tin(ll) chloride dihydrate (26 g, 12 mmol) in methanol (100 mL) were heated at reflux for 3 hours. The reaction mlxture was transferred into a 1L Erlenmeyer flask equipped with a stirring barand containing ice. While stirring the reaction mixture, 1N sodium hydroxide was added until pH - 4-5. At this point solid sodium bicarbonate was added until pH - 8. The mixture was transferred to a separatory funnel and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography using 30 % ethyl acetate/hexanes afforded 2.4 g (47%) of methyl 3-amino-5-cyanobenzoate as a light brown solid.

[0113] Formaldehyde, 37 wt. % solution in water, (4.3 mL, 57 mmol), solld sodium cyanoborohydride (752 mg, 11 mmol), and then acetic acid (909 μ,ί, 16 mmol) were added to methyl 3-amino-5-cyanobenzoate (500 mg, 2.8 mmol) in aceton itri le (10 mL). After stirring at ambient temperature for 5 hours, the reaction mixture was transferred to a separatory funnel and then ethyl acetate was added. The organic layer was washed with water and saturated brine, cfried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography using 15% ethyl acetate/hexanes afforded 390 mg (55%) methyl-3-cyano-5-dimethylaminobenzoate.

[0114] A solution of methyl-3-cyano-5-dimethylaminobenzoate (318 mg, 1.6 mmol) in tetrahydrofuran (5 ml) was treated with 0.5 N lithium hydroxide (3.7 mL, 1.9 mmol). The reaction was stirred at 70'C for 30 minutes and then the solvent was removsd in vacuo. The residue was dissolved in a small amount oí water and then acidified by the dropwise

addition of 2 /Vhydrogen chloride until a white precipitate no longer formed. Following extraction of the aqueous layer with diethyl ether, the organic layer was then washed with water and saturated brine, dried over anhydrous sodium sulfate, flltered, and concentrated to afford 308 mg (quantitative) of 3-cyano-5-dimethylaminobenzoic acid.

3-cyano-5-(2-methoxyethoxy)benzoic acid [0115] <img file="IS2564B_D0059.tif" /> [0116] A mixture of methyl 3-allyloxy-5-cyanobenzoate (1.5 g, 6.9 mmol) and tetrabutylammonium iodide (2.8 g, 7.6 mmol) in dichloromethane (38 mL) at -78 ’C, under argon, was treated with a solution of 1M boron trichloride in dichloromethane (24 mL, 24 mmol). After 5 minutes at -78 ‘C, the reaction mlxture was stirred at ambient temperature for 1 hour. The reaction was then quenched with ice water and stirred for an additional 30 minutes. The organic layer was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography using a gradient of 20-30% ethyl acetate/hexanes afforded 811 mg (67%) of methyl 3-cyano-5-hy-droxybenzoate as a light yellow solid.

[0117] A mixture of methyl 3-cyano-5-hydroxybenzoate (302 mg, 1.7 mmol), polassium carbonate (471 mg, 3.4 mmol) and 2-chloroethyl methyl ether (309 μΙ. mg, 3.4 mmol) in N,/V-dimethylformamide (4 mL) was heated in a sealed vial at 140 "C for 15 minutes. The reaction was cooled, diluted with ethyl acetate, washed with water and saturated brine, filtered and concentrated. Filtration through silica gel using dichloromethane afforded 375 mg (93%) of methyl 3-cyano-

5-(2-methoxyethoxy)benzoate.

[0118] A solution of methyl 3-cyano-5-(2-methoxyethoxy)benzoate (375 mg, 1.6 mmol) in íetrahydrofuran (4 mL) was treated with 0.5 N lithium hydroxide (3.8 mL, 1.9 mmol). The reaction was stirred at 70'C for 30 minutes and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified with 2 N hydrogen chloride until pH - 2. Following extraction of the aqueous layer with ethyl acetate, the organic layer washed with water and saturated brine, dried overanhydrous sodium sulfate, filtered, and concentrated to afford 343 mg (97%) of 3-cyano-

5-(2-methoxyethoxy)benzoic acid.

3-cyano-5-(1 H-imidazol-1-yl-methyl)benzoic acid [0119] <img file="IS2564B_D0060.tif" /> [0120] A mixture of methyl 3-(bromomethyl)-5-iodobenzoate (500 mg, 1.4 mmol), potassium carbonate (388 mg, 2.8 mmol), and imidazole (96 mg, 1.4 mmol) in N, /V-dimethylformamide (4 mL) was heated at 70 ’C for 3 hours. After cooling, the reaction mixture was diluted with water and then extracted with dichloromethane. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography using 100% ethyl aceiate afforded 242 mg (51 %) of methyl 3-(imidazol-1-ylmethyl)-5-iodobenzoate as a white solid.

[0121] After bubbling argon into a solution of methyl 3-(imidazol-1-ylmethyl)-5-iodobenzoate (242 mg, 0.70 mmol) in N ,N-dimethylformamide (2 mL) for 5 minutes, zinc cyanide (90 mg, 0.77 mmol) and tetrakis(tripheny Iphosp h i n e) pa 11 ad i u m (0) (80 mg, 0.070 mmol) were added. The reaction mixture was heated at 80'C for 30 minutes under argon. Following cooling, the reaction mixture was diluted with ethyl acetate and then the precipitate that formed was removed by filtration. The filtrate was washed with water and saturated brine, driad ovar anhydrous sodlum sulfate, filtered, and concentrated. The residue was triturated with 20 % diethyl ether/hexanes, filtered, and dried in vacuo to afford 150 mg (89%) of 3-

cyano-5-(1 H-imidazol-1 -yl-methyl)benzoate as a white solid.

[0122] A solution of 3-cyano-5-(1 H-im idazol-1 -y l-methyl)benzoate (150 mg, 0.62 mmol) in tetrahydrofuran (2 mL) was treated with 0.5 N lithium hydroxide (1.5 mL, 0.75 mmol). The reaction was stirred at 70’C for 10 minutes and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH - 4) by the addition ot 2/V hydrogen chlorlde. The precipitate was collected and dried to afford 140 mg (quantitative) of 3-cyano-

5-(1 H-imidazol-1 -yl-methyl)benzoic acid.

3-cyano-5-(methoxymethyl)benzoic acid [0123] <img file="IS2564B_D0063.tif" /> [0124] A mixture of methyl 3-(bromomethyl)-5-iodobenzoate (400 mg, 1.1 mmol) and potassium carbonate (311 mg, 2.3 mmol) in methanol/tetrathydrofuran (5 ml75 mL) was heated at 55 'C for 1 hour. 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, 325 mg (94%) of methyl 3-(methoxymethyl)-5-iodobenzoate was isolated as a white solid.

[0125] Atter bubbling argon into a solution of methyl 3-(methoxymethyl)-5-iodobenzoate (316 mg, 1.03 mmol) in N, N-dimethylformamide (3 mL) for5minutes, zinccyanide (133 mg, 1.13 mmol) and tetrakis(triphenylphosphine)palladium (0) (119 mg, 0.010 mmol) were added. The reactíon mixture was heated at 80'C for 15 minutes under argon. Following cooling, the reaction mixture was diluted with ethyl acetate and then the precipitate that formed was removed by filtration. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography using 10-30% ethyl acetate/hexanes afforded 184 mg (86%) of methyl 3-cyano-5-(methoxyme-thyl)benzoate as a colorless oil.

[0126] A solution of methyl 3-cyano-5-(methoxymethyl)benzoate (184 mg, 0.75 mmol) in tetrahydrofuran (2.1 mL) was treated with 0.5 N lithlum hydroxide (1.8 mL, 0.90 mmol). The reaction was stirred at 70'C for 30 minutes and then after cooling the sotvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified with 2 N hydrogen chloride until pH - 2-3. Following extraction of the aqueous layer with ethyl acetate, the organic layer washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 145 mg (quantitative) of 3-cyano-5-(methoxymethyl)benzoic acid.

3-cyano-5-ethoxybenzoic acid [0127] <img file="IS2564B_D0064.tif" /> [0128] A solution of methyl 3-cyano-5-hydroxybenzoate (270 mg, 1.5 mmol) and potassium carbonate (482 mg, 3.4 mmol) in acetone (5.5 mL) was prepared. To this, ethyl iodide (272 μι., 3.4 mmol) was added and the reaction was heated at 52”C for 2.5 hours. The reaction mixture was concentrated, re-dissolved in ethyl acetate and washed with water and saturated brine. The organic solvent layer was collected, dried over anhydrous sodium sulphate, filtered, and concentrated. 321 mg (99%) of methyl 3-cyano-5-ethoxybenzoate was isolated as a light brown solid.

[0129] Methyl 3-cyano-5-ethoxybenzoate (312 mg, 1.5 mmol) was hydrolyzed as previously described to afford 290 mg (quantitative) of 3-cyano-5-ethoxybenzoic acid as an off-white solid.

3-cyano-5-propoxybenzoic acid [0130] <img file="IS2564B_D0067.tif" /> [0131] A solution of methyl 3-cyano-5-hydroxybenzoate (200 mg, 1.3 mmol) and potassium carbonate (357 mg, 2.6 mmol) in acetone (4.0 mL) was prepared. To this, propyl iodide (245 μ,Ι_, 2.5 mmol) was added and the reaction was heated at 50‘C for 5 hours. The reaction mixture was concentrated, re-dissolved in ethyl acetate and washed with water and saturated brine. The organic solvent layer was collected, dried over anhydrous sodium sulphate, filtered, and concentrated. 222 mg (90%) of methyl 3-cyano-5-propoxybenzoate was isolated as a light brown solid.

[0132] Methyl 3-cyano-5-propoxybenzoate (222 mg, 1.0 mmol) was hydrolyzed as previously described to afford 169 mg (80%) of 3-cyano-5-propoxybenzoic acid as an off-white solid.

3- cyano-5-hexyloxybenzoic acid [0133] <img file="IS2564B_D0068.tif" /> [0134] A solution of methyl 3-cyano-5-hydroxybenzoate (170 mg, 0.95 mmol) and potassium carbonate (304 mg, 2.2 mmol) in acetone (4.0 mL) was prepared. To this, 1-bromohexane (300 μΙ, 2.1 mmol) was added and the reaction was heated at 50‘C overnight. The reaction mlxture was concentrated, re-dissolved in ethyl acetate and washed with water and saturated brine. The organic solvent layer was collected, dried over anhydrous sodium sulphate, filtered, and concentrated. Trituration with hexanes afforded 250 mg (quantitative) of methyl 3-cyano-5-hexyloxybenzoate as a light brawn solid.

[0135] Methyl 3-cyano-5-ethoxybenzoate (250 mg, 0.95 mmol) was hydrolyzed as previously described to afford 247 mg (quantitative) of 3-cyano-5-hexyloxybenzoic acid as an ofí-white solid.

4- Amino-3-bromo-5-trifluoromethoxybenzoic acid [0136] <img file="IS2564B_D0069.tif" /> [0137] To a solution ot 4-amino-3-trifluoromethoxybenzoic acid (5 g, 22.6 mmoles) in acetic acid (50 mL), bromine (3.98 g, 24.9 mmoles) in acetic acid(10 mL) was added dropwise at room temperature. After the reaction mixture was

kept stirring for one hour, water was added into the mixture. The solid was filtered and washed with water to give 4-amino-3-bromo-5-tritluoromethoxybenzoic acid (3.9 g, 54.9%).

3-Bromo-5-trifluorometboxybenzoic acld [0138] <img file="IS2564B_D0073.tif" /> [0139] 4-Amino-3-bromo-5-trifluoromethoxybenzoic acid (1.5 g, 5 mmoles) was mixed with ethanol (15 mL) at 0 'C and then concentrated sulfuric acid (2.26 g, 10.2 mmoles) wad added. The sodium nitrite (0.38 g, 5.5 mmoles) water solution (1.2 mL) was added dropwise at 0 "C for 1 hour. After the reaction mixture was warmed to room temperature and then heated to reflux for 45 minutes, water was added. The mixture was extracted with dichloromethane. The dichloromethane layer was dried and concentrated. The residue was dissolved ίη 1M sodium hydroxide and extracted with ether. The aqueous solution was acidified with 2M HCI to pH = 2 to give 3-bromo-5-trifluoromethoxybenzoic acid (1.08 g, 75.5%).

3-Cyano-5-trifluoromethoxybenzoic acid [0140] <img file="IS2564B_D0074.tif" /> [0141] To an ether solution of 3-bromo-5-trifluoromethoxybenzoic acid (1.08 g, 3.79 mmloes), trimethylsilylmethyl azide was added in and stirred at roorn temperature for 10 minutes. The reaction was quenched with methanol and passed column with 2% ethyl acetate in hexanes to give colorless oil (0.84 g). This colorless oil was mixed with zinc cyanide (0.33 g, 2.8 mmoles) and tetrakís(triphenylphosphine)palladium(0) (Pd(PPh3)4, 467 mg, 0.404 mmol) in N,N-dimethylformamide( 10 mL) under argon at 85‘C overnight. The reaction mixture was diluted with dichloromethane and washed with water twice. The dichloromethane layer was dried and concentrated. The residue was mixed with M sodium hydroxide (8 mL) and methanol (4 mL) and stirred at room temperature for 2 hours. The mlxture was acidified with 1M HCI to pH=l ~ 2 and extracted with ethyl acetate. The ethyl acetate layer was washed with Brine and concentrated. The residue was passed column with 2% ethyl acetate in hexanes to give 3-cyano-5-trifluoromethoxybenzoic acid, which contained 3-[imino(methoxy)methyl]-5-trifluoromethoxybenzoic acid (3:1,145 mg, 16.6%)

3-Fluoro-5-(3-pyridyl)benzoic acid [0142]

<img file="IS2564B_D0077.tif" /> [0143] Asolution of3-Bromo-5-f!uorobenzoic acid (2.00 g, 9.13mmol) in thionylchloride (16 ml)anddimethylformamide (0.4 ml) was stirred at 80'C for 1 h. The reaction mixture was concentrated in-vacuo and the residue was dissolved in methanol (15 ml) and left stirring at room temperature overnight. The reaction mixture was concentrated in-vacuo, and the resldue was dissolved in ethyl acetate (50 ml). Organic phase was sequentially washed with water (50 ml), saturated sodium bicarbonate (50 ml, aqueous), water (50 ml) and brine (50 ml), dried (sodium sulfate), filtered and concentrated in-vacuo to provide the title compound (1.97 g, 92%) as yellow oil.

[0144] To the solution of Methyl-3-bromo-5-fluorobenzoate (1,97 g, 8.44 mmol) In toluene (40 ml) added Pyridine-3-boronic acid-1 ,3-propanediol ester (1.79 g, 7.63 mmol), potassium carbonate (11.66 g, 84.4 mmol) and tetrakis(triphe-nylphoshine)palladium (0) (0.49, 0.42 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 120'C under argon overnight. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated in-vacuo. The residue was purified on silica gel using 1 % methanol in dichloromethane to isolate the title compound (0.92 g, 47%) as a yellow solid.

[0145] In a 100 ml round bottom flask equipped with stir bar added Methyl-3-f luoro-5-(3-py ridyl)benzoate (0.92 g, 3.93 mmol), methanol (10 ml) and sodium hydroxide (5.89 ml, 5.89 mmol, 1N aqueous). Stirred the resulting mixture at 50’C for 2 h. The reaction mixture was cooled to room temperature, concentraled ίη-vacuo and the residue was dissolved in methanol (20 ml). To thís mixture added hydrochloric acid (1N diethyl ether) dropwise and stirred at room temperature for 10 min. The reaction mixture was concentrated in-vacuo and the residue was triturated with diethyl ether to provide the crude hydrochloride salt of title compound (1.00 g) as an off white solid.

3-Bromo-5-(3-pyridyl)benzoic acid [0146] <img file="IS2564B_D0078.tif" /> [0147] A solution of 3-Bromo-5-iodobenzoic acid (5.00 g, 15.3 mmol) in methanol (30 ml) and hydrochloric acid (15.3 ml, 15,3 mmol, 1N diethyl ether) was stirred at room temperature for 48h. The reaction mixture was concentrated in-vacuo and the residue was diluted with dichloromethane (100 ml). The organic phase was sequentially washed with sodium hydroxide (100 ml, 1N aqueous), water (100 ml) and brine (100 ml), dried (sodium sulfate), filtered and concentrated in~vacuo. The crude residue was dissolved in 10% ethyl acetate in hexanes (100 ml) and filtered through a pad of silica gel. Upon concentrating in-vacuo, isolated the methyl ester (4.98 g, 95%) as yellowish white solid.

[0148] To the solution of Methyl-3-bromo-5-iodobenzoate (2.00 g, 5.87 mmol) in toluene (50 ml) added Pyridine-3-boronic acid-1,3-propanediol ester (1.24 g, 7.63 mmol), potassium carbonate (8.11 g, 58.7 mmol) and tetrakis(triphe-nylphoshine)palladium (0) (0.34, 0.29 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 80‘C under argon for 10 h, The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated in-vacuo. The resídue was purified on silica gel using 3% methanol in dichloromethane to isolate Methyl-3-bromo-5-(3-pyridyl)benzoate (1.16 g, 67%) as a white solid.

[0149] In a 100 ml round bottom flask equipped with stir bar added Methyl-3-bromo-5-(3-pyridyl)benzoate (1.16 g,

3.96 mmol), methanol (15 ml) and sodium hydroxide (5.94 ml, 5.94 mmol, 1N aqueous). Stirred the resulting mixture at 50'C for 2 h. The reaction mixture was cooled to room temperature, concentrated in-vacuo and the residue was dissolved in methanol (20 ml). To this mixture added hydrochloric acid (1N diethyl ether) dropwise and stirred at room temperature for 10 min. The reaction mixture was concentrated in-vacuo and the residue was triturated with diethyI ether to provide the crude hydrochloride salt of title compound (1.50 g) as a white solid.

3-Fluoro-5-methoxybenzoic acid [0150] <img file="IS2564B_D0081.tif" /> [0151] In a 250 ml round bottom flask equipped with stir bar added 3,5-Dif luorobenzonitrile (4.2 g, 30.4 mmol), sodium methoxide (10.4 ml, 45.6 mmol, 25% methanol) and dimethylformamide (40 ml). Stirred the resulting reaction mixture at room temperature, overnight. The reaction mixture was concentrated in-vacuo and residue was dissolved in dichloromethane (200 ml). The organic phase was washed sequentially with water (150 ml) and brine (150 ml), dried (sodium sulfate) and concentrated in-vacuo. The crude residue was purified on silica gel using 10% diethyl ether in hexanes to isolate 3-Fluoro-5-methoxybenzonitrile (1.63 g) as a white solid.

[0152] In a 50 ml round bottom flask equipped with stir bar and reflux condensor added 3-Fluoro-5-methoxybenzonitrile (0.62 g, 4.10 mmol), methanol (6.2 ml) and sodium hydroxide (6.2 ml, 6N aqueous). Stirred the resulting reaction mixture at 100’C overnight. Reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was diluted with dichloromethane (100 ml) and acidified using hydrochloric acid (1N aqueous). The organic phase was separated, sequentially washed with water (100 ml) and brlne (100 ml), dried (sodium sulfate) and concentrated in-vacuo, to yield the title compound (0.64g, 91 %) as a white solid.

3-Cyano-5-thiomethylbenzoic acid [0153]<img file="IS2564B_D0082.tif" /> [0154] 3-bromo-5-thiomethylbenzoic acid (519.6 mg, 2.1 mmol) was dissolved in diethyl ether (20 mL). Diazomethane in diethyl ether was added to the benzoic acid solution until the mixture ceased to bubble and a yellow colour persisted. Glaclal acetic acid was added dropwise to this solution untll the yellow colour disappeared. The reaction was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate and solvent was removed in vacuo to yield 537 mg (98%) of 3-bromo-5-thiomethylesteras a colourless oil. 3-bromo-5-thiomethylester (536 mg, 2.05 mmol) was dissolved in anhydrous /V,/V-dimethylformamide (5 mL) ln an argon atmosphere. Zinc cyanide (42 mg, 0.36 mmol) and tetrakis (tri pheny Iphosphine) pa lladium(O) (41 mg, 0.356 mmol) was added to the reaction mixture, which was stirred at 80 ’C íor 10 hours. After cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The compound was purified by column chromatography on silica to yield 356 mg (85%) of 3-cyano-5-thiometh-ylester, which was a white solid.

[0155] 3-cyano-5-thiomethylester (360 mg, 1.74 mol) was dissolved in anhydrous tetrahydrofuran (22 mL) and 21.6 mL of aqueous lithium hydroxide (0.5 M) and 11 mL of methanol was added. The reaction was refluxed for 45 minutes.

The reaction was cooled and the solvent was removed in vacuo. The mixture was diluted with water and washed with ethyl acetate. The aqueous layer was then acidified to pH 1 with HCI (1M) and extracted with ethyl acetate. The organic extractlons were combined and dried over anhydrous sodium sulfate and solvent was removed in vacuo to give 330 mg (98%) of 3-cyano-5-thiomethylbenzoic acid as a white solid.

5-Fluoro-3-thiomethylbenzoic acid [0156] <img file="IS2564B_D0085.tif" /> [0157] A solution of 3,5-difluorbromobenzene (1.0 g, 5.18 mmol) in A/./V-dimethylformamide (15 mL) was cooled to 0 ’C and sodiumthiomethoxide (363 mg, 5.18 mmol) was added. The reaction stirred for 30 minutes before the mixture was diluted with water and extracted with hexanes. The organic extracts were washed with brine and dried over anhydrous sodium sulphate. Solvent was removed in vacuo and the product was eluted Ihrough an SPE tube (10g) wíth hexanes to yield 618 mg (54%) of a colourless oil.

[0158] The 5-Fluoro-3-thiomethylbromobenzene (618 mg, 2.80 mmol) was dissolved in Λ/,Ν-dimethylformamide (6 mL) and zinc cyanide (329 mg, 2.80 mmol) and tetrakis (triphenylphosphine)palladium (0) (324 mg, 0.28 mmol) were added to the solution. The reaction was stlrred at 80 ’C lor 12 hours. The reaction mixture was cooled to R.T., diluted with water and extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and the solvent was removed in vacuo. Silica gel chromatography using 5% ethyl acetate in hexanes afforded 430 mg (92%) of a white solid, 5-Fluoro-3-cyanothiomethylbenzene (430 mg, 2.57 mmol) that was dissolved in water (6.0 ml) and aqueous sodium hydroxide (6M, 6.0 mL) and refluxed for 12 hours. The reaction mixture was acidified to pH 3 and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulphate and the solvent was removed in vacuo to yield 470 mg (98%) of the title compound as a white solid.

5-Fluoro-3-thioethylbenzoic acid [0159] <img file="IS2564B_D0086.tif" /> [0160] A solution of 3,5-difluorobromobenzene (1.0 g, 5.18 mmol) in W,/V-dimethylformamide (15 mL) was cooled to 0 'C and sodiumthioethoxide (436 mg, 5.18 mmol) was added. The reaction stirred for 30 minutes before the mixture was diluted with water and extracted with hexanes. The organic extracts were washed with brine and dried over anhydrous sodium sulphate. Solvent was removed in vacuo and the product was eluted through an SPE tube (10g) with hexanes to yreld 366 mg (30%) of a colourless oil,

5-Fluoro-3-thioethylbromobenzene (365 mg, 1.55 mmol) that was dissolved in /V,W-dimethylformamide (5 mL) and zinc cyanide (182 mg, 1.55 mmol) and tetrakis (triphenylphosphine)palladium (0) (179 mg, 0.16 mmol) were added to the solution. The reaction was stirred at 80 'C for 3 hours. The reaction mixture was cooled to R.T., diluted with water and extracted with ethyl acetate, washed with brine, drled over anhydrous sodium sulphate and solvent was removed in vacuo. Silica gel chromatography using 5% ethyl acetate in hexanes afforded 241 mg (86%) of a white solid, 5-Fluoro-3-cyanothioethylbenzene (240 mg, 1.32 mmol) that was dissolved in water (3.0 ml) and aqueous sodium hydroxide (6M, 3.0 mL) and refluxed for 12 hours. The reaction mixture was acidified to pH 3 and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulphate and the solvent was removed in vacuo

to yield 274 mg (103%) of an ofí-white solid.

3,5-dimethoxyphenylamidoxirne [0161] <img file="IS2564B_D0089.tif" /> [0162] 3,5-dimethoxybenzonitrile (228 mg, 1.4 mmol) and 5M hydroxylamine hydrochloride (0.336 mL, 1.68 mmol) in ethanol (2 mL) and 1 N sodium hydroxide (1.68 mL, 1.68 mmol), were heated at reflux overnight. Standard work up afforded 250 mg (91%) of 3,5-dimethoxyphenylamidoxime.

3-FI uoro-5-( 1 H-imidazol-1 -yl)phenyl-amidoxime [0163] <img file="IS2564B_D0090.tif" /> [0164] 3-Fluoro-5-(l H-imidazol-1 -yI)benzonitrile (950 mg, 5.08 mmol) and 5M hydroxylamine hydrochloride (1.02 mL, 5.08 mmol) in ethanol (5 mL) and 1 Wsodium hydroxide (5.08 mL, 5.08 mmol), were heated at reflux for 1 hour and 20 minutes. Slandard work up afforded 901 mg (81.4%) of 3-bromo-5-fluorophenylamidoxime.

6-Cyano-4-methoxypyrid-2-yl-amidoxime [0165] <img file="IS2564B_D0091.tif" /> [0166] Chelidamic acid monohydrate (2.01 g, 10 mmol) was mixed with 1M HCI (20 mL, 20 mmol, ether) in ethanol

(50 mL) and heated at 85 ’C for 24 hours. The solvent was removed in vacuo and mixed with ethyl acetate and water. The ethyl acetate layer was dried and concentrated. The residue was triturated with hexanes and ether to give 1.6 g (66%) diethyl 4-hydroxy-2,6-pyridinedicarboxylate.

[0167] To a suspension of 60% sodium hydride (0.351 g, 8.77 mmol) in dimethylformamide(7.5 mL), a solution of diethyl 4-hydroxy-2,6-pyrid inedicarboxy late (1.4 g, 5.85 mmol) in dimethylformamide (9 mL) was added dropwise under argon at room temperature and the reaction mixture was stirred for 5 minutes. lodomethane (1.245 g, 8.77 mmol) was added and the reaction was stirred at room temperature for 20 hours. The mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was dried, concentrated to give 1.45 g (97.8%) diethyl 4-methoxy-

2,6-pyridinedicarboxylate.

[0168] Diethyl 4-methoxy-2,6-pyridinedicarboxylate (1.45 g, 5,73 mmol) was stirred with concentrated ammonium (40 mL) at room temperature for 10 minutes. The precipitate was filtered to give 0.93 g (83%) of 4-methoxypyridine-2,6-dicarboxamide.

4-methoxypyridine-2,6-dicarboxamide (900 mg, 4.6 mmol) was mixed with trifluoroacetic anhydride (2.32 g, 11.1 mmol) and pyridine (1.6 g, 20.2 mmol) in dichloromethane (20 mL) and stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and washed with water. Standard work up, afforded 461 mg of 2,6-dicyano-

4- methoxypyridine.2,6-Dicyano-4-methoxypyridine (460 mg, 2.89 mmol) and 5M hydroxylamine hydrochloride (0.578 mL, 2.89 mmol) in ethanol (3 mL) and 1 /Vsodium hydroxide (2.89 mL, 2.89 mmol), were stirred at room temperature overnight. Standard work up afforded 180 mg (32.4%) of 6-cyano-4-methoxypyrid-2-yl-amidoxime.

3-Methoxybenzamidoxime [0169] <img file="IS2564B_D0095.tif" /> [0170] Using tha general procedure forthe synthesis of amidoximes, hydroxylamine hydrochloride (7.65 g, 110 mmol), sodium hydroxide (11 mL of 10 N, 110 mmol), and 3-methoxybenzylnitrile (12.2 mL, 100 mmol) afforded 9.9 g (60%) of 3-methoxybenzamidoxime.

5- Chloropyrid-2-ylamidoxime [0171]<img file="IS2564B_D0096.tif" /> [0172] A mixture of 2,5-dichloropyridine (1.48 g, 10 mmol), zinc cyanide (705 mg, 6 mmol), zinc (dust, 29 mg, 0.45 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(ll), complex with dichloromethane (1:1) (0.18 g, 0.22 mmol) in /V,N-dimethylformamide (10 mL) was heated at reflux for 5 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatography afforded 735 mg (53%) of 2-cyano-5-chloropyridine.

[0173] Using the general procedure forthe synthesis of amidoximes, 2-cyano-5-chloropyridine (735 mg, 5.3 mmol), a solution of hydroxylamine hydrochloride (1.2 mL of 5 M, 6 mmol) in ethanol (7 mL), and sodium hydroxide (0.61 mL of 10 N, 6.1 mmol), were heated at reflux for 24 hours. Standard work up afforded 707 mg (77%) of 5-chloropyrid-2-ylamidoxime.

5-Methoxypyrid-2-ylamidoxime [0174] <img file="IS2564B_D0099.tif" /> [0175] A solution of 2-cyano-5-fluoropyridine (0.65 g, 5.3 mmol) in sodium methoxide (1.83 mL of 25% wt. solution in methanol, 7.95 mmol) was stirred at 0 ’C for 1.5 hours and 2 hours at ambient temperature. The reaction was then diluted with ethyl acetate and washed with water and brine. Removal of the solvent in vacuo afforded 304 mg (43%) of 2-cyano-5-methoxypyridine.

[0176] Usingthegeneral procedureforthesynthesis ofamidoximes, 2-cyano-5-methoxypyridine (270 mg, 2.01 mmol), a solution of hydroxylamine hydrochloride (0.457 ml of 5 M, 2.28 mmol) in ethanol (4 mL), and sodium hydroxide (0.230 mL of 10 N, 2.30 mmol) were heated at reflux for 24 hours. Standard work up afforded 79 mg (24%) of 5-methoxypyrid-

2- ylamidoxime.

3- Fluoropyrid-2-ylamidoxime [0177] <img file="IS2564B_D0100.tif" /> [0178] A mixture of 2,3-dichloropyridine (1.48 g, 10 mmol), zinc cyanide (705 mg, 6 mmol,), zinc (dust, 29 mg, 0.45 mmol), [1,1 ’-bis(diphenylphosphino)ferrocene) dichloropalladium(ll), complex with dichloromethane (1:1) (0.18 g, 0.22 mol) in N,A/-dimethylformamide (10 mL) was heated at reflux for 5 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. Removal of the solvent and silica gel chromatography afforded 1.05 g (76%) of 2-cyano-3-chloropyridine..

[0179] A solution of 2-cyano-3-chloropyridine (1 g, 7.22 mmol) in 1 -methyl-2-pyrrolidinone (25 mL) was treated with potassium fluoride (1.26 g, 21.68 mmol) and heated at reflux for 18 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatography afforded 442 mg (50%) of 2-cyano-3-fluoropyridine.

[0180] Using the general procedure for the synthesis of amidoximes, 2-cyano-3-fluoropyridine (442 mg, 3.62 mmol), a solution of hydroxylamine hydrochloride (0.82 mL of 5 M, 4.1 mmol) in ethanol (5 mL), and sodium hydroxide (0.415 ml of 10 N, 4.15 mmol) were heated at reflux for 24 hours. Standard work up afforded 368 mg (66%) of 3-fiuoropyrid-2-ylamidoxime.

Quinol-2-ylamidoxime [0181]<img file="IS2564B_D0101.tif" />

[0182] Using the general procedure for the synthesis of amldoxlmes, 2-quinolinecarbonitrile (1.02 g, 6.6 mmol), a solution of hydroxylamine hydrochloride (1.44 mLof 5 N solution, 7.2 mmol) in ethanol (10 mL), and sodium hydroxide (0.72 mL of 10 N solution, 7.2 mmol) were heated at reflux for 18 hours.

Standard work up afforded 990 mg (80%) of quinol-2-ylamidoxime.

EXAMPLE 2: Synthesis of Carboxylic Acid Intermediates

5-Allyloxy-3-(methoxycarbonyl)benzoic acid [0183] <img file="IS2564B_D0105.tif" /> [0184] A stirred suspension of dimethy15-hydroxyisophthlate (5.0 g, 23.8 mmol) and potassium carbonate (7.5 g, 54.5 mmol) in acetone (120 mL) was treated with allyl bromide (4.6 mL, 53.0 mmol). The mixture was stirred at room temperature for 3 days. The mixture was then filtered and concentrated. The residue was dissolved in ethyl acetate and washed with water and brine. The remaining organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated. Trituration with hexane afforded 5.0 g (84 %) of dimethyl 5-allyloxy-isophthalate [0185] A mixture of dimethyl 5-allyloxy-isophthalate (3.7 g, 14.9 mmol) in methanol (75 mL) was treated with 1M sodium hydroxide (13.4 mL, 13.4 mmol) and the reaction stirred at room temperature for 16 hours. The mixture was concentrated under vacuum and the resulting residue was dissolved in water. The aqueous layer was washed with ethyl acetate (3 x), and then acidified (pH 1) by the addition of aqueous HCI. The aqueous solution was then extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated to afford 2.6 g (74%) of 3-allyloxy-5-(methoxycarbonyl)benzoic acid.

3-Methoxycarbonyl-5-methoxybenzoic acid [0186] <img file="IS2564B_D0106.tif" /> [0187] In a similar fashion, dimethyl 5-hydroxyisophthlate (1.0 g, 4.8 mmol), potassium carbonate (1.5 mg, 10.9 mmol), and methyl iodide (0.7 mL, 10.6 mmol) in acetone (25 mL) afforded 1.1 g (99%) of dimethyl 5-methoxyisophthalate. Hydrolysis and standard work up afforded 0.7 g (68%) of 3-methoxycarbonyl-5-methoxybenzoic acid.

3-Bromo-5-cyanobenzoic acid [0188]

<img file="IS2564B_D0109.tif" /> [0189J A mixture of 3-bromo-5-iodobenzoic acid (9.0 g) in methanol (40 mL) was treated with 1M HCI in dlethyl ether (27.5 mL). The reaction was heated overnight at 40 ’C. The solvent was then removed /n vacuo, and the residue dissolved in ethyl acetate. The organic solution was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to afford 8.8 g (94%) of methyl 3-bromo-5-iadobenzoate.

[0190] A solution of methyl 3-bromo-5-iodobenzoate (4.5 g, 13.2 mmol) in W,W-dimethylformamide (36 ml_) wastreated with zinc cyanide (1.7 g, 14.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 1.5 g, 1.3 mmol). The reaction mixture was heated, under an argon atmosphere, for 1 hour at 80 ‘C. After cooling the mixture was diluted with ethyl acetate. The resulting organic solutíon was washed with water (3x), saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel ctiromatography using a gradient of hexane to 10% ethyl acetate in hexane afforded 1.9 g (61 %) of methyl 3-bromo-5-cyanobenzoate.

[0191] Hydrolysis of the methyl ester (1.9 g, 8.0 mmol) in methanol (20 mL) and 1M sodium hydroxide (8.0 mL, 8.0 mmol), afforded, after standard work up 1.6 g (88 %) of 3-bromo-5-cyanobenzoic acid.

3-Methoxycarbonyl-5-iodobenzoic acid [0192] <img file="IS2564B_D0110.tif" /> [0193] In a similar fashion, hydrolysis of dimethyl-5-íodoisophthlate (4.5 g, 14.058 mmol) in methanol (60 mL) with 1M NaOH (12.6 mL, 12.6mmol)afforded, afterstandardworkup3.43g (80%) of 3-methoxycarbonyl-5-iodobenzoicacid.

3-Cyano-5-iodobenzoic acid [0194] <img file="IS2564B_D0111.tif" /> [0195] A solution of 3-methoxycarbonyl-5-iodobenzoic acid (3 g, 10 mmol) in thionyl chloride (2 mL) was heated for 2 hours at 60 ’C. The reaction mixture was cooled and concentrated in vacuo. The intermediate acid chloride was then diluted with tetrahydrofiiran (10 mL) and cooled to 0 'C. The mixture was then treated with a solution of 2M ammonia (20 ml, 40 mmol, methanol) and the reaction stirred for 1 hour at 0 ‘C. The mixture was then filtered and the solvent remaved ín vacuo. Recrystallization from methanol afíorded 2.5 g (82%) o13-methoxycarbonyl-5-iodobenzamide, as a white solid.

[0196] A mixture of 3-methoxycarbonyl-5-iodobenzamide (2.5 g, 8.2 mmol) in thionyl chloride (2 mL) was heated for 2 hours at 90 ’C. The reaction mixture was cooled and concentrated in vacuo. Silica gel chromatography afforded 670 mg (29%) of methyl-3-cyano-5-iodobenzoate, as a white solld.

[0197] A solution of methyl-3-cyano-5-iodabenzoate (640 mg, 2.3 mmol) in tetrahydrofuran (8 mL) was treated with 0.5M LiOH (5.5 mL, 2.75 mmol) and methanol. The reaction mixture was heated at reflux for 1 hour. The solvent was concentrated in vacuo and the mixture treated with 1N HCI. The resulting white precipitate was filtered and the filtrate was extracted with dichloromethane. The residue and the extracted filtrate were combined and concentrated in vacuo to afford 590 mg (94%) of 3-cyano-5-iodobenzoic acid, as a white solid.

5-fluoro-3-(thiomethyl)benzoic acid [0198] <img file="IS2564B_D0115.tif" /> [0199] 1 -Bromo-3,5-difluorobenzene (1.00 g, 5.18 mmol) was dissolved in anhydrous DMF (10 mL). The solution was chilled in an ice bath, and NaSMe (0.36 g, 5.18 mmol) was added. After 30 minutes the reaction mixture was poured into water (100 mL) and extracted with hexanes. The organic phase was washed with water and brine, dried (MgSO4), filtered, and concentrated to provide the titls compound as a colourless oil. The crude product was used directly in the next step. Using the standard cyanation procedure, 5-cyano-3-fluoro-1-(thiomethyl)benzene was prepared as a yellow oil. The crude producl was used directly in the next step. Using the standard saponif ication procedure, the title compound was prepared in 0.60 g yield (63% over 3 steps) as a colourless solid.

3-Fluoro-5-(1 H-imidazol-1-yl)benzoic acid [0200] <img file="IS2564B_D0116.tif" /> [0201] 1-Bromo-3,5-difluorobenzene (1.00 g, 5.18 mmol) wasdissolved inanhydrous DMF (10 mL). Thesolution was chilled in an ice bath. Imidazole (0.36 g, 5.18 mmol) and K2CO3 (0.72 g, 5.18 mmol) were added. The reaction mixture was stirred at room temperalure for 16 hours, and at 80 'C íor 24 hours. The reaction mixture was poured ínto water (100 mL) and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), fillered, and concentrated. The intermediate 3-Fluoro-5-Bromo-(1 H-imidazol-1-yl)-benzene was used directly in the next step. Using the standard cyanation procedure, 3-Fluoro-5-cyano-(1 H-imidazol-1 -yl)-benzene was prepared as a colourless solid. The crude product was used directly in the next step. Using the standard saponification procedure, the title compound was prepared as a colourless solid. The crude product was used directly in the next step.

3-lodo-5-T rif luoromethylbenzoic acid [0202]

<img file="IS2564B_D0119.tif" /> [0203] The title product was prepared according to the literature procedure (Fujiki, Kanji; Kashiwagi, Mitsuyoshi; Miyamoto, Hideyuki; Sonoda, Akinari; lchikawa, Junji; et al J.FIuorine Chem. 1992, 57, 307-321) from 3,5-bis(trifluor-omethyl)benzene (7.3 mL, 47 mmol) and iodine (11.95 g, 47 mmol) in 30% oleum (30 mL) at 55 degrees for 15h. Quenching with ice was followed by extraction of the crude product into ether, sequential washing of the aqueous layer with sodium sulfite (1M) and water. Sodium hydroxide (1N, - 150 mL) was added to the crude ether solution until pH basic, the layers were separated and the aqueous layer was then acidif ied using HCI (12N, -10 mL, pH acidic). Extraction into ether followed by drying over magnesium sulfate yielded the crude acid (4.3 g, 29%). The material was insutf icient ly pure for use( so the product was esterified using acetyl chloride in methanol, purified using flash chromatography (silica gel, 20% dichloromethane in hexane) and hydrolyzed with sodium hydroxide in methanol yielding 2.95 g (69%) of pure 3-iodo-5-Tntluoromethylbenzoic acíd.

3-Allyloxy-5-cyanobenzoic acid [0204] <img file="IS2564B_D0120.tif" /> [0205] A suspension of 3-allyloxy-5-(methoxycarbonyl)benzoic acid (5.5 mg, 23 mmol) in thionyl chloride (30 mL) was heated at reflux for 2 hours. The excess thionyl chloride was then removed /n vacuo and the intermediate acid chloride dissolved in dichloromethane (25 mL). After cooling to 0 'C the solution was treated with 0.5 M ammonia in 1,4-dioxane (100 mL) and then allowed to warm to room temperature. After 2 hours of stirring the solvent was removed ín vacuo and the residue was titurated with water. The precipitate was collected, washed with water, and dried in vacuoto afford the 5.0 g (92 %) of methyl 3-(allyloxy)-(5-aminocarbonyl)benzoate as a white solíd.

[0206] A suspension of methyl 3-(allyloxy)-(5-aminocarbonyl)benzoate (5.0 g, 21 mmol) in a dichloromethane (70 mL) at 0 'C was treated with pyridine (3.5 mL, 43 mmol) and then trifluoroacetic anhydride drop-wise (3.6 mL, 25 mmol). The reaction was stirred at 0 "C for 20 mlnutes and then stirred overnight at ambient temperature. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography using a 10 % ethyl acetate/hexanes afforded 3.8 g (81 %) of methyl 3-(allyloxy)-5-cyanobenzoate as a white solid.

[0207] A solution of methyl 3-(allyloxy)-5-cyanobenzoate (1.5 g, 6.9 mmol) in methanol-tetrahydrofuran (1:2,30 mL) was treated with 0.5 N llthium hydroxíde (17 mL, 8.3 mmol). The reaction was stirred at 70‘C for 30 minutes and then the solvent was removed In vacuo. The residue was dissolved in a small amount of water and then acidified (pH ~ 4) by the addition of 2N hydrogen chloride. The precipitate was collected and dried to afford 1.0 g (74%) of 3-allyloxy-5-cyanobenzoic acid as a white solid.

3-Cyano-5-propoxybenzoic acid [0208]

<img file="IS2564B_D0123.tif" /> [0209] A suspension of 3-allyloxy-5-(methoxycarbonyl)benzoic acid (5.5 mg, 23 mmol) in thionyl chloride (30 mL) was heated at reflux for 2 hours. The excess thionyl chloride was then removed in vacuo and the intermediate acid chloride dissolved in dichloromethane (25 mL). After cooling to 0 'C the solution was treated with 0.5 M ammonla in 1,4-dioxane (100 mL) and then allowed to warm to room temperature. After 2 hours of stirring the solvent was removed in vacuo and the residue was titurated with water. The precipitate was collected, washed with water, and dried in vacuo to afford the 5.0 g (92 %) of methyl 3-(allyloxy)-(5-aminocarbonyl)benzoate as a white solid.

[0210] Methanol (20 mL) and dichloromethane (20 mL) were added to round bottom flask that contained methyl 3-(allyloxy)-(5-aminocarbonyl)benzoate (2.0 g, 8.5 mmol) and palladlum(10 wt.% on activated carbon, 200 mg) under argon. The flask was evacuated using a water aspirator and then filled with hydrogen from a balloon. The balloon filled was hydrogen was attached to the flask as the reaction stirred for 2 hours. The palladium on carbon was remove by filtration through celite. The solvent was removed using a roto-evaporator and then the sample was dried under vacuum to afford 2.0 (97%) of methyl 3-(aminocarbonyl)-5-propoxybenzoate as a white solid.

[0211 ] A suspension of methyl 3-(aminocarbonyl)-5-propoxybenzoate (2.0 g, 8.2 mmol) in a dichloromethane (25 mL) at 0 'C was treated with pyridine (1.3 mL, 17 mmol) and then trifluoroacetic anhydride dropwise (1.4 mL, 9.9 mmol). The reaction was stirred at 0 ‘C for 20 minutes and then stirred overnight at ambient temperature. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, fíltered and concentrated, Silica gel chromatography using a 40 % dichloromethane/hexanes afforded 1.5 g (84%) of methyl 3-cyano-5-propoxybenzoate as a white solid.

[0212] A solution of methyl 3-cyano-5-propoxybenzoate (1.5 g, 6.8 mmol) in methanol-tetrahydrofuran (1:2, 30 mL) was treated with 0.5 M lithium hydroxide (16 mL, 8.2 mmol). The reaction was stirred at 70‘C for 30 minutes and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH - 4) by the addition of 2N hydrogen chloride. The precipitate was collected and dried to afford 1.2 g (86%) of 3-cyano-5-propoxybenzoic acid.

3-Cyano-5-nitrobenzoic acid [0213] <img file="IS2564B_D0124.tif" /> [0214] Using the same procedure as for 3-allyloxy-5-cyanobenzoic acid, 3-cyano-5-nitrobenzoic acid (2.0 g, 10.7 mmol) was prepared from monomethyl 5-nitroisophthalate (5.0 g, 22 mmol).

3-Cyano-5-dimethylaminobenzoic acid [0215]

<img file="IS2564B_D0127.tif" /> [0216] Methyl 3-cyano-2-nitrobenzoate (6.0g, 29 mmol) and tin(ll) chloride dihydrate (26 g, 12mmol) inmethanol (100 mL) were heated at reflux for 3 hours. The reaction mixture was transferred into a 1L Erlenmeyer flask equipped with a stirring bar and coniainlng ice. While stirring the reaction mlxture, 1N sodium hydroxide was added until pH - 4-5. At this point solid sodium bicarbonate was added until pH - 8. The mixture was transferred to a separatory funnel and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography using 30 % ethyl acetate/hexanes afforded 2.4 g (47%) of methyl 3-amino-5-cyanobenzoate as a light brown solid.

[0217] Formaldehyde, 37 wt. % solutlon in water, (4.3 mL, 57 mmol), solid sodium cyanoborohydride (752 mg, 11 mmol), and then acetlc acid (909 μ,!_, 16 mmol) were added to methyl 3-amino-5-cyanobenzoate (500 mg, 2.8 mmol) in acetonitrile (10 mL). After stirring at ambient temperature for 5 hours, the reaction mixture was transferred to a separatory funnel and then ethyl acetate was added. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography using 15% ethyl acetate/hexanes afforded 390 mg (55%) methyl-3-cyano-5-dimethylaniinobenzoate.

[0218] A solution of methyl-3-cyano-5-dimethylaminobenzoate (318 mg, 1.6 mmol) in tetrahydrofuran (5 mL) was treated witb 0.5 N lithium hydroxide (3.7 mL, 1.9 mmol). The reaction was stirred at 70'C for 30 minutes and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified by the dropwise addition of 2 N hydrogen chloride until a white precipitate no longer formed. Following extraction of the aqueous layer with diethyl ether, the organic layer was then washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 308 mg (quantitative) of 3-cyano-5-dimethylaminobenzoic acid.

3-cyano-5-(2-methoxyethoxy)benzoic acid [0219] <img file="IS2564B_D0128.tif" /> [0220] A mixture of methyl 3-allyloxy-5-cyanobenzoate (1.5 g, 6.9 mmol) and tetrabutylammonium iodide (2.8 g, 7.6 mmol) In dichloromethane (38 mL) at -78 ’C, under argon, was treated with a solution of 1M boron trichloride in dichloromethane (24 mL, 24 mmol). After 5 mlnutes at -78 'C, the reaction mixture was stirred at ambient temperature for 1 hour. The reaction was then quenched with ice water and stirred for an additional 30 minutes. The organic layer was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography usíng a gradient of 20-30% ethyl acetate/hexanes afforded 811 mg (67%) of methyl 3-cyano-5-hy-droxybenzoate as a light yellow solid.

[0221] A mixture of methyl 3-cyano-5-hydroxybenzoate (302 mg, 1.7 mmol), potassium carbonate (471 mg, 3.4 mmol) and 2-chloroethyl methyl ether (309 μΐ mg, 3.4 mmol) in Λ/,Ν-dimethylformamide (4 mL) was heated in a sealed vial at 140 ’C for 15 minutes. The reaction was cooled, diluted with ethyl acetate, washed with water and saturated brine, filtered and concentrated. Filtration through silica gel using dichloromethane afforded 375 mg (93%) of methyl 3-cyano-

5-(2-methoxyethoxy)benzoate.

[0222] A solution of methyl 3-cyano-5-(2-methoxyethoxy)benzoate (375 mg, 1.6 mmol) in tetrahydrofuran (4 ml) was treated with 0.5 N lithium hydroxide (3.8 ml, 1.9 mmol). The reaction was stirred at 70'C for 30 minutes and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified with 2 N hydrogen chloride until pH - 2. Following extraction of the aqueous layer with ethyl acetate, the organic layer washed with water

and saturated brine, dried over anhydrous sodium sulfate, f iltered, and concentrated to afford 343 mg (97%) of 3-cyano-5-(2-methoxyethoxy)benzoic acid.

3-cyano-5-(1 H-imidazol-1-yl-methyl)benzoic acid [0223] <img file="IS2564B_D0131.tif" /> [0224] A mixture of methyl 3-(bromomethyl)-5-iodobenzoate (500 mg, 1.4 mmol), potassium carbonate (388 mg, 2.8 mmol), and imidazole (96 mg, 1.4 mmol) in /V,/V-dimethylformamide (4 mL) was heated at 70 ’C for 3 hours. After cooling, the reaction mixture was diluted with water and then extracted with dichloromethane. The organic layer was washed with water ard saturated brlne, dried over anhydroussodium sultate, filtered, and concentrated. Silica gel chromatography using 100% ethyl acetate afforded 242 mg (51 %) of methyl 3-(imidazol-1-ylmethyl)-5-iodobenzoate as a white solid.

[0225] After bubbling argon into a solution of methyl 3-(imidazol-1-ylmethyl)-5-iodobenzoate (242 mg, 0.70 mmol) in N,N-dimethylformamide (2 mL) for 5 minutes, zinc cyanide (90 mg, 0.77 mmol) and tetrakis(tripheny lphosphine)pal lad ium (0) (80 mg, 0.070 mmol) were added. The reaction mixture was heated at 80'C for 30 minutes under argon. Following cooling, the reaction mixture was diluted with ethyl acetate and then the p recipitate that formed was removed by f iltration. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was triturated with 20 % diethyl ether/hexanes, filtered, and dried in vacuo to afford 150 mg (89%) of 3-cyano-5-(lH-imidazol-1-yl-methyl)benzoate as a white solid.

[0226] A solution of Ο-εγθηο-δ-ίΙΗ-ίπικΙθζοΙ-Ι-γΙ-ηηεΙΙιγΙ^θηζοβίβ (150 mg, 0.62 mmol) in tetrahydrofuran (2 mL) was treated with 0.5 N lithium hydroxide (1.5 mL, 0.75 mmol). The reaction was stirred at 70’C for 10 minutes and then the solvent was removed In vacuo. The residue was dissolved in a small amount of water and then acidified (pH - 4) by the addition of 2N hydrogen chloride. The precipitate was collected and dried to afford 140 mg (quantitative) of 3-cyano-

5-(1 H-imidazol-1 -yl-methyl)benzoic acid.

3-cyano-5-(methoxymethyl)benzoicacid [0227]<img file="IS2564B_D0132.tif" /> [0228] A mixture of methyl 3-(bromomethyl)-5-iodobenzoate (400 mg, 1.1 mmol) and potassium carbonate (311 mg, 2.3 mmol) in methanol/tetrathydrofuran (5 mL/5 mL) was heated at 55 ’C for 1 hour. After cooling, the reaction mixture was diluted wíth 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, 325 mg (94%) of methyl 3-(methoxymethyl)-5-iodobenzoate was isolated as a white solid.

[0229] After bubbling argon into a solution of methyl 3-(methoxymethyl)-5-iodobenzoate (316 mg, 1.03 mmol) in N, N-dimethylformamide (3 mL) f or 5 minutes, zinc cyanide (133 mg, 1.13 mmol) and tetraki s (trip h e ny I phosph i n e) pa 11 adi u m (0) (119 mg, 0.010 mmol) were added. The reaction mixture was heated at 80’C for 15 minutes underargon. Following cooling, the reaction mixture was diluted with ethyl acetate and then the precipitate that formed was removed by filtration. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography using 10-30% ethyl acetate/hexanes afforded 184 mg (86%) of methy 13-cyano-5-(methoxyme-thyl)benzoate as a colorless oil.

[0230] A solution of methyl 3-cyano-5-(methoxymethyl)benzoate (184 mg, 0.75 mmol) in tetrahydrofuran (2.1 mL) was treated with 0.5 N lithium hydroxide (1.8 mL, 0.90 mmol). The reaction was stirred at 70'C for 30 minutes and then after cooling the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified witti 2 N hydrogen chloride until pH - 2-3. Following extraction of the aqueous layer with ethyl acetate, the organic layer washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 145 mg (quantitative) of 3-cyano-5-(methoxymethyl)benzoic acid.

3-cyano-5-ethoxybenzoic acid [0231] <img file="IS2564B_D0135.tif" /> [0232] A solution of methyl 3-cyano-5-hydroxybenzoate (270 mg, 1.5 mmol) and potassium carbonate (482 mg, 3.4 mmol) in acetone (5.5 mL) was prepared. To this, ethyl íodide (272 μι, 3.4 mmol) was added and the reaction was heated at 52‘C for 2.5 hours. The reaction mixture was concentrated, re-dissolved in ethyl acetate and washed with water and saturated brine. The organic solvent layer was collected, dried over anhydrous sodium sulphate, fihered, and concentrated, 321 mg (99%) of methyl 3-cyano-5-ethoxybenzoate was isolated as a light brown solid.

[0233] Methyl 3-cyano-5-ethoxybenzoate (312 mg, 1.5 mmol) was hydrolyzed as previously described to afford 290 mg (quantitative) of 3-cyano-5-ethoxybenzoic acid as an off-white solid.

3-cyano-5-propoxybenzoic acid [0234] <img file="IS2564B_D0136.tif" /> [0235] A solution of methyl 3-cyano-5-hydroxybenzoate (200 mg, 1.3 mmol) and potassium carbonate (357 mg, 2.6 mmol) in acetone (4.0 mL) was prepared. To this, propyl iodide (245 μι, 2.5 mmol) was added and the reaction was heated at 50’C for 5 hours. The reaction mixture was concentrated, re-dissolved in ethyl acetate and washed with water and saturated brine. The organic solvent layer was collected, dried over anhydrous sodium sulphate, filtered, and concentrated. 222 mg (90%) of methyl 3-cyano-5-propoxybenzoate was isolated as a light brown solid.

[0236] Methyl 3-cyano-5-propoxybenzoate (222 mg, 1.0 mmoJ) was hydrolyzed as previously described to afford 169 mg (80%) of 3-cyano-5-propoxybenzoic acid as an off-white solid.

3-cyano-5-hexyloxybenzoic acid [0237]

<img file="IS2564B_D0139.tif" /> [0238] A solution of methyl 3-cyano-5-hydroxybenzoate (170 mg, 0.95 mmol) and potassium carbonate (304 mg, 2.2 mmol) in acetone (4.0 mL) was prepared. To this, 1-bromohexane (300 pL, 2.1 mmol) was added and the reaction was heated at 50‘C overnight. The reaction mixture was concentrated, re-dissolved in ethyl acetate and washed with water and saturaied brine. The organic solvent layer was collected, dried over anhydrous sodium sulphate, filtered, and concentrated. Trituration with hexanes afíorded 250 mg (quantitative) of methyl 3-cyano-5-hexyloxybenzoate as a light brown solid.

[0239] Methyl 3-cyano-5-ethoxybenzoate (250 mg, 0.95 mmol) was hydrolyzed as previously described to afford 247 mg (quantitative) of 3-cyano-5-hexyloxybenzoic acid as an off-white solid.

4-Amino-3-bromo-5-trifluoromethoxybenzoic acid [0240] <img file="IS2564B_D0140.tif" /> [0241] To a solution of 4-amino-3-trifluoromethoxybenzoic acid (5 g, 22.6 mmoles) in acetic acid (50 mL), bromine (3.98 g, 24.9 mmoles) in acetic acid(10 mL) was added dropwise at room temperature. After the reaction mixture was kept stirring for one hour, water was added into the mixture. The solid was filtered and washed wilh water to give 4-amino-3-bromo-5-tritluoromethoxybenzoic acid (3.9 g, 54.9%).

3-Bromo-5-trifluoromethoxybenzoic acid [0242] <img file="IS2564B_D0141.tif" /> [0243] 4-Amino-3-bromo-5-trifluoromethoxybenzoic acid (1.5 g, 5 mmoles) was mixed wlth ethanol (15 mL) at 0 ’C and then concentrated sulfuric acid (2.26 g, 10.2 mmoles) wad added. The sodium nitrite (0.38 g, 5.5 mmoles) water solution (1.2 mL) was added dropwise at 0 'C for 1 hour. After the reaction mixture was warmed to room temperature and then healed to reflux for 45 minutes, water was added. The mixture was extracted with dichloromethane. The dichloromethane layer was dried and concentrated. The residue was dissolved in 1M sodium hydroxide and extracíed with ether. The aqueous solution was acidified with 2M HCI to pH = 2 to give 3-bromo-5-trifluoromethoxybenzoic acid (1.08 g, 75.5%).

3-Cyano-5-trifluoromethoxybenzoic acid [0244] <img file="IS2564B_D0145.tif" /> [0245] Το an ether solution of 3-bromo-5-trifluoromethoxybenzoic acid (1.08 g, 3.79 mmloes), tirmethylsilylmethyl azide was added in and stirred at room temperature for 10 minutes. The reaction was quenched with methanol and passed column with 2% ethyl acetate in hexanes to give colorless oil (0.84 g). This colorless oil was mixed with zinc cyanide (0.33 g, 2.8 mmoles) and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 467 mg, 0.404 mmol) in N,N-dimethylformarnide(10 mL) under argon at 85 'C overnight. The reaction rnixture was diluted with dichloromethane and washed with water twice. The dichloromethane layer was dried and concentrated. The residue was mixed with 1M sodium hydroxide (8 mL) and methanol (4 mL) and stirred at room temperature for 2 hours. The mixture was aciditied with 1M HCI to pH = 1 ~ 2 and extracted with ethyl acetate, The ethyl acetate layer was washed with Brine and concentrated. The residue was passed column with 2% ethyl acetate in hexanes to gíve 3-cyano-5-trifluoromethoxybenzoic acid, which contained 3-[imino(methoxy)methyl]-5-trifluoromethoxybenzoicacid (3:1,145 mg, 16.6%)

3-Fluoro-5-(3-pyridyl)benzoic acid [0246] <img file="IS2564B_D0146.tif" /> [0247] Asolutionof3-Bromo-5-fluorobenzoicacid (2.00g, 9.13mmol) inthionyl chloride (16 ml) and dimethylformamide (0.4 ml) was stirred at 80’C for 1h. The reaction mixture was concentrated in-vacuo and the residue was dissolved in methanol (15 ml) and left stirring at room temperature overnight. The reaction mixture was concentrated /n-vacuo, and the residue was dissolved in ethyl acetate (50 ml). Organic phase was sequentially washed with water (50 m I), saturated sodium bicarbonate (50 ml, aqueous), water (50 ml) and brine (50 ml), dried (sodium sulfate), filtered and concentrated in-vacuo to provide the title compound (1.97 g, 92%) as yellow oil.

[0248] To the solution of Methyl-3-bromo-5-fluorobenzoate (1.97 g, 8.44 mmol) in toluene (40 ml) added Pyridine-3-boronic acid-1 ,3-propanediol ester (1.79 g, 7.63 mmol), potassium carbonate (11.66 g, 84.4 mmol) and tetrakis(triphe-nylphoshine)palladium (0) (0.49, 0.42 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 120’C under argon overnight. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated in-vacuo. The residue was purified on silica gel using 1 % methanol in dichloromethane to isolate the title compound (0.92 g, 47%) as a yellow solid.

[0249] In a 100 ml round bottom flask equipped with stirbaradded Methyl-3-fluoro-5-(3-pyridyI)benzoate (0.92 g, 3.93 mmol), methanol (10ml) and sodium hydroxide (5.89 ml, 5.89 mmol, 1N aqueous). Stirred the resulting mixture at 50’C for 2 h. The reaction mixture was cooled to room temperature, concentrated in-vacuo and the residue was dissolved in methanol (20 ml). To this mixture added hydrochloric acid (1N diethyl ether) dropwise and stirred at room temperature for 10 min. The reaction mixture was concentrated in-vacuo and the residue was triturated with diethyl ether to provide the crude hydrochloride salt of title compound (1.00 g) as an off white solid.

3-Bromo-5-(3-pyridyl)benzoic acid [0250] <img file="IS2564B_D0149.tif" /> [0251] A solution of 3-Bromo-5-iodobenzoic acid (5.00 g, 15.3 mmol) in methanol (30 ml) and hydrochloric acid (15.3 ml, 15.3 mmol, 1N diethyl ether) was stirred at room temperature for 48h. The reaction mixture was concentrated in-vacuoand the residue was diluted with dichloromethane (100 ml). The organic phase was sequentially washed with sodium hydroxide (100 ml, 1N aqueous), water(IOOml) and brine (100 ml), dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was dissolved in 10% ethyl acetate in hexanes (100 ml) and filtered through a pad of silica gel. Upon concentrating ίη-vacuo, isolated the methyl ester (4.98 g, 95%) as yellowish white solid.

[0252] To the solution of Methyl-3-bromo-5-iodobenzoate (2.00 g, 5.87 mmol) in toluene (50 ml) added Pyridine-3-boronic acid-1 ,3-propanediol ester (1.24 g, 7.63 mmol), potassium carbonate (8.1 g, 58.7 mmol) and tetrakis(triphenyl· phoshine)palladium (0) (0.34, 0.29 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 80'C under argon for 10 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated in-vacuo. The residue was purified on silica gel using 3% methanol in dichloromethane to isolate Methyl-3-bromo-5-(3-pyridyl)benzoate (1.16 g, 67%) as a white solid.

[0253] In a 100 ml round bottom flask equipped with stir bar added Methyl-3-bromo-5-(3-pyridyl)benzoate (1.16 g, 3.96 mmol), methanol (15 ml) and sodium hydroxide (5.94 ml, 5.94 mmol, 1N aqueous). Stirred the resulting mixture at 50Ό for 2 h. The reaction mixture was cooled to room temperature, concentrated in-vacuo and the residue was dissolved in methanol (20 ml). To this mixture added hydrochloric acid (1N diethyl ether) dropwise and stirred at room temperature for 10 min. The reaction mixture was concentrated in-vacuo and the residue was triturated with diethyl ether to provide the crude hydrochloride salt of title compound (1.50 g) as a white solid.

3-Fluoro-5-methoxybenzoic acid [0254] <img file="IS2564B_D0150.tif" /> [0255] In a 250 ml round bottom flask equipped with stir bar added 3,5-Difluorobenzonitrile (4.2 g, 30.4 mmol), sodium methoxide (10.4 ml, 45.6 mmol, 25% methanol) and dimethylformamide (40 ml). Stirred the resulting reaction mixture at room temperature, ovemight. The reaction mixture was concentrated irt-vacuo and residue was dissolved in dichloromethane (200 ml). The organic phase was washed sequentially with water(150 ml) and brine (150 ml). dried (sodium sulfate) and concentrated in-vacuo. The crude residue was purified on silica gel using 10% diethyl ether in hexanes to isolate 3-Fluoro-5-methoxybenzonitrile (1.63 g) as a white solid.

[0256] In a 50 ml round bottom flask equipped with stir bar and reflux condensor added 3-Fluoro-5-methoxybenzonitrile (0.62 g, 4.10 mmol), methanol (6.2 ml) and sodium hydroxide (6.2 ml, 6N aqueous). Stirred the resulting reaction mixture at 100'C overnight. Reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was diluted with dichloromethane (100 ml) and acidified using hydrochloric acid (1N aqueous). The organic phase was separated, sequentially washed with water (100 ml) and brine (100 ml), dried (sodium sulfate) and concentrated in-vacuo, to yield the title compound (0.64g, 91 %) as a white solid.

3-Cyano-5-thiomethylbenzoic acid [0257] <img file="IS2564B_D0153.tif" /> [0258] 3-bromo-5-thiomethylbenzoic acid (519.6 mg, 2.1 mmol) was dissolved in diethyl ether (20 mL) Diazomethane in diethyl ether was added to the benzoic acid solution until the mixture ceased to bubble and a yellow colour persisted. Glacial acetlc acid was added dropwise to this solution until the yellow colour disappeared. The reaction was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate and solvent was removed in vacuo to yield 537 mg (98%) of 3-bromo-5-thiomethylester as a colourless oil. 3-bromo-5-thiomethylester (536 mg, 2.05 mmol) was dissolved in anhydrous /V,N-dimethylformamide (5 mL) in an argon atmosphere. Zinc cyanide (42 mg, 0.36 mmol) and tetrakis (tripheny Iphosphine) pallad ium (0) (41 mg, 0.356 mmol) was added to the reaction mixture, which was stirred at 80 ’C for 10 hours. After cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The compound was purified by column chromatography on silica to yield 356 mg (85%) of 3-cyano-5-thiometh-ylester, which was a white solid.

[0259] 3-cyano-5-thiomethylester (360 mg, 1.74 mol) was dissolved in anhydrous tetrahydrofuran (22 mL) and 21.6 mL of aqueous lithium hydroxide (0.5 M) and 11 mL of methanol was added. The reaction was refluxed for 45 minutes. The reaction was cooled and the solvent was removed in vacuo. The mixture was diluted with water and washed with ethyl acetale. The aqueous layer was then acidified to pH 1 with HCI (1M) and extracted with ethyl acetate. The organic extractions were combined and dried over anhydrous sodium sulfate and solvent was removed in vacuo to give 330 mg (98%) of 3-cyano-5-thiomethylbenzoic acid as a white solid.

5-Fluoro-3-thiomethylbenzoic acid [0260] <img file="IS2564B_D0154.tif" /> [0261] A solution of 3,5-difluorbromobenzene (1.0 g, 5.18 mmol) in Ν,Ν-dimethylforrriamide (15 mL) was cooled to 0 'C and sodiumthiomethoxide (363 mg, 5.18 mmol) was added. The reaction stirred for 30 mlnutes before the mixture was diluted with water and extracted with hexanes. The organic extracts were washed with brine and dried overanhydrous sodium sulphate. Solvent was removed in vacuo and the product was eluted through an SPE tube (1 Og) with hexanes to yield 618 mg (54%) of a colourless oil.

[0262] The 5-Fluoro-3-thiomethylbromobenzene (618 mg, 2.80 mmol) was dissolved in Λ/,Ν-dimethylformamide (6 mL) and zinc cyanide (329 mg, 2.80 mmol) and tetrakis (triphenylphosphine)palladium (0) (324 mg, 0.28 mmol) were added to the solution. The reaction was stirred at 80 ’C for 12 hours. The reaction mixture was cooled to R.T., diluted with water and extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and the solvent was removed in vacuo. Silica gel chromatography using 5% ethyl acetate in hexanes afforded 430 mg (92%) of a white solid, 5-Fluoro-3-cyanothiomethylbenzene (430 mg, 2.57 mmol) that was dissolved in water (6.0 ml) and aqueous sodium hydroxide (6M, 6.0 mL) and refluxed for 12 hours. The reaction mixture was acidified to pH 3 and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulphate and the solvent was removed in vacuo to yield 470 mg (98%) of the title compound as a white solid.

5-Fluoro-3-thioethylbenzoic acid [0263]<img file="IS2564B_D0157.tif" /> [0264] Asolution of 3,5-difluorobromobenzene (1.0 g, 5.18 mmol) in /V,/V-dimethylformamide (15 mL) was cooled to 0 ‘C and sodiumthioethoxide (436 mg, 5.18 mmol) was added. The reaction stirred for 30 minutes before the mixture was diluted with water and extracted with hexanes. The organic extracts were washed with brine and dried over anhydrous sodium sulphate. Solvent was removed in vacuo and the product was eluted through an SPE tube (1 Og) with hexanes to yield 366 mg (30%) of a colourless oil,

5-Fluoro-3-thioethylbromobenzene (365 mg, 1.55 mmol) that was dissolved in N,/V-dimethylformarnide (5 mL) and zinc cyanide (182 mg, 1.55 mmol) and tetrakis (triphenylphosphine)palladium (0) (179 mg, 0.16 mmol) were added to the solution. The reaction was stirred at 80 'C for 3 hoqrs. The reaction mixture was cooled to R.T., diluted with water and extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and solvent was removed in vacuo. Silica gel chromatography using 5% ethyl acetate in hexanes afforded 241 mg (86%) of a white solid, 5-Fluoro-3-cyanothioethylbenzene (240 mg, 1,32 mmol) that was dissolved in water (3.0 ml) and aqueous sodium hydroxide (6 M, 3.0 mL) and refluxed for 12 hours. The reaction mixture was acidified to pH 3 and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulphate and the solvent was removed in vaouo to yield 274 mg (103%) of an off-white solid.

3-chloro-5-cyanobenzoic acid [0265] <img file="IS2564B_D0158.tif" /> [0266] A mixture of methyl 3,5-dichlorobenzoate (14.66 g, 71.5 mmol), zinc cyanide (5.04 g, 42.9 mmol) zinc (dust, 0.21 g, 3.21 mmol), [1,1 ’Bis(diphenylphosphino)ferrocene] dichloropalladium(ll), complex wíth dichloromethane (1:1) (1.3 g, 1.57 mmol) in /V,/V-dimethylformamide (70 mL) was heated at reflux for 5 hours. After cooling the reaction was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatography afforded 2.34g (17%) methyl

2- chloro-5-cyanobenzoate.

[0267] The intermediate ester was treated with a solution of sodium hydroxide (7.5 mL of 4 N solution, 30 mmol) in methanol (50 mL) and stirred at ambient temperature for18 hours. The solvent was removed ín vacuo and the residue dissolved in ethyl acetate. The organic solution was washed with 5% HCI and brine. Removal of the solvent afforded 1.8 g (83%) of 3-chloro-5-cyanobenzoic acid.

3- chloro-5-fluorobenzoic acid [0268]

<img file="IS2564B_D0161.tif" /> [0269] Amixtureof 1-bromo-3-chloro-5-fluorobenzene (25.0 g, 120mmol), zinccyanide (8.45 g, 72 mmol)zinc (dust, 235 mg, 3.6 mmol), [1,1'Bis(diphenylphosphino)ferrocene] dichloropalladium(ll), complex with dichloromethane (1:1) (1.5 g, 1.8 mmol) in N, N-dimethylformamide (70 ml) was heated at reflux for 1 hour. After cooling the reaction was diluted wlth ethyl acetate and extracted with water and brlne. Silica gel chromatography afforded 15.9g (85%) 3-chloro-5-fluorobenzonitrile.

[0270] The intermediate nitrile was treated wíth a solution of sodium hydroxide (100 mL of 10 N solution, 1 mol) in 100 mL water and heated at reflux for 2 hours. After this time the solution was cooled and acidified with concentrated hydrochloric acid. Extraction with dichloromethane and evaporation of the solvent, afforded 15.14g (85%) of 3-chloro-5-fluorobenzoic acid.

3-chloro-5-fluorobenzoic acid [0271]<img file="IS2564B_D0162.tif" /> [0272] 3-Chloro-5-fluorobenzoic acid (13.74g, 78.7 mmol) was treated with 50 ml thionyl chloride and heated at reflux for 2 hours. The excess thionyl chloride was removed in vacuo and the residue treated with 100 ml dry methanol to afford 13.6g (92%) of methyl 3-chloro-5-fluorobenzoate.

[0273] A mixture of the methyl 3-chloro-5-fluorobenzoate, zinc cyanide (8.46g, 72.3 mmol) zinc (dust, 235 mg, 3.6mmol), [1 J’bis(diphenylphosphlno)ferrocene) dichloropalladium(ll), complex with dichloromethane (1:1) (1.5 g, 1.8 mmol) in /V,/V-dimethylformamÍde (70 ml) was heated at reflux for 1 hour. The reaction was cooled to ambient temperature and diluted with ethyl acetate. The organic solution was extracted with water and brine and concentrated in vacuo, to afford crude methyl 3-chloro-5-cyanobenzoate.

[0274] The crude methyl 3-chloro-5-cyanobenzoate was treated with a solution of sodium hydroxide (45 ml of 4 N solution, 180 mmol) in methanol (350 mL) at ambient temperature for 4 hours. The solvent was removed in vacuo and the residue dissolved in ethyl acetate. The organic solution was washed with 5% aqueous HCI and brine. Silica gel chromatography afforded 7.0 g (54%) of 3-fluoro-5-cyanobenzoic acid.

EXAMPLE 3: Synthesis of 3-Chlorobenzhydrazide for Triazole Syntheses

3-chlorobenzhydrazide [0275] <img file="IS2564B_D0163.tif" /> [0276] A mixture of 3-chlorobenzoic acid (0.5 g, 3.19 mmol), 1,3-dicyclohexylcarbodiimide (0.72 g, 3.51 mmol), 4-dimethylaminopyridine (0.04 g, 0.32 mmol) in ethanol was stirred at ambient temperature for 1.5 hour. The white solid

was filtered off and the fíltrate diluted with dichloromethane (100 mL). The organic solution was washed with 1 N sodium hydrogen sulfate (100 mL), saturated sodium bicarbonate (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude residue was dissolved in ethanol (15 mL) and treated with hydrazine monohydrate (0.46 mL, 9.58 mmol). The resulting clear solution was stirred overnight at ambient temperature. The reaction mixture was then concentrated to dryness in vacuo. Silica gel chromatography.of the residue, using 3% methanol in dichloromethane, afforded 0.29 g (53%) of 3-chlorobenzhydrazide as a white solid.

EXAMPLE4

3-(2-Pyridyl)-5-dichlorophenyl)-1,2,4-oxadiazole [0277]

B2 <img file="IS2564B_D0167.tif" /> [0278] A mixture of 3,5-dichlorobenzoyl chloride (2.1 g, 10 mmol) and pyrid-2-ylamidoxime (1.37 g, 10 mmol) in pyridine (5 mL) was heated in sealed tube at 190 'C for 2 hours. After this time, the reaction mixture was added to ice cold water to precipitate the oxadíazole. The solid was collected by filtration, washed with water and then recrystal I ized from ethanol to yield 2.1 g (72%) of 3-(2-pyridy!)-5-(3,5-dichlorophenyl)-1,2,4-oxadiazole: mp 162-166 'C; GC/EI-MS gave m/z(rel. int.) 291 (M+, 38), 293 (25), 261 (1), 173 (6), 145 (13), 120 (100), 90 (20), 78 (28), 51 (15).

3-(2-Pyridyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole [0279]

B3 <img file="IS2564B_D0168.tif" /> [0280] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-chlorobenzoyl chloride (127 μΐ_, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at reflux for 4 hours. Standard work up afforded 156 mg (61 %) of 3-(2-pyridyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole: mp 136-140 'C; GC/EI-MS gave m/z(rel. int.) 257 (M+, 64), 259 (21), 227 (3), 120 (100), 111 (22), 90 (24), 78 (32), 75 (26), 51 (20).

3-(2-Pyridyl)-5-(3-methoxyphenyl)-1,2,4-oxadiazole [0281]

B1 <img file="IS2564B_D0169.tif" />

[0282] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-anisoyl chlorlde (151 ixL, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at reflux for 4 hours. Standard work up afforded 200 mg (79%) of 3-(2-pyridyl)-5-(3-methoxyphenyl)-1,2,4-oxadiazole: mp 96-99 'C; GC/EI-MS gave m/z (rel. int.) 253 (M+, 100), 223 (3), 179 (3), 135 (74), 133 (90), 92 (27), 78 (29), 77 (32), 64 (23), 63 (23).

3-(2-Pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole [0283]<img file="IS2564B_D0173.tif" /> [0284] Usingthegeneral procedureforthesynthesisof 1,2,4-oxadiazoles, 2-chlorobenzoyl chloride (127 p.L, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at reflux for 4 hours. Standard work up afforded 157 mg (61 %) of 3-(2-pyridyl)-5-(2-chlorophenyl)-1,2,4-oxadiazole: mp 93-94 ‘C; GC/EI-MS gave m/z (rel. int.) 257 (M+, 76), 259 (26), 227 (4), 139 (11), 120 (100), 111 (21), 90 (27), 78 (35), 75 (29), 51 (21).

3-(2-Pyridyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole [0285]<img file="IS2564B_D0174.tif" /> [0286] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-(1rlfluoromethyljbenzoyl chlorlde (151 μΐ, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at reflux for 16 hours. Standard work up afforded 233 mg (80%) of 3-(2-pyridyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: mp 116-118 'C; GC/EI-MS gave m/z(rel. int.) 291 (M+, 81), 272 (7), 173 (6), 145 (25), 120 (100), 90 (20), 78 (23), 51 (11).

3-(2-Pyridyl)-5-(3-fluorophenyl)-1,2,4-oxadiazole [0287] <img file="IS2564B_D0175.tif" /> [0288] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-fluorobenzoyl chloride (122 μι, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at reflux for 16 hours. Standard work up afforded 176 rng (73%) of 3-(2-pyridyl)-5-(3-fluoraphenyl)-1,2,4-oxadiazole: mp 88-98 ’C; GC/EI-MS gave m/z (rel. int.) 241 (M+, 95), 211 (5), 120 (100), 107 (13), 95 (30), 90 (21), 78 (27), 75 (19), 51 (15).

3-(2-Pyridyl)-5-(3-methylphenyl)-1,2,4-oxadiazole [0289]

B9 <img file="IS2564B_D0179.tif" /> [0290] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-toluoyl chloride (264 pL, 2 mmol) and pyrid-2-ylamidoxime (274 mg, 2 mmol) in pyridine (1 mL) were heated in a sealed tube at 200 ’C for 2 hours, Standard work up afforded 387 mg (82%) of 3-(2-pyridyl)-5-(3-toluoyl)-1,2,4-oxadiazole: mp 127-128 'C; GC/EI-MS gave m/z (rel. int.) 237 (M+, 100), 222 (2), 207 (8), 120 (68), 117 (24), 91 (29), 90 (29), 78 (32), 65 (26), 51 (23).

3-(2-Pyridyl)-5-(1 -naphthyl)-1,2,4-oxadiazole [0291]

B10 <img file="IS2564B_D0180.tif" /> [0292] Usingthegeneral procedureforthesynthesisof 1,2,4-oxadiazoles, 1-naphthoyl chloride (150 p.L, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated in a sealed tube at 200 ’C for 3 hours. Standard work up afforded 50 mg (18%) of 3-(2-pyridyl)-5-(1 -naphthyl)-1,2,4-oxadiazole: mp 132-136 "C; GC/EI-MS gave m/z (rel. int.) 273 (M+, 75), 195 (5), 169 (88), 153 (100), 139 (12), 127 (66), 126 (29), 105 (23), 78 (14), 51 (14).

3-(2-Pyridyl)-5-[3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazole [0293]

B11 <img file="IS2564B_D0181.tif" /> [0294] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-(trifluoromethoxy)benzoyl chloride (220 mg, 1 mmol), and pyrid-2-ylannidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated in a sealed tube at 200 'C for 3 hours. Standard work up afforded 175 mg (57%) of 3-(2-pyridyl)-5-[3-(trifluoromethoxy)phenyl]-1,2,4-oxadiazole: mp 86-88 'C; GC/EI-MS gave m/z(rel. int.) 307 (M+, 73), 277 (3), 222 (3), 189 (6), 161 (5), 120 (100), 78 (21), 69 (17), 51 (10).

3-(2-Pyridyl)-5-(2,3-difluorophenyl)-1,2,4-oxadiazole [0295]

ΒΊ6 <img file="IS2564B_D0185.tif" /> [0296] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 2,3-difluorobenzoyl chloride (124 pL, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml_) were heated at 100 ‘C for 16hours, Standard work upafforded 158 mg (61 %) of 3-(2-pyridyl)-5-(2,3-difluorophenyl)-1,2,4-oxadiazole: mp 120-121 'C; GC/EI-MS gave m/ z (rel. int) 259 (M+, 97), 229 (5), 228 (4), 141 (11), 120(100), 113 (26), 90 (27), 78 (34), 51 (17).

3-(2-Pyridyl)-5-(2,5-difluorophenyl)-1,2,4-oxadiazole [0297]

B17 <img file="IS2564B_D0186.tif" /> [0298] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 2,5-difluorobenzoyl chloride (124 μ|_, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at 100 'C for 16 hours. Standard work upafforded 3-(2-pyridyl)-5-(2,5-difluorophenyl)-1,2,4-oxadiazole: mp 120-126 ’C; GC/EI-MS gave m/z(rel. int) 259 (M+, 91), 229 (5), 228 (4), 141 (13), 120 (100), 113 (25), 90 (23), 78 (27), 51 (14).

3-(2-Pyridyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole [0299]

B18 <img file="IS2564B_D0187.tif" /> [0300] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3,5-difluorobenzoyl chloride (1.25 mL, 10 mmol) and pyrid-2-ylamidoxime (1.37 g, 10 mmol) in pyridine (5 mL) were heated in a sealed tube at 200 ’C for 4 hours. Standard work up afforded 1.2 g (46%) of 3-(2-pyridyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole: mp 115-119 'C; GC/EI-MS gave mlz(rel. int) 259 (M+, 100),229(4),228(5), 141 (9), 125 (13), 113(30),90 (19), 78(27), 63 (23), 51 (15).

3-(2-Pyridyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole [0301]

Β21 <img file="IS2564B_D0191.tif" /> [0302] Using the general procedure forthe synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl chloride (165 mg, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at 100 ‘C for 72 hours. Standard work up afforded 158 mg (64%) of 3-(2-pyridyl)-5-(3-cyanophenyl)-1,2,4-oxadlazole: mp 148-149 ’C; GC/EI-MS gave mtz (rel. int.) 248 (M+, 85), 218 (5), 130 (6), 120 (100), 114 (9), 102 (28), 90 (26), 78 (37), 75 (19), 51 (30).

3-(2-Pyridyl)-5-(3,5-dimethoxyphenyl)-1,2,4-oxadiazole [0303]

B23 <img file="IS2564B_D0192.tif" /> [0304] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3,5-dimethoxybenzoyl chloride (200 mg, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at 100 'C for 72 hours. Standard work up afforded 210 mg (74%) of 3-(2-pyridyl)-5-(3,5-dimethoxyphenyl)-1,2,4-oxadiazole: mp 145-148 'C; GC/EI-MS gavem/z(rel. ínt.)283(M+, 100),253(3),165 (69),163(19),137(36), 122 (33),107(17),90(10),78 (25),63(19),51 (19).

3-(2-Pyridyl)-5-(2,3-dichlorophenyl)-1,2,4-oxadiazole [0305]

B25 <img file="IS2564B_D0193.tif" /> [0306] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 2,3-dichlorobenzoyl chloride (209 mg, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at 100 'C for48 hours. Standard work up afforded 236 mg (81%) of 3-(2-pyridyl)-5-(2,3-dichlorophenyl)-1,2,4-oxadiazole: mp 128-133 ’C; GC/EI-MS gave m/ z (rel. int.) 291 (M+, 66), 293 (43), 256 (6), 173 (10), 145 (11), 120 (100), 90 (19), 78 (27), 51 (14).

3-(2-Pyridyl)-5-(3-chloro-5-cyanophenyl)-1,2,4-oxadiazole [0307]

Β26 <img file="IS2564B_D0197.tif" /> [0308] 3-Chloro-5-cyanobenzolc acid (0.82 g, 4.97 mmol) was treated with a solution of oxalyl chloride (10 mL of 2.5 M in dichloromethane, 25 mmol) and a catalytic amount of Ν,Ν-dimethylformamide. The reaction was stirred at ambient temperature for 2.5 hours. The excess oxalyl chloride was removed in vacuo to afford 3-chloro-5-cyanobenzoyl chloride. [0309] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, the 3-chloro-5-cyanobenzoyl chloride and pyrid-2-ylamidoxime (682 mg, 5 mmol, 1 equivalent) in pyridine (5 mL) were heated in a sealed tube at 175 'C for 4 hours. Standard work up and recrystallization from 2-propanol afforded 250 mg (19%) of 3-(2-pyridyl)-5-(3-chloro-5-cyanophenyl)-1,2,4-oxadiazole: GC/EI-MSgave m/z(rel. int.) 282 (M+, 100), 283 (18), 284 (34), 251 (4), 136 (10), 120 (53),100 (10),78(15),51 (6).

3-(2-Pyridyl)-5-(3-fluoro-5-cyanophenyl)-1,2,4-oxadiazole [0310]

B27 <img file="IS2564B_D0198.tif" /> [0311] 3-Fluoro-5-cyanobenzoic acid (2.5 g, 15.14 mmol) was treated with a solution of oxalyl chloride (30 mL of 2.5 M in dichloromethane, 75 mmol) and a catalytic amount of /V,A/-dimethylformamide. The reaction was stirred at ambient temperature for 2.5 hours. The excess oxalyl chloride was removed in vacuoto afford 3-fluoro-5-cyanobenzoyl chloríde. [0312] Using the general procedure forthe synthesis of 1,2,4-oxadiazoles, the 3-fluoro-5-cyanobenzoyl chloride and pyrid-2-ylamidoxime (2.076 g, 15.15 mmol, 1 equivalent) in pyridine (5 mL) were heated in a sealed tube at 175 ’C for 4 hours. Standard work up and recrystallization from 2-propanol afforded 1.5 g (37%) of 3-(2-pyridyl)-5-13-fluoro-5-cyanophenyll-1,2,4-oxadiazole: GC/EI-MS gave m/z(rel. int.) 266 (M+, 81), 267 (13), 235 (5), 132 (12), 120 (100), 100 (18),90(18), 78 (35),51 (20).

3-(2-Pyridyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-oxadiazole [0313]

B28 <img file="IS2564B_D0199.tif" /> [0314] 3-Chloro-5-fluorobenzoic acid (400 mg, 2.3 mmol) was treated with a solution of oxalyl chloride (4.6 mL of 2.5 M in dichloromethane, 11.5 mmol) and a catalytic amount of /V,/V-dirnethy Ifo rmamide. The reaction was stirred at ambient temperaturefor2.5 hours. Theexcess oxalyl chloride was removed in vacuoto afford 3-chloro-5-fluorobenzoyl chloride.

[0315] Using the general procedure for the synthesis of 1,2,4-oxadíazoles, the 3-chloro-5-fluorobenzoyl chloride and pyrid-2-ylamidoxime (314 mg, 2.3 mmol, 1 equivalent) in pyridine (5 mL) were heated in a sealed tube at 175 ’C for 4 hours. Standard work up and recrystallization from 2-propanol afforded 250 mg (39%) of 3-(2-pyridyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-oxadiazole: GC/EI-MS gave m/z (rel. int.) 275(M+, 89), 276 (14), 277 (29), 129 (26), 120 (100), 109 (7),90 (20),78 (31),51 (14).

3-(5-Chloropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole [0316]

B29 <img file="IS2564B_D0203.tif" /> [0317] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl chloride (675 mg, 4mmol) and 5-chloropyrid-2-ylamidoxime (686 mg, 4 mmol) in pyridine (5 mL) were heated in a sealed tube at 175 'C for 4 hours. Standard work up and recrystallization from 2-propanol afforded 357 mg (32%) of 3-(5-chloropy rid-2-y l)-5-(3-cyanophe-nyl)-1,2,4-oxadiazole: GC/EI-MS gave m/z(rel. int.) 282 (M+, 85), 283 (14), 284 (27), 156 (31), 154(100), 112 (19), 102 (30), 76 (28),64(13).

3-(5-Fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole [0318]

B30 <img file="IS2564B_D0204.tif" /> [0319] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl chloride (0.534 g, 3.2 mmol) and 5-fluoropyrid-2-ylamidoxime (0.5 g, 3.2 mmol) in pyridine (5 mL) were heated in a sealed tube at 175 ’C for 4 hours. Standard work up and recrystallization from 2-propanol afforded 370 mg (43%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole: GC/EI-MS gave m/z(rel. int.) 266 (M+, 100), 267 (10), 138 (80), 114 (8), 102 (19), 96 (22), 76 (17), 57 (8).

3-(5-Fluoropyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole [0320]

B31 <img file="IS2564B_D0205.tif" /> [0321] 3-Fluoro-5-cyanobenzoic acid (1.0 g, 6 mmol) was treated with a solution of oxalyl chloride (12 mL of 2.5 M in dichloromethane, 30 mmol) and a catalytic amount of N,/V-dimethylformamide. The reaction was stirred at ambient

temperature for 2.5 hours. The excess oxalyl chloride was removed in vacuo to afford 3-fluoro-5-cyanobenzoyl chloride. [0322] Using the general procedure forthe synthesis of 1,2,4-oxadiazoles, the 3-fluoro-5-cyanobenzoyl chloride (1.1 g, 6 mmol) and 5-fluoropyrid-2-ylamidoxime (0.93 g, 6 mmol) in pyridine (5 mL) were heated in a sealed tube at 175 'C for 4 hours. Standard work up and recrystallization from 2-propanol aftorded 0.41 g (24%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole: GC/EI-MS gave m/z(rel. int.) 284 (M+, 100), 285 (16), 253 (2), 138 (99), 120 (23),108 (16),96 (25),82 (15), 57(11).,

3-(3-Fluoropyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole [0323]

B32 <img file="IS2564B_D0209.tif" /> [0324] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl chloride (107 mg, 0.64 mmol) and 3-fluoropyrid-2-ylamidoxime (0.1 g, 0.64 mmol) in pyridine (5 mL) were heated in a sealed tube at 175 ‘C for 4 hours. Standard work up, silica gel chromatography, and recrystallization from 2-propanol, afforded 32 mg (19%) of 3-(3-fluoropyrid-2-yl)-5-(3-cyanophenyl)-1 ,2,4-oxadiazole: GC/EI-MS gave m/z (rel. int.) 266 (M+, 75), 267 (12), 138 (100), 114(11), 102 (19),96(17),76 (16),57 (5),51 (5).

3-(5-Fluoropyrid-2-yl)-5-(3,5-dimethoxyphenyl)-1,2,4-oxadiazole [0325]

B33 <img file="IS2564B_D0210.tif" /> [0326] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3,5-dimethoxybenzoyl chloride (0.10 g, 0.5 mmol) and 5-fluoropyrid-2-ylamidoxime (78 mg, 0.5 mmol) in pyridine (3 mL) were heated in a sealed tube al 175 •C for 4 hours. Standard work up, silica gel chromatography, and recrystallization from 2-propanol afforded 94 mg (62%) of 3-(5-fluoropyrid-2-yl)-5-(3,5-dimethoxyphenyl)-1,2,4-oxadiazole: GC/EI-MS gave m/z (rel. int.) 301 (M+, 100), 302 (17), 165 (41), 137 (23), 122 (27), 96 (15), 77 (11), 63 (12).

3-(5-Methoxypyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole [0327]

B34 <img file="IS2564B_D0211.tif" />

[0328] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl chloride (79 mg, 0.47 mmol) and 5-methoxypyrid-2-ylamidoxime (79 mg, 0.47 mmol) in pyridine (2.5 mL) were heated in a sealed tube at 175 'C for 4 hours. Standard work up, silica gel chromatography, and recrystallization from 2-propanol afforded 59 mg (45%) of 3-(5-methoxypyrid-2-yl)-5-(3-cyanophenyl)-1,2,4’Oxadiazole.· GC/EI-MS gave m/z(rel. int.) 278 (M+, 100), 279 (16), 150 (56), 128 (7), 107 (21), 102 (17), 80 (12), 64 (5).

3-(2-Quinolinyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole [0329]

B35 <img file="IS2564B_D0215.tif" /> [0330] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl chloride (68 mg, 0.41 mmol) and quinol-2-ylamidoxime (75.9 mg, 0.405 mmol) in pyridine (0.5 mL) were heated in a sealed tube at 165 'C for 22 hours. Standard work up, recrystallization from ethanol, and solid phase extraction (SPE) afforded 23.7 mg (20%) of 3-(2-quinolinyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.62 (s, 1H), 8.54 (d, 1H), 8.36 (d, 2H), 8.28 (d, 1H), 7.90 (d, 2H), 7.80 (t, 1H), 7.72 (t, 1H), 7.64 (t, 1H).

3-(3-chloro-5-trifluoromethylpyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole [0331]

B36 <img file="IS2564B_D0216.tif" /> [0332] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl chloride (66 mg, 0.40 mmol) and 3-chloro-5-trifluoromethylpyrid-2-ylamidoxime (96.5 mg, 0.403 mmol) in pyridine (0.5 mL) were heated in a sealed tube at 165 ’Cfor22 hours. Standard work up and solid phase extraction (SPE) afforded 45.9 mg (33%) of 3-(3-chloro-5-trifluoromethylpyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole. 1H-NMR(CDCI3), δ (ppm): 8.99 (s, 1H), 8.57 (s, 1H), 8.49 (d, 1H), 8.19 (s, 1H), 7.92 (d, 1H), 7.72 (t, 1H).

3-(2-pyridyl)-5-(5-chloro-2-methoxyphenyl)-1,2,4-oxadiazole [0333]

B37 <img file="IS2564B_D0217.tif" /> [0334] 5-Chloro-O-anisic acid (187 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in

dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2 hours. The excess oxalyl chloride was removed in vacuo to afford 5-chloro-2-methoxybenzoyl chloride. [0335] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, the 5-chloro-2-methoxybenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at 115 'C for 17 hours. Standard work up, and silica gel chromatography afíorded 49 mg (17%) of 3-(2-pyridy 1)-5-(5 -chloro-2-methoxypheny I)-1,2,4-oxadiazole.1H-NMR (CDCI3), δ (ppm): 4.00(s, 3H), 7.03 (d, J = 8.9Hz, 1H), 7.42-7.47 (m, 1H), 7.50 (dd, J = 8.9 Hz, 2.8 Hz, 1H), 7.87 (ddd, J = 1.4 Hz, 7.4 Hz, 8.2 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.84 (m, 1H).

3-(2-pyridyl)-5-(2,3-dimethoxypheny!)-1,2,4-oxadiazole [0336]

B38 <img file="IS2564B_D0221.tif" /> [0337] 2,3-Dimethoxybenzoic acid (182 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of Ν,Ν-dimethylformamide. The reaction was stirred at ambient temperature for 2 hours. The excess oxalyl chloride was removed in vacuo to afford 2,3-dimethoxybenzoyl chloride.

[0338] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, the 2,3-dimethoxybenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at 115 'C for 17 hours. Standard work up and silica gel chromatography afforded 120 mg (42%) of 3-(2-pyridyl)-5-(2,3-dimethoxyxyphenyl)-1,2,4-oxadiazole.

3-(2-pyridyl)-5-(2-ch!oro-5-methylthiophenyl)-1,2,4-oxadiazole [0339]

B39 <img file="IS2564B_D0222.tif" /> [0340] 2-Chloro-5-methylthiobenzoic acid (182 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N./V-dimethylfomnamide. The reaction was stirred at ambient temperature for 2 hours. The excess oxalyl chloride was removed in vacuo to afford 2-chloro-5-methylthiobenzQyl chloride.

[0341] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, the 2-chloro-5-methylthiobenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at 115'Cfor 17hours. Standard work up and silica gel chromatography afforded 250 mg (82%) of 3-(2-pyridyl)-5-(2-chloro-5-methylthiophenyl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 7.37 (dd, J = 2.4Hz, 8.2 Hz, 1H), 7.40-7.50 (m, 2H), 7.89 (ddd, J = 1.4 Hz, 7.4 Hz, 8.2 Hz, 1H ), 8.05 (d, J = 2.4 Hz, 1H), 8.23 (dd, J = 2.2 Hz, 8.0 Hz, 1 x H), 8.85 (m, 1H).

3-(2-Pyridyl)-5-(3-phenoxyphenyl)-1,2,4-oxadiazole [0342]

Β40 <img file="IS2564B_D0225.tif" /> [0343] 3-Phenoxybenzoic acid (214 mg, 1.0 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of A/,/V-dimethylfomnamide. The reaction was stirred overnight at ambienl temperature. The excess oxalyl chloride was removed in vacuoto afford 3-phenoxybenzoyl chloride [0344] Using the general procedure for Ihe synthesis of 1,2,4-oxadiazoles, the 3-phenoxybenzoyl chloride and pyrid-

2- ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated in a sealed vial overnight at 110 'C. Standard work up afíorded 118 mg (37%) of 3-(2-pyridyl)-5-(3-phenoxyphenyl)-1,2,4-oxadiazole as a white solid.

3- (2-Pyridyl)-5-(3-benzoylphenyl)-1,2,4-oxadiazole [0345]

B41 <img file="IS2564B_D0226.tif" /> [0346] 3-Benzoylbenzoic acid (226 mg, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of A/,A/-dimethylformamide. The reaction was stirred ovemight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afíord 3-benzoyl-benzoyl chloride.

[0347] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, the 3-benzoylbenzoyl chloride and pyrid-

2- ylamÍdoxime (137 mg, 1 mmol) in pyridíne (1 mL) were heated ín a sealed vial overnight at 110 ’C. Standard work up and filtration through silica gel (with dichloromethane) afforded 200 mg (61 %) of 3-(2-pyrldy l)-5-(3-benzoy I pheny I)-1,2,4-oxadiazole as a white solid. 1H NMR (CDCI3), δ (ppm): 8.85 (d, 1H), 8.68 (m, 1H), 8.53 (dd, 1H), 8.23 (d, 1H), 8.07 (m, 1H), 7.88 (m, 3H), 7.70 (m, 2H), 7.49 (m, 3H).

3- (2-Pyridyl)-5-(2-bromo-5-methoxyphenyl)-1,2,4-oxadiazole [0348]

B42 <img file="IS2564B_D0227.tif" /> [0349] 2-Brorrio-5-methoxybenzoic acid (231 mg, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of A/,N-dimethylformamide. The reaction was stirred overnight at ambient temperature, The excess oxalyl chloride was removed in vacuo to afíord 2-bromo-5-methoxybenzoyl chloride.

[0350] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, the 2-bromo-5-methoxybenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated In a sealed vial overnight at 110 ’C. Standard

work up and filtration through silica gel (with dichloromethane) afforded 147 mg (44%) of 3-(2-pyridyl)-5-(2-bromo-5-methoxyphenyl)-1,2,4-oxadiazole. 1H NMR (CDCI3), δ (ppm): 8.85 (d, 1H), 8.24 (d, 1H), 7.89 (m, 1H), 7.65 (m, 2H), 7.47 (m, 1H), 6.99 (m, 1H), 3.89 (S, 3H).

3-(2-Pyridyl)-5-(2-chloro-5-(trifluoromethyl)phenyl)-1,2,4-oxadiazole [0351]

B43 <img file="IS2564B_D0231.tif" /> [0352] 2-Chloro-5-(trifluoromethyl)benzoic acid (224 mg, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N, N-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afford

2- chloro-5-(trifluoromethyl)benzoyl chloride.

[0353] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, the 2-chloro-5-(trifluoromethyl)benzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated in a sealed vial overnight at 110 ‘C. Standard work up and filtration through silica gel (with dichloromethane) afforded 136 mg (42%) of 3-(2-pyridyl)-5-(2-chloro-5-(trifluoromethyl)phenyl)-1,2,4-oxadiazole asabeige solid. 1H NMR (CDCI3), δ (ppm): 8.87 (d, 1H), 8.56 (s, 1H), 8.25 (d, 1H), 7.89 (m, 1H), 7.78 (m, 2H), 7.50 (m, 1H).

3- (2-Pyridyl)-5-(3,4,5-trif!uorophenyl)-1,2,4-oxadiazole [0354]

B44 <img file="IS2564B_D0232.tif" /> [0355] 3,4,5-Trifluorobenzoic acid (0.176 g, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of /V,/V-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed /n vacuo to afford 3,4,5-trifluorobenzoyl chloride.

[0356] Using the general procedure for the synthesis of 1,2,4-oxadiazoles, the 3,4,5-trifluorobenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated in a sealed vial overnight at 110'C. Standard work up and silica gel chromatography (with 10-30% ethyl acetate in hexane) afforded 15 mg (5%) of 3-(2-pyridyl)-5-(3,4,5-trifluorophenyl)-1,2,4-oxadiazole as a white solid.

3-(2-pyridyl)-5-(2,5,6-trifluorophenyl)-1,2,4-oxadiazole [0357]

Β45 <img file="IS2564B_D0235.tif" /> [0358] 2,5,6-Trifluorobenzoic acid (176 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of A/,N-dimethylfomnamide. The reaction was stirred at ambient temperature for 16 hours. The excess oxalyl chloride was removed in vacuo to afford 2,5,6-trifluorobenzoyl chloride.

[0359] A solution of the intermediate 2,5,6-trifluorobenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in dichloromethane was stirred at ambient temperature for 0.5 hours, Silica gel chromatography afforded 151 mg (51 %) of /V-[(2,5,6-triftuorobenzoyl) oxy]pyridine-2-carboximidamide.

[0360] A solution of N-((2,5,6- trifiuorobenzoyl)oxy)pyridine-2-carboximldamlde (50 mg, 0.169 mmol) in pyridine (0.3 mL) was heated at 115'C for 17 hours. Standard work up, and silica gel chromatography, afforded 9.5 mg (20%) of 3-(2-pyridyl)-5-(2,5,6-trifluorophenyl)-1,2,4-oxadiazole.

3-(3-Methoxyphenyl)-5-(2-pyridyl)-1,2,4-oxadiazole [0361]

B8 <img file="IS2564B_D0236.tif" /> [0362] Using modifications of the method of Shine et al., J. Heterocyclic Chem. (1989) 26:125-128, a solution of picolinic acid (123 mg, 1 mmol) in pyridine (1 mL) was treated with 1,1 ’-carbonyldiimidazole (162 mg, 1 mmol) and the reaction stirred at ambient temperature until the evolution of carbon dioxide ceased (30 min). The intermediate acylim· idazole was then treated with 3-methoxybenzamidoxime (166 mg, 1 mmol) and the reaction heated at reflux for 1 hour. Ice cold water was added to the reaction mixture to precipitate the oxadiazole. The solid was collected by filtration, washed with water and dried to afford 80 mg (32%) of 3-(3-methoxyphenyl)-5-(2-pyridyl)-1,2,4-oxadiazole: mp 90-94 *C; GC/EI-MS gave m/z (rel. int.) 253 (M+, 100), 254 (17), 179 (2), 175 (2), 149 (77), 133 (33), 119 (4), 106 (29), 78 (45),51 (18).

3-(Pyrid-2-yl)-5-(2-hydroxyphenyl)-1,2,4-oxadiazole [0363]

B46 <img file="IS2564B_D0237.tif" /> [0364] Using the method of Korbonits et al„ J. Chem. Soc. Perkin Trans. I (1982) 759-766, a mixture of ethyl salicylate (200 mg, 1.2 mmol), pyrid-2-ylamidoxime (82.5 mg, 0.6 mmol), 21 % sodium ethoxide (19.4 mL, 6 mmol) in ethanol (12mL) was healed at reflux for 16 hours. After cooling, the reaction mixture was diluted with dichloromethane (50 mL) and washed with water and saturated sodium hydrocarbonate. The organic layer was dried with sodium sulfate and concentrated in vacuo. Recrystallization from diethyl ether afforded 15 mg (5%) of 3-(Pyrid-2-yl)-5-(2-hydroxyphenyl)-

1,2,4-oxadiazole.

3-(2-pyridyl)-5-(5-chloro-2-hydroxyphenyl)-1,2,4-oxadiazole [0365]

B47 <img file="IS2564B_D0241.tif" /> [0366] In a similar fashion, methyl 5-chloro-2-hydroxybenzoale (372 mg, 2 mmol), pyrid-2-ylamidoxime (137 mg, 1 mmol), 21 % sodium ethoxide (32.4 mL, 10 mmol) in ethanol (20 mL) were heated at reflux for 16 hours. Standard work up and recrystallization from diethyl ether afforded 14.2 mg (5%) of 3-(2-pyridyl)-5-(5-chloro-2-hydroxyphenyl)-l,2,4-oxadiazola.

3-(2-pyridyl)-5-(2-aminophenyl)-1,2,4-oxadiazole [0367]

B48 <img file="IS2564B_D0242.tif" /> [0368] UsingmodificationsfromtheprocedureofNagaharaeial., Chem. Pharm. Bull., (1975)23:3178-3183, amixture of isatoic anhydride (163 mg, 1 mmol) and pyrid-2-ylamldoxime (137 mg, 1 mmol) in pyridine (1 ml) was heated at 115 'C for 17 hours. After cooling the reaction, the mixture was diluted with 50 mL of dichloromethane and washed with water and saturated sodium hydrocarbonate. The organic layer was dried over sodium sulfate, filtered through silica gel and concentrated in vacuo. Recrystallization from diethyl ether afforded 45.6 mg (19%) of 3-(2-pyridyl)-5-(2-aminophe-nyl)-1,2,4-oxadiazole.

3-(2-pyridyl)-5-(2-aminophenyl)-1,2,4-oxadiazole [0369]

B49 <img file="IS2564B_D0243.tif" /> [0370] In a similar fashion, 5-chloroisatoic anhydride (197 mg, 1 mmol) and pyrid-2-ylaniidoxime (137 mg, 1 mmol) in pyridine (1 mL) was heated at 115 'C for 17 hours. Work up afforded 138 mg (51 %) of 3-(2-pyridyl)-5-(2-am inophenyl)-

1,2,4-oxadiazole.

2-[3-chlorophenyl]-4-[pyridin-2-yl]-1,3-oxazole [0371]

B5O <img file="IS2564B_D0247.tif" /> [0372] Using the procedures oí Kelly et al., J. Org. Chem., (1996) 61:4623-4633, a solution of 2-bromoacetylpyridine (120 mg, 0.6 mmol) in toluene (5mL) was treated with 3-chlorobenzamide (300 mg, 1.9 mmol) and the mixture heated in a sealed vial at reflux for 60 hours, The mixture was then cooled and the solvent was removed in vacuo. Silica gel chromatography using a gradient of hexane to ethyl acetate afforded 38 mg (9%) of 2-[3-chlorophenyl]-4-[pyridin-2-yI]-1,3-oxazole as a pale yellow solid. 1H-NMR (CDCI3), δ (ppm): 8,62 (d, 1H), 8.35 (s, 1H), 8.15 (m, 1H), 8.00 (m, 2H), 7.80 (td, 1H), 7.42 (m, 2H), 7.23 (m, 1H).

2-[3-Bromophenyl]-4-[pyridin-2-yl]-1,3-oxazoíe [0373]

B51 <img file="IS2564B_D0248.tif" /> [0374] In a similar fashion 2-bromoacetylpyrídine (500 mg, 2.5 mmol) and 3-chlorobenzamida (1,2g, 6 mmol) in toluene (10 mL) was heated in a sealed vial at reflux for 60 hours. Work up and silica gel chromatography using a gradient of hexane to ethyl acetate afforded 50 mg (7%) of 2-[3-bromophenyl]-4-[pyridin-2-yl]-1,3-oxazole as a white solid. ’H-NMR (CDCIg), δ (ppm): 8.60 (d, 1H), 8.34 (s, 1H), 8.30 (t, 1H), 8.00 (m, 2H), 7.80 (td, 1H), 7.60 (dd, 1H), 7.35 (t, 1H), 7.23 (m, 1H).

2-[3-cyanophenyl]-4-[pyridin-2-yl]-1,3-oxazole [0375]

B52 <img file="IS2564B_D0249.tif" /> [0376] A mixture of 2-[3-bramophenyl]-4-[pyridin-2-yl]-1,3-oxazole (23 mg, 0.076 mmol) and zinc cyanide (112 mg, 0.96 mmol) in Λ/,/V-dimethylformamide (2 mL) was treated with Pd(PPh3)4 (74 mg, 0.064 mmol) and heated overnight at 80’C. Standard work up and chromatography afforded 6 mg (32 %) of 2-[3-cyanophenyl]-4-[py ridin-2-y l]-1,3-oxazole as a white solid. 1H-NMR (CDCI3), δ (ppm); 8.61 (d, 1H), 8.45 (s, 1H), 8.38 (s, 1H), 8.36 (m, 1 H),8.00 (d, 1H), 7.80 (m, 2H), 7.61 (t, 1H), 7.23 (m, 1H).

5-[3-hydraxyphenyl]-3-[pyridin-2-yl]-1,2-oxazole [0377]

Β53 <img file="IS2564B_D0253.tif" /> [0378] A stirred solution of pyridine-2-carbohydroxinnoyl chloride (300 mg, 1.9 mmol) and 3-hydroxyphenylacetylene (760 mg, 6.4 mmol) in a 1:1 mixture of THF/CH2CI2 (10 mL) at 0 ’C was treated with triethylamine (2 mL, 1.45 g, 15 mmol). The mixture was allowed to warm to room temperature ovemight. The solvent was removed in vacuo. The residue was dissolved in dichloromethane, washed with brine and dried over anhydrous sodium sulphate. Removal of the solvent in vaœofollowed by trituration wlth 10% ethylacetate in hexane afforded 200 mg (44%) of 5-[3-hydroxypheny l]-3-[py ridin-

2- yl]-1,2-oxazole as a beige solid.

5-[3-cyanophenyl]-3-[pyridin-2-yl]-1,2-oxazole [0379]

B54 <img file="IS2564B_D0254.tif" /> [0380] A mixture of 5-[3-trifluoromethanesulfonylphenyl]-3-[pyridin-2-yl]-1,2-oxazole (98 mg, 0.26 mmol), KCN (230 mg, 4 mmol), NiBr2(PPh3)2 (52.4 mg, 0.07 mmol), and PPh3 (42 mg, 0.16 mmol) in acetonrtrile (1 mL) was treated with zinc powder (20 mg, 0.3 mmol) and the mixture was heated overnight at 60 'C. Silica gel chromatography of the resulting mixture using a gradient of hexane to ethyl acetate afforded 15 mg (23 %) of 5-[3-cyanophenyl]-3-[pyridin-2-yl]-1,2-oxazole as a white solid.

3- (2-Pyridyl)-5-(3-chlorophenyl)-1,2,4-triazole [0381]

B55 <img file="IS2564B_D0255.tif" /> [0382] Using the procedures of Browne et al., Aust. J. Chem., (1975) 28:2543-2546, a solution of 2-cyanopyridine (0.1 mL, 1.00 mmol) in methanol (5 mL) was treated with sodium metal (6.9 mg, 0.30 mmol) and stirred for at ambient temperature for 1 hour. Afterthis time, a solution of 3-chlorobenzhydrazide (0.17 g, 1.0 mmol) in methanol (5 mL) was added and the resulting solution heated at reflux for 3 hours. The reaction mixture was concentrated in vacuo, and the resulting yellow solid (100 mg) dissolved in toluene (2 mL). The mixture was heated at 175 ’C for 3 hours and then stirred overnight at ambient temperature. Evaporation of the solvent in vacuo and silica gel chromatography using 1 % methanol in dichloromethane aflorded 29 mg (11 %) of 3-(2-pyridyl)-5-(3-chlorophenyl)-1,2,4-triazole as an off-white solid.

3-(2-Pyridyl)-5-(3-iodophenyl)-1,2,4-triazole [0383]

Β56 <img file="IS2564B_D0259.tif" /> [0384] In a similar fashíon, 2-cyanopyridine (0,15 mL, 1.53 mmol), sodium metal (10.5 mg, 0.46 mmo!) and 3-iodo-benzhydrazide (0.40 g, 1.53 mmol) afforded, after work up and chromatography, 210 mg (40%) of 3-(2-pyridyl)-5-(3-iodophenyl)-1,2,4-triazole as a white solid.

EXAMPLE 5

3-(5-Methyl-pyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole [0385]

B57 <img file="IS2564B_D0260.tif" /> [0386] A suspension of 5-methylpyrid-2-ylamidoxime (449.5 mg, 2.97 mmol) in dichloromethane (10 mL) was treated with 3-cyanobenzoyl chloride (495 mg, 2.99 mmol) and the mixture strrred 30 minutes. The solvent was removed in vacuo and the intermediate dissolved in /V,/V-dlmethylformaniide (15 mL). The reaction was heated, under an argon atmosphere, for 20 hours at 120 "C. After this time, the reaction mixture was cooled and the solvent removed in vacuo. Silica gel chromatography using a gradient of 20% to 75% ethyl acetate in hexane afforded 674 mg (86%) of 3-(5-methyl-pyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole; 'H-NMR (CDCI3), δ (ppm):DD8.69 (s, 1H), 8.60 (s, 1H), 8.51 (d, 1H), 8.12 (d, 1H), 7.90 (d, 1H), 7.72 (t, 2H).

3-(5-Cyano-pyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole [0387]

B58 <img file="IS2564B_D0261.tif" /> [0388] Method A: In a similar fashion, a solution of 5-tert-butoxycarbonylpyríd-2-ylamidoxime (89.5 mg, 0.38 mmol) In dichloromethane (5 mL) was treated with 3-cyanobenzoyl chloride (64.9 mg, 0.39 mmol) and stirred 2 minutes at room temperature. Saturated sodium bicarbonate (1 mL) was added and the resulting mixture stirred vigorously for 30 minutes. The mixture was passed through an EX-TUBE (3 mL) and the produci was eluted with dichloromethane (25 mL). The organic wash was concentrated in vacuo, and the intermediate dissolved in W,A/-dimethylformamide (2.5 mL). The solution was heated in sealed tube for 21 hours at 120 ’C. After this time, the reaction mixture was added to ice cold water and the crude oxadiazole collected and dried. Silica gel chromatography using a gradient of 10% to 30%

ethyl acetate in hexane afforded 114.2 mg (87%) of 3-(5-tert-butoxycarbonyl-2-pyridyl)-5-(3-cyanophenyl)-1,2,4-oxadi-azole.

[0389] Method B: A mixture of 3-(5-cyanopyridyl)amidoxime (95mg, 0.586 mmol) 3-cyanobenzoyl chloride (96mg, 0.586 mol) and triethylamine (175 mg, 1.74 mmol) in dichloromethane were stirred for 5 min. Then DMF (1ml) was added to the reaction mixture. The mixture was heated to 120 'C for 16 hrs. After cooling the mixture was poured into water. The solid was filtered and washed with water, then triturat ed in ether to provide 125 mg, (78%) of 3-(5-tert-butoxycarbonyl-

2- pyridyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole, [0390] A mixture of 3-(5-íert-butoxycarbonylpyrid-2-yl)-5-(3-cyanopbenyl)-1,2,4-oxadiazole (114 mg, 0.33 mmol) in formic acid (98%, 6 mL) was heated for 2 days at 45 'C. The incomplete reaction was resubjected to additional formic acid (96%, 6 mL) for 1 day at 45 ’C. Co-evaporation of the solvent ín vacuo using toluene afforded 103.6 mg of 3-(5-hydroxycarbonylpyrid-2-yl)-5-(3-cyanophenyl)-l ,2,4-oxadiazole, as a white solid.

[0391 ] A suspension of 3-(5-hydroxycarbonylpyrid-2-yl)-5-(3-cyanophenyl)-1,2,4-oxadiazole (49.7 mg, 0.17 mmol) in dichloromethane (5 mL) was treated with 2M oxalyl chloride (0.19 mL, 0.38 mmol, dichloromethane) and a catalytic amount of /V,/V-dimethyIformannide. The reaction was stlrred at ambient temperature for 1 hour and solvents removed in vacuo. The acid chloride was dissolved in dichloromethane (5 mL) and treated with concentrated ammonium hydroxide (1 mL) for 1 hour. The aqueous layer was removed and the remaining organic solvent evaporating in vacuo, azeotroping with ethanol.

[0392] The crude amide in thionyl chloride (1.5 mL) was heated for 4.5 hours at 80 'C. After cooling, the excess thionyl chloride was removed in vacuo and the residue dissolved in dichloromethane. The organic solution was washed with aqueous sodium carbonate and dried by passing through an EX-TUBE. Silica gel chromatography using a gradient of 20% ethyl acetate in hexane to 100% ethyl acetate afforded 22.2 mg (47%) of 3-(5-cyano-pyrid-2-yl)-5-(3-cyanophenyl)-

1,2,4-oxadiazole: 1H-NMR(CDCI3),6(ppm):aO9.11 (s, 1H),8.59 (s, 1H), 8.51 (d, 1H), 8.37 (d, 1H), 8.20 (dd, 1H), 7.94 (d, 1H), 7.75 (t, 1H).

3- (5-Cyano-2-pyridyl)-5-(3-bromophenyl)-1,2,4-oxadiazole [0393]

B59 <img file="IS2564B_D0265.tif" /> [0394] A mixture of 3-bromobenzoyl chloride (0.17 mL, 1.28 mmol) and 5-tert-butoxycarbonylpyrid-2-ylamidoxime (302 mg, 1.27 mmol) in dichloromethane (10 mL) wasstirred at room temperature for 30 minutes. The solvent was removed /n vacuo. The intermediate was dissolved in N.AFdimethylformamide (7.5 mL) and heated in sealed tube at 120 ’C for 23 hours. The solvent was then removed in vacuo. Silica gel chromatography uslng a gradient of 5% to 10% ethyl acetate in hexane afforded 329 mg (64%) of 3-(5-tert-butoxycarbonyl-2-pyrldyl)-5-(3-bromophenyl)-1,2,4-oxadia-zole.

[0395] A mixture of 3-(5-fert-butoxycarbonylpynd-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole (100 mg, 0.25 mmol) in formic acid (98%, 6 mL) was beated at 45 "C for 23 hours. Evaporation of the solvent in vacuo followed by trituration with dichloromethane afforded 3-(5-hydroxycarbonylpyrid-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole (65.4 mg, 76%) as awhite solid.

[0396] A mixture of 3-(5-hydroxycarbonylpyrid-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole (269.4 mg, 0.78 mmol) in dichloromethane (15 mL) was treated with 2M oxalyl chloride (0.90 mL, 1.8 mmol, dichloromethane) and a catalytic amount /V,/V-dimethylformamide. The resulting mixture was stirred at ambient temperature for 1.5 bours and the solvení and excess oxalyl chloride removed, in vacuo. The acid chlorlde in dichloromethane (5 mL) was then treated with solid ammonium chloride (450 mg, 8.4 mmol) and pyridine (1.5 mL, 18.5 mmol). The mixture was stirred vigorously at ambient temperature for 15 hours, and then treated with 2M ammonia (5 mL, 10 mmol, methanol). The solvent was then removed in vacuo, and the residue treated with water. Collectíon of the precipítate by filtration afforded crude 3-(5-aminocarbo-nylpyrid-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole.

[0397] A solution of this intermediate amide in thionyl chloride (5 mL) was heated for 6 hours at 80 ’C. After ccoling, the excess thionyl chloride was removed in vacuo. The residue was dissolved in dichloromethane, washed with aqueous sodium carbonate and dried by passing through an EX-TUBE. Silica gel chromatography using a gradient of 5% to 30%

ethyl acetate in hexane, afforded 130.8 mg (51 %) of 3-(5-cyano-2-pyridy l)-5-(3-bromopheny!)-1,2,4-oxadiazole:1H-NMR (CDCI3), δ (ppm): 9.10 (s, 1H), 8.45 (s, 1H), 8.36 (d, 1H), 8.18 (m, 2H), 7.78 (dd, 1H), 7.47 (t, 1H).

3-(5-Cyano-2-pyridyl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole [0398]

B60 <img file="IS2564B_D0267.tif" /> [0399] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-fluorobenzoyl chloride was prepared from 3-cyano-5-fluorobenzoic acid (106 mg, 0.63 mmol). The acid chloride in dichloromethane (2.5 mL) was treated with 5-tert-butoxycarbonylpyrid-2-ylamidoxime (149 mg, 0.63 mmol). The mixture stirred at room temperature for 2 hours and the solvent removed in vacuo. The intermediate was dissolved in Λ/,Ν-dimethylformamide (2.5 mL) and heated in sealed tube for 13 hours at 120 "C. Atter cooling, water was added and the product collected by filtration. Silica gel chromatography using a gradient of 10% to 30% ethyl acetate in hexane afforded 71.2 mg (31 %) of 3-(5-tert-butoxycarbonyl-2"pyridyl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole.

[0400] A mixture of 3-(5-tert-butoxycarbonylpyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (69 mg, 0.19 mmol) in formic acid (98%, 3.5 mL) was heated at 40 '0 for 17 hours. Evaporation of the solvent in vacuo afforded crude 3-(5-hydroxycarbonylpyrid-2-yl)-5-(3-cyano-5-flourophenyl)-1,2,4-oxadiazole as a white solid.

[0401] A solution of crude 3-(5-hydroxycarbonylpyrid-2-yl)-5-(3-cyano-5-flouorphenyl)-1,2,4-oxadiazole in dichloromethane (5 mL) was treated with 2M oxalyl chloride (0.25 mL, 0.5 mmol, dichloromethane) and a catalytic amount of Ν,Ν-dimethylforrnamide. The mixture was stirred at room temperature for 1.5 hour and the solvent and excess reagent removed ín vacuo. The crude product was dissolved in dichloromethane (5 mL) and treated with 0.5M ammonia (2 mL, 1 mmol, dioxane). The mixture was stirred at room temperature for 1 hour and the solvents removed in vacuo. The crude amide, in dichloromethane (2 mL) and pyridíne (0.10 mL, 1.23 mmol), was treated with trifluoroacetic anhydride (0.09 mL, 0.64 mmo(). The mixture was stirred at room temperature for 12 hours anddiluted with dichloromethane. The organic solution was washed with dilute aqueous sodium bicarbonate and brine, and dried over sodium sulfate and silica gel. Filtration and removal of the solvent /n vacuo afforded the crude product. Silica gel chromatography using a gradient of 20% to 50% ethyl acetate in hexane, afforded 48.8 mg (88%) of 3-(5-cyano-2-pyridyl)-5-(3-cyano-5-t luoropheny l)-1,2,4-oxadiazole: 1H-NMR (C0CI3), δ (ppm):DD9.10 (s, 1H), 8.37 (m, 2H), 8.22 (m, 2H), 7.64 (m, 1H).

3-(5-Cyano-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazol [0402]

B61 <img file="IS2564B_D0268.tif" /> [0403] Using the general procedure for the preparation of acid chlorides, 3-bromo-5-fluorobenzoyl chloride was prepared from 3-bromo-5-fluorobenzoic acid chloride (554 mg, 2.52 mmol). The acid chloride in dichloromethane (10 mL) wastreated with 5-tert-butoxycarbonylpyrid-2-ylamidoxime (601 mg, 2.53 mmol). The mixture was stirred at room temperature for 30 minutes and the solvent was removed ín vacuo. The intermediate was dissolved in DMF (15 mL) and heated in sealed tube at 120 ’Cfor 13 hours. After cooling the solvent was removed in vacuo. Silica gel chromatography

using a gradient of 5% to 10% ethyl acetate in hexane, afforded 556 mg of crude 3-(5-tert-butoxycarbonyl-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole.

[0404] A mixture of this crude intermediate in tormic acid (98%, 20 mL) was heated at 40 ‘C for 17 hours. Evaporation of the solvent in vacuo afforded 3-(5-hydroxycarbonylpy rid-2-y l)-5-(3-bromo-5-f luoropheny I)· 1,2,4-oxadiazole as a white solid.

[0405] The crude acid in dichloromethane (20 mL) was treated with 2M oxalyl chlorlde (1.4 mL, 2.8 mmol, dichloromethane) and a catalytic amount of /V,W-dimethylformamide. The mixture was stirred at room temperature for 2 hours and the solvent and excess reagent removed in vacuo. The crude product was dissolved in dichloromethane (25 mL) and and treated with 0.5M ammonia (10 mL, 5 mmol, dioxane) and the mixture stirred at room temperature for 1 hour. Removal of the solvent in vacuo afforded the crude amide.

[0406] The crude amide in a mixture of dichloromethane (7.5 mL) and pyridine (0.46 mL, 5.6 mmol) was treated with trif I uoroacetic anhydride (0.44 mL, 3.1 mmol). The mlxture was stirred at room temperature for 12 hours and then diluted with ethyl acetate. The organic solution was washed with dilute aqueous sodium bicarbonate and brine, and then dried over sodium sulfate and silica gel. Filtration and removal of the solvent in vacuo afforded the crude product. Silica gel chromatography using 10% ethyl acetate in hexane afforded 22 mg (6%) of 3-(5-cyano-2-pyridyl)-5-(3-bromo-5-fluor-ophenyl)-1,2,4-oxadiazole: 1H-NMR (CDCI3), δ (ppm):DD9.10 (s, 1H), 8.36 (d, 1H), 8.25 (s, 1H), 8.18 (dd, 1H), 7.91 (dd, 1H), 7.53 (dd, 1H).

3-(2-Pyridyl)-5-(5-brorno-2-methoxyphenyl)-1,2,4-oxadiazole [0407]

B62 <img file="IS2564B_D0271.tif" /> [0408] A mixture of 5-bromo-2-methoxybenzoic acld (1.49 g, 6.45 mmol) in dichloromethane (10 mL) was treated with 2M oxalyl chloride (9.7 ml, 19.4 mmol, dichloromethane) and 3 drops of N./V-dimethylformamide. The mixture was stirred 4 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with pyrid-2-ylamidoxime (884 mg, 6.45 mmol) arid triethylamine (1.95 g, 19.35 mmol) in dichloromethane (10 mL). The mixture was then heated in dimethylformamide (10 mL) for 2 hours at 120 'C. Standard work up, afforded 1.2 g (67%) of 3-(2-pyridyl)-5-(5-bromo-2-methoxyphenyl)-l ,2,4-oxadiazole.

3-(2-Pyridyl)-5-(5-bromo-2-fluorophenyl)-1,2,4-oxadiazole [0409]

B63 <img file="IS2564B_D0272.tif" /> [0410] In a similar fashion, 5-bromo-2-fluorobenzoy| chloride was prepared from 5-bromo-2-fluorobenzoic acid (2.19 g, 10 mmol). Treatment of the acid chloride with pyríd-2-ylamidoxime (1.37 g, 10 mmol) and triethylamine (3.03 g, 30 mmol) in dichloromethane (20 mL), followed by heating in dimethylfornriamide (20 rnl.) at 120 ’C for 2 hours, afforded 3.2 g (100%) of 3-(2-pyridyl)-5-(5-bromo-2-fluorophenyl)-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(5-cyano-2-f!uorophenyl)-1,2,4-oxadiazole [0411]

B64 <img file="IS2564B_D0275.tif" /> [0412] In a similar fashion, 5-cyano-2-fluorobenzoyl chloride was prepared from 5-cyano-2-fluorobenzoic acid (185 mg, 1.12 mmol). Treatment of the acid chloride with pyrid-2-ylamidoxime (1.153 g, 1.12 mmol) and triethylamine (340 mg, 3.36 mmol) in dichloromethane (3 mL), followed by heating in dimethylformamide (2 mL) at 120 'C for 16 hours, afforöed 17 mg (6%) of 3-(2-pyridyl)-5-(5-cyano-2-fluorophenyl)-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(5-bromopyrid-3-yl)-1,2,4-oxadiazole [0413]

B65 <img file="IS2564B_D0276.tif" /> [0414] In a similar fashion, 5-bromonicotinoyl chloride was prepared from 5-bromonicolinic acid (2.02 g, 10 mmol). Treatment of the acid chloride with pyrid-2-ylamidoxime (1.37 g, 10 mmol) and triethylamine (4.04 g, 40 mmol) in dichloromethane (20 mL), followed by heating in dimethylformamide (20 mL) at 120 'C for 16 hours. After this time water was added and the precipitate collected and dried. Filtration through silica gel using dichloromethane followed by trituration with hexane afforded 2.58 g (85%) of 3-(2-pyridyl)-5-(5-bromopyrid-3-yl)-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(5-chloro-pyrid-3-yl)-1,2,4-oxadiazole [0415]

B66 <img file="IS2564B_D0277.tif" /> [0416] In a similar fashion, 5-chloronicotinoyl chloride was prepared from 5-chloronicotinic acid (157 mg, 1 mmol). Treatment of the acid chloride with pyrid-2-ylamidoxime (137 mg, 1 mmol) and triethylamine (404 mg, 4 mmol) in dicnioromelhane (2 mL), followed by heating in dimethylformamide (2 mL) at 120 'C for 3 hours afforded 149 mg (58%) of 3-(2-pyridyl)-5-(5-chloro-pyrid-3-yl)-1,2,4-oxadiazole (149 mg, 57.6 %).

3-(5-Cyanopyrid-2-yl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole [0417]

Β67 <img file="IS2564B_D0281.tif" /> [0418] In a similar fashion, 5-bromonicotinoyl chloride was prepared from 5-bromonicotinic acid (262.6 mg, 1.3 mmolesj.Treatmentof the acid chloride with 5-cyanopyrid-2-ylamidoxime (162mg, 1 mmol) and triethylamine (404 mg, 4 mmol) in dichloromethane (2 mL), follawed by heating in dimethylformamide (2 mL) at 120 ’C for 16 hours afforded 230 mg (70%) of 3-(5-cyanopyrid-2-yl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole.

3-(5-Fluoropyrid-2-yl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole [0419]

B68 <img file="IS2564B_D0282.tif" /> [0420] ln a similar fashion, 5-bromonicotinoyl chloride was prepared from 5-bromonicotinic acid (202 mg, 1 mmol). Treatmentof the acid chloride with 5-fluoropyrid-2-ylamidoxime (155.13 mg, 1 mmol) and triethylamine (404 mg, 4 mmol) in dichloromethane (2 mL), followed by heating in dimethylformamide (2 mL) at 120 'C for 3 hours afíorded 216.5 mg (67%) of 3-(5-fluoropy rid-2-yl)-5-(5-bromo-pyrid-3-y l)-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(2-thiomethoxy-pyrid-3-yl)-1,2,4-oxadiazole [0421]

B69 <img file="IS2564B_D0283.tif" /> [0422] Ina similar fashion, 2-thiomethoxynicotinoyl chloride wasprepared from 2-thiomethoxynicotinic acid (169 mg, 1 mmol).Treatmentof the acid chloride with pynd-2-ylamidoxime (137mg, 1 mmole) and triethylamine (404 mg, 4mmol) in dichloromethane (2mL), followed by heating in dimethylformamide (2 mL) at 120'Cfor 16 hoursaflorded 20 mg (7%) of 3-(2-pyridyl)’5-(2-thiomethoxy-pyrid-3-yl)-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(5-methylpyrid-3-yl)-1,2,4-oxadiazole [0423]

Β70 <img file="IS2564B_D0287.tif" /> [0424] In a similar fashion, 5-methylnicotinoyl chloride was prepared from 5-methylnicotinic acid (548 mg, 4 mmoles). Treatmentof the acid chloride with pyrid-2-ylamidoxlme (822 mg, 6 mmol) and triethylamine (1.2g, 12 mmol) in dichloromethane (6 mL), followed by heating in dimethylformamide (6 mL) at 120 'C for 2.5 hours, afforded 448 mg (47%) of 3-(2-pyridyl)-5-(5-methyl-pyrid-3-yl)-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(5-hydroxypyrid-3-yl)-1,2,4-oxadiazole [0425]

B71 <img file="IS2564B_D0288.tif" /> [0426] In a similar fashion, 5-hydroxynicotinoyl chloride was prepared from 5-hydroxynicotinic acid hydrochloride, which was obtained from the hydrolysis of 5-hydroxynicotinic acid methyl ester (1.53 g, 10 mmol). T reatment of the acid chloride with pyrid-2-ylamidoxime (1.37 g, 10 mmol) and triethylamine (4.04g, 40 mmol) in dichloromethane (10 mL), followed by heating in dimethylformamide (20 mL) at 120 ’C for 2 hours afforded 497 mg (21 %) 3-(2-pyridyl)-5-(5-hydroxy-pyrid-3-yl)-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(5-mattioxypyrid-3-yl)-1,2,4-oxadiazole [0427]

B72 <img file="IS2564B_D0289.tif" /> [0428] In a similar fashion, 5-methoxynicotinoyl chloríde was prepared from 5-methoxynicotinic acid hydrochloride (112.7 mg, 0.59 mmoles). Treatment of the acid chloride with pyrid-2-ylamidoxime (80.8 mg, 0.59 mmol) and tri ethy lamine (0.3 mL) in dichloromethane (2 mL), followed by heating in dimethylformamide (1 mL) at 120 *C for 2.5 hours afforded 25 mg (17%) of 3-(2-pyridyl)-5-(5-methoxypyrid-3-yl)-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(3-cyano-5-methylphenyl)-1,2,4-oxadiazole [0429]

Β73 <img file="IS2564B_D0293.tif" /> [0430] A solution ot 5-methylisophalonitrile (1.0 g, 7.03 mmol) in methanol (9 mL) at 64 'C was treated dropwise with a solution o! 20% NaOH (0.78 g, 19.5 mmol). The reaction was stirred an additional 14 hours at this temperature. Work up and silica gel chromatography, afforded 0.420 g (37%) of 3-cyano-5-methylbenzamide, The intermediate amide (0.110 g, 0.69 mmol) was treated with 70 wt.% H2SO4 (3.75 mL) and sodium nitrite (0.071 g, 1.03 mmol) and the mixture stirred at 40 'C for 1 hour, The reaction was cooled and the precipitate collected to afford 0.0447 g (42%) of 3-methyl-5-cyanobenzoic acid.

[0431 ] Using the general procedure for the preparation of acid chlorides, 3-methyl-5-cyanobenzoyl chloride was prepared from 3-methyl-5-cyanobenzoic acid (0.0447 g, 0.28 mmol). The acid chloride and pyrid-2-ylamidoxime (0.038 g, 0.28 mmol) in Λ/,/V-dimethylformamide (4 mL) was heated in sealed tube at 120 Ό for 12 hours. Standard work up and silica gel chromatography afforded 0.480g (80%) of 3-(2-pyridyl)-5-(3-cyano-5-methylphenyl)-1,2,4-oxadiazole: 1HNMR (CDCI3), δ (ppm): 8.85 (d, 1H), 8.36 (d, 2H), 8.22 (d, 1H), 7.89 (t, 1H), 7.70 (S, 1H), 7.48 (t, 1H), 2.52 (s, 3H),

3-(2-Pyridyl)-5-(3-fluoro-5-bromvphenyl)-1,2,4-oxadiazole [0432]

B74 <img file="IS2564B_D0294.tif" /> [0433] Using the general procedure for the preparation of acid chlorides, 3-fluoro-5-bromobenzoyl chloride was prepared from 3-fluoro-5-bromobenzoic acid (300 mg, 1.369 mmol). The acid chloride was treated with pyrid-2-ylamidoxime (187.7 mg, 1.369 mmol) in pyridine (2 mL) and the mixture heated in sealed tube at 130 'C for 16 hours. After cooling, the reaction was treated with water and the solid collected by filtration. Recrystallization from ethanol afforded 168.3 mg (38%) of 3-(2-pyridyl)-5-(3'fluoro,5-bromophenyl)-1,2,4-oxadiazole: 1H-NMR (CDCI3), δ (ppm): 8.82 (d, 1H), 8.25 (s, 1H), 8.21 (d, 1H), 7.92 (td, 2H), 7.50 (m, 2H).

3-(2-Pyridyl)-5-(3-iodo-5-bromophenyl)-1,2,4-oxadiazole [0434]

B75 <img file="IS2564B_D0295.tif" /> [0435] Using the general procedureforthe preparation of acid chlorides, 3-iodo-5-bromobenzoyl chloride was prepared

from 3-iodo-5-bromobenzoic add (1.0 g, 3.058 mmol). The acid chloride was treated with pyrid-2-ylamidoxime (419.3 mg, 3.058 mmol) in pyridine (5 mL) and the mixture heated in sealed tube at 130 ‘C for 16 hours. After cooling, the reaction was treated with water and the solid collected by filtration. Recrystallization from ethanol afforded 140 mg (10.7%) of 3-(2-pyridyl)-5-(3-iodo-5-bromophenyl)-1,2,4-oxadiazole; 1H-NMR (CDCI3), δ (ppm); 8.84 (d, 1H), 8.57 (s, 1H), 8.42 (s, 1H), 8.22 (dd, 1H), 8.10 (s, 1H), 7.90 (t, 1H), 7.49 (td, 1H).

3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-bromophenyl)-1,2,4-oxadiazole [0436]

B76 <img file="IS2564B_D0299.tif" /> [0437] Using the general procedure for the preparation of acid chlorides, 3-fluoro-5-bromobenzoyl chloride was prepared 3-fluoro-5-bromobenzoic acid (350 mg, 1.598 mmol). The acid chloride was treated 5-fluoropyrid-2-ylamidoxime (223 mg, 1.438 mmol) in dimethylformamide (5 mL) and the mixture heated in sealed tube at 130 ’C for 16 hours. After cooling, the reaction was treated with water and the solid collected by filtration. Recrystallization from ethanol aflorded 218 mg (45%) of 3-(5-fluoro-2-pyridyl)-5-(3-fluoro-5-bromophenyl)-1,2,4-oxadiazole: Ή-NMR (CDCI3), δ (ppm): 8.70 (d, 1H), 8.28 (s, 1H), 8.27 (dd, 1H), 7.93 (td, 1H), 7.61 (td, 1H), 7.53 (td, 1H).

3-(2-Pyridyl)-5-(3-allyloxy-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole [0438]

B77 <img file="IS2564B_D0300.tif" /> [0439] Using the general procedure for the preparation of acid chlorides, 3-allyloxy-5-(methoxycarbonyl)benzoyl chloride was prepared from 3-allyloxy-5-(methoxycarbonyl)benzoic acid (3.24 g, 13.7 mmol). A solution of the acid chloride in dichloromethane (20 mL) at 0'C was treated with pyrid-2-ylamidoxime (1.9 g, 13.9 mmol) and then slirred at ambient temperature for 2 hours. After this time, the reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N,N-dimethylformamide (50 mL) and heated at 120 'C for 16 hours. Standard work up and silica gel chromatography using hexanes:ethyl acetate: dichloromethane (3.5:0.5:4) afforded 1.8 g (39%) of 3-(2-pyridyl)-5-(3-allyloxy-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole: 1H NMR (DMSO): δ - 8.81 (d, 1H), 8.28 (s, 1H), 8.20 (d, 1H), 8.07 (t, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.66 (m, 2H), 6.09 (m, 1H), 5.47 (dd, 1H), 5.33 (dd, 1H), 4.81 (d, 2H), 3.93 (s, 3H).

3-(2-Pyrldyl)-5-(3-iodo-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole [0440]

Β78 <img file="IS2564B_D0303.tif" /> [0441] Using the general procedure forthe preparation of acid chlorides, 3-iodo-5-(methoxycarbonyl)benzoyl chloride was prepared from 3-iodo-5-(methoxycarbonyl)benzoic acid (1.7 g, 5.554 mmol). The acid chloride was treated with pyrid-2-ylamidoxime (0.685 g, 4.998 mmol) in dimethylformamide (10 mL) and the mixture heated in sealed tubeat 130 'C for 16 hours. After cooling, the reaction was treated with water and the solid collected by filtration. Recrystallization from ethanol afforded 357 mg (17.8%) of 3-(2-py ridyl)-5-(3-iodo-5-(methoxy carbonyl) pheny l)-1,2,4-oxadiazole:1H-NMR (CDCI3), δ (ppm): 8.85 (s, 1H), 8.84 (m. 1H), 8.82 (m, 1H), 8.60 (s, 1H), 8.25 (dd, 1H), 7.91 (td, 1H), 7.50 (dd, 1H), 4.05 (s, 3H).

3-(2-Pyridyl)-5-(3-methoxy-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole [0442]

B79 <img file="IS2564B_D0304.tif" /> [0443] Using the general procedure for the preparation of acid chlorides, 3-methoxy-5-(methoxycarbonyl)benzoyl chloride was prepared from 3-methoxy-5-(methoxycarbonyl)benzoic acid (400 mg, 1.9 mmol). The acid chloride in dichloromethane (20 mL) at 0 ’C was treated with pyrid-2-ylamidoxime (261 mg, 1.9 mmol) and the mixture stirred at room temperature for 1 hour. The reaction mixture was then washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in /V.W-dimethylformamide (4 mL) and heated overright at 110 ’C. Standard work up and silica gel chromatography using a mixture of hexane:ethyl acetate:dichlo-romethane (3:1:4) afforded 191.3 mg (32%) of 3-(2-pyridyl)-5-(3-methoxy-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3): δ - 8.86 (d, 1H), 8.55 (s, 1H), 8.25 (d, 1H), 7.99 (m, 1H), 7.90 (t, 1H), 7.82 (s, 1H), 7.47 (m, 1H), 3.98 (s, 3H), 3.96 (s, 3H).

3-(2-Pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole [0444]

B80 <img file="IS2564B_D0305.tif" />

[0445] Using the general procedure for the preparation of acid chlorides, 3-bromo-5-cyanobenzoyl chloride was prepared from 3-bramo-5-cyanobenzoic acid (1.6 g, 7.0 mmol). The acid chloride in dlchloromethane (20 mL) at 0 'C was treated with pyrid-2-ylamidoxime (965 mg, 7.0 mmol) and the mixture stirred at rocm temperature for 2 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N,N-dimethylformamide (30 mL) and heated overnight at 110 ’C. Standard work up and silica gel chromatography using a mixture of hexane:ethyl acetate:dichloromethane (3:1:4) afforded 739 g (32 %) of 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole: Ή NMR (CDCI3): δ - 8.87 (d, 1H), 8.70 (s, 1H), 8.52 (s, 1H), 8.23 (d, 1H), 8.03 (s, 1H), 7.92 (t, 1H), 7.51 (m, 1H).

3-(2-Pyridyl)-5-(5-cyano-3-iodophenyl)-1,2,4-oxadiazole [0446]

B81 <img file="IS2564B_D0309.tif" /> [0447] Using the genera! procedure for the preparation of acid chlorides, 3-cyano-5-iodobenzoyl chloride was prepared from 3-cyano-5-iodobenzoic acid (570 mg, 2.1 mmol). The acid chloride in dichloromethane (5 ml) was treated with pyrid-2-ylamidoxime (287 mg, 2.1 mmol) and triethylamine (1 mL) and the mixture stirred for 1 hour at room temperature. The solvent was removed in vacuo, and the residue dissolved in Λ/,/V-dimethylforrnamide (5 mL). The mixture was heated overnight at 120 ’C. Removal of the solvent in vacuo, and trituration with 20% ethylacetate in hexane afforded 250 mg (32% yield) of 3-(2-pyridyl)-5-(5-cyano-3-iodophenyl)-1,2,4-oxadiazole: 1H-NMR (CDCI3), S ppm: 8.85 (m, 2H), 8.54 (s, 1H), 8.22 (d, 1H), 8.20 (s, 1H), 7.90 (t, 1H), 7.45 (m, 1H). GC/EI-MS gave m/z 374 (M+)

3-(2-Pyridyl)-5-(3-/V, A/-dimethylaminophenyl)-1,2,4-oxadiazole [0448]

B82 <img file="IS2564B_D0310.tif" /> [0449] Using the general procedure for the preparation of acid chlorides, 3-dimethylaminobenzoyl chloride was prepared from 3-dimethylaminobenzoic acid (632 mg, 3.1 mmol). The acid chloride in dichloromethane (20 mL) at 0 ‘C was treated with pyrid-2-ylamidoxime (430 mg, 3.1 mmol). The mixture was then stirred at room temperature for 2 hours. Standard work up afforded a residue which was dissolved in /V,N-dimethylformamide (15 mL) and heated overnight at 110 ’C. Aftercooling, the solvent was removed in vacuo. The residue was dissolved in dichloromethane and then washed with water and saturated brine, dried overanhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography using a mixture of hexane:ethyl acetate:dichloromethane (3:1:4) followed by trituration with 10 % d lethyl ether in hexane, afforded 27 mg (3 %) of 3-(2-pyridyl)-5-(3-N,N-dimethylaminophenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3): δ - 8.86 (d, 1H), 8.24 (d, 1H), 7.88 (t, 1H), 7.60 (m, 2H), 7.46 (m, 1H), 7.37 (m. 1H), 6.95 (d, 1H), 3.06 (s, 6H).

3-(5-Chloropyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole [0450]

B83 <img file="IS2564B_D0313.tif" /> [0451] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-fluorobenzoyl chloride was prepared trom 3-cyano-5-tluorobenzoic acid (0.10 g, 0.6 mMol). Treatment of the intermediate acid chloride in dichloromethane with 5-chloropyrid-2-ylamidoxime (0.103 g, 0.6 mmol) followed by heating in A/,A/-dimethylformamide overnight at 110 'C afforded crude product. Standard work up and purification by silica gel chromatography, and recrystallization afforded 30 mg (16%) 3-(5-chloropyríd-2-yl)-5-(3-cyano-5-fluoropheny!)-1,2,4-oxadiazole.

3-(5-Chloropyrid-2-yl)-5-(3-cyano-5-chlorophenyl)-1.2,4-oxadiazole [0452]

B84 <img file="IS2564B_D0314.tif" /> [0453] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-chlorobenzoyl chloride was prepared from 3-cyano-5-chlorobenzoic acid (0.10 g, 0.55 mmol). Treatment of the intermediate acid chloride in dichloromethane with 5-chloropyrid-2-ylamidoxime (0,094 g, 0.55 mMol) followed by heating in Ν,Ν-dimethylformamide overnight at 110 "C afforded crude product. Standard work up and purification by silica gel chromatography, and recrystallization afforded 4.5 mg (2.6%) 3-(5-chloropyrid-2-yl)-5-13-cyano-5-chlorophenyl)-1,2,4-oxadiazole.

3-(5-Chloropyrid-2-yl)-5-(3-chlorO’5’fluorophenyl)-1,2,4-oxadiazole [0454]

B85 <img file="IS2564B_D0315.tif" /> [0455] Using the general procedure for the preparation of acid chlorides, 3-chloro-5-fluorobenzoyl chloride is prepared from 3-chloro-5-fluorcbenzoic acid using a solution of oxalyl chloride in dichloromethane and a catalytic amount of N,

N-dimethylfo rmamide. T reatment of the intermediate acid chloride in dichloromethane with 1 equivalení of 5-ch loropy rid-

2- ylamidoxime followed by heating in N,/V-dimethylformamide overnight at 110 "C affords crude product. Standard work up and purif ication by one or more methods, including silica gel chromatography, recrystall ization, and trituration, affords purified 3-(5-chloropyrid-2-yl)-5-(3-chloro-5-fluorophenyl)-1,2,4-oxadiazole.

3- (5-Chloropyrid-2-yl)-5-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole [0456]

B86 <img file="IS2564B_D0319.tif" /> [0457] Using the general procedure forthe preparation of acid chlorides, 3-cyano-5-methoxybenzoyl chloride is prepared from 3-cyano-5-methoxybenzoic acid using a solution of oxalyl chtoride in dichloromethane and a catalytic amount of Λ/,Ν-dimethylformamide. Treatment of the intermediate acid chloride in dichloromethane with 1 equivalent of 5-chlo-ropyrid-2-ylamidoximefollowed by heating in N,N-dimethylformamide overnight at 110 'C affords crude product. Standard work up and purilication by one or more methods, including silica gel chromatography, recrystallization, and trituration, affords purified 3-(5-chloropyrid-2-yl)-5-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole.

3-(5-Fluoropyrid-2-yl)-5-(3-cyano-5-chlorophenyf)-1,2,4-oxadiazole [0458]

B87 <img file="IS2564B_D0320.tif" /> [0459] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-chlorobenzoyl chloríde was prepared trom 3-cyano-5-chlorobenzoic acid (0.10 g, 0.55 mMol). Treatment of the intermediate acid chloride in dichloromethane with 5-ftouropyrid-2-ylamidoxime (0.086 g, 0.55 mMol) followed by heating in /V,/V-dimethylformamide overnight at 110 'C afforded crude product. Standard work up and purification by silica gel chromatography, and recrystallization afforded 1.8 mg (1 %) 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-chlorophenyl)-1,2,4-oxadiazole.

3-(5-Fluoropyrid-2-yl)-5-(3-fluoro-5-chlorophenyl)-1,2,4-oxadiazole [0460]

B88 <img file="IS2564B_D0321.tif" />

[0461] Using the general procedure for the preparation of acid chlorides, 3-chloro-5-fluorobenzoyl chloride is prepared from 3-chloro-5-fluorobenzoic acid using a solution of oxalyl chloride in dichloromethane and a catalytic amount of N, M-dimethylformamide, Treatment of the intermediate acid chloride in dichloromethane with 1 equivalent of 5-f luoropy rid-

2- ylamidoxime followed by heating in N,W-dimethylformamide overnight at 110 'C affords crude product. Standard work up and purif ication by one or more methods, including silica gel chromatography, recrystall ization, and trituration, affords purified 3-(5-fluoropyrid-2-yl)-5-(3-chloro-5-fluorophenyl)-1,2,4-oxadiazole.

3- (5-Fluoropyrid-2-yl)-5-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole [0462]

B89 <img file="IS2564B_D0325.tif" /> [0463] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-methoxybenzoyl chloride is prepared from 3-cyano-5-methoxybenzoic acid using a solution of oxaly I chloride in dichloromethane and a catalytic amount of NyWrnetbylfcrrnamide. Treatment of the intermediate acid chloride in dichloromethane with 1 equivalent of 5-fluor-opyrid-2-ylamidoximefollowed by heating in Ν,/V-dimethylformamide overnight at 110’C affordscrude product. Standard work up and purification by one or more methods, including silica gel chromatography, recrystallization, and trituration, affords purilied 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole.

3-(5-Cyanopyrid-2-yl)-5-(3-cyano-5-chlorophenyl)-1,2,4-oxadiazole [0464]

B90 <img file="IS2564B_D0326.tif" /> [0465] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-chlorobenzoyl chloride was prepared from 3-cyano-5’Chlorobenzoic acid (0.10 g, 0.55 mMol). Treatment of the intermediate acid chloride in dichloromethane with 5-cyanopyrid-2-ylamidoxime (0.099 g, 0.65 mmol) followed by heating in W,N-dimethylformamide overnight at 110 'C afforded crude product. Standard work up and purification by silica gel chromatography, and recrystallization afforded 1.1 mg (0.65%) 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-chlorophenyl)-1,2,4-oxadiazole.

3-(5-Cyanopyrid-2-yl)-5-(3-fluoro-5-chlorophenyl)-1,2,4-oxadiazole [0466]

Β91 <img file="IS2564B_D0329.tif" /> [0467] Using the general procedure for the preparation of acid chlorides, 3-chloro-5-fluorobenzoyl chloride is prepared from 3-chloro-5-fluorobenzoic acid using a solution of oxalyl chloride in dichloromethane and a catalytic amount of N, M-dimethylformarride. T reatment of the intermediate acid chloride in dichloromethane with 1 equivalent of 5-cyanopyrid-

2- ylamidoxime followed by heating in /V,N-dimethylformamide overnight at 110 'C affords crude product. Standard work up and purification by one or more methods, including silica gel chromatography, recrystallization, and trituration, affords purified 3-(5-cyanopyrid-2-yl)-5-(3-chloro-5-fluorophenyl)-1,2,4-oxadiazole.

3- (5-Cyanopyrid-2-yl)-5-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole [0468]

B92 <img file="IS2564B_D0330.tif" /> [0469] cyano-5-methoxybenzoic acid using a solution of oxalyl chloride in dichloromethane and a catalytic amount of W,W-dimethylformarriide. Treatment of the intermediate acid chloride in dichloromethane with 1 equivalent of 5-cyano· pyrid-2-ylamidoxime followed by heating in N,A/-dimethylformamide ovemight at 110 'C affords crude product. Standard work up and purification by one or more methods, including silica gel chromatography, recrystallization, and trituration, affords purilied 3-(5-cyanopyrid-2-yl)-5-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole.

3-(5-Fluoropyrid-2-yl)-5-(3,5-di-cyanophenyl)-1,2,4-oxadiazole [0470]

B93 <img file="IS2564B_D0331.tif" /> [0471] Using the general procedure for the preparation of acid chlorides, 3,5-dicyanobenzoyl chloride is prepared from 3,5-dicyanobenzoic acid using a solution of oxalyl chloride in dichloromethane and a catalytic amount of N,N-dimethylformamide. Treatment of the intermediate acid chloride ín dichloromethane with 1 equivalent of 5-fluoropyrid-2-ylamidoximefollowed by heating in W./V-dimethylformamideovernightat 110 'C affords crude product. Standard work up and purification by one or more methods, íncluding silica gel chromatography, recrystall ization, and trituration, affords purified 3-(5-fluoropyrid-2-yl)-5-(3,5-dicyanophenyl)-1,2,4-oxadiazole.

3- (3-(4-Dimethylaminobutoxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole [0472]

B94 <img file="IS2564B_D0335.tif" /> [0473] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-fluorobenzoyl chloride is prepared from 3-cyano-5-fluorobenzoic acid using a solution of oxalyl chloride in dichloromethane and a catalytic amount of N, N-dimethylformamide. Treatmentofthe intermediate acid chloride in dichloromethane wlth 1 equivalentof 3-(4-dimeth-ylaminobutoxy)pyrid-2-y1amidoxime followed by heating in Ν,Ν-dimethylformamide overnight at 110 'C affords crude product. Standard work up and pu rif ication by one or more methods, including silica gel chromatography, recry stal I izat ion, trituration, and reversed-phase high-performance liquid chromatography (RP-HPLC) affords purified 3-(3-(4-dimethyl-aminobu1oxy)-pyrid-2-yl)-5-(3-cyano-5-fliiorophenyl)-1,2,4-oxadiazole.

[0474] Alternatively, treatment of 3-(3-fluoropyrid-2-yl)-5-(3-fluoro-5-cyanophenyl)-1,2,4-oxadiazole with potassium

4- dimethylaminobutoxide in /V,/V-dimethylformamide with a catalytic amount of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) and heating at 110 'C affords crude product. Standard work up and purification by one or more methods, including silica gel chromatography, recrystallization, trituration, and reversed-phase high-perfornnance liquid chromatography (RP-HPLC) affords purified 3-(3-(4-dimethylaminobutoxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-cxadi-azole.

3-(3-(5-Dimethylaminopentyloxy)-pyrid-2-yl)-6-(3-Cyano-5-fluorophenyl)-1,2,4-oxadiazole [0475]

B95 <img file="IS2564B_D0336.tif" /> [0476] Using the general procedure forthe preparation of acid chlorides, 3-cyano-5-fluorobenzoyl chloride is prepared from 3-cyano-5-fluorobenzic acid using a solution of oxalyl chloride in dichloromethane and a catalytic amount of N,N-dimethylformamide. Treatment of the intermediate acid chloride in dichloromethane with 1 equivalent of 3-(5-dimethyl-aminopenty!oxy)pyrid-2-ylamidoxime followed by heating in Ν,Μ-dimethylformamide overnight at 110'C affords crude product. Standard work up and purif ication by one or more methods, including silica gel chromatography, recrystall ization, trituration, and reversed-phase high-performance liquid chromatography (RP-HPLC) affords purified 3-(3-(5-dimethyl-aminopentyloxyJ-pyrid^-yO-B-tS-cyano-S-fluorophenylJ-I.Z^-oxadiazole.

[0477] Alternatively, treatment of 3-(3-fluoropyrld-2-yl)-5-(3-fliioro-5-cyanophenyl)-1,2,4-oxadiazole with potassium

5- dimethylaminopentyloxide in N,A/-dimethylformamide with a catalytic amount of 1,4, 7,10,13,16-hexaoxacycloocta-decane (18-crown-6) and heating at 110 'C affords crude product. Standard work up and purification by one or more methods, including silica gel chromatography, recrystallization, trituration, and reversed-phase high-performance liquid chromatography (RP-HPLC) affords purified 3-(3-(5-dimethylaminopentyloxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophanyl)-

1,2,4-oxadiazole.

3-(3-(6-Dimethylaminohexyloxy)-pyrid-2-yl)-5-(3-cyano-5-fluoropheny!)-l,2,4-oxadiazole [0478]

B96 <img file="IS2564B_D0339.tif" /> [0479] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-fluorobenzoyl chloride is prepared from 3-cyano-5-fluorobenzic acid using a solution of oxalyl chloride in dichloromethane and a catalytic amount of N,N-dimethylformamide. Treatment of the intermediate acid chloride in dichloromethane with 1 equivalent of 3-(6-dimethyl-aminohexyloxy)pyrid-2-ylamidoxime followed by heating in N,/V-dimethylformamide overnight at 110‘C affords crude product. Standard work up and pu rification by one or more methods, including silica gel chromatography, recry stal lizat ion, trituration, and reversed-phase high-performance liquid chromatography (RP-HPLC) affords purified 3-(3-(6-dimethyl-aminohexyloxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole.

[0480] Alternatively, treatment of 3-(3-fluoropyrid-2-yl)-5-(3-fluoro-5-cyanophenyl)-1,2,4-oxadiazole with potassium

6-dimethylaminohexyloxide in W,/V-dimethylformamide with a catalytic amount of 1,4,7,10,13,16-hexaoxacyclooctade-cane (18-crown-6) and heating at 110 ‘C affords crude product. Standard work up and purífication by one or more methods, including silica gel chromatography, recrystallization, trituration, and reversed-phase high-performance liquid chromatography (RP-HPLC) affords purified 3-(3-(6-dimethylaminohexyloxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-

1,2,4-oxadiazole.

3-(5-Fluoropyrid-2-yl)-5-(5-fluoro-3-(thiomethyl)phenyl)-1,2,4-oxadiazole [0481]

B153 <img file="IS2564B_D0340.tif" /> [0482] Using the general procedure for the preparation of acid chlorides 5-fluoro-3-(thiomethyI)benzoyI chloride was prepared from 5-fIuoro-3-(thiomethyl)benzoic acid using a solution of oxalyl chloride ín dichloromethane and a catalytic

amount of Λ/,/V-dimethylformamide. T reatment of the intermediate acid chloride in dichloromethane with 1 equivalent of 5-fluoropyrid-2-ylamidoxime followed by heating in N, W-dimethylformamide overnight at 110 ’C atforded crude product. Standard work up and purification by silica gel chromatography afforded the purified title compound in 52 mg yield (54%) as a colourless solid.

5-(2-Py ridyl)-3-[3-(1 H-imidazol-1 -yI)-5-Fl uorophenyl)]-1,2,4-oxadiazole [0483]

B154 <img file="IS2564B_D0343.tif" /> [0484] Using the general procedure for the preparation of acid chlorides 3-f luoro-5-(1 H-im idazol-1 -yl Jbenzoy I chloride was prepared from 3-fluoro-5-(1H-imidazol-1-yl)benzoic acid using a solution of oxalyl chloride in dichloromethane and a catalytic amount of N,/V-dimethylformamide. Treatment of the intermediate acid chloride in dichloromethane with 1 equivalent of 2-pyridylamidoxime followed by heating in /V,N-dimethylformamide overnight at 110 ’C afforded crude product. Standard wcrk up and purification by silíca gel chromatograpliy followed by preperative reversed-phase HPLC afforded the title compound in 6.9 mg yield (5% over 4 steps) as a colourless solíd.

3-(2-Pyridyl)-5-(3-cyano-5-trifluoromethylphenyl)-1,2,4-oxadiazole [0485]

B155 <img file="IS2564B_D0344.tif" /> [0486] 3-Fluoro-5-trifluoromethylbenzoyl chloride (0.11 mL, 0.73 mmol) wasadded in a dropwise mannerto a solution of pyridylamidoxime (99.3 mg, 0.73 mmol) in dichloromethane (10 mL) under argon. The reaction mixture was stirred at room temperature for 10 minutes and the solvent was removed in vacuo. DMF (4 ml) was added to the oily rssidue and the resulting solution was stirred at 120‘C for 16 h under argon. Atter the reaction mixture was cooled to room temperature, the solvent was removed in vacuo. Flash chromatography on silica gel (15%-20% ethyl acetate in hexanes) yielded 150 mg (66.9%, GC/MS product RT 7.59 min, 98% purity) of 3-(2-pyridy!)-5-(3-cyano-5-trifluoromethylphenyl)-

1,2,4-oxadiazole. 1H-NMR (CDCI3), 3 (ppm): 8.86 (d, 1H), 8.40 (S, 1H), 8.24 (d, 1H), 8.18 (d, 1H), 7.90 (dt, 1H), 7.59 (d, 1H), 7.49 (m, 1H).

3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-trifluoromethylphenyl)-1,2,4-oxadiazole [0487]

B156 <img file="IS2564B_D0347.tif" /> [0488] 3-Fluoro-5-trifluoromethylbenzoyl chloride (0.10 mL, 0.65 mmol) was added to a solution of 5-fluoropyridyla-midoxime (102.9 mg, 0.66 mmol) indichloromethane (2 mL).Thesolution was stirred at roomtemperaturefor 10 minutes and then concenlrated in vacuo. DMF (4mL) was added to the residue and the resulting solution was stirred at 120'C for 16 h under argon. After the reaction mixture was cooled to room temperature, the solvent was removed in vacuo. Flash chromatography on silica gel (10%-20% ethyl acetate in hexane) yielded 131.1 mg (62.5%, GC/MSproduct RT 7.34 min, 96% pure) of 3-(5-fluoro-2-pyridyl)-5-(3-fluoro-5-trifluoromethylphenyl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.70 (d, 1H), 8.38 (s, 1H), 8.28 (dd, 1H), 8.17 (d, 1H), 7.60 (dt, 2H).

3-(5-Cyanopyrid-2-yl)-5-(3-alloxy-5-cyanopheny!)-1,2,4-oxadiazole [0489]

B157 <img file="IS2564B_D0348.tif" /> [0490] Using the general procedure for the preparation of acid chlorides, 3-allyloxy-5-cyanobenzoyl chloride was prepared from 3-allyloxy-5-cyanobenzoic acid (203 mg, 1.0 mmol). A solution of the acid chloride in dichloromethane (2 mL) at 0’C was treated with 5-cyanopyrid-2-ylamidoxime (162 mg, 1.0 mmol) and triethylamine (418 μΙ_, 3.0 mmol) and then stirred at ambíent temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N,/V-dimethylformamide (5 mL) and heated at 120 ’C for 16hours. Standard workuparid silica gel chromatography using hexanes:ethyl acetate: dichloromethane (3.5:0.5:4) aflorded 131 mg (40%) of 3-(5-cyanopyrid-2-yl)-5-(3-allyloxy-5-cyanophenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 9.11 (d, 1H), 8.39 (d, 1H), 8.22 (s, 1H), 8.21 (d, 1H), 8.01 (s, 1H), 7.42 (s, 1H), 6.05 (m, 1H), 4.48 (dd, 1H), 4.40 (dd, 1H), 4.69 (d, 2H).

3-(5-fluoropyrid-2-yl)-5-(3-alloxy-5-cyanophenyl)-1,2,4-oxadiazole [0491]

B158 <img file="IS2564B_D0349.tif" />

[0492] Using the general procedure for the preparation of acid chlorides, 3-allyloxy-5-cyanobenzoyl chloride was prepared from 3-allyloxy-5-cyanobenzoic acid (203 mg, 1.0 mmol). A solution of the acid chloride in dichloromethane (2 mL) at O’C was treated with 5-fluoropyrid-2-ylamidoxime (155 mg, 1.0 mmol) and triethylamine (418 μΙ_, 3.0 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolvad in N,N~dimethylformamide (5 mL) and heated at 120 'C for 16 hours. Standard work up and silica gel chromatography using hexanes:ethyl acetate: dichloromethane (3.5:0.5:4) afforded 59 mg (18%) of 3-(5-fluoropyrid-2-yl)-5-(3-allyloxy-5-cyanophenyl)-1,2,4-oxadiazole: Ή NMR (CDCI3), δ (ppm): 8.70 (d, 1H), 8.27 (m, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.62 (m, 1H), 7.41 (s, 1H), 6.04 (m, 1H), 5.48 (dd, 1H), 5.34 (dd, 1H), 4.69 (d, 2H).

3-(5-Cyanopyrid-2-yl)-5-(3-cyano-5-propoxyphenyl)-1,2,4-oxadiazole [0493]

B159 <img file="IS2564B_D0353.tif" /> [0494] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-propoxybenzoyl chloride was prepared from 3-cyano-5-propoxybenzoic acid (205 mg, 1.0 mmol). A solution of the acid chloride in dichloromethane (2 mL) at 0”C was treated with 5-cyanopyríd-2-ylamidoxime (162 mg, 1.0 mMol) and triethylamine (418 pd_, 3.0 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, ard concentrated. The residue was dissolved in /V,N-dimethylformamide (5 mL) and heated at 120 'C for 16 hours. Standard work up and silica gel chromatography using hexanes:ethyl acetate: dichloromelhane (3.7:0.3:4) afforded 65 mg (20%) of 3-(5-cyanopyrld-2-yl)-5-(3-cyano-5-propoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 9.11 (s, 1H), 8.39 (d, 1H), 8.22 (d, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 7.42 (s, 1H), 4.06 (t, 2H), 1.89 (m, 2H), 1.09 (s, 3H).

3-(5-Fluoropyrid-2-yl)-5-(3-cyano-5-propoxyphenyl)-1,2,4-oxadiazole [0495]

B160 <img file="IS2564B_D0354.tif" /> [0496] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-propoxybenzoyl chloride was prepared from 3-cyano-5-propoxybenzoic acid (205 mg, 1.0 mmol). A solution of the acid chloride in dichloromethane (2 mL) at 0'C was treated with 5-fluoropyrid-2-ylamidoxime (155 mg, 1.0 mMol) and triethylamine (418 pL, 3.0 mMol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in /V,/V-dimethylformamide (5 mL) and heated at 120 ’C for 16 hours. Standard work up and silica gel chromatography using hexanes:ethyl acetate: dichloromethane (3.7:0.3:4) afforded 120 mg (37%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-propoxyphenyl)-1,2,4-oxadiazole; 1H NMR (CDCI3), δ (ppm); 8.70 (d, 1H), 8.27 (m, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.62 (m, 1H), 7.39 (s, 1H), 4.06 (t, 2H), 1.88 (m, 2H), 1.08 (s, 3H).

3-(2-Pyridyl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole [0497]

B161 <img file="IS2564B_D0357.tif" /> [0498] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-nitrobenzoyl chloride was prepared from 3-cyano-5-nitrobenzoic acid (1.0 g, 5.1 mmol). Asolutionof theacid chloride in dichloromethane (5 mL) atO'C was treated with pyrid-2-ylamidoxime (700 mg, 5.1 mMol) and triethylamine (2.1 mL, 15.3 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N,/V-dimethylformamide (5 mL) and heated at 110 ’C for 4 hours. Standard work up and silica gel chromatography using hexanes;ethyl acetate'.dichloromethane (3.5:0.5:4) afforded 149 mg (50%) of 3-(2-pyridyl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 9.35 (d, 1H), 8.91 (s, 1H), 8.89 (d, 1H), 8.75 (s,1 H), 8.26 (d, 1H), 7.94 (m, 1H), 7.53 (m, 1H).

3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole [0499]

B162 <img file="IS2564B_D0358.tif" /> [0500] Using the general procedure forthe preparation of acid chlorides, 3-cyano-5-nitrobenzoyl chloride was prepared from 3-cyano-5-nitrobenzoic acid (1.0 g, 5.1 mmol). Asolution of the acid chloride in dichloromethane (5 mL) at 0’C was treated with 5-fluoropyrid-2-ylamidoxime (791 mg, 5.1 mMol) and triethylamine (2.1 mL, 15.3 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissoived ín N,N-dimethyltormamide (5 mL) and heated at 110 ‘C for 4 hours. Standard work up and silica gel chromatography using hexanes:ethyl acetate:dichloromethane (3.5: 0.5:4) afforded 131 mg (8%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 9.34 (s, 1H), 8.89 (s, 1H), 8.74 (d, 2H), 8.30 (m, 1H), 7.66 (m, 1H).

3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-dimethylaminophenyl)-1,2,4-oxadiazole [0501]

Β163 <img file="IS2564B_D0361.tif" /> [0502] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-dimethylaminobenzoyl chloride was prepared from 3-cyano-5-dimethylaminobenzoicacid (190 mg, 1.0 mmol). Asolution of the acid chloride in dichloromethane (3 mL) at O'C was treated with 5-fluoropyrid-2-ylamidoxime (155 mg, 1.0 mmol) and triethylamine (697 μί, 5.0 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in Λ/,ΛΖ-dimethylfor-mamide (5 mL) and heated at 120 ‘C for 16 hours. After cooling, water was added to the reaction mixture and then the precipitate was collected and dried. Filtration through silica gel using dichloromethane followed by trituration with dichloromethane afforded 14 mg (5%) of 3-(5-f luoropy rid-2-y l)-5-(3-cyano-5-dimethylaminopheny I)· 1,2,4-oxadiazole:1H NMR (CDCI3), δ (ppm): 8.70 (d, 1H), 8.27 (m, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 7.62 (m, 1H), 7.08 (s, 1H), 3.11 (s, 6H).

3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-(2-methoxyethoxy)phenyl)-1,2,4-oxadiazole [0503]

B164 <img file="IS2564B_D0362.tif" /> [0504] Usingthegeneralprocedureforthepreparationofacidchlorides,3-cyano-5-(2-methoxyethoxy)benzoylchloride was prepared trom 3-cyano-5-(2-methoxyethoxy)benzoic acid (221 mg, 1.0 mmol). A solution of the acid chloride in dichloromethane (2 mL) at 0'C was treated with 5-fluoropyrid-2-ylamidoxime (155 mg, 1.0 mmol) and triethylamine (418 μΙ_, 3.0 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried overanhydroussodiumsulfate,filtered,andconcentrated.TheresiduewasdissolvedinN,N-dimeth-ylformamide (2 mL) and heated at 120 ‘C for 16 hours. After cooling, water was added to the reaction mixture and then the precipitate wascollected and dried. Silica gel chromatography using 40% ethyl acetate/hexanes followed by trituration with diethyl ether afforded 169 mg (50%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-(2-methoxyethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm); 8.70 (d, 1H), 8.27 (m, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 7.62 (m, 1H), 7.44 (s, 1H), 4.27 (t, 2H), 3.81 (t, 2H), 3.48 (s, 3H).

3-{5-fluoropyrid-2-yl)-5-(3-cyano-5-(1 H-imidazol-1 -ylmethyl)phenyl)-1,2,4-oxadiazole [0505]

B165 <img file="IS2564B_D0363.tif" />

[0506] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-(1 H-imidazol-1 -y l-methy))benzoy I chloride was prepared from 3-cyano-5-(1 H-imidazol-1-yl-methyl)benzoic acid (140 mg, 0.62 mmol). A solution of the acid chloride in dichloromethane (2 mL) at O’C was treated with 5-fluoropyrid-2-ylamidoxime (96 mg, 0.62 mmol) and triethylamine (258 μΐ., 1.9 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in /V,/V-dimethylformamide (2 mL) and heated at 120 °C for 16 hours. After cooling, water was added to the reaction mixture and then the precipitate was collected and dried. Silica gel chromatography using 40% ethyl acetate/ hexanes followed by trit uration with diethyl ether afforded 4 mg (2%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-(1 H-imidazol-1-ylmethyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm); 8.71 (d, 1H), 8.53 (s, 1H), 8.33 (s, 1H), 8.28 (m, 1H) 7.63 (m, 3H), 7.21 (s, 1H), 6.97 (s, 1H), 5.30 (s, 2H).

3-(2-Pyndyl)-5-(3-cyano-5-(methoxymethyl)phenyl)-1,2,4-oxadiazole [0507]

B166 <img file="IS2564B_D0367.tif" /> [0508] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-(methoxymethyl)benzoyl chloride was prepared from 3-cyano-5-(methoxymethyl)benzoic acid (157 mg, 0.82 mmol). A solution of the acid chloride in dichloromethane (2 mL) at 0'C was treated with pyrid-2-ylamidoxime (113 mg, 0.82 mmol) and triethylamine (343 μΙ_, 2.5 mmol) and then stirred at ambienl temperature for 3 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N,N-dimethylfor-mamide (2 mL) and heated at 120 ’C for 16 hours. After cooling, water was added to the reaction mixture and the precipitate that formed was collected and dried. The solid was dissolved in dichloromethane and silica gel was added to the solution to remove the dark color. The silica gel was then filtered off and the filtrate was concentrated to dryness. T ritu ration of the residue with diethyl ether afforded 44 mg (18%) of 3-(2-pyridyl)-5-(3-cyano-5-(methoxymethyl)phenyl)-1,2,4-oxadiazole as a white solid: 1H NMR (CDCI3), δ (ppm): 8.87 (d, 1H), 8.50 (s, 2H), 8.23 (d, 1H), 7.94 (m, 1H), 7.89 (s, 1H), 7.50 (m, 1H), 4.59 (s, 2H), 3.49 (s, 3H).

3-(3-cyano-5-methoxyphenyl)-5-(2-pyridyl)-1,2,4-oxadiazole [0509]

B167 <img file="IS2564B_D0368.tif" /> [0510] Using the general procedure forthe preparation of acid chlorides, picolinoy I chloride was prepared from picolinic acid (300 mg, 2.4 mmol). A solution of the acid chloride in dichloromethane (2 mL) at 0‘C was treated with of 3-cyano-5-methoxyphenyl-amidoxime (100 mg, 0.52 mmol) and triethylamine (1.0 mL, 7.2 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in /V,/V-dimethylformamide (2 mL) and heated at 120 'C

for 16 hours. Standard work up and silica gel chromatography using 10-20% ethyl acetate/hexanes followed by trituration with hexanes afforded 10 mg (7%) of 3-(3-cyano-5-methoxyphenyl)-5-(2-pyridyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.90 (d, 1H), 8.32 (d, 1H), 8.13 (s, 1H), 7.98 (m, 2H), 7.58 (dd, 1H), 7.31 (s, 1H), 3.94 (s, 3H).

3-(3-Cyano-5-methoxyphenyl)-5-(5-fluoropyrid-2-yl)-1,2,4-oxadiazole [0511]

B168 <img file="IS2564B_D0371.tif" /> [0512] Using the general procedure for the preparation of acld chlorides, 5-fluoropicol inoyl chloride was prepared from 5-fluoro-picolinic acid hydrochloride (177 mg, 1.0 mmol). A solution of the acid chloride in dichloromethane (2 mL) at 0’C was treated with oí 3-cyano-5-methoxyphenyl-amidoxime (100 mg, 0.52 mmol) and tríethy lamine (418 μΙ_, 3.0 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried overanhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N,/V-dimethylformamide (2 mL) and heated at 120 'C for 16 hours. Standard work up and silica gel chromatography using 10-20% ethyl acetate/ hexanes followed by trituration with diethyl ether/hexanes afforded 20 mg (19%) of 3-(3-cyano-5-methoxyphenyl)-5-(5-fluoropyrid-2-yl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.75 (s, 1H), 8.40 (dd, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.68 (m, 1H), 7.38 (s, 1H), 3.94 (s, 3H).

S-fb-fluoropyrid-Z-yp-S-fS-cyano-S-ethoxyphenylJ-I.ZA-oxadiazole [0513]

B169 <img file="IS2564B_D0372.tif" /> [0514] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-ethoxybenzoyl chloride was prepared from 3-cyano-5-ethoxybenzoic acid (145 mg, 0.75 mmol). A solution of the acid chloride in dichloromethane (2 mL) at 0’C was ireated with 5-fluoropyrid-2-ylamidoxime (117 mg, 0.75 mmol) and triethylamine (315 μί, 2.26 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried overanhydrous sodium sulíate, filtered, and concentrated. The residue was dissolved in W./V-dimethylformamide (2 mL) and heated at 120 ’C for 16 hours. Standard work up and silica gel chromatography using 5-20% ethyl acetate/ hexanes followed by trituration with díethyl ether aflorded 54 mg (23%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-ethoxy-phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.69 (d, 1H), 8.26 (dd, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.60 (m, 1H), 7.38 (s, 1H), 4.16 (q, 2H), 1.49 (t, 3H).

3-(5-Cyanopyrid-2-yl)-5-(3-cyano-5-ethoxyphenyl)-1,2,4-oxadiazole [0515]

Β170 [0516] Using the general procedure for the preparation of<img file="IS2564B_D0375.tif" />acid chlorides, 3-cyano-5-ethoxybenzoyl chloride was prepared from 3-cyano-5-ethoxybenzoic acid (145 mg, 0.75 mmol). A solution of the acid chloride in dichloromethane (2 mL) at O'C was treated with 5-cyanopyrid-2-ylamidoxime (122 mg, 0.75 mmol) and triethylamine (315 μΙ_, 2.3 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried cver anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in /V,N-dimethylformamide (2 mL) and heated at 120 ’C for 16 hours. Standard work up and silica gel chromatography using 5-20% ethyl acetate/ hexanes followed by trituration with diethyl ether afíorded 85 mg (35%) of 3-(5-cyanopyrid-2-yl)-5-(3-cyano-5-ethoxy-phenyl)-1,2,4-oxadiazole:1H NMR (CDCI3), δ (ppm): 9.11 (s, 1H), 8.38 (d, 1H), 8.20 (dd, 1H), 8.13 (s, 1H), 7.98 (d, 1H), 7.40 (s, 1H), 4.17 (q, 2H), 1.50 (t, 3H).

3-(5-Chloropyrid-2-yl)-5-(3-allyloxoy-5-cyanophenyl)-1,2,4-oxadiazole [0517]

B171 <img file="IS2564B_D0376.tif" /> [0518] Using the general procedure for the preparation of acid chlorides, 3-al1yloxy-5-cyanobenzoyl chloride was prepared from 3-allyloxy-5-cyanobenzoic acid (279 mg, 1.4 mmol). A solution of the acid chloride in dichloromethane (3 mL) at 0’C was treated with 5-chloropyrid-2-ylamidoxime (231 mg, 1.4 mmol) and triethylamine (574 μΐ_, 4.1 mmol) and then stirred at ambient temperature tor 1 hour. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, fillered, and concentrated. The residue was dissolved in Λ/,Μ-dimethylformamide (3 mL) and heated at 120 "C for 16 hours. Standard work up and silica gel chromatography using 5-20% ethyl acetate/ hexanes followed by trituration with diethyl ether afforded 192 mg (42%) of 3-(5-chloropyrid-2-yl)-5-(3-allyloxy-5-cyan-ophenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.79 (d. 1H), 8.18 (d, 1H), 8.14 (m, 1H), 7.99 (s, 1H), 7.88 (d, 1H), 7.40 (s, 1H), 6.07 (m, 1H), 5.40 (m, 2H), 4.67 (d, 2H).

3-(5-Chloropyrid-2-yl)-5-(3-cyano-5-propoxyphenyl)-1,2,4-oxadiazole [0519]

B172 <img file="IS2564B_D0377.tif" /> [0520] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-propoxybenzoyl chloride was

prepared from 3-cyano-5-propoxybenzoic acid (93 mg, 0.45 mmol). A solution of the acid chloride in dichloromethane (2 mL) at O'C was treated with 5-chloropyrid-2-ylamidoxime (76 mg, 0.45 mmol) and triethylamine (188 ixL, 1.4 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in /V,/V-dimethylformamide (2 mL) and heated at 120 ’C for 16 hours. Standard work up and silica gel chromatography using 10% ethyl acetate/ hexanes afforded 7 mg (4%) of 3-(5-chtoropyrid-2-yl)-5-(3-cyano-5-propoxyphenyl)-1,2,4-oxadiazole:1H NMR (CDCI3), δ (ppm); 8.80 (d, 1H), 8.18 (d, 1H), 8.11 (s, 1H), 7,98 (s, 1H), 7.88 (dd, 1H), 7.39 (s, 1H), 4.05 (t, 2H), 1.87 (m, 2H), 1.08 (t. 3H).

3-(5-Chloropyrid-2-yl)-5-(3-cyano-5-ethoxyphenyl)-1,2,4-oxadiazole [0521]

B173 <img file="IS2564B_D0381.tif" /> [0522] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-ethoxybenzoyl chloride was prepared from 3-cyano-5-ethoxybenzoic acid (189 mg, 0.94 mmol). A solution of the acid chloride in dichloromethane (2 mL) at 0'C was treated with 5-chloropyrid-2-ylamidoxime (159 mg, 0.94 mmol) and triethylamine (399 μΙ_, 2.9 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N,N-dimethylformamide (2 mL) and heated at 120 'C for 16 hours. After cooling, water was added to the reaction mixture and then the precipitate was collected and dried. Filtration through silica gel using dichloromethane followed by trituration with diethyl ether afforded 193 mg (62%) of 3-(5-chloropyrid-2-yl)-5-(3-cyano-5-ethoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.79 (d, 1H), 8.18 (d, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.88 (dd, 1H), 7.38 (s, 1H), 4.16 (q, 2H), 1.49 (t, 3H).

3-(5-Fluoropyrid-2-yl)-5-(3-cyano-5-hexyloxyphenyl)-1,2,4-oxadiazole [0523]

B174 <img file="IS2564B_D0382.tif" /> [0524] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-hexyloxybenzoyl chloride was prepared from 3-cyano-5-hexyloxybenzoic acid (247 mg, 0.96 mmol). A solution of the acid chloride in dichloromethane (2 mL) at 0’C was treated with 5-fluoropyrid-2-ylamidoxime (149 mg, 0.96 mmol) and triethylamine (399 μΙ_, 2.9 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N,N-dimethylformamide (2 mL) and heated at 120 ’C for 16 hours. Standard work up and filtration through silica gel using dichloromethane followed by trituration with diethyl ether afforded 75 mg (21 %) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-hexyloxyphenyl)-1,2,4-oxadiazole: Ή NMR (CDCI3), δ (ppm): 8.69 (d, 1H), 8.27 (dd, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.62 (m, 1H), 7.39 (s, 1H), 4.09 (t, 2H), 1.84 (m, 2H), 1.49 (m, 2H), 1.37 (m, 4H), 0.93 (t, 3H).

3-(5-Fluoropyrid-2-yl)-5-(3-cyano-5-(methoxymethyl)phenyl)-1,2,4-oxadiazole [0525]

B175 <img file="IS2564B_D0385.tif" /> [0526] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-(rnethoxymethyl)benzoyl chloride was prepared trom 3-cyano-5-(methoxymethyl)benzoic acid (143 mg, 0.75 mmol). A solution of the acid chloride in dichloromethane (2 mL) at O'C was treated with 5-fluoropyrid-2-ylamidoxime (123 mg, 0.75 mmol) and triethylamine (313 |xL, 2.2 mmol) and then stirred at ambient temperature for 3 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N, /V-dimethylformainide (2 mL) and heated at 120 ‘C for 16 hours. After cooling, water was added to the reaction mixture and the precipitate that tormed was collected and dried. The solid was dissolved in dichloromethane and silica gel was added to the solution to remove the dark color. The silica gel was then filtered off and the filtrate was concentrated to dryness. Trituration of the residue with diethyl ether afforded 60 mg (25%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-(meth-oxymethyl)phenyl)-1,2,4-oxadiazole as a white solid: 1H NMR (CDCI3), δ (ppm): 8.69 (d, 1H), 8.48 (s, 2H); 8.27 (dd, 1H), 7.89 (s, 1H), 7.62 (m, 1H), 4.59 (s, 2H), 3.49 (s, 3H).

3-(5-Fluoro-pyrid-2-yl)-5-(5-cyano-2-methoxyphenyl)-1,2,4-oxadiazole [0527]

B176 <img file="IS2564B_D0386.tif" /> [0528] A mixture of 5-cyano-2-methoxybenzoic acid (1.77mg, 1 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (2 ml, 4 mmol, dichloromethane) and 1 drops of N,/V-dimethylformamide. The mixture was stirred 2 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 5-fluoropyrid-2-ylamidoxirne (155 mg, 1 mmol) and triethylamine (404 mg, 4 mmol) in dichloromethane (10 mL). The mixture was then heated in dimethylformamide (1 mL) for 3 hoursat 120 'C. Standard work up, afforded 75 mg (25.3%) of 3-(5-Fluoro-pyrid-2-yl)-5-(5-cyano-2-methoxyphenyl)-1,2,4-oxadiazole. 1H NMR (CDCI3), δ (ppm): 8.69 (d, 1H), 8.59 (d, 1H), 8.26 (dd, 1H), 7.85 (dd, 1H), 7.60 (m, 1H), 7.19 (d, 1H), 4.10 (s, 3H).

5-(5-Cyano-2-methoxyphenyl)-3-(5-cyano-pyrid-2-yl)-1,2,4-oxadiazole [0529]

Β177 <img file="IS2564B_D0389.tif" /> [0530] A mixture of 5-cyano-2-methoxybenzoic acid (1.77mg, 1 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (2 ml, 4 mmol, dichloromethane) and 1 drops of /V,N-dimethylformamide. The mixture was stirred 2 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 5-cyanopyrid-2-ylamidoxime (162 mg, 1 mmol) and triethylamine (404 mg, 4 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (1 mL) for 3 hours at 120 ’C. Standard work up, afforded 67 mg (22%) of 5-(5-cyano-2-methoxyphenyl)-3-(5-cyano-pyrid-2-yl)-1,2,4-oxadiazole. 1H NMR (CDCI3), δ (ppm): 9.10 (s, 1H), 8.58 (d, 1H), 8.37 (dd, 1H), 8.19 (dd, 1H), 7.86 (dd, 1H), 7.20 (d, 1H), 4.11 (s, 3H).

3-(5-Fluoro-pyrid-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole [0531]

B178 <img file="IS2564B_D0390.tif" /> [0532] To the dichloromethane solution (2 mL) of 5-fluoropyrid-2-ylamidoxime (155 mg, 1 mmol) and triethylamine (404 mg, 4 mmol), 3-bromobenzoyl chloride (1.77mg, 1 mmol) was added at room temperature. The mixture was then heated in dimethylformamide (1 mL)for40minutes at 120-130 "C. Standard work up, afforded 225 mg (70.3%) of 3-(5-Fluoro-pyrid-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole.

5-(3-Chloro-5-methyl-pyrid-4-yl)-3-(2-pyridyl)-1,2,4-oxadiazole [0533]

B179 <img file="IS2564B_D0391.tif" /> [0534] A mixture of 2-cbloro-6-methylisonicotinic acid (1.71 g, 10 mmol) in dichloromethane (15 mL) was treated with 2M oxalyl chloride (15 ml, 30 rnmol, dichloromethane) and 3 drops of A/,A/-dimethylformamide. The mixture was stirred 2 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 2-pyriðylamidoxime (1.37 g, 10 mmol) and triethylamine (3.03 g, 30 mmol) in dichlorometbane (15 mL). Toe mixture was then heated in dimethylformamide (10 mL) for 1 hours at 120 'C. Standard work up, afforded 1,63 g (60%) of 5-(3-chloro-5-methyl-pyrid-4-yl)-3-(2-pyridyl)-1,2,4-oxadiazole.

5-(3-Chloro-5-methoxy-pyrid-4-yl)-3-(2-pyridyl)-1,2,4-oxadiazole [0535]

B180 <img file="IS2564B_D0395.tif" /> [0536] A mixture of 2-chloro-6-methoxyisonicotinic acid (1.87 g, 10 mmol) in dichloromethane (15 mL) was treated with 2M oxalyl chloride (15 ml, 30 mmol, dichloromethane) and 3 drops of N,A/-dimethylformamide. The mixture was stirred 2 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 2-pyridylamidoxime (1.37 g, 10 mmol) and triethylamine (3.03 g, 30 mmol) in dichloromethane (15 mL). The mixture was then heated in dimethylformamide (10 mL) for 1 hours at 120 'C. Standard work up, afforded 1.63 g (60%) of 3-(2-pyridyl)-5-(3-chloro-5-methoxy-pyrid-4-yl)-1,2,4-oxadiazole.

3-(3-Cyano-5-methylphenyl)-5-(2-pyridyl)-1,2,4-oxadiazole [0537]

B181 <img file="IS2564B_D0396.tif" /> [0538] A mixture of picolinic acid (123 mg, 1 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (2 ml, 4 mmol, dichloromethane). The mixture was stirred 2 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 3-cyano-5-methylphenylamidoxime (80 mg, 0.457 mmol) and triethylamine (303 mg, 3 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethyltormamide (2 mL) for 1 hours at 120 'C. Standard work up, afíorded 5.8 mg (4.8%) of 3-(3-cyano-5-methylphenyl)-5-(2-pyridyl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.89 (d, 1H), 8.30 (s,m, 3H), 7.96 (dt, 1H), 7.60 (s,dd, 2H), 2.50 (s, 3H).

3-(5-Bromo-pyrid-3-yl)-5-(2-pyridyl)-1,2,4-oxadiazole [0539]

B182 <img file="IS2564B_D0397.tif" />

[0540] A mixture of picolinic acid (123 mg, 1 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (2 ml, 4 mmol, dichloromethane). The mixture was stirred 2 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 5-bromopyrid-3-ylamidoxime (216 mg, 1 mmol) and triethylamine (303 mg, 3 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (2 mL) for 1 hours at 120 'C. Standard work up, afforded 103 mg (34%) of 3-(5-bromo-pyrid-3-yl)-5-(2-pyridyl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 9.36 (d, 1H), 8.90 (d, 1H), 8.84 (d, 1H), 8.68 (t, 1H), 8.32 (d, 1H), 7.98 (dt, 1H), 7.58 (dd, 1H).

3-(3-Cyano-5-fluorophenyl)-5-(2-pyrídyl)-1,2,4-oxadiazole [0541]

B183 <img file="IS2564B_D0401.tif" /> [0542] A mixture of picolinic acid (184.6 mg, 1.5 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (3 ml, 6 mmol, dichloromethane). The mixture was stirred overnight at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 3-cyano-5-fluorophenylamidoxime (100 mg, 0.558 rnmol) and triethylamine (558 mg, 5.58 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (1 mL) for 1 hours at 120 "C. Standard work up, afforded 43 mg (28.9%) of 3-(5-cyano-3-fluorophenyl)-5-(2-pyridyl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.89 (d, 1H), 8.34 (s,d, 3H), 8.10 (d, 1H), 7.59 (m, 2H).

3-(3-lodophenyl)-5-(2-pyridyl)-1,2,4-oxadiazole [0543]

B184 <img file="IS2564B_D0402.tif" /> [0544] A mixture of picolinic acid (300 mg, 2.4 mmol) in dichlorometbane (2 mL) was treated with 2M oxalyl chloride (2 ml, 4 mmol, dichloromethane). The mixture was stirred 5 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 3-iodophenyl-amidoxime (263 mg, 1 mmol) and triethylamine (303 mg, 3 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (2 mL) for 1 hours at 120 - 130'C. Standard work up, afforded 64.5 mg (18.5 %) of 3-(3-iodophenyl)-5-(2-pyridyl)-1,2,4-oxadiazole. 1H-NMR (CDCIg), δ (ppm): 8.88 (d, 1H), 8.61 (s, 1H), 8.31 (d, 1H), 8.20 (d, 1H), 7.96 (t, 1H), 7.87 (d, 1H), 7.56 (m, 1H), 7.25 (m, 1H).

3-(3-Cyanophenyl)-5-(2-pyridyl)-1,2,4-oxadiazole [0545]

Β186 <img file="IS2564B_D0405.tif" /> [0546] A mixture of picolinic acid (300 mg, 2.4 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (2 ml, 4 mmol, dichloromethane). The mixture was stirred 5 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 3-iodophenyl-ainidoxime (161 mg, 1 mmol) and triethylamine (303 mg, 3 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (2 mL) for 1 hours at 120-130 'C. Standard work up, afforded 21.1 mg (8.5%) of 3-(3-cyanophenyl)-5-(2-pyridyl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.89 (d, 1H), 8.55 (s, 1H), 8.47 (d, 1H), 8.32 (d, 1H), 7.97 (t, 1H), 7.82 (d, 1H), 7.65 (t, 1H), 7.58 (m, 1H).

3-(3-Cyano-5-dimethylamino-phenyl)-5-(2'pyridyl)-1,2,4-oxadiazoie [0547]

B187 <img file="IS2564B_D0406.tif" /> [0548] A mixture of picolinic acid (300 mg, 2.4 mmoi) in dichloromethane (2 mL) was treated wíth 2M oxalyl chloride (2 ml, 4 mmol, dichloromethane). The mixture was stirred 5 hours at room temperature. The solvent and excess raagent were removed in vacuo. The residue was treated with 3-cyano-5-dimethylaminophenyl-arnidoxime (100 mg, 0.5 mmol) and triethylamine (303 mg, 3 mmol) in dichloromethane (2 ml). The mixture was then heated in dimethylformamide (2 mL) for 1 liours at 120-130 ’C. Standard work up, afforded 11.8 mg (8.1 %) of 3-(3-cyano-5-dimethylamino-phenyl)-5-(2-pyridyl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.88 (d, 1H), 8.32 (d, 1H), 7.97 (t, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.57 (m, 1H), 7.01 (s, 1H), 3.08 (s, 6H).

3-(3-Cyano-5-methylphenyl)-5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazQle [0549]

B188 <img file="IS2564B_D0407.tif" /> [0550] A mixture of 5-fluoro-picolinic acid hydroch loride (177 mg, 1 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (2 ml, 4 mmol, dichloromethane). The mixture was stirred 2 hours at room temperature. The solvent

and excess reagent were removed in vacuo. The residue was treated with 3-cyano-5-methylphenyl-amidoxime (90 mg, 0.5 mmol) and triethylamine (303 mg, 3 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethyIfor-mamide (2 mL) for 1 hours at 120 "C. Standard work up, afforded 37.4 mg (26.7%) of 3-(3-cyano-5-methylphenyl)-5-(5-f luoro-pyrid-2-yl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.73 (d, 1H), 8.36 (m, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 7.69 (m, 1H), 7.62 (s, 1H), 2.50 (s, 3H).

3-(3-Cyano-5-fluorophenyl)-5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole [0551]

B189 <img file="IS2564B_D0411.tif" /> [0552] Amixtureof 5-fluoro-picolinic acid hydrochloride (177 mg, 1 mmol) indichloromethane (2mL) was treated with 2M oxalyl chloride (2 ml, 4 mmol, dichloromethane). The mixture was stirred 2 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 3-cyano-5-fluorophenyl-amidoxime (120 mg, 0.67 mmol) and triethylamine (303 mg, 3 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (2 mL) for 1 hours at 120 ’C. Standard work up, afforded 33 mg (17.3%) of 3-(3-cyano-5-fluorophenyl)-5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole. 'H-NMR (CDCI3), δ (ppm); 8.73 (d, 1H), 8.36 (m, 2H), 8.18 (dd, 1H), 7.69 (dt, 1H), 7.53 (d, 1H).

5-(4-Cyanophenyl)-3-(6-cyano-pyrid-2-yl)-1,2,4-oxadiazole [0553]

B190 <img file="IS2564B_D0412.tif" /> [0554] To a dichloromethane solution (1 mL) of 6-cyanopyrid-2-ylamidoxime (81 mg, 0.5 mmol) and triethylamine (202 mg, 2 mmol), 4-cyanobenzoyl chloride (91 mg, 0.55 mmol) was added at room temperature. The mixture was then heated in dimethylformamide (1 mL) for 2 hours at 120-130 ’C. Standard work up, afforded 63.4 mg (46.4%) of 5-(4-cyanophenyl)-3-(6-cyano-pyrid-2-yl)-1,2,4-oxadiazole. 1H-NMR (C DC l3), δ (ppm): 8.24 (ιτι, 3H), 8.06 (t, 1H), 7.92 (d, 3H)

5-(3-Cyano-5-trifluoromethoxyphenyl)-3-(2-pyridyl)-1,2,4-oxadiazole [0555]

Β191 <img file="IS2564B_D0415.tif" /> [0556] A mixture of 3-cyano-5-trifluoromethoxybenzoic acid, which 3-[imino(methoxy)methyl]-5-trifluoromethoxyben-zoic acid (3:1,50 mg, 0.2165mmoles) in dichloromethane (1 mL) was treated with 2M oxaiyl chloride (0.433 ml, 0.866 mmol, dichloromethane). The mixture was stirred 3 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 2-pyridyl-amidoxime (29.7 mg, 0.216 mmol) and triethylamine (87 mg, 0.866 mmol) in dichloromethane (1 ml_). The mixture was then heated in dimethylformamide (0.5 ml) for 3 hoursat 120 'C. Standard work up, purified by prep HPLC (C18 column, CH3CN:H2O = 60:40), afforded 3.2 mg (4.5%) of 5-(3-Cyano-5-trifluoromethoxyphenyl)-3-(2-pyridyl)-1,2,4-oxadiazole [1H-NMR (CDCI3), δ (ppm): 8.86 (w, 1H), 8.56 (s, 1H), 8.40 (s, 1H), 8.24 (d, 1H), 7.92 (t, 1H), 7.72 (S, 1H), 7.73 (m, 1H)]

5-(3-methoxycarbonyl-5-trifluoromethoxyphenyl)-3-(2-pyridyl)-1,2,4-oxadiazole [0557]

B192 <img file="IS2564B_D0416.tif" /> [0558] A mixture of 3-cyano-5-trifluoromethoxybenzoíc acid, which 3-[imino(methoxy)methyl]-5-trifluoromethoxyben-zoic acid (3:1,50 mg, 0.2165mmoles) in dichloromethane (1 mL) was treated with 2M oxalyl chloride (0.433 ml, 0.866 mmol, dichloromethane). The mixture was stirred 3 hours at room temperalure. The solvent and excess reagent were removed in vacuo. The residue was treated with 2-pyridyl-amidoxime (29.7 mg, 0.216 mmol) and triethylamine (87 mg, 0.866 mmol) in dichloromethane (1 mL). The mixture was then heated in dimethylformamide (0.5 mL) for 3 hours at 120 ”C. Standard work up, purifiad by prep HPLC (C18 column, CH3CN:H2O = 60:40), afforded 1.2 mg (1.5%) of 5-(3-methoxycarbonyl-5-trifluoromethoxyphenyl)-3-(2-pyridyl)-1,2,4-oxadiazole [1H-NMR (COCI3), δ (ppm): 8.86 (d, w, 2H), 8.36 (s, 1H), 8.25 (d, 1H), 8.15 (s, 1H), 7.90 (t, 1H), 7.51 (m, 1H), 4.01 (s, 3H)].

5-(3-Cyano-5-trifluoromethoxyphenyl)-3-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole [0559]

<img file="IS2564B_D0419.tif" />Β193 [0560] A mixture of 3-cyano-5-trifluoromethoxybenzoic acid, which contained 3-[imino(methoxy)methyl]-5-trifluor· omethoxybenzoic acid (3:1,50 mg, 0.2165mmoles) in dichloromethane (1 mL) was treated with 2M oxalyl chloride (0.433 ml, 0.866 mmol, dichloromethane). The mixture was stirred 3 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 5-fluoropyrid-2-ylamidoxime (33.6 mg, 0.216 mmol) and triethylamine (87 mg, 0.866 mmol) in dichloromethane (1 mL). The mixture was then heated in dimethylformamide (0.5 mL) for 3 hours at 120 ’C. Standard work up, purified by prep HPLC (C18 column, CH3CN:H2O = 60:40), afforded 14.9 mg (19.6%) of 5-(3-cyano-5-trifluoromethoxyphenyl)-3-(5-fluoropyrid-2-yl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm); 8.72 (s, 1H), 8.56 (s, 1H), 8.39 (s, 1H), 8.25 (m, 1H), 7.78 (s, 1H), 7.61 (m, 1H).

3-(5-Cyaro-pyrid-2-yl)-5-(3-cyano-5-trifluoromethoxyphenyl)-1,2,4-oxadiazole [0561]

B194 <img file="IS2564B_D0420.tif" /> [0562] A mixture of 3-cyano-5-trifluoromethoxybenzoic acid, which 3-[ímino(methoxy)methyl]-5-trifluoromethoxyben-zoic acid (3:1,50 mg, 0.2165mmoles) in dichloromethane (1 mL) was Ireated with 2M oxalyl chloride (0,433 ml, 0.866 mmol, dichloromethane). The mixture was stirred 3 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 5-cyanopyrid-2-ylanfiidoxime (33.6 mg, 0.216 mmol) and triethylamine (87 mg, 0.866 mmol) in dichloromethane (1 mL). The mixture was then heated in dimethylformamide (0.5 mL) for 3 hours at 120 'C. Standard work up, purified by prepHPLC (C18column, CH3CN:H2O = 60:40), afforded 18mg (22.2%) of5-(3-cyano-5-trifluoromethoxyphenyl)-3-(5-fluoropyrid-2-yl)-1,2,4-oxadiazole. 1H-NMR(CDCI3),8(ppm):9.12(d, 1H), 8.50 (s, 1H), 8.38 (s, d, 2H), 8.20 (d, 1H), 7.79 (s, 1H).

3-(3-Cyano-5-dimethylaminophenyl)-5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole [0563]

B195

<img file="IS2564B_D0423.tif" /> [0564] A mixture of 5-fluoro-picolinic acid acid (177.5 mg, 1 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (2 ml, 4 mmol, dichloromethane). The mixture was stirred 2 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 3-cyano-5-dimethy!aminophenyl-amidoxime (102 mg, 0.5 mmol) and triethylamine (404 mg, 4 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (1 mL) for 1 hoursat 130 "C. Standard work up, afforded 24 mg (15.5%) of 3-(3-cyano-5-dimethyaminophe-nyl)-5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.72 (d, 1H), 8.37 (dd, 1H), 7.81 (s, 1H), 7.68 (dt, 2H), 7.02 (d, 1H), 3.10 (s, 6H).

5-(5-Chloro-pyrid-2-yl)-3-(3-cyano-5-dimethylanriinophenyl)-1,2,4-oxadiazole [0565]

B196 <img file="IS2564B_D0424.tif" /> [0566] A mixture of 5-chloro-picolinic acid hydrochloride (72 mg, 0.4 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (0.8 ml, 1.6 mmol, dichloromethane). The mixture was stirred at room temperature overnight. The solvent and excess reagent were removed in vacuo. The residue was treated with 3-cyano-5-dimethylaminophenyl-amidoxime (40.8 mg, 0.2 mmol) and triethylamine (162 mg, 1.6 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (1 mL) for 4 hours at 130 'C. Standard work up, afforded 3.8 mg (5.8%) of 5-(5-chloro-pyrid-2-yl)-3-(3-cyano-5-dimethyaminophenyl)-1,2,4-oxadiazole. 'H-NMR (CDCI3), δ (ppm): 8.82 (d, 1H), 8.27 (d, 1H), 7.95 (dd, 1H), 7.78 (S, 1H), 7.66 (d, 1H), 7.01 (d, 1H), 3.06 (S, 6H).

5-(5-Chloro-pyrid-2-yl)-3-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole [0567]

B197 <img file="IS2564B_D0425.tif" />

[0568] A mixture of 5-chloropicolinic acid hydrochloride (72 mg, 0.4 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (0.8 ml, 1.6 mmol, dichloromethane). The mixture was stirred at room temperature overníght. The solvent and excess reagent were removed in vacuo. The residue was treated with 3-cyano-5-methoxyphenyl-amidoxime (76 mg, 0.4 mmol) and triethylamine (162 mg, 1.6 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (1 mL) for 4 hours at 130 'C. Standard work up, afforded 45.8 mg (36.6%) of 5-(5-chloro-pyrid-2-yl)-3-(3-cyano-5-methoxyphenyl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.85 (d, 1H), 8.27 (d, 1H), 8.10 (s, 1H), 7.95 (m, 2H), 7.12 (d, 1H), 3.92 (s, 3H).

5-(5-Chloro-pyrid-2-yl)-3-(6-cyano-4-methoxy-pyrid-2-yl)-1,2,4-oxadiazole [0569]

B198 <img file="IS2564B_D0429.tif" /> [0570] A mixture of 5-chloropicolinic acid hydrochloride (72 mg, 0.4 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (0.8 ml, 1.6 mmol, dichloromethane). The mixture was stirred at room temperature overnight. The solvent and excess reagent were removed in vacuo. The residue was treated with 6-cyano-4-methoxypyrid-2-yl-amidoxime (38.4 mg, 0.2 mmol) and triethylamine (162 mg, 1.6 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (1 mL) for 4 hours al 130 ’C. Standard work up, afforded 1.9 mg (3%) of 5-(5-chloro-pyrid-2-yl)-3-(6-cyano-4-methoxypyrid-2-yl)-1,2,4-oxadlazole. [1H-NMR (CDCI3), δ (ppm): 8.85 (d, 1H), 8.36 (d, 1H), 7.97 (m, 2H), 7.38 (d, 1H), 4.03 (s, 3H)].

5-(5-chlora-pyrid-2-yl)-3-(6-cyano-4-hydroxy-pyrid-2-yl)-1,2,4-oxadiazole [0571 ]

B199 <img file="IS2564B_D0430.tif" /> [0572] A mixture of 5-chloropicolinic acid hydrochloride (72 mg, 0.4 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (0.8 ml, 1.6 mmol, dichloromethane). The mixture was stirred at room temperature overnight. The solvent and excess reagent were removed in vacuo. The residue was treated with 6-cyano-4-methoxypyríd-2-yl-amidoxime (38.4 mg, 0.2 mmol) and triethylamlne (162 mg, 1.6mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (1 mL) for 4 hours at 130 'C. Standard work up, afíorded 2.2 mg (3.67%) of 5-(5-chloro-pyrid-2-yl)-3-(6-cyano-4-hydroxypyrid-2-yl)-1,2,4-oxadiazole I1 H-NMR (CDCI3), δ (ppm): 8.87 (d, 1H), 8.43 (d, 1H), 8.23 (dd, 1H), 7.91 (d, 1H), 7.57 (d, 1H).].

5-(5-Chloro-pyrid-2-yl)-3-(3-cyano-5-trifluoromethoxyphenyl)-1,2,4-oxadiazole [0573]

Β200 <img file="IS2564B_D0433.tif" /> [0574] A mixture of 5-chloropícolinic acid hydrochloride (72 mg, 0.4 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (0.8 ml, 1.6 mmol, dichloromethane). The mixture was stirred at room temperature overnight. The solvent and excess reagent were removed in vacuo. The residue was treated with 3-cyano-5- trifluoromethoxyphenyl-amidoxime (68.6 mg, 0.28 mmol) and triethylamine (162 mg, 1.6 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (1 mL) for 4 hours at 130 ’C. Standard work up, afforded 17.4 mg (16.9%) of 5-(5-chloro-pyrid-2-yl)-3-(3-cyano-5-trifluoromethoxyphenyl)-1,2,4-oxadiazole. ’H-NMR (CDCI3), δ (ppm): 8.84 (d, 1H), 8.46 (s, 1H), 8.30 (m, 2H), 7.96 (dd, 1H), 7.68 (d, 1H).

' 5-(5-Chl oro-py rid-2-y I)-3-(3-cyanopheny l)-1,2,4-oxadiazole [0575]

B201 <img file="IS2564B_D0434.tif" /> ’ [0576] A mixture of 5-chloropicolinic acid hydrochloride (72 mg, 0.4 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (0.8 ml, 1.6 mmol, dichloromethane). The mixture was stirred at room temperature overnight. The solvant and excess reagent were removed in vacuo. The residue was treated with 3-cyanophenyl-amidoxime (64.4 mg, 0.4 mmol) and triethylamine (162 mg, 1.6 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (1 mL) for 4 hours at 130 ‘C. Standard work up, afforded 24.5 mg (21.7%) of 5-(5-chloro-pyrid-2> yl)-3-(3-cyanophenyt)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.84 (d, 1H), 8.53 (s, 1H), 8.45 (dd, 1H), 8.26 (d, 1H), 7.95 (dd, 1H), 7.83 (d, 1H), 7.66 (t, 1H).

5-(5-Chloro-pyrid-2-yl)-3-(3-cyano-5-methylphenyl)-l,2,4-oxadiazole ) [0577]

Β202 <img file="IS2564B_D0437.tif" /> [0578] A mixture of 5-chloropicolinic acid hydrochloride (72 mg, 0.4 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (0.8 ml, 1.6 mmol, dichloromethane). The mixture was stirred at room temperature overnigrt. The solvent and excess reagent were removed in vacuo. The residue was treated with 3-cyano-5-methylphenyl-ami-: doxime (24 mg, 0.137 mmol) and triethylamine (162 mg, 1.6 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (1 mL) for 4 hours at 130 ‘C. Standard work up, afforded 21.2 mg (52%) of 5-(5-chloro-pyrid-2-yl)-3-(3-cyano-5-mefriylphenyl)-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 8.84 (d, 1H), 8.28 (m, 3H), 7.9d (dd, 1H), 7.62 (s, 1H), 2.48 (s, 3H).

' 5-(5-Chloro-pyrid-2-yl)-3-(3-cyanO'5-íluoTOphenyl)-1,2,4-oxadiazole [0579]

B203 ><img file="IS2564B_D0438.tif" /> [0580] A mixture of 5-chloropicolinic acid hydrochloride (72 mg, 0.4 mmol) in dichloromethane (2 mL) was treated with 2M oxalyl chloride (0.8 ml, 1.6 mmol, dichloromethane). The mixture was stirred at room ternperature overnight. The solvent and excess reagent were removed in vacuo. The residue was treated with 3-cyano-5-f luorophenyl-amidoxime (71.6 mg, 0.4 mmol) and triethylamine (162 mg, 1.6 mmol) in dichloromethane (2 mL). The mixture was then heated in J dimethylformamide (1 mL) for 4 hours at 130 'C. Standard work up, afforded 70.4 mg (58.5%) of 5-(5-chloro-pyrid-2yl)-3-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm):8.82 (d, 1H), 8.34 (d, 1H), 8.27 (d, 1H), 8.16 (dd, 1H), 7.97 (dd, 1H), 7.52 (dd, 1H).

3-(3-Cyano-5-trifluoromethoxyphenyl)-5-(2-pyridyl)-1,2,4-oxadiazole [0581]

B204

[0582] A mixture of picolinic acid (123 mg, 1 mmol) and triethylamine (404 mg, 4 mmol) in tetrahydrofuran (2 mL) was treated with isobutylchloroformate (0.118 ml, 1.1 mmol) at room temperature. The mixture was stirred for 1.5 hours and treated with 3-cyano-5-trifluoromethoxyphenyl-amidoxime (50 mg, 0.204 mmol). The mixture was then heated in dimethylformamide (1 mL) for 4 hours at 130 ’C. Standard work up, afforded 7.1 mg (10.5%) 3-(3-cyano-5-trifluoromethoxy-phenyl)-5-(2-pyridy!)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.90 (d, 1H), 8.50 (s, 1H), 8.34 (m, 2H), 8.00 (dt, 1H), 7.66 (S, 1H), 7.60 (dd, 1H).

3-(3-Fluoro-5-methoxyphenyl)-5-(2-pyridyl)-1,2,4-oxadiazole [0583]

B205

I<img file="IS2564B_D0442.tif" /> [0584] A mixture of picolinic acid (123 mg, 1 mmol) and triethylamine (404 mg, 4 mmol) in tetrahydrafuran (2 mL) was ' treated with isobutylchloroformate (0.118 ml, 1.1 mmol) at room temperature. The mixture was stirred for 1.5 hours and treated with 3-fluoro-5-methoxyphenyl-amidoxime (73.8 mg, 0.4 mmol). The mixture was then heated in dimethylformamide (1 mL) for 4 hours at 130 ’C. Standard work up, afforded 40.1 mg (37%) 3-(3-f!uoro-5-methoxyphenyl)-5-(2-py ridy I)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm); 8.90 (d, 1H), 8.30 (d, 1H), 7.95 (dt, 1H), 7.56 (m, 3H), 6.80 (dd, 1H), 3.73 (s, 3H).

)

3-(3-Cyanophenyl)-5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole [0585]

B206 ><img file="IS2564B_D0443.tif" /> [0586] A mixture of 5-fluoropicolinic acid hydrochloride (45.8 mg, 0.3 mmol) in dichloromethane (1 mL) was treated with 2M oxalyl chloride (0.6 ml, 1.2 mmol, dichloromethane). The mixture was stirred at room temperature for 3 hours. The solvent and excess reagent were removed in vacuo. The residue was treated with 3-cyanophenyl-amidoxime (24.2 ’ mg, 0.15 mmol) and triethylamine (121mg, 1.2 mmol) in dichloromethane (1 mL). The mixture was then heated in dimethylformamide (1 mL) for 6 hours at 130 'C. Standard work up, afforded 10.6 rmg (26.5%) of 3-(3-cyanophenyl)-5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.72 (d, 1H), 8.53 (s, 1H), 8.45 (dd, 1H), 8.37 (dd, 1H), 7.83 (d, 1H), 7.68 (m,2H).

> 3-(3-Cyano-5-trifluoromethoxyphenyl)-5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole [0587]

Β207 <img file="IS2564B_D0446.tif" /> [0588] A mixture of 5-fluoropicolinic acid hydrochloride (45.8 mg, 0.3 mmol) in dichloromethane (1 mL) was treated wlth 2M oxalyl chloride (0.6 ml, 1.2 mmol, dichloromethane). The mixture was stirred at room temperature for 3 hours. The solvent and excess reagent were removed in vacuo. The residue was treated with 3'Cyano-5-trifluoromethoxyphenyl-amidoxime (36.5 mg, 0.15 mmol) and triethylamine (121mg, 1.2 mmol) in dichloromethane (1 mL). The mixture was i then heated in dimethylformamide (1 mL) for 6 hours at 130 ’C. Standard work up, afforded 7.2 mg (14.4%) of 3-(3-cyano-5-trifluoromethoxyphenyl)-5-(5-fluoropyrid-2-yl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.74 (d, 1H), 8.49 (S, 1H), 8.38 (dd, 1H), 8.30 (S, 1H), 7.70 (m, 2H).

3-(3-Fluoro-5-methoxyphenyl)-5-(5-fluoropyrid-2-yl)-1,2,4-oxadiazole [0589]

B208

5<img file="IS2564B_D0447.tif" /> [0590] A mixture of 5-fluoropicolinic acid hydrochloride (45.8 mg, 0.3 mmol) in dichloromethane (1 mL) was treated with 2M oxalyl chloride (0.6 ml, 1,2 mmol, dichloromethane). The mixture was stirred at room temperature tor 3 hours. The solvent and excess reagent were removed ín vacuo. The residue was treated with 3-fluoro-5-methoxyphenyl-amidoxime (27.7 mg, 0.15 mmol) and triethylamine (121 mg, 1.2 mmol) in dichloromethane (1 mL). The mixture was 5 then heated in dimethylformamide (1 mL) for 6 hoursat 130 ’C. Standard work up, afforded 9.0 mg (20%) of 3-(3-fluoro5-methoxyphenyl)-5-(5-fluoropyrid-2-yl)-1,2,4-oxadíazole. 1H-NMR (CDCI3), δ (ppm): 8.73 (d, 1H), 8.35 (dd, 1H), 7.65 (m, 1H), 7.55 (m, 2H), 6.80 (dd, 1H), 3.92 (s, 3H).

3-(3,5-Dimeíhoxyphenyl)-5-(5-fluoropyrid-2-yl)’1,2,4-oxadiazole o

[0591]

Β209 <img file="IS2564B_D0450.tif" /> [0592] A mixture of 5-fluoropicolinic acid hydrochloride (45.8 mg, 0.3 mmol) in dichloromethane (1 mL) was treated with 2M oxalyl chloride (0.6 ml, 1.2 mmol, dichtoromethane). The mixture was stirred at room temperature for 3 hours. The solvent and excess reagent were removed in vacuo. The residue was treated with 3,5-dimethoxyphenyl-amidoxime (29.4 mg, 0.15 mmol) and triethylamine (121 mg, 1.2 mmol) in dichloromethane (1 mL). The mixture was then heated in dimethylformamide (1 mL) for 6 hours at 130 ‘C. Standard work up, afforded 12 mg (26.6%) of 3-(3,5-dimethoxyphenyl)-5-(5-fluoropyrid-2-yl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.71 (d, 1H), 8.37 (dd, 1H), 7.64 (dt, 1H), 7.37 (s, 2H), 6.61 (S, 1H), 3.87 (S, 6H).

3-[3-Fluoro-5-(1 H-imidazol-1-yl)]phenyl]-5-(2-pyridyl)-1,2,4-oxadiazole [0593]

B210 <img file="IS2564B_D0451.tif" /> [0594] A mixture of picolinic acid (62 mg, 0.5 mmol) and triethylamine (202 mg, 2 mmol) in tetrahydrofuran (1 mL) was treated with isobutylchloroformate (0.059 ml, 0.55 mmol) at room temperature. The mixture was stirred for 2 hours and treated with 3-fluoro-5-( 1 H-imidazol-1 -yl)]phenyl-amidoxime (100 mg, 0.45 mmol). The mixture was then heated in dimethylformamide (1 mL) at 130 'C overnight. Standard work up, afforded 24.4 mg (17.6%) 3-[3-f luoro-5-( 1 H-imidazol-1-yl)]phenyl]-5-(2-pyridyl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.90 (d, 1H), 8.32 (d, 1H), 8.10 (s, 1H), 7.7.98 (m, 3H), 7.58 (dd, 1H), 7.39 (s, 1H), 7.29 (m, 2H).

3-(5-Fluoro-2-pyridyl)-5-(3-ftuoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole [0595]

Β211 <img file="IS2564B_D0454.tif" /> [0596] A mixture of the hydrochloride salt of 3-Fluoro-5-(3-pyridyl)benzoic acid (1.00 g, 3.93 mmol) in dichloromethane (10 ml) was treated with oxalyl chloride (5.9 ml, 11.8 mmol, 2M dichloromethane) and 3 drops of /V,N-dimethylformamide. The mixture was stirred 4 hours at room temperature. The solvent and excess reagent were removed in-vacuo. The residue was treated with 5-Fluoro-2-pyridylannidoxime (0.61 g, 3.93 mmol) and triethylamine (1.64 ml, 11.8 mmol) in dichloromethane (10 mL). The mixture was then heated in dimethylformamide (10 mL) at 120'C, overnight. Standard work up followed by trituration with diethyl ether afforded 3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole (452 mg) as a light yellow solid.

3-(5-Fluoro-2-pyridyl)-5-(3-bromo-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole [0597]

B212 <img file="IS2564B_D0455.tif" /> [0598] A mixture of the hydrochloridesalt of3-Bromo-5-(3-pyridyl)benzoic acid (1.50 g, 4.78 mmol) in dichloromethane (10 ml) was treated with oxalyl chloride (7.2 ml, 14.3 mmol, 2M dichloromethane) and 3 drops of N,/V-dimethylformamide. The mixture was stirred 4 hours at room temperature. The solvent and excess reagent were removed in-vacuo. The residue was treated with 5-Fluoro-2-pyridylamidoxime (0.74 g, 4.78 mmol) and triethylamine (2.0 ml, 14.3 mmol) in dichloromethane (10 mL). The mixture was then heated in dimethylfcrmamide (10 mL) at 120'C, overnight. Standard work up followed by trituration with diethyl ether afforded 3-(5-Fluoro-2-pyridyl)-5-(3-bromo-5-(3-pyridyl)phenyl)-1,2,4-oxadiazola (457 mg) as an off white solid.1H-NMR (CDCI3), δ (ppm): 8.91 (s, 1H), 8.70 (s, 2H), 8.42 (d, 2H), 8.27 (dd, 1H), 7.94 (m, 2H), 7.61 (dt, 1H), 7.44 (dd, 1H).

3-(5-Fluoro-2-pyridyl)-5-(3-tluoro-5-methoxyphenyl)-1,2,4-oxadiazole [0599]

Β213 <img file="IS2564B_D0458.tif" /> [0600] A mixture of 3-Fluoro-5-methoxybenzoic acid (0.20 g, 1.18 mmol) in dichloromethane (2.5 mL) was treated with oxalyl chloride (1.76 ml, 3.53 mmol, 2M dichloromethane) and 3 drops of /V,/V-dimethylformamide. The mixture was stirred 4 hours at roonri temperature. The solvent and excess reagent were removed in-vacuo. The residue was treated with 5-Fluoro-2-pyridylamidoxime (182 mg, 1.18 mmol) and triethylamine (0.49 ml, 3.53 mmol) in dichloromethane (2.5 mL). The mixture was then heated in dimethylformamide (2.5 mL) at 120"C, overnight. Standard work up followed by purification on silica gel using 20% ethyl acetate in hexanes afforded the title compound (43.1 mg, 13%) as a light yellow solid. 1H-NMR (CDCI3), δ (ppm): 8.69 (d, 1H), 8.26 (dd, 2H), 7.60 (m, 3H), 6.87 (m, 1H).

3-(Pyrid-2-yl)-5-(3-cyano-5-thiomethylphenyl)-1,2,4-oxadiazole [0601]

B214 <img file="IS2564B_D0459.tif" /> [0602] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-thioniethylbenzoyl chloride was prepared from 3-cyano-5-thiomethylbenzoic acid (330 mg, 1.71 mmol). A suspension of pyrid-2-ylamidoxime (123 mg, 0.9 mmol) in dichloromethane (4 mL) was treated with 3-cyano-5-thiomethylbenzoyl chloride (190 mg, 0.9 mmol) and the mixture stirred 30 minutes. The solvent was removed in vacuo and the intermediate dissolved in N,/V-dimethylfor-mamide (8 mL). The reaction was heated, under an argon atmosphere, for 20 hours at 120 ’C. The reaction mixture was cooled and the solvent removed in vacuo. Silica gel chromatography using a gradient of 0% to 10% ethyl acetate in dichloromethane atforded 159 mg (60%) of 3-(pyrid-2-yl)-5-(3-cyano-5-thiomethylphenyl)-l ,2,4-oxadiazole as a white solid: 1H-NMR (CDCI3), δ (ppm): 8.82 (t, 1H), 8.31 (d, 2H), 8.24 (d, 1H), 7.91 (t, 1H), 7.66 (s, 1H), 7.49 (t, 1H), 2.61 (s, 3H).

3-(5-Fluoro-pyrid-2-yl)-5-(3-cyano-5-thiomethylphenyl)-1,2,4-oxadiazole [0603]

B215 <img file="IS2564B_D0460.tif" /> [0604] Using the general procedure for the preparation of acid chlorides, 3-cyano-5-thiomethylbenzoyl chloride was

prepared from 3-cyano-5-thiomethylbenzoic acid (330 mg, 1.71 mmol). A suspension of 5-fluoro-pyrid-2-ylamidoxime (161 mg, 1.04 mmol) in dichloromethane (4 mL) was treated with 3-cyano-5-thiomethylbenzoyl chloride (220 mg, 1.04 mmol) and the mixture stirred 30 minutes. The solvent was removed in vacuo and the intermediate dissolved in N,N-dimethyltormamide (8 mL). The reaction was heated, under an argon atmosphere, for 20 hours at 120 ‘C. After this time, the reaction mixture was cooled and the solvent removed in vacuo. Silica gel chromatography using a gradient of 5% to 50% ethyl acetate in hexanes afforded product that was not yet pure. The product was rec rysta II ized from hexanes and methanol to yield 78 mg (24%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-thiornethylphenyl)-1,2,4-oxadiazole as white solid: 1H-NMR (CDCIg), δ (ppm):DD8.70 (s, 1H), 8.27 (t, 3H), 7.62 (m, 2H), 2.61 (s, 3H).

3-(Pyrid-2-yl)-5-(3-fluoro-5-thiomethylphenyl)-1,2,4-oxadiazole [0605]

B216 <img file="IS2564B_D0464.tif" /> [0606] Using the general procedure for the preparation of acid chlorides, 5-fluoro-3-thiomethylbenzoyl chloride was prepared from 5-fluoro-3-thiomethylbenzoic acid (470 mg, 2.52 mmol). A suspension of pyrid-2-ylamidoxime (346 mg, 2.52 mmol) in dichloromethane (3 mL) was treated with 5-fluoro-3-thiomethylbenzoy I chloride and the mixture was stirred 3 hours. The solvent was removed in vacuo and the intermediate dissolved in W,N-dimethylformamide (10 mL). The reaction was heated, under an argon atmosphere, for 4 hours at 120 'C. After this time, the reaction mixture was cooled and the solvent removed in vacuo. Silica gel chromatography using a gradient of 0% to 4% ethyl acetate in dichloromethane afforded 567 mg (78%) of 3-(pyrid-2-yl)-5-(5-fluoro-3-thiomethylphenyl)-1,2,4-oxadiazole as a white solid: 1H-NMR (CDCI3), δ (ppm): 8.85 (t, 1H), 8.21 (d, 1H), 7.89 (m, 2H), 7.72 (m, 1H), 7.47 (m, 1H), 7.15 (m, 1H), 2.57 (s, 3H).

3-(Pyrid-2-yl)-5-(3-fluoro-5-thiomethylsulphoxidephenyl)-1,2,4-oxadiazole [0607]

B217 <img file="IS2564B_D0465.tif" /> [0608] 3-(Pyrid-2-yl)-5-(3-fluoro-5-thiomethylphenyl)-1,2,4-oxadiazole (50 mg, 0.17 mmol) was dissolved in dichloromethane in an argon atmosphere at -78 ‘C and a solution of m-chloroperoxybenzoic acid (30 mg, 0.17 mmol) in dichloromethane was added. After 10 minutes, the reaction was allowed to warm to 0 'C and quenched with aqueous sodium bicarbonate. The reaction extracted with dichloromethane, washed with water and dried over anhydrous sodium sulphate. Column chromatography using 5% methanol in dichloromethane yielded 31 mg (59%) of 3-(Pyrid-2-yl)-5-(3-fluoro-5-thiomethylsulphoxidephenyl)-1,2,4-oxadiazole as an off-white solid. 1H-NMR (CDCI3), δ (ppm): 8.83 (d, 1H), 8.20 (t, 2H), 8.06 (m, 1H), 7.89 (m, 1H), 7.73 (m, 1H), 7.47 (m, 1H), 2.82 (s, 3H).

3-(Pyrid-2-yl)-5-(3-fluoro-5-thioethylphenyl)-1,2,4-oxadiazole [0609]

Β218 <img file="IS2564B_D0468.tif" /> [0610] Using the general procedure for the preparation of acid chlorides, 5-fluoro-3-thioethylbenzoyl chloride was prepared from 5-fluoro-3-thioethylbenzoic acid (274 mg, 1.37 mmol). A suspension of pyrid-2-ylamidoxíme (188 mg, 1.37 mmol) in dichloromethane (3 mL) was treated with 5-fluoro-3-thioethylbenzoyl chloride and the mixture was stirred 3 hours. The solvent was removed ín vacuo and the intermediate dissolvsd in W,W-dimethylformarriide (5 mL). The reaction was heated, under an argon atmosphere, for 12 hours at 120 'C. After this time, the reaction mixture was cooled and the solvent removed in vacuo. Silica gel chromatography using a gradient of 0% to 4% ethyl acetate in dlchlorometh-ane afforded 245 mg (59%) of 3-(pyrid-2-yl)-5-(5-fluoro-3-thioethylphenyl)-1,2,4-oxadiazole as a white solid: 1H-NMR (CDCIg), δ (ppm): 8.76 (t, 1H), 8.12 (d, 1H), 7.83 (t, 1H), 7.77 (m, 1H), 7.65 (m, 1H), 7.39 (m, 1H), 7.12 (m, 1H), 2.96 (q, 2H), 1.28 (t, 3H).

3-(Pyrid-2-yl)-5-(3-fluoro-5-thioethylphenyl)-1,2,4-oxadiazole [0611]

B219 <img file="IS2564B_D0469.tif" /> [0612] Using the general procedure for the preparation of acid chlorides, 5-fluoro-3-thioethylbenzoyl chloride was prepared from 5-fluoro-3-thioethylbenzoic acid (274 mg, 1.20 mmol). A suspension of pyrid-2-ylamidoxime (165 mg, 1.20 mmol) in dichloromethane (3 mL) was treated with 5-fluoro-3-thiotertbutylbenzoyl chloride and the mixture was stirred 3 hours. The solvent was removed in vacuo and the intermediate dissolved in /V,A/-dimethylformamide (6 mL). The reaction was heated, under an argon atmosphere, for 12 hours at 120 ’C. After this time, the reaction mixture was cooled and the solvent removed in vacuo. Silica gel chromatography using dichloromethane afforded 31 mg (8%) of 3-(pyrid-2-yl)-5-(5-fluoro-3-thiotertbutylphenyl)-1,2,4-oxadiazole asawhitesolid: 1H-NMR(CDCI3),5(ppm):8.85 (t, 1H), 8.24 (d, 1H), 7.97 (m, 1H), 7.89 (m, 1H), 7.48 (m, 1H), 1.34 (t, 9H).

(a) 3-(5-Fluoropyrid-2-yl)-5-(3-cyano-5-methytphenyl)-1,2,4-oxadiazole [0613]

Β220 <img file="IS2564B_D0472.tif" /> [0614] Το a mixture of 3-cyano-5-methylbenzoic acid (80 mg, 0.5 mmol), oxalyl chloride (1 mis, 2M solution in CH2CI2, 2 mmol) in CH2CI2 (5 ml) was added a few drops of DMF (one pipette drops) and the mixture was stirred at room temperature for 3 h. The solvent was then removed in vacuo. The residue was then dissolved in CH2CI2 (5 ml) followed by the addition of 5-Fluoro-2-pyridyl amidoxime (78 mg, 0.5 mmol) and Et3N (0.2 ml) and stirring was continued for a further 1 h. Removal of the solvent in vacuo gave the crude residue which was dissolved in DMF (5 ml). The resulting solution was heated to 120Ό overnight after which the solvent was removed in vacuo and the residue was triturated with 20% ethylacetate/hexane giving the product as a white solid (21 mg, 15% yield). 1HNMRJCDCI3) □: 8.70 (d, 1H), 8.37 (s, 1H), 8.34 (s, 1H), 8.28 (dd, 1H), 7.70 (s, 1H), 7.60 (dt, 1H), 2.50 (s, 3H).

(b) 3-(5-cyanopyrid-2-yl)-5-(3-cyano-5-methylphenyl)-1,2,4-oxadiazole [0615]

B221 <img file="IS2564B_D0473.tif" /> [0616] Toa mixture of3-cyano-6-mathylbenzoic acid (81 mg, 0.5 mmol), oxalyl chloride (1 mls, 2M solution in CH2CI2, 2 mmol) in CH2CI2 (5 ml) was added a few drops of DMF (one pipette drops) and the mixture was stirred at room temperature for 3 h. The solvent was then removed in vacuo. The residue was then dissolved in CH2CI2 (5 ml) followed by the addition of 5-cyano-2-pyridyl amídoxime (78 mg, 0.5 mmol) and Et3N (0.2 ml) and stirring was continued for a further 1 h. Removal of the solvent in vacuo gave the crude residue which was dissolved in DMF (5 ml). The resulting solution was heated to 120'C overnight after which the solvent was removed in vacuo and the residue was triturated with 20% ethylacetate/hexane giving the product as an off- white solid (10 mg, 7% yield). 1HNMR(CDCI3) □: 9.10 (d, 1H), 8.39 (d, 1H), 8.37 (s, 1H), 8.34 (s, 1H), 8.20 (dd, 1H), 7.75 (s, 1H), 2.60 (s, 3H).

B222 <img file="IS2564B_D0474.tif" /> [0618] To a mixture of 4-cyano-2-thiophenecarboxylic acid (70 mg, 0.46 mmol), oxalyl chloride (1 mls, 2M solution in

CH2CI2, 2 mmol) in CH2CI2 (5 ml) was added a few drops of DMF (one pipette drops) and the mixture was stirred at room temperature for 3 h. The solvent was then removed in vacuo. The residue was then dissolved in CH2CI2 (5 ml) followed by the addition of 5-cyano-2-pyridyl amidoxime (71 mg, 0.46 mmol) and Et3N (0.2 ml) and stirring was continued for a further 1 h. Removal of the solvent in vacuo gave the crude residue which was dissolved in DMF (2 ml). The resulting solution was heated to 120 ‘C overnight after which the solvent was removed in vacuo and the residue was triturated with 20% ethylacetate/hexane giving the product as an off- white solid (20 mg, 16% yield). 1HNMR(CDCI3) □ : 8.68 (d, 1H), 8.25 (d, 1H), 8.22 (s, 1H), 8.17 (S, 1H), 7.61 (S, 1H).

EXAMPLE 6

3-(2-Pyridyl)-5-(5-cyano-2-methoxyphenyl)-1,2,4-oxadiazole [0619]

B97 <img file="IS2564B_D0478.tif" /> [0620] A mixture of 3-(2-pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (66.4 mg, 0.2 mmol), zinc cyanide (35.1 mg, 0,3 mmol), and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4,23.1 mg, 0.02 mmol) in N,W-dimethylfor-mamide (2 mL) was heated under an argon atmosphere at 80 'C for 16 hours. After cooling, the reaction mixture was poured into water and the crude product extracted with dichloromethane. Silica gel chromatography using 30% ethyl acetate in hexane afforded 6.9 mg (12%) of 3-(2-pyridyl)-5-(5-cyano-2-methoxyphenyl)-1,2,4-oxadiazole.

3-(2-pyridyl)-5-(2-cyano-5-methoxyphenyl)-1,2,4-oxadiazole [0621]

B98 <img file="IS2564B_D0479.tif" /> [0622] In a similar fashion, a mixture of 3-(2-pyridyl)-5-(2-bromo-5-methoxyphenyl)-1,2,4-oxadiazole (33.2 mg, 0.1 mmol), zinccyanide (17.6 mg, 0.15 mmol) and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in /V,/V-dimethyltormamide (1 mL) was heated under an argon atmosphere at 80 'C for 16 hours. After cooling, the reaction mixture was poured into water and the crude product extracted with dichloromethane. Silica gel chromatography using 50% ethyl acetate in hexane afíorded 1.1 mg (4 %) of 3-(2-pyridyl)-5-(2-cyano-5-methoxyphenyl)-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(5-cyano-pyrid-3-yl)-1,2,4-oxadiazole [0623]

Β99 <img file="IS2564B_D0482.tif" /> [0624] ln a similar fashion, mixture of 3-(2-pyridyl)-5-(3-(5-bromo-pyridyl)1 -1,2,4-oxadiazole (90.9 mg, 0.3 mmol), zinc cyanide (24.6 mg, 0.21 mmol) and Pd(PPh3)4 (34.7 mg, 0.03 mmol) in /V,/V-dirnethylformamide (1 mL) was stirred under an argon atmosphere at 80 "C for 16 hours. After cooling, the reaction mixture was poured into water and the crude product extracted with dichloromethane. Silica gel chromatography afforded 16 mg (21 %) of 3-(2-pyridyl)-5-(5-cyano-pyrid-3-yl)-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(3'cyano-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole [0625]

B100 <img file="IS2564B_D0483.tif" /> [0626] In a similar fashion, a solution of 3-(2-py ridyl)-5-(3-iodo-5-(methoxycarbony l)phenyl)-1,2,4-oxadíazole (50 mg, 0.122 mmol) in Ν,Ν-dimethylformaniide (2 mL) was treated with zinc cyanide (22.5 mg, 0.191 mmol), and Pd(PPh3)4 (14 mg, 0.012 mmol). The reaction mixture was heated at 80 "C under an argon atmosphere for 2 hours. The mixture was then diluted with ethyl acetate (25 mL) and washed with water (3x5 mL) and brine (3x5 mL). The organic solution was then dried over anhydrous MgSO4, filtered and concentrated in vacuo. Silica gel chromatography using 30% ethyl acetate in hexane afforded 29.2 mg (78%) of 3-(2-pyridyl)-5-(3-cyano-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole:1H-NMR (CDCI3), δ (ppm): 9.19 (s, 1H), 8.89 (d, 1H), 8.80 (s, 1H), 8.59 (s, 1H), 8.25 (d, 1H), 7.95 (t, 1H), 7.50 (m, 1H), 4.09 (s, 3H).

3-(2-Pyridyl)-5-(3-cyano-5-trifluoromethylphenyl)-1,2,4-oxadiazole [0627]

B223 <img file="IS2564B_D0484.tif" /> [0628] Using the general procedure for the preparation of acid chlorides, 3-iodo-5-trifluoromethylbenzoyl chloride was prepared from 3-iodo-5-trifluoromethylbenzoic acid (711 mg, 4.46 mmol). To a solution of the acid chloride in dichloromethane (10 mL), pyridylamidoxime (217.7 mg, 1.588 mmol) was added. The solution was stirred at room temperature for 10 minutes and then concentrated in vacuo. DMF (8mL) was added to the residue and the resulting solution was stirred at 120’C for 16 h under argon. After the reaction mixture was cooled to room temperature, the solvent was

removed in vacuo. Flash chromatography on silica gel (10%-20% ethyl acetate in hexane) yielded 439 mg (66%) of 3-(2-pyridyl)-5-(3-iodo-5-trifluoromethylphenyl)-1,2,4-oxadiazole. This intermediate (100.8 mg, 241.6 mmol), zinc cyanide (34.7 mg, 296 mmol) and tetrakistriphenyphosphine palladium(O) (Pd(PPh3)4, 30.5mg, 0.026mmol) were mixed and flushed with argon. DMF (1 mL) was added and the resulting solution was stirred for 2 h at 80 ’C. After cooling to room temperature the reaction mixture was filtered through celite and washed with ethyl acetate (50 mL). The crude mixture was extracted into ethyl acetate (100 mL), washed sequentially with water (3X50mL) and brine (50mL), and dried over sodium sulfate. Flash chromatography on silica gel (50% ethyl acetate in hexane) yielded 53 mg (69%, GC/MS purity 97%) of 3-(2-pyridyl)-5-(3-cyano-5-trifluoromethylphenyl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.87 (d, 1H), 8.80 (s, 1H), 8.78 (s, 1H), 8.24 (d, 1H), 8.15 (s, 1H), 7.92 (m, 1H), 7.51 (m, 1H).

3-(5-Fluoro-2-pyridyl)-5-(3-cyano-5-trifluoromethylphenyl)-1,2,4-oxadiazole [0629]

B224 <img file="IS2564B_D0488.tif" /> [0630] In a similar fash ion, 3-iodo-5-trifluoromethylbenzoyl chloride was prepared from 3-iodo 5-trifluoromethylbenzoic acid (118. 2 mg, 0.374 mmol). To a solution of the acid chloride in dichloromethane (2 mL), 5-fluoropyridylamidoxime (124.4 mg, 0.3861 mmol) was added. The solution was stirred at room temperature for 10 minutes and then concentrated in vacuo. DMF (8mL) was added to the residue and the resulting solution was stirred at 120'C for 16 h under argon. After the reaction mixture was cooled to room temperature, the solvent was removed in vacuo. Flash chromatography on silica gel (10%-20% ethyl acetate in hexane) yielded 38.6 mg (24.4%) of 3-(5-fluoro-2-pyridyl)-5-(3-iodo-5-trifluor-omethylphenyl)-1,2,4-oxadiazole. This intermediate (38.6 mg, 0.089 mmol), zinc cyanide (16.8 mg, 0.143 mmol) and Pd(PPh3)4 (11.8mg, 0.01 mmol) were mixed and flushed wíth argon. DMF (2 mL) was added and the resulting solution was stirred for 1 h at 80 ‘C. Aftercooling to room temperature the reaction mixture was filtered through celite and washed with ethyl acetate (50 mL). The crude mixture was extracted into ethyl acetate (300 mL), washed sequentially with water (6X50mL) and brine (50mL), and dried over sodium sulfate. Trituration of the solid with ether yielded 7.5 mg (26%) of 3-(5-fluoro-2-pyridyl)-5-(3-cyano-5-trifluoromethylphenyl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 8.78 (s, 1H), 8.75 (s, 1H), 8.72 (s, 1H), 8.27 (m, 1H), 8.16 (s, 1H), 7.63 (m, 1H).

EXAMPLE 7

3-(2-Pyridyl)-5-(3-cyano-5-(4-pyridyl)phenyl)-1,2,4-oxadiazole [0631]

B1O1

<img file="IS2564B_D0490.tif" /> [0632] A mixture of 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (70 mg, 0.21 mmol), 4-pyridylboronic acid (53 mg, 0.43 mmol), and tetrakis(triphenylphosphine) palladium(O) (Pd(PPh3)4, 25 mg, 0.021 mmol) in a solution of ethylene glycol dimethyl ether (3mL) and 2M sodium carbonate (3 mL) was headed in a sealed vial at 100’C for 1 hour with vigorous stirring. The reaction was cooled and diluted with chloroform. The organic solution was washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography of the residue using a gradient of 50% ethyl acetate in hexane to 100% ethyt acetate followed by trituration with 5% ethyl acetate in diethyl ether affordsd 6 mg (9 %) of 3-(2-pyridyl)-5-(3-cyano-5-(4-pyridyl)phenyl)-1,2,4-oxadiazole: 1H NMR (C0CI3): δ - 8.88 (d, 1H), 8,78 (m, 3H), 8.64 (s, 1H), 8.26 (d, 1H), 8.15 (s, 1H), 7.93 (t, 1H), 7.61 (m, 2H), 7.52 (m, 1H).

3-(2-Pyridyl)-5-[2-methoxy-5-(4-pyridyl)phenyl]-1,2,4-oxadiazole [0633]

B102 <img file="IS2564B_D0491.tif" /> [0634] In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (66.4 mg, 0.2 mmol), 4-pyri-dylboronic acid (48.8 mg, 0.4 mmol), and Pd(PPh3)4 (23 mg, 0.02 mmol) in a solution of 2M sodium carbonate (2 mL) and ethylene glycol dimethyl ether (2 mL) was heated overnight at 105 ’C. Standard work up, afforded 6.6 mg (10%) of 3-(2-pyridyl)-5-[2-methoxy-5-(4-pyridyl)phenyl]-1,2,4-oxadiazole,

3-(2-Pyridyl)-5-[2-fluoro-5-(4-pyridyl)phenyl]-1,2,4-oxadiazole [0635]

B103 <img file="IS2564B_D0492.tif" /> [0636] In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-2-fluorophenyl)-1,2,4-oxadiazole (100 mg, 0.312 mmole), 4-py-ridylboronic acid (76.7 mg,0.6265 mmol) and Pd(PPh3)4 (36.1 mg, 0.03123 mmol) in a solution of 2M sodium carbonate (4 mL) and ethylene glycol dimethyl ether (4 mL) was heated overnight at 105 ’C. Standard work up, afforded 4.1 mg (4%) of 3-(2-pyridyl)-5-[2-fluoro-5-(4-pyridyl) phenyl]-1,2,4-oxadiazole.

3- (2-Pyridyl)-5-(3-fluoro-5-(4-pyridyl)phenyl)-1,2,4-oxadiazole [0637]

B104 <img file="IS2564B_D0496.tif" /> [0638] In a similar fashion, 3-(2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (30 mg, 0.093 mmol), pyridine-

4- boronic acid (17.1 mg, 0.093 mmol), and Pd(PPh3)4 (10.4 mg, 0.0093 mmol) In a solution of and ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1mL) was heated in a sealed vial at 100Ό for 1 hour. Standard work up and silica gel chromatography using a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate afforded 2 mg (7%) of 3-(2-pyridyl)-5-(3-fluoro-5-(4-pyridyl)phenyl)-1,2,4-oxadiazole: 1H-NMR (CDCI3), δ (ppm): 8.88 (d, 1H), 8.79 (d, 2H), 8.40 (s, 1H), 8.25 (d, 1H), 8.06 (md, 1H), 7.90 (td, 1H), 7.60 (m, 3H), 7.50 (ddd, 1H).

3-(2-Pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole [0639]

B105 <img file="IS2564B_D0497.tif" /> [0640] A mixture of 3-(2-pyridyl)-5-(3-bromo-5-f1uorophenyl)-1,2,4-oxadiazole (100 mg, 0.312 mmol), pyridine-3-bo-ronic acid 1,3-propanediol cyclic ester (102 mg, 0.624 mmol), and tetrakis(triphenylphosphine)pa!ladium(0) (Pd (PPh3)4, 35.8 mg, 0.031 mmol), in a solution of ethylene glycol dimethyl ether (3 mL) and 2M sodium carbonate (3 mL) was heated in a sealed vial at 100Ό for 1 hour. The reaction was cooled, diluted with chloroform, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate afforded 19 mg (19%) 3-(2-pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole: 1H-NMR (CDCI3), 5 (ppm): 8.92 (s, 1H), 8.84 (d, 1H), 8.70 (d, 1H), 8.39 (s, 1H), 8.25 (d, 1H), 8.00 (m, 2H), 7.90 (td, 1H), 7.65 (m, 1H), 7.55 (m, 2H).

3-(2-Pyridyl)-5-[2-fluoro-5-(3-pyridyl)phenyl]-1,2,4-oxadiazole [0641]

Β106 <img file="IS2564B_D0500.tif" /> [0642] Ina similar fashion, 3-(2-pyridyl)-5-(5-bromo-2-fluorophenyl)-1,2,4-oxadiazole (100 mg, 0.312 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (101.8 mg, 0.625 mmol) and Pd(PPh3)4 (36.1 mg, 0.0312 mmole) in a solution of 2M sodium carbonate (4 mL) and ethylene glycol dimethyl ether (4 mL) was heated overnight at 105 'C. Standard work up afforded 8.7 mg (9%) 3-(2-pyridyl)-5-[2-f luoro-5-(3-py ridy l)pheny l]-1,2,4-oxadíazole.

3-(2-Pyridyl)-5-[2-methoxy-5-(3-pyridyl)phenyl]-1,2,4-oxadiazole [0643]

B107 <img file="IS2564B_D0501.tif" /> [0644] In a similarfashlon, 3-(2-pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (66.4 mg, 0.2 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (65 mg, 0.4 mmol), and Pd(PPh3)4 (23 mg, 0.02 mmol) in a solution of 2M sodium carbonate (2 mL) and ethylene glycol dimethyl ether (2 mL) was heated overnight at 105 'C. Standard work up afforded 21 mg (32%) 3-(2-pyridyl)-5-[2-methoxy-5-(3-pyridyl)phenyl]-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(3-cyano-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole [0645]

B108 <img file="IS2564B_D0502.tif" /> [0646] In a similar fashion, 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (71 mg, 0.22 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (70 mg, 0.43 mmol), and Pd(PPh3)4 (25 mg, 0.022 mmol) in a solution of ethylene glycol dimethyl ether (3 mL) and 2M sodium carbonate (3 mL) was heated in a sealed vial at 100"C for 1 hour. Standard work up and silica gel chromatography using a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate followed by trituration with 5% ethyl acetate in diethyl ether afforded 16 mg (22 %) of 3-(2-pyridyl)-5-(3-cyano-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3); δ · 8.94 (d, 1H), 8.88 (d, 1H), 8.74 (m, 2H), 8.61 (s, 1H), 8.25 (d,

Η), 8.00 (s, 1 Η), 7.98 (m, 1 Η), 7.93 (m, 1Η), 7.50 (m, 2H),

3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole [0647]

B109 <img file="IS2564B_D0506.tif" /> [0648] In a simílar fashion, 3-(5-fluoro-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (60 mg, 0.154 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (50.4 mg, 0.309 mmol), and Pd(PPh3)4 (17.8 mg, 0.015 mmol), in a solution of ethylene glycol dimethyl ether (2 mL) and 2M sodium carbonate (2 mL) was heated in a sealed vial at 100‘C for 1 hour. Standard work up and silica gel chromatography using a gradient of 50% to 70% ethyl acetate in hexane afforded 24.7 mg (48%) of 3-(5-fluoro-2-pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole: 1H-NMR (CDCI3), δ (ppm): 8.92 (d, 1H), 8.71 (m, 2H), 8.31 (s, 1H), 8.30 (dd, 1H), 8.00 (m, 2H), 7.62 (td, 1H), 7.57 (td, 1H), 7.45 (dd, 1H).

3-(5-Fluoropyrid-2-yl)-5-[5-(3-pyridyl)-pyrid-3-yl)]-1,2,4-oxadiazole [0649]

B11O <img file="IS2564B_D0507.tif" /> [0650] In a similar fashion, 3-(5-fluoropyrid-2-yl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (164 mg, 0.5 mmole), pyri-dine-3-boronic acid 1,3-propanediol cyclic ester (163.0 mg, 1 mmol) and Pd(PPh3)4 (57.8 mg, 0.05 mmol) in a solution of 2M sodium carbonate (2.5 mL) and ethylene glycol dimethy I ether (2.5 mL) was heated at 105 'C for 1 hour. Standard work up afforded 57 mg (18%) of 3-(5-fluoropyrid-2-yl)]-5-[5-(3-pyridyl)-pyrid-3-yl)]-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-[5-(3-pyridyl)-pyrid-3-yl]-1,2,4-oxadiazole [0651]

B111

<img file="IS2564B_D0510.tif" /> [0652] ln a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (60.6 mg, 0.2 mmole), pyridine-3-boronic acld 1,3-propanediol cyclic ester (48.9 mg, 0.3 mmol) and Pd(PPh3)4 (34.65 mg, 0.03 mmole) in a solution of 2M sodium carbonate (2 mL) and ethylene glycol dimethyl ether (2 mL) was heated overnight at 105 'C. Standard work up afforded 21 mg (35%) 3-(2-pyridyl)-5-[5-(3-pyridyl)-pyrid-3-yl]-1,2,4-oxadiazole.

3-(5-Cyanopyrid-2-yl)-5-(3-(pyrid-3-yl)phenyl)-1,2,4-oxadiazole [0653]

B112 <img file="IS2564B_D0511.tif" /> [0654] In a similar fashion, 3-(5-cyanopyrid-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole (50 mg, 0.15 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (50.5 mg, 0.31 mmol) and Pd(PPh3)4 (24 mg, 0.021 mmol) in a solution of ethylene glycol dimethyl ether (2 mL) and 2M sodium carbonate (2 mL) were heated in a sealed tube at 90 'C for 45 min. Standard work up, silica gel chromatography (gradient of 20% to 50% ethyl acetate in hexane) and trituration (diethyl ether) of the hydrochloride salt, afforded 11.7 mg (42%) of 3-(5-cyanopyrid-2-yl)-5-(3-(pyrid-3-yl)phenyl)-1,2,4-oxadia-zole dihydrochloride: 1H-NMR (CDCI3), δ (ppm):LO9.15 (s, 1H), 9.00 (s, 1H), 8.80 (s, 1H), 8.66 (d, 1H), 8.52 (s, 1H), 8.34 (m, 2H), 8.17 (dd, 1H), 8.02 (m, 1H), 7.95 (d, 1H), 7.75 (t, 1H).

3-(5-Cyanopyrid-2-yl)-5-(3-fluoro-5-(pyrid-3-yl)phenyl)-1,2,4-oxadiazole [0655]

B113 <img file="IS2564B_D0512.tif" /> [0656] ln asimilarfashion, 3-(5-cyanopyrid-2-yl)-5-(3-brorno-5-fluorophenyl)-1,2,4-oxadiazole (16.7 mg, 0.048 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (24 mg, 0.15 mmol) and Pd(PPh3)4 (12 mg, 0.01 mmol) in asolution of ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) were heated in a sealed tube at 90 'C for for 1 hour. Standard work up, silica gel chromatography (gradient of 20% to 50% ethyl acetate in hexane) and trituration (dichloromethane) of the hydrochloride salt, afforded 4.9 mg (24%) of 3-(5-cyanopyrid-2-yl)-5-(3-fluoro-5-(pyrid-3-yl) phenyl)-1,2,4-oxadiazole dihydrochloride (4.9 mg, 24%): 1H-NMR (CD3OD/CDCI3), δ (ρριτι):ΠΠ9.36 (s, 1H), 9.10 (s,

1H), 9.0S (d, 1 Η), 8.95 (d, 1 Η), 8.55 (s, 1 Η), 8.45 (m, 2Η), 8.27 (t, 1 Η), 8.20 (d, 1H), 8.01 (d, 1H).

3-(2-Pyridyl)-5-[(3-(3-fluorophenyl)-5-fluorophenyl)]-1,2,4-oxadiazole [0657]

B114 <img file="IS2564B_D0516.tif" /> [0658] A mixture of 3-(2-pyridyl)-5-[(3-bromo-5-fluorophenyl)]-1,2,4-oxadiazole (55.5mg, 0.173mmol), 3-fIuorophenyI boronicacid (48.4mg, 0.346mmol), tetrakis(triphenylphosphine)palladium(O) (Pd(PPh3)4 (20mg, 0.017mmol) in a solution of dimethoxy ethane (1.5 mL) and 2M sodium carbonate (1.5mL) was heated in a sealed vial overnight at 100 ’C. After cooling, the reaction mixture was treated with water and the product extracted with dichloromethane (3x). Silica gel chromatography of the crude product using 30% ethyl acetate in hexane afforded 21,2mg (37%) of 3-(2-pyridyl)-5-[3-(3-fluorophenyl)-5-fluorophenyl)]-1,2,4-oxadiazole: m.p. 146-150 "C.

3-(2-Pyridyl)-5-(3-cyano-5-(3-thiophene)phenyl)-1,2,4-oxadiazole [0659]

B115 <img file="IS2564B_D0517.tif" /> [0660] In a similar fashion, 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (70 mg, 0.21 mmol), 3-thi-opheneboronic acid (55 mg, 0.43 mmol), Pd(PPh3)4 (25 mg, 0.021 mmol) in a solution of 2M sodium carbonate (3 mL) and ethyleneglycol di methyl ether (3 mL) was heated at 100'C for 1 hour. Standard work up and silica gel chromatography using a gradient of 10% to 30% ethyl acetate in hexane afforded 22 mg (31 %) of 3-(2-pyridyl)-5-(3-cyano-5-(3-thiophene) phenyl)-1,2,4-oxadlazole: 1H NMR (CDCI3): δ-8.87 (d, 1H), 8.71 (s, 1H), 8.46 (s, 1H), 8.25 (d, 1H), 8.08 (s, 1H), 7.92 (t, 1H), 7,69 (s, 1H), 7.50 (m, 3H).

3-(2-Pyridyl)-5-[5-(3-thienyl)-pyrid-3-yl]-1,2,4-oxadiazole [0661]

Β116 <img file="IS2564B_D0520.tif" /> [0662] In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (42 mg, 0.1385 mmol), 3-thi-opheneboronic acid (26.6 mg, 0.208 mmol), and Pd(PPh3)4 (24.0 mg, 0.021 mmole) in a solution of 2M sodium carbonate (1.5 mL) and ethylene glycol dimethyl ether (1.5 mL) was heated ovemight at 105 'C. Standard work up afforded 3.2 mg (8%) of 3-(2-pyridyl)-5-[5-(3-thienyl)-pyrid-3-yl]-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-[5-(3-furyl)-pyrid-3-yl]-1,2,4-oxadiazole [0663]

B117 <img file="IS2564B_D0521.tif" /> [0664] In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (152 mg, 0.5 mmol), 3-furylboronic acid (111.9 mg, 1.0 mmole) and Pd(PPh3)4 (57.8 mg, 0.05 mmole) in a solution of 2M sodium carbonate (3 mL) and ethylene glycol dimethyl ether (3 mL) was heated overnight at 105 ’C. Standard work up afforded 47 mg (32%) of 3-(2-pyridyl)-5-[5-(3-furyl)-pyrid-3-yl]-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(5-phenyl-pyrid-3-y1)-1,2,4-oxadiazole [0665]

B118 <img file="IS2564B_D0522.tif" /> [0666] ln a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (152 mg, 0.5 mmol), phenylboronic acid (121.9 mg, 1.0 mmol) and Pd(PPh3)4 (57.8 mg, 0.05 mmol) in a solution of 2M sodium carbonate (3 mL) and ethylene glycol dimethyl ether (3 ml) was heated overnight at 105 ’C. Standard work up afforded 45 mg of 3-(2-pyridyl)-

5-(5-phenyl-pyrid-3-yl)-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-[5-(3-methoxyphenyl)-pyrid-3-yl]-1,2,4-oxadiazole [0667]

Β119 <img file="IS2564B_D0526.tif" /> [0668] In a similar fashion, 3-(2-pyridyl)-5-[3-(5-bromo-pyridyl)]-1,2,4-oxadiazole (45 mg, 0.148 mmol), 3-methoxy-phenylboronic acid (45mg, 0.296 mmol), and Pd(PPh3)4 (25 mg, 0.022 mmol) in a solution of 2M sodium carbonate (1 mL) and ethylene glycol dimethoxy ether (1 mL) was heated at 105 'C for2 hours. Standard work upafforded 14.8 mg of 3-(2-pyridyl)-5-[5-(3-methoxyphenyl)-pyrid-3-yl]-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(3-cyano-5-(5-pyrimidyl)phenyl)-1,2,4-oxadiazole [0669]

B12O <img file="IS2564B_D0527.tif" /> [0670] In a similar fashion, 3-(2-pyridyl)-5-(3-broiTio-5-cyanophenyl)-1,2,4-oxadiazole (71 mg, 0.22 mmol), pyrimidyl-5-boronic acid pinacolate (89 mg, 0.43 mmol), and Pd(PPh3)4 (25 mg, 0.022 mmol) in a solution of 2M sodium carbonate (3 mL) and ethylene glycol dimethyl ether (3 mL) was heated in a sealed vial at 100‘C for 1 hour. Standard work up and silica gel chromatography using a gradient of 30% ethyl acetate in hexane to 100% ethyl acetate, followed by trituration with ethyl acetate afforded 4 mg (6 %) of 3-(2-pyridyl)-5-(3-cyano-5-(5-pyrimidyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3): δ - 9.37 (S, 1H), 9.07 (s, 2H), 8.89 (d, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 8.26 (d, 1H), 8.11 (s, 1H), 7.94 (t, 1H), 7.52 (m, 1H).

3-(2-Pyridyl)-5-(3-cyano-5-(3-aminophenyl)phenyl)-1,2,4-oxadiazole [0671]

B121 <img file="IS2564B_D0528.tif" /> [0672] ln a similar fashion, 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (70 mg, 0.21 mmol), 3-ami-nophenylboronic acid (66 mg, 0.43 mmol), and Pd(PPh3)4 (25 mg, 0.021 mmol), in a solution of ethylene glycol dimethyl

ether (3 mL) and 2M sodium carbonate (3 mL) was heated in a sealed vial at 100"C for 1 hour. Standard work up and silica gel chromatography using a gradient of 30% ethyl acetate in hexane to 100% ethyl acetate, followed by trituration with 50% ethyl acetate in hexane afforded 32mg (45 %) of 3-(2-pyridyl)-5-(3-cyano-5-(3-aminophenyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3): ð - 8.82 (d, 1H), 8.57 (s, 2H), 8.40 (s, 1H), 8.22 (d, 1H), 8.08 (t, 1H), 7.66 (m, 1H), 7.20 (t, 1H), 7.00 (m,2H), 6.69 (d, 1H).

3-(2-Pyridyl)-5-(3-cyano-5-(3-fluorophenyl)phenyl)-1,2,4-oxadiazole [0673]

B122 <img file="IS2564B_D0532.tif" /> [0674] lnasimilarfashion,3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (70 mg, 0.21 mmol), 3-fluoroph-enylboronic acíd (60 mg, 0.43 mmol), and Pd(PPh3)4 (25 mg, 0.022 mmol) in a solution of ethylene glycol dimethyl ether (3 mL) and 2M sodium carbonate (3 mL) was heated in a sealed vial at 100 'C for 1 hour. Standard work up and silica gel chromatography using a mixture of hexane:ethyl acetate:dichloromethane (3.5:0.5:4), followed by trituration with diethyl ether afforded 27 mg (36 %) of 3-(2-pyridyl)-5-(3-cyano-5-(3-fluorophenyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3): δ - 8.86 (d, 1H), 8.70 (s, 1H), 8.55 (S, 1H), 8.24 (d, 1H), 8.07 (s, 1H), 7.91 (t, 1H), 7.49 (m, 3H), 7.40 (m, 1H), 7.19 (m, 1H).

3-(2-pyridyl)-5-[5-(5-pyrimidyl)-pyrid-3-yl]-1,2,4-oxadiazole [0675]

B123 <img file="IS2564B_D0533.tif" /> [0676] In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl) -1,2,4-oxadiazole (42 mg, 0.1385 mmole), 5-pyrimidyl-boronic acid (26.6 mg,0.208 mmole) and Pd(PPh3)4 (23.99 mg, 0.021 mmole) in a solution of 2M sodium carbonate (1.5 mL) and ethylene glycol dimethyl ether (1.5 mL) was heated overnight at 105 ’C. Standard workup afforded 3.2 mg (8%) of 3-(2-pyridyl)-5-[5-(5-pyrimidyl)-pyrid-3-yl]-1,2,4-oxadiazole (3.2 mg, 7.6 %).

3-(5-Fluoro-pyrid-2-yl)-5-[3-(3-pyridyl)phenyl]-1,2,4-oxadiazole [0677]

Β225 <img file="IS2564B_D0536.tif" /> [0678] A mixture of 3-(5-fluoro-pyrid-2-yl)-5-(3-bromophenyl)-1,2,4-oxadiazole (100 mg, 0.313 mmol), pyridine-3-bo-ronic acid 1,3-propanediol cyclic ester (102 mg, 0.624 mmol), and tetrakis(triphenylphosphíne)palladium(0) (Pd (P Ph3)4, 50.8 mg, 0.044 mmol), in a solution of ethylene glycol dimethyl ether (2 mL) and 2M sodium carbonate (2 mL) was heated in a sealed vial at 110'C for 1 hour. The reaction was cooled, diluted with dichloromethane, washad with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 50% ethyl acetate in hexane to 100% ethyl acetate afforded 50 mg (50.2%) 3-(5-1 luoropyrid-2-y l)-5-[3-(3-py ridyl)pheny l]-1,2,4-oxadiazole.1H-NMR (CDCI3), δ (ppm): 8.91 (d, 1H), 8.69 (d, 1H), 8.64 (d, 1H), 8.49 (s, 1H), 8.28 (m, 2H), 8.00 (m, 1H), 7.84 (dd, 1H), 7.69 (t, 1H), 7.60 (td, 1H), 7.44(dd, 1H).

5-[3-Methyl-5-(3-pyridyl)-pyrid-4-yl]-3-(2-pyridyl)-1,2,4-oxadiazole [0679]

B226 <img file="IS2564B_D0537.tif" /> [0680] A mixture of 5-(3-chloro-5-methyl-pyrid-4-yl)-3-(2-pyridyl)-1,2,4-oxadiazole (75 mg, 0.275 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (75 mg, 0.46 mmol), and tetrakis(tríphenylphosphine)palladium(0) (Pd(PPh3)4, 30 mg, 0,026 mmol), in a solution of ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100'C for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 40% ethyl acetate in hexane to 100% ethyl acetate afforded 5.4 mg (7.4%) of 5-[3-methyl-5-(3-pyridyl)-pyrid-4-yl]-3-(2-pyridyl)-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 9.32 (s, 1H), 8.87 (d, 1H), 8.70 (d, 1H), 8.30 (m, 2H), 8.25 (s, 1H), 8.00 (s, 1H), 7.90 (d, 1H), 7.47 (m, 2H), 2.77 (s, 3H).

5-[3-Methoxy-5-(3-pyridyl)-pyrid-4-yl]-3-(2-pyridyl)-1,2,4-oxadiazole [0681]

Β227 <img file="IS2564B_D0540.tif" /> [0682] A mixture of 3-(2-pyridyl)-5-(3-chloro-5-methoxy-pyrid-4-yl)-1,2,4-oxadiazole (75 mg, 0.260 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (75 mg, 0.46 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd (PPh3)4, 30 mg, 0.026 mmol), in a solution of ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100’C for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using 40% ethyl acetate in hexane and 100% ethyl acetate afforded 3.5 mg (4.1 %) 3-(2-pyridyl)-5-[3-methoxy-5-(3-pyridyl)-pyrid-4-yl]-l ,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm): 9.39 (s, 1H), 8.91 (d, 1H), 8.72 (d, 1H), 8.42 (d, 1H), 8.25 (d, 1H), 8.20 (s, 1H), 7.92 (dt, 1H), 7.63 (dd, 1H), 7.50 (m, 2H), 4.12 (s, 3H).

5-(2-pyridyl)-3-[5’(3-pyridyl)-pyrid-3-yl]-1,2,4-oxadiazole [0683]

B228 <img file="IS2564B_D0541.tif" /> [0684] A mixture of 3-(5-bromo-pyrid-3-yl)-5-(2-pyridy I)-1,2,4-oxadiazole 30.3 mg, 0.1 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (32.5 mg, 0.2 mmol), and tetrakís(tríphenylphosphine)palladíum(0) (Pd(PPh3)4, 15 mg, 0.013 mmol), in a solution of ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100’C tor 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brlne, filtered, and concentrated. Silica gel chromatography using 50% ethyl acetate in hexane and 100% ethyl acetate afforded 13 mg (43.2%) 5-(2-pyridyl)-3-[5-(3-pyridyl)-pyrid-3-yl]-1,2,4-oxadiazole. 1H-NMR (CDCI3), δ (ppm); 9.49 (d, 1H), 9.01 (d, 1H), 8.93 (dd, 2H), 8.72 (t, 2H), 8.35 (d, 2H), 8.00 (dt, 1H), 7.59 (m, 1H), 7.47 (dd, 1H).

5-(2-pyridyl)-3-[3-(3-pyridyl)-phenyl]-1,2,4-oxadiazole [0685]

Β229 <img file="IS2564B_D0544.tif" /> [0686] A mixture of 3-(3-iodophenyl)-5-(2-pyridyl)-1,2,4-oxadiazole (55 mg, 0.158 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (51.4 mg, 0.3152 mmol), and tetrakís(triphenylphosphine)palladium(0) (Pd(PPh3)4, 25 mg, 0.0216 mmol), in a solution of ethylene glycol dimethyl ether (1.5 mL) and 2M sodium carbonate (1.5 mL) was heated in a sealed vial at 100'C for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using 40% and 60% ethyl acetate in hexane and then the treatment of 1M HCI (0.2 mL) afforded 29.4 mg (55.45%) 5-(2-pyridy1)-3-[3-(3-pyridyl)-phenyl]-1,2,4-oxadiazole hydrochloride. 1H-NMR (CDCI3), δ (ppm); 9.34 (s, 1H), 8.88 (m, 3H), 8.54 (s, 1H), 8.40 (d, 1H), 8.28 (d, 1H), 8.16 (d, 1H), 8.00 (m, 3H), 7.82 (m, 2H).

5-(5-Fluoro-pyrid-2-yl)-3-[3-fluoro5-(3-pyridyl)-phenyl]-1,2,4-oxadiazole [0687]

B230 <img file="IS2564B_D0545.tif" /> [0688] A mixture of 5-fluoro-picolíníc acid hydrochloride (177.5 mg, 1 mmol): in dichloromethane (2 mL) was treated with 2M oxalyl chloride (2 ml, 4 mmol, dichloromethane). The mixture was stirred 2 hours at room temperature. The solvent and excess reagent were removed in vacuo. The residue was treated with 3-bromo-5-fluorophenyl-amidoxime (102 mg, 0.5 mmol) and triethylamine (404 mg, 4 mmol) in dichloromethane (2 mL). The mixture was then heated in dimethylformamide (1 mL) for 1 hours at 130 'C. Standard work up, afforded 80 mg (47%) of 3-(3-bromo-5-ffuorophenyl)· 5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole.

[0689] A mixture of 3-(3-bromo-5-fluorophenyl)-5-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole (80 mg, 0.236 mmol), pyridine-3-boronic acid 1,3-propanediol cydic ester (80 mg, 0.49 mmol), and tetrakis(triphenylphosphine)pal1adium(0) (Pd (PPh3)4, 40 mg, 0.0346 mmol), in a solution of ethylene glycol dimethyl ether (1.5 mL) and 2M sodium carbonate (1.5 mL) was heated in a sealed vial at 100Ό for 1 hour. The reaction was cooled, dlluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 50 % ethyl acetate in hexane, afforded 14 mg (17.7%) 5-(5-fluoropyrid-2-yl)-3-[3-fluoro-5-(3-pyridyl)-phenyl]-1,2,4-oxadiazole. 1H· NMR (CDCI3), δ (ppm): 8.95 (s, 1H), 8.76 (d, 1H), 8.66 (d, 1H), 8.37 (dd, 2H), 8.25 (s, 1H), 7.95 (d, 2H), 7.43 (m, 2H).

3-(2-Pyridyl)-5-(3-cyano-5-(2-pyridyl)phenyl)-1,2,4-oxadiazole [0690]

Β124 <img file="IS2564B_D0548.tif" /> [0691] A mixture of 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (101 mg, 0.31 mmol), tetrakis(triphe-nylphosphine) palladium(O) (Pd(PPh3)4,25 mg, 0.021 mmol) and tri-n-butyl(2-pyridyl)tin in tetrahydrofuran (2 mL) was heated overnight at 100 ’C. The reaction mixture was cooled and transferred directly onto a flash silica column. Elution with a gradient of hexane:ethyl acetate:chloroform 3:1:4 to 2.5:1:4 followed by trituration with hexane in dichloromethane afforded 22 mg (22%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-pyridyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3): δ - 9.12 (s, 1H), 8.88 (d, 1H), 8.78 (d, 1H), 8.64 (s, 1H), 8.61 (s, 1H), 8.26 (d, 1H), 7.89 (m, 3H), 7.51 (m, 1H), 7.40 (m, 1H).

3-(2-Pyridyl)-5-[2-methoxy-5-(2-pyridyl)phenyl]-1,2,4-oxadiazole [0692]

B125 <img file="IS2564B_D0549.tif" /> [0693] In a similar fashion, a mixture of 3-(2-pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (110 mg, 0.331 mmol), py ridine-2-tributy Itin (138.8 mg,0.663 mmole) and Pd(PPh3)4 (38.5 mg, 0.0333 mmole) in tetrahydrofuran (1 mL) was heated in a sealed vial overnight at 100 "C. Standard work up afforded 13.9 mg (13%) 3-(2-pyridyl)-5-[2-methoxy-5-(2-pyridyl)phenyl]-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-[2-fluoro-5-(2-pyridyl)phenyl]-1,2,4-oxadiazole [0694]

B126 <img file="IS2564B_D0550.tif" /> [0695] ln a similar fashion, 3-(2-pyridyl)-5-(5-bromo-2-1l uoropheny I)-1,2,4-oxadiazole (100 mg, 0.312 mmol), pyridine-2-tributyltin (172 mg, 0.468 mmol) and Pd(PPh3)4 (36.1 mg, 0.0312 mmol) in tetrahydrofuran (1 mL) was heated in sealed vial overnight at 100 'C. Standard work up afforded 11,3 mg (11 %) of 3-(2-pyridyl)-5-[2-fluoro-5-(2-pyridyl) phenyl]-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(3-aminomethyl-5-cyanophenyl)-1,2,4-oxadiazole [0696]

B127 <img file="IS2564B_D0554.tif" /> [0697] A mixture of 3-(2-pyridyl)-5-(3-cyano-5-methylphenyl)-1,2,4-oxadiazole (0.5 g, 1.91 mmol), /V-bromosuccinim-ide (0.339 g, 1.91 mmol), and benzoyl peroxide (.0010 g, 0.04 mmol) in carbon tetrachloride (25 mL) was heated at 80 'C for 18 hours. After this time the reactíon míxture was cooled and diluted with dichloromethane. The organic solution was washed with water and brine to afford 0.595 g (91%) of 3-(2-pyridyl)-5-(3-bromomethyl"5-cyanophenyl)-1,2,4-oxa-diazole.

[0698] A solution of 3-(2-pyridyl)-5-(3-bromomethyl-5-cyanophenyl)-1,2,4-oxadiazole (0.5 g, 1.91 mmol) in dichloromethane (1.5 mL) was treated with a 0.5M ammonia (1.5 mL, 1.5 mmol, díoxane) and heated at 50 "C for 90 mínutes. After this time the reaction mixture was cooled and diluted with dichloromethane. The organic solution was washed with water and brine. Silica gel chromatography of the crude product afforded 3.5 mg (5.5%) of 3-(2-py ridyl)-6-(3-am inomethyl-5-cyanophenyl)-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-[5-(2-propenyl)-pyrid-3-yl]-1,2,4-oxadiazole [0699]

B128 <img file="IS2564B_D0555.tif" /> [0700] Under an argon atmosphere, a solution of 5-bromonicotinic acid (1.01 g, 5 mmol) in tetrahydrofuran (10 mL) at-78 ’C was treated dropwise with a 1.6M solution of n-butyllitium (6.99 ml, 11 mmol, hexane). Afterthereactionmixture was stirred for 16 minutes, acetone (1 mL) was added. The reaction mixture was then warmed to room temperature and quenched with 1N HCI. The solution was then concentrated in vacuo. The residue was treated with excess thionyl chloride (10 mL) and heated to 80 ’C for 10 minutes. The excess thionyl chloride was then removed. The acid chloride in dichloromethane (10 mL) was treated with pyrid-2-ylamidoxlme (0.685g, 5 mmol) and triethylamine (2.02 g, 20 mmoles) and stirred at room temperature for 15 minutes. /V.M-Dimethylformamide (10 mL) was then added and the reaction mixture heated at 120 ‘C for 16 hours. The reaction was quenched by the addition of water and the preci pitate collected and dried. Silica gel chromatography of this material using 20% ethyl acetate in hexane afforded 153 mg (12%) of 3-(2-pyridyl)-5-[5-(2-propenyl)-pyrid-3-yl]-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(3-cyano-5-vinylphenyl)-1,2,4-oxadiazole [0701]

Β129 <img file="IS2564B_D0558.tif" /> [0702] A mixture of 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (1.005 g, 3.21 mmol) and Pd(PPh3)4 (369 mg, 0.32 mmol) in tetrahydrofuran (10 mL) was treated with vinyl tributyl tin (0.985 mL, 3.36 mmol). The reaction mixture was heated in a sealed tube at 85 'C for 18 hours. After cooling, the mixture was diluted with dichloromethane and water. The organic layer was dried by filtration through an EX-TUBE. Silica gel chromatography afíorded 691 mg (78%) of 3-(pyrid-2-yl)-5-(3-cyano-5-vinylphenyl)-1,2,4-oxadiazole: 1H-NMR (CDCI3), δ (ρριτ):ΟΠΠΠΠΟ (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.23 (d, 1H), 7.90 (m, 2H), 7.48 (m, 1H), 6.78 (dd, 1H), 5.98 (d, 1H), 5.55 (d, 1H).

3-(2-Pyridyl)-5-(3-cyano-5-(2-hydroxyethyl)phenyl)-1,2,4-oxadiazole [0703]

B130 <img file="IS2564B_D0559.tif" /> [0704] A mixture of 3-(2-pyridyl)-5-(3-cyano-5-vinylphenyl)-1,2,4-oxadiazole (83 mg, 0.30 mmol) in dichloromethane (2 mL) was treated with 9-BBN dimer (40 mg, 0.16 mmol) and the reaction mixture stirred at room temperature for 4 hours. Sodium perborate tetrahydrate (157 mg, 1.02 mmol) and water (1 mL) were added and the resulting biphasic mixture was stirred vigorously for 18 hours. The mixture was diluted with dichloromethane and water and the organic layer dried by filtration through an EX-TUBE. Silica gel chromatography using a gradient of 20% to 75% ethyl acetate in hexane, followed by trituration in 10% ethyl acetate in hexane afforded 3.4 mg (3.7%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-hydroxyethyl)phenyl)-1,2,4-oxadiazole: 'H-NMR (CDCl3), δ (ppm):DD8.85 (d, 1H), 8.43 (s, 2H), 8.22 (d, 1H), 7.90 (t, 1H), 7.80 (s, 1H), 7.48 (m, 1H), 3.99 (m, 2H), 3.02 (t, 2H).

3-(2-Pyridyl)-5-(3-cyano-5-(2,3-dichloropropoxy)phenyl)-1,2,4-oxadiazole [0705]

B131 <img file="IS2564B_D0560.tif" /> [0706] A stirred suspension of 3-(2-pyridyl)-5-(3-alloxy-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole (160 mg, 0.47

mmol) in methanol (5 mL) at ambient temperature was treated with 1M sodium hydroxide (0.8 mL, 0.80 mmol). The reaction was stirred 16 hours and solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified with 1 N hydrogen chloride. Extraction of the aqueous phase with dichloromethane followed by concentration in vacuo afforded 104.5mg of 3-(2-pyridyl)-5-(3-alloxy-5-(hydroxycarbonyl)phenyl)-1,2,4-oxadiazole.

[0707] The carboxylic acid (104.5 mg, 0.32 mMol) was treated with excess thionyl chloride (2.5 mL) and the resulting mixture heated at reflux for 2 hours. The thionyl chloride was then removed in vacuo the acid chloride dissolved in chloroform (2.5 mL). The solution was cooled to 0 ’C and treated with 2 M ammonia in methanol. The reaction mixture was then stirred at ambient temperature for additional 2 hours. After this time the reaction was filtered and concentrated to afford 86 mg of crude 3-(2-pyridyl)-5-(3-alloxy-5-(carboxamide)phenyl)-1,2,4-oxadiazole.

[0708] The intermediate benzamide (86 mg) was treated with thíonyl chloríde (2 mL) and heated in a sealed víal for 16 hours. The thionyl chloride was then rempved in vacuo. The residue was dissolved in water followed by addition of 10 % sodium bicarbonate and the crude product extracted into ethyl acetate. Silica gel chromatography using a gradient of 30 % ethyl acetate in hexanes to 40 % ethyl acetate in hexanes afforded 15.4 mg (9%) of 3-(2-pyridyl)-5-(3-cyano-5-(2,3-dichloropropoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3): δ - 8.87 (d, 1H), 8.30 (m, 2H), 8.10 (s, 1H), 7.89 (m, 1H), 7.50 (m, 2H), 4.50 (m, 3H), 3.91 (m, 2H).

3-(2-Pyridyl)-5-(3-carboxy-5-methoxyphenyl)-1,2,4-oxadiazole [0709]

B132 <img file="IS2564B_D0564.tif" /> [0710] A stirred suspension of 3-(2-pyridyl)-5-(3-methoxycarbonyl-5-methoxyphenyl)-1,2,4-oxadiazole (191.3 mg, 0.62 mmol) in methanol-tetrahydrofuran (1:1,10 mL) was treated with 1M sodium hydroxide (1.5 mL, 1.5 mmol). The reaction was stirred at 50‘C for 5 hours and the solvent then removed /n vacuo. The residue was dissolved in a small amount of water and tben acidified (pH 4 - 5) by the addition of 2 N hydrogen chloride. The precipitate was collected and dried to afford 131.8 (72 %) of 3-(2-pyridyl)-5-(3-carboxy-5-methoxyphenyl)-1,2,4-oxadiazole: 1H NMR (DMSO): δ - 8.81 (d, 1H), 8.28 (s, 1H), 8.21 (d, 1H), 8.06 (t, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.65 (m, 1H), 3.95 (s, 3H).

3-(2-Pyridyl)-5-(3-(carboxamido)-5-methoxyphenyl)-1,2,4-oxadiazole [0711]

B133 <img file="IS2564B_D0565.tif" /> [0712] A solution of 3-(2-pyridyl)-5-(3-carboxy-5-nriethoxyphenyl)-1,2,4-oxadiazole (131.8 mg, 0.44 mMol) in thionyl chloride (2 mL) and a catalytic amount of A/./V-dimethylformamide was heated at reflux for 2 hours. The excess thionyl chloride was then removed ín vacuo and the íntermediate acid chloríde dissolved in chloroform (2 mL). After cooíing to

°C the solution was then treated with 2 M ammonia in methanol (2 mL). The reaction mixture was then stirred at ambient temperature for 30 minutes. The precipitate was collected, washed with water and dried in vacuo. Silica gel chromatography of this material using a gradient of 50% ethyl acetate in hexane to 100 % ethyl acetate afforded 106.7 rrig (81 %) of 3-(2-pyridyl)-5-(3-(carboxamido)-5-rnethoxyphenyl)-1,2,4-oxadiazole: 1H NMR (DMSO): δ - 8.81 (d, 1H), 8.31 (s, 2H), 8.22 (d, 1H), 8.08 (t, 1H), 7.80 (d, 2H), 7.66 (t, 2H), 3-95 (s, 3H).

3-(2-Pyridyl)-5-(3-cyano-5-methcixyphenyl)-1,2,4-oxadiazole [0713]

B134 <img file="IS2564B_D0568.tif" /> [0714] A solution of 3-(2-pyridyl)-5-(3-(carboxamido)-5-methoxyphenyl)-1,2,4-oxadiazole (56.3 mg) in thionyl chloride (1.5 mL) was heated at reflux for 3 hours. The excess thionyl chloride was then removed in vacuo. Standard work up and silica gel chromatography using a mixture of hexanes, ethyl acetate, and dichloromethane (3.5:0.5:4) afforded 12.1 mg (23%) of 3-(2-pyrídyl)-5-(3-cyano-5-methoxyphenyl)-1 ,2,4-oxadíazole: 1H NMR (CDCI3): δ - 8.86 (d, 1H), 8.23 (d, 1H), 8.16 (S, 1H), 8.02 (s, 1H), 7.92 (t, 1H), 7.50 (t, 1H), 7.40 (s, 1H), 4.04 (s, 3H).

3-(2-Pyridyl)-5-(3-allyloxy-5-carboxyphenyl)-1,2,4-oxadiazole [0715]

B135 <img file="IS2564B_D0569.tif" /> [0716] A stirred suspension of 3-(2-Pyridyl)-5-(3-allyloxy-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole (1.8 g, 5.28 mmol) in methanol (40 mL) was treated with 1M sodium hydraxide (7.9 mL, 7.9 mmol) and the reaction stirred at ambient temperature for 36 hours. The solvent was removed in vacuo, and the residue was dissolved in water (30 mL) and then acidified (pH 4 - 5) by the addition of 2N hydrogen chloride. The resulting precipitate was collected and dried to afford 1.6 (94 %) of 3-(2-pyridyl)-5-(3-allyloxy-5-carboxyphenyl)-1,2,4-oxadiazole: 1H NMR (DMSO); δ - 8.81 (d, 1H), 8.29 (s, 1H), 8.22 (d, 1H), 8.05 (m, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.65 (m, 1H), 6.09 (m, 1H), 5.47 (dd, 1H), 5.33 (dd, 1H), 4.80 (d, 2H).

3-(2-Pyridyl)-5-(3-allyloxy-5-cyanophenyl)-1,2,4-oxadiazole [0717]

Β136 <img file="IS2564B_D0572.tif" /> [0718] Asolution of 3-(2-pyridyl)-5-(3-allyloxy-5-(carboxy)phenyl)-1,2,4-oxadiazole (1.2g, 3.7mmol) inthionyl chloride (24 mL), and a catalytic amount of N,/V-dimethylforrnamide was heated at reflux for 1.5 hours. The thionyl chloride was then removed in vacuo and the acid chloride was dissolved in chloroform (20 mL). The solution was cooled to 0 ’C and treated with a solution of 0.5M ammonia in dioxane (22 mL). The reaction mixture was then stirred at ambient temperature for 30 minutes. The resulting precipitate was collected and dried to afford 1.1 g of 3-(2-pyridyl)-5-(3-allyloxy-5-(carbox-amide)phenyl)-1,2,4-oxadiazole.

[0719] A suspension of 3-(2-pyridyl)-5-(3-allyloxy-5-(carboxamide)phenyl)-1,2,4-oxadiazole (1.1 g, 3.6 mmol) in a dichloromethane at 0 ’C was treated with pyridine (0.6 mL, 7.6 mmol) and then trifluoroacetic anhydride (0.636 mL, 4.5 mmol). The reaction was stirred at 0 ‘C for 20 mlnutes and then stirred overnight at ambient temperature. The reaction mixture was then washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography using a mixture of hexanes, ethyl acetate, and dichloromethane (3.5:0.5:1) afforded 1.0 g (91 %) of 3-(2-pyridyl)-5-(3-allyloxy-5-cyanophenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3); δ - 8.87 (d, 1H), 8.23 (d, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.91 (t, 1H), 7.50 (m, 1H), 7.41 (s, 1H), 6.06 (m, 1H), 5.48 (dd, 1H), 5.38 (dd, 1H), 4.68 (d, 2H).

3-(2-Pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole [0720]

B137 <img file="IS2564B_D0573.tif" /> [0721] A mixture of 3-(2-pyridyl)-5-(3-allyloxy-5-cyanophenyl)-1,2,4-oxadiazole (1.0 g, 3.4 mmol) and tetrabutylammonium iodide (1.4 g, 3.8 mmol) in dichloromethane (18 mL) at-78 'C, under argon, wastreated with a solution of 1M boron trichloride in dichloromethane (22 mL, 22 mmol). After 5 minutes at -78 ’C the reaction mixture was stirred at ambient temperature for 1 hour. The reaction was then quenched with ice water and stirred for 30 mínutes. The mixture was then washed with saturated sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, f iltered and concentrated. Silica gel chromatography using a gradient of 10% ethyl acetate in hexanes to 80% ethyl acetate in hexanes afforded 460 mg (51 %) of 3-(2-pyridyl)-5-(3-cyano-5-hydrox-yphenyl)-1,2,4-oxadiazole; 1HNMR (CDCIa/MeOD); δ - 8.81 (d, 1H), 8.23 (d, 1H), 8.01 (s, 1H), 7.95 (m, 1H), 7.92 (m, 1H), 7.54 (m, 1H), 7.35 (m, 2H).

3-(2-Pyridyl)-5-(3-cyano-5-(2-N,N-dimethylaminoethoxy)phenyl)-1,2,4-oxadiazole [0722]

Β138 <img file="IS2564B_D0576.tif" /> [0723] A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (374mg, 2.7 mmol) and 2-dimethylaminoethyl chloride hydrochloride (46 mg, 0.32 mmol) in W,M-dimethylforma-mide (1 mL) were heated in a sealed vial at 150’C for 5 minutes. The reaction was cooled, diluted with dichloromethane, washed with water (3 x) and saturated brine, filtered and concentrated. Silica gel chromatography using a gradient of 1 % methanol in dichloromethane to 5% methanol in dichloromethane afforded 24 mg (53%) ot 3-(2-pyridyl)-5-(3-cyano-5-(2-dimethylaminoethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3): δ - 8.86 (d, 1H), 8.23 (d, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.91 (t, 1H),7.49(m, 1H), 7.43 (s, 1H),4.20 (t, 2H), 2.80 (t, 2H), 2.37 (s, 6H).

3-(2-Pyridyl)-5-(3-cyano-5-(N,N-dimethylaminopropoxy)phenyl)-1,2,4-oxadiazole [0724]

B139 <img file="IS2564B_D0577.tif" /> [0725] ln a similar fashion, 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (31 mg, 0.12 mmol), potassium carbonate (381 mg, 2.8 mmol) and 2-dimethylaminopropyl chloride hydrochloride (51 mg, 0.32 mmol) in /V,/V-dímethyl-formamide (1 mL) were heated in a sealed vial at 150 'C for 5 minutes. Standard work up and chromatography afforded 10 mg (24 %) of 3-(2-pyridyl)-5-(3-cyano-5-(dimethylaminopropoxy)phenyl)-1,2,4-oxadiazole:1H NMR (CDCI3); δ - 8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.91 (t, 1H), 7.49 (m, 1H), 7.41 (s, 1H), 4.17 (t, 2H), 2.49 (t, 2H), 2.28 (s, 6H), 2.02 (q, 2H).

3-(2-Pyridyl)-5-(3-cyano-5-(2-aminoethoxy)phenyl)-1,2,4-oxadiazole [0726]

B140 <img file="IS2564B_D0578.tif" /> [0727] In a similar fashion, 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (63 mg, 0.24 mmol), triphenylphosphine (100 mg, 0.38 mmol), W-(tert-butoxycarbonyl)ethanolamine (60 mg, 0.37 mmol) in tetrahydrofuran (2 mL) was treated with diethyl azodicarboxylate (0.060 mL, 0.38 mmol) dropwise and the reaction mixture was stirred overnight.

Standard work up and chromatography afforded the Boc-protected intermediate.

[0728] A solution of the Boc-protected intermediate in dichloromethane (2 mL) was treated with trifluoroacetic acid (1 mL) at O'C. After stirring for 1.5 hours, saturated sodlum bicarbonate was added to the reaction mixture and the crude product extracted with dichloromethane. Silica gel column chromatography using a gradient of 1 % methanol in dichloromethane to 10% methanol in dichloromethane afforded 27 mg (37%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-aminoethoxy) phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3/MeOD): δ - 8.85 (d, 1H), 8.23 (d, 1H), 8.17 (s. 1H), 8.04 (s, 1H), 7.93 (t, 1H), 7.49 (m, 1H), 7.44 (S, 1H), 4.17 (t, 2H), 3.17 (m, 2H).

3-(2-Pyridyl)-5-(3-cyano-5-prapoxyphenyl)-1,2,4-oxadiazole [0729]

B141 <img file="IS2564B_D0582.tif" /> [0730] A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (20 mg, 0.077 mmol), potassium carbonate (107 mg, 0.77 mmol) and propyl iodide (0.023 mL, 0.23 mmol) in N,/V-dimethylformamide (1 mL) were heated in a sealed vial at 150 ‘C for 5 minutes. After cooling the reaction was diluted with dichloromethane, washed with water (3 times) and saturated brine, filtered and concentrated. Silica gel chromatography using a mixture of hexanes, ethyl acetate, and dichloromethane (3.5:0.5:4) followed by trituration with diethyl ether and hexanes afforded 9 mg (40 %) of 3-(2-pyridyl)-5-(3-cyano-5-propoxyphenyl)-1,2l4-oxadiazole: 1H NMR (CDCI3): δ - 8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.91 (t, 1H), 7.49 (m, 1H) 7.39 (s, 1H), 4.06 (t, 2H), 1.88 (m, 2H), 1.08 (t, 3H).

3-(2-Pyridyl)-5-(5-cyano-3-[3-hydroxypropyn-1-yl]phenyl)-1,2,4-oxadiazole [0731]

B142 <img file="IS2564B_D0583.tif" /> [0732] A mixture of the 3-(2-pyridyl)-5-(5-cyano-3-iodophenyl)-1,2,4-oxadiazole (140 mg, 0.374 mmol), Pd(PPh3)4 (10 mg, 0.009), and Cul (30 mg, 0.158 mmol) in /V,/V-dimethylformamide (3 mL) was treated with triethylamine (1 mL, 726 mg, 7 mmol). The reaction mixture was cooled to 0 ’C and treated with propargyl alcohol (56 mg, 1 mmol), The mixture was stirred at ambient temperature 5 hours and then filtered through a short plug of silica gel, washing with ethyl acetate. The organic sofutíon was concentrated in vacuo. Silica gel chromatography afforded 20 mg (18%) of 3-(2-pyridyl)-5-(5-cyano-3-[3-hydroxypropyn-1-yl]phenyl)-1,2,4-oxadiazole: 1H-NMR (MeOH-d4), δ ppm: 8.80 (d, 1H), 8.60 (S, 1H), 8.58 (s, 1H), 8.30 (d, 1H), 8.10 (m, 2H), 7.60 (m, 1H), 4.5 (s, 2H).

3-(2-Pyridy 1)-5-(5-(3-N-benzyl-1, 2,5,6-tetrahydropyridine)-pyrid-3-yl]-1,2,4-oxadiazole [0733]

B143 <img file="IS2564B_D0586.tif" /> [0734] A mixture of 5-bromonicotinic acid (1.01 g, 5 mmoles) in tetrahydrofuran (10 ml), under an argon atmophere, was cooled to -78 ’C and treated dropwise with a solution of 1.6M n-butyllithium (6.99 mL, 11 mrriole, hexane). The reaction mixture was stirred for 15 minutes at -78 *C, and then treated with N-benzyl-3-piperidinone (1 89g, 10 mmoles). The reaction mixture was then allowed to warm to room temperature where it was quenched by the addition of 1N HCI. The reaction mlxture was concentrated to dryness in vacuo. The residue was treated with thionyl chloride (10 mL) and the mixture heated for 10 minutes at 80 'C. The excess thionyl chloride was removed in vacuo, and the residue treated with ethanol. Silica gel chromatograph using 1% methanol in dichloromethane afforded 120 mg (8%) of the nicotinic ethyl ester intermediate. Hydrolysis of the ester to the corresponding acid was accomplished using 1 Nsodium hydroxide (1 mL) and methanol (2 mL).

[0735] Activation of the intermediate acid using oxalyl chloride followed by treatment with pyrid-2-ylamidoxime (120 mg, 0.876 mmoles) and triethylamine (0.404 g, 4 mmol) in dichloromethane (10 mL) followed by heating at 120 'C in N, W-dimethylformamide (2 mL) for 4 hours, afforded, afterstandard work up 14.5 mg (10%) of 3-(2-py ri dy I)-5-[5-(3-N-benzyl-

1,2,3,6-tetrahyd ropy ridine)-py rid-3-y l]-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(2-N-methylaminophenyl)-1,2,4-oxadiazole [0736]

B144 <img file="IS2564B_D0587.tif" /> [0737] AmixtureofN-methyl-isatoicacidanhydride(177.2mg, 1 mmol)andpyrid-2-ylamidoxime(137.14mg, 1 mmol) in toluene (2 mL) was heated to 120 'C for 5 hours. After cooling, the solid was filtered, dissolved in ethylene glycol (1 mL) and heated at 125 ’C for 6 hours. The solution was poured into water. Collection of the solid by filtration afforded 54 mg (21 %) 3-(2-pyridyl)-5-(2-N-methylaminophenyl)-1,2,4-oxadiazole.

3-(2-Pyridyl)-5-(3-cyano-5-(2-hydroxyethoxy)phenyl)-1,2,4-oxadiazole [0738]

Β231 <img file="IS2564B_D0590.tif" /> [0739] A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (40 mg, 015 mmol), potassium carbonate (42 mg, 0.30 mmol) and bromoethane (30 mg, 0.23 mmol) in A/.N-dimethylformamide (1 mL) was heated in a sealed vial at 100 'C for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3 x) and saturated brine, filtered and concentrated. Silica gel chromatography using 2% methanol in dichloromethane afforded 18 mg (39%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-hydroxyethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCIa/MeOD), δ (ppm): 8.80 (d, 1H), 8.27 (d, 1H), 8.17 (s, 1H), 8.07 (s, 1H), 8.00 (t, 1H), 7.58 (m, 1H), 7.53 (s, 1H), 4.24 (t, 2H), 3.99 (t, 2H).

3-(2-Pyridyl)-5-(3-cyano-5-isopropoxyphenyl)-1,2,4-oxadiazole [0740]

B232 <img file="IS2564B_D0591.tif" /> [0741 ] A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadlazole (30 mg, 0.12 mmol), potassium carbonate (32 mg, 0.23 mmol) and 2-iodopropane (17 μι, 0.17 mmol) in Λ/,/V-dirnethylformamide (1 mL) was heated in a sealed vial at 90 "C for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3 x) and saturated brine, filtered and concentrated. Silica gel chromatography using a hexanes/ethyl acetate/dichloromethane (3.5:0.5:4) afforded 24 mg (68%) of 3-(2-pyridyl)-5-(3-cyano-5-isopropoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm); 8.86 (d, 1H), 8.23 (d, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.91 (m, 1H), 7.49 (m, 1H), 7.36 (s, 1H), 4.71 (m, 1H), 1.41 (m, 6H).

3-(2-Pyridyl)-5-(3-cyano-5-ethoxyhenyl)-l,2,4-oxadiazole [0742]

B233 <img file="IS2564B_D0592.tif" />

A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (25 mg, 0.095 mmol), potassium carbonate (26 mg, 0.19 mmol) and iodoethane (11 μΙ, 0.14 mmol) in A/,A/-dimethylfoimamide (1 mL) was heated in a sealed vial at 70"C for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water (3 x) and saturated brine,

filtered and concentrated. Silica gel chromatography of the residue using hexanes/ethyl acetate/dichloromethane (3.5: 0.5:4) followed by trituration with diethyl ether afforded 11 mg (39%) of 3-(2-pyridyl)-5-(3-cyano-5-ethoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.91 (m, 1H), 7.49 (m, 1H), 7.38 (s, 1H), 4.17 (q, 2H), 1.49 (t, 3H).

3-(2-Pyridyl)-5-(3-cyano-5-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-oxadiezole [0743]

B234 <img file="IS2564B_D0596.tif" /> [0744] A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (25 mg, 0.095 mmol), potassium carbonate (53 mg, 0.38 mmol) and 2-iodo-1,1,1-trifluoroethane (28 μΙ., 0.28 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 150 "C tor 5 miniites hour. The reaction was cooled, diluted with dichloromethane, washed with water (3 x) and saturated brine, filtered and concentrated. Silica gel chromatography of the residue using hexanes/ ethyl acetate/dichloromethane (3.5:0.5:4) afforded 9 mg (27%) of 3-(2-pyridyl)-5-(3-cyano-5-(2,2,2-trifIuoroethoxy)phe-nyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.87 (d, 1H), 8.27 (s, 1H), 8.24 (d, 1H), 8.08 (s, 1H), 7 92 (t, 1H), 7.50 (m, 2H), 4.53 (q, 2H).

3-(2-Pyridyl)-5-(3-cyano-5-cyclopropylmethoxyphenyl)-1,2,4-oxadiazole [0745]

B235 <img file="IS2564B_D0597.tif" /> [0746] A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadlazole (25 mg, 0.095 mmol), potassium carbonate (26 mg, 0.19 mmol) and (bromomethyl)cyclopropane (14 μΙ., 0.14 mmol) in /V,N-dimethylformamide (1 mL) was heated in a sealed vial at 90 'C for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3 x) and saturated brine, f iltered and concentrated. Silica gel chromatography of the residue using hexanes/ethyl acetate/ dichloromethane (3.5:0.5:4) followed by trituration with diethyl ether afforded 12 mg (41%) of 3-(2-pyridyl)-5-(3-cyano-5-cylopropylmethoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 7.99 (S, 1H), 7.91 (t, 1H), 7.50 (m, 1H), 7.40 (s, 1H), 3.95 (d, 2H), 1.21 (m, 1H), 0.72 (m, 2H), 0.41 (m, 2H).

3-(2-Pyridyl)-5-(3-amino-5-cyanophenyl)-1,2,4-oxadiazole [0747]

Β236 <img file="IS2564B_D0600.tif" /> [0748] 3-(2- Pyridyl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole (30 mg, 0.10 mmol) and tin(ll) chloride dihydrate (115 mg, 0.51 mmol) in ethanol (1 mL) were sealed in a glass vial and then heated at 78 oC for 2 hours. The reaction was cooled and dichloromethane was added to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography of the residue using hexanes:ethyl acetate:dichloromethane 1:3:4 followed by recrystall ization using methanol afforded 2.8 mg (10%) of 3-(2-Pyridyl)-5-(3-amino-5-cyanophenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.85 (d, 1H), 8.22 (d, 1H), 7.91 (m, 2H), 7.78 (s, 1H), 7.48 (m, 1H), 7.11 (s, 1H), 4.17 (bs, 2H).

3-(5-fluoropyrid-2-yl)-5-(3-amino-5-cyanophenyl)-1,2,4-oxadiazole [0749]

B237 <img file="IS2564B_D0601.tif" /> [0750] 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazols (30 mg, 0.096 mmol) and tin(ll) chloride dihydrate (109 mg, 0.48 mmol) in ethanol (1 mL) were sealed in a glass vial and then heated at 78 oC for 2 hours. The reaction was cooled and dichloromethane was added to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography of the residue using hexanes:ethyl acetate:dichloromethane 1:3:4 followed by recrystallization using methanol afforded 6.3 mg (23%) of 3-(5-fluoropyrid-2-yl)-5-(3-amino-5-cyanophenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.69 (d, 1H), 8.25 (m, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.61 (m, 1H), 7.11 (s, 1H), 4.17 (bs, 2H).

3-(2-Pyridyl)-5-(3-cyano-5-(trifluoromethylsijlfonyloxy)phenyl)-1,2,4-oxadiazole [0751]

B238 <img file="IS2564B_D0602.tif" /> [0752] Trifluoromethanesulfonic anhydride (22.9 μΙ, 0.14 mmol) and triethylamine (23.7 μΙ_, 0.17) were added under argon to a vial containing 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol) in dichloromethane (1 mL). The vial was then sealed and the reaction was left stirring overnight at ambient temperature. The reaction mixture was placed directly onto a flash column and purified by eluting with hexanes:ethyl acetate:dichlorometh-

ane 3.5:0.5:4 to afford 11 mg (25%) of 3-(2-pyridyl)-5-(3-cyano-5-(trifluoromethylsulfonyloxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), 5 (ppm): 8.88 (d, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.24 (d, 1H), 7.93 (t, 1H), 7.83 (s, 1H), 7.52 (m, 1H).

3-(2-Pyridyl)-5-(3-cyano-5-(2-methoxy-2-oxoethoxy)phenyl)-1,2,4-oxadiazole [0753]

B239 <img file="IS2564B_D0606.tif" /> [0754] A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (31 mg, 0.23 mmol) and methyl bromoacetate (16 μΙ, 0.17mmol) in Ν,Λ/’dimethylformamide (1 mL) was heated in a sealed vial at 100 ‘C for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3 x) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3.5:0.5:4 followed by trituration with diethyl ether afforded 10 mg (26%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-methoxy-2-oxoethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.87 (d, 1H), 8.23 (d, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.92 (t, 1H), 7.50 (t, 1H), 7.42 (s, 1H), 4.81 (S, 2H), 3.86 (s, 3H).

3-(2-Pyridyl)-5-(3-cyano-5-(2-tert-butoxy-2-oxoethoxy)phenyl)-1,2,4-oxadiazole [0755]

B24O <img file="IS2564B_D0607.tif" /> [0756] A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (80 mg, 0.30 mmol), potassium carbonate (84 mg, 0.61 mmol) and tert-butylbromoacetate (67 μΐ, 0.46 mmol) ín Λ/,/V-dimethylformamide (1 mL) was heated in a sealed vial at 90 °C for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water (3 x) and saturated brine, f iltered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3.5: 0.5:4 afforded 62 mg (62%) 3-(2-pyridyl)-5-(3-cyano-5-(2-tert-biitoxy-2-oxoethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCIg), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.91 (t, 1H), 7.50 (t, 1H), 7.28 (s, 1H), 5.30 (s, 2H), 1.52 (s, 9H).

3-(2-Pyridyl)-5-(3-cyano-5-(methoxymethoxy)phenyl)-1,2,4-oxadiazole [0757]

Β241 <img file="IS2564B_D0610.tif" /> [0758] A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (31 mg, 0.23 mmol) and chloromethyl methyl ether (26 μΙ_, 0.34 mmol) in /V,/V-dimethylformamide (1 mL) was heated in a sealed vial at 70 'C for 2 hour. The reaction was cooled, diluted with dichloromethane, washed with water (3 x) and saturated brine, filtered and concentrated. Silica gel chromatography using 20 - 30% hexanes/ethyl acetate atforded 19 mg (54%) of 3-(2-Pyridyl)-5-(3-cyano-5-(methoxymethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.86 (d, 1H), 8.24 (d, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.91 (t, 1H), 7.56 (s, 1H), 7.49 (m, 1H), 5.31 (s, 2H), 3.52 (s, 3H).

3-(2-Pyridyl)-5-(3-cyano-5-(2-methoxyethoxy)phenyl)-1,2,4-oxadiazole [0759]

B242 <img file="IS2564B_D0611.tif" /> [0760] A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (40 mg, 0.15 mmol), potassium carbonate (42 mg, 0.30 mmol) and 2-chloroethyl methyl ether (83 μΐ, 0.91 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 150 ’C for 5 minutes. The reaction was cooled, diluted with dichloromethane, washed with water (3 x) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate: dichloromethane 1:1:2 followed by trituration with diethyl ether afforded 24 mg (50%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-methoxyethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.87 (d, 1H), 8.23 (d, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.91 (t, 1H), 7.49 (m, 1H), 7.45 (s, 1H), 4.27 (t, 2H), 3.81 (t, 2H), 3.48 (s, 3H).

3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-cyclopentylamlnophenyl)-1,2,4-oxadiazole [0761]

B243 <img file="IS2564B_D0612.tif" /> [0762] A mixture of 3-(5-fluoropyrid-2-yl)-5-(3-amino-5-cyanophenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), cyclopentanone (24 μ.Ι_, 0.26 mmol), sodium cyanoborohydride, 1.0 M solution in tetrahydrofuran, (128 μ.!_, 0.12 mmol) in acetíc acid (4 mL) was heated at 60 ’C for 1 hour. After cooling, the reactlon mixture was diluted with ethyl acetate and then washed with water (2X) and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel

chromatography using 20% ethyl acetate/hexanes afforded 15 mg (39%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-cy-clopentylaminophenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.69 (d, 1H), 8.25 (m, 1H), 7.79 (s, 1H), 7.61 (m, 2H), 6.99 (s, 1H), 4.17 (d, 1H), 3.88 (m, 1H), 2.10 (m, 1H), 1.74 (s, 2H), 1.50 (m, 1H), 1.27 (m, 2H), 0.87 (m, 2H).

3-(2-Pyridyl)-5-(3-cyano-5-hexyloxyphenyl)-1,2,4-oxadiazole [0763]

B244 <img file="IS2564B_D0616.tif" /> [0764] A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (31 mg, 0.12 mmol), potassium carbonate (32 mg, 0.24 mmol) and hexyl bromide (25 μι., 0.18 mmol) in A/,A/-dimethylformamide (1 mL) was heated in a sealed vial at 90 ’C for 35 minutes. The reaction was cooled, diluted with dichloromethane, washed with water (3 x) and saturated brine, filtered and concentrated. Silica gel chromatography using 2% methanol in dichloromethane afforded 18 mg (39%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-hydroxyethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.91 (dd, 1H), 7.49 (dd, 1H). 7.38 (s, 1H), 4.09 (t, 2H), 1.84 (m, 2H), 1.49 (m, 2H), 1.37 (m, 4H), 0.93 (t, 3H).

3-(2-Pyrldyl)-5-(3-cyano-5-ldimethylaminolcarbonylphenyl)-1,2,4-oxadiazole [0765]

B245 <img file="IS2564B_D0617.tif" /> [0766] A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (39 mg, 0.15 mmol), potassium carbonate (32 mg, 0.30 mmol) and dimethylcarbamyl chloride (27 μΙ-, 0.30 mmol) in /V,/V-dimethylformamide (1 mL) was heated in a sealed vial at 140 'C for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3 x) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichlo-romethane 3.5:0.5:4 afforded 3 mg (29%) of 3-(2-pyridyl)-5-(3-cyano-5-(dimethylamino)carbonylphenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.85 (d, 1H), 8.40 (s, 1H), 8.29 (s, 1H), 8.22 (d, 1H), 7.89 (m, 1H), 7.73 (s, 1H), 7.48 (dd, 1H), 3.14 (s, 3H), 3.06 (s, 3H).

3-(5-Fluoropyrid-2-yl)-5-(3-cyano-5-ethylaminophenyl)-1,2,4-oxadiazole [0767]

Β246 <img file="IS2564B_D0620.tif" /> [0768] A mixture of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol) and ethyl iodide (98 p,L, 1.2 mmol) in A/,A/-dimethylformamide (1 mL) was heated in a sealed vial at 140 ‘C for 2 hours. The reaction was cooled, diluted with ethyl acetate, washed with water (3 x) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3: 1:4 afforded 6 mg (38%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-ethylaminophenyl)-1,2,4-oxadiazole: 1H NMR (CDCI3), δ (ppm): 8.69 (d, 1H), 8.26 (dd, 1H), 7.80 (s, 1H), 7.61 (m, 2H), 6.99 (s, 1H), 4.12 (br, s, 1H), 3.26 (q, 2H), 1.32 (t, 3H).

3-(5-Fluoropyrid-2-yl)-5-(3-cyano-5-diethylamlnophenyl)-1,2,4-oxadiazole [0769]

B247 <img file="IS2564B_D0621.tif" /> [0770] A mixture of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol) and ethyl iodide (98 μ!_, 1.2 mmol) in A/,/V-dimethylformamide (1 mL) was heated in a sealed vial at 140"C for 2 hours. The reaction was cooled, diluted with ethyl acetate, washed with water (3 x) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3: 1:4 aflorded 3 mg (20%) of 3-(5-fluoropyrid-2-yl)-5-(3-cyano-5-diethylaminophenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.69 (d, 1H), 8.27 (dd, 1H), 7.78 (s, 1H), 7.60 (m, 2H), 7.04 (s, 1H), 3.45 (q, 4H), 1.23 (t, 6H).

3-(5-Huoro-pyrid-2-yl)-5-[3-fluoro-5-(1 M-tetraazol-5-yl)-phenyl]-1,2,4-oxadiazole [0771]

B248 <img file="IS2564B_D0622.tif" />

To a mixture of 2 M trimethylaluminum (0.45 mL, 0.9 mmole, toluene) with toluene (1 mL) at 10 'C, trimethylsilyl azide (0.119mL, 0.9 mmole) was added, followed by the addition of 5-(3-cyano-5-fluorophenyl)-3-(5-fluoro-pyrid-2-yl)-1,2,4-

oxadiazole. The reaction was heated at 80 ‘C for 2 hours and then quenched with 6 N hydrochloride (2 mL) and solid was collected by filtration. The product was recrystallized with dimethylformamide to give 59 mg (36%) of 3-(5-fluoro-pyrid-2-yl)-5-[3-fluoro-5-(1 /7-tetraazol-5-yl)-phenyl]-1,2,4-oxadiazole. 1H-NMR (DMSO-d6), δ (ppm): 8.83 (d, 1H), 8.70 (s, 1H), 8.31 (m, 1H), 8.10 (m, 2H), 8.04 (dt, 1H).

5-[3-Fluoro-5-( 1 -methy I-1 H-tetraazol-5-y l)-pheny l]-3-(5-f luoro-py rid-2-y l)-1,2,4-oxadiazole [0772]

B249 <img file="IS2564B_D0626.tif" />

To a solution of 3-(5-fluoro-pyrid-2-yl)-5-[3-fluoro-5-(1 H-tetraazol-5-yl)-phenyl]-1,2,4-oxadiazole (30mg, 0.092 mmol) in tetrahydrofuran (1 mL), 0.5 M diazomethane (1 mL, 0.5 mmol, ether) was added. The reaction was quenched with water and extracted with dichloromethane. The product was purified by column chromatography with 20% ethyl acetate in hexanes to give 6.7 mg (21.4%) of 5-[3-fluoro-5-(1 -methyl-1 H-tetraazol-5-yl)-phenyl]-3-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole.1H-NMR (CDCl3), δ (ppm): 8.87 (s, 1H), 8.70 (d, 1H), 8.29 (dd, 1H), 8.10 (m, 2H), 7.62 (dt, 1H), 4.46 (s, 3H).

3-(5-Fluoro-2-pyridyl)-5-(3-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-5-fluorophenyl)-1,2,4-oxadiazole [0773]

B25O <img file="IS2564B_D0627.tif" /> ln a screw cap vial equipped with stir bar added 3-(5-Fluoro-2-pyrldyl)-5-(3-fluoro-5-(3-py ridy1)pheny l)-1,2,4-oxadiazole (100 mg, 0.30 mmol), acetonitrile (2 ml) and benzyl bromíde (0.05ml, 0.39 mmol). Stirred the resultíng mixture at 90'C for 4h. Cooled the mixture to room temperature, concentrated in-vacuo and tritu rated the residue with 30% ethyl acetate in hexanes to isolate the quarternary salt. The isolated solid was dissolved in methanol (2 ml) and treated with sodium borohydride (22.6 mg, 0.60 mmol) at 0’C. The bright yellow reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in-vacuo ard the residue was dissolved in dichloromethane (20 ml). The organic phase was sequentially washed with water (20 ml) and brine (20 ml), dried (sodium sulfate), 1 iltered and concentrated in-vacuo. The crude residue was purified on silica gel using 30% ethyl acetate in hexanes to isolate the title compound (10.1 mg, 8%) as yellow oil. 1H-NMR (CDCI3), δ (ppm): 8.69 (d, 1H), 8.26 (dd, 1H), 8.02 (s, 1H), 7.80 (dd, 1H), 7.60 (dt, 1H), 7.32 (m, 6H), 6.34 (m, 1H), 3.73 (s, 2H), 3.40 (bs, 2H), 2.63 (t, 2H), 2.39 (m, 2H).

3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-(1H-imldazol-4-yl)phenyl)-1,2,4-oxadiazoJe [0774]

B251 <img file="IS2564B_D0630.tif" /> [0775] A mixture of 3-Bromo-5-fluorobenzoic acid (0.41 g, 1.87 mmol) in dichloromethane (5 mL) was treated with oxalyl chloride (2.8 ml, 5.60 mmol, 2M dichloromethane) and 3 drops of N,N-dimethylformamide. The mixture was stirred 4 hours at room temperature. The solvent and excess reagent were removed in-vacuo. The residue was treated with 5-Fluoro-2-pyridylamidoxime (0.29 g, 1.87mmol) and triethylamine (0.78 ml, 5.60 mmol) in dichloromethane (5 m!_). The mixture was then heated in dimethylformamide (5 mL) at 120"C, overnight. Standard work up followed by purification on silica gel using 20% ethyl acetate in hexanes afforded 3-(5-Fluoro-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxa-diazole (150 mg).

[0776] To the solution of 4-Tributylstannyl-1 -trityl-1 H-imidazole (106 mg, 0.18 mmol) in tetrahydrofuran (5 ml) added 3-(5-Fluoro-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (50.0 mg, 0.15 mmol) and tetrakis(triphenyl-phoshine)palladium (0) (17.1 mg, 0.01 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 100’C under argon overnight. The reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was purified on silica gel using 30% ethyl acetate in hexanes to isolate 3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-d -trityl-1 H-imidazol-4-yl)phenyl)-1,2,4-oxadiazole (20.0 mg).

[0777] To a solution of 3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-(1-trityl-1 H-imidazol-4-yl)phenyl)-1,2,4-oxadiazole (20.0 mg, 0.04 mmol) in tetrahydrofuran (0.5 ml) added hydroch loric acid (0.14 ml, 2N aqueous). The resulting reaction mixture was heated at reflux for 45 min. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 ml), washed successively with sodium hydroxide (30 ml, 1N aqueous), water (30 ml) and brine (30 ml), dried (sodium sulfale), filtered and concentrated in-vacuo. The isolated residue was purified on silica gel using 5% methanol in dichloromethane to yield the title compound (1.7 mg) as abeige solid. 1H-NMR (CDCI3), δ (ppm): 9.64 (bs, 1H), 8.69 (d, 1H), 8.44 (s, 1H), 8.29 (dd, 1H), 7.81 (m, 3H), 7.61 (dt, 1H), 7.54 (s, 1H).

-(3-Cyanopheny l)-4-(5-f I uo ro-2-py r idy t)-1 H-imidazole [0778]

B252 <img file="IS2564B_D0631.tif" /> [0779] To asolution of 4-lodo-1-trityl-1H-imidazole (5.0 g, 11.6 mmol) in dichloromethane (100 ml) added Ethylmagnesium bromide (3M in diethyl ether) (4.6 ml, 13.9 mmol). Stirred the reaction under argon atmosphere at room temperature for 1 h. At this point added tributyltin chloride (4.1 ml, 13.9 mmol) to the reaction mixture and left the resulting mixture stirring at room temperature overnight. The reaction mixture was diluted with dichloromethane (100 ml), successively washed with saturated ammonium chloride (100 ml), water (100 ml) and brine (100 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo to yield 4-Tributylstannyl-1 -trityl-1 H-imidazole (2.35 g)

as a white waxy solid.

[0780] To the solution of 4-Tributylstannyl-1 -trityl-1 H-imidazole (1.00 g, 1.67 mmol) in toluene (10 mi) added 2-Chloro-5-fl uoropyridine (0.31 g, 2.38 mmol) and tetrakis(triphenylphoshine)palladium (0) (0.19 g, 0.17 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at reflux under argon overnight. The reaction mixture was cooled to room temperature and concentrated in-vacuo. The residue was purified on silica gel using 30% diethyl ether in hexanes to isolate 4-(5-Fluoro-2-pyridyl)-1 -trityl-1 H-imidazole (0.23 g) as a clear oil.

[0781 ] To a solution of 4-(5-Fluoro-2-pyridyl)-1 -trityl-1 H-imidazole (0,23 g, 0.56 mmol) in tetrahydrofuran (4 ml) added hydrochloric acid (2.4 ml, 2N aqueous). The resulting reaction mixture was heated at reflux for 45 min. The reaction mixture was cooled to room temperature and concentrated in-vacuo. The isolated residue was triturated with diethyl ether to yield 4-(5-Fluoro-2-pyridyl)imidazole (0.06 g) as the hydrochloride salt.

[0782] In a screw-cap vial, added 4-(5-Fluoro-2-pyridyl)imidazole (0.06 g, 0.30 mmol), 3-Fluorobenzonitrlle (0.04 ml, 0.36 mmol), potassium carbonate (0.21 g, 1.5 mmol) and dimethylformamide (1 ml). Stirred the resulting reaction mixture at 110'0 overnight. Cooled the reaction mixture to room temperature, diluted with chloroform (50 ml), sequentially washed with water (50 ml) and brine (50 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was triturated with 10% diethyl ether in hexanes to yield the title compound (45 mg) as a dirty yellowcolored solid.1H-NMR (CDCI3), δ (ppm): 8.43 (d, 1H), 8.04 (dd, 1H), 7.93 (dd, 2H), 7.70 (m,4H), 7.48 (dt, 1H).

3-(2-Pyridyl)-5-(3-(1H-imidazol-1-yl)-5-thiomethoxyphenyl)-1,2,4-oxadiazole [0783]

B253 <img file="IS2564B_D0634.tif" /> ln a screw cap vial equipped with stir bar added 3-(2-Pyridyl)-5-(3-fluoro-5-thiomethoxyphenyl)-1,2,4-oxadiazole (20 mg, 0.07 mmol), potassium carbonate (17.5 mg, 0.13 mmol), imidazole (4.3 mg, 0.06 mmol) and dimethylformamide (1 ml). Stirred the resulting mixture at 150Ό for 4 days. The reaction mixture was diluted with chloroform (30 ml) and washed with water (30 ml). The aqueous phase was re-extracted with chloroform (30 ml) and the combined organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purifíed on silica gel usíng 2% methanol in dichloromethane to isolate the free base of the desired compound. The free base was converted to it’s hydrochloride salt (4.5 mg), yellow solid. 1H-NMR (DMSO), δ (ppm): 9.64 (bs, 1H), 8.83 (d, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 8.13 (m, 4H), 7.86 (bs, 1H), 7.70 (dt, 1H).

3-(3-Cyano-5-(1 H-lmldazol-1 -y l)phenyl)-5-(2-pyridyl)-1,2,4-oxadiazole [0784]

Β254 <img file="IS2564B_D0636.tif" /> ln a screw cap vial equipped with stir bar added 3-(3-Cyano-5-fl uorophe nyl)-5-(2-Pyridy I)-1,2,4-oxadiazole (20 mg, 0.08 mmol), potassium carbonate (20.8 mg, 0.15 mmol), imidazole (7.7 mg, 0.11 mmol) and dimethylformamide (1 ml). Stirred the resulting mixture at 120'C for 2 h. The reaction mixture was diluted with chloroform (30 ml) and washed with water (30 ml). The aqueous phase was re-extracted with chloroform (30 ml) and the combined organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purified on silica gel using 1 % methanol in dichloromethane to isolate the free base of the desired compound as a white solid. The free base was converted to it’s hydrochloride salt (11.7 mg), white solid. 1H-NMR (DMSO), δ (ppm): 9.81 (s, 1H), 8.83 (m, 4H), 8.42 (m, 2H), 8.19 (dt, 1H), 7.92 (s, 1H), 7.80 (dd, 1H).

3-(2-Pyridyl)-5-(3-cyano-5-(1H-imidazol-1-yl)phenyl)-1,2,4-oxadiazole [0785]

B255 <img file="IS2564B_D0637.tif" /> ln a screw cap vial equipped with stir bar added 3-(2-Pyridyl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole (20 mg, 0.08 mmol), potassium carbonate (20.8 mg, 0.15 mmol), imidazole (7.7 mg, 0.11 mmol) and dimethylformamide (1 ml). Stirred the resulting mixture at 120Ό for 2 h. The reaction mixture was diluted with chloroform (30 ml) and washed with water (30 ml). The aqueous phase was re-extracted with chloroform (30 ml) and the combined organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The cruds residue was purified on silica gel using 2% methanol in dichloromethane to isolate the free base of the desired compound as a white solid. The free base was converted to it’s hydrochloride salt (10.0 mg), white solid. 1H-NMR (DMSO), δ (ppm): 9.85 (s, 1H), 8.86 (m, 4H), 8.49 (s, 1H), 8.23 (d, 1H), 8.13 (t, 1H), 7.95 (s, 1H), 7.73 (dd, 1H).

EXAMPLE 8

2-(3-lodophenyl)-4-(pyridin-2-yl)-1,3-thiazole [0786]

Β145 <img file="IS2564B_D0640.tif" /> [0787] A suspension of 3-iodobenzoic acid (4.04 g, 16.2 mmol) in dichloromethane (30 mL) was treated with 2M oxalyl chloride (16 mL, 32 mmol, hexane) followed by two drops of /V,/V-dimethylformamide and stirred at ambient temperature for 2 hours. After this time the solvent was removed in vacuo and the residue dissolved in tetrahydrofuran (30 ml). The solution was cooled to 0 'C and treated with 2M ammonia (20 mL, 40 mmol, methanol) and the mixture stirred for 30 minutes. The mixture was then filtered and the solvent removed in vacuo. Recrystallization of the residue from methanol afforded 3.5 g (87%) of 3-iodobenzamide, as a white solid.

[0788] A mixture of 3-iodobenzamide (500 mg, 2.0 mmol) in toluene (5 mL) was treated with Lawesson’s reagent (404 mg, 1 mmol) and the mixture heated at reflux for 16 hours. After cooling, silica gel chromatography afforded 260 mg (99% yield) of 3-iodothiobenzamide, as a yellow solid.

[0789] Asolution of 2-bromoacetylpyridine (400 mg, 2.0 mmol) in ethanol (5 mL) wastreated with 3-iodothiobenzamide (1,2g, 6 mmol) and the mixture heated at reflux for 16 hours. After cooling the mixture was concentrated in vacuo. Silica gel chromatography of the residue using a gradient of hexane to ethyl acetate afforded 302 mg (55 %) of 2-(3-iodopheny I)-

4-(pyridin-2-yl)-1,3-thiazole, as a white solid.

2-(3-Cyanophenyl)-4-(pyridin-2-yl)-1,3-thiazole [0790]

B146 <img file="IS2564B_D0641.tif" /> [0791] A mixture of 2-(3-iodophenyl)-4-(pyridin-2-yl)-1,3-thiazole (130 mg, 0.36 mmol), zinc cyanide (117 mg, 1.0 mmol) and Pd(PPh3)4 (10 mg, 0.009 mmol) in /V.N-dimethylformanriide (2 mL) was heated overnight at 80 "C. The mixture was cooled and diluted with toluene (5 mL). The organic solution was washed with 2N NH4OH (2 x 10 mL). The mixture was then extracted with ethyl acetate and the organic extract was washed with brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concantrated in vacuo. Silica gel chromatography afforded 28 mg (30 %) of 2-(3-cyanophenyl)-4-(pyridin-2-yl)-1 ,3-thiazole: 1H-NMR (CDCI3), δ ppm: 8.65 (d, 1H), 8.38 (s, 1H), 8.25 (m, 2H), 8.15 (s, 1H), 7.85 (m, 1H), 7.72 (m, 1H), 7.6 (t, 1H), 7.28 (m, 1H). GC/EI-MS gave m/z263 (M+)

2-(3-Bromo-5-iodophenyl)-4-(pyridin-2-yl)-1,3-oxazole [0792]

Β147 <img file="IS2564B_D0644.tif" /> [0793] Asolution of 2-bromoacetylpyridine(1.0g, 5mmol) intoluene (5 mL)wastreatedwith3-bromo-5-iodobenzamide (2.0 g, 6 mmol) and the mixture heated at reflux for 60 hours. The mixture was then cooled and the solvent was removed in vacuo. Silica gel chromatography using a gradient of hexane to ethyl acetate afforded 10 mg (1 %) of 2-(3-bromo-5-iodophenyl)-4-(pyridin-2-yl)-1,3-oxazole: 1H-NMR (CDCI3), δ ppm: 8.62 (d, 1H), 8.42 (m, 1H), 8.38 (s, 1H), 8.24 (m, 1H), 8.00 (t, 1H), 7.95 (d, 1H), 7.8 (m, 1H), 7.27 (m, 1H).

2-(2-Pyridyl)-5-(3-iodophenyl)-1,3,4-oxadiazole [0794]

B148 <img file="IS2564B_D0645.tif" /> [0795] A mixture of picolínic acid (0.47g, 3.82mmol), 3-iodobenzhydrazide (1.00 g, 3.82 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (0.80 g, 4.20 mmol), and 4-dimethylaminopyridine (0.05 g, 0.38 mmol) in dichloromethane (10 mL) was stirred ovemight at ambient temperature. After this time, the reaction mixture was diluted with dichloromethane (200 mL). The organic solution was washed sequentially with water (100 mL), saturated sodium bicarbonate (150 mL), water (100 mL) and brine (100 mL). Theorganic phase was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to afford 0.33 g of the intermediate diacyl hydrazide.

[0796] The intermediate diacyl hydrazide.(0.15g, 0.41 mmol) was then treated wlth phosphorus oxychloride (2 mL) and heated at 110'C for 40 minutes. After cooling the reaction was diluted with dichloromethane (1 Oml). The organic solution was washed sequentially with 1 Nsodium hydroxide (10 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography using 30% ethyl acetate in hexanes afforded 0.03 g (22%) of 2-(2-pyridyl)-5-(3-iodophenyl)-1,3,4-oxadiazole.

2-(2-Pyridyl)-5-(3-cyanophenyl)-1,3,4-oxadiazole [0797]

B149 <img file="IS2564B_D0646.tif" />

[0798] Under an argon atmosphere, a mixture of 2-(2-pyridyl)-5-(3-iodophenyl)-1,3,4-oxadiazole (0.03 g, 0.08 mmol), zinc cyanide (0.01 g, 0.12mmol), and Pd(PPh3)4 (9.1 mg, 0.01 mmol) in A/,N-dimethylformamide (2ml) was heated at 80 ‘C for 2.5 hours. After cooling the reaction mixture was diluted with ethyl acetate and sequentially washed with water (3 x 50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Recrystallization of the crude productfrom 5% ethyl acetate in hexanes, afforded 5.8 mg (30%) of 2-(2-pyridyl)-

5-(3-cyanophenyl)-1,3,4-oxadiazole.

2-(2-Pyridyl)-5-(3-cyanophenyl)-1,3,4-triazole [0799]

B150 <img file="IS2564B_D0650.tif" /> [0800] A solution of 3-cyanobenzoic acid (1.0 g, 6.80 mmol) in tetrahydrofuran (10 mL) at 0 'C was treated with triethylamine (2.84 mL, 20.4 mmol) and ethyl chloroformate (0.78 mL, 8.16 mmol) and stirred at 0’C for 1h. The resulting white precipitate was removed by filtration and the filtrate cooled back to 0’C. Hydrazine monohydrate (1.00 mL, 20.4 mmol) was added and the mixture stirred at ambient temperature for 3.5 hours. The reaction mixture was then concentrated to dryness in vacuo and the residue was dissolved in dlchloromethane (150 mL). The organic phase was sequentially washed with water (100 mL), 1 /Vsodium hydroxide (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, Silica gel chromatography using 3% methanol in dichloromethane afforded 0.32 g (30%) of 3-cyanobenzhydrazide.

[0801] A solution of 2-cyanopyridine (0.18 mL, 1.86 mmol) in methanol (5 mL) was treated with sodium metal (12.8 mg, 0.56 mmol) a stirred at ambient temperature for 1 hour. The reaction mixture was then treated with a solution of 3-cyanobenzbydrazide (0.30 g, 1.86 mmol) in methanol (5 mL) and heated at reflux for 3 hours. The reaction mixture was then concentrated iri vacuo. The resulting yellow solid was dissolved in toluene (2 mL) and heated overnight at 175 ’C. The reaction mixture was concentrated in vacuo. Silica gel chromatography using 2% methanol In dichloromethane afforded 0.12 g (26%) of 2-(2-pyridyl)-5-(3-cyanophenyl)-1,3,4-triazole.

4-(3-Cyanophenyl)-1 -(2-py ridyl)-1 H-imidazole [0802]

B151 <img file="IS2564B_D0651.tif" /> [0803] A mixture of 4-bromo-1-trityl-1H-imidazole (0.2g, 0.51mmol), 3-cyanophenylboronic acid (0.11 g, 0.77mmol), and Pd(PPh3)4 (0.06g, 0.05mmol) in a solution of ethylene glycol dimethyl ether (2 mL) and 2M sodium carbonate (2 mL) was heated in a sealed vial ovemight at 120"C. After cooling, the reaction mixture was diluted with dichloromethane (30 mL) and washed with water (50 mL) and brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography of the crude residue using 2% ethyl acetate in hexanes afforded 0.07 g (34%) 4-(3-cyanophenyl)-1-trityl-1 H-imidazole as white foam.

[0804] A solution of 4-(3-cyanophenyl)-1-trityl-1H-imidazote (0.07 g, 0.17 mmol) in tetrahydrofuran (1.36 mL) was treated with 2N hydrochloric acid (0.68 mL) and the resulting mixture was heated at reflux for 45 minutes. After cooling the reaction mixture was concentrated in vacuo and the residue dissolved in dichloromethane (20 mL). The organic

phase was successively washed with 1/Vsodium hydroxide (10 mL), waler (20 mL) and brine (20 mL). The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated in vacua. Silica gel chromatography of the residues using 3% methanol in dichloromethane afforded 0.02 g (72%) of 4-(3-cyanophenyl)imidazole as a white solid. [0805] A solution of 4-(3-cyanophenyl)imidazole (0.02 g, 0.11 mmol) in A/-methylpyrrolidinone (0.5 mL) was treated with 2-bromopyridine (1.05 mL, 11.1 mmol) and the reaction mixtqre heated overnight at 160’C. After cooling the reaction mixture was diluted with dichloromethane (40 mL) and the organic phase was successively washed with water (10 x 50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography using 30% ethyl acetate in hexanes afforded 2.5mg (9%) of 4-(3-cyanophenyl)-1 -(2-pyridyl)-

H-imidazole, as an off-white solid.

4-(2-Py ridyl)-1 -(3-cyanophenyl)-1 H-imidazole [0806]

ΒΊ52 <img file="IS2564B_D0654.tif" /> [0807] Under an argon atmosphere, a solution of 4-iodo-1 -trityl-1 H-imidazole (1.00 g, 2.29 mmol) in dichloromethane (10 mL) was treated with isopropylmagnesium bromide (2.75 mL of 1M, 2.75 mmol, in tetrahydrofuran) and stirred at ambient temperature for 1 hour. After this time, the reaction was treated with tributyltin chloride (0.81 mL, 2.98 mmol) and the resulting mixture stirred overnight at ambient temperature. The reaction mixture was then diluted with dichloromethane (50 mL) and successively washed with saturated ammonium chloride (50 mL), water (50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated ín vacuo to afford 1.37 g of crude 4-tributylstannyl-1 -trityl-1 H-imidazole.

[0808] The crude 4-tributylstannyl-1-trityl-1H-irnidazole (1.37g) in toluene (10 mL) was treated sequentially with 2-bromopyridine (0.33 mL, 3.43 mmol) and Pd(PPh3)4 (0.26 g, 0.23 mmol). The reaction mixture was heated at reflux under an argon atmosphere for 4 hours. After cooling, the reaction mixture was concentrated in vacuo. The residue was dissolved in chloroform (50 mL) and sequentially washed with aqueous saturated potassium f luoride (75 mL), water (75 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in-vacuoto afíord 0.69 g of crude 4-(2-pyridyl)-1 -trityl-1 H-imidazole.

[0809] A solution of the crude 4-(2-pyridyl)-1 -trityl-1 H-imidazole (0.69g) in tetrahydrofuran (14 mL) was treated with

N hydrochloric acid (7.2 mL) and heated at reflux for45 minutes. After cooling the reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (20 mL). The organic solution was successively washed with aqueous 1 Nsodium hydroxide (10 mL), water (20 mL) and brine (20 mL). The organic solution was then dried over anhydrous sodium sulfate, filtered, and concentrated ln-vacuo to afford 0.12 g of crude 4-(2-py ridy l)imidazole, as a sticky white solid.

[0810] To a flame dried, argon purged screw-cap vial, containing copper (I) triflate.benzene complex (0.01 g, 0.03 mmol), 1,10-phenanthroline (0.10 g, 0.54mmol),trans-dibenzylideneacetone (0.01 g, 0.03 mmol) and cesium carbonate (0.20g, 0.60mmol) was added a solution of 4-(2-pyridyl)imidazole (0.08 g, 0.54 mmol) and 3-iodobenzonitrile (0.19 g, 0.82 mmol) in ortho-xylene (2 mL). The resulting brownish black reaction mixture was heated overnight at 120'C. After cooling, the reaction mixture was diluted with dichloromethane (20 mL) and washed sequentially with saturated ammonium chloride (20 mL) and brine (20 mL). The organicphase was then dried with sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography of the crude residue using 1 % methanol (2 M in ammonia) in dichloromethane afforded 11 mg of 4-(2-pyridyl)-1 -(3-cyanophenyl)-1 H-imidazole, as an off-white solid.

EXAMPLE 9

3-(2-Pyridyl)-2-(3-cyanophenyl)-furan [0811]

Β256 <img file="IS2564B_D0656.tif" /> [0812] A solution of n-butyllithium (6.8 mL, 1,6M in hexanes, 11.0 mmol) was added in a dropwise mannerto a solution of tetrahydro-2-(2-propynyloxy)-2H-pyran (1.43 mL, 10.0 mmol) in THF (30 mL) at -78 ‘C and the reaction mixture was stirred at -50'C for 30 min prior to the dropwise addition of 3-cyanobenzaldehyde (1.44 mL, 11.0 mmol) at -78’C. The resulting mixture was stirred for 30 min at-78’0. After the reaction mixture was warmed to room temperature, it was quenched by pouring over ice. The crude product was partitioned between ethyl acetate (450 mL) and sodium hydrogen sulfate (1M, aqueous). The organic layer was washed sequentially with water and brine, and dried over sodium sulfate. Removal of the solvent in vacuoyielded the crude product (2.87 g, 100%).

[0813] A solution of this crude product in dichloromethane (5 mL) was added to a mechanically stirred heterogenous mixture of manganese dioxide (9.660 g, 4.42 mol) in dichloromethane (25 mL) at 0 'C and stirred at this temperature for 1 hour. The reaction mixture was f iltered through magnesium sulfate, and the solvent was removed in vacuo yielding the crude acetylenic ketone. Pyridinium-p-toluene sulfonate (220.0 mg) was added to a solution of the crude acetylenic ketone in ethanol (25 mL). The resulting mixture was stirred at 50 "C for 4 h. After allowing the mixture to cool to room temperature, it was diluted with ethyl acetate (80mL), washed sequentially with water (3x50mL) and brine (50mL), and dried over sodium sulfate. After removal of the solvent in vacuo, flash chromatography on silica gel (10%-20% ethyl acetate in hexanes) yielded the crude deprotected alcohol (793.1 mg, 30% over 2 steps).

[0814] To a stirred solution of the deprotected alcohol (793.1 mg, 4.28 mmol) and dichloromethane (3 mL), HBr in acetic acid (30%, 1.69 mL) was added dropwise at 0"C. The reaction mixture was stirred for 1.5 h at 0 ’C. The reaction mixture was diluted with ethyl acetate (50 mL) and then quenched by pouring it over ice, ether and sodium bicarbonate. The crude product was then taken into ethyl acetate (300mL), washed sequentially with water, sodium sulfite and brine, and dried over sodium sulfate. The solvent was removed in vacuo. Flash chromatography on silica gel (0-5% ethyl acetate in hexane) yielded 1.5098 g (100% yield) of 3-bromo-2-(3-cyanophenyl)-furan. The oil was taken on to the next step wittiout further p urification.

[0815] A solution of 3-bromo-2-(3-cyanophenyl)-furan (112 mg, 0.45 mmol), pyridyl 2-trimethyl stannane (240 mg, 0.996 mmol) and Pd(PPh3)4 (20 mg, 0.02 mmol) in anhydrous toluene (5 mL) was stirred at 110‘C for 3 days. After cooling to room temperature, the product was filtered through 1 g SPE tube and washed through with dichloromethane (50mL), and the solvent was removed in vacuo. Flash chromatography on silica gel (15-50% ethyl acetate in hexanes) yielded 32.4 mg (42%, GC/MS RT 9.209 min, 100%pure) of 3-(2-pyridyl)-2-(3-cyanophenyl)-furan. 1H-NMR (CDCI3), δ (ppm): 8.61 (d, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.92 (m, 1H), 7.71 (m, 1H), 7.53 (m, 3H), 7.27 (s, 1H), 7.19 (m, 1H).

3-(5-fluoro-2-pyridyl)-2-(3-cyanophenyl)-furan [0816]

B257 <img file="IS2564B_D0657.tif" /> [0817] In a similar fashion, a solution of 3-bromo-2-(3-cyanophenyl)-furan (110 mg, 0.44 mmol), 5-fluoro-pyridyl 2-trimethyl stannane (172 mg, 0.66 mmol) and Pd(PPh3)4 (20 mg, 0.02 mmol) in anhydrous toluene (5 mL) was stirred at

110'C for 3 days. After cooling to room temperature, the product was filtered through 1 g SPE tube and washed through with dichloromethane (50mL), and the solvent was removed in vacuo. Chromatography (5g silica SPE tube, 10% ethyl acetate in hexanes) yielded 29.3 mg (35%, GC/MS RT 9.029, 97%pure) of 3-(5-fluoro-2-pyridyl)-2-(3-cyanophenyl)-furan.1H-NMR (C DCI3), δ (ppm): 8.47 (d, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.92 (dd, 1H), 7.40-7.57 (m, 5H), 7.21 (s, 1H).

3-(5-chloro-2-pyridyl)-2-(3-cyanophenyl)-furan [0818]

B258 <img file="IS2564B_D0660.tif" /> [0819] In a similar fashion, a solutlon of 3-bromo-2-(3-cyanophenyl)-furan (98.04 mg, 0.395 mmol), 5-chloro-pyridyl 2-trimethyl stannane (170 mg, 0.35 mmol) and Pd(PPh3)4 (20 mg, 0.02 mmol) in anhydrous toluene (5 mL) was stirred at 110'C for 3 days. After cooling to room temperature, the product was f iltered through 1 g SPE tube and washed through with dichloromethane (50mL), and the solvent was removed in vacuo. Chromatography (5g silica SPE tube, 10% ethyl acetate in hexanes) yielded 5.9 mg (7.3%, GC/MS RT 9.876 min., 100%pure) of 3-(5-chloro-2-pyridyl)-2-(3-cyanophenyl)-furan. 1H-NMR (CDCIg), δ (ppm): 8.56 (d, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7,92 (d, 1H), 7.57 (dAB, 1H), 7.53 (dAB, 3H), 7.46 (d, 1H), 7.23 (S, 1H).

2-(2-Pyridyl)-5-(5-fluoro-3-(1 -imidazolyl)phenyl)-furan [0820]

B259 <img file="IS2564B_D0661.tif" /> [0821] Intermediates: 5-Bromo-2-(2-pyridyl)-furan [0822] N-Bromosuccinimide (187 mg, 1.05 mmol) and p-toluensulfonic acid (11 mg) were added to a solution of 2-pyridyl-2-furan (150 mg, 1.03 mmol) in benzene (12.5 ml_) under argon. The resulting solution was stirred at 80 "C for 2 h. After cooling to raom temperature, the product was washed sequentially with aqueous sodium sulfite (3 x 5mL), water (5 mL) and brine (5 mL), and dried by passing through an EX-TUBE (3 mL), usíng additional solvent (dlchlorometh-ane) to rinse. Chromatography (5g silica gel SPE tube, 70-100% dichloromethane in hexane) afforded 180 mg (69% based on 88% purity by GC/MS) of 5-bromo-2-(2-pyridyl)-furan as a light brown oil. 1-(3-bromo-5-fluoro-phenyl)· 1H-imidazole : 1-Bromo-3,5-difluorobenzene (1.78 mL, 15.5 mmol) was added to a solution of imidazole (1.07 g, 15.7 mmol) and potassium carbonate (2.2 g, 15.9 mmol) in DMF (20 mL). The resulting mixture was stirred at 110 ’C for 36 h. After cooling to room temperature, water (75 mL) was added and the product was extracted into ethyl acetate (3 x 150 mL). The organic layer was washed seq uentially with water (3 x 100 mL) and brine (100 mL) and dríed over sodíum sulfate. The solvent was removed ín vacuoto afford 2.35 g of the crude product, which was contaminated with 5-bromo-1,3-bis (1 -imidazolyl)benzene. A 320 mg portion ot the product was f urther purified by chromatography (5g silica gel SPE tube, 1-5% methanol in dichloromethane) afforded 193.6 mg (38%) of 1-(3-bromo-5-fluoro-phenyl)-1H-imidazole.

[0823] Title compound synthesis: Pd(PPh3)4 (10 mg, 0.009 mmol) was added to a solution of hexamethylditin (169 mg, 0.52 mmol) and 5-bromo-2-(2-pyridyl)-furan (90 mg, 88% purity, 0.36 mmol) in toulene (2 mL) under argon, The

resulting solution was stírred at 80 'C for 19 h. After cooling to room temperature, a second portion of Pd(PPh3)4 (10 mg, 0.009 mmol) and 1-(3-bromo-5-fluoro-phenyl)-1H-ímidazole (86 mg, 0.36 mmol) were added and the resulting solution was stirred at 110 'C for 36 h. After cooling to room temperature, the solvent was removed in vacuo. Chromatography (5g silica gel SPE tube, 0-3% methanol in 1:1 chloroform:ethy I acetate) afforded 72.3 mg (66%) of 2-(2-pyridy I)-

5-(5-fluoro-3-(1-imidazolyl)phenyl)-furan. 1H-NMR (CDCI3), δ (ppm): 8.63 (d, 1H), 7.93 (s, 1H), 7.78 (m, 2H), 7.57 (s, 1H), 7.45 (m, 1H), 7.35 (s, 1H), 7.23 (m, 3H), 7.03 (m, 1H), 6.91 (d, 1H).

3-(5-(2-pyridyl)-2-furyl)-benzonitrile [0824]

B260 <img file="IS2564B_D0664.tif" /> [0825] Similarly, Pd(PPh3)4 (22 mg, 0.019 mmol) was added to a solution of 3-(5-bromofuran-2-yl)-benzonitrile (35 mg, 0.14 mmol) and 2-tributylstannylpyridine (71 mg, 0.19 mmol) in toluene (2 mL) under argon. In a similar manner, benzylbis(triphenylphosphine)palladium(ll) chloride (10.5 mg, 0.014 mmol) was added to a solution of 3-(5-bromofuran-

2- yl)-benzonitrile (35 mg, 0.14 mmol) and 2-tributylstannylpyridine (75 mg, 0.20 mmol) in toluene (2 mL) under argon. Both solutions were stirred at 110 'C for 18 h. After cooling to room temperature, the mixtures were combined since TLC of both reactions proved to be identical. The solvent was removed in vacuo fram the combined product. Chromatography (5g silica gel SPE tube, dichloromethane) followed by triturating with 10% ethyl acetate in hexanes afforded 26.2 mg (38%) of 3-(5-(2-pyridyl)-2-furyl)-benzonitrile. 1H-NMR (CDCI3), δ (ppm): 8.63 (d, 1H), 8.05 (s, 1H), 7.96 (d, 1H), 7.77 (m, 3H), 7.54 (m, 2H), 7.20 (m, 1H), 6.89 (d, 1H).

3- (5-(5-choro-2-pyridyl)-2-furyl)-benzonitrile [0826]

B261 <img file="IS2564B_D0665.tif" /> [0827] Pd(PPh3)4 (5 mg, 0.004 mmol) was added to a solution of hexamethylditin (160 mg, 0.49 mmol) and 5-chloro-

2- bromopyridine (76 mg, 0.395 mmol) in toulene (1 mL) under argon. The resulting solution was stirred at 80 ’C for 16 h. After cooling to room temperature, a second portion of Pd(PPh3)4 (20 mg, 0.019 mmol) and 3-(5-bromofuran-2-yl)-benzonitrile (79 mg, 0.32 mmol) were added and the resulting solirtion was stirred at 110 'C for 14 h. After cooling to room temperature, the solvent was removed in vacuo. Chromatography (5g silica gel SPE tube, 25-50% chloroform in hexane to 2% ethyl acetate in 1:1 chloroform:hexane) followed by tritu rating with hexanes and purif ication by preparative TLC (90% dichloromethane in hexane) afforded 15.7 mg (17%) of 3-(5-(5-choro-2-pyridyl)-2-furyl)-benzonitrile (97.5% pure by GC/MS, contaminated with 2.5% dimer). 1H-NMR (CDCI3), δ (ppm): 8.55 (d, 1H), 8.03 (s, 1H), 7.94 (dd, 1H), 7.73 (s, 2H), 7.54 (m, 12), 7.16 (d, 1H), 6.88 (d, 1H).

3- (5-(5-cyano-2-pyridyl)-2-furyl)-benzonitrile [0828]

Β262 <img file="IS2564B_D0668.tif" /> [0829] In a similar fashion, Pd(PPh3)4 (10 mg, 0.009 mmol) was added to a solution of 2-trimethylstannyl-5-cyano-pyridine (22.7 mg, 0.085 mmol) and 3-(5-bromofuran-2-yl)-benzonitrile (31 mg, 0.125 mmol) in toluene (1 mL) under argon. The resulting solution was stirred at 110 ‘C for 15 h. After cooling to room temperature, the solvent was removed in vacuo. Chromatography (5g silica gel SPE tube, 50% chloroform in hexane to 20% ethyl acetate in 1:1 chloroform: hexane) followed by triturating with 50% dichloromethane in hexane afforded 5.3 mg (23%) of 3-(5-(5-cyano-2-pyridyl)-

2- fu ryl)-benzonitrile (91 % pure by GC/MS, contaminated by 9% dimer).1H-NMR (CDCI3), δ (ppm): 8.85 (s, 1H), 7.87-8.05 (m, 5H), 7.52-7.63 (m, 3H), 7.36 (d, 1H), 6.95 (d, 1H), dimer impurity caused peak intensity to increase in region 8.00, 7.92,7.49-7.57, plus 2 peaks additional peaks exactly overlapping with pure dimer @ δ (ppm): 6.87 (d) & 6.80 (d).

3- (5-(5-fluoro-2-pyridyl)-2-furyl)-benzonitrile [0830]

B263 <img file="IS2564B_D0669.tif" /> [0831] In asimilarfashion, Pd(PPh3)4 (25 mg, 0.022 mmol) was added to a solution of hexamethylditin (163 mg, 0.50 mmol) and 5-fluoro-2-brornopyridine (87 mg, 0.49 mmol) in toulene (4 mL) under argon. The resulting solution was stirred at 80 ’C for 15 h. After cooling to room temperature, a second portion of Pd(PPh3)4 (25 mg, 0.022 mmol) and 3-(5-bromofuran-2-yl)-benzonitrile (105 mg, 0.42 mmol) were added and the resulting solution was stirred at 110 ’C for 48 h. Aftercooling to room temperature, the mixture was diluted with dichloromethane and passed through a 1 g silica gel SPE tube using dichloromethane to elute the product. Flash chromatography (silica gel, 50-100% dichloromethane in hexane) afforded 48.4 mg (43%) of 3-(5-(5-fluoro-2-pyridyl)-2-furyl)-benzonitrile (pure by GC/MS). 1H-NMR (CDCI3), δ (ppm): 8.48 (d, 1H), 8.03 (s, 1H), 7.95 (m, 1H), 7.81 (m, 1H), 7.51 (m, 3H), 7.1 (d, 1H), 6.87 (d, 1H).

3-Fluoro-5-(5-(2-pyridyl)-2-furyl)-benzonitrile [0832]

B264 <img file="IS2564B_D0670.tif" /> [0833] 3-(5-Bromofuran-2-yl)-5-fluoro-benzonltrile intermediate: In a similar fashion, 3-(5-Bromofuran-2-yl)-5-fluoro-benzonitrile was prepared from N-bromosuccinimide (123 mg, 0.69 mmol), p-toluensulfonic acid (8 mg) and 3-furan-2-yl-benzonitrile (128 mg, 0.68 mmol) in benzene (10 mL) at 80 °C for 2.5 h. Standard workup and chromatography (5g silica gel SPE tube, 2.5-5% ethyl acetate in hexane) afforded 181 mg (86% based on 86% purity by GC/MS) of 3-(5-bromofuran-2-yl)-5-fluorobenzonitrile.

[0834] Pd(PPh3)4 (10 mg, 0.009 mmol) was added to a solution of 3-(5-bromofuran-2-yl)-5-fluoro-benzonitrile (180 mg, 86% purity, 0.59 mmol) and 2-trimethylstannylpyridine (193 mg, 0.80 mmol) in toluene (2.5 mL) under argon. The resulting solution was stirred at 110 "C for 48 h. After cooling to room temperature, the solvent was removed in vacuo. Flash chromatography (silica gel, 35-100% dichloromethane in hexane) afforded 67.7 mg (43%) of 3-fluoro-5-(5-(2-pyridyl)-2-furyl)-benzonitrile. 1H-NMR (CDCI3), δ (ppm): 8.64 (d, 1H), 7.76-7.83 (m, 3H), 7.66 (m, 1H), 7.24 (m, 2H), 7.19 (d, 1H), 6.92 (d, 1H).

Example 10

Oxazoles via Oxazolone intermediate

General Synthesis of 3-Cyano-5-substituted benzamides:

[0835] To a mixture of aqueous ammonium hydroxide and ethylacetate (ratio of 1: 5) at 0 ‘C was added slowly the benzoyl chloride (also prepared from the acid and oxalyl chloride). The mixture was stirred at room temperature for 15 minutes after which the ethylacetate layer was seperated. The aqueous layer was extracted vigorously with ethylacetate, the combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the product.

General Synthesis of the 2-Aryloxazolones:

[0836] To a solution of the benzamide in 1,2-dichloroethane was added oxalyl chloride (4-5 equivalents) and the mixture was heated to reflux for 18 h. The solvent was removed in vacuo and the crude acyl isocyanates dissolved in dry ether and diazomethane (prepared from N-methyl-N-nitrosourea and 50% aqueous KOH) in ether was added from a dropping funnel very slowly until the bubbling ceases. The mixture was then filtered to give the 2-aryloxazolone.

General Synthesis of the 2-Aryl-4-trifluoromethanesulphonyloxy-1,3-oxazole:

[0837] To a solution of the 2-Aryloxazolone and 2,6-lutidine (2 eqv.) in CH2CI2 at 0'C was added triflic anhydride (1.5 eqv.) dropwise over 15 minutes. The mixture was alíowed to come to room temperature and stirred overnight. The solvent was removed in vacuo and then purified by flash column chromatography on silica gel with CH2CI2 as eluant

General synthesis of 2-Aryl-4-pyrid-2-yl-1,3-oxazoles:

[0838] To a míxture of 2-Aryl-4-trifluoromethanesulphonyloxy-1,3-oxazole, LiCI, and 2-trimethylstannylpyridine in dioxane under argon was added Pd(PPh3)4 and the mixture was heated to 100"C overnight. After cooling to room tem-perature, the solvenl was removed in vacuo and the residue was purified by flash column chromatography on silica gel to afford the final product.

[0839] Thus, using the general method for synthesis of oxazoles via oxazolone intermediate the following compounds were obtained:

2-(3-cyanophenyl)-4-(5-Fluoropyrid-2-yl)-1,3-oxazole [0840]

B265 <img file="IS2564B_D0674.tif" /> [0841] 2-(3-cyanophenyl)-4-(5-Fluoropyrid-2-yl) -1,3-oxazole (an off-white solid, 180 mg, 72% yield); 1HNMR(CDCI3) □: 8.48 (d, 1H), 8.41 (s, 1H), 8.35 (m, 1H), 8.30 (m, 1H), 8.00 (dd, 1H), 7.75 (m, 1H), 7.62 (t, 1H), 7.52 (dt, 1H).

2-(3-cyano-5-fluorophenyl)-4-(5-Fluoropyrid-2-yl)-1,3-oxazole [0842]

B266 <img file="IS2564B_D0676.tif" /> [0843] 2-(3-cyano-5-fluorophenyl)-4-(5-Fluoropyrid-2-yl)-1,3-oxazote (a white solid, 65 mg, 55% yield); 1HNMR (CDCI3) 0: 8.48 (d, 1H), 8.31 (s, 1H), 8.23 (d, 1H), 8.07 (m, 1H), 8.00 (dd, 1H), 7.52 (m, 1H), 7.46 (m, 1H).

2-(3-cyano-5-fluoro phenyl)-4-(2-pyridyl)-1,3-oxazole [0844]

B267 <img file="IS2564B_D0677.tif" /> [0845] 2-(3-cyano-5-fluorophenyl)-4-(2-pyridyl) -1,3-oxazole (a white solid, 75 mg, 65% yield); 1HNMR(CDCI3) □:

8.62 (d, 1H), 8.38 (s, 1H), 8.23 (s, 1H), 8.07 (m, 1H), 8.00 (d, 1H), 7.80 (dt, 1H), 7.46 (m, 1H), 7.24 (m, 1H).

2-(5-allyloxy-3-cyanophenyl)-4-(5-Fluoropyrid-2-yl)-1,3-oxazole [0846]

B268 <img file="IS2564B_D0678.tif" /> [0847] 2-(5-ally loxy-3-cyanophenyl)-4-(5-Fluoropyrid-2-y I) -1,3-oxazole (an off white solid, 11 mg, 15% yield); 1HNMR (CDCI3) □: 8.47 (d, 1H), 8.28 (s, 1H), 7.99 (m, 2H), 7.86 (s, 1H), 7.51 (m, 1H), 7.24 (s, 1H), 6.05 (m, 1H), 5.40 (m, 2H),

4.65 (d, 2H).

2-(3-cyano-5-methoxyphenyl)-4-(pyrid-2-yl)-1,3-oxazole [0848]

B269 <img file="IS2564B_D0682.tif" /> [0849] 2-(3-cyanO’5-methoxyphenyl)-4-(pyrid-2-yl) -1,3-oxazole (a white solid, 600 mg, 65% yield); 1 HNMR(CDCI3) □: 8.62 (d, 1H), 8.34 (s, 1H), 7.92 (m, 2H), 7.84 (s, 1H), 7.78 (m, 1H), 7.78 (t, 1H), 7.25 (t, 1H), 3.94 (s, 3H).

2-(3-cyano-5-methoxyphenyl)-4-(5-Fluoropyrid-2-yl)-1,3-oxazole [0850]

B27O <img file="IS2564B_D0683.tif" /> [0851] 2-(3-cyano-5-methoxyphenyl)-4-(5-Fluoropyrid-2-yl) -1,3-oxazole (a white solid, 35 mg, 35% yield); 1HNMR (CDCI3) □: 8.47 (d, 1H), 8.29 (s,1 H), 8.02 (d,1H), 7.99 (s, 1H), 7.85 (s, 1H), 7.50 (m, 1H), 7.24 (s, 1H), 3.93 (s, 3H).

2-(3-cyano-5-n-propyloxyphenyl)-4-(5-Fluoropyrid-2-yl)-1,3-oxazole [0852]

B271 · <img file="IS2564B_D0684.tif" /> [0853] 2-(3-cyano-5-n-propyloxyphenyl)-4-(5-Fluoropyrid-2-yl) -1,3-oxazole (a white solid, 430 mg, 55% yield) 1HNMR (CDCI3) □: 8.46 (d, 1H), 8.27 (s, 1H), 8.00 (m,1 H), 7.95 (s, 1H), 7.83 (s, 1H), 7.50 (m, 1H), 7.23 (s, 1H), 4.02 (t, 3H),

1.85 (m, 1H), 1.07 (t, 3H).

2-(3-cyano-5-methoxyphenyl)-4-(pyrid-2-yl)-5-chloro-1,3-oxazole [0854]

B272 <img file="IS2564B_D0688.tif" />

N-chlorosuccinimide (32 mg, 0.24 mmol) and benzoyl peroxide (4.6 mg, 0.019 mmol) were added to a solution of 2-(3-cyano-5-methoxyphenyl)-4-(5-pyrid-2-yl)-1,3-oxazole (52 mg, 0.19mmol) in carbon tetrachloride (2 mL). The reaction was heated at 80 ’C for 4 hours. The solvent was removed in vacuo and the compound was purified by eluting through and 5g SPE tube with a gradient of 5-10% ethyl acetate in hexanes. 2-(3-cyano-5-methoxyphenyl)-4-(pyrid-2-yl)-5-chloro-1,3-oxazole was afforded as a white solid (30 mg, 51 % yield).

1HNMR(CDCI3) □: 8.75 (d, 1H), 8.03 (d, 1H), 7.97 (S, 1H), 7.82 (m, 2H), 7.29 (d, 2H), 3.93 (S, 3H).

EXAMPLE 11: Assay of Group I receptor antagonist activity [0855] Primary astrocyte cultures were prepared from 3-5 day old Sprague-Dawley rat pups using a modification of Miller (Miller et al, J. Neuroscience, 15(9): 6103-6109, 1995). In brief, primary cultures were plated on poly-L lysine coated flasks in Dulbecco's modlfied Eagle’s medium (DMEM) containing fetal calf serum (FCS). After 6 days, cell cultures were shaken over night at 280 rpm, then transferred to astrocyte-defined media (ADM) containing growth factors that up-regulate the expression of mGluR5 (Miller et al., 1995). For cuvette analysis, cultures were up-regulated with growth factors in flasks for 3-5 days, then harvested and prepared for measurement of [Ca2+]i mobil ization as previously described (Nemeth et al., 1998).

[0856] For FLIPR analysis, cells were seeded on poly-D lysine coated clear bottom 96-well plates with black sides and analysis of [Ca2+J, mobilization was performed 3 days following the growth factor up-regulation. Cell cultures in the 96-well plates were loaded with a 4 μΜ solution of acetoxymethyl ester form of the fluorescent calcium indicator fluo-3 (MolecularProbes, Eugene, Oregon) in 0.01 % pluronic. All assays were performed ina buffercontaining 127 mM NaCI, 5 mM KCI, 2 mM MgCI2, 0.7 mM NaH2PO4, 2 mM CaCI2, 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).

[0857] 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 180 μι. of bufíer present in each well of the cell plate. A 20 μΙ. addition from the antagonist plate was followed by a 50 μ!_ addítíon from the agonist plate. After each addition the fluorescence signal was sampled 50 times at 1 second intervals followed by 3 samples at 5 second intervals. Responses were measured as the peak height of the response within the sample period.

[0858] EC50/IC50 determinations were made from data obtained from 8 point concentration response curves (CRC) performed in duplicate. Agonist CRC were generated by scaling all responses to the maximal response observed for the plate. Antagonist block of the agonist challenge was normalized to the average response of the agonist challenge in 14 control wells on the same plate. Compounds of the present invention antagonized mGluR5 as determined by their IC50 values which fell into the range of 11 - 9140 nM.

Contents13

95 members in 31 offices

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Document	Office	Kind	Date
26984701	United States of America	P	2001-02-21
26984701	United States of America	P	2001-02-21
0204689	United States of America	W	2002-02-19
0204689	United States of America	W	2002-02-19
60269847	–	–	–
US20010269847P	–	–	–
WO2002US04689	–	–	–

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CA2381975A1	Canada	A1	2001-02-22
WO0112627A1	World Intellectual Property Organization (WIPO)	A1	2001-02-22
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Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists

Abstract

Term

EXAMPLES

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Priority claims7

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Classification