MX2010013399A - Novel 1,2,4 oxadiazole compounds and methods of use thereof. - Google Patents

Abstract

The invention relates to 1,2,4 oxadiazole compounds and analogs thereof, represented by formula (II), and compositions and methods of use thereof.

Description

UEVOS COMPUESTOS DE 1.2.4-OXADIAZOL AND ITS ME OF USE mpo of the invention The invention relates to novel compounds and compounds comprising oxadiazole derivatives, and methods thereof of the invention.

The endogenous cholinergic neurotransmitter, acetylcholine, has its biological effect via two types of acetylcholine muscarinic receptor receptors (mAChR) and acetylcholine receptors (nAChR). The nAChRs are sheric of subunits that surround a pore ce quea the flow of ions of Na +, K + and Ca2 +. At least 16 subunits, ie a2-a10, ß1-ß10,?, D and e, denoted in neuronal tissues. These subunits for a great variety of homomeric combinations and het determine the different subti os of the rece tor. For the highs in areas involved with learning and m gain a key role in the neurotransmission of different reg ions. The reduced cholinergic activity and disregu NN Rs have been correlated with conditions of cognitive deficits, progressive dementia, and consequently, these NNs are involved in a physiological and pathophysiological corrections related to cognitive, learning and memory, recognition, Waiting and analgesia (reviewed in Gopalakrishnan, Ion channels - Ligand-gated, Compinal Chemistry II, Edited by Triggle, D., and Collaboration Reference Works, Elsevier, Unit 2.22, pp. 877-918, Nicotinic neuronal receptors, neurotransmitters of neuronal nicotinic acetaminophen a4ß2 have been responsible for pain and several diseases of the central nervous system Antisense interference of the non-anemic subunit of the medulla oblongata, particularly in Cchiaro G, et al., J Pharmacol Exp Ther. 313 5). However, the a4ß2 stimulation of the GABAergic and glycerinergic tr ibitoria in the spinal cord contribute (Rashid H, et al., Pain 125 6).

Central a3 * nAChRs can contribute to otinics (Khan IM, et al., J NeurocytoL 33 4), but a3β4 ligands are of little interest in autonomic side effects. In fact, since the neural nicotinic receptor a3 * (NNR) has been avoided, emetic liability limitation of computational doses has been attributed to the activation of a3 that ChRs. The nAChRs a3 * are expressed in the Iberian system as well as in other components of the Riférico and central systems. The postrema area and nucleus of the ferid tract as Compound A in this application) was effective. A number of nociception rodent models include acute, chemogenic, neuropathic, and visceral mycosis (Deckers, Expert Opinion on Investigational Drugs, 0, 2001) . The available data suggest that the linkage activity for the a4ß2 nAChRs with respect to the efiβ4 is preferred for adverse event profiles b ría, the therapeutic index could be extended by (a) ivity of a3β4 or (b) increase the effectiveness of regimen the activity of a3ß4. The latter can reach a selective positive allosteric dimer a4ß2 (PA) combined with the exogenous a4ß2 agonist. Positive mo- ticers can reinforce the improved effects and potency of agonists. As a result, a selective positive allosteric dimer of a4ß2 can ectively affect the nAhRs a4ß2 subtypes of the nA hR. s as a3ß4 (for example, see WO 2006/1 14400, pu bli November 2006).

Pain is an untreated medical need, and the treatments available for such indications are scarce, making continuous efforts to treat nAChR nyst pain, robust efficacy in pain may limit the amount of side effects associated with its use, not two or differentiation. In light of the importance of the pain limitations in their treatment, it would be beneficial to identify all of them to treat such disorders, particularly one of the adverse ganglionic effects such as in the trointestinal (eg, vomiting). It would be particularly useful to describe compounds and compositions which offer an advantageous therapeutic window for nicotinic agonists (nAG), and improved efficacy with ligands for the treatment of other diseases of the nervous system is also desirable. wherein Ar1 and Ar2 are independently substituted aryl or heteroaryl, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to pharmaceutical compositions comprising compounds of the invention positions can be administered according to an invention, usually as part of a regimen to the treatment or prevention of conditions and involving the activity of nACh R, and more positive allosteric modulator characteristic of nACh R a4ß2.

Yet another aspect of the invention relates to modulating the positive allosteric modulating activity d 2. The method is useful for treating, preventing or treating and conditions and disorders related to the positive serum activity of nACh R a4ß2, particularly in mammal.

A method of this invention provides for the treatment of diseases or positions for the treatment of individuals with conditions mediated with nAChR, and particularly for CNS disorders, which involve a combination of otinic with an a4ß2 positive allosteric modulator. .

In one embodiment, the invention relates to m positions comprising (i) a ligand of the acetylcholine receptor; and (ii) a positive allosteric modulator selec subtype of the nicotinic acetylcholine receptor, in addition to a pharmaceutically acceptable excipient.

See Description of Drawings Figures 1A and 1B depict the nicotinic receptor responses of the representative cetilcholine, tidin-2-ylmethoxy] -2-chloropyridine (Compound A) in the absence of an a4ß2 positive allosteric modulator of the nicotinic acetylcholine eptor, 3- (3- (pyridin-3-yl) -1, 2,4-o) benzonitrile (PAM, Compound 1), in subtypes of the oticic acetylcholine a4 2 or a3 4 human ex resad. Again, the data demonstrate a shift toward the potency (EC50 value) of the nAChR agonist in nACh or not in a3ß4.

Figures 3A and 3B graphically represent the positive a4ß2 allosteric e dulator by enhancing the partial effect of nAChR, such as 2-methyl rolidinylmethoxy) pyridine (Compound C, also known as T-089; Reuter, LE, et al., CNS Drug Rev 7-182, 2004). The Compound alone does not evokes a response or that when co-applied with the PAM, 3- (3- (pyridin-3-diazol-5-yl) benzonitrile (Compound 1), evoked responses to the aH2 nAChRs (Figure 3A), but not in nAChRs a3). Compound C is a representative of other nicotinic reils.

Figures 4A and 4B graphically represent the positive allosteric effector a4ß2 by improving the effect - - - - ivation of a4ß2 nAChRs by several acetic acid otinic ligands in the presence and absence of a P 3- (pyridin-3-yl) -1, 2,4-oxadiazol-5-yl) benzonitrile (Compuest eral, these nicotinic ligands are found to increase nAChRs a4ß2 in the presence of PAM a4ß2 (Compu Figure 6A graphically depicts the effect of a P 3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzonitrile (Compound efficiency by 5 - [(2R) -azetidin-2-ylmethoxy] ] -2-clo mpuesto A) in reversing neuropathic pain.

Figure 6B graphically depicts the effect of PAM a4ß2, 3- (3- (pyridin-3-yl) -1, 2,4-oxadiazol-5-yl) bemote 1), improving the efficacy of neuropathic pain R) -azetidin -2-ylmethoxy] -2-chloropyridine (Compound A).

The presence of Compound A (1 nmol / kg) demonstrates a cyclin effect with several doses of MAP a4ß2 (Compound 1).

Figure 7A shows rheostatic dose-dependent effects of 5- 2R-azetidin-2-ylmethoxy -2-clo mpuesto A) alone, PAM a4ß2, 3- (3- (pyridin-3-yl) -1, 2,4-oxa-enzonitrile (Compound 1), alone and a combination of C 3.5 pmol / kg) with several doses of Compound A. A P 1) only does not cause vomiting, and does not change the dose setting of Compound A in the ferret model of the Figure 8A and 8B show the analysis of the level in pl delos of neuropathic pain and vomiting. The effectiveness of the C s displaced to the left as shown in the f or does not change in effect on the vomit as shown 8B. The maximum efficacy of Compound A can be neuropathic pain without incidence of vomiting, in the presence of 2, 3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzonitrile (C The data show that the therapeutic window of nAChR a4ß2 is wider in the presence of P Figure 9 shows the efficacy of a p D D agonist, in the presence and absence of a4β2 PAM, 3- (3- (1-24-oxadiazol-5-yl benzonitrile Compound 1. In the radioligand [3H] -3- ( 5- (pyridin-3-yl) -1, 2,4-oxa-enzonitrile ([3 H] -POB, nM).

Detailed Description of the Invention Inition of the Terms For a variable that occurs more than once in the constituent or the compound of the invention or any formulas herein, its definition in each occurrence dependent on its definition in each other occurrence of substituent binations are allowed only binations give rise to compounds stable As it is used through this specification, the appended indications, the designation Cx-Cy, where x integers from 1 to 10 refers to an interval of a bonus in the hydrocarbon portion of the group which is m example, the designation "haloalkyl" Ci-CQ "refers to a halogen added to the parent molecular moiety to pentyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-eptenyl, 2-methyl-1-heptenyl, and 3-decenyl .

The term "alkoxy", as used herein, if alkyl, as defined herein, is attached to the parent molecule through an oxygen atom. Alkoxy representatives include, but are not limited to, X, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hex The term "alkoxyalkoxy", as used in the invention, means an alkoxy group, as defined herein, to a parent molecular moiety through another alkoxy group, ine. Representative examples of al, but are not limited to, tert-butoxymethoxy, 2-ethoxytoxyethoxy, and methoxymethoxy.

The term "alkoxyalkoxyalkyl", as used in the definition of an alkoxyalkoxy group, as defined by the parent molecular moiety through an alkyloxyethyl, and methoxymethyl.

The term "alkoxycarbonyl", as used in the invention, refers to an alkoxy group, as defined herein, to a parent molecular moiety through a carbonyl group, ine. Examples of oxycarbonyl include, but are not limited to, methoxycarbonyl, and tert-butoxycarbonyl.

The term "alkoxycarbonylalkyl", as used herein, means an alkoxycarbonyl group, as defined, appended to the parent molecular moiety through the group, as defined herein. Alkoxycarbonylalkyl reagents include, but are not 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and oxycarbonylethyl.

The term "alkoxycarbonylamino", as used herein, means an alkoxycarbonyl group, as defined by the appended itan a, t-butoxycarbonylaminomethyl and methoxycarbonylamino The term "alkoxysulfonyl", as used in the alkoxy group, as defined herein, refers to a molecular moiety through a sulphonyl group, as defined herein. Exemplary oxysulfonyl examples include, but are not limited to, methoxy xylsulfonyl and propoxysulfonyl.

The term "alkalyl", as used herein, follows straight or branched chaincarbon containing carbon dioxide. Representative examples are, but are not limited to, methyl, ethyl, n-propyl, iso-p-yl, sec-butyl, iso-butyl, tere-butyl, n-pentyl, pentyl, n-hexyl, 3- methylhexyl, 2,2-dimethylpentyl ethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term "alkylamino", as used in the definition of an alkyl group, as defined herein, a The term "alkylcarbonylalkyl", as used herein, means a alkylcarbonyl group, as defined, appended to the parent molecular moiety through uilo, as defined herein. Examples of alkylcarbonylalkyl include, but are not limited to, 2-o-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.

The term "alkylcarbonyloxy," as used in the embodiment, is an alkylcarbonyl group, as defined in the moiety to the molecular moiety through a gene. Representative examples of alkylcarbonyloxy or are not limited to acetyloxy, ethylcarbonyloxy, and tert-butylcar The term "alkylcarbonyloxylalkyl", as used, means an alkylcarbonyloxy group, as defined, appended to the parent molecular moiety through it.

The term "alkylene", as used herein, "ru" or "divalent" derived from a hydrocarbon n They are, but are not limited to, methylsulfinyl and ethylsulfinyl.

The term "alkylsulfinylalkyl", as used in the definition of an alkylsulfinyl group, as defined by the moiety to the parent molecular moiety through a group is defined herein. Examples represented by Isulfi or lalkyl include, but are not limited to, methylsulfin sulfinylmethyl.

The term "alkylsulfonyl", as used in the definition of an alkyl group, as defined herein, is a parent molecular moiety through a sulfonyl group, ine. Examples of repulsylsulfonyl include, but are not limited to, methylsulphonyl.

The term "alkylsulfonylalkyl", as used in the definition of an alkylsulfonyl group, as defined in the parent molecular moiety through an alkyl or is defined in the re n.

It designates an alkyl group, as defined herein, to a parent molecular moiety through an alkyl moiety, as defined herein. Representative examples of uthioalkyl include, but are not limited to, methylthiom ilthio) ethyl.

The term "alkynyl", as used herein, is a straight or branched chain hydrocarbon group containing 10 carbon atoms and containing at least one carbon-carbon chain. Representative examples of, but not limited to, acetylenyl, 1-propynyl, 2-pro inyl, 2-pentynyl, and 1-butynyl.

The term "amino", as used in the present, if po -NH2.

The term "aminoalkyl", as used in the at least one amino group, as defined, is appended to the parent molecular moiety through incarbonyl, methylaminocarbonyl, dimethylaminocarbmethylaminocarbonyl.

The term "aryl," as used herein, ilo, a bicyclic aryl or a tricyclic aryl. The bi-tyl aryl, a phenyl fused to a cycloalkyl, or a phenyl-cycloalkenyl phenyl. Representative examples of the aryl are, but are not limited to, dihydroindenyl, indenyl idronaphthalenyl, and tetrahydronaphthalenyl. The aryl tric racene or phenanthrene, or a bicyclic aryl fused loalkyl, or a bicyclic aryl fused to a cycloalkyl or bicyclic fused to a phenyl. Examples of the tricyclic aryl ring include, but are not limited to, idroanthracenyl, fluorenyl, and tetrahydrophenanthrenyl.

The aryl groups of this invention can be substituted 3, 4 or 5 substituents independently selected uenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, aleo oxycarbonyl alkoxycarbon Ñai ui lo l uil ecular mother through an alkoxy group, as defined. Representative examples of arylalkoxy include limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, and 5-phenylpentyl The term "arylalkyl", as used herein, aryl group, as defined herein, appended to ecular mother through an alkyl group, as it is defined. Representative examples of arylalkyl are limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naft-2 The term "aryloxy", as used herein, if po aryl, as defined herein, attached to the ecular mother through an oxygen atom. The aryloxy representatives include, but are not limited to, thioxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy, ethoxyphenoxy.

The term "carbonyl", as used herein, group -C (O).

The term "carboxy" as used in the resent or is used herein, are transitory terms, l synonymous with "including", "containing", or "carac", are inclusive or extendable and do not exclude additional, unrecorded method elements.

The term "concurrent administration" refers to the addition of a4β2 receptor even patient, which has been prescribed) at least one of an a4β2 PAM, in or operated so that the patient's symptoms can or may be sig nificant. the simultaneous administration of a ligand PA of the a4ß2 receptor, or the administration of drugs at different times, but appropriate adjustment of a dosing schedule that is suitable for a person skilled in the art, who treats various pain states.

The term "cyano", as used in the present, if po -CN.

The term "cyanoal uilo" as used in the removal of two hydrogens. Examples of cycloalkenyl include, but are not limited to, 2-cyclohexe lohexen-1-yl, 2,4-cyclohexadiene-1-ylo and 3-cyclopenten-1-yl The term "cycloalkyl", as used in A monocyclic, bicyclic, or tricyclic monocyclic ring system is exemplified by saturated cyclic rocarbide containing from 3 to 8 binary. Examples of monocyclic ring systems lopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl. The bicyclic ring systems are exemplified as a monocyclic ring-bridge in which two adjacent or non-adjacent ring bicycles are monocyclic by an alkylene bridge of between one and three additional bonus. Representative examples of sis 11 or bicyclic include, but are not limited to, bicyclo [3.1 .1 iclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2. iclo 3.3.1 nonano bicyclo 4.2.1 nonane. The systems which consists of alkenyl, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, boxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, roxyalkyl, mercapto, oxo, -NZ1Z2, and ( NZ3Z4) carbonyl.

The term "cycloalkylalkyl", as used in the cycloalkyl group, as defined in the moiety to the parent molecular moiety through a group or is defined herein. Examples represented by alkylalkyl include, but are not limited to, cyclopropyl lobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cyclohexyl.

The term "dialkylamino," as used in the pre ire to two independent alkyl groups, as defined, is appended to the parent molecular moiety through group, as defined herein. Dialkylamino esentatives include, but do not sit, meaning a g ru po -S02N = C H-N (alkyl) 2.

The term "formyl", as used herein, if po -C (0) H.

The term "formylalkyl", as used in the form of a formyl group, as defined herein, is a parent molecular moiety through an alkyl moiety, hereby incorporated by reference. Representative examples of for, but are not limited to, formylmethyl and 2-formylethyl.

The term "halo" or "halogen", as used in the nifica -Cl, -Br, -I or -F.

The term "haloalkoxy", as used herein, is the least halogen, as defined herein, by a parent molecular assembly through an alkoxy group, as herein. Representative examples of haloalkoxy or are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoro tafluoroethoxy "" Bonilo, as defined in this. Representative haloalkyl or ilcarbonyl include, but not loromethylcarbonyl and trifluoromethylcarbonyl.

The term "heteroaryl", as used in the monocyclic heteroaryl or a monocyclic bicycloaromethyl heteroaryl, is a ring of 5 or 6 members that at least one heteroatom selected from the group which is cogen, oxygen and sulfur. The 5-membered ring with the links and the 6-membered ring contains three aces. The 5- or 6-membered heteroaryl is present in a molecular connection through any C-atom or substitutable nitrogen atom, provided that the valence is maintained in representative examples of monocyclic heteroaryl or is not limited to , furyl, imidazolyl, isoxazolyl, is diazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, zolyl, aryl, tetrazolyl, bicyclic eroaryl, provided that the opiate is maintained. Representative examples of heteroaryl include, but are not limited to, azaindolyl, benzim zo [d] [1,3] dioxolyl, benzofuranyl, benzoxa zo [d] imidazolyl, benzo [d] imidazl-2 (3H) -thione, benzo zoisothiazole, benzooxazole, benzoo zo [d] [1, 2, 3] thiadiazolyl, 1,3-benzothiazolyl, benz zo [d] [1, 2, 3] triazolyl, cinnolinyl, uorobenzo [d] [1,3] dioxolyl, furopyridine, imidazopyridinyl, azolyl, isobenzofuran, isoindolyl, isoquinolinyl, na zolopyridine, pyrazolopyrimidinyl, pyrro pyridinyl, q noxalinyl, thienopyridinyl, and [1, 2,4] triazolopyridinyl.

The heteroaryl groups of the invention are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of alkenyl oxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbo oxysulfonyl, and the like.

"S" means a monocyclic heterocycle, a hcyclic heterocycle or a tricyclic heterocycle. The heterocyclic monocyclic 11 or 3, 4, 5, 6 or 7 members containing by the eroatomo selected independently of the system of O, N, and S. The ring of 3 or 4 members c eroátomo selected from the group consisting of O , N 11 or 5 members contains zero or one or two dibs in or three heteroatoms selected from the group that is S. The 6 or 7 member ring contains zero, one odds and one, two or three heteroatoms selected from the g O, N and S. The monocyclic heterocycle is a mother molecular link through any atom of C any nitrogen atom contained within the nocyclic h. Representative examples of nocyclic h include, but are not limited to, azetidinyl, ridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-d-dimethylamino imidazolinyl imi. 5 or 6 members fused to a cycloalkyl, or a 5- or 6-membered nocyclic compound fused to a 5 or 6 membered monocyclic cycloalkene cycloalkyl fused monocyclic erocycle. The bicyclic heterocycle is a mother molecular link through any atom of any nitrogen atom contained within the hcyclic. Representative examples of heterocycle include, but are not limited to, 1, 3-benzodioxolyl, 1,3-benz-dihydro-1,4-benzodioxinyl, benzodioxolyl, 2, 3-zofuranyl, 2,3-dihydro-1 - benzothienyl, chromenyl, and rahydroquinolinyl. The tricyclic heterocycle is a halogen fused to a phenyl, or a bicyclic heterocycle cycloalkyl, or a bicyclic heterocycle fused loalkenyl, or a bicyclic heterocycle fused to a noncyclic h. The tricyclic heterocycle is connected to the lecular mother through any carbon atom or mo of nitro n n n uylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxt, urthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydro or, mercapto, oxo, -NZ1Z2 and (NZ3Z4) carbonyl.

The term "hydroxy", as used herein, if po -OH.

The term "hydroxyalkyl", as used in the definition of at least one hydroxy group, as defined, is attached to the parent molecular moiety through alkyl, as defined herein. Examples of hydroxyalkyl include, but are not, methyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxy-tyl-4-hydroxyheptyl.

The term "hydroxy protecting group" or "group protects a substituent which protects undesirable hydroxyl groups during synthetic post-protective hydroxy procedures generally used in TW .M. Wuts, Protective Groups in Organic Synthesis, 3 n Wiley &Sons , New York (1999).

The term "lower alkenyl", as used in a subset of alkenyl, as defined in the foregoing, refers to an alkenyl group containing from 2 to 4 bonus. Examples of lower alkenyl are ethenyl, pro enyl.

The term "lower alkoxy," as used in the pre-subset of alkoxy, as defined herein, and lower alkyl group, as defined herein, is a molecular parent through an oxygen atom, ine in the present. Representative examples include, but are not limited to, methoxy, ethoxy, pr-poxy, butoxy, and tert-butoxy.

The term "lower alkyl", as used in the pre-addition of the uyl as defined in the resent lower haloalkoxy include, but are not limited to, trifluoromomethoxy, dichloromethoxy, fluoromethoxy, and pentafluoroethoxy The term "lower haloalkyl", as used in the a haloalkyl subset, as defined in the foregoing, is a haloalkyl chain group Linear or ramifi has 1 to 4 carbon atoms. Examples of lower haloalkyl include, but are not limited to, trifluoromethyl, dichloromethyl, fluoromethyl, and pentafluoroethyl.

The term "mammal" includes humans and animals, os, dogs, pigs, cattle, horses, and the like.

The term "methylenedioxy," as used in the group, denotes an -OCH20 group in which the oxyndioxy atoms are attached to the parent molecular moiety through adjacent carbon atoms.

The term "nitrogen protecting group", as used, means those groups desired to protect against undesirable reactions during friction.

The term "NZ1Z2," as used in the present, sig, Z1 and Z2, which are attached to the dre portion through a nitrogen atom, Z1 and Z2 are independently independently of the group which, with hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, alkyl In certain cases within the invention, Z 1 and Z 2 to the nitrogen atom to which they are attached form an erocyclic.Representative examples of NZiZ 2 are limited to, amino, methylamino, acetylamino, acetyl ilamino, benzylamino, azetidinyl, pyrrolidinyl and piperidinyl The term "NZ3Z4", as used in the present, sig, Z3 and Z4, which are attached to the dre portion through a nitrogen atom. independently of the group that with rheogen, alkyl, aryl and arylalkyl Examples of NZ3Z4 include, but are not limited to, amino, myally benzylamino. primary carbon atoms and dialkyl amines of secondary carbon. In the case of the secondary amines, it can also be in the form of a higher heterocycle containing a nitrogen atom. Preferred are derivatives of ammonia, primary alkyl amides of carbon and secondary dialkyl amides of carbon. The amides of the compounds of the formula can be prepared according to conventional pharmaceutically acceptable methods, they can be prepared with primary amine groups or by reacting the compound containing a alkyl anhydride, aryl anhydride, aroyl urea halide. . In the case of compounds containing carboxylic acid, the pharmaceutically acceptable esters of the compounds containing the boxyl groups by the reaction of the compound with a tilamine base have a dehydrating agent such as carbodiumaceutically acceptable.

The term "pharmacologically acceptable prodrug of drug" as used herein, represents drugs of the compounds of the invention that are, within the judgment of the medical judgment, suitable for touching the tissues of humans and animals, undue infirmity, irritation. , allergic response, and similar portion with a reasonable benefit / risk ratio, and the desired use. The prodrugs of the invention rapidly form a living compound in vivo, for example, by hydrolysis in a careful discussion in Higuchi T., and co-drugs as Novel Delivery Systems, V. 14 of th posium Series, and in Edward B. Roche, ed., Bior rriers in Drug Design, American Pharmaceutical Asso rgamon Press (1987).

The term "pharmaceutically acetable carrier" Acisternal, oral, rectal, intravenous, or intraperitoneal.

The term "sulfinyl", as used herein, -S (O) - group.

The term "sulfonamide", as used in the amino, amino alkylamino, or dialkyl amino group, herein abbreviated to the molecular moiety, refers to the sulfonyl group, as defined herein. The reentatives include, but are not limited to, amino tilaminosulfonyl, and diethylaminosulfonyl.

The term "sulfonyl", as used herein, group -S02-.

The term "tautomer", as used herein, changes the proton of an atom from one compound to another or compound where two or more compounds are in an equilibrium with each other.

The term "radiomercable" refers to a compound m The term "treatment" or "treating" includes any ion, application, therapy, or the like, wherein the human being is provided with medical help to improve the condition of the subject, direct or indirect by slowing down the progression of a patient. condition or disorder in the Although it can be usually recognized that an asty to indicate that the exact composition of the subu receptor is uncertain, for example a4ß2 * indicates a rec has the subunit proteins a4 and ß2 in combination subunits.

It has been found that the efficacy of otinic ligands can be surprisingly improved by combining a nicotinic acetylcholine receptor, particularly an α4β2 receptor (agonist, partial agonist), with a selective positive of the a4ß2 subtype of the acetylcholine receptor (PAM). Such combinations are very efficient for the efficiency of the li eptor a4ß2 or agonists that activate the receptor. The nicotinic acetylcholine lig eptor a4ß2 suitable for the invention include complete agonists or partial agonists which modulate the activity of the acetylcholine receptor subtype are suitable for the invention in the way in which they interact with the receptor.

One way to characterize receptor ligands is a binding assay. The binding values of [3 H] -citi t ") of the compounds of the invention range from about 1 nanomolar to more than 1 00 micromolar.Consides for the composition demonstrate approximately 0.001 nanomolar to 10 micromolar. of an ion to [3 H] -citisin, without details for carrying out the analyzes may obtain International Publication No. WO 99/32480; North America No. 5,948, 793 and 5, 914, 328; WO 200 North American Tenor No. 6 809 1 05 WO 00/71 534 9, and U.S. Patent No. 5,914,328, published io of 1,999); N-substituted diazabicyclic derivatives mplo International Publication No. WO 2004/01 86107, September 23, 2004, and Patente Norteameric 09, 105, published on October 26, 2004); heterocyclic substituted azacycles (see for example, First Publication WO 00/71 534, published November 30, 2000, American No. 6, 833,370, published on Dec. 21, 4); all of which are hereby incorporated in their entirety. A description and techniques have been reported to prepare the compounds in the patent applications, and internal patent publications.

Additional examples of binders of the receptacle for the invention include, but are not, azapolyclic binder fused with aryl (see by doxylalkyl (see, for example, International Publication 040682, published December 19, 1996); by reference in its entirety, given the description and additional methods for prescriptions in the cited patents and publications.

Other compounds reported as demonstrating a4ß2 include, but are not limited to, TC-1734 (ispr S-21, 4 hydroxy-GTS-21, TC-5619, TC-2696, dian enicline, which are all described in the literature). wearable Specific examples of compounds contemplated ligands of the a4ß2 receptor include, but are not limited to, 5 - [(2R) -azetidin-2-ylmethoxy] -2-chloropyridine; (3R) -1-pyridin-3-pyrrolidin-3-amine; 2- methyl-3- (2- (S) -pyrrolidinylmethoxy) pyridine; 3- 56-dichlor-iri in- -il -1 - - tanopyrido [2 \ 3 ': 5,6] pyran [2, 3-d] azepine; 3- [1 - (2,4-dimethoxy-phenyl) -met- (E) -ylidene] -3J4,5I6-tetrahi '] bipi-ridinyl; Y 3- [1 - (2-methoxy-4-hydroxyphenyl) -met- (E) -ylidene] -3,4,5,6-ahydro- [2, 3 '] bipyridinyl; or pharmaceutically acceptable salts thereof. Positive Allosteric Dilators of the Subti-Acetic Acid Receptor Positive allosteric modulators (PAMs) reinforce the recipient's responses to acetylcholine without triggering the activation of the receptor, or any other, reclosure.

One way to characterize the positive metal activity of a4ß2 is by characterization in cells expressing the a4ß2 subtype of the human nico tylcholine receptor, particularly by the use of I Plate techno in Fluorescent. The steroid hormones represent a family of variation of modulatory effects in nAChRs as well as members of the LGIC superfamily. For example, the positive serum level of nAChRs human a4β2 expressed in or opus or in human embryonic kidney cells is 17β-estradiol (Curtís L, et al., Rmacology, 61: 127-135, 2002). Examples of co-charged as selectively positive allosteric modulators derived from oxadiazole, for example as described WO 2006/114400.

Another positive a4ß2 allosteric modulator suitable nylisoxazole, which is available from Sigma Aldrich, S souri, USA.

Other suitable examples of allosteric modulators include, but are not limited to, suitable oxadiazole oxadiate derivatives may include derivatives - or are the salts and prodrugs thereof pharmaceutically, wherein X is a bond, O, NR1, S, or alkylene of from 1 to 3 a bonus; Y represents an aryl, cycloalkyl, heteroaryl monocyclic group; Ar 1 represents an aryl group or a monocyclic heteroaryl R 1 is hydrogen, alkyl, haloalkyl or arylalkyl.

X is selected from a carbon, O, N R 1, S, or carbon alkyl, wherein R 1 is selected from hydrogen or alkyl, and arylalkyl. Preferably, X is a fermentably, R1 is hydrogen or alkary.

Y represents an aryl, cycloalkyl, mono-cyclic heteroaryl group, which may be substituted or unsubstituted. Examples of heterocycle rings should be included, but not limited to, pyrrolidine, pipelines. The ones in the right heteroaryl rings Suitable eroaryls include, but are not limited to, thienyl, olyl, pyrazolyl, thiazolyl, 1,4-thiadiazolyl, and pyridine. They should be unsubstituted or substituted by one or two of the selected alkyl, cycloalkyl, or alkyl radicals. , halo, haloalkyl, hydroxyl, alkoxy, ho, cyano, and amino.

In one embodiment, the 2,5-disubstituted diazole derivatives may have the formula (I) wherein X is an enyl, cycloalkyl, heterocycle, or heteroaryl; and Ar1 is monocyclic eroaryl.

In another embodiment, suitable 2,5-disubstituted diazo derivatives may have the formula (I) wherein ace; Y is cycloalkyl, phenyl, thienyl, furyl, pyridinyl, rolidinyl, or optionally substituted monocyclic piperidinyl or more substituents selected from the group such as alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy 1 Suitable diazol can have the formula (I) wherein ace; And it is pyridyl; and Ar 1 is phenyl, pyrimidinyl, pyranyl optionally substituted with one or more constituents selected from the group consisting of oxygen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro, 1Z2, wherein Z1 and Z2 are hydrogen, alkyl, alkyl-oxycarbonyl, aryl , arylalkyl, or formyl.

Other suitable examples of the positive α4ß2 allosteric dulators report are derived from or example as described in WO 2006 on November 2, 2006. Examples of oxadiazole compounds which are positive allosteric d4 a2ß2 in the docum 100826, published on December 19, 2002.

Still other suitable examples of α4β2 modulators include, but are not limited to, halogenated compounds, haloalkyl of 1 to 6 carbon atoms of 6 to 10 carbon atoms, cycloalkyl of 4 to 7 át bono, alkenyl of 2 to 4 carbon atoms. to 6 carbon atoms, carbon alkynyl, heteroaryl of 5 to 10 erocycle atoms of 4 to 10 carbon atoms, alkyl of 1 to 6 to bond, - (alkyl of 1 to 6 carbon atoms) N HC ( 0) 0- (to 6 carbon atoms), hydroxyalkyl of 1 to 6 carbonyl atoms of 1 to 6 carbon atoms, amino, o-alkyl-C (O) -, haloalkyl-S02-, alkyl-S02-, 2N H (alkyl of 1 to 6 carbon atoms), -S02N (carbon mon alkyl) 2, cyano, n itro, acylamino of 1 to 6 at b bond, alkoxy of 1 to 6 carbon atoms, -C (0) N H2, uilo of 1 to 6 carbon atoms), and carboxy; Y Ar3 is aryl or heteroaryl, wherein the aryl or optionally hetero-substituted, and, when substituted, the eroaryl is substituted with a suitable selected diazo substituent, may have the formula (I) in which monocyclic or substituted monocyclic heteroaryl, which substituted or unsubstituted, and Ar3 is the aryl or substituted heteroaryl, which may be substituted or unsubstituted. C aryl or heteroaryl for Ar 2 is substituted by the halo substitution, haioalkyl of 1 to 6 carbon atoms, 10 carbon atoms, cycloalkyl of 4 to 7 carbon atoms of 2 to 6 carbon atoms, alkynyl of 2 to 6 to bond, heteroaryl of 5 to 10 carbon atoms, heterocyclic carbon atoms, alkyl of 1 to 6 carbon atoms, 1 to 6 carbon atoms) NHC (0) 0- (alkyl of 1 to 6 to bond), hydroxyalkyl of 1 to 6 carbon atoms, alkyl 1 to 6 carbon atoms, amino, hydroxyl, haloalkyl or alkyl-S02-, alkyl-S02-, -S02NH2, -S02NH (carbon alkyl), -S02N (alkyl of 1 to 6 atoms of e, nitro, acylamino of 1 to 6 carbon atoms, carbon alkoxy-C 0 NH-0 0- to uyl of 1 to 6 to oxy of 1 to 6 atoms of carbon, -N (alkyl of 1 to 6 to bond) 2, and carboxy The ones referred to heteroaryl mono-dina-3-yl, pyridin-4-yl, and pyridine-2 (1 H) -one.

In another embodiment, suitable 3,5-disubstituted diazo derivatives may have the formula (II) wherein it is pyridinyl, which may be substituted or unsubstituted, substituted; and Ar 3 is pyridinyl, which may be substituted, or substituted phenyl. The pyridinyl group, qua tuted, with fluoro. The phenyl group is substituted with preferred cyan that the pyridinyl group for Ar2 or Ar3 is pyridine or preferred phenyl is substituted with fluoro, sulfamide or feria cyano.

Specific examples of allosteric modulators 2 are, for example, derivatives of 3,5-disubstituted-1, 2,4-0 as: 3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzonitrile; - i iri i - - - - 5- (2,3-difluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 5- (pyrazin-2-yl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 5- (3,5-difluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 5- (2,3,5-trifluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 5- (2,4,5-trifluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 5- (2,5-difluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 5- (4-Chloro-2,5-difiuorophenyl) -3- (pyridin-3-yl) -1, 2,4-oxadia 5- (5-methylpyrazin-2-yl) -3- (pyridin-3-) il) -1, 2,4-oxadiazole; 4- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzonitrile; 2,3,6-trifluoro-5- (3- (pyridin-3-yl) -1,2) 4-oxadiazol-5-yl) phen 2-fluoro-5- (3- (pyridin-3-yl) -1 , 2,4-oxadiazol-5-yl) phenol; 2-fluoro-4- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) phenol; 5- (3-chloro-4-fluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 5- (3,4-dichlorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 2-nitro-5- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) phenol; 5- (2,3,6-trifluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 222-trifluoro-1- 4- - iri in- -il -1 - - - 3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzenesulfonamia 5- (2,4-difluorophenyl) -3- (pyridin-3-yl) -1,2, 4-oxadiazole; 5- (2,3,4-trifluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 5- (3,4,5-trifluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 5- (4-chloro-3-fluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 5- (3-nitrophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 5- (3- (methylsulfonyl) phenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 3- (2-chloropyridin-4-yl) -5- (pyridin-3-yl) -1,2,4-oxadiazole; 3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzamide; 4- (5- (pyridin-3-yl) -1,2,4-oxadiazol-3-yl) pyridin-2 (1 H) -one; tert-butyl 3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzo 2-amino-5- (3- (pyridin-3-yl) -1,2, 4-oxadiazol-5-yl) phenol; N, N-dimethyl-4- (5- (pyridin-3-yl) -1,2,4-oxadiazol-3-yl) pyridine; [3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzoic acid; 5- (3- (1H-tetrazol-5-yl) phenyl) -3- (pyridin-3-yl) -1, 2,4-oxadia N N -diethyl-3-3-iridin-3-yl-1 24-oxadiazole-5- encensulfonamide; 3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) aniline; (3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) phenyl) methanamine 5- (2-chloropyridin-4-yl) -3- (pyridin-3-yl) -1, 2,4-oxadiazole; 4- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) pyridin-2 (1 H) -one; 3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzylcarbamateyl; 5- (3-bromophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 1- (3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) phenyl) pyrrolidin-3- (3- (pyridin-3-yl) -1, 2,4 -oxadiazol-5-yl) phenylcarbamate ilo; N.N-dimethyl-1-IS-1-ipyridin-S-1-1 ^ -oxadiazole-S-enyl) methanamine; 5- (3- (piperazin-1-yl) phenyl) -3- (pyridin-3-yl) -1, 2,4-oxadiazo 1- (3- (3- (pyridin-3-yl) -1, 2,4-oxadiazol-5-yl) phenyl) ethanone; 3- (6-chloropyridin-3-yl) -5- (213-difluorophenyl) -1,4, 2,4-oxadia, 3-6-chloro-iridin-3-yl -5- 34-difluorophenyl-1-24-oxadia or pharmaceutically acceptable salts thereof. Other specific examples of a4ß2 itivos modulators are, for example, 2,5-disubstituted-1, 3,4-oxadiazole derivatives, such as 2- (imidazo [1,5-a] pyridin-6-yl) -5- (pyridin-3-yl) -1,3, 4-oxadi 2,5-di (pyridin-3-yl) -1, 3,4-oxadiazole; 2- 5-bromopyridin-3-yl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole; 2-pyridin-3-l) -5- (4- (trifluoromethyl) phenyl) -1,4,4-oxadiazol-2-pyridin-3-l) -5-o-tolyl-1, 3,4-oxadiazole; 2-pyridin-3-l) -5-m-tolyl-1, 3,4-oxadiazole; 2-pyridin-3-yl) -5-p-tolyl-1, 3,4-oxadiazole; 2- (pyridin-3-yl) -1,4,4-oxadiazol-2-yl) phenol; 3- 5- (pyridin-3-yl) -1, 3,4-oxadiazol-2-yl) phenol; 4- (pyridin-3-yl) -1,4,4-oxadiazol-2-yl) phenol; 2-3-methoxyphenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole; 2-4-methoxyphenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole; 2- 2-f luorofen i l -5- iridin-3-yl-34-oxadiazole 3- (5- (pyridin-3-yl) -1,4,4-oxadiazol-2-yl) benzonitrile; - (5- (pyridin-3-yl) -1,4,4-oxadiazol-2-yl) benzonitrile; N, N-dimethyl-3- (5- (pyridin-3-yl) -1, 3,4-oxadiazol-2-yl) anilin N, N-dimethyl-4- (5- (pyridin-3-yl) -1, 3,4-oxadiazol-2-yl) anilin 2- < [pyridin-3-M) -5- (3- (trifluoromethyl) phenyl) -1,4,4-oxadiazole 2-I pyridin-3-yl) -5- (3- (trifluoromethoxy) phenyl) -1, 3,4-oxadiaz 2-i [4-phenoxyphenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole; 2-I (4- (benzyloxy) phenyl) -5- (pyridin-3-ii;) -1, 3,4-oxadiazole; 2-i (3,4-dimethylphenyl) -5- (pyridin-3-yl) -1 1, 3,4-oxadiazole; 2-i [3,5-dimethylphenyl] -5- (pyridin-3-yl) -1 1, 3,4-oxadiazole; 2- (2,5-dimethylphenyl) -5- (pyridin-3-yl) - "1, 3,4-oxadiazole; 2- (2,4-dimethylphenyl) -5- (pyridin-3-yl) - '1, 3,4-oxadiazole; 2- (3,4-dimethylphenyl) -5- (pyridin-3-yl) - "1, 3,4-oxadiazole; 2- (2,3-dimethoxyphenyl) -5- (pyridin-3-yl) 1-1, 3,4-oxadiazole; 2- (2,4-dimethoxyphenyl) -5- (pyridin-3-yl] -1, 3,4-oxadiazole; 2- (2,5-dimethoxyphenyl) -5- (pyridin-3-yl] -1, 3,4-oxadiazole; - - im xif nil - - iri n- - - - -methyl-5- (5- (pyridin-3-yl) -1,4,4-oxadiazol-2-yl) phenol; - (3-fluoro-2-methylphenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole; - (5-fluoro-2-methylphenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole; - (3-fluoro-4-methylphenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole; - (2t3-difluorophenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole; - (2,4-difluorophenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole; - (2,5-difluorophenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole; - (3,5-difluorophenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole; - (4- (5- (pyridin-3-yl) -1,4,4-oxadiazol-2-yl) phenyl) ethanone; - (4-isopropylphenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole; - (3-methoxy-4-methylphenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole - (4-ethoxyphenyl) -5- (pyridin-3-yl) -1, 3,4 -oxadiazole; - (4- (methylthio) phenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole; - (3-fluoro-4-methoxyphenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazo - (naphthalen-1-yl) -5- (pyridin-3-yl) -1, 3 , 4-oxadiazole; - (naphthalen-2-yl) -5- (pyridin-3-yl) -1,3,4-oxadiazole; -chloro-2-5-iridin-3-yl-1-oxadiazol-2-yl-phenol 2- (2-methoxy-4- (methylthio) phenyl) -5- (pyridin-3-yl) -1, 3,4-oxadia 2- (4- (methylsulfonyl) phenyl) -5- (pyridin-3-) il) -1, 3,4-oxadiazole; 2- (2-chloro-5- (methylthio) phenyl) -5- (pyridin-3-M) -1, 3,4-oxadia 2- (2-fluoro-5- (trifluoromethyl) phenyl) -5- ( pyridin-3-yl) -1, 3,4-diazole; 2- (2-chloro-5- (trifluoromethyl) phenyl) -5- (pyridin-3-yl) -1, 3,4-O 2- (2-phenethylphenyl) -5- (pyridin-3-yl) -1,3,4-oxadiazole; 2- (2-bromo-5-methoxyfen M) -5- (pyridin-3-yl) -1, 3, 4-oxadiaz 2- (5-bromo-2-chlorophenyl) -5- (pyridin-3-) il) -1, 3,4-oxadiazole; 2- (2-iodophenyl) -5- (pyridin-3-yl) -1, 3,4-oxadiazole; 2- (3-iodophenyl) -5- (pyridin-3-yl) -1, 3, 4-oxadiazole; 2- (4-iodophenyl) -5- (pyridin-3-yl) -1, 3, 4-oxadiazole; 2- (pyridin-3-yl) -5- (pyrimidin-5-yl) -1, 3,4-oxadiazole; 2- (5-methyl-1-pyrazin-2-yl) -5- (pyrid-n-3-yl) -1,3,4-oxadiazole; 2- (2-Chloro-6-methylpyridin-3-yl) -5- (pyridin-3-yl) -1, 3,4-oxadi 2- (2-methyl-6- (trifluoromethyl) pyridin-3-yl) ) -5- (pyridin-3-yl) -1, zl 2- (2,6-dichloropyridin-3-yl) -5- (pi-ridin-3-yl) -1,4-oxadiazole 2- (2-chloropyridin-3-yl) -5- (pyridin-3) -yl) -1,4,4-oxadiazole; 2- (pi Ridin-3-yl) -5- (qu inolin-3-yl) -1, 3,4-oxadiazole; Y 2- (2-t2-difluorobenzo [d] [1, 3] dioxol-5-yl) -5- (pyridin-3-yl) -1, diazole; or pharmaceutically acceptable salts thereof. you PAMs a4ß2 of the Present I nvention Various embodiments of the invention described in the invention, but are not limited to, salts, amides, esters and pro-aceutically acceptable thereof.

Another embodiment of the invention is a compound of, wherein Ar2 and Ar3 are independently aryl, dazinyl, pyrimidinyl, triazinyl, or a heteroaryl independently substituted with 0, 1, 2, 3, or 4 substituted from the group consisting of alkoxy, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, alkynyl, alkynylcarbonyl to alkylsulfonyl amido aminoalkylaryl , wherein Ar2 is pyridinyl or substituted pyrimidinyl option Another embodiment of the invention is a compound d, wherein Ar2 is optionally substituted bicyclic heteroaryl Another embodiment of the invention is a compound d, wherein Ar3 is pyridinyl, pyrimidinyl or pyridazinyl.

Another embodiment of the invention is a compound d, wherein Ar 3 is optionally substituted bicyclic heteroaryl Another embodiment of the invention is a compound d, wherein Ar 2 and Ar 3 are independently, optionally substituted bicyclic or bicyclic, in monocyclic eroaryl it is six-membered heterocycle, where when one of Ar 2 and Ar 3 is pyridinyl, the other is not pi Where Ar3 is pyridinyl, Ar2 is not pyrazinyl.

Another embodiment of the invention is a compound d, wherein Ar2 and Ar3 are independently, Another embodiment of the invention is a compound d, wherein u of Ar2 and Ar3 is bicyclic heteroaryl selected from the group consisting of zimidazolyl, benzo [d] [1,3] dioxolyl, benz zo [d] imidazolyl, benzooxazole, benzo [d] [1, 2, 3] thiadiazole zothiazolyl, benzo [d] [1, 2, 3] triazolyl, uorobenzo [d] [1, 3] dioxolyl, imidazopyridinyl, indolyl, zolopyrimidinyl, pyrrolopyridinyl, and [1, 2, 4] triazolopyridinyl Another embodiment of the invention is a compound d, selected from the group of compounds exemplified mpios 79-1 34 described below.

Another embodiment of the invention is a compound d, selected from the group of compounds exemplified mpios 79-1 05 described below.

Another embodiment of the invention is a compound d, selected from the group of exemplified compounds - - - , selected from the group of compounds exemplified mpios 90-91 described below.

Another embodiment of the invention is a compound of, selected from the group of compounds exemplified mplos 106-134 described below.

Another embodiment of the invention is a compound of, selected from the group of compounds exemplified mpios 106-118, 123-131 and 134 described below.

Another embodiment of the invention is a compound of, selected from the group of compounds exemplified mplos 119-122 and 132-133 described below.

Another embodiment of the invention is 5- (2,3-difluorimidin-5-yl) -1,2,4-oxadiazole.

Another embodiment of the invention is 5- (pyridin-3-yl) -3- (py 1, 2,4-oxadiazole.

Another embodiment of the invention is 2-fluoro-N, N-dim and i-lyl-24-xyl-nilin.

Another embodiment of the invention is 5- (4-fluorophenyl) -3- () -1, 2,4-oxadiazole.

Another embodiment of the invention is 5- (3-fluorophenyl) -3- () -1,2,4-oxadiazole.

Another embodiment of the invention is 3- (pyrimidin-5-yl) -ophorophenyl) -1,2,4-oxadiazole.

Another embodiment of the invention is 5- (2-chloropyridi imidin-5-yl) -1,2,4-oxadiazole.

Another embodiment of the invention is 3- (3- (pyridazin-4-diazol-5-yl) benzonitrile.

Another embodiment of the invention is 5- (3-fluorophenyl) -3- () -1,2,4-oxadiazole.

Another embodiment of the invention is 3- (pyridazin-4-yl) -uorophenyl) -1,2,4-oxadiazole.

Another embodiment of the invention is 5- (3,5-difluor idazin-4-yl) -1,2,4-oxadiazole. - - - - idazin-4-yl) -1 ^^ - oxadiazol-S-phenylsulfoni formimidamid Another embodiment of the invention is 5- (3,4-difluor imidin-5-yl) -1,2,4-oxadiazole.

Another embodiment of the invention is 3- (3,4-difluorimidin-5-yl) -1,2,4-oxadiazole.

Another embodiment of the invention is 3- (pyrimidin-5-yl) uorophenyl) -1,2,4-oxadiazole.

Another embodiment of the invention is 3- (pyrimidin-5-yl) luo-phenyl) -1,2,4-oxadiazole.

Another embodiment of the invention is 3- (pyrimidin-5-yl) -5- afluorophenyl) -1, 2,4-oxadiazole.

Another embodiment of the invention is 3- (pyrimidin-5-yl) uorophenyl) -1,2,4-oxadiazole.

Another embodiment of the invention is 3- (pyrimidin-5-yl) -5-fluoro-phenyl) -1,2,4-oxadiazole.

Another embodiment of the invention is 5- (imidazo [1, 5-a] pir - - - - Another embodiment of the invention is 5- (benzo [d] [1,2,3] thia - (pyridin-3-yl) -1,2,4-oxadiazole.

Another embodiment of the invention is 5- (1 H -benzo [d] imid pyridin-3-yl) -1, 2,4-oxadiazole.

Another embodiment of the invention is 5- (1 H -benzo [d] [1, 2,) -3- (pyridin-3-yl) -1,2,4-oxadiazole.

Another embodiment of the invention is 5- (benzo [d] thiaz idin-3-yl) -1, 2,4-oxadiazole.

Another embodiment of the invention is. 3- (pi rid -3-Olo [2,3-b] pyridin-5-yl) -1,2,4-oxadiazole.

Another embodiment of the invention is 5- (1 H-indol-5-yl) -3- (1, 2,4-oxadiazole.

Another embodiment of the invention is 5- (benzofura ridin-3-yl) -1, 2,4-oxadiazole.

Another embodiment of the invention is 5- (1- zo [d] imidazol-5-yl) -3- (pyridin-3-yl) -1,2,4-oxadiazole. - - ) -1, 2, 4-oxadiazole.

Another embodiment of the invention is 5 - ([1, 2, 4] tri a iridin-6-yl) -3- (pyridin-3-yl) -1, 2,4-oxadiazole.

Another embodiment of the invention is 5- (3- (pyridin-3-diazol-5-yl) benzo [d] oxazol-2 (3H) -one.

Another embodiment of the invention is 5- (3- (pyridin-3-diazol-5-yl) -1 H -benzo [d] imidazol-2 (3 H) -thione.

Another embodiment of the invention is 1,3-dimethyl-5- (3- (py, 4-oxadiazol-5-yl) -1 H -benzo [d] imidazol-2 (3H) -one.

Another embodiment of the invention is 6- (3- (pyridin-3-diazol-5-yl) benzo [d] oxazol-2 (3H) -one.

Another embodiment of the invention is 5- (3- (pyridin-3-diazol-5-yl) -1 H -benzo [d] imidazol-2 (3H) -one.

Another embodiment of the invention is 6- (3- (pyridin-3-diazol-5-M) benzo [d] oxazol-2-amine.

Another embodiment of the invention is 6- (3- (pyridin-3 di zol-5-yl nz d ox l.

Another embodiment of the invention is 5- (pyridazin-4-yl) -3- (, 2,4-oxadiazole.

Another embodiment of the invention is 3- (3,4-difluorimidin-5-yl) -1,2,4-oxadiazole.

The names of the compounds are assigned or oritmo named Structure = Name, which is part of the CH EMDRA W® ULTRA v. 9.0.7 Geometric isomers may exist in the p. The invention contemplates the various metrics and mixtures thereof resulting from the di substituents around a double carbon-carbon double carbon-nitrogen bond, a cycloalkyl group, or erocycloalkyl. Substituents around a carbon-bond or carbon-nitrogen are referred to as Figure Z or E, and substituents around an erocycloalkyl ring are designated as being of config ur compounds or drawings of the formulas.

Paration of Compounds The preparation of the appropriate compounds of the invention can be understood with respect to synthetic schemes and examples, which illustrate which compounds can be prepared. Methods for the nicotinic receptor ligands and suitable allosteric modulators of the a4ß2 nicot acetylcholine subtype are readily available. Suitable compounds can all be prepared conventionally for chemical synthesis with readily available ace. The receptor ligands and the acetylcholine and allosteric modulators of the subti otic acetylcholine may also be available.

L a vi i n (dibenzylidineacetone) palladium (0) (Pd2 (dba) 3) > (diphenylphosphino) ferrocene] dichloropalladium (ll) (PdCI2 (dppf)), I Modified by Dulbecco (DMEM), fetal bovine serum (til-D-glucamine (NMDG), and 4- (2-hydroperoxy-ethane sulphonic acid (HEPES) .

The oxadiazole derivatives suitable for the composition can be prepared according to convention methods by some suitable methods for preparing such diazole in the schemes and examples below. Without further em- ployment it is desired only for reference and not a way to limit the scope of the invention.

Reaction Scheme 1 (1) (2) (M As shown in Reaction Scheme 1, the comp 2. 3 As shown in Reaction Scheme 2, the compounds den to be reacted with compounds of formula (5) in POCI3 at temp 00 ° C for 1-24 hours to provide the compounds of the formula of Ar2 and Ar3, are as defined in the formula (II) above. Alternatives of formula (4) may be reacted with the compounds in the presence of triphenylphosphine, which may optionally be the linkage of acetone-acetonitrile. The mixture can be heated in a roundabout at 1 00 - 175 ° C for 5-30 minutes as described by er, D. R.; Djuric, S. W. Tetrahedron. Lett. 2006, 47, 105-108. Another combines compounds of formula (4) and compounds of formula such as methylene chloride in the presence of ethylimidazolinium chloride and a base such as triethylamine at 5-35 ° C for 10 or is described by Isobe, T. Ishikawa, T. J. Org. Chem. 1 999, 64, 6989-6 Reaction Scheme 3 (8) ula (1) and (7) can be combined in pyridine at 20-1 10 ° C for 1-24 to prepare compounds of formula (8). Compounds of formula rse with POCI3 at 25-100 ° C for 1-24 hours to provide the formulas (9). The compounds of formula (9) can be reacted resence of a base such as lithium bis (trimethylsilyl) amide, bis (sodium trimethyl, potassium bis (trimethylsilyl) amide, potassium f-butoxide, potassium hydrate, potassium carbonate, sodium, cesium or carbonate in a solven hydrofuran, 1-methyl-2-pyrrolidinone, dimethyl sulfoxide, or at temperatures of -20 ° C to 150 ° C for 1 -48 hours to provide com ula (I).

Reaction Scheme 4 (I " As shown in Reaction Scheme 4, the compounds of Ar2 and Ar3, as defined in the formula (I I), can prepare As shown in the Reaction Scheme of formula (II), wherein Ar2 and Ar3 are as above, they can be prepared as defined in the Reaction Scheme 5. Compounds of formula are either obtained from a commercial source or Prepa formula seats (11). The amides of the formula (12) are stopped by reacting compounds of the formula ammonium oxide The subsequent dehydration of the formula (12) with a dehydrating agent, for example, to phosphorus oxychloride or trifluanhydride AA) / triethylamine gives compounds of the formula (1) Positions of formula 13 can be made by reacting formula (1) obtainable from an agent or by treatment of the compound of formula (1C) of chlorination treatment, such as thionyl chloride, in a solvent such as but not li dina or THF at 60-110 ° C.

Reaction Scheme 6 Ai ^ -halo (23) (17) III umento EP0979814. Compounds of formula (15) with compounds of formula (13) in the presence of e, such as but not limited to triethylamine, Na 2 CO 3 and K solvent, such as toluene, at a temperature ranging from 10-40 hours to provide compounds of for or described by Humphrey, GR; Wright, S. H. erocyclic Chem. (1989, 26, 23-24).

The compounds of formula (17), wherein halo is chloro, when treated with organoborans of formulated formulas of formulas (19), such as t (pinacolato) diboro or heximeti lid tin, respect ame of Rm or Rn they are hydrogen, alkyl or aryl, in palladium presenter, such as, but not limited to I 2 (PPh 3) 2, Pd (PPh 3) 4, PdCl 2 (dppf), Pd 2 (dba) 3 provides tin or boronic or corresponding boronic esters d), where M is -Sn- (Rn) 3 or -B (ORm) 2. The computations can be reacted with compounds of organotin compounds, organoboronic acid esters of organoboronic esters of formula (23), in -Sn- (Rn) 3 or -B (ORm) 2. The compounds of formula (23) are also prepared by the initial treatment of computer (16) with s-BuLi at a temperature of -90 ° C after the reaction with a boronic ester of the formula (organotin compound of formula (22). Compounds (23) can be reacted with compounds d) in the presence of a palladium catalyst, such as Pd (OAc) 2) PdCl 2 (PPh 3) 2, Pd (PPh 3) 4, Pd 2 (dba) 3, and a base, such as but not limited to CsF, C03 and K3P0 to provide compounds of formula (? Reaction Scheme 7 (24) 25 2 mule (25) can be reacted with compounds d), wherein Ar3 is defined in formulas (II) and (III), ranging from 80-140 ° C for 1-6 hours to give computer (26). The compounds of formula (26) are made hydroxylamine in acetic acid at ambient temperature to provide the compounds of formula (III) as defined by Lin, Y.-I, et al., J. Org. Chem., 44, 4160-416 Furthermore, the compounds of formula (II) and (III), in which one of Ar1 and Ar2 is a heteroaryl containing N, is converted to compounds with N + -0"by the treatment with examples of the oxidizing agent include, but not aqueous hydrogen peroxide and acid m-chloroperbenztion is generally carried out in a solvent such asare added to acetonitrile, water, dichloromethane, acetone or the same, preferably a mixture of acetonitrile and temperature from about 0 ° C to about a period of about 1 hour a roximad optional treatment with activated carbon, chromatography, distillation various pressures, sublimation under uration, as described for example in "Vogel's Te ctical Organic Chemistry", 5th edition (1989), by F prarators, pub. Longman Scientific &; Technical, Ess, England.

The compounds and processes suitable for posts for the composition of the invention are understood with respect to the following examples, which are illustrated and not a limitation with respect to the alloy.

Paration of 2,5-Disubstituted-1, 3,4-Oxadiazo Derivatives. 2,5-Disubstituted-1, 3,4-Cuados derivatives were prepared using readily available raw materials, International Publication WO 02/100826, December 2002, describes the preparation of some oxadiazole. However, the com ue to provide the 2,5-disubstituted-1, 3,4-respondent. The free base was then dissolved in Et and treated with hydrochloric acid (Aldrich, 4 M in divalent dioxides) at room temperature for 5-10 h or thereafter filtered and dried to provide acidic acid salt. 2, 5-disubstituted-1, 3,4-oxadiazole corresponding.

Method B: A Smith process bottle (a stir bar) was charged to the boxyl box (0.1 mmol), nicotinic hydrazide (Aldrich, 13.7 iol), PS-PPh3 (Fluka, 2.2 mmol / g, 136 mgs, 0.3 tonitrile (anhydrous, Aldrich, 2 ml), followed by CCI3CN 8 mgs, 0.20 mmol) The reaction vessel was sealed and ° C for 15 minutes using an Emrys ™ Opti rounds (Personal Chemistry, www.personalchemi after cooling, the reaction vessel was uncovered and resin was filtered by filtration.

- [Waters, column: Sunfire OBD C8 5 pm (30 I); solvent: acetonitrile / aqueous ammonium acetate 10 m / 0; flow rate 50 ml / minute]. The fractions were based on mass signal threshold obj ected the fractions selected after mass electrometry of the flow injection analysis method previously described.

Paration of 2,5-Disubstituted-1, 2,4-Oxadiaz Derivatives 2,5-disubstitued-1, 2,4-lactate derivatives were prepared using readily available raw materials, International Publication WO 02/100826, public December 2002, describes the preparation of some oxadiazole. However, the compounds of formula (b) can also be prepared according to the following isles. all C: To a solution of a carboxylic acid deroaryl 1.0 mmol in im i f rm i n i or vacuum to give the title compound. When the reaction failed to give a precipitate, the reaction was extracted with EtOAc (3 x 30 ml). The binases were concentrated and the residue was purified with chromatography / EtOAc) or preparative HPLC [Waters, column: p C18 5 μ, OBD ™ 30 x 100 mmt solvent: acetoni = 10, prepared with NH4HCO3ZNH3-H2O) or acetonitrile /% TFA), 5/95 to 95/5, flow rate of 40 ml / ml fractions based on the threshold of.].

Method D: To a solution of N'-Hydroxy aryl or h-boximidamide (1.0 mmol) in pyridine (5 ml) was added aryl or heteroaryl carbonyl (1.0 mmol). After stirring at a temperature of 80-100 ° C for 2-10 h, the reaction was cooled to room temperature and triturated with precipitated water, filtered and dried under vacuum to yield the mixture. When the reaction mixture fails Example 1 3- (3- (pyridin-3-ih-1, 2,4-oxadiazol-5-yl) benzoriitrile 3-pyridylamidoxime (Aldrich, 5.5 g, 40 mm pyridine and 3-cyanobenzoyl chloride (Aldri) was added. The reaction mixture was heated to reflux and then cooled to room temperature, washed with water (500 mL), filtered, and the solid was collected and the 1 H NMR (300 MHz, CD3OD) d ppm 7.87 (td, J = 8.0, 0.7 0 (dt, J = 8.1, 1.4 Hz, 1H), 8.23 (ddd, J = 8.1, 5.6, 0.8 Hz, d, J = 8.0, 1.7, 1.2 Hz, 1H), 8.64 (td, J = 1.7, 0.7 Hz, 1H), .4, 1.0 Hz, 1H), 9.23 (dt, J = 8.1, 1.7 Hz, 1H), 9.57 (d, J, EM (+ ESI) m / z 249 (M + H) +.

Example 2 3. 5-di (pyridin-3-yl) -1, 2,4-oxadiazole 3-Pyridylamidoxime (5.5 g, 40 mmol) was dissolved in dyne and nicotinoyl chloride hydrochloride was added (nr flu for Example 3A 3-cyano-N'-hydroxybenzimidamide Hydroxylamine (Aldrich, 7.65 g, 100 mmol) or ml) was treated with 10 N sodium hydroxide (10 mL, 100 mmol). After stirring, the isophthalonitrile (Aldrich, 12.8 g, 100 ml of ethanol) was added, the reaction mixture was heated to reflux and then cooled to room temperature, and the residue was purified with flash chromatography (5%). methanol / dichloromethane) provided by title: 1H NMR (300 MHz, DEMO-d6) d 5.98 9 (t, J = 7.4 Hz, 1H), 8.06-8.0 (m, 2H), 9.89 (s, 1H) I / NH3) m / z 162 (M + H) +.

Example 3B 3- (5- (pyridin-3-ih-1, 2,4-oxadiazol-3-yl) benzonitrile 3-Cyano-N'-hydroxybenzimidamide (0.322 g, pyridine (10 ml) was dissolved and nicotinoyl chloride was added (Aldri ln the mzlrr fl Example 4 3- (5- (6-fluoropyridin-3-yl) -1, 2,4-oxadiazol-3-yl) benzonitr Example 4A 3-cyano-N'-hydroxybenzimidamide Hydroxylamine (Aldrich, 7.65 g, 100 mmol) in ethanol (1 or 10 N NaOH (10 mL, 100 mmol) was added to this phthalonitrile (Aldrich, 12.8 g, 100 mmol) in 100 ml of nitrogen. The reaction was refluxed after cooling to room temperature, the residue was removed or the residue was purified and the residue was purified by chromatography in tancane (5% methanol / dichloromethane) to give the reaction: 1H RN (300 MHz, DEMO-d6) d 5.98 (bs, 2H), 7.59 (1H), 8.06-8.0 (m, 2H), 9.89 (s, 1H) ppm, MS (DCI / NH3) H) +.

Example 4B 3- (5- (6-fluoropyridin-3-yl) -1, 2,4-oxadiazol-3-yl) benzonitr - - '- 9 (m, 1H), 8.8-8.74 (m, 1H), 9.11-9.0 (m, 1H) ppm; MS (267 (M + H) +.

Example 5 5- (5-Bromopyridin-3-yl) -3- (pyridin-3-yl) -1,2,4-oxadiazo The title compound according to the procedure of Example 1 was prepared using N'-hydroxynicotini drich) and chloride of 5-bromochloride (Alpha). HRN (3 MO-d6) d 8.65-8.69 (m, 1H), 8.45-8.49 (m, 1H), 8.79 (t, J), 8.84 (dd, J = 1.7, 2.0 Hz, 1H), 9.07 (d , J = 2 Hz, 1H), 1H), 9.34 (d, J = 1.7 Hz, 1H) ppm; MS (DCI / NH3) m / z 303 Example 6 3- (pyridin-3-yl) -5- (3- (trifluoromethylsulfonyl) phen) -1.2,4-oxa Example 6A Acid 3 - (trifluoromethylsulfoniPenzoic acid A solution of 3- (trifluoromethylthio) 2 mgf 1 mmol) in dichloromethane (10 ml) was stirred with c.drich oxide 2.0 mm.l. ol) in dichloromethane (10 ml) with oxalyl dichloride (Al) and 1 drop of dimethylformamide at room temperature. The title compound was obtained by removing the or vacuum as a yellow oil (250 mg) and the c used directly in the next step.

Example 6C 3- (pyridin-3-in-5- (3- (trifluoromethylsulfonyl) phenyl) -1,2,4-oxad The title compound according to the procedure of Example 1 was prepared using N'-hydroxynicotinyl rich) and the compound of Example 6B . 1 H NMR (300 MHz d 7.73 (dd, J = 4, 5.0 Hz, 1H), 7.85 (t, J = 8 Hz, 1H), 8.13 3 (m, 1H) 8.5 (m, 1H), 8.6 (m, 1H), 8.92 (m, 1H), 9.37, MS (DCI / NH3) m / z 356 (M + H) +.

Example 7 3- (3- (6-Methylpyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzonitri Example 7A N'-Hydroxy-6-methyl-trimetimidamide (DCI / NH3) m / z 152 (M + H) +.

Example 7B 3- (3- (6-methylpyridin-3-i0-1.2.4-oxadiazol-5-yl) benzonitri The title compound according to the procedure of Example 1 was prepared using N'-hydroxynicotinyl mplo 7A) and 3-chloro chloride. cyanobenzoyl (Aldrich). 1H R z, DEMO-d6) d 2.59 (s, 3H), 7.52 (d, J = 8.1 Hz, 1H), 7.39, 1H), 8.23-8.21 (m, 1H), 8.36-8.32 (m, 1H) , 8.53-8.49 4 (m, 1H), 9.14 (m, 1H), ppm; MS (DCI / NH3) m / z 263 (+ Example 8 5- (5- (pyrrol-1-inpyridin-3-yn-3- (pyridin-3-yl) -1.2.4-oxadia To a solution of 5- (1 H-pyrrol-1-yl) Nicotinic acid (M mg, 1.00 mmol) in dimethylformamide (anhydrous, 5 ml) N- (3-methylaminopropyl) -N'-ethylcarbodiimidehydrate, 192 mg, 1.00 mmol) and 1-hydroxybohydrate BT) (Fluka, 153 mg, 1.00 mmol). The m r n 20 minutes. Go to H) +.

Example 9 5- (3- (pyridin-3-iP-1,2,4-oxadiazol-5-thpyridin-3-ol The title compound according to Example 8 was prepared using N'-hydroxynicotinir rich) and 5-hydroxynicotinic acid ( Matrix Scientific). 1H z, DEMO-d6) d 7.66 (ddd, J = 8.0, 4.9, 1.0 Hz, 1H), 7.86 (d Hz, 1H), 8.31 -8.55 (m, 2H), 8.83 (s, 2H ), 9.26 (s, 1H) I / NH3) m / z 241 (M + H) +.

Example 10 5- (3,4-difluorophenin-3- (pyridin-3-in-1.2.4-oxadiazole The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotini drich) and 3,4-difluorobenzoic acid (Aldrich) 1 H NMR (3OD) d 7.52 - 7.67 (m, 2H), 8.12 (ddd, J = 8.7, 4.3, 1.5 9 (ddd, J = 10.8, 7.5, 2.0 Hz, 1H), 8.55 (dt, J = 8.1 , 1.9 Hz, = Hz 1H 9.2 dd = 2 .7 Hz 1H 1?), 9.29 (dd, J = IA, 0.8 Hz, 1H) ppm; MS (DCI / NH3) H) +.

Example 12 5- (pyrazin-2-yl) -3- (pyridin-3-yl) -1, 2,4-oxadiazole The title compound was prepared according to Example 8 using N'-hydroxynicotinir rich) and pyrazine-2-carboxylic acid (Aldrich). 1 H NMR (3OD) d 7.66 (ddd, J = 8.0, 4.9, 1.0 Hz, 1H), 8.60 (dt, J = 8.0), 8.77 (dd, J = 5.0, 1.8 Hz, 1H), 8.86 -8.89 (m , 1H), 8.89, 9.34 (dd, J = 2.4, 0.8 Hz, 1H), 9.56 (d, J = 1.6 Hz, 1H) I / NH3) m / z 226 (M + H) +.

Example 13 5- (3,5-difluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotinyl drich) and acid 3,5-difluorobenzoic acid (Aldrich). 1 H NMR ( = = 30D) d 7.55-7.68 (m, 2H), 7.83-7.90 (m, 1H), 8.57 (Hz, 1H), 8.75 (dd, J = 5.1, 1-7 Hz, 1H), 9.30 (dd, J = l 2, 0.; E (DCI / NH3) m / z 278 (M + H) +.

Example 15 5- (2,4,5-trifluoropheni0-3- (pyridin-3-yl) -1,2,4-oxadiazole The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotini drich) and acid 2.4 , 5-trifluorobenzoic acid (Aldrich). 1H RN (3OD) d 7.55 (td, J = 10.3, 6.4 Hz, 1H), 7.64 (ddd, J = 8.1,, 1H), 8.23 (ddd, J = 10.3, 8.6, 6.4 Hz, 1H), 8.56 ( dt, J = 8.1), 8.75 (dd, J = 5.1, 1.7 Hz, 1H), 9.29 (d, J = 1.4 Hz, 1H) I / NH3) m / z 278 (M + H) +.

Example 16 5- (2,5-difluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole The title compound according to Example 8 was prepared using N'-hydroxynicotinir dri h - ifl nzoic acid. h. 1 HOUR z, CD3OD) d 7.65 (ddd, J = 8.0, 4.9, 1.0 Hz, 1H), 7.73 (d Hz, 1H), 8.18 (dd, J = 8.8, 6.1 Hz, 1H), 8.57 (dt, J = 8.1 ), 8.75 (dd, J = 4.7, 1.7 Hz, 1H), 9.30 (dd, J = 2.2, 0.8 Hz, (DCI / NH3) m / z 294 (M + H) +.

Example 18 5- (5-Methylpyrazin-2-yl) -3- (pyridin-3-yl) -1,2,4-oxadiazole The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotini drich) and acid 5-methylpyrazine-2-carboxylic acid (Aldrich). 1H z, CD3OD) d 2.71 (s, 3H), 7.66 (ddd, J = 8.0, 5.1, 0.8 Hz,, J = 7.9, 1.8 Hz, 1H), 8.74 -8.78 (m, 2H), 9.33 (dd, J = 2.0), 9.40 (d, J = 1.2 Hz, 1H) ppm; MS (DCI / NH3) m / z 240 (M + Example 19 4- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzonitrile The title compound according to Example 1 was prepared using N'-hydroxynicotini drich 4-ianob-chloride Aldri h. 1H NMR drich) and 2,4,5-trifluoro-3-hydroxybenzoic acid (Aldrich). 0 MHz, CD3OD) d 7.63 - 7.76 (m, 2H), 8.44 (dt, J = 7.9), 8.83 (dd, J = 4.8, 1.6 Hz, 1H), 9.25 (d, J = 1.6 Hz, 1H) Example 21 2-Fluoro-5- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) phenol The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotini drich) and 4-fluoro-3-hydroxybenzoic acid (Aldrich). 1H R z, DEMO-d6) d 7.45 (dd, J = 11.1, 8.7 Hz, 1H), 7.62 - 7.71 8 (dd, J = 8.3, 2.0 Hz, 1H), 8.43 (dt, J = 1.9, 1.8 Hz , 1H), .0, 1.8 Hz, 1H), 9.24 (d, J = 2.0 Hz, 1H) ppm; MS (DCI / (+ H) +.

Example 22 2-fluoro-4- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) phenol The title compound was prepared according to the procedure N '-hydroxynicotine yield of Example 8 using N' -hydroxinicotini drich) and 3-chloro-4-fluorobenzoic acid (Aldrich). 1H R z, CD3OD) d 7.54 (t, J = 8.8 Hz, 1H), 7.64 (ddd, J = 8.1, 5.0), 8.24 (ddd, J = 8.6, 4.6, 2.0 Hz, 1H), 8.39 (dd, J = 7.0, 2.2 5 (dt, J = 8.1, 1.9 Hz, 1H), 8.74 (dd, J = 4.9, 1.5 Hz, 1H), .2, 0.8 Hz, 1H) ppm; MS (DCI / NH3) m / z 276 (M + H) +.

Example 24 5- (3,4-dichlorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotini drich) and 3,4-acid. dichlorobenzoic acid (Aldrich). H NMR (3OD) d 7.64 (ddd, J = 8.0, 5.1, 0.8 Hz, 1H), 7.82 (d, J = 8.3 4 -8.19 (m, 1H), 8.40 (d, J = 2.0 Hz, 1H), 8.56 (dt, J = 7.9), 8.75 (dd, J = 5.2, 1.6 Hz, 1H), 9.29 (dd, J = 2.2, 1.0 Hz, (DCI / NH3) m / z 292 (M + H) +.

Example 25 - - - - - - - - l- -i f Example 26 5- (2,3,6-trifluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotini-drich) and acid 2.3, 6-trifluorobenzoic (Aldrich). 1 H NMR (3OD) d 7.26 - 7.35 (m, J = 9.4, 9.4, 3.8, 2.0 Hz, 1H), 7.62 -), 8.57 (dt, J = 8.0, 1.9 Hz, 1H), 8.76 (dd, J = 4.8, 1.6 Hz,, J = 2.4, 0.8 Hz, 1H) ppm; MS (DCI / NH3) m / z 278 (M + H) +.

Example 27 2.2.2-Trifluoro-1 - (4- (3- (pyridin-3-yl) -1-oxadiazol-5-yl) phenyl) ethanone trifluoroacetate The title compound according to Example 8 was prepared using N'-hydroxynicotini drich) and 4- (2,2,2-trifluoroacetyl) benzoic acid (Aldrich). O MHz, CD3OD) d 7.81 (ddd, J = 7.9, 5.2, 0.8 Hz, 1H), .3 Hz, 2H), 8.28 (d, J = 8.7 Hz, 2H), 8.76 (dt, J = 8.2, 1.8 2 dd J = 5.2 1.6 Hz 1H 9.38 d J = 1.6 Hz 1H, 8.56 (dt, J = 8.0, 1.9 Hz, 1H), 8.74 (dd, J = 5.2, 1.6 Hz,, J = 2.0, 0.8 Hz, 1H ) ppm; E (DCI / NH3) m / z 242 (M + H) +.

Example 29 5- (4-fluorophenyl) -3- (pyridin-3-yl) -1.2.4-oxadiazole The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotinir rich) and 4-fluorobenzoic acid (Aldrich) . 1 H NMR (3 3OD) d 7.39 (t, J = 8.9 Hz, 2H), 7.64 (ddd, J = 7.9, 4.8, 0.8 7 -8.35 (m, 2H), 8.55 (ddd, J = 8.1, 2.0, 1.8 Hz, 1H), .0, 1.8 Hz, 1H), 9.29 (dd, J = 2.2, 1.0 Hz, 1H) ppm; MS (242 (M + H) +.

Example 30 5- (2-fluorophenyl) -3- (pyridin-3-yl) -1.2.4-oxadiazole The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotini drich) and 2-fluorobenzoic acid (Aldrich) . 1 H NMR (3 OD d 7.38 - 7.49 m 2 H 7.64 ddd J = 8.0 4.9 1.0 z, CD3OD) d 7.65 (ddd, J = 8.0, 5.1, 0.8 Hz, 1H), 7.95 (dd, 1.6 Hz, 1H), 8.32 (ddd, J = 8.7, 2.6, 1.4 Hz, 1H), 8.46 1H), 8.58 (ddd, J = 8.1, 2.0, 1.8 Hz, 1H), 8.76 (dd, J = 5.2, 9.31 (dd, J = 2.0 0.8 Hz, 1H) ppm; MS (DCI / NH3) H) Example 32 Hydrochloric acid of 3- (2,3-difluorophenin-5- (pyridin-3-yl) -1-oxadiazole Example 32A 3- (2,3-difluorophenyl) -5- (pyridin-3-yl) -1,2,4-oxadiazole The title compound according to Example 1 was prepared using 2,3-dif roxybenzimidamide (Tiger Scientific) and hydrochloride of the same. otinoyl (Aldrich). H NMR (300 MHz, DEMO-d6) d 7.42 -, 7.67 - 7.85 (m, 2H), 7.91 - 8.04 (m, 1H), 8.57 (dt, J = 8.1, 8.92 (dd, J = 4.8, 1.6 Hz , 1H), 9.36 (dd, J = 2.4, 0.8 Hz, DCI / NH3 m / z 260 M + H +. , 1?), 7.49 - 7.63 (m, 1?), 7.93 -8.07 (m, 1H), 8.24 (dd, J, 1H), 9.10 (dd, J = 5.8, 1.4 Hz, 1H), 9.23 (dt , J = 8.0, 1.8 6 (d, J = 2.0 Hz, 1H) ppm; MS (DCI / NH3) m / z 260 (M + H) \ Example 33 hydrochloric acid 3- (3,4-difluorophenyl) -5- (pyridin-3-yl) -1, 2,4-o Example 33A 3- (3,4-difluorophenyl) -5- (pyridin-3-yl) -1.2.4-oxadiazole The title compound according to the procedure of Example 1 was prepared using 3,4-di-roxybenzimidamide (Tiger Scientific) and hydrochloride of the same. otinoyl (Aldrich). 1 HJ MN (300 MHz, DEMO-d6) d 7.74 (d Hz, 1H), 8.60 (dt, J = 7.8, 2.1 Hz, 1H), 8.93 (dd, J = 4.8), 9.38 (dd, J = 2.2 , 1.0 Hz, 1H), 9.44 -9.48 (m, 3H) I / NH3) m / z 260 (M + H) \ Example 33B 3- (3,4-difluorophenyl) -5- (pyridin-3-iP-1 hydrochloric acid oxadiazole Example 34 5- (2,6-difluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotini drich) and acid 2,6- difluorobenzoic (Aldrich). 1 H NMR (3OD) d 7.29 (t, J = 8.6 Hz, 2H), 7.65 (ddd, J = 8.0, 4.9, 1.0 7 (tt, J = 8.6, 6.1 Hz, 1H), 8.57 (ddd, J = 8.3 , 1.9, 1.7 Hz,, J = 4.7, 1.7 Hz, 1H), 9.30 (dd, J = 2.2, 0.8 Hz, 1H) I / NH3) m / z 260 (+ H) +.

Example 35 3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzenesulfonam The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotine drich) and 3-sulfamoylbenzoic acid. (Oakwood). H NMR (3OD) d 7.65 (ddd, J = 8.0, 4.9, 1.0 Hz, 1H), 7.83 (t, J = 7.9 1 (ddd, J = 1.9, 1.8, 1.0 Hz, 1H), 8.45 (dt, J = 7.9, 1.4 Hz, J = 8.0 1.9 Hz 1H 8.73 -8.77 m 2H 9.31 dd J = 2.2 .1, 1.7 Hz, 1H), 9.30 (dd, J = 2.2, 0.8 Hz, 1H) ppm; EM (260 ( M + H) +.

Example 37 5- (2,3,4-trifluorophenyl) -3- (pyridin-3-yl) -1,2,4-oxadiazole The title compound was prepared according to Example 8 using N'-hydroxynicotini drich) and acid 2,3,4-trifluorobenzoic acid (Aldrich). 1 H NMR (3OD) d 7.37-7.48 (m, J = 9.3, 9.3, 7.1, 2.4 Hz, 1H), 7. .9, 5.0, 1.0 Hz, 1H), 8.08 -8.18 (m, 1H), 8.56 ( dt, J = 8.0), 8.75 (dd, J = 5.0, 1.8 Hz, 1H), 9.30 (dd, J = 2.0, 0.8 Hz, (DCI / NH3) m / z 278 (M + H) +.

Example 38 SQ ^ S-trifluoropheni-S-pyridin-S-iD-1, 2,4-oxadiazole The title compound was prepared according to Example 8 using N'-hydroxynicotini drich) and 3,4,5-trifluorobenzoic acid ( Aldrich). 1 H NMR (OD d 7.64 ddd J = 8.0 4.9 1.0 Hz 1H 8.01 -8.13 m Hz, 1H), 8.07 (ddd, J = 8.3, 2.0, 0.8 Hz, 1H), 8.12 (dd, J 1H), 8.55 (dt, J = 7.9, 2.0 Hz, 1H), 8.74 (dd, J = 5.0 1.8-8 -9.30 (m, 1H) ppm; MS (DCI / NH3) m / z 276 (+ H) +.

Example 40 5- (3-nitropheni0-3- (pyridin-3-yl) -1, 2,4-oxadiazole The title compound according to Example 8 was prepared using N'-hydroxynicotini rich) and 3-nitrobenzoyl chloride (Aldrich). 1 H NMR (3 Cl 3) d 7.44-7.55 (m, 1H), 7.82 (t, j = 8.3 Hz, 1H), 8.43, 8.80 (dd, J = 4.7, 1.7 Hz, 1H), 9.07 -9.13 (m, 1H), 9.42 1H) ppm; MS (DCI / NH3) m / z 269 (M + H) +.

Example 41 5- (3- (Methylsulfonyl) phenyl) -3- (pyridin-3-yl) -1,2,4-oxadiaz The title compound was prepared according to the procedure of Example 8 using N'-hydroxynicotini rich) and - (methylsulfonyl) benzoic (Aldrich). 1H z CD OD d 3.24 s 3H 7.65 ddd J = 8.0 4.9 1.0 Hz rich, 0.73 g, 5.27 mmol), and hydroxylamine (Aldrich, 50 wt. 27 mmol) in methanol (10 ml) at reflux and stirred for 1 in. Volatiles under reduced pressure to give the title. 1 H NMR (300 MHz, DEMO-d 6) d 6.09 (s, 2 H), .4, 1.4 Hz, 1 H), 7.73 (d, J = 2.0 Hz, 1 H), 8.40 (d, J = 5.2 22 (s, 1H) ppm; MS (DCI / NH3) m / z 172 (M + H) +, 174 (M + H Example 42B 3- (2-chloropyridin-4-yl) -5- (pyridin-3-yl) -1,2,4-oxadiazole The title compound according to Example 1 was prepared using the product of the nicotinoyl chloride hydride emulsion ( Aldrich). 1 H NMR (3 MO-de) d 7.73 (ddd, J = 8.0, 4.9, 1.0 Hz, 1H), 8.04 -8.13 9 (dt, J = 7.9, 2.0 Hz, 1H), 8.71 (d, J = 5.2 Hz , 1H), 8.92 (d Hz, 1H), 9.38 (dd, J = 2.2, 1.0 Hz, 1H) ppm; MS (DCI / NH3 H) +, 261 (M + H) +.

Example 43 3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzamide , J = 7.9, 2.0 Hz, 1H), 8.68 -8.73 (m, 1H), 8.83 (dd, J = 4.8), 9.28 (dd, J = 2.2, 1.0 Hz, 1H) ppm; MS (DCI / NH3) H) +.

Example 44 hydrochloric acid of 4- (5- (pyridin-3-in-1, 2,4-oxadiazol-3-yl) 2 (1H) -one A solution of the product of Example 42 (100 mg, 0. concentrated hydrochloric acid (Aldrich, 36.5%, 3.0 ml) was a microwave Emry ™ Creator at 150 ° C at 300 watt minutes .Then it was concentrated. Ethanol / ethyl acetate (v. 1/1, 5 ml) at a temperature of 1 hour.The title compound was collected and dried.1H NMR (300 Hz, DEMO-d6) d 6.75 (dd, J, 1H) , 7.04 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 5.9 Hz, 1H), 7., 1H), 8.56 (dt, J = 8.0, 1.9 Hz, 1H), 8.91 (dd, J = 5.0, 1.8 1 -9.40 (m, 1H) ppm; MS (DCI / NH3) m / z 241 (M + H) \ In the 45 Example 46 2-amino-5- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) phenol A solution of the product of Example 25 (2 ol) in tetrahydrofuran (10 ml) was stirred with Raney® nickel (Ald) under hydrogen at room temperature for 2 hr aligner was then removed by filtration and organic confection to give the title compound.1 H NMR (δ) d 5.67 (s, 2H), 6.74 ( d, J = 8.1 Hz, 1H), 7.41 - 7.50 2 (dd, J = 8.3, 4.6 Hz, 1H), 8.39 (dt, J = 8.2, 1.9, 1.7 Hz,, J = 4.7f 1.7 Hz, 1H) , 9.20 (d, J = 1.7 Hz, 1H), 9.74 (s (am; MS (DCI / NH3) m / z 255 (+ H) +.

Example 47 N, N-dimethyl-4- (5- (pyridin-3-yl) -1.2.4-oxadiazol-3-inpyridin-2 A solution of the product of Example 42 (100 mg, 0. dimethylformamide (2.0 ml) and hydroxide of ammonium (0.5 ml) was stirred at 150 ° C in a microwave Emry ™ Creator at 60 minutes: Then a solution of the product of Example 45 6 mmol) in methylene chloride (5 ml) was stirred with acid. Trifluoroa at room temperature for 4 hours, then the residue was concentrated and the residue was stirred in water (15 ml) while the precipitate was collected by filtration and dried for 1 h NMR (300 MHz, DEMO-d6) d 7. .9 , 4.8, 0.8 Hz, 1H), 7.83 (t, J = 7.5 Hz, 1H), 8.28 (ddd, J Hz, 1H), 8.42 -8.51 (m, 2H), 8.70 (t, J = 1.6 Hz, 1H ), .0, 1.8 Hz, 1H), 9.28 (dd, J = l 2, 1.0 Hz, 1H) ppm; MS (268 (+ H) +.

Example 49 Hydrochloric acid 5- (3- (1 H -tetrazol-5-yl) phenan-3- (pyridin-3-yl) oxadiazole A solution of the product of Example 1 (24 ol) in toluene (anhydrous, 10 ml) was stirred with azidotributyl drich, 498 mg, 1.50 mmol) at 110 ° C for 15 hours when cooled to room temperature at 100 Hz, 0.2H), 9.33 (dd, J = 2.2, 0.8 Hz, 0.8H) ppm; MS (DCI / (M + H) +.

Example 50 , N-diethyl-3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzenesulf Example 50A S-d ^ N -diethylsulfamadiDenzoic acid Diethylamine (Aldrich, 2.5 ml, 24 mmol) was added to a 3- (chlorosulfonyl) benzoic acid (Aldrich, 2.0 g, 9.1 loromethane anhydrous (20 ml) at 0 ° C. The mixture was then added for 2 hours. The residue was treated with hydrogen sulfate-bear (1.10 ml) and then extracted with ethyl acetate, the combined extracts were dried over sodium sulfate and then concentrated to give the IN compound (300 ml). MHz, CD3OD) d 1.13 (t, J = 7.1 Hz, 6H), 3.22 -3.30 9 (t, J = 7.8 Hz, 1H), 8.03 (ddd, J = 7.9, 1.9, 1.4 Hz, 1H), .8 1.4 Hz 1H 8.40 t J = 1.7 Hz 1H m EM DCI /, 8.48 (dt, J = 7.9, 1.5 Hz, 1H), 8.58 (dt, J = 8.1, 1.9 Hz, J = 1.5 Hz, 1H), 8.75 ( dd, J = 5.1, 1.7 Hz, 1H), 9.31 (dd, J 1H) ppm, MS (DCI / NH3) m / z 359 (M + H) +.

Example 51 2-Fluoro-5- (3- (pyridin-3-yn-1, 2,4-oxadiazol-5-yl) benzonit The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotini drich) and acid 3-cyano-4-fluorobenzoic acid (Aldrich). 1H R z, CD3OD) d ppm 7.62-7.71 (m, 2H), 8.54 -8.63 (m,, J = 5.9, 2.2 Hz, 1H), 8.75 (dd, J = 4.9, 1.5 Hz, 1H), 9.30 ( d Hz, 1H); MS (DCl / NH3) m / z 267 (M + H) +.

Example 52 hydrochloric acid 3- (3- (1 H-tetrazol-5-yl) phenyl) -5- (pyridin-3-oxadiazole It prepared e! composed of title of agreement procedure of Example 49 using the product of the dottributiltannana Aldrich. 1 H NMR 300 MHz Demog, 36.1 mmol) and hydroxylamine (Aldrich, 50% p, 2.38 g, 3 methanol (100 mL) at reflux and stir for 1 h.) Volatiles under reduced pressure to give the compound NMR (300 MHz, DEMO-d6) d 6.03 (s, 2H), 7.54 (d, J = 8.7 7 (dd, J = 8.3, 2.4 Hz, 1H), 8.67 (d, J = 2.8 Hz, 1H), 9.9; MS (DCI / NH3) m / z 172 (M + H) +, 189 (M + H) +.

Example 53B 3- (6-chloropyridin-3-yl) -5- (pyridin-3-yl) -1.2.4-oxadiazole The title compound according to the procedure of Example 1 was prepared using the product of the nicotinoyl chloride hydrate Ahem ( Aldrich). 1 H NMR (3OD) d 7.62-7.75 (m, 2H), 8.53 (dd, J = 8.1, 2.4 Hz, 1 7 (m, 1H), 8.85 (dd, J = 5.1, 1.7 Hz, 1H), 9.14 ( dd, J = 2.4), 9.39 (dd, J = 2.2, 0.8 Hz, 1H) ppm, MS (DCI / NH3) H) +, 261 (M + H) +.

Eem lo 54 Example 55 5- (5- (pyridin-3-yl) -1,2,4-oxadiazol-3-yl) pyridine-2 (1 H) -o A solution of the product of Example 53B 9 mmol) was heated in concentrated hydrochloric acid (1.0 ml rounds at 150 ° C at 300 watts for 60 minutes.) It was concentrated under reduced pressure and the residue was chromatographed [silica gel, CHCl3 / methanol (with ammonium oxide), v. 90/10] to give 1 H NMR (300 MHz, DE 0-d6) d 6.28 -6.73 (m, 1H), 7., 1H), 7.98 (dd, J = 9.5, 2.7 Hz, 1H), 8.14 (d, J) = 2.4 Hz, 1 6 (m, 1H), 8.89 (dd, J = 4.7, 1.7 Hz, 1H), 9.32 (d, J = 1.4 17 (s, 1H) ppm, MS (DCI / NH3) m / z 241 (M + H) +, 258 (M + N Example 56 5- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-inpyridin-2 (1 H) -o The title compound according to the procedure of Example 55 was prepared using the product of Ex NMR 300 MHz DEMO-d d 6.55 d J = 9.2 Hz 1H yield of Example 50A using azosulfonyl) benzoic acid (Aldrich) and methylamine (Aldrich). 1H z, CD3OD) d 2.54 (s, 3H), 7.70 (t, J = 7.8 Hz, 1H), 8.02), 8.23-8.28 (m, 1H), 8.45 (t, J = 1.9 Hz, 1H) ppm; MS (233 (M + NH4) +.

Example 57B -methyl-3- (3- (pyridin-3-yl) -1 ^^ -oxadiazole-S-iQbenzenesulfo The title compound was prepared according to Example 8 using N'-hydroxynicotini drich) and the product of Example 57A . H NMR (300 MHz, .60 (s, 3H), 7.65 (ddd, J = 8.1, 5.0, 0.8 Hz, 1H), 7.87 (t,), 8.15 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H ), 8.48 (ddd, J = 7.8, 1.), 8.58 (dt, Jy8.1, 1.9 Hz, 1H), 8.67 (t, J = 1.5 Hz, 1H), .7, 1.7 Hz, 1H), 9.31 (dd, J = 2.2, 0.8 Hz, 1H) ppm; MS (317 (M + H) +.

Example 58 3- (3- (pyridin-3-i0-1, 2,4-oxadiazol-5-yl) dihydrochloride Example 58B 3- (3- (Pyridin-3-ih-1, 2,4-oxadiazol-5-yl) a -Dihydrochloride a A solution of the product of Example 58A 5 mmol) was stirred in ethyl acetate (2 ml) with hydrochloric acid (n dioxane, 0.14 ml, 0.55 mmol) at room temperature. The title compound was collected by filtration or vacuum. 1 H NMR (300 MHz, DEMO-d 6) d 7.44 (d, J = 7.9 2 (t, J = 7.9 Hz, 1H), 7.80 (dd, J = 7.9, 5.2 Hz, 1H), 7.85-), 8.60 ( d, J = 7.9 Hz, 1H), 8.90 (d, J = 4.8 Hz, 1H), 9.31 (s, (DCI / NH3) m / z 239 (M + H) +, 256 (M + NH4) +.

Example 59 Bis (hydrochloric acid) of (3- (3- (pyridin-3-yl) -1,2,4-oxadia il) phenyl) methanamine A solution of the product of Example 62 4 mmol) in ethyl acetate (5 ml) was stirred with hydrochloric acid (in dioxane, 0.5 ml, 2.0 mmol) at room temperature. The reci tiate was collected by filtration method of Example 1 using N'-hydroxynicotini drich) and 2-chloroisonicotinoyl chloride (Maybridge). 1H z, DEMO-d6) d 7.68 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 8.16 (d Hz, 1H), 8.23 (dd, J = 1.5, 0.8 Hz, 1H), 8.42 -8.54 ( m,, J = 5.1, 0.7 Hz, 1H), 8.84 (dd, J = 4.7, 1.7 Hz, 1H), 9.28 (d Hz, 1H) ppm; MS (DCl / NH3) m / z 259 (M + H) \ 261 (M + H) \ Example 61 hydrochloric acid of 4- (3- (pyridin-3-yl) -1.2.4-oxadiazol-5-yl) 2 (1H) -one The title compound according to Example 44 was prepared using the NMR-axis product (300 MHz, DEMO-d6) d 6.81 (dd, J = 6.6, 1.9 Hz, 1.4 (m, 1H), 7.67-7.76 ( m, 2H), 8.51 (dt, J = 8.0, 1.9, 1.7 6 (dd, J = 4.9, 1.5 Hz, 1H), 9.28 (d, J = 1.4 Hz, 1H) I / NH3) m / z 241 ( M + H) \ E em lo 62 Example 63 5- (3-bromophenyl) -3- (pyridin-3-i0-1.2,4-oxadiazole The title compound according to the procedure of Example 1 was prepared using N'-hydroxynicotini drich) and 3-bromobenzoyl chloride (Aldrich) . 1 H NMR (O-d 6) d 7.60-7.71 (m, 2H), 7.98 (ddd, J = 8.1, 2.0, 1.0 2 (ddd, J = IA, 1.6, 1.3 Hz, 1H), 8.35 (t, J = 1.8 Hz, 1H), .9, 2.0 Hz, 1H), 8.83 (dd, J = 4.8, 1.6 Hz, 1H), 9.27 (dd, J 1H) ppm; MS (DCl / NH3) m / z 302 (M + H) +, 304 (+ H) +.

Example 64 1- (3- (3- (pyridin-3-yn-1,2,4-oxadiazole-5H-phenyl) pyrrolidin-2 A solution of the product of the Omg-axis, 0.66 mmol) and pyrrolidin-2-one (Aldrich, mg, 0.99 ene (anhydrous 10 ml) and purged with nitrogen three times, cesium (Aldrich, 324 mg, 0.993 mmol) and a (dibenzylideneacetone) dipalladium (0) (Aldrich, 12.1 mg, 0.01-bis diphenylphosphine -9.9 -dimethylxanthene Aldrich 23.0 m, 1H), 8.64 (t, J = 2.0 Hz, 1H), 8.82 (dd, J = 5.0, 1.8 Hz,, J = IA, 0.8 Hz, 1H) ppm, MS (DCI / NH3) m / z 307 (M + H) +.

Example 65 - (3- (pyridin-3-yl) -1, 2,4-oxadiazol-5-infenylcarbamate of ter The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotini drich) and 3- (tert. -butoxycarbonylamino) benzoic acid (Ald i (300 MHz, CDCl 3) d 1.56 (s, 9H), 6.71 (s, 1H), 7.39 -), 7.68 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 8.24 5 (d, J = 7.9 Hz, 1H), 8.77 (d, J = 4.8 Hz, 1H), 9.40 (s, 1H) I / NH3) m / z 339 (M + H) +, 356 (+ NH4) +.

Example 66 N, N-dimethyl-1- (3- (3- (pyridin-3-yl) -1,2,4-oxadiazole-5- iD-phenylmethanamine, salt of the hydrochloric acid The free base of the title compound of the process was prepared of Example 8 use Roxinicotinimidamide Aldrich i I / NH3) m / z 281 (M + H) +.

Example 67 is (hydrochloric acid) of 5- (3- (piperazin-1 -yl) phenyl) -3- (pyridine) 1, 2,4-oxadiazole Example 67A (3- (3- (pyridin-3-yl) -1,4-oxadiazol-5-yl) phenyl) piperazin-1 -ca tere-butyl A solution of the product of the Omg Ex, 0.66 mmol) and tere-butyl piperazine-1-carboxylate mg, 0.66 mmol) was degassed in toluene (anhydrous, 10 ml) and progen peroxide three times, sodium t-butoxide (Al. , 0.66 mmol) and tris (dibenzylidene ketone) dipalladium (0) (Ald, 0.013 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene .O mg, 0.040 mmol, xantho), degassed and purge three times . The mixture was then heated to 100 ° or nitrogen for 15 hours. It was then when environment ambient diluted with ethyl acetate 50 ml Example 67B is (hydrochloric acid) of 5- (3- (piperazin-1 -yl) phenyl) -3- (pyridine) 1, 2,4-oxadiazole The title compound according to Example 59 was prepared using the NMR axis product (300 MHz, CD3OD) d 3.40 -3.48 (m, 4H), 3.54 -3.62 2 (ddd, J = 8.3, 2.8, 0.8 Hz, 1H), 7.58 (t, J = 8.1 Hz, 1H), 7., 2H), 8.24 -8.39 (m, 1H), 9.08 (d, J = 5.9 Hz, 1H) t 9.32 (Hz, 1H), 9.59 (d, J = 1.6 Hz, 1H) ppm; MS (DCI / NH3) H) +.

Example 68 1 - . 1- (3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) phenyl) ethanone The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotini drich) and 3-acetylbenzoic acid (Aldrich). H NMR (3 3OD) d 2.72 (s, 3H), 7.66 (ddd, J = 8.0, 4.9, 1.0 Hz, 1H) .1 Hz, 1H, 8.31 ddd, J = 8.1 1.4 1.2 Hz 1H 8.47 dd d 7.41 - 7.59 (m, 1?), 7.76 - 7.93 (m, 2H), 8.05 (dd, J 1H), 8.48 (dd, J = 8.3, 2.5 Hz, 1H), 9.08 (d, J = 2.4 Hz, (DCI NH 3) m / z 294 (M + H) +, 296 (M + H) +.

Example 70 3- (6-chloropyridin-3-yl) -5- (3,4-difluorophenyl) -1,2,4-oxadia The title compound according to the procedure of Example 1 was prepared using the product of the Example 3, 4-difluorobenzoyl (Aldrich). 1 H NMR (300 MH d ppm 7.70-7.83 (m, 2H), 8.03-8.15 (m, 1H), 8.22-8.36 8 (dd, J = 8.1, 2.4 Hz, 1H), 9.08 (d, J = 2.4 Hz , 1H) I / NH3) m / z 294 (M + H) +, 296 (M + H) \ Example 71 (hydrochloric acid) of (R) -3- (pyridin-3-in-5- (3- (pyrrolidin-2) 1, 2,4-oxadiazole Example 71 A (3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) phenyl) pyrrolidin-1-ca of (R) -tert-butyl At room temperature, stirred for another 30 minutes before adding a solution of Pro 63 (0.30 g, 1.0 mmol) in tetrahydrofuran (anhydrous, (tri-t-butylphosphine) palladium (0) (Strem, 10.2 mg 0.02 mmol) was mixed at room temperature for 15 hours with ammonium hydroxide (5 ml), ethyl acetate (3 x 20 ml) was extracted, the binases were concentrated and purified by chromatography / ethyl acetate = 1. / 1, Rf = 0.5) to give the comp. 1H RN (300 MHz, CD3OD) d 1.19 (s (broad), 6H) plio), 3H), 1.83-2.00 (m, 2H), 2.37 -2.55 (m, J = 8.1, 8.1 7 -3.72 (m, 2H), 4.90 -5.14 (m, 1H), 7.47-7.73 (m, 3 5 (m, 2H), 8.56 (dt, J = 8.3, 1.8 Hz, 1H), 8.74 (dd, J = 5.1), 9.29 (dd, J = 2.0, 0.7 Hz, 1H) ppm; MS (DCI / NH3) H) +.

Example 71 B hydrochloric acid) of (R) -3- (pyridin-3-yl) -5- (3- (pyrrolidin-2 Example 72 5- (3- (1H-pyrazol-3-infenin-3- (pyridin-3-in-1.2.4-oxadia The title compound according to the procedure of Example 8 was prepared using N'-hydroxynicotini-drich) and - (1 H-pyrazol-3-yl) benzoic (Maybridge) 0 MHz, DEMO-de) d 6.91 (d, J = 2.4 Hz, 1H), 7.62 - 7.69 2 (t, J = 7.8 Hz, 1H) , 7.79-7.92 (m, 1H), 7.82-7.88 (m, 1 0 (m, 3H), 8.49 (dt, J = 8.2, 1.9, 1.7 Hz, 1H), 8.64 (s, 1H), .1, 1.7 Hz, 1H), 9.29 (dd, J = 2.2, 0.8 Hz, 1H) ppm, MS (290 (M + H) +.

Example 73 1- (3- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) pheninetanol A solution of the product of Example 68 (26 ol) in ethanol (5 ml) was stirred with sodium borohydride. (Aldrich, 8 ol) at room temperature for 16 hours.Rangent was filtered with a syringe filter and the Gilson reagent HPLC mixture was purified Xbrid e® column 5 +?) +.

Example 74 3- (3- (6-chloropyridin-3-yl) -1, 2,4-0X3018201-5-11) be nzonitr The title compound according to the procedure of Example 1 was prepared using the product of the Example 3 cyanobenzoyl (Aldrich). 1 H NMR (300 MHz, 2 (d, J = 7.8 Hz, 1 H), 7.75 (t, J = 8.0 Hz, 1 H), 7.93 (d, J = 7.8 0 -8.50 (m, 2 H), 8.54 (s, 1H), 9.19 (d, J = 2.4 Hz, 1H) I / NH3) m / z 283 (M + H) +, 300 (M + NH4) +.

Example 75 3- (4-fluorophenyl) -5- (pyridin-3-ih-1,2,4-oxadiazole) 4-Fluoro-N'-hydroxybenzimidamide (0.154 g, pyridine (10 ml) was dissolved and nicotinoyl chloride (Aldri 1 The reaction mixture was heated to reflux and then cooled to room temperature.

The reaction mixture was then added with water (25 ml) and the solid was fi xed additionally with procedure of Example 4B using 3-roxybenzimidamide (Example 4A) and 6-chloron drich chloride). 1 H NMR (300 MHz, DEMO-d 6) 57.87 (m, 2 H), 8.17 (m, 1 H), 8.43 (d, J = 1.7 Hz, 1 H), 8.6 (m, 1 H), 9.25 (d,) ppm; MS (DCl / NH3) m / z 283 (M + H) +.

Example 77 3- (5- (2-f luoropi ridin * 3-yl) -1, 2,4-oxadiazole-3-i0benzonit The title compound according to Example 4B was prepared using 3-roxybenzimidamide (Example 4A) and chloride of 2-fluoron drich). 1 H NMR (300 MHz, DEMO-d 6) d 7.87 (m, 1 H), 7.95 7 (m, 1 H), 8.17 (m, 1 H), 8.43 (m, 1 H), 8.6 (m, 1 H), 8.; MS (DCl / NH3) m / z 267 (M + H) +.

Example 78 3-Fluoro-5- (5- (pyridin-3-yl) -1,2,4-oxadiazol-3-yl) benzonit The title compound according to Example 79A was re-established.

Pyrimidine-5-carboxamide A solution of pyrimidine-5-carboxylate of 0.0 mmol) in methanol (40 ml) was stirred with ammonium hydroxide mmol) in a sealed tube at 50 ° C for 10 hours. The reaction mixture was concentrated and the nucleol / ethyl acetate (v / v 1/4, 50 ml) was stirred at a temperature of 2 hours. The precipitate was collected by filtration and dried to give the title compound. 0 MHz, DEMO-d6) d 7.85 [s (broad), 1H], 8.33 [s (amp 8 (s, 2H), 9.32 (s, 1H) ppm; MS (DCI / NH3) m / z 124 (M NH4) +.

Example 79B Pyrimidine-5-carbonitrile Slowly added to a suspension of the prodrug 79A (6.75 g, 54.8 mmol) and triethylamine (Aldrich, mmol in anhydrous CI CH Aldrich 400 ml one sol Example 79C N'-hydroxypyrimidine-S-carboximidamide A solution of the product of Example 79B (5%) and aqueous hydroxylamine (Aldrich, 50%, 2.3 ml, 78 tanol (50 ml) at 65 ° C for 1 hour was stirred and then reduced concession to remove volatiles. The re Ac (30 mL) was triturated, the precipitates were harvested by fi ron to give the title compound.1H NMR (300 MH d 6.14 (s, 2H), 9.03 (s, 2H), 9.18 (s, 1H). ), 10.06 (s, 1H) I / NH3) m / z 139 (M + H) +, 156 (M + NH4) +.

Example 79D 5- (2,3-difluorophenyl) -3- (pyrimidin-5-yl) -1,2,4-oxadiazo The title compound was prepared according to Method D using the product of the 2,3-difluorobenzoylidemide ( Aldrich). 1 H NMR (300 MHz, 7 - 7.39 (m, 1H), 7.42 - 7.56 (m, 1H), 7.95-8.08 (m, 1H), 9.49 (s, 2H) ppm; MS (DCI / NH3) m / z 261 (M + H) +.

Example 81 Fluoro-N, N-dimethyl-4- (3- (pyrimidin-5-ih-1, 2,4-oxadiazole-5) The title compound was prepared according to Method C using the product of Example 3.4 -difluorobenzoic acid (Aldrich) .H NMR (300 MHz, 6 (s, 3H), 3.07 (s, 3H), 6.89 (t, J = 8.7 Hz, 1H), 7.76-7.9 6 (s, 1H), 9.43- 9.47 (m, 2H) ppm; MS (DCI / NH3) m / z 286 Example 82 3- (3- (pyrimidin-5-yl) -1,2,4-oxadiazol-5-yl) benzonitrile The title compound was prepared according to Method D using the product of the 3-cyanobenzoyl ether (Aldrich) . 1 H NMR (300 MHz, DE 1 (t, J = 7.9 Hz, 1H), 8.24 (dt, J = 7.7, 1.4, 1.2 Hz, 1H), .1, 1.4, 1.2 Hz, 1H), 8.67 (t, J = 1.8 Hz, 1H), 9.45 (s, 1H)) ppm; MS (DCI / NH3) m / z 250 (M + H) +.

Example 83 5- (3,4-Difluorophenyl) -3-iridazin-4-i-1-24-o-hydrochloride Ac (3 x 100 mi). The combined extracts were washed (2 x 20 mL) and dried over magnesium sulfate, drying agent and the organic solution was concentrated and the title compound was dried. H NMR (300 Hz, DE O-d6) d 3.3 0 (dd, J = 5.2, 2.4 Hz, 1H), 9.52 (dd, J = 5.2, 1.2 Hz, 1H), .2, 1.4 Hz, 1H) ppm; MS (DCI / NH3) m / z 139 (+ H) +.

Example 83B P irid azi? -4-carboxa mida The title compound according to Example 79A was prepared using the product of the Ex and ammonium hydroxide (Aldrich). 1 H NMR (300 MHz, DE 0 (dd, J = 5.2, 2.4 Hz, 1 H), 8.46 [s (broad), 2 H], 9.44 (d Hz, 1 H), 9.55 (dd, J = 2.2, 1.4 Hz, 1H) ppm; MS (DCI / NH3 + H)? 141 (M + NH4) +.

Example 83C pyridazin-4-carbonitrile The title list of acuer and hydroxylamine (Aldrich) was reviewed. 1 H NMR (300 MHz, DMSO-d 2 H), 7.87 (dd, J = 5.4, 2.4 Hz, 1 H), 9.25 (dd, J = 5.4, 1.4 6 (dd, J = 2.4, 1.4 Hz, 1H), 10.36 (s, 1 H) ppm; MS (DCI / 1 (M + H) 156 (M + NH 4) +.

Example 83E 5- (3,4-difluorophenyl) -3- (pyridazin-4-yl) -1,2,4-oxadiazo The title compound was prepared according to Method D using the 3,4-boron Aureus product. difluorobenzoyl (Aldrich). 1 H NMR (300 MH d 7.80 (dt, J = 10.5, 8.3 Hz, 1 H), 8.08 -8.19 (m, 1 H), .4, 2.4 Hz, 1 H), 8.31 -8.38 (m, 1 H), 9.55 (dd) , J = 5.4, 1.4 2 (dd, J = 12, 1.2 Hz, 1H) ppm; MS (DCI / NH3) m / z 261 (M + Example 83F 5- (3,4-d.fluorophenyl) -3- (pyridazin-4-yl) -1.2.4-o hydrochloride. A solution of the product of Example 83E 4 mmol) was stirred in ethyl acetate (5.0 ml) with hydrochloric acid I in dioxan 25 Method D yield using the product of the nicotinoyl chloride hydrate (Aldrich). H NMR (MO-d6) d 7.75 (ddd, J = 8.0, 4.9, 0.7 Hz, 1H), 8.32 (dd, J 1H), 8.61 (dt, J = 8.2, 1.8 Hz, 1H), 8.93 (dd, J = 5.1, 1.7 9 (dd, J = 2.2, 0.8 Hz, 1H), 9.55 (dd, J = 5.4, 1.4 Hz , 1H), .2, 1.2 Hz, 1H) ppm; MS (DCl / NH3) m / z 226 (M + H) +.

Example 85 N, N-dimethyl-N, - (4- (3- (pyrimidin-5-yl) -1,2,4-oxadiazole- D-phenylsulfonium-formimidamide The title compound was prepared according to Method D using the product of the dimethylformamide Example of 4-sulfamide Aesar chloride). 1 H NMR (300 MHz, DEMO-d 6) d 2.94 (s, 3 H),), 8.06 (d, J = 8.8 Hz, 2 H), 8.30 (s, 1 H), 8.37 (d, J = 8.8 5 (s, 1H), 9.46 (s, 2H) ppm, MS (DCI / NH3) m / z = 359 (M + NH4) +. em l The title compound according to Method D was prepared using the product of the Ahem luorobenzoyl chloride (Aldrich). 1 H NMR (300 MHz, DE 1 - 7.71 (m, 1 H), 7.72 - 7.84 (m, 1 H), 8.04 (ddd, J = 9.3 1 H), 8.07 -8.12 (m, 1 H), 9.45 (s, 3 H) ppm, MS (DCI / N 3 (M + H) 260 (M + NH 4) +.

Example 88 3- (pyrimidin-5-yl) -5- (3A5-triluoropheniD-1, 2,4-oxadiazo) The title compound was prepared according to Method D using the 3,4,5-trifluorobenzoyl ether product (Aldrich 1 H NMR (3 MO-d 6) d 8.24 (dd, J = 8.0, 6.6 Hz, 2H), 9.44 (s, 2H), 9.4 m, MS (DCI / NH3) m / z = 279 (M + H ) +, 296 (M + NH4) +.

Example 89 5- (2-Chloropyridin-4-yl) -3- (pyrimidin-5-yl) -1, 2,4-oxadiaz The title compound was prepared according to Method D using the product of E em ger) and pyrimidine-5-carboxylic acid (Maybridge). 1H R z, DEMO-d6) d 7.68 (ddd, J = 8.0f 4.9, 1.0 Hz, 1H), 8.48 (Hz, 1H), 8.84 (dd, J = 4.7, 1.7 Hz, 1H), 9.29 (dd, J = 2.4), 9.51 (s, 1H), 9.56 (s, 2H) ppm; MS (DCI / NH3) m / z = 22 (M + NH4) +.

Example 91 5- (Pyridazin-4-yl) -3- (pyridin-3-yl) -1,4, -2-oxadiazole The title compound was prepared according to Method C using N'-hydroxynicotini drich) and pyridazin- 4-carboxylic acid (Aldrich). 1 H NMR (3OD) d 7.67 (ddd, J = 8.1t 5.0, 0.8 Hz, 1H), 8.45 (dd, J = 5.) t 8.60 (dt, J = 8.1, 1.9 Hz, 1H), 8.78 (dd, J = 5.1, 1.7 Hz,, J = 2.2, 0.8 Hz, 1H), 9.55 (dd, J = 5.4, 1.4 Hz, 1H), 9.94 (Hz, 1H) ppm; MS (DCl / NH3) m / z = 226 (M + H) +.

Example 92 3- (3- (pyridazin-4-yl) -1 ^^ -oxadiazole-S-iPbenzonitrile The title compound was reacted. The title compound was prepared according to Method D using the product of the Example of 3-fluorobenzoyl (Aldrich). 1 H NMR (300 MHz, 5- 7.53 (m, 1H), 7.69 (td, J = 8.1, 5.6 Hz, 1H), 8.00 (dd, 1.4 Hz, 1H), 8.11 (dt) , J = 7.9, 1.2 Hz, 1H), 8.39 (dd, J, 1H), 9.45 (dd, J = 5.2, 1.2 Hz, 1H), 9.87 (dd, J = 2.2, 1.

; MS (DCl / NH3) m / z = 243 (M + H) +.

Example 94 3- (Pyridazin-4-ih-5- (3A5-trifluorophenyl) -1, 2,4-oxadiaz The title compound was prepared according to Method D using the 3,4,5-trifluorobenzoyl ether product. (Aldrich) .H NMR (3 3OD) d 8.04 -8.16 (m, 2H), 8.38 (dd, J = 5.4, 2.2 Hz, 1H), .4, 1.4 Hz, 1H), 9.86 (dd, J = 2.4 , 1.2 Hz, 1H) ppm; MS (= 279 (M + H) +.

Example 95 5- (3,5-difluorophenyl) -3- (pyridazin-4-yl) -1.2.4-oxadiazo The title compound according to Method D was prepared using the product of 4-fluorobenzoyl ether (Aldrich). 1 H NMR (300 MHz, 6 - 7.45 (m, 2H), 8.29 -8.40 (m, 3H), 9.45 (dd, J = 5.6, 1.2 6 (dd, J = 2.4, 1.2 Hz, 1H) ppm; MS ( DCI / NH3) m / z = 243 ( Example 97 3- (pyridazin-4-iD-5- (pyrimidin-5-yl) -1,2, 2,4-oxadiazole The title compound was prepared according to Method C using the pyrimidine-5-carboxylic acid product ( Maybridge). 1 H NMR (3 3OD) d 8.41 (dd, J = 5.4, 2.4 Hz, 1H), 9.44 (s, 1H), 9.47 (Hz, 1H), 9.59 (s, 2H), 9.90 (dd, J = 2.2, 1.2 Hz, 1H) Example 98 3- (Pyridazin-4-yl) -5- (2.3.6-trifluorophenyl) -1.2.4-oxadiaz The title compound was prepared according to Method D using the product of the Method D Method using the product of the 2,3,4-trifluorobenzoyl ether (Aldrich). 1 H NMR (3 3OD) d 7.40-7.50 (m, J = 9.3, 9.3, 7.0, 2.2 Hz, 1H), 8.10), 8.39 (dd, J = 5.4, 2.4 Hz, 1H), 9.46 (dd, J = 5.3, 1.2 Hz,, J = 12, 1.2 Hz, 1H) ppm; MS (DCI / NH3) m / z = 279 (M + H) +.

Example 100 N.N-dimethyl-N '- (4- (3- (pyridazin-4-yl) -1,2,4-oxadiazol-yl) phenylsulfonyl) formimidamide The title compound according to Method D was prepared using the product of the dimethylformamide Example of 4-sulfamide fa. Aesar) chloride. H NMR (300 MHz, CD3OD) d 2.95 (s, 3H), 3.1 6 (d, J = 8.5 Hz, 2H), 8.29 (s, 1H), 8.31 (dd, J = 5.3, 2.2 7 (d, J = 8.8 Hz, 2H), 9.54 (dd, J = 5.1, 1.4 Hz, 1H), 9.83 (Hz, 1H) ppm, MS (DCI / NH3) m / z = 359 (M + H) +.

Example 101 Example 1Q1B 5- (3,4-Difluorophenyl) -3- (pyrimidin-5-yl) -1, 2,4-ox tosylate A solution of the product from Example 101A (52 mg, ethyl acetate (5 ml) was stirred with a solution toluene sulfonic acid nohydrate (Aldrich, 46.0 mg, 0. ethyl acetate (1.0 ml) at room temperature du, The precipitates were collected by filtration to give the title compound.1H NMR (300 Hz, CDCl3), 7.25 (d. , J = 8.2 Hz, 2H), 7.36 - 7.53 (m, 1H), 7.83 (d, J), 8.03-8.12 (m, 2H), 9.57 (s, 1H), 9.71 (s, 2H), E ( DCI / 1 (M + H) +.

Example 102 3- (3,4-difluorophenyl) -5- (pyrimidin-5-i0-1, 2,4-oxadiazo) The title compound was prepared according to Method D using 3,4-di-roxybenzimidamide Ti-irimidine chloride -5-carb Example 103 3- (Pyrimidin-5-in-5- (2,3,4-trifluorophenyl) -1,2,4-oxadiaz The title compound was prepared according to Method D using the product of the Example of 2,3,4-urea. -trifluorobenzoyl (Aldrich) .1H NMR (3? -de) d 7.58-7.75 (m, 1?), 8.03-8.26 (m, 1H), 9.44 (s, 1H) ppm; MS (DCI / NH3) m / z 279 (M + H)? 296 (M + NH4) +.

Example 104 3- (pyrimidin-5-yl) -5- (2.3.6-trifluorophenyl) -1,2,4-oxadiaz The title compound was prepared according to Method D using the product of the Example of 2, 3,6-trifluorobenzoyl (Aldrich). 1 H NMR (3 MO-d 6) d 7.48-7.61 (m, 1H), 7.89-8.07 (m, 1H), 9.44 5 (s, 1H) ppm; MS (DCI / NH3) m / z 279 (M + H) +, 296 (M + NH Example 105 3- (pyrimidin-5-yl) -5- (2,3,4,5-tetrafluorophenyl) -1, 2,4-oxadi The title compound was reacted according to hydroxynicotinimidamide (Tiger). H NMR (300 MHz, DE 7 (ddd, J = 8.1, 4.8, 1.0 Hz, 1H), 7.76 (d, J = 1.4 Hz, 1H) f 7., 2H), 8.21 (s, 1H), 8.46 ( dt, J = 8.2, 1.8 Hz, 1H), 8.83 (d Hz, 1H), 9.27 (dd, J = 2.2, 0.8 Hz, 1H), 9.69 (dd, J = 1.7ppm, EM (DCI / NH3) m / z 264 (M + H) +.

Example 107 5- (1 H-indol-6-yl) -3- (pyridin-3-yl) -1,2,4-oxadiazole The title compound was prepared according to the procedure by using 1 H-indole-6-acid. carboxylic (Aldrich) roxinicotinimidamide (Tiger). 1 H NMR (300 MHz, DEMO-d, J = 3.0, 1.9, 0.8 Hz, 1 H), 7.62 - 7.71 (m, 2 H), 7.76 -, 8.27 -8.33 (m, J = 1.4 Hz, 1 H), 8.46 ( dt, J = 8.2, 1.9, 1.7 2 (dd, J = 4.7, 1.7 Hz, 1H), 9.27 (dd, J = 2.2, 0.8 Hz, 1H),) ppm; MS (DCI / NH3) m / z 263 (M + H) +.

Example 108 - -dim il zolo - - - - - - - - Example 109 (2,2-difluorobenzordiri, 31-dioxol-5-yl) -3- (pyridin-3-in-1.2.4- The title compound was prepared according to the reaction by using 2,2-difluorobenzo [d] [1] acid. , 3] dioxole-5-c drich) and N'-hydroxynicotinimidamide (Tiger). 1 H NMR (MO-d 6) d 7.66 (ddd, J = 8.1, 4.8, 1.0 Hz, 1H), 7.73 (d,, 8.14 (dd, J = 8.5, 1.7 Hz, 1H), 8.25 (d, J = 1.7 Hz, 1H), .2, 1.9, 1.7 Hz, 1H), 8.82 (dd, J = 4.7, 1.7 Hz, 1H), 9.25 (Hz, 1H) ppm; MS (DCl / NH3) m / z 304 (M + H) +.

Example 110 5- (2-methylbenzofuran-5-yn-3- (pyridin-3-yl) -1.2.4-oxadia The title compound was prepared according to the procedure by carrying out 2-methylbenzofuran-5-carboxylic acid (Chembrid roxinicotinimidamide ( Tiger). H NMR (300 Hz, DEMO-3H), 6.58 -6.97 (m, 1H), 7.66 (ddd, J = 8.0, 4.9, 1.0 Hz, J = 8.5 Hz, 1H), 8.40 -8.55 (m, 2H), 8.82 (dd, J = 4.7, 1.7 7 dd J = 2.2 0.8 Hz 1H m EM DCI / NH m / z 278 M ) ppm; MS (DCl / NH3) m / z 282 (M + H) +.

Example 112 5-? H-benzordlimidazol-5-yl) -3- (pyridin-3-i0-1.2,4-oxadi) The title compound was prepared according to the procedure using 1 H-benzo [d] imidazole-5-carboxylic acid (Aldric). roxinicotinimidamide (Tiger). H NMR (300 Hz, OD Odd, J = 8.1, 4.8, 1.0 Hz, 1H), 7.75- 7.98 (m, 1H), 7.99 -8.17 4 -8.56 (m, 3H), 8.82 ( dd, J = 5.1, 1.7 Hz, 1H), 9.28 (dd, J 1 H) ppm, MS (DCI / NH3) m / z 264 (M + H) +.

Example 113 5- (1H-benzordU1.2.31triazol-5-yl) -3- (pyridin-3-yl) -1,2,4-oxa The title compound was prepared according to the procedure using 1 H-benzo acid [d] [1,2,3] triazole-5-carboxylic acid (Aldr roxinicotinimidamide (Tiger). 1 H NMR (300 MHz, DEMO-d, J = 8.0, 4.9, 0.7 Hz, 1H), 8.10-8.20 (m, 1H), 8.22 -8.31 9 (dt, J = 8.1, 2.0, 1.7 Hz, 1H), 8.75-8.92 (m, 2H), 9.30 (d Hz 1H m EM DCI / NH m / z 265 M + H +.

Example 115 3- (pyridin-3-in-5-M-H-pyrrolor-2,3-blpyridin-5-in-1, 2,4-oxad) The title compound was prepared according to the procedure using 1 H-pyrrolo acid [2,3 -b] pyridine-5-carboxylic acid (Ade roxinicotinimidamide (Tiger). 1H NMR (300 MHz, DEMO-d J = 3.4 Hz, 1H), 7.66 (ddd, J = 1.9, 4.8, 0.8 Hz, 1H), 7.70, 1H), 8.47 (dt, J = 8.1, 1.9 Hz, 1H), 8.78 -8.86 (m, 2H), .0 Hz, 1H), 9.28 (dd, J = 2.2, 0.8 Hz, 1H) ppm; MS (DCI / (M + H) +.

Example 116 5- (1H-indol-5-in-3- (pyridin-3-in-1.2.4-oxadiazole) The title compound was prepared according to the procedure by using 1 H-indole-5-carboxylic acid (Aldrich) roxynicotinimidamide (Tiger). 1 H NMR (300 MHz, DEMO-d, J = 2.3, 1.4 Hz, 1 H), 7.55 (t, j = 2.7 Hz, 1 H), 7.62 - 7.70 4 (dd, J = 8.8, 1.7 Hz, 1H), 8.46 (dt, J = 8.1, 1.9 Hz, 1H), 8 1H 8.81 dd J = 4.7 1.7 Hz 1H 9.27 dd J = 2.2. , 8.60 (d, J = 1.4 Hz, 1H), 8.82 (dd, J = 4.7, 1.7 Hz, 1H), .2, 0.8 Hz, 1H) ppm; MS (DCI / NH3) m / z 264 (M + H) +.

Example 118 - (1 -metí 1-1 H-benzo [dlimidazol-5-il) -3- (pyridin-3-yl) -1, 2,4-o The title compound was prepared according to the one by raising 1-methyl-1H-benzo [d] imidazole-5-c-abridge) and N'-hydroxynicotinimidamide (Tiger). H NMR (MO-d6) d7.65 (ddd, J = 8.0, 4.9, 0.7 Hz, 1H), 7.68-7.88 1H), 7.87 -8.10 (m, 2H), 8.14 -8.37 (m, 1H), 8.46 (dt, J 1H), 8.82 (dd, J = 4.7, 1.7 Hz, 1H), 9.27 (dd, J = 2.0, 0.m, EM (DCI / NH3) m / z 278 (M + H) +.

Example 119 3- (imidazo H.sub.2 -alpyridin-6-yl) -5- (pyridin-3-yl) -1, 2,4-oxadi The title compound was prepared according to the II raising N'- hydroxyimidazo [1,2-a] pyridine-6-carboxy onet) and nicotinoyl chloride, hydrochloric acid (Aldrich). 0 MHz DEMO-d d 7.62 - 7.91 m 4H 8.20 s 1H .3 Hz, 1H), 8.20 (s, 1H), 8.59 (dd, J = 8.5, 2.6 Hz, 1H), .4, 0.8 Hz, 1H) , 9.47 (t, J = 1.4 Hz, 1H) ppm; MS (DCI / 8 (M + H) +, 300 (M + H) +.

Example 121 - (6-fluropyridin-3-in-3- (imidazon.2-a1pyridin-6-in-1.2.4-ox The title compound was prepared according to the I nizing N'-hydroxyimidazo [1,2-a] pyridine-6-carboxy onet) and 6-fluoronicotinic acid (Frontier). 1H RN (?? - of) d 7.55 (ddd, J = 8.5, 2.7, 0.7 Hz, 1H), 7.70 (d,, 7.73- 7.86 (m, 2H), 8.20 (s, 1H), 8.75 (ddd, J = 8.1, 2.5 8 (dt, J = 1.7, 0.8 Hz, 1H), 9.46 (dd, J = 1.7, 1.0 Hz, 1H) CI / NH3) m / z 282 (M + H) +.

Example 122 - (5-fluropyridin-3-yn-3- (imidazof1.2-a1pyridin-6-yl) -1, 2,4-ox The title compound was prepared according to the I nizing N'-hydroxyimidazo [1, 2-a] pyridine-6-carboxy - 1 roxinicotinimidamida (Tiger). 1 H NMR (300 MHz, DE O-, J = 1.9, 4.8 Hz, 1H), 7.8 (d, J = 8.7 Hz, 1H), 8.2 (dd, J = 8.), 8.4 (s, 1H) 8.5 ( dt, J = 1.9, 1.8 Hz, 1H), 8.7 (s, 1H) .8, 1.6 Hz, 1H), 9.3 (d, J = 2.0 Hz, 1H), 13.6 (s, 1H) I / NH3) m / z 264 (M + H) \ Example 124 - (n.2.41triazolor4.3-alpyridin-6-yl) -3- (pyridin-3-yl) -1.2t4-ox Example 124 A 5- (6-chloropyridin-3-yn-3- (pyridin-3-yl) -1,2,4-oxadiazole The title compound was prepared according to the procedure using N'-hydroxynicotinimidamide (Tiger) and ronicotinoyl chloride (Aldrich 1 H NMR (300 MHz, CDCl 3) d .6, 5.3 Hz, 1 H), 7.57 (d, J = 8.5 Hz, 1 H), 8.40 -8.48 (m,, J = 4.7, 1.7 Hz, 1 H), 9.24 (d, J = 2.4 Hz, 1H), 9.40 (d,) ppm; MS (DCl / NH3) m / z 259 (M + H) +, 261 (M + H) +.

Example 124B 5- (6-Hydrazinyl iridin-3-yl-3-iri-yl-2 - 1H), 8.58 (dt, J = 4.0, 1.9 Hz, 1H), 8.75-8.84 (m, 1H), 12, 0.8 Hz, 1H) ppm, MS (DCI / NH3) m / z = 255 (M + H ) + Example 124C - (ri.2,41-triazol-4,3-a1-pyridin-6-yn-3- (pyridin-3-yl) -1,2,4-ox. A suspension of the product of the Example, 0.31 mmol) in triethoxymethane (Aldrich, 4 ml) was heated. ) at reflow d ras. The reaction mixture was cooled to room temperature and the volatiles were mined under vacuum. The residue is purified by chromatography (Si02, EtOAcZCH2CI2 = 1/9) to give the residue. 1HRMN (DEMO-d6): d 7.68 (dd, J = 8.1, 5.0 Hz, 1H), 7, 2H), 8.46 (dt, J = 7.9, 2.0 Hz, 1H), 8.84 (dd, J = 4.8, 1.6 7 (d, J = 2.0 Hz, 1H), 9.44 (s, 1H), 9.68 (s, 1H) ppm, MS (= 265 (M + H) + Example 125 5- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-inbenzordloxazole-2 (3) The title compound was prepared according to the procedure by using 2-oxo-23-dihydrobodium oxol 5-c The title compound was prepared according to the lapping 2-mercapto-5-benzimidazolecarboxylic acid (Pri hydroxynicotinimidamide (Tiger). 1 H NMR (300 MHz, CD3O J = 8.5 Hz, 1H), 7.65 (ddd, J = 8.0, 4.9 , 0.7 Hz, 1H), 7.86 1H), 8.00 (dd, J = 8.1, 1.7 Hz, 1H), 8.45 (dt, J = 8.0, 1.9 1 (dd, J = 4.9, 1.5 Hz, 1H), 9.26 (dd, J = 2.2, 0.9 Hz , 1H) I / NH3) m / z 296 (M + H) +.

Example 127 1. 3-dimethyl-5- (3- (pyridin-3-yl) -1.2.4-oxadiazol-5-in-1H-benzoidlimidazole-2 (3H) -one The title compound was prepared according to the procedure 1, 3-dimethyl-2-oxo-2,3-dihydro-1 H-benzoyboxylic acid (Matrix) and N'-hydroxynicotinimidamide (Tiger). 0 MHz, CD3OD) d 3.49 (s, 3H), 3.53 (s, 3H), 7.36 (d,), 7.64 (ddd, J = 8.0, 5.1, 0.8 Hz, 1H), 7.98 (d, J = 1.6 Hz ,,, J = 8.3, 1.6 Hz, 1H), 8.55 (dt, J = 8.0, 1.9 Hz, 1H), 8.73 (Hz 1H 9.29 d J = 1.2 Hz 1 H EM DCI / NH m / z 308) ppm; MS (DCl / NH3) m / z 281 (M + H) +.

Example 129 trifluoroacetic acid of 5- (3- (pyridin-3-yl) -1,2,4-oxadiazol-benzordimidazole-2 (3H) -one A solution of 2-oxo-2,3-di nzo [d] imidazole-5-carboxylic acid (Princeton, 178 mg, 1.0 2 Cl2 (anhydrous, 5.0 mL) was stirred with oxalyl chloride (Aldrich, 2 Cl2, 1.0 mL) in the presence of 2 drops of ambient dimethylformate for 1 hour, it was then c centered and dried under reduced pressure, the rdina was dissolved (5.00 ml) and then stirred with N-hydroxynicotini, 137 mg, 1.0 mmol) at 100 °. C for 16 hours. Reaction was carried out at room temperature, diluted with E, washed with water (2 x 10 mL) and brine. The atmosphere was concentrated under reduced pressure, purified with HPLC pr aters, column: Xbridge ™ Prep C18 5 μ? T ?, OBD ™ 30 x vente: acetonitrile / a v.1% TFA 5/95 at 95/5 vel Example 13QA 2-Nitro-5- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) phenol The title compound was prepared according to the reaction by using 3-hydroxy-4-nitrobenzoic acid. (Aldrich) roxinicotinimidamida (Tiger). 1 H NMR (300 MHz, DEMO- d, J = 1.9, 4.8, 0.8 Hz, 1H), 7.76 (dd, J = 8.5, 1.8 Hz, 1H) 1.6 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 8.45 (dt, J = 7.9, 2.03 (dd, J = 4.8, 1.6 Hz, 1H), 9.26 (d, J = 1.2 Hz, 1H)) I / NH3) m / z 285 (M + H ) \ Example 130B 2-amino-5- (3- (pyridin-3-M) -1,2,4-oxadiazol-5-yl) phenol A solution of the product of Example 132 2 mmol) in THF (20.0 ml) was stirred with nickel of Raney (Aldric or H2 (30 psi) for 2 hours.) The catalyst was then passed through filtration and the reaction was concentrated to give the title compound.1H NMR (300 MH d 5.67 s 2H 6.74 J = 8.1 H- Then, at 50 ° C for 10 h, it was cooled to room temperature (40 ml). The precipitate was filtered and dried under vacuum title compound. 1 H NMR (300 MHz, DEMO-d 6) d 7.42 1 H), 7.65 (dd, J = 7.8, 5.1 Hz, 1 H), 7.98 (s, 2 H), 8.02 (d Hz, 1 H), 8.12 (d, J = 1.7 Hz, 1H), 8.44 (dt, J = 8.1, 1.9 Hz,, J = 4.7, 1.7 Hz, 1H), 9.26 (d, J = 1.4 Hz, 1H) ppm; MS (280 (M + H) +.

Example 131 6- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzo fdloxaz A solution of the product of Example 132B mmol) was stirred in triethyl orthoformate (Aldrich, 20 ml, 120 mmol) 10 hours. It was then cooled to room, and then triturated with hexanes (50 ml). The precipitate was dried under vacuum to give the title compound. 1H z, DEMO-d6) d 7.67 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 8.10, 1H), 8.28 (dd, J = 8.3, 1.6 Hz, 1H), 8.48 (dt, J = 7.9 , 2.0 6 d J = 1.6 Hz 1. = Good for 16 hours. It was then that reduced concision. The residue was stirred with water (10 mL) d, and extracted with EtOAc (3 x 10 mL). Concentrations are combined in the title compound. 1 H NMR (30D) d 7.17-2.22 (m, 1H), 7.28-7.34 (m, 2H) I / NH3) m / z 178 (+ NH4) +.

Example 132B N, -hydroxy-2-oxo-213-dihydrobenzord-1-oxazole-5-carboximid A solution of the product of Example 134A mmol), hydroxylammonium chloride (Aldrich, 64.0 mg, 1.9 tilamine (Aldrich, 227 mg, 2.3 mmol) was stirred, methanol (10 min after 2 h, cooled to room temperature, then reduced pressure) The residue was triturated with EtOAc (1% filtered and dried under vacuum to give the mixture 1 H NMR (300 MHz, CD 3 OD) d 7.22 (d, J = 8.33 Hz, 1 3 (m, 2 H) .MS (DCI / NH3) m / z 194 (M + H) +.

Example 133 - (5- (6-chloropyridin-3-in-1, 2,4-oxadia-20-yl-3-yl) benzoid-oxazoone The title compound was prepared according to the procedure of the product of Example 134B and 6-chloro-otinoyl (Aldrich). 1 H NMR (300 MHz, CD 3 OD) d 7.33 (d,), 7.73 (dd, J = 8.3, 0.8 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H), .3, 1.6 Hz, 1H), 8.57 (dd, J = 8.3, 2.4 Hz, 1H), 9.19 (d,) ppm. MS (DCI / NH3) m / z 315317 (+ H) +.

Example 134 5- (benzordlf1,31dioxol-5-in-3- (pyridin-3-yl) -1,2,4-oxadia The title compound was prepared according to the acidic benzo [d] [1, 3] dioxol-5 -carboxylic (Aldric roxinicotinimidamide (Tiger). 1 H NMR (300 MHz, DEMO-2 H), 7.20 (d, J = 8.1 Hz, 1 H), 7.61 - 7.69 (m, 2 H), 7.81 (d Hz, 1 H), 8.42 (dt, J = 8.2, 1.9, 1.7 Hz, 1H), 8.81 (dd, J 1H 9.24 dd J = 2.2 0.8 Hz 1Hm EM DCI / NH alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum and whether non-toxic ammonium and quaternary ammonium ions, onium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, triethylamine, diethylamine, ethylamine and the like Representative organic acids useful for base addition formation include ethylenediamine, ethanolamine, eridine diet, piperazine and the like.

Other possible compounds include amides and pharmaceutically acceptable. For a description of pharmaceutically acceptable prodrugs, see Bund. (1 985) Desig n of Prodrugs, Elsevier Science P sterdam, which is hereby incorporated by reference are usually formed from the carboxylic acid with alcohol. Generally, ester formation can conventional synthetic techniques. (See, for example, vanced Or anic Chemistry 3rd Ed. John Wile &Sons positions, which are both esters as described, and at the same time are pharmaceutically salts thereof.

For a description of pharmaceutically-active amides or prodrugs, see Bundgaard, H. , Ed. , (1985) D drugs, Elsevier Science Publishers, AEmterdam. These are usually free from the corresponding carboxylic acid ina. Generally, the formation of the amide can conventional synthetic realities. (See, for example, anic Chemistry, 3rd ed., John Wiley &Sons, New York, 85) and Mark et al. Encyclopedia of chology, John Wiley & Sons, New York (1 980), which will be this medium by reference. This invention also includes these compositions, which are amides, as disclosed, and at the same time are pharmaceutically salts thereto.

It will also be easy to see for n It is convenient to administer to a patient (by mammalian, such as a human) in need of the same β2 and a receptor of the α4β2 ligand. Such a combination, which is useful in the expansion of the dosing interval, has therapeutically beneficial effects.

The dosage interval in which MAP a4ß2 and u I receptor a4ß2 will be concurrently administered. The specific dosage will be chosen by the patient who considers the compounds to be taken, the severity of the patient's disease, which condition or diseases the patient is suffering from, and the potential for interaction or adverse event, the response previous medication, and other factors. Adequacy intervals for the a4ß2 MAP are from approximately / kg to 100 mg / kg per body weight. The intervals for dosing for the preparation of the a4 2 receptor The invention is also carried out by administering a to a ligand of the a4ß2 receptor of any effective levels of the compounds at the same time. Normally, the combination will be adly.

However, the invention is not limited to the administration of the invention, it should be interpreted to cover any administration that is appropriate for the medi-cides and for the patient. For example, intradermal administration may be very desirable for patients who are irresponsible or irritant to take the medicine or may be appropriate for patients who take medication. One of the drugs can be administered to, such as orally, and the others can be administered podermally, percutaneously, intravenously, intramuscularly, rarectal, in particular circumstances. The ADI pathway may be varied in any way, limited by the following progesteric drugs), opioid analgesics (m allytic adjuvants or co-analgesics (antiepilepressive drugs) .In a simplified classification, the opioids are Used primarily to relieve moderate to moderate pain, adjuvant analgesics (Gabino Gab) are used to alleviate neuropathic pain. Allergic opioids are used to treat severe pain origins, depending on the prescribed dosage.

The nicotinic acetylcholine receptor ligands multiply alignments through the trajectory of pain d viar. The ligands of the nicotinic receptor of a are found in the primary sensory neurons (where the nociceptive information is initiated, in the cellular region of these neu rones (ie, the ganglion of rai G), the dorsal spinal cord where the tumor is located. First pain, in the regions of the cell body of the medulla oblonating the descending innervation as well as in those of the nAChR in persistent or neuropathic pain.

Another aspect of the invention is the potential for acia of other drugs used to treat C bina pain with an a4ß2 MAP. As noted above, the present macos axes used include opioids, Gabino gab, duloxetine and others. The mechanisms of no or cannabinoids, calcium channel quencher receptor antagonists, and channel blockers are being developed for the treatment of the pain of these mechanisms, it is emerging that a complication can be conducted for the activation of in-cendent inputs. For example, opioid analgesics may require pain transmission, in part decreasing inhibitory procedures to modulate pain at the spinal level (Pasternack, G. uropaharmcol. 16: 1, 1993; Lauretti, G. T., Expert R urothera eutics 6: 613-622. 2006 Since these are factors that will improve the treatment of chronic pain.

Other diseases or disorders mediated by nACh to benefit from such administration concurrentization of nAC h R a4ß2 ligands and selective PAMs to be used for the treatment of diseases related to the cholinergic system of the nervous system peripheral nervous system, diseases or other diseases. smooth muscle contraction, endocrine diseases, diseases or disorders related to neurodegeneration, diseases or disorders relacion lamación, and symptoms of absti nencia caused by te I abuse of chemical substances, in for example nicotine, lor. In a particular modality, the combination is conditions and disorders related to the deficit disorder, hyperactivity disorder of the attention deficit and its en gins), Alzheimers disease, uizophrenia, co nitive deterioration, slight deterioration of the blood vessel foundation. associated with healing of s particularly circulation around an eye, need for new growth of the vessel sciated with vascularization of skin grafts, amation, sepsis, wound healing, and other complications with diabetes, among other activities sist roin munomoduladoras. The method is useful for conditions related to conditions and disorders neurophysiological and cognitive dysfunction, for example Alzheimer's disease, bipolar disorder, schizophrenia, uizoaffective, and other related disorders characterized neurophysiological and cognitive function, particularly.

For example, one modality relates to a method of treating or preventing a cognitive characterization or disorder condition or disorder, such as DHD disease, between another condition and disorders. The method of administering na can i administering a therapeutically effective positive allosteric dulator amount of the a4β2 acetylcholine subtype receptor to a subject in need thereof in an antipsychotic agent.

BIOLOGICAL ACTIVITY Example A: The positive allosteric modulator of a4ß2 etoses of the nicotinic agonists.

Savo Calcium Flow Using Cells Expressing nAChR Experimental procedure: Kidney cells and anas (HEK) 293 stably expressing the human 4 combination are grown to confluence in tissue culture flasks in D EM medium supplemented with 10% FBS and 25 pg / ml 00 pg / ml Hygromycin B. Neuroblastoma I R-cells bind to confluence in tissue culture flasks of minimum 162 cm minimum supplemented with 10% FBS and 1 mM p 1% non-essential amino acids 1% antibiotic-antimic Molecular Devices, Sunnyvale, CA) or fluo-4 (Invitrogen). The mother tin of the dye dissolving in each vial supplied a buffer in a solution of balanced salt solution of Hank mM of NMDG, 20 mMs of CaCl2 containing 10 mM of motherhood was diluted 1:20 using the same buffer before removal of the medium of cell growth. The C μ? of the dye per well and incubated at room temperature by a for the stable HEK 293 clonal cell lines or were used - 45 minutes at 37 ° C for the fluorescence measurements of cé simultaneously in all the wells by means of a Fluorometric Gene Reader (FLIPR ) at an excitation wavelength and an emission wavelength of 520 nm. The base fluoride was measured during the first 6 seconds in which 3X compounds of the modulator / test compounds were agglomerated to the plate 50 μ? and incubated for five minutes. The intensity was captured every second for the first 1 minute followed by four additional minutes. This procedure is whether the enzonitrile (Compound 1) and 3,5-di (pyridin-3-yl) -1, 2,4-mpuesto 2) can be identified by measuring its potassium bios fluorescence in intracellular calcium using a fluorimetric ca. The enhancing effect of a modulator to a4ß2 eptor can also be illustrated by response to a4ß2 agonists, for example 5 - [(2R) -a ethoxy] -2-chloropyridine (Compound A) and (3R) -1-pyridin-3 Inhibitor (Compound B), in the presence of a fixed concentration or shown in Figures 1A and 2A, in the presence of an example r, 3- (3- (pyridin-3-yl) -1, 2,4-oxadiazole -5-il) be mpuesto 1) to 10 μ?), The responses of a4β2 agonist concentrations, for example 5 - [(2R) -azetidin-2-yl ropyridine (Compound A) and (3R) -1-pyridin- 3-ilpyrrolidi mpuesto B), they are normally exchanged for 1 - 2 unirol (10 - 100 times) to the left giving as result EC50 more potent to the agonists. In addition to the known nicotinic compounds, the desired type, iz, a4ß2, can be changed without effect on other otinic subtypes and thus improve the in vivo selectivity of the agonist.

Table 1 indicates the results for the compounds of this invention. The activity intervals (effects of fluorescence response allocations) are defined co means the activity range of 200-400%, "b" if activity range of 150-200%, "c" means an activity of 120- 150% and "d" means a range of activity.

Selected examples of allosteric modulators Example B: The positive allosteric modulator of a4ß2 nicotinic ligand ets with efficacy of agonist i and low.

Ensa or Flu or Calcium: The cells HEK-293 est cells and 100-150 μ? per well of 3.5 x 105 cell-cell cells (-50,000 -100,000 cells / ml) were placed in 96-well black tubes (poly-D-lysine covered previously and kept for 24-48 hours in a tissue incubator). 37 ° C under an atmosphere of 5% C02 Other clonal cell lines or associated cortical neurons expressing nicotinic receptors can also be used in this assay, and the calcium calcium-3 assay kit was measured (Molecular nnyvale, CA) or fluo-4 (Invitrogen). A solution was prepared by dissolving in each bottle supplied by the Hank's balanced salt solution monitor (HBS of NMDG, 20 mMs of CaCl2 containing 10 mM of HE was diluted 1:20 using the same master is to be used The growth medium of the cells was removed with 100 μl of the dye per well and ambient environment for up to one hour for the lines placed for five minutes. The intensity was captured every second during the The first 1 minute was at 5 seconds for 4 additional minutes This proc followed by 50 μ of the 4X concentration of the agonist and was read for a period of 3-5 minutes as above. As a function of concentration, the concentration of changes in response was determined by the non-linear regression test (Graph P Diego, CA) to obtain EC50 values.

PAMs a4ß2 can also improve partial efficacy (the compounds that bind, but ac ChRs a4ß2 with low intrinsic efficiency that otherwise have barely perceptible effects on calcification responses, responses to 2-methyl-3- (2- ( S) -pyrrolidinylmethod C) in the presence and absence of PAM as measured. substantial calcium only; however, when uban with PAM a4ß2, responses are improved by nAChR a4ß2 (Figure 4A), but not in nAChRs a3. These observations provide mechanical support such as 2-methyl-3- (2- (S) -pyrrolidinylmethoxy) pyr, 5S) -3- (3,6-diaza-bicyclo [3.2.0] hept-3-yl) - quinoline you aces when they are co-applied with the PAM. The a4ß2 potentiation by PAM may have the ability to optimize efficacy in indications such as ADHD, Alzhiemer cognitive deficits, and pain.

Figure 5 shows a comparison of the values of calcium fluorescence ao (FLIPR) using the 2 of several nicotinic agonists including rrethonic in the presence and absence of the itivo modulator. The potency (EC50 values) of the agonists is not present in the presence of the positive allosteric modulator.

In the C: The a4 2 PAM praises the effectiveness of the AAALAC Combats in Abbott Laboratories in a regulated setting with lights on between 0700 and 20 food and water was available ad libitum except d eba. All animal and animal handling were approved by an animal care institute committee (IACUC). All the experiments are in light cycle.

Chemical Products: 5 - [(2R) -Azetidin-2-loropyridine (Compound A, 1-100 nmol / kg) and 3- (3-pyr, 4-oxadiazol-5-yl) benzonitrile (PAM a4ß2 Compound ol / kg, ip). Compound A and D were prepared in saline and in a volume of 2 ml / kg body weight 30 minutes after the performance evaluation. Compound 1, 3- (3- (1, 2,4-oxadiazol-5-yl) benzonitrile was prepared in roxibetacyclodextrin and injected in solution in one vol. Kg body weight immediately before the compound studies with Compound D the doses stolen from L5 and L6, and tied tightly with the thread after hemostasis, the wound was sutured and covered with ibidic.The rats were allowed to recover and hatched in a soft bed cage for 7 - 14 days It was behavioral for mechanical allodynia.

The tactile allodynia was measured using calibrated von Fre filaments (Stoelestañog, Wood Dale, I L). Briefly, the rats in the individual plexiglass containers were acclimated for 1 5-20 minutes before the threshold of abstinence was increased and the stimulation was decreased and was estimated using a Dixon p-meter (Chaplan et al., 1994; Cha h FW, Pogrel JW, Ch ung J and Yaksh TL (1 994) J all 53: 55-63). Only the rats with umbra count considered allodynics and were used in an additional test for a maximum possible effect percent (% of M. P. stolen according to the formula: threshold pronounced mechanical allodynia induced by L5-L6 with a decrease in mechanical withdrawal threshold (PWT) in vehicle group 2.6 mpuesto 1, 3- (3- (pyridin-3-yl) -1, 2, 4-oxadiazol-5-yl) be M, 10 mg / kg, ip) did not produce the mechanical significant retreat induced by nerve injury (PWT: 3.3 yor of 0.05 against the vehicle group). Compound ol / kg, i.p.) produced significant but weak regression of metabolic (PWT: 5.6 ± 0.3g, P less than 0.001 against icle). When co-administered, the + 3- (3- (pyridin-3-diazol-5-yl) benzonitrile (Compound 1, PA) pronounced prodrug of the nerve-induced mechanical allodynia (PWT: 12.1 ± 0.5 g) which was Significantly vehicle (P less than 0.001), but also Compound (P less than 0.001) and 3- (3- (pyridin-3-yl) -1, 2,4-oxenzonitrile, Compound 1, only (P minor of 0.00 udio demues ra u la ni dose. An ineffective dose of Compound A (1 nmol / kg) combined with several doses of PAM (3- (3- (pyridin-3-diazol-5-yl) benzonitrile, Compound 1) the dose levels increase in efficiency, It is close to that of gabapentin, a drug used clinically for neuropathic pain.

Figure 7A shows the dependent effects of roentgenous or neu of 5 - [(2R) -azetidin-2-ylmethoxy] -2-chloropram A) alone, PAM a4ß2 (3- (3- (pi ridin-3-il) -1, 2, 4-oxa-enzonitrile, Compound 1) alone and a combination of C 3.5 mol / kg) with several doses of Compound A. P mote 1) is only ineffective, but is capable of reversing the response curve. of dose of the Chungkin delo Compound of neuropathic pain.

Example D: Analysis of the effects of the compound on v oñes.

Male humates bonded Marshall BioResourc Figure 7B shows the effects on vomiting. It effects of 5 - [(2R) -azetidin-2-ylmethoxy] -2-chloropyridine (C alone, PAM a4ß2 (Compound 1) alone and a combined put 1 (3.5 μ? T ??? / kg) with several doses of Compound 2 (Compound 1) alone does not cause vomiting, and the dose response of Compound A does not change in the ito model.

Figures 8 A and 8B show the analysis of neuropathic pain and vomiting levels and models. Observe the effect on the left of Compound A in the fi nal no change in vomiting effects in Figure 8B. The maximum efficacy of Compound A can be implemented in a ropático without incidence of vomiting, in the presence of P mpuesto 1), thus extending the therapeutic window of nAChR a4ß2.

Example E: The a4ß2 partial agonists may be the inversion of neuroatomic pain in the presence of the P4 a4ß2 modulation (Compound 1). Compound D c inistra alone is ineffective in relieving pain. When PAM a4ß2 (Compound 1), Compound D ra, and shows significant relief of neutropathic pain or is previously shown, PAM (Compound 1) is only acterization of acetic icotinic receptor ligands In addition to the previously described assays for d positive allosteric modulators of the icotylcholine receptor (fluorescence-based measurements, ctrophysiology using Xenopus oocytes or lines c receptor interactions of allosteric modulators nACh Rs a4ß2 they can also be evaluated according to [3H] -BOB binding, which was carried out as described. ion of (f3H1-POB) f3H1-3- (5- (pyridin-3-yl) -1 .2, 4-oxa-enzonitrile Concentrations of [3 H] -POB (10-250 n M) in quadrupled ogenates containing 100-200 μg of the protein were a final volume 500 μ? d ute 75 minutes at 4 ° C. The eciency was determined in the presence of 30 μ? 3- (5- (pyrim, 4-oxadiazol-3-yl) benzonitrile unlabelled.) Under these, the saturable binding of [3H] -POB binding in membrane fragments of the human frontal cortex (fi) Kd and Bmax were 60 + 1 6 nM and 2900 + 500 fm theine, respectively. The membrane preparations ecies (rat, mouse, ferret) and cell lines affected that express the cloned a4ß2 nAChRs can also be used in this test of union.

For use in baron concentration inhibition assays, seven concentrations of log d log dilution containing 100-200 μg of protein, and 50 n M of [.4 Ci / mmol) in a final volume of 500 μ? d ute 75 twice. The binding is not efficient, it was determined in resoruted using the GraphPad Prism (Graphpad Softw go, CA). The IC50 values were determined by regr al in Microsoft® Excel or Assay Explorer. The IC5oS are calculated using the Cheng-Pr equation of K¡ = IC50 / (1+ [Ligand] / KD]).

The [3H] -POB was obtained according to the procedures described generally in Example 135, continued.

Example 135 ÍH1-3- (5- (pyridin-3-yl) -1,2,4-oxadiazol-3-yl) benzonitrile Example 135A 3- (5- (5-bromopyridin-3-i0-1,2,4-oxadiazol-3-iDbenzonit) The title compound according to the procedure of Example 4B was prepared using 3-roxybenzimidamide and 5-bromonicotinoyl chloride (Alpha). MHz, DEMO-de) d 7.67 (m, 1H) t 7.74 (m, 1H), 8.41 (m, . 4 to provide the tritiated raw product. The raw material was plowed by HPLC by fastening a 30 minute analysis with 40% a-cratic (LunaC18 column, 254 nm) to give u 0 mCi (1 ml, methanol).

The radiochemical purity of [3H] -POB pair was found and determined the specific activity to be 16.4 Ci / mmo The ligands of the nicotinic acetylcholine receptor according to the invention exhibit K, values ranging from nomolar to about 10 micromolar by the [3 H] -POB assay, many have a K 5 micromolar. Compounds that modulate the ChRs a4ß2 function by altering receptor activity or signaling for the composition. More specifically, spositions that work like alosté modulators will improve the efficacy and / or potency of acetylcholine or an: otinic. The multiple binding sites in nAChRs a4 aryl or heteroaryl is substituted with 1, 2, 3, or 4 substitutes of halo, haloalkyl of 1 to 6 carbon atoms 6 to 10 carbon atoms, cycloalkyl of 4 to 7 ato bond , alkenyl of 2 to 6 carbon atoms, carbon alkynyl, heteroaryl of 5 to 10 erocycle atoms of 4 to 10 carbon atoms, alkyl of 1 to 6 to carbon, - (alkyl of 1 to 6 carbon atoms) NHC (0) 0- (6 carbon atoms), hydroxyalkyl of 1 to 6 carbonyl atoms of 1 to 6 carbon atoms, amino, loalkyl-C (O) -, haloalkyl-S02-, alkyl-S02-, 2NH (alkyl of 1 to 6 carbon atoms), -S02N (carbon mon alkyl) 2, cyano, nitro, acylamino of 1 to 6 to rbono, alkoxy of 1 to 6 carbon atoms, -C (0) NH2, 1 to 6 carbon atoms), and carboxy; Y Ar3 is aryl or heteroaryl, wherein the aryl or hetero-tituted or unsubstituted, and, when substituted, the terroaryl is substituted with a substitutable reactant lecció within a compound of formula (γ) is a radioisotope. A particular radioactive compound d) is [3H] -3- (5- (pyridin-3-yl) -1,2,4-oxadiazol-3-yl) benzonitrile compounds are suitable for use in the determination of binding of nicotinic nicotinic acetylcholine receptor-type allosteric modulators a4ß2.

Another embodiment of the invention is a radio formula (? G) compound, wherein Ar 2 and Ar 3 are independently phenyl, pyrazinyl, pyridinyl, pi idacin, triazinyl, or a bicyclic heteroaryl, independently with 0, 1, 2, 3 or 4 selected from the group consisting of alkoxy, alkoxycarbonyl, alkoxycarboxylaminoalkyl, alkyl, alkylamino, alkyl-sulphonyl, amido, amino, aminoalkyl, carboxy, dialkylaminoalkyl, halo, haloalkyl, haloalkyl, teroaryl, heterocycle, hydroxy, hydroxyalkyl, cyan, Ifonamide and dialkylsulfonylformimidamide; on condition that several changes and modifications, including without regard to the compounds, substituents, without any use of the invention, can be made without the spirit and scope thereof. The examples described are intended to illustrate only and not to limit the invention as defined in the claims and equivalents thereof.

Claims (1)

1. CLAIMS 1. A compound of formula (II): where Ar2 and Ar3 are independently, aryl or optionally substituted. 2. A compound of formula (II): where Ar2 and Ar3 are independently aryl, pyrazinyl, pi idinyl, pyrimidinyl, triazinyl, or bicyclic heteroaryl, independently with 0, 1, 2, 3, or 4 pharmaceutically acceptable sele substituents thereof. 3. The compound of claim 2, or its pharmaceutically acceptable compound, wherein Ar2 is faith 4. The compound of claim 2, or pharmaceutically acceptable thereof, wherein Ar2 is pi The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Ar2 is h icic. 6. The compound of claim 2, or pharmaceutically acceptable thereof, wherein Ar 3 is pi iridazinyl. 7. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Ar 3 is h icic. 8. The compound of claim 2, or a pharmaceutically acceptable compound thereof, wherein Ar 2 and independently phenyl, pyridazinyl, piperidinyl, pyrimim 5- (3,4-difluorophenyl) -3- (pyridazin-4-yl) -1, 2 , 4-oxadiazole; 3- (pi ridazin-4-yl) -5- (pyrid i n-3-yl) -1, 2,4-oxadiazole; N, N-dimethyl-N '- (4- (3- (pyrimidin-5-yl) -1,2,4-oxadiazol-5-enylsulfonyl) formimidamide; 5-4-fluorophenyl) -3- (pyrimidin-5-yl) -1,2,4-oxadiazole; 5- 3-fluorophenyl) -3- (pyrimidin-5-yl) -1,2,4-oxadiazole; 3- pyrimidin-5-yl) -5- (3,4,5-triluorophenyl) -1,2,4-oxadiazole; 5- 2- chloropyridin-4-yl) -3- (pyrimidin-5-yl) -1, 2,4-oxadiazole; 3-pyridin-3-yl) -5- (pyrimidin-5-yl) -1,2,4-oxadiazole; 5- pyridazin-4-yl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 3- 3- (pyridazin-4-yl) -1,2,4-oxadiazol-5-yl) benzonitrile; 5-3-fluorophenyl) -3- (pyridazin-4-yl) -1,2,4-oxadiazole; 3- pyridazin-4-yl) -5- (3,4,5-trifluorophenyl) -1,4, 2,4-oxadiazole-3,5-difluorophenyl) -3- (pyridazin-4-yl) -1, 2 , 4-oxadiazole; 5-4-fluorophenyl) -3- (pyridazin-4-yl) -1, 2,4-oxadiazole; 3- pyridazin-4-yl) -5- (pyrimidin-5-yl) -1,2,4-oxadiazole; 3- pyridazin-4-yl) -5- (2,3,6-trifluorophenyl) -1,2,4-oxadiazole 5- (imidazo [1,5-a] pyridin-6-yl) -3- (pyridine -3-yl) -1, 2,4-oxad 5- (1 H -indol-6-yl) -3- (pyridin-3-yl) -1, 2,4-oxadiazole; 5- (2,7-dimethylprazrazolo [1,5-a] pyrimidin-6-yl) -3- (pyridin-3-yl adiazole; 5- (2,2-difluorobenzo [d] [1, 3] dioxol-5-yl) -3- (pyridin-3-yl) -1-adiazole; 5- (2-methylbenzofuran-5-yl) -3- (pyridin-3-yl) -1, 2,4-oxadiaz 5- (benzo [d] [1,2,3] thiadiazol-5-yl) - 3- (pyridin-3-yl) -1,2,4-ox 5- (1 H -benzo [d] imidazol-5-yl) -3- (pyridin-3-yl) -1, 2,4 -oxadi 5- (1 H -benzo [d] [1, 2,3] triazol-5-yl) -3- (pyridin-3-yl) -1, 2,4- 5- (benzo [d] thiazole) -5-yl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 3- (pyridin-3-yl) -5- (1 H -pyrrolo [2,3-b] pyridin-5-yl) -1,2,4-ox 5- (1 H -indol-5-yl) - 3- (pyridin-3-yl) -1,2,4-oxadiazole; 5- (benzofliran-5-yl) -3- (pyridin-3-yl) -1, 2,4-oxadiazole; 5- (1-methyl-1H-benzo [d] imidazol-5-yl) -3- (pyridin-3-yl) -1,2-adiazole; 3- (imidazo [1,2- a] pyridin-6-yl) -5- (pyridin-3-yl) -1,2,4-oxad diazole; 5- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzo [d] oxazole-2 5- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) -1 H -benzo [d] imid H) -thione; 1 ^ -dimethyl-S-CS-ipyridin-S-i-l ^^ -oxadiazol-S-i-IH-b imidazol-2 (3H) -one; 6- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzo [d] oxazole-2 a; 5- (3- (pyridin-3-yl) -1, 2,4-oxadiazol-5-M) -1 H -benzo [d] imid H) -one; 6- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) benzo [d] oxazol-2 6- (3- (pyridin-3-yl) -1, 2,4 -oxadiazol-5-yl) benzo [d] oxazole; 5- (5- (pyridin-3-yl) -1,2,4-oxadiazol-3-yl) benzo [d] oxazole-2 5- (5- (6-chloropyridin-3-yl) -1,2,4-oxadiazol-3-yl) benzo [d] or H) -one; Y 5- (4-fluorophenyl) -3- (pyridazin-4-yl) -1,2,4-oxadiazole; 3- (pyridazin-4-yl) -5- (2,3,6-trifluorophenyl) -1,2,4-oxadiazole; 3- (pyridazin-4-yl) -5- (2,3I4-trifluorophenyl) -1, 2,4-oxadiazole or a pharmaceutically acceptable salt thereof. 11. The compound of claim 2, selected to consist of 5- (2-chloropyridin-4-yl) -3- (pyrimidin-5-yl) -1,2,4-oxadiazole; 5- (2,3-difluorophenyl) -3- (pyrimidin-5-yl) -1,2,4-oxadiazole; 5- (3-fluorophenyl) -3- (pyrimidin-5-yl) -1,2,4-oxadiazole; 3- (Pyrimidin-5-yl) -5- (3,4,5-triluorophenyl) -1,2,4-oxadiazole 5- (4-fluorophenyl) -3- (pyrimidin-5-yl) -1,2 , 4-oxadiazole; 5- (3,4-difluorophenyl) -3- (pyrimidin-5-yl) -1,2,4-oxadiazole; 3- (Pyrimidin-5-yl) -5- (2,3,4-trifluorophenyl) -1,2,4-oxadiazole 3- (pyrimidin-5-yl) -5- (2,3,6-trifluorophenyl) -1, 2,4-oxadiazol 3- (pyrimidin-5-yl) -5- (2,3,4,5-tetrafluorophenyl) -1, 2,4-oxadi or a pharmaceutically acceptable salt thereof. 12. The compound of claim 2 selected S-benzotdltl ^ .Sltiadiazol-Si-a-Ípiridin-Si -l, 2,4-ox 5- (1 H -benzo [d] imidazol-5-yl) -3- ( pyridin-3-yl) -1, 2,4-oxadi 5- (1 H -benzo [d] [1,2,3] triazol-5-yl) -3- (pyridin-3-yl) -1,2 , 4- or 5- (benzo [d] thiazol-5-yl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 3- (pyridin-3-yl) -5- (1 H -pyrrolo [2,3-b] pyridin-5-yl) -1, 2,4-oxa iH-indol-5-yl) -3- (pyrid) N-3-yl) -1,2,4-oxadiazole; 5- (benzofuran-5-yl) -3- (pyridin-3-yl) -1,2,4-oxadiazole; 5- (1-methyl-1H-benzo [d] imidazol-5-yl) -3- (pyridin-3-yl) -1,2, diazole; 5- (1 H-indazol-5-yl) -3- (pyridin-3-M) -1,2,4-oxadiazole; 5 - ([1,2,4] triazolo [4, 3-a] pyridin-6-yl) -3- (pyridin-3-yl) -1,2,4 diazole; 5- (3- (pyridin-3-M) -1,2,4-oxadiazol-5-yl) benzo [d] oxazole-2; 5- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) -1 H -benzo [d] imid H) -thione; 1,3-dimethyl-5- (3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl) -1H-b or a pharmaceutically acceptable salt thereof. 13. The compound of claim 2 selected by which consists of 3- (imidazo [1,2- a] pyridin-6-yl) -5- (pyridin-3-yl) -1, 2,4-oxadi 5- (6-chloropyridin-3-yl) -3- ( imidazo [1,2-a] pyridin-6-yl) -1,2, diazole; 5- (6-fluropyridin-3-yl) -3- (imidazo [1,2- a] pyridin-6-yl) -1,4, 2,4-diazole; 5- (5-fluropyridin-3-yl) -3- (imidazo [1,2- a] pyridin-6-yl) -1,2,4 diazole; 5- (5- (pyridin-3-yl) -1,2,4-oxadiazol-3-yl) benzo [d] oxazole-2; Y 5- (5- (6-chloropyridin-3-yl) -1,2,4-oxadiazol-3-yl) benzo [d] or H) -one; or a pharmaceutically acceptable salt thereof. 14. A radiolabelled compound of formula (II *): uylcarbonyl, alkylsulphonyl, amido, amino, aminoalkyl, lyalkylamino, dialkylaminoalkyl, halo, o-alkylcarbonyl, heteroaryl, heterocycle, hydroxy, hydro, nitro, sulfonamide and dialkylsulfonylformimidamide; that when one of Ar2 and Ar3 is pyridinyl or aryl, the one or idinyl; when Ar3 is pyridyl, Ar2 is not pyrazinyl; or a pharmaceutically acceptable salt thereof. 15. A pharmaceutical composition comprising a therapeutically effective compound of a vindication compound 2, or a salt thereof, and a carrier or a pharmaceutically acceptable carrier. 16. The composition of claim 1 optionally comprises a ligand of the single-nicotin receptor. The composition of claim 16, wherein the nicotinic acetylcholine receptor is an a4ß2 type ligature of the nicotinic acetylcholine receptor that is given by a patient, comprising: (i) administering a therapeutically effective amount of claim 2; Y (ii) administer a pain medication that contains a compound selected from an opioid, gabapentin, pre-oxetine, a cannabinoid ligand, a vanilloid antagonist, a calcium channel blocker, and a sodium block where a pathway is activated. that is shared or is commonly activated nicotinic receptor canine a4ß2. 20. A method to treat or prevent the deficit disorder, hyperactivity disorder, attention deficit, Alzheimer's disease (AD), bipolar disorder, deterioration, deterioration of memory associated with age (AAMI), il, AIDS dementia, Pick, dementia Lewy bodies, dementia associated with syndrome uizofrenia, schizoaffective disorder, quit smoking,