MX2008007008A - 8-azabicyclo[3.2.1]octane derivatives useful as monoamine reuptake inhibitors - Google Patents

Abstract

The present invention relates to a 8-azabicyclo[3.2.1]octane derivative of Formula I, wherein R1is H or C1-5alkyl;Y is O, S or O(CH2)m;m is 1 or 2;n is 0 or 1;Ar1is phenylene or pyridylene, said phenylene and pyridylene being 1,3-linked with respect to O and when n is 1 with Y and when n is 0 with Ar2, said phenylene or pyridylene being optionally substituted with one or two substituents independently selected from halogen, C1-5alkyl, C1-5alkoxy, C3-6cycloalkyl, C2-5alkenyl, C2-5alkynyl, phenyl, CN and hydroxy, wherein said C1-5alkyl and C1-5alkoxy are optionally substituted with one to three halogens and wherein the oxygen of said hydroxy is optionally bonded to Ar2to form a 5-membered ring;Ar2is phenyl or a 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl being optionally substituted with one to three substituents independently selected from halogen, C1-5alkyl, C1-5alkoxy, CN, CONR2R3, CO2R4, NHCOR5and hydroxy, wherein said C1-5alkyl and C1-5alkoxy are optionally substituted with one to three halogens and wherein the oxygen of said hydroxy is optionally bonded to Ar1to form a 5-membered ring;R2-R4are independently H or C1-5alkyl and R5is C1-5alkyl, or a pharmaceutically acceptable salt or solvate thereof. The present invention also relates to a pharmaceutical composition comprising a 8- azabicyclo[3.2.1]octane derivative according to the present invention in admixture with one or more pharmaceutically acceptable auxiliaries and to the use of a 8- azabicyclo[3.2.1]octane derivative according to the present invention in therapy.

Description

DERIVATIVES OF 8-AZABICICLOr3.2.110CTANO USEFUL AS MONOAMINE REABSORING INHIBITORS Description of the Invention The present invention relates to 8-azabicyclo [3.2.1] octane derivatives, for pharmaceutical compositions comprising these compounds and their use in therapy. Monoamine reuptake inhibitors have found widespread use in therapy, in particular, in the treatment of depression, a common, serious and dangerous disorder that affects life with persistent and debilitating side effects. Older tricyclic absorption inhibitors that include imipramine and amitriptyline are effective antidepressants but these compounds also have deleterious cardiovascular and anticholinergic side effects that can lead to serious toxicity in overdoses and poor patient compliance. Newer drugs, such as selective serotonin reuptake inhibitors (SSRIs), although they are antidepressants with improvements over old ones have their own particular pattern of side effects including sleep disturbances, gastrointestinal symptoms and sexual problems. . The monoamine reuptake inhibitors are also indicated to be useful in the treatment of other disorders such as pain, panic disorders, depression, anxiety, attention deficit hyperactivity disorder (ADHD) or obsessive compulsive disorder.

In view of the deficiencies of currently available monoamine reuptake inhibitors, the search continues for new compounds that are safe and effective. In particular, there has been recently renewed interest in drugs that inhibit the reabsorption of monoamine in one or more of the serotonin, noradrenaline and dopamine transporters.

WO 04/113334 discloses the 8-azabicyclo [3.2.1 Joctane derivatives indicated to be inhibitors of reabsorption monoamine neurotransmitters and as such useful in the treatment of diseases or disorders responsive to the inhibition of monoamine neurotransmitter reabsorption in the system central nervous A further example of an 8-azabicyclo derivative [3.2.1 Joctane, shown to bind weakly to the serotonin and dopamine transporters is described in Bioorg. and Med. Chem. Lett., 2002, 12, 2225-2228. The 2-phenylquinazoline group is a key feature of all the dopamine transporter ligands described. The derivative 8-azabicyclo [3.2.1 Joctane described, is not indicated to inhibit the reuptake of serotonin or dopamine. GB 1164555 discloses tropine derivatives, including 8-alkyl-3-aryloxy-8-azabicyclo [3.2.1] octane indicated to possess pharmacologically effective properties and unexpected 8-Methyl-3- (2-phenylphenoxy) -8-azabicyclo [3.2.1] octane is specifically described. In a first aspect the present invention provides an 8-azabicyclo [3.2.1] octane derivative of the formula I wherein R1 is H or C5 alkyl; And it is O, S u 0 (CH2) m; m is 1 or 2; n is 0 or 1; Ar is phenylene or pyridylene, phenylene and pyridylene which is 1,3-linked with respect to O and when n is 1 with Y when n is 0 with Ar2, the phenylene or pyridylene is optionally substituted with one or two substituents independently selected from halogen, C1-5 alkyl, Ci-5 alkoxy, C3-6 cycloalkyl > C 2-5 alkenyl, C 2-5 alkynyl, phenyl, CN and hydroxy, wherein C 1-5 alkyl, and C 1-5 alkoxy, are optionally substituted with one to three halogens and wherein the hydroxy oxygen is optionally linked to Ar 2 for form a 5-membered ring; Ar2 is phenyl or a 5-6 membered heteroaryl, 5-6 membered phenyl or heteroaryl is optionally substituted with one to three substituents independently selected from halogen, C1-5 alkyl, C1-5 alkoxy, CN, CONR2R3, C02R4, NHCOR5 and hydroxy, wherein the C5 alkyl and C1-5 alkoxy are optionally substituted with one to three halogens and wherein the hydroxy oxygen is optionally links to Ar1 to form a 5-membered ring; R2-R4 are independently H or C5 alkyl and R5 is C1-5 alkyl or a pharmaceutically acceptable salt or solvate thereof. The term C 1-5 alkyl, as used herein, represents a branched or unbranched alkyl group having 1-5 carbon atoms. Examples of such groups are methyl, ethyl, isopropyl, butyl and tertiary pentyl. The term Ci-5 alkoxy, as used herein, represents a branched or unbranched alkoxy group having 1-5 carbon atoms. Examples of such groups are methoxy, ethoxy, isopropyloxy and tertiary butyloxy. The term C3-6 cycloalkyl, as used herein, represents a branched or unbranched cyclic alkyl group having 3-6 carbon atoms. Examples of such groups are cyclopropyl, cyclopentyl and 2-methylcyclopentyl. The term C2-5 alkenyl, as used herein, represents a branched or unbranched alkenyl group having 2-5 carbon atoms and at least one double bond. Examples of such groups are ethenyl and propenyl. The term C2-5 alkynyl, as used herein, represents a branched or unbranched group of alkynyl having 2-5 carbon atoms and at least one triple bond. Examples of such groups are ethynyl and propynyl. The term 5-6 membered heteroaryl ring, as used herein, represents a 5-6 membered heteroaromatic ring comprising 1-2 heteroatoms selected from N, O and S. Examples of such groups include furanyl, pyrrolyl , thienyl, pyridinyl, oxazolyl, imidazolyl, thiazolyl and pyrimidinyl. The term "halogen", as used herein, represents an atom of F, Cl, Br or I. The skilled person will appreciate that when Ar1 is 1,3-linked pyridylene with respect to O and when n is 1 with Y and when n is 0 with Ar2, the term '1, 3-linked' refers to the binding ratio of pyridylene with respect to O and when n is 1 with Y and when n is 0 with Ar2 and not with respect to the numbering of pyridylene . Thus, the skilled person will appreciate that with respect to the pyridylene numbering Ar 1 is, for example, a 2,6-pyridylene or a 2,4-pyridylene but not a 1,3-pyridylene. In one embodiment of the present invention R1 is H. In a further embodiment R1 is methyl. In another embodiment n is O. In another embodiment Y is O and n is 1. In another embodiment Ar1 is phenylene or pyridylene optionally substituted with one or two substituents independently selected from halogen, Ci-5 alkyl, C 1-5 alkoxy, or CN.

In another embodiment Ar1 is phenylene or pyridylene optionally substituted with one or two substituents independently selected from chloro, fluoro, methyl, methoxy or CN. Another embodiment of the present invention is an 8-azabicyclo [3.2.1] octane derivative of formula II formula II where? ', Z "and Z'" are CH or N provided that only one of? ', Z "and Z"' can be N at the same time and where R1 and Ar2 have the previously defined meanings . Yet another embodiment of the present invention is an 8-azabicyclo [3.2.1] octane derivative of formula II, wherein Z 'and Z "are CH, Z" is CH or N and wherein R1 and Ar2 have the meanings previously defined. In another embodiment Ar2 is phenyl or a 5-6 membered heteroaryl, 5-6 membered phenyl or heteroaryl is optionally substituted with one or two substituents independently selected from halogen, C1-5 alkyl, Ci-5 alkoxy and CN where the alkyl d-5 is optionally substituted with 1-3 halogen. In yet an additional embodiment Ar2 is phenyl or pyridyl, the phenyl or pyridyl is optionally substituted with one to two substituents independently selected from chloro, fluoro, methyl, methoxy, CN or CF3. Another embodiment of the present invention is an 8-azabicyclo [3.2.1] octane derivative of formula III formula III wherein R and Ar1 have the previously defined meanings and wherein X is CH or N and R6 is H, methoxy, fluoro, chloro, CN or CF3.

A further embodiment of the present invention is an 8-azabicyclo [3.2.1 Joctane derivative of formula IV formula IV where R has the previously defined meanings,? ', Z "and Z'" are CH or N provided that only one of? ', Z "and Z'" can be N at the same time and where X is CH or N and R6 is H, methoxy, fluoro, chloro, CN or CF3.

Another embodiment of the present invention is an 8-azabicyclo [3.2.1] octane derivative selected from: 3-exo- (5-chlorobiphenyl-3-yloxy) -8-azabicyclo [3.2.1] octane; exo 5- (8-azabicyclo [3.2.1] oct-3-yloxy) biphenyl-3-carbonitrile; EXO 3- (8-azabicyclo [3.2.1] oct-3-yloxy) -5-phenoxybenzonitrile; 3-exo- (4'-methoxybiphenyl-3-yloxy) -8-azabicyclo [3.2.1 Joctane; exo 3 '- (8-azabicyclo [3.2.1] oct-3-yloxy) biphenyl-4-carbonitrile; 3-exo- (3-pyridin-4-ylphenoxy) -8-azabicyclo [3.2.1] octane; exo 2- (8-azabicyclo [3.2.1] oct-3-yloxy) -chloropyridin-2-yl} benzonitrile; exo 2- (8-azabicyclo [3.2.1] oct-3-yloxy) -6 (2-cyanophenyl) isonicotinonitrile exo 3 - [(8-azabicyclo [3.2.lucct-S-iOoxn-S- -chloropyridin-Zi benzonitrile; exo 3- (8-azabicyclo [3.2.1] oct-3-yloxy) -5-cyanophenyl) n-trinonitrile; EXO 3- (8-azabicyclo [3.2.1] oct-3-yloxy) -5- (3-fluoropyridin-2-yl) benzonitrile; EXO 3 '- (8-azabicyclo [3.2.1] oct-3-yloxy) biphenyl-2-carbonitrile; exo 2- [6- (8-azabicyclo [3.2.1] oct-3-yloxy) pyridin-2-yl-benzonitrile; 3 '- (8-azabicyclo [3.2.1] oct-3-exo-yloxy) -2'-fluorobiphenyl-4-carbonitrile and 2- (8-azabicyclo [3.2.1] oct-3-exo-yloxy) - 6-phenylisonicotinonitrile or a pharmaceutically acceptable salt or solvate thereof.

The 8-azabicyclo [3.2.1] octane derivatives of the formula I are prepared by methods well known in the art of organic chemistry, see for example, J. March. 'Advanced Organic Chemistry' 4th Edition, John Wiley and Sons. During synthetic sequences it may be necessary and / or desirable to protect sensitive or reactive groups in any of the referred molecules. This is achieved by conventional protection groups, such as those described in the protective groups of TW Greene and PGM Wutts 'Protective Groups in Organic Synthesis' 3rd Edition, John Wiley and Sons, 1999. Protective groups are optionally removed in a convenient back stage using methods well known in the art.

Reaction Scheme 1 Compounds of formula I, wherein R, n, Y, Ar 1 and Ar 2 have meanings as previously defined (except that R 1 is not H), are prepared compounds of formula V by reductive amination with suitable aldehydes in the presence of a convenient reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a convenient solvent such as methanol. Alternatively, for for example, the compounds of the formula can be prepared by alkylation of compounds of the formula V with an alkyl halide or an alkyl sulfonate in the presence of a base such as potassium carbonate or cesium carbonate in a convenient solvent such as acetonitrile or ethyl acetate (Reaction Scheme 1). The compounds of the general formula V are prepared by substitution of the hydroxyl group in 8-azabicyclo [3.2.1] octan-3-a-ol or 8-azabicyclo [3.2.1 joctan-ß-??, temporarily protected in nitrogen by a PG protecting group such as the t-butyloxycarbonyl (Boc) labile acid group, with the compounds of the formula VI wherein n, Y, Ar1 and Ar2 have the meanings as previously defined. For example, the substitution reaction is carried out using the Mitsunobu reaction with the aid of coupling reagents known in the art of organic chemistry, such as DEAD (diethylazodicarboxylate) and PPh3 (triphenylphosphine), ADDP (1,1 '). - (azodicarbonyl) dipiperidine) and PBu3 (tributylphosphine), or (4,4-Dιmethyl-1,1-dioxide-1, 2,5-thiadiazolidin-2-yl) triphenylphosphonium, in solvents such as THF, or DCM to produce N-protected 3-substituted-8-azabicyclo [3.2.1 joctans of formula VII. Treatment of compounds of formula VII with convenient reagents to remove the protecting group, such as trifluoroacetic acid to remove the f-butyloxycarbonyl (Boc) group, gives 3-substituted-8-azabicyclo [3.2.1 joctans of the Formula V (Reaction Scheme 2). of solvent i, deprotection V Reaction Scheme 2 Alternatively, the compounds of the general formula VII are prepared by displacement of a starting group of a 3-substituted-8-azabicyclo [3.2.1] octane VIII, where LG is a convenient starting group, and PG is a convenient protection group such as the t-butyloxycarbonyl (Boc) labile acid group, with the compounds of formula VI using a convenient base such as sodium hydride, in a solvent such as DMF. Suitable starting groups are, for example, a halide or an alkyl or aryl sulfonate (Reaction Scheme 3).

Reaction Scheme 3 Alternatively, it will be easily appreciated by the expert that the compounds of the general formula VII can be prepared by a nucleophilic aromatic substitution reaction involving the displacement of a halogen, for example fluorine, of a compound such as IX, wherein n, Y, Ar1 and Ar2 have the meanings as previously defined and Hal is a halogen, with alkoxide of 8-azabicyclo [3.2.1] octan-3-a-ol or 8-azabicyclo [3.2.1] octan-3-p-ol temporarily protected in nitrogen by a group of PG protection. Suitable bases for the formation of alkoxide include, for example, sodium hydride in a solvent such as DMF (Reaction Scheme 4).

Reaction Scheme 4 The compounds of the general formula VI wherein n, Y, Ar1 and Ar2 have the meanings as previously defined, are obtained from commercial sources, or are prepared by literature procedures or modifications of literature procedures known to those skilled in the art. For example, in the case where n is 0, the compounds of the general formula XI are prepared by the Suzuki reaction of a convenient aryl or boronic acid heteraryl X or with a scheme of reaction (a) of triflate or heteroaryl halide, wherein Q is a halide or a triflate. Furthermore, it will be readily appreciated by the person skilled in the art that the compounds of the general formula XI are also prepared using the opposite coupling standards, for example reaction scheme 5 (b). Alternatively, the compounds of the general formula VI can be prepared by a variety of catalyzed metal-Carbon-carbon bonding reactions well known to those skilled in the art, see for example Ei-ichi Negishi (Editor), Armin de Meijere (Associate Editor) Handbook of OPrganopaladio Chemistry for Organic Synthesis, John Willey and Sons, 2002.

Afi-Q HCr \ Ar1 B (OH) 2 H0 NAr2 XI (a) Suzuki Ara-BÍOHV XII (b) XI Reaction Scheme 5 The compounds of the general formula VI, wherein n is 1 and Y is O, are prepared from a boronic acid XIII wherein PG is a convenient protecting group such as a methyl ether, with a nucleophile Ar2- Convenient OH, where Ar2 has the previously defined meaning, using methods previously described in the literature (Steven V. Ley, Andrew W. Thomas, Angewandte Chemie International Edition, 2003, Volume 42, Issue 44, 5400-5449). The treatment of the compounds of the formula XIV with the suitable reagents to remove the protecting group, such as pyridine hydrochloride or tribomide boron to deprotect the methyl ether, gives compounds of the formula VI, wherein Y is O and n is 1 (scheme 6). Furthermore, it will be readily appreciated by the skilled person that the compounds of the general formula VI can also be prepared using the opposite coupling patterns, for example reaction scheme 6 (b) (b) Reaction Scheme 6 Alternatively, the compounds of the general formula VI, wherein n is 1 can be prepared by the Ullmann coupling of a convenient nucleophile such as phenol and a suitable aryl or a heteroaryl of the formula XVI wherein Q is halide or triflate, temporarily protected by a PG protection group. Suitable catalysts include CuBr with a base such as cesium carbonate in a convenient polar aprotic solvent such as DMF of reaction scheme 7 (a). It will be readily appreciated by the expert that the compounds of General formula VI can also be prepared by a nucleophilic aromatic substitution reaction of a convenient nucleophile such as phenol with a convenient electrophile such as formula XVI wherein Q is a halogen, preferably fluoro temporarily protected by a PG protecting group. They include convenient bases of sodium hydride, in a polar aprotic solvent such as DMF. Furthermore, the person skilled in the art will readily appreciate that the compounds of the general formula VI are also prepared using the coupling standards for example of the reaction scheme 7 (b), wherein n, Y, Ar1, Ar2, PG and Q have the previously defined meanings.

Reaction Scheme 7 The compounds of the general formula X, XII, XIII, XV, XVI and XVII are obtained from commercial sources, or are prepared by procedures or modifications of the literature of the literature procedures known to those skilled in the art. . For example, by electrophilic aromatic substitution such as bromination with bromine or N-bromosuccinamide; chlorination with, for example, N-chlorosuccinamide and trifluoroacetic acid in a solvent such as DCM; diazotization and then hydrolysis of commercially available aniline precursors using sodium nitrite and cone, sulfuric acid, or cyanation for example using zinc (II) cyanide with a convenient catalyst such as tetrakis (triphenylphosphinepalladium (0) in a convenient solvent such as DMF, see for example, Leo Paquette, Editor-in-Chief, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995. It will be readily appreciated by the person skilled in the art that the compounds of the general formula I can be prepared using the general procedures and / or reaction sequences described above in any convenient order For example, while the processes detailed above describe the coupling of Ar1-Q and groups (HO) 2B-Ar2 before Mitsunobu coupling, it will be recognized that , in some cases, the Ar1-Q and (OH) 2B-Ar2 or Ar1-B (OH) 2 and Ar2-Q groups, can be coupled after the substitution reaction with 8-azabicyclo [3.2.1 ] octan-3-a-ol The present invention also includes within its scope all stereoisomeric forms of a derivative of 8 azabicyclo [3.2.1 joctane as described herein. In particular, the invention includes exo and endo stereoisomers that result when the 3-substituent is in the exo and endo configuration respectively. In the case of individual stereoisomers of the compounds of the formula I or salts or solvates of the same, the present invention includes the aforementioned substantially free stereoisomer, ie, associated with less than 5%, preferably less than 2% and in particular less than 1% of another stereoisomer. Mixtures of stereoisomers in any of the proportions are also included within the scope of the present invention. The present invention also includes within its scope all isotopically-labeled forms of the 8-azabicyclo [3.2.1] octane derivatives described herein. For example, compounds isotopically labeled with 2H, 3H, 1C, 13C, 14C, 131 | 125 | 123 | and? ß? The labeled compounds are useful as diagnostic tools, radio tracers, or monitoring agents in various diagnostic methods and for the in vivo receptor image. The present invention also includes within its scope the 8-azabicyclo [3.2.1] octane derivatives of the present invention in the form as a free base and in the form of a pharmaceutically acceptable salt. These salts are also obtained by treating the free base with an organic and inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid and ascorbic acid. All salts, if they are pharmaceutically acceptable or are not included within the scope of the present invention. The 8-azab-cyclo [3.2.1] octane derivatives of the present invention exist in solvated and unsolvated forms, including hydrated forms. Both forms are understood within the scope of the present invention. The 8-azabicyclo [3.2.1] octane derivatives of the present invention also exist as amorphous forms. Multiple crystalline forms are also possible. All of these physical forms are included within the scope of the present invention. The 8-azabicyclo [3.2.1] octane derivatives of the present invention are, among them, neurotransmitter reabsorption inhibitors as demonstrated in vitro for their ability to inhibit the reabsorption of one or more serotonins, noradrenalines and dopamines in stable transfected cells with the human transporters of serotonin, noradrenaline and dopamine. Therefore, the 8-azabicyclo [3.2.1] octane derivatives of the present invention are useful in therapy. Such as, the 8-azabicyclo [3.2.1] pctane derivatives of the present invention are useful in the manufacture of a medicament for the treatment or prevention of diseases for which the inhibition of reabsorption of one or more monoamines contributes to the effect therapeutic. In another embodiment, the 8-azabicyclo [3.2.1] octane derivatives of the present invention are useful for manufacture of a medicament for the treatment or prevention of a disease or disorder of the nervous system, central and peripheral which is responsible for the resorption of the neurotransmission of monoamine. In a further aspect the 8-azabicyclo [3.2.1 Joctane derivatives of the present invention are useful for the treatment or prevention of depression, anxiety, pain, panic disorders, attention deficit hyperactivity disorder (ADHD), or obsessive compulsive disorder. Depression states in the treatment in which the 8-azabicyclo [3.2.1 Joctane derivatives of the present invention and their pharmaceutically acceptable salts and solvates are particularly useful, are those classified as mood disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revised, American Psychiatric Association, Washington DC (2000), including episodes of humor, depressive disorders, bipolar disorders and other mood disorders. The present invention further includes a method for the treatment of a mammal, including a human, that suffers from or is prone to suffer from any of the aforementioned diseases or disorders, which method comprises administering an effective amount of an 8-azabicyclo derivative [ 3.2.1] octane of the present invention or a pharmaceutically acceptable salt or solvate thereof.

The amount of an 8-azabicyclo [3.2.1] octane derivative of the present invention or of a pharmaceutically acceptable salt or solvate thereof, is also referred to herein as the active ingredient, which is required to achieve a therapeutic effect, of course, it varies with the particular compound, the route of administration, age and condition of the recipient, and the particular disorder or disease that is treated. A convenient daily dose for any of the above disorders will be in the range of 0.001 to 50 mg per kilo of body weight of the receptor (eg, human) per day, preferably in the range of 0.01 to 20 mg per kilo of body weight per day. . The desired dose may be presented as a multiple sub-dose administered at appropriate intervals throughout the day. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. The present invention therefore also provides a pharmaceutical composition comprising an 8-azabicyclo [3.2.1 joctane derivative according to the present invention in admixture with one or more pharmaceutically acceptable excipients, such as those described in Gennaro et al. Remmington: The Science and Practice of Pharmacy, 20th Edition, Lippincott, Williams and Wilkins, 2000; see especially part 5: pharmaceutical manufacturing. Suitable excipients are described for example in, Handbook of Pharmaceutical Excipient, 2nd Edition; Editors A. Wade and PJWeller, American Pharmaceutical Association, Washington, The Pharmaceutical Press, London, 1994. The compositions include those suitable for oral, nasal, topical (including buccal, sublingual and transdermal), parenteral (including subcutaneous) administration , intravenous and intramuscular) or rectal. Mixtures of an 8-azabicyclo [3.2.1] octane derivative according to the present invention and one or more pharmaceutically acceptable excipients or excipients may be compressed into solid dosage units, such as tablets, or processed into capsules or suppositories. By means of pharmaceutically convenient liquids the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, for example a nasal or buccal spray. The use of conventional additives such as fillers, dyes, polymeric binders and the like is contemplated to make the dosage units for example tablets. In general, any pharmaceutically acceptable additive can be used. The 8-azabicyclo [3.2.1 Joctane derivatives of the present invention are also suitable for use in implants, patch, a gel or any other preparation for immediate and / or controlled release. Convenient fillers with which the pharmaceutical compositions can be prepared and administered include lactose, starch, cellulose and derivatives thereof, and the like, or mixtures thereof used in convenient amounts. The following examples further illustrate the compounds of the present invention and methods for their synthesis. The following examples are proposed to provide those skilled in the art with disclosure and description of how compounds, compositions and methods are made and evaluated herein, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what inventors appreciate as their invention. Unless otherwise indicated, the percent is weight percent given to the component and the total weight of the composition, the temperature is in ° C or is at room temperature, and the pressure is at or near atmospheric. Commercial reagents were used without further purification. Methods General Chemical Procedures. All reagents were purchased from common commercial sources or synthesized according to literature procedures using commercial sources. Mass spectra were recorded on a Shimadzu LC-8A (CLAR) PE Sciex API 150EX CLEM. The analytical inverse phase CLEM analysis was performed on the LUNA C18 column (5μ 30 x 4.6 mm) under gradient conditions (90% water / 0.1% formic acid to 90% acetonitrile / 0.1% formic acid) in a flow of 4 mL / min. The SCX cartridges (strong cation exchange) were purchased from Phenomenex.

Abbreviations Dimethylformamide (DMF), dichloromethane (DCM), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), high pressure liquid chromatography (HPLC), diisopropylethylamine (DIPEA), triethylamine (TEA), trifluoroacetic acid (TFA), tert-butyloxycarbonyl ( Boc), ethylene glycol dimethyl ether (DME), preparative dimethyl acetamide (DMA) CLEM refers to preparative high pressure liquid chromatography with mass spectrometric detection. In the following section, examples of the synthesis of common precursors and intermediates for the compounds of the present invention are described. (4. -Dimet 1-1.1-dioxide-1, 2,5-thiadiazolidin-2-yl-rifenylphosphonium (4, 4-D i I inserted 1-1, 1-dioxide-1, 2,5-thiadiazolidin-2-yl) triphenylphosphonium was prepared as described in J. Org. Chem., 1994,59,2289-2291 tert-butylester of 3-endo-hydroxy-8-azabicyclo3.2.1-octane-8-carboxylic acid endo-8-Azabicyclo [3.2.1] octan-3-ol (3.6 g, 28.3 mmol) was dissolved in DCM (50 mL) and cooled to 0 ° C. Triethylamine (7.8 mL, 56.7 mmol) was added followed by the addition of di-tert-butyl dicarbonate (7.4 g, 33.9 mmol). The reaction mixture was warmed to room temperature and stirred for 12 h. The reaction mixture was diluted with water. The organic layer was separated and washed with saturated citric acid (aq), water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 3-endo-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butylester as a white solid (6.45 g, 28.4 mmol , 100%). E.M. (ESI) (m / z): 228 [M + H] + tert-butylester of 3-exo-H id roxy-8-azabi cyclo f3.2.noctane-8-carboxylic acid Dietiazodicarboxylate (1.74 ml, 11 mmol) was added dropwise to a solution of tert-butylester of 3-endo-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid (2.09 g, 9.2 mmol), triphenylphosphine ( 2.89 g, 11 mmol) and 4-nitrobenzoic acid (1.69 g, 10 mmol) in THF (25 mL). The reaction mixture was stirred under a nitrogen atmosphere for 18 h at room temperature. The volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel. Elution with DCM produced the ester as a pale yellow solid (2.6 g, 6.9 mmol, 75%). 4N sodium hydroxide (aq) (3.6 mL, 14 mmol) was added to a solution of ester in THF (25 mL) and the reaction mixture stirred at room temperature for 3 days. Diethyl ether (35 ml) and water (10 ml) were added to the reaction mixture. The 2N sodium hydroxide solution (aq) was added to the organic layer which was removed, dried in Na 2 SO 4 and the solvent evaporated in vacuo. The crude material was purified by chromatography on silica gel. Elution with DCM with a gradient to 5:95 methane: DCM yielded 3-exo-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butylester (1.4 g, 6.2 mmol, 89%) EM (ESI) (m / z): 228 [M + H] + tert-butylester of 3-exo-Methansulfonyloxy-8-azabicyclo3.2.11octane-8-carboxylic acid A solution of tert-butylester of 3-exo-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid (230 mg, mmol) and triethylamine (0.148 mL, 11 mmol) in DCM (4 mL) was stirred under a nitrogen atmosphere and cooled to 0 ° C. Methanesulfonyl chloride (0.082 mL, 1.1 mmol) was added dropwise to the reaction mixture, which was left to reach the room temperature. The reaction mixture was stirred for a further 18 h. The reaction mixture was evaporated in vacuo and the residue purified by chromatography on silica gel. Elution with DCM with a gradient at 2:98 acetone: DCM afforded 3-exo-methanesulfonyloxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butylester (298 mg, 0.98 mmol, 97%). 3-endo-methanesulfonyloxy-8-azabicyclo3.2.11octane-8-carboxylic acid tert-butylester A solution of tert-butylester of 3-endo-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid (5.0 g, 22 mmol) and triethylamine (3.3 ml, 24 mmol) in dry DCM (40 ml) it was stirred under an argon atmosphere and cooled to 0 ° C. Sulfonyl chloride methane (1.85 ml, 24 mmol) was added dropwise to the reaction mixture, which was allowed to warm to room temperature. The reaction mixture was stirred for another 18 h, and the reaction mixture cooled by the addition of water. The organic layer was separated, dried over Na2SC0, absorbed on silica gel and purified by chromatography on silica gel. Elution with ethyl 1: 4 acetate: heptane gave 3-endo-methanesulfonyloxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butylester (4.0 g, 13 g). mmol, 60%). 4-Bromo-3-f enoxyphenol and 2,4-Dibromo-5-phenoxyphenol 3-Phenoxyphenol (700 mg, 3.8 mmol) was stirred at 0 ° C in DCM (7 mL) and bromine (0.154 mL, 3.0 mmol) was added dropwise. The reaction was stirred at room temperature for 10 min and then the solvents removed in vacuo to yield a crude which was purified by preparative HPLC to produce, in the elution, 4-bromo-3-phenoxyphenol (126 mg, 0.5 mmol, 16% EM (ESI) (m / z): 263,265 [MH]; and 4,6-dibromo-3-phenoxyphenol (201 mg, 0.6 mmol, 39%) E.M. (ESI) (m / z): 341.343.345 [MH] + They were similarly prepared: 6-Bromobiphenyl-3-ol 4-Bromobiphenyl-3-ol 4-chloro-3-phenoxyphenol and 2-chloro-5-f enoxyphenol 3-Phenoxyphenol (1.00 g, 5.4 mmol) was dissolved in MeCN (40 mL) and TFA (0.5 mL) N-Clorosuccinimide (717 mg, 5.4 mmol) was added and the reaction was stirred at room temperature for 48 h. The solvents were removed in vacuo to yield the crude product as oil (2.15 g). 300 mg of this crude material was purified by HPLC to produce in the elution 4-chloro-3-phenoxyphenol (68 mg, 0.31 mmol, 41%) E.M. (ESI) (m / z): 219,221 [MH] +; and 6-chloro-3-phenoxyphenol (73 mg, 0.33 mmol, 44%) E.M. (ESI) (m / z): 219.221 [MH] +. Similarly, they were prepared: e-Chloro-biphenyl-3-oi 4-chloro-phenyl-3-ol-4-chloro-3- (4-f-luo-phenoxy) -phenol 2-Bromo-1-chloro-4-methoxybenzene (200 mg, 0.9 mmol), cesium carbonate (588 mg, 1.8 mmol), 4-fluorophenol (202 mg, 1.8 mmol), Cul (17 mg, 0.09 mmol) and N-methylpyrrolidine (1 ml) were sealed in a microwave container and heated in a microwave at 200 ° C for 1800s. The crude reaction mixture was purified by chromatography on silica gel. Elution with 10:90 acetate: ethyl heptane with a gradient at 30:70 ethyl acetate: heptane yielded 1-chloro-2- (4-fluorophenoxy) -4-methoxybenzene (112 mg, 0.44 mmol, 49% ). 1 -Cloro-2- (4- fluorophenoxy) -4-methoxybenzene (110 mg, 0.44 mmol) prepared above, was dissolved in DCM (5.00 ml) and stirred under argon at -78 ° C. Tribomide boron (1.0 M in DCM, 2.20 ml) was then added and the reaction stirred at -78 ° C for 1 h. The reaction was allowed to warm to room temperature overnight, quenched with saturated Na2CO3 (aq) and then the aqueous and organic layers were separated. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel. Elution with 2:98 acetate: ethyl heptane with a gradient at 20:80 ethyl acetate: heptane yielded 4-chloro-3- (4-fluorophenoxy) phenol (92 mg, 0.38 mmol, 87%). E.M. (ESI) (m / z): 237.239 [MH] '5-Bromo-2-methyl phenol A solution of concentrated sulfuric acid (6 ml) in distilled water (75 ml) was added to 5 bromo-2-methylaniline (1 g, 5.38 mmol). The resulting suspension was heated to 90 ° C and stirred for 4.5 h. The reaction mixture was then cooled using an ice bath and a solution of sodium nitrite (384 mg, 5.57 mmol) in water (5 ml) was added to the reaction mixture at 0 ° C. The reaction was allowed to warm to room temperature. The reaction mixture was then added to an acid solution concentrated sulfuric (6 ml) in water (75 ml) which had been preheated to 90 ° C. The reaction mixture was stirred for 1 h at 90 ° C and allowed to cool, at rest, overnight. A precipitate was observed in the reaction mixture. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to yield 5-bromo-2-methylphenol as a brown solid (510 mg, 2.73 mmol, 51%). E.M. (ESI) (m / z) 185.187 [M-H] - Similarly prepared were: 3-Fluoro-5-lodofenol 5-Fluorobiphenyl-3-ol Palladium (II) acetate (2.4 mg, 0.01 mmol) was added to a suspension of 3-fluoro-5-iodophenol (250 mg, 1.05 mmol), phenylboronic acid (154 mg, 1.26 mmol) and sodium carbonate (3.34 g) , 3.15 mmol) in water (5 ml), under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then filtered through a dicalite buffer to remove the black precipitate. The dicalite was washed with MeOH. The filtrate was diluted with water (250 ml) and then adjusted to pH2 using 2M HCl (aq). The product was extracted in DCM, dried in Na2SO4 and concentrated to the vacuum The crude material was purified by chromatography on silica gel. Elution with 10:90 of acetate: ethyl heptane yielded 5-fluorobiphenyl-3-ol (186 mg, 0.988 mmol, 94%) E.M.

(ESI) (m / z): 187 [MH] \ Similarly prepared: 6-Fluorobiphenyl-3-ol 5-Bromobiphenyl-3-ol M.1'.3'.1"lTerfenl-5'-ol 5-Chloro-phenyl-3-ol-3-thiophen-2-ylphenol 4-Phenylpyridin-2-ol Tetrakis (triphenylphosphine) palladium (0) (164 mg, 0.14 mmol) was added to a stirred suspension of phenylboronic acid (345 mg, 2.84 mmol) and 4-bromo-2-hydroxypyridine (494 mg, 2.84 mmol) in DME (10 my). The reaction mixture was stirred under an argon atmosphere for 90 min. The degassed solution of 2N potassium carbonate (ac) (10 mL) was added and the reaction mixture was stirred with heating at 90 ° C for 72 h. The solvent was evaporated in vacuo, and the residue partitioned between ethyl acetate and water. The aqueous layer was washed with acetate of ethyl (x2). The organics were combined, dried in Na 2 SO 4 and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel. Elution with DCM with a gradient to 5:95 methanol CDC produced 4-phenylpyridin-2-ol (31 1 mg, 1.82 mmol, 64%) E.M. (ESI) (m / z): 172 [M + H] +. were similarly prepared: 2- phenylpyridine-4-ol 6-phenylpyridine-2-ol 2'-Chloro-biphenyl-3-ol 3'-chlorobiphenyl-3-ol 4'-chlorobiphenyl-3-ol 4'-trifluoromethyl-biphenyl-3-ol 3'-trifluoromethoxy-3-ol 4'-Trif luorometoxibifenil-3-ol 2'-Methylphenyl-3-ol 3'-methylbiphenyl-3-ol 3'-Hydroxybiphenyl-2-carbonitrile 3'-Hydroxybiphenyl-4-carbonitrile 2 '-Fluorobifenil-3-ol 3'-Fluorobiphenyl-3-ol 2'-Trif luorometilbifenil-3-ol 3'-Hydroxybiphenyl-3-carbonitrile 3- pyridin-3-ylphenol 4- Chlorobiphenyl-3-ol 3"-Metoxib Phenyl-3-ol 2'-Fluorobiphenyl-3-ol 3'-trifluoromethyl-biphenyl-3-ol 4'-Methoxybiphenyl-3-ol 2'-Trif luorometilbifenil-3-ol 2'-Methoxybiphenyl-3-ol 3'-Methoxybiphenyl-3-ol 3 '-Hydroxybiphenyl-3-carbonitrile 5-Hydroxybiphenyl-3-carbonitrile' Tetrakis (triphenylphosphine) palladium (0) (1 16 mg, 0.1 mmol) was added to 5 bromobiphenyl-3-ol (250 mg, 1 mmol) and zinc cyanide (117 mg, 10.0 mmol) dissolved in DMF (5 ml) in a microwave container. The reaction vessel was sealed and then heated to 200 ° C for 300 seconds. The reaction was quenched with water and the product was extracted into DCM. The solution was filtered and then concentrated in vacuo. The crude material was then purified by chromatography on silica gel. Elution with 10:90 of acetate: ethyl heptane gave 5-hydroxybiphenyl-3-carbonitrile (74 mg, 0.379 mmol, 38%). E.M. (ESI) (m / z): 194 [MH] \ Similarly, they were prepared: 5-Hydroxybiphenyl-2-carbonitrile 2-Methyl-3-phenoxyphenol 1 - . 1-Bromo-3-fluoro-2-methylbenzene (388 mg, 2.05 mmol), and (4-methoxyphenyl) methanol 5 (0.511 mL, 4 mmol) were dissolved in DMF (5 mL) in a microwave vessel. Sodium hydride as a 60% dispersion in mineral oil (164 mg, 4.0 mmol) was added in portions under a nitrogen flow in 10 min. The reaction vessel was then sealed and heated to 180 ° C for 900s. The crude reaction mixture was poured into 1: 1 water: brine (6 ml) and DCM (10 ml). The biphasic mixture was stirred at room temperature for 1 h and then the organics and aqueous layers were separated. The combined organics were dried on Na 2 SO 4 and concentrated in vacuo. The crude material was then purified by chromatography on silica gel. Elution with 5:95 of ethyl acetate: heptane yielded 1-bromo-3- (4-methoxybenzyloxy) -2-methylbenzene (289 mg, 0.9 mmol, 46%). Sodium hydride as a 60% dispersion in mineral oil (56 mg, 1.4 mmol) was added in portions to a solution of phenol (0.35 M in DMF, 2 ml). The resulting solution was added to a mixture of 1-bromo-3- (4-methoxybenzyloxy) -2-methylbenzene (215 mg, 0.7 mmol) and cesium carbonate (228 mg, 0.7 mmol) in a microwave vessel. Copper (I) bromide (10 mg) was added, the vessel was sealed and the reaction was heated to 180 ° C for 900s. 1N NaOH (aq) (2 mL) and DCM (5 mL) was added to the cooled reaction mixture and the organic layer was separated and concentrated in vacuo. The crude material was then purified by chromatography on silica gel. Elution with 5:95 of acetate: ethyl heptane yielded 1- (4-methoxybenzyloxy) -2-methyl-3-phenoxybenzene (205 mg, 0.64 mmol, 91%). 1- (4-Methoxybenzyloxy) -2-methyl-3-phenoxybenzene (205 mg, 0.64 mmol) was dissolved in ethanol (5 mL) and palladium on charcoal 10% by weight (60 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere (1 atm) for 72 h. The crude reaction mixture was filtered on dicalite and the solvents removed in vacuo. The crude product was taken up in DCM (4 ml) and 1N NaOH (aq.) (4 ml) and the aqueous layer was separated, then acidified to pH 1 with 5N HCl (aq). The aqueous layer was extracted with DCM (10 ml) and the organics were combined concentrated in vacuo. The crude material was then purified by chromatography on silica gel. Elution with 5:95 acetate: ethyl heptane yielded 2-methyl-3-phenoxyphenol (43 mg, 0.21 mmol, 34%). Similary were prepared: 2,3-dimetil-5-phenoxyphenol 3-phenoxy-4-trif luoromethylphenol 3-phenoxy-5-trifluoromethyl phenol 4-methy1-3-phenoxyphenol 2-Fluoro-3-methoxy-5-phenoxyphenol 5-phenylpyridin-3-ol Tetrakis (triphenylphosphine) palladium (0) (242 mg, 0.21 mmol) was added to a stirred solution of boronic acid phenyl (510 mg, 4.18 mmol) and 3-bromo-5-methoxypyridine (786 mg, 4.18 mmol ) in DME (10 mi). The reaction mixture was stirred under an argon atmosphere for 30 min. The degassed potassium carbonate (ac) (10 ml) was added and the reaction mixture was stirred with heating at 90 ° C for 18 h. The solvent was evaporated in vacuo, and the residue partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate. The organics were combined, dried in Na 2 SO 4 and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel. Elution with 10:90 of acetate: ethyl isohexane with a gradient of 15:85 acetate. ethyl isohexane produced a yellow oil. The oil was dissolved in DCM, and cooled to -78 ° C under a nitrogen atmosphere. The bromine tribomide (1.0 M in DCM, 9.15 ml) was added dropwise during 20 min and the reaction mixture was warmed to room temperature and stirred at this temperature for 18 h. The resulting mixture was basified to pH8 by dropwise addition of saturated sodium hydrogen carbonate (ac). The The organic extracts were removed and the aqueous residue was extracted into ethyl acetate (x3). The organic layers were combined, dried over Na 2 SO 4 and evaporated in vacuo to give 5-phenylpyridin-3-ol (245 mg, 1.43 mmol, 47%) E.M. (ESI) (m / z): 172 [M + H] +. Similarly, they were prepared: 2-Fluorobiphenyl-3-ol 2'-Fluoro-3'-hydroxybiphenyl-4-carbonitrile 2,4-Dichloro-6-hydroxypyridine Sodium nitrite (64 mg, 0.93 mmol) dissolved in water (0.6 ml) was added dropwise to a stirred solution of 2-amino-4,6-dichloropyridine (prepared according to the method described in Red. Trav. Chim Pays-Bas, 1950, 69, 673) (126 mg, 0.77 mmol) in 5% sulfuric acid (aq.) (5 ml) at 0 ° C, for 5 minutes. The mixture was stirred at 0 ° C for 1 h and then diluted with water (20 ml) and extracted with DCM (3 x 20 ml). The combined extracts were washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo to yield 2,4-dichloro-6-hydroxypyridine (116 mg, 0.71 mmol, 92%) E.M. (ESI) (m / z) 164.166 [M + H] +. The present invention is further illustrated by the following examples: Process I EXAMPLE 1.1: 3-exo- (3-phenoxyphenoxy) -8-azabicyclo3.2.noctane Diethyloazodicarboxylate (1.89 ml, 12 mmol) was added dropwise to a solution of tert-butylester of 3-endo-methanesulfonyloxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid (2.27 g, 10 mmol), triphenylphosphine ( 3.15 g, 12 mmol) and 3-phenoxyphenol (1.93 ml, 12 mmol) in THF (60 ml). The reaction mixture was stirred under a nitrogen atmosphere for 72 h at room temperature. The volatiles were removed under reduced pressure. The resulting material was dissolved in DCM (50 mL) and TFA (5 mL) was added. The reaction mixture was stirred at room temperature for 12 h. The volatiles were removed under reduced pressure, the crude product dissolved in methanol (40 ml) and the solution loaded in an SCX cartridge (20 g). The cartridge was eluted with methanol (40 ml) to remove the triphenylphosphine oxide. Elution with ammonia in methanol (2M, 40 ml) followed by evaporation in vacuo gave 3- (3-phenoxyphenoxy) -8-azabicyclo [3.2.1 crude joctane as oil. The crude material was then purified by chromatography on silica gel. Elution with 98: 2 DCM: MeOH with a gradient at 90: 10: 0.5 DCM: MeOH: ammonia, produced the product as an oil. The product was dissolved in methanol (5 ml) and treated with hydrochloric acid in methanol until the solution was acidic. The solution was concentrated in vacuum and the Diethyl ether was added to precipitate the product. The precipitate was collected by filtration and recrystallized from methanol / diethyl ether to yield 3-exo- (3-phenoxyphenoxy) -8-azabicyclo [3.2.1 Joctane as the hydrochloride salt (1.08 g, 3.26 mmol, 33%). E.M. (ESI) (m / z): 296 [M + H] +. Similarly, they were prepared: EXAMPLE I.2: 3-exo- (4-Chloro-3- (4-f-luo-phenoxy) -phenoxy) -8-azabicyclo3.2.11octane MS (ESI) (m / z): 348, 350 [M + H] +.

EXAMPLE 1.3: 3-exo- (5-chlorobiphenyl-3-yloxy) -8-azabicyclo r3.2.11octane MS (ESI) (m / z): 314.316 [M + H] +. EXAMPLE I.4: 3-exo- (5-Bromobiphenyl-3-yloxy) -8-azabicyclo r3.2.noctane E.M. (ESI) (m / z): 358, 360 [M + H] +. EXAMPLE 1.5: Exo 5- (8-Azabicyclo3.2) Hoct-3-ylox¡ Ibifeni 1-3-carbonitrile MS (ESI) (m / z): 305 [M + H] +. EXAMPLE 1.6: 3-exo-f G1.1 ': 3'.1"1Terphenyl-5'-yloxy) -8-azabicyclo r3.2.11octane E.M. (ESI) (m / z): 356 [M + H] +. EXAMPLE L7j 3-exo- (5-FI) uorobiphenyl-3-yloxy-8-azabicyclo3.2.11octane E.M. (ESI) (m / z): 298 [M + H] \ EXAMPLE 1.8: 3-exo- (6-FI uorobifeni l-3-i loxi) -8- azabicyclo3.2.noctane E.M. (ESI) (m / z): 298 [M + H] +. EXAMPLE I.9: 3-exo- (Biphenyl-3-yloxy) -8-azabicochlor3.2.11octane E.M. (ESI) (m / z): 280 [M + H] +.

EXAMPLE 1.10; 3-exo- (6-chlorobiphenyl-3-yloxy) -8-azabicyclo f3.2.noctane E.M. (ESI) (m / z): 314, 316 [M + H] \ EXAMPLE 1.11: 3-exo- (4-Chloro-3-phenoxyphenoxy-8-azabicyclo r3.2.11octane E.M. (ESI) (m / z): 330, 332 [M + H] +. EXAMPLE 1.12: 3-exo- (2-Chloro-5-phenoxyfenoxt) -8-azabicyclo r3.2.11octane E.M. (ESI) (m / z): 330.332 [M + H] +. EXAMPLE 1.13: 3-exo- (4-Bromobiphenyl-3-ylox -8-azabicyclo r3.2.noctane E.M. (ESI) (m / z): 358, 360 [M + H] +. EXAMPLE 1.14: 3-exo- (6-Bromobiphenyl-3-yloxy) -8-azabicyclo r3.2.noctane E.M. (ESI) (m / z): 358, 360 [M + H]? EXAMPLE 1.15: 3-exo- (4-Bromo-3-phenoxyphenoxy) -8-azabicyclo r3.2.11octane E.M. (ESI) (m / z): 374.376 [M + H] +. EXAMPLE 1.16: Exo 5- (8-Azabicyclo3.2.1loct-3-yloxybiphenyl-2-carbonitrile E.M. (ESI) (m / z): 305 [M + H] +. EXAMPLE 1.17: 3-exo- (Di benzof u ran-2-i loxi i- (8-azabicyclo3.2.noctane E.M. (ESI) (m / z): 294 [M + H] +.

EXAMPLE 1.18: 3-exo- (3-phenylethoxyphenoxy) - (8-azabicyclo3.2.noctane) E.M. (ESI) (m / z): 324 [M + H] +. EXAMPLE 1.19: 3-exo-f 3-thiophen-2-ylphenoxy) - (8-azabiciclof3.2.? Octane E.M. (ESI) (m / z): 286 [M + H] +. Method II EXAMPLE 11.1: 3-exo-f 4-Fluoro-3-phenoxyphenoxy) - (8-azabicyclo f 3.2.11 octane) Diethylazodicarboxylate (1.65 ml, 10.5 mmol) was added dropwise to a solution of tert-butylester of 3-endo-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid (2.16 g, 9.5 mmol), triphenylphosphine ( 2.75 g, 10.5 mmol) and 4-fluoro-3-bromophenol (2.0 g, 10.5 mmol) in THF (95 mL). The reaction mixture was stirred under a nitrogen atmosphere for 72 hours at room temperature ambient. The volatiles were removed under reduced pressure, the residue was then triturated with heptane: diethyl ether 5: 1 followed by filtration to remove the precipitated triphenylphosphine oxide. The filtrate was concentrated in vacuo. The crude material was purified by chromatography on silica gel. Elution with 15:85 ethyl acetate: heptane, followed by a wash with 1N NaOH (aq.) (50 ml) then the concentration in vacuo gave 3-exo- (3-bromo-4-) tert-butylester. fluorophenoxy) -8-azabicyclo [3.2.1] octane-8-carboxylic acid (2.18 g, 5.5 mmol, 57%). 3-Exo- (3-Bromo-4-fluorophenoxy) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butylester (150 mg, 0.37 mmol), cesium carbonate (244 mg, 0.75 mmol) ), phenol (70.5 mg, 0.75 mmol) and copper iodide (i) (7 mg, 0.04 mmol) were combined with N-methylpyrrolidine (1 ml) in a microwave container. The reaction was heated to 200 ° C by 1800s. TFA (1 mL) was then added and the reaction stirred at room temperature for 16 hours. DCM (2 mL) was added followed by 1N NaOH (ac) at pH 10. The aqueous and organic layers were separated and the combined organics were concentrated in vacuo. The crude product was purified by preparative LCMS to produce 3-exo- (4-fluoro-3-phenoxyphenoxy) -8-azabicyclo [3.2.1 joctane as the trifluoroacetic acid salt (20.6 mg, 0.05 mmol, 13%) E.M. (ESI) (m / z): 314 [M + H] +. Similarly, they were prepared: EXAMPLE 11.2: 3-exo- (3- (3-C lorophenoxy) -4-f Iorophenoxy) -8-azabicyclo3.2.11octane E.M. (ESI) (m / z): 348, 350 [M + H] +. EXAMPLE 11.3: 3-exo- (3- (3,4-Dichlorophenoxy-4-fluorophenoxy) -8-azabicyclol3.2.1 loctane E.M. (ESI) (m / z): 382, 384 [M + H] +. EXAMPLE II.4: 3-exo- (3- (4-Chlorophenoxy-4-fluorophenoxy) -8-azabicyclo3.2.11octane E.M. (ESI) (m / z): 348, 350 [M + H]? EXAMPLE 11.5: 3-exo- (4-Fluoro-3- (3-methoxyphenoxy) phenoxy) -8-azabicyclo3.2.noctane E.M. (ESI) (m / z): 344 [M + H] +. EXAMPLE 11.6: exo 3-r5- (8-Azabicichlor3.2.1 loct-3-loxi) -2-fluorophenoxybenzonitrile E.M. (ESI) (m / z): 339 [M + H] +. EXAMPLE 11.7: exo 3-r3- (Pyridin-3-yloxy) phenoxy) -8-azabicyclol3.2.11octane E.M. (ESI) (m / z): 297 [M + H] +. Method III EXAMPLE III.1: 3-exo- (6-phenylpyridl? -2-i lox!) -8-azabicyclo3.2.11octane A solution of 6-phenylpyridin-2-ol (75 mg, 0.44 mmol) in DMF (2.5 mL) was added dropwise to a stirred suspension of sodium hydride (21 mg, 0.53 mmol) in DMF (0.5 mL) in a microwave container. The resulting suspension was stirred under a nitrogen atmosphere for 30 min. Tert-butyl ester 3-endo-methanesulfonyloxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid (147 mg, 0.48 mmol) was added to the reaction mixture. The reaction vessel was sealed and then heated at 80 ° C for 600 seconds then at 100 ° C for 1200 seconds. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate and the combined organics dried over Na2SO4 and the solvent evaporated in vacuo. The residue was purified by chromatography on silica gel. Elution with DCM with a gradient of 1:99 methaneLDCM yielded a yellow gum. The crude material was dissolved in MeOH and the solution loaded in an SCX cartridge (500 mg). The cartridge was rinsed with methanol (15 ml) to remove unreacted starting material then with ammonia in methanol (2 M, 7.5 ml) which was evaporated in vacuo. The resulting material was dissolved in DCM (1.5 ml) and TFA (0.5 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. The volatiles were removed in vacuo, the crude material dissolved in methanol (3 ml) and the solution loaded in an SCX cartridge (500 mg). The cartridge was rinsed with methanol (15 ml) to remove impurities. Elution with ammonia in methanol (2 m, 7.5 ml) followed by evaporation in vacuo afforded 3-exo- (6-phenylpyridin-2-yloxy) -8-azabicyclo [3.2.1] octane (17.1 mg, 0.25 mmol, 58 %). E.M. (ESI) (m / z): 281 [M + H] +. Similarly, they were prepared: EXAMPLE III.2: 3-exo- (2-phenylpyridin-4-yloxy) -8-azabicyclo3.2.1 loctane E.M. (ESI) (m / z): 281 [M + H] +. EXAMPLE III.3: 3-exo- (4-Phenylpyridin-2-yloxy) -8-azabicyclo3.2.11octane E.M. (ESI) (m / z): 281 [M + H] +. EXAMPLE III.4: 3-exo- (3-pyridin-3-ylphenoxy) -8-azabicyclo3.2.1 loctane E.M. (ESI) (m / z): 281 [M + H] + EXAMPLE III.5: 3-endo- (3-Phenoxyphenoxy-8-azabicyclof3.2.11octane E.M. (ESI) (m / z): 296 [M + H] \ The title compound was prepared from 3-exo-methanesulfonyloxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butylester EXAMPLE III. 6: exo 1 -r3 '- (8-Azabicichlor3.2.1 loct-3-yloxy) bifeni I-4-yltanone E.M. (ESI) (m / z): 322 [M + H] +. Method IV EXAMPLE IV.1: 3-exo- (4'-Trifluoromethylbiphenyl-3-yloxy) -8-azabicyclo3.2.11octane (4,4-Dimethyl-1,1-dioxide-1,2,5-thiadiazolidin-2-yl) trife were not ionic (172 mg, 0.420 mmol) was added to a solution of tert-butylester of acid 3 -endo-hydroxy-8-azabicyclo (3.2.1) octane-8-carboxylic acid (95 mg, 0.42 mmol), and 4'-trifluoromethylbiphenyl-3-ol (50 mg, 0.21 mmol) in THF (2 mL). The reaction mixture was stirred for 18 hours at room temperature. The volatiles were removed under reduced pressure. The resulting material was dissolved in DCM (1 ml) and was added TFA (1 mi). The reaction mixture was stirred at room temperature for 4 hours. The volatiles were removed under reduced pressure, the crude product dissolved in methanol (2 ml) and the solution loaded in an SCX cartridge (5 g). The cartridge was rinsed with methanol (3x10 ml) to remove the triphenylphosphine oxide. Elution with ammonia in methanol (2 m, 10 ml) followed by evaporation in vacuo afforded 3- (4'-trifluoromethylbiphenyl-3-yloxy) -8-azabicyclo [3.2.1] octane as an oil. The crude material was then purified with preparative LCMS to produce 3-exo- (4'-trifluoromethylbiphenyl-3-yloxy) -8-azabicyclo [3.2.1 joctane as trifluoroacetic acid salt (36.9 mg, 0.88 mmol, 38%). ^ M. (ESI) (m / z): 348 [M + H] +. They were similarly prepared: EXAMPLE IV.2: 3-exo- (4-C lorobiphenyl-3-yloxy¾-8-azabicyclo3.2.1 loctane E.M. (ESI) (m / z): 314.316 [M + H] +. EXAMPLE IV.3: 3-exo- (2'-C-lorobiphenyl-3-i loxi) -8-azabiciclof3.2. ? octane E.M. (ESI) (m / z): 314, 316 [M + H] +. EXAMPLE IV.4: 3-exo- (3'-C lorobifen i l-3-i loxi) -8-azabicyclo3.2.11 octane E.M. (ESI) (m / z): 314, 316 [M + H] +. EXAMPLE IV.5: 3-exo- (4'-Chloro-phenyl-3-yloxy) -8-azabicyclof3.2.11 octane E.M. (ESI) (m / z): 314, 316 [M + H] +.

EXAMPLE IV.6: 3-exo- (2'-Fluorobiphenyl-3-yloxy) -8-azabicyclo3.2.1loctane E.M. (ESI) (m / z): 298 [M + H] +. EXAMPLE IV.7: 3-exo- (4'-FI uorobifen i l-3-i loxi) -8-azabiciclof3.2.1 loctane E.M. (ESI) (m / z): 298 [M + H] +. EXAMPLE IV.8: 3-exo- (2'-Trifluoromethylbiphenyl-3-yloxy) -8-azabicyclo3.2.1 loctane E.M. (ESI) (m / z): 348 [M + H] +. EXAMPLE IV.9: 3-exo- (2-Fluoro-3-methoxy-5-phenoxyphenoxy) -8-azabicyclo3.2.noctane E.M. (ESI) (m / z): 344 [M + H] +. EXAMPLE IV.10: 3-exo- (3'-Trifluoromethoxybiphenyl-3-yloxy) -8-azabicyclo3.2.11octane E.M. (ESI) (m / z): 364 [M + H] +. EXAMPLE IV.11: 3-exo- (2'-Methylbiphenyl-3-yloxy) -8-azabicyclo3.2.1 loctane E.M. (ESI) (m / z): 294 [M + H] +. EXAMPLE IV.12: 3-exo- (3'-Methylbiphenyl-3-yloxy) -8-azabicyclo3.2.1 loctane E.M. (ESI) (m / z): 294 [M + H] +. EXAMPLE IV.13: 3-exo- (3-Phenoxy-4-trifluoromethylphenoxy) -8-azabicyclo3.2.noctane E.M. (ESI) (m / z): 364 [M + H] +. EXAMPLE IV.14: exo 3 '- (8-Azabicyclo3.2.1 loct-3-yloxy) bphenyl-2-carbonitrile E.M. (ESI) (m / z): 305 [M + H] +. EXAMPLE IV.15: exo 3 '- (8-Azabicichlor3.2.1 loct-3-yloxy) biphenyl-3-carbonitrile E.M. (ESI) (m / z): 305 [M + H] +. EXAMPLE IV.16: exo 3 '- (8-Azabicyclo3.2.noct-3-yloxy biphenyl-4-carbonitrile E.M. (ESI) (m / z): 305 [M + H] +. EXAMPLE IV.17: 3-exo- (3-Phenoxy-5-trifluoromethylfenoxn-8-azabicyclol3.2.11octane E.M. (ESI) (m / z): 364 [M + H] +. EXAMPLE IV.18: 3-exo- (4-Methyl-3-phenoxyphenoxy) -8-azabicyclo3.2.1 loe ta no E.M. (ESI) (m / z): 310 [M + H] +. EXAMPLE IV.19: 3-exo- (3-Chloro-5-phenoxyphenoxy) -8-azabicyclo3.2.1octane E.M. (ESI) (m / z): 330, 332 [M + H] +. EXAMPLE IV.20: Exo 3- (8-Azabicyclo3.2.1 loct-3-loxi) -5-phenoxybenzonitrile E.M. (ESI) (m / z): 321 [M + H] +. EXAMPLE IV.21: 3-exo- (3'-FI uorobifen i I -3-I oxy) -8-azabicyclo3.2.11 octane E.M. (ESI) (m / z): 298 [M + H] \ EXAMPLE IV.22: 3-exo- (3'-Trif I uoromethylbifeni I -3-yloxy) -8-azabicyclol3.2.11 octane E.M. (ESI) (m / z): 348 [M + H] +. EXAMPLE IV.23: 3-exo- (4'-Trif Ioromethoxy biphenyl-3-yloxy) -8 azabicyclo3.2.11octane E.M. (ESI) (m / z): 364 [M + H] +. EXAMPLE IV.24: 3-exo- (2'-Methoxy-biphenyl-3-yloxy) -8-azabicyclo3.2.11 octane E.M. (ESI) (m / z): 310 [M + H] \ EXAMPLE IV.25: 3-exo- (3'-Methoxy bifen i I -3-i loxi) -8-azabicyclo3.2.11octane E.M. (ESI) (m / z): 310 [M + H] \ EXAMPLE IV.26: S-exo- '- ethoxybifeni l-3-yloxy) -8-azabicyclo3.2.11octane E.M. (ESI) (m / z): 310 [M + H] +. EXAMPLE IV.27: 3-exo- (5-Phenylpyridin-3-yloxy) -8-azabiciclof 3.2.noctane E.M. (ESI) (m / z): 281 [M + H] +. EXAMPLE IV.28: 3-exo- (2-Fluorobiphen-l-3-yloxy) -8-aza bi c ic I o G3.2.11 octane E.M. (ESI) (m / z): 298 [M + H] +. EXAMPLE IV.29: 3-exo- (4-Meti I bifeni I -3-i loxi ¾-8-azabicyclo3.2.1 loctane E.M. (ESI) (m / z): 294 [M + H] +. EXAMPLE IV.30: exo 3 '- (8-Azabicyclo3.2.1 oct-3-yloxy -2'-f luorobiphenyl-4-carbonitrile E.M. (ESI) (m / z): 323 [M + H] +. EXAMPLE IV.31: Exo 3- (2'-Trifluoromethoxybiphenyl-3-yloxy) -8-azab-cyclo3.2.11octane E.M. (ESI) (m / z): 364 [M + H] +. EXAMPLE IV.32: exo 3 '- (8-Azabicyclo3.2.11oct-3-yloxy) -biphenyl-3-carbonitrile E.M. (ESI) (m / z): 305 [M + H] +. Procedure V EXAMPLE V.1: exo 3 '- (8-Methyl-8-azabicyclo3.2.noct-3-yloxy) b-phenyl-4-carbonitrile 3 '- (8-Azabicyclo [3.2.1] oct-3-exo-yloxy) biphenyl-4-carbonitrile (10 mg, 0.029 mmol) was dissolved in methanol (0.5 ml) and a 37% formaldehyde solution in water (11.5 μ? _) Was added. Sodium triacetoxyborohydride (12.5 mg) was added and the reaction was stirred at room temperature for 2 h. DCM (3 ml) and 1N NaOH (aq.) (3 ml) were then added to the reaction, the organic and aqueous layers were separated, and the organic layer was concentrated in vacuo. The crude product was purified by preparative LCMS to produce 3 '- (8-methyl-8-azabicyclo [3.2.1] oct-3-exo-yloxy) biphenyl-4-carbonitrile as the trifluoroacetic acid salt (6.4 mg, 0.015 mmol , 52%) EM (ESI) (m / z): 319 [M + H] \ Similarly, they were prepared: EXAMPLE V.2: 3-exo- (3-Chloro-5-f-enoxyphenoxy) -8-methyl-8-azabicyclo3.2.1 loctane E.M. (ESI) (m / z): 344, 346 [M + H] +.

Procedure VI EXAMPLE VI.1: 3-exo- (6-Meti I bifen i l-3-i loxi) -8-azabicyclo3.2.1 loctane Potassium carbonate (659 mg, 4.27 mmol), phenylboronic acid (388 mg, 3.18 mmol), 2-bromo-4-fluorotoluene (0.20 ml, 1.59 mmol), and tetrakis (triphenylphosphine) palladium (0) (92 mg, 5 mol), in DME (3 ml) were sealed in a microwave container and heated at 80 ° C for 1200s, then 120 ° C for 1200s. Ethyl acetate (5 ml) was added and the reaction was filtered and concentrated in vacuo. The crude material was then purified by flash column chromatography on silica gel. Elution with 10:90 ethyl acetate.heptane yielded 3-fluoro-6-methylphenyl (253 mg, 1.36 mmol, 86%). A solution of tert-butylester of 3-exo-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid (122 mg, 0.563 mmol) in DMF (1.5 ml) was added to a stirred suspension of 60% Sodium hydride in mineral oil (22 mg, 0.536 mmol) in DMF (0.5 ml) under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. A solution of 3-fluoro-6-methylbiphenyl (50 mg, 0.268 mmol) in DMF (0.5 ml) was then added and the reaction was heated in a microwave at 180 ° C for 1200s. The reaction mixture was concentrated in vacuo, DCM (1 mL) and TFA (1 mL) were added, and the reaction was stirred for 2 h. The crude reaction mixture was charged in a SCX cartridge. The cartridge was eluted with methanol (3x10 ml) to remove the impurities. Elution with ammonia in methanol (2M, 10 ml) followed by evaporation in vacuo afforded the crude 3-exo- (6-methylbiphenyl-3-yloxy) -8-azabicyclo [3.2.1] octane. The crude material was then purified by preparative LCMS to produce 3-exo- (6-methylbiphenyl-3-yloxy) -8-azabicyclo [3.2.1 Joctane as a trifluoroacetic acid salt (13 mg, 0.032 mmol, 12%). E.M. (ESI) (m / z): 294 [M + H] +. They were similarly prepared: EXAMPLE VI.2: 3-exo- (4-Methylbiphenyl-3-loxi) -8-azabi cid? G3.2.1 loctane E.M. (ESI) (m / z): 294 [M + H] +. EXAMPLE: VI.3: 3-exo- (6-Trif luorometi I biphenyl-3-yloxy) -8-azabicyclo3.2.noctane E.M. (ESI) (m / z): 348 [M + H] +. EXAMPLE VI.4: exo 3- (3-Fluoro-5-pyridi n-4-ylphenoxy) -8-azabicyclof3.2.1 loctane E.M. (ESI) (m / z): 299 [M + H]? EXAMPLE VI.5: exo 3- (3-Chloro-5-pyridin-4-ylphenoxy) -8-azabiciclof 3.2.noctane E.M. (ESI) (m / z): 315, 317 [M + H] +. EXAMPLE VI. S: exo 3-r4-Chloro-3- (pyridin-3-yloxhphenoxy-8-azabicyclo3.2.1 loctane E.M. (ESI) (m / z): 315.317 [M + H] +. EXAMPLE VI.7: Exo 3- (4-Methyl-3-pyridin-4-ylphenoxy) -8-azabicyclo3.2.11octane E.M. (ESI) (m / z): 295 [M + H] +. EXAMPLE VI.8: Exo 5- (8-Azabicyclo3.2.1 loct-3-yloxy) -bifen I-3,4'-dicarbonitrile E.M. (ESI) (m / z): 330 [M + H] +. EXAMPLE VI.9: exo 3 '- (8-Azabicyclo3.2.noct-3-yloxy) -5'-chlorobiphenyl-4-carbonitrile E.M. (ESI) (m / z): 339, 341 [M + H] +. Procedure VII EXAMPLE VII: 1 3-exo- (4-C paro-6-phenyl pyridi n-2-loxi) -8-azabicyclo3.2.noctane 2,4-dichloro-6-hydroxypyridine (696 mg, 4.2 mmol) tert-butylester of the acid, 3-exo-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylic acid (965 mg, 4.2 mmol) and (4.4-D-methyl-1, 1-dioxide-1, 2,5-thiazolidin-2-yl) trphenylphosphon (4.31 g, 10.5 mmol) in THF ( twenty mi) were stirred for 16 h. Ethyl acetate (50 ml) and water (20 ml) were added and the organic and aqueous layers were separated. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was then purified by chromatography on silica gel. Elution with 10:90 acetate: ethyl heptane yielded the tere butyl ester of 3-exo- (4,6-dichloropyridin-2-yloxy) -8-azabicyclo [3.2.1] octane-8-carboxylic acid ester (1.29 g, 3.6 mmol, 82%). E.M. (ESI) m / z: 373.375 [M + H] +. 3-Exo- (4,6-Dichloropyridin-2-yloxy) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tere-butyl ester (200 mg, 0.54 mmol), phenylboronic acid (78 mg, 0.64 mmol), tetrakis (triphenylphosphine) palladium (0) (31 mg, 5 mol%) and potassium carbonate (201 mg, 1.45 mmol) in DME (2.5 ml) were heated in microwave at 100 ° C for 900s. Ethyl acetate (20 ml) and water (10 ml) were added and the aqueous and organic rs were separated, dried over Na 2 SO 4 and concentrated in vacuo. The crude material was then purified by chromatography on silica gel. Elution with 5:95 ethyl acetate: heptane produced 3-exo- (4-chloro-6-phenylpyridin-2-yloxy) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butylester ( 68 mg, 0.16 mmol, 30%). E.M. (ESI) m / z: 415.417 [M + H] \ 3-Exo- (4-chloro-6-phenylpyridin-2-yloxy) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butylester (30 mg, 0.072 mmol) was dissolved in DCM (2 mL) and TFA (2 mL) and stirred for 30 min and then the solvents were removed in vacuo. The raw material was then purified by Preparative LCMS to produce 3-exo- (4-chloro-6-phenylpyridin-2-yloxy) -8-azabicyclo [3.2.1] octane as the trifluoroacetic acid salt (13 mg, 0.030 mmol, 42%). E.M. (ESI) m / z: 315, 317 [M + H] +. They were similarly prepared: EXAMPLE VII: 3-exo-f 4.6-Diphenylpyridin-2-yloxy) -8-azabicyclo3.2.noctane E.M. (ESI) m / z: 357 [M + H] +. EXAMPLE VI 1.3: exo 4-r6- (8-Azabicichlor3.2.1 loct-3-yloxy) -4-chloropyridin-2-illbenzonitrile E.M. (ESI) m / z: 340, 342 [M + H] +. EXAMPLE VII.4: exo 4-r2- (8-Azabicichlor3.2.1 loct-3-i loxi) -6-chloropyridin-4-illbenzonitrile E.M. (ESI) m / z: 340, 342 [M + H] +.

EXAMPLE VI 1.5: 3-exo- (3-pyridin-4-ylphenoxy) -8-azabicyclo3.2.11 octane E.M. (ESI) m / z: 281 [M + H] +. EXAMPLE VII.6: exo 4-í 6- (8-Azabi ci chlor3.2.1 loct-3-loxi) pi rid i n-2-inbenzonitrile E.M. (ESI) m / z: 306 [M + H] +. EXAMPLE VI 1.7: exo 2-14- (8-Azabicichlor3.2.1 loct-3-loxi) -6-croro-pyridin-2-inbenzonitrile E.M. (ESI) m / z: 340, 342 [M + H] +.

EXAMPLE VM.8; exo2-. { e- (8-Azabicyclo3.2.11oct-3-yloxy) -4-chloropyridin-2-ylbenzonitrile E.M. (ESI) m / z: 340, 342 [M + H] +. EXAMPLE VII.9: exo 2-. { 6-f8-Azabicyclo3.2.11oct-3-yloxy-4-chloropyridin-2-yl Ibenzamide E.M. (ESI) m / z: 358, 360 [M + H] +. chloroDridin-4-illbenzonitrile E.M. (ESI) m / z: 340, 342 [M + H] +. Example VII.11: exo2-r6- (8-Azab1cichlor3.2.1loct-3-ilox¡) Dridino-2-inbenzonitrile E.M. (ESI) m / z: 306 [M + H] +.

EXAMPLE VII.12: exo 4-r2- (8-Azabicichlor3.2.1 loct-3-yloxy) pyridin-4-yl-1-benzonitrile E.M. (ESI) m / z: 306 [M + H] +. EXAMPLE VII.13: exo 4-r4- (8-Azabicyclo3.2.11oct-3-yloxy) pyridin-2-M1benzonitrile E.M. (ESI) m / z: 306 [M + H] +. EXAMPLE VI 1.14: EXO 3- (4.5-Dif I Io robifen i I -3-i loxi) -8-azabicyclo3.2.1loctane E.M. (ESI) m / z: 316 [M + H] +. EXAMPLE VII. Exo 3- (5-Trif Ioromethyl I biphenyl-3-yloxy) -8-azabicyclo3.2.11octane E.M. (ESI) m / z: 348 [M + H] +. Method VIII Example VI 11.1: 2- (8-Azabicyclo3.2.1 loct-3-exo-yloxy) -6-phenylisonicotinonitrile 3-Exo- (4-Chloro-6-pyridin-2-yloxy) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert-butylester (30 mg, 0.072 mmol) prepared as above, zinc (II) ) (5 mg, 0.043 mmol), and tetrakis (triphenylphosphine) palladium (O) (4.2 mg, 5 mol%) in DMF (0.5 ml) were sealed in a microwave container and heated at 180 ° C for 900s. The crude reaction mixture was filtered through a short dicalite cushion. The crude material was then purified by preparative LCMS to produce 3-exo- (4-cyano-6-phenylpyridin-2-yloxy) -8-azabicyclo [3.2.1] octane-8-carboxylic acid tert -butylester (20 mg ) which was treated directly with DCM (1 ml) and TFA (1 ml), stirred for 30 min and then the solvents were removed in vacuo. The crude material was purified by preparatory LCMS to produce 2- (8-azabicyclo [3.2.1] oct-3-exo-yloxy) -6-phenylisonicotinonitrile as a trifluoroacetic acid salt (4.2 mg, 0.010 mmol, 14%). E.M. (ESI) m / z: 306 [M + H] +. Similarly, they were prepared: EXAMPLE VI 11.2: exo 2- (8-Azabicyclo3.2.1loct-3-loxH-6- (4-cyanopheniDisonicotinonitrile E.M. (ESI) m / z: 331 [M + H] +. EXAMPLE VIH.3: exo 2- (8-Azabiciclor3.2.1 loct-3-ilox¡) -6- (2-cianofeniDisonicotinonitrilo E.M. (ESI) m / z: 331 [M + H] +. EXAMPLE VIII.4: Exo 2- (8-Azabicyclo3.2.noct-3-yloxy) -6- (2-trifluoromethylphen-Disonicotinonitrile E.M. (ESI) m / z: 374 [M + H] +.

EXAMPLE VIII.5: Exo 2- (8-Azabicyclo3.2.1 loct-3-yloxy) -6- (2-methoxypheniDisonicotinonitrile E.M. (ESI) m / z: 336 [M + H] EXAMPLE VIII.6: exo 2-r6- (8-Azabicyclo3.2.1 loct-3-loxi) -4-chloropyridin-2-1 benzoic acid E.M. (ESI) m / z: 350 [M + H] +. EXAMPLE VIII.7: exo 2- (8-Azabicyclo3.2.1 loct-3-yloxy) -6- (3- f-lorofeniDisonicotinonitrile E.M. (ESI) m / z: 324 [M + H] +. Method IX Example IX.1: Exo 3- (8-Azabicyclo3.2.11oct-3-yloxy) -5- (3-fluoropyridin-2-yl) benzonitrile 3-Bromo-5-fluorobenzonitrile (8.62 g, 43 mmol) was dissolved in DMF (20 mL). Sodium hydride (2.46 g, 62 mmol) was added in portions to the stirred solution under a nitrogen atmosphere. Exo-tere-butyl of 3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate (7.0 g, 31 mmol) was then added and the reaction was then stirred at room temperature for 30 minutes. The reaction was quenched with water after the solution was extracted with DCM. The organic layers were combined and dried in MgSO4. The organic layer was concentrated to leave a brown gum, which was dissolved in DCM (50 ml) and washed with water (3x40 ml). The organic layer was combined and dried in MgSO4. The organic layer was concentrated in vacuo to leave a brown gum. The crude material was then purified by chromatography on silica gel. Elution with 10:90 of ethyl acetate: heptane yielded the exo tere-butyl of 3- (3-bromo-5-cyanophenoxy) -8-azabicyclo [3.2.1] octane-8-carboxylate (7.23 g, 17.8 mmol , 58%) as a pale yellow solid.

Exo tere-butyl of 3- (3-bromo-5-cyanophenoxy) -8- azabicyclo [3.2.1] octane-8-carboxylate (2.1 g, 5.2 mmol) in THF (20.6 mL) was treated with triisopropyl borate (3.3 mL, 2.7 g, 14 mmol), followed by 1.6M n-butylithium in hexane (4.0 ml, 6.4 mmol) for 5 minutes at -78 ° C, under nitrogen atmosphere. The reaction was stirred at -78 ° C for 2 h then heated to room temperature for 60 minutes. The reaction mixture was poured into 2N HCl (20 mL) and extracted with diethyl ether. The combined organic extracts were concentrated in vacuo to yield the crude product. The crude product was purified on a short plug of silica gel using 25:75 ethyl acetate: heptane to remove impurities after methanol to produce exo 3- [8- (tert-butoxycarbonyl) -8-azabicyclo [3.2. 1] oct-3-yloxy] -5-cyanophenylboronic acid (1.72 g, 4.6 mmol, 90%). Exo acid 3- [8- (tert-butoxycarbonyl) -8-azabicyclo [3.2.1] oct-3-yloxy] -5-cyanophenylboronic acid (80 mg, 0.21 mmol), 2-chloro-3-fluoropyridine (22 mg, 17 pL, 0.2 mmol), PCys (7.2 mg, 0.03 mmol), Pd2 (dba) 3 (6.5 mg, 7.1 Mmol), and K3P04 (78 mg, 0.37 mmol) were placed in a 5 ml microwave vessel followed by the addition of dioxane (2 ml) and water (0.5 ml). The container was then sealed. The reaction was heated to 100 ° C for 600 seconds. The reaction was quenched by the addition of EtOAc (10 mL) and water (5 mL) and the aqueous and organic layers were separated. The organic layer was washed with water (2 x 5 mL), then dried over MgSO and concentrated in vacuo. The crude material was then purified by gel chromatography of silica. Elution with 1: 3 acetate: ethyl heptane yielded the exo tere-butyl of 3- [3-cyano-5- (3-fluoropyridin-2-yl) phenoxy] -8-azabicyclo [3.2.1] octe -8-carboxylate (84 mg, 0.20 mmol, 92%). Ex tere-butyl of 3- [3-cyano-5- (3-fluoropyridin-2-yl) phenoxy] -8-azabicyclo [3.2.1] octe-8-carboxylate (84 mg, 0.20 mmol) was dissolved in DCM (2 mi) TFA (1 mL) was added and the reaction was placed on a mechanical shaker for 1 hour. The solvents were then removed in vacuo. The crude reaction mixture was loaded into an SCX cartridge. The cartridge was eluted with methanol (3x10 ml) to remove impurities. Elution with ammonia in methanol (2M, 10 ml) followed by evaporation in vacuo gave exo 3- (8-azabicyclo [3.2.1] oct-3-yloxy) -5- (3-fluoropyridin-2-yl) benzonitrile (37 mg, 0.12 mmol, 58%). E.M. (ESI) m / z: 324 [M + H] +. Similarly, they were prepared: Example IX.2: Exo 3- (8-Azabicyclo3.2.1 loct-3-yloxy) -5- (3-chloropyridin-2-yl) benzonitrile E.M. (ESI) m / z: 340, 342 [M + H] +. Example IX.3: exo 6- (3- (8-Azabiciclof3.2.1 loct-3-yloxy) -5-cyanophenethichonitrile E.M. (ESI) m / z: 331 [M + H] +. Example IX.4: Exo 3- (8-Azabicyclo3.2.11oct-3-yloxy) -5- (3- (trifluoromethyl) pyridin-2-D-benzonitrile E.M. (ESI) m / z: 374 [M + H] +. Example IX.5; exo 3- (8-Azabicyclo3.2.11oct-3-yloxy) -5- (pyridin-2-yl) benzonitrile E.M. (ESI) m / z: 306 [M + H] + Example IX.6: exo 3- (8-Azabicycloclo 3.2.1 loct-3-yloxy) -5- (3,5-dichloropyridin-2-yl) benzonitrile E.M. (ESI) m / z: 374, 376, 378 [M + H] +. Example IX.7: exo 3- (8-Azabicyclol 3.2.1 loct-3-i loxi) -5- (3-methoxypyridin-2-yl) benzonitrile E.M. (ESI) m / z: 336 [M + H] +.

Example IX.8: Exo N- (2- (8-Azabicyclo3.2.1 loct-3-yloxy) -5-cyanophenyl) pyridin-3-yl) acetamide E.M. (ESI) m / z: 363 [M + H] +. Example IX.9: exo 3- (8-Azabicyclo3.2.1loct-3 -loxy) -5-cyanopheniDnicotinonitrile E.M. (ESI) m / z: 331 [M + H] +.

Example IX.10: exo 3- (8-Azabiciclol3.2.1 loct-3-yloxy) -5- (pyrimidin-2-yl) benzonitrile E.M. (ESI) m / z: 307 [M + H] +.

Example IX.11: exo 3- (8-Azabicyclo3.2.1loct-3-yloxy) -5- (pyrimidin-5-yl) benzonitrile E.M. (ESI) m / z: 307 [M + H] +. Example IX.12: Exo 3- (8-Azabicyclo3.2.1loct-3-yloxy) -5- Msoquinolin-1-yl) benzonitrile E.M. (ESI) m / z: 356 [M + H] Procedure X Example X.1: 3-exo- (5-Chloro-6-phenoxypyridin-2-yloxy) -8-azabicyclo3.2.11octane Exo-tere-butyl of 3- (5,6-dichloropyridin-2-yloxy) -8-azabicyclo [3.2.1] octane-8-carboxylate (150 mg, 0.4 mmol) prepared according to general procedure I was dissolved in DMA (0.5 ml) and added to a solution of phenol (56 mg, 0.6 mmol) and sodium hydride (60% in mineral oil, 15 mg, 0.6 mmol) in DMA (0.5 ml). The reaction was heated to 180 ° C for 900s using microwave irradiation. Sodium hydride (60% in mineral oil, 10 mg, 0.4 mmol) was added and the reaction was heated to 180 ° C for another 900s using microwave irradiation. The reaction was quenched by the addition of 1M to aqueous NaOH (5 mL) and extracted into DCM (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was then purified by chromatography on silica gel. Elution with 20:80 ethyl acetate: heptane produced exo tere-butyl of 3- (5-chloro-6-phenoxypyridin-2-yloxy) -8-azabicyclo [3.2.1] octane-8-carboxylate (77 mg , 0.18 mmol, 45%). Exo-tere-butyl of 3- (5-chloro-6-phenoxypyridin-2-yloxy) -8-azabicyclo [3.2.1] octane-8-carboxylate (77 mg, 0.18 mmol) was dissolved in DCM (2 mL) and TFA (1 mL) and stirred at room temperature for 1 h. The solvents were removed in vacuo and the crude material was purified by preparative LCMS to produce 3-exo- (5-chloro-6-phenoxypyridin-2-yloxy) -8-azabicyclo [3.2.1] octane (7.1 mg, 0.02 mmol , 9%). E.M. (ESI) m / z: 331, 333 [M + H] +. They were similarly prepared: Example X.2: 3-exo- (6-phenoxypyridin-2-yloxy) -8-azabiciclof3.2.11 octane E.M. (ESI) m / z: 297 [M + H] +. Procedure XI: Monoamine uptake analysis The in vitro test for the inhibition of dopamine and serotonin reuptake was performed on the Chánese Hamster Ovary cells expressing the human dopamine transporter (hDAT) or the human serotonin transporter (hSERT). The in vitro test for the inhibition of norepinephrine reabsorption was performed on Medin Darby Canine Kidney cells (MDCK) expressing the human noradrenaline transporter (hNET). Briefly, stable cell lines that over express the appropriate human transporter were propagated and plated according to standard cell culture techniques. After placing on plates, the cells were left to adhere for one or two days. A serial 6-point dilution (usually 1E-10M) of reference compounds and test was prepared, added to the washed cells and incubated for 5 minutes at room temperature by the overexpression dopamine or serotonin transporter and at 37 ° C for Overexpression cells of noradrenaline. Then, a final concentration of 20 nM of the appropriate neurotransmitter (mixture of [3H] -neurotransmitter and unlabeled neurotransmitter) was added and the cells were incubated for three or five minutes at room temperature by the cells of overexpression of the dopamine transporter or serotonin or ten minutes at 37 ° C per over expression of noradrenaline cells. After the completion of the analysis, Microscint-20 was added directly to the cells and the amount of radioactivity absorbed by the cells was estimated by the scintillation count. The pEC50 values indicating the inhibition of monoamine absorption were calculated using standard curve fitting techniques. Table 1 indicating the potency of the representative compounds of the invention.

Table 1 + + + pEC50 > 7 + + pEC506-7 + pEC50 < 6

Claims (11)

1. Derivative of 8-azabicyclo [3.2.1] octane of the formula I, Formula I wherein R 1 is H or C 1-5 alkyl; And it is O, S u 0 (CH2) m; m is 1 or 2; n is 0 or 1; Ar1 is phenylene or pyridylene, phenylene and pyridylene which is 1,3-linked with respect to O and when n is 1 with Y when n is 0 with Ar2, phenylene or pyridylene is optionally substituted with one or two substituents independently selected from halogen, C5 alkyl, C5 alkoxy, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, phenyl, CN and hydroxy, wherein alkyl d5, and C5 alkoxy, are optionally substituted with one to three halogens and wherein the hydroxy oxygen is optionally linked to Ar2 to form a 5-membered ring; Ar2 is phenyl or a 5-6 membered heteroaryl, 5-6 membered phenyl or heteroaryl is optionally substituted with one to three substituents independently selected from halogen, C1-5 alkyl, C1-5 alkoxy, CN, CONR2R3, C02R4, NHCOR5 and hydroxy, wherein the C5 alkyl and C1.5 alkoxy are optionally substituted with one to three halogens and wherein the hydroxy oxygen is optionally links to Ar to form a 5-membered ring; R2-R4 are independently H or C1.5 alkyl and R5 is alkyl d-5 or a pharmaceutically acceptable salt or solvate thereof.

2. Derivative of 8-azabicyclo [3.2.1] octane according to claim 1 wherein R is H or methyl.

3. Derivative of 8-azabicyclo [3.2.1] octane according to any of claims 1-2, wherein n is O.

4. Derivative of 8-azabicyclo [3.2.1] octane Derivative of 8-azabicyclo [3.2 .1] octane according to any one of claims 1-2, wherein Y is O and n is 1.

5. Derivative of 8-azabicyclo [3.2.1] octane according to any of claims 1-4, wherein Ar 1 is phenyl or pyridyl optionally substituted with 1-2 substituents selected from chloro, fluoro, methyl, methoxy or CN.

6. Derivative of 8-azabicyclo [3.2.1] octane according to any of claims 1-5, wherein Ar2 is phenyl or pyridyl optionally substituted with 1-2 substituents selected from chloro, fluoro, methyl, methoxy, CN or CF3.

7. Derivative of 8-azabicyclo [3.2.1] octane selected from: 3-exo- (5-chlorobiphenyl-3-yloxy) -8-azabicyclo [3.2.1] octane; exo 5- (8-azabicyclo [3.2.1] oct-3-yloxy) biphenyl-3-carbonitrile; Exo 3- (8-azabicyclo [3.2.1] oct-3-yloxy) -5-phenoxybenzonitrile 3-exo- (4'-methoxybiphenyl-3-yloxy) -8-azabicyclo [3.2.1] octane; exo 3 '- (8-azabicyclo [3.2.1] oct-3-yloxy) biphenyl-4-carbonitrile; 3-exo- (3-pyridin-4-ylphenoxy) -8-azabicyclo [3.2.1] octane; exo 2- (8-azabicyclo [3.2.1] oct-3-yloxy) -chloropyridin-2-yl} benzonitrile; exo 2- (8-azabicyclo [3.2.1] oct-3-yloxy) -6- (2-cyanophenyl) isonicotinonitrile exo 3 - [(8-azabicyclo [3.2.1] oct-3-M) oxy] -5- (3-chloropyridin-2-yl) benzonitrile; exo 3- (8-azabicyclo [3.2.1] oct-3-yloxy) -5-cyanophenyl) nicotinonitrile; EXO 3- (8-azabicyclo [3.2.1] oct-3-yloxy) -5- (3-fluoropyridin-2-yl) benzonitrile; exo 3 '- (8-azabicyclo [3.2.1] oct-3-yloxy) biphenyl-2-carbonitrile; exo 2- [6- (8-azabicyclo [3.2.1] oct-3-yloxy) pyridin-2-yl] benzonitrile; 3 '- (8-azabicyclo [3.2.1] oct-3-exo-yloxy) -2'-fluorobiphenyl-4-carbonitrile and 2- (8-azabicyclo [3.2.1] oct-3-exo-yloxy) - 6-phenylisonicotinonitrile or a pharmaceutically acceptable salt or solvate thereof.

8. Derivative of 8-azabicyclo [3.2.1 Joctane according to any of claims 1-7 for use in therapy.

9. Pharmaceutical composition comprising a derivative of 8-azabicyclo [3.2.1 Joctane according to any of claims 1-7 in admixture with one or more acceptable pharmaceutical auxiliaries.

10. Use of an 8-azabicyclo derivative [3.2.1 Joctane according to any of claims 1-7 for the manufacture of a medicament for the treatment or prevention of a disease or disorder which is sensitive to the reabsorption of the monoamine neurotransmitter in the nervous system.

11. Use according to claim 10, wherein the medicament is for treatment or prevention of depression or pain. SUMMARY The present invention relates to an 8-azabicyclo [3.2.1] octane derivative of the formula I, wherein R 1 is H or C 1-5 alkyl; And it is O, S u 0 (CH2) m; m is 1 or 2; n is 0 or 1; Ar 1 is phenylene or pyridylene, phenylene and pyridylene is 1,3-linked with respect to O and when n is 1 with Y and when n is 0 with Ar 2, phenylene or pyridylene is optionally substituted with one or two substituents independently selected from halogen, C5 alkyl, C1-5 alkoxy, C3.6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, phenyl, CN and hydroxy, wherein alkyl d.5, and C5 alkoxy, are optionally substituted with one to three halogens and wherein the hydroxy oxygen is optionally linked to Ar2 to form a 5-membered ring; Ar2 is phenyl or a 5-6 membered heteroaryl, 5-6 membered phenyl or heteroaryl is optionally substituted with one to three substituents independently selected from halogen, d-5 alkyl, Ci-5 alkoxy, CN, CONR2R3, C02R4, NHCOR5 and hydroxy, wherein the C1-5 alkyl and C1-s alkoxy are optionally substituted with one to three halogens and wherein the hydroxy oxygen is optionally linked to Ar1 to form a 5-membered ring; R2-R4 are independently H or C5 alkyl and R5 is C5 alkyl, or a pharmaceutically acceptable salt or solvate thereof. The present invention also relates to a pharmaceutical composition comprising an 8-azabicyclo [3.2.1] octane derivative according to the present invention in admixture with one or more pharmaceutically acceptable auxiliaries and with the use of an 8-azabicyclo [3.2.1] octane derivative according to the present invention in therapy.