WO2004031185A1 - 8-azabicyclo[3.2.1]octane ether derivatives and their use as neurokinin receptor antagonists - Google Patents

Abstract

The present invention relates compounds of the formula (I) : wherein X represents hydrogen, C1-4alkyl optionally substituted by a hydroxy, methoxy or benzyloxy group, or CO2(C1-2alkyl); Z is -CR9R10CH2- or -CH2CR9R10-; and R1, R2, R3, R4, R5 and R6 are as defined herein. The compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migaine, emesis or postherpetic neuralgia.

Description

-AZABICYLCθ j3 .2 . l θCTANE ETHER DERIVATIVES AND THEIR USE AS NEUROKININ RECEPTO R ANTAGONISTS

This invention relates to a class of azabicyclic compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are substituted benzylether derivatives of l-phenyl-8- azabicyclo[3.2.1]octane, which are useful as neurokinin 1 (NK-1) receptor antagonists.

The present invention provides compounds of the formula (I):

10

(I)

wherein

X represents hydrogen, Cι-4alkyl optionally substituted by a 15 hydroxy, methoxy or benzyloxy group, or Cθ2(Cι-2alkyl);

Z is -CR^SR^WCHa- or -CH₂CR⁹R¹⁰-;

R¹ is hydrogen, halogen, Ci-βalkyl, Ci-βalkoxy, fluoroCi-βalkyl, fluoroCi-βalkoxy, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, NO2, CN, SR^a, SO ^a, SO₂R^a, CO₂R^a, CONR^aR^b, C₂-₆alkenyl, C₂-6alkynyl or Cι-₄alkyl 20 substituted by Cι-4alkoxy, wherein R^a and R^b each independently represent hydrogen or Cι-4alkyl;

R² is hydrogen, halogen, Cι-6alkyl, fluoroCi-βalkyl or Ci-βalkoxy substituted by Cι-4alkoxy; R³ is hydrogen, halogen or fluoroCi-βalkyl;

R⁴ represents hydrogen, halogen, Ci-βalkyl, Ci-β l osy, CF3, OCF3, NO₂, CN, SR^a, SOR^a, SO₂R^a, CO₂R^a, CONR^aR^b, Cjwsalkenyl, C₂-₆alkynyl or Cι-4alkyl substituted by Cι-4alkoxy, where R^a and R^b are as previously defined;

R⁵ represents hydrogen, halogen, Ci-βalkyl, CF3 or Ci-βalkoxy substituted by Cι-4alkoxy;

R⁶ represents hydrogen, hydroxy, COR^a, CO₂R^a, COCONR^aR , COCO₂R^a, Ci-βalkyl, C₂-6alkenyl, or Ci-βalkyl substituted by a group selected from CO₂R^a, CONR^aR^b, hydroxy, CN, COR^a, NR^aR ,

C(NOH)NR^aR^b, CONHphenyl(Cι-₄alkyl), COCO₂R^a, CONHNR^aR^b, C(S)NR^aR , CONR^aCι.₆alkylRⁱ⁴, CONR¹¹C₂-6alkenyl, CONR^HG^ealkynyl, COCONR^aR^b, CONR^aC(NR^b)NR^aR^b, CONR^aheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from Ci-βalkyl, Ci-βalkoxy, halogen and trifluoromethyl; or R⁶ represents a group of the formula -CH₂C≡CCH₂NR⁷R⁸ where R⁷ and R⁸ are as defined below; or R⁶ represents Ci-βalkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms optionally substituted by =O or =S and optionally substituted by a group of the formula — Y-NR⁷R⁸ where

Y is Ci-βalkylene or C3-6cycloalkyl;

R⁷ represents hydrogen or Cι-4alkyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, or C₂-4alkyl substituted by Cι-4alkoxy or hydroxyl; R⁸ represents hydrogen or Ci-βalkyl, Ci-ealkoxy, C3-7cycloalkyl,

C3-7cycloalkylCι-4alkyl, phenyl or Cι-4alkyl substituted by a group selected from Cι-4alkoxy, hydroxyl, CO₂R^a, NR^aR^b, aryl, aryloxy, heteroaryl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R⁷, R⁸ and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from methyl, hydroxy, CO₂(Cι-₂alkyl), phenyl, benzyl or Cι-4alkoxy optionally substituted by a Cι-4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O) or a second nitrogen atom which will be part of a NH or NR^C moiety where R^c is Cι-4alkyl, hydroxyCi-4alkyl, Cι-4alkoxyCι-4alkyl, phenyl or benzyl; or R⁷, R⁸ and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Y, R⁷ and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;

R⁹ represents hydrogen, hydroxy, oxo, Ci-βalkyl, C₂-6alkenyl, C₂-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, fluoroCi-βalkyl, Ci-βalkoxy, fluoroCi-βalkoxy, hydroxyCi-βalkyl, Cι-6alkoxyCι-4alkyl, Cι-6alkoxyCι-4alkoxy, fiuoroCi-βalkoxyCwalkyl, C₂-6alkenyloxy,

C₂-6alkynyloxy, C3-7cycloalkoxy, C3-7cycloalkylCι-4alkoxy, aryl, aryl(CH₂), aryloxy, aryl(CH₂)oxy, cyano, halogen, NR⁷R⁸, CH₂NR⁷R⁸, SRⁱ², SOR¹², SO₂R¹², OSO₂ i², NR^aCOR¹², CH(OH)R¹², COR¹², CO₂Rⁱ², CONR⁷R⁸, CONHNH₂, CH₂OR¹³, heteroaryl or

wherein R^a is as previously defined;

R¹⁰ represents hydrogen, halogen or hydroxy;

R¹¹ represents hydrogen or Ci-ealkyl;

R¹² represents hydrogen, Ci-βalkyl, Ci-βalkoxy, fluoroCi-βalkyl or phenyl optionally substituted by one, two or three substituents selected from Ci-βalkyl, Ci-βalkoxy, halogen or trifhioromethyl;

R¹³ represents Ci-4alkyl substituted by a group selected from hydroxy, COR , CO₂R^a, CONR^aR^b and heteroaryl, where R^a is as previously defined;

R¹⁴ represents OR , CONR^aR^b or heteroaryl; and pharmaceutically acceptable salts or N-oxides thereof. A preferred class of compound of formula (I) is that wherein X is hydrogen, methyl or hydroxymethyl.

Another preferred class of compound of formula (I) is that wherein R¹ is hydrogen, Cι-4alkyl, Cι-4alkoxy, halogen or CF3. Another preferred class of compounds of formula (I) is that wherein

R² is hydrogen, Cι-4alkyl, Cwalkoxy, halogen or CF3.

Also preferred is the class of compounds of formula (I) wherein R³ is hydrogen, fluorine, chlorine or CF3.

A particularly preferred class of compounds of formula (I) is that wherein R¹ is fluorine, chlorine or CF3.

Another particularly preferred class of compounds of formula (I) is that wherein R² is hydrogen, fluorine, chlorine or CF3.

Also particularly preferred is the class of compounds of formula (I) wherein R³ is hydrogen, fluorine, chlorine or CF3. Preferably R¹ and R² are in the 3 and 5 positions of the phenyl ring.

More preferably R¹ is 3-fluoro or 3-CF3.

More preferably R² is 5-fluoro or 5-CF3.

More preferably R³ is hydrogen.

Most preferably R¹ is 3-F or 3-CF₃, R² is 5-CF₃ and R³ is hydrogen. A further preferred class of compound of formula (I) is that wherein

R⁴ is a hydrogen atom or a fluorine atom.

Another preferred class of compound of formula (I) is that in which R⁵ is a hydrogen atom.

A further preferred class of compound of formula (I) is that wherein R⁶ is a hydrogen atom or a Ci-βalkyl group (especially methyl) or a

Cι-3alkyl group, in particular CH₂, CH(CB-3) and CH2CH2 and especially CH₂, substituted by a 5-membered heterocyclic ring containing 2 or 3 nitrogen atoms as previously defined.

In particular, the 5-membered ring is a heterocyclic ring selected from l,3-imidazol-4-yl, l,2,4-triazol-3-yl, l,2,3-triazol-4-yl, 2-oxo-l,3- imidazol-4-yl and 3-oxo-l,2,4-triazol-5-yl, any of which rings being optionally substituted by the group -Y-NR⁷R⁸.

Particularly preferred heterocyclic rings are selected from:

Most especially, the 5-membered heterocyclic ring is a 1,2,4-triazol-

3-yl or 3-oxo-l,2,4-triazol-5-yl group.

Another preferred class of compound of formula (I) is that wherein R⁹ represents hydrogen, hydroxy, oxo, Ci-ealkoxy, Cι-6alkoxyCι-4alkyl, hydroxyCwalkyl, cyano, NR⁷R⁸, CH₂NR⁷R⁸, SO₂R^d, CH(OH)Rⁱ², CORⁱ², CO₂Ri², CONR⁷R⁸, phenyl, heteroaryl, heteroarylCwalkyl or CH₂OR¹³, where said phenyl is optionally substituted by one or two substituents selected from

Cι-4alkoxy, halogen or trifluoromethyl.

A further preferred class of compound of formula (I) is that wherein R⁹ represents hydrogen, hydroxy, Cι-4alkoxyCι-₂alkyl (especially methoxymethyl), hydroxyCι-₂alkyl (especially hydroxymethyl), cyano,

CH₂NR⁷R⁸, SO2R¹² (especially where R¹² is phenyl), CH(OH)R¹² (especially where R¹² is phenyl), COR¹² (especially where R¹² is phenyl), CO₂R¹² (especially where R¹² is Cι-₂alkyl, e.g. methyl), CONR⁷R⁸, heteroaryl, or CH₂OR¹³. When the group R⁹ represents NR⁷R⁸, CH₂NR⁷R⁸ or CONR⁷R⁸, R⁷ is preferably hydrogen, or Cι-4alkyl (especially methyl); and R⁸ is preferably hydrogen, Ci-βalkyl, Cι-4alkoxy or Cι-3alkyl substituted by a group selected from methoxy, hydroxy, amino, methylamino, dimethylamino, phenyl, phenyloxy, or heteroaryl, wherein said phenyl or phenyloxy groups may be optionally substituted by one, two or three halogen atoms or methoxy groups, and wherein said heteroaryl group is preferably furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, pyridyl or quinolinyl, each of which heteroaryl groups may be optionally substituted by a methyl or phenyl group; or R⁷ and R⁸, together with the nitrogen atom to which they are attached, represent a heteroaliphatic ring selected from azetidinyl, pyrolidinyl, piperidinyl, morpholinyl, or piperazinyl, wherein said piperidinyl group may be optionally substituted by a methyl, CO₂(Ci-₂alkyl), phenyl or benzyl group and, optionally, a hydroxy group, and wherein said piperazinyl group may be optionally substituted on the free nitrogen atom by a phenyl or benzyl group.

When the group R⁹ represents a heteroaryl group, said group is preferably oxazolyl, thiazolyl, triazolyl or tetrazolyl, each of which groups may be optionally substituted by Cι-4alkyl, Cι-₂alkoxyCι-₂alkyl, hydroxyCι-₄alkyl, fluoroCι- alkyl, CH₂CONR^aR^b, CH₂COR^a, CH₂CO₂R^a, CH₂SR¹², CH₂SOR¹² or CH₂SO₂R¹².

Another preferred class of compounds of formula (I) is that wherein R¹⁰ represents hydrogen, fluorine or hydroxy, and in particular that wherein R¹⁰ is hydrogen. One favoured group of compounds of the present invention are of the formula (la) and pharmaceutically acceptable salts thereof:

(la) wherein R¹, R³, R⁴ and X are as defined in relation to formula (I) and Z is preferably

With respect to compounds of the formula (I), Y (where present), may be a linear, branched or cyclic group. Favourably Y contains 1 to 4 carbon atoms and most favourably 1 or 2 carbon atoms. A particularly favourable group Y is CH₂.

Where the group NR⁷R⁸ represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring contains a double bond, a particularly preferred group is 3-pyrroline.

Where the group NR⁷R⁸ represents a non-aromatic azabicyclic ring system, such a system may contain between 6 and 12, and preferably between 7 and 10, ring atoms. Suitable rings include 5-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl, 6-azabicyclo [3.2.2] decyl, 7-azabicyclo [4.3.1] decyl, 7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially 5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.

Where R⁸ represents a Cι-4alkyl group substituted by a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S, suitable rings include azetidinyl, pyrrolidino, piperidino, piperazino, morpholino, or thiomorpholino. Particularly preferred are nitrogen containing heteroaliphatic rings, especially pyrrolidino and morpholino rings. Particularly suitable moieties -Y-NR⁷R⁸ include those wherein Y is

CH₂ or CH₂CH₂ and NR⁷R⁸ is amino, methylamino, dimethylamino, diethylamino, azetidinyl, pyrrolidino and morpholino.

In particular, Y is preferably CH and NR⁷R⁸ is preferably dimethylamino, azetidinyl or pyrrolidino, especially dimethylamino. When any variable occurs more than one time in formula (I) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence.

It will be appreciated that, where R⁹ represents an oxo (=O) group, then R¹⁰ will be absent and the group Z will in fact represent -C(O)CH₂- or -CH₂C(O)-.

As used herein, the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

As used herein, the terms "fluoroCi-βalkyl" and fluoroCi-βalkoxy" mean a Ci-βalkyl or Gi-βalkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Similarly, the term "fluoroCι-4alkyl" means a Cwalkyl group in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Particularly preferred are fluoroCι-3alkyl and fluoroCι-3alkoxy groups, for example, CF₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, OCF₃, OCH₂CH₂F, OCH₂CHF₂ or OCH2CF3, and most especially CF₃, OCF3 and OCH₂CF₃. As used herein, the term "hydroxyCi-βalkyl" means a Ci-βalkyl group, in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by a hydroxy group. Preferred are hydroxyCι-3alkyl groups, especially where one hydrogen atom has been replaced by a hydroxy group, for example, CH₂OH, CH₂CH₂OH and C(CH₃)₂OH. The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable cycloalkylalkyl group may be, for example, cyclopropylmethyl.

Similarly cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy. As used herein, the terms "alkenyl" and "alkynyl" as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propargyl.

As used herein, the term "aryl" as a group or part of a group means a monocyclic, fused-bicyclic or linear bicyclic aromatic ring containing 6, 10 or 12 carbon atoms, any of which rings is optionally substituted by one, two or three substituents selected from halogen, Ci-βalkyl, Ci-βalkoxy, or trifluoromethyl. Particular examples of such groups include phenyl, naphthyl and biphenyl. Phenyl is especially preferred.

As used herein, the term "heteroaryl" as a group or part of a group means a monocyclic or fused-bicylic heteroaromatic ring containing between 5 and 10 ring members, of which 1 to 4 may be heteroatoms selected from N, O and S, and wherein any of which rings is optionally substituted by one or two substituents selected from halogen, Ci-βalkyl, Ci-βalkoxy, CO₂R^a, trifluoromethyl or phenyl. Particular examples of such groups include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indole, benzofuran, benzthiophene, benzimidazole, benzoxazole, benzthiazole and quinolinyl. Furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl and pyridyl are particularly preferred. Where said rings are substituted, preferred substituents include methyl and phenyl groups.

When used herein the term "halogen" means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.

In a further aspect of the present invention, the compounds of formula (I) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.

For use in medicine, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in υacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.

The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.

The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.

The compounds according to the invention have at least three asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

The preferred compounds of formula (I) and (la) will have the stereochemistry of the 1, 2 and 5 positions as possessed by, for instance, the compound of Example 1, i.e. as shown in formula (lb)

(lb)

It will be appreciated that the preferred definitions of the various substituents recited herein may be taken alone or in combination and, unless otherwise stated, apply to the generic formula for compounds of the present invention as well as to the preferred class of compound represented by formula (la) and formula (lb). The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.

Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred. A more detailed description of pharmaceutical compositions that are suitable for the formulation of compounds of the present invention is disclosed in US patent No. 6,071,927, the content of which is incorporated herein by reference (see in particular, column 8, line 50 to column 10, line 4). The present invention further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), which process comprises bringing a compound of formula (I) into association with a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity. A comprehensive listing of clinical conditions, uses and methods of treatment for which the compounds of the present invention will be useful is disclosed in US patent No. 6,071,927, the content of which is incorporated herein by reference (see, in particular, column 10, line 14 to column 22, line 18).

In particular, the compounds of the present invention are useful in the treatment of a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; and anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders.

The compounds of the present invention are also particularly useful in the treatment of nociception and pain. Diseases and conditions in which pain predominates, include soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, migraine, episiotomy pain, and burns.

The compounds of the present invention are also particularly useful in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; in the treatment of inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; and in the treatment of allergic disorders such as eczema and rhinitis. The compounds of the present invention are also particularly useful in the treatment of gastrointestinal (Gl) disorders, including inflammatory disorders and diseases of the Gl tract such as ulcerative colitis, Crohn's disease and irritable bowel syndrome.

The compounds of the present invention are also particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formula (I) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy; by radiation including radiation therapy such as in the treatment of cancer; and in the treatment of post-operative nausea and vomiting.

The excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimising the risk of unwanted side effects.

In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day. For example, in the treatment of conditions involving the neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

In the treatment of emesis, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. In the treatment of psychiatric disorders, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg kg per day, and especially 0.01 to 3 mg kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician. As used herein, the term "treatment" includes prophylactic use to prevent the occurrence or recurrence of any of the aforementioned conditions.

According to a general process (A), compounds of formula (I) may be prepared by the reaction of a compound of formula (II) with a compound of formula (III)

(II) (III)

wherein LG represents a leaving group; in the presence of a base, followed by deprotection, if required.

Suitable leaving groups include halo, for example, chloro, bromo or iodo, or sulphonate derivatives such as tosylate, mesylate or triflate.

Favoured bases of use in the reaction include alkali metal amides and hydrides, such as potassium bis(trimethylsilyl)amide, sodium hydride or potassium hydride.

The reaction is conveniently carried out in a suitable organic solvent, such as dimethylformamide or an ether, for example, 1,2-dimethoxyethane, at a temperature in the region of 0°C. According to another general process (B), compounds of formula (I), in which X is methyl or hydroxymethyl, may be prepared by the reaction of a compound of formula (TV)

(IV)

under either:

(a) (where R⁶ is methyl) catalytic hydrogenation conditions (e.g. B-2, Pd(OH)₂ on carbon) in a suitable solvent such as an ester, for example, ethyl acetate or an alcohol, for example, ethanol, or a mixture thereof; or

(b) (where R⁶ is hydroxymethyl) reducing conditions (e.g. borane or BH3.THF) followed by treatment with hydrogen peroxide and a base such as sodium hydroxide, conveniently in a solvent such as an ether, for example, tetrahydrofuran, or water, or a mixture thereof.

According to another general process (C), compounds of formula (I) may be prepared by the interconversion of a corresponding compound of formula (I) in which R⁶ is H, hereinafter referred to as formula (V)

(V) by reaction with a compound of formula (VI):

LG-R 6a (VI)

where R^6a is a group of the formula R as defined in relation to formula (I)

(other than H) or a precursor therefor and LG is a leaving group such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine); and, if R ^a is a precursor group, converting it to a group R (in which process any reactive group may be protected and thereafter deprotected if desired).

This reaction may be performed in conventional manner, for example in an organic solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate. Suitable alternative methods for introducing the group R⁶ are described, for instance, in International Patent Specification No.

WO 95/18124.

According to another general process (D), compounds of formula (I), wherein X is hydrogen, may be prepared by the reduction of a compound of formula (VII)

(VII) Suitable reducing conditions include: catalytic hydrogenation using a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as alcohol, e.g. methanol or ethanol, or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or a mixture thereof; or reduction using trifluoroacetic acid and triethylsilane.

According to another general process (E), compounds of formula (I), wherein X is CO₂CH3 may be prepared by the reaction of a compound of formula (II) with a diazo compound of formula (VIII)

(VIII)

The reaction is conveniently effected in the presence of a rhodium catalyst such as rhodium (II) acetate dimer, in a suitable solvent such as a halogenated hydrocarbon, for example, 1,2-dichloroethane, or an aromatic hydrocarbon, for example, benzene. The reaction is preferably effected at an elevated temperature, for example at the reflux temperature of the solvent.

Compounds of formula (I) wherein X is CH₂OH or CH3 may be prepared from a corresponding compound of formula (I) wherein X is CO₂CH3 by convention methodology. For instance, by reduction to the primary alcohol using a borohydride such as sodium borohydride in a suitable solvent such as an alcohol, for example, methanol, at a reduced temperature, for example, at between 0°C and 15°C, preferably at between 5°C and 10°C. The corresponding compound of formula (I) wherein X is CH3 may be prepared from the primary alcohol by a two-step reaction. Firstly, reaction with iodine in the presence of imidazole and triphenylphosphine converts the CH₂OH group to a CH₂I group. The desired compound is then obtained by treatment of the iodide under conditions of catalytic hydrogenation, for instance, hydrogen in the presence of palladium on charcoal catalyst and triethylamine, in a suitable solvent such as methanol.

Further details of suitable procedures will be found in the accompanying Examples.

Intermediates of formula (II) may be prepared by reduction of a corresponding compound of formula (IX):

(IX)

Suitable reducing agents will be readily apparent to one skilled in the art and include, for example, metallic hydrides, such as lithium aluminium hydride or, preferably, sodium borohydride. The reduction is conveniently effected in a suitable solvent such as an ether, for example, tetrahydrofuran, or an alcohol, for example, methanol, or a mixture thereof. Where they are not commercially available, the intermediates of formula (III) above may be prepared by the procedures described in the accompanying Examples or by alternative procedures which will be readily apparent to one skilled in the art.

Compounds of formula (IX) may be prepared from a compound of formula (X)

(X)

by catalytic hydrogenation using a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as alcohol, for example, methanol or ethanol, or an ester, for example, ethyl acetate, or an organic acid, for example, acetic acid, or a mixture thereof.

Intermediates of formula (II) may also be prepared from a compound of formula (X) by treatment with K-Selectride™ (potassium tri- sec-butylborohydride) in tetrahydrofuran.

Compounds of formula (X), wherein R⁶ is α-methylbenzyl, benzyl or allyl, may be prepared from a compound of formula (XI)

(or a corresponding compound wherein the O^~ is OH, and the compound is associated with a counterion, such as a bromide or chloride ion) by reaction with a vinyl compound of the formula R⁹CH=CH₂, in particular where R⁹ is cyano, SO₂R¹³ (especially where R¹³ is phenyl) or CO₂R¹³ (especially where R¹³ is tert-buty ), in the presence of an organic base such as a trialkylamine, for example, triethylamine. The reaction is conveniently effected in an aprotic solvent such as an aromatic hydrocarbon, for example, toluene.

The reaction of a compound of formula (XI) with acrylonitrile is particularly suitable for preparing compounds where the R⁹ substituent is situated on either of the carbon atoms of the two-carbon bridge.

Compounds of formula (IV) may be prepared from a compound of formula (XII)

(XII)

by reaction with dimethyltitanocene in a solvent such as toluene, pyridine or tetrahydrofuran, or a mixture thereof.

Compounds of formula (XII) may be prepared by the reaction of a compound of formula (II) with L-Selectride™ (lithium tri-sec- butylborohydride) followed by treatment with a compound of formula (XIII)

(XIII) wherein Hal is a halogen atom, preferably chlorine.

Compounds of formula (VII) may be prepared by reaction of a compound of formula (XIV)

(XIV)

with a compound of formula (III) according to the method of general process (A), above. Compounds of formula (XIII) may be prepared from the corresponding compound of formula (X) by reduction using, for example, metallic hydrides, such as lithium aluminium hydride or, preferably, sodium borohydride. The reduction is conveniently effected in a suitable solvent such as an ether, for example, tetrahydrofuran, or an alcohol, for example, methanol, or a mixture thereof.

In a preferred embodiment of the aforementioned processes, R⁶ is a benzyl group. The various reduction reactions described above may conveniently replace the benzyl group with a hydrogen atom. It will be appreciated from the discussion above that compounds of formula (I) wherein R⁶ is a hydrogen atom are particularly preferred precursors to other compounds of formula (I).

Compounds of formula (VIII) are either known compounds or may be prepared by methods analogous to those known in the literature (see, for instance, R. T. Lewis et al, J. Org. Chem. (2000) 65:2615). Compounds of formula (XI) and (XIII) are either known compounds or may be prepared by methods analogous to those described herein. It will be appreciated that the general methodology described above may be adapted, using methods that are readily apparent to one of ordinary skill in the art, in order to prepare further compounds of the present invention. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No. WO 93/01165. The compounds were found to be active with IC50 at the human NKi receptor of less than lOOnM on said test method.

The following non-limiting Examples serve to illustrate the preparation of compounds of the present invention:

DESCRIPTION 1 N-Benzyl-3- ydroxy-2-phenylpyridinium bromide

A suspension of 3-hydroxy-2-phenylpyridine (20g, 116mmol) in toluene (250ml) was heated at reflux for 30 minutes. Benzyl bromide (20ml) was added and the reaction mixture was heated at reflux for 6 hours then cooled using an ice bath. The solid residue was collected by filtration and washed twice with ether to give crude N-benzyl-3-hydroxy-2-phenylpyridinium bromide (36.5g, 91%) which was used in the next step without further purification. δ_H (360 MHz, CDCI₃): 11.88 (1H, s), 9.47 (1H, d, J7.2Hz), 8.16 (1H, d, 8.1Hz), 8.05 (1 H, dd, J 6.0Hz, 8.8Hz), 7.60-7.45 (3H, m), 7.37-7.22 (5H, m), 6.88 (2H, dd, J 6.2Hz, 7.9Hz), 5.61 (2H, s).

DESCRIPTION 2 (1H*,5S*,6f?*)-8-Benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]oct-3- en-2-one

A mixture of N-benzyl-3-hydroxy-2-phenylpyridinium bromide (Description 1 ; 4.91 g, 14.3mmol), phenyl vinyl sulphone (4.2g, 25mmol), triethylamine (2.8ml, 20mmol) and 1 ,4-dioxane (50ml) was heated at reflux overnight. After cooling to room temperature, the reaction mixture was poured onto saturated aqueous NaHCO₃ and extracted with ethyl acetate (3x100ml). The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel ( so-hexane:diethyl ether 10-70%) to give the title compound (4.84g, 78%) as a yellow-orange foam. Crystallisation from iso- hexane:diethyl ether gave the product as yellow rhombs. δ_H (360 MHz, CDCI₃): 7.75-7.60 (5H, m), 7.48 (2H, t, J 7.7Hz), 7.41 -7.25 (8H, m), 6.86 (1H, dd, J4.8Hz, 9.6Hz), 6.23 (1H, d, J 9.6Hz), 4.25 (1 H, d, J4.8Hz), 3.65 (1H, d, J 13.4Hz), 3.56 (1H, dd, J 4.0Hz, 9.4Hz), 3.43 (1 H, d, J 13.5Hz), 2.83 (1H, dd, J 3.9Hz, 14.9Hz), 2.56 (1H, dd, J9.4Hz, 15.0Hz). DESCRIPTION 3 (1 /?\5S*₅6/?*)-8-Benzyl-1 -phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octan-2-one

10% Palladium on carbon (1g) was added as a slurry in water (2ml) to a solution of (1 R*,5S*,6H*)-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]oct-3- ene-2-one (Description 2; 11 g, 25.6mmol) in methanol (50ml) and ethyl acetate (50ml). The mixture was hydrogenated at 30psi for one hour. The reaction mixture was filtered through a pad of Celite™. The filter cake was washed with dichloromethane (1 L) and the combined filtrates concentrated in vacuo to give the title compound (10.8g, 98%). δ_H(400 MHz, CDCI₃): 7.79 (2H, d, J7.2Hz), 7.68 (1H, t, J6.4Hz), 7.51 (2H, t, J 7.6Hz), 7.41-7.25 (10H, m), 3.94 (1H, br s), 3.73-3.69 (1H, d, J 14.0Hz), 3.63 (1H, t, J7.7Hz), 3.36 (1H, d, J 14.0Hz), 2.71-2.54 (5H, m), 1.77 (1H, m).

DESCRIPTION 4

(1 R*,2R*,5S*, 6/? 8-BenzyI-1 -phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1 ]octan-2-oI

(1 H*,5S *,6H*)-8-Benzyl-1 -phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1 ]octan-2- one (Description 3; 3.05g, 7.03mmol) was dissolved in hot THF (10ml) and methanol (150ml) was added. The mixture was heated at reflux for 2 minutes and cooled to +5°C. Sodium borohydride (600mg, 15.8mmol) was added. The reaction mixture was stirred for 20 minutes at +5°C. The cooling bath was removed and the mixture was stirred for 90 minutes at ambient temperature. Saturated aqueous NaHCO₃ (10ml) was added and the mixture was concentrated in vacuo. The residue was treated with water and extracted with ethyl acetate (3x50ml). The combined organic extracts were dried (Na,SO₄) and concentrated. The solid residue was crystallised from acetone: iso-hexane to give the title compound (2.95g, 97%) as white crystals. δ_H (360 MHz, CDCI₃): 7.71 (2H, dm, J 8.1 Hz), 7.60 (3H, m), 7.50-7.35 (8H, m), 7.29 (2H, m), 4.35 (1H, br s), 4.15 (1H, d, J 14.7Hz), 3.84 (1 H, br s), 3.79 (1H, d, J 14.6Hz), 3.47 (1H, dd, J5.5Hz, 9.3Hz), 2.43 (1H, dd, J5.5Hz, 14.0Hz), 2.29 ( H, m), 2.23 (1H, dd, J9.3Hz, 14.1 Hz), 1.98 (3H, m), 1.04 (1H, m). DESCRIPTIONS 5a and 5b (1 ?* 2RS,5S*, 6/?*)-8-Benzyl-1 -phenyI-6-pheny lsulphonyI-8- azabicyclo[3.2.1]oct-3-en-2-oI

Sodium borohydride (450mg, 11.δmmol) was added to a stirred suspension of (1 R*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulρhonyl-8-azabicyclo[3.2.1]oct-3-en- 2-one (Description 2; 3.5g, 8.1mmol) in methanol (40ml) at +5°C. The reaction mixture was stirred for 1 hour and quenched with saturated NaHCO₃ and concentrated in vacuo to removed methanol. The aqueous phase was extracted with ethyl acetate (3x50ml). The combined organic extracts were dried (Na₂SO₄) and concentrated to give a 4.4:1 mixture of epimeric alcohols. The diastereoisomers were separated by flash chromatography followed by crystallisation.

DESCRIPTION 5a - (1 R*,2R*, 5S*, 6f?*) isomer:- δ_H (360 MHz, CDCQ: 7.7-7.2 (15H, m), 6.16 (1H, dd, J 4.1 Hz, 9.5Hz), 5.96 (1 H, dd, J4.8Hz, 9.5Hz), 4.37 (1H, d, J 4.0Hz), 4.04 (1H, d, J4.9Hz), 3.82 (1H, d, J 14.1 Hz), 3.74 (1H, d, J 14.1 Hz), 3.39 (1H, dd, J3.5Hz, 9.4Hz), 2.39 (1H, dd, J3.6Hz, 14.8Hz), 2.14 (1H, dd, J 9.4Hz, 14.8Hz), 1.81 (1H, br s).

DESCRIPTION 5b - (1 R*,2S*, 5S*, 6R*) isomer:- δ_H (360 MHz, CDCI₃): 7.8-7.2 (15H, m), 5.85 (2H, m), 4.98 (1H, d, J4.4Hz), 3.81 (1H, d, J3.6Hz), 3.53 (1H, dd, J 3.8Hz, 9.5Hz), 3.45 (2H, s), 3.08 (1 H, dd, J 9.6Hz, 14.9Hz), 2.45 (1 H, dd, J 3.6Hz, 15.1Hz), 1.70 (1H, d, J 5.1 Hz).

DESCRIPTION 6 (1fl*2S*5S*6 ? -8-Benzyl-2-{[3,5-bis(trifluoromethyI)phenyl]methoxy}-1- phenyl-6-phenylsulphonyl-8-azabicycIo[3.2.1]oct-3-ene

Sodium hydride (94mg, 60% in oil, 2.45mmol) was added to a stirred solution of (1 H*2S*,5S*6R")-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]oct-3- en-2-ol (Description 5b; 256mg, 0.6mmol) and 3,5-bis(trifluoromethyl)benzyl bromide (0.8ml) in dry THF (3ml) at room temperature. The reaction mixture was stirred at +50°C for 30 minutes, then cooled to room temperature and treated with diethyl ether (70ml). The mixture was washed twice with water, brine. The combined organic extracts were dried (Na₂SO₄) and concentrated. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-30%) to give the title compound (400mg, quant.). δ_H (400 MHz, CDCI₃): 7.81 (3H, s), 7.72 (2H, dd, J 1.0Hz, 6.3Hz), 7.60 (3H, m), 7.45 (2H, t, j 8.1 Hz), 7.36 (4H, d, J 8.1 Hz), 7.34-7.23 (4H, m), 6.15 (1H, dd, J 2.3Hz, 9.8Hz), 5.97 (1H, dd, J4.6Hz, 9.8Hz), 4.99 (1H, d, J 12.3Hz), 4.79 (1H, d, J 12.3Hz), 4.69 (1H, br s), 3.90 (1H, d, J4.6Hz), 3.52 (1H, dd, J3.8Hz, 9.7Hz), 3.54 (1H, d, J 13.2Hz), 3.48 (1H, d, J 13.2Hz), 3.21 (1H, dd, J9.6Hz, 14.8Hz), 2.48 (1H, dd, J 3.8Hz, 14.8Hz).

DESCRIPTION 7

(1R*2 ?* 5S*,6R 8-Benzyl-2-[3,5-bls(trifluoromethyl)benzoyloxy]-1-phenyl- 6-phenylsulphonyl-8-azabicyclo[3.2.1]octane

A solution of (1 H*,2fi*,5S*,6ft 8-benzyl-1-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octan-2-ol (Description 4; 0.98g, 2.25mmol), triethylamine (0.6ml), N,N-dimethylaminopyridine (100mg) and 3,5-bis(trifIuoromethyl)benzoyl chloride (0.6ml, 3.33mmol) in dry dichloromethane (10ml) was stirred at room temperature for 6 days. The reaction mixture treated with saturated aqueous NaHCO₃ and extracted with dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 5-30%) to give the title compound (1.05g, 69%). δ_H (400 MHz, CDCI₃): 8.38 (2H, s), 8.03 (1H, s), 7.77 (2H, dd, J 1.3Hz, 7.2Hz), 7.64-7.59 (3H, m), 7.50-7.43 (5H, m), 7.37-7.22 (4H, m), 5.83 (1H, m), 4.19 (1H, d, J 14.6Hz), 4.06 (1H, d, J 14.6Hz), 3.97 (1H, br s), 3.51 (1H, dd, J5.4Hz, 9.3Hz), 2.58 (1H, dd, J 5.4Hz, 14.4Hz), 2.34 (1H, dd, J9.3Hz, 14.4Hz 2.32-2.00 (3H, m), 1.11 (1H, m).

DESCRIPTION 8 (1β*,2R*5R^!i)-8-Benzyl-2-[3,5-bis(trifluoromethyl)benzoyloxy]-1-phenyI-8- azabicyclo[3.2.1]octane

10% sodium amalgam (6.4g) was added in three portion to a stirred mixture of (1 H^*,2H*5S*,6H")-8-benzyl-1-phenyl-6-phenylsulphonyl-bicyclo[3.2.1]octan-2-ol (Description 4; 1.9g, 4.36mmol), disodium hydrogen orthophosphate (4.5g), THF (15ml) and methanol (30ml) at -20°C. The reaction mixture was stirred at -20- 0°C for one hour and cooled to -20°C prior each addition. The reaction mixture was quenched with brine, carefully decanted and extracted with ethyl acetate (4x50ml). The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 1 :1) to give a 2:1 inseparable mixture (1 R*, 2H^*,5H^*)-8-benzyl-1 -phenyl-8- azabicyclo[3.2.1]octan-2-ol and (1 H^*2H^-N-benzyl-1-amino-1-phenylcyclohept-5- en-2-ol. This mixture was treated with dichloromethane (10ml), triethylamine (1.5ml), N,N-dimethylaminopyridine (100mg) and 3,5-bis(trifluoromethyl)benzoyl chloride (1.33ml) and stirred at ambient temperature for 26 hours, then quenched with saturated aqueous NaHCO₃ and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso- 7exane:diethyl ether 0-4%) to give the title compound (1.13g, 48%) and (1H^*,2H 1-amino-N-benzyl-2-[3,5- bis(trifluoromethyl)benzoyloxy]-1-phenylcyclohept-5-ene (0.6g, 26%).

(1A?*2/?*,5β^-8-Benzyl-2-[3₅5-bis(trifIuoromethyl)benzoyloxy]-1-phenyl-8- azabicyclo[3.2.1]octane:- δ_H (400 MHz, CDCI₃): 8.50 (2H, s), 8.04 (1H, s), 7.49 (4H, m), 7.39 (1 H, t, J7.7Hz), 7.30-7.18 (4H, m), 7.15 (1H, t, J7.2Hz), 5.52 (1H, s), 4.19 (1 H, d, J 15.0Hz), 3.71 (1H, d, J 15.0Hz), 3.52 (1 H, m), 2.30-2.05 (5H, m), 1.91 (1 H, d, J 10.6Hz), 1.73 (1 H, m), 1.7 (1 H, m).

(1 f?*,2/? 1 -Amino-N-benzyl-2-[3.5-bis(trif luoromethyl)benzoyloxy]-1 - phenyIcyclohept-5-ene:- δ_H (360 MHz, CDCI₃): 8.13 (2H, s), 8.00 (1H, s), 7.60 (1H, dd, J 1.3Hz, 8.5Hz), 7.47 (1H, d, J7.4Hz), 7.36 (1H, t, J7.7Hz), 7.30-7.18 (3H, m), 7.13 (1H, m), 6.09 (1H, m), 5.90 (1H, m), 5.47 (1H, m), 3.75 (1H, d, J 13.1Hz), 3.65 (1H, d, J 13.1 Hz), 2.89 (1H, dd, J4.3Hz, 15.0Hz), 2.71 (1H, dd, J 8.0Hz, 15.0Hz), 2.45-2.30 (2H, m), 2.04 (1 H, m), 2.00-1.87 (2H, m). m/z (ES⁺) 534 [M+H]⁺.

DESCRIPTION 9 (1 ?*2/?*5/? 8-Benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol

Lithium naphthalenide (200ml, 0.6M in teterahydrofuran) was added dropwise into a -78°C solution of (1 H^*2H^*,5S^*,6H 8-benzyl-1-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octan-2-ol (Description 4; 25g, 57.7mmol) in THF (350ml). The mixture was quenched by addition of saturated ammonium chloride and warmed to room temperature The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was washed (x2) with water then dried (MgSO , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5, 15 and 40% ethyl acetate / iso-hexanes to yield the title compound (14.3g, 84.6%). m/z (ES⁺) 294 ([M+H]⁺).

DESCRIPTION 10 2-(4-Fluorophenyl)-3-hydroxypyridine

2-Bromo-3-hydroxypyridine (50g, 0.29mol), sodium carbonate (64g, 0.60mol), toluene (600ml), and water (300ml) were combined in a 2 litre 3-necked flask with condenser and N₂ bubbler. A steady stream of N₂ was passed over the reaction mixture while warming to 50°C over 30 minutes. Tetrakis(triphenylphosphine) palladium(O) (1 Og) was slurried in water then added to the reaction mixture then 4-fluorobenzeneboronic acid (46g, 0.33mol) was slurried in ethanol (100ml) and added. The reaction mixture was refluxed for 5 hours then cooled and stirred at room temperature for 3 days. The organic layer was decanted off and concentrated in vacuo and the aqueous layer saturated with potassium carbonate and extracted with ethyl acetate (x4). The organics were combined and concentrated in vacuo then ethyl acetate (200ml) added and the mixture heated. A yellow powder settled in the flask which was filtered off to give the title compound (25.1 g, 46%). m/z (ES⁺) 191 «M+H]⁺).

DESCRIPTION 11 1-Benzyl-2-(4-fluorophenyl)-3-oxypyridinium betaine 2-(4-Fluorophenyl)-3-hydroxypyridine (Description 10; 24.25g, 0.13mol) was heated in toluene (300ml) to 80°C under N₂ then benzyl bromide (15.46ml, 0.13mol) added and the mixture stirred at 115°C for 16 hours. The reaction mixture was then cooled in ice and the solid filtered off and washed with diethyl ether (x2) to give the title compound as a yellow solid (30.33g, 66%). m/z (ES⁺) 281 ([M+Hf). DESCRIPTION 12 (1 ?*5S*6f? -8-Benzyl-1-(4-fluorophenyl)-6-phenylsulphonyI-8- azabicyclo[3.2.1]oct-3-ene-2-one 1-Benzyl-2-(4-fluorophenyl)-3-oxypyridinium betaine (Description 11 ; 30.33g) was stirred in methanol (500ml) with Amberlite™ ISA 400(CI) resin (prewashed with 4N sodium hydroxide, water and methanol) for 1 hour at room temperature. The resin was filtered off and the filtrate concentrated in vacuo to give a brown oil (24.35g, 87.28mmol). The oil was dissolved in 1 ,4 dioxane (150ml) and phenyl vinyl sulphone (24.96g, 148.38mmol) added and the mixture stirred under N₂ at reflux for 24 hours. The reaction mixture was diluted with ethyl acetate (100ml) and washed with saturated sodium hydrogen carbonate solution. The organics were removed and the aqueous further extracted with ethyl acetate (x2). The combined organics were dried (MgSO₄) then concentrated in vacuo to give a brown oil. The reaction mixture was purified by flash column chromatography [30% diethyl ether in iso-hexane] to give the title compound as an orange oil (13.88g, 23%). m/z (ES⁺) 448 ([M+H]⁺).

DESCRIPTION 13

(1β*5S*6 ? 8-Benzyl-1-(4-fluorophenyl)-6-phenylsulphonyI-8- azabicyclo[3.2.1 ]octan-2-one

(1 R*,5S*,6R*)-8-Benzy\-l -(4-fluorophenyl)-6-ρhenylsulphonyl-8- azabicyclo[3.2.1]oct-3-ene-2-one (Description 12; 13.88g, 31.05mmol) was dissolved in methanol (25ml) and ethyl acetate (25ml) and 10% palladium hydroxide (1.80g) added and the mixture hydrogenated at 30psi for 30 minutes.

The mixture was filtered and concentrated in vacuo to give the title compound as a yellow oil (11.65g, 84%). m/z (ES⁺) 450 ([M+H]⁺). DESCRIPTION 14 (1f.*,2^β*,5S*,6/^:ϊ^-8-Benzyl-1-(4-fluorophenyl)-6-phenylsulphonyl-8- azabicyclo[3.2.1]octan-2-ol

(1 H*,5S*,6f. 8-Benzyl-1 -(4-f luorophenyl)-6-phenylsulphonyl-8- azabicyclo[3.2.1]octan-2-one (Description 13; 11.65g, 25.95mmol) was stirred in methanol (100ml) then sodium borohydride (981 mg, 25.95mmol) added and the mixture stirred at room temperature for 2 hours. The reaction mixture was quenched with water then concentrated in vacuo and partitioned between water and ethyl acetate. The organics were collected, dried (MgSO₄), and concentrated in vacuo to give a cream solid which was triturated in diethyl ether and filtered to give the title compound as a cream-coloured solid (7.26g, 62%). m/z (ES⁺) 452 ([M+H]⁺).

DESCRIPTION 15 (1 R* 2R*, 5/? 8-BenzyM-(4-fluorophenyl)-8-azabicyclo[3.2.1]octan-2-ol

(1 f?*2H*5S*,6R*)-8-Benzyl-1-(4-fluorophenyl)-6-phenylsulphonyl-8- azabicyclo[3.2.1]octan-2-ol (Description 14; 10.72g, 23.77mmol) was dissolved in THF (200ml) then cooled to -78°C and lithium naphthalenide added until a permanent green colour was observed. Each portion was then quenched with saturated ammonium chloride solution then extracted with ethyl acetate (x3) and the extracts dried (MgSO₄) and concentrated in vacuo. The extracts were combined to give a yellow oil/solid. This was purified by flash column chromatography [20%-40% ethyl acetate in iso-hexane] to give a yellow solid which was repurified by flash column chromatography [25% ethyl acetate in iso- hexane] to give the title compound as a clear yellow oil (5.37g, 73%). m/z (ES⁺) 312 ([M+H]⁺).

DESCRIPTION 16 (1 ?*2 ?*5 ?^,f)-8-Benzyl-2-(3,5-bis(trifluoromethyl)benzoyl)-1-(4- fluorophenyl)-8-azabicyclo[3.2.1]octane

(1 H*2f?^>t,5H -8-Benzyl-1-(4-fluorophenyl)-8-azabicyclo[3.2.1]octan-2-ol (Description 15; 1.23g, 3.95mmol), and triethylamine (0.61ml, 4.35mmol) in dichloromethane were stirred with 4-dimethylaminopyridine (5 crystals) and 3,5-bis(trifluoromethyl)benzoyl chloride at room temperature for a weekend. The reaction mixture was poured into water and extracted with dichloromethane (x3), dried (MgSO₄) and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [10%-20% ethyl acetate in iso-hexane] to give the title compound as a yellow solid (1.27g, 58%). m/z (ES⁺) 552 ([M+H]⁺).

DESCRIPTION 17 (1 ?*2ff*5 ?^-Benzyl-2-{1-[3,5-bis(trifluoromethyl)phenyl]ethenyloxy}-1-(4- fluorophenyl)-8-azabicyclo[3.2.1]octane

Dimethylbis(cyclopentadienyl)titanium (11.23ml, 1.23M in toluene, 13.8mmol) was added to (1 H*,2H*5H benzyl-2-(3,5-bis(trifluoromethyl)benzoyI)-1-(4- fluorophenyl)-8-azabicyclo[3.2.1]octane (Description 16; 1.27g, 2.30mmol) and the reaction mixture stirred in the dark under N₂ for 3 hours at 80°C. The reaction mixture was stirred with methanol (5ml), water (0.5ml) and sodium hydrogen carbonate at 40°C for 1 hour. The mixture was then cooled, filtered and concentrated in vacuo to give a green oil. This was purified by flash column chromatography [5% ethyl acetate in iso-hexane] to give the title compound as an orange oil (923mg, 73%). m/z (ES⁺) 550 ([M+Hf).

DESCRIPTIONS 18a and 18b (1 fl*,5S*,6flS)-8-Benzyl-6-(tert-butoxycarbonyl)-1 -phenyl-8- azabicyclo[3.2.1]oct-3-en-2-one A mixture of N-benzyl-3-hydroxy-2-phenylpyridinium bromide (255g, 0.745mol), tetf-butyl acrylate (470ml), triethylamine (150m!) and 1,4-dioxane (11) was heated at reflux for 15 hours and cooled to room temperature. The reaction mixture was poured onto saturated aqueous NaHCO₃ (11) and extracted into an 1:1 mixture of /sohexane:diethyl ether (3x500ml). The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (750g, /so-hexane:diethyl ether 0-20%) to give a 2:1 mixture of (1 H*,5S^*,6R*)-8-benzyl-6-(tør.-buιoxycarbonyl)-1 -phenyl-8-azabicyclo[3.2.1 ]oct-3- en-2-one and (1 H\5S*,6S*)-8-benzyl-6-(terf-butoxycarbonyl)-1-pbenyl-8- azabicyclo[3.2.1]oct-3-en-2-one (205g, 70%) as a yellow-orange foam. The isomers were separated on silica gel (/so-hexane:diethyl ether) and crystallised from /sσ-hexane:diethyl ether giving yellow rhombs:

DESCRIPTION 18a: (1 R*,5S\6/?*)-isomer:- δ_H (360 MHz, CDCI₃): 7.83 (1 H, dd, J 1.4Hz, 8.6Hz), 7.40-7.25 (8H, m), 6.91 (1H, dd, J4.8Hz, 9.7Hz), 6.18 (1H, d, J 9.7Hz), 4.10 (1H, d, J4.8Hz), 3.67 (1H, d, J 13.0Hz), 3.51 (1 H, d, J 14.0Hz), 2.99 (1H, dd, J 2.6Hz, 14.2Hz), 2.84 (1H, dd, J2.6Hz, 9.0Hz), 2.39 (1 H, dd, J 9.0Hz, 14.2Hz), 1.43 (9H, s).

DESCRIPTION 18b: (1 ff*,5S*,6S*)-isomer:- δ_H (360 MHz, CDCI₃): 7.70 (1H, dd, J 1.3Hz, 8.7Hz), 7.40-7.25 (8H, m), 6.88 (1 H, dd, J 4.8Hz, 9.8Hz), 6.25 (1 H, d, J 9.8Hz), 4.02 (1H, dd, J 5.0Hz, 6.0Hz), 3.65-3.50 (3H, m), 2.60 (2H, m), 1.43 (9H, s).

DESCRIPTIONS 19a and 19b (1 R*,5S*,6flS)-8-Benzyl-6-(tert-butoxycarbonyl)-1 -phenyl-8- azabicyclo[3.2.1 ]octan-2-one

A mixture of (1 HM5S*,6flS)-8-benzyl-6-(terf-butoxycarbonyl)-1-phenyl-8- azabicylco[3.2.1]oct-3-en-2-one (Description 18; 26g, 66mmol), 10% palladium on charcoal (3.5g, 3.3mmol), ethyl acetate (50ml) and methanol (100ml) was stirred under hydrogen atmosphere (1atm) at room temperature for 1 hour. The reaction mixture was treated with dichloromethane (500ml), filtered through a pad of Celite™. The filter cake was well washed with dichloromethane and the filtrate was concentrated to give the title compound as a solid (26g, 100%). The isomers were separated on silica gel (/so-hexane:ethyl acetate) and crystallised from acetone: so-hexane yielding pure ketones as a colourless crystals.

DESCRIPTION 19a - (6 ?*)-isomer: δ_H (360 MHz, CDCI₃): 7.50 (2H, dm, J 7.2Hz), 7.41 (2H, d, J7.3Hz), 7.33 (4H, m), 7.25 (2H, m), 3.72 (1H, m), 3.70 (1H, d, J 15.0Hz), 3.44 (1H, d, J 14.6Hz), 2.91 (1H, dd, J5.2Hz, 9.5Hz), 2.75-2.45 (5H, m), 1.97-1.87 (1H, m), 1.46 (9H, s). DESCRIPTION 19b - (6S*)-isomer: δ_H (360 MHz, CDCQ: 7.50-7.20 (1 OH, m), 3.75 (1H, d, J 14.7Hz), 3.61 (1H, dd, J3.5Hz, 6.3Hz), 3.52 (1H, d, J 14.8Hz), 3.46 (1 H, dt, J 6.7Hz, 11.6Hz), 2.95 (1H, m), 2.90 (1H, dd, J 7.0Hz, 14.4Hz), 2.53-2.36 (2H, m), 2.26 (1H, dd, J 11.6Hz, 14.0Hz), 1.94 (1H, d, J 14.0Hz), 1.91 (1H, m), 1.46 (9H, s).

DESCRIPTION 20 (1 fl*,2fl*,5S*,6fl 8-Benzyl-6-(tert- utoxycarbonyl)-1 -phenyl-8- azabicyclo[3.2.1]octan-2-ol

Sodium borohydride (8.7g, 0.23mol) was added to a stirred suspension of (1 f?*,5S *6H 8-benzyI-6-(fe/f-butoxycarbonyl)-1 -_phenyl-8- azabicyclo[3.2.1]octan-2-one (Description 19a; 76g, 0.23mol) in methanol (700ml) at room temperature. The reaction mixture was stirred overnight, quenched with water and concentrated in vacuo. The residue was extracted into ethyl acetate. The combined organic extracts were dried (MgSO₄) and concentrated in vacuo to give the title compound as a white solid. δ_H (400 MHz, CDCI₃): 7.55 (2H, dd, J 1.2Hz, 8.6Hz), 7.40-7.20 (8H, m), 4.08 (1H, d, J 15.2Hz), 4.08 (1H, br s), 3.68 (1 H, br s), 3.44 (1H, d, J 15.2Hz), 2.77 (1H, dd, J 5.1 Hz, 9.4Hz), 2.63 (1H, dd, 5.1 Hz, 13.7Hz), 2.21 (1H, dd, J9.4Hz, 13.3Hz), 2.14 (1H, ddd, J 2.4Hz, J5.5Hz, 13.3Hz), 1.95 (1H, ddt, J3.9Hz, J5.9Hz, 13.3Hz), 1.85 (1H, dd, J 5.5Hz, 14.9Hz), 1.52 (1H, d, J 6.6Hz), 1.43 (9H, s), 1.34 (1H, m).

DECSRIPTIONS 21a and 21b (1 ?*2 ?*5S*,6S^-8-Benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-aza bicyclo[3.2.1]octan-2-ol; and (1 /?* 2S*,5S*,6S 8-Benzyl-6-(fe/ -butoxycarbonyl)-1 -phenyl-8- azabicyclo[3.2.1]octan-2-ol

(1 H*5S*,6S 8-Benzyl-6-(te/ι.-butoxycarbonyl)-1 -phenyl-8- azabicyclo[3.2.1]octan-2-one (Description 19b; 750mg, 1.91 mmol) was dissolved in THF (5ml) and methanol (25ml) was added. The mixture was cooled to +5°C and treated with sodium borohydride (184mg, 4.8mmol). The reaction mixture was stirred for 45 minutes, quenched with saturated aqueous NH₄CI (10ml) and concentrated in vacuo. The aqueous residue was extracted with dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated to give crude product as a 10:1 mixture of diastereoisomers. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0- 30%) to give the (1

(7l0mg, 92%) and the (1 H*,2S*,5S*6S'¹)-isomer (59mg, 8%) of the title compound. DESCRIPTION 21a - (1 R*, 2f?*,5S*,6S isomer:- δ_H (400 MHz, CDCI₃): 7.45- 7.20 (10H, m), 4.14 (1H, d, J 15.3Hz), 3.66 (1H, s), 3.49 (1 H, s), 3.46 (1 H, dt, J 6.6Hz, 12.1Hz), 3.26 (1H, d, J 15.2Hz), 3.05 (1H, br), 2.70 (1H, dt, J 5.5Hz, 13.7Hz), 2.37 (1H, d, j 11.8Hz), 2.09 (1H, ddd, J3.5Hz, J5.5Hz, 13.0Hz), 2.03 (1H, m), 1.75-1.50 (1H, m), 1.45 (9H, s).

DESCRIPTION 21b - (1 R*, 2S*, 5S* 6S*)-isomer:- δ_H (360 MHz, CDCI₃): 7.74 (1 H, d, J 7.4Hz), 7.40-7.20 (8H, m), 3.92 (1 H, dd, J 5.6Hz, 10.2Hz), 3.76 (1 H, d, J 14.7Hz), 3.54 (1H, dt, J6.2Hz, 12.6Hz), 3.38 (1H, dt, J2.8Hz, 7.0Hz), 3.04 (1H, d, J 14.7Hz), 2.86 (1 H, dd, J 5.6Hz, 13.3Hz), 2.35 (1 H, t, J 12.6Hz), 1.97-1.87 (1H, m), 1.84-1.75 (2H, m), 1.70-1.52 (1H, m), 1.46 (9H, s), 1.15 (1 H, br s).

DESCRIPTION 22

(Ifl'^fϊ^δS^βS^-δ-Benzyl^- jδ-bis rifluoromethy phenyηmethoxy}^- (fert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane

Sodium hydride (60% in oil, 110mg, 2.75mmol) was added to a stirred mixture of (1 R*,2R*, 5S^*,6S 8-benzyl-6-(terf-butoxycarbonyl)-1 -phenyl-8- azabicyclo[3.2.1]octan-2-ol (Description 21a; 670mg, 1.1mmol), 3,5- bis(trifluoromethyl)benzyl bromide (1ml, 5.45mmol) in N,N-dimethylformamide (5ml) at room temperature. The reaction mixture was stirred for 20 hours, quenched with saturated aqueous NH₄CI and extracted into a 1:1 mixture of iso- hexane:diethyl ether. The combined organic extracts were washed with water, dried (Na^SO and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-5%) to give the title compound (826mg, 78%). δ_H (360 MHz, CDCl₃): 7.73 (1H, s), 7.68 (2H, s), 7.52 (1H, d, J7.6Hz), 7.42 (1H, d, J 7.4Hz), 7.45-7.20 (6H, m), 4.75 (1H, d, J 12.9Hz), 4.73 (1H, s), 4.46 (1H, d, J 12.9Hz), 4.13 (1 H, d, J 15.7Hz), 4.02 (1H, s), 3.73 (1H, d, J 15.7Hz), 3.59 (1H, d, J 5.6Hz), 3.33 (1 H, dt, J 6.3Hz, 12.3Hz), 2.42 (1 H, dd, J6.3Hz, 13.7Hz), 3.26 (1H, d, J 15.2Hz), 3.05 (1H, br), 2.70 (1H, dt, J 5.5Hz, 13.7Hz), 2.13 (3H, m), 1.94 (1H, m), 1.45 (9H, s), 1.35 (1H, m), DESCRIPTIONS 23a, 23b, 23c and 23d (1 R*, 5S* 6 ?S)-6-Cyano-1 -phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1 ]oct-3-en- 2-one; and (1 R*, 5fl*,6f?S)-7-cyano-1 -phenyI-8-(prop-2-enyl)-8-azabicyclo[3.2.1 ]oct-3-en- 2-one

A suspension of 3-hydroxy-2-phenylpyridine (15g, 116mmol) in toluene (250ml) was heated at reflux for 30 minutes. Allyl bromide (30ml) was added and the reaction mixture was heated at reflux for 20 hours and cooled using the ice bath. Solid was filtered off and washed twice with ether to afford crude 3-hydroxy-2- phenyl-N-(prop-2-enyl)-pyridinium bromide, which was used treated with acrylonitrile (100ml), triethylamine (15ml) and 1 ,4-dioxane (200ml) was heated at reflux for 28 hours and cooled to room temperature. The reaction mixture was poured onto saturated aqueous NaHCO₃ and extracted with ethyl acetate. The combined organic extracts were dried (Na₂SO₄) and concentrated to give a crude mixture of regio and stereoisomers in ratio (6R*):(6S^,i):(7H^,l):(7S^,()=7:8:1:5. Isomers were separated by chromatography on silica gel (iso-hexane:ethyl acetate). DESCRIPTION 23a - (\R*,5S*,6R*)-isomer.- δ_H (400 MHz, CDCI₃): 7.67 (2H, m), 7.40 (3H, m), 7.31 (2H, m), 6.91 (1H, dd, J4.7Hz, 9.4Hz), 6.19 (1H, d, J

9.8Hz), 5.83 (1H, dddd, J4.3Hz, 6.6Hz, 10.2Hz, 17.2Hz), 5.34 (1 H, dq, J 1.7Hz, 17.2Hz), 5.20 (1H, dm, J 10.2Hz), 4.37 (1H, d, J4.7Hz), 3.20 (1H, ddt, J 2.0Hz, 4.3Hz, 14.9Hz), 3.05 (1H, dd, J6.6Hz, 14.5Hz), 3.01 (1H, dd, J4.3Hz, 7.4Hz), 2.72-2.63 (2H, m). DESCRIPTION 23b -

δ_H (400 MHz, CDCI₃): 7.51 (2H, m), 7.36 (3H, m), 7.28 (2H, m), 7.06 (1H, dd, J4.7Hz, 9.8Hz), 6.33 (1H, d, J 9.8Hz), 5.76 (1H, dddd, J 5.1 Hz, 6.5Hz, 10.2Hz, 17.2Hz), 5.22-5.09 (2H, m), 4.29 (1H, t, J 5.1 Hz), 3.44 (1H, ddd, J5.9Hz, 6.7Hz, 9.8Hz), 3.08-2.94 (2H, m), 2.71 (1H, dd, J 10.2Hz, 14.1 Hz), 2.47 (1H, dd, J 7.0Hz, 14.1 Hz). DESCRIPTION 23c - (1 ?* 5S*,7S*)-isomer:- δ_H (360 MHz, CDCl₃): 7.60 (2H, m), 7.46-7.32 (5H, m), 7.11 (1H, dd, J4.9Hz, 9.8Hz), 6.29 (1 H, d, J 9.8Hz), 5.84 (1H, dddd, J5.6HZ, 6.0Hz, 10.2Hz, 17.2Hz), 5.23 (1H, dq, J 1.7Hz, 17.2Hz), 5.18 (1H, dm, J 10.5Hz), 4.12 (1H, dd, J5.3Hz, 6.0Hz), 3.40 (1H, dd, J3.2Hz, 10.9Hz), 3.10 (2H, dt, J 1.7HZ, 6.0Hz), 2.70 (1H, ddd, J6.3HZ, 10.9Hz, 13.0Hz), 2.17 (1H, dd, J 3.1 Hz, 12.6Hz).

DESCRIPTION 23d - (1 R% 5S* 7f?*)-isomer (distinguished signals from the mixture):- δ_H (360 MHz, CDCI₃): 6.93 (1H, dd, J4.6Hz, 9.8Hz), 6.12 (1H, d, J 9.8Hz), 5.91 (1H, dddd, J3.9Hz, 7.1Hz, 10.2Hz, 17.2Hz), 5.27 (1H, ddd, J2.1 Hz, 3.5Hz, 17.2Hz), 4.14 (1H, dd, J4.9Hz, 6.0Hz), 3.45 (1H, dd, J7.4Hz, 8.8Hz), 3.31 (2H, ddt, J2.1Hz, 3.9Hz, 14.7Hz), 3.09 (1H, dd, J7.4Hz, 15.0Hz), 2.55 (1H, ddd, J 6.3Hz, 7.4Hz, 12.3Hz), 2.35 (1H, dd, J 9.1 Hz, 11.9Hz).

DESCRIPTION 24

(1 R*, 2R*,5S*,6f?*)-6-Cyano-1 -phenyl-8-(prop-2-enyI)-8- azabicyclo[3.2.1]octan-2-ol

A solution of K-Selectride^® in THF (1M, 20ml, 20mmol) was added dropwise to a stirred solution of (1 R^*,5S*, 6H 6-cyano-1 -phenyl-8-(prop-2-enyl)-8- azabicyclo[3.2.1]oct-3-en-2-one (Description 23a; 1.6g, 6mmol) in THF (20ml) at - 70°C. The reaction mixture was slowly warm up to 0°C over 90minutes and carefully quenched with a mixture of 2M NaOH (40ml) and H₂O₂ (35%, 10ml). The mixture was stirred for 15 minutes and extracted into dichloromethane (3x100ml). The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso- hexane:ethyl acetate 0-4%) to give the title compound (1.1g, 68%). δ_H (360 MHz, CDCI₃): 7.44-7.33 (3H, m), 7.31-7.25 (2H, m), 5.84 (1H, dddd, J 5.3Hz, 5.6Hz, 10.5Hz, 17.2Hz), 5.34 (1H, dq, J 1.7Hz, 17.2Hz), 5.17 (1H, dq, J 1.4Hz, 10.5Hz), 3.97 (1 H, t, J 2.8Hz), 3.75 (1 H, br s), 3.55 (1 H, ddt, J 1.7Hz, 5.3Hz, 15.1Hz), 3.10 (1H, ddt, J 1.4Hz, 6.0Hz, 15.4Hz), 2.91 (1H, dd, J5.3Hz, 9.5Hz), 2.55 (1 H, br), 2.52 (1H, dd, J 9.5Hz, 13.4Hz), 2.38 (1H, dd, J5.3Hz, 13.4Hz), 2.11 (1H, ddt, J2.8Hz, 6.0Hz, 13.7Hz), 1.87-1.68 (2H, m), 1.39 (1 H, m).

DESCRIPTION 25 (1 R*, 2/7* 5S*,7S*)-7-Cyano-1 -phenyl-8-(proρ-2-enyl)-8- azabicyclo[3.2.1]octan-2-ol

A solution of K-Selectride^® in THF (1M, 6.5ml, 6.5mmol) was added dropwise to a stirred solution of (1 R^*,δS^*, 7S^*)-7-cyano-1 -phenyI-8-(prop-2-enyl)-8- azabicyclo[3.2.1]oct-3-en-2-one (Description 23c; 295mg, 1.11mmol) in THF (7ml) at -78°C. The reaction mixture was slowly warm up to +15°C over 6 hours and carefully quenched with a mixture of 2M NaOH (8ml) and H₂O₂ (35%, 2ml). The mixture was stirred for 20 minutes. The mixture was treated with saturated aqueous Na₂SO₃and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (50mg, 17%). δ_H (360 MHz, CDCI₃): 7.49-7.36 (4H, m), 7.36-7.28 (1H, m), 5.87 (1H, dddd, J 5.3Hz, 5.6Hz, 10.5Hz, 17.2Hz), 5.34 (1 H, dm, J 17.2Hz), 5.16 (1 H, dm, J

10.2Hz), 3.73 (1H, m), 3.70 (1H, m), 3.64 (1 H, dt, J3.4Hz, 7.2Hz), 3.16 (1H, dd, J 5.3Hz, 9.5Hz), 3.03 (1H, dd, J5.3Hz, 15.8Hz), 2.62-2.46 (2H, m), 2.24 (1H, dd, J 9.5Hz, 13.3Hz), 2.06 (1H, m), 1.89 (2H, m), 1.87-1.68 (2H, m), 1.28 (1 H, m).

DESCRIPTION 26

(1f.*2ff*5/?*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-8-(4-chlorobut-2- ynyI)-1-phenyl-8-azabicyclo[3.2.1]octane

A solution of (1 H*2H*5H -2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl- 8-azabicyclo[3.2.1]octane (Example 60; 400mg, 0.93mmol) in dimethylformamide (4ml) was added to 1 ,4-dichlorobutyne (0.23ml, 2.33mmol) and potassium carbonate (386mg, 2.79mmol) in dimethylformamide (2ml) at 60°C. The reaction mixture was stirred under N₂ at 60°C overnight. The mixture was diluted with water and extracted with ethyl acetate (x3), dried (MgSO₄) and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [2.5% -7.5% methanol in dichloromethane] to give the title compound as a brown oil. m/z (ES⁺) 516/518 ([M+H]⁺).

DESCRIPTION 27 (1f?*2H*5 ? 8-(4-Azidobut-2-ynyl)-2-{[3,5-bis(trifluoromethyl)phenyl]- methoxy}-1 -phenyl-8-azabicyclo[3.2.1 ]octane

(1 H*2f?*,5H^Ii)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-8-(4-chlorobut-2-ynyl)- 1-phenyl-8-azabicyclo[3.2.1]octane (Description 26; 254mg, 0.49mmol) and sodium azide (35mg, 0.54mmol) were stirred in dimethylformamide (3ml) at room temperature overnight. The reaction mixture was diluted with water and the product extracted with ethyl acetate (x3), dried (MgSO₄) and concentrated in vacuo to give the title compound as an orange oil. m/z (ES⁺) 523 ([M+H]⁺).

DESCRIPTIONS 28a and 28b (1 R*,2R*, 5S* 6/?*)-8-Benzyl-2-{(1 S*)-1 -[3,5-bis(trif luoromethyl)phenyl]-2- iodoethoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane; and

(1 R*,2R*, 5S* 6/?*)-8-Benzyl-2-{(1 R*A -[3,5-bis(trif luoromethyl)phenyl]-2- iodoethoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (1 R^* 2 ?^* 5S^* 6fl^*)-8-Benzyl-2-{(1 S^*)-1 -[3,5-bis(trif luoromethyl)phenyl]-2- hydroxyethoxy}-6-(terf-butoxycarbonyl)-1 -phenyl-8-azabicyclo[3.2.1 ]octane and (1 R*,2R*,5S*, 6H*)-8-benzyl-2-{(1 R^*)-λ -[3,5-bis(trif luoromethyl)phenyl]-2- hydroxyethoxy}-6-(tert-butoxycarbonyl)-1 -phenyl-8-azabicyclo[3.2.1 ]octane (Example 127; 398mg, 0.61 mmol) in dichloromethane was treated with triphenylphosphine (241 mg, 0.92mmol), imidazole (63mg, 0.92mmol) and iodine (234mg, 0.92mmol). The mixture was concentrated in vacuo and the residue purified by flash column chromatography, eluting with hexane. The title compounds were isolated as a white solid (306mg, 66%). m/z (ES⁺) 760 ([M+H]⁺).

DESCRIPTION 29 (1 R*,5S*,6R*)-8-Benzyl-6-cyano-1 -phenyl-8-azabicyclo[3.2.1]oct-3-ene-2-one

N-benzyl-3-hydroxy-2-phenylpyridinium bromide (20g, 58.3mmol), acrylonitrile (50ml, 755mmol) and triethylamine (20ml, 143mmol) were mixed and stirred at reflux for 20 hours in 1 ,4-dioxane (150ml). The mixture was partitioned between saturated sodium hydrogen carbonate and ethyl acetate. The organic layer was separated, dried (MgSO₄), filtered and concentrated. The residue was chromatographed on silica gel eluting with 25, 35 and 45% diethyl ether/ so hexanes to yield the title compound (4.4g, 24%). δ_H (400MHz, CDCI₃): 7.75-7.73 (2H,m), 7.48-7.28 (8H,m), 6.83 (1 H, dd, J4.8Hz, 9.7Hz), 6.24 (1H, d, J9.7Hz), 4.12 (1H,m), 3.81 (1H, d, J 14.1 Hz), 3.52 (1H, d, J 14.1Hz), 3.00 (1H, dd, J3.5Hz, 8.3Hz), 2.80-2.69 (2H, m).

DESCRIPTION 30

(1R*,5S*,6R*)-8-Benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-one

Palladium hydroxide (20%) (700mg) was added to a solution of (1 R*,5S*,6R*)-8- benzyl-6-cyano-1 -phenyl-8-azabicyclo[3.2.1]oct-3-ene-2-one (Description 29; 7.1 g, 22.6mmol) in methanol (100ml). The mixture was transferred to the Parr™ apparatus and hydrogenated at 45psi for 20 minutes. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The organic layer was separated, dried (MgSO₄), filtered and concentrated to yield the title compound (6.9g, 96%). δ_H (400MHz, CDCI₃): 7.75-7.73 (4H,m), 7.51-7.36 (4H,m), 7.32-7.28 (2H,m), 3.86 (1 H,s), 3.83 (1H, d, J 14.4HZ), 3.51 (1H, d, J 14.4Hz), 3.03 (1 H, dd, J4.7Hz, 9.5Hz), 2.91 (1H, dd, J 9.5Hz, 14.0Hz), 2.67-2.35 (4H,m), 1.92-1.85 (1 H,m).

DESCRIPTION 31 (1R*2/?*5S*6 ?*)-8-Benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (1 R*,5S*, 6H^*)-8-Benzyl-6-cyano-1 -phenyl-8-azabicyclo[3.2.1]octan-2-one

(Description 30; 6.9g, 21.8mmol) was taken up a mixture of methanol (100ml) and THF (30ml). To this suspension was added sodium borohydride (0.5g,13mmol). The mixture was stirred for 30 minutes then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate. The organic layer was separated, dried (MgSOJ, filtered and concentrated.

Chromatography on silica gel eluting with 35 and 50% ethyl acetate / iso-hexanes afforded the title compound (4.8g, 70%). δ_H (400MHz, CDCI₃): 7.54-7.25 (10H, m), 4.18 (1H, d, J 14.9Hz), 3.91 (1H, br s), 3.80 (1H, s), 3.70 (1 H, d, J 14.9Hz), 2.92 (1H, dd, J5.2Hz, 9.4Hz), 2.61-2.47 (2H, m), 2.18-2.09 (1H, m), 1.91-1.76 (2H, m), 1.35-1.30 (1H, m). DESCRIPTION 32 (1R*,2R*5S*_J6R 8-Benzyl-2-[3,5-bls(trifluoromethyl)benzoyloxy]-6-cyano-1- phenyI-8-azabicyclo[3.2.1]octane

3,5-Bis(trifluoromethyl)benzoyl chloride (2.76g, 10mmol) was added dropwise to an ice-cold solution of (1

azabicyclo[3.2.1]octan-2-ol (Description 31; 3g, 9.4mmol), triethylamine (2g, 20mmol) and 4-N,N-dimethylaminopyridine (200mg, 1.6mmol) in dichloromethane (30ml). The mixture was stirred at room temperature for 20 hours. The mixture was concentrated in vacuo then partitioned between ethyl acetate and brine. The organics were separated, dried (MgSO₄), filtered and concentrated. The residue was chromatographed on silica gel eluting with 10 and 20% ethyl acetate / iso- hexanes to afford the title compound (4.87g, 93%). δ_H (400MHz, CDCI₃):8.45 (2H, s), 8.07 (1 H, s), 7.57-7.21 (10H, m), 5.72 (1 H, s), 4.27 (1H, d, J 15.0Hz), 4.09 (1H, d, J 15.0Hz), 3.95 (1H, s), 2.96 (1H, dd, J 4.6Hz, 9.4Hz), 2.59 (1H, dd, J9.4Hz, 13.9Hz), 2.42 (1H, dd, J4.5Hz, 13.9Hz), 2.36-2.01 (3H, m), 1.39-1.33 (1H, m).

DESCRIPTIONS 33a and 33b (1 τ.*2/?*5S*,6 ?*)-8-Benzyl-2-[3,5-bis(trifluoromethyl)benzoyloxy]-6-(2- methyl-2H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (isomer A); and (1/?*_!2 ?*,5S*6/? 8-benzyl-2-[3_>5-bis(trifluoromethyl)benzoyloxy]-6-(1- methyl-1 H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (isomer B) Sodium azide (1g, 14.9mmol), (1 H^*,2H^*,5S^*6H^-8-benzyl-2-[3,5- bis(trifluoromethyl)benzoyloxy]-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Description 32; 2.76g, 4.95mmol) and ammonium chloride (0.8g, 14.9mmol) were stirred at 120°C for 18 hours. On cooling the mixture was partitioned between brine and ethyl acetate. The organic layer was separated and washed (x3) with water, then dried (MgSO₄), filtered and concentrated to give (1 H*,2H*5S*6H^,,)-8-benzyl-2-[3,5-bis(trifluoromethyl)benzoyloxy]-6-(tetrazol-5- yl)-1-phenyl-8-azabicyclo[3.2.1]octane (60%). This was taken up in acetonitrile (60ml). To this solution was added potassium carbonate (1.42g, lOmmol) and methyl iodide (1.42g, 10mmol). After 30 minutes the mixture was concentrated in vacuo then partitioned between ethyl acetate and water. The organic layer was dried (MgSO₄), filtered and concentrated. The residue was chromatographed on silica gel eluting with 10, 20 and 50% ethyl acetate / iso-hexanes to give the title compounds: isomer A (1.28g, 43%) and isomer B (0.83g, 27%). DESCRIPTION 33a - (isomer A):- δ_H (400MHz, CDCI₃): 8.46 (2H, s), 8.04 (1H, s), 7.60-7.58 (2H, m), 7.37-7.35 (2H, m), 7.30-7.17 (6H, m), 5.90 (1H, s), 4.36 (3H, s), 4.26 (1H, d, 15.1 Hz), 4.04 (1H, d, J 15.1 Hz), 3.78 (1H, s), 3.60 (1H, dd, J 4.8Hz, 9.3Hz), 2.72 (1H, dd, J4.8Hz, 13.8Hz), 2.61 (1H, dd, J9.3Hz, 13.7Hz), 2.48-2.23 (2H, m), 2.18-2.05 (1H, m), 1.50-1.42 (1H, m). DESCRPITION 33b - (isomer B):- δ_H (400MHz, CDCI₃): 8.46 (2H, s), 8.05 (1H, s), 7.66-7.63 (2H, m), 7.34-7.20 (8H, m), 5.90 (1H, s), 4.24 ( H, d, J 15.1 Hz), 4.08 (1H, d, J 15.2Hz), 3.92 (3H, s), 3.60 (1 H, s), 3.43 (1 H, dd, J4.7Hz, 9.2Hz), 3.00 (1H, dd, J 4.6Hz, 13.7Hz), 2.62 (1H, dd, 9.3Hz, 13.8Hz), 2.50-2.28 (2H, m), 2.18-2.16 (1H, m), 1.46-1.40 (1H, m).

DESCRIPTION 34

(1R*2/?*,5S*6R 8-Benzyl-2-{1-[3,5-bis(trifluoromethyl)phenyl3ethenyloxy}- 6-(1-methyI-1H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane

Dimethylbis(cyclopentadienyl)titanium (12ml, 0.45M solution in toluene) was added to a solution of (1 H*,2f7^*5S^*,6H^!i)-8-benzyl-2-[3,5- bis(trifiuoromethyl)benzoyloxy]-6-(1 -methyl-1 H-tetrazol-5-yl)-1 -phenyl-8- azabicyclo[3.2.1]octane (Description 33b; 0.83g, 1.35mmol) in toluene (20ml). The mixture was stirred at 100°C for 3 hours. On cooling to room temperature the mixture was poured into 100ml of 1:1 diethyl ether : iso-hexanes. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10, 20 and 50% ethyl acetate / iso-hexanes to yield the title compound (0.57g, 69%). δ_H (400MHz, CDCI₃): 7.91 (2H, s), 7.77 (1H, s), 7.67-7.65 (2H, m), 7.36-7.15 (2H, m), 7.36-7.15 (8H, m), 5.00 (1H, d, J 3.6Hz), 4.91 (1H, s), 4.58 (1H, d, J3.6Hz), 4.11 (1H, d, J 15.0Hz), 3.98 (1H, d, J 15.1 Hz), 3.90 (3H, s), 3.50 ( 1 H,s), 3.42 (1 H, dd, J 4.6Hz, 9.2Hz), 2.99 (1 H, dd, J 4.5Hz, 13.7Hz), 2.54 (1 H, dd, J 9.3Hz, 13.7Hz), 2.44-2.12 (3H, m), 1.37-1.30 (1H, m). DESCRIPTION 35 (1R*2f?*,5S*,6R 8-Benzyl-2-{1-[3,5-bis(trifluoromethyl)phenyl]ethenyloxy}- 6-(2-methyl-2H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane

Prepared in an analogous manner to (1H*,2R^*,5S^*,6/^:?^s,)-8-benzyl-2-{1-[3,5- bis(trifluoromethyl)phenyl]ethenyloxy}-6-(1 -methyl-1 H-tetrazol-5-yl)-1 -phenyl-8- azabicyclo[3.2.1]octane (Description 34) from the product of Description 33a. δ_H (360MHz, CDCI₃): 7.91 (2H, s), 7.76 (1H, s), 7.61-7.58 (2H, m), 7.35-7.14 (8H, m), 4.99 (1H, d, J3.5Hz), 4.89 (1H, s), 4.57 (1H, d, J3.5Hz), 4.37 (3H, s), 4.11 (1 H, d, J 15.1 Hz), 3.94 (1 H, d, J 15.2Hz), 3.67 (1 H, s), 3.57 (1 H, dd, J 4.6Hz, 9.25Hz), 2.72 (1 H, dd, 4.6Hz, 13.6Hz), 2.54 (1 H, dd, J 9.4Hz, 13.7Hz), 2.31 -2.21 (3H, m), 1.42-1.35 (1H, m).

DESCRIPTION 36 (1 R*, 5S* 6S*)-8-Benzyl-6-ethoxycarbonyl-6-f luoro-1 -phenyl-8- azabicyclo[3.2.1]oct-3-en-2-one

A mixture of N-benzyl-3-hydroxy-2-phenylpyridinium bromide (5g, 14.6mmol), ethyl 1-fluoroacrylate (7g, 59mmol), triethylamine (3ml, 21mmol), hydroquinone (50mg) and 1 ,4-dioxane (20m!) was heated at reflux for 20 hours and cooled to room temperature. The reaction mixture was poured onto saturated aqueous NaHCO_g and extracted into an 1:1 mixture of iso-hexane:diethyl ether. The combined organic extracts were washed with water (3x), dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso- hexane:diethyl ether 0-20%) to give the title compound (470mg, 8.5%). δ_H (360 MHz, CDCI₃): 7.86 (2H, m), 7.38 (2H, ), 7.33-7.19 (6H, m), 6.82 (1H, ddd, J 1.7Hz, 4.9Hz, 9.8Hz), 6.18 (1H, dd, J0.7Hz, 9.8Hz), 4.38-4.25 (2H, m), 4.20 (1H, dd, J 1.4Hz, 4.6Hz), 3.72 (1H, dd, J 1.4Hz, 14.0Hz), 3.56 (1H, d, J 14.0Hz), 3.22 (1H, dd, J 8.1Hz, 15.1Hz), 2.53 (1H, dd, J 14.7Hz, 23.9Hz), 1.31 (3H, t, J 7.0Hz). DESCRIPTION 37 (1R*5S*,6S 8-Benzyl-6-ethoxycarbonyl-6-fluoro-1-phenyl-8- azabicyclo[3.2.1 ]octan-2-one

A mixture of (1 H^*5S^*,6S 8-benzyl-6-ethoxycarbonyl-6-fluoro-1-phenyl-8- azabicyclo[3.2.1]oct-3-en-2-one (Description 36; 795mg, 66mmoI), 10% palladium on charcoal (250mg), ethyl acetate (5ml) and ethanol(10ml) was stirred under hydrogen atmosphere (1atm) at room temperature for 1 hour. The reaction mixture was treated with dichloromethane (500ml), filtered through a pad of Celite™. The filtrate was concentrated to give the title compound. δ_H (400 MHz, CDCI₃): 7.53 (2H, m), 7.44-7.24 (8H, m), 4.37-4.26 (2H, m), 3.86 (1H, d, J 14.5Hz), 3.75 (1H, d, J4.3Hz), 3.50 (1 H, d, J 14.5Hz), 3.03 (1 H, t, J 15.3Hz), 2.92 (1H, dt, J 9.4Hz, 15.3Hz), 2.74 (1H, dd, J 15.3Hz, 25.0Hz), 2.61 (1H, dd, J 8.2Hz, 15.3Hz), 2.47 (1H, m), 1.34 (3H, t, J 7.0Hz).

DESCRIPTION 38

(1 R*, 2R*, 5S* 6S 8-Benzyl-6-ethoxycarbonyl-6-f luoro-1 -phenyl-8- azabicyclo[3.2.1 ]octan-2-ol

Sodium borohydride (100mg, 2.6mmol) was added to a stirred mixture of (1 R*,5S*,6S")-8-benzyl-6-ethoxycarbonyl-6-fluoro-1 -phenyl-8- azabicyclo[3.2.1]octan-2-one (Description 37), THF (2ml) and methanol (8ml) at room temperature. The reaction mixture was stirred for 15 minutes, quenched with saturated aqueous ammonium chloride and extracted into 1:1 mixture of iso- hexane:diethyl ether. The combined organic extracts were washed with brine, dried (MgSO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyI ether 0-25%) to give the title compound. δ_H (400 MHz, CDCI₃): 7.73 (2H, m), 7.42 (2H, m), 7.37 (2H, d, J7.8Hz), 7.29 (3H, m), 7.22 (1H, m), 4.60 (1H, d, J3.5Hz), 4.37-4.17 (3H, m), 3.85 (1H, d, J 15.3Hz), 3.65 (1H, s), 2.86 (1H, dd, J 12.5Hz, 14.9Hz), 2.43 (1H, m), 2.92 (1H, m), 2.17 (1 H, dd, J 14.5Hz, 24.7Hz), 1.97 (1 H, dd, J 6.3Hz, 15.2Hz), 1.90 (1 H, s), 1.52 (1 H, m), 1.29 (3H, t, J 7.4Hz). DESCRIPTIONS 39a and 39b (1 R*, 5S*,6fiS)-8-Benzyl-6-cyano-1 -phenyl-8-azabicyclo[3.2.1 ]oct-3-en-2-one

A mixture of N-benzyl-3-hydroxy-2-phenylpyridinium bromide (150g, 0.44mol), acrylonitrile (300ml), triethylamine (95ml), hydroquinone (125mg) and 1,4-dioxane (650ml) was heated at reflux (80°C) for 68 hours and cooled to room temperature. The reaction mixture was poured onto saturated aqueous NaHCO₃ (11) and extracted into an 1 :1 mixture of iso-hexane:diethyl ether (3x500ml). The combined organic extracts were dried (Na₂SO₄) and concentrated to give a mixture of regio and stereoisomers in the ratio (6H*):(6S^,i).(7/^:?'^,):(7S^,')=5:4.2:1 :1.9. Isomers were separated by chromatography on silica gel (iso-hexane:diethyl ether).

DESCRIPTION 39a - (1 f?*,5S*,6 ?^! isomer:- δ_H (360 MHz, CDCI₃): 7.82 (2H, d, J 7.4HZ), 7.46-7.23 (8H, m), 6.83 (1 H, dd, J4.9Hz, 9.8Hz), 6.24 (1 H, d, J 9.5Hz), 4.13 (1 H, d, J 4.9Hz), 3.81 (1 H, d, J 14.0Hz), 3.54 (1 H, d, J 14.0Hz), 3.00 (1 H, dd, J 3.5Hz, 8.1Hz), 2.78 (1H, dd, J3.5Hz, 14.7Hz), 2.72 (1 H, dd, J 8.1 Hz, 14.4Hz).

DESCRIPTION 39b - (1 /?* 5S*,6S*)-isomer:- δ_H (400 MHz, CDCI₃): 7.68 (2H, m), 7.47-7.23 (8H, m), 7.02 (1 H, dd, J4.7Hz, 9.8Hz), 6.43 (1H, d, J 9.8Hz), 4.07 (1 H, dd, Jδ.OHz, 5.7Hz), 3.64 (1 H, d, J 13.7Hz), 3.55 (1 H, d, 14.1 Hz), 3.47 (1 H, ddd, J 5.8Hz, 7.0Hz, 10.2Hz), 2.84 (1 H, dd, J 9.8Hz, 13.7Hz), 2.56 (1 H, dd, J 7.0Hz, 14.1 Hz).

DESCRIPTION 40 (1 ff*,5S*6S 8-Benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-one A mixture of (1 H*,5S*,6S*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]oct-3- en-2-one (Description 39b; 44g, 140mmol), 10% palladium on charcoal (11g, 10mmol), ethyl acetate (200ml) was stirred under hydrogen atmosphere (1atm) at room temperature for 1.5 hours. The reaction mixture was treated with dichloromethane (500ml), filtered through a pad of Celite™. The Celite™ cake was well washed with dichloromethane to dissolve solid product. The filtrate was concentrated to give the title compound. δ_H (360 MHz, CDCl₃): 7.53-7.22 (10H, m), 3.72 (1 H, d, J 14.4Hz), 3.66 (1 H, m 3.49 (1 H, d, j 14.4Hz), 3.49 (1 H, m), 2.93 (1 H, ddd, j 9.1 Hz, 14.0Hz, 18.2Hz), 2.73 (1 H, dd, J 6.7Hz, 14.4Hz), 2.67-2.53 (3H, m), 2.39 (1H, ddd, J 1.8Hz, 9.3Hz, 13.4Hz).

DESCRIPTION 41 (1 R*, 2R *,5S*, 6S 8-Benzyl-6-cyano-1 -phenyl-8-azabicyclo[3.2.1]octan-2-ol

Sodium borohydride (1.8g, 47mmol) was added to a stirred, ice-cooled solution of (1 H^*5S^*,6S 8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-one (Description 40) in methanol (300ml). The reaction mixture was stirred for 30 minutes, quenched with saturated aqueous NaHCO₃ and extracted into ethyl acetate. The combined organic extracts were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-20%) to give the title compound (31 g). δ_H (400 MHz, CDCI₃): 7.48-7.25 (10H, m), 4.16 (1H, d, J 14.9Hz), 3.86 (1H, br s), 3.58 (1 H, dt, J 3.1 Hz, 6.7Hz), 3.37 (1H, dt, J 5.9Hz, 12.5Hz), 3.24 (1H, d, J 14.9Hz), 2.64 (1 H, br), 2.61 (1 H, t, J 13.0Hz), 2.43 (1 H, dd, J 5.9Hz, 13.7Hz), 2.29-2.12 (2H, m), 1.92 (1H, m), 1.76 (1H, m).

DESCRIPTION 42 (1 ?*2 ?*5S*6S^,l)-8-Benzyl-2-(ferf-butyldimethylsilyloxy)-6-cyano-1-phenyl- 8-azabicyclo[3.2.1]octane t-Butyldimethylsilyl trifluoromethanesulphonate (23ml, 76mmol) was added dropwise to a stirred solution of (1 fi*2F?^*5S^*6S'V8-benzyl-6-cyano-1-phenyl-8- azabicyclo[3.2.1]octan-2-ol (Description 41; 31g), triethylamine (18ml, 243mmol) in dichloromethane (100ml) at room temperature over 30 minutes. The reaction mixture was stirred for 15 minutes, quenched with saturated aqueous NaHCO₃ and extracted into diethyl ether (3x100ml). The combined organic extracts were washed with water, brine, dried (Na₂SO₄) and concentrated to give the title compound. δ_H (400 MHz, CDCI₃): 7.48 (2H, m), 7.39-7.28 (7H, m), 7.22 (1H, m), 4.35 (1H, br s), 4.23 (1H, d, J 15.6Hz), 3.82 (1H, d, J 16.0Hz), 3.60 (1H, dd, J 2.0Hz, 6.7Hz), 3.23 (1H, dt, J 6.3Hz, 11.7Hz), 2.35-2.23 (3H, m), 2.18 (1 H, dd, J5.9Hz, 13.3Hz), 1.98 (1H, m), 1.58 (1H, m), 0.80 (9H, s), 0.11 (3H, s), -0.12 (3H, s). DESCRIPTION 43 (1f.*,2R*,5S*,6S'^,)-8-Benzyl-2-(tert-butyldimethylsilyloxy)-6-[1-(2- methoxyethoxymethyl)tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.l]octane (isomer A); and (1/?*2/?*,5S*,6S")-8-benzyl-2-(tert-butyldimethylsilyloxy)-6-[2-(2- methoxyethoxymethyl)tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (isomer B)

A mixture of (1 H^*,2H^*,5S^*,6S^,,)-8-benzyl-2-(te/ -butyldimethylsilyloxy)-6-cyano-1- phenyl-8-azabicyclo[3.2.1]octane (Description 42; 43g), sodium azide (27g), triethylamine hydrochloride (55g) and N,N-dimethylformamide (150ml) was stirred at +130°C for 7 hours. The reaction mixture was cooled to room temperature, treated with water (500ml) and extracted into ethyl acetate (4x200ml). The combined organic extracts were washed with water (3x200ml) and brine. The combined water layers were extracted again with ethyl acetate (2x200ml). The organic phase was washed with small amount of water (50ml). The combined organic extracts were dried (Na₂SO₄) and concentrated to give crude (1 H*2/?*5S*6S^I,)-8-benzyl-2-(tørt-butyldimethylsilyloxy)-1-phenyl-6-(tetrazol-5- yl]-8-azabicyclo[3.2.1]octane (47g), which was mixed with potassium carbonate (25g) and acetonitrile (220ml), warmed up to +70°C and finally treated with 2-methoxyethoxymethyl chloride (20ml). The reaction mixture was stirred for 15 minutes, cooled to room temperature, then treated with water (500ml) and extracted into ethyl acetate (3x200ml). The combined organic extracts were dried (Na,SO₄) and concentrated to give a 1:1.5 mixture of isomers A and B, respectively. Regioisomers were separated by chromatography on silica gel (iso- hexane:diethyl ether).

DESCRIPTION 43a - (isomer A):- δ_H (360 MHz, CDCI₃): 7.59 (2H, d, J 7.0Hz), 7.44 (2H, d, J7.4Hz), 7.35 (4H, m), 7.24 (2H, m), 5.65 (2H, s), 4.52 (1 H, d, J 2.5Hz), 4.24 (1H, d, J 16.1 Hz), 4.02 (1H, d, J 16.1 Hz), 3.83 (1H, dt, J 6.3Hz, 11.9Hz), 3.71 (1H, m), 3.63 (2H, m), 3.39 (2H, m), 3.25 (3H, s), 2.89 (1 H, dd, J 6.3Hz, 13.3Hz), 2.61 (1 H, m), 2.33 (1H, dd, J 12.3Hz, 13.0Hz), 2.18 (1 H, m), 1.65 (1H, dd, J 5.6Hz, 14.7Hz), 0.78 (9H, s), 0.69 (1H, dd, J 6.0Hz, 14.0Hz), 0.09 (3H, s), -0.11 (3H, s). DESCRIPTION 43b - (isomer B):- δ_H (360 MHz, CDCI₃): 7.60 (2H, d, J 7.0Hz), 7.46 (2H, d, J 7.4Hz), 7.34 (4H, m), 7.23 (2H, m), 5.90 (2H, s), 4.47 (1H, s), 4.33 (1H, d, J 15.8Hz), 4.00 (1H, d, J 15.8Hz), 3.92 (1H, dt, J6.7Hz, 11.6Hz), 3.79 (1H, m), 3.77 (2H, m), 3.53 (2H, m), 3.30 (3H, s), 2.71 (1H, dd, J6.7Hz, 13.7Hz), 2.33 (1H, t, J 12.3Hz), 2.26-2.10 (2H, m), 1.59 (1H, m), 0.83 (1H, m), 0.78 (9H, s), 0.08 (3H, s), -0.12 (3H, s).

DESCRIPTIONS 44a and 44b (1 ?*₅2ff*,5S*,6S^ϊ,)-8-Benzyl-2-(tert-butyldimethylsilyloxy)-6-fluoro-6-[1-(2- methoxyethoxymethyl)-1 H-tetrazol-5-yl]-1 -phenyl-8-azabicyclo[3.2.1 ]octane; and

(1 R*,2 ?*,5S*6f? 8-benzyl-2-(fert-butyldimethylsilyloxy)-6-fluoro-6-[1-(2- methoxyethoxymethyl)-1H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane A solution of π-butyl lithium in hexanes (1.6M, 14ml, 22.4mmol) was added dropwise to a stirred solution of 1 H^*2H^*,5S^*6S'^,)-8-benzyl-2-(te/ιf- butyldimethylsilyloxy)-6-[1 -(2-methoxyethoxymethyl)-1 H-tetrazol-5-yl]-1 -phenyl-8- azabicyclo[3.2.1]octane (Description 43a; 10.7g, 19mmol) in THF (50ml) at -78°C over 10 minutes. The mixture was stirred for 5 minutes and a solution of N- fluorobenzenesulphonimide (10.4g, 33mmol) in THF (40ml) was added over 10 minutes. The reaction mixture was stirred at -78°C for 1 hour, quenched with brine and extracted into a 1 :1 mixture iso-hexane:diethyl ether. The organic phase was washed twice with 2M NaOH, water and brine and dried (Na₂SO₄) and concentrated to give a 1 :1 mixture of epimers, which were separated by chromatography on silica gel (iso-hexane:diethyl ether). DESCRIPTION 44a - (1 ?* 2R*,5S*, 6S*)-isomer:- δ_H (360 MHz, CDCI₃): 7.75

(2H, d, J 7.4Hz), 7.37 (2H, t, J 8.1 Hz), 7.24 (2H, m), 7.14-6.99 (4H, m), 5.87 (1 H, d, J 10.9Hz), 5.68 (1 H, dd, J 1.4Hz, 11.2Hz), 4.70 (1 H, br s), 4.20 (1 H, d, J 15.8Hz), 3.93 (1H, d, J 15.8Hz), 3.61 (1H, s), 3.56-3.43 (2H, m), 3.21 (3H, s), 3.07 (1H, ddd, J2.8Hz, 4.6Hz, 11.2Hz), 2.98 (1H, ddd, J2.5Hz, 4.6Hz, 10.9Hz), 2.85 (1H, ddd, J2.5Hz, 8.1Hz, 10.9Hz), 2.46 (1H, dd, J 15.1 Hz, 26.3Hz), 2.28 (1H, m), 1.98 (1H, dd, J4.9Hz, 15.1 Hz), 1.62 (1H, m), 0.82 (9H, s), 0.22 (3H, s), 0.08 (3H, s). DESCRIPTION 44b - (1 R*, 2R*, 5S*, 6 ? isomer:- δ_H (360 MHz, CDCI₃): 7.62 (2H, d, J .7Hz), 7.53 (2H, d, J7.4Hz), 7.35 (4H, m), 7.24 (2H, m), 5.88 (1H, d, J • 10.9Hz), 5.76 (1H, dd, J 1.4Hz, 10.9Hz), 4.61 (1H, d, J2.5Hz), 4.33 (1 H, d, J 16.5Hz), 4.18 (1H, d, J 16.5Hz), 3.96 (1H, d, J 13.0Hz), 3.70 (1H, ddd, J3.2Hz, 6.0Hz, 10.9Hz), 3.61 (1 H, ddd, J 3.2Hz, 5.6Hz, 11.2Hz), 3.46 (1 H, dd, J 15.4Hz, 24.2Hz), 3.37 (2H, m), 3.21 (3H, s), 2.52 (1H, dd, J 15.8Hz, 37.2Hz), 2.45 (1H, m), 2.14 (1H, m), 1.66 (1H, dd, J5.6Hz, 15.4Hz), 0.79 (9H, s), 0.52 (1H, dd, J 6.3Hz, 14.7Hz), 0.12 (3H, s), -0.03 (3H, s).

DESCRIPTION 45

(1 R*,2R*,5S*, 6S*)-8-Benzyl-6-f luoro-6-[1 -(2-methoxyethoxymethyl)-1 H- tetrazol-5-yl]-1 -phenyl-8-azabicyclo[3.2.1 ]octan-2-ol

A mixture of (1 R*,2R*,5S*, 6S")-8-benzyl-2-(tørf-butyldimethylsilyloxy)-6-fluoro-6- [1 -(2-methoxyethoxymethyl)-1 H-tetrazol-5-yl]-1 -phenyl-8-azabicyclo[3.2.1 ]octane (Description 44a; 4.5g, 7.7mmol), 1 M solution of hydrogen chloride in ether (30ml) and methanol (50ml) was stirred at room temperature for 90 minutes. The reaction mixture was treated with saturated aqueous NaHCO₃ and extracted into ethyl acetate. The combined organic extracts were dried (Na_aSO₄) and concentrated. The residue was purified by chromatography on silica gel (iso- hexane:diethyl ether 20-80%) to give the title compound (2.5 g, 70%). δ_H (360 MHz, CDCy: 7.87 (2H, d, J7.4Hz), 7.47 (2H, t, J 8.1 Hz), 7.32 (2H, m), 7.15-7.00 (4H, m), 5.87 (1H, d, J 10.9Hz), 5.69 (1H, dd, J 1.7Hz, 11.2Hz), 4.68 (1H, br s), 4.20 (1H, d, J 14.7Hz), 3.82 (1 H, d, J 15.1 Hz), 3.60 (1H, s), 3.58 (1H, dd, J 12.6Hz, 15.1Hz), 3.28 (1 H, ddd, J2.4Hz, 7.7Hz, 10.5Hz), 3.21 (3H, s), 3.09 (1 H, ddd, J 2.8Hz, 4.6Hz, 11.2Hz), 2.96 (1 H, ddd, J 2.8Hz, 4.6Hz, 10.9Hz), 2.87 (1H, ddd, J 2.5Hz, 8.1Hz, 10.9Hz), 2.52 (1H, dd, J 14.7Hz, 26.3Hz), 2.47 (1H, m), 2.31 (1H, m), 2.05 (1H, dd, J5.6Hz, 15.1 Hz), 1.98 (1H, br s), 1.66 (1H, m). DESCRIPTION 46 (1 R*,2R*, 5S* 6S*)-8-Benzyl-2-{(1 R*)A -[3,5-bis(trif luoromethyl)phenyl]-2- iodoethoxy}-6-fluoro-6-[1-(2-methoxyethoxymethyl)-2H-tetrazol-5-yl]-1- phenyl-8-azabicyclo[3.2.1]octane (1 R*,2R*,5S*,6S*)-8-Benzy\-2-{(l fl")-1 -[3,5-bis(trifluoromethyl)phenyl]-2- hydroxyethoxy}-6-f luoro-6-[1 -(2-methoxyethoxymethyl)-1 /-/-tetrazol-5-yl]-1 -phenyl- 8-azabicyclo[3.2.1]octane (Example 176; 0.2g, 0.28mmol), triphenylphosphine (0.11g, 0.415mmol), imidazole (28mg, 0.415mmol) and iodine (105mg, 0.415mmol) were stirred at room temperature for 18 hours. The reaction mixture was partitioned between 5% sodium thiosulfate and ethyl acetate. The organic layer was dried (MgSOJ, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10 and 20% ethyl acetate / iso- hexanes to afford the title compound, 193mg, 84%. δ_H (400MHz, CDCQ: 7.80 (1H, s), 7.51 (2H, s), 7.19-6.98 (10H, m), 5.92-5.85 (2H, m), 4.71 -4.69 (1 H, m), 4.49 (1 H, d, J 16.0Hz), 4.07-4.04 (2H, m), 3.90 (1 H, s), 3.74-3.71 (2H, m), 3.48-3.46 (2H, m), 3.36-3.34 (1H, m), 3.30 (3H, s), 3.29- 3.26 (1H, m), 3.11-3.04 (1H, m), 2.55-2.30 (3H, m), 1.77-1.70 (1H, m).

DESCRIPTION 47 (1 R*,2R*, 5R 1-Phenyl-8-azabicyclo[3.2.1]octan-2-ol

10% Palladium on carbon (4g) was added as a slurry in water (25ml) to a solution of (1 fi*2H*,5H 8-benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 29.3g, lOOmmol) and 1 ,4-cyclohexadiene (80g, 1mol) in ethanol (250ml). The mixture was heated at 60°C for 6 hours. On cooling to room temperature the mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5 and 10% methanol / dichloromethane / 1% ammonia to yield the title compound (12.2g, 60%). δ_H (400MHz, CDCI₃): 7.35-7.20 (5H, m), 3.70 (1H, s), 3.69-3.62 (1H, m), 2.22-1.34 (8H, m). DESCRIPTION 48 (1 S,2S,5S)-1-Phenyl-8-azabicyclo[3.2.1loctan-2-ol (-)-dibenzoyl tartrate

A solution of (-)-dibenzoyl tartaric acid (4.85g, 13.5mmol) in ethyl acetate (100ml) was added dropwise to a solution of (1fl*_l2R*,5R'^l)-1-phenyl-8- azabicyclo[3.2.1]octan-2-ol (Description 47; 11g, 54.2mmol) in hot ethyl acetate (250ml). Iso-propyl alcohol (500ml) was added and the mixture heated at reflux for 1 hour. The mixture was allowed to cool slowly to room temperature then filtered to yield the title compound (4.8g, 46%, e.e. >99%). δ_H (400MHz, CDCI₃): 8.17-8.15 (4H, m), 7.57-7.53 (2H, m), 7.45-7.27 (12H, m), 5.89 (2H, s), 4.04-4.02 (2H, m), 3.88-3.87 (2H, m), 2.66-2.58 (2H, m), 2.26-1.98 (6H, m), 1.77-1.59 (2H, m), 1.25-1.14 (2H, m).

DESCRIPTION 49 (1 f?₅2 ?,5f?)-1-Phenyl-8-azabicyclo[3.2,1]octan-2-ol (+)-dibenzoyl tartrate The mother liquors from the crystallisation in Description 48 were neutralised with 10% sodium carbonate and extracted with dichloromethane. The organic extracts were dried (MgSO₄), filtered and concentrated in vacuo, then treated with (+)-dibenzoyl tartaric acid in an analogous manner to Description 48 to yield the title compound (4.98g, 48%, e.e. >99%).

DESCRIPTION 50 (1 R,2R,5R)-A -Phenyl-8-azabicyclo[3.2.13octan-2-ol A mixture of (1 H,2H,5H)-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (+)-dibenzoyl tartrate salt ((Description 49; 4.5g, 5.9mmol), dichloromethane (100ml), water (1 OOml) and saturated aqueous NaHCO₃ (50ml) was stirred vigorously at room temperature for 15 minutes. The phases were separated and the aqueous phase was extracted with dichloromethane (10x50ml). The combined organic extracts were dried (Na₂SO₄) and concentrated to give the title compound (2.2g, 92%).

DESCRIPTION 51

(1 ?,2/?,5f?)-1-Phenyl-2-triethylsilyloxy-8-azabicyclo[3.2.1]octane

Triethylsilyl trifluoromethenesulphonate (2.6ml, 11.5mmol) was added dropwise to a stirred solution of (1 H,2H,5 7)-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 50; 2.2g, 10.7mmol), triethylamine (4ml, 28mmol) and dichloromethane (20ml) at room temperature over 10 minutes. The reaction mixture was stirred for 20 minutes and quenched with saturated aqueous NaHCO₃. The phases were separated. The aqueous phase was extracted with dichloromethane (3x50ml). The combined organic extracts were dried (Na₂SO₄) and concentrated to give the title compound (4.33g). δ_H (360 MHz, CDCI₃): 7.32-7.25 (2H, m), 7.24-7.16 (3H, m), 4.00 (1H, br), 3.84 (1H, dd, J 2.6Hz, 6.6Hz), 3.81 (1H, t, J 1.9Hz), 2.30-2.13 (2H, m), 2.07-1.93 (2H, m), 1.75-1.59 (2H, m), 1.41 (1H, m), 0.71 (9H, d, J 8.1 Hz), 0.32-0.11 (6H, m).

DESCRIPTION 52 (1 ?,2f?,5 ?)-8-Benzyl-1 -phenyl-2-triethy lsilyloxy-8-azabicyclo[3.2.1 loctane

A mixture of (1R,2R,5R)-1-phenyl-2-triethylsilyloxy-8-azabicycIo[3.2.1]octane (Description 51; 100mg, 0.315mmol), benzyl bromide (0.5ml), potassium carbonate (380mg) and N,N-dimethylformamide (2ml) was stirred at room temperature for 30 minutes. The reaction mixture was treated with diethyl ether, washed with water, brine, dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel to give the title compound (107mg, 83%). δ_H (360 MHz, CDCI₃): 7.53 (2H, d, J 8.1 Hz), 7.43 (2H, d, J 7.4Hz), 7.35-7.10 (6H, m), 4.20 (1H, br s), 4.16 (1H, d, J 15.6Hz), 3.65 (1H, d, J 15.6Hz), 3.35 (1H, m), 2.23 (1H, tdd, J 1.9Hz, 5.0Hz, 13.4Hz), 2.12-1.96 (2H, m), 1.92-1.77 (2H, m), 1.69 (1H, dd, J 4.2Hz, 14.4Hz), 1.57 (1H, m), 1.05 (1H, m), 0.86 (9H, d, J 7.7Hz), 0.56-0.45 (6H, m).

DESCRIPTION 53

(1 ?,2/?,5 7)-8-Benzyl-1 -phenyl-8-azabicyclo[3.2.1]octan-2-ol

A mixture of (1 ff,2H,5fT)-8-benzyl-1-phenyl-2-triethylsiIyloxy-8- azabicyclo[3.2.1]octane (Description 52; 107mg, 0.26mmol), 2M hydrochloric acid (3ml) and methanol (6ml) was stirred at +55°C for 15 minutes, then concentrated in vacuo and quenched with saturated aqueous NaHCO₃. The mixture was extracted with dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated to give the title compound (79mg, 96%). δ_H (400 MHz, CDCI₃): 7.46-7.17 (10H, m), 4.02 (1H, d, J 14.9Hz), 3.06 (1H, d, J 14.9Hz), 3.46 (1H, br s), 3.36 (1H, br), 3.29 (1H, m), 2.27-2.13 (3H, m), 1.99 (1H, tdd, J2.7Hz, 5.5Hz, 13.3Hz), 1.87 (1H, tdd, J3.1Hz, 5.1Hz, 13.7Hz), 1.74-1.61 (2H, m), 1.30 (1 H, m).

DESCRIPTION 54 (1S,2S,5S)-1-Phenyl-8-azabicyclo[3.2.1loctan-2-ol A mixture of (1S,2S,5S)-1-ρhenyl-8-azabicyclo[3.2.1]octan-2-ol (-)-dibenzoyl tartrate salt (Description 48; 614g, O.δmmol), dichloromethane (50ml), 5% aqueous NaHCO₃ (50ml) was stirred vigorously at room temperature for 15 minutes. The phases were separated and the aqueous phase was extracted with dichloromethane (5x15ml). The combined organic extracts were dried (Na₂SO₄) and concentrated to give the title compound (326mg, quant.).

DESCRIPTION 55

(1S,2S,5S)-2-(fer -Butyldimethylsilyloxy)-1-phenyl-8-azabicyclo[3.2.1]octane f-Butyldimethylsilyl trifluoromethenesulphonate (0.35ml, 1.5mmol) was added dropwise to a stirred solution of (1 S,2S,5S)-1-phenyl-8-azabicyclo[3.2.1]octan-2- ol (Description 54; 326mg, 1.6mmol), triethylamine (0.7ml) and dichloromethane (5ml) at room temperature over 30 minutes. The reaction mixture was stirred for 20 minutes and quenched with saturated aqueous NaHCO₃. The phases were separated. The aqueous phase was extracted with dichloromethane (3x50ml). The combined organic extracts were dried (Na₂SO₄) and concentrated to give the title compound (592mg). δ_H (360 MHz, CDCI₃): 7.30-7.11 (5H, m), 3.74 (1H, t, J2.5Hz), 3.65 (1H, m), 3.05 (1 H, br s), 2.20-2.07 (2H, m), 2.01 (1H, tdd, J2.8Hz, 5.3Hz, 13.7Hz), 1.93-1.80 (2H, m), 1.70-1.56 (2H, m), 1.34 (1H, m), 0.73 (9H, s), -0.19 (3H, s), -0.70 (3H, s).

DESCRIPTION 56 (1 S,2S,5S)-2-(tert-Butyldimethylsilyloxy)-1 -phenyl-8-(prop-2-enyl)-8- azabicyclo[3.2.1 T ctane

A mixture of (1 S,2S,5S)-2-(te/f-butyldimethylsilyloxy)-1-phenyl-8- azabicyclo[3.2.1]octane (Description 55; 237mg), allyl bromide (0.4ml), potassium carbonate (230mg) and N,N-dimethylformamide (2ml) was stirred at room temperature for 2 hours. The reaction mixture was treated with diethyl ether, washed with water and brine, then dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-25%) to give the title compound (230mg, 98% two steps). δ_H (360 MHz, CDCI₃): 7.44 (2H, d, J 7.4Hz), 7.31 (2H, t, J 8.1 Hz), 7.19 (1H, m), 5.90 (1H, m), 5.24 (1H, dq, J 1.8Hz, 17.2Hz), 5.07 (1 H, d, J 10.2Hz), 4.14 (1H, br s), 3.60 (1H, dd, J 6.3Hz, 15.7Hz), 3.57 (1H, t, J 6.1 Hz), 3.19 (1H, dd, J4.4Hz, 15.7Hz), 2.20 (1H, m), 2.11-1.96 (2H, m), 1.86 (1H, ddd, J4.6Hz, 9.5Hz, 13.7Hz), 1.81-1.66 (2H, m), 1.60 (1H, ddd, J4.2Hz, 9.8Hz, 12.3Hz), 1.11 (1H, m), 0.78 (9H, s), 0.00 (3H, s), -0.20 (3H, s).

DESCRIPTION 57 (1S,2S,5S)-1-Phenyl-8-(proρ-2-enyl)-8-azabicyclo[3.2.1]octan-2-ol A mixture of (1 S,2S,5S)-2-(tert-butyldimethylsilyloxy)-1 -phenyl-8-(prop-2-enyl)-8- azabicyclo[3.2.1]octane (Description 56; 230mg, 0.64mmol), 2M hydrochloric acid (3ml) and methanol (6ml) was stirred at +55°C over 5 days, then concentrated in vacuo and quenched with saturated aqueous NaHCO₃. The mixture was extracted with dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol:ammonia) to give the title compound (116mg, 74%). δ_H (360 MHz, CDCI₃): 7.40-7.20 (5H, m), 5.90 (1 H, dddd, J4.2Hz, 6.7Hz, 10.3Hz, 17.1Hz), 5.24 (1H, dq, J 1.8Hz, 17.2Hz), 5.07 (1H, dm, J 10.2Hz), 3.38-3.34 (4H, m), 2.51 (1H, dd, J 7.0Hz, 15.1 Hz), 2.22-2.10 (3H, m), 2.02 (1H, tdd, J2.5Hz, 5.3Hz, 13.0Hz), 1.85 (1H, tdd, J 1.7Hz, 5.6Hz, 13.0Hz), 1.74-1.64 (2H, m), 1.40 (1H, dddd, J 1.4Hz, 3.2Hz, 5.3Hz, 13.0Hz).

DESCRIPTION 58 N-[(/?,S)-α-(2-Furyl)benzyl]-1 (S)-pheny lethylamine

A mixture of 2-benzoylfuran (9.98g, 58.0mmol), 1 (S)-phenylethylamine (9.0ml, 70mmol) and titanium(IV) isopropoxide (25ml, 85mmol) was stirred at 80^QC for two hours. The mixture was allowed to cool to room temperature, diluted with methanol (300ml) and cooled in an ice-bath. Sodium borohydride (2.63g, 69.5mmol) was added portionwise, the cooling bath removed and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo then the residue triturated with water (90ml) to give a solid. Diluted with methanol (450ml), filtered and washed the filter cake with methanol. The filtrate was evaporated, diluted with water (200ml) and extracted with dichloromethane (3 x 100ml). The combined extracts were dried (MgSO₄) and evaporated to give the title compound (15.30g, 95%) as a yellow oil. m/z (ES⁺) 278 ([M+H]⁺), 156 (100%).

DESCRIPTION 59 1 -(1 (S)-Phenylethyl)-3-oxy-2-phenylpyridinium betaine A solution of N-[(H,S)-α-(2-furyl)benzyl]-1 (S)-phenylethylamine (Description 58; 10.67g, 38.5mmol) in THF (80ml) was diluted with water (40ml) and cooled to 2^δC. Bromine (2.2ml, 43mmol) was added dropwise over five minutes and the resulting mixture stirred at 0⁹C for twenty minutes. The cooling bath was removed and the mixture stirred overnight. The reaction mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate (200ml) and extracted with dichloromethane (3 x 50ml). The combined extracts were dried (MgSO₄) and concentrated to a small volume and ethyl acetate added. The mixture was evaporated to give a solid which was triturated with ethyl acetate (20ml), the resultant solid collected under suction, washed with ethyl acetate and dried in vacuo to afford the title compound (3.13g, 30%). A further crop of the title compound (1.37g, 22%) was obtained by evaporation of the ethyl acetate filtrate, purification by flash chromatography eluting with 5-20% methanol in dichloromethane and crystallisation from ethyl acetate. δ_H (400 MHz, CDCI₃): 7.57-7.32 (9H, m), 7.26-7.14 (3H, m), 6.98 (1H, d, J5.8Hz), 5.68 (1H, q, J6.3Hz), 1.83 (3H, d, J6.3Hz). DESCRIPTION 60 (1 S,5 ?,6S,9S)-6-(ferf-Butoxycarbonyl)-1 -ρhenyl-8-(1 -phenyIethyl)-8- azabicyc!o[3.2.1]oct-3-en-2-one

A mixture of 1-(1(S)-phenylethyl)-3-oxy-2-phenylpyridinium betaine (Description 59; 1.49g, 5.41 mmol), terf-butyl acrylate (16ml, 0.11 mol) and hydroquinone (21.5mg, 0.20mmol) in toluene (100ml) was stirred at 95^SC for four days. The reaction mixture was concentrated in vacuo and purified by flash chromatography, eluting with 2:1 dichloromethane/ iso-hexane, dichloromethane then 5% diethyl ether in dichloromethane, to give the title compound (0.463g, 21%). A further crop of product (0.300g, 14%) was obtained by iso-hexane recrystallization of an impure fraction from the chromatography. m/z (ES⁺) 404 ([M+H]⁺).

DESCRIPTION 61 (1 S,5/?,6S,9S)-6-(fe/f-Butoxycarbonyl)-1 -phenyl-8-(1 -phenylethyl)-8- azabicyclo[3.2.1]octan-2-one

5% Palladium on carbon (79.8mg) was added to a solution of (1 S,5H,6S,9S)-6- (tørt-butoxycarbonyl)-l -phenyl-8-(1 -phenylethyl)-8-azabicyclo[3.2.1 ]oct-3-en-2- one (Description 60; 0.754g, 1.87mmol) in ethyl acetate (75ml) and the mixture hydrogenated on a Parr™ apparatus (30psi max.) for two hours. Filtration and evaporation gave the title compound (0.76g, 100%) as an off-white solid, m/z (ES⁺) 406 ([M+H]⁺).

DESCRIPTION 62 (1 S,2S,5/?,6S,9S,11 S)-2-(1 -(3,5-Bis(trif luoromethyl)phenyl)-2-iodo)ethoxy-6- (ferf-butoxycarbonyl)-1-phenyl-8-(1-phenylethyl)-8-azabicyclo[3.2.1]octane

Iodine (1.72g, 6.78mmol) was added to a solution of (1 S,2S,5R,6S,9S,11 S)-2-(1 - (3,5-bis(trifluoromethyl)phenyl)-2-hydroxy)ethoxy-6-(ϊert-butoxycarbonyl)-1- phenyl-8-(1-phenylethyl)-8-azabicyclo[3.2.1]octane (Example 185; 3.00g, 4.52mmol), triphenylphosphine (1.78g, 6.79mmol) and imidazole (0.46g, 6.76mmo!) in dichloromethane (60ml). The mixture was stirred at room temperature for forty-five minutes, diluted with iso-hexane (60ml) and filtered. The filtrate was evaporated, the residue dissolved in 10% ethyl acetate/ iso- hexane and treated with silica. The mixture was filtered and the silica washed with 10% ethyl acetate/ iso-hexane. The filtrate was evaporated to afford the title compound (3.07g, 88%) as a white solid. m/z (ES⁺) 774 ([M+H]⁺).

EXAMPLE 1

(1f?*2f?*5S*,6f?*,8S 8-Benzyl-2-{[3,5-bis(trifIuoromethyl)phenyl]methoxy}-

1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane

Sodium hydride (182mg, 60% in oil, 4.55mmol) was added to a stirred solution of (1 R^*,2R*, 5S*,6fi 8-benzyl-1 -_phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1 ]octan-

2-ol (Description 4; 1.08g, 2.5mmol), 18-crown-6 (132g, O.δmmol) and

3,5-bis(trifluoromethyl)benzyi bromide (1.5ml, 7.8mmol) in dry THF (10ml) at room temperature. The reaction mixture was stirred for 4 days, then quenched with brine and extracted with dichloromethane (3x50ml). The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-30%) to give the title compound as a solid (1.36g, 83%). m/z (ES⁺) 661 [M+H]⁺

EXAMPLE 2

(1f?*,2/?*,5S*,6 ?'^,)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-6- phenylsulphonyl-8-azabicyclo[3.2.1]octane

A mixture of (1H*2H*5S*,6H^*,8S 8-benzyl-2-[3,5-bis(trifluoromethyl)- phenylmethoxy]-1 -phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1 ]octane (Example 1 ; 450mg, 0.68mmol), 5% palladium on charcoal (1 g, 0.47mmol) and ethanol

(20ml) was stirred under hydrogen atmosphere (1atm) at +65°C for 8 hours. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated and purified by flash chromatography to give the title compound (233mg, 60%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI. m/z (ES⁺) 430 [M+H]. EXAMPLE 3 (1R*,2R*5f?*)-2-{[3_J5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8- azabicyclo[3.2.1]octane hydrochloride

10% sodium amalgam (400mg) was added in two portion to a stirred mixture of (1 R*,2R*, 5S*,6H 2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1 -phenyl-6- phenylsulphonyl-8-azabicyclo[3.2.1]octane (Example 2; 233mg, 0.41 mmol), disodium hydrogen orthophosphate (420mg), THF (1ml) and methanol (4ml). The reaction mixture was stirred at room temperature for 2 hours, quenched with brine, carefully decanted and extracted with dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol) to give the free base of the title compound (30mg) (contaminated by products of partial defluorination). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI. m/z (ES⁺) 430 [M+Hf.

EXAMPLE 4 (1 ?*2S*,5S*6H 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-6- phenylsulphonyl-8-azabicyclo[3.2.1]octane A mixture of (1 R*, 2S*,5S*,6F?^!,)-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]oct-3-ene (Description 6; 390g, 0.59mol), 10% palladium on charcoal (473mg) and ethanol (25ml) was stirred under hydrogen atmosphere (1atm) at +70°C for 2 hours and at room temperature overnight. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated and purified by flash chromatography to give the title compound (250mg, 74%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI and recrystallized from dichloromethane-ether. m/z (ES⁺) 430 [M+H]. EXAMPLES 5a and 5b (1 ?*,2fl* 5S* 6/?^-2-{(1 S [3,5-Bis(trif luoromethyl)phenyl]ethyloxy}-1 - phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane; and (1 ?* 2ff * 5S* 6/? 2-{(1 ? [3,5-bϊs(trifluoromethyl)phenyl]ethyloxy}-1 - phenyl-6-phenylsulphonyl-8-azabicycIo[3.2.1]octane

(IH^H^^S^eR^-δ-Benzyl^-IS.δ-bis^rifluoromethy benzoyloxyj-l-phenyl-e- phenylsulphonyl-8-azabicydo[3.2.1]octane (Description 7; 595mg, 0.88mmol) was treated with a solution of dimethylbis(cyclopentadienyl)titanium in toluene (0.2M, 40ml). The reaction mixture was stirred in the dark at 90°C for 40 hours. The mixture was cooled to 40°C, than solid Na₂CO₃ (2.7g) added followed by a mixture of methanol-water (9:1 , 20ml). The mixture was stirred for 2 hours and filtered through a pad of Celite™. The filtrate was dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso- hexane:ethyl acetate 0-35% containing 0.5% triethylamine) to give a 1.3:1 mixture of (1 fl^*,2f?^*,5S* 6fl 2-{1 -[3,5-bis(trif luoromethyl)phenyl]ethenyloxy}-1 -phenyI-6- phenylsuIρhonyl-8-azabicyclo[3.2.1]octane and (1 fl^*,2R*,5S*,6f.'^,)-8-benzyl-2- [3,5-bis(trifluoromethyl)benzoyloxy]-1-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octane (556mg). The crude mixture (200mg) was treated with /-propanol (5ml), ethyl acetate (5ml) and 10% palladium on charcoal (450mg) and stirred under hydrogen atmosphere (1atm) at 50°C for 20 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite™ and concentrated. The residue was purified by chromatography on silica gel (iso-hexane: ethyl acetate) to give the title compounds (20mg each). The hydrochloride salt of the (1 S*)-isomer was prepared by treatment with ethereal HCI and recrystallised from dichloromethane:iso-hexane.

EXAMPLE 5a - (1S*) isomer (HCI salt):- δ_H (400 MHz, MeOH-cQ: 7.97 (2H, dm, J 7.8Hz), 7.97 (1H, t, J7.3Hz), 7.75-7.66 (3H, m), 7.31 (5H, s), 7.15 (1H, t, j 7.3Hz), 4.75 (1 H, q, J 6.5Hz), 4.34 (1 H, br s), 3.62 (2H, br s), 2.96 (1 H, dd, J 9.1Hz, 14.8Hz), 2.45 (1H, m), 2.30 (1H, t, J 15.7Hz), 2.16 (2H, d, J 10.9Hz), 1.63 (1H, t, J 14.6Hz), 1.79 (1H, d, J 14.0Hz), 1.40 (3H, d, J 6.4Hz); m/z (ES⁺) 584 [M+H]⁺. EXAMPLE 5b - (1/?") isomer (free base):- δ_H (360 MHz, CDCI₃): 7.85 (2H, dd, J 1.3Hz, 8.4Hz), 7.71 (1 H, s), 7.65 (1H, s), 7.62-7.45 (2H, m), 7.54 (2H, s), 7.40- 7.25 (5H, m), 4.08 (1H, br s), 3.63 (1H, q, J6.4Hz), 3.53 (1H, dd, J 5.1 Hz, 8.7Hz), 3.34 (1H, br s), 2.43 (1 H, dd, J8.8Hz, 14.4Hz), 2.29 (1H, dd, J 5.0Hz, 14.7Hz), 2.05 (1H, br s), 1.95 (1H, ddt, J 3.1 Hz, 5.7Hz, 13.1 Hz), 1.60-1.30 (2H, m), 0.94 (3H, d, J 6.5Hz).

EXAMPLES 6a and 6b (IR^fϊ^ S^β/ϊ^-δ-benzyl^- IS^-tS^-bisttrifluoromethy phenyl]^- hydroxyethyloxy}-1-phenyI-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane; and (1 R*, 2R*, SS*, 6H*)-8-benzyl-2-{(1 fi*)-[3,5-bis(trif luoromethyl)phenyl]-2- hydroxyethyIoxy}-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane A solution of borane-THF complex in THF (1 M, 3ml) was added dropwise to a stirred solution of the 1.3:1 mixture of (1H*2fl^*5S^*,6H 2-{1-[3,5- bis(trifluoromethyl)phenyl]ethenyloxy}-1-phenyI-6-phenylsulphonyl-8- azabicydo[3.2.1]octane and (1 H^*,2H*,5S^*6H*)-8-benzyl-2-[3,5- bis(trifluoromethyl)benzoyloxy]-1-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octane (intermediates from preparation in Example 5; 356mg) in THF (7ml) at -15°C. The reaction mixture was slowly warm up to room temperature and then stirred overnight. After cooling using ice-bath, a mixture of aqueous sodium hydroxide (2M, 6ml) and hydrogen peroxide (1.5ml) was added dropwise to the mixture. The ice-bath was removed and the reaction mixture was stirred at ambient temperature for 30 minutes and treated with 10% aqueous sodium sulphite (60ml). The mixture was extracted with ethyl acetate (3x30ml). The combined organic extracts were dried (Na^O and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compounds (100mg each).

EXAMPLE 6a - (1/?*) isomer:- δ_H (400 MHz, CDCI₃): 7.75 (1H, s), 7.55 (2H, dm, J7.3Hz), 7.53-7.30 (10H, m), 7.09 (1H, t, j 7.1Hz), 7.02 (1H, t, j 7.8Hz), 6.96 (1H, t, J 7.3Hz), 4.57 (1H, dd, J4.5Hz, 7.1Hz), 4.10 (1H, d, J 12.2Hz), 3.94 (1H, br s), 3.91 ( H, d, J 11.2Hz), 3.85 (1 H, br s), 3.63 (1 H, dd, J 7.2Hz, 11.5Hz), 3.55 (1 H, dd, J4.4Hz, 11.5Hz), 3.37 (1H, dd, J5.5Hz, 9.3Hz), 2.25 (1H, dd, J2.4Hz, 12.0Hz), 2.17 (1H, dd, J5.4Hz, 14.6Hz), 2.03 (1H, dd, J9.3Hz, 14.3Hz), 1.89 (1 H, m), 1.71 (1 H, m), 1.56 (1 H, br s), 1.04 (1 H, m).

EXAMPLE 6b - (1S*) isomer:- δ_H (400 MHz, CDCI₃): 7.86 (2H, s), 7.83 (1H, s), 7.65 (2H, dm, J7.4Hz), 7.47-7.28 (13H, m), 4.53 (1 H, dd, J 4.0Hz, 7.0Hz), 4.30 (1H, s), 4.16 (1H, d, J 15.0Hz), 4.05 (1H, d, J 15.0Hz), 3.78 (1H, s), 3.54 (2H, m), 3.37 (1H, dd, J 5.5Hz, 9.2Hz), 2.39 (1H, dd, J5.4Hz, 14.3Hz), 2.21 (1H, dd, J 9.3Hz, 14.3Hz), 1.92 (1H, m), 1.78-1.61 (3H, m), 1.49 (1H, dd, J4.6Hz, 15.5Hz), 0.79 (1H, dd, J 4.1 Hz, 12.4Hz).

EXAMPLE 7

(1 R*, 2R*,5S*, 6fi*)-2-{(1 ff *)-[3,5-Bis(trif luoromethyI)phenyl]-2- hydroxyethyloxy}-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane

The mixture of (1 R*,2f?*,5S*,6R^,,)-8-benzyl-2-{(1 H")-[3,5- bis(trifluoromethyl)phenyl]-2-hydroxyethyloxy}-1-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octane (Example 6a; 100mg, 0.143mmol), 10% palladium on charcoal (300mg) and ethanol (10ml) was stirred under the atmosphere of hydrogen (1 atm) at 65°C for 6 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite™ and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (58mg, 67%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI. m/z (ES⁺) 600 [M+H]⁺

EXAMPLE 8 (1 R*, 2R*, 5S*, 6/?*)-2-{(1 S*H3,5-Bis(trif luoromethyl)phenyl]-2- hydroxyethyloxy}-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane

The mixture of (1 R*,2R*,5S^*, 6H^*)-8-benzyI-2-{(1 S")-[3,5- bis(trifluoromethyl)phenyl]-2-hydroxyethyloxy}-1-phenyl-6-phenylsulphonyl-8- azabicyclo[3.2.1]octane (Example 6b; 99mg, 0.14mmol), 10% palladium on charcoal (300mg) and ethanol (10ml) was stirred under hydrogen atmosphere (1atm) at 65°C for 6 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite™ and concentrated. The residue was purified by chromatography on silica gel (iso-hexane: ethyl acetate) to give the title compound (65mg). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI and recrystallised from dichloromethane:iso-hexane. m/z (ES⁺) 600 [M+Hf

EXAMPLES 9a and 9b

(1 R*,2fl*,5/? 2-{1 -(S^-[3,5-Bis(trifluoromethyl)phenyl]ethyloxy}-1 -phenyl-8- azabicyclo[3.2.1]octane; and

(1 R*, 2R*, 5/?*)-2-{1 -(/? [3,5-bis(trifluoromethyl)phenyl]ethyloxy}-1 -phenyl-8- azabicyclo[3.2.1]octane (1 /?*,2H*5H 8-Benzyl-2-[3,5-bis(trifluoromethyl)benzoyloxy]-1 -phenyl-8- azabicyclo[3.2.1]octane (Description 9; 821 mg, 1.54mmol) was treated with a solution of dimethylbis(cyclopentadienyl)titanium in toluene (0.2M, 30ml). The reaction mixture was stirred in the dark at 82°C for 2.5 hours. The mixture was cooled to 40°C, than solid Na₂CO₃ (2g) added followed by a mixture of methanol- water (9:1 , 20ml). The mixture was stirred for 1 hour at 40°C and filtered through a pad of Celite™. The filtrate was dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-35% containing 0.5% triethylamine) to give a 10:1 mixture of (1 R^*,2R^*,5S^*,6R*)-2-{l- [3,5-bis(trifluoromethyl)phenyl]ethenyloxy}-1-phenyl-8-azabicyclo[3.2.1]octane and (1 H*,2H*,5S*,6H -8-benzyl-2-[3,5-bis(trifluoromethyl)benzoyloxy]-1 -phenyl- 8-azabicyclo[3.2.1]octane. 2/5 of this crude mixture was treated with /-propanol (8ml), ethyl acetate (8ml) and 10% palladium on charcoal (340mg) and stirred under hydrogen atmosphere (1atm) at room temperature for 12 hours. The mixture was filtered through a pad of Celite™ and concentrated to give a 7:1 (S*:R*) mixture of the title compounds. The isomers were separated by preparative TLC (dichloromethane:methanol) and converted into hydrochloride salts.

EXAMPLE 9a - (S*) isomer (HCI salt):- δ_H (400 MHz, MeOH- ₄): 7.72 (1H, s),

7.32 (2H, s), 7.30 (3H, m), 7.12 (2H, m), 4.61 (1 H, q, J 6.5Hz), 4.13 (1 H, m), 3.02 (1 H, s), 2.63 (1 H, ddd, J 4.0Hz, J 9.8Hz, 14.0Hz), 2.35-1.95 (6H, m), 1.76 (1 H, m), 1.41 (3H, d, J 6.5Hz); m/z (ES⁺) 444 [M+H]⁺

EXAMPLE 9b - (/?*) isomer (HCI salt):- δ_H (360 MHz, CDCI₃): 10.9 (1H, s), 9.7 (1H, s), 7.74 (1H, s), 7.64 (2H, dm, J7.8Hz), 7.59 (2H, s), 7.52-7.37 (3H, m), 4.38 (1H, m), 3.56 (1H, q, J6.3Hz), 3.44 (1H, m), 2.74 (1H, m), 2.51 (1H, m), 2.36 (2H, m), 1.82 (2H, m), 1.61 (1H, m), 1.44 (1H, d, J 13.3Hz), 1.18 (3H, d, J 5.9Hz); m/z (ES⁺) 444 [M+H]⁺.

EXAMPLES 10a and 10b

(1 ?*2 ?*5 ? 8-Benzyl-2-{(1/?S)-[3,5-bis(trifluoromethyi)phenyl]-2- hydroxyethoxy}-1-phenyl-8-azabicyclo[3.2.1]octane

A solution of borane-THF complex in THF (1 , 4ml) was added dropwise to stirred solution of ( R*,2R*,5S*,QR*)-2-{1-[3,5- bis(trifluoromethyl)phenyl]ethenyioxy}-1 -phenyl-8-azabicyclo[3.2.1]octane (from the preparation of Example 9) in THF (7ml) at -25°C. The reaction mixture was slowly warm up to room temperature (6 hours) and then stirred overnight. After cooling using ice-bath, a mixture of aqueous sodium hydroxide (2M, 6mi) and hydrogen peroxide (1.5ml) was added dropwise to the mixture. The ice-bath was removed and the reaction mixture was stirred at ambient temperature for 30 minutes and treated with 10% aqueous sodium sulphite (60ml). The mixture was extracted with ethyl acetate (3x25ml). The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-80%) to give the (1 R^*) isomer of the title compound (183mg) and the (1 S*) isomer of the title compound (202mg).

EXAMPLE 10a - (Iff") isomer:- δ_H (400 MHz, CDCI₃): 7.71 (1H, s), 7.4 (2H, d, J 7.3Hz), 7.40-7.25 (10H, m), 4.57 (1H, dd, J3.8Hz, 7.8Hz), 4.04 (1H, d, J 14.8Hz), 3.57 (1H, dd, J8.6Hz, 11.2Hz), 3.50-3.25 (4H, m), 2.20-1.88 (5H, m), 1.82-1.70 (1H, m), 1.70-1.57 (1H, m), 1.30-1.20 (1H, m). EXAMPLE 10b - (1 S") isomer:- δ_H (400 MHz, CDCI₃): 7.96 (2H, s), 7.82 (1 H, s), 7.62 (2H, d, J7.7Hz), 7.55 (2H, d, J7.4Hz), 7.42-7.35 (4H, m), 7.30-7.24 (2H, m), 4.32 (1H, dd, J 3.2Hz, 7.6Hz), 4.14 (1H, d, J 15.3Hz), 3.71 (1 H, s), 3.48 (1H, d, J 15.4Hz), 3.45-3.38 (1H, m), 3.38-3.27 (2H, m), 2.25-2.00 (3H, m), 1.90-1.67 (2H, m), 1.60 (1H, m), 1.41 (1H, m), 1.18 (1H, m), 1.05 (1H, m). EXAMPLE 11 (1 R*,2R*,5R*)-2-{Cl 77 [3,5-Bis(trif luoromethyl)phenyl]-2-hydroxyethoxy}-1 - phenyl-8-azabicyclo[3.2.1]octane

The mixture of (1 R^*,2R^*,5R^*)-8-benzy\-2-{(l fl -[3.5-bls(trifluoromethyl)phenyI]-2- hydroxyethoxy}-1-phenylphonyl-8-azabicyclo[3.2.1]octane (Example 10a; 106mg, 0.192mmol), 10% palladium on charcoal (330mg) and ethanol (10ml) was stirred under the atmosphere of hydrogen (1atm) at 65°C for 1.5 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite™ and concentrated to give the title compound as an oil. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI and recrystallised from dichloromethane:diethyl ether, m/z (ES⁺) 460 [M+H]⁺

EXAMPLE 12 (1 F? * 2 ? * 5fl *)-2-{(1 S*)-[3,5-Bis(trif luoromethyl)phenyl]-2-hydroxyethoxy}-1 - pheny l-8-azabicyclo[3.2.1 Joctane

The mixture of (1 ?*,2R*,5f?^s)-8-benzyI-2-{(1S^,,)-[3,5-bis(trifluoromethyl)phenyl]-2- hydroxyethoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 10b; 100mg, 0.18mmol), 10% palladium on charcoal (350mg) and ethanol (10ml) was stirred under hydrogen atmosphere (1atm) at 65°C for 1 hour. After cooling to room temperature, the mixture was filtered through a pad of Celite™ and concentrated to give the title compound as an oil. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI and recrystallised from dichIoromethane:iso-hexane. m/z (ES⁺) 460 [M+H]⁺

EXAMPLE 13 (1/?*2 ?*5 ? 8-Benzyl-2-[2,5-bis(trifluoromethyl)phenylmethoxy]-1-phenyl- 8-azabicyclo[3.2.1 loctane (1 R*,2R*,5R*)-8-Benzy\-l -_phenyl-8-azabicyclo[3.2.1 ]octan-2-ol (Description 9;

151mg, 0.52mmol) was treated with sodium hydride (41 mg, 60% in oil, 1.03mmol) at 0°C in a solution of THF (2ml) and allowed to warm to room temperature. The mixture was recooled to 0°C and 2,5-bis(trifluoromethyi)benzyI bromide (0.24ml, 1.30mmol) added and the mixture heated to 50°C for 2 days. A further 1.30mmol of the benzyl bromide was added and the mixture further heated for 50°C for 2 days. The reaction mixture was poured into water and extracted with ethyl acetate (x3), dried (MgSO₄) and concentrated in vacuo to give a yellow solid. This was purified by flash column chromatography [25% ethyl acetate in iso-hexane] to give the title compound.

EXAMPLE 14 (1 ?*2fl*5R^-2-[2,5-Bis(trifluoromethyl)phenylmethoxy]-1-phenyl-8- azabicyclo[3.2.1]octane hydrochloride

(1H*,2/^:?*5R^;()-8-Benzyl-2-[2,5-is(trifluoromethyl)phenylmethoxy]-1-phenyl-8- azabicyclo[3.2.1]octane (Example 13; 321 mg, 0.62mmol) was dissolved in ethyl acetate (5ml) and glacial acetic acid (1 ml) and 10% palladium hydroxide (50mg) added. The mixture was hydrogenated at 40psi overnight. The reaction mixture was then filtered and concentrated in vacuo. The oil was basified (1 N sodium hydroxide), extracted with ethyl acetate (x3), dried (MgSO₄), and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [10% methanol in dichloromethane] to give the free base of title compound. The hydrochloride salt was made by adding 1 equivalent of 1 N hydrogen chloride in diethyl ether to a solution in diethyl ether and the solid filtered off and dried at 60°C in vacuo. m/z (ES⁺) 430 ([M+H]⁺).

EXAMPLE 15 (1 ?*, 2fi* 5R*)-8-BenzyI-2-[(2-methoxy-5-trif luoromethoxyphenyl)methoxy]-1 - phenyl«8-azabicyclo[3.2.1]octane

(1 R*,2H*,5H 8-Benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 348mg, 1.19mmol) was dissolved in THF then sodium hydride (71 mg, 60% in oil, 1.79mmol) added and the reaction mixture stirred for 10 minutes. 2-methoxy-5- trifluoromethoxybenzyl bromide was added and the reaction mixture stirred at 50°C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (x3), dried (MgSO₄) and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [5%-15% ethyl acetate in iso- hexane] to give the title compound. (205mg, 35%). m/z (ES⁺) 498 ([M+H]⁺).

EXAMPLE 16

(1 ?*2fl*5/? 2-[(2-Methoxy-5-trifluoromethoxy)phenylmethoxy]-1-phenyl-8- azabicyclo[3.2.1]octane

(1H*,2/^:?^,l _J5 ^:?^-8-Benzyl-2-[(2-methoxy-5-trifluoromethoxy)phenylmethoxy]-1- phenyl-8-azabicyclo[3.2.1]octane (Example 15; 205mg, 0.41 mmol) was dissolved in ethyl acetate (5ml) and glacial acetic acid (1 ml) and degassed with N₂ for 5 minutes. 10% palladium hydroxide (30mg) was added and the mixture hydrogenated at 50psi overnight. The reaction mixture was filtered, washed with methanol and concentrated in vacuo to give a clear oil. This was basified (1 N sodium hydroxide) and extracted with dichloromethane (x3), dried (MgSO₄) and concentrated in vacuo to give a clear oil which was purified by flash column chromatography [5%-7.5% methanol in dichloromethane] to give a white solid which was triturated in diethyl ether then filtered off and dried in vacuo at 60°C to give the title compound (20mg, 12%). m/z (ES⁺) 408 ([M+H]⁺).

EXAMPLE 17 (1 ?*2R*5 ?^-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-(4- fluorophenyl)-8-azabicyclo[3.2.1]octane Sodium hydride (320mg, 60% in oil, 7.98mmol) was washed with iso-hexane (x3) then THF (8ml) and (1 R*,2R^*, 5H 8-benzyl-1 -(4-fluorophenyl)-8- azabicyclo[3.2.1]octan-2-ol (Description 15; 1.24g, 3.99mmol) added and the mixture stirred at room temperature for 10 minutes then 3,5-bis(trifluoromethyl) benzyl bromide added and the reaction mixture stirred at 60°C overnight. The reaction mixture was poured into water and extracted with ethyl acetate (x3), dried (MgSO₄) and concentrated in vacuoXo give a yellow oil. This was purified by flash column chromatography [5% ethyl acetate in iso-hexane] to give the title compound (1.51g, 58%). m/z (ES⁺) 538 ([M+H]⁺). EXAMPLE 18 (1f?*,2R*,5f?^-2-{[3₅5-Bis(trifluoromethyl)phenyl]methoxy}-1-(4- fluorophenyl)-8-azabicyclo[3.2.1]octane (1 R*,2f?*,5/^:.'^,)-8-BenzyI-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1 -(4- fluorophenyl)-8-azabicy o[3.2.1]octane (Example 17; 1.51g, 2.81 mmol) was dissolved in ethyl acetate (20ml) and glacial acetic acid (2ml) and 10% palladium hydroxide (200mg) added and hydrogenated at 45psi overnight. The reaction mixture was filtered then concentrated in vacuo. The oil was basified (4N sodium hydroxide) and the solution extracted with ethyl acetate (x3). The organics were dried (MgSO₄) and concentrated in vacuo. The mixture was purified by flash column chromatography [7.5% methanol in dichloromethane] to give a yellow oil which solidified on standing to give the title compound (506mg, 40%). The hydrochloride salt was made by adding 1 equivalent of 1 N hydrogen chloride in diethyl ether to the title compound (31 mg, 0.06mmol). A white solid formed which was triturated in diethyl ether and filtered then dried at 60°C in vacuo (29.8mg, 89%). m/z (ES⁺) 448 ([M+H]⁺).

EXAMPLE 19

(IR^^R^SR -Z- ^-Bisttrifluo omethy phenyllmethoxyJ-l^- fluorophenyl)-8-[(1,2,4-triazol-3-yl)methyl]-8-azabicyclo[3.2.1]octane hydrochloride

(1 r?*,2H*5/^:?^-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-(4-fluorophenyl)-8- azabicyclo[3.2.1]octane (Example 18; 268mg, 0.60mmol), potassium carbonate (332mg, 2.40mmol), and N-formyl-2-chloroacetamidrazone (138mg, 1.02mmol) were combined in dimethylformamide (3ml) and heated at 60°C for 45 minutes. The reaction mixture was then poured into water and extracted with ethyl acetate (x2), dried (MgSO₄), and concentrated in vacuo. The crude compound was then dissolved in toluene and heated overnight at 120°C. The reaction mixture was poured into water and extracted with ethyl acetate (x3), dried (MgSO₄) and concentrated in vacuo to give a brown foam. This was purified by flash column chromatography [5% methanol in dichloromethane] to give an orange solid (148mg, 47%). The hydrochloride salt was made by adding 1 equivalent of 1N hydrogen chloride in diethyl ether to a solution in diethyl ether. The solid formed was triturated then filtered off and dried in vacuo at 60°C to give the title compound as a beige solid (108mg, 68%). m/z (ES⁺) 529 ([M+H]⁺).

EXAMPLE 20 (1 R*, 2/?* 5/?*)-2-{[3,5-Bis(trif luoromethyl)phenyl]methoxy}-1 -(4- fluorophenyl)-8-[(1 -methyl-1 ,2,4-triazol-3-yl)methyl]-8- azabicyclo[3.2.1]octane hydrochloride

(1 F?^*2f?^*5/^:?^,,)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-(4-fluorophenyl)-8- azabicyclo[3.2.1]octane (Example 18; 101mg, 0.23mmol), potassium carbonate (159mg, 1.15mmol), and 1-methyl-3-chloromethyl-1 ,2,4 triazole (386mg, 2.30mmol) were combined in dimethylformamide and heated at 80°C for 5 days. The reaction mixture was poured into water and extracted with ethyl acetate (x3), dried (MgSO₄) and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [7.5% methanol in dichloromethane] to give desired product. The hydrochloride salt was made by adding 1 equivalent of 1N hydrogen chloride in diethyl ether to a solution in diethyl ether. The salt was further purified by SCX cartridge eluting with methanol then ammonia in methanol. The ammonia washings were collected and concentrated In vacuo and the hydrochloride salt made by adding 1 equivalent of 1 hydrogen chloride in diethyl ether to a solution in diethyl ether. The solid formed was filtered and dried at 60°C in vacuo to give the title compound. m/z (ES⁺) 544 ([M+Hf).

EXAMPLES 21a and 21b (1 fl*,2/?*,5/?*)-2-{(1 R [3,5-Bis(trif luoromethyl)pheny.]ethoxy}-1 -(4- fluorophenyI)-8-azabicyclo[3.2.1]octane; and (1 /?*, 2 ?* 5/?*)-2-{(1 S [3,5-bis(trifluoromethyl)phenyl]ethoxy}-1 -(4- fluorophenyl)-8-azabicyclo[3.2.1]octane

(1 H*2H*,5 ?^-8-benzyl-2-{1 -[3,5-bis(trifluoromethyl)phenyl]ethenyloxy}-1 -(4- fluorophenyl)-8-azabicyclo[3.2.1]octane (Description 17; 923mg, 1.68mmol) was dissolved in ethyl acetate (20ml) and glacial acetic acid (2ml) and 10% palladium hydroxide (100mg) added. The reaction mixture was hydrogenated at 40psi overnight at room temperature. The mixture was filtered then concentrated in vacuo, basified (4N sodium hydroxide) and extracted with ethyl acetate (x3), dried (MgSO₄) and concentrated in vacuo to give an orange oil. The mixture of 2 isomers was purified by first, flash column chromatography [5% methanol in dichloromethane] to give the undesired isomer, then by lobar chromatography [7.5% methanol in dichloromethane] to give the desired isomer.

The free base of the (1 H^*)-isomer (200mg) and the (1 S*)-isomer (25mg) were made into the hydrochloride salt by adding 1 equivalent of 1 N hydrogen chloride in diethyl ether to a solution in diethyl ether. The solid was filtered and dried in vacuo at 60°C (60mg). EXAMPLE 21a - (Iff*) isomer (HCI salt):- δ_H (360MHz, MeOH-d₄): 7.87 (3H, s), 7.41 (2H, m), 7.26 (2H, m), 4,25 (1H, m), 4.14 (1H, m), 3.84 (1H, br s), 2.74-2.66 (1H, m), 2.32-1.93 (5H, m), 1.68 (1H, m), 1.56 (1H, m), 0.99 (3H, d, J6.4Hz); m/z (ES⁺) 462 ([M+Hf).

EXAMPLE 21b - (1S*) isomer (HCI salt):- δ_H (360MHz, MeOH-d₄): 7.74 (1H, s), 7.37 (2H, s), 7.16 (2H, m), 7.03 (1H, m), 4.68 (1H, m), 4.15 (1H, m), 3.55 (1H, br s), 2.67-2.59 (1 H, m), 2.33-1.95 (6H, m), 1.77 (1 H, m), 1.43 (3H, d, J 6.48Hz); m/z (ES⁺) 462 ([M+Hf).

EXAMPLE 22 (1ff*2ff*,5S*6S*)-2-{[3₅5-Bis(trifluoromethyl)phenyl]methoxy}-6-(fert- butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane A mixture of (I

bis(trifluoromethyl)phenyl]methoxy}-6-(tøtιf-butoxycarbonyl)-1-phenyl-8- azabicyclo[3.2.1]octane (Description 22; 826mg, 1.33mmol), 10% palladium on charcoal (470mg, 0.44mmol), ethyl acetate (10ml) and ethanol (10ml) was stirred under hydrogen atmosphere (1atm) at +60°C for 1 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound (500g, 71%). δ_H (400 MHz, CDCI₃): 7.67 (1H, s), 7.45-7.25 (7H, m), 4.49 (1 H, d, J 12.9Hz), 4.32 (1H, br), 4.15 (1H, d, J 12.9Hz), 3.81 (1H, br), 3.61 (1H, br s), 2.80 (1H, dd, J 6.2Hz, 14.1Hz), 2.50-2.25 (2H, m), 2.70 (1H, dt, J5.5Hz, 13.7Hz), 2.00 (1H, m), 1.95-1.50 (2H, m), 1.51 (9H, s).

EXAMPLE 23 (1ff*2ff*5S*6S*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6- methoxycarbonyl-1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride A mixture of (1 R*,2R^*5S*6S^*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(te/t- butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 22; 50mg,

0,094mmol), methanol (0.3ml) and 1M HCI in diethyl ether was stirred at room temperature for 10 days and heated at reflux for 5 hours. The mixture was concentrated in vacuo to give the title compound as a white solid, m/z (ES⁺) 488 [M+H]⁺

EXAMPLE 24 (1R*2R*5S*,6ff*)-8-Benzyl-2-{[3,5-bis(trifluoromethyI)phenyl]methoxy}-6- (te/f-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane A solution of (1 H*,2f?*,5S*,6H^-8-benzyl-6-(terf-butoxycarbonyl)-1-phenyl-8- azabicyclo[3.2.1]octan-2-ol (Description 20; 5.8g, 14.7mmol) and 18-crown-6

(5.3g, 20mmol) in THF (50ml) was added to a stirred, ice-bath cooled suspension of sodium hydride (60% in oil, 800mg, washed twice with THF) in THF (10ml). The mixture was stirred for 5 minutes and 3,5-bis(trifluoromethyl)benzyl bromide (1 ml, 5.45mmol) was added via syringe. The reaction mixture was stirred for 6 days and poured onto saturated aqueous NH₄CI and extracted into a 1 :1 mixture of iso-hexane:diethyl ether (3x100ml). The combined organic extracts were washed with brine, dried (Na^OJ and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether) to give the title compound (4.92g, 54%). δ_H (400 MHz, CDCI₃): 7.74 (3H,s), 7.57 (1 H, d, J 7.4Hz), 7.39 (1 H, d, J 7.4Hz),

7.35-7.15 (6H, m), 4.83 (1H, d, J 12.9Hz), 4.59 (1H, d, J 12.8Hz), 4.11 (1H, br s), 4.09 (1H, d, J 15.8Hz), 3.82 (1H, d, J 15.8Hz), 3.69 (1H, br s), 2.73 (1H, dd, J 4.3Hz, 9.0Hz), 2.48 (1H, dd, J4.3Hz, 12.0Hz), 2.20 (1H, ddd, J2.3Hz, J 5.1 Hz, 13.3Hz), 2.11 (1H, dd, 5.1Hz, 15.2Hz), 2.02 (1H, dd, J 9.0Hz, 13.3Hz), 1.44 (9H, s), 1.21 (1H, m).

EXAMPLE 25 (1R*,2f?*,5S*,6ff'^,)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(fert- butoxycarbonyl)-1 -pheny l-8-azabicyclo[3.2.1 Joctane

A mixture of (1 R*,2R*,5S*,6 ^:?^I,)-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-6-(tørt-butoxycarbonyl)-1-phenyl-8- azabicyclo[3.2.1]octane (Example 24; 240mg, 0.39mmol), 10% palladium on charcoal (470mg, 0.40mmol) ethanol (10ml) was stirred under hydrogen atmosphere (1atm) at +65°C for 1 hour and at room temperature overnight. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-25%) to give the title compound (135g, 66%). m/z (ES⁺) 530 [M+H]⁺

EXAMPLE 26 (1ff*,2ff*,5S*,6 ?'^l)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6- methoxycarbonyl-1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride

A mixture of (1 R*,2f?*,5S*,6f?^,,)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tørt- butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 44mg, O.Oδmmol), methanol (0.1ml), dichloromethane (0.6ml) and 1 M HCI in diethyl ether (1 ml) was kept at room temperature for 3 weeks. The mixture was concentrated to give the title compound as a white solid, m/z (ES⁺) 488 [M+Hf

EXAMPLE 27 (1ff*,2ff*5S*,6ff^,,)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8- azabicyclo[3.2.1]octan-6-carboxylic acid hydrochloride

A mixture of (1 R*,2/^:?*,5S*6H^,,)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tøt - butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 20mg, 0.04mmol), dichloromethane (1ml) and 1M HCI in diethyl ether (0.5ml) was kept at room temperature for 2 weeks. The white solid was filtered off, washed with a 1 :1 mixture dichloromethane:diethyl ether to give the title compound (11mg). m/z (ES⁺) 474 [M+Hf

EXAMPLE 28

(1ff*₅2fl*,5S*6ff*)-8-BenzyI-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6- hydroxy methyl-1 -pheny l-8-azabicyc!o[3.2.1 Joctane

A solution of DIBAL-H in dichloromethane (1M, 1.3ml, 1.3mmol) was added dropwise to a stirred solution of (1 R*, 2R*,5S^*, 6H*)-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8- azabicyclo[3.2.1]octane (Example 25; 100mg, 0.16mmol) in dichloromethane (2ml) at room temperature. The mixture was stirred for 45 minutes, then diluted with dichloromethane (25ml) and quenched with small amount of saturated aqueous Na₂SO₄ and stirred for additional 1 hour. The mixture was filtered through a pad of Celite™, concentrated and purified by chromatography on silica gel (iso-hexane: ethyl acetate) to give the title compound (85mg, 96%). δ_H (360 MHz, CDCI₃): 7.74 (1H, s), 7.71 (2H, s), 7.56 (2H, m), 7.36 (6H, m), 7.25 (2H, m), 4.87 (1 H, d, J 12.6Hz), 4.60 (1H, d, J 12.6Hz), 4.22 (2H, m), 4.12 (1H, dd, J 2.1 Hz,14.7Hz), 3.88 (1H, d, J 15.1 Hz), 3.64 (2H, m), 3.30 (1 H, br s), 2.79 (1 H, br), 2.30 (1 H, ddd, J 2.8Hz, J 5.6Hz, 13.3Hz), 2.20-1.95 (4H, m), 1.72 (1 H, d, J 11.6HZ), 1.16 (1H, dd, J 4.2Hz, 13.7Hz).

EXAMPLE 29 (1ff*₅2ff*5S*6ff*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6- hydroxymethyl-1 -phenyl-8-azabicyclo[3.2.1 ]octane

A mixture of (1 f?*2H*5S^*,6R'^l)-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-6-hydroxymethyI-1-phenyl-8- azabicyclo[3.2.1]octane (Example 28; 85mg 0.15mmol), 10% palladium on charcoal (125mg, 0.12mmol) ethanol (10ml) was stirred under hydrogen atmosphere (1atm) at +65°C for 45 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI and recrystallised from ethylacetate: iso-hexane. m/z (ES⁺) 460 [M+Hf

EXAMPLE 30

(1/?*,2ff*5S*6ff^Λ)-2-{[3,5-Bis(trifluoromethyl)phenyl3methoxy}-6-(1-methyl- 1 ,2,4-triazol-3-yl)methoxymethyl-1 -phenyl-8-azabicyclo[3.2.1 ]octane hydrochloride

(I H^R^SS^eH^-δ-Benzyl^-lfS.S-bis^rifluoromethy phenylJmethoxyJ-β- hydroxymethyl-1-phenyl-8-azabicyclo[3.2.1]octane (Example 23; 100mg,

O.lδmmol), 15-crown-5 (δOmg, 0.36mmol) and sodium hydride (60% dispersion in oil; 22mg, 0.55mmol) in THF were treated with 3-chloromethyl-1 -methyl-1 ,2,4- triazole hydrochloride, and stirred at 60°C for 1δ hours. The mixture was diluted with water and extracted with ethyl acetate. The organics were collected, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 50-75% ethyl acetate/hexane to afford a clear oil (75mg, 64%). This N-benzyl compound (75mg, 0.12mmol), palladium, 5% on carbon (40mg), methanol (10ml) and 2N hydrochloric acid (0.5ml) was hydrogenated using the Parr™ apparatus for 36 hours. The mixture was filtered and concentrated in vacuo. The residue was taken into dichloromethane and washed with water. The organics were separated and dried (MgSO and concentrated in vacuo. The residue was treated with ethereal hydrogen chloride and the resultant salt crystallised from methanol/diethyl ether to give the title compound (33mg, 56%). m/z (ES⁺) 555 ([M+Hf).

Prepared in an analogous manner were the following four compounds:

EXAMPLE 31 (1r?*,2ff*5S*6ff 2-{[3,5-Bis(trifluoromethyl)phenyI]methoxy}-6- methoxy methyl-1 -pheny l-8-azabicyclo[3.2.1]octane hydrochloride m/z (ES⁺) 474 ([M+H]⁺). EXAMPLE 32 (Iff^ff^δS^^βff^^- ^-Bis rifluoromethy phenyηmethoxyl-e-tN^- dimethylacetamidoyloxymethyl)methoxymethyl-1-phenyl-8- azabicyclo[3.2.1 ]octane hydrochloride m/z (ES⁺) 545 ([M+Hf).

EXAMPLE 33 (1ff*2ff*5S*,6ff*)-2-{[3₅5-Bis(trifluoromethyl)phenyl]methoxy}-6-(3- hydroxypropyloxymethyl)methoxymethyl-1-phenyl-8- azabicyclo[3.2.1]octane hydrochloride m/z (ES⁺) 518 ([M+H]⁺).

EXAMPLE 34 (Iff'^ff^δS^βff^- ^-Bisttrifluoromethy henyOmethoxy}^^- methoxypropyloxymethyl)methoxymethyl-1 -phenyl-8- azabicyclo[3.2.1]octane hydrochloride m/z (ES⁺) 532 ([M+Hf).

EXAMPLE 35 (1 R*,2R * 5S* 6ff 8-Benzyl-2-{[3,5-bis(trif luoromethyl)phenyl]methoxy}-6-(1 - hydroxy-1-methylethyl)-1-phenyl-8-azabicyclo[3.2.1]octane

A solution of methyl magnesium bromide in diethyl ether (3M, 1ml, 3mmol) was added to a stirred solution of (1 R^H^δS^H ^-iCS.δ- bis(trifluoromethyl)phenyl]methoxy}-6-(ferf-butoxycarbonyl)-1-phenyl-δ- azabicyclo[3.2.1]octane (Example 25; 73mg, 0.12mmol) in THF (4ml) at room temperature. The mixture was stirred for 20 hours and additional portion of methyl magnesium bromide (1ml) was added. After next δ hours, the reaction mixture was quenched with saturated aqueous NH₄CI (15ml) and 25% aqueous ammonia (15m!) solutions and extracted into ethyl acetate. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane: ethyl acetate 0-20%) to give the title compound (56mg, δ2%). δ_H (360 MHz, CDCI₃): 7.73 (1H, s), 7.76 (2H, s), 7.δ8 (2H, dm, J 8.1 Hz), 7.39 (2H, dm, J 7.4Hz), 7.35-7.21 (6H, m), 4.87 (1 H, d, J 12.6Hz), 4.60 (1H, d, J 12.6Hz), 4.24 (1H, br s), 4.07 (1H, d, J 14.0Hz), 3.83 (1H, d, J 14.0Hz), 3.65 (1 H, br), 3.45 (1H, br s), 2.35 (1H, m), 2.14 (1H, m), 2.10-1.92 (3H, m), 1.86 (1H, t, J 7.0Hz), 1.12 (1H, dd, J 1.1Hz, 14.3Hz), 1.07 (3H, s), 1.05 (3H, s).

EXAMPLE 36 (1ff*2ff*5S*,6ff 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(1-hydroxy- 1-methylethyl)-1 -pheny l-8-azabicyclo[3.2.1]octane A mixture of (1 R*,2R*,5S*,6R*)-8-benzy\-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-6-(1 -hydroxy-1 -methylethyl)-1 -phenyl-8- azabicyclo[3.2.1]octane (Example 35; 56mg O.IOmmol), 10% palladium on charcoal (200mg, 0.2mmol) ethanol (1 Oml) was stirred under hydrogen atmosphere (1atm) at +60°C for 2 hours. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI and recrystallised from ethyl acetate:iso-hexane. m/z (ES⁺) 630 [M+H]⁺.

EXAMPLE 37 (1ff*2ff*,5S*₅6ff 8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(N- methoxy-N-methylcarbamoyI)-1 -pheny l-8-azabicyclo[3.2.1 ]octane A mixture of (1 R*,2R*, 5S*,6H^,()-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(ferf- butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 340mg,

O.δδmmol), dichloromethane (8ml) and trifluoroacetic acid (2ml) was stirred at room temperature for 24 hours and concentrated. The residue was treated with dichloromethane (2.5ml) followed by N,O-dimethylhydroxylamine hydrochloride (204mg, 2.1mmol), triethylamine (0.7ml, 5mmol), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (450mg, 2.35mmol), 4-N,N- dimethylaminopyridine (26mg, 0.21 mmol). The mixture was stirred for 6 hours, quenched with saturated aqueous NaHCO_g and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (260mg, 78%). δ_H (360 MHz, CDCI₃): 7.76 (3H, s), 7.62 (2H, dd, J 1.4Hz, 7.4Hz), 7.41 (2H, d, J 7.7Hz), 7.3δ-7.2δ (4H, m), 7.19 (2H, m), 4.84 (1H, d, J 13.0Hz), 4.69 (1H, d, J 13.0Hz), 4.13 (1H, br s), 4.09 (1H, d, J 16.δHz), 3.83 (1H, d, J 16.1 Hz), 3.62 (3H, s), 3.59 (1H, s), 3.19 (3H, s), 3.06 (1H, dd, J4.6Hz, 8.1Hz), 2.68 (1H, dd, J 4.6Hz, 13.3Hz), 2.27-1.95 (4H, m), 1.21 (1H, m).

EXAMPLE 38 (1ff*2 ?*5S*6ff^-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(N-methoxy- N-methylcarbamoy l)-1 -phenyl-8-azabicyclo[3.2.1 loctane

A mixture of (1 ^*,2r?^*,5S^*,6ff^-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-6-(N-methoxy-N-methylcarbamoyl)-1-phenyl- 3-azabicyclo[3.2.1]octane (Example 37; 420mg 0.69mmol), 10% palladium on charcoal (375mg, 0.35mmol) ethanol (25ml) was stirred under hydrogen atmosphere (1atm) at +60°C for 1 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI and recrystallised from ethyl acetate. m/z (ES⁺) δ17 [M+H]⁺

EXAMPLE 39 (1ff*,2ff*5S*,6ff^-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-6- phenylcarbonylo-8-azabicyclo[3.2.1] ctane hydrochloride

A solution of phenyl lithium (1.8M in cyclohexane-ether, 1.5ml, 2.7mmol) was added droipwise to a stirred suspension of 1 H^*,2H*,5S^*6H^,,)-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-6-(N-methoxy-N-methylcarbamoyl)-1-phenyI- 8-azabicycIo[3.2.1]octane hydrochloride (Example 38; 310mg, 0.56mmol) in THF (8ml) at -78°C. The reaction mixture was stirred at -7δ°C for 3 hours and the cold bath was removed. The mixture was stirred at ambient temperature for 10 minutes, then quenched with saturated aqueous NH₄CI and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso- hexane:ethyl acetate) to give the free base of the title compound. The hydrochloride salt was prepared by treatment the amine with ethereal HCI and recrystallised from ethyl acetate:diethyl ether. m/z (ES⁺) 534 [M+H]⁺

EXAMPLES 40a and 40b (1ff*2ff*5S*,6f?'⁽)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-6- [(ffS)-1-phenylhydroxymethyl]-8-azabicyclo[3.2.1]octane A solution of DIBAL-H in dichloromethane (1 M, 4ml, 4mmol) was added dropwise to a stirred solution of (1

bis(trifluoromethyl)phenyl]methoxy}-6-(tørt-butoxycarbonyl)-1-phenyl-δ- azabicyclo[3.2.1]octane (Example 25; 750mg, 1.4mmol) in dichloromethane (5ml) at -7δ°C. The reaction mixture was stirred at -78°C for 20 minutes and quenched with ethyl acetate (0.5ml) followed by dichloromethane (30ml) and few drops of water. The mixture was warm up to room temperature and stirred with solid Na₂SO₄ for 1 hour. The mixture was filtered through a pad of Celite™. The filtrate was concentrated to give a crude aldehyde (5δ3mg), which was used in the next step without purification. A solution of phenyl magnesium bromide in diethyl ether (3M, 0.5ml, 1.5mmol) was added dropwise to a stirred solution of aldehyde (184mg) in THF at +5°C. the reaction mixture was stirred for 1 hour and quenched with saturated aqueous NH₄CI (15ml) and 25% aqueous ammonia (15ml) solutions and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-20%) to give a 1.4:1 mixture of epimeric alcohols which were separated by preparative TLC. Hydrochloride salts were prepared by treatment amines with ethereal HCI. EXAMPLE 40a - 6-[(S)-1-phenylhydroxymethyl]-epimer (HCI salt):- δ_H (400 MHz MeOH-c₄): 7.68 (1H, s), 7.40 (2H, dm, J 7.1 Hz), 7.35-7.20 (10H, m), 4.82 (1 H, d, J4.7Hz), 4.45 (1H, d, J 12.9Hz), 4.08 (1H, d, J 12.5Hz), 3.88 (1H, br), 3.63 (1H, s), 2.47 (1H, dt, J4.3Hz, 9.4Hz), 2.39 (1H, dd, J9.4Hz, 13.7Hz), 2.00 (1H, dd, J 3.9Hz, 13.3Hz), 1.98-1.89 (2H, m); m/z (ES⁺) 535 [M+H]⁺ EXAMPLE 40b - 6-[(ff)-1-phenylhydroxymethyl]-epimer (HCI salt):- δ_H (360 MHz, MeOH-d₄): 7.δ0 (1H, s), 7.55 (2H, s), 7.46-7.23 (10H, m), 4.92 (1H, d, J 5.0Hz), 4.69 (1 H, d, J 12.4Hz), 4.20 (1 H, d, J 12.6Hz), 4.00 (1 H, br s), 3.δδ (1 H, br s), 2.δ2 (1H, dt, J4.7Hz, 9.5Hz), 2.66 (1H, dd, J9.δHz, 14.5Hz), 2.22 (1H, dd, J4.7Hz, 14.2Hz), 2.1δ-2.04 (3H, m), 1.δO (1H, m); m/z (ES⁺) 53δ [M+H]⁺

EXAMPLE 41 (1ff*,2ff*,5ff'^,)-8-Benzyl-2-{[3,5-bis(trifluoromethyI)phenyl]methoxy}-1- phenyl-8-azabicyc!o[3.2.1]octan-6-one A solution of n-butyl lithium (1.δM in hexanes, 0.46ml, 0.67mmol) was added dropwise to a stirred solution of (1 R*,2R^*,5S^*,6R*, δS*)-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-6-phenylsulphonyi-8- azabicyclo[3.2.1]octane (Example 1; 340mg, 0.51 mmol) in THF (10ml) at -75°C. The reaction mixture was stirred at -75 to -60°C for 15 minutes and oxygen gas was passed through for 15 minutes. The reaction mixture was warm up to 0°C, quenched with saturated aqueous NH₄CI and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0- 100%) to give the title compound (53mg, 20%) and starting compound (250mg, 73%). δ_H (360 MHz, CDCI₃): 7.77 (1H, s), 7.70 (2H, s), 7.68 (2H, d, J δ.lHz), 7.44-7.19 (δH, m), 4.7δ (1 H, d, J 12.6Hz), 4.44 (1H, d, J 12.6Hz), 4.20 (1H, d, J 16.1 Hz), 4.0δ (1H, br s), 3.73 (1H, d, J 15.1 Hz), 3.40 (1H, br s), 2.69 (1H, d, J 1δ.2Hz), 2.4δ (1H, d, J 1δ.2Hz), 2.33-2.11 (2H, m), 2.02-1.65 (1H, m), 1.57 (1 H, m).

EXAMPLE 42 (1ff*,2ff*,5S 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8- azabicyclo[3.2.1 ]octan-6-one A mixture of (I H^^fl^δS -δ-benzyl^-ffS.δ-bis rifluoromethy phenylJmethoxyJ-l- phenyl-δ-azabicyclo[3.2.1]octan-6-one (Example 41 ; 53mg 0.1 mmol), 5% palladium on charcoal (230mg, 0.11 mmol) ethanol (10ml) was stirred under hydrogen atmosphere (1atm) at room temperature for 45 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI and recrystallised from dichloromethane:diethyl ether, m/z (ES⁺) 444 [M+H]⁺.

EXAMPLE 43 (Iff^^ff^δS^eS^-δ-Benzyl^-itS^-bis rifluo omethy henyllmethoxyj-l- phenyl-8-azabicyclo[3.2.1]octan-6-ol Sodium borohydride (55mg, 1.44mmol) was added to a stirred solution of (1 H^H^δS^-δ-benzyl^-llS.δ-bis^rifluoromethy phenyljmethoxyJ-l -phenyl-8- azabicyclo[3.2.1]octan-6-one (Example 41; δOmg 0.09mmol) in methanol (3ml) at +5°C. The reaction mixture was stirred for 15 minutes and quenched with saturated aqueous NaHCO₃ and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 10-45%) to give the title compound (35mg, 70%). δ_H (360 MHz, CDCI₃): 7.74 (1H, s), 7.72 (2H, s), 7.63 (2H, d, J7.7Hz), 7.40-7.27 (6H, m), 7.27-7.17 (2H, m), 4.37 (1H, d, J 13.0Hz), 4.63 (1 H, m), 4.63 (1H, d, J 13.0Hz), 4.21 (1H, br s), 4.16 (1H, d, J 15.1 Hz), 3.δδ (1H, d, 15.4Hz), 3.33 (1 H, br d, J 5.3Hz), 2.26 (1 H, dd, J 10.9Hz, 13.7Hz), 2.31 (1 H, m), 2.21 -2.03 (2H, m), 1.76 (1H, dd, J 4.2Hz, 13.7Hz), 1.72 (1H, br), 1.46 (1H, m).

EXAMPLE 44 (1ff*2ff*5S*,6S^-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8- azabicyclo[3.2.1]octan-6-ol

A mixture of (1H*,2H*5S*,6S^*)-δ-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-δ-azabicyclo[3.2.1]octan-6-ol (Example 43; 3δmg 0.06δmmol), 6% palladium on charcoal (1δ0mg, 0.07mmol) ethanol (10ml) was stirred under hydrogen atmosphere (1atm) at +6δ°C for 1 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI and recrystallised from iso- hexane:diethyl ether, m/z (ES⁺) 446 [M+Hf.

EXAMPLE 45

(1ff*2ff*5S*,6S -8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6- methoxy-1 -phenyl-8-azabicyclo[3.2.1 Toctane

A mixture of (1 H*2H*,5S*,6S 8-benzyl-2-{[3,δ- bis(trif luoromethyl)phenyl]methoxy}-1 -phenyl-δ-azabicyclo[3.2.1 ]octan-6-ol (Example 43; 22mg 0.041 mmol), methyl iodide (0.6ml), sodium hydride (40mg, 1mmol) and THF (2ml) was stirred at room temperature for 24 hours, quenched quenched with saturated aqueous NH₄Cl and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by preparative TLC on silica gel (iso-hexane:diethyl ether 30%) to give the title compound (17mg, 76%). δ_H (360 MHz, CDCI₃): 7.74 (1H, s), 7.72 (2H, s), 7.63 (2H, d, J7.7Hz), 7.41-7.13 (8H, m), 4.δ6 (1H, d, J 13.0Hz), 4.56 (1H, d, J 13.0Hz), 4.19 (1H, d, J 15.4Hz), 4.1 δ (1 H, br d, J3.δHz), 4.11 (1 H, dt, J4.9Hz, 10.6Hz), 3.38 (1H, d, J 15.4Hz), 3.50 (1H, br s), 3.33(3H, s), 2.36-2.25 (1H, m), 2.29 (1H, dd, J 10.6Hz, 13.7Hz), 2.18-1.99 (2H, m), 1.77 (1H, dd, J4.2Hz, 13.7Hz), 1.72 (1H, br), 1.34 (1 H, m).

EXAMPLE 46 (1ff*,2ff*5S*6S^,,)-2-{[3₅5-Bis(trifluoromethyl)phenyl]methoxy}-6-methoxy-1- phenyl-8-azabicyclo[3.2.1]octane A mixture of (1 R*2fl*,δS*,6S 3-benzyl-2-{[3,δ- bis(trifluoromethyl)phenyl]methoxy}-6-methoxy-1-phenyl-8- azabicyclo[3.2.1]octane (Example 45; 17mg, 0.031 mmol), 5% palladium on charcoal (106mg, O.Oδmmol) ethanol (10ml) was stirred under hydrogen atmosphere (1atm) at +65°C for 1 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound. δ_H (400 MHz, MeOH-d₄): 7.30 (1H, s), 7.56 (2H, s), 7.45-7.35(3H, m), 7.29-7.23 (2H, m), 4.70 (1H, d, J 12.6Hz), 4.31 (1H, m), 4.21 (1H, d, J 12.6Hz), 4.13 (1 H, dt, J 2.9Hz, 6.4Hz), 3.91 (1H, t, J 2.0Hz), 3.47 (3H, s), 2.62 (1H, dd, J4.7Hz, 14.6Hz), 2.55 (1H, dd, J9.9Hz, 14.6Hz), 2.33 (1H, tdd, J 4.1 Hz, 7.3Hz, 13.7Hz), 2.14-1.97 (3H, m).

EXAMPLE 47

(1ff*,2ff*,5S*,6ff'^,)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-formyl-1- phenyl-8-azabicyc!o[3.2.1]octane

(1H^*,2H^*,5S*,6H^],)"2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-hydroxymethyl-1- phenyl-δ-azabicyclo[3.2.1]octane (Example 29; 1.3δg, 2.5mmol) in dichloromethane (6ml) at room temperature was treated with Dess-Martin periodinane (1.07g, 2.5mmol) and stirred for 1 hour. The mixture was treated with 5% sodium hydrogen sulfite (50ml) and saturated sodium hydrogen carbonate (30ml) and stirred for 5 minutes. The organics were collected, washed with brine, dried (MgSO₄) and concentrated in vacuo to afford the title compound as a yellow foam (1.24g, 91 %). m/z (ES⁴) 566 ([M+H₃0f)

EXAMPLE 48 (1ff*,2ff*5S*,6ff^,,)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-((1- methylpyrrolid-2-on-5-yl)methyl)aminomethyl-1 -phenyl-8- azabicyclo[3.2.1]octane hydrochloride

(1H*2H*,5S*6H δ-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-formyl- 1-phenyl-δ-azabicyclo[3.2.1]octane (benzyl derivative of Example 47; 125mg, 0.23mmol) and 5-aminomethyl-1-methylpyrrolidin-2-one (93mg, 0.46mmol) in dichloroethane were stirred for 16 minutes, and treated with sodium triacetoxyborohydride (97mg, 0.46mmol). The mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate. The organics were collected, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 6%methanol/dichloromethane. The title compound was isolated as a clear oil and debenzylated as described previously, m/z (ES⁺) 670 ([M+H]⁺). Prepared in an analogous manner were the following four compounds:

EXAMPLE 49 (1ff*_J2ff*5S*6ff^! -2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(1-(3- methoxy)propyl)aminomethyl-1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride m/z (ES⁺) 531 ([M+H]⁺).

EXAMPLE 50 (1 ff *,2ff*,5S* 6ff*)-2-{[3,5-Bis(trif luoromethyl)phenyl]methoxy}-6-(1 - morpholinyl)methyl-1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride m/z (ES⁺) 529 ([M+Hf).

EXAMPLE 51 (1ff*2 ?*₅5S*6ff^If)-2-{[3₅5-Bis(trifluoromethyl)phenyl]methoxy}-6-(piperizin-3- on-1-yl)methyl-1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride m/z (ES⁺) 542 ([M+H]⁺).

EXAMPLE 52 (1ff*,2ff*5S*6ff 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-[(3-methyl- 3-ethoxycarbonyl)piperidin-1-yl]methyl-1-phenyI-8-azabicyclo[3.2.1]octane hydrochloride m/z (ES⁺) 613 ([M+Hf).

EXAMPLE 53

(1ff*2ff*5S*6ff 8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1- phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid trifluoroacetate

A mixture of (1 r?^*2r?^*,5S*,6r? -8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-6-(tøt -butoxycarbonyl)-1-phenyl-3- azabicyclo[3.2.1]octane (Example 24; 3.37g, 5.43mmol), trifluoroacetic acid (4ml) and dichloromethane (6ml) was stirred at reflux for 4.5 hour then concentrated in vacuo to give crude title compound which crystallised from dichloromethane. δ_H (360 MHz, MeOH-αQ: 7.36 (1H, s), 7.69 (2H, s), 7.60-7.39 (10H, m), 74.93 (1 H, br), 4.δ9 (1 H, d, J 13.0Hz), 4.60 (1 H, d, J 12.6Hz), 4.22 (1 H, br s), 4.07 (1 H, d, J 13.7Hz), 3.33 (1H, d, J 14.0Hz), 3.61 (1H, br s), 2.67 (1H, dd, J3.9Hz, 9.5Hz), 2.41-2.30 (1H, m), 2.35 (1H, dd, J 9.δHz, 14.0Hz), 2.16 (1H, dd, J 5.6Hz, Iδ.δHz), 2.03 (1H, dd, J4.2Hz, 14.0Hz), 1.96 (1H, m), 1.27 (1H, m).

EXAMPLE 54 (1ff*2f?*5S*,6ff 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-hydroxy-1- phenyl-8-azabicyclo[3.2.1]octane hydrochloride Triphenylthioantimonate in anhydrous ether (5ml) under nitrogen was treated with the ester prepared from (1 R^H^δS^δR^-δ-benzyl^-ICS^- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-δ-azabicyclo[3.2.1]octan-6- carboxylic acid (free base of Example 53) and N-hydroxy-4-methylthiazolinethione (by the procedure published in the Journal of Organic Chemistry, 1993, 58, 2468- 2477, Overman et al) in anhydrous ether (5ml) and stirred for 5 minutes. The flask was then opened to the atmosphere and stirred for 3 hours. The mixture was passed through a plug of Celite™, and the filtrate washed with 10% potassium carbonate solution. The organic layer was collected and the aqueous washed with ether. The combined organics were dried (MgSO₄), filtered and concentrated in vacuo The residue was purified by flash column chromatography eluting with 0-5% methanol/dichloromethane to afford a clear oil, 153mg, 77%. Debenzylation by the method described previously and subsequent crystallisation from diethylether/hexane gave the title compound, m/z (ES⁺) 446 ([M+Hf).

EXAMPLE 55 (1ff*2ff*,5S*6ff^5l)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-cyano-1- phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octane Sodium hydride (60% in oil, 10Omg, 2.5mmol) was added to a stirred mixture of 1 R*,2R*,5S*,6R*)-6-cyano-l -phenyl-3-(prop-2-enyl)-δ~azabicyclo[3.2.1 ]octan-2-ol (Description 24; 400mg, 1.49mmol), 3,δ-bis(trifluoromethyl)benzyl bromide (1ml, δ.45mmol) and 18-crown-6 (87mg, 0.33mmol) in THF (5ml) at room temperature. The reaction mixture was stirred for 22 hours, quenched with water and extracted into dichloromethane. The combined organic extracts were washed with water, dried (Na^SO,,) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (530mg, 72%). δ_H (360 MHz, CDCI₃): 7.74 (1H, s), 7.49-7.40 (2H, m), 7.39-7.31 (2H, m), 7.27 (1H, m), 5.δ3 (1H, m), 6.33 (1H, dm, J 17.4Hz), 5.13 (1H, dm, J 11.2Hz), 4.73 (1 H, d, J 12.6Hz), 4.46 (1 H, d, J 12.6Hz), 4.00 (1 H, br s), 3.97 (1 H, br s), 3.50 (1H, dd, J 7.0Hz, 16.1 Hz), 3.27 (1H, dm, J 16.1 Hz), 2.δ9 (1H, dd, J4.6Hz, 9.1Hz), 2.36 (1H, dd, J9.5Hz, 13.7Hz), 2.16 (1H, dd, J4.6Hz, 13.7Hz), 2.11 (1 H, m), 1.77 (1H, m), 1.30 (1 H, m).

EXAMPLE 56 (1ff*2ff*5S*6ff 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-cyano-1- phenyl-8-azabicyclo[3.2.1]octane Tetrakis(triphenylphosphine)palladium(0) (64mg, O.Oδδmmol) was added to a stirred mixture of (1 R^*,2R*,5S^*, 6H")-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6- cyano-1-pheny]-3-(prop-2-enyl)-δ-azabicyclo[3.2.1]octane (Example 55; 500mg, 1.01 mmol), 1 ,3-dimethylbarbituric acid (465mg, 3.0mmol) in dichloromethane (1 Oml) at room temperature. The reaction mixture was stirred at 30-36°C for 90 minutes and treated with 2M aqueous NaOH (10ml). The mixture was stirred for 5 minutes, then diluted with water (30ml) and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 10-40%) to give the title compound (392mg, 65%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI. m/z (ES⁺) 455 [M+Hf.

EXAMPLE 57 (1ff*2ff*,5S*7S^il)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-7-cyano-1- phenyI-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octane Sodium hydride (60% in oil, 28mg, 0.7mmol) was added to a stirred mixture of 1 ?*,2H^*,5S*,7S*)-7-cyano-1 -phenyl-δ-(prop-2-enyl)-δ-azabicyclo[3.2.1 ]octan-2-ol (Description 26; 50mg, O.lδmmol), 3,5-bis(trifluoromethyl)benzyl bromide (0.6ml, 3.27mmol) and 1δ-crown-6 (3δmg, 0.14mmol) in THF (4ml) at room temperature. The reaction mixture was stirred for 20 hours, quenched with brine and extracted into dichloromethane. The combined organic extracts were washed with water, dried (Na^SOJ and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (68mg, 74%). δ_H (360 MHz, CDCI₃): 7.71 (1 H, s), 7.51 (2H, s), 7.39 (2H, m), 7.39 (3H, m), 7.32 (2H, m), 5.67 (1H, dddd, J4.3Hz, 6.6Hz, 10.2Hz, 17.2Hz), 5.26 (1H, ddt, J 1.6Hz, 2.0Hz, 17.2Hz), 5.12 (1H, ddt, J 1.2Hz, 2.0Hz, 10.2Hz), 4.65 (1H, d, J 12.5Hz), 4.35 (1H, d, J 12.5Hz), 3.93 (1H, br s), 3.76 (1H, dt, J 3.1 Hz, 6.6Hz), 3.54 (1H, dd, J 6.6Hz, 16.0Hz), 3.37 (1H, dm, J 16.0Hz), 2.99 (1H, dd, Jδ.δHz, 9.3Hz), 2.42 (1H, m), 2.22 (1H, dd, J9.4Hz, 12.9Hz), 2.19-2.01 (2H, m), 1.82 (1H, dddd, J3.9HZ, 5.9Hz, 12.9Hz, 15.3Hz), 1.19 (1H, ddd, J2.0Hz, 5.1Hz, 13.7Hz).

EXAMPLE 58 (1fl*,2ff*5S*7S 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-7-cyano-1- phenyl-8-azabicyclo[3.2.1]octane

Tetrakis(triphenylphosphine)palladium(0) (13mg, 0.011 mmol) was added to a stirred mixture of (1 f?*2f?*,5S*,7S^-2-{[3,δ-bis(trifluoromethyl)phenyl]methoxy}-7- cyano-1-phenyl-δ-(prop-2-enyl)-δ-azabicyclo[3.2.1]octane (Example 57; 63mg, 0.14mmol), 1 ,3-dimethylbarbituric acid (70mg, O.δmmol) in dichloromethane (3ml) at room temperature. The reaction mixture was stirred at 30-35°C for 1 hour and treated with 2M aqueous NaOH (5ml). The mixture was stirred for 5 minutes, then diluted with water (30ml) and extracted into dichloromethane. The combined organic extracts were dried (Na_;,SO₄) and concentrated. The residue was purified by chromatography on silica gel to give the title compound (37mg, 60%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI. m/z (ES⁺) 455 [M+Hf

EXAMPLE 59 (1 ?*2ff*5ff 8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1- phenyl-8-azabicyclo[3.2.1]octane

(1 β*2H*5H 8-Benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 1.69g, 3.90mmol) in THF (2δml) at 0°C was treated with sodium hydride (217mg, 9.02mmol) and allowed to warm to room temperature. The mixture was recooled to 0°C then 3,δ-bis(trifluoromethyl)benzyl bromide added and the mixture heated to 50°C overnight. The mixture was poured into water then extracted with ethyl acetate (x2), dried (MgSO₄) and concentrated in vacuoXo give a yellow oil. This was purified by flash column chromatography [5% ethyl acetate in iso-hexane] to give the title compound as a yellow oil (1.43g, 61%). m/z (ES⁺) 520 ([M+Hf).

EXAMPLE 60 (1 ff * 2ff * 5ff 2-{[3,5-Bis(trif luoromethyl)phenyl]methoxy}-1 -phenyl-8- azabicyclo[3.2.1 ]octane

(1 H*,2H^*5H^-δ-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8- azabicyclo[3.2.1]octane (Example 59; 1.21g, 2.33mmol) was dissolved in ethyl acetate (20ml) then 10% palladium hydroxide(0.13mg) added. Glacial acetic acid (2ml) was added and the mixture hydrogenated at room temperature at 40psi overnight. The reaction mixture was filtered then concentrated in vacuo. The yellow oil was basified (saturated sodium hydrogen carbonate solution), and the solution extracted with dichloromethane (x3), dried (MgSO₄) and concentrated in vacuo to give a yellow oil. The reaction mixture was purified by flash column chromatography [5% - 16% methanol in dichloromethane] to give the title compound as a yellow oil (0.80g, δ0%). m/z (ES⁺) 430 ([M+Hf).

EXAMPLE 61 (1 ff * 2ff * 5ff *)-2~{[3,5-Bis(trif luoromethyI)phenylJmethoxy}-8-methyl-1 - phenyl-8-azabicyclo[3.2.1]octane hydrochloride

(I R^^R^δH^^-ifS.δ-Bis rifluorometh phenyπmethoxyJ-l-phenyl-δ- azabicyclo[3.2.1]octane (Example 60; 117mg, 0.27mmo!) was dissolved in dimethylformamide (2ml) and potassium carbonate (149mg, I .Oδmmol) and methyl iodide (0.02ml, 0.32mmol) added and the mixture stirred at room temperature for 1 hour. The reaction mixture was poured into water then extracted with ethyl acetate (x2), dried (MgSO₄), and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [7.5% - 10% methanol in dichloromethane] to give a yellow oil. The oil was dissolved in diethyl ether (2ml) and 1 equivalent of 1 hydrogen chloride in diethyl ether added to give the title compound as a yellow solid which was filtered and dried at 60°C in vacuo. m/z (ES⁺) 444 ([M+H]⁺).

EXAMPLE 62 (1 ff *,2ff * 5ff 2-{[3,5-Bis(trif luoromethyl)phenyl]methoxy}-1 -phenyl-8-[(1 ,2,4- triazol-3-yl)methyl]-8-azabicyclo[3.2.1]octane hydrochloride (1 R*,2R*, 5H 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1 -phenyl-8- azabicyclo[3.2.1]octane (Example 60; 202mg, 0.47mmol), N-formyl-2- chloroacetamidrazone (δ2mg, O.δ2mmol) and potassium carbonate (260mg, 1.δδmmol) were stirred in dimethylformamide (2ml) at 60°C for 1 hour. The reaction mixture was poured into water and extracted with dichloromethane (x3), dried (MgSO₄) and concentrated in vacuo. The crude oil was dissolved in toluene and heated at 120°C overnight. The reaction mixture was poured into water and extracted with ethyl acetate (x3), dried (MgSO₄), and concentrated in vacuo. The brown oil was purified by flash column chromatography [5% methanol in dichloromethane] to give an orange oil which when triturated with diethyl ether gave a cream-coloured foam. The foam was dissolved in diethyl ether and 1 equivalent of 1 N hydrogen chloride in diethyl ether added to give the hydrochloride salt which was dried at 60°C in vacuo. m/z (ES⁺) 511 ([M+H]⁺).

EXAMPLE 63

(1 ff * 2ff * 5ff *)-2-{[3,5-Bis(trif luoromethyl)phenylJmethoxy}-1 -pheny l-8-[(1 ,2,4- triazol-3-on-5-yl)methyl]-8-azabicyclo[3.2.1]octane hydrochloride

(1 H*2f?*5H^-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8- azabicyclo[3.2.1]octane (Example 60; 1δ0mg, 0.42mmol), N-methoxycarbonyl-2- chloroacetamidrazone (1 2mg, 0.74mmol), and potassium carbonate were heated in dimethylformamide (2ml) at 60°C for 1 hour. The reaction mixture was poured into water then extracted with dichloromethane (x3), dried (MgSO₄), and concentrated in vacuo. The crude oil was dissolved in toluene and heated at 120°C overnight. The reaction mixture was poured into water and extracted with ethyl acetate (x3), dried (MgSO₄), and concentrated in vacuoXo give a brown solid. This was purified by lobar chromatography [6%methanol in dichloromethane] to give a yellow solid. The solid was dissolved in diethyl ether and 1 equivalent of hydrogen chloride in diethyl ether added to give the hydrochloride salt which was filtered off and dried at 60°C in vacuo. m/z (ES⁺) 627 ([M+Hf).

EXAMPLE 64 (1ff*2ff*5ff 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-8-(2- bromoacetyl)-1 -phenyl-8-azabicyclo[3.2.1 ]octane

(1 ?*2H^*,5ff 2-{[3,δ-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-δ- azabicyclo[3.2.1]octane (Example 60; 162mg, 0.33mmol) was dissolved in THF (3ml) and triethylamine (0.069ml, 0.42mmol) added. The reaction mixture was cooled to 0°C then bromoacetyl bromide (0.037ml, 0.42mmol) added, then the mixture warmed to room temperature. A further 1.1 equivalents of triethylamine (0.069ml), and bromoacetyl bromide (0.037ml) were added and the reaction mixture stirred at room temperature for 16 minutes. The reaction mixture was poured into water, extracted with ethyl acetate (x3), dried (MgSO₄), and concentrated in vacuo to give the title compound. δ_H (360 MHz, CDC J:, 7.δ0 (1H, s), 7.72 (2H, s), 7.66-7.46 (2H, m), 7.34-7.32 (2H, m), 7.19 (1H, m), 5.00 (1H, br s), 4.δ2 (1H, d, J 12.0Hz), 4.65 (1H, d, J 12.0Hz) , 4.29 (1 H, br s), 3.21 (1 H, d, J 11.7 Hz), 3.05 (1 H, d, J 11.δ Hz), 2.29- 1.99 (6H, m), 1.71 (1H, m), 1.46-1.42 (1H, m).

EXAMPLE 65 (1ff*,2ff*5ff^-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8- (pyrrolidin-1 -yl)acetyl-8-azabicyclo[3.2.1 loctane (1 ff*,2H*,5H^,t)-2-{[3,δ-Bis(trifiuoromethyl)phenyl]methoxy}-8-(2-bromoacetyl)-1- phenyl-δ-azabicyclo[3.2.1]octane (Example 64; 143mg, 0.26mmol) was stirred with pyrrolidine (0.024ml, 0.29mmol), and triethylamine (0.040ml, 0.29mmol) in THF (2ml) for 4 hours. The reaction mixture was concentrated in vacuo then purified by flash column chromatography [10% methanol in dichloromethane] to give a brown oil which when triturated in diethyl ether gave a pale brown solid. The solid was dissolved in diethyl ether and 1 equivalent of !N hydrogen chloride in diethyl ether added to a solution in diethyl ether to give the hydrochloride salt which was filtered off and dried in vacuo at 60°C. m/z (ES⁺) 541 ([M+H]⁺).

EXAMPLE 66 (1ff*2ff*5ff -2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-8-[5- dimethylaminomethyl-(1,2₅3,triazo-4-yl)methyl]-1-phenyl-8- azabicyclo[3.2.1]octane hydrochloride

To (1 R *,2ff*,5R^ϊi)-8-(4-azidobut-2-ynyl)-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-δ-azabicyclo[3.2.1]octane (Description 27; 256mg, 0.54mmol) in 1 ,4-dioxane (3ml) was added an excess of dimethylamine. The reaction mixture was heated at δO°C in a sealed tube for 3 hours after which the reaction was cooled and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [5% - 20% methanol in dichloromethane] to give a brown solid. The solid was triturated in diethyl ether and the hydrochloride salt made by adding 1 equivalent of hydrogen chloride in diethyl ether (1N). The solid was filtered off and dried at 60°C in vacuo. (65mg, 20%). m/z (ES⁺) 668 ([M+H]⁺).

EXAMPLE 67 (1ff*2ff*5ff 2-{[3,5-Bis(trifluoromethyl)phenyI]methoxy}-8-(2- hydroxyethyl)-1-phenyI-8-azabicyclo[3.2.1]octane hydrochloride

(1 H*,2H*,5ff^-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8- azabicyclo[3.2.1]octane (Example 60; 345mg, O.δOmmol) was dissolved in dimethylformamide (3ml) and potassium carbonate (331 mg, 2.40mmol) added. This was stirred for 5 minutes at room temperature then 2-bromoethanol (O.Oδδml, 1.21 mmol) added and the reaction mixture heated for 5 days at 60°C. Only a small amount of starting material had converted to product so a further 25 equivalents of 2-bromoethanol (1.42ml, 20mmol) was added and the temperature increased to δ0°C overnight. The reaction mixture was poured into water and extracted with ethyl acetate (x3), dried (MgSO₄) and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [5% -20% ethyl acetate in iso-hexane] to give a yellow oil and the hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether (1N). The title compound was filtered off and dried at 60°C in vacuo. m/z (ES⁺) 474 ([M+Hf).

EXAMPLE 68 (1ff*,2ff*5ff^-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-8-(2- mesyloxyethyl)-1 -phenyI-8-azabicyclo[3.2.1]octane

(1 ff*,2ff*,5 ^:? -2-{[3₎5-Bis(trifluoromethyl)phenyl]methoxy}-8-(2-hydroxyethyl)-1- phenyl-3-azabicyclo[3.2.1]octane (Example 67; 173mg, 0.37mmol) was dissolved in dichloromethane (2ml) and cooled to 0°C. Triethylamine (0.062ml, 0.44mmol) was added followed by methanesulphonyl chloride (0.029ml, 0.37mmol). The mixture was extracted between water and dichloromethane (x3) and the organics dried (MgSO₄) and concentrated in vacuo to give the title compound as a clear oil (201 mg, 100%). m/z (ES⁴) 492 ([M+Hf).

EXAMPLE 69

(1ff*,2ff*5ff^!l)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-{2- (1 ,2,4-triazoM -yl)ethyl}-8-azabicyclo[3.2.1 ]octane hydrochloride

1 ,2,4-Triazole (25mg, 0.37mmol) was dissolved in acetonitrile (2mi) and sodium hydroxide (44mg, 1.11 mmol). This was stirred at room temperature for 30 minutes then tetrabutylammonium hydrogen sulphate and (1 ff^H^δH ^-fP.δ- bis(trifluoromethyl)phenyl]methoxy}-δ-(2-mesyloxyethyl)-1-phenyl-δ- azabicyclo[3.2.1]octane (Example 6δ; 201 mg, 0.37mmol) added. The reaction was heated to reflux for 2.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x3), dried (MgSO₄), and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [5% methanol in dichloromethane] to give a brown oil and the hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether (1 N) and the title compound filtered off and dried in vacuo at 60°C. m/z (ES⁺) 62δ ([M+Hf).

EXAMPLE 70 (1 ff * 2ff * 5ff *)-8-Benzyl-2-{(1 S*)-1 -[3,5-bis(trif luoromethyl)phenyl]- (methoxycarbonyl)methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane

Slow addition of methyl 2-diazo-2-(3,5-bis(trifluoromethyl)phenyl)acetate (604mg, 1.61 mmol) as a solution in benzene (3ml) to (1 ff*2ff^*5ff^-δ-benzyl-1-phenyl-δ- azabicyclo[3.2.1]octan-2-ol (Description 9; 430mg, 1.47mmol) in benzene (3ml) was carried out in the presence of catalytic rhodium acetate (5mg) at reflux under N₂. The reaction mixture was concentrated in vacuo to give a green oil then purified by flash column chromatography [15% ethyl acetate in iso-hexane] to give the title compound as a yellow oil (mainly 1 isomer) (735mg, 37%). m/z (ES⁺) 57δ ([M+Hf).

EXAMPLE 71

(1 ff * 2ff *,5ff *)-2-{(1 S*)-1 -[3,5-Bis(trif luoromethyl)phenyl]- (methoxycarbonyl)methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane

(1 H*2H*,5ff*)-δ-Benzyl-2-{(1 S 1 -[3,5-bis(trifluoromethyl)phenyl]- (methoxycarbonyl)methoxy}-1 -phenyl-δ-azabicyclo[3.2.1 ]octane (Example 70; 73δmg, 1.27mmol) was dissolved in ethyl acetate (10ml) with glacial acetic acid (O.δml) and 10% palladium hydroxide (40mg) added. The mixture was hydrogenated on a Parr™ at 40psi overnight. The mixture was filtered through Celite™, then concentrated in vacuo and the residue basified with saturated sodium hydrogen carbonate solution. The solution was then extracted with ethyl acetate (x3) and the extracts dried (MgSO₄) and concentrated in vacuo. The obtained oil was purified by flash column chromatography [10% methanol in dichloromethane] to give the title compound as a yellow oil. (6:1 desired:undesired). (323mg, 62%). m/z (ES⁺) 4δδ ([M+Hf). EXAMPLE 72 (1 ?*2 ?*,5 ? 2-{(1 S*)-1-[3,5-Bis(trifluoromethyl)phenyl]- (methoxycarbonyl)methoxy}-1-phenyl-8-[(1,2,4-triazol-3-on-5-yl)methyl]-8- azabicyclo[3.2.1]octane (1 R*,2R*,SR*)-2-{( S^*)-1 -[3,5-Bis(trif luoromethyl)phenyl]-

(methoxycarbonyl) methoxy}- 1 -phenyl-8-azabicyclo[3.2.1]octane (Example 71 ; 323mg, 0.66mmol), potassium carbonate (365mg, 2.64mmol), and N-methoxycarbonyl-2-chloroacetamidrazone (192mg, 1.16mmol) were heated at 60°C in dimethylformamide for 1 hour. The reaction mixture was then cooled and washed with water (20ml) and extracted with ethyl acetate (x2), dried (MgSO₄) and concentrated in vacuo to give an orange oil. This was dissolved in toluene (5ml) and heated at 120°C overnight. The reaction mixture was cooled and concentrated in vacuo to give a brown oil which was purified by flash column chromatography [5% methanol in dichloromethane] to give the title compound as an orange solid (164mg, 42%). m/z (ES⁴) 5δ5 ([M+Hf).

EXAMPLE 73 (1 ff * 2ff * 5ff *)-2-{(1 ff Η3,5-Bis(trif Iuoromethyl)phenyI]-2-hydroxyethoxy)-1 - phenyl-8-[(1,2,4-triazol-3-on-5-yl)methyl]-8-azabicyclo[3.2.1]octane hydrochloride

(1 R *,2R*,5R*)-2-{( ff*)-1 -[3,5-Bis(trifluoromethyl)phenyl]- (methoxycarbonyl)methoxy}-1-phenyl-δ-[(1 ,2,4-triazol-3-on-5-yl)methyl]-δ- azabicyclo[3.2.1]octane (prepared from the "undesired" isomer of Example 71 according to the method of Example 72; 164mg, 0.23mmol) was dissolved in diethyl ether (2ml) and sodium borohydride added and the mixture stirred for 2 hours at room temperature. The reaction mixture was then quenched with water and extracted with diethyl ether (x3). The organics were dried (MgSO₄) and concentrated in vacuo to give a yellow solid which was purified by flash column chromatography [5% methanol in dichloromethane] to give a pale yellow solid and the hydrochloride salt made by adding 1 equivalent of hydrogen chloride (1N) in diethyl ether and the title compound filtered off and dried in vacuo at 60°C (53mg, 32%). m/z (ES⁺) 557+([M+Hf).

EXAMPLE 74 (1ff*2ff*5ff*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-[(2- methyl-1 ,2,4-triazol-5-yl)methyI]-8-azabicyclo[3.2.1]octane hydrochloride

(1ff*2ff*5ff^5,)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-δ- azabicyclo[3.2.1]octane (Example 60; 99mg, 0.23mmol) was combined with potassium carbonate (127mg, 0.92mmol) and N-formyI-N-methyl-2- chloroacetamidrazone (59mg, 0.39mmol) in dimethylformamide and heated at δ0°C overnight. A further 0.78mmol (118mg) of amidrazone was added and the mixture further stirred at δ0°C for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate (x3), dried (MgSO₄) and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [5% methanol in dichloromethane] to give a yellow oil. The oil was dissolved in methanol and purified using an SCX cartridge eluting with methanol then 10% ammonia in methanol. The ammonia containing fractions were concentrated to give a brown oil. The hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether (1 N) and the title compound was filtered off and dried at 60°C in vacuo. m/z (ES⁺) 525+([M+Hf).

EXAMPLE 75 (1ff*,2ff*,5S*6ff 8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1- phenyl-8-azablcyclo[3.2.1]octan-6-carboxamide A solution of (1 R*,2R*,5S^*,6R*)-8-benzy\-2-{[3,5- bis(trif luoromethyl)phenyl]methoxy}-1 -phenyl-3-azabicyclo[3.2.1 ]octan-6- carboxylic acid trifluoroacetate (Example 53; 2.7mmol) was treated with ammonia solution in dioxane (0.5M, 10ml, 5mmoI), triethylamine (0.6ml, 4.3mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (960mg, 5.02mmol), and 4-N,N-dimethylaminopyridine (120mg, 1 mmol). The mixture was stirred for 24 hours, diluted with ethyl acetate (100ml), washed with 10% aqueous citric acid, saturated aqueous NaHCO₃, dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (δ50mg, 56%). δ_H (360 MHz, CDCI₃): 7.74 (1H, s), 7.70 (2H, s), 7.δδ (2H, m), 7.42 (2H, m), 7.36- 7.27 (6H, m), 6.72 (1H, br), 4.93 (1H, br), 4.δ9 (1H, d, J 13.0Hz), 4.60 (1H, d, J 12.6Hz), 4.22 (1H, br s), 4.07 (1H, d, J 13.7Hz), 3.δ3 (1H, d, J 14.0Hz), 3.61 (1H, br s), 2.67 (1H, dd, J3.9Hz, 9.5Hz), 2.41-2.30 (1H, m), 2.35 (1H, dd, J9.δHz, 14.0Hz), 2.16 (1H, dd, J5.6Hz, Iδ.δHz), 2.03 (1H, dd, J4.2Hz, 14.0Hz), 1.96 (1H, m), 1.27 (1 H, m).

EXAMPLE 76

(1ff*,2ff*5S*6ff^lf)-8-Benzyl-2-{[3₃5-bis(trifluoromethyl)phenyl]methoxy}-6-[4- methyloxazol-2-yl]-1-phenyl-8-azabicyclo[3.2.1]octane

A mixture of

bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-δ-azabicyclo[3.2.1]octan-6- carboxamide (Example 76; 2δ0mg, 0.44mmol), chloroacetone (1 ml) and

N,N-dimethylforamide (4ml) was stirred at 120°C for 24 hours. After cooling to room temperature the reaction mixture was diluted with diethyl ether (70ml), washed with saturated aqueous NaHCO₃, water and brine. The organic phase was dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (63mg, 12%). δ_H (400 MHz, CDCI₃): 7.76 (1 H, s), 7.73 (2H, s), 7.59 (2H, d, J7.4Hz), 7.37-7.27 (5H, m), 7.26-7.13 (4H, m), 4.64 (1H, d, J 12.9Hz), 4.57 (1H, d, J 12.9Hz), 4.15 (1H, br s), 4.12 (1H, d, J 15.6Hz), 3.δ6 (1H, d, J 15.6Hz), 3.71 (1H, br s), 3.36 (1H, dd, J 4.7Hz, 9.4Hz), 2.67 (1H, dd, J4.3Hz, 13.3Hz), 2.36 (1H, dd, J9.4Hz, 13.7Hz), 2.22 (1H, m), 2.17 (3H, d, J 1.6Hz), 2.15 (1H, m), 2.03 (1H, m), 1.31 (1H, m).

EXAMPLE 77 (1ff*,2ff*5S*6ff^],)-2-{[3,5-Bis(trifluoromethyl)phenyI]methoxy}-6-[4- methyloxazol-2-yl]-1 -phenyl-8-azabicyclo[3.2.1 ]octane

A mixture of (1 H*,2H*5S*,6H 8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-6-[4-methyloxazol-2-yl]-1-phenyl-6- azabicyclo[3.2.1]octane (Example 76; 53mg, 0.09mmol), 10% palladium on charcoal (135mg) ethanol (10ml) was stirred under hydrogen atmosphere (1atm) at +65°C for 30 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated and purified by preparative TLC (dichloromethane:methanol) to give the title compound (3δmg, δ4%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI. m/z (ES⁺) 611 [M+Hf.

EXAMPLE 78

(1R*,2ff*,5S*,6ff^,,)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-[4- methylthioazol-2-yl]-1-phenyl-8-azabicyclo[3.2.1]octane

A mixture of (1 R*,2R *5S*,6S 8-benzyl-2-{[3,δ-bis(trifluoromethyl)ρhenyl]- methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxamide (Example 75; 300mg, 0.53mmol), Lawsson's reagent (128mg) and toluene was stirred at δ0°C for 50 minutes and concentrated in vacuo. The residue was treated with N,N-dimethylforamide (2ml) and chloroacetone (0.4ml) and stirred at 110 C for 20 minutes. After cooling to room temperature the reaction mixture was quenched with saturated aqueous NaHCO₃ and extracted into diethyl ether. The combined organic extracts were washed with water, dried (Na,SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether) to give the title compound (50mg, 1δ%). δ_H (400 MHz, CDCI₃): 7.73 (1H, s), 7.70 (2H, s), 7.61 (2H, d, J 7.0Hz), 7.44 (2H, d, J7.4Hz), 7.34 (4H, m), 7.24 (2H, m), 6.76 (1H, s), 4.73 (1H, d, J 12.9Hz), 4.52 (1H, d, J 12.9Hz), 4.1 δ (1H, br s), 4.20 (1 H, d, J 15.3Hz), 3.91 (1H, d, J 1δ.3Hz), 4.01 (1H, dt, J 6.6Hz, 11.7Hz), 3.77 (1H, t, J 3.1 Hz), 2.66 (1 H, dd, J 7.1 Hz, 13.3Hz), 2.44 (1H, dd, J4.3Hz, 13.3Hz), 2.42 (3H, d, JO.δHz), 2.24-2.03(2H, m), 1.84 (1H, m), 1.15 (1H, m). EXAMPLE 79 (1 ff*2ff*,5S*6ff 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-[4- methylthioazol-2-yI]-1-phenyl-8-azabicyclo[3.2.1]octane

A solution of (1 H^*2ff^*,5S^*,6ff^*)-3-Benzyl-2-{[3,δ-bis(trifluoromethyl)phenyl]- methoxy}-6-[4-methylthioazoI-2-yl]-1 -phenyl-δ-azabicyclo[3.2.1 ]octane (Example 7δ; 50mg, 0.081 mmol) in diethyl ether (2ml) was treated 1 M etheral HCI (0.3ml). The mixture was concentrated in vacuo. The residue was treated with 10% palladium on charcoal (1δ0mg) ethanol (10ml) was stirred under hydrogen atmosphere (1atm) at +65°C for 30 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated and purified by preparative TLC (dichloromethane: methanol) to give the title compound (15mg, 35%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI. m/z (ES⁺) 527 [M+Hf

EXAMPLE 80 (1 ff*2ff*5S*6ff^-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(fert- butoxycarbonyl)-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1J ctane A mixture of (1 R*,2R*, 5S*,6ff^,l)-2-{ 3,δ-bis(trifluoromethyl)phenyl]methoxy}-6-(fer.- butoxycarbonyl)-1-phenyl-δ-azabicydo[3.2.1]octane (Example 26; 424mg, O.δmmol), potassium carbonate (770mg), allyl bromide (0.5ml) and N,N-dimethylforamide (3ml) was stirred at room temperature for 3 days. The reaction mixture was treated withl :1 mixture diethyl etheπiso-hexane, washed with water, dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether) to give the title compound (362mg, 79%). δ_H (400 MHz, CDCI₃): 7.71 (1H, s), 7.53 (2H, s), 7.43 (2H, m), 7.31 (2H, m), 7.23 (1 H, m), 5.δ6 (1 H, dddd, J δ.1 Hz, 6.3Hz, 10.2Hz, 16.8Hz), 5.19 (1 H, ddt, J 1.6Hz, 2.0Hz, 17.2Hz), 5.07 (1 H, ddt, J 1.5Hz, 1.δHz, 10.2Hz), 4.63 (1 H, d, J 12.9Hz), 4.34 (1 H, d, J 12.9Hz), 3.32 (1 H, br s), 3.75 (1 H, br d, J 6.6Hz), 3.54 (1 H, ddt, J 1.2Hz, 6.5Hz, 15.6Hz), 3.31 (1H, dt, J 6.2Hz, 12.3Hz), 3.03 (1H, ddt, J 1.6Hz, J 5.4Hz, 15.7Hz), 2.40 (1 H, dd, j 6.0Hz, 13.7Hz), 2.02 (1 H, dd, J 9.0Hz, 13.3Hz), 2.10-2.01 (3H, m), 1.67 (1H, dd, J2.5Hz, 9.4Hz), 1.49 (9H, s), 1.44 (1H, d, J δ.2Hz).

EXAMPLE 81 (1ff*,2ff*,5S*,6ffS^,,)-2-{[3₅5-Bis(trifluoromethyl)phenyl]methoxy}-6-(feιf- butoxycarbonyl)-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.13octane

A solution of potassium bis(trimethylsilyl)amide in toluene (0.5M, 1.5ml, 0.75mmol) was added to a stirred solution of (1 R^*,2R ^*,5S*,6R -2-{[3,5- bis(trifluoromethyl)-phenyl]methoxy}-6-(tørt-butoxycarbonyl)-1-phenyl-8-(prop-2- enyl)-8-azabicyclo[3.2.1]octane (Example δO; 362mg, 0.635mmol) in THF (5ml) at +5°C. The mixture was stirred for 16 minutes and quenched with saturated aqueous NH₄Cl and extracted into diethyl ether. The organic extracts was washed with water, dried (Na₂SO₄) and concentrated to give the title compound as a 4.6:1 mixture diastereoisomers. δ_H (400 MHz, CDCI₃): 7.72 (1H, s), 7.62 (2H, s), 7.46 (2H, m), 7.31 (2H, m), 7.23 (1H, m), δ.76 (1H, dddd, J4.3Hz, 6.7Hz, 10.6Hz, 17.2Hz), δ.22 (1H, dm, J 17.0Hz), 6.03 (1H, dm, J 10.3Hz), 4.71 (1H, d, J 12.9Hz), 4.44 (1 H, d, J 12.9Hz), 3.96 (1H, dd, J 1.4Hz, 3.6Hz), 3.39 (1H, t, J2.4Hz), 3.46 (1H, ddt, J 1.1 Hz, 6.7Hz, 16.0Hz), 3.12 (1H, ddt, J2.0Hz, 3.9Hz, 15.9Hz), 2.73 (1H, dd, J4.7Hz, 9.4Hz), 2.33 (1H, dd, J 5.0Hz, 13.3Hz), 2.13 (1H, m), 2.03 (1H, dd, J 9.6Hz, 13.3Hz), 1.88 (1H, m), 1.47 (9H, s), 1.27 (1H, m).

EXAMPLE 82 (1ff*2ff*5S*6ff 8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1- phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid 2-acetylhydrazide

A mixture of (1 ?*2ff *,5S*6HS")-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6- (terf-butoxycarbonyl)-l -phenyl-8-(prop-2-enyl)-δ-azabicyclo[3.2.1 ]octane (Example 31), trifluoroacetic acid (4ml) and dichloromethane (6ml) was stirred at room temperature overnight and concentrated in vacuo. The residue was treated with acetic hydrazide (164mg, 2.21 mmol), triethylamine (0.5ml, 3.6mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (350mg, l.δmmol), and 4-N,N-dimethylaminopyridine (47mg, 0.33mmol). The mixture was stirred for 5 hours, quenched with saturated aqueous NaHCO₃ and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (180mg, 50%). δ_H (360 MHz, CDCI₃): 10.01 (1H, d, J 6.0Hz), 9.10 (1H, d, J 5.3Hz), 7.73 (1H, s), 7.61 (2H, s), 7.43 (2H, m), 7.37 (2H, m), 7.26 (1 H, m), 6.06 (1 H, dddd, J 4.4Hz, 9.0Hz, 9.3Hz, 17.0Hz), 5.16 (1H, dm, J 17.2Hz), 5.12 (1H, dm, J 10.2Hz), 4.78 (1H, d, J 12.9Hz), 4.51 (1H, d, J 12.9Hz), 4.16 (1H, br s), 3.84 (1H, br s), 3.59 (1H, dd, Jδ.δHz, 14.7Hz), 3.47 (1H, ddt, J l.δHz, 4.3Hz, 14.3Hz), 2.77 (1H, dd, J 4.2Hz, 9.5Hz), 2.31 (1H, dd, J9.5Hz, 14.0Hz), 2.20 (1H, m), 2.06 (3H, s), 1.99 (1H, dd, J 4.2Hz, 14.0Hz), 1.93 (1H, m), 1.25 ( H, dd, J4.6Hz, 13.5Hz).

EXAMPLES 83a and 83b (1ff*2ff*,5S*,6ffS^!,)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(5- methyloxa-3,4-diazo-2-yl)-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octane A mixture of (1 R*,2ff*,5S*6H^J<)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]- methoxy}-1-phenyl-δ-azabicyclo[3.2.1]octan-6-carboxylic acid 2-acetylhydrazide (Example 62; 1δ0mg, 0.32mmol), phosphorus pentaoxide (140mg) and xylene (3ml) was stirred at reflux for 3 hours. The mixture was cooled to room temperature, treated with saturated aqueous NaHCO₃ and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso- hexane:ethyl acetate 0-50%) to give the title compounds (6S*-isomer; δ2mg, 47%) and (5f?*-isomer; 34mg, 20%). EXAMPLE 83a - (6S*)-isomer:- δ_H (360 MHz, CDCI₃): 7.73 (1H, s), 7.64 (2H, s), 7.48 (2H, m), 7.33 (2H, m), 7.24 (1H, m), 5.72 (1H, dddd, J4.0Hz, 7.1Hz, 10.5Hz, 17.3Hz), 5.10 (1H, ddt, J 1.4Hz, 2.1Hz, 17.2Hz), 4.98 (1H, ddt, J 1.1 Hz, 2.0Hz, 10.3Hz), 4.78 (1H, d, J 12.6Hz), 4.52 (1H, d, J 12.6Hz), 4.10 (1H, br s), 3.91 (1H, br s), 3.51 (1H, dd, J7.4Hz, 16.1 Hz), 3.43 (1H, dd, J 6.0Hz, 8.4Hz), 3.26 (1H, ddt, J 2.1 Hz, 3.9Hz, 16.8Hz), 2.53 (3H, s), 2.43-2.30 (2H, m), 2.29-2.09 (2H, m), 2.01 (1 H, m), 1.36 (1 H, dd, J 2.6Hz, 5.4Hz, 13.6Hz).

EXAMPLE 83b - (6ff*)-isomer:- δ_H (360 MHz, CDCI₃): 7.71 (1H, s), 7.59 (2H, s), 7.47 (2H, m), 7.34 (2H, m), 7.25 (1H, m), 5.86 (1 H, dddd, J 4.7Hz, 7.0Hz, 10.2Hz, 17.2Hz), 5.20 (1H, ddt, J 1.2Hz, 1.9Hz, 17.3Hz), 5.09 (1 H, ddt, J 1.3Hz, 1.7Hz, 10.3Hz), 4.63 (1H, d, J 12.5Hz), 4.40 (1H, d, J 12.5Hz), 4.00 (1 H, d, J2.3Hz), 3.94 (1H, dt, J 3.5Hz, 6.3Hz), 3.74 (1H, dt, J6.7Hz, 11.7Hz), 3.59 (1H, ddt, J 1.3Hz, 7.0Hz, 15.7Hz), 3.22 (1H, ddt, J 1.9Hz, 4.7Hz, 15.7Hz), 2.71 (1 H, dd, J 6.7Hz, 13.7Hz), 2.53 (3H, s), 2.35 (1H, dd, J 11.7Hz, 13.3Hz), 2.24-2.03 (2H, m), 1.84 (1H, dd, J 4.3Hz, 14.5Hz), 1.01 (1H, ddd, J 2.0Hz, 4.7Hz, 14.1 Hz).

EXAMPLE 84 (1ff*2ff*5S*₅6S 2-{[3,5-B«s(trifluoromethyI)phenyl]methoxy}-6-(5- methy!oxa-3,4-diazo-2-yl)-1 -phenyl-8-azabicyclo[3.2.1 ]octane Tetrakis(triphenylphosphine)palladium(0) (28mg, 0.024mmol) was added to a stirred mixture of (1 ff*,2f?*5S* eS -2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6- (5-methyloxa-3,4-diazo-2-yl)-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octane (Example 83a; 82mg, 1.4δmmol), 1 ,3-dimethylbarbituric acid (130mg, 0.δ4mmol) in dichloromethane (3ml) at room temperature. The reaction mixture was stirred at +40°C for 35 minutes and treated with 2M aqueous NaOH (5ml). The mixture was stirred for 5 minutes, then diluted with water (30ml) and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by preparative TLC on silica gel (dichloromethane:methanol 5%) to give the title compound (75mg, 96%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI. m/z (ES⁺) 512 [M+Hf

EXAMPLE 85 (1 ff * 2ff * 5S*₅6S*)-8-Benzyl-2-{[3,5-bis(trif luoromethyl)phenyl]methoxy}-1 - phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid semicarbazϊde

A mixture of (1 ff^*2fl*,5S*,6S^-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-6-(ferf-butoxycarbonyl)-1-phenyl-δ- azabicyclo[3.2.1]octane (Description 22; 250mg, 0.4mmol), trifluoroacetic acid (O.δml) and dichloromethane (1.2ml) was stirred at room temperature overnight and concentrated in vacuo. The residue was treated with semicarbazide hydrochloride (355mg, 3.2mmol), triethylamine (1ml, 7.2mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (457mg, 4.2mmol), and 4-N,N-dimethylaminopyridine (35mg, 0.28mmol). The mixture was stirred at room temperature over weekend, quenched with saturated aqueous NaHCO₃ and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol:ammonia) to give the title compound (27δmg, 55%). δ_H (360 MHz, CDCI₃): δ.75 (1H, d, J2.5Hz), 7.75 (1 H, s), 7.69 (2H, s), 7.5δ (2H, m), 7.45 (2H, t, J δ.lHz), 7.39-7.22 (6H, m), 6.60 (1H, br), 4.88 (1H, d, J 12.6Hz), 4.61 (1 H, s), 4.60 (1H, d, J 12.6Hz), 4.22 (1H, br s), 4.05 (1H, d, J 13.7Hz), 3.85 (1 H, d, J 13.7Hz), 3.49 (1 H, br s), 2.75 (1 H, dd, J 4.6Hz, 9.8Hz), 2.35 (1 H, dd, J 9.8Hz, 14.0Hz), 2.17 (1H, dd, J5.3Hz, 15.0Hz), 2.04 (1H, dd, J3.9Hz, 14.0Hz), 1.95 (1H, m), 2.06 (3H, s), 1.99 (1H, dd, J4.2Hz, 14.0Hz), 1.28 (1H, m).

EXAMPLE 86 (Iff^ff^δS^βS^-β-Benzyl^-p^-bis^rifluoromethy phenyUmethoxyl-e- (2,4-dihydro-3H-1,2,4-triazol-3-on-5-yl)-1 -pheny l-8-azabicyclo[3.2.1]octane

A mixture of (1 fl^*2ff^*,5S^*6S^-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6- carboxylic acid semicarbazide (Example 85; 273mg, 0.44mmol) and 1 M aqueous NaOH (20ml) was stirred at reflux for 40 minutes. After cooling to room temperature the mixture was acidified using 2M hydrochloric acid, treated with saturated aqueous NaHCO₃ and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The crystalline residue was heated at reflux with a small amount of dichloromethane to give the title compound as a solid (120mg, 45%). δ_H (360 MHz, MeOH-d₄): 7.87 (2H, s), 7.81 (1H, s), 7.65 (2H, m), 7.32 (2H, t, J 7.9Hz), 7.26-7.10 (6H, m), 4.98 (1H, d, J 13.4Hz), 4.67 (1H, d, 13.4Hz), 4.30 (1H, br s), 4.12 (1H, d, J 15.5Hz), 3.79 (1H, d, J 15.5Hz), 3.46 (1H, br s), 3.14 (1H, dd, j 4.2Hz, 9.2Hz), 2.56 (1H, dd, J4.2Hz, 13.7Hz), 2.27 (1H, dd, Jδ.9Hz, 13.4Hz), 2.31-2.03 (3H, m), 1.31 (1H, ddd, J 2.0Hz. 5.0Hz, 13.2Hz). EXAMPLE 87 (1ff*,2ff*5S* 6S'⁽)-2-{[3_J5-Bis(trifluoromethyl)phenyl]methoxy}-6-(2,4- dihydro-3ff-1,2,4-triazol-3-on-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane

A mixture of (1 fl^*,2fl^*,5S^*, 6S*)-8-benzyl-2-{[3,5- bis(trif luoromethyl)phenyl]methoxy}-6-(2,4-dihydro-3H-1 ,2,4-triazol-3-on-5-yl)-1 - phenyl-8-azabicyclo[3.2.1]octane (Example 66; 66mg, 0.11 mmol), 10% palladium on charcoal (1δ0mg), ethanol (10ml) was stirred under hydrogen atmosphere (1atm) at +60°C for 1.5 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI. δ_H (400 MHz, MeOH-d₄): 7.61 (1H, s), 7.57 (2H, s), 7.41 (3H, m), 7.32 (2H, m), 4.73 (1 H, d, J 12.6Hz), 4.36 (1 H, br s), 4.24 (1 H, d, J 12.6Hz), 3.91 (1 H, br s), 3.71 (1 H, dd, J 5.3Hz, 9.6Hz), 3.12 (1H, dd, J9.6Hz, 14.6Hz), 2.73 (1H, dd, J 5.3Hz, 14.6Hz), 2.35-2.10 (3H, m), 1.99 (1H, m).

EXAMPLE 88 1-N,N-Dimethylaminoacetic acid 2-(1 ff*,2ff*5S* 6ff^-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6- carbohydrazide

A mixture of (1 ff*,2ff*5S*6ff 8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-3-azabicyclo[3.2.1]octan-6- carboxylic acid trifluoroacetate (Example 53; 212mg, 0.31 mmol), triethylamine (0.3ml, 2.15mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (226mg, 1.2mmol), 4-N,N-dimethylaminopyridine (20mg, 0.16mmol), N,N- dimethylglycine hydrazide hydrochloride (165mg, 0.97mmol) and dichloromethane (4ml) was stirred at room temperature for one hour and diluted with ethyl acetate. The organic solution was washed with saturated aqueous NaHCO₃, water and brine. The organic layer was dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol) to give the title compound (170mg, 82%). δ_H (360 MHz, CDCI₃): 9.15 (1H, s), 7.75 (1H, s), 7.74 (1H, s), 7.72 (2H, s), 7.46 (2H, t, J 7.2Hz), 7.39 (2H, d, J 7.0Hz), 7.35-7.19 (6H, m), 4.39 (1H, d, J 12.6Hz), 4.63 (1H, d, J 12.6Hz), 4.23 (1H, br s), 4.06 (1H, d, J 13.7Hz), 3.86 (1H, d, J 13.7Hz), 3.51 (1H, br s), 3.09 (2H, s), 2.75 (1H, dd, J3.9Hz, 9.5Hz), 2.36 (1H, dd, J 9.5Hz, 14.0Hz), 2.33 (6H, s), 2.16 (1H, dd, J4.2Hz, 14.4Hz), 1.96 (1 H, m), 1.27 (1H, m).

EXAMPLE 89 (1ff*,2ff*5S*6ff")-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6- [(5-dimethylaminomethyl)oxa-3,4-diazo-2-yl]-1-phenyl-8- azabicyclo[3.2.1]octane A mixture of 1 -N,N-dimethylaminoacetic acid 2-(1 ff *,2R *,5S* 6fi*)-8-benzyl-2- {[3,5-bis(trif luoromethyl)phenyl]methoxy}-1 -phenyl-8-azabicyclo[3.2.1 ]octan-6- carbohydrazide (Example 88; 162mg, 0.24mmol), phosphorus pentaoxide (50mg) and xylene (4ml) was stirred at reflux for 3.5 hours. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous NaHCO₃ and extracted into ethyl acetate. The combined organic extracts were dried (Na,SO₄) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol) to give the title compound (58mg, 37%). δ_H (400 MHz, CDCI₃): 7.76 (1H, s), 7.74 (2H, s), 7.62 (2H, m), 7.33 (2H, t, J 7.8Hz), 7.30-7.12 (6H, m), 4.88 (1H, d, J 12.9Hz), 4.63 (1H, d, J 12.9Hz), 4.22 (1 H, br s), 4.10 (1 H, d, J 15.3Hz), 3.88 (1 H, d, J 15.6Hz), 3.75 (2H, s), 3.67 (1 H, br s), 3.44 (1H, dd, J4.3Hz, 9.4Hz), 2.66 (1H, dd, J4.3Hz, 13.7Hz), 2.40 (1H, dd, J 9.4Hz, 13.7Hz), 2.34 (6H, s), 2.28 (1H, ddt, J2.7Hz, 5.5Hz, 13.3Hz), 2.20 (1H, m), 2.07 (1H, ddd, J3.5Hz, 5.4Hz, 13.1Hz), 1.33 (1H, ddd, J2.3Hz, 5.6Hz, 13.5Hz).

EXAMPLE 90 (1ff*,2ff*,5S* 6ff^!,)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-[(5- dimethylaminomethyl)oxa-3,4-diazo-2-yl]-1-phenyl-8- azabicyclo[3.2.1]octane A mixture of (1

bis(trifluoromethyl)phenyl]methoxy}-6-[(5-dimethylaminomethyl)oxa-3,4-diazo-2- yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Example 89; 58mg, 0.09mmol), 10% palladium on charcoal (121mg), ethanol (20ml) was stirred under hydrogen atmosphere (1 atm) at +6δ°C for 1 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated. The residue was purified by chromatography on silica gel (dichloromethane: methanol) to give the title compound (36mg, 72%). m/z (ES⁺) δδδ [M+Hf.

EXAMPLE 91 (1 ff*2ff*,5S*6ff*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1- phenyl-8-azabicyclo[3.2.1]octan-6-carbohydrazide A mixture of (1 ff*,2ff^*,5S^*,6ff^, -8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6- carboxylic acid trifluoroacetate (Example 53; 1.6g, 2.35mmol), triethylamine (1ml, 7.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (910mg, 4.7mmol), 4-N,N-dimethylaminopyridine (20mg, 0.16mmol), dichloromethane (1δml) and hydrazine (1 M solution in THF, 6ml, 5mmol) was stirred at room temperature over the weekend. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO₃, water and brine. The organic layer was dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol) to give the title compound (1g, 74%). δ_H (400 MHz, CDCl₃): 7.91 (1H, s), 7.74 (1H, s), 7.69 (2H, s), 7.54 (2H, m), 7.43 (2H, t, J 7.4Hz), 7.40-7.27 (6H, m), 4.88 (1H, d, J 12.9Hz), 4.60 (1H, d, J 12.9Hz), 4.21 (1 H, br s), 4.06 (1H, d, J 13.7Hz), 3.86 (1H, d, J 13.7Hz), 3.68 (2H, br), 3.40 (1H, br s), 2.72 (1H, dd, J4.3Hz, 9.8Hz), 2.34 (1H, dd, J9.8Hz, 14.1 Hz), 2.33 (1H, m), 2.15 (1 H, dd, Jδ.δHz, 1δ.7Hz), 1.97 (1H, dd, J3.9Hz, 13.7Hz), 1.94 (1H, m), 1.24 (1H, dd, Jδ.δHz, 13.8Hz).

EXAMPLE 92 (1R*2ff*5S*,ffff^],)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(5- trifluoromethyloxa-3,4-diazo-2-yl)-1-phenyl-8-azabicyclo[3.2.1]octane

A mixture of (1ff*,2ff^*5S^,t,6ff^I,)-8-benzyl-2-{[3,6- bis(trifluoromethyl)phenyl]methoxy}-1 -phenyl-8-azabicyclo[3.2.1 ]octan-6- carbohydrazide (Example 91; 10δmg, 0.18mmol), trifluoroacetic anhydride (0.05ml), triethylamine (0.2ml) and dichloromethane (2ml) was stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated aqueous NaHCO₃ and extracted with dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was treated with xylene (4ml) and phosphorus pentaoxide (60mg) and stirred at reflux for 3 hours. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous NaHCO₃and extracted into ethyl acetate. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue (2.5:1 mixture of diastereoisomers) was purified by chromatography on silica gel (iso- hexane-ethyl acetate 0-40%) to give the title compound (36mg, 30%). δ_H (400 MHz, CDCI₃): 7.76 (1H, s), 7.73 (2H, s), 7.61 (2H, d, J7.4Hz), 7.36 (2H, t, J 7.4Hz), 7.31-7.14 (6H, m), 4.89 (1H, d, J 12.6Hz), 4.64 (1H, d, J 12.6Hz), 4.26 (1 H, br s), 4.11 (1H, d, J 15.4Hz), 3.86 (1H, d, J 15.1Hz), 3.66 (1H, br s), 3.66 (1H, dd, Jδ.3Hz, 8.4Hz), 2.66-2.42 (2H, m), 2.38-2.17 (2H, m), 2.05 (1H, m), 1.35 (1 H, ddd, J 2.8Hz, 5.2Hz, 13.2Hz).

EXAMPLE 93 (1 ff*2ff*5S* 5ff 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(5- trifluoromethyloxa-3,4-diazo-2-yl)-1-phenyl-8-azabicyclo[3.2.1]octane A mixture of (1 R*,2R*,5S*, 6R -8-benzyl-2-{[3,6- bis(trifluoromethyl)phenyI]methoxy}-6-(5-trifluoromethyloxa-3,4-diazo-2-yl)-1- phenyl-8-azabicyclo[3.2.1]octane (Example 92; 36mg, O.Oδmmol), 10% palladium on charcoal (125mg) and ethanol (10ml) was stirred under hydrogen atmosphere (1 atm) at +65°C for 3 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol) to give the title compound. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI. m/z (ES⁺) 566 [M+Hf. EXAMPLE 94 (1ff*,2ff*,5S*,6fl 8-Allyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert- butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane

(1 ff^*,2ff*,5S^*,6ffⁱ)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(ferf- butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 25; 2.1 g, 4.0mmol), potassium carbonate (1.7g, 12.0mmol) and allyl bromide (0.42ml, 4.8mmol) in dimethylformamide (10ml) were stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate and washed with water. The organics were collected, dried (MgSO₄) and concentrated in vacuo. The residue was purified by column chromatography, eluting with 10% ethyl acetate/iso- hexane, (1.8g, 80%). δ_H (360 MHz, CDCI₃): 7.72 (1H, s), 7.63 (2H, m), 7.46 (2H, m), 7.34-7.21 (3H, m), 5.66 (1H, m), 5.20 (1H, m), 5.01 (1H, m), 4.71 (1H, d, J 12.7Hz), 4.49 (1H, d, J 12.7Hz), 3.96 (1H, s), 3.89 (1H, s), 3.47 (1H, m), 3.12 (1 H, m), 2.72 (1H, m), 2.32 (1 H, m), 2.02 (3H, m), 1.92(1 H, m), 1.46 (9H, s), 1.26 (1 H, m).

EXAMPLE 95 (1 ff*2ff*,5S*,6ff 8-AHyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6- (methoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane Acetyl chloride (5ml) was cautiously added to methanol (25ml) and

(1ff*,2ff*5S*,6ff^l,)-8-allyl-2-{[3,δ-bis(trifluoromethyl)phenyl]methoxy}-6-(tø/f- butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 94; 1.23g, 2.16mmol) dissolved in the resulting solution. After standing for 4 weeks, the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (26ml) and saturated aqueous sodium carbonate (2x1 δml), the organic layers dried (MgSO₄) and evaporated to leave the title compound as a gum. (1.07g, 94%). δ_H (360MHz, CDCI₃): 7.72 (1 H, s), 7.62 (2H, s), 7.44 (2H, d, J 7.3 Hz), 7.33-7.20 (3H, m), δ.79-6.73 (1 H, m), δ.17 (1 H, dd, J 17.2 Hz, J 1.6 Hz), 6.03 (1 H, dd, J 10.3 Hz, J 1.0 Hz), 4.71 (1H, d, J 12.8 Hz), 4.44 (1H, d, J 12.8 Hz), 3.96 (2H, s), 3.72 (3H, s), 3.46 (1H, dd, J 16.8 Hz, J6.δ Hz), 3.10 (1 H, dt, J 15.8 Hz, J2.2 Hz), 2.83 (1H, dd, 9.4 Hz, J4.9 Hz), 2.38 (1H, dd, J 13.6 Hz, J4.9 Hz), 2.16-2.03 (3H, m), 1.96-1.82 (1 H, m), 1.32-1.26 (1 H, m). EXAMPLE 96 (1ff*,2ff*₅5S*,6ff")-8-Allyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(3- methyl-1,2,4-oxadiazol-5-yl])-1-phenyl-8-azabicyclo[3.2.1]octane Powdered 4A molecular sieves (100mg), followed after 15 minutes by sodium hydride (60% dispersion in mineral oil; 30mg, 0.75mmol), were added to a suspension of acetamide oxime (δδmg, 0.7δmmol) in THF (δml). The mixture was stirred for 46 minutes before adding a solution of (1 ff ^*,2ff *,5S* 6ff ^-8-allyl-2- {[3,δ-bis(trifluoromethyl)phenyl]methoxy}-6-(methoxycarbonyl)-1-phenyl-8- azabicyclo[3.2.1]octane (Example 95) in THF (10ml). The resulting mixture was stirred under reflux for 2 hours, allowed to stand overnight at room temperature, and reflux resumed for a further 1.5 hours. The residue remaining after removal of solvent was partitioned between water (1δml) and ethyl acetate (2x10ml), the organic layers dried, (MgSO₄), evaporated, and the residue purified by column chromatography, eluting with 36% ethyl acetate in iso-hexane, to give the title compound as a gum (200mg, 76%). m/z (ES⁺) 652 ([M+Hf).

EXAMPLE 97 (1ff*,2ff*5S*6ff'^,)-2-{[3₅5-Bis(trifluoromethyl)phenyl]methoxy}-6-(3-methyl- 1 ,2,4-oxadiazol-5-yl)-1 -phenyl-8-azabicyclo[3.2.1]octane

(1 ff*,2ff*,5S*,6ff^,,)-8-Allyl-2-{[3,5-bis(trifluoromethyi)phenyl]methoxy}-6-(3-methyl- 1,2,4-oxadiazoI-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 96; 81 mg, O.lδmmol) was combined with tetrakis(triphenylphospnine)palladium(0) (10mg) and N,N'-dimethylbarbituric acid (70mg, 0.46mmol) in dichloromethane and stirred at 36°C for 3 hours. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution and extracted with dichloromethane (x3). The organics were dried (MgSO₄) and concentrated in vacuo to give a dark red solid. The solid was purified by preparative thin layer chromatography [6% methanol in dichloromethane] to give the title compound as a yellow oil. m/z (ES⁺) 511 ([M+Hf). EXAMPLE 98 (1ff*,2ff*5S*6ff^-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-ethynyl-1- phenyl-8-azabicyc!o[3.2.1]octane

(1 ff*,2R*,5S*,6ff^,,)-2-{[3,6-Bis(trifluoromethyl)phenyl]methoxy}-6-formyl-1-phenyl- 8-azabicyclo[3.2.1]octane (Example 47; 165mg, 0.3mmol) in methanol (3ml) at 0°C was treated with potassium carbonate (83mg, O.βmmol) and dimethyl 1- diazo-2-oxopropylphosphonate (81 mg, O.δmmol) and stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and hexane. The organics were collected, dried (MgSO₄), filtered and concentrated in vacuo to afford the title compound as a white crystalline solid (123mg, 76%). m/z (ES⁺) 544 ([M+Hf).

EXAMPLE 99 (1 ff * 2ff *,5S*, 6ff ")-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(1 ,2,3- triazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride

(1 ff*,2ff*5S*6ff^-2-{[3,5-Bis(trifluoromethyl)ρhenyl]methoxy}-6-ethynyl-1-phenyl- 8-azabicyclo[3.2.1]octane (Example 98; 136mg, 0.3mmol) and trimethylsilylazide (0.1ml, 0.8 mmol) in toluene were heated in a sealed tube at 130°C for 48 hours. The mixture was allowed to cool and quenched with methanol and water. The mixture was concentrated in vacuo, and the residue purified by flash column chromatography, eluting with δ% methanol/dichloromethane. The debenzylated product was treated with 1.Oeq HCI in ether and the title compound isolated as a white crystalline solid (20mg, 13%). m/z (ES⁺) 497 ([M+Hf).

EXAMPLE 100 (1ff*,2ff*5S*,6ff'^l)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(1- phenylthiomethyl-1,2,3-triazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane; and (1ff*,2ff*5S*6ff'^l)-2-{[3,5-bis(trifluoromethyI)phenyl]methoxy>-6-(3- phenylthiomethyl-1 ,2,3-triazol-5-yl)-1 -phenyl-8-azabicyclo[3.2.1 ]octane

(1 ff *,2ff ^δS^ΘR^^-flS.δ-Bis^rifluoromethy phenylJmethoxyJ-e-ethynyl-l -phenyl-

8-azabicyclo[3.2.1]octane (Example 98; 96mg, 0.2mmol) and azidomethyl phenyl sulfide (30μl, 0.2mmol) in toluene (2ml), were heated in a sealed tube at 110°C for 18 hours. The mixture was allowed to cool and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 10-50% ethyl acetate/hexane. The title compounds were isolated a brown solid (62mg, 50%). m/z (ES⁺) 710 ([M+Hf).

EXAMPLES 101a and 101b (1ff*2ff*5S*,6ff^,<)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(1-methyl- 1 ,2,3-triazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane; and (Iff'^ff^SS^βff^^-ttS^-bisttrifluoromethy phenyπmethoxy e-tS-methyl- 1,2,3-triazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane A mixture of (1ff*,2ff*,5S*6ff'⁽)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(1- phenylthiomethyl-1 ,2,3-triazol-δ-yl)-1-phenyl-8-azabicyclo[3.2.1]octane and (1ff*,2ff*5S*,6ff'^,)-2-{[3,δ-bis(trifluoromethyl)phenyl]methoxy}-6-(3- phenylthiomethyl-1 ,2,3-triazol-5-yl)-1 -phenyl-8-azabicyclo[3.2.1 ]octane (Example 100; 99mg, 0.1 mmol) and nickel(ll)chloride hexahydrate (233mg, I .Ommol) in methanol (6ml) and THF (2ml) at 0°C was treated with sodium borohydride (112mg, 2.9mmol). A black precipitate was formed and the mixture was stirred for 20 minutes. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The isomers were separated by preparative TLC eluting with 1 :1 ethyl acetate/hexane to afford the title compounds (3-methyl-1 ,2,3-triazol- 6-yl isomer: 17mg) and (1 -methyl-1 ,2,3-triazol-δ-yl isomer: 34mg), in a combined yield of 61%. EXAMPLE 101a:- δ_H (400 MHz, CDCI₃): 7.72 (3H, m), 7.54 (2H, m), 7.45 (1H, s), 7.36 (1H, m), 7.30 (8H, m), 4.91 (1H, d, J 12.9 Hz), 4.64 (1H, d, J 12.5 Hz), 4.26 (1H, s), 4.11 (1H, d, J 14.9 Hz), 3.94 (1H, d, J 14.9 Hz), 3.89 (3H, s), 3.46 (1H, s), 3.16 (1H, m), 2.60 (1H, m), 2.37 (1H, m), 2.26 (1H, m), 2.12 (1H, m), 1.92 (1H, m). EXAMPLE 101b:- δ_H (400 MHz, CDCI₃): 7.73 (3H, m), 7.66 (2H, m), 7.29 (9H, m), 4.89 (1 H, d, J 12.9 Hz), 4.61 (1H, d, J 12.8 Hz), 4.23 (1H, s), 4.10 (1H, d, J 14.7 Hz), 4.04 (3H, s), 3.89 (1H, J 14.7 Hz), 3.41 (2H, m), 2.60 (1H, m), 2.30 (1H, m), 2.17 (2H, m), 1.96 (1H, m), 1.26 (1H, m). EXAMPLE 102 (Iff^ff^δS^^βff^-ttS^-Bis^rifluoromethy phenyll ethoxy^β-tl-methyl- 1,2,3-triazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride

Prepared from (1 ff *,2R^* 5S^*,6ff 2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6- (1 -methyl-1 ,2,3-triazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 101a) by an analogous method to those previously described. m/z (ES⁺) 611 ([M+Hf).

EXAMPLE 103 (1ff*,2ff*,5S*,6ff 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(3-methyl- 1,2,3-triazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride

Prepared from (1 R^*,2R *,5S^* 6ff ")-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6- (3-methyl-1,2,3-triazol-5-yl)-1-phenyI-8-azabicyclo[3.2.1] octane (Example 101b) by an analogous method to those previously described. m/z (ES⁺) 511 ([M+Hf).

EXAMPLE 104 (1fl*,2ff*,5S*6ff^I,)-6-Acetamidoazido-8-benzyI-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicycIo[3.2.1]octane (1 R*,2R *,5S*,6R 8-Benzyl-2-{[3,5-bis(trif luoromethyl)phenyl]methoxy}-1 -phenyl- 8-azabicyclo[3.2.1]octan-6-carboxylic acid (free base of Example 53; 377mg, 0.67mmol) was dissolved in dichloromethane (10ml) and dimethylformamide (2 drops) and the mixture cooled to 0°C then oxalyl chloride (0.063ml, 0.72mmol) added. The mixture was then left to warm to room temperature and stirred for 2 hours. The mixture was concentrated in vacuo then carried through crude. Acid chloride (389mg, 0.67mmol) was taken up in dichloromethane (10ml) and sodium azide (48mg, 0.74mmol) added and the mixture stirred at room temperature for 3 days. A further 48mg of sodium azide was added and the mixture further stirred overnight. The reaction mixture was then concentrated in vacuo and carried through crude. The isocyanate (394mg, 0.70mmol) was dissolved in THF (3ml) and water (3ml) and the mixture refluxed for 4 hours. The reaction mixture was then extracted with ethyl acetate (x2), dried (MgSO₄) and concentrated in vacuo to give the title compound as a beige solid (307mg, 82%). m/z (ES⁺) 604 [M+Hf).

EXAMPLE 105 (1ff*2ff*5S*,6ff")-6-Acetamidoazido-2-{[3₅5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride

(1 ff*2ff*5S*,6ff 6-Acetamidoazido-8-benzyl-2-{[3,5- bisftrif luoromethyl)phenyl]methoxy}-1 -phenyl-8-azabicyclo[3.2.1 Joctane (Example

104; 240mg, 0.40mmol) was dissolved in ethyl acetate (10ml) and glacial acetic acid (1 ml) then 10% palladium hydroxide (30mg) added and the mixture hydrogenated at 45psi overnight. The reaction mixture was then filtered and the mixture further hydrogenated with fresh catalyst (30mg) overnight. The reaction mixture was filtered then concentrated in vacuo, basified (saturated sodium hydrogen carbonate solution), extracted with dichloromethane (x3), dried (MgSO₄), and concentrated in vacuo. The crude product was purified by flash column chromatography [10% methanol in dichloromethane] to give an oil which when concentrated with iso-hexane gave a white solid. The hydrochloride salt was made by dissolving in diethyl ether and adding 1 equivalent of hydrogen chloride in diethyl ether. The title compound was filtered off and dried in vacuo at 60°C. m/z (ES⁺) 489 [M+Hf).

EXAMPLE 106 (1fl*,2ff*5S*,6ff^,t)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1- phenyl-8-azabicyclo[3.2.1]octan-6-carbamic acid methyl ester

(I R^R^δS^eR^-δ-Benzyl^-ftS.δ-bis^rifluoromethy phenylJmethoxyJ-l-phenyl- 8-azabicyclo[3.2.1]octan-6-carboxamide (Example 75; 127mg, 0.23mmol) was stirred in methanol (5ml). A solution of potassium hydroxide (5.36g) in water (93ml) was made up and bromine (1g) added. 10ml of the bromine solution was added to the amide in methanol then the reaction mixture heated to 70°C for 3 hours. The reaction mixture was concentrated in vacuo then extracted with dichloromethane (x3), dried (MgSO₄), and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [25% ethyl acetate in iso- hexane] to give the title compound (92mg, 69%). m/z (ES⁺) 592 ([M+Hf).

EXAMPLE 107

(1ff*,2ff*,5S*,6ff^l,)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8- azabicyclo[3.2.1]octan-6-carbamic acid methyl ester hydrochloride

(1 ff^*,2R^*5S*6R^*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl- 6-phenylsulfonyl-8-azabicyclo[3.2.1]octane (Example 1; 92mg, 0.16mmol), was dissolved in ethyl acetate (5ml) and glacial acetic acid (0.5ml), then 10% palladium hydroxide (20mg) added and the reaction mixture hydrogenated at 40psi overnight. The mixture was then filtered, washed with methanol and concentrated in vacuo. The oil was basified (saturated sodium hydrogen carbonate solution) then extracted with dichloromethane (x3) and the organics dried (MgSO₄) and concentrated in vacuo to give a clear oil. The hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether to a solution in diethyl ether and the solid filtered off and dried at 60°C in vacuo to give the title compound, m/z (ES⁺) 503 ([M+Hf).

EXAMPLE 108 (1ff*2ff*,5S*6ff*)-6-Amino-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (1 R*,2R*5S*,6R^-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl- 8-azabicyclo[3.2.1]octan-6-carboxamide (Example 75; 2.38g, 4.23mmol) was dissolved in 'butanol (27ml). A solution of potassium hydroxide (10.72g) in water (186ml) was made up and bromine (2g) added. 35ml of the bromine solution was added to the amide in ^utanol and the mixture stirred at room temperature for 1 hour then at 70°C for 30 minutes. The reaction mixture was then concentrated in vacuo, extracted with dichloromethane (x3), dried (MgSO₄) and concentrated in vacuo. The oil was purified by flash column chromatography [10%-20% methanol in dichloromethane] to give the title compound as a yellow solid (1.73g, 76%). m/z (ES⁺) 536 ([M+Hf). EXAMPLE 109 (1ff*,2fl*,5S*6ff*)-6-Acetamido-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (I ff^ff^S^eR^-e-Amino-S-benzyl^-fP.e-bis rifluoromethy phenyljmethoxy}- 1-phenyl-8-azabicyclo[3.2.1]octane (Example 108; 475mg, 0.89mmol), glacial acetic acid (0.076ml, 1.34mmol), triethylamine (0.14ml, 0.98mmol), 1-(3- dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (257mg, 1.34mmol) and 4-dimethylaminopyridine (2 crystals) were combined in dichloromethane (4ml) and stirred overnight at room temperature. The reaction mixture was washed with water and extracted with dichloromethane (x3). The organics were dried (MgSO₄), and concentrated in vacuo to give the title compound as a yellow oil (384mg, 75%). m/z (ES⁺) 677 ([M+Hf).

EXAMPLE 110 (1ff*,2ff*,5S*,6ff^J,)-8-BenzyI-2-{[3,5-bis(trifluoromethyI)phenyl]methoxy}-6-(5- methyl-1W-tetrazol-1-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (1 ff*2ff*,5S^*,6ff 6-Acetamido-8-benzyl-2-{[3,δ- bis(trifluoromethyl)phenyl]methoxy}-1 -phenyl-8-azabicyclo[3.2.1]octane (Example 109; 384mg, 0.67mmol) and sodium azide in dichloromethane (10ml) were cooled to 0°C and trifluoromethanesulphonic anhydride (0.11ml, 0.67mmol) added. The reaction was warmed to room temperature and stirred for 3 hours then quenched with saturated sodium hydrogen carbonate solution and extracted with dichloromethane (x3). The organics were dried (MgSO₄) and concentrated in vacuo to give a brown solid. This was purified by flash column chromatography [2.6% methanol in dichloromethane] to give the title compound as a cream- coloured solid (134mg, 34%). m/z (ES⁺) 602 ([M+Hf). EXAMPLE 111 (1ff*,2ff*,5S*,6ff 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(5-methyl- 1 ff-tetrazol-1 -yl)-1 -phenyl-8-azabicyclo[3.2.1 ]octane hydrochloride

(1 R*2R^*5S*6R^,t)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(5- methyl-1/-/-tetrazol-1-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 110;

134mg, 0.22mmol) was dissolved in methanol (10ml) and hydrochloric acid (2N) (1 ml) and 10% palladium hydroxide (δOmg) added and the mixture hydrogenated at 40psi overnight. The reaction mixture was then filtered and concentrated in vacuo. The oil was partitioned between saturated sodium hydrogen carbonate solution and dichloromethane and the organics dried (MgSO₄) and concentrated in vacuo. The solid was purified by flash column chromatography [δ% methanol in dichloromethane]. The hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether to a solution in diethyl ether. The title compound was filtered off and dried in vacuo (32mg, 26%). m/z (ES⁺) 612 ([M+Hf).

EXAMPLE 112 (1ff*,2ff*5S*,6ff^!,)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(3- methoxypropoxamido)-1-phenyl-8-azabicyclo[3.2.1J ctane (I R^^R^δS^eR^-e-Amino-δ-benzyl^tS.δ-bis^rifluoromethy phenyπmethoxy}- 1-phenyl-8-azabicyclo[3.2.1]octane (Example 108; 627mg, 0.99mmol), 3-methoxypropionic acid (0.14ml, 1.49mmol), triethylamine (0.15ml,1.09mmol), 1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (286mg, 1 ,49mmoI) and 4-dimethylaminopyridine (5 crystals) were combined in dichloromethane (4ml) and stirred at room temperature overnight. The mixture was partitioned between dichloromethane and water and the organics collected. The aqueous was further extracted with dichloromethane (x2) and the organics combined and dried (MgSO₄) and concentrated in vacuo to give a yellow oil which was purified by flash column chromatography [2.6% methanol in dichloromethane] to give the title compound as a yellow oil (368mg, 60%). m/z (ES") 621 ([M+Hf). EXAMPLE 113 (1ff*2ff*,5S*6ff^!,)-2-{[3_J5-Bis(trifluoromethyl)phenyl]methoxy}-6-(3- methoxypropoxamide)-1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride

(1R*,2R*,5S*,6R^,,)-8-Benzyl-2-{[3,δ-bis(trifluoromethyl)phenyl]methoxy}-6-(3- methoxypropoxamide)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 112; 179mg, 0.29mmol) was dissolved in methanol (δml) with 2N hydrochloric acid (1 ml) and 10% palladium hydroxide (40mg) added. The mixture was hydrogenated at 40psi for 30 minutes. The reaction mixture was then filtered and concentrated in vacuo then partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organic layer was collected and the aqueous further extracted with dichloromethane (x2). The organics were dried (MgSO₄) and concentrated in vacuo then the crude purified by flash column chromatography [δ% methanol in dichloromethane] to give a cream-coloured solid. The hydrochloride salt was made by adding 1 equivalent of 1 N hydrogen chloride in diethyl ether to a solution in diethyl ether and the title compound filtered and dried in vacuo at 60°C (55mg, 35%). m/z (ES⁺) 531 ([M+Hf).

EXAMPLE 114 (1 ff * 2ff * 5S*,6ff *)-8-Benzyl-2-{[3,5-bis(trif luoromethyl)phenyl]methoxy}-1 - phenyl-6-(1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane

(1R*,2R*,5S*,6R' -6-Amino-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}- 1-phenyl-8-azabicyclo[3.2.1]octane (Example 108; 211mg, 0.40mmol), N,N'-dimethylformamide azine (84mg, 0.59mg), and p-toluenesulphonic acid (38mg, 0.20mmol) were combined in toluene (4ml) and heated at reflux under N₂ overnight. The reaction mixture was cooled and concentrated in vacuo. The crude was purified by flash column chromatography [7.6%-10% methanol in dichloromethane] to give the title compound as a brown oil (175mg, 75%). m/z (ES⁺) 587 ([M+Hf). EXAMPLE 115 (Iff^ff^SS^βff^- ^-Bisttrifluoromethy phenyllmethoxy^l-phenyl-β- (1 ,2,4-triazol-4-yl)-8-azabicycIo[3.2.1]octane hydrochloride

(I ff^R^δS^eR^-δ-Benzyl^-tfS.δ-bis rifluoromethy phenyljmethoxyJ-l-phenyl- 6-(1 ,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane (Example 114; 17δmg, 0.30mmol), was dissolved in methanol (5ml) and 2N hydrochloric acid (0.5ml) and 10% palladium hydroxide (40mg, 10%) added and the reaction mixture hydrogenated at 45psi for 1 hour. The mixture was then filtered and concentrated in vacuo. The oil was partitioned between saturated sodium hydrogen carbonate solution and dichloromethane and the organic layer collected. The aqueous was further extracted with dichloromethane (x2) and the organics combined, dried (MgSO and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [δ% methanol in dichloromethane] to give a cream-coloured solid (72mg, 49%). The hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether to a solution in diethyl ether and the title compound filtered and dried in vacuo at 60°C. m/z (ES⁺) 497 ([M+Hf).

EXAMPLE 116 (1 ff * 2ff *,5S* 6ff *)-8-Benzyl-2-{[3,5-bis(trif luoromethyl)phenylTmethoxy}-1 - phenyl-6-(1ff-tetrazol-1-yl)-8-azabicyclo[3.2.1]octane

(I R^R^δS^eR^-δ-Amino-δ-benzyl^-ltS.δ-bis^rifluoromethy phenyπmethoxy}- 1-phenyl-8-azabicyclo[3.2.1]octane (Example 108; 209mg, 0.39mmol) in triethylorthoformate (3.δml, 19.22mmol) and glacial acetic acid (1ml) was heated to 90°C. Sodium azide (260mg, 3.8δmmol) was added and the mixture further heated at 90°C overnight. The mixture was cooled and partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organics were dried (MgSO₄) and concentrated in vacuo. The reaction mixture was purified by flash column chromatography [2.6% methanol in dichloromethane] to give the title compound as a cream-coloured foam (1 δ4mg, 66%). m/z (ES⁺) 588 ([M+Hf). EXAMPLE 117 (1ff*2ff*,5S*,6ff 2-{[3,5-Bis(trifluoromethyl)phenyi]methoxy}-1-phenyl-6- (1 ff-tetrazol-1 -yl)-8-azabicyclo[3.2.1]octane hydrochloride

I R^R^δS^eff^-δ-Benzyl^- .δ-bis^rifluoromethy phenyllmethoxyJ-l-phenyl- 6-(1 H-tetrazol-1-yl)-3-azabicyclo[3.2.1]octane. (Example 116; 154mg, 0.26mmol) was dissolved in methanol (30ml) and 2N hydrochloric acid (0.5ml) and 10% palladium hydroxide (40mg, 10%) added. The mixture was hydrogenated at 35psi for 1 hour. The reaction mixture was then filtered and concentrated in vacuo and the oil partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organics were collected, dried (MgSO₄) and concentrated in vacuo to give an orange foam which was purified by flash column chromatography [7.5% methanol in dichloromethane] then further isolated by thin layer chromatography [7.5% methanol in dichloromethane] to give a clear oil. The hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether (1.0M) to a solution in diethyl ether and the title compound filtered and dried in vacuo at 60°C (25mg, 16%). m/z (ES⁺) 49δ ([M+Hf).

EXAMPLE 118 (1 ff* 2ff *,5S*,6ff 6-Acetamido-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane

To (1 R*,2R* 5S*, 6R*)-6-amino-8-benzyl-2-{[3,5- b.s(trifluoromethyl)phenyl]methoxy}-1 -phenyl-8-azabicyclo[3.2.1 ]octane (Example 108; 256mg, 0.48mmol) and sodium azide (75mg, 1.15mmol) in triethylorthoformate (0.25ml) was added glacial acetic acid (2.5ml) and the reaction mixture heated at 90°C for 3 hours. The reaction mixture was cooled then concentrated in vacuo and partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organics were dried (MgSO₄) and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [5% methanol in dichloromethane] to give the title compound (66mg, 24%). m/z (ES⁺) 577 ([M+Hf). EXAMPLE 119 (Iff^ff^δS^eff^-e-Acetamido^- .S-bis^rifluoromethy phenyllmethoxy}- 1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride

(1 R*,2R*,5S*,6R 6-Acetamido-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1 -phenyI-8-azabicyclo[3.2.1]octane (Example 118; 66mg, 0.11 mmol) was dissolved in methanol (δml) and^'2N hydrochloric acid (1 ml) and 10% palladium hydroxide (20mg) added. The reaction mixture was hydrogenated at 40psi for 1 hour. The mixture was then filtered and concentrated in vacuo then the oil basified (saturated sodium hydrogen carbonate solution) and extracted with dichloromethane (x3), dried (MgSO₄) and concentrated in vacuo to give a clear oil. The oil was purified by thin layer chromatography [10% methanol in dichloromethane] to give a white solid. The hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether (1.0M) to a solution in diethyl ether and the title compound filtered and dried in vacuo at 60°C. m/z (ES⁺) 487 ([M+Hf).

EXAMPLE 120 (1ff*,2ff*,5S*,6ff'^,)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6- piperidinylcarbonyl-1-phenyl-8-azabicyclo[3.2.1]octane A 0.07M solution of (1 R*,2R* 5S* 6R^*)-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6- carboxylic acid trifluoroacetate (Example 63) in dichloromethane (2.δml, 0.18mmol) was added to a mixture of piperidine (0.2δml, 2.δmmol), triethylamine (0.1ml, 0.7mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66mg, 0.34mmol), and 4-N,N-dimethyIaminopyridine (12mg, 0.1 mmol). The mixture was stirred at room temperature overnight and purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (100mg, 8δ%). δ_H (360 MHz, CDCI₃): 7.76 (3H, s), 7.61 (2H, d, J 6.1 Hz), 7.40 (2H, d, J7.4Hz), 7.36-7.13 (6H, m), 4.84 (1H, d, J 13.0Hz), 4.60 (1H, d, J 13.0Hz), 4.12 (1H, br s), 4.08 (1 H, d, J 16.1Hz), 3.82 (1H, d, J lδ.δHz), 3.79 (1 H, br), 3.62 (1H, s), 3.47- 3.16 (3H, m), 2.96-2.34 (2H, m), 2.27-1.92 (4H, m), 1.69-1.17 (6H, m). EXAMPLE 121 (1ff*,2ff*,5S*6ff 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6- piperidinylcarbonyl-1-phenyl-8-azabicyclo[3.2.1]octane

A mixture of (1 ff ^*,2ff *,5S*,6ff 8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-6-piperidinylcarbonyl-1-phenyl-δ- azabicyclo[3.2.1]octane (Example 120; 100mg, 0.16mmol), 10% palladium on charcoal (180mg) and ethanol (10ml) was stirred under hydrogen atmosphere (1 atm) at +65°C for 1 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated and purified chromatography on silica gel to give the title compound (83mg, 90%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI.

HCI salt:- δ_H (360 MHz, MeOH-d₄): 7.81 (1 H, s), 7.58 (2H, s), 7.45-7.28 (5H, m), 4.72 (1 H, d, J 12.6Hz), 4.37 (1H, s), 4.23 (1H, d, J 12.6Hz), 3.91 (1H, s), 3.69 (1 H, dd, J 5.0Hz, 9.9Hz), 3.65-3.45 (4H, m), 3.21 (1H, dd, J9.9Hz, 14.0Hz), 2.29- 2.11 (4H, m), 1.89 (1H, m), 1.76-1.43 (6H, m).

Compounds listed in the Table 1 were prepared using the above protocol.

Table 1.

EXAMPLE 122 (1ff*,2ff*5S*6ff^!,)-2-{[3,5-Bis(trifIuoromethyl)phenyl]methoxy}-1-phenyl-8- azabicyclo[3.2.1]octan-6-carboxylic acid trifluoroacetate

A mixture of (1 ff*,2ff *5S*,6ff *)-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6- carboxylic acid trifluoroacetate (Example 53; 2.7g, 4mmol), 10% palladium on charcoal (500mg) and ethanol (30ml) was stirred under hydrogen atmosphere (1atm) at +40°C for 20 minutes. The reaction mixture was cooled to room 0 temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound (2.6g) as a white solid. δ_H (360 MHz, DMSO-d₆): 9.75 (1H, br d, Jδ.δHz), 9.27 (1H, br d, J δ.4Hz), 7.94 (1 H, S), 7.66 (2H, s), 7.42-7.29 (5H, m), 4.73 (1H, d, J 13.0Hz), 4.33 (1H, s), 4.20 (1 H, d, J 13.0Hz), 3.63 (1H, s), 3.40 (1H, dd, J5.6Hz, 10.2Hz), 3.01 (1H, dd, J 5 10.6Hz, 14.0Hz), 2.37 (1H, dd, J 6.1 Hz, 14.4Hz), 2.12-1.91 (3H, m), 1.79 (1H, m). EXAMPLE 123 (Iff^ff^δS^βff -e-^-Benzylpiperazin-l-y carbonylJ^-itSjS- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane

A mixture of (1 ff^*,2R*,5S^*,6R 2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1- phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid trifluoroacetate (Example 122; 100mg, 0.19mmol), N-benzylpiperazine (0.1ml), triethylamine (0.1ml, 0.7mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44mg, 0.23mmol) and 4-N,N-dimethylaminopyridine (12mg, 0.1mmol)was prepared. The mixture was stirred at room temperature for 20 hours and purified by chromatography on 0 silica gel (dichloromethane:methanol) to give the title compound (102mg, 86%). δ_H (400 MHz, CDCI₃): 7.66 (2H, s), 7.37-7.18 (6H, m), 4.43 (1H, d, J 12.1 Hz), 4.02 (1 H, d, J 12.6Hz), 3.80 (1H, br s), 3.69 (1 H, brt), 3.56-3.38 (4H, m), 3.09 (1H, dd, J 4.7Hz, 9.0Hz), 2.51-2.35 (7H, m), 2.15 (1H, dd, J4.3Hz, 12.9Hz), 2.06-1.93 (2H, m), 1.85 (1 H, m), 1.50 (1 H, m). 5

Compounds listed in the Table 2 were prepared using the above protocol.

Table 2.

EXAMPLE 124 (1 ff * 2ff *,5S* 6ff*)-8-Benzyl-2-{(1 S*)-1 -[3,5-bis(trif luoromethyl)phenyl]- (methoxycarbonyl)methoxy}-6-(tert-butoxycarbonyI)-1-phenyl-8- 5 azabicyclo[3.2.1]octane; and

(1 ff * 2ff * 5S* 6ff*)-8-benzyl-2-{(1 ff *)-1 -[3,5-bis(trif luoromethyl)phenyl]-

(methoxycarbonyl)methoxy}-6-(terf-butoxycarbonyl)-1-phenyl-8- azabicyclo[3.2.1 joctane

To a solution of (1 R*2R^*,5S^*,6R^*)-8-Benzyl-6-(tøtt-butoxycarbonyl)-1-phenyl-8-

10 azabicyclo[3.2.1]octan-2-ol (Description 21a; 0.67g, l.δmmol) and catalytic rhodium acetate (9mg, 0.02mmol) in benzene (10ml) at reflux under nitrogen, was added methyl 2-diazo-2-(3,δ-bis(trifluoromethyl)phenyl)acetate [prepared by the method of R.T. Lewis etal. J. Org. Chem., 2000, 65, 2616] slowly in benzene (δml). After evaporation and chromatography of the residue (eluent 10% ethyl

15 acetate/hexane), the title compounds were isolated as a solid (836mg, 36%). δ_H (400 MHz, CDCI₃): 1.43 (9H, s), 2.02 (3H, m), 2.23-2.63 (2H, m), 2.60 (1H, m) 3.63 and 3.77 (3H, s, diastereomers a and b), 3.70 (1H, br s), 3.76 (1H, d, J 16.9Hz), 4.10 (1H, br s), 4.30 (1 H, d, J 15.9Hz), 4.66 and 5.18 (1H, s diastereomers b and a), 7.11-7.36 (10H, m), 7.70 and 7.82 (2H, s, diastereomers

20 b and a), 7.78 and 7.95 (2H, s, diastereomers b and a). EXAMPLE 125 (1 ff *,2ff * 5S* 6ff*)-8-Benzyl-2-{(1 S*)-1 -[3,5«bis(trif luoromethyl)phenyl]- (methoxycarbonyl)methoxy}-6-(fert-butoxycarbonyl)-1-phenyl-8- azabicyclo[3.2.1]octan-6-carboxylic acid trifluoroacetate; and

(1 ff * 2ff * 5S* 6ff*)-8-benzyl-2-{(1 ff *)-1 -[3,5^«bis(trif luoromethyl)phenyl]-

(methoxycarbonyl)methoxy}-6-(ferf-butoxycarbonyl)-1-phenyl-8- azabicyclo[3.2.1]octan-6-carboxylic acid trifluoroacetate

(1 R*,2ff *,5S*,6R*)-8-Benzyl-2-{(1 S*)-1 -[3,δ-bis(trifluoromethyl)phenyl]- (methoxycarbonyl)methoxy}-6-(te/f-butoxycarbonyl)-1 -phenyl-3- azabicyclo[3.2.1]octane and (1 ff^*2ff^*5S^*6ff^*)-8-benzyl-2-{(1 R")-1-[3,5- bis(trifluoromethyl)phenyl]-(methoxycarbonyl)methoxy}-6-(tert-butoxycarbonyl)-1- phenyl-δ-azabicyclo[3.2.1]octane (Example 124; 437mg, 0.65mmol) and trifluoroacetic acid (3ml) in dichloromethane (10ml), were stirred at room temperature for 1δ hours. The mixture was concentrated in vacuo and the title compounds crystallised from ethyl acetate/hexane in quantitative yield, m/z (ES⁺) 622 ([M+Hf).

EXAMPLE 126 (1 ff * 2ff * 5S* 6ff*)-2-{(1 ff *)-1 -[3,5-bis(trif luoromethyl)phenyl]-2- hydroxyethoxy}-6-(1 -morpholinocarbonyl)-1 -phenyl-8- azabicyclo[3.2.1]octane hydrochloride

(1 fl^*,2ff *,5S*,6ff*)-8-Benzyl-2-{(1 S")-1 -[3,5-bis(trifluoromethy!)phenyl]- (methoxycarbonyl)methoxy}-6-(fe/ -butoxycarbonyl)-1-phenyl-δ- azabicyclo[3.2.1 ]octan-6-carboxylic acid trifluoroacetate and (1 ff *2ff *,6S* 6R*)-δ- benzyl-2-{(1 R*)-1-[3,δ-bis(trifluoromethyl)phenyl]-(methoxycarbonyl)methoxy}-6- (terf-butoxycarbonyl)-l -phenyl-3-azabicy o[3.2.1 ]octan-6-carboxylic acid trifluoroacetate (Example 1253δ4mg, 0.62mmol), triethylamine (0.15ml, 1. Oδmmol), 4-dimethylaminopyridine (64mg, 0.62mmol), morpholine (0.1ml, 1.Oδmmol) and 1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride were stirred at room temperature for 72 hours. The mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate and 10% citric acid. The organics were collected, dried (MgSO₄) and concentrated in vacuo to afford a white solid (279mg). This material was treated with lithium borohydride (30mg) in THF until the reduction was complete. The mixture was quenched with water and extracted with ethyl acetate. The organics were collected, dried (MgSO and concentrated in vacuo. The product diastereomers were separated using preparative thin layer chromatography, eluting with 3:2 dichloromethane/diethyl ether. (1 R* 2R*,5S^* 6R*)-δ-benzyl-2-{(1 ff 1 -[3,5- bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-6-(1-morpholinocarbonyl)-1-phenyl- 8-azabicyclo[3.2.1]octane was isolated as a white solid (118mg) and (1 R* 2R* 5S* 6ff*)-δ-benzyl-2-{(1 S*)-1 -[3,5-bis(trifIuoromethyl)phenyl]-2- hydroxyethoxy}-6-(1 -morpholinocarbonyl)-1 -phenyl-8-azabicyclo[3.2.1 ]octane (80mg), total yield 96%. (1 R*,2ff*,5S*6R*)-δ-benzyl-2-{(1 R")-1-[3,5- bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-6-(1-morpholinocarbonyl)-1-phenyl- δ-azabicyclo[3.2.1]octane was debenzylated and the hydrochloride salt prepared as described previously to afford the title compound. m/z (ES⁺) 673 ([M+H]⁺).

EXAMPLE 127 (1 ff * 2ff * 5S* 6ff*)-8-Benzyl-2-{(1 S*)-1 -[3,5-bis(trif luoromethyl)phenyl]-2- hydroxyethoxy}-6-(terf-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane; and

(1 ff *,2ff *,5S*, 6ff*)-8-Benzyl-2-{(1 ff *)-1 -[3,5-bis(trif luoromethyl)phenyl]-2- hydroxyethoxy}-6-(te/t-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (1 R*,2R*,5S*_J6R*)-8-Benzyl-2-{(1 S 1 -[3,5-bis(trifluoromethyl)phenyl]- (methoxycarbonyl)methoxy}-6-(te/ -butoxycarbonyl)-1-phenyl-δ- azabicyclo[3.2.1]octane and (1 R*,2R*,5S*,6R*)-3-benzyl-2-{(1 ff")-1-[3,5- bis(trifluoromethyl)phenyl]-(methoxycarbonyl)methoxy}-6-(tø/f-butoxycarbonyl)-1- phenyl-8-azabicyclo[3.2.1]octane (Example 125; 0.99g, 1.5mmol) in methanol (15ml) at 0°C was treated with sodium borohydride (5δmg, 1.4mmol) and stirred at room temperature. The reaction was quenched with acetone and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the organics were separated, dried (MgSO₄), filtered and concentrated in vacuoXo afford the title compounds as a clear foam (869mg, 92%). m/z (ES⁺) 650 ([M+H]⁺). EXAMPLES 128a and 128b (1 ff*,2ff*,5S*6ff*)-8-BenzyI-2-{(1 S")-1-[3,5- bis(trifluoromethyI)phenyl]ethoxy}-6-(ter -butoxycarbonyl)-1-phenyl-8- azabicyclo[3.2.1]octane; and

(1 ff *,2ff *,5S* 6ff*)-8-Benzyl-2-{(1 ff *)-1 -[3,5- bis(trifluoromethyl)phenyl]ethoxy}-6-(fe/ -butoxycarbonyl)-1-phenyl-8- azabicyclo[3.2.1]octane

(1 ff *,2ff * 5S* 6ff*)-8-Benzyl-2-{(1 S*)-l -[3,5-bis(trif luoromethyl)phenyl]-2- iodoethoxy}-6-(tørf-butoxycarbonyl)-1-phenyl-8-azabicycIo[3.2.1]octane and (1 ff * 2ff *,5S*, 6R*)-8-benzyl-2-{(1 ff ")-1 -[3,δ-bis(trifluoromethyl)phenyl]-2- iodoethoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 28; 306mg, 0.40mmol), triethylamine (61 mg, 0.6mmol), palladium 10% on charcoal (100mg), ethyl acetate (6ml) and methanol (1ml) were reacted with hydrogen using the Parr™ apparatus for 3 hours. The mixture was filtered and the catalyst washed with acetic acid. The filtrate was concentrated in vacuo, the residue was dissolved in dichloromethane and washed with saturated sodium hydrogen carbonate, 10% citric acid solution and 5% sodium thiosulphate solution. The organics were collected, dried (MgSO₄) and concentrated in vacuo. The title compounds were isolated as a white crystalline solid (230mg, 90%).

EXAMPLES 128a and 128b:- δ_H (400 MHz, CDCI₃): 1.33 and 1.48 (3H, d, J6.5 Hz, diastereomers a and b), 1.42 (9H, s), 1.92 (2H, m), 2.30 (2H, m), 2.69 (1H, m), 3.65 (1H, d, J 16.3 Hz). 3.90 (2H, m), 4.18 (1H, m), 4.55 and 4.63 (1H, q, diastereomers a and b), 7.10-7.46 (10H, m), 7.59 and 7.85 (2H, s, diastereomers b and a), 7.70 and 7.77 (1 H, s, diastereomers a and b); m/z (ES⁺) 635 ([M+H]⁺). EXAMPLE 128a:- δ_H (400 MHz, CDCl₃): 7.77 (1H, s), 7.59 (2H, s), 7.45 (2H, m), 7.33-7.10 (8H, m), 4.63 (1H, m), 4.18 (1H, d, J 16.2Hz), 3.92 (1H, d, J 16.1 Hz), 3.8δ (1H, br s), 3.69, (1H, br s), 2.66 (1H, m), 2.35-2.10 (2H, m), 1.91 (2H, m), 1.50 (3H, d), 1.25 (2H, m); m/z (ES⁺) 634 ([M+Hf). EXAMPLE 129 (1 ff*2ff*,5S*,6ff*)-8-Benzyl-2-{(1 S")-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy}-6-(1-morpholinocarbonyl)-1-phenyl-8- azabicyclo[3.2.1]octane hydrochloride Prepared from a mixture of (1 ff *,2ff *,5S^* 6ff*)-8-benzyl-2-{(1 S^*)-1 -[3,5- bis(trifluoromethyl)phenyl]ethoxy}-6-(tø/ -butoxycarbonyl)-1-phenyl-δ- azabicyclo[3.2.1]octane and (1 ff*,2R*,5S^*6ff*)-8-benzyI-2-{(1 R*)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy}-6-(tørf-butoxycarbonyl)-1-phenyl-8- azabicyclo[3.2.1]octane (Example 128) in an analogous manner to that described for Example 126. m/z (ES⁺) 557 ([M+H]⁺).

EXAMPLE 130 (1 ff * 2ff * 5S* 6ff *)-8-Benzyl-2-{(1 S*)-1 -[3,5- bis(trif luoromethyl)phenyl]ethoxy}-1 -phenyl-8-azabicyclo[3.2.1 ]octan-6- carboxylic acid

(1 ff *, 2R*,5S* 6ff ^*)-8-Benzyl-2-{(1 S^*)-l -[3,5-bis(trif luoromethyl)phenyl]ethoxy}-6- (tørf-butoxycarbonyl)-1-phenyI-δ-azabicyclo[3.2.1]octane (Example 128a; 3.28g, 5.1δmmol) was dissolved in dichloromethane (30ml) and trifluoroacetic acid added (δml) and the reaction mixture stirred overnight at room temperature. The reaction mixture was concentrated in vacuo then triturated with diethyl ether (x3) to give the title compound as a brown solid (4.δ2g). m/z (ES⁺) 67δ ([M+Hf).

EXAMPLE 131

(1 ff * 2ff * 5S*,6ff *)-8-Benzyl-2-{(1 S*)-1 -[3,5- bis(trifluoromethyl)phenyl]ethoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6- carboxamide

(1 R*,2ff * 5S* 6R")-δ-Benzyl-2-{(1 S^-1 -[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1 - phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid (Example 130; 4.82g,

6.99mmol), triethylamine (2.93ml, 20.97mmol), 1-(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride (2.6δg, 13.98mmol), 4-dimethylaminopyridine (10mg), and ammonia in dioxane (41.94ml, 20.97mmol, 0.5M solution) were combined in dichloromethane (40ml) and stirred in a sealed flask for 2 hours at room temperature. The reaction mixture was then diluted with water and the organics removed and the aqueous further extracted with dichloromethane (x2). All organics were combined, dried (MgSO₄) and concentrated in vacuo to give a brown oil which was purified by flash column chromatography [3% methanol in dichloromethane] to give the title compound as a cream-coloured solid (1.76g, 60%). m/z (ES⁺) 677 ([M+H]⁺).

EXAMPLE 132

(1 ff*2ff*5S*6ff 6-Amino-8-benzyl-2-{(1 S*)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy}-1-phenyl-8-azabicyclo[3.2.1]octane

To a solution of potassium hydroxide (5.36g) in water (93ml) was added bromine (1 g) and 60 ml of this solution was added (1 R^*,2R *,5S*,6R 3-Benzyl-2-{(1 s^*)-1 - [3,5-bis(trifluoromethyl)phenyl]ethoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6- carboxamide (Example 131; 1.76g, 3.06mmol) in f-butanol and the mixture stirred at room temperature for 30 minutes then at 70°C for 2 hours. The reaction mixture was cooled and concentrated in vacuo. The aqueous was extracted with dichloromethane (x2), dried (MgSOJ and concentrated in vacuo to give a cream- coloured foam. This was purified by flash column chromatography [3%-10%-15% methanol in dichloromethane] to give the title compound as a yellow solid (660mg, 40%). m/z (ES⁺) 549 [M+H]⁺).

EXAMPLE 133

(1 ff* 2ff*,5S*,6ff 8-Benzyl-2-{(1 S*)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy}-1-phenyl-6-(1,2,4-triazol-4-yl)-8- azabicyclo[3.2.1]octane

(1 ff^2ff*5S'^l,6ff'^,)-6-Amino-3-benzyl-2-{(1 S^*)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy}-1 -phenyl-8-azabicyclo[3.2.1]octane (Example 132; 220mg, 0.40mmol), N,N'-dimethylformamide azine (34mg, 0.69mmol) and p-toluenesulphonic acid (38mg, 0.20mmol) were combined in toluene and heated at reflux for 4 hours under N,. The reaction mixture was cooled and concentrated in vacuo to give a yellow oil which was purified by flash column chromatography [6% methanol in dichloromethane] to give the title compound as a yellow foam (185mg, 77%). m/z (ES⁺) 601 ([M+H]⁺).

EXAMPLE 134 (1 ff * 2ff *,5S*,6ff *)-2-{(1 S*)-1-[3,5-Bis(trif luoromethyl)phenyl]ethoxy}-1 - phenyl-6-(1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane hydrochloride (1 R*,2R* 5S* 6R*)-δ-Benzyl-2-{(1 S*)-1 -[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1 - phenyl-6-(1 ,2,4-triazol-4-yl)-δ-azabicyclo[3.2.1]octane (Example 133; 1 δδmg,

0.31 mmol) was dissolved in methanol (δml) and 2N hydrochloric acid (O.δml) and 10% palladium hydroxide (δOmg) added. The mixture was hydrogenated at 45psi for 1.6 hours. The reaction mixture was filtered then concentrated in vacuo. The residue was partitioned between saturated sodium hydrogen carbonate solution and dichloromethane and the organics removed, dried (MgSO₄) and concentrated in vacuo. The oil was purified by flash column chromatography [6% methanol in dichloromethane] and the hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether (1.0M) to a solution in diethyl ether and the title compound filtered and dried in vacuo at 60°C (27mg, 16%). m/z (ES⁺) 511 ([M+Hf).

EXAMPLE 135 (1 ff*,2ff*5S*,6ff *)-8-Benzyl-2-{(1 S*)-1-[3,5- bis(trif luoromethyl)phenyl]ethoxy}-1 -pheny l-6-(1 H-tetrazol-1 -yl)-8- azabicyclo[3.2.1]octane

(1 ff*,2ff*5S*,6ff 6-Amino-8-benzyl-2-{(1 S*)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy}-1 -phenyI-3-azabicyclo[3.2.1 ]octane (Example 132; 150mg, 0.27mmol) in glacial acetic acid (2ml) with triethylorthoformate (3ml) was heated to 90°C. Sodium azide (17δmg, 2.74mmol) was then added and the mixture stirred at 90°C overnight. The reaction mixture was cooled and partitioned between saturated sodium hydrogen carbonate solution and dichloromethane and the organics dried (MgSO₄) and concentrated in vacuo to give the title compound as a yellow oil (158mg, 96%). m/z (ES⁺) 602 ([M+Hf).

EXAMPLE 136 (1 R* 2ff *,5S*,6ff *)-2-{(1 S*)-1 -[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-1 - phenyl-6-(1 ff-tetrazol-1-yl)-8-azabicyclo[3.2.1]octane hydrochloride

(1 ff*,2ff ^*,5S* 6ff 8-Benzyl-2-{(1 S*)-l -[3,δ-bis(trifluoromethyl)ρhenyl]ethoxy}-1 - phenyl-6-(1H-tetrazol-1-yl)-δ-azabicyclo[3.2.1]octane (Example 136; 1δδmg, 0.26mmol) was dissolved in methanol (δml) and 2N hydrochloric acid (O.δml) and 10% palladium hydroxide (40mg) added and the mixture hydrogenated at 50psi for 30 minutes. The reaction mixture was then filtered and concentrated in vacuo. The oil was partitioned between saturated sodium hydrogen carbonate solution and dichloromethane and the organics dried (MgSO₄) and concentrated in vacuo to give a yellow oil. This was purified by thin layer chromatography [5% methanol in dichloromethane] to give a white solid. The hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether to a solution in diethyl ether and the title compound filtered and dried in vacuo at 60°C (41 mg, 2δ%). m/z (ES⁺) 512 ([M+Hf).

EXAMPLE 137 (1ff*2ff*,5S*6ff*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6- cyano-1-phenyl-8-azabicyclo[3.2.1]octane

Sodium hydride (0.3g, 7.5mmol, 60% in oil) was added portionwise to a solution of 3,5-bis(trifluoromethyl)benzyl bromide (2.5g, 8.3mmol) and (1 R *2ff * 6S* 6R*)- δ-benzyl-6-cyano-1-phenyl-δ-azabicyclo[3.2.1]octan-2-ol (Description 31 ; 1.4g, 4.4mmol) in THF (20ml). The mixture was stirred at 60°C for 18 hours then cooled with an ice-bath and quenched by dropwise addition of water. The mixture was partitioned between brine and ethyl acetate. The organic layer was separated, dried (MgSO₄), filtered and concentrated. Chromatography on silica gel eluting with 2.6, 5, 10 and 20% ethyl acetate / iso-hexanes afforded the title compound (2.12g, 8δ%). δ_H (360MHz, CDCI₃): 7.76 (1H, s), 7.70 (2H, s), 7.56-7.23 (10H, m), 4.81 (1H, d, J 12.7Hz), 4.54 (1H, d, J 12.7Hz), 4.15-4.07 (3H, m), 3.92 (1H, d, J 15.6Hz), 3.83 (1H, s), 2.88 (1H, dd, J4.δHz, 9.2δHz), 2.42 (1H, dd, J9.2δHz, 13.7Hz), 2.30 (1H, dd, J 4.5Hz, 13.7Hz), 2.22-2.10 (2H, m), 1.86-1.77 (1H, m).

EXAMPLE 138 (1 ff * 2ff * 5S*,6ff *)-8-Benzyl-2-{[3,5-bis(trif luoromethyl)phenyl]methoxy}-1 - phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane

(Iff^R^δS^βR^-δ-Benzyl^-fp.δ-bis^rifluoromethy phenylJmethoxyJ-β-cyano- 1-phenyl-δ-azabicyclo[3.2.1]octane (Example 137; 4g, 7.4mmol), sodium azide (1.4g, 22mmoI) and ammonium chloride (1.2g, 22mmol) were stirred at 120°C in N,N-dimethylformamide (1δml) for 20 hours. On cooling to room temperature the mixture was poured into water (260ml) and extracted (x2) with ethyl acetate. The combined organic extracts were washed (x3) with water then dried (MgSO₄), filtered and concentrated. Residue was chromatographed on silica gel eluting with 1 , 2 and 4% methanol / dichloromethane to give the title compound (2.7g, 63%). δ_H (400MHz, CDCI₃): 7.76 (1H, s), 7.72 (2H, s), 7.61-7.28 (10H, m), 4.92 (1H, d, J 12.6Hz), 4.65 (1H, d, J 12.6Hz), 4.28 (1H, s), 4.09 (1 H, d, J 13.7Hz), 3.91 (1H, d, J 13.7Hz), 3.70 (1 H, dd, J3.6Hz, 9.4Hz), 3.45 (1H, s), 2.57 (1H, dd, J 9.4Hz, 14.1Hz), 2.47-2.38 (1H, m), 2.27 (1H, dd, J 5.0Hz, 15.3Hz), 2.16-2.09 (1H, m), 1.86 (1 H, dd, J 3.2Hz, 14.1 Hz), 1.44 (1 H, dd, J δ.OHz, 13.4Hz).

EXAMPLES 139a and 139b (1ff*2ff*5S*6ff*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(1- methyl-1H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (isomer B); and (1ff*_!2ff*5S*6ff")-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(2- methyl-2H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (isomer A) (1 R*2R*,5S*,6R^-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl- 6-(tetrazoI-6-yl)-3-azabicyclo[3.2.1]octane (Example 136; 0.5g, O.δδmmol), methyl iodide (0.3g, 2.1 mmol) and potassium carbonate (0.29g, 2.1 mmol) were stirred at 60°C in acetonitrile (20ml) for 2 hours. Concentrated in vacuo then partitioned between dichloromethane and water. The organic layer was separated, dried (MgSO₄), filtered and concentrated. The residue was chromatographed on silica gel eluting with 20, 60 and 76% ethyl acetate / iso-hexanes to afford the title compounds: isomer A (0.2δg, 49%) and isomer B (0.17g, 33%). EXAMPLE 139a - (isomer B):- δ_H (400MHz, CDCI₃): 7.76 (1 H, s), 7.73 (2H, s), 7.69-7.67 (2H, d, J8.6Hz), 7.38-7.14 (8H, m), 4.89 (1H, d, J 12.8Hz), 4.64 (1H, d, J 12.δHz), 4.25 (1H, s), 4.07 (1H, d, J 14.δHz), 3.92 (1H, d, J 14.8Hz), 3.8δ (3H, s), 3.49 (1H, s), 3.40 (1H, dd, J4.7Hz, 9.3Hz), 2.δ6 (1H, dd, J4.6Hz, 13.6Hz), 2.46 (1H, dd, 9.3Hz, 13.6Hz), 2.42-2.04 (3H, m), 1.27-1.25 (1H, m). EXAMPLE 139b - (isomer A):- δ_H (400MHz, CDCI₃): 7.74 (3H, s), 7.63 (2H, d, J 7.3Hz), 4.88 (1H, d, J 12.9Hz), 4.62 (1H, d, J 12.8Hz), 4.34 (3H, s), 4.22 (1H, s), 0 4.12 (1H, d, J 15.7Hz), 3.69 (1H, d, J 15.7Hz), 3.6δ (1H, s), 3.63 (1H, dd, J 4.6Hz, 9.3Hz), 2.59 (1H, dd, J4.7Hz, 13.6Hz), 2.47 (1H, dd, J9.3Hz, 13.6Hz), 2.27-2.06 (3H, m), 1.33-1.33 (1H, m).

Compounds listed in the Table 3 were prepared in an analogous manner using 5 appropriate halide.

Table 3.

EXAMPLE 140 (1ff*2ff*,5S*,6ff*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-{2- [2-(f-butoxycarbonylamino)ethyl]-2ff-tetrazol-5-yl}-1-phenyl-8- azabicyclo[3.2.1]octane

Diethylazodicarboxylate, 0.15g, 0.86mmol was added to a solution of (1 ff*,2R*,5S*,6R -δ-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl- 6-(tetrazol-5-yl)-δ-azabicyclo[3.2.1]octane (Example 133; 0.5g, O.δδmmol), [N-(f-butoxy-carbonyl)ethanolamine] (0.15g, 0.93mmol) and triphenylphosphine 0 (0.23g, O.δδmmol) in dichloromethane (20ml). The mixture was stirred at room temperature for 2 hours then concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10, 20 and 30% ethyl acetate / iso- hexanes to yield the title compound (543mg, δδ%). δ_H (400MHz, CDCI₃): 7.74 (3H, s), 7.65-7.63 (2H, m), 7.35-7.13 (3H, m), 4.δ9 (1H, 5 d, J 12.9Hz), 4.71-4.70 (2H, m), 4.63 (1 H, d, J 12.9Hz), 4.24-4.20 (1H, m), 4.13 (1 H, d, J 15.6Hz), 3.90 (1H, d, J 1δ.6Hz), 3.76 (2H, m), 3.61 (1H, s), 3.54 (1H, dd, J 4.6Hz, 9.4Hz), 2.58 (1H, dd, J4.5Hz, 13.6Hz), 2.46 (1H, dd, J 9.4Hz, 13.6Hz), 2.32-2.08 (3H, m), 1.44 (9H, s), 1.44-1.41 (1H, m).

EXAMPLE 141 (1ff*2ff*,5S*,6ff*)-6-[2-(2-AminoethyI)-2r -tetrazol-5-yl]-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane

(1 ff*2R*,5S*6R^,,)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-{2-[2-(t- butoxycarbonylamino)ethyl]-2 -/-tetrazol-5-yl}-1 -phenyl-3-azabicyclo[3.2.1 ]octane (Example 140; 0.54g) was stirred in 20% trifluoroacetic acid / dichloromethane for 90 minutes. The mixture was concentrated in vacuo. The residue was partitioned between saturated sodium carbonate and dichloromethane. The organic layer was separated, dried (MgSO₄), filtered and concentrated to yield the title compound (0.45g, 96%). δ_H (400MHz, CDCI₃): 7.74 (3H, s), 7.65-7.63 (2H, m), 7.35-7.13 (8H, m),4.89 (1H, d, J 12.9Hz), 4.67-4.61 (3H, m), 4.23-4.18 (1H, m), 4.14 (1H, d, J 15.7Hz), 3.88 (1H, d, J 15.7Hz), 3.64 (1H, s), 3.55 (1H, dd, J4.6Hz, 9.4Hz), 3.35-3.32 (2H, m), 2.62 (1H, dd, J4.6Hz, 13.6Hz), 2.45 (1H, dd, J9.4Hz, 13.6Hz), 2.28-2.12 (3H, m), 1.39-1.35 (1H, m).

EXAMPLE 142

(1ff*2ff*5S*6ff*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-{2- [2-(methylsulphonylamino)ethyl]-2H-tetrazol-5-yl}-1-phenyl-8- azabicyclo[3.2.1 ]octane

Methanesulphonyi chloride (90mg, 0.78mmol) was added to a solution of (1 R*2R*5S*6R)-6-[2-(2-aminoethyl)-2R-tetrazol-5-yl]-δ-benzyl-2-{[3,5- bis(trif luoromethyl)phenyl]methoxy}-1 -phenyl-8-azabicyclo[3.2.1 ]octane (Example 141; 0.46g, 0.71 mmol) and triethylamine (101mg, 1mmol) in dichloromethane (10ml). The reaction mixture was stirred at room temperature for 3 hours then washed with water (x2). The organic layer was separated, dried (MgSO₄), filtered and concentrated to yield the title compound (0.47g, 94%). δ_H (360MHz, MeOH-c/₄): 7.87 (2H, s), 7.80 (1H, s), 7.68-7.66 (2H, m), 7.33-7.10 (8H, m), 4.99 (1 H, d, J 13.1 Hz), 4.81 -4.70 (2H, m), 4.68 (1 H, d, J 13.1 Hz), 4.34 (1H, s), 4.12 (1H, d, J 16.6Hz), 3.81 (1H, d, J 16.6Hz), 3.72-3.66 (2H, m), 3.59- 3.56 (2H, m), 2.87 (3H, s), 2.56-2.62 (2H, m), 2.31-2.21 (3H, m), 1.37-1.35 (1H, m).

EXAMPLE 143 (1ff*2ff*,5S*,6ff*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-{2- [2-(N,N-dimethylamino)ethyl]-2H-tetrazol-5-yl}-1-phenyl-8- azabicyclo[3.2.1 ]octane

Prepared in analogous manner to

bis(trifluoromethyl)phenyl]methoxy}-6-{2-[2-(f-butoxycarbonylamino)ethyl]-2 -- tetrazol-5-yl}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 140) using N,N-dimethylethanolamine. m/z (ES⁺) 669 [M+Hf.

EXAMPLES 144a and 144b (1ff*2ff*5S*,6ff*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(2- methoxycarbonylmethyl-2ff-tetrazol-5-yl)-1-phenyl-8- azabicyclo[3.2.1]octane (isomer A); and

(1ff*,2ff*,5S*,6ff*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(1- methoxycarbonylmethyl-1 ff-tetrazol-5-yl)-1 -phenyl-8- azabicyclo[3.2.1]octane (isomer B)

(1 ff*,2ff*,5S*6R^-8-Benzyl-2-{[3,δ-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl- 6-(tetrazol-δ-yl)-δ-azabicyclo[3.2.1]octane (Example 13δ; 2g, 3.4mmol), methyl bromoacetate (O.δml, δ.1 mmol) and potassium carbonate (0.7δg, 0.51 mmol) were stirred in acetonitrile (20ml) at 45°C for 90 minutes. After this time the mixture was concentrated in vacuo and the residue partitioned between brine and ethyl acetate. The organic layer was dried (MgSO₄), filtered and concentrated. The residual clear oil was chromatographed on silica gel eluting with 10, 20 and 60% ethyl acetate / iso-hexanes to yield the title compounds: isomer A (1.2g, 64%) and isomer B (0.9g, 40%). EXAMPLE 144a - (isomer A):- δ_H (400MHz, CDCI₃): 7.74 (3H, s), 7.62-7.59 (2H, m), 7.33-7.13 (8H, m), 5.46-5.36 (2H, m), 4.δ8 (1H, d, J 12.8Hz), 4.62 (1H, d, J 12.8Hz), 4.22 (1H, s), 4.13 (1H, d, J 15.7Hz), 3.89 (1H, dd, J4.6Hz, 9.4Hz), 3.83 (3H, s), 3.71 (1H, s), 3.57 (1H, dd, J4.6Hz, 9.4Hz), 2.66 (1H, dd, J4.5Hz, 13.6Hz), 2.47 (1H, dd, J 9.4Hz, 13.6Hz), 2.32 -2.08 (3H, m), 1.27-1.24 (1H, m). EXAMPLE 144b - (isomer B):- δ_H (400MHz, CDCI₃): 7.75 (1H, s), 7.69 (2H, s), 7.67-7.64 (2H, m), 7.39-7.18 (8H, m), 5.36 (1H, d, J 17.6Hz), 4.91 (1H, d, J 17.6Hz), 4.38 (1H, d, J 12.7Hz), 4.61 (1H, d, J 12.7Hz), 4.25 (1H, s), 4.11 (1H, d, J 15.1Hz), 3.62 (3H, s), 3.48-3.46 (2H, m), 2.69 (1H, dd, Jδ lHz, 13.8Hz), 2.44 (1H, dd, J9.5Hz, 13.8Hz), 2.41-2.22 (3H, m), 1.27-1.24 (1H, m).

EXAMPLE 145 (1ff*2ff*,5S*6ff 8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(2- carboxymethyI-2H-tetrazol-5-yI)-1-phenyl-8-azabicyclo[3.2.1]octane

Lithium hydroxide (40mg, 0.9mmol) was added to a solution of (1 R^*2R*,5S*6R 8-benzyl-2-{[3,δ-bis(trifluoromethyl)phenyl]methoxy}-6-(2- methoxycarbonylmethyl-2H-tetrazol-δ-yl)-1 -phenyl-δ-azabicyclo[3.2.1 ]octane (Example 144a; 0.6g, 0.91 mmol) in water (5ml) and THF (5ml). The reaction mixture was stirred at room temperature for 30 minutes then partitioned between 5% citric acid solution and ethyl acetate. The organic layer was separated, dried (MgSO₄), filtered and concentrated to yield the title compound (O.δδg, 94%). δ_H (400MHz, CDCI₃): 7.74 (1H, s), 7.64 (2H, s), 7.57-7.66 (2H, m), 7.33-7.02 (8H, m), 5.36-6.21 (2H, m), 4.80 ( 1H, d, J 12.9Hz), 4.48 (1H, d, J 12.9Hz), 4.14 (1 H, d, J 15.3Hz), 4.00 (1H, s), 3.83 (1H, s), 3.67-3.52 (2H, m), 2.81 -2.7δ (1H, m), 2.58-2.52 (1H, m), 2.32-2.00 (3H, m), 1.43-1.39 (1H, m).

EXAMPLE 146 (1 ff*,2ff*5S*6ff*)-8-BenzyI-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-{2- [(N,N-dimethyIcarbamoyl)methyl]-2H-tetrazol-5-yl}-1-phenyl-8- azabicyclo[3.2.1 loctane

Prepared in analogous manner to (1 R^*2R*,5S*,6R^*)-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6- carboxamide (Example 75) using dimethylamine (2.0M solution in THF) and (1R*,2R^*,5S*6R^5,)-8-benzyl-2-{[3,δ-bis(trifluoromethyl)phenyl]methoxy}-6-(2- carboxymethyl-2R-tetrazol-δ-yl)-1 -phenyl-δ-azabicyclo[3.2.1 ]octane (Example 146). δ_H (400MHz, CDCI₃): 7.74 (3H, s), 7.62-7.60 (2H, m), 7.32-7.12 (8H, m), 6.61-6.42 (2H, m), 4.87 (1H, d, J 12.9Hz), 4.61 (1H, d, J 12.9Hz), 4.21 (1H, s), 4.12 (1H, d, J 16.8Hz), 3.8δ (1H, d, J 1δ.8Hz), 3.72 (1H, s), 3.57 (1H, dd, J4.6Hz, 9.4Hz), 3.10 (3H, s), 3.03 (3H, s), 2.67 (1H, dd, J4.6Hz, 13.6Hz), 2.44 (1H, dd, J 9.4Hz, 13.6Hz). 2.25-2.11 (3H, m), 1.38-1.36 (1H, m).

EXAMPLE 147 (1ff*2ff*₅5S*,6ff*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-[2- (2-hydroxypropyl)-2H-tetrazol-5-yl]-1-phenyI-8-azabicycIo[3.2.1]octane Sodium borohydride (13 mg, 0.34mmol) was added to a solution of

(1 ff*,2R*,5S*,6R^,,)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-[2-(2- oxopropyl)-2 -/-tetrazol-δ-yl]-1-phenyl-3-azabicyclo[3.2.1]octane (Compound 3i in Table 3; 0.2g, 0.31 mmol) in methanol (10ml) and THF (2ml). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between saturated sodium hydrogen carbonate and ethyl acetate. The organic layer was separated, dried (MgSO₄), filtered and concentrated. The residue was chromatographed on silica gel eluting with 26 and 35% ethyl acetate / iso-hexanes to yield the title compound (189mg, 95%). δ_H (400MHz, CDCI₃): 7.67 (3H, s), 7.57-7.54 (2H, m), 7.28-7.24 (2H, m), 7.18-7.06 (6H, m), 4.81 (1H, d, J 12.8Hz), 4.61-4.44 (3H, m), 4.31 (1H, br s), 4.17 (1H, s), 4.06 (1H, d, J 15.6Hz), 3.62 (1H, d, J 15.6Hz), 3.56 (1H, s), 3.50-3.47 (1 H, m), 2.56-2.51 (1H, m), 2.41-2.35 (1H, m), 2.21-2.03 (3H, m), 1.36-1.31 (1H, m), 1.29- 1.26 (3H, m).

EXAMPLE 148 (1ff*2ff*5S*,6ff*)-8-Benzyl-2-{[3,5-bis(trifluoromethyI)phenyl]methoxy}-6-[2- (2-hydroxy-2-methylpropyl)-2H-tetrazol-5-yl]-1-phenyl-8- azabicyclo[3.2.1]octane Methylmagnesium bromide (3.0M solution in THF, 0.7ml, 2.1 mmol) was added dropwise to a -78°C solution of (1 R*2R*,5S* 6R")-8-benzyl-2-{[3,6- bis(trifluoromethyl)phenyl]methoxy}-6-[2-(2-oxopropyl)-2H-tetrazol-δ-yl]-1-phenyl- δ-azabicyclo[3.2.1]octane (Compound 3i in Table 3; 1.1g, 1.7mmol) in THF (25ml). The mixture was warmed to 0°Cfor 30 minutes then quenched by addition of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and brine. The organic layer was separated, dried (MgSO₄), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 2.5, 5 and 10% ethyl acetate / iso-hexanes to yield the title compound (0.43g, 39%). δ_H (400MHz, CDCI₃): 7.67 (3H, s), 7.57-7.55 (2H, m), 7.28-7.24 (2H, m), 7.18-7.06 (6H, m), 4.82 (1H, d, J 12.9Hz), 4.56 (1H, d, J 12.9Hz), 4.53 (2H, s), 4.17 (1H, s), 4.04 (1H, d, J 15.5Hz), 3.57 (1H, s), 3.50 (1H, dd, J4.6Hz, 9.4Hz), 2.54 (1H, dd, J 4.6Hz, 13.6Hz), 2.38 (1 H, dd, J 9.4Hz, 13.6Hz), 2.32-2.05 (3H, m), 1.38- 1.31(1H, m), 1.18 (6H, s).

EXAMPLE 149 (1ff*2ff*5S*6ff*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(2- methanesulphonylmethyl-2H-tetrazol-5-yl)-1 -phenyl-8- azabicyclo[3.2.1]octane

Oxone® (370mg, 0.6mmol) was added to a suspension of (1 R^^R^δS^β ^-δ- benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(2-methylthiomethyl-2R- tetrazo!-5-y!)-1-phenyl-δ-azabicyclo[3.2.1]octane (Compound 3g in Table 3; 130mg, 0.2mmol) and wet alumina (200mg) in chloroform (10ml). The mixture was heated to 50°C for 1δ hours, then filtered through Celite™ and the filtrate concentrated in vacuo to yield the title compound (92mg, 6δ%). δ_H (400MHz, CDCI₃): 7.76 (1H, s), 7.73 (2H, s), 7.62-7.69 (2H, m), 7.34-7.12 (3H, m), δ.δθ-δ.70 (2H, m), 4.δ8 (1H, d, J 12.9Hz), 4.62 (1H, d, J12.8Hz), 4.26 (1H, s), 4.12 (1H, d, J 15.6Hz), 3.δδ (1H, d, J 15.6Hz), 3.70 (1H, s), 3.5δ (1H, dd, J 4.5Hz, 9.3Hz), 3.07 (3H, s), 2.62 (1H, dd, J4.5Hz, 13.7Hz), 2.44 (1H, dd, J 9.4Hz, 13.7Hz), 2.32-2.14 (3H, m), 1.42-1.36 (1H, m).

EXAMPLE 150 (1ff*2ff*,5S*6ff*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-[2- (2-methoxyethyl)-2H-tetrazol-5-yl]-1 -pheny l-8-azabicyclo[3.2.1]octane lodomethane, 8δmg, 0.6mmol was added to suspension of (1 ff *,2R*,5S* 6R^-3- benzyl-2-{[3,δ-bis(trifluoromethyl)phenyl]methoxy}-6-[2-(2-hydroxyethyl)-2H- tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Compound 3a in Table 3; 250mg, 0.4mmol) and sodium hydride (24mg, 0.6mmol, 60% in oil). The reaction mixture was stirred at 60°C for 2 hours then quenched by addition of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and brine. The organic layer was dried (MgSO₄), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1 :2 ethyl acetate / iso-hexanes to yield the title compound (246mg, 95%). δ_H (400MHz, CDCI₃): 7.75 (3H, s), 7.64-7.62 (2H, m), 7.33-7.12 (δH, m), 4.δ7 (1H, d, J 12.9Hz), 4.79-4.72 (2H, m), 4.62 (1H, d, J 12.9Hz), 4.22 (1 H, s), 4.11 (1H, d, J 15.7Hz), 3.93-3.95 (2H, m), 3.88 (1 H, d, J 15.8Hz), 3.66 (1 H, s), 3.54 (1 H, dd, J 4.6Hz, 9.3Hz), 3.37 (3H, s), 2.65 (1H, dd, J4.5Hz, 13.6Hz), 2.45 (1H, dd, J 9.4Hz, 13.6Hz), 2.25-2.15 (3H, m), 1.36-1.32 (1H, m).

EXAMPLE 151 (1 ff * 2ff * 5S*,6ff *)-2-{[3,5-Bis(trif luoromethyl)phenyl]methoxy}-6-(1 -methyl- 1 ff-tetrazol-5-yl)-1 -phenyl-8-azabicyclo[3.2.1]octane

Palladium on carbon (10%) 100mg was added to a solution of (1 ff^*2R^*5S*,6R^,l)- 3-benzyl-2-{[3,6-bis(trifluoromethyl)phenyl]methoxy}-6-(1 -methyl-1 -/-tetrazol-δ-yl)- 1-phenyl-δ-azabicyclo[3.2.1]octane (Example 139a; 170mg, 0.3mmol) in methanol (10ml). The mixture was transferred to the Parr™ apparatus and hydrogenated at 4δpsi. for 2 hours. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1δ0:δ:1 dichloromethane:methanol:ammonia to yield the title compound (δ4mg, δδ%). The hydrochloride salt was prepared by treatment with ethereal HCI. m/z (ES⁺) 512 [M+Hf.

EXAMPLE 152 (1ff*2ff*,5S*6ff^,,)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(2-methyl- 2ff-tetrazol-5-yl)-1 -phenyl-8-azabicyclo[3.2.1]octane hydrochloride

Prepared in an analogous manner to (1 ff ^*2ff ^*5S*6ff ")-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-6-(1 -methyl-1 H-tetrazol-5-yl)-1 -phenyl-3- azabicyclo[3.2.1]octane (Example 151) from Example 139b. δ_H (360MHz, MeOH-d₄): 7.60 (1H, s), 7.6δ (2H, s), 7.44-7.31 (5H, m), 4.74 (1H, d, J 12.5Hz), 4.60 (1H, s), 4.30 (3H, s), 4.26 (1H, d, J 12.5Hz), 4.00 (1H, dd, J 5.1Hz, 9.8Hz), 3.97 (1H, s), 3.42 (1H, dd, J9.9Hz, 14.5Hz), 2.86 (1H, dd, J 5.1Hz, 14.6Hz), 2.32-2.23 (3H, m), 2.10-2.07 (1H, m).

EXAMPLES 153a and 153b (1 ff *,2ff *,5S*,6ff *)-2-{(1 S*)-1-[3,5-Bis(trif luoromethyl)phenyl]ethoxy}-6-(1 - methyI-1ff-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octahe (isomer A); and (1 ff*,2ff *,5S* 6ff *)-2-{(1 ff *)-1-[3,5-Bis(trif luoromethyl)phenyl]ethoxy}-6-(1 - methyl-1 ff-tetrazol-5-yl)-1 -phenyl-8-azabicyclo[3.2.1 joctane (isomer B)

Palladium hydroxide, 100mg was added as a slurry in water, 1ml to a solution of (1 ff *,2ff *5S*,6ff *)-δ-benzyl-2-{1 -[3,5-bis(trifluoromethyl)phenyl]ethenyloxy}-6-(1 - methyl-1 H-tetrazol-δ-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 34; 360mg, O.δδmmol) in methanol (10ml). The mixture was transferred to the Parr™ apparatus and hydrogenated at 4δpsi for one hour. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was chromatographed using medium pressure Lo-Bar™ chromatography eluting with 1.5% methanol / dichloromethane to yield the title compounds: Isomer A (1 4mg, 40%), isomer B (71 mg, 23%). The hydrochloride salts were prepared by treatment with ethereal HCI.

EXAMPLE 153a - (isomer A) - HCI salt:- δ_H (400MHz, MeOH- ₄): 7.39 (1H, s), 7.δδ (2H, s), 7.56-7.41 (5H, m), 4.60 (1H, s), 4.21 (1H, q, J 6.4Hz), 4.16-4.13 (1H, m), 4.10 (3H, s), 3.93 (1H, s), 3.46 (1H, dd, J 10Hz, 14.4Hz), 2.62 (1H, dd, J 5.4Hz, 14.4Hz), 2.31-2.16 (2H, m), 2.00 1.96 (1H, m), 1.72-1.69 (1H, m), 0.99 (3H, d, J 6.4Hz); m/z (ES⁺) 526 [M+Hf.

EXAMPLE 153b - (isomer B) - HCI salt:- δ_H (400MHz, MeOH-d₄): (isomer B) 7.74 (1H, s), 7.35 (2H, s), 7.32-7.29 (3H, m), 7.19-7.16 (2H, m), 4.67 (1H, q, J 6.4Hz), 4.59 (1H, s), 4.15 (1H, dd, J5.4Hz, 9.9Hz), 4.09 (3H, s), 3.71 (1H, s), 3.36 (1H, dd, J 9.6Hz, 14.4Hz), 2.61 (1H, dd, 5.4Hz, 14.4Hz), 2.36-2.09 (4H, m), 1.44 (3H, d, J 6.4Hz); m/z (ES⁺) 626 [M+H]⁺.

Compounds listed in the Table 4 were prepared in an analogous manner. Table 4.

EXAMPLES 154a and 154b (1 ff *2ff * 5S* 6ff *)-2-{(1 S 1 -[3,5-Bis(trif luoromethyl)phenyl]ethoxy}-6-(2- methyl-2H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (isomer A); and (1 ff *,2ff * 5S* 6ff *)-2-{(1 ff 1 -[3,5-bis(trif luoromethyl)phenyI]ethoxy}-6-(2- methyl-2H-tetrazol-5-yl)-1 -phenyl-8-azabicyclo[3.2.1 J ctane (isomer B) Prepared in an analogous manner to Example 153 from Description 35. EXAMPLE 154a - (isomer A) - HCI salt:- δ_H (400MHz, MeOH-c₄): 7.89 (1 H, s), 7.86 (2H, s), 7.55-7.42 (5H, m), 4.62 (1H, s), 4.30 (3H, s), 4.20 (1 H, q, J6.4Hz),

10 4.02 (1H, dd, J 5.1 Hz, 9.9Hz), 3.97 (1H, s), 3.38 (1H, dd, J9.9Hz, 14.6Hz), 2.86 (1H, dd, J 5.1 Hz, 14.6Hz), 2.27-1.91 (3H, m), 1.72-1.68 (1H, m), 0.99 (3H, d, J 6.4Hz); m/z (ES⁺) 526 [M+H]⁺.

EXAMPLE 154b - (isomer B):- δ_H (360MHz, CDCl₃): 7.62 (1H, s), 7.15-7.13 (7H, m), 4.31 (1H, q, J6.4Hz), 4.21 (3H, s), 3.92 (1H, s), 3.56 (1H, dd, J4.7Hz,

15 9.1Hz), 3.42 (1 H, s), 2.62 (1H, dd, 9.4Hz, 13.4Hz), 2.23 (1H, dd, 4.6Hz, 13.4Hz), 2.06-1.97 (3H, m), 1.72-1.70 (1 H, m), 1.36 (3H, d, J6.4Hz); m/z (ES⁺) 526 [M+Hf.

EXAMPLE 155 (1 ff *,2ff *,5S* 6ff*)-8-Benzyl-2-{(1 ff*)-1-[3,5-bis(trifluoromethyl)phenyl]- (methoxycarbonyl)methoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1 ι|octane

A mixture of (1 ff*,2ff*,5S*,6ff'^l)-3-benzyl-6-cyano-1-phenyl-δ- azabicyclo[3.2.1]octan-2-ol (Description 31 ; 7.1δ6g, 22.6mmol) and rhodium(ll) acetate dimer (0.216g, 0.452mmol) in benzene (30ml) was heated to reflux, and treated slowly with a solution of methyl 2-diazo-2-(3,5-bis(trifluoromethyl)phenyl)- acetate [prepared by the method of R.T. Lewis etal. J. Org. Chem., 2000, 65, 2615] (7.7563g, 24.δ6mmol) in benzene (30ml). After the addition was complete the mixture was concentrated in vacuo and the residue purified by flash column chromatography, eluting with 10-20% ethyl acetate/hexane to give a mixture of diastereomers (6.0g, 2.6:1 ratio). The major diastereomer was separated by crystallisation with ethyl acetate/hexane to afford the title compound in two crops (3.31 g). m/z (ES⁺) 690 ([M+Hf).

EXAMPLE 156

(1 ff *,2ff *,5S* 6ff*)-8-Benzyl-2-{(1 ff 1 -[3,5-bis(trif luoromethyl)phenyl]-2- hydroxyethoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane

(1 ff *,2R *,5S*,6ff*)-8-Benzyl-2-{(1 ff *)-1 -[3,5-bis(trifluoromethyl)phenyl]- (methoxycarbonyl)methoxy}-6-cyano-1-phenyl-δ-azabicyclo[3.2.1]octane (Example 166; 2.40δg, 4mmol) in methanol (25ml) was treated with sodium borohydride (2.269δg, 0.60mmol) potionwise at 5-10°C. The reaction was quenched with acetone and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the organics separated and dried (MgSO₄) and concentrated in vacuo to afford the title compound as a white foam in quantitative yield. δ_H (400 MHz, CDCI₃): 7.78 (1H, s), 7.53 (2H, m), 7.29-7.17 (10H, m), 4.60 (1H, m), 4.13 (1H, d, J 15.4Hz), 3.93 (1H, d, J 15.4Hz), 3.66 (1H, s), 3.64 (3H, m), 2.87 (1H, m), 2.38 (1H, m), 2.29-2.17 (3H, m), 1.69 (1H, m), 1.27 (1H, m). EXAMPLE 157 (1 ff *,2ff *,5S*,6fl*)-8-Benzyl-2-{(1 ff *)-1 -[3,5-bis(trif luoromethyl)phenyl]-2- phenylmethoxyethoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (1 ff * 2ff *,5S* 6R*)-8-Benzyl-2-{(1 ff *)-1 -[3,5-bis(trifluoromethyl)phenyl]-2- hydroxyethoxy}-6-cyano-1 -phenyl-δ-azabicyclo[3.2.1 ]octane (Example 156; 0.7749g, 1.35mmol), benzyl bromide (0.461 δg, 0.321ml, 2.7mmol), 1δ-crown-6 (0.714g, 2.7mmol) and sodium hydride (0.1037g, 4.32mmol) in THF (6ml) were heated at 60^°C for 1hour. The mixture was diluted with water and extracted into ethyl acetate. The organics were collected and dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 15% ethyl acetate/iso-hexane, to afford the title compound as a clear oil (712mg, 79%). δ_H (400 MHz, CDCI₃): 7.80 (1H, s), 7.51 (4H, m), 7.40-7.10 (13H, m), 4.67 (1H, m), 4.61 (1 H, d, J 12.0Hz), 4.52 (1 H, d, J 11.9Hz), 4.26 (1 H, d, J 16.0Hz), 4.03 (1H, d, J 16.0Hz), 3.93 (1H, s), 3.81 (1H, s), 3.66 (1H, m), 3.46 (1H, m), 2.84 (1H, m), 2.31 (3H, m), 2.12 (1H, m), 1.73 (1H, m), 1.21 (1H, m).

EXAMPLE 158 (1 ff *,2ff * 5S* 6ff*)-8-Benzyl-2-{(1 ff *)-1 -[3,5-bis(trif luoromethyl)phenyl]-2- phenylmethoxyethoxy}-1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane

(1 ff *2ff *,5S*,6ff*)-8-Benzyl-2-{(1 R 1 -[3,5-bis(trifluoromethyl)phenyl]-2- phenylmethoxyethoxy}-6-cyano-1 -phenyI-δ-azabicyclo[3.2.1 ]octane (Example 157; 0.71 Oδg, 1.07mmol), sodium azide (0.2037g, 3.21 mmol) and ammonium chloride (0.172g, 3.21 mmol) in dimethylformamide (10ml) were heated at 120°C for 1 δ hours. A further 3.0eq of sodium azide and 3.0eq of triethylamine hydrochloride were added and the mixture heated for a further 1 δ hours. The mixture was diluted with ethyl acetate and washed with water. The organics were collected, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with δ% methanol/dichloromethane to give the title compound (400mg, 53%). δ_H (400 MHz, CDCI₃): 7.62 (1H, s), 7.56 (2H, s), 7.41-7.17 (15H, m), 4.7δ (1H, m), 4.56 (1H, d, J 11. δHz), 4.66 (1H, d, J 11.9Hz), 4.30 (1H, d, J 14.6Hz), 4.13 (2H, m), 3.68 (1H, m), 3.61 (1H, m), 3.50 (1H, m), 3.46 (1H, s), 2.43 (3H, m), 2.02 (1H, m), 1.70 (1H, m), 1.35 (1 H, m).

EXAMPLES 159a and 159b (1 ff *,2ff * 5S* 6ff*)-8-Benzyl-2-{(1 ff *)-1 -[3,5-bis(trif luoromethyl)phenyl]-2- phenylmethoxyethoxy}-6-(2-methyl-2ff-tetrazol-5-yl)-1-phenyl-8- azabicyclo[3.2.1]octane (isomer A); and

(1 ff *,2ff * 5S* 6ff*)-8-benzyl-2-{(1 ff 1 -[3,5-bis(trif luoromethyl)phenyl]-2- phenylmethoxyethoxy}-6-(1 -methyl-1 ff-tetrazol-5-yl)-1 -phenyl-8- azabicyclo[3.2.1]octane (isomer B)

(1 ff *2ff * 5S*,6ff*)-8-Benzyl-2-{(1 ff ^*)-1 -[3,5-bis(trifluoromethyl)phenyl]-2- phenylmethoxyethoxy}1-phenyl-6-(tetrazol-δ-yl)-δ-azabicyclo[3.2.1]octane (Example 168; 0.403g, .57mmol), methyl iodide (0.2427g, 0.107ml, 1.71 mmol) and potassium carbonate (0.236g, 1.71 mmol) in acetonitrile (10ml) were heated at 60°C for 2 hours. The mixture was quenched with water and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organics were collected, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 1% methanol/dichloromethane to give the title compounds (isomer A; 60mg) and (isomer B; 70mg), together with mixed fractions.

EXAMPLE 159a - (isomer A):- δ_H (400 MHz, CDCI₃): 7.79 (1H, s), 7.58 (2H, s), 7.31 -7.08 (15H, m), 4.72 (1 H, m), 4.68 (1 H, d, J 11.8Hz), 4.63 (1 H, d, J 11.9Hz), 4.30 (3H, s) 4.22 (1H, d, J 14.6Hz), 4.08 (1H, s), 4.01 (1H, d, J 14.8Hz), 3.69 (2H, m), 3.49 (2H, m), 2.36 (4H, m), 2.01 (1H, m), 1.36 (1H, m). EXAMPLE 159b - (isomer B):- δ_H (400 MHz, CDCI₃): 7.80 (1 H, s), 7.57 (2H, s), 7.32-7.12 (15H, m), 4.78 (1H, m), 4.58 (1H, d, J 11.6Hz), 4.53 (1H, d, J 11.9Hz), 4.22 (1H, d, J 14.6Hz), 4.10 (1H, s), 4.01 (1H, d, J 14.6), 3.36 (3H, s), 3.69 (1H, m), 3.50 (2H, m), 3.46 (1H, s), 2.53 (1H, m), 2.35 (3H, m), 2.01 (1H, m), 1.36 (1 H, m). EXAMPLE 160 (1 ff * 2ff *,5S*)-2-{(1 ff -1 -[3,5-Bis(trif luoromethyl)phenyl]-2-hydroxyethoxy}-6- (1-methyl-1ff-tetrazol-5-yl)-1-phenyI-8-azabicyclo[3.2.1]octane hydrochloride

(1 ff ^*2ff *6S^* 6ff^*)-3-Benzyl-2-{(1 ff ^*)-1 -[3,5-bis(trifiuoromethyl)phenyl]-2- phenylmethoxyethoxy}-6-(1 -methyl-1 H-tetrazol-5-yl)-1 -phenyl-3- azabicyclo[3.2.1]octane (Example 159b; 0.0721 g, 0.1 mmol), palladium 5% on charcoal (60mg) and acetic acid (0.5ml) in methanol (10ml) were hydrogenated on the Parr™ apparatus for 4δ hours. The mixture was filtered using a Whatman™ 0.2 micrometer filter. The filtrate was concentrated in vacuo, taken into dichloromethane and washed with saturated sodium hydrogen carbonate. The organic phase was separated using a bond elute cartridge and concentrated in vacuo. The product was isolated as the hydrochloride salt, recrystallised from methanol/diethyl ether to give the title compound as a white crystalline solid, m/z (ES⁺) 542 ([M+Hf).

EXAMPLE 161 (1 ff *,2ff * 5S*,6ff*)-2-{(1 ff *)-1 -[3,5-Bis(trif luoromethyl)phenyl]-2- hydroxyethoxy}-6-(2-methyl-2H-tetrazol-5-yl)-1-phenyl-8- azabicyclo[3.2.1]octane hydrochloride Prepared according to the method of Example 160 from Example 159a. δ_H (400 MHz, MeOH-d₄): 7.77 (1H, s), 7.38 (3H, m), 7.24 (5H, m), 4.74 (1H, t, J 5.6Hz), 4.62 (1H, s), 4.30 (3H, s), 4.04 (1H, m), 3.73 (1H, s), 3.59 (2H, d, J 5.72Hz), 2.79 (1H, m), 2.40 (2H, m), 2.13 (2H, m); m/z (ES⁺) 542 ([M+H]⁺).

EXAMPLE 162

(1fl*,2ff*,5S*6ff 8-Benzyl-2-{[3,5-bis(trifIuoromethyl)phenyl]methoxy}-1- phenyl-8-azabicyclo[3.2.1]octan-6-thioamide

Lawesson's reagent (0.23g, 0.57mmol) was added to a solution of (1 ff*,2R*,5S*6ff")-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl- 3-azabicyclo[3.2.1]octan-6-carboxamide (Example 75; 0.64g, 1.14mmol) in toluene (20ml). The mixture was stirred at 100°C for 1 hour then concentrated in vacuo. The residue was chromatographed on silica gel eluting with 2 and 3% methanol / dichloromethane to yield the title compound (0.162g, 25%). δ_H (400MHz, CDCI₃): 7.74 (1H, s), 7.68 (2H, s), 7.51-7.50 (2H, m), 7.45-7.41 (2H, m), 7.36-7.26 (6H, m), 4,90 (1H, d, J 12.7Hz), 4.60 (1H, d, J 12.7Hz), 4.24 (1H, s), 4.05 (1H, d, J 13.6Hz), 3.83 (1H, d, J 13.6Hz), 3.49 (1H, s), 3.36 (1H, dd, J 2.5Hz, 9.6Hz), 2.51 (1H, dd, J 9.6Hz, 14.2Hz), 2.39-2.35 (1H, m), 2.19-2.14 (1 H, m), 2.02-1.97 (1H, m), 1.91 (1H, dd, J 4.1 Hz, 14.2 Hz), 1.35-1.32 (1H, m).

EXAMPLE 163 (1ff*2ff*5S*6ffO-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(3- methyl-1 ,2,4-triazo-5-yl)-1 -phenyl-8-azabicyclo[3.2.1 ]octane (1 ff * 2ff *5S* 6ff 8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1 -phenyl- 3-azabicyclo[3.2.1]octan-6-thioamide (Example 162; 0.16g, 0.27mmol), acetylhydrazide (0.2g, 2.7mmol) and crushed molecular sieves were stirred in xylenes at reflux for 24 hours. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1 , 2 and 5% methanol / dichloromethane to yield the title compound (88mg, 53%). δ_H (400MHz, CDCI₃): 7.74 (1H, s), 7.72 (2H, s), 7.54-7.62 (2H, m), 7.41-7.34 (6H, m), 7.30-7.26 (2H, m), 4.90 (1H, d, J 12.8Hz), 4.62 (1H, d, J 12.7Hz), 4.23 (1H, s), 4.03 (1H, d, J 14.0Hz), 3.δδ (1H, d, 14.0Hz), 3.52 (1H, s), 3.37 (1H, dd, J 3.9Hz, 9.5Hz), 2.46 (1 H, dd, J 9.5Hz, 13.9Hz), 2.44-2.42 (1 H, m), 2.31 (3H, s), 2.23-2.18 (1H, m), 2.06-2.04 (1H, m), 1.95 (1H, dd, J3.3Hz, 13.3Hz), 1.36-1.33 (1H, m).

EXAMPLE 164 (1ff*2ff*,5S*,6ff^,,)-8-Benzyl-2-{[3,5-bis(trifluoromethyI)phenyl]methoxy}-6- (1 ,3-imidazol-2-yl)-1 -phenyl-8-azabicyclo[3.2.1]octane

A solution of glyoxal (40% in water, 0.15ml, O.δδmmol) and (1 ff ^*2ff*,5S*6ff ^-δ- benzyl-2-{[3,δ-bis(trifluoromethyl)phenyl]methoxy}-6-formyl-1-phenyl-δ- azabicyclo[3.2.1]octane (benzyl derivative of Example 47; 0.3g, O.δδmmol) in ethanol (20ml) was added to a saturated solution of ammonia in ethanol (10ml). Ammonia gas was bubbled through the solution for a further 6 minutes then left to stir for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and brine. The organic layer was separated, dried (MgSO , filtered and concentrated in vacuo to yield the title compound (307mg, 96%). δ_H (400MHz, CDCI₃): 7.74 (1H, s), 7.72 (2H, s), 7.56-7.53 (2H, m), 7.43-7.32 (6H, m), 7.31-7.25 (2H, m), 6.77 (2H, s), 4.91 (1H, d, J 12.7Hz), 4.62 (1H, d, J 12.7Hz), 4.25 (1H, s), 4.10 (1H, d, J 13.δHz), 3.88 (1H, d, J l3.8Hz), 3.45 (1H, s), 3.33 (1H, dd, J 3.9Hz, 9.4Hz), 2.46 (1H, dd, J9.4Hz, 13.9Hz), 2.40-2.32 (1H, ), 2.22-2.05 (2H, m), 1.87 (1H, dd, J3.9Hz, 13.9Hz), 1.37-1.33 (1 H, m).

EXAMPLE 165 (1ff*2ff*,5S*,6ff 8-BenzyI-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(4- methyl-1 ,3-imidazol-2-yl)-1 -phenyl-8-azabicyclo[3.2.1]octane

Prepared in an analogous manner to (1ff^*,2ff*,5S^*,6R^-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-6-(1,3-imidazol-2-yl)-1-phenyl-δ- azabicyclo[3.2.1]octane (Example 164) using methyl glyoxal. δ_H (400MHz, CDCI₃): 7.74 (1H, s), 7.72 (2H, s), 7.55-7.52 (2H, m), 7.43-7.21 (3H, m), 6.42 (1H, s), 4.90 (1H, d, J 12.7Hz), 4.62 (1H, d, J 12.7Hz), 4.23 (1H, s), 4.06 (1 H, d, J 13.6Hz), 3.87 (1H, d, J 13.7Hz), 3.43 ( 1H,s), 3.32-3.28 (1H, m), 2.45 (1H, dd, J 9.4Hz, 13.9Hz), 2.40-2.16 (3H, m), 2.12 (3H, s), 1.87 (1H, dd, J 3.8Hz, 13.9Hz), 1.35-1.32 (1H, m).

EXAMPLE 166 (Iff^ff^δS^eff^^- jS-Bis rifluoromethy henyπmethoxyH^S-methyl- 1 ,2,4-triazol-5-yl)-1 -phenyl-8-azabicyclo[3.2.1 joctane hydrochloride Prepared in an analogous manner to Example 153a. m/z (ES⁺) 511 [M+H]⁺.

EXAMPLE 167 (1 ff*2fl*,5S*6ff*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(1,3- imidazol-2-yl)-1-phenyl-8-azabicyclo[3.2.1]octane dihydrochloride Prepared in an analogous manner to Example 153a. m/z (ES⁺) 496 [M+H]⁺. EXAMPLE 168 (1ff*2ff*,5S*6ff^, -2-{[3_J5-Bis(trifluoromethyl)phenyl]methoxy}-6-(1-methyl- 1,3-imidazol-2-yl)-1-phenyl-8-azabicyclo[3.2.1]octane dihydrochloride

Prepared in an analogous manner to Example 153a. m/z (ES⁺) 510 [M+H]⁺.

EXAMPLE 169 (1ff*,2ff*,5S*6ff^,,)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-(4-methyl- 1,3-imidazoI-2-yl)-1-phenyl-8-azabicyclo[3.2.1]octane dihydrochloride Prepared in an analogous manner to Example 153a. m/z (ES⁺) 510 [M+Hf.

EXAMPLE 170 (1ff*2ff*5S*6S 8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6- ethoxycarbonyl-6-f luoro-1 -phenyl-8-azabicyclo[3.2.1 loctane

Sodium hydride (60% in oil, 100mg, 2.5mmol) was washed twice with iso-hexane and added as a suspension in THF (3ml) to a stirred mixture of (1 ff*2R*,5S*6S 8-benzyl-6-ethoxycarbonyl-6-fluoro-1-phenyl-8- azabicyclo[3.2.1]octan-2-ol (Description 33; 512mg, 1.3mmol), 3,5-bis(trifluoromethyl)benzyl bromide (0.5ml, 2.7mmol), 1δ-crown-6 (360mg, 1.37mmol) in THF (5ml) at room temperature. The reaction mixture was stirred for 40 hours, quenched with saturated aqueous NH₄Cl and extracted into a 1 :1 mixture of iso-hexane:diethyl ether. The combined organic extracts were washed with water, dried (Na,SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether) to give the title compound (494mg, 61%). δ_H (400 MHz, CDCI₃): 7.75 (1H, s), 7.74 (2H, s), 7.61 (2H, m), 7.39-7.17 (8H, m), 4.92 (1H, d, J 12.6Hz), 4.65 (1H, d, J 13.0Hz), 4.39-4.19 (3H, m), 4.12 (1H, d, J 15.4Hz), 3.89 (1H, d, J 15.4Hz), 3.69 (1H, s), 2.95 (1H, dd, J 12.3Hz, 15.1Hz), 2.37-2.12 (3H, m), 2.18 (1H, dd, J 14.7Hz, 24.6Hz), 1.55 (1 H, m), 1.30 (3H, t, J 7.0Hz). EXAMPLE 171 (1ff*2ff^5S^6S 2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6- ethoxycarbonyl-6-f luoro-1 -phenyl-8-azabicyclo[3.2.1 Joctane

A mixture of ((1 R*,2R*5S*,6S*)-8-benzyl-2-{[3,5- bis(trifluoromethyl)phenyl]methoxy}-6-ethoxycarbonyl-6-fluoro-1-phenyl-8- azabicyclo[3.2.1]octane (Example 170; 52mg, O.Oδδmmol), 10% palladium on charcoal (123mg), ethanol (10ml) was stirred under hydrogen atmosphere (1atm) at +65°C for 40 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol) to give the title compound (13mg, 30%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI. m/z (ES⁺) 620 [M+Hf.

EXAMPLE 172 (1ff*2ff*,5S*,6S 8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6- f luoro-6-[1 -(2-methoxyethoxymethyl)-1 H-tetrazol-5-yl]-1 -phenyl-8- azabicyclo[3.2.1 ]octane (1 ff * 2ff *,5S*,6S*)-8-benzyl-6-fluoro-6-[1 -(2-methoxyethoxymethyl)-1 H-tetrazol-5- yl]-1-phenyl-δ-azabicyclo[3.2.1]octan-2-ol (Description 46; 20δmg, 0.44mmol) was added to a stirred mixture of sodium hydride (60% in oil, 60mg, l.δmmol, washed twice with iso-hexane) in THF (2ml) followed by 18-crown-6 (40mg, 1.δmmol) and 3,5-bis(trifluoromethyl)benzyl bromide (0.4ml, 2.16mmol) at room temperature. The reaction mixture was warm up to reflux and stirred at room temperature overnight, then quenched with saturated aqueous NH₄CI and extracted into diethyl ether. The combined organic extracts were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso- hexane:diethyl ether10-70%) to give the title compound (303mg, 97%). δ_H (360 MHz, CDCI₃): 7.81 (5H, m), 7.40 (2H, t, J 8.1Hz), 7.28 (1H, m), 7.14-6.96 (δH, m), 6.89 (1 H, d, J 11.2Hz), 6.70 (1 H, dd, J 1.4Hz, 11.2Hz), 4.96 (1 H, d, J 13.0Hz), 4.72 (1 H, d, J 12.6Hz), 4.40 (1 H, br s), 4.06 (1 H, d, J 15.1 Hz), 3.85 (1 H, d, J 14.7Hz), 3.68 (1H, dd, J 12.6Hz, 14.7Hz), 3.64 (1H, s), 3.47 (1H, ddd, J 2.5Hz, 6.1Hz, 10.5Hz), 3.21 (3H, s), 3.06 (1H, ddd, J2.5Hz, 4.6Hz, 11.2Hz), 2.9δ (1H, ddd, J 2.6Hz, 4.6Hz, 10.9Hz), 2.64 (1H, ddd, J2.5Hz, δ.1 Hz, 10.9Hz), 2.53 (1H, dd, J 15.1Hz, 26.3Hz), 2.44-2.15 (3H, m), 1.69 (1H, m).

EXAMPLES 173a and 173b

(1ff*,2ff*5S*6S^,,)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6- fluoro-6-(1 -methyl-1 ff-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (isomer A); and (1ff*2ff*,5S*6S 8-benzyl-2-{[3,5-b«s(trifluoromethyl)phenyl]methoxy}-6- f Iuoro-6-(2-methyl-2H-tetrazol-5-yl)-1 -phenyl-8-azabicyclo[3.2.1 ]octane (isomer B)

A mixture of (1 ff*2ff^*,5S*,6S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]- methoxy}-6-f luoro-6-[1 -(2-methoxyethoxymethyl)-1 H-tetrazol-5-yl]-1 -phenyl-δ- azabicyclo[3.2.1]octane (Example 172; 1δ0mg, 0.22mmol), 1M solution of hydrogen chloride in ether (3ml) and methanol (3ml) was stirred at reflux for 9 hours. The reaction mixture was concentrated. The residue (170mg) was treated with dichloromethane (3ml), methanol (0.5ml), triphenylphosphine (220mg, O.δδmmol) and diethyl azodicarboxylate (0.12ml, 0.56mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo to give a 1 :3.3 mixture of isomers A and B, respectively. Both isomers were separated by chromatography on silica gel (iso-hexane: ethyl acetate 0-20%). EXAMPLE 173a - (isomer A):- δ_H (400 MHz, CDCI₃): 7.77 (3H, s), 7.71 (2H, d, J 7.1Hz), 7.36 (2H, t, J7.δHz), 7.27 (1H, m), 7.13 (3H, m), 6.99 (2H, m), 4.95 (1H, d, J 12.9Hz), 4.72 (1H, d, J 12.9Hz), 4.40 (1H, br s), 4.09 (1H, d, J 15.3Hz), 3.97 (3H, d, J2.0Hz), 3.69 (1H, d, J 14.5Hz), 3.64 (1H, dd, J 12.1Hz, 14.9Hz), 3,56 (1H, br s), 2.54 (1H, dd, J 14.9Hz, 26.2Hz), 2.43-2.21 (2H, m), 1.66 (1H, m). EXAMPLE 173b - (isomer B):- δ_H (360 MHz, CDCI₃): 7.76 (3H, s), 7.67 (2H, d, J 7.4Hz), 7.33 (2H, t, J 8.1 Hz), 7.24 (1H, m), 7.13 (3H, m), 6.93 (2H, m), 4.96 (1H, d, J 13.0Hz), 4.67 (1H, d, J 12.6Hz), 4.38 (4H, br s), 4.13 (1 H, d, J 15.4Hz), 3.91 (1H, s), 3.87 (1H, d, J 16.8Hz), 3.02 (1H, dd, J 11.2Hz, 14.7Hz), 2.54 (1 H, dd, J 15.1Hz, 24.6Hz), 2.44 (1H, m), 2.34-2.17 (2H, m), 1.73 (1H, m). EXAMPLE 174 (1ff*,2ff*,5S*,6S^Λ)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-fluoro-6-(2- methyl-2ff-tetrazol-5-yl)-1 -phenyl-8-azabicyclo[3.2.1 ]octane

A mixture of (1 ff ^*,2ff *,5S*,6S 3-benzyl-2-{[3,δ-bis(trifluoromethyl)phenyl]- methoxy]-6-f luoro-6-(2-methyl-2H-tetrazol-δ-yl)-1 -phenyl-8- azabicyclo[3.2.1]octane (Example 173b; 74mg, 0.12mmol) was treated with an etheral solution of hydrogen chloride and concentrated. The residue was dissolved in ethanol (20ml) and 10% palladium on charcoal (109mg) was added. The mixture was stirred under hydrogen atmosphere (1atm) at +60°C for 30 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated and the residue was purified by chromatography on silica gel (dich!oromethane:methanol:ammonia) to give the title compound (62mg, 82%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI. m/z (ES⁺) 530 [M+Hf

EXAMPLE 175

ff,S)-1 -[3,5-bis(trif luoromethyl)phenyI]- (methoxycarbonyI)methoxy}-6-f luoro-6-[1 -(2-methoxyethoxymethyl)-1 H- tetrazol-5-yl]-1 -pheny l-8-azabicyclo[3.2.1]octane

Slow addition of methyl 2-diazo-2-[3,5-bis(trifluoromethyl)phenyl]acetate (1.86g, 5.9mmol) as a solution in 1.2-dichloroethane (10ml) to (1 ff*,2ff*6S*,6S^-8- benzyl-6-fluoro-6-[1 -(2-methoxyethoxymethyl)- 1 H-tetrazol-δ-yl]-1 -phenyl-δ- azabicydo[3.2.1]octan-2-ol (Description 46; 10.2g, 2.2mmol) in 1,2- dichloroethane (10ml) was carried out in the presence of catalytic rhodium(ll) acetate dimer (4δmg) at reflux under N₂. The reaction mixture was concentrated in vacuo to give a green oil then purified by flash column chromatography [1 δ% ethyl acetate in iso-hexane] to give a yellow oil (550mg) as a mixture of diastereoisomers. EXAMPLE 176 (1 ff * 2ff * 5S*,6S 8-Benzyl-2-{(1 ff *)-1 -[3,5-bis(trif luoromethyl)phenyl]-2- hydroxyethoxy}-6-f luoro-6-[1 -(2-methoxyethoxymethyl)-1 ff-tetrazol-5-yl]-1 - phenyl-8-azabicyclo[3.2.1]octane Lithium borohydride (15mg, 0.69mmol) was added to a solution of

(1 ff *,2ff * 5S*,6S*)-8-benzyl-2-{(1 ff,S)~1 -[3,5-bis(trifluoromethyl)phenyl]- (methoxycarbonyl)methoxy}-6-fluoro-6-[1-(2-methoxyethoxymethyl)-1H-tetrazol-5- yl]-1-phenyl-3-azabicyclo[3.2.1]octane (Example 176; O.δg, 0.66mmol) in diethyl ether (20ml). After one hour the mixture was partitioned between saturated sodium hydrogen carbonate and ethyl acetate. The organic layer was dried

(MgSO₄), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5 and 10% ethyl acetate / dichloromethane to yield the title compound (0.203g, 43%). δ_H (360MHz, CDCI₃): 7.δδ (1H, s), 7.62 (2H, s), 7.18-7.06 (8H, m), 5.99-5.91 (2H, m), 4.76-4.74 (1H, m), 4.27 (1H, s), 4.25 (1H ,d, J lδ.δHz), 4.13 (1H, d, Jlδ.δhz), 3.97 (1H, s), 3.80-3.71 (4H, m), 3.66-3.53 (2H, m), 3.37 (3H, s), 3.23-3.16 (1H, m), 2.51-2.34 (3H, m), 1.98-1.96 (2H, m), 1.81-1.78 (1H, m).

EXAMPLE 177 (1 ff * 2ff * 5S*,6S 8-BenzyI-2-{(1 S*)-1 -[3,5- bis(trifluoromethyl)phenyl]ethoxy}-6-fluoro-1-phenyl-6-(tetrazol-5-yl)-8- azabicyclo[3.2.1]octane

Palladium on charcoal (60mg) was added to a solution of (1 ff *2ff *,5S^* 6S*)-8- benzyl-2-{(1 ff *)-1 -[3,δ-bis(trifluoromethyl)phenyl]-2-iodoethoxy}-6-f luoro-6-[1 -(2- methoxyethoxymethyl)-1 /--tetrazol-5-yl]-1 -phenyl-8-azabicyclo[3.2.1 ]octane (Description 46; 193mg, 0.23mmol) and triethylamine (38mg, 0.3δmmol) in methanol (3ml) and ethyl acetate (δml). The mixture was hydrogenated at 40psi. for 3 hours using the Parr™ apparatus. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was taken up in a mixture of 1.0M Hydrochloric acid in diethyl ether (δml) and methanol (δml) and stirred at reflux for 13 hours. The mixture was concentrated in vacuo to yield the title compound (90mg, 7δ%). δ_H (400MHz, CDCI₃): 7.81 (1H, s), 7.63 (2H, s), 7.28-7.15 (10H, m), 4.77 (1H, q, J 6.4Hz), 4.31-4.11 (3H, m), 3.64 (1H, s), 2.84-2.72 (1H, m), 2.54-2.31 (4H, m), 1.75-1.67 (1H, m),1.56 (3H, d, J6.4Hz).

EXAMPLE 178

bis(trifluoromethyl)phenyl]ethoxy}-6-fluoro-6-(2-methyl-2ff-tetrazol-5-yl)-1- phenyl-8-azabicyclo[3.2.1]octane

Prepared in an analogous manner to Example 140. δ_H (400MHz, CDCI₃): 7.72 (1 H, s), 7.54 (2H, s), 7.18-7.00 (1 OH, s), 4.70 (1 H, q, J 6.4Hz), 4.28 (3H, s), 4.19 (1H, d, J 15.9Hz), 4.14 (1H, s), 4.00 (1H, d, J 15.4Hz), 3.8δ (1H, s), 3.09 (1H, dd, J 11.3Hz, 14.8Hz), 2.41-2.20 (4H, m), 1.68-1.65 (1H, m), 1.47 (3H, d, Jβ.δHz).

EXAMPLE 179

(1ff*2ff*5S*65^:i)-2-{(1S 1-[3_s5-Bis(trifluoromethyl)phenyl]ethoxy}-6-fluoro-

6-(2-methyI-2H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride

Prepared in an analogous manner to Example 153a. m/z (ES⁺) 544 [M+H]M

EXAMPLE 180 (1ff,2ff,5ff)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8- azabicyclo[3.2.1]octane Sodium hydride (60% in oil, 90mg, 2.25mmol) was washed twice with THF and treated with a solution of (1 R,2R,5R)-8-benzyl-1-phenyl-δ-azabicyclo[3.2.1]octan- 2-ol (Description 53; 79mg, 0.25mmol), 3,5-bis(trifluoromethyl)benzyl bromide (360mg, 1.14mmol), 1δ-crown-6 (110mg, 0.41 mmol) in THF (5ml). The reaction mixture was stirred at room temperature for 24 hours, quenched with saturated aqueous NH₄CI and extracted into diethyl ether. The combined organic extracts were washed with water, dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether) to give the title compound (165mg). δ_H (360 MHz, CDCI₃): 7.73 (1H, s), 7.71 (2H, s), 7.53 (2H, m), 7.43 (2H, d, J 7.7Hz), 7.37-7.15 (6H, m), 4.72 (1H, d, J 13.0Hz), 4.41 (1H, d, J 13.0Hz), 4.10 (1H, d, J 15.4Hz), 3.69 (1H, br s), 3.67 (1H, d, J 15.4Hz), 3.43 (1 H, m), 2.26-1.90 (6H, m), 1.65 (1H, m), 1.14 (1H, m).

EXAMPLE 181 (1ff,2ff,5ff)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8- azabicyclo[3.2.1]octane A mixture of (1 ff,2ff,5ff)-δ-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1- phenyl-8-azabicyclo[3.2.1]octane (Example 180; 16δmg), 10% palladium on charcoal (216mg) and ethanol (15ml) was stirred under hydrogen atmosphere (1atm) at +65°C for 45 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated. The residue was purified by chromatography on silica gel (dichloromethane:methanol:ammonia) to give the title compound (64mg, 59%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI. m/z (ES⁺) 430 [M+H]M

EXAMPLE 182

(1S,2S,5S)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-(prop-2- enyl)-8-azabicyclo[3.2.1 joctane

Sodium hydride (60% in oil, 67mg, 1.67mmol) was washed twice with THF and treated with a solution 1S,2S,5S)-1-phenyl-8-(prop-2-enyl)-δ- azabicyclo[3.2.1]octan-2-ol (Description 67; 116mg, 0.47mmol),

3,5-bis(trifluoromethyl)benzyl bromide (430mg, 1.4mmol), 18-crown-6 (33mg, 1.2δmmol) in THF (2ml). The reaction mixture was stirred at room temperature overnight, quenched with saturated aqueous NH₄CI and extracted into diethyl ether. The combined organic extracts were washed with water, dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel (iso- hexane.-diethyl ether) to give the title compound. δ_H (360 MHz, MeOH-d₄): 7.77 (1H, s), 7.72 (2H, s), 7.44 (2H, m), 7.28 (2H, m), 7.19 (1H, m), 6.89 (1H, dddd, Jδ.δHz, 6.4Hz, 10.2Hz, 16.7Hz), 6.1 δ (1H, dq, J 1.5Hz, 17.2Hz), 5.07 (1H, d, J9.9Hz), 4.69 (1H, d, J 12.9Hz), 4.25 (1H, d, J 12.6Hz), 3.63 (1H, br s), 3.60 (1H, br s), 3.50 (1H, dd, J5.9Hz, 14.6Hz), 2.89 (1 H, dd, J6.7HZ, 14.9Hz), 2.19-1.90 (6H, m), 1.74 (1H, m), 1.31 (1H, d, J 12.9Hz).

EXAMPLE 183

(1S,2S,5S)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8- azabicyclo[3.2.1 joctane

Tetrakis(triphenylphosphine)palladium(0) (97mg, 0.084mmol) was added to a stirred mixture of (1S,2S,5S)-2-{[3,δ-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl- δ-(prop-2-enyl)-δ-azabicyclo[3.2.1]octane (Example 1δ2), 1 ,3-dimethylbarbituric acid (270mg, 1.9mmol) in dichloromethane (10ml) at room temperature. The reaction mixture was stirred at 30-3δ°C overnight and treated with 2M aqueous NaOH (δml). The mixture was stirred for 30 minutes, then treated with water (30ml) and extracted into dichloromethane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography on silica gel to give the title compound (166mg, 81 % two steps). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCI. m/z (ES⁺) 430 [M+H]M

EXAMPLE 184 (1 S,2S,5ff,6S,9S)-6-(fe/f-Butoxycarbonyl)-2-hydroxy-1 -phenyl-8-(1 - phenyIethyl)-8-azabicyclo[3.2.1]octane Sodium borohydride (0.63g, 16.7mmol) was added portionwise to a solution of (1 S,5ff,6S,9S)-6-(terf-butoxycarbonyl)-1 -phenyl-8-(1 -phenylethyl)-δ- azabicyclo[3.2.1]octan-2-one (Description 61; 6.79g, 16.7mmol) in THF/methanol (1:1, 150ml). The mixture was stirred at room temperature under nitrogen for fifty minutes, concentrated in vacuo and diluted with water (250ml). The mixture was extracted with ethyl acetate (2 x 250ml), washed the combined extracts with saturated brine (250ml), combined, dried (MgSO₄) and evaporated to afford the title compound (6.7δg, 9δ%) as a white solid, m/z (ES⁺) 40δ ([M+H]⁺). EXAMPLE 185 (1 S,2S,5ff,6S,9S,11 S)-2-(1 -(3,5-Bis(trif luoromethyl)phenyl)-2- hydroxy)ethoxy-6-(tert-butoxycarbonyl)-1-phenyl-8-(1-phenylethyl)-8- azabicyclo[3.2.1]octane A solution of methyl 2-diazo-2-(3,5-bis(trifluoromethyl)phenyl)acetate [prepared by the method of R.T. Lewis etal. J. Org. Chem., 2000, 65, 2616] (7.41 g, 23.7mmol) in 1,2-dichloroethane (50ml) was added dropwise over three hours to a refluxing solution of (1 S,2S,5ff,6S,9S)-6-(te/f-butoxycarbonyl)-2-hydroxy-1-phenyl-8-(1- phenylethyl)-8-azabicydo[3.2.1]octane (Example 184; 6.32g, Iδ.δmmol) and rhodium(ll) acetate dimer (322.4mg, 0.73mmo!) in 1 ,2-dichloroethane (100ml). After the addition was complete, the mixture was stirred at reflux for a further thirty minutes, allowed to cool, filtered and concentrated in vacuo. The residue was dissolved in 10% ethyl acetate in iso-hexane and treated with silica. Filtered and washed silica with 10% ethyl acetate in iso-hexane. The filtrate was evaporated to give an orange foam (12.77g). This was dissolved in methanol (260ml) and treated in three portions with sodium borohydride (9.1 Og, 0.24mol), with the exotherm being moderated by use of a cold water bath. The resulting mixture was stirred at room temperature for an hour, concentrated to a small volume, diluted with water (600ml) and extracted with ethyl acetate (2 x 2δ0ml). The extracts were washed with saturated brine (260ml), combined, dried (MgSO₄) and evaporated. The residue was purified by flash chromatography, eluting with 0-5% diethyl ether in dichloromethane, iso-hexane crystallisation of impure fractions and further chromatography of the mother liquors to afford the title compound as the more polar diastereoisomer (5.62g, 66%). m/z (ES⁺) 664 ([M+H]⁺); [α]_D +23.1 ^e.(c 0.66, CH₂CI₂).

EXAMPLE 186 (1 S,2S,5ff,6S,9S,11 ff)-2-(1 -(3,5-Bis(trif luoromethyl)phenyl))ethoxy-6-(terf- butoxycarbonyl)-1-phenyl-8-(1-phenylethyl)-8-azabicyclo[3.2.1]octane 20% Palladium hydroxide on carbon (0.62g) was added to a solution of (1 S,2S,5ff,6S,9S,11 S)-6-(terf-butoxycarbonyl)-2-(1 -(3,5- bis(trifluoromethyl)phenyl)-2-iodo)ethoxy-1-phenyl-δ-(1-phenylethyl)-δ- azabicyclo[3.2.1]octane (Description 62; 3.07g, 4.52mmol) and triethylamine (1ml) in ethyl acetate/methanol (1:1, 80ml) and the mixture hydrogenated on a Parr™ apparatus (40psi max.) for three hours. The mixture was filtered and concentrated in vacuo. The residue was treated with saturated aqueous sodium hydrogen carbonate (50ml) and saturated aqueous sodium thiosulfate (50ml) then extracted with dichloromethane (2 x 50ml). The combined extracts were dried (MgSO₄), diluted with iso-hexane and evaporated to give the title compound (2.35g, 91%) as a pale cream-coloured solid. m/z (ES⁺) 648^'([M+H]⁺).

EXAMPLE 187

(1 S,2S,5ff,6S,9S,11 ff)-2-(1 -(3,5-Bis(trif luoromethyl)phenyl))ethoxy-6- (methylaminocarbonyl)-l -phenyl-8-(1 -phenylethyl)-8- azabicyclo[3.2.1]octane

Trifluoroacetic acid (30ml) was added to a solution of (1 S,2S,5ff,6S,9S,11 ff)-2-(1- (3,δ-bis(trif luoromethyl)phenyl))ethoxy-6-(tert-butoxycarbonyl)-1 -phenyl-8-(1 - phenylethyl)-δ-azabicyclo[3.2.1]octane (Example 166; 1.93g, 2.98mmol) in dichloromethane (70ml) and the mixture stirred at room temperature overnight (17 hours). The mixture was concentrated in vacuo, diluted with toluene (δml) and evaporated to an oil. This was dissolved in diethyl ether and evaporated to give a foam (2.44g). A portion of this material (0.7δg, ~0.92mmol) was dissolved in dichloromethane (1δml), treated with triethylamine (0.60ml, 3.6mmol) and DMAP (23.1 mg, 0.19mmol) and the mixture cooled to 0^QC. Methylamine in THF (2.0M; 2.5ml, δ.Ommol) followed by 1-(3-dimethylamino)propyl)-3-ethyIcarbodiimide hydrochloride (0.44g, 2.30mmol) were added, the flask capped and the mixture stirred at room temperature overnight (16 hours). The mixture was poured into water (60ml) and extracted with dichloromethane (2 x 2δml). The organic extracts were washed with 0.5M hydrochloric acid (50ml), saturated sodium hydrogen carbonate (25ml) then saturated brine (60ml), combined, dried (MgSO₄) and evaporated. Purification by flash chromatography, eluting with 2.5 to 5% methanol in dichloromethane, gave the title compound (293.2mg, 63%) as a white solid, m/z (ES⁺) 606 ([M+H]⁺), 501 ([M-PhCHCH₃+2Hf). EXAMPLE 188 (1 S,2S,5ff,6S,9S,11 ff)-2-(1-(3,5-Bis(trifluoromethyl)phenyl))ethoxy-6-(1- methyltetrazol-5-yl)-1-phenyl-8-(1-phenylethyl)-8-azabicyclo[3.2.1]octane

Trifluoromethanesulfonic anyhydride (1 OOμl, 0.59mmo!) was added to a cooled mixture of (1 S,2S,5ff,6S,9S,11 ff)-2-(1 -(3,5-bis(trifluoromethyl)phenyI))ethoxy-6- (methylaminocarbonyl)-l -phenyl-8-(1 -phenylethyl)-δ-azabicyclo[3.2.1 ]octane (Example 1δ7; 2δδ.δmg, 0.47δmmol) and sodium azide (δl .δmg) in dichloromethane (δml) [CAUTION: explosions have been reported with reactions involving sodium azide and dichloromethane]. The mixture was allowed to warm up from 0⁹C to room temperature over 10 minutes then stirred overnight (21 hours). The reaction mixture was poured into saturated sodium hydrogen carbonate (2δml) and extracted with dichloromethane (2 x 20ml). The combined extracts were dried (MgSO₄), evaporated and the residue purified by flash chromatography, eluting with 1 :1 ethyl acetate-iso-hexane, to give the title compound (143.2mg, 4δ%) and recovered starting material (47.δmg, 16%). m/z (ES⁺) 630 ([M+H]⁺), 526 ([M-PhCHCH₃+2Hf).

EXAMPLE 189 (1 S,2S,5R,6S,9ff)-2-(1 -(3,5-Bis(trif luoromethyl)phenyl))ethoxy-6-(1 -methyl- 1 H-tetrazol-5-yl)-1 -phenyl-8-azabicyclo[3.2.1]octane hydrochloride

20% Palladium hydroxide on carbon (71.5mg) was added to a solution of (1 S,2S,5R,6S,9S,11 ff)-2-(1 -(3,5-bis(trifluoromethyl)pheny)))ethoxy-6-(1 - methyltetrazol-5-yI)-1 -phenyl-8-(1 -phenylethyl)-δ-azabicyclo[3.2.1 ]octane (Example 1δδ; 140.6mg, 0.223mmol) in methanol (10ml) containing 1M hydrogen chloride in diethyl ether (250μl, 0.2δmmol). The mixture was hydrogenated on Parr™ apparatus (δOpsi max.) for 3 hours, filtered, evaporated and the residue recrystallized from methanol-diethyl ether to give the title compound in two crops (106.6mg, 85%). m/z (ES⁺) 526 ([M+H]⁺); [α]_D +61⁹ (c 0.2, MeOH). EXAMPLE 190 (1S,2S,5R,6S,9ff)-2-(1-(3,5-Bis(trifluoromethyl)phenyl))ethoxy-6- (methylaminocarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane hydrochloride

Prepared in an analogous manner to Example 189 from (1 S,2S,5R,6S,9S,11 R)-2- (1-(3,δ-bis(trifluoromethyl)phenyl))ethoxy-6-(methylaminocarbonyl)-1-phenyl-8-(1- phenylethyl)-δ-azabicyclo[3.2.1]octane (Example 167). m/z (ES⁺) 601 ([M+H]⁺).

EXAMPLE 191 (1 S,2S,5R,6S,9fl)-2-(1 -(3,5-Bis(trif luoromethyl)phenyl))ethoxy-6-

[(methyIamino)(methyIimino)methyl]-1-phenyl-8-azabicyclo[3.2.1]octane dihydrochloride

Trimethylaluminium in hexanes (2.0M; 1.8ml, 3.6mmol) was added via syringe to a suspension of methylamine hydrochloride (226.5mg, 3.3δmmol) in toluene (δml) at 0^QC. Stirred at 0-C for δ minutes, removed cooling bath and allowed to warm to room temperature. Stirred at room temperature for 30 minutes to give a colourless solution. This solution was added via syringe to a solution of (1 S,2S,δR,6S,9S,11 ff)-6-(fe/f-butoxycarbonyl)-2-(1-(3,5- bis(trifluoromethyl)phenyl))ethoxy-1-phenyl-δ-(1-phenylethyl)-δ- azabicyclo[3.2.1]octane (Example 166; 40δ.6mg, 0.63mmol) in toluene (δml). The resulting mixture was stirred at 90^QC under nitrogen for 24 hours. The reaction mixture was cooled to 0-C and quenched by the addition of saturated aqueous potassium sodium tartrate. Stirred at room temperature for one hour, diluted with 2M sodium hydroxide and extracted with ethyl acetate (2 x 60ml). The extracts were washed with saturated brine (25ml), combined, dried (MgSO₄) and evaporated to give a pale yellow foam (429.1 mg). This material was dissolved in THF (50ml) and treated with 2M hydrochloric acid (50ml). The resulting mixture was stirred at reflux for 2 days, poured into water (50ml) and extracted with dichloromethane (3 x 25ml). The aqueous phase was basified by the addition of 4M sodium hydroxide (δml) and extracted with dichloromethane (2 x 2δml). The extracts were washed with saturated brine (25ml), combined, dried (MgSO₄) and evaporated. The residue was dissolved in diethyl ether and treated with excess 1 M hydrogen chloride in diethyl ether to give a gum. Purification was effected by chromatography on a Varian C-1δ Mega Bond Elut™ cartridge (10g) with gradient elution from 10%-δ0% methanol in water. Fractions containing pure title compound were combined and evaporated. The residue was dissolved in methanol, diluted with diethyl ether and filtered. The filtrate was evaporated and the residue dried in vacuo to afford the title compound (75.1 mg) as a foam. m/z (ES⁺) 514 ([M+H]⁺).

EXAMPLE 192 (1 S,2S,5ff,6S,9S,11 S)-2-(1 -(3,5-Bis(trif luoromethyl)phenyl)-2- phenylmethoxy)ethoxy-6-(fert-butoxycarbonyl)-1 -phenyl-8-(1 -phenylethyl)- 8-azabicyclo[3.2.1 loctane

Sodium hydride (60% dispersion in oil; 0.1 δg, 4.5mmol) was added to a THF (25ml) solution of (1S,25,5ff,6S,9S,11 S)-2-(1-(3,δ-Bis(trifluoromethyl)phenyl)-2- hydroxy)ethoxy-6-(tert-butoxycarbonyl)-1-phenyl-δ-(1-phenylethyl)-δ- azabicyclo[3.2.1]octane (Example 1δ5) and 1δ-crown-6 (0.10g, 0.33mmol). The resulting mixture was stirred at room temperature under nitrogen for 20 minutes, treated with benzyl bromide (0.50ml, 4.2mmol) and stirred at 60²C (oil bath temperature) for 2 hours. The reaction mixture was poured into water (125ml) and extracted with ethyl acetate (2 x 50ml). The extracts were washed with saturated brine (60ml), combined, dried (MgSOJ and evaporated. Crystallisation from iso-hexane gave the title compound (2.66g, 93%) in three crops, m/z (ES⁺) 754 ([M+H]⁺).

EXAMPLE 193 (1 S,2S,5ff,6S,9S,11 S)-2-(1-(3,5-Bis(trifluoromethyl)phenyl)-2- phenylmethoxy)ethoxy-6-(1 -(2-cyanoethyl)-1 H-tetrazol-5-yl)-1 -phenyl-8-(1 - phenylethyl)-8-azabicyclo[3.2.1]octane

Trifluoroacetic acid (30ml) was added to a solution (1 S,2S,5ff,6S,9S,11 S)-6-(tert- butoxycarbonyl)-2-(1-(3,δ-bis(trifluoromethyl)phenyl)-2-phenylmethoxy)ethoxy-1- phenyl-8-(1 -phenylethyl)-δ-azabicydo[3.2.1]octane (Example 192; 2.54g,

3.37mmol) in dichloromethane (70ml) and the mixture stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, diluted with toluene (δml) and evaporated to an oil. This was dissolved in diethyl ether and evaporated to give a foam (3.21 g). This material was dissolved in dichloromethane (60ml), treated with triethylamine (2.35ml, 16.9mmol), 3-aminopropionitrile (0.62ml, δ.4mmol) and 4-dimethylaminopyridine (δδ.3mg, 0.72mmol) and the mixture cooled to 0^QC. 1 -(3-Dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (1.62g, δ.45mmol) was added and the mixture stirred at room temperature for 16 hours. The mixture was poured into 1 M hydrochloric acid (1 OOmi) and extracted with dichloromethane (2 x 50ml). The organic extracts were washed with saturated sodium hydrogen carbonate (100ml) then saturated brine (50ml), combined, dried (MgSO₄) and evaporated to a yellow foam (2.62g). This crude amide was dissolved in dichloromethane (35ml), sodium azide (0.27g, 4.15mmol) added and the mixture cooled to 0⁹C. Trifluoromethanesulfonic anhydride (0.70ml, 4.16mmo!) was added and the mixture stirred at 0^SC for 10 minutes. The cooling bath was removed and the reaction mixture stirred at room temperature for 26 hours. The reaction mixture was poured into saturated sodium hydrogen carbonate (100ml) and extracted with dichloromethane (2 x 25ml). The combined extracts were dried (MgSO₄), evaporated and the residue purified by flash chromatography, eluting with 40% ethyl acetate-iso-hexane, to give the title compound (O.δδg, 33%). m/z (ES⁺) 776 ([M+Hf), 671 ([M-PhCHCH₃+2H]⁺).

EXAMPLE 194 (1 S,2S,5ff,6S,9S,11 S)-2-(1 -(3,5-Bis(trifluoromethyl)phenyl)-2- phenylmethoxy)ethoxy-1-phenyl-6-(tetrazol-5-yl)-8-(1-phenylethyl)-8- azabicyclo[3.2.1]octane (1 S,2S,5R,6S,9S, 11 S)-2-(1 -(3,5-Bis(trif luoromethyl)phenyl)-2- phenylmethoxy)ethoxy-6-(1 -(2-cyanoethyl)-1 -/-tetrazol-5-yl)-1 -phenyl-8-(1 - phenylethyl)-8-azabicyclo[3.2.1]octane (Example 193; 0.85g, 1.1 mmol) in methanol (20ml) was treated with 10% sodium hydroxide (4ml) and stirred at room temperature overnight. The mixture was concentrated in vacuo, the residue dissolved in water and extracted with dichloromethane. The organics were dried (MgSO and concentrated in vacuoXo give the title compound as a pale yellow solid (0.595g, 84%). m/z (ES⁺) 722 ([M+H]⁺). EXAMPLES 195a and 195b (1 S,2S,5ff,6S,9S,11 S)-2-(1-(3,5-Bis(trifluoromethyl)phenyI)-2- phenylmethoxy)ethoxy-6-(1 -methyl-1 H-tetrazol-5-yl)-1 -phenyl-8-(1 - phenylethyl)-8-azabicyclo[3.2.1]octane (isomer A); and

(1 S,2S,5ff,6S,9S,11 S)-2-(1 -(3,5-bis(trif luoromethyl)phenyI)-2- phenylmethoxy)ethoxy-6-(2-methyl-2ff-tetrazoI-5-yl)-1-phenyl-8-(1- phenylethyl)-8-azabicyclo[3.2.1]octane (isomer B)

(1 S,2S,5ff,6S,9S,11 S)-2-(1-(3,5-Bis(trifluoromethyl)phenyl)-2- phenylmethoxy)ethoxy-1 -phenyl-6-(tetrazol-5-yl)-8-(1 -phenylethyl)-δ- azabicyclo[3.2.1]octane (Example 194; 0.3245g, 0.4δmmol), methyl iodide (0.6417.1, 1.3δmmol) and potassium carbonate (0.19g, 1.3δmmoI) in dimethylformamide (16ml) were heated at 60°C for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The organics were collected, dried (MgSOJ and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 40% ethyl acetate/ iso-hexane to afford isomer B as an oil (136mg) and isomer A as a white solid (89mg). EXAMPLE 195a - (isomer A):- δ_H (400 MHz, CDCI₃): 7.92 (1H, s), 7.86 (2H, s), 7.61 (2H, m), 7.34-7.26 (6H, m), 7.14-7.09 (7H, m), 4.91 (1H, m), 4.75 (1H, m), 4.53 (2H, d, J 11.9Hz), 4.20 (1 H, s), 3.62 (1 H, m), 3.71 (3H, s), 3.60 (1 H, m), 3.17 (1H, s), 3.06 (1H, m), 2.59 (1H, d, J 4.1 Hz), 2.45-2.30 (4H, m), 2.04 (1H, m), 1.18 (1H, m), 0.83 (3H, d, J 6.5Hz); m/z (ES⁺) 736 ([M+H]⁺).

EXAMPLE 195b - (isomer B):- δ_H (400 MHz, CDCI₃): 7.90 (1H, s), 7.85 (2H, s), 7.48 (2H, m), 7.33-7.09 (13H, m) 4.90 (1H, m), 4.75 (1H, m), 4.58 (2H, d, J 11.9Hz), 4.33 (3H, s), 4.17 (1H, s), 3.83 (1H, m), 3.60 (1H, m), 3.37 (1H, s), 3.28 (1H, m), 2.59 (1H, d, 4.1 Hz), 2.35 (3H, m), 2.04 (1H, m), 1.18 (1H, m), 0.83 (3H, d, J6.5Hz); m/z (ES⁺) 736 ([M+H]⁺).

EXAMPLE 196 (1S,2S,5ff,6S,9S)-2-(1-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxy)ethoxy-6- (1 -methyl-1 ff-tetrazol-5-yl)-1 -phenyi-8-azabicyclo[3.2.1 ]octane hydrochloride (1 S,2S,5R,6S,9S,11 S)-2-(1-(3,5-Bis(trifluoromethyl)phenyl)-2- phenylmethoxy)ethoxy-6-(1 -methyl-1 H-tetrazol-5-yl)-1 -phenyl-8-(1 -phenylethyl)-δ- azabicyclo[3.2.1]octane (Example 19δa; 0.09g, 0.1 mmol) and palladium hydroxide 20% on carbon (30mg) in methanol (δml) were hydrogenated using the Parr™ apparatus for 2 hours. The mixture was filtered using a Whatman™ 0.2 micrometer filter. The filtrate was concentrated in vacuo, taken into dichloromethane and washed with saturated sodium hydrogen carbonate. The organic phase was separated using a bond elute cartridge and concentrated in vacuo. The hydrochloride salt was made in the usual manner and recrystallized from methanol/diethyl ether to give the title compound (37mg, 64%). m/z (ES⁺) 642 ([M+H]⁺).

EXAMPLE 197

(1S,2S,5ff,6S,9S)-2-(1-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxy)ethoxy-6- (2-methyl-2H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane

(1 S,2S,5ff,6S,9S,11 S)-2-(1-(3,δ-Bis(trifluoromethyl)phenyl)-2- phenylmethoxy)ethoxy-6-(2-methyl-2/-/-tetrazol-δ-yl)-1-phenyl-8-(1-phenylethyl)-δ- azabicyclo[3.2.1]octane (Example 19δb; 0.14g, 0.19mmol) and palladium hydroxide 20% on carbon (118mg) in methanol (δml) were hydrogenated using the Parr™ apparatus for 2 hours. The mixture was filtered using a Whatman™ 0.2 micrometer filter. The filtrate was concentrated in vacuo, taken into dichloromethane and washed with saturated sodium hydrogen carbonate. The organic phase was separated using a bond elute cartridge and concentrated in vacuo to afford the title compound as a white foam (93mg, 93%). m/z (ES⁺) 642 ([M+Hf).

EXAMPLE 198 (1 ff *, 2ff * 5S* 6ff *)-8-Benzyl-2-{(1 ff*)-1 -[3,5-bis(trif luoromethyl)phenyl]-2- methoxyethoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane

(1 ff * 2ff * 5S* 6ff *)-8-Benzyl-2-{(1 fl*)-1 -[3,5-bis(trifluoromethyl)phenyl]-2- hydroxyethoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Example 156; 0.3g, O.δmmol), methyl iodide (0.04g, 0.02ml, 0.3mmol), sodium hydride (0.04g, 1.6mmol) and 18-crown-6 (0.3g, Immol) in N,N-dimethylformamide (3ml) was heated at 60°C for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organics were collected, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 30% ethyl acetate/hexane. The title compound was isolated as a white crystalline solid (285mg, 97%). δ_H (400MHz, CDCQ: 7.79 (1H, s), 7.54 (4H, m), 7.38 (2H, m), 7.20 (3H, m), 7.14 (3H, m), 4.59 (1H, m), 4.27 (1H, d, J 15.9Hz), 4.03 (1 H, d, J 16.0Hz), 3.94 (1H, s), 3.82 (1H, s), 3.δδ (1H, m), 3.40 (4H, m), 2.84 (1H, m), 2.32 (3H, m), 2.16 (1H, m), 1.69 (1 H, m).

EXAMPLE 199 (1 ff * 2ff * 5S*,6ff 8-Benzyl-2-{(1 ff*)-1 -[3,5-bis(trif luoromethyl)phenyl]-2- methoxyethoxy}-1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane

(1 ff *,2ff ^*,δS^*,6ff ^,,)-δ-Benzyl-2-{(1 ff*)-1 -[3,5-bis(trifluoromethyl)phenyl]-2- methoxyethoxy}-6-cyano-1-phenyl-δ-azabicyclo[3.2.1]octane (Example 196; 0.3g, O.δmmol), sodium azide (0.2g, 1.4mmol), ammonium chloride (0.1g, 1.4mmol) and N,N-dimethylformamide (3ml) were heated under nitrogen at 120°C for 43 hours. The mixture was allowed to cool and diluted with water, the organics were extracted into ethyl acetate and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 5% methanol/dichloromethane to afford the title compound (56mg, 19%). δ_H (400MHz, CDCI₃): 7.δ4 (1H, s), 7.60 (2H, s), 7.46-7.15 ( 10H, m), 4.75 (1H, m), 4.33 (1H, d, j 14.1 Hz), 4.16 (1H, s), 4.10 (1H, d, J 14.1 Hz), 3.56 (1H, m), 3.64 (1H, m), 3.4δ (1H, m), 3.42 (4H, m), 2.69 (1H, m), 2.62 (1H, m), 2.40 (3H, m), 2.01 (1H, m).

EXAMPLE 200 (1 ff * 2ff * 5S* 6ff *)-8-BenzyI-2-{(1 ff*)-1 -[3,5-bis(trif luoromethyl)phenyl]-2- methoxyethoxy}-6-(2-methy 1-1 H-tetrazol-5-yl)-1 -phenyl-8- azabicyclo[3.2.1]octane

(1 R^*,2R^*,5S*,6R'^l)-8-Benzyl-2-{(1 R*)-1 -[3,5-bis(trifluoromethyl)phenyl]-2- methoxyethoxy}-1 -phenyl-6-(tetrazol-δ-yl)-δ-azabicyclo[3.2.1 ]octane (Example 199; O.Oδg, 0.1 mmol), methyl iodide (0.04g 0.02ml, 0.3mmol) and potassium carbonate (0.04g, 0.3mmol) in acetonitrile were heated at 60°C for 1.6 hours. The mixture was quenched with water and concentrated in vacuo, the residue was partitioned between water and dichloromethane using a bond elute cartridge. The organics were collected and concentrated in vacuo and the residue purified by preparative thin layer chromatography eluting with 5% methanol/dichloromethane. The title compound was isolated as a white solid (33mg, 56%). m/z (ES⁺) 646 ([M+H]⁺).

EXAMPLE 201 (1 ff * 2ff *,5S*,6ff *)-2-{(1 ff*)-1 -[3,5-Bis(trif luoromethyl)phenyl]-2- methoxyethoxy}-6-(2-methyl-1 H-tetrazol-5-yl)-1 -phenyl-8- azabicyclo[3.2.1]octane

(1 ff *2ff *, 5S*,6ff *)-8-BenzyI-2-{(1 ff*)-1 -[3,δ-bis(trifluoromethyl)phenyl]-2- methoxyethoxy}-6-(2-methyl-1 H-tetrazol-δ-yl)-1 -phenyl-8-azabicyclo[3.2.1 ]octane (Example 200; 0.03g, O.Oδmmol), palladium, 6% on carbon (20mg) and acetic acid (O.δml) were placed on the Parr™ apparatus for 2 hours. The mixture was filtered using a Whatman™ 0.2«m filter and concentrated in vacuo. The residue was taken into dichloromethane and washed with NaHCO₃ and the phases separated using a bond elute cartridge. The organics were concentrated in vacuo and the title compound isolated as the hydrochloride salt, m/z (ES⁺) 566 ([M+H]⁺).

Claims

CLAIMS;

A compound of the formula (I):

(I)

wherein

X represents hydrogen, Cι-4alkyl optionally substituted by a hydroxy, methoxy or benzyloxy group, or Cθ2(Cι-2alkyl); Z is -CR⁹R¹⁰CH₂- or -CH₂CR⁹R¹⁰-;

R¹ is hydrogen, halogen, Ci-βalkyl, Ci-βalkoxy, fluoroCi-βalkyl, fluoroCi-βalkoxy, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, NO2, CN, SR^a, SOR^a, SO₂R^a, CO₂R^a, CONR^aR^b, Cstβal enyl, C₂-₆alkynyl or Cwalkyl substituted by Cι-4alkoxy, wherein R^a and R^b each independently represent hydrogen or Cι-4alkyl;

R² is hydrogen, halogen, Cι-6alkyl, fluoroCi-βalkyl or Ci-βalkoxy substituted by Cι-4alkoxy;

R³ is hydrogen, halogen or fluoroCι-6alkyl;

R⁴ represents hydrogen, halogen, Ci-βalkyl, Ci-βalkoxy, CF3, OCF3, NO2, CN, SR^a, SOR^a, SO₂R^a, CO₂R^a, CONR^aR^b, G^al enyl, C₂-₆alkynyl or Cι-4alkyl substituted by Cι-4alkoxy, where R^a and R^b are as previously denned; R⁵ represents hydrogen, halogen, Ci-βalkyl, CF3 or Ci-βalkoxy substituted by Cι-4alkoxy; ⁶ represents hydrogen, hydroxy, COR , CO₂R^a, COCONR^aR , COCO2 ^a, Ci-βalkyl, C2-6alkenyl, or Ci-βalkyl substituted by a group selected from CO₂R^a, CONR^aR^b, hydroxy, CN, COR^a, NR^aR^b,

C(NOH)NR^aR , CONHphenyl(Cι.₄alkyl), COCO₂R^a, CONHNR^aR^b, C(S)NR^aR^b, CONR^aCι-₆alkylRⁱ⁴, CONR^UC^ealkenyl, CONR^UC^ealkynyl, COCONR^aR^b, CONR^aC(NR )NR^aR , CONR^aheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from Ci-βalkyl, Ci-βalkoxy, halogen and trifluoromethyl; or R⁶ represents a group of the formula -CEføC≡CCEkNRTl⁸ where R⁷ and R⁸ are as defined below; or R⁶ represents Ci-βalkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms optionally substituted by =O or =S and optionally substituted by a group of the formula — Y-NR⁷R⁸ where

Y is Ci-βalkylene or C3-6cycloalkyl;

R⁷ represents hydrogen or Cwalkyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, or C2-4alkyl substituted by Cι-4alkoxy or hydroxyl; R⁸ represents hydrogen or Ci-βalkyl, Ci-βalkoxy, C3-7cycloalkyl,

C3-7cycloalkylCι-4alkyl, phenyl or Cι-₄alkyl substituted by a group selected from Cι-4alkoxy, hydroxyl, CO2 ^a, NR^aR^b, aryl, aryloxy, heteroaryl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S; or R⁷, R⁸ and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from methyl, hydroxy, CO2(Ci-2alkyl), phenyl, benzyl or Cι-4alkoxy optionally substituted by a Cι-4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NR^C moiety where R^c is Cι-4alkyl, hydroxyCι-4alkyl, Cι-4alkoxyCι-4alkyl, phenyl or benzyl; or R⁷, R⁸ and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or Y, R⁷ and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;

R⁹ represents hydrogen, hydroxy, oxo, Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, fluoroCi-βalkyl, Ci-βalkoxy, fluoroCi-βalkoxy, hydroxyCi-βalkyl, Cι-6alkoxyCι-4alkyl, Cι-6alkoxyCι-4alkoxy, fluoroCι-6alkoxyCι-4alkyl, C2-βalkenyloxy, C2-6alkynyloxy, C3-7cycloalkoxy, C3-7cycloalkylCι-4alkoxy, aryl, aryKCBfe), aryloxy, aryl(CH₂)oxy, cyano, halogen, NR⁷R⁸, CH₂NR⁷R⁸, SR*², SORⁱ², SO2R¹², OSO2R¹², NR^aCOR¹², CH(OH)R¹², COR¹², CO2R¹², CONR⁷R⁸, CONHNH2, CH2OR¹³, heteroaryl or heteroarylCι-4alkyl, wherein R^a is as previously defined;

R¹⁰ represents hydrogen, halogen or hydroxy;

R¹¹ represents hydrogen or Ci-βalkyl;

R¹² represents hydrogen, Ci-βalkyl, Ci-βalkoxy, fluoroCi-βalkyl or phenyl optionally substituted by one, two or three substituents selected from Ci-βalkyl, Ci-βalkoxy, halogen or trifluoromethyl;

R¹³ represents Cι-4alkyl substituted by a group selected from hydroxy, COR^a, CO2R^a, CONR^aR^b and heteroaryl, where R^a is as previously defined; R¹⁴ represents OR^a, CONR^aR^b or heteroaryl; or a pharmaceutically acceptable salt or N-oxide thereof.

2. A compound as claimed in Claim 1 wherein R¹ is hydrogen, Cι-4alkyl, Cι-4alkoxy, halogen or CF3.

3. A compound as claimed in Claim 1 or Claim 2 wherein R² is hydrogen, Cι-4alkyl, Cι-4alkoxy, halogen or CF3.

4. A compound as claimed in any one of Claims 1 to 3 wherein R³ is hydrogen, fluorine, chlorine or CF3.

5. A compound as claimed in any one of Claims 1 to 4 wherein R⁴ is hydrogen or fluorine.

6. A compound as claimed in any one of Claims 1 to 5 wherein

R⁵ is hydrogen.

7. A compound as claimed in any one of Claims 1 to 6 wherein R⁶ is hydrogen or Ci-βalkyl, or a Cι-3alkyl group substituted by a 5-membered heterocyclic ring containing 2 or 3 nitrogen atoms as defined in Claim 1.

8. A compound as claimed in any one of Claims 1 to 7 wherein Z is -CR⁹R¹⁰CH₂-.

9. A compound as claimed in any one of Claims 1 to 8 wherein R⁹ is hydrogen, hydroxy, oxo, Ci-βalkoxy, Cι-6alkoxyCι-4alkyl, hydroxyCwalkyl, cyano, NR⁷R⁸, CH₂NR⁷R⁸, SO₂R^d, CH(OH)R¹², COR¹², CO2R¹², CONR⁷R⁸, phenyl, heteroaryl, heteroarylC^alkyl or CH2OR¹³, where said phenyl is optionally substituted by one or two substituents selected from Cι-4alkyl, Cι-4alkoxy, halogen or trifluoromethyl.

10. A compound as claimed in any one of Claims 1 to 9 wherein Rio js hydrogen, fluorine or hydroxy.

11. A compound as claimed in any one of Claims 1 to 10 wherein X is hydrogen, methyl or hydroxymethyl.

12. A compound of the formula (la):

(la)

wherein R¹, R³ and R⁴ are as defined in Claim 1 and Z is -CR⁹R¹⁰CH₂-; or a pharmaceutically acceptable salt thereof.

13. A compound as claimed in any one of Claims 1 to 11 wherein the stereochemistry of the 1- 2-, and 5-positions is as shown in formula (lb):

(lb)

14. A compound according to any one of Claims 1 to 13 for use in therapy.

15. A pharmaceutical composition comprising a compound as claimed in any one of Claimsl to 13, together with at least one pharmaceutically acceptable carrier or excipient.

16. A method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound according to Claim 1.

17. A method according to Claim 16 for the treatment or prevention of pain or inflammation, migraine, emesis, postherpetic neuralgia, depression or anxiety.

18. The use of a compound according to any one of Claims 1 to 13 for the manufacture of a medicament for the treatment or prevention of physiological disorders associated with an excess of tachykinins.

19. The use of a compound according to any one of Claims 1 to 13 for the manufacture of a medicament for the treatment or prevention of pain or inflammation, migraine, emesis, postherpetic neuralgia, depression or anxiety.