NOVEL BISPIDINE ANTIARRHYTHMIC COMPOUNDS

Abstract: There is provided a compound of formula (I), wherein R<1>, R<2>, R<9>, R<10>, R<11>, R<12>, X, A and B have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.

Description: NOVEL BISPIDINE ANT I ARRH YTHMI C COMPOUNDS Field of the Invention This invention relates to novel pharmaceutically useful compounds, in particular compounds which are useful in the treatment of cardiac arrhythmias. Background and Prior Art Cardiac arrhythmias may be defined as abnormalities in the rate, regularity, or site of origin of the cardiac impulse or as disturbances in conduction which causes an abnormal sequence of activation. Arrhythmias may be classified clinically by means of the presumed site of origin (i.e. as supraventricular, including atrial and atrioventricular, arrhythmias and ventricular arrhythmias) and/or by means of rate (i.e. bradyarrhythmias (slow) and tachyarrhythmias (fast)). In the treatment of cardiac arrhythmias, the negative outcome in clinical trials (see, for example, the outcome of the Cardiac Arrhythmia Suppression Trial (CAST) reported in New England Journal of Medicine, 321, 406 (1989)) with "traditional" antiarrhythmic drugs, which act primarily by slowing the conduction velocity (class I antiarrhythmic drugs), has prompted drug development towards compounds which selectively delay cardiac repolarization, thus prolonging the QT interval. Class III antiarrhythmic drugs may be defined as drugs which prolong the trans-membrane action potential duration (which can be caused by a block of outward K + currents or from an increase of inward ion currents) and refractoriness, without affecting cardiac conduction. One of the key disadvantages of hitherto known drugs which act by delaying repolarization (class III or otherwise) is that they all are known to exhibit a unique form of proarrhythmia known as torsades de pointes (turning of points), which may, on occasion be fatal. From the point of view of safety, the minimisation of this phenomenon (which has also been shown to be exhibited as a result of administration of non-cardiac drugs such as phenothiazines, tricyclic antidepressants, antihistamines and antibiotics) is a key problem to be solved in the provision of effective antiarrhythmic drugs. Most antiarrhythmic drugs (including class III antiarrhythmic drugs) have a duration of action of between 3 and 12 hours. For example, the recently registered (approved, as of December 1997, in the US, Sweden, the UK, Denmark, Belgium, Netherlands, Finland, Italy and Austria) selective class III antiarrhythmic drug ibutilide (Pharmacia Upjohn) has a half-life of elimination which averages at around 6 hours when the drug is administered intravenously to a human patient. In the minimisation of the side effects (including torsades de pointes) associated with antiarrhythmic drugs, compounds which are effective, yet short acting, when administered intravenously, are expected to be of benefit. Accordingly, compounds which have a duration of action which is relatively short (hereinafter referred to as "short acting compounds") may be expected to have clinical advantages when used in the acute conversion of arrhythmias, including reduced monitoring and hospitalisation time. By "short acting" in this context, we mean a half life (t 1/2 ), as measured in the test described below, of between 1 and 120 minutes, preferably between 1 O 99/31100 3 and 60 minutes, more preferably between 1 and 30 minutes and especially between 1 and 15 minutes. Antiarrhythmic drugs based on bispidines (3,7-diazabicyclo[3.3.1]nonanes), are known from inter alia international patent application WO 91/07405, European patent applications 306 871 , 308 843 and 655 228 and US patents 3,962,449, 4,556,662, 4,550,112, 4,459,301 and 5,468,858, as well as journal articles including inter alia J. Med. Chem. 39, 2559, (1996), Pharmacol. Res. , 24, 149 (1991), Circulation, 90, 2032 (1994) and Anal. Sci. 9, 429, (1993). Known bispidine-based antiarrhythmic compounds include bisaramil (3-methyl-7-ethyl-9α,4'-(Cl-benzoyloxy)-3,7- diazabicyclo[3.3. l]nonane), tedisamil (3',7'-bis(cyclopropylmethyl)spiro- (cyclopentane-1 ,9'-3,7Jdiazabicyclo-[3.3. ljnonane), SAZ-VII-22 (3-(4- cWorobenzoyl)-7-isopropyl-3,7-diazabicyclo[3.3. ljnonane), SAZ-VII-23 (3- benzoyl-7-isopropyl-3,7-diazabicyclo[3.3. ljnonane), GLG-V-13 (3-[4-(lH- imidazol-l-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3. ljnonane), KMC- IV-84 (7-[4'-(lH-imidazolo-l-yl)benzenesulphonylJ-3-isopropyl-3,7-diaza- bicyclo[3.3. ljnonane dihydro-perchlorate and ambasilide (3-(4- aminobenzoyl)-7-benzy 1-3 , 7-diazabicyclo[3.3.1] nonane) . We have surprisingly found that a novel group of bispidine-based compounds exhibit electrophysiological activity, preferably class III electrophysiological activity, and in particular short-acting class III electrophysiological activity, and are therefore expected to be useful in the treatment of cardiac arrhythmias. 99/31100 Disclosure of the Invention According to the invention there is provided a compound of formula I, wherein R 1 and R 2 independently represent H, C M alkyl or together form -O-(CH 2 ) 2 -O-, -(CH 2 ) 4 - or -(CH 2 ) 5 -; R 9 represents C 2 alkyl, phenyl, naphthyl, C w alkylphenyl (which four groups are all optionally substituted or terminated by one or more substituents selected from -OH, halo, cyano, nitro, C alkyl or C l alkoxy) or -(CH 2 ) q Cy 1 ; R 10 represents H or -OH; R u represents H or C alkyl; R 12 represents one or more optional substituents selected from OH, cyano, halo, amino, nitro, C 6 alkyl, C^ alkoxy, -N(H)S(O) 2 R 16 , -OS(O) 2 R 16a , -N(H)C(O)N(H)R 17 or -C(O)N(H)R 18 ; A represents a single bond, C alkylene, -(CH 2 ) n N(R 20 )-, -(CH 2 ) n S(O) p -, -(CH 2 ) n O- (in which three latter groups, the -(CH 2 ) n - group is attached to the carbon atom bearing R 10 and R 11 ), -C(O)N(R 20 )- (in which latter group, the -C(0)- group is attached to the carbon atom bearing R I0 and R 11 ), -N(R 20 )C(O)O(CH,) n -, -N(R 20 )(CH 2 ) n - (in which two latter groups, the N(R 20 ) group is attached to the carbon atom bearing R 10 and R u ) or -(CH 2 ) m C(H)(OH)(CH 2 ) n - (in which latter group, the -(CH 2 ) m - group is attached to the carbon atom bearing R 10 and R 11 ); B represents a single bond, C^ alkylene, -N(R 23 )(CH 2 ) r - or -O(CH 2 ) r - (in which two latter groups, the -(CH 2 ) r - group is attached to the bispidine nitrogen atom); m represents 1 , 2 or 3; n and r independently represent 0, 1 , 2, 3 or 4; p represents 0, 1 or 2; q represents 0, 1, 2 or 3; X represents O or S; Cy 1 represents a five to seven-membered heterocyclic ring containing one or more heteroatom selected from O, N or S, which ring is optionally substituted by one or more substituent selected from C(O)R 21 or C(O)OR 22 ; R 16 , R 16a , R 20 and R 23 independently represent H or C alkyl; and R 17 , R 18 , R 21 and R 22 independently represent H or C alkyl; or a pharmaceutically acceptable derivative thereof. Pharmaceutically acceptable derivatives include salts and solvates. Salts which may be mentioned include acid addition salts. Pharmaceutically acceptable derivatives also include, at the bispidine nitrogens, C alkyl quaternary ammonium salts and N-oxides, provided that, when a N-oxide is present at a bispidine nitrogen, X does not represent S and/or p does not represent 0 when A represents -(CH 2 ) n S(O) p -. The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. 99/31100 The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included wimin the scope of the invention. Alkyl groups which R 1 , R 2 , R 9 , R u , R 12 , R 16 , R 16a , R 17 , R 18 , R 20 , R 21 , R 22 and R 23 may represent, and with which R 9 may be substituted, may be linear or branched, may be saturated or unsaturated, may be cyclic, acyclic or part cyclic/acyclic, and may be interrupted by oxygen and/or substituted by one or more fluoro or hydroxy group. Alkylene groups which A and B may represent, and -(CH 2 ) m -, -(CH 2 ) n -, -(CH 2 ) q - and -(CH 2 ) r - chains which A, B and R 9 (as appropriate) may include, may be linear or branched, may be saturated or unsaturated, may be cyclic or acyclic and may be interrupted by oxygen. Alkoxy groups which R 12 may represent, and with which R 9 may be substituted, may be linear or branched, may be saturated or unsaturated and may be cyclic or acyclic. Alkylphenyl groups which R 9 may represent may be linear or branched and mav be saturated or unsaturated. ΛΛ „„ nft 99/31100 7 Heterocyclic groups which Cy 1 may represent may be aromatic or non- aromatic in character. Halo groups which R 12 may represent, and with which R 9 may be substituted, include fluoro, chloro, bromo and iodo. Abbreviations are listed at the end of this specification. Preferred compounds of the invention include those in which: R 1 represents H, C alkyl or, together with R 2 , represents -O(CH 2 ) 2 O- or -(CH 2 ) 4 -; R 2 represents H or together with R 1 represents -O(CH 2 ) 2 O- or -(CH 2 ) 4 -; R 9 represents optionally substituted phenyl, optionally substituted C 3 alkylphenyl, optionally substituted, optionally unsaturated, linear, branched or cyclic, C l 2 alkyl (which latter group may also be interrupted by an O atom), or -(CH^Cy 1 ; R u represents H, CH 3 or CH,OH; R 12 is absent or represents one or more substituents selected from cyano, OH, nitro, N(H)S(O) 2 R 16 , N(H)C(O)N(H)R 17 , C(O)N(H)R 18 , OS(O) 2 R 16a , amino and C alkyl; X represents O; A represents a single bond, O, -CH 2 -, -(CH 2 ) r , -CH 2 O-, -(CH 2 ) 2 O-, -CH 2 S-, -CH 2 N(R 20 )-, -C(O)N(R 20 )-, -N(R 20 )C(O)O(CH 2 ) n -, -CH 2 CH(OH)- or N(R 20 )(CH 2 ) n -; B represents optionally unsaturated, linear or branched, C M alkylene (which group is also optionally interrupted by O); when the bispidine nitrogen bearing B optionally bears a C alkyl group, thus forming a quaternary ammonium salt, the alkyl group is a methyl group. 99/31100 When R 12 represents a substituent in the para position (e.g. when a single substituent is present in this position), preferred substituents include cyano, nitro and N(H)S(O) 2 R 16 (in which latter group R 16 represents C^ alkyl, especially methyl, ethyl or rc-propyl). When R 9 represents -(CH 2 ) q Cy', preferred compounds of the invention include those in which q is 0, 1 or 2 and Cy 1 contains at least one nitrogen atom (e.g. Cy 1 represents a six-membered ring containing one or two nitrogen atoms). Preferred ring systems that may be represented by Cy 1 include piperidine and piperazine (e.g. piperidin-4-yl and piperazin-1-yl). Preferred optional substituents on the ring include those in which R 21 and R 22 independently represent C alkyl, preferably substituted in the 4 position relative to the point of attachment to -(CH^-. More preferred compounds of the invention include the compounds of Examples 1 to 74 described hereinafter. Particularly preferred compounds of me invention include those in which: R 1 represents H; R 2 represents H; R 9 represents linear or branched C 2 . 7 alkyl, particularly linear C 3 _ 5 alkyl and especially branched C 3 _ 5 alkyl (e.g. iso-pτopyl, iso-bu yl or ten-butyl); R 10 represents -OH; R u represents H; R 12 represents cyano, particularly in the para position relative to A; A represents a single bond or -CH 2 O-; B represents -CH 2 - or -(CH 2 ) 2 -. 99/31100 Preparation According to the invention there is also provided a process for the preparation of compounds of formula I which comprises: (a) reaction of a compound of formula II, wherein R 1 , R 2 , R 10 , R u , R 12 , A and B are as hereinbefore defined with a compound of formula III, R 9 XC(O)L' III wherein L 1 represents a leaving group, such as Hal, imidazolyl or -OC(O)XR 9 , Hal represents Cl, Br or I, and R 9 and X are as hereinbefore defined, for example at or above room temperature in the presence of a suitable base (e.g. aqueous NaOH, K 2 CO 3 or TEA) and an appropriate organic solvent (e.g. DCM, THF, acetonitrile, toluene, or mixtures of such solvents); (b) for compounds of formula I in which B represents CH 2 and R 10 represents OH, reaction of a compound of formula IV, wherein R\ R 2 , R 9 and X are as hereinbefore defined, with a compound of formula V, wherein R 11 , R 12 and A are as hereinbefore defined, for example at elevated temperature (e.g. 60°C to reflux) in the presence of a suitable solvent (e.g. a lower alkyl alcohol (e.g. IPA), acetonitrile, or a mixture of a lower alkyl alcohol and water); (c) reaction of a compound of formula IV, as hereinbefore defined, with a compound of formula VI, wherein L 2 represents a leaving group (e.g. mesylate, tosylate or Hal, where Hal is as hereinbefore defined) and R 10 , R 11 , R 12 , A and B are as hereinbefore defined, for example at elevated temperature (e.g. between 35°C and reflux temperature) in the presence of a suitable base (e.g. TEA or K 2 CO 3 ) and an appropriate organic solvent (e.g. acetonitrile or DMSO); (d) for compounds of formula I in which R 11 represents H, reduction of a compound of formula VIII, wherein R 1 , R 2 , R 9 , R 12 , A, B and X are as hereinbefore defined, in the presence of a suitable reducing agent and under appropriate reaction conditions; for example, for formation of compounds of formula I in which R 10 represents OH, reduction may be performed under mild reaction conditions in the presence of e.g. sodium borohydride and an appropriate organic solvent (e.g. THF); and for formation of compounds of formula I in which R 10 represents H, reduction may be performed by activating the C =O group using an appropriate agent (such as tosylhydrazine) in the presence of a suitable reducing agent (e.g. sodium borohydride or sodium cyanoborohydride) and an appropriate organic solvent (e.g. a lower alkyl alcohol); (e) for compounds of formula I in which R 1 and R 2 both represent H, reduction of a corresponding compound of formula IX, wherein R 9 , R 10 , R u , R 12 , X, A and B are as hereinbefore defined, and in which the C=O group may be activated using an appropriate agent, such as tosylhydrazine, in the presence of a suitable reducing agent (e.g. sodium borohydride or sodium cyanoborohydride) and an appropriate organic solvent (e.g. a lower alkyl alcohol); when the C =O group is activated, the activation step may be carried out at between room and reflux temperature in the presence of an appropriate organic solvent (e.g. a lower alkyl alcohol such as methanol, ethanol or IPA), whereafter the reducing agent may be added to the reaction mixture and the reduction carried out at between 60 °C O 99/31100 13 and reflux, advantageously in the presence of a suitable organic acid (e.g. acetic acid); (f) for compounds of formula I in which R 1 and R 2 together represent -O(CH 2 ) 2 O-, reaction of a corresponding compound of formula IX as hereinbefore defined wi ethane- 1 ,2-diol under appropriate reaction conditions, for example, provided that R 9 does not represent rerr-butyl, by refluxing in the presence of pTSA and an appropriate organic solvent (e.g. toluene), or, when R 9 represents tert-butyl, under mild and/or non-acidic conditions such as those which are known to those skilled in the art; (g) for compounds of formula I which are bispidine-nitrogen N-oxide derivatives, oxidation of the corresponding bispidine nitrogen of a corresponding compound of formula I, in the presence of a suitable oxidising agent (e.g. mCPBA), for example at 0°C in the presence of a suitable organic solvent (e.g. DCM); (h) for compounds of formula I which are C alkyl quaternary ammonium salt derivatives, in which the alkyl group is attached to a bispidine nitrogen, reaction, at the bispidine nitrogen, of a corresponding compound of formula I with a compound of formula XI, R Hal XI wherein R b represents C alkyl and Hal is as hereinbefore defined, for example at room temperature in the presence of an appropriate organic solvent (e.g. DMF), followed by purification (using e.g. HPLC) in the presence of a suitable counter-ion provider (e.g. NH 4 OAc); O 99/31100 14 (i) for compounds of formula I in which R 10 and R u represent H, B represents C w alkylene and A represents -N(R 20 )(CH 2 ) n -, reaction of a compound of formula XII, wherein B a represents C 6 alkylene and R 1 , R 2 , R 9 , R 20 and X are as hereinbefore defined widi a compound of formula XIII, wherein R 12 , n and Hal are as hereinbefore defined, for example at 40°C in the presence of a suitable organic solvent (e.g. acetonitrile); (j) reaction of a compound of formula II, as hereinbefore defined, with a compound of formula XIV, R 9 XH XIV wherein R 9 and X are as hereinbefore defined, in the presence of 1 ,1'- carbonyldiimidazole, for example by refluxing in the presence of a suitable organic solvent (e.g. THF); or 99/311 15 (k) conversion of one R 12 substituent to another using techniques well known to those skilled in me art. Compounds of formula II may be prepared by reaction of a compound of formula XV, wherein R 1 and R 2 are as hereinbefore defined, with a compound of formula VI as hereinbefore defined, for example as described hereinbefore for synthesis of compounds of formula I (process step (c)), or, in the case of compounds of formula II wherein B represents CH 2 and R 10 represents OH, with a compound of formula V as hereinbefore defined, for example as described hereinbefore for syndiesis of compounds of formula I (process step (b)). Compounds of formula II in which R 1 and R 2 both represent H may be prepared by reduction of a compound of formula XVI, wherein R 10 , R u , R 12 , A and B are as hereinbefore defined, and in which the C=O group may be activated using an appropriate agent, such as tosylhydrazine, for example as described hereinbefore for synthesis of compounds of formula I (process step (e)). Compounds of formula IV may be prepared by reaction of a compound of formula XV, as hereinbefore defined, with a compound of formula III as hereinbefore defined, for example as described hereinbefore for synthesis of compounds of formula I (process step (a)). Compounds of formula IV may alternatively be prepared by reaction of a compound of formula XV, as hereinbefore defined, with a compound of formula XIV, as hereinbefore defined, in the presence of 1 ,1'- carbonyldiimidazole, for example as described hereinbefore for synthesis of compounds of formula I (process step (j)). Compounds of formula IV in which R 1 and R 2 represent H may alternatively be prepared by reduction of a corresponding compound of formula XVIII, XVIII R 9 wherein R 9 and X are as hereinbefore defined, and in which the C = O group may be activated using an appropriate agent, such as tosylhydrazine, for example as described hereinbefore for compounds of formula I (process step (e)). Compounds of formula V may be prepared in accordance with techniques which are well known to those skilled in the art. For example, compounds of formula V in which: (1) A represents -CH 2 O- may be prepared by reaction of a compound of formula XIX, wherein R 12 is as hereinbefore defined, with a compound of formula XX, wherein R u is as hereinbefore defined, for example at elevated temperature (between 60°C and reflux temperature) in the presence of a suitable base (e.g. K 2 CO 3 or NaOH) and an appropriate organic solvent (e.g. acetonitrile or toluene water), or as otherwise described in me prior art; (2) A represents -CH 2 O- may be prepared by reaction of a compound of formula XIX, as hereinbefore defined, with a compound of formula XXI, wherein R u is as hereinbefore defined, for example between room temperature and elevated temperature (e.g. 40°C) in the presence of a suitable base (e.g. K 2 CO 3 or potassium ethoxide) and an appropriate organic solvent (e.g. acetonitrile or DMF); (3) A represents a single bond and R 11 represents H may be prepared by reduction of a compound of formula XXII, wherein R 12 is as hereinbefore defmed, for example at between -15°C and room temperature in the presence of a suitable reducing agent (NaBH 4 ) and an appropriate organic solvent (e.g. THF), followed by elimination of me resultant intermediate, for example at room temperature in the presence of a suitable base (e.g. K 2 CO 3 ) and an appropriate organic solvent (e.g. acetonitrile); or (4) A represents C alkylene, -(CH 2 ) n N(R 20 )-, -(CH 2 ) π S(O) 2 - or -(CH 2 ) n O- (in which latter three groups n represents 1 , 2, 3 or 4) or -(CH 2 ) m C(H)(OH)(CH 2 ) n - may be prepared by oxidation of a compound of formula XXIII, XXIII in which A a represents a single bond, C^ alkylene, -(CH 2 ) n . 1 N(R 20 )-, -(CH 2 ) n . 1 S(O) 2 - or -(CH 2 ) n . 1 O- (in which latter three groups n represents 1 , 2, 3 or 4) or -(CH 2 ) m . 1 C(H)(OH)(CH 2 ) n - (in which latter group n is as hereinbefore defined) and R 20 and m are as hereinbefore defined, in the presence of a suitable oxidising agent (e.g. CPBA), for example by refluxing in the presence of a suitable organic solvent (e.g. DCM). Compounds of formula VI may be prepared by standard techniques. For example compounds of formula VI in which: (1) A represents -(CH 2 ) n O- may be prepared by coupling a compound of formula XIX, as hereinbefore defined, to a compound of formula XXIV, L 4 -(CH 2 ) n -C(R 10 )(R π )-B-L 2 XXIV wherein L 4 represents a suitable leaving group (e.g. Hal) and Hal, n, R 10 , R 11 , B and L 2 are as hereinbefore defined; (2) A represents -C(O)N(R 20 )- may be prepared by coupling a compound of formula XXV, wherein R 12 and R 20 are as hereinbefore defined, to a compound of formula XXVI, L 4 -C(O)-C(R 10 )(R U )-B-L 2 XXVI wherein L 4 , R 10 , R 11 , B and L 2 are as hereinbefore defined; or (3) R 10 represents -OH and R 11 represents methyl substituted by hydroxy, oxidation of a compound of formula XXVI A, XXVIA wherein R 12 , A, B and L 2 are as hereinbefore defined, in all three cases, under conditions which are well known to those skilled in die art (e.g. as described hereinafter). Compounds of formula V and VI in which A represents -(CH 2 ) π S(O)- or -(CH 2 ) n S(O) 2 - may be prepared by oxidation of a corresponding compound of formula I wherein A represents -(CH 2 ) n S-, wherein n is as hereinbefore defined, in the presence of an appropriate amount of a suitable oxidising agent (e.g. CPBA) and an appropriate organic solvent. Compounds of formula VIII may be prepared in a similar fashion to compounds of formula I (see, for example, process steps (a) or (c)). Alternatively, compounds of formula VIII in which B represents C 2 alkylene may be prepared by reaction of a compound of formula IV, as hereinbefore defined with a compound of formula XXVII, wherein A and R 12 are as hereinbefore defined, for example a room temperamre in the presence of a suitable organic solvent (e.g. ethanol). Compounds of formula XII may be prepared by removing an optionally substituted benzyloxycarbonyl unit from a corresponding compound of formula I in which R 10 and R 11 bom represent H and A represents -N(R 20 )C(O)O(CH 2 )-, B represents B a and B a is as hereinbefore defined under conditions which are well known to those skilled in me art. Compounds of formula XV are known in the literature or are readily available using known techniques. For example, compounds of formula XV in which R 1 and R 2 , togedier wi the carbon atom to which they are attached, represent -O-(CH 2 ) 2 -O-, -(CH 2 ) 4 - or -(CH 2 ) , may be prepared by reduction of a compound of formula XXVIII, XXVIII wherein R la and R 2a , together with the carbon atom to which they are attached, represent -O-(CH 2 ) 2 -O-, -(CH 2 ) 4 - or -(CH 2 ) 5 -, in the presence of a suitable reducing agent (e.g. LiAlH 4 ) under conditions which are well known to those skilled in the art. Compounds of formula IX may be prepared in analogous fashion to compounds of formula I. For example compounds of formula IX may be prepared by reaction of a compound of formula XVI, as hereinbefore defined, and a compound of formula III, as hereinbefore defined, for example as described hereinbefore for synthesis of compounds of formula I (process step (a)). Compounds of formulae IX, XVI and XVIII, may be prepared, advantageously, by reaction of (as appropriate) either (i) a compound of formula XXIX, wherein R )9 9 and X are as hereinbefore defined, or (ii) 4-piperidone (or a protected derivative thereof), wim (as appropriate) either (l) a compound of formula XXXI, wherein R 10 , R u , R 12 , A and B are as hereinbefore defined, or (2) NH 3 (or a protected (e.g. benzyl) derivative thereof), in all cases in the presence of a formaldehyde (i.e. an appropriate source of formaldehyde, such as paraformaldehyde or formalin solution). The formation of compounds of formulae IX, XVI and XVIII may be carried out in this way for example at between room temperature and reflux (depending upon die concentration of the reactants) in the presence of an appropriate solvent (e.g. ethanol or methanol) and, preferably, in die presence of an organic acid (e.g. a C carboxylic acid, especially acetic acid). We have advantageously found that this process may be used to prepare bispidine derivatives incorporating a carbamate group (-NC(O)XR 9 , where N is one of the bispidine nitrogens) directly from readily available starting materials, us avoiding the need for long-winded, multi-step, synmeses, involving me coupling of a -C(O)XR 9 group to a bispidine unit, following formation of the latter (as well as avoiding any further protection/deprotection steps which are necessary). It will be also appreciated by diose skilled in me art that compounds of formula XV in which R 1 and R 2 bodi represent H may also be prepared via mis memod (i.e. by reaction of a compound of 4-piperidone (or a protected derivative thereof) wim NH 3 (or a protected derivative thereof) in the presence of a formaldehyde), provided mat the intermediate so formed is subsequently reduced under appropriate reaction conditions. Compounds of formula XXVIII may be prepared in accordance with techmques which are well known to those skilled in the art. For example compounds of formula XXVIII in which R la and R 2a together represent -(CH 2 ) 4 - or -(CH 2 ) 5 - may be prepared by reaction of a compound of formula XXXII, XXXII wherein R la' and R 2a' together represent -(CH 2 ) 4 - or -(CH 2 ) r , with a mixture with a mixture of phosphoric acid and sulfuric acid, for example at 120°C. Compounds of formula XXXI are well known in the literature or are readily available using known techniques. For example, compounds of formula XXXI wherein R 10 represents OH, R 11 represents H and B represents CH 2 may be prepared by reaction of a compound of formula V in which R 11 represents H with ammonium hydroxide under conditions which are well known to those skilled in the art. Compounds of formulae III, XI, XIII, XIV, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVIA, XXVII, XXIX and XXXII, and derivatives thereof, are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions. Substituents on the aryl (e.g. phenyl), and (if appropriate) heterocyclic, group(s) in compounds of formulae I, II, III, IV, V, VI, VIII, IX, XII, XIII, XIV, XVI, XVIII, XIX, XXII, XXIII, XXV, XXVIA, XXVII, XXIX and XXXI may be converted to other claimed substituents using techniques well known to those skilled in me art. For example, nitrobenzene may be reduced to an aminobenzene, hydroxy may be converted to alkoxy, alkoxy may be hydrolysed to hydroxy etc. The compounds of me invention may be isolated from meir reaction mixtures using conventional techniques. It will be appreciated by diose skilled in die art that, in die process described above, die functional groups of intermediate compounds may be, or may need to be, protected by protecting groups. Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. rerr-butyldimethylsilyl, tert- butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and alkylcarbonyloxy groups (e.g. memyl- and ethylcarbonyloxy groups). Suitable protecting groups for amino include benzyl, fert-butyloxycarbonyl, 9-fluorenylmemoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C^ alkyl or benzyl esters. The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore. Protecting groups may be removed in accordance widi techniques which are well known to those skilled in die art and as described hereinafter. Many protected derivatives of the intermediate compounds described hereinbefore are commercially available. The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by J W F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 2nd edition, T W Greene & P G M Wutz, Wiley-Interscience (1991). Persons skilled in die art will appreciate diat, in order to obtain compounds of the invention in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned herein may be performed in a different order, and/or die individual reactions may be performed at a different stage in die overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to diose associated hereinbefore widi a particular reaction). This will depend inter alia on factors such as the nature of odier functional groups present in a particular substrate, the availability of key intermediates and die protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and me sequence for accomplishing the syndiesis. It will also be appreciated by diose skilled in the art diat, aldiough certain protected derivatives of compounds of formula I, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, d ey may be administered parenterally or orally and thereafter metabolised in me body to form compounds of die invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Moreover, we have found diat certain compounds of formula I may act as prodrugs of odier compounds of formula I. All prodrugs of compounds of formula I are included widiin the scope of the invention. Some of the intermediates referred to hereinbefore are novel. According to a further aspect of die invention mere is mus provided: (a) a novel compound of formula IV as hereinbefore defined or a protected derivative thereof; (b) a novel compound of formula IX as hereinbefore defined or a protected derivative tihereof; (c) a novel compound of formula XVI as hereinbefore defined or a protected derivative thereof; and (d) a novel compound of formula XVIII as hereinbefore defined or a protected derivative mereof. Medical and pharmaceutical use The compounds of die invention are useful because diey possess pharmacological activity. They are therefore indicated as pharmaceuticals. Thus, according to a further aspect of die invention diere is provided die compounds of die invention for use as pharmaceuticals. In particular, die compounds of die invention exhibit myocardial electrophysiological activity, for example as demonstrated in die test described below. The compounds of die invention are thus expected to be useful in bodi d e prophylaxis and the treatment of arrhythmias, and in particular atrial and ventricular arrhythmias. The compounds of me invention are thus indicated in die treatment or prophylaxis of cardiac diseases, or in indications related to cardiac diseases, in which arrhythmias are believed to play a major role, including ischaemic heart disease, sudden heart attack, myocardial infarction, heart failure, cardiac surgery and diromboembolic events. In die treatment of arrhythmias, compounds of me invention have been found to selectively delay cardiac repolarization, thus prolonging me QT interval, and, in particular, to exhibit class III activity. Although compounds of me invention have been found to exhibit class III activity in particular, in die treatment of arrhythmias, their mode(s) of activity is/are not necessarily restricted to this class. Compounds of me invention have also been found to be potent, yet possess a duration of action which is relatively short (e.g. 1 to 120, preferably 1 to 60, more preferably 1 to 30 and particularly 1 to 15 minutes, as measured in die test described below) when compared to compounds known in die prior art. Compounds of me invention are therefore expected to possess me advantages hereinbefore mentioned for short acting compounds. According to a further aspect of the invention, mere is provided a method of treatment of an arrhydimia which method comprises administration of a merapeutically effective amount of a compound of die invention to a person suffering from, or susceptible to, such a condition. Pharmaceutical preparations The compounds of die invention will normally be administered subcutaneously, intravenously, mtraarterially, transdermally, intranasally, by inhalation, or by any odier parenteral route, in me form of pharmaceutical preparations comprising the active ingredient eidier as a free base, a pharmaceutical acceptable ion exchanger or a non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form. Depending upon die disorder and patient to be treated, as well as the route of administration, me compositions may be administered at varying doses. The compounds of die invention may also be combined widi any odier drugs useful in die treatment of arrhythmias and/or odier cardiovascular disorders. According to a furdier aspect of the invention mere is thus provided a pharmaceutical formulation including a compound of me invention in admixture wim a pharmaceutically acceptable adjuvant, diluent or carrier. Suitable daily doses of the compounds of die invention in therapeutic treatment of humans are about 0.05 to 5.0 mg/kg body weight at parenteral administration. The compounds of me invention have the advantage diat diey are effective against cardiac arrhythmias. Compounds of die invention have also been found to possess a shorter duration of action than compounds known in the prior art and are dierefore expected to be particularly useful when used in me acute conversion of arrhythmias as mentioned hereinbefore. Compounds of die invention may also have me advantage diat they may be more efficacious man, be less toxic than, have a broader range of activity (including exhibiting any combination of class I, class II, class III and/or class IV activity (especially class I, class II and/or class IV activity in addition to class III activity)) than, be more potent than, produce fewer side effects (including a lower incidence of proarrhydimias such as torsades de pointes) t±ian, be more easily absorbed than, or that they may have other useful pharmacological properties over, compounds known in me prior art. Biological Tests Test A Primary Electrophysiological Effects In Anaesd etised Guinea Pigs Guinea pigs weighing between 660 an 1100 g were used. The animals were housed for at least one week before the experiment and had free access to food and tap water during that period. Anaesthesia was induced by an intraperitoneal injection of pentobarbital (40 to 50 mg/kg) and cadieters were introduced into one carotid artery (for blood pressure recording and blood sampling) and into one jugular vein (for drug infusions). Needle electrodes were placed on die limbs for recording of ECGs (lead II). A diermistor was placed in die rectum and the animal was placed on a heating pad, set to a rectal temperature of between 37.5 and 38.5°C. A tracheotomy was performed and me animal was artificially ventilated widi room air by use of a small animal ventilator, set to keep blood gases widiin the normal range for the species. In order to reduce autonomic influences bom vagi were cut in die neck, and 0.5 mg/kg of propranolol was given intravenously, 15 minutes before me start of die experiment. The left ventricular epicardium was exposed by a left-sided moracotomy, and a custom-designed suction electrode for recording of the monophasic action potential (MAP) was applied to me left ventricular free wall. The electrode was kept in position as long as an acceptable signal could be recorded, odierwise it was moved to a new position. A bipolar electrode for pacing was clipped to die left atrium. Pacing (2 ms duration, twice the diastolic direshold) was performed widi a custom-made constant current stimulator. The heart was paced at a frequency just above die normal sinus rate during 1 minute every fifth minute throughout the study. The blood pressure, die MAP signal and die lead II ECG were recorded on a Mingograph ink-jet recorder (Siemens-Elema, Sweden). All signals were collected (sampling frequency 1000 Hz) on a PC during the last 10 seconds of each pacing sequence and me last 10 seconds of die following minute of sinus rhythm. The signals were processed using a custom-made program developed for acquisition and analysis of physiological signals measured in experimental animals (see Axenborg and Hirsch, Comput. Memods Programs Biomed. 41, 55 (1993)). The test procedure consisted of taking two basal control recordings, 5 minutes apart, during both pacing and sinus rhythm. After die second control recording, the first dose of die test substance was infused in a volume of 0.2 mL into me jugular vein catheter for 30 seconds. Three minutes later, pacing was started and a new recording was made. Five minutes after the previous dose, die next dose of test substance was administered. Six to ten consecutive doses were given during each experiment. Data analysis Of die numerous variables measured in mis analysis, diree were selected as die most important for comparison and selection of active compounds. The three variables selected were die MAP duration at 75 percent repolarization during pacing, die atrio- ventricular (AV) conduction time (defined as the interval between die atrial pace pulse and die start of the ventricular MAP) during pacing, and die heart rate (defined as die RR interval during sinus rhythm). Systolic and diastolic blood pressure were measured in order to judge die haemodynamic stams of the anaesdietised animal. Further, the ECG was checked for arrhydunias and/or morphological changes. The mean of the two control recordings was set to zero and the effects recorded after consecutive doses of test substance were expressed as percentage changes from this value. By plotting diese percentage values against die cumulative dose administered before each recording, it was possible to construct dose-response curves. In this way, each experiment generated diree dose-response curves, one for MAP duration, one for AV- conduction time and one for die sinus frequency (RR interval). A mean curve of all experiments performed widi a test substance was calculated, and potency values were derived from the mean curve. All dose-response curves in ese experiments were constructed by linear connection of the data points obtained. The cumulative dose prolonging the MAP duration by 10% from me baseline was used as an index to assess die class III electrophysiological potency of the agent under investigation (D 10 ). Test B Metabolic Stability of Test Compounds An in vitro screen was set up to determine me metabolic stability of the compounds of die invention. The hepatic S-9 fraction from dog, man, rabbit and rat with NADPH as co- factor was used. The assay conditions were as follows: S-9 (3 mg/mL), NADPH (0.83 mM), Tris-HCi buffer (50 mM) at pH 7.4 and 10 μM of test compound. The reaction was started by addition of test compound and terminated after 0, 1 , 5, 15 and 30 minutes by raising the pH in me sample to above 10 (NaOH; 1 mM). After solvent extraction, die concentration of test compound was measured against an internal standard by LC (fluorescence/UV detection). The percentage of test compound remaining after 30 minutes (and dius t 1/2 ) were calculated and used as a measure for metabolic stabdity. The invention is illustrated by way of die following examples. Examples General Experimental Procedures Mass spectra were recorded on a Finnigan MAT TSQ 700 triple quadrupole mass spectrometer equipped widi an electrospray interface (FAB-MS) and VG Platform II mass spectrometer equipped with an electrospray interface (LC-MS), a Hewlett Packard model 6890 gas chromatograph connected to a Hewlett-Packard model 5973A mass spectrometer via a Hewlett Packard HP-5-MS GC column, or a Shimadzu QP-5000 GC/mass spectrometer (CI, methane). 'H NMR and 13 C NMR measurements were performed on a BRUKER ACP 300 and Varian UNITY plus 400 and 500 spectrometers, operating at l H frequencies of 300, 400 and 500 MHz respectively, and at I3 C frequencies of 75.5, 100.6 and 125.7 MHz respectively. Alternatively, 13 C NMR measurements were performed on a BRUKER ACE 200 spectrometer at a frequency of 50.3 MHz. 35 π U - I - 1998 Rot-amers may or may not be denoted in spectra depending upon ease of interpretation of spectra. Unless otherwise stated, chemical shifts are given in ppm with me solvent as internal standard. Syndiesis of intermediates Example A 4-(2-Oxiranylmethoxy)benzonitrile Epichlorohydrin (800 mL) and K 2 CO 3 (414 g) were added to a stirred solution of -cyanophenol (238 g) in 2.0 L MeCN and the reaction mixture was refluxed under inert atmosphere for 2 h. The hot solution was filtered and die filtrate concentrated giving a clear oil which was crystallized from di-wσ-propyl ether giving die product in 75 % yield. 13 C NMR (CDC1 3 ): δ 44.4, 49.7, 69.0, 104.5, 115.3, 118.9, 134.0, 161.6 Example B 2-{[(3-Nitrophenyl)sulfonyloxylmethyl}oxirane -Nitrobenzensulfonylchloride (12.6 g; 57 mmol) was added to a cold (-20°C) solution of (R)-( + )-glycidol (5.5 g; 74 mmol) and TEA (10.3 mL; 74 mmol). The reaction mixture was stirred at -20°C for 96 h. The solution was filtered and the filtrate washed widi tartaric acid (10% w/w), brine, H 2 O and concentrated giving the title compound in a 97% yield. 'H NMR (CDCI 3 ): δ 2.62 (dd. lH), 2.84 (dd,lH), 3.22 (m, lH), 4.07 (dd. lH), 4.49 (dd, lH), 7.80 (t, lH), 8.25 (m, lH), 8.52 (m, lH), 8.78 (m,lH) Example C 4- r(2S)-Oxirany lmethoxyj benzonitrile The title compound was prepared in a 90% yield according to the procedure described in Example A above starting from (R)-(-)- epichlorohydrin. Example D 4-[(2R)-OxiranylmethoxyJbenzonitrile The title compound was prepared according to die procedure described in Example A above starting from (.S)-(-)-epichlorohydrin. [ α ] D 2o = _ 14 1 ° ( C = i.o; acetone) Η NMR (CDC1 3 ): δ 2.79 (1H, m); 2.98 (1H, m); 3.39 (1H, m); 3.98 (1H, m); 4.37 (1H, m); 6.99 (2H, d); 7.60 (2H, d) Example E 3-Benzyl-3 ,7-diazabicyclo [3.3.1] nonane (a) 3 ,7-Dibenzyl-3 ,7-diazabicyclo[3.3. ljnonane The sub-title compound was prepared according to me method described in J. Org. Chem. 41, 1593, (1976) except that 3,7-dibenzyl-3,7- diazabicyclo[3.3.1Jnonan-9-one (also prepared according to the method described in J. Org. Chem. 41, 1593 (1976)) was used instead of N- benzyl-N-methylbispidone . (b) 3-Benzyl-3 ,7-diazazbicyclo[3.3. ljnonane 3, 7-Dibenzyl-3,7-diazabicyclo[3.3. ljnonane (1.97 g; 6.4 mmol; from step (a) above) was dissolved in EtOH (95%) and hydrogenated over 5% Pd/C at 1 atm. until tic indicated mat die reaction was complete. The catalyst was removed by filtration through a pad of celite and the residue was concentrated under reduced pressure to give die title compound in a quantitative yield. 13 C NMR (CDC1 3 ): δ 30.1, 33.4, 36.0, 52.5, 59.6, 64.3, 126.9, 128.3, 128.7, 138.8 Example F tgrt-Butyl 3,7-diazabicyclor3.3. lJnonane-3-carboxylate (a) tgrt-Butyl 7-benzyl-9-oxy-3,7-diazabicyclo[3.3.1Jnonane-3-carboxylate Paraformaldehyde (4.00 g; 127 mmol) was added to a solution of benzylamine (13.7 g; 126 mmol) in e anol (190 mL). The solution was heated to 60°C and a solution of acetic acid (15.2 g; 252 mmol) in emanol (160 mL) was added over 2 hours. After additional stirring for 1 hour, the solution was cooled to room temperature. This solution was added (over 2 hours) to a mixture of l-tgrr-butoxycarbonyl-4-piperidone (25.5 g; 127 mmol) and paraformaldehyde (4.80 g; 152 mmol) in emanol (270 mL) which had been heated to 60°C. After reflux overnight, the solution was cooled to room temperamre. The ethanol was removed by evaporation. Extractive work-up was performed in toluene -.water and the material was filtered dirough silica in a toluene: ethyl acetate system. Evaporation of the eluate gave a solid material (37.4 g). The purity was 90 area% (HPLC) and die was yield 60% . By performing a crystallisation in /.rø-propanol, a compound widi a purity of 98 area% (HPLC) and a yield of 70% was obtained. MS (El; 70 eV): m/z 91 (100%), m/z 57 (42%), m/z 273 (32%), m/z 330 (5 %) 13 C NMR (CDC1 3 ): δ 28.72, 47.71 , 49.91 , 50.60, 58.83, 59.16, 61.96, 80.18, 127.37, 128.45, 128.89. 137.57, 154.89, 213.66 ppm using TMS as reference. (b) tgrt-Butyl 7-benzyl-9-oxy-3,7-diazabicyclo[3.3.1Jnonane-3-carboxylate (alternative preparation) Benzylamine (6.51 g; 60.2 mmol), acetic acid (72.3 g, 1200 mmol), paraformaldehyde (3.71 g; 120 mmol) and l-tg/ -butoxycarbonyl-4- piperidone (12.0 g; 60.2 mmol), were added to emanol (300 mL). The solution was heated to 65°C and stirred at this temperamre for 2 hours. The same work-up procedure as that described in step (a) above was performed, yielding 15.78 g of material with a purity of 92 area% (HPLC) and a yield of 70% . Recrystallisation from wo-propanol yielded a compound widi a purity of 94 area% (HPLC) in a yield of 54% . (c) tgrt-Butyl 7-benzyl-3,7-diazabicyclor3.3. lJ-nonane-3-carboxylate A mixture of 4-toluenesulfonehydrazide (12.4 mmol; 2.30 g) and tert- butyl 7-benzyl-9-oxy-3 ,7-diazabicyclo[3.3.1 Jnonane-3-carboxylate (10.1 mmol; 4.00 g; 83.3 %; from step (a) above) were dissolved in isopropanol (30 mL) and heated at reflux for 2 hours. Acetic acid (2.5 mmol; 0.15 g) and sodium cyanoborohydride (12.1 mmol, 0.76 g) were added and die mixture was again heated at reflux for 2 hours. The slurry was cooled to ambient temperamre and filtered. The filtrate was concentrated and an extractive work-up was performed in toluene: water. The toluene solution was concentrated to give 0.95 g of sub-title compound, widi a purity of 90 area% (GC) in a yield of 60% . MS (El; 70 eV): m/z 259 (100%), m/z 91 (95 %), m/z 169 (45 %), m/z 57 (35 %), m/z 316 (25 %) 13 C NMR (CDC1 3 ): δ 28.67, 28.95, 31.11 , 47.55, 48.38, 58.70, 58.96, 63.46, 78.71 , 126.57, 128.00, 128.53, 138.94, 155.20 ppm using TMS as a reference (d) tgrt-Butyl 3,7-diazabicyclo[3.3. lJnonane-3-carboxylate tgrt-Butyl 7-benzyl-3,7-diazabicyclo[3.3. l]nonane-3-carboxylate (from step (c) above) was debenzylated according to the method described in Example E(b) above to give the title compound in quantitative yield. 13 C NMR (CDCI 3 ): δ 28.05, 28.29, 31.33, 48.35, 49.11 , 51.53, 79.34, 155.16 Example G 4-r3-(3,7-Diazabicyclo[3.3.1Jnon-3-yl)-2-hydroxypropoxyJbenzonitrile HCl-samrated EtOAc (600 mL) was added to a solution of tgrr-butyl 7-[3- (4-cyanophenoxy)-2-hydroxypropyl]-3 ,7-diazabicyclo[3.3. lJnonane-3- carboxylate (62 g; see Example 2 below) in EtOAc (600 mL) and die mixture was stirred at rt. for 4 h. The solvent was removed under reduced pressure, die residue was dissolved in MeCN (1.3 L) and K 2 CO 3 (100 g) was added. The suspension was stirred for 12 h and filtered. Concentration of the filtrate gave the title compound in a 90% yield. 13 C NMR (CDCI 3 ): δ 28.9, 29.2, 32.3, 50.9, 57.7, 60.8, 62.1 , 66.0, 71.2, 104.0, 115.3, 119.1 , 133.9, 162.1 (The title compound was also readily converted to die hydrochloride salt (also used as an intermediate in die examples below) using standard techniques.) Example H t ' so-Propyl 3,7-diazabicyclo 3.3. lJnonane-3-carboxylate (a) /so-Propy! 7-benzyl-3 , 7-diazabicyclo[3.3.1] nonane-3-carboxylate NaOH (6.0 mL; 10M), H 2 O (10 mL) and wσ-propylchloroformate (55 mmol) were added to a solution of 3-benzyl-3,7-diazabicyclo[3.3. ljnonane (10.8 g; 50 mmol; see Example E above) in DCM (50 mL) The reaction mixmre was stirred for 3 h and die phases were then separated. The organic phase was washed widi H 2 O and brine, dried and concentrated to give die sub-title compound in a 95 % yield. (b) /so-Propyl 3,7-diazabicyclo 3.3. lJnonane-3-carboxylate The title compound was prepared according to die method described in Example E(b) above from wo-propyl 7-benzyl-3,7-diazabicyclo- [3.3.1]nonane-3-carboxylate (from step (a) above). FAB-MS (M + 1) + 213 (m z) 13 C NMR (CD 3 CN): δ 22.53, 29.34, 32.23, 49.46, 52.40, 68.67, 156.24 Example I tgrt-Butyl 9-oxy-3 , 7-diazabicyclo f 3.3.1 J -nonan-3 -carboxy late tgrt-Butyl 7-benzyl-9-oxy-3 , 7-diazabicyclo [3.3.1 J-nonan-3-carboxylate (1.2 g; 3.17 mmol) and palladium on charcoal paste (0.10 g; 5% Pd/C; 63 % water) were added to edianol (20 mL). The hydrogenolysis was performed by applying a pressure of 4 bars of hydrogen. After die reaction was completed, d e suspension was filtered, concentrated and purified wim flash chromatography, yielding 0.20 g of material wim a purity of 93 area % (GC). MS (El; 70 eV): m/z 57 (100%), m/z 96 (80%), m/z 41 (40%), m/z 140 (35%), m/z 110 (30%), m/z 183 (30%), m/z 240 (15%) 13 C NMR (CDC1 3 ): δ 28.52, 49.36, 50.48, 55.48, 80.96, 154.87, 213.41 ppm using TMS as a reference Example J Ethyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-9-oxy-3,7-diazabicyclo- [3.3. lJnonane-3-carboxylate (a) 3-(4-Cyanophenoxy)-2-hydroxypropylamine IPA (300 mL) was added to a stirred suspension of 4-(2- oxiranylmethoxy)benzonitrile (100 g; 571 mmol; see Example A above) in NH 3 (500 mL; cone), and die reaction mixmre was stirred at rt. for 3 days. The precipitate was filtered off and the residue concentrated and recrystallized from MeCN to give the sub-title compound in a 46% yield. (b) Ethyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-9-oxy-3,7- diazabicyclo 3.3. lJnonane-3-carboxylate A solution of AcOH (0.30 g; 5.0 mmol) in MeOH (5 mL), followed by paraformaldehyde (0.33 g; 11.0 mmol), were added to a stirred suspension of 3-(4-cyanophenoxy)-2-hydroxypropylamine (0.96 g; 5.0 mmol; from step (a) above) in MeOH (5 mL) under inert atmosphere (N 2 ). The temperature was raised to 55°C and a solution of l-ethoxycarbonyl-4- piperidone (0.86 g; 5.0 mmol) in MeOH (5 mL) was added and me reaction mixmre stirred for 6 h. The solids were filtered off and die solution was concentrated. The solid residue was partitioned between water and diediyl edier. The aqueous phase was collected and die pH adjusted to 10 (4M NaOH) and extracted with DCM. The combined organic layers were concentrated and purified using column chromatography (DCM:MeOH; 19: 1) to give the sub-title compound in a 30% yield. 13 C NMR (CDC1 3 ): δ 14.5, 48.0, 50.6, 57.3, 61.2, 62.2, 65.4, 70.3, 104.2, 115.3, 119.0, 133.9, 157.9, 161.9, 211.7 Preparation of Compounds of Formula I Example 1 Ethyl 7- f 3-(4-cyanophenoxy )-2-hydroxypropylJ -3 , 7-diazabicyclo [3.3.1]- nonane-3-carboxylate Ethylchloroformate (930 mg; 8.4 mmol) was added to a stirred solution of 4-[3-(3,7-diazabicyclo[3.3. lJnon-3-yl)-2-hydroxypropoxyJbenzonitrile (2.3 g; 7.6 mmol; see Example G above) and NaOH (1.5 mL; 10 M) in DCM (60 mL). The solution was stirred at rt. for 1 h, washed widi water and die organic layer was separated, dried (Na 2 SO 4 ) and concentrated. Purification using column chromatography (DCM:MeOH; 19: 1) gave the title compound (1.4 g). 13 C NMR (CDCI 3 ): δ 14.7, 29.2, 32.7, 48.6, 56.7, 60.2, 61.3, 62.6, 65.0, 70.8, 104.0, 115.4, 129.8, 133.9, 157.6, 162.2 Example 2 t g rr-Butyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo- [3.3.1 J nonane-3 -carboxy late A mixmre of t g rr-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (2.3 g; 10 mmol; see Example F above) and 4-(2-oxiranylmethoxy)benzonitrile (1.8 g; 10 mmol; see Example A above) in IPA (10 mL) and H 2 O (1 mL) was stirred at 60°C for 12 h. The reaction mixture was concentrated under reduced pressure and die residue dissolved in DCM and washed wim brine, H 2 O, dried and concentrated. Purification using column chromatography (DCM:MeOH; 19: 1) gave the title compound in a 81 % yield. 13 C NMR (CDC1 3 ): δ 28.44, 28.77, 29.33, 31.93,47.53, 49.34, 56.87, 60.14, 61.60, 65.03, 70.70, 79.37, 103.85, 115.32, 119.13, 133.79, 155.91 , 162.16 Example 3 3,7-Diazabicyclo[3.3.1Jnonane-3-carboxylic acid, 7-[(2S)-3-(4-cyano- phenoxy)-2-hydroxypropylJ-l , 1-dimemyledιyl ester 4-[(2S)-OxiranylmethoxyJbenzonitrile (5.19 g; 29.6 mmol; see Example C above) was added to a stirred solution of tgrr-butyl 3,7- diazabicyclo[3.3.1Jnonane-3-carboxylate (6.7 g; 29.6 mmol; see Example F above) in IPA (30 mL) and H 2 O (3 mL) The reaction mixmre was stirred at 60°C for 12 h and dien at rt. for 48 h. The reaction mixmre was concentrated, die residue dissolved in DCM, dried (MgSO 4 ) and concentrated. The residue was purified using column chromatography (hexane: EtOAc: MeOH; 50:45:5) to give me title product as a white foam in a 56% yield (6.65 g). [αJ 20 D = 16 (c= 1.0; MeOH). ESI-MS (M + 1) + 402 (m z) 13 C NMR (CDCI 3 ): δ 28.44, 28.77, 29.33, 31.93,47.53, 49.34, 56.87, 60.14, 61.60, 65.03, 70.70, 79.37, 103.85, 115.32, 119.13, 133.79, 155.91 , 162.16 Example 4 tgrt-Butyl 7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo- [3.3. lJnonane-3-carboxylate The title compound was prepared analogously to die method described in Example 3 above from 4-[(2R)-oxiranylmethoxyJbenzonitrile (0.98 g; 5.59 mmol; see Example D above) and tgrt-butyl 3,7- diazabicyclo[3.3.1Jnonane-3-carboxylate (1.26 g; 5.59 mmol; see Example F above). After the reaction was complete, the residue was dissolved in DCM and washed wid brine, separated, dried (Na 2 SO 4 ) and concentrated. The residue was dissolved in MeOH (10 mL) and 1 eq. tartaric acid was added. Freeze-drying gave the product as die corresponding tartaric acid salt in 88 % yield (2.7 g). 13 C NMR (CDC1 3 ): δ 28.44, 28.77, 29.33, 31.93,47.53, 49.34, 56.87, 60.14, 61.60, 65.03, 70.70, 79.37, 103.85, 115.32, 119.13, 133.79, 155.91 , 162.16 Example 5 iso-Propyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo- [3.3.1 Jnonane-3-carboxylate Prepared according to the method described in Example 1 above, starting with iO-propylchloro formate. ESI-MS (M + 1) + 388 (m/z) 13 C NMR (CDCI 3 ): δ 22.38, 29.22, 29.49, 32.82, 48.49, 49.43, 56.46, 60.09, 62.47, 64.85, 68.38, 70.83, 103.96, 115.33, 119.26, 133.90, 157.32, 162.20 Example 6 tgrt-Pentyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo- [3.3.1] nonane-3 -carboxylate (a) tgrt-Pentyl 7-benzyl-3,7-diazabicyclof3.3. lJnonane-3-carboxylate Di-tgrr-pentyl dicarbonate (6.1 mL; 25 mmol) was added to a stirred solution of 3 -benzy 1-3, 7-diazabicyclo [3.3. ljnonane (5.41 g; 25 mmol; see Example E above) in THF (50 mL). The reaction mixmre was stirred 12 h at rt. and die solvent evaporated. (b) tgrt-Pentyl 3,7-diazabicyclor3.3. lJnonane-3-carboxylate tgrt-Pentyl 7-benzyl-3,7-diazabicyclo[3.3.1Jnonane-3-carboxylate (8.67 g; from step (a) above) was dissolved in EtOH (45 mL) and hydrogenated over 5 % Pd/C at 1 atm. for 10 h. The catalyst was removed by filtration and die residue was concentrated giving the sub-title compound. (c) tgrr-Pentyl 7-r3-(4-cyanophenoxy)-2-hydroxypropylJ-3 ,7-diazabicyclo- [3.3. lJnonane-3-carboxylate tgrr-Pentyl 3,7-diazabicyclo[3.3.1Jnonane-3-carboxylate (1.0 g; 4.16 mmol; from step (b) above) was dissolved in IPA:H 2 O (9: 1; 4 mL) and 4- (2-oxiranylmethoxy)benzonitrile (1.46 g; 8.32 mmol; see Example A above) was added to die resultant solution. The reaction mixmre was stirred at 60°C for 3 h, concentrated and die residue subjected to column chromatography (DCM:MeOH; gradient 1 :0 to 68:32) giving the title compound (1.45 g). 13 C NMR (CDC1 3 ): δ 8.2, 25.8, 28.6, 31.8, 33.8, 47.4, 49.2, 56.6, 59.9, 61.3. 64.8, 70.6, 81.5, 103.6, 115.2, 119.0, 133.6, 155.7, 162.0 Example 7 Isopropyl 7-[(24 )-3-(4-cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo- [3.3. lJnonane-3-carboxylate The title compound was prepared according to die method described in Example 3 above, using sø-propyl 3,7-diazabicyclo[3.3.1]nonane-3- carboxylate (see Example H above). The yield was 90% . ESI-MS (M + 1) + 388 (m/z) 13 C NMR (CDC1 3 ): δ 22.13, 22.20, 29.06, 29.31 , 32.59, 48.30, 49.23, 56.34, 59.90, 62.24, 64.74, 68.14, 70.72, 103.74, 115.20, 119.02, 133.68, 157.07, 162.07 Example 8 yo-Butyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo- [3.3.1 Jnonane-3-carboxylate The tide compound is prepared according to die method described in Example 47 below, using wσ-butylchloroformate and 1.5 eq. of K 2 CO 3 as base. ESI-MS (M + 1) + 402 (m z) 13 C NMR (CDCI 3 ): δ 19.09, 19.22, 27.84, 29.17, 29.34, 32.69, 48.33, 49.35, 56.48, 60.05, 62.36, 64.90, 70.85, 71.55, 103.71 , 115.34, 119.16, 133.79, 157.67, 162.19 99/31100 47 Example 9 Cyclopentyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo- [3.3. lJnonane-3-carboxylate The title compound was prepared according to die method described in Example 1 above, using cyclopentylchloroformate. FAB-MS (M + 1) + 414 (m/z) 13 C NMR (CD 3 OD; 55°C): δ 23.56, 23.70, 29.18, 29.46, 32.70, 32.95, 33.42, 48.28, 49.50, 56.35, 60.09, 62.38, 64.94, 70.84, 77.86, 103.92, 115.32, 119.32, 133.65, 157.44, 162.21 Example 10 tgrt-Butyl 7- {3 - [(4-cyano-2-(cyclopropylcarbamoyl)phenoxy ] -2- hydroxypropyl}-3,7-diazabicyclo[3.3.1Jnonane-3-carboxylate (a) Methyl 5-bromo-2-hydroxybenzoate Br 2 (52 g) was slowly added to a stirred solution of methyl salicylate (50 g; 330 mmol) in 300 mL acetic acid. The reaction mixmre was stirred at rt. for 10 h, poured on ice- water and die precipitate recrystallized from MeOH, giving me sub-title compound in a 83% yield. (b) Methyl 5-cyano-2-hydroxybenzoate Methyl 5-bromo-2-hydroxybenzoate (190.8 g; from step (a) above) and CuCN (73.9 g) were refluxed in DMF (500 mL) for 7 h. The temperamre was allowed to decrease to 80°C and HCl (500 mL) and FeCl 3 (165.0 g) were added. The reaction mixture was stirred for 30 min. , concentrated and partitioned between H 2 O and DCM. The organic layer was dried, concentrated die residue recrystallized from methylethyl ketone giving the sub-title compound in a 61 % yield. 9/31100 48 (c) N 1 -Cyclopropyl-5-cyano-2-hydroxybenzamide Cyclopropyl amine (14.3 g) and Νa (100 mg) were added to a solution of methyl 5-cyano-2-hydroxybenzoate (10.0 g; from step (b) above) in DMSO (40 mL). The reaction mixmre was heated at 80°C in a sealed steel vessel overnight, diluted with H 2 O, acidified and extracted with EtOAc giving the sub-title compound (11.0 g), after concentration of the organic layer. (d) N 1 -Cyclopropyl-5-cyano-2(2-oxiranylmethoxy)benzamide The sub-title compound was prepared according to die method described in Example A above from N 1 -cyclopropyl-5-cyano-2-hydroxybenzamide (from step (c) above). (e) tgrt-Butyl 7-{3-[(4-cyano-2-(cyclopropylcarbamoyl)phenoxyJ-2- hydroxypropyl}-3 , 7-diazabicyclo [3.3.1 Jnonane-3-carboxylate The title compound was prepared according to die method described in Example 2 above from N 1 -cyclopropyl-5-cyano-2(2-oxiranylmethoxy)- benzamide (from step (d) above). 13 C ΝMR (CDC1 3 ): δ 6.5, 23.0, 28.0, 31.5, 47.5, 49.0, 57.0, 61.5, 72.0, 79.5, 105.0, 113.0, 118.0, 123.0, 136.0, 156.5, 159.0, 164.0 9/31100 49 Example 11 tgrt-Butyl 7-{3-[(4-cyano-2-(/.y<3-propylcarbamoyl)phenoxy]-2- hydroxpropyl } -3 , 7-diazabicyclo [3.3.1 Jnonane-3-carboxylate (a) N 1 -t 0-Propyl-5-cyano-2-hydroxybenzamide Medryl 5-cyano-2-hydroxybenzoate (8.85 g; 50 mmol; see Example 10(b) above) and ΝaCΝ (250 mg; 5 mmol) were dissolved in DMSO (10 mL) and MeOH (50 mL) and wopropyl amine (25 mL) was added. The reaction mixmre was heated (60°C ) in a sealed steel vessel for 10 h, the MeOH was removed under reduced pressure and H 2 O (500 mL) was added. The solution was acidified widi HCl (pH 1), filtered and the precipitate was washed widi H 2 O giving the sub-title compound in a 93 % yield. (b) N 1 -isopropyl-5-cyano-2(2-oxiranylmethoxy)benzamide The sub-title compound was prepared according to die method described in Example A above from N 1 -t5o-propyl-5-cyano-2-hydroxybenzamide (from step (a) above). (c) tgrt-Butyl 7-{3-[(4-cyano-2-( .y6>-propylcarbamoyl)phenoxyJ-2- hydroxypropyl}-3 ,7-diazabicyclo[3.3.1 Jnonane-3-carboxylate The title compound was prepared according to the method described in Example 2 above from N 1 -isopropyl-5-cyano-2(2-oxiranylmethoxy)- benzamide (from step (b) above). 13 C ΝMR (CDC1 3 ): δ 22.64, 28.65, 28.76, 29.30, 31.73, 41.86, 47.64, 49.37, 60.35, 61.24, 64.93, 71.81, 79.49, 104.94, 113.45, 118.40, 123.71, 135.91, 136.47, 155.15, 159.64, 162.12 Example 12 tgrt-Butyl 7-[2-hydroxy-3-(4-nitrophenoxy)propylJ-3,7-diazabicyclo- [3.3. lJnonane-3-carboxylate (a) 2[(4-Nitrophenoxy)methylloxirane The sub-title compound was prepared according to die method described in Example A above from 4-nitrophenol. (b) tgrt-Butyl 7-[2-hydroxy-3-(4-nitrophenoxy)propylJ-3,7-diazabicyclo- [3.3.1 Jnonane-3-carboxylate The sub-title compound was prepared according to die method described in Example 2 above from 2[(4-nitrophenoxy)methylJoxirane (from step (a) above). 13 C NMR (CDC1 3 ): δ 28.64, 28.75, 29.35, 31.98, 47.54, 49.42, 56.83, 60.15, 61.55, 65.00, 71.10, 79.43, 93.82, 114.57, 125.73, 141.43, 155.94, 163.92 Example 13 tgrt-Butyl 7-[3-(4-aminophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo- [3.3. lJnonane-3-carboxylate The tide compound was prepared quantitatively from tgrt-butyl 7-[2- hydroxy-3-(4-nitrophenoxy )propylJ -3 , 7-diazabicyclo [3.3.1 J nonane-3- carboxylate (see Example 12 above) using catalytic hydrogenation on 5 % Pd/C in EtOH at 1 atm. 13 C NMR (CDCI 3 ): δ 28.64, 28.82, 29.36, 30.97, 31.78, 47.61 , 49.28, 58.19, 60.30, 62.07, 65.28, 71.15, 79.41 , 115.71 , 116.29, 140.02, 152.04, 155.15 Example 14 tgrt-Butyl 7-{2-hydroxy-3-[4-(memylsulfonamido)phenoxyJpropyl}-3,7- diazabicyclo[3.3.1Jnonane-3-carboxylate MsCl (0.50 g; 4.40 mmol) was added to a stirred solution of tgrr-butyl 7- [3-(4-aminophenoxy)-2-hydroxypropylJ-3 , 7-diazabicyclo [3.3. lJnonane-3- carboxylate (1.68 g; 4.29 mmol; see Example 13 above) in pyridine (20 mL). The reaction mixmre was stirred for 2.5 h and subsequently concentrated. The residue was partitioned between DCM and NaHCO 3 (sat.), die organic layer separated, dried and concentrated. Purification using column chromatography (gradient 0 to 10% MeOH in DCM) gave die title compound in a 87% yield. 13 C NMR (CDC1 3 ): δ 28.70, 28.70, 28.84, 29.09, 29.42, 31.93, 38.77, 47.64, 49.42, 57.01 , 60.29, 61.84, 65.20, 70.79, 79.50, 115.48, 116.32, 124.53, 129.40, 155.94, 157.28 Example 15 tg/T-Butyl 7-[3-(4-cyano-2-methylphenoxy)-2-hydroxypropylJ-3 ,7- diazabicyclo[3.3.1Jnonane-3-carboxylate (a) 2-Methyl-4-cyanophenol The sub-title compound was prepared according to the method described in Example 10(b) above from 2-methyl-4-bromophenol. (b) 3-Methyl-4-(2-oxiranylmethoxy)benzonitrile The sub-title compound was prepared according to the method described in Example A above from 2-methyl-4-cyanophenol (from step (a) above). (c) tgrt-Butyl 7-[3-(4-cyano-2-methylphenoxy)-2-hydroxypropylJ-3,7- diazabicyclo[3.3. lJnonane-3-carboxylate The title compound was prepared according to die method described in Example 2 above from 3-methyl-4-(2-oxiranylmethoxy)benzonitrde (from > step (b) above). 13 C NMR (CDC1 3 ): δ 22.84, 28.52, 28.70, 28.89, 32.06, 47.61 , 49.51 , 56.96, 60.28, 62.00, 65.14, 68.32, 70.65, 79.5, 103.53, 111.26, 119.44, 128.25, 131.85, 133.87, 156.01 , 160.40 Example 16 (tgrt-Butyl 7-[3-(2-amino-4-cyanophenoxy)-2-hydroxypropyl]-3,7-diaza- bicyclo[3.3.1Jnonane-3-carboxylate (a) 3-Nitro-4-(2-oxiranylmethoxy)benzonitrile 4-Cyano-2-nitrophenol (0.80 g; 4.9 mmol) and K 2 CO 3 (0.68 g; 4.9 mmol) were refluxed in MeCN (40 mL) for 1 h. The solvent was removed on a rotary evaporator and die residue dissolved in DMF (10 mL). 2-{[(3- Nitrophenyl)sulfonyloxyJmethyl}oxirane (1.2 g, 4.9 mmol; see Example B above) was added to die resultant solution. The solution was stirred at 40 °C for 12 h and filtered. The precipitate was washed with H 2 O to give die sub-title compound in a 65 % yield. (b) tgrt-Butyl 7-[3-(4-cyano-2-nitrophenoxy)-2-hydroxypropylJ-3 ,7- diazabicyclo[3.3.1Jnonane-3-carboxylate 3-Nitro-4-(2-oxiranylmethoxy)benzonitrile (2.9 g; 13.2 mmol; from step (a) above) was added to a stirred solution of tgrt-butyl 3,7- diazabicyclo[3.3.1]nonane-3-carboxylate (3 g; 13.2 mmol; see Example F above) in IPA:H 2 O (12.5 mL; 9: 1), and die reaction mixmre was refluxed for 3 h. Concentration of die reaction mixmre and purification by column chromatography (DCM:MeOH; 15: 1) gave the title compound in a 54% yield. 13 C NMR (CDC1 3 ): δ 28.4, 31.8, 47.4, 49.8, 56.7, 59.8, 60.5, 65.0, 71.9, 79.2, 103.7, 116.1 , 116.7, 129.3, 137.3, 139.3, 155.4, 155.8 (c) (tgrt-Butyl 7-[3-(2-amino-4-cyanophenoxy)-2-hydroxypropylJ-3 ,7- diazabicyclo[3.3. lJnonane-3-carboxylate The title compound was prepared in a 98% yield according to the method described in Example 13 above from tgrt-butyl 7-[3-(4-cyano-2- nitrophenoxy)-2-hydroxypropylJ-3 ,7-diazabicyclo[3.3.1 Jnonane-3- carboxylate (from step (b) above). 13 C NMR (CDCI 3 ): δ 28.2, 31.7, 47.3, 49.2, 56.7, 59.9, 61.3, 65.4, 71.0, 79.2, 103.8, 111.5, 116.5, 119.6, 122.6, 137.4, 149.3, 155.7 Example 17 tgrt-Butyl 7-{3-[(4-cyano-2-(methylsulfonamido)phenoxyJ-2-hydroxy- propyl}-3 ,7-diazabicyclo[3.3. lJnonane-3-carboxylate The title compound was prepared in a 80% yield according to the mediod described in Example 14 above from tgrt-butyl 7-[3-(2-amino-4- cyanophenoxy)-2-hydroxypropylJ -3 , 7-diazabicyclo [3.3. lJnonane-3- carboxylate (see Example 16 above). 13 C NMR (CDCI 3 ): δ 28.2, 28.5, 30.6, 39.4, 57.1 , 59.4, 59.6, 64.9, 71.2, 77.4, 79.8, 104.3, 112.2, 118.4, 124.6, 129.5, 152.6, 155.7 Example 18 tgrt-Butyl 7- [3-(4-cy ano-2- { [(ethy lamino)carbony 1J amino } phenoxy J -2- hydroxypropy 1 } -3 , 7-diazabicyclo [3.3.1] nonane-3-carboxy late (a) N-(5-Cyano-2-hydroxyphenyl)-N'-ethylurea Ethyl isocyanate (7.1 g; 100 mmol) was added to a stirred solution of 2- amino-4-cyanophenol (13.4 g; 100 mmol) in MeCN (250 mL), and the resultant solution was stirred for 12 h. The precipitate was filtered off and dried (vacuum) to give the sub-title compound in a 70% yield. (b) N-[5-Cyano-2-(oxiranylmethoxy)phenylJ-N , -emylurea The sub-title compound was prepared in a 52% yield according to die method described in Example 16(a) above from N-(5-cyano-2- hydroxyphenyl)-N'-ethylurea (from step (a) above). (c) tgrt-Butyl 7- [3-(4-cyano-2- { [(ethy lamino)carbony 1J amino jphenoxyj -2- hydroxypropyl}-3 , 7-diazabicyclo [3.3. l]nonane-3-carboxylate The title compound was prepared in a 40% yield according to die mediod described in Example 16(b) above from N-[5-cyano-2- (oxiranylmethoxy)phenylJ-N'-edιylurea (from step (b) above). 13 C NMR (CDC1 3 ): δ 15.28, 28.63, 31.66, 34.73, 47.60, 49.42, 57.23, 59.70, 60.24, 65.79, 72.54, 79.71, 105.00, 113.17, 119.58, 121.22, 125.75, 131.44, 149.84, 155.50 99/31100 55 Example 19 tgrt-Butyl 7-[3-(3,4-dicyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo- [3.3.1 lnonane-3-carboxylate (a) 4-(2-Oxiranylmethoxy)phthalonitrile A stirred suspension of 4-hydroxyphthalonitrile (3.5 g; 24.3 mmol), K 2 CO 3 (4.03 g; 29.2 mmol) and 2-{[(3-nitrophenyl)sulfonyloxyJmethyl}- oxirane (6.50 g; 25.0 mmol; see Example B above) in MeCN (170 mL) was refluxed for 1.5 h. The cooled reaction mixmre was filtered, die filtrate concentrated and die solid residue recrystallized from IPA to give die sub-title compound. (b) tgrt-Butyl 7-[3-(3 ,4-dicyanophenoxy)-2-hydroxypropyl]-3 ,7- diazabicyclo[3.3.1 Jnonane-3-carboxylate The title compound was prepared in a 55% yield according to die method described in Example 2 above (using MeCN as solvent) from 4-(2- oxiranylmethoxy)phdιalomtrUe (from step (a) above). 13 C NMR (CDC1 3 ): δ 28.8, 29.35, 31.96, 47.55, 49.45, 56.75, 60.12, 61.19, 65.14, 71.5, 79.47, 107.14, 115.19, 115.65, 117.15, 119.60, 120.06, 135.04, 155.98, 162.18 Example 20 tgrt-Butyl 7-[2-(phenylcarbamoyl)ethylJ-3,7-diazabicyclo[3.3.1Jnonane-3- carboxylate (a) N 1 -Pheny lacry lamide Acryloyl chloride (28.5 mL; 350 mmol) was added to a stirred solution of phenylamine (30 mL; 320 mmol) and TEA (56 mL; 400 mmol) in THF (1 L) at 0°C. The reaction mixmre was stirred for 3 h, poured onto brine and extracted with diethyl edier. The organic layer was dried, concentrated and recrystallized from hexane: EtOAc (3: 1) to give the subtitle compound in a 79% yield. (b) N-Phenyl-S^-benzyl-S -diazabicycloP.S. lJnon-S-y^propanamide N-Phenylacrylamide (1.0 g; 6.8 mmol; from step (a) above) was added to a stirred solution of 3-benzyl-3,7-diazabicyclo[3.3. ljnonane (1.5 g; 6.8 mmol; see Example E above) in EtOH (7 mL). The reaction mixture was stirred for 10 h and concentrated to give die sub-title compound in a 97 % yield. (c) tgrt-Butyl 7- [2-(pheny lcarbamoyl)ethyl] -3 , 7-diazabicyclo [3.3.1 J nonane- 3-carboxylate A solution of N 1 -phenyl-3-(7-benzyl-3,7-diazabicyclo[3.3.1]non-3-yl)- propanamide (2.5 g; 6.8 mmol; from step (b) above) and di-tgrt-butyl dicarbonate (3.3 g; 15 mmol) in EtOH (25 mL) was hydrogenated over 5 % Pd/C at 1 atm for 20 min. , filtered through a pad of celite and concentrated. Purification by column chromatography (DCM:MeOH; 19: 1) gave the title compound in a 90% yield. 13 C ΝMR (CDC1 3 ): δ 28.55, 30.29, 35.84, 48.00, 49.14, 55.08, 58.09, 79.29, 120.15, 123.79, 128.87, 138.47, 156.07, 171.41 Example 21 tgrt-Butyl 7-[3-(4-cyanophenoxypropyl)J-3,7-diazabicyclo[3.3.1Jnonane-3- carboxylate (a) 4-(3-Bromopropoxy)benzonitrile 1 ,3-Dibromopropane (1.02 L; 10 mol) was added to a stirred suspension of /7-cyanophenol (238 g; 2 mol), K 2 CO 3 (276.4 g; 2 mol) in MeCN (2.7 L). The reaction mixmre was refluxed for 4 h, filtered and concentrated. The residue was recrystallized from wø-propyl edier to give die sub-title compound in a 69% yield. (b) tgrt-Butyl 7-[3-(4-cyanophenoxypropyl)J-3 ,7-diazabicyclo- [3.3. lJnonane-3-carboxylate A stirred solution of 4-(3-bromopropoxy)benzonitrile (1.2 g; 52 mmol; from step (a) above), TEA (0.35 mL) and tgrr-butyl 3,7- diazabicyclo[3.3.1Jnonane-3-carboxylate (1.17 g; 52 mmol; see Example F above) in DMSO (2 mL) was heated to 60°C for 12 h. The reaction mixmre was partitioned between Na 2 CO 3 (aq.) and DCM and die organic layer separated, dried and subjected to column chromatography (DCM:MeOH; 22:1) to give the title compound in a 74% yield. FAB-MS (M + 1) + 386 (m/z) 13 C NMR (CDC1 3 ): δ 26.47, 28.52, 28.87, 31.31 , 47.54, 48.72, 55.21 , 58.29, 59.26,66.56, 78.46, 103.42, 115.19, 119.21 , 133.78, 154.98, 162.28 Example 22 tgrt-Butyl 7- {2- [(4-cy anopheny Qcarbamoy 1J ediyl } -3 , 7-diazabicyclo- [3.3. llnonane-3-carboxylate (a) N 1 -(4-Cyanophenyl)-3-chloropropanamide 3-Chloropropionylchloride (1.08 g; 8.5 mmol) was added to a cooled (10°C) solution of 4-cyanoaniline (1.0 g; 8.5 mmol) and pyridine (0.69 mL; 8.5 mmol) in DCM (40 mL), and the reaction mixmre was stirred at rt. for 1 h. The reaction mixmre was extracted widi HCl (2Ν), washed widi water, dried and concentrated to give die sub-title compound in a 81 % yield. (b) tgrt-Butyl 7-{2-[(4-cyanophenyl)carbamoyl]emyl}-3 ,7-diazabicyclo- [3.3. l]nonane-3-carboxylate The title compound was prepared in a 74% yield according to the method described in Example 21(b) above from N 1 -(4-cyanophenyl)-3- chloropropanamide (from step (a) above). 13 C ΝMR (CDC1 3 ): δ 28.5, 30.5, 36.5, 48.1 , 49.3, 55.1 , 59.0, 79.5, 106.4, 119.1, 120.0, 133.1 , 142.7, 156.3, 172.1 Example 23 tg/7-Butyl 7-[3-(4-cyanoanilino)propyl]-3 ,7-diazabicyclo[3.3. lJnonane-3- carboxylate LiBH 4 (300 mg; 13.6 mmol) was added to a stirred solution of tgrt-butyl 7-{2-[(4-cyanophenyl)carbamoylJemyl}-3,7-diazabicyclo[3.3.1Jnonane-3- carboxylate (1.36 g; 3.41 mmol; see Example 22 above) in toluene (10 mL) and THF (5 mL) and die reaction mixture was stirred for 45 min. The solvents were removed and die residue partitioned between DCM and NaHCO 3 (aq.). The organic layer was concentrated and subjected to column chromatography (DCM:MeOH; 9: 1) to give the title compound in a 10% yield. 13 C NMR (CDC1 3 ): δ 25.5, 28.6, 31.2, 41.1 , 47.7, 48.8, 56.9, 59.0, 79.0, 97.4, 111.8, 120.7, 133.6, 151.7, 155.3 Example 24 Λro-Propyl 7-[2-(4-cyanophenyl)-2-hydroxyethylJ-3,7-diazabicyclo[3.3.1J- nonane-3-carboxylate (a) 4-(2-Oxiranyl)benzonitrile NaBH 4 (1.6 g; 40 mmol) was added to a stirred solution of 4- cyanophenacyl bromide (8.8 g; 40 mmol) in THF (100 mL), and die reaction mixture was stirred until tic indicated mat the reaction was complete. The solvent was evaporated and die residue partitioned between DCM and H 2 O, and die organic layer was separated, dried and concentrated. The residue was treated widi K 2 CO 3 (0.08 mol) in MeCN (85 mL) at room temperamre overnight. The solvent was removed on a rotary evaporator and die residue partitioned between CH 2 C1 2 and H 2 O. The organic layer was washed widi H 2 O (2 x 100 mL), separated and dried to give die sub-title compound in 90% overall yield. (b) t ' 0-Propyl 7-[2-(4-cyanophenyl)-2-hydroxyethylJ-3,7-diazabicyclo- [3.3.1 Jnonane-3-carboxylate The crude reaction mixture from step (a) above was condensed wi iso- propyl 3, 7-diazabicyclo [3.3. lJnonane-3-carboxylate (5.2 g; see Example H above) according to die method described in Example 7 above to give the title compound in a 73% overall yield. FAB-MS (M + 1) + 358 (m/z) 13 C NMR (CDC1 3 ): δ 22.39, 29.18, 32.76, 48.50, 49.38, 56.17, 59.90, 68.06, 68.46, 110.84, 119.03, 126.58, 132.04, 148.37, 157.32 Example 25 iso-Propyl 7-(4-cyanophenethyl)-3,7-diazabicyclo[3.3.1Jnonane-3- carboxylate (a) 4-Cyanophenedιyl methanesulfonate MsCl (18.6 g; 164 mmol) was added to a stirred solution of 4-(2- hydroxyethyl)benzonitrile (20 g; 136 mmol) and TEA (20.6 g; 204 mmol) in DCM (200 mL) at 0°C. The reaction mixture was stirred at rt. until tic indicated diat die reaction was complete. Water (200 mL) was added and die organic layer was separated, dried and concentrated to give die subtitle compound in a quantitative yield. (b) iso-Pτopyl 7-(4-cyanophenedιyl)-3,7-diazabicyclo[3.3.1Jnonane-3- carboxylate wo-Propyl 3, 7-diazabicyclo [3.3. lJnonane-3-carboxy late (1.06 g; 5 mmol; see Example H above) was added to a stirred suspension of 4- cyanophenediyl memanesulfonate (1.13 g; 5 mmol; from step (a) above) and K 2 CO 3 (0.96 g; 7 mmol) in MeCN (5 mL) under an inert atmosphere (N 2 ), and die reaction mixture was stirred for 10 h. The solvent was evaporated and die residue partitioned between DCM and NaHCO 3 (aq.). The organic layer was separated, dried and concentrated. Purification using column chromatography (DCM: MeOH; 19:1) gave the title compound in a 88% yield. FAB-MS (M + 1) + 342 (m/z) 13 C NMR (CD 3 CN): δ 22.61 , 22.67, 30.12, 30.16, 32.20, 34.02, 49.02, 49.18, 58.99, 59.68, 60.98, 68.26, 110.21 , 119.89, 130.57, 132.99, 148.19, 156.33 Example 26 tgrt-Butyl 7-(2-{[(benzyloxy)carbonyl]amino}ethyl)-3,7-diazabicyclo- [3.3. lJnonane-3-carboxylate (a) Benzyl-N-(2-bromoethyl)carbamate A solution of CBz-Cl (7.7 mL; 54 mmol) in dioxane (5 mL) was added to a cold (0°C) stirred solution of 2-bromoethylamine hydrobromide (10.0 g; 49 mmol) in 40 mL IM ΝaOH:dioxane (3: 1) under Schotten-Bauman conditions. The reaction mixture was allowed to attain rt. and extracted widi CHC1 3 . The organic layer was separated, concentrated and purified by column chromatography (CHC1 3 ) to give me sub-title compound in a 92% yield. (b) tgrt-Butyl 7-(2- { [(benzyloxy)carbonylj amino} ethyl)-3 , 7-diazabicyclo- [3.3.1 Jnonane-3-carboxylate The title compound was prepared in a 44% yield according to the method in Example 25(b), using benzyl-N-(2-bromoethyl)carbamate (from step (a) above). I3 C ΝMR (CDC1 3 ): δ 28.64, 31.96, 37.89, 47.67, 49.38, 57.72, 59.30, 66.30, 79.11 , 127.71 , 128.05, 128.30, 137.08, 155.77, 156.88 Example 27 tgrt-Butyl 7-{2-[4-cyanobenzylaminoJethyl}-3,7-diazabicyclo[3.3.1J- nonane-3 -carboxylate (a) tgrt-Butyl 7-[2-aminoethylJ-3,7-diazabicyclo[3.3. lJnonane-3- carboxylate The sub-title compound was prepared according to die method described in Example E(b) in a quantitative yield from tgrt-butyl 7-(2-{[(benzyloxy)- carbonyl] amino} ethyl)-3 , 7-diazabicyclo [3.3.1] nonane-3 -carboxylate (see Example 26 above). (b) tgrt-Butyl 7-{2-[4-cvanobenzylamino]ethyl}-3,7-diazabicyclo[3.3.1]- nonane-3 -carboxylate /?-Cyanobenzylbromide (0.765 g; 3.9 mmol) was added to a stirred solution of t g rt-butyl 7-[2-aminoethylJ-3,7-diazabicyclo[3.3.1Jnonane-3- carboxylate (1.04 g; 3.9 mmol; from step (a) above) in MeCN (15 mL) and die reaction mixmre was stirred at 40°C for 32 h. The solvent was evaporated and die residue subjected to column chromatography (EtOAc) to give the title compound in a 74% yield. 13 C NMR (CD 3 OD): δ 27.65, 29.17, 31.06, 51.92, 57.34, 58.41 , 78.86, 110.41 , 118.41 , 129.23, 131.89, 145.74, 155.91 Example 28 (R,R)- and (R,S) or (S,R)- and (S, S)-tgrt-Butyl 7-[4-(4-cyanophenyl)-2,4- dihydroxybutylJ-3 , 7-diazabicyclo [3.3.1 ]nonane-3 -carboxylate (a) 4- Acetoxy-4-(p-cyanophenyl)- 1 -butene The sub-title compound was prepared according to die method described in J. Am. Chem. Soc , 110, 3601 (1988). (b) 1 -(4-Cyanophenyl)-2-(2-oxiranyl)ethyl acetate CPBA (2.86 g; 70%) was added to a stirred solution of 4-acetoxy-4-(p- cyanophenyl)-l -butene (2.5 g; 11.6 mmol; from step (a) above) in DCM (20 mL), and die reaction mixture was refluxed for 3 h and dien cooled. The w-chlorobenzoic acid was removed by filtration and die filtrate was washed widi NaHCO 3 (aq.), dien widi water, die phases were separated, dried, concentrated and purified by column chromatography (DCM) to give the sub-title compound in a 50% yield. (c) tgrt-Butyl 7-[4-(4-cyanoρhenyl)-2-hydroxy-4-(medrylcarbonyloxy)- butylj -3 , 7-diazabicyclo [3.3.1] nonane-3-carboxy late The sub-title compound was prepared in a 82% yield according to die method described in Example 2 above using l-(4-cyanophenyl)-2-(2- oxiranyl)ethyl acetate (from step (b) above). FAB-MS (M + 1) + 458 (m/z) 13 C NMR (CDC1 3 ): δ 21.04, 28.57, 29.34, 31.81 , 41.88, 47.58, 56.97, 60.51 , 62.43, 65.46, 72.47, 79.41 , 111.36, 118.59, 126.82, 132.22, 145.85, 155.99, 169.83 (d) (R,R)- and (R,S) or (S.R)- and (S, ^-tgrt-Butyl 7-[4-(4-cyanophenyl)- 2 , 4-dihydroxybuty 1] -3 , 7-diazabicyclo [3.3.1] nonane-3-carboxylate tgrt-Butyl 7-[4-(4-cyanophenyl)-2-hydroxy-4-(methylcarbonyloxy)butylJ- 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.88 g; 4.12 mmol; from step (c) above) was deprotected as follows: A solution of NaOH (0.21 g; 5 mmol) in MeOH (2 mL) was added to a stirred solution of the protected intermediate in MeOH (2 mL). The reaction mixmre was refluxed for 2 h, partitioned between diediyl edier and water, and die organic layer separated, dried, concentrated and subjected to column chromatography (DCM:MeOH; 49: 1) to give two separable diastereomeric pairs in a 88% yield. The title compound was isolated as the less polar diastereoisomers. ESI-MS (M + 1) + 417 (m z) 13 C NMR (CDC1 3 ): δ 28.25, 28.88, 30.69, 31.54, 43.18, 47.19, 48.31 , 49.02, 56.29, 59.68, 64.65, 66.34, 72.97, 79.13, 110.09, 118.55, 126.10, 131.57, 149.93, 155.59 Example 29 dihydroxybuty 1J -3 , 7-diazabicyclo [3.3.1 J nonane-3 -carboxylate The title compound was isolated as the more polar diastereoisomers from Example 28 above. ESI-MS (M + 1) + 416 (m/z) 13 C NMR (CDCI 3 ): δ 28.35, 29.00, 30.78, 31.62, 42.07, 47.24, 48.32, 49.13, 56.34, 59.86, 63.16, 64.27, 70.15, 79.23, 110.00, 118.73, 126.15, 131.68, 150.59, 155.68 Example 30 tgrt-Butyl 7- [4-(4-cyanopheny l)-4-hydroxy buty 1J -3 , 7-diazabicyclo [3.3.1]- nonane-3-carboxylate (a) 4- 1 (-{ [ 1 -(tgrt-Butyl)- 1 , 1 -dimemylsilylj oxy } -3-butenyl)benzonitrile' Imidazole (11.5 g; 170 mmol) was added to a stirred solution of 1- J- cyanophenyl)-3-buten-l-ol (11.5 g; 87 mmol) and tgrt-butyldimethylsilyl chloride (12 g; 80 mmol) in DMF (50 mL), and die reaction mixmre was stirred under N 2 (g) for 10 h. The solvent was evaporated and the residue partitioned between water and diediyl edier. The organic layer was separated, dried, concentrated and subjected to column chromatography (DCM) to give the sub-title compound in a 86% yield. (b) 4- !(-{[! -(tgrt-Butyl)- 1 , l-dimethylsilylloxy}-4-hydroxybutyl) benzonitrile Borane-methyl sulfide complex (13 mL; 2M; 26 mmol) was added to a stirred and cooled (0°C) solution of 4-l(-{[l-(tgrt-butyl)-l ,l- dimethylsdyl]oxy}-3-butenyl)benzonitrile (15.2 g; 53 mmol; from step (a) above) in THF (100 mL). The temperature was raised to rt. and stirred until tic indicated complete consumption of die starting material. The temperamre was lowered to 0°C and a solution of sodium perborate tetrahydrate (19 g; 123 mmol) in water (55 mL) was added and die resultant reaction mixmre was stirred at rt. for 12 h. Brine (100 mL) and diethyl edier (150 mL) was added and the organic layer was separated, dried, concentrated and subjected to column chromatography (hexane: EtOAc; 1 : 1) to give die sub-title compound in a 85 % yield. (c) 4-{[-l-(tgrt-Butyl)-l,l-dimethylsilylJoxy}-4-(4-cyanophenyl)butyl medianesulfonate The sub-title compound was prepared in a 98 % yield according to die method described in Example 25(a) above from 4-l(-{[l-(tgrt-butyl)-l ,l- dimethylsilyl]oxy}-4-hydroxybutyl)benzonitrile (from step (b) above). (d) tgrt-Butyl 7-[4-(4-cyanophenyl)-4-{[-l-(tgrt-butyl)-l , 1-dimethylsilylJ- oxy}butyll-3 ,7-diazabicyclo[3.3. l]nonane-3-carboxylate The sub-title compound was prepared in 96% yield according to the mediod described in Example 25(b) above from 4- {[-1 -(tgrt-butyl)- 1 ,1- dimethylsilylJoxy}-4-(4-cyanophenyl)butyl medianesulfonate (from step (c) above) and tgrt-butyl 3, 7-diazabicyclo [3.3. lJnonane-3 -carboxylate (see Example F above). (e) tgrt-Butyl 7- [4-(4-cyanophenyl)-4-hydroxybuty 1J -3 , 7-diazabicyclo- [3.3. l]nonane-3-carboxylate Tefrabutylammomum fluoride (0.95 mmol) was added to a stirred solution of t g rt-butyl 7-[4-(4-cyanophenyl)-4-{[-l -(tgrt-butyl)- 1 ,1-dimethylsilylJ- oxy}butylJ-3,7-diazabicyclo[3.3.1Jnonane-3-carboxylate (0.44 g; 0.85 mmol; from step (d) above) in THF (5 mL), and die resultant reaction mixture was stirred for 2 h. The solvent was evaporated and die residue was subjected to column chromatography (MeCN: MeOH; gradient 0 to 10% MeOH) to give the title compound in a 70% yield. ESI-MS (M + 1) + 400 (m z) 13 C NMR (CDC1 3 ): δ 22.26, 28.37, 30.10, 37.26, 37.63, 47.68, 48.53, 57.73, 58.34, 59.12, 72.49, 78.95, 110.03, 119.05, 126.59, 131.71 , 151.05, 155.58 Example 31 /so-Propy 1 7- [4-(4-cyanophenyl)-4-hydroxybuty IJ -3 , 7-diazabicyclo [3.3.1 J - nonane-3-carboxylate (a) 3-(4-Cyanophenyl)-4-hydroxybutylJ-3,7-diazabicyclo[3.3. ljnonane HCl-samrated EtOAc (200 mL) was added to a stirred solution of tert- butyl 7-[4-(4-cyanophenyl)-4- {[-1 -(tgrt-butyl)- 1 , l-dimethylsilyljoxy}- buty IJ -3, 7-diazabicyclo [3.3. lJnonane-3 -carboxylate (4.60 g; see Example 30(d) above) in EtOAc (50 mL), and die reaction mixmre was stirred for 2 h. The solvent was evaporated and die residue dissolved in EtOH and passed dirough an ion-exchange resin (Amberlyst IRA 400), concentrated and lyophilized to give the sub-title compound in a quantitative yield. (b) /so-Propyl 7-[4-(4-cyanophenyl)-4-hydroxybutylJ-3,7-diazabicyclo- [3.3.1 Jnonane-3-carboxylate The title compound was prepared in a 77 % yield according to die method described in Example H(a) above from 3-(4-cyanophenyl)-4- hydroxybutylJ-3,7-diazabicyclo[3.3. ljnonane (from step (a) above). FAB-MS (M + 1) + 386 (m/z) 13 C NMR (CDC1 3 ): δ 22.33, 23.02, 28.57, 28.71 , 30.78, 37.35, 48.21 , 57.91 , 58.50, 58.89, 59.46, 68.13, 72.54, 73.07, 110.17, 119.21 , 126.61, 131.84, 151.26, 156.03 Example 32 ΛSO-Propyl 7-[(25)-3-(4-cyanophenoxy)-2-hydroxy-2-metiιylpropyl]-3,7- diazabicyclo[3.3.1Jnonane-3-carboxylate (a) [(2S)-2-Methyloxiran-2-ylJmethyl 3-nitro-l-benzenesulfonate The sub-title compound was prepared according to the method described in Example B above from R-(+)-2-methylglycidol. (b) 4- { [(2^-Medιyloxiran-2-ylJ memoxy }benzonitrile A suspension of [(2.S)-2-memyloxiran-2-yl]methyl 3-nitro-l-benzenesulfonate (37.7 g; 138 mmol; from step (a) above), K 2 CO 3 (28 g) and p- cyanophenol (23.8 g; 200 mmol) in MeCN (300 mL) was refluxed for 20 h. The reaction mixmre was filtered and the filtrate concentrated under reduced pressure, dissolved in edier and washed widi 2M NaOH and dien brine. The organic layer was concentrated and subjected to column chromatography (petroleum ether: EtOAc; 3: 1) to give the sub-title compound. (c) t ' ^o-Propyl 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropylJ-3,7- diazabicvclo[3.3. lJnonane-3-carboxylate The title compound was prepared according to the method described in Example 7 above from 4-{[(2S)-methyloxiran-2-ylJmethoxy}benzonitrile (from step (b) above). 13 C NMR (CDC1 3 ): δ 22.38, 22.80, 29.20, 29.56, 31.11 , 48.09, 60.93, 61.78, 64.19, 68.83, 71.32, 72.24, 103.91 , 115.42, 119.25, 134.01 , 155.26, 161.94 Example 33 tgrt-Butyl 7-[(2.S)-3-(4-cyanophenoxy)-2-hydroxy-2-methyrpropylJ-3,7- diazabicyclo[3.3.1] nonane-3-carboxylate The title compound was prepared according to the method described in Example 2 above from 4-{[(2^-methyloxiran-2-ylJmethoxy}benzonitrile (see Example 32(b) above). ESI-MS (M + 1) + 416 (m/z) 13 C NMR (CDC1 3 ): δ 22.55, 28.57, 29.51 , 30.92, 47.93, 48.62, 60.82, 62.04, 63.84, 71.41 , 80.0, 104.01 , 119.23, 134.09, 154.74, 161.92 Example 34 2-Hydroxy-l , 1-dimethyledιyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ- 3 , 7-diazabicyclo [3.3.1 Jnonane-3-carboxylate (a) Edιyl-2-(chlorocarbonyloxy)-2-methylpropanoate The sub-title compound was prepared according to die mediod described in Zh. Org. Khim. , 7, 1875 (1971). (b) 2-Ethoxy-l , l-dimethyl-2-oxymethyl 7-benzyl-3,7-diazabicyclo[3.3.1J- nonane-3-carboxylate A solution of 3-benzyl-3,7-diazabicyclo[3.3. ljnonane (23.8 g; 110 mmol; see Example E above) in toluene (100 mL) was added to a stirred solution of euιyl-2-(chlorocarbonyloxy)-2-methylpropanoate (100 mmol) in toluene (25 mL). The reaction mixmre was cooled to 0°C and TEA (25 mL; 180 mmol) was added. After 2 h, the salts were filtered off and die residue concentrated, dissolved in DCM and washed widi NaHCO 3 (aq.). The organic layer was separated, dried and concentrated to give die sub-title compound in a 90% yield. (c) 2-Hydroxy- 1 , 1 -dimethylethyl 7-benzyl-3 ,7-diazabicyclo[3.3.1 J-nonane- 3-carboxylate LiBH 4 (0.6 g; 26.7 mmol) was added to a stirred solution of 2-ethoxy-l ,l- dimethyl-2-oxymethyl 7-benzy 1-3 , 7-diazabicyclo [3.3.1 ] -nonane-3 - carboxylate (5 g; 13.35 mmol; from step (b) above) in THF (30 mL) and toluene (20 mL), and the reaction mixture was heated at 100°C for 30 min. Water (10 mL) and NaHCO 3 (aq.) was added and the solution was extracted widi DCM. The organic layer was washed widi water (3 x 100 mL), separated, dried, concentrated and subjected to column chromatography (DCM:MeOH sat. with NH 3 ; 35: 1) to give the sub-title compound in a 20% yield. (d) 2-Hydroxy-l , 1-dimethyledιyl 7-[3-(4-cyanophenoxy)-2-hydroxy- propylj -3 , 7-diazabicyclo [3.3.1 Jnonane-3-carboxylate 2-Hydroxy-l , 1-dimedιyledιyl 7-benzyl-3 ,7-diazabicyclo[3.3.1 J-nonane-3- carboxylate (from step (c) above) was debenzylated according to die method described in Example E(b) above and subsequently reacted widi 4- (2-oxiranylmethoxy)benzonitrile (see Example A above) in accordance widi the method described in Example 2 above to give the title compound in an overall yield of 88 % . ESI-MS (M + 1) + 418 (m/z) 13 C NMR (CDC1 3 ): δ 26.02, 26.66, 29.25, 29.47, 32.73, 48.91 , 49.65, 56.52, 60.07, 62.27, 65.08, 69.85, 70.63, 72.86, 104.08, 115.33, 119.17, 133.90, 157.68, 162.12 Example 35 1 -Cyano- 1 -methylediyl 7- [3 -(4-cyanophenoxy )-2-hydroxypropylJ -3,7- diazabicyclo [3.3.1 J nonane-3-carboxylate (a) 1 -Cyano- 1 -methylediyl chloroformate A solution of acetone cyanohydrin (5 g; 59 mmol) in pyridine (5 mL) was added to a stirred solution of COCl 2 (30 mL; 1.92 M; 59 mmol) at -15°C. The temperamre was raised to rt. and die reaction mixmre was stirred for 2 h. The precipitate was filtered off and die filtrate was concentrated and used directly in me next step wimout further purification. (b) 1 -Cyano- 1 -methylediyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ- 3,7- diazabicyclo[3.3.1 Jnonane-3-carboxylate 1 -Cyano- 1 -methylediyl chloroformate (0.4 g; 1.65 mmol; from step (a) above) was added to a stirred solution of 4-[3-(3,7-diazabicyclo[3.3.1]non- 3-yl)-2-hydroxypropoxyJbenzonitrile (0.5 g; 1.65 mmol; see Example G above) and K 2 CO 3 (0.7 g) in MeCN (25 mL). The reaction mixmre was stirred at 40°C for 2 h. The salts were filtered off and die filtrate was concentrated and subjected to column chromatography (DCM:MeOH; 19: 1) to give the title compound in a 59% yield. ESI-MS (M + 1) + 413 (m z) 13 C NMR (CDC1 3 ): δ 27.29, 27.78, 28.60, 29.13, 31 ,31 , 48.30, 49.22, 57.90, 60.29, 61.52, 65.66, 68.90, 70.67, 104.101 , 115.46, 119.22, 120.29, 133.96, 153.58, 162.19 Example 36 3 ,4-DimethoxyphenedιyI 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3 ,7- diazabicyclo[3.3.1 J nonane-3-carboxylate (a) 3,4-Dimethoxyphenedιyl 7-benzyl- 3,7-diazabicyclo[3.3.1Jnonane-3- carboxylate 3,4-Dimethoxyphenedιyl alcohol (3.64 g; 20 mmol) was added to a stirred suspension of l ,l'-carbonyldiimidazole (3.24 g; 20 mmol) in THF (20 mL), and die mixmre was refluxed for 12 h. A solution of 3-benzyl-3,7- diazabicyclo [3.3. ljnonane (4.33 g; 20 mmol; see Example E above) in THF (20 mL) was added and die reaction mixmre was refluxed overnight. The solvent was removed and die residue dissolved in H 2 SO 4 (2M; 25 mL) and extracted widi diediyl edier. NaOH (3.5 mL; 5M) was added and die aqueous phase extracted widi DCM. The organic layer was separated, dried and subjected to column chromatography (DCM:MeOH; gradient 0 to 30% MeOH) to give the sub-title compound in a 29% yield. (b) 3,4-Dimethoxyphenedιyl 3, 7-diazabicyclo [3.3. lJnonane-3-carboxylate The sub-title compound was prepared in a 70% yield according to die method described in Example E(b) above from 3,4-dimethoxyphenedτyl 7- benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (a) above). (c) 3 ,4-Dimethoxyphenedιyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ- 3 , 7-diazabicyclo [3.3.1] nonane-3 -carboxylate The title compound was prepared in a 45 % yield according to die method described in Example 2 above from 3,4-dimethoxyphenedιyl 3,7- diazabicyclo[3.3.1]nonane-3-carboxylate (from step (b) above). I3 C NMR (CDC1 3 ): δ 28.9, 32.3, 34.8, 48.3, 49.0, 55.5, 56.2, 59.5, 62.0, 64.6, 65.7, 70.6, 103.6, 111.0, 112.2, 115.0, 118.8, 120.7, 130.8, 133.5, 147.3, 148.5, 157.1 , 161.8 Example 37 Phenyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo[3.3.1J- nonane-3-carboxylate Phenyl chloroformate (0.36 mL; 2.9 mmol) and NaOH (0.52 mL; 10M, 5.2 mmol) were added to a stirred solution of 4-[3-(3,7- diazabicyclo[3.3.1Jnon-3-yl)-2-hydroxy-propoxyJbenzonitrile (0.796 g; 2.6 mmol; see Example G above) in toluene (5 mL). The reaction mixmre was stirred at rt. for 15 min. DCM was added and die organic layer was separated, dried, concentrated and recrystallized from IPA to give the title compound in a 86% yield. 13 C NMR (CDCI 3 ): δ 28.8, 29.2, 32.0, 48.6, 49.6, 56.9, 60.0, 62.1 , 65.1 , 70.5, 103.7, 115.2, 119.0, 121.6, 124.9, 128.9, 133.6, 151.1, 154.9, 162.0 Example 38 Benzyl 7- [3-(4-cy anophenoxy)-2-hydroxypropylJ -3 , 7-diazabicyclo [3.3.1]- nonane-3-carboxylate The title compound was prepared in quantitative yield according to die method described in Example 1 above from CBz-OSu, using TEA, instead of NaOH, as a base. ESI-MS (M + 1) + 436 (m/z) 13 C NMR (CDCI 3 ): δ 29.31 , 32.70, 48.88, 49.55, 56.77, 60.21 , 62.47, 65.13, 67.28, 70.86, 104.04, 115.40, 119.23, 127.93, 128.43, 133.94, 136.91 , 157.39,166.22 Example 39 tgrt-Butyl 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropylJ-9-(l ,2-ethylene- dioxy )-3 , 7-diazabicyclo [3.3.1] nonane-3 -carboxylate (a) 3,7-Dibenzyl 9-(l ,2-ethylenedioxy)-3,7-diazabicyclo[3.3. ljnonane A solution of 3, 7-dibenzyl-3, 7-diazabicyclo [3.3. l]nonane-9-one (10.0 g; 29.8 mmol; Bionet), ethylene glycol (20 g) and p-TSA (12.5 g; 65.7 mmol) in toluene (200 mL) was refluxed in a Dean-Stark apparatus for 12 h. NaOH (200 mL, 2M) was added and die organic layer separated, dried and concentrated to give die sub-title compound in a quantitative yield. (b) tgrt-Butyl 7-benzyl-9-(l ,2-ethylenedioxy)-3,7-diazabicyclo[3.3.1J- nonane-3 -carboxylate The sub-title compound was prepared in a 92% yield according to die method described in Example 20(c) above from 3,7-dibenzyl 9-(l ,2- edιylenedioxy)-3,7-diazabicyclo[3.3. ljnonane (from step (a) above). (c) tgrt-Butyl 9-(l,2-ethylenedioxy)-3,7-diazabicyclo[3.3. lJnonane-3- carboxylate The sub-title compound was prepared in quantitative yield according to die method described in Example E(b) above from tgrt-butyl 7-benzyl-9-(l,2- edιylenedioxy)-3,7-diazabicyclo[3.3.1Jnonane-3-carboxylate (from step (b) above). (d) tgrt-Butyl 7-[(25)-3-(4-cyanophenoxy)-2-hydroxypropyl1-9-(l .,2- edιylenedioxy)-3 , 7-diazabicyclo [3.3.1] nonane-3-carboxylate The title compound was prepared in a 44% yield according to die method described in Example 3 above from tgrt-butyl 9-(l ,2-edιylenedioxy)-3,7- diazabicyclo[3.3.1Jnonane-3-carboxylate (from step (c) above). 13 C NMR (CDC1 3 ): δ 28.78, 37.71 , 38.37, 46.00, 47.42, 53.83, 57.81 , 60.81 , 64.40, 65.45, 70.80, 79.81 , 104.06, 106.95, 115.44, 119.24, 133.93, 156.24, 162.27 Example 40 tgrt-Buty 1 7- [3-(4-cyanophenoxy)-2-hydroxypropylJ -9 , 9-pentamethylene- 3 ,7-diazabicyclo[3.3.1 Jnonane-3-carboxylate (a) N-(Cyanoacetyl) benzylamide A mixture of benzyl amine (150 mL; 1.4 mol) and methyl cyanoacetate (130 mL; 1.4 mol) was stirred at 100°C for 16 h with continuous removal of MeOH. The reaction mixmre was allowed to attain rt. and die precipitate filtered off and washed widi cold EtOH to give die sub-title compound in a 78 % yield. (b) Ediyl (2-cyclopentylidene)cyanoacetate The sub-title compound was prepared in a 69% yield analogously to die method described in Organic Synthesis, 39, 25 (1959) from cyclopentanone and ediyl cyanoacetate. (c) 8-Benzyl-7 , 9-dioxo-8-azaspiro [4 , 5] decane-6 , 10-dicarbonitrile N-(Cyanoacetyl) benzylamide (2.30 g; 13.2 mmol; from step (a) above) and ethyl (2-cyclopentylidene)cyanoacetate (2.36 g; 13.2 mmol; from step (b) above) were added to a stirred solution of sodium edioxide (13 mmol) in EtOH (20 mL), and die reaction mixmre was stirred at rt. for 96 h. Water (16 mL) and HCl (5 mL, cone.) were added and the precipitate filtered off, washed widi water and dried in vacuo to give the sub-title compound in a 55 % yield. (d) 3-Benzyl-9,9-pentamethylene-3,7-diazabicyclo[3.3.1Jnonane-2,4,6,8- tetraone 8-Benzyl-7,9-dioxo-8-azaspiro[4,5Jdecane-6,10-dicarbonitrile (4.0 g; 13 mmol; from step (c) above) was stirred in H 2 SO 4 (20 mL, cone.) and H 3 PO 4 (85 %) for 40 min. at 120°C. The hot reaction mixmre was poured on ice-water and die precipitate filtered off, washed with EtOH and dried in vacuo to give the sub-title compound in a 43 % yield. (e) 3-Benzyl-9,9-pentamemylene-3 ,7-diazabicyclo[3.3. ljnonane 3-Benzyl-3,7-diazabicyclo[3.3.1Jnonane-2,4,6,8-tetraone (from step (d) above) was reduced widi LiAlH 4 in dioxane using standard procedures to give the sub-title compound in a quantitative yield. (f) tgrt-Butyl 7-benzy 1-9 , 9-pentamethylene-3 , 7-diazabicyclo [3.3.1] nonane- 3-carboxylate Di-tgrt-butyl dicarbonate (0.92 g; 4.2 mmol) was added to a solution of 3- benzyl-9,9-pentamethylene-3,7-diazabicyclo[3.3. ljnonane (1.15 g; 4.2 mmol; from step (e) above) in THF (50 mL) and die reaction mixmre was stirred until tic indicated diat die reaction was complete. The solvent was removed on a rotary evaporator to give the sub-title compound in a 79% yield. 13 C NMR (CDCI 3 ): δ 23.80, 28.64, 30.26, 34.87, 35.21 , 37.40, 42.43, 46.09, 46.68, 55.92, 56.46, 62.80, 78.58, 126.53, 128.00, 128.32, 139.53, 155.37 (g) tgrt-Butyl 7- [3-(4-cyanophenoxy)-2-hydroxypropylJ -9 , 9-penta- medιylene-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate The title compound was prepared in a 53 % overall yield according to die memods described in Examples E(b) and 2 above from tgrt-butyl 7-benzyl- 9,9-pentamethylene-3,7-diazabicyclo[3.3.1Jnonane-3-carboxylate (from step (f) above). 13 C NMR (CDCI 3 ): δ 23.83, 28.68, 35.13, 37.30, 42.77, 45.82, 46.84, 47.02, 54.26, 57.90, 61.04, 65.34, 70.77, 79.32, 104.03, 115.44, 119.17, 133.85, 156.00, 162.34 Example 41 7-(tg/-t-Butyloxycarbonyl)-3-[3-(4-cyanophenoxy)-2S-hydroxypropylJ-3- methyl-7-aza-3-azomabicyclo[3.3. ljnonane acetate Mel (1.5 mmol) was added to a stirred solution of tgrt-butyl 7- [3 -(4- cyanophenoxy)-2-hydroxypropylJ -3 , 7-diazabicyclo [3.3.1] nonane-3 - carboxylate (0.5 g; 1.24 mmol; see Example 2 above) in DMF (4 mL), and die reaction mixmre was stirred at rt. for 48 h. Toluene was then added and die solvents removed under vacuum. The residue was purified using HPLC (MeCN:H 2 O; 70:30 isocratic; NH 4 O Ac-buffer; C8 column). The resultant salt was obtained by freeze-drying die appropriate fractions. FAB-MS (M + 1) + 416 (m/z) 13 C NMR (CD 3 OD): δ 25.88, 27.24, 27.66, 57.76, 64.42, 66.18, 70.48, 81.93, 104.18, 115.40, 118.52, 133.84, 156.04, 162.12 Example 42 7-(tgrt-Butyloxycarbonyl)-3-[3-(4-cyanophenoxy)-2-hydroxypropylJ-7-aza- 3-azoniabicyclo[3.3.1Jnonan-3-olate CPBA (300 mg; 70% ; 1.22 mmol) was added to a stirred solution of tgrt-butyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo- [3.3.1Jnonane-3-carboxylate (490 mg; 1.22 mmol; see Example 2 above) in DCM (10 mL) at 0°C. The reaction mixture was stirred for 1 h and dien washed with NaHCO 3 (aq.). The organic layer separated, dried, concentrated and subjected to column chromatography (DCM:MeOH; 19: 1) to give the title compound in a 98 % yield. FAB-MS (M + 1) + 418 (m/z) 13 C NMR (CDC1 3 ): δ 27.63, 28.52, 46.16, 65.30, 68.45, 70.53, 72.03, 72.53, 78.98, 104.23, 115.28, 119.04, 133.96, 155.51 , 161.68 Example 43 7-(tgrt-Butyloxycarbonyl)-3-[(2^-3-(4-cyanophenoxy)-2-hydroxypropylJ- 7-aza-3-azoniabicyclo[3.3.1Jnonan-3-olate The title compound was prepared in a 70% yield according to die method described in Example 42 above from 3, 7-diazabicyclo [3.3. lJnonane-3- carboxylic acid, 7-[(2.S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-l,l- dimethylediyl ester (see Example 3 above). FAB-MS (M + 1) + 417 (m/z) Example 44 7-(Cyclopentyloxycarbonyl)-3-[3-(4-cyanophenoxy)-2-hydroxypropyl]-7- aza-3-azoniabicyclo[3.3.1] nonane-3-olate The title compound was prepared in a 86% yield according to die method described in Example 42 above from cyclopentyl 7-[3-(4-cyanophenoxy)- 2-hydroxypropylJ-3,7-diazabicyclo[3.3.1Jnonane-3-carboxylate (see Example 9 above). FAB-MS (M + 1) + 430 (m/z) 13 C NMR (CDC1 3 ): δ 23.68, 27.41 , 32.61 , 45.80, 65.21 , 68.29, 70.30, 72.17, 72.71 , 77.60, 104.43, 115.10, 115.21 , 118.95, 133.83, 134.11 , 156.10, 161.45 Example 45 7-(tgrt-Butyloxycarbonyl)-3-[3-(4-cyanophenoxy)propyl]-7-aza-3- azoniabicyclo[3.3. l]nonan-3-olate The title compound was prepared in a 80% yield according to die method described in Example 42 above from tgrt-butyl 7-(3-cyanophenoxypropyl)- 3, 7-diazabicyclo [3.3. lJnonane-3 -carboxylate (see Example 21 above). FAB-MS (M + 1) + 402 (m/z) 13 C NMR (CDCI 3 ): δ 22.40, 27.12, 27.31 , 28.50, 46.00, 66.04, 69.46, 70.58, 79.41 , 104.23, 115.15, 119.05, 134.03, 155.54, 161.68 Example 46 7-(tgrt-Butyloxycarbonyl)-3-[3-(4-cyanoanilino)propylJ-7-aza-3- azoniabicyclo[3.3. lJnonan-3-olate The title compound was prepared in a 6% yield according to die method described in Example 42 above from tgrt-butyl 7-[3-(4- cyanoanilino)propyl]-3,7-diazabicyclo[3.3.1Jnonane-3-carboxylate (see Example 23 above). FAB-MS (M + 1) + 401 (m/z) 13 C NMR (CDC1 3 ): δ 18.5, 22.3, 25.4, 27.3, 27.4, 28.6, 72.8, 79.2, 97.3, 112.1 , 121.0, 133.6, 152.0, 155.5 Example 47 n-Butyl 7- [3-(4-cyanophenoxy)-2-hydroxypropylJ -3 , 7-diazabicyclo [3.3.1]- nonane-3-carboxylate 4-[3-(3 ,7-Diazabicyclo[3.3. l]non-3-yl)-2-hydroxypropoxyJbenzonitrile hydrochloride, (1 g; 2.96 mmol; see Example G above) was suspended in CH 2 C1 2 (20 mL) and saturated NaHCO 3 (40 mL). n-Butyl chloroformate was added (1.12 eq. ; 3.33 mmol) and die reaction was stirred at room temperamre overnight (18 to 20 h) under N 2 . The crude material was chromatographed on a 3 cm x 18 cm silica gel column eluting with hexanes: ediyl acetate (2: 1). All fractions containing the desired material were combined to give 420 mg (1.20 mmol; 41 % yield) of die title compound. Η NMR (CDCI 3 ): δ 7.58 (d, 2H), 6.95 (d, 2H), 4.40-3.90 (m, 8H), 3.30-2.85 (m, 4H), 2.60-1.20 (m, 12 H), 0.95 (t, 3H) 13 C NMR (CDCI 3 ): δ 162.0, 157.5, 133.0, 119.0, 115.5, 104.0, 71.0, 70.5, 66.0, 65.5, 65.0, 62.5, 62.0, 61.0, 60.0, 58.0, 56.5, 49.5, 48.5, 33.0, 32.0, 31.0, 29.5, 29.0, 19.0, 13.5. CI-MS (M + 1) + 402 (m/z) Example 48 2-Chloroethyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo- [3.3. lJnonane-3 -carboxylate Prepared according to the method described in Example 47 above using 2- chloroediyl chloroformate, yielding 783 mg (2.03 mmol; 69% yield) of die title compound. Η NMR (CDC1 3 ): δ 7.55 (d, 2H), 6.95 (d, 2H), 4.50-4.10 (m, 6H), 4.10-3.90 (m, 3H), 3.90-3.60 (m, 2H), 3.30-3.00 (m, 5H), 2.65-2.29 (m, 3H), 2.20-2.05 (m, 2H), 1.95-1.65 (m, 5H) 13 C NMR (CDC1 3 ): δ 162.0, 134.0, 119.0, 115.5, 71.0, 70.5, 66.2, 65.0, 62.5, 62.0, 61.0, 60.0, 58.0, 56.5, 49.5, 48.5, 48.4, 43.0, 42.5, 32.7, 32.0, 29.5, 29.0 CI-MS (M + 1) + 408 (m/z) mp 104-105°C Example 49 Allyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo[3.3.1J- nonane-3-carboxylate Prepared according to me method described in Example 47 above using allyl chloroformate, yielding 828 mg (2.15 mmol; 73 % yield) of title compound. Η NMR (CDCI 3 ): δ 7.52-7.40 (d, 2H), 6.95-6.80 (d, 2H), 5.90-5.75 (m, IH), 5.25-5.05 (m, 2H), 4.75-4.40 (m, 2H), 4.40-3.80 (m, 6H), 3.20- 2.80 (m, 4H), 2.60-1.50 (m, 8H) 13 C NMR (CDCI 3 ): δ 162.0, 134.0, 133.5, 119.0, 117.0, 115.0, 104.5, 71.0, 70.5, 66.0, 65.5, 62.5, 62.0, 60.0, 58.0, 57.0, 49.0, 48.0, 32.0, 31.5, 29.5 CI MS (M + 1) + 386 (m/z) Example 50 ft-Propyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylj-3,7-diazabicyclo- [3.3. lJnonane-3-carboxylate Prepared according to die method described in Example 47 above using n- propyl chloroformate, yielding 780 mg (2.01 mmol; 68 % yield) of die title compound. Η NMR (CDC1 3 ): δ 7.65-7.55 (d, 2H), 7.05-6.95 (d, 2H), 4.45-3.90 (m, 9H), 3.30-2.85 (m, 4H), 2.60-2.00 (m, 4H), 1.95-1.60 (m, 5H), 1.00- 0.90 (t, 3H) 13 C NMR (CDCI 3 ): δ 162.0, 134.0, 119.0, 117.0, 104.0, 71.5, 67.5, 65.5, 63.0, 61.5, 57.5, 49.5, 49.0, 33.0, 32.0, 29.5, 22.0, 11.0 CI MS (M + 1) + 388 (m/z) Example 51 4-Nitrobeπzyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo- [3.3. lJnonane-3-carboxylate Prepared according to die method described in Example 47 above using 4- nitrobenzyl chloroformate, yielding 958 mg (2.00 mmol; 68% yield) of die title compound as a yellow crystalline solid. Η NMR (CDCI 3 ): δ 8.25-8.15 (d, 2H), 7.65-7.45 (m, 4H), 7.05-6.90 (d, 2H), 5.40-5.10 (m, 2H), 4.48-4.15 (m, 3H), 4.05-3.85 (m, 3H), 3.34- 2.90 (m, 5H), 2.63-2.30 (m, 4H), 2.00-1.69 (m, 4H) 13 C NMR (CDCI 3 ): δ 162.0, 144.5, 134.0, 128.0, 123.5, 119.0, 115.5, 71.5, 71.0, 66.1 , 66.0, 65.0, 62.5, 62.0, 61.0, 60.05, 58.0, 56.5, 49.5, 49.0, 32.5, 31.8, 29.5, 29.0 CI MS (M + 1) + 481 (m/z) mp 165-166°C Example 52 4-Fluorophenyl 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diaza- bicyclo[3.3. lJ-nonane-3-carboxylate Prepared according to die method described in Example 47 above using 4-fluorophenyl chloroformate, yielding 886 mg (2.02 mmol, 68 % yield) of die title compound as a white crystalline solid. Η NMR (CDC1 3 ): δ 7.60-7.50 (m, 2H), 7.15-6.88 (m, 6H), 4.51-4.25 (m, 2H), 4.20-3.90 (m, 6H), 3.45-3.00 (m, 4H), 2.65-2.15 (m, 4H), 2.00-1.70 (m, 4H), 1.55 (s, 2H) 13 C NMR (CDCI 3 ): δ 161.8, 147.5, 134.0, 123.5, 119.0, 116.0, 115.5, 71.0, 66.0, 65.5, 62.5, 61.8, 60.5, 58.5, 57.0, 50.0, 49.5, 49.0, 43.0, 32.5, 31.5, 29.5, 29.0 CI-MS (M + 1) + 440 (m z) mp 145-146°C Example 53 4-Methylphenyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3 ,7-diaza- bicyclo[3.3.1 Jnonane-3-carboxylate Prepared according to die method described in Example 47 above using p- tolyl chloroformate, yielding 790 mg (1.81 mmol, 61 % yield) of die title compound as a white crystalline solid. Η NMR (CDCI 3 ): δ 7.60-7.55 (m, 2H), 7.15-6.80 (m, 6H), 4.50-4.30 (m, 2H), 4.20-3.85 (m, 3H), 3.35-3.00 (m, 5H), 2.65-2.15 (m, 7H), 2.00-1.55 (m, 4H) 13 C NMR (CDCI 3 ): δ 162.3, 134.6, 133.9, 133.2, 129.6, 121.5, 119.2, 115.5, 104.0, 70.9, 66.2, 65.5, 62.5, 61.6, 60.3, 59.9, 58.6, 57.3, 49.8, 48.8, 48.7, 32.3, 31.6, 29.5, 29.1 , 20.8 CI-MS (M + 1) + 436 (m/z) mp 125-126°C Example 54 4-Methoxyphenyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3 ,7-diaza- bicyclo[3.3. lJnonane-3-carboxylate Prepared according to die method described in Example 47 above using 4- methoxyphenyl chloroformate yielding 655 mg (1.45 mmol; 49% yield) of die title compound as a fine white crystalline solid. Η NMR (CDCI 3 ): δ 7.60-7.45 (m, 2H), 7.10-6.70 (m, 6H), 4.55-4.20 (m, 3H), 4.20-3.85 (m, 4H), 3.75 (d, 3H), 3.60-3.00 (m, 4H), 2.75-1.60 <m, 7H) 13 C NMR (CDCI 3 ): δ 162.5, 162.3, 157.1, 155.8, 154.8, 145.2, 134.1 , 133.5, 123.5, 122.9, 119.4, 115.7, 114.4, 104.3, 71.1 , 66.4, 65.7, 62.7, 61.8, 60.5, 60.3, 58.7, 55.8, 50.0, 49.4, 49.1, 32.5, 31.7, 29.8, 29.4 CI-MS (M + 1) + 452 (m/z) mp no-lire Example 55 (-)Menmyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo- [3.3.1 Jnonane-3-carboxylate Prepared according to die method described in Example 47 above using (-)menmyl chloroformate, yielding 270 mg (0.56 mmol; 19% yield) of die title compound as a white crystalline solid. Η NMR (CDCI 3 ): δ 7.65-7.50 (d, 2H), 7.05-6.90 (t, 2H), 4.70-3.90 (m, 8H), 3.50-2.85 (m, 5H), 2.60-1.20 (m, 18H), 1.20-0.60 (m, IH) 13 C NMR (CDCI 3 ): δ 162.4, 157.4, 134.0, 119.3, 115.6, 104.1 , 75.8, 74.9, 71.4, 71.1 , 65.1 , 64.9, 62.4, 60.3, 60.1 , 56.7, 56.5, 49.7, 48.7, 48.4, 48.3, 47.6, 41.9, 41.5, 34.6, 32.9, 32.8, 31.4, 31.2, 29.7, 29.3, 26.4, 23.7, 23.3, 22.4, 22.2, 21.6, 21.1 , 17.0, 16.7 CI-MS (M + 1) + 484 (m/z) m l l l-112°C Example 56 ngQ-Pentyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo- [3.3. lJnonane-3-carboxylate Prepared according to die method described in Example 47 above using neo-Tpentyl chloroformate, yielding 960 mg (2.31 mmol; 78% yield) of die title compound as a white crystalline solid. Η NMR (CDCI 3 ): δ 7.60-7.50 (d, 2H), 7.00-6.90 (d, 2H), 4.45-3.60 (m, 8H), 3.30-2.90 (m, 4H), 2.55-2.30 (m, 2H), 2.15-2.00 (m, 2H), 1.90- 1.60 (m, 4H), 1.10-0.90 (s, 9H) 13 C NMR (CDCI 3 ): δ 162.5, 158.1 , 134.1, 119.4, 115.6, 104.3, 75.3, 71.1, 70.7, 66.8, 65.2, 62.9, 62.3, 60.9, 60.4, 58.5, 49.7, 49.0, 48.7, 33.1, 32.1, 31.7, 29.8, 29.6, 26.8 CI-MS (M + 1) + 416 (m/z) mp 146-147°C Example 57 2-Methoxyedιyl 7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-3 , 7-diazabicyclo [3.3.1] nonane-3 -carboxylate Prepared according to the method described in Example 47 above using 2- methoxyediyl chloroformate, yielding 420 mg (1.04 mmol, 35 % yield) of die title compound as a pale yellow oil. Η NMR (CDC1 3 ): δ 7.60-7.50 (d, 2H0, 7.00-6.90 (d, 2H), 4.40-4.10 (m, 5H), 4.05-3.90 (m, 3H), 3.65-3.55 (m, 2H), 3.40-3.35 (s, 3H), 3.30-2.90 (m, 4H), 2.60-2.10 (m, 4H), 1.90-1.60 (m, 4H) 13 C NMR (CDCI 3 ): δ 162.4, 157.6, 134.1 , 133.4, 119.3, 115.5, 104.3, 71.2, 71.0, 70.7, 66.4, 65.3, 64.6, 62.7, 62.1 , 60.8, 60.3, 58.9, 58.2, 56.9, 49.7, 48.9, 32.8, 31.9, 29.8, 29.7, 29.5 CI-MS (M + 1) + 404 (m/z) Example 58 tgrt-Butyl 7-[3-(4-tgrt-butylphenoxy)-2-hydroxypropylJ-3,7-diazabicyclo- [3.3.1 J nonane-3 -carboxylate (a) 4-tgrt-Butyl- 1 -(2-oxiranylmemoxy)benzene A mixmre of epichlorohydrin (15.3 g; 0.165 mol), 4-tgrt-butylphenol (5.0 g; 0.033 mol) and potassium carbonate (6.9 g; 0.050 mol) in acetonitrile (50 mL) was refluxed for 5 h. The resulting heterogeneous mixmre was cooled to below reflux temperature and vacuum filtered dirough fritted glass. The organics were concentrated to give die crude product (7.9 g) as a liquid. Flash chromatography on silica gel (CH 2 C1 2 : EtOAc; 19: 1) gave the desired product (5.2 g; 76%) as a liquid. Η NMR (CDCI 3 ): δ 1.33 (s, 9H), 2.78 (m, IH), 2.92 (t, IH), 3.36 (m, IH), 3.97 (dd, IH), 4.21 (dd, IH), 6.88 (d, 2H), 7.32 (d, 2H) (b) tgrt-Butyl 7-[3-(4-tgrt-butylphenoxy)-2-hydroxypropylJ-3 -diaza- bicy clo [3.3.1] nonane-3-carboxylate A mixture of tgrt-butyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (2.2 g; 9.70 mmol; see Example F above) and 4-tgrt-butyl-l-(2- oxiranylmethoxy)benzene (2.0 g; 9.70 mmol; from step (a) above) in 2- propanol (10 mL) and water (1 mL) was stirred at 60 °C for 18 h. The reaction mixmre was concentrated to give an oil which was dissolved in hexanes and allowed to stand until solids formed. The solids were collected and dried to give the desired product (0.28 g; 7 %) as a white solid. mp 75-77°C Η NMR (CDCI 3 ): δ 1.32 (s, 9H), 1.47 (s, 9H), 1.62-1.78 (m, 2H), 1.79- 1.96 (m, 2H), 2.13-2.38 (m, 2H), 2.42-2.57 (m, 2H), 2.87-3.25 (m, 4H), 3.82-4.30 (m, 5H), 6.86 (d, 2H), 7.31 (d, 2H) 13 C NMR (CDCI 3 ): δ 28.9, 29.1 , 29.4, 29.7, 31.3, 31.7, 32.1 , 34.3, 47.9, 48.1 , 48.9, 49.6, 57.4, 58.1 , 60.6, 61.9, 62.5, 65.5, 65.9, 70.7, 77.4, 79.7, 114.3, 126.4, 143.6, 155.8, 156.2, 156.8 CI-MS (M + 1) + 433 (m/z) Example 59 tgrt-Butyl 7-[3-(phenoxy)-2-hydroxypropylJ-3,7-diazabicyclo[3.3.1]- nonane-3-carboxylate (a) 1 -(2-Oxiranylmethoxy)benzene Prepared according to the method described in Example 58(a) above using phenol (5.0 g; 0.053 mol), yielding 7.8 g (98%) of die sub-title compound as a liquid. Η NMR (CDC1 3 ): δ 2.77 (m, IH), 2.90 (t, IH), 3.37 (m, IH), 3.98 (dd, IH), 4.24 (dd, IH), 6.87-7.03 (m, 3H), 7.22-7.35 (m, 2H) (b) tgrt-Butyl 7-[3-(phenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]- nonane-3-carboxylate Prepared according to die method described in Example 58(b) above from l-(2-oxiranylmethoxy)benzene (2.0 g; 13.3 mmol; from step (a) above), yielding 2.4 g (48%) of die sub-title compound as a white solid. mp 86-88 °C Η NMR (CDCI 3 ): δ 1.47 (s, 9H), 1.58-1.97 (m, 4H), 2.14-2.38 (m, 2H), 2.43-2.58 (m, 2H), 2.87-3.26 (m, 4H), 3.84-4.32 (m, 5H), 6.89-6.98 (m, 3H), 7.22-7.33 (m, 2H) 13 C NMR (CDCI 3 ) δ 28.9, 29.1, 29.3, 29.6, 31.3, 32.1 , 47.9, 48.8, 49.6, 57.4, 58.1 , 60.5, 61.8, 62.3, 65.5, 65.8, 70.6, 79.6, 114.8, 120.9, 129.5, 155.6, 156.0, 159.1 CI-MS (M + 1) + 377 (m/z) Example 60 tgrt-Butyl-7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-9,9-dimethyl-3,7- diazabicyclo [3.3.1] nonane-3 -carboxylate (a) Ethyl (2,2' -dimethylidene)cyanoacetate A mixmre of acetone (30.8 g; 0.530 mol), ethyl cyanoacetate (50.0 g; 0.442 mol), ammonium acetate (6.80 g; 88.4 mmol), and glacial acetic acid (21.2 g; 0.354 mol) in benzene (100 mL) was heated under reflux for 9 h widi azeotropic removal of water. The mixmre was washed widi water (3 x 50 mL), and die aqueous layer was extracted widi ediyl acetate (50 mL). The combined organic extracts were dried over Na 2 SO 4 , and evaporated to an orange oil which was distilled under vacuum at 70-75 °C at 0.5 mm Hg to afford the sub-title compound (43.1 g; 64%) as a colourless liquid. Η NMR (CDClj) δ 4.20 (q, J=7.9 Hz, 2H), 2.33 (s, 3H), 2.25 (s, 3H), 1.30 (t, J=7.9 Hz, 3H) (b) 1 -Benzyl-3 ,5-dicy ano-4 , 4-dimethyl-2 , 6-dioxopiper idone Sodium metal (6.1 g; 0.264 mol) was added in pieces to absolute emanol (375 mL) at 25 °C under nitrogen. After all the sodium had been dissolved, N-(cyanoacetyl) benzylamide (46.9 g; 0.270 mol; see Example 40(a) above) and ediyl (2,2'-dimethylidene)cyanoacetate (41.3 g; 0.270 mol; from step (a) above) were added sequentially. The dark orange mixmre was stirred 3 days at 25 °C, poured into water (300 mL), and concentrated hydrochloric acid (100 mL) was men added, following which a solid precipitated. The solid was collected via filtration over a sintered- glass funnel to yield die sub-title compound (39.5 g, 52%) as a tan solid. mp 140-145 °C Η NMR (DMSO-d 6 ): δ 7.20-7.38 (m, 5H), 5.08 (s, 2H), 4.90 (s, 2H), 1.37 (s, 3H), 1.18 (s, 3H) (c) 3-Benzyl-9 , 9-dimethy 1-3 , 7-diazabicyclo [3.3.1] nonane-2 ,4,6 , 8-tetraone A mixmre of l-benzyl-3,5-dicyano-4,4-dimethyl-2,6-dioxopiperidone (9.5 g; 43.5 mmol; from step (b) above) in phosphoric acid (50 mL) and sulfuric acid (50 mL) was heated at 120°C for 1 h. The mixmre was cooled and poured into ice- water (100 mL). The mixmre was extracted widi chloroform (3 x 100 mL), dried over Na 2 SO 4 , and evaporated to a white residue which was recrystallized from methanol to afford the subtitle compound (980 mg; 8 %) as a white solid. mp 243-245 °C Η NMR (CDC1 3 ): δ 7.22-7.37 (m, 3H), 7.10-7.18 (m, 2H), 4.82 (s, 2H), 3.83 (s, 2H), 1.12 (s, 3H), 1.08 (s, 3H) (d) 3-Benzy 1-9 , 9-dimemyl-3 , 7-diazabicyclo [3.3.11 nonane A solution of 3-benzyl-9,9-dimediyl-3,7-diazabicyclo[3.3.1]nonane- 2,4,6,8-tetraone (980 mg; 3.26 mmol; from step (c) above) in 1 ,4-dioxane (25 mL) was added dropwise to a suspension of lithium aluminium hydride (990 mg; 26.1 mmol) in 1 ,4-dioxane (30 mL) at 0°C. The mixmre was refluxed overnight, cooled to 0°C whereafter water (1.0 mL), 15 % aqueous sodium hydroxide (1.0 mL), and more water (3.0 mL), were added sequentially. After stirring for 1 h at 0°C, die mixmre was filtered through a small pad of Celite, washing the Celite cake widi ediyl acetate (100 mL). The filtrate was evaporated to give die sub-title compound (676 mg; 85 % crude yield) as a colourless oil which was used directly in the next step widiout further purification. Η NMR (CDCI 3 ): δ 7.15-7.38 (m, 5H), 3.52-3.80 (m, 2H), 3.40 (s, 2H), 3.18-3.30 (m, 2H), 2.53-2.89 (m, 5H), 1.10-1.32 (m, 2H), 1.14 (s, 3H), 1.10 (s, 3H) 13 C NMR (CDCI 3 ): δ 138.8, 128.6, 128.3, 126.9, 77.4, 63.6, 55.0, 48.5, 39.5, 26.8, 26.1 CI-MS (M + 1) + 245 (m z) (e) tgrt-Buty l-7-benzyl-9 , 9-dimethy 1-3 , 7-diazabicycl [3.3.1] nonane-3- carboxylate A mixmre of 3 -benzyl-9,9-dimethyl-3, 7-diazabicyclo [3.3. ljnonane (650 mg, 2.66 mmol; from step (d) above) and di-tgrt-butyl dicarbonate (580 mg; 2.66 mmol) in THF (8.0 mL) was stirred for 3 hours at 25 °C. The mixmre was evaporated to afford the sub-title compound (940 mg; 104% crude yield) as pale yellow oil which was used directly in the next step widiout further purification. Η NMR (CDCI 3 ): δ 7.18-7.40 (m, 5H), 3.84-3.96 (m, 2H), 3.66-3.77 (m, IH), 3.35-3.60 (m, 4H), 2.57-2.75 (m, 4H), 1.50 (s, 9H), 1.25-1.43 (m, 2H), 1.08 (s, 6H) 13 C NMR (CDCI 3 ): δ 173.8, 155.2, 139.4, 128.3, 128.1 , 126.6, 78.7, 62.6, 55.4, 54.8, 46.5, 46.0, 38.5, 30.0, 28.7, 27.4, 25.6 CI-MS (M + 1) + 345 (m/z) (f) tert-Buty 1-9 , 9-dimethyl-3 , 7-diazabicycl [3.3.1] nonane-3 -carboxylate A mixmre of tgrt-butyl-7-benzyl-9,9-dimethyl-3,7-diazabicycl[3.3.1]- nonane-3 -carboxylate (900 mg; 2.61 mmol; from step (e) above) and 10% palladium on carbon (w/w; 90 mg) in absolute e anol (12 mL) was stirred overnight under 1 atmosphere of hydrogen. The catalyst was removed by filtration through a pad of Celite washing the Celite with ethyl acetate (50 mL). The filtrate was concentrated to an oil which was chromatographed on silica gel eluting with methanol: methylene chloride (1 : 10) to yield die sub-title compound (326 mg, 50%) as a pale yellow oil. Η NMR (CDC1 3 ): δ 3.68-3.83 (m, 2H), 3.37-3.48 (m, 2H), 3.15-3.29 (m, 2H), 2.80-2.90 (m, 2H), 2.56 (bs, IH), 1.40 (s, 9H), 1.18-1.30 (m, 2H), 1.14 (s, 3H), 1.04 (s, 3H) 13 C NMR (CDCI 3 ): δ 155.6, 79.7, 48.3, 37.8, 30.3, 28.5, 26.9, 25.7, 24.4 CI-MS (M+ 1) + 255 (m/z) (g) tgrr-Butyl-7-[3-(4-cyanophenoxy)-2-hydroxypropylJ-9,9-dimemyl-3,7- diazabicyclo[3.3.1 Jnonane-3-carboxylate A mixmre of tgrt-butyl-9,9-dimethyl-3,7-diazabicycl[3.3.1Jnonane-3- carboxylate (306 mg; 1.20 mmol; from step (f) above) and 4-(2- oxiranylmethoxy)benzonitrile (211 mg; 1.20 mmol; see Example A above) in isopropanol: water (2.0 mL; 9: 1) was heated at 60°C for 20 h. The mixmre was concentrated to an oil which was partitioned widi water (15 mL) and methylene chloride (2 x 20 mL). The organic layer was separated, dried over Na 2 SO 4 , and evaporated to an od which was chromatographed on silica gel eluting wim methylene chloride: methanol (98:2). Fractions containing die desired product were combined and concentrated to afford die title compound (220 mg; 43 %) as a colourless oil. Η NMR (CDCI 3 ): δ 7.55 (d, J=9.7 Hz, 2H), 6.97 (d, J=9.7 Hz), 3.71- 3.99 (m, 8H), 2.42-2.99 (m, 6H), 1.45-1.50 (m, 2H), 1.42 (s, 9H), 1.13 (s, 6H) 13 C NMR (CDCI 3 ): δ 162.0, 155.5, 133.7,118.9, 115.3, 103.8, 79.1 , 70.5, 65.2, 60.5, 60.0, 56.5, 53.8, 53.2, 46.3, 38.2, 38.0, 28.3, 25.8, 25.4 CI-MS (M + 1) + 430 (m/z) Example 61 tgrt-Butyl-7- [[3-(4-cyanophenoxy)- 1 , 1 -dimethyl-2-hydroxy jpropylj -3 , 7- diazabicyclo[3.3. l]nonane-3-carboxylate (a) 2,3-Oxiranyl-3-medryl-l-butanol mCPBA (56% ; 33.75 g; 1.1 eq.) was added to a solution of 3-medιyl-2- buten-1-ol (8.6 g; 100 mmol; 10.2 mL) in chloroform (500 mL) at 0°C, and die solution was stirred for 10 min. at 0°C. The reaction was then stirred at room temperamre for 40 minutes, quenched widi saturated K 2 CO 3 solution (200 g) and stirred for 2 h.. The organic layer was separated, dried over K 2 CO 3 and concentrated in vacuo to give a clear, colourless oil (8.6 g, 84%). The oil was used immediately in the next step. Η NMR (CDCI 3 ): δ 3.87 (dd, IH), 3.67 (dd, IH), 3.00 (m, IH), 1.37 (s, 3H), 1.32 (s, 3H) (b) 2 , 3-Oxiranyl-3-methyl- 1 -butyl p-toluenesulfonate A solution of tosyl chloride (20.7 g; 110 mmol) in CH 2 C1 2 (300 mL) was added dropwise to a 0°C solution of 2,3-oxiranyl-3-methyl-l-butanol (8.60 g; 84.3 mmol; from step (a) above) and triethylamine (21 mL; 150 mmol) in CH 2 C1 2 (300 mL). The reaction was stirred at 0°C for 1 h and stored in a freezer at -10°C for 36 h. Intermittently, the reaction vessel was removed from the freezer, shaken and then placed back into the freezer. The reaction mixture was washed widi brine (250 mL) and die CH 2 C1 2 layer was separated. The aqueous layer was extracted widi CH 2 C1 2 (4 x 75 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo to give an orange residue. The residue was subjected to column chromatography on silica gel eluting wim a gradient of EtOAc in hexane (1 :9 to 1 :4). Fractions containing the desired compound were combined and concentrated to afford 21.34 g (98 %) of a colourless oil. Η NMR (CDC1 3 ): δ 7.82 (d, 2H), 7.37 (d, 2H), 4.13 (m, 2H), 2.98 (m, IH), 2.46 (s, 3H), 1.31 (s, 3H), 1.23 (s, 3H) (c) 4-(3-Methyl-2,3-oxiranylbutoxy)benzonitrile A solution of 4-cyanophenol (10.41 g; 87 mmol) in dry DMF (100 mL) was added dropwise to a suspension of sodium hydride (2.08 g; 87 mmol) in dry DMF (200 mL). The solution was stirred for 1 h at room temperamre followed by die addition of a solution of 2,3-oxiranyl-3- methyl-1 -butyl -toluenesulfonate (21.34 g; 83 mmol; from step (b) above) in dry DMF (100 mL). The reaction was stirred at room temperamre overnight. The reaction mixmre was carefully poured into ice cold H 2 O (400 mL) followed by extraction with CHC1 3 (1 x 500 mL, 3 x 100 mL). The combined organic extracts were dried over Na 2 SO 4 and concentrated in vacuo to afford an off white solid. The desired product was dien isolated via crystallization from isopropyl ether (8.88 g, 53 %). Η NMR (CDCI 3 ): δ 7.60 (d, 2H), 7.00 (d, 2H), 4.23 (dd, IH), 4.09 (dd, IH), 3.15 (m, IH), 1.42 (s, 3H), 1.39 (s, 3H) (d) tgrt-Butyl-7-[[3-(4-cyanophenoxy)-l , l-dimethyl-2-hydroxy]propylJ- 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate A mixmre of 4-(3-methyl-2,3-oxiranylbutoxy)benzonitrile (0.956 g; 4.70 mmol; from step (c) above) and tgrt-buty 1-3, 7-diazabicyclo [3.3. ljnonane- 3-carboxylate (1.06 g; 4.70 mmol; see Example F) was refluxed in iso- propanol:H 2 O (10: 1; 10 mL) for 5 days. The reaction mixture was concentrated in vacuo. The residue was dissolved in CH 2 C1 2 (150 mL), washed widi water (50 mL), brine (50 mL), dried over Na 2 SO 4 and concentrated in vacuo to afford a light yellow oil. Purification via column chromatography on silica gel eluting with CH 2 Cl 2 :CH 3 OH (80: 1) gave 0.540 g (27 %) of the title compound. R f 0.43 (CH 2 Cl 2 :CH 3 OH (25: 1)) Η NMR (CDC1 3 ) δ 7.61 (d, 2H), 6.98 (d, 2H), 3.88-4.62 (m, 5H), 3.65 (brs, IH), 2.89-3.33 (m, 6H), 2.78 (m, 2H), 1.66 (brs, IH), 1.48 (s, 9H), 1.26 (s, 3H), 1.17 (s, 3H) CI-MS (M + 1) + 430 (m/z) Example 62 tgrt-Butyl 7-[3-(4-cyano-2-hydroxyphenoxy)propylJ-3,7-diazabicyclo- [3.3.1 Jnonane-3-carboxylate (a) 4-(3-Chloropropoxy)-3-hydroxybenzonitrde NaH (0.20 g; 8.14 mmol) was added to a room temperamre solution of 3,4-dihydroxybenzonitrile (1.00 g; 7.40 mmol) in DMF. After stirring for 15 minutes, l-bromo-3-chloropropane (1.3 g; 8.14 mmol) was added to die mixmre. The reaction was stirred for 40 h at room temperature, and dien quenched widi water and extracted with EtOAc (100 mL). The EtOAc extract was washed with brine (4 x 100 mL), dried over Na 2 SO 4 and concentrated in vacuo. The resulting crude product was chromatographed on a column of silica (5 cm x 18 cm) eluting widi a mixmre of EtOAc and hexanes (1 :4). Fractions containing the desired product were combined and concentrated in vacuo to afford die sub-title compound as an oil (0.5 g; 32%). CI-MS (M + 1) + 212 (m/z) Η NMR (CDC1 3 ): δ 2.34 (m, 2H), 3.78 (t, 2H), 4.25 (t, 2H), 6.37 (br s, IH), 6.92 (d, IH), 7.17 (m, 2H) (b) tgrt-Butyl 7-[3-(4-cyano-2-hydroxyphenoxy)propylJ-3,7-diazabicyclo- [3.3. lJnonane-3-carboxylate A solution of 4-(3-chloropropoxy)-3-hydroxybenzonittile (0.50 g; 2.36 mmol; from step (a) above) and tgrt-butyl 3,7-diazabicyclo[3.3.1]nonane- 3-carboxylate (0.80 g; 3.54 mmol; see Example F above) in acetonitrile (20 mL) was stirred for 20 h at 47°C. The reaction was concentrated in vacuo and die residue chromatographed on a column of silica (4 cm x 24 cm) eluting with a mixmre of CH 2 C1 2 and CH 3 OH (98:2). After eluting 1 litre of the above eluant, die ratio of CH 2 C1 2 to CH 3 OH was changed to 95:5. Fractions containing die desired product were combined and concentrated in vacuo to afford 0.49 g of a semi-solid. This material was slurried widi hexane to afford die title compound as an off white solid (0.40 g; 42%). mp 127-130°C CI-MS (M + 1) + 402 (m/z) Η NMR (CDCI 3 ): δ 1.42 (s, 9H), 1.65 (br s, 2H), 1.92 (m, 4H), 2.25 (m, 4H), 3.01 (m, 4H), 4.12 (m, 4H), 6.91 (d, IH), 7.18 (m, 2H) 13 C NMR (CDCI 3 ): δ 26.2, 28.5, 31.2, 47.9, 49.2, 55.1 , 58.2, 59.1 , 67.5, 79.6, 104.2, 102.5, 118.2, 119.5, 125.3, 146.8, 150.5, 155.8 Example 63 tgrt-Butyl 7- [4-(4-cyanopheny l)-2-hydroxybuty IJ -3 , 7-diazabicyclo [3.3.1]- nonane-3-carboxylate (a) 4-(3-Butenyl)benzonitrile ZnCl 2 (15.0 g; 110 mmol) was heated widi a blow torch under vacuum until fused for about 20 min. After cooling to room temperature, magnesium turnings (2.7 g; 110 mmol) were added and heated again until ZnCl 2 was partially fused again (ca. 5 min). The mixmre was cooled to room temperamre, placed under N 2 and dry THF (100 mL) was added. 4- Bromo-1 -butene (11.0 mL; 110 mmol) was then added and die mixmre was treated widi sonication and warming for 2 h followed by stirring at room temperature for 1.5 days. Pd(Ph 3 P) 4 (6.00 g; 5.19 mmol) in THF (60 mL) was added to diis mixmre, followed by 4-bromobenzonitrde (20.0 g; 110 mmol) in THF (100 mL). The mixmre was stirred for 24 h at room temperamre. The reaction was quenched by die addition of 3N HCl (500 mL) and extracted widi edier (2 x 400 mL). The organic layer was dried over MgSO 4 , filtered and evaporated to give 20.1 g of an oil/solid mixmre. The residue was purified on a wet-packed silica gel column (6.5 x 40 cm; 10% EtO Ac/Hex) eluting wim 10% EtOAc/hexanes. After a 500 mL forerun, 200 mL fractions were collected. Fractions 3-6 were combined and evaporated to give 13.6 g (79%) of a clear semi-solid. Analysis by H NMR showed the sub-title product and 4- bromobenzonitrile (in a 2.2/1 ratio (approximately)). This material was used directly in me next step. (b) 4-(3-Oxiranylbutyl)benzonitrile wCPBA (49.0 g; 288 mmol) was added to a solution of die product from step (a) above; 13.6 g; 57.7 mmol) in CH 2 C1 2 (550 mL). The solution was stirred at room temperamre for 2 days. To this solution was added CH 2 C1 2 (200 mL) and die organic layer was washed with samrated NaHCO 3 (500 mL), 10% Na 2 S 2 O 3 (2 x 400 mL), samrated NaHCO 3 (400 mL) and brine (200 mL). The organic layer was then dried over MgSO 4 , filtered and evaporated to give 13.9 g of a semi-solid. Analysis by ! H NMR showed die presence of the sub-title product and 4- bromobenzonitrile. This material was used directly in die next step. (c) tgrt-Butyl 7-[4-(4-cyanophenyl)-2-hydroxybutylJ-3 ,7-diazabicyclo- [3.3. lJnonane-3-carboxylate The product mixture from step (b) above (400 mg; 2.31 mmol) was heated in the presence of tgrt-butyl 3,7-diazabicyclo[3.3.1Jnonane-3-carboxylate (374 mg; 1.65 mmol; see Example F above) in 2-propanol (5 mL) at 60°C for 7 h. The solution was stirred at room temperamre for 2 days. The solvent was evaporated and die residue chromatographed on a wet-packed sdica gel column (3.5 x 24 cm, 1 : 1 EtOAc/hexane) eluting wim EtOAc:hexane (1 : 1). After a 50 mL forerun, 15 mL fractions were collected. Fractions 66-70 were combined and evaporated to give 433 mg (66%) of the title product as an off-white solid. mp 88-93°C CI-MS (M + 1) + 400 (m/z) Η NMR (CDC1 3 ): δ 7.56 (d, J = 8.2 Hz, 2 H), 7.31 (d, J = 8.2 Hz, 2 H), 3.99- 4.25 (m, 2 H), 3.60-3.69 (m, 1 H), 3.5 (br s, 1 H), 2.69-3.15 (m, 6 H), 2.47 (m, 1 H), 1.75-2.4 (m, 6 H), 1.54-1.72 (m, 3 H) 1.47 (s, 9 H) 13 C NMR (CDCI 3 ): δ 148.5, 132.3, 129.5, 119.3, 109.7, 79.6, 65.6, 65.2, 60.7, 57.7, 57.1 , 49.5, 48.8, 47.8, 36.2, 32.2, 32.1 , 31.4, 29.6, 29.0, 28.9 Example 64 tgrt-Butyl 7- [4-(4-cyanophenoxy)-2-hydroxybuty IJ -3 , 7-diazabicyclo [3.3.1]- nonane-3-carboxylate (a) 4-(2-Oxiranylethoxy)benzonitrile /72CPBA (15.9 g; 65 mmol) was added to a stirred solution of 4-(4'- cyanophenoxy)but-l-ene (7.5 g; 56 mmol; prepared according to die method described in J. Chem. Soc. Perkin Trans. 1 , 9 (1992) 1145-1148) in CH 2 C1 2 (175 mL) and die reaction mixmre was stirred at room temperamre for 4 h. The reaction mixmre was washed widi NaHCO 3 (aq.) and die organic layer separated, dried and concentrated to give tihe sub- tide compound (7.23 g; 38 mmol). (b) tgrt-Butyl 7-[4-(4-cyanophenoxy)-2-hydroxybutylJ-3,7-diazabicyclo- [3.3.1 Jnonane-3-carboxylate 4-(2-Oxiranylethoxy)benzonitrile (0.946 g; 5.0 mmol; from step (a) above) was added to a stirred solution of tgrt-butyl 3,7- diazabicyclo[3.3.1Jnonane-3-carboxylate (1.13 g; 5.0 mmol; see Example F above) in MeCN (50 mL) and die reaction mixmre was stirred at 75 °C for 72 h. The reaction mixture was concentrated and die residue subjected to column chromatography (CH 2 Cl 2 :MeOH; 15: 1) to give the title compound in a 88% yield (1.84 g; 4.42 mmol). FAB-MS (M + l) + 416 (m/z) 13 C NMR (CDCI 3 ): δ 28.74, 29.53, 32.22, 34.31 , 47.13, 49.44, 56.92, 60.45, 62.89, 65.38, 79.96, 104.01 , 115.22, 119.36, 134.03, 156.06, 162.41 Example 65 tgrt-Butyl 7-{3-[(4-cyanophenyl)thioJ-2-hydroxypropyl}-3,7-diazabicyclo- [3.3. lJnonane-3-carboxylate The title compound was prepared according to die procedure described in Example 64 above using (4-cyanophenylsulfonylmethyl)oxirane (prepared according to die mediod described in Example A above from p- cyanodiiophenol). FAB-MS: (M+ l) + 418 (m/z) 13 C NMR (CDCI 3 ): δ 29.79, 30.54, 33.10, 37.80, 48.70, 50.52, 58.05, 59.07, 61.32, 65.12, 66.36, 80.66, 109.24, 120.03, 128.08, 133.18, 146.14, 156.93 Example 66 tgrt-Butyl 7- [4-(4-cy anophenoxy)-2-butenylJ -3 , 7-diazabicyclo [3.3.1 J - nonane-3-carboxylate (a) 4-(4-Cyanophenoxy)- 1 -chloro-2-butene 1 ,4-Dichlorobutene (750 g; 5 mol) was added to a stirred suspension of 4- cyanophenol (119.12 g; 1 mol) and K 2 CO 3 (345 g; 2.5 mol) in MeCN (1000 mL) and die reaction mixture was refluxed for 4 h. The reaction mixmre was filtered and concentrated. The residue was dissolved in di- /.sø-propyl ether (2000 mL) and after 24 h die precipitate was filtered off. The filtrate was concentrated giving die sub-title compound as a yellow oil which solidified upon standing (186 g; 0.89 mol). (b) tgrt-Butyl 7-[4-(4-cyanophenoxy)-2-butenylJ-3 ,7-diazabicyclo[3.3.1]- nonane-3-carboxylate tgrt-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.13 g; 5 mmol; see Example F above) was added to a stirred solution of 4-(4- cyanophenoxy)-l-chloro-2-butene (1.04 g; 5 mmol; from step (a) above) in MeCN (25 mL) and the reaction mixmre was stirred at room temperamre overnight. The reaction mixmre was concentrated and partitioned between diediyl ether and KHSO 4 (0.3 M). The aqueous layer was treated widi NaOH (2M) and subsequently extracted widi CH 2 C1 2 . The organic layer was washed with water, dried, concentrated and purified using column chromatography (CH 2 Cl 2 :MeOH; 95:5) to give the tide compound (0.84 g; 2.1 mmol). 13 C NMR (CDC1 3 ): δ 28.75, 32.18, 47.90, 49.04, 58.19, 59.05, 60.76, 68.77, 78.49, 103.93, 115.65, 119.37, 125.66, 133.95, 155.39, 161.96 Example 67 tgrt-Butyl 7- {2- [2-(4-cyanophenoxy )ethoxy J ediyl } -3 , 7-diazabicy clo- [3.3.1 Jnonane-3-carboxylate (a) 4-(2-Bromoemoxy)benzonitrile The sub-title compound was prepared according to die method described in J. Chem. Soc, (1942) 103, 114, but using K 2 CO 3 as the base. (b) 2-(4-Cyanophenoxy)edιoxyJedιanol Ediylene glycol (12 mL, 220 mmol) was added to a suspension of NaH (2.8 g; 66 mmol) in DMF (10 mL) and die reaction mixmre was stirred for 10 minutes. 4-(2-Bromoethoxy)benzonitrile (5 g; 22 mmol; from step (a) above) was added and die reaction mixture was stirred at 80 °C for 3 h and dien overnight at room temperature. The reaction mixmre was filtered and subjected to column chromatography (hexane: EtOAc; 1 : 1) giving die sub-title compound in 50% yield. (c) tgrt-Butyl 7-{2-[2-(4-cyanophenoxy)ethoxy]ethyl}-3,7-diazabicyclo- [3.3.1 Jnonane-3-carboxylate Mesylchloride (2.9 g; 29 mmol) was added to a stirred -5°C solution of 2- (4-cyanophenoxy)euιoxyJedιanol (5.0 g; 24 mmol; from step (b) above) in CH 2 C1 2 (50 mL) and die reaction mixture was stirred at room temperature for 2 h. The reaction mixmre was washed widi H 2 O and die organic layer separated, dried and concentrated. Part of the ody residue (2.0 g; 7 mmol) was dissolved in MeCN (50 mL) and K 2 CO 3 (1.5 g; 10.5 mmol) and tgrt-butyl 3,7-diazabicyclo[3.3.1Jnonane-3-carboxylate (1.6 g; 7.0 mmol; see Example F above) were added. The suspension was refluxed overnight and die salts were filtered off. The filtrate was concentrated and purified using column chromatography (EtOAc) giving the title compound (1.0 g; 2.4 mmol). ESI-MS (M+ 1) + 417 (m z) 13 C NMR (CDC1 3 ): δ 28.66, 29.13, 31.54, 47.74, 48.88, 58.15, 58.72, 59.54, 67.73, 69.07, 69.90, 78.51 , 104.01, 115.35, 119.24, 133.93, 155.2 Example 68 tgrt-Butyl 7- [4-(4-cyanopheny Qbuty IJ -3 , 7-diazabicyclo [3.3.1] nonane-3 - carboxylate (a) 2-[2-(4-Cyanophenoxy)ethyl]malonic acid dimethyl ether NaH (3.05 g; 127 mmol) was added at 0°C to a stirred solution of malonic acid dimethyl ester (17 g; 129 mmol) in MeCN (225 mL). A solution of 4- cyanophenediyl medianesulfonate (9.7 g; 43.1 mmol; see Example 25(a) above) in MeCN (50 mL) was added and die reaction mixture was refluxed overnight. NaHCO 3 (3 g) was added and die slurry was filtered and concentrated. The residue was partitioned between diethyl edier and H 2 O and die organic layer was separated, dried and concentrated. The residue was purified using column chromatography (toluene :di-/.rø-propyl ether; 1 :3) giving the sub-title compound (14.6 g; contaminated widi malomc acid dimethyl ester). This product was used directly in the next step widiout further purification. (b) 4-(4-Cyanophenoxy)butyric acid methyl ester A mixmre of 2-[2-(4-cyanophenoxy)ethylJmalonic acid dimethyl ether (11.07 g; 42.4 mmol; from step (a) above), NaCl (2.64 g; 45 mmol), H 2 O (1.62 g; 90 mmol) and DMSO (35 mL) was refluxed for 36 h. H 2 O (400 mL) was added and die mixture was extracted widi diediyl edier. The organic layer was washed widi H 2 O, dried and concentrated. Purification using column chromatography (toluene :di-Λrø-propyl ether; 1 :3) gave the sub-title compound (5.04 g ; 24.8 mmol) . (c) 4-(4-Cyanophenoxy)- 1 -butanol LiBH 4 (1.5 g; 71.1 mmol) was added to a stirred solution of 4-(4-cyano- phenoxy)butyric acid methyl ester (9.63 g; 47.4 mmol; from step (b) above), MeOH (2.87 mL; 71.1 mmol) and diethyl ether (158 mL) and the reaction mixture was refluxed overnight. The ether phase was collected and die residue was extracted with diethyl edier (3 x 50 mL). The combined organic phase was dried, concentrated and purified using column chromatography (EtOAc :hexane; 1 :3) to give the sub-title compound (3.82 g; 21.8 mmol). (d) Medianesulfonic acid 4-(4-cyanophenoxy)-butyl ester Mesylchloride (2.32 mL; 30 mmol) was added to a stirred 0°C solution of 4-(4-cyanophenoxy)-l-butanol (5.2 g; 29.7 mmol; from step (c) above) and TEA (4.35 mL) in CH 2 C1 2 (50 mL), and die reaction mixture was stirred for 4 h. H 2 O (150 mL) was added and die organic layer separated, dried and concentrated to give die sub-title compound which was used widiout further purification. (e) tgrt-Butyl 7-[4-(4-cyanophenyl)butylJ-3,7-diazabicyclo[3.3.1]nonane- 3-carboxylate The title compound was prepared in 73 % yield from methanesulfonic acid 4-(4-cyanophenoxy)-butyl ester and tgrt-butyl 3,7-diazabicyclo[3.3.1]- nonane-3-carboxylate (from step (d) above) according to the method described in Example 25(b) above. 13 C NMR (CDC1 3 ): δ 26.23, 28.72, 29.09, 31.56, 36.01, 47.67, 48.72, 58.31, 58.81, 59.19, 78.39, 109.38, 119.19, 129.17, 129.42, 131.91, 132.16, 148.41, 155.05 Example 69 7-[2-(4-Cyanophenoxy)ethylJ-3,7-diazabicyclo[3.3.1Jnonane-3-carboxylic acid tgrt-butyl ester tgrt-Buty 1-3, 7-diazabicyclo [3.3. IJ nonane-3 -carboxylate (3.62 g; 16 mmol; see Example F above) was added to added to a stirred solution of 4-(2- bromoethoxy)benzonitrile (3.62g; 16 mmol; see Example 67(a) above) and TEA (3.34 mL; 24 mmol) in MeCN (70 mL) and die reaction mixmre was stirred at 60 °C overnight and dien stored at room temperamre for 48 h. The solids were filtered off, washed widi IPA (2 x 100 mL) and die filtrate concentrated. The residue was partitioned between DCM and NaHCO 3 (sat.), die organic layer was separated, dried (MgSO 4 ) and concentrated. The ody residue was subjected to column chromatography (DCM: MeOH; 25: 1) to give the title compound in a 72% yield. 13 C NMR (CDC1 3 ): δ 29.73, 30.25, 30.44, 32.73, 48.83, 50.00, 58.24, 59.71 , 60.48, 68.04, 79.67, 104.48, 116.37, 120.65, 135.04, 156.35, 163.23 Example 70 Methyl 7- [3-(4-cyanophenoxy)-2-hydroxypropylJ -3 ,7-diazabicyclo [3.3.1]- nonane-3-carboxylate The tide compound was prepared according to die method described in Example 1 above, starting wim methylchloroformate. Example 71 7-[2-(4-Cyanophenoxy)-2-hydroxypropylJ-3 , 7-diazabicyclo [3.3. lj-nonane- 3-carboxylic acid l-tgrt-butoxycarbonyl-piperidine-4-yl ester N-(tgrt-Butyloxycarbonyl)-4-piperidinol (470 mg; 2.3 mmol; see Tetrahedron Lett. ; 37; 36 (1996) 6439-6442) was added to a stirred solution of carbonyl diimidazole (379 mg; 2.3 mmol) in MeCN, and die reaction mixmre was stirred for 48 h. 4-[3-(3,7-Diazabicyclo[3.3.1Jnon-3- yl)-2-hydroxypropoxylbenzonitrile (692 mg; 2.3 mmol; see Example G above) was added in one portion and the reaction mixmre was refluxed for 2 h. The solvent was removed on a rotary evaporator and the residue partitioned between DCM and NaHCO 3 (sat.). The organic layer was collected, dried, concentrated and purified using column chromatography (DCM:MeOH; 25:1) to give the title compound in a 74% yield. 13 C NMR (CDC1 3 ): δ 29.51, 30.23, 30.52, 32.05, 33.75, 49.66, 50.60, 54.53, 57.56, 59.45, 61.26, 61.84, 62.56, 63.47, 65.98, 67.27, 71.04, 71.51, 71.92, 80.59, 106.52, 116.42, 120.25, 134.98, 155.84, 157.74, 163.26 FAB-MS: (M+ l) + 529.1 (m z) Example 72 7-[3-(4-Cyanophenoxy)-2(S)-hydroxypropylJ-3,7-diazabicyclo[3.3.1J- nonane-3-carboxylic acid cyclopropylmethyl ester A cooled solution of cyclopropanemethanol (1.8 g; 25 mmol) in THF (7 mL) was added to a stirred 0°C dispersion of CDI (4.05 g; 25 mmol) in THF (15 mL), and die reaction mixmre was stirred for 30 minutes. A fraction of this solution (3.75 mL; 4.35 mmol) was added to a dispersion of 4-[3-(3,7-diazabicyclo[3.3.1Jnon-3-yl)-2(^>)-hydroxypropoxy)benzo- nitrile (2.25 g; 6.0 mmol; dihydrochloride salt; prepared from 3,7- diazabicyclo[3.3.1Jnonane-3-carboxylic acid and 7-[(2S)-3-(4-cyano- phenoxy)-2-hydroxypropyl]-l,l-dimemylediyl ester, analogously to die memod described in Example G above) and K 2 CO 3 (2.0 g; 14.5 mmol) in THF (10 mL). The reaction mixture was heated (85 °C) in a sealed steel vessel for 24 hours, was then concentrated, and die residue partitioned between DCM and water. The organic layer was collected, dried, concentrated and subjected to column chromatography (DCM:MeOH; 95:5) to give the title compound in a 29% yield. FAB-MS (M + 1) + 400.0 (m/z) Example 73 7-[3-(4-Cyanophenoxy)-2-hydroxypropylJ-3,7-diazabicyclo[3.3.1Jnonane- 3-carboxylic acid 2-(4-acetylpiperazin-l-yl) ethyl ester (a) l-[4-(2-Hydroxyethyl)piperazin-l-yl]ethanone Acetic acid anhydride (5.1 g; 50 mmol) was added to a stirred solution of N-(2-hydroxyedιyl)piperazine (6.5 g; 50 mmol) in DCM (5 mL). The reaction mixmre was stirred until die exodiermic reaction was complete. The solvent was evaporated and die residue co-evaporated widi toluene. The crude sub-title compound was used witiiout further purification. (b) 7- [3-(4-Cyanophenoxy)-2-hydroxypropyll-3 , 7-diazabicyclo [3.3.1]- nonane-3-carboxylic acid 2-(4-acetylpiperazin-l-yl) ethyl ester A solution of CDI (0.5 g; 3.1 mmol) in DCM (20 mL) was added to a stirred solution of l-[4-(2-hydroxyethyl)-piperazin-l-yl]ethanone (0.5 g; 2.9 mmol; from step (a) above) in DCM (5 mL), and die reaction mixmre was stirred for 1 hour. Water was added and the organic layer collected, dried and concentrated to give die imidazolide in a 80% yield. A solution of 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxyJbenzonitrile (375 mg; 1.25 mmol; see Example G above) in MeCN (25 mL) was added to a portion of the imidazolide (333 mg; 1.25 mmol) and KCO 3 (s) in MeCN (10 mL), and the reaction mixmre was stirred for 15 hours. The solvent was removed on a rotary evaporator and the residue partitioned between DCM and water. The organic layer was collected, dried, concentrated and subjected to column chromatography (DCM: MeOH; 95:5) to give the title compound in a 35% yield. FAB-MS (M + 1) + 499.4 (m/z) Example 74 7-[3-(4-Cyanophenoxy)-2-hydroxy-2-hydroxymethylpropylJ-3,7-diaza- bicyclo[3.3.1Jnonane-3-carboxylic acid tgrt-butyl ester (a) 4-(2-Chloromethylallyloxy)benzonitrde A solution of 4-cyanophenol (11.9 g; 0.1 mol) in 1 ,2-dimethoxyedιane (100 mL) was slowly added to a stirred and cooled (0°C) suspension of NaH (4.0 g; 0.1 mol; 55% dispersion) in 1 ,2-dimethoxyedιane (250 mL). The reaction mixmre was refluxed for 1 hour and dien allowed to cool to room temperamre. 3-Chloro-2-chloromethyl-propene (20 g; 0.16 mol) was added in one portion and die reaction mixmre was stirred at 45 °C for 40 hours. The reaction mixmre was partitioned between DCM and NaHCO 3 (satd.) and die organic layer collected, dried, concentrated and purified using column chromatography (DCM:MeOH; 50:1) to give the sub-title compound in a 66% yield. (b) 4-(3-Chloro-2-hydroxy-2-hydroxymethylpropoxy)benzonitrde N-Methyl morpholine N-oxide (490 mg; 3.64 mmol) and osmium tetroxide (80 μL; 4 wt. % solution in water) were added to a stirred solution of 4-(2-chloromethylallyloxy)benzonitrde (630 mg; 3.0 mmol; from step (a) above) in 10 mL wet acetone (12% H 2 O). The reaction mixmre was stirred at room temperamre for 36 hours. Na 2 SO 3 (1.0 g) was added and after 1 hour the solids where filtered off. The filtrate was concentrated and the residue subjected to column chromatography (DCM:MeOH; 50: 1) to give the sub-title compound in a 50% yield. (c) 7-[3-(4-Cyanophenoxy)-2-hydroxy-2-hydroxymethylpropylj-3,7-diaza- bicyclo[3.3.1Jnonane-3-carboxylic acid tgrt-butyl ester A mixmre of 4-(3-chloro-2-hydroxy-2-hydroxymethylpropoxy)benzonitrile (180 mg; 0.74 mmol; from step (b) above), tgrt-butyl 3,7-diazabicyclo- [3.3.1]nonane-3-carboxylate (230 mg; 1.0 mmol; see Example F above) and K 2 CO 3 (140 mg; 1.0 mmol) in MeCN (5 mL) was refluxed for 48 hours. The reaction mixmre was filtered and die filtrate concentrated. The residue was dissolved in diediyl ether and die solution was acidified widi KHSO 4 (aq.). The aqueous layer was collected and NaHCO 3 (satd.) was added followed by edier extraction. The organic layer was collected, dried, concentrated and subjected to column chromatography (DCM:MeOH; 20: 1) to give the title compound in a 31 % yield. 13 C NMR in D 2 O (MeOH as internal standard): δ 28.49, 29.05, 30.46, 47.81, 48.55, 60.25, 60.94, 61.19, 65.15, 69.41, 70.08, 72.93, 79.78, 104.13, 115.31 , 119.03, 133.91 , 154.98, 161.72 FAB-MS (M + 1) + 431.7 (m/z) Example 75 The tide compounds of me above Examples 1 to 74 were tested in Test A above and were all found to exhibit an D 10 value of more than 6.0. Abbreviations AcOH = acetic acid ADDP = 1 , 1 '-(azodicarbonyl)piperidine aq. = aqueous atm. = atmospheres CBz = benzyloxycarbonyl CDI = carbonyl diimidazole Bu = butyl DCM = dichloromethane DMF = dimethylformamide DMSO = dimethylsulfoxide Et = ediyl EtOAc = ethyl acetate EtOH = etiianol ESI = electron spray interface eq. = equivalents FAB = fast atom bombardment h = hours IPA = tro-propanol i-PrOH = wø-propanol LC = liquid chromatography HPLC = high performance liquid chromatography mCPBA = mgtø-chloroperbenzoic acid Me = mediyl MeCN = acetonitrile MeOH = methanol mesyl = medianesulfonate min. = minutes 1 1 1 Ms = mesylate MS = mass spectroscopy NADPH = nicotinamide adenine dinucleotide phosphate, reduced - form NMR = nuclear magnetic resonance OSu = O-succinyl Pd/C = palladium on carbon /?TSA = /κzra-toluenesulfonic acid rt. = room temperamre satd. = samrated TEA = triethylamine THF = tetrahydrofuran dc = diin layer chromatography TMS = tetramethylsilane Prefixes n, s, i and t have their usual meanings: normal, iso, secondary and tertiary.

Claims: 99/31100 1 12 Claims 1. A compound of formula I, wherein R 1 and R 2 independently represent H, C alkyl or together form -O-(CH 2 ) 2 -O-, -(CH 2 ) 4 - or -(CH 2 ) 5 - ; R 9 represents C 2 alkyl, phenyl, naphdiyl, C^ alkylphenyl (which four groups are all optionally substimted or terminated by one or more substituents selected from -OH, halo, cyano, nitro, C alkyl or C alkoxy) or -(CH^Cy 1 ; R 10 represents H or -OH; R u represents H or C l alkyl; R 12 represents one or more optional substituents selected from OH, cyano, halo, amino, nitro, C μ6 alkyl, C^ alkoxy, -N(H)S(O) 2 R 16 , -OS(O) 2 R 16a , -N(H)C(O)N(H)R 17 or -C(O)N(H)R 18 ; A represents a single bond, C M alkylene, -(CH 2 ) n N(R 20 )-, -(CH 2 ) n S(O) p -, -(CH 2 ) n O- (in which diree latter groups, the -(CH 2 ) n - group is attached to die carbon atom bearing R 10 and R 11 ), -C(O)N(R 20 )- (in which latter group, die -C(O)- group is attached to die carbon atom bearing R 10 and R u ), -N(R 20 )C(O)O(CH 2 ) n -, -N(R 20 )(CH 2 ) n - (in which two latter groups, the N(R 20 ) group is attached to die carbon atom bearing R 10 and R 11 ) or -(CH 2 ) m C(H)(OH)(CH 2 ) n - (in which latter group, the -(CH 2 ) m - group is attached to die carbon atom bearing R 10 and R u ); B represents a single bond, Cj. 6 alkylene, -N(R 23 )(CH 2 ) r - or -O(CH 2 ) r - (in which two latter groups, die -(CH 2 ) r - group is attached to die bispidine nitrogen atom); m represents 1 , 2 or 3; n and r independently represent 0, 1 , 2, 3 or 4; p represents 0, 1 or 2; q represents 0, 1 , 2 or 3; X represents O or S; Cy 1 represents a five to seven-membered heterocyclic ring containing one or more heteroatom selected from O, N or S, which ring is optionally substimted by one or more substiment selected from C(O)R 21 or C(O)OR 22 ; R 16 , R 16a , R 20 and R 23 independently represent H or C 14 alkyl; and R 17 , R 18 , R 21 and R 22 independently represent H or C { . 6 alkyl; or a pharmaceutically acceptable derivative thereof. 2. A compound as claimed in Claim 1 , wherein R 1 represents H, C lΛ alkyl or, together with R 2 , represents -O(CH 2 ) 2 O- or -(CH 2 ) 4 -. 3. A compound as claimed in Claim 1 or Claim 2, wherein R 2 represents H or, together with R 1 , represents -O(CH 2 ) 2 O- or -(CH 2 ) 4 -. 4. A compound as claimed in any one of me preceding claims, wherein R 9 represents optionally substimted phenyl, optionally substimted .-, alkylphenyl, optionally substimted, optionally unsaturated, linear, branched or cyclic, C 2 alkyl (which latter group may also be interrupted by an O atom), or -(CH 2 ) q Cy 1 . 5. A compound as claimed in Claim 4, wherein R 9 represents linear or branched C 2 . 7 alkyl. 6. A compound as claimed in any one of die preceding claims, wherein R 10 represents -OH. 7. A compound as claimed in any one of die preceding claims, wherein R 11 represents H, CH 3 or CH 2 OH. 8. A compound as claimed in any one of me preceding claims, wherein R 12 is absent or represents one or more substituents selected from cyano, OH, nitro, N(H)SO 2 R 16 , N(H)C(O)N(H)R 17 , C(O)N(H)R 18 , OS(O) 2 R 16a , amino and Cj. 6 .alkyl. 9. A compound as claimed in Claim 8, wherein, when R 12 is in die para- position, it represents cyano, nitro or N(H)S(O) R 16 (in which R 16 represents C j - 3 alkyl). 10. A compound as claimed in any one of die preceding claims, wherein X represents O. 11. A compound as claimed in any one of die preceding claims, wherein A represents a single bond, O, -CH 2 -, -(CH 2 ) 2 -, -CH 2 O-, -(CH 2 ) 2 O-, -CH 2 S-, -CH 2 N(R 20 )-, -C(O)N(R 20 )-, -N(R 20 )C(O)O(CH 2 ) n -, -CH 2 CH(OH)- or N(R 20 )(CH 2 ) n -. 12. A compound as claimed in any one of die preceding claims, wherein B represents optionally unsaturated, linear or branched, C alkylene (which group is also optionally interrupted by O). 13. A compound as claimed in any one of die preceding claims, wherein, when die bispidine nitrogen bearing B also bears a C alkyl group, thus forming a quaternary ammonium salt, the alkyl group is methyl. 14. A compound as claimed in any one of die preceding claims, wherein, when R 9 represents -(CH^Cy 1 , q is 0, 1 or 2 and Cy 1 contains at least one nitrogen atom. 15. A pharmaceutical formulation including a compound as defined in any one of Claims 1 to 14 in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier. 16. A pharmaceutical formulation for use in die prophylaxis or the treatment of an arrhythmia, comprising a compound as defined in any one of Claims 1 to 14. 17. A compound as defined in any one of Claims 1 to 14 for use as a pharmaceutical. 18. A compound as defined in any one of Claims 1 to 14 for use in me prophylaxis or die treatment of an arrhythmia. 19. The use of a compound as defined in any of one Claims 1 to 14 as active ingredient in die manufacture of a medicament for use in the prophylaxis or die treatment of an arrhythmia. 20. The use as claimed in Claim 19, wherein the arrhythmia is an atrial or a ventricular arrhythmia. 21. A method of prophylaxis or treatment of an arrhythmia which method comprises administration of a therapeutically effective amount of a compound as defined in any one of Claims 1 to 14 to a person suffering from, or susceptible to, such a condition. 22. A process for the preparation of a compound of formula I as defined in Claim 1 which comprises: (a) reaction of a compound of formula II, wherein R 1 , R 2 , R 10 , R 11 , R 12 , A and B are as defined in Claim 1 with a compound of formula III, R 9 XC(O)L l m wherein L 1 represents a leaving group and R 9 and X are as defined in Claim l; (b) for compounds of formula I in which B represents CH 2 and R 10 represents OH, reaction of a compound of formula IV, wherein R 1 , R 2 , R 9 and X are as defined in Claim 1, with a compound of formula V, wherein R u , R 12 .and A are as defined in Claim 1; (c) reaction of a compound of formula IV, as defined above, widi a compound of formula VI, wherein L 2 represents a leaving group and R 10 , R u , R 12 , A and B are as defined in Claim 1; (d) for compounds of formula I in which R 11 represents H, reduction of a compound of formula VIII, wherein R 1 , R 2 , R 9 , R 12 , A, B and X are as defined in Claim 1; (e) for compounds of formula I in which R 1 and R 2 bodi represent H, reduction of a corresponding compound of formula IX, wherein R 9 , R 10 , R 11 , R 12 , X, A and B are as defined in Claim 1 , and in which die C =O group may be activated; (f) for compounds of formula I in which R 1 and R 2 togedier represent -O(CH 2 ) 2 O-, reaction of a corresponding compound of formula IX, as defined above, wim ethane- 1 ,2-diol; (g) for compounds of formula I which are bispidine-nitrogen N-oxide derivatives, oxidation of die corresponding bispidine nitrogen of a corresponding compound of formula I; (h) for compounds of formula I which are C alkyl quaternary ammonium salt derivatives, in which the alkyl group is attached to a bispidine nitrogen, reaction, at the bispidine mtrogen, of a corresponding compound of formula I with a compound of formula XI, R b Hal XI wherein R represents C M alkyl and Hal represent CI, Br or I; (i) for compounds of formula I in which R 10 and R u represent H, B represents Cj. 6 alkylene and A represents -N(R 20 )(CH 2 ) n -, reaction of a compound of formula XII, wherein B a represents C w alkylene and R 1 , R 2 , R 9 , R 20 and X are as defined in Claim 1, widi a compound of formula XIII, wherein R 12 and n are as defined in Claim 1 and Hal is as defined above; (j) reaction of a compound of formula II, as defined above, widi a compound of formula XIV, R 9 XH XIV wherein R 9 and X are as defined in Claim 1 , in the presence of 1 ,1'- carbonyldiimidazole; or (k) conversion of one R 12 substiment to another. 23. A compound of formula IV, as defined in Claim 22, or a protected derivative diereof. 24. A compound of formula IX, as defined in Claim 22, or a protected derivative diereof. 25. A compound of formula XVI, wherein R 10 , R u , R 12 , A and B are as defined in Claim 1 , or a protected derivative thereof. 26. A compound of formula XVIII, wherein R 9 and X are as defined in Claim 1 , or a protected derivative diereof. 27. A process for the preparation of a compound of formula IX, XVI or XVIII, which comprises reaction of (as appropriate) either: (i) a compound of formula XXIX, wherein R 9 and X are as defined in Claim 1; or (ii) 4-piperidone, widi (as appropriate) eidier (1) a compound of formula XXXI, wherein R 10 , R u , R 12 , A and B are as defined in Claim 1; or (2) NH 3 , in all cases in the presence of a formaldehyde. 28. A process as claimed in Claim 27, in which die reaction is carried out in die presence of an organic acid 29. A process as claimed in Claim 28, in which me organic acid is acetic acid.

Inventors: ALSTERMARK CHRISTER, BJOERE ANNIKA, BJOERSNE MAGNUS, FRANTSI MARIANNE, HALVARSSON TORBJOERN, HOFFMANN KURT-JUERGEN, LINDSTEDT EVA-LOTTE, POLLA MAGNUS, STRANDLUND GERT, ALSTERMARK, CHRISTER, BJOERE, ANNIKA, BJOERSNE, MAGNUS, FRANTSI, MARIANNE, HALVARSSON, TORBJOERN, HOFFMANN, KURT-JUERGEN, LINDSTEDT, EVA-LOTTE, POLLA, MAGNUS, STRANDLUND, GERT
Applicants: ALSTERMARK CHRISTER, ASTRA AB, BJOERE ANNIKA, BJOERSNE MAGNUS, FRANTSI MARIANNE, HALVARSSON TORBJOERN, HOFFMANN KURT JUERGEN, LINDSTEDT EVA LOTTE, POLLA MAGNUS, STRANDLUND GERT, ALSTERMARK, CHRISTER, ASTRA AKTIEBOLAG, BJOERE, ANNIKA, BJOERSNE, MAGNUS, FRANTSI, MARIANNE, HALVARSSON, TORBJOERN, HOFFMANN, KURT-JUERGEN, LINDSTEDT, EVA-LOTTE, POLLA, MAGNUS, STRANDLUND, GERT
Application year: 1998
Main classification: C07D471
IPC codes: A61K31, A61P9, C07D471, C07D491