AU6032400A - New bispidine compounds useful in the treatment of cardiac arrhythmias - Google Patents

Description

WO 00/77000 PCT/SE00/01254 1 NEW BISPIDINE COMPOUNDS USEFUL IN THIE TREATMENT OF CARDIAC ARRHYTHMIAS Field of the Invention 5 This invention relates to novel pharmaceutically useful compounds, in particular compounds which are useful in the treatment of cardiac arrhythmias. o10 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 15 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)). 20 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 25 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 WO 00/77000 PCT/SE00/01254 2 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 5 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 o10 phenothiazines, tricyclic antidepressants, antihistamines and antibiotics) is a key problem to be solved in the provision of effective antiarrhythmic drugs. Antiarrhythmic drugs based on bispidines (3,7-diazabicyclo[3.3.1]nonanes), are known from inter alia international patent application WO 91/07405, 15 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 20 include bisaramil (3-methyl-7-ethyl-9c,4'-(Cl-benzoyloxy)-3,7 diazabicyclo[3.3.1]nonane), tedisamil (3',7'-bis(cyclopropylmethyl)spiro (cyclopentane-1,9')-3,7-diazabicyclo[3.3.1]nonane), SAZ-VII-22 (3-(4 chlorobenzoyl)-7-iso-propyl-3,7-diazabicyclo[3.3.1] nonane), SAZ-VII-23 (3-benzoyl-7-iso-propyl-3,7-diazabicyclo[3.3.1]nonane), GLG-V-13 (3-[4 25 (1H-imidazol- 1 -yl)benzoyl]-7-iso-propyl-3,7-diazabicyclo[3.3.1]nonane), KMC-IV-84 (7-[4'-(1H-imidazolo-1-yl)benzenesulfonyl]-3-iso-propyl-3,7 diazabicyclo[3.3.1]nonane dihydroperchlorate and ambasilide (3-(4 aminobenzoyl)-7-benzyl-3,7-diazabicyclo[3.3.1]nonane).

WO 00/77000 PCT/SE00/01254 3 We have surprisingly found that a novel group of bispidine-based compounds exhibit electrophysiological activity, preferably class III electrophysiological activity, and are therefore expected to be useful in the treatment of cardiac arrhythmias. 5 Disclosure of the Invention According to the invention there is provided compounds of formula I, R2 45 R43 R41 R5 R44 O R B AN R46 R42 N SN-- R4

R

6 10

R

3 wherein R' and R 2 independently represent H, C 1

-

4 alkyl, OR 2 b or N(R2c)R 2 d, or 15 together form -O-(CH,)2-O-, -(CH 2

)

3 -, -(CH 2

)

4 - or -(CH 2

)

5 -;

R

2 b, R 2 c and R 2 d independently represent H or C.

6 alkyl;

R

3 represents H, C 1

.

6 alkyl or, together with R 4 , represents C 3

-

6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is 20 optionally substituted by one or more C 1

-

3 alkyl groups);

R

4 represents H, C 1

,

2 alkyl, C 1

-

6 alkoxy (which latter two groups are both optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, C 1

-

4 alkyl and/or Cl- 4 alkoxy), WO 00/77000 PCT/SE00/01254 4 -(CH2)q-aryl, -(CH 2 )q-Oxyaryl, -(CH 2 )q-Het 1 (which latter three groups are optionally substituted (at the -(CH 2 )q, - part and/or the aryl/Het' part) by one or more substituents selected from -OH, halo, cyano, nitro, -C(O)Ri,

-C(O)OR"

1 , -N(H)S(O) 2 Rlla, C1 6 alkyl and/or C 1

-

6 alkoxy), 5 -(CH,)qN(H)C(O)R', -(CH 2 )qS(O) 2

R

8 , -(CH,)qC(O)R', -(CH,)qC(O)OR s ,

-(CH

2 )qC(O)N(R 9

)R

8 or, together with R 3 , represents C 3

-

6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C,- 3 alkyl groups); q represents 0, 1, 2, 3, 4, 5 or 6; 10 R 8 represents H, C 1

-

6 alkyl, aryl (which latter group is optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, -C(O)R'o, -C(O)OR", -N(H)S(O),Rlla, C1,- 6 alkyl and/or C, 6 alkoxy) or, together with R 9 , represents C 3

-

7 alkylene;

R

9 represents H, C14 alkyl or, together with R 8 , represents C 3

-

7 alkylene; 15 Het' represents a five to twelve-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more = O substituents;

R

41 , R 42 , R 43 , R 4 , R 45 or R 46 independently represent H or CI- 3 alkyl; 20

R

5 represents H, halo, CI 3 alkyl, -OR' 2 , -N(R 3

)R

2 or, together with R 6 , represents = O;

R

6 represents H, C1,.

4 alkyl or, together with R 5 , represents =O;

R

12 represents H, C 1 6 alkyl, -S(O),_-C1 4 -alkyl, -C(O)R 1 4 , -C(O)OR 14 25 -C(O)N(R15)R 5 a or aryl (which latter group is optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, -C(O)Ro, -C(O)OR", -N(H)S(O) 2

R

i ta, C 1

-

6 alkyl and/or C-6 alkoxy); R 1 3 represents H or C, 4 alkyl; WO 00/77000 PCT/SE00/01254 5

R

1 4 represents H orC 1

-

6 alkyl;

R

5 and R 1 5a independently represent H or C 1 ,-4 alkyl, or together represent

C

3 -6 alkylene, optionally interrupted by an O atom; 5 A represents a single bond, C 1

-

6 alkylene, -N(R1 6

)(CH

2 )r - or -O(CH 2 )r- (in which two latter groups, the -(CH.,)r,- group is attached to the bispidine nitrogen atom); B represents a single bond, C 1 4 alkylene, -(CH 2 )nN(R")-, -(CH2)nS(O)p-,

-(CH

2 )nO- (in which three latter groups, the -(CH,) n - group is attached to o10 the carbon atom bearing R 5 and R 6 ), -C(O)N(R 1 7 )- (in which latter group, the -C(O)- group is attached to the carbon atom bearing R 5 and R 6 ), -N(Rl 7

)C(O)O(CH

2 )n-, -N(R 17

)(CH

2 )n- (in which two latter groups, the

N(R

1 7 ) group is attached to the carbon atom bearing R 5 and R 6 ) or

-(CH

2 )mC(H)(OH)(CH 2 )n- (in which latter group, the -(CH 2 )m- group is 15 attached to the carbon atom bearing R 5 and R 6 ); m represents 1, 2 or 3; n and r independently represent 0, 1, 2, 3 or 4; p represents 0, 1 or 2;

R

16 and R 17 independently represent H or C- 4 alkyl; 20

R

7 represents C 1

-

6 alkyl, aryl or Het 2 , all of which groups are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from -OH, cyano, halo, amino, nitro, Het 3 , -C(O)R'

O

, -C(O)OR", Cl- 6 alkyl, C1- 6 alkoxy, -N(H)S(O) 2

R

18 , -S(O) 2

R"

9 , -OS(O) 2

R

2 0 , 25 -N(H)C(O)N(H)R 1 , -C(O)N(H)R 22 and/or aryl (which latter group is optionally substituted by one or more cyano groups); Het 2 and Het 3 independently represent a five to twelve-membered heterocyclic group containing one or more heteroatoms selected from WO 00/77000 PCT/SE00/01254 6 oxygen, nitrogen and/or sulfur, and which also optionally includes one or more =0O substituents; R", R' 9 and R 20 independently represent C, 6 alkyl;

R

2 ' and R 22 independently represent H or C 1

-

6 alkyl (optionally terminated 5 by cyano); and R1 0 and R" independently represent, at each individual occurrence, H or

C,

6 alkyl;

R'

l a represents, at each individual occurrence, C 1 6 alkyl; 10 or a pharmaceutically acceptable derivative thereof; provided that: (a) when A and B are both single bonds and R 7 is optionally substituted 15 aryl, then R 5 and R 6 do not both represent H; (b) when A represents a single bond, then R 5 and R 6 do not together represent =O; and (c) when R 5 represents -OR 2 or -N(R13)R 2 , then: (i) A does not represent -N(R 6

)(CH

2 )r - or -O(CH 2 )r-; and/or 20 (ii) n does not represent 0 when B represents -(CH 2 )nN(R 7 )-, -(CH2)nS(0)p- or -(CH2)nO-, which compounds are referred to hereinafter as "the compounds of the invention". 25 Aryl groups that may be mentioned include C 6

-

1 0 aryl groups, such as phenyl, naphthyl and the like. Oxyaryl groups that may be mentioned include C 6

-

10 oxyaryl groups, such as oxyphenyl (phenoxy), oxynaphthyl WO 00/77000 PCT/SE00/01254 7 (naphthoxy) and the like. When substituted, aryl and aryloxy groups are preferably substituted by one to three substituents. Het 1 , Het 2 and Het 3 groups that may be mentioned include those 5 containing 1 to 4 heteroatoms (selected from the group oxygen, nitrogen and/or sulfur) and in which the total number of atoms in the ring system are between five and twelve. Het (Het', Het 2 and Het 3 ) groups may be wholly/partly aromatic in character and may be bicyclic. Heterocyclic groups that may be mentioned include morpholinyl, thiazolyl, oxazolyl, o10 isoxazolyl, cinnolinyl, quinazolinyl, phthalazinyl, purinyl, benzimidazolyl, pyrimindinyl, piperazinyl, pyrazinyl, piperidinyl, pyridinyl, triazolyl, imidazolyl, quinolinyl, isoquinolinyl, dioxanyl, benzodioxanyl, benzodioxolyl, benzodioxepanyl, benzomorpholinyl, indolyl, pyrazolyl, pyrrolyl, benzothiophenyl, thiophenyl, chromanyl, thiochromanyl, 15 benzofuranyl, pyranyl, tetrahydropyranyl, tetrahydrofuranyl, furanyl and the like. Values of Het' that may be mentioned include tetrahydropyranyl, isoxazolyl, benzodioxolyl, benzodioxepanyl and thiophenyl. Values of Het 2 that may be mentioned include quinolinyl, isoquinolinyl, benzomorpholinyl, benzodioxanyl, piperazinyl, indolyl and pyrazolyl. 20 Values of Het 3 that may be mentioned include imidazolyl. Substituents on Het (Het', Het 2 and Het 3 ) groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of Het (Het', Het 2 and Het 3 ) groups may be via any atom in the ring system including (where appropriate) a heteroatom. Het (Het', Het 2 25 and Het 3 ) groups may also be in the N- or S-oxidised form. 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, 4 alkyl WO 00/77000 PCT/SE00/01254 8 quaternary ammonium salts and N-oxides, provided that when a N-oxide is present: (a) no Het (Het', Het 2 , Het 3 ) group contains an unoxidised S-atom; and/or (b) p does not represent 0 when B represents -(CH 2 )nS(O)p-. 5 The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. The compounds of the invention may also contain one or more asymmetric 10 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. 15 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 20 stereoisomers are included within the scope of the invention. Alkyl groups that R', R 2 , R 2 b, R 2 c, R 2 d, R 3 , R 4 , R 5 , R 6 , R 7 , R s, R 9 , R 0 , R", Ril a , R 2 , R 13 , R 14 , R 15 , R 1 5a , RI 6 , R 7 , R 8 , R 19 , R 20 , R 21 , R 22 , R 41

R

42 , R 43 , R 4 , R 45 and R 46 may represent, that R 1 2 may include, and with 25 which R 3 , R 4 , R 7 , R 8 and R 1 2 may be substituted; and alkoxy groups that

R

4 may represent, and with which R 4 , R 7 , R 8 and R 1 2 may be substituted; may be linear or, when there is a sufficient number (i.e. three) of carbon atoms, be branched and/or cyclic. Further, when there is a sufficient number (i.e. four) of carbon atoms, such alkyl and alkoxy groups may WO 00/77000 PCT/SE00/01254 9 also be part cyclic/acyclic. Such alkyl and alkoxy groups may also be saturated or, when there is a sufficient number (i.e. two) of carbon atoms, be unsaturated and/or interrupted by oxygen. 5 Alkylene groups that R 3 and R 4 , R 8 and R 9 , R" 5 and Rl sa , A, and B, may represent; and -(CH 2 )m-, -(CH 2 )n-, -(CH 2

)

q - and -(CH 2

)

r - chains that A, B and R 4 (as appropriate) may include, may be linear or, when there is a sufficient number (i.e. two) of carbon atoms, be branched. Such alkylene groups and -(CH 2 )- containing chains may also be saturated or, when there o10 is a sufficient number (i.e. two) of carbon atoms, be unsaturated and/or interrupted by oxygen. Halo groups that R 5 may represent, and with which R 4 , R 7 , R 8 and R1 2 may be substituted, include fluoro, chloro, bromo and iodo. 15 For the avoidance of doubt, each R 1 o, R", and R t l a , group identified herein is independent of other R 1 o, R 1 ", and R 1 a , groups, respectively. For example, when R 4 and R' both represent aryl substituted by -C(O)R 10 , the two individual -C(O)R 1 0 substituents are independent of one another, and are 20 not necessarily identical (though this possibility is not excluded). Abbreviations are listed at the end of this specification. According to a further aspect of the invention there is provided 25 compounds of formula I as hereinbefore defined, but with the further provisos that: (a) when A represents -N(R1 6

)(CH

2 )r - or -O(CH,)r-, then r does not represent 0 or 1; and WO 00/77000 PCT/SE00/01254 10 (b) when R 5 represents -OH or -N(R13)R 12 , then B does not represent -N(R17)C(O)O(CH)n- or -N(R 17

)(CH

2 )n-. Preferred compounds of the invention include those in which: 5 R 1 represents H;

R

2 represents H;

R

3 represents H;

C

1

.

2 alkyl; or, 10 together with R 4 represents C 45 alkylene, optionally interrupted by an 0 atom and/or optionally substituted by one or more methyl groups;

R

4 represents H; linear or branched and/or saturated or unsaturated and/or cyclic, 15 acyclic and/or part cyclic/acyclic C,_ alkyl (which alkyl group is optionally substituted by one or more cyano or halo groups and/or interrupted by an O atom);

C

1 6 alkoxy; -(CH,)qS(O) 2

R

8 , -(CH 2 )qC(O)OR 8 , -(CH 2 )qN(H)C(O)R 8 , 20 -(CH 2 )qC(O)R , (in which latter four groups, q represents 0, 1 or 2 and R 8 represents linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic CI-4 alkyl, or phenyl (which phenyl group is optionally substituted by one or more cyano and/or C 1

-

3 alkyl groups));

-(CH

2 )qC(O)N(R 9

)R

8 (in which latter group, q represents 0, 1 or 2 25 and R' and R 9 independently represent H, linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic CI-4 alkyl, or together represent C46 alkylene);

-(CH

2 )q-phenyl, -(CHz)q-oxyphenyl or -(CHz)q-Het' (in which latter three groups, q represents 0, 1, 2 or 3, the -(CH 2

)

qpart is optionally WO 00/77000 PCT/SE00/01254 11 substituted by a cyano group, and the phenyl, or Het 1 , part is optionally substituted with one or more substituents selected from cyano, nitro, linear or branched C 1 4 alkyl, linear or branched C 14 alkoxy and N(H)S(O) 2 RIla); or, 5 together with R 3 , represents C4 5 alkylene, optionally interrupted by an O atom and/or optionally substituted by one or more methyl groups;

R

5 represents H; fluoro; 10 OR 12 (in which R1 2 represents H, phenyl (optionally substituted by one or more methoxy groups) or C(O)N(H)R s a (in which R' 5a represents linear or branched CI- 4 alkyl));

-N(R

3 )(R 1 2 ) (in which R' 1 2 represents H, Ci- 2 alkyl, -S(O) 2 -C,-2 alkyl,

-C(O)RI

4 (in which R 4 represents C1- 2 alkyl), -C(O)OR 1 4 (in which RI 4 15 represents linear or branched C.

5 alkyl) or -C(O)N(R15)(R Sa) (in which R 1 5 and R 15a independently represent H or linear or branched C,- 3 alkyl or together represent C4 5 alkylene, which alkylene group is optionally interrupted by an O atom) and R 13 represents H or C 2 alkyl); or, together with R 6 , represents = O (especially in the case where R 7 20 represents alkyl or Het 2 );

R

6 represents H or C1-2 alkyl or together with R 5 represents = O (especially in the case where R 7 represents alkyl or Het 2 ); A represents a single bond, linear or branched C, 4 alkylene (which group is also optionally interrupted by O), -N(H)(CH 2 )r,- or -O(CH 2 )r - (in which 25 latter two groups r is 1 or 2); B represents a single bond, C, 4 alkylene, -(CH 2 )nO-, -(CH 2 )nS(O) 2 -,

-(CH

2 )nN(H)- or -N(H)(CH 2 ),- (in which latter four cases n is 0, 1, 2 or 3);

R

7 represents WO 00/77000 PCT/SE00/01254 12 linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic

C

1

-

6 alkyl (optionally substituted and/or terminated by OH); Het 2 (optionally substituted by one or more substituents selected from cyano, C 1

-

3 alkyl, phenyl (which latter group is optionally substituted with 5 one or more cyano groups), =0O, C(O)Ro (in which Ro is linear or branched C 1 3 alkyl) or S(O) 2

R

19 (in which RI 9 is C- 2 alkyl)); or phenyl (optionally substituted by one or more substituents selected from cyano, nitro, linear or branched C 1

-

3 alkyl, linear or branched C,-3 alkoxy, fluoro, chloro, C(0)N(H)R 2 (in which R 22 represents linear or io branched and/or acyclic, cyclic and/or part cyclic/acyclic C 14 alkyl, which alkyl group is optionally terminated by cyano), N(H)S(O) 2

R"

8 (in which R" 8 represents C 1

-

2 alkyl) or Het 3 );

R

4 1 , R 42 , R 43 , R 44 , R 45 and R 46 all represent H. 15 More preferred compounds of the invention include those in which:

R

3 represents H;

R

5 represents H, OH or -N(H)C(O)N(R15)(Rsa);

R

6 represents H; A represents -CH 2 - or -(CH 2

)

2 -; 20 B represents a single bond, -CHN(H)- or -CH 2 0- (where, for the avoidance of doubt, the -CH 2 - part is attached to the carbon atom bearing R 5 and R 6 );

R

7 represents phenyl (substituted by a cyano group (preferably in the 4 position relative to B) and by one or more optional C(O)N(H)R 2 2 substituent). 25 Preferred compounds of the invention include the compounds of the Examples disclosed hereinafter.

WO 00/77000 PCT/SE00/01254 13 Preparation According to the invention there is also provided a process for the preparation of compounds of formula I which comprises: 5 (a) for compounds of formula I in which R 3 is H, reaction of a compound of formula II, R2 45 R43 R R41 R5 R44 R-/N R46 R42 N H B A R6 10 wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 4 1 , R 42 , R 43 , R 4 , R 45 , R 46 , A and B are as hereinbefore defined with a compound of formula III,

R

4 -N=C=O III 15 wherein R 4 is as hereinbefore defined, for example at between 0 0 C and reflux temperature in the presence of an appropriate organic solvent (e.g. dichloromethane), or via solid phase synthesis under conditions known to those skilled in the art; 20 (b) reaction of a compound of formula II, as hereinbefore defined, with a carbonic acid derivative of formula IV,

(R

3

)(R

4

)NC(O)-L

1

IV

WO 00/77000 PCT/SE00/01254 14 wherein L' represents a leaving group such as halo, imidazole or R 23 0 (wherein R 23 represents, for example, C 1

-

10 alkyl, aryl or C,- 3 alkylaryl, which groups are optionally substituted by one or more halo or nitro groups) and R 3 and R 4 are as hereinbefore defined, for example at between room 5 and reflux temperature in the presence of a suitable base (e.g. triethylamine or potassium carbonate) and an appropriate organic solvent (e.g. dichloromethane, THF, acetonitrile, toluene, or mixtures thereof); (c) reaction of a compound of formula V, 10 R2 45 R43' R R41 R4 R, AV

R

5 R44 R B AN R46 R42 N O

R

6 wherein R', R 2 , R 5 , R 6 , R 7 , R 41 , R 42 , R 43 , R 44 ,

R

45 , R

:

"

, A, B and L' are as hereinbefore defined with a compound of formula VA, 15 (R 3

)(R

4 )NH VA wherein R 3 and R 4 are as hereinbefore defined, for example at between room and reflux temperature in the presence of a suitable base (e.g. triethylamine or potassium carbonate) and an appropriate organic solvent (e.g. dichloromethane, THF, acetonitrile, toluene, or mixtures thereof), or 20 via solid phase synthesis under conditions known to those skilled in the art; WO 00/77000 PCT/SE00/01254 15 (d) for compounds of formula I in which A represents CH 2 and R 5 represents -OH or -N(H)R 2 , wherein RI 2 is as hereinbefore defined, reaction of a compound of formula VI, 1R2 45 R43 R R41 R44 O N R46 R42N H N - R4 5

R

3 wherein R', R 2 , R 3 , R 4 , R 4 1 , R 42 , R 43 , R, 4 4

R

45 and R 4 6 are as hereinbefore defined, with a compound of formula VII,

R

6 10 R7B 6 X VII 10 EB wherein X represents O or N(R 12 ) and R 6 , R 7 , R 12 and B are as hereinbefore defined, for example at elevated temperature (e.g. 60 0 C to reflux) in the presence of a suitable solvent (e.g. a lower alkyl alcohol (e.g. IPA), 15 acetonitrile, or a mixture of a lower alkyl alcohol and water); (e) reaction of a compound of formula VI, as hereinbefore defined, with a compound of formula VIII, WO 00/77000 PCT/SE00/01254 16 5 R7 -A-L 2 B

R

6 VIII wherein L 2 represents a leaving group (e.g. mesylate, tosylate or halo) and

R

5 , R 6 , R 7 , A and B are as hereinbefore defined, for example at elevated 5 temperature (e.g. between 35 0 C and reflux temperature) in the presence of a suitable base (e.g. triethylamine or K 2

CO

3 ) and an appropriate organic solvent (e.g. acetonitrile or DMSO); (f) for compounds of formula I in which R 5 represents H or OH and R 6 o10 represents H, reduction of a compound of formula IX, R2 45 R43 R2 R41 Ix 0R"0 R A R46 R42 N R7A N / N-----R4

R

3 15 wherein R', R 2 , R 3 , R 4 , R 7 , R 4 1 , R 4 2 , R 4 3 , R 4 , R 45 , R', A and B 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 5 represents OH, reduction may be performed under mild reaction conditions in the presence of e.g. sodium borohydride and an 20 appropriate organic solvent (e.g. THF); and for formation of compounds of formula I in which R 5 represents H, reduction may be performed by WO 00/77000 PCT/SE00/01254 17 activating the relevant 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 (e.g. C 1 6) alkyl alcohol); 5 (g) for compounds of formula I in which R' and R 2 both represent H, reduction of a corresponding compound of formula X, O 0x 45 R43 R 4 1 R5 kR44 O R B AN R46 R42 I

R

7 1-- 7+ N

R

6

R

3 10 wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 41 , R 42 , R 43 , R 4 , R 45 , R 4 , A and B are as hereinbefore defined, and in which the bridgehead C= O group may be activated using an appropriate agent, such as tosylhydrazine, in the presence 15 of a suitable reducing agent (e.g. sodium borohydride, sodium cyanoborohydride) and an appropriate organic solvent (e.g. a lower alkyl alcohol), or under standard Wolff-Kischner conditions known to those skilled in the art; 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 20 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 WO 00/77000 PCT/SE00/01254 18 mixture and the reduction carried out at between 60'C and reflux, advantageously in the presence of a suitable organic acid (e.g. acetic acid); (h) for compounds of formula I in which R' and R 2 together represent 5 -O(CH 2

)

2 0-, reaction of a corresponding compound of formula X as hereinbefore defined with ethane-1,2-diol under appropriate reaction conditions, for example by refluxing in the presence of pTSA and an appropriate organic solvent (e.g. toluene); 10 (i) for compounds of formula I in which B represents -(CH 2 )nO-, reaction of a compound of formula XI, 1 R 2 XI 45 / R 4 3 R2 R41 R43 R4 O HO-(CH2 ) A N R46 R42

R

6 R

R

3 wherein R', R 2 , R 3 , R 4 , R 5 , R 6 , R 4 1 , R 42 , R 43 , R 44 , R 45 , R 4 6 , A and n are as 15 hereinbefore defined, with a compound of formula XIA,

R

7 OH XIA in which R 7 is as hereinbefore defined, for example under Mitsunobu-type conditions e.g. at between ambient (e.g. 250C) and reflux temperature in the presence of a tertiary phosphine (e.g. tributylphosphine or 20 triphenylphosphine), an azodicarboxylate derivative (e.g. diethylazodicarboxylate or 1,1'-(azodicarbonyl)dipiperidine) and an appropriate organic solvent (e.g. dichloromethane or toluene); WO 00/77000 PCT/SE00/01254 19 (j) 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 0 C in the presence of a 5 suitable organic solvent (e.g. DCM); (k) 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 o10 of formula I with a compound of formula XII, RbL 3 XII wherein Rb represents C 1

-

4 alkyl and L 3 is a leaving group such as halo, alkane sulfonate or aryl sulfonate, for example at room temperature in the presence of an appropriate organic solvent (e.g. DMF), followed by 15 purification (using e.g. HPLC) in the presence of a suitable counter-ion provider (e.g. NH 4 OAc); (1) for compounds of formula I in which R 5 and R 6 represent H, A represents C 1

-

6 alkylene and B represents -N(R 1 7

)(CH

2 ),-, reaction of a 20 compound of formula XIII, 45 R 4 3 R41 kR44 XIII

R

44 O R17 N R 46 R42N N- CH -- Aa H N R 4

R

3 WO 00/77000 PCT/SE00/01254 20 wherein A a represents C 1

,

6 alkylene and R 1 , R 2 , R 3 , R 4 , R 4 1 , R 42 , R 43 , R",

R

45 , R 4 and R 17 are as hereinbefore defined with a compound of formula XIV, R'-(CH,)n-L 2 XIV 5 wherein R 7 , n and L 2 are as hereinbefore defined, for example at 40'C in the presence of a suitable organic solvent (e.g. acetonitrile); (m) for compounds of formula I in which R 5 represents -NH 2 , reduction of a corresponding compound of formula XV, R2 45 R43 R2 R41 ARR'jXV N3 N R6 R44 O R 7B A RaeR4 R6 N R4 10

R

3 wherein R', R 2 , R 3 , R 4 , R 6 , R 7 , R 4 1 , R 42 , R 43 , R 4 , R 45 , R 46 , A and B are as hereinbefore defined, for example by hydrogenation at a suitable pressure in the presence of a suitable catalyst (e.g. palladium on carbon) and an 15 appropriate solvent (e.g. a water-ethanol mixture); (n) for compounds of formula I in which R 5 represents

-N(R

1 3 )C(O)NH(R15), reaction of a corresponding compound of formula I in which R 5 represents -N(R1 3 )H with a compound of formula XVI, 20 R15N=C=O XVI wherein R1 5 is as hereinbefore defined, for example at ambient temperature (e.g. 25 0 C) in the presence of a suitable solvent (e.g. benzene); WO 00/77000 PCT/SE00/01254 21 (o) for compounds of formula I in which R 5 represents -N(RI 3

)C(O)R

4 , reaction of a corresponding compound of formula I in which R 5 represents

-N(R

13 )H with a compound of formula XVII,

RI

4 C(O)Rx XVII 5 wherein Rx represents a suitable leaving group, such as CI-4 alkoxy, halo (e.g. Cl, Br) or p-nitrophenyl, and R 14 is as hereinbefore defined, for example at between ambient and reflux temperature in the presence of a suitable solvent (e.g. dichloromethane or acetonitrile) and optionally in the presence of a suitable base (e.g. triethylamine or potassium carbonate); 10 (p) for compounds of formula I in which R 5 represents -N(H)R 2 , wherein R1 2 is as previously defined provided that it does not represent H, reaction of a corresponding compound of formula I, in which R 5 represents -NH 2 with a compound of formula XVIII, 15 R1 2 aL' XVIII wherein RI 2 a represents RI 2 as hereinbefore defined except that it does not represent H and L' is as hereinbefore defined, for example under conditions that are well known to those skilled in the art; 20 (q) for compounds of formula I in which R 5 represents -OR 1 2 in which R1 2 represents C 1

-

6 alkyl or optionally substituted aryl, reaction of a corresponding compound of formula I in which R 5 represents -OH with a compound of formula XIX, R1 2 aOH XIX 25 wherein RI 2 a represents C- 6 alkyl or optionally substituted aryl, for example at between ambient (e.g. 250C) and reflux temperature, under Mitsunobu type conditions (i.e. in the presence of e.g. triphenylphosphine, an azodicarboxylate derivative (e.g. 1,1'-(azodicarbonyl)dipiperidine) and a suitable organic solvent (e.g. dichloromethane)); WO 00/77000 PCT/SE00/01254 22 (r) for compounds of formula I in which R' represents -ORI 2 , in which R' 2 represents C,_6 alkyl or optionally substituted aryl, reaction of a compound of formula XX, R2 45 R43 R2 R41 XX L2 R44 R BN R46 R42 N R71_1 + AN -----. R4 R6N 5

R

3 wherein L 2 , R', R 2 , R 3 , R 4 , R 6 , R 7 , R 4 1 , R 4 2

R

43 , R 44 , R 4 5 , R , A and B are as hereinbefore defined with a compound of formula XIX as hereinbefore o10 defined, for example at between ambient (e.g. 25 0 C) and reflux temperature, under Williamson-type conditions (i.e. in the presence of an appropriate base (e.g. KOH or NaH) and a suitable organic solvent (e.g. dimethylsulfoxide or DMF)); 15 (s) for compounds of formula I in which R 5 represents OR 12 and RI 2 represents C(O)R 14 and R 14 is as hereinbefore defined, reaction of a corresponding compound of formula I as hereinbefore defined in which R 5 represents OH with a compound of formula XXI, R1 4 CO,H XXI 20 wherein R 14 is as hereinbefore defined, for example at ambient temperature (e.g. 25'C) in the presence of a suitable coupling agent (e.g. 1-(3 dimnethylaminopropyl)-3-ethylcarbodiimide), an appropriate catalyst (e.g. 4 dimethylaminopyridine) and a reaction-inert organic solvent (e.g. THF); WO 00/77000 PCT/SE00/01254 23 (t) for compounds of formula I in which R 5 represents halo, substitution of a corresponding compound of formula I in which R 5 represents -OH, using an appropriate halogenating agent (e.g., for compounds in which R 5 represents fluoro, reaction with diethylaminosulfurtrifluoride); 5 (u) for compounds of formula I in which R 3 and/or R 4 as appropriate represent alkyl groups (e.g. C 1 -6 or C -1 2 alkyl, as appropriate), alkylation of a corresponding compound of formula I, in which R 3 and/or R 4 (as appropriate) represent H under conditions well known to those skilled in the io art; (v) conversion of one R 4 group to another (e.g. conversion of

-(CH

2 )qC(O)OR 8 to -(CH 2 )qC(O)N(R 9

)R

8 , wherein R', R 9 and q are as hereinbefore defined) using techniques well known to those skilled in the 15 art; or (w) for compounds of formula I in which one of R' and R 2 represents H, and the other represents -OH, reduction of a corresponding compound of formula X, as hereinbefore defined, in the presence of a mild reducing 20 agent, e.g. sodium borohydride, and an appropriate organic solvent (e.g. a lower alcohol such as methanol or ethanol); (x) for compounds of formula I in which one of R 2 and R 3 represents -NH, and the other represents H, reduction of a compound of formula 25 XXIA, WO 00/77000 PCT/SE00/01254 24 NOH 45 R 43 R41 XXIA R5 R44O R B R 4 6 R42 N

NN

R7 1-'B+ R R6N R4

R

3 wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 4 1 , R 42 , R 4 3 , R 44 , R 45 , R 46 , A and B are as 5 hereinbefore defined, in the presence of a suitable reducing agent (e.g. LiAlH 4 ), for example under conditions that are well known to those skilled in the art; (y) for compounds of formula I in which one or both of R' and R 2 10 represent -N(R 2 c)R 2 d in which one or both of R 2 c and R 2 d represents C 1 -6 alkyl, alkylation of a corresponding compound of formula I in which R' and/or R 2 represent -N(R 2 c)R 2 d (as appropriate) in which R 2 c and/or R 2 d (as appropriate) represent H, using a compound of formula XXIB,

R

2 eLI XXIB 15 wherein R 2e represents C 1 6 alkyl and L' is as hereinbefore defined, for example under conditions that are well known to those skilled in the art; or (z) conversion of one substituent on R 7 to another using techniques well 20 known to those skilled in the art.

WO 00/77000 PCT/SE00/01254 25 Compounds of formula II may be prepared by reaction of a compound of formula XXII, 1 R2 45 R43 R41 XXII

R

4 4 R 6 R44 42 NX HN R46 R4 " H 5 wherein R', R

-

, R 41 , R 42 , R 43 , R 4 , R 45 and R'" are as hereinbefore defined, with a compound of formula VIII as hereinbefore defined, for example as described hereinbefore for synthesis of compounds of formula I (process step (e)), or, in the case of compounds of formula II wherein A represents o10 CH 2 and R 5 represents OH or N(H)R 1 2 , with a compound of formula VII as hereinbefore defined, for example as described hereinbefore for synthesis of compounds of formula I (process step (d)). Compounds of formula II in which R' and R 2 both represent H may be 15 prepared by reduction of a compound of formula XXIII, O 45 R43 R41 XXIII

R

5 R44 N R4 6

R

4 2 H R7R

R

6 WO 00/77000 PCT/SE00/01254 26 wherein R 5 , R 6 , R 7 , R 41 , R 42 , R 43 , R 4 , R 45 , R', 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 (g)). 5 Compounds of formula IV may be prepared by reaction of a compound of formula VA, as hereinbefore defined, with a compound of formula XXIV, L'-C(0)-L 1 XXIV wherein L' is as hereinbefore defined, and in which the two L' groups may 1o be the same or different, for example at between 0 0 C and reflux temperature in the presence of a suitable base (e.g. triethylamine or potassium carbonate) and an appropriate organic solvent (e.g. toluene or dichloromethane). 15 Compounds of formula V may be prepared by reaction of a compound of formula II, as hereinbefore defined, with a compound of formula XXIV, as hereinbefore defined, for example as described hereinbefore for the synthesis of compounds of formula IV. 20 Compounds of formula VI may be prepared by reaction of a compound of formula XXII, 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)), or with a compound of formula IV, as hereinbefore defined, for example as described hereinbefore for 25 synthesis of compounds of formula I (process step (b)). Compounds of formula VI may alternatively be prepared by reaction of a compound of formula XXII, as hereinbefore defined, with a compound of formula XXIV, as hereinbefore defined, for example as described WO 00/77000 PCT/SE00/01254 27 hereinbefore for synthesis of compounds of formula IV, followed by reaction of the resultant intermediate with a compound of formula VA, as hereinbefore defined, for example as described hereinbefore for the synthesis of compounds of formula I (process step (c)). 5 Compounds of formula VI in which R' and R 2 represent H may alternatively be prepared by reduction of a corresponding compound of formula XXV, O 45 R43 R41 kR44 XXV N R4 6 R 42 IN N RN H / N

-

- ..

R 4

R

3 10 wherein R 3 , R 4 , R 41 , R 42 , R 43 , R 4 , R 45 and R'" are as hereinbefore defined, and in which the C= 0 group may be activated using an appropriate agent, such as tosylhydrazine, for example as described hereinbefore for compounds of formula I (process step (g)). 15 Compounds of formula VI in which one or more of R 4 1 , R 42 , R 45 and/or R 46 represent C 1

-

3 alkyl may be prepared by reaction of a compound of formula VI in which R 41 , R 42 , R 45 and/or R 46 (as appropriate) represent H, with an appropriate alkylating agent (e.g. dimethyl sulfate), for example in the 20 presence of a suitable strong base (e.g. s-BuLi), N,N,N',N' tetramethylethylenediamine and a reaction-inert solvent (e.g. THF).

WO 00/77000 PCT/SE00/01254 28 Compounds of formula VII may be prepared in accordance with techniques which are known to those skilled in the art. For example, compounds of formula VII in which: 5 (1) B represents -CH20- and X represents O may be prepared by reaction of a compound of formula XIA as hereinbefore defined, with a compound of formula XXVI, L2 R O XXVI 10 wherein R 6 and L 2 are as hereinbefore defined, for example at elevated temperature (e.g. between 60 0 C and reflux temperature) in the presence of a suitable base (e.g. K 2 C0 3 or NaOH) and an appropriate organic solvent (e.g. acetonitrile or toluene/water), or as otherwise described in the prior 15 art; (2) R 6 represents H and X represents O may be prepared by reduction of a compound of formula XXVII, O R7 1 B XXVII 20 Br wherein R 7 and B are as hereinbefore defined, for example at between -15 0 C and room temperature in the presence of a suitable reducing agent (e.g. NaBH 4 ) and an appropriate organic solvent (e.g. THF), followed by 25 an internal displacement reaction in the resultant intermediate, for example WO 00/77000 PCT/SE00/01254 29 at room temperature in the presence of a suitable base (e.g. K 2

CO

3 ) and an appropriate organic solvent (e.g. acetonitrile); (3) B represents C 1

-

4 alkylene, -(CH 2 )nN(R1 7 )-, -(CH 2 )nS(O) 2 - or -(CH 2 )nO 5 (in which latter three groups n represents 1, 2, 3 or 4) or

-(CH

2 )mC(H)(OH)(CH 2 )n - and X represents O may be prepared by oxidation of a compound of formula XXVIII,

R

7 R BXXVIII R6 in which B a represents a single bond, Cl- 3 alkylene, -(CH,)n 1 -N(R17)-, 10 -(CH 2 )n-IS(0) 2 - or -(CH,)n.

1 0- (in which latter three groups n represents 1, 2, 3 or 4) or -(CH,)miC(H)(OH)(CH 2

)

n- (in which latter group n is as hereinbefore defined), and in all cases RI 7 and m are as hereinbefore defined, in the presence of a suitable oxidising agent (e.g. mCPBA), for example by refluxing in the presence of a suitable organic solvent (e.g. 15 DCM); or (4) B represents -(CH2)nO- and X represents N(R 12 ) and R 12 represents

-S(O)

2

-C

1 4 -alkyl or -C(0)OR 14 may be prepared by cyclisation of a compound of formula XXVIIIA, 20

R

6

L

2 XXVIIIA

N(H)R

1 2 a RTO

(CH

2 )n wherein R 12a represents -S(0) 2

-C,

1

-

4 -alkyl or -C(0)ORI 4 and n, R 6 , R 7 , RI 4 and L 2 are as hereinbefore defined, for example at between 0 0 C and reflux 25 temperature in the presence of a suitable base (e.g. sodium hydroxide), an appropriate solvent (e.g. dichloromethane, water, or a mixture thereof) WO 00/77000 PCT/SE00/01254 30 and, if necessary a phase transfer catalyst (such as tetrabutylammonium hydrogensulfate). Compounds of formula VIII may be prepared by standard techniques. For 5 example compounds of formula VIII in which: (1) B represents -(CH,)nO- may be prepared by coupling a compound of formula XIA, as hereinbefore defined, to a compound of formula XXIX,

L

4

-(CH

2 )n-C(RS)(R 6

)-A-L

2 XXIX 10 wherein L 4 represents a suitable leaving group (e.g. halo) and n, R 5 , R 6 , A and L 2 are as hereinbefore defined; or (2) B represents -C(O)N(R" 7 )- may be prepared by coupling a compound of formula XXX, 15 R 7

N(H)R

17 XXX wherein R 7 and R" 7 are as hereinbefore defined, to a compound of formula XXXI,

L

4

-C(O)-C(R

5

)(R

6

)-A-L

2 XXXI wherein L 4 , R 5 , R 6 , A and L 2 are as hereinbefore defined; 20 in both cases, under conditions which are well known to those skilled in the art. Compounds of formula VIII in which A represents C 2 -alkylene and R 5 25 represents OR 2 , in which R 2 represents C,6 alkyl or optionally substituted aryl may alternatively be prepared by reaction of a compound of formula XIX as hereinbefore defined with a compound of formula XXXIA, WO 00/77000 PCT/SE00/01254 31 6 B ORY XXXIA

R

7 wherein R y represents C 14 alkyl or aryl (which two groups are optionally substituted with one or more substituents selected from C I 4 alkyl or halo) and R 6 , R 7 and B are as hereinbefore defined, for example at between 5 ambient temperature (e.g. 25 0 C) and reflux temperature in the presence of a suitable base (e.g. K 2

CO

3 ) and an appropriate organic solvent (e.g. acetonitrile), followed by conversion of the ester functionality to an L 2 group (in which L 2 is as hereinbefore defined), under conditions that are well known to those skilled in the art. 10 Compounds of formulae VII and VIII in which B represents -(CH2)nS(O)- or

-(CH

2 )nS(O) 2 - may be prepared by oxidation of corresponding compounds of formulae VII and VIII wherein B represents -(CH 2 )nS-, wherein n is as hereinbefore defined, in the presence of an appropriate amount of a suitable 15 oxidising agent (e.g. mCPBA) and an appropriate organic solvent. Compounds of formulae IX and XI may be prepared in a similar fashion to compounds of formula I (see, for example, process steps (a), (b), (c) or (d)). 20 Alternatively, compounds of formula IX in which A represents C, alkylene may be prepared by reaction of a compound of formula VI, as hereinbefore defined with a compound of formula XXXII, R'-B-C(O)-CH = CH, XXXII 25 wherein B and R 7 are as hereinbefore defined, for example a room temperature in the presence of a suitable organic solvent (e.g. ethanol).

WO 00/77000 PCT/SE00/01254 32 Compounds of formula XIII may be prepared by removing an optionally substituted benzyloxycarbonyl unit from (i.e. deprotecting) a corresponding compound of formula I in which R 7 represents optionally 5 substituted phenyl, R 5 and R 6 both represent H, B represents -N(R17)C(O)O(CH 2 )-, A represents A a and A a is as hereinbefore defined under conditions which are well known to those skilled in the art. Compounds of formula XV may be prepared by reaction of a o10 corresponding compound of formula I, as hereinbefore defined, in which

R

5 represents -OH, with a compound of formula XXXIII

RYS(O)

2 C1 XXXIII wherein R Y is as hereinbefore defined, for example at between -10 and 25 0 C in the presence of a suitable solvent (e.g. dichloromethane), 15 followed by reaction with a suitable source of the azide ion (e.g. sodium azide) for example at between ambient and reflux temperature in the presence of an appropriate solvent (e.g. DMF) and a suitable base (e.g. NaHCO 3 ). 20 Compounds of formula XV may alternatively be prepared by reaction of a corresponding compound of formula VI, as hereinbefore defined with a compound of formula XXXIIIA,

R

7

-B-C(R

6

)(N

3

)-A-L

2 XXXIIIA wherein L 2 , R 6 , R 7 , A and B are as hereinbefore defined, for example 25 under analogous conditions to those described hereinbefore for preparation of compounds of formula I (process step (e)).

WO 00/77000 PCT/SE00/01254 33 Compounds of formula XX may be prepared by replacement of the OH group of a compound of formula I in which R 5 represents OH with an L 2 group under conditions that are well known to those skilled in the art. 5 Compounds of formula XXIA may be prepared by reaction of a corresponding compound of formula X with hydroxylamine, for example at elevated temperature (e.g. at reflux) in the presence of a suitable organic solvent (e.g. methanol). 10 Compounds of formula XXII are known in the literature or are readily available using known techniques. For example, compounds of formula XXII in which R' and R 2 together represent -O-(CH2) 2 -O-, -(CH 2

)

3 -,

-(CH

2

)

4 - or -(CH 2

)

5 -, and R 4 1 , R 42 , R 43 , R 44 , R 45 and R' all represent H, may be prepared by reduction of a compound of formula XXXIV, 15 Rla 2a OO O 0 NN NH H" wherein R a and R 2a together represent -O-(CH 2

)

2 -O-, -(CH 2

)

3 -, -(CH 2

)

4 - or -(CH2) 5 -, in the presence of a suitable reducing agent (e.g. LiAlH 4 ) under 20 conditions which are well known to those skilled in the art. Compounds of formula XXXIIIA may be prepared in analogous fashion to compounds of formula XV (i.e. from the corresponding alcohol).

WO 00/77000 PCT/SE00/01254 34 Compounds of formulae X, XXIII and XXV (in which, in all cases, R 45 and

R

6 both represent H), may be prepared, advantageously, by reaction of (as appropriate) either (i) a compound of formula XXXV, 0 R43 R44 XXXV R41 N

R

4 2 O' OR z wherein R z represents Co alkyl or C_3 alkylaryl (e.g. alkylphenyl, such as benzyl) and R 4 1,

R

42 ,

R

43 and R 4 are as hereinbefore defined, or (ii) 4 piperidone (or a protected derivative thereof), with (as appropriate) either (1) a compound of formula XXXVI,

R

7-B- C (R 5)(R 6 ) -A - N H 2 XXXVI lo wherein R 5,

R

6,

R

7, A and B are as hereinbefore defined, or (2) NH3 (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) and, in the case of compounds of formulae X and XXV, conversion of the C(O)ORz group in the resultant 15 intermediate to a C(O)N(R3)(R 4) group using techniques such as those described herein (e.g. process step (c) above). The formation of compounds of formulae X, XXIII and XXV may be carried out in this way for example at between room temperature and reflux 20 (depending upon the concentration of the reactants) in the presence of an appropriate solvent (e.g. ethanol or methanol) and, preferably, in the presence of an organic acid (e.g. a C1-6 carboxylic acid, especially acetic acid).

WO 00/77000 PCT/SE00/01254 35 It will be also appreciated by those skilled in the art that compounds of formula XXII in which R 1 and R 2 both represent H may also be prepared via this method (i.e. by reaction of a compound of 4-piperidone (or a 5 protected derivative thereof) with NH 3 (or a protected derivative thereof) in the presence of a formaldehyde), provided that the intermediate so formed is subsequently reduced under appropriate reaction conditions. The skilled person will also appreciate that this process may also be used 10 to prepare compounds of formula I in which R 4 1 and R 42 are H, and R 45 and/or R 46 are other than H, for example by: (i) reacting a compound of formula XXXV in which R 4 1 and/or R 42 is/are other than H with, for example, benzylamine or a derivative thereof; 15 (ii) removal of the -C(O)ORz unit; (iii) reaction at the free bispidine nitrogen of the resultant compound with a compound of formula VIII as hereinbefore defined; (iv) removal of the benzyl protecting group; and (v) reaction at the free bispidine nitrogen of the resultant compound 20 with, for example, a compound of formula III or IV as hereinbefore defined, under conditions well known to those skilled in the art including those described hereinbefore. This reaction will be accompanied by, at some point, conversion of the bridgehead carbonyl functionality to the desired 25 R'/R 2 groups. Compounds of formula XXXIV may be prepared in accordance with techniques which are well known to those skilled in the art. For example, compounds of formula XXXIV in which RI a and R 2a together represent WO 00/77000 PCT/SE00/01254 36 -(CH2) 3 -, -(CH 2

)

4 - or -(CH2) 5 - may be prepared by reaction of a compound of formula XXXVII, Rla '

R

2 a ' NC N C1. N C NXXXVII ON 0 H wherein R a ' and R 2 a ' together represent -(CH 2

)

3 -, -(CH 2

)

4 - or -(CH 2

)

5 -, 5 with a mixture of phosphoric acid and sulfuric acid, for example at 120 0 C. Compounds of formula XXXVI are well known in the literature or are readily available using known techniques. For example, compounds of formula XXXVI wherein R 5 represents OH, R 6 represents H and A o10 represents CH, may be prepared by reaction of a compound of formula VII in which R 6 represents H and X represents O with ammonium hydroxide under conditions which are well known to those skilled in the art. 15 Compounds of formulae III, VA, XIA, XII, XIV, XVI, XVII, XVIII, XIX, XXI, XXIB, XXIV, XXVI, XXVII, XXVIII, XXVIIIA, XXIX, XXX, XXXI, XXXIA, XXXII, XXXIII, XXXV and XXXVII and derivatives thereof, are either commercially available, are known in the literature, or may be obtained either by analogy with the processes 20 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, 25 group(s) in compounds defined herein may be converted to other claimed WO 00/77000 PCT/SE00/01254 37 substituents using techniques well known to those skilled in the art. For example, nitrobenzene may be reduced to an aminobenzene, hydroxy may be converted to alkoxy, alkoxy may be hydrolysed to hydroxy, etc. 5 The compounds of the invention may be isolated from their reaction mixtures using conventional techniques. It will be appreciated by those skilled in the art that, in the process described above, the functional groups of intermediate compounds may be, 10 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. tert-butyldimethylsilyl, tert 15 butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and alkylcarbonyloxy groups (e.g. methyl- and ethylcarbonyloxy groups). Suitable protecting groups for amino include benzyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C16 alkyl or benzyl esters. 20 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 with techniques which are 25 well known to those skilled in the art and as described hereinafter. The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by J W F McOmie, Plenum Press (1973), and WO 00/77000 PCT/SE00/01254 38 "Protective Groups in Organic Synthesis", 2nd edition, T W Greene & P G M Wutz, Wiley-Interscience (1991). Persons skilled in the art will appreciate that, in order to obtain compounds 5 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 the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those o10 associated hereinbefore with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the 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 15 synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis. It will also be appreciated by those skilled in the art that, although certain protected derivatives of compounds of formula I, which may be made prior 20 to a final deprotection stage, may not possess pharmacological activity as such, they may be administered parenterally or orally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Moreover, we have found that certain compounds of formula I 25 may act as prodrugs of other compounds of formula I. All prodrugs of compounds of formula I are included within the scope of the invention.

WO 00/77000 PCT/SE00/01254 39 Some of the intermediates referred to hereinbefore are novel. According to a further aspect of the invention there is thus provided: (a) a compound of formula II, as hereinbefore defined or a protected derivative thereof, 5 provided that R 7 does not represent optionally substituted phenyl; (b) a compound of formula V, as hereinbefore defined or a protected derivative thereof, provided that R 7 does not represent optionally substituted phenyl; (c) a compound of formula X as hereinbefore defined or a protected derivative thereof; (d) a compound of formula XI as hereinbefore defined or o10 a protected derivative thereof; (e) a compound of formula XIII, as hereinbefore defined or a protected derivative thereof; (f) a compound of formula XV, as hereinbefore defined or a protected derivative thereof; (g) a compound of formula XX, as hereinbefore defined or a protected derivative thereof; (h) a compound of formula XXIII, as hereinbefore defined or a 15 protected derivative thereof, provided that R 7 does not represent optionally substituted phenyl; and (i) a compound of formula XXV, as hereinbefore defined or a protected derivative thereof. Medical and pharmaceutical use 20 The compounds of the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceuticals. Thus, according to a further aspect of the invention there is provided the 25 compounds of the invention for use as pharmaceuticals.

WO 00/77000 PCT/SE00/01254 40 In particular, the compounds of the invention exhibit myocardial electrophysiological activity, for example as demonstrated in the test described below. 5 The compounds of the invention are thus expected to be useful in both the prophylaxis and the treatment of arrhythmias, and in particular atrial and ventricular arrhythmias. The compounds of the invention are thus indicated in the treatment or o10 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 thromboembolic events. 15 In the treatment of arrhythmias, compounds of the invention have been found to selectively delay cardiac repolarization, thus prolonging the QT interval, and, in particular, to exhibit class III activity. Although compounds of the invention have been found to exhibit class III activity in particular, in the treatment of arrhythmrnias, their mode(s) of activity is/are 20 not necessarily restricted to this class. According to a further aspect of the invention, there is provided a method of treatment of an arrhythmia which method comprises administration of a therapeutically effective amount of a compound of the invention to a person 25 suffering from, or susceptible to, such a condition.

WO 00/77000 PCT/SE00/01254 41 Pharmaceutical preparations The compounds of the invention will normally be administered orally, subcutaneously, intravenously, intraarterially, transdermally, intranasally, 5 by inhalation, or by any other parenteral route, in the form of pharmaceutical preparations comprising the active ingredient either as a free base, a pharmaceutically acceptable ion exchanger or a non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route lo of administration, the compositions may be administered at varying doses. The compounds of the invention may also be combined with any other drugs useful in the treatment of arrhythmias and/or other cardiovascular disorders. 15 According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Suitable daily doses of the compounds of the invention in therapeutic 20 treatment of humans are about 0.05 to 5.0 mg/kg body weight at parenteral administration. The compounds of the invention have the advantage that they are effective against cardiac arrhythmias. 25 WO 00/77000 PCT/SE00/01254 42 Compounds of the invention may also have the advantage that they may be more efficacious than, 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 5 addition to class III activity)) than, be more potent than, be longer acting than, produce fewer side effects (including a lower incidence of proarrhythmias such as torsades de pointes) than, be more easily absorbed than, or that they may have other useful pharmacological properties over, compounds known in the prior art. 10 Biological Tests Test A Primary Electrophysiological Effects In Anaesthetised Guinea Pigs 15 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 20 to 50 mg/kg) and catheters 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 the limbs for recording of ECGs (lead II). A thermistor was placed in the rectum and the animal was placed on a heating pad, set to a rectal temperature of between 37.5 and 25 38.5 0 C. A tracheotomy was performed and the animal was artificially ventilated with room air by use of a small animal ventilator, set to keep blood gases within WO 00/77000 PCT/SE00/01254 43 the normal range for the species. In order to reduce autonomic influences both vagi were cut in the neck, and 0.5 mg/kg of propranolol was given intravenously, 15 minutes before the start of the experiment. 5 The left ventricular epicardium was exposed by a left-sided thoracotomy, and a custom-designed suction electrode for recording of the monophasic action potential (MAP) was applied to the left ventricular free wall. The electrode was kept in position as long as an acceptable signal could be recorded, otherwise it was moved to a new position. A bipolar electrode o10 for pacing was clipped to the left atrium. Pacing (2 ms duration, twice the diastolic threshold) was performed with a custom-made constant current stimulator. The heart was paced at a frequency just above the normal sinus rate during 1 minute every fifth minute throughout the study. 15 The blood pressure, the MAP signal and the 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 the last 10 seconds of the following minute of sinus rhythm. The signals were processed using a custom-made program 20 developed for acquisition and analysis of physiological signals measured in experimental animals (see Axenborg and Hirsch, Comput. Methods Programs Biomed. 41, 55 (1993)). The test procedure consisted of taking two basal control recordings, 5 25 minutes apart, during both pacing and sinus rhythm. After the second control recording, the first dose of the test substance was infused in a volume of 0.2 mL into the jugular vein catheter for 30 seconds. Three minutes later, pacing was started and a new recording was made. Five minutes after the previous dose, the next dose of test substance was WO 00/77000 PCT/SE00/01254 44 administered. Six to ten consecutive doses were given during each experiment. Data analysis 5 Of the numerous variables measured in this analysis, three were selected as the most important for comparison and selection of active compounds. The three variables selected were the MAP duration at 75 percent repolarization during pacing, the atrio-ventricular (AV) conduction time (defined as the i0 interval between the atrial pace pulse and the start of the ventricular MAP) during pacing, and the heart rate (defined as the RR interval during sinus rhythm). Systolic and diastolic blood pressure were measured in order to judge the haemodynamic status of the anaesthetised animal. Further, the ECG was checked for arrhythmias and/or morphological changes. 15 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 these percentage values against the cumulative dose administered before each recording, it was 20 possible to construct dose-response curves. In this way, each experiment generated three dose-response curves, one for MAP duration, one for AV conduction time and one for the sinus frequency (RR interval). A mean curve of all experiments performed with a test substance was calculated, and potency values were derived from the mean curve. All dose-response 25 curves in these experiments were constructed by linear connection of the data points obtained. The cumulative dose prolonging the MAP duration by 10% from the baseline was used as an index to assess the class III electrophysiological potency of the agent under investigation (Do 10

).

WO 00/77000 PCT/SE00/01254 45 Test B Metabolic Stability of Test Compounds An in vitro screen was set up to determine the metabolic stability of the 5 compounds of the 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 pM of test o10 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 the sample to above 10 (NaOH; 1 mM). After solvent extraction, the concentration of test 15 compound was measured against an internal standard by LC (fluorescence/UV detection). The percentage of test compound remaining after 30 minutes (and thus tl/2) were calculated and used as a measure for metabolic stability. 20 The invention is illustrated by way of the following examples. Examples 25 General Experimental Procedures Mass spectra were recorded on a Finnigan MAT TSQ 700 triple quadrupole mass spectrometer equipped with 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 WO 00/77000 PCT/SE00/01254 46 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 13C NMR measurements were performed on a BRUKER ACP 300 and Varian UNITY plus 400 and 500 spectrometers, 5 operating at 'H frequencies of 300, 400 and 500 MHz respectively, and at 13C frequencies of 75.5, 100.6 and 125.7 MHz respectively. Alternatively, 13C NMR measurements were performed on a BRUKER ACE 200 spectrometer at a frequency of 50.3 MHz. 10 Rotamers 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 the solvent as internal standard. Synthesis of intermediates 15 Example A 4-(2-Oxiranylmethoxy)benzonitrile Epichlorohydrin (800 mL) and K-,CO 3 (414 g) were added to a stirred solution of p-cyanophenol (238 g) in 2.0 L MeCN and the reaction 20 mixture was refluxed under an inert atmosphere for 2 h. The hot solution was filtered and the filtrate concentrated, giving a clear oil which was crystallized from di-iso-propyl ether giving the product in 75% yield. 13C NMR (CDC13): 8 44.4, 49.7, 69.0, 104.5, 115.3, 118.9, 134.0, 161.6 25 Example B 2(S)-Oxiranylmethyl 3-nitrobenzenesulfonate m-Nitrobenzensulfonylchloride (12.6 g; 57 mmol) was added to a cold WO 00/77000 PCT/SE00/01254 47 (-20 0 C) solution of (R)-(+)-glycidol (5.5 g; 74 mmol) and TEA (10.3 mL; 74 mmol). The reaction mixture was stirred at -20 0 C for 96 h. The solution was filtered and the filtrate washed with tartaric acid (10% w/w), brine, H 2 0 and concentrated giving the title compound in a 97% yield. 5 1 H NMR (CDC13): 6 2.62 (dd,1H), 2.84 (dd,1H), 3.22 (m,1H), 4.07 (dd,1H), 4.49 (dd,1H), 7.80 (t,1H), 8.25 (m,1H), 8.52 (m,1H), 8.78 (m, 1H) 10 Example C 4- [(2S)-Oxiranylmethoxy]benzonitrile The title compound was prepared in a 90% yield according to the procedure described in Example A above starting from (R)-(-) epichlorohydrin. 15 Example D 4-[(2R)-Oxiranylmethoxy]benzonitrile The title compound was prepared according to the procedure described in Example A above starting from (S)-(-)-epichlorohydrin. 20 [uCD 20 = -14.10 (c = 1.0; acetone) 'H NMR (CDCl 3 ): 8 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) 25 WO 00/77000 PCT/SE00/01254 48 Example E 3-Benzyl-3,7-diazabicyclo[3.3. 1]lnonane (a) 3,7-Dibenzyl-3,7-diazabicyclo[3.3.1] nonane 5 The sub-title compound was prepared according to the method described in J. Org. Chem. 41, 1593, (1976) except that 3,7-dibenzyl-3,7 diazabicyclo[3.3.1]nonan-9-one (also prepared according to the method described in J. Org. Chem. 41, 1593 (1976)) was used instead of N benzyl-N-methylbispidone. 10 (b) 3-Benzyl-3,7-diazazbicyclo[3.3.1]nonane 3,7-Dibenzyl-3,7-diazabicyclo[3.3.1]nonane (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 tlc indicated that the reaction was complete. The catalyst 15 was removed by filtration through a pad of Celite® and the residue was concentrated under reduced pressure to give the title compound in a quantitative yield. 13 C NMR (CDCl 3 ): 8 30.1, 33.4, 36.0, 52.5, 59.6, 64.3, 126.9, 128.3, 20 128.7, 138.8 Example F tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate 25 (a) tert-Butyl 7-benzyl-9-oxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate Paraformaldehyde (4.00 g; 127 mmol) was added to a solution of benzylamine (13.7 g; 126 mmol) in ethanol (190 mL). The solution was heated to 60 0 C and a solution of acetic acid (15.2 g; 252 mmol) in ethanol (160 mL) was added over 2 hours. After additional stirring for 1 hour, the WO 00/77000 PCT/SE00/01254 49 solution was cooled to room temperature. This solution was added (over 2 hours) to a mixture of 1-tert-butoxycarbonyl-4-piperidone (25.5 g; 127 mmol) and paraformaldehyde (4.80 g; 152 mmol) in ethanol (270 mL) which had been heated to 60oC. After reflux overnight, the solution was 5 cooled to room temperature. The ethanol was removed by evaporation. Extractive work-up was performed in toluene:water and the material was filtered through silica in a toluene:ethyl acetate system. Evaporation of the eluant gave a solid material (37.4 g). The purity was 90 area% (HPLC) and the yield was 60%. By performing a crystallisation in iso-propanol, a 10 compound with a purity of 98 area% (HPLC) and a yield of 70% was obtained. MS (EI; 70 eV): m/z 91 (100%), m/z 57 (42%), m/z 273 (32%), m/z 330 (5%) 15 13 C NMR (CDCl 3 ): 8 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 (using TMS as reference) (b) tert-Butyl 7-benzyl-9-oxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate 20 (alternative preparation) Benzylamine (6.51 g; 60.2 mmol), acetic acid (72.3 g, 1200 mmol), paraformaldehyde (3.71 g; 120 mmol) and 1-tert-butoxycarbonyl-4 piperidone (12.0 g; 60.2 mmol), were added to ethanol (300 mL). The solution was heated to 65 0 C and stirred at this temperature for 2 hours. 25 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 iso-propanol yielded a compound with a purity of 94 area% (HPLC) in a yield of 54%.

WO 00/77000 PCT/SE00/01254 50 (c) tert-Butyl 7-benzyl-3,7-diazabicyclo [3.3.1]-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]nonane-3-carboxylate (10.1 mmol; 4.00 g; 83.3%; from step (a) above) were dissolved in iso-propanol 5 (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 the mixture was again heated at reflux for 2 hours. The slurry was cooled to ambient temperature and filtered. The filtrate was concentrated and an extractive work-up was performed in toluene:water. The toluene solution io was concentrated to give 0.95 g of sub-title compound, with a purity of 90 area% (GC) in a yield of 60 %. MS (EI; 70 eV): m/z 259 (100%), m/z 91 (95%), m/z 169 (45%), m/z 57 (35%), m/z 316 (25%) 15 3 C NMR (CDCl 3 ): 8 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 (using TMS as a reference) (d) tert-Butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate 20 tert-Butyl 7-benzyl-3,7-diazabicyclo[3.3.1]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 (CDCl 3 ): 5 28.05, 28.29, 31.33, 48.35, 49.11, 51.53, 79.34, 25 155.16 WO 00/77000 PCT/SE00/01254 51 Example G 4-[3-(3,7-Diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]benzonitrile HCl-saturated EtOAc (600 mL) was added to a solution of tert-butyl 7-[3 (4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonane-3 5 carboxylate (62 g; see Example 2 of international patent application No. PCT/SE98/02276) in EtOAc (600 mL) and the mixture was stirred at rt. for 4 h. The solvent was removed under reduced pressure, the 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 io compound in a 90% yield. 13 C NMR (CDCl 3 ): 5 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 15 (The title compound was also readily converted to the hydrochloride salt using standard techniques.) Preparation of Compounds of Formula I 20 Example 1 7-[(2S)-3-(4-Cyanophenoxy)-2-hydroxypropyl]-N-ethyl-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide Ethyl isocyanate (1.42 g, 16.6 mmol) was added to a solution of 4-{[(2S) 3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropyl]oxy}benzonitrile) 25 (5.0 g, 20 mmol, see Example G above) in 30 mL of dichloromethane. The mixture was stirred for 4 hours at room temperature and was then concentrated in vacuo and purified by column chromatography on silica, eluting with dichloromethane: methanol (95:5), to yield 3.2 g (51%) of the title compound.

WO 00/77000 PCT/SE00/01254 52 13C NMR (CDC1 3 ): 6 15.52, 29.19, 29.50, 31.89, 35.77, 48.00, 49.17, 57.21, 60.49, 61.83, 65.41, 70.71, 103.88, 115.34, 119.15, 133.78, 133.84, 158.87, 162.19 5 Example 2 7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N-(cyclopropylmethyl)-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide (a) Cyclopropylmethyl isocyanate o10 Cyclopropylmethylamine (1.4 g, 19.7 mmol) was added to a suspension of 1,1'-carbonyldiimidazole (3.2 g, 19.7 mmol) in THF (10 mL). The resulting solution was stirred overnight at room temperature before being subjected to distillation, yielding 0.4 g (21%) of the sub-title compound. 15 (b) 7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N-(cyclopropylmethyl)-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide Cyclopropylmethyl isocyanate (0.4 g, 4 mmol, from step (a) above) was added to a solution of 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxy propoxy]benzonitrile (1.2 g, 4 mmol, see Example G above) in DCM. 20 The solution was stirred overnight, then concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol (93:7), to yield 0.85 g (50%) of the title compound. 25 13 C NMR (CDCl 3 ): 8 3.29, 11.21, 29.31, 29.61, 32.10, 46.11, 48.14, 49.39, 57.24, 60.58, 62.04, 65.46, 70.76, 104.03, 115.37, 119.18, 133.88, 158.97, 162.22 WO 00/77000 PCT/SE00/01254 53 Example 3 4-({ (2S)-2-Hydroxy-3-[7-(4-morpholinylcarbonyl)-3,7-diazabicyclo [3.3.1] non-3-yl]propyl} oxy)benzonitrile A solution of 4- { [(2S)-3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxy 5 propyl]oxy}benzonitrile) (2.0 g, 6.6 mmol, prepared analogously to the method described in Example G above) in DCM (10 mL) was treated with aqueous NaOH (0.8 mL of 10 M), followed by 4-morpholinecarbonyl chloride (1.2 g, 8 mmol). The resulting mixture was stirred for 30 min. at room temperature, before water was added. The organic layer was o10 separated, washed with 2 M NaOH followed by brine, before being separated, dried (MgSO 4 ) and concentrated in vacuo. The residue was recrystallised twice, firstly from iso-propanol and then from ethanol, to yield 0.73 g (26.5%) of the title compound. 15 " 3 C NMR (CDCl 3 ): 8 23.36, 29.59, 30.05, 32.34, 47.45, 49.51, 52.18, 56.86, 60.78, 62.82, 65.35, 66.66, 70.82, 104.03, 115.33, 119.17, 133.88, 162.23, 164.99 Example 4 20 7- {3-(4-Cyanophenoxy)-2-[(methanesulfonyl)amino]-propyl}-N-ethyl-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide (a) 4-(3-Amino-2-hydroxypropoxy)benzonitrile 4-(2-Oxiranylmethoxy)benzonitrile (100 g, 0.57 mol, see Example A 25 above) was added to a mixture of concentrated aqueous ammonium hydroxide (500 mL) and iso-propanol (300 mL). The resulting slurry was stirred at room temperature for 3 days. The reaction mixture was filtered to remove the insoluble by-product, and the filtrate was concentrated in WO 00/77000 PCT/SE00/01254 54 vacuo to give a crude product, which was crystallised from acetonitrile to yield 50 g (46%) of the sub-title compound. (b) 2-(4-Cyanophenoxy)-1- { [(methanesulfonyl)amino] methyl} ethyl 5 methanesulfonate Methanesulfonyl chloride (17.5 g, 153 mmol) was slowly added to a cooled (-10°C) solution of 4-(3-amino-2-hydroxypropoxy)benzonitrile (13.3 g, 69 mmol, from step (a) above) and 4-(dimethylamino)pyridine (0.2 g, 1.64 mmol) in pyridine (100 mL). The yellow solution was stirred o10 at rt for 1.5 hours, concentrated in vacuo and then redissolved in DCM. This solution was washed twice with 2 M HCI and once with NaHCO 3 solution before the organic phase was separated, dried (MgSO 4 ) and concentrated in vacuo to yield 23.5 g (100%) of the sub-title compound. 15 (c) 4- { [1-(Methanesulfonyl)aziridin-2-yl]methoxy}benzonitrile A stirred solution of 2-(4-cyanophenoxy)-1- { [(methanesulfonyl)amino] methyl}ethyl methanesulfonate (23.5 g, 67 mmol, from step (b) above) in acetonitrile (200 mL), was treated with potassium carbonate (30 g, 210 mmol), forming a thick precipitate. After 1 hour, a further portion of 20 K 2

CO

3 (30 g, 210 mmol) was added. Stirring was continued for 2 h at rt before the reaction mixture was filtered and the filtrate concentrated in vacuo. The resulting oil (13 g) was crystallised from toluene to give 8 g (47%) of the sub-title compound. 25 mp 79-81oC WO 00/77000 PCT/SE00/01254 55 (d) N-{2-(7-Benzyl-3,7-diazabicyclo[3.3.1]non-3-yl)-1- [(4-cyanophenoxy) methyl] ethyl}methanesulfonamide A mixture of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (2 g, 10 mmol, see Example E above) and 4- { [1 -(methanesulfonyl)aziridin-2 5 yl]methoxy}benzonitrile (2.5 g, 10 mmol, from step (c) above) in iso propanol was refluxed overnight. The mixture was then concentrated in vacuo, giving a residue which was then dissolved in water (pH 3) and extracted with ether. The aqueous layer was made basic with 2 M NaOH and extracted with DCM. The dichloromethane layer was separated, dried o10 and concentrated in vacuo to give a residue which was purified by column chromatography, eluting with a gradient of DCM:methanol:methanolic ammonia (98:2:0 to 97:0:3) to give 2.5 g (53%) of the sub-title compound. 15 (e) N-[2-(4-Cyanophenoxy)-1-(3,7-diazabicyclo[3.3.1]non-3-ylmethyl) ethyl]methanesulfonamide A solution of N- {2-(7-benzyl-3,7-diazabicyclo[3.3.1]non-3-yl)-1-[(4 cyanophenoxy)methyl]ethyl}methanesulfonamide (2.3 g 4.9 mmol, from step (d) above) in aqueous ethanol (95%; 55 mL) was hydrogenated over 20 5 % Pd/C at ambient pressure. The catalyst was removed by filtration through a pad of Celite® and the residue was concentrated in vacuo to give 1.6 g of a crude product. This was recrystallised from methanol to yield 0.3 g (16%) of the sub-title compound. 25 (f) 7- {3-(4-Cyanophenoxy)-2- [(methanesulfonyl)amino]propyl}-N-ethyl 3,7-diazabicyclo[3.3.1] nonane-3-carboxamide A suspension of N-[2-(4-cyanophenoxy)- 1-(3,7-diazabicyclo[3.3.1]non-3 ylmethyl)ethyl]methanesulfonamide (0.29 g, 0.77 mmol, from step (e) above) in DCM (10 mL) was treated with ethyl isocyanate (66 pL, WO 00/77000 PCT/SE00/01254 56

R

2 and R 3 independently represent H, C1- 4 alkyl (optionally substituted and/or terminated with one or more nitro or cyano groups), OR 7 ,

N(R

7 a)R 7 b, OC(O)R' or together form -O-(CH 2

)

2 -O-, -(CH 2

)

3 -, -(CH 2

)

4 - or 5 -(CH 2

)

5 -;

R

7 and R 8 independently represent H, C 1

_

6 alkyl or -(CH 2 )b-aryl (which latter two groups are optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, C1- 4 alkyl and/or

C

1

-

4 alkoxy); 10 R 7a and R 7 b independently represent H or C 1 6 alkyl; b represents 0, 1, 2, 3 or 4;

R

4 represents H or C 1 6 alkyl; 15 D represents H, C 1

-

4 alkyl, -OR 9 , or -(CH2)cN(Ro)(R1);

R

9 represents H, C 1

-

6 alkyl, -C(O)R 12 , -(CH2)d-aryl or -(CH 2 )d-Het 2 (which latter three groups are optionally substituted by one or more substituents selected from -OH, halo, cyano, nitro, Cl- 4 alkyl, C 1

-

4 alkoxy, C(O)R 13

C(O)OR

14 and/or -N(H)S(O)eR 15 ); 20 R 1 o represents H, C 1

-

6 alkyl, -(CH2)f-aryl, -C(NH)NH 2 ,

_S(O)

2

R

15 a, -[C(O)]gN(R 16 )(R17), -C(O)R" 8 or -C(O)OR19; e represents 0, 1 or 2; g represent 1 or 2;

R

1 1 represents H, C1- 6 alkyl, -C(O)R 2 0 or -(CH 2 )h-aryl (which latter group 25 is optionally substituted and/or terminated (as appropriate) by one or more substituents selected from -OH, cyano, halo, amino, nitro, C 1

-

6 alkyl and/or Cl- 6 alkoxy);

R

12 , R 13 , R 14 , R 1 6 , R 17 , R 8 , R 19 and R 20 independently represent H, C 1 -6 alkyl, Het 3 or -(CH 2 )j-aryl (which latter three groups are optionally WO 00/77000 57 PCT/SE00/01254 0.84 mmol) to give a clear solution. The mixture was stirred for 1 h at rt, concentrated in vacuo and then purified by column chromatography, eluting with 5% MeOH in DCM, to give the title compound in 73 % yield. 5 1 3 C NMR (CDCl 3 ): 6 15.41, 28.88, 29.18, 30.77, 35.87, 41.78, 47.93, 48.65, 49.98, 58.24, 58.51, 60.15, 68.82, 104.51, 115.28, 118.95, 134.05, 158.58, 161.55 Example 5 1o 7-[(2S)-3-(4-Cyanophenoxy)-2-hydroxypropyl]-N-iso-propyl-3,7 diazabicyclo[3.3. 1]nonane-3-carboxamide (a) 7-Benzyl-N-iso-propyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide iso-Propyl isocyanate (1.7 g, 20 mmol) was slowly added to a solution of 15 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (3.1 g, 14.3 mmol, see Example E above) in DCM (10 mL). The mixture was stirred at rt overnight and then concentrated in vacuo to yield 4.2 g (97%) of the sub-title compound. (b) N-iso-Propyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide 20 A solution of 7-benzyl-N-iso-propyl-3,7-diazabicyclo[3.3.1]nonane-3 carboxamide (4.2 g, 14 mmol, from step (a) above) in methanol/water (17 mL of a 15:2 mixture) was hydrogenated over 5% Pd/C at ambient pressure. The catalyst was removed by filtration through a pad of Celite®, and the filtrate concentrated in vacuo to yield 2.6 g (87 %) of the sub-title 25 compound.

WO 00/77000 58 PCT/SE00/01254 (c) 7-[(2S)-3-(4-Cyanophenoxy)-2-hydroxypropyl]-N-iso-propyl-3,7-diaza bicyclo[3.3.1]nonane-3-carboxamide A mixture of 4-[(2S)-oxiranylmethoxy]benzonitrile (0.55 g, 3.14 mmol, see Example C above) and N-iso-propyl-3,7-diazabicyclo[3.3.1]nonane-3 5 carboxamide (0.85 g, 4 mmol, from step (b) above) in iso-propanol/water (6.5 mL of a 12:1 mixture) was stirred overnight at 60 0 C. The mixture was then concentrated in vacuo and the residue re-dissolved in DCM. The organic solution was washed with water then brine, dried (MgSO 4 ) and concentrated in vacuo to give the title compound in 91% yield. 10 "C NMR (CDC1 3 ): 8 23.49, 29.29, 31.78, 42.26, 47.71, 49.09, 56.92, 60.27, 61.65, 65.19, 70.61, 103.54, 115.21, 119.09, 133.65, 158.11, 162.08 15 Example 6 7-[(2R)-3-(4-Cyano-2- { [(2-cyanoethyl)amino]carbonyl} phenoxy)-2-hydroxypropyl]-N-ethyl-3,7-diazabicyclo[3.3.1]nonane-3 carboxamide 20 (a) 7-Benzyl-N-ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide A cooled (00C) solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (32.45 g, 0.15 mol, see Example E above) in DCM (300 mL) was treated with ethyl isocyanate (11.4 g, 0.16 mol), added dropwise. The solution was stirred for 2 h at rt before being concentrated in vacuo. The resulting 25 residue was purified by chromatography on silica gel, eluting with a gradient of DCM:MeOH (100:0 to 90:10) to yield 36.4 g (84%) of the sub-title compound. 30 WO00/77000 59 PCT/SE00/01254 (b) N-Ethyl-3,7-diazabicyclo[3.3. 1]nonane-3-carboxamide A solution of 7-benzyl-N-ethyl-3,7-diazabicyclo[3.3.1]nonane-3 carboxamide (4.4 g, 15.3 mmol, from step (a) above) in aqueous ethanol (25 mL of 95%) was hydrogenated over 5% Pd/C at ambient pressure. 5 The catalyst was removed by filtration through a pad of Celite®, and the residue was concentrated in vacuo to yield 2.88 g (95%) of the sub-title compound. (c) Methyl 5-bromo-2-hydroxvbenzoate o10 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 mixture was stirred at rt. for 10 h, poured onto ice-water and the precipitate recrystallized from MeOH, giving the sub-title compound in a 83% yield. 15 (d) Methyl 5-cyano-2-hydroxybenzoate Methyl 5-bromo-2-hydroxybenzoate (190.8 g; from step (c) above) and CuCN (73.9 g) were refluxed in DMF (500 mL) for 7 h. The temperature was allowed to decrease to 80'C and HC1 (500 mL) and FeCl 3 (165.0 g) were added. The reaction mixture was stirred for 30 min., concentrated 20 and partitioned between H,O and DCM. The organic layer was dried, concentrated the residue recrystallized from methylethyl ketone giving the sub-title compound in a 61% yield. (e) 5-Cyano-N-(2-cyanoethyl)-2-hydroxybenzamide 25 A mixture of methyl 5-cyano-2-hydroxybenzoate (20 g, 0.113 mol, from step (d) above), 3-aminopropanenitrile (15.4 g, 0.22 mol) and sodium cyanide (1 g, 20 mmol) in methanol (200 mL) was refluxed overnight. Tlc showed incomplete reaction, so DMSO (50 mL) was added, and reflux was continued for a further 5 h. The solution was concentrated in vacuo, WO 00/77000 60 PCT/SE00/01254 water added, followed by cone. HC1, until a precipitate formed. The product was filtered off, washed with water and dried to yield 19.4 g (80%) of the sub-title compound. 5 (f) 5-Cyano-N-(2-cyanoethyl)-2-[(2R)-oxiranylmethoxy]benzamide A mixture of 5-cyano-N-(2-cyanoethyl)-2-hydroxybenzamide (2.1 g, 9.8 mmol, from step (e) above) and 10 equivalents of (S)-epichlorohydrin in iso-propanol:water (55 mL of 10:1) was refluxed overnight. The mixture was concentrated in vacuo and the residue purified by column o10 chromatography, eluting with ethyl acetate to yield 0.63 g (24%) of the sub-title compound. (g) 7-[(2R)-3-(4-Cyano-2- { [(2-cyanoethyl)amino]carbonyl}phenoxy)-2 hydroxypropyl] -N-ethyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxamide 15 A mixture of 5-cyano-N-(2-cyanoethyl)-2-[(2R)-oxiranylmethoxy] benzamide (0.63 g, 2.3 mmol, from step (f) above) and N-ethyl-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide (0.59 g, 3 mmol, from step (b) above) in iso-propanol:water (33 mL of 10:1) was stirred under reflux overnight. The reaction mixture was concentrated in vacuo and the 20 residue purified by column chromatography, eluting with DCM:MeOH (9:1), to yield 0.78 g (73%) of the title compound.

"

3 C NMR (CDCl 3 ): 6 15.40, 15.55, 17.94, 28.04, 29.21, 29.55, 31.31, 32.03, 35.69, 35.89, 36.21, 47.93, 48.65, 49.36, 57.00, 60.47, 61.05, 25 65.32, 72.21, 105.39, 114.37, 118.22, 118.45, 123.28, 136.36, 136.45, 158.53, 159.20, 160.08, 163.75 ES-MS (M+1)

+

469.0 (m/z) WO 00/77000 61 PCT/SE00/01254 Example 7 7-((2S)-3-{4-Cyano-2-[(cyclopropylamino)carbonyl] phenoxy}-2-hydroxypropyl)-N-ethyl-3,7-diazabicyclo[3.3.1]nonane-3 carboxamide 5 (a) N'-Cyclopropyl-5-cyano-2-hydroxybenzamide Cyclopropylamine (14.3 g) and Na (100 mg) were added to a solution of methyl 5-cyano-2-hydroxybenzoate (10.0 g; from step (d) above) in DMSO (40 mL). The reaction mixture was heated at 80 0 C in a sealed steel io vessel overnight, diluted with HzO, acidified and extracted with EtOAc, giving the sub-title compound (11.0 g), after concentration of the organic layer. (b) 5-Cyano-N-cyclopropyl-2-[(2S)-oxiranylmethoxy]benzamide 15 A mixture of N'-cyclopropyl-5-cyano-2-hydroxybenzamide (1.56 g, 7.7 mmol, from step (a) above), (2S)-oxiranylmethyl 3-nitrobenzene sulfonate (2 g, 7.7 mmol, see Example B above) and K 2

CO

3 (1.16 g, 8.4 mmol) in 2-butanone (15 mL) was stirred at 60 0 C for 18 h. The mixture was concentrated in vacuo and the residue crystallised from di-iso-propyl 20 ether:MeCN (9:1) to yield 0.97 g (97%) of the sub-title compound. (c) 7-((2S)-3- {4-Cyano-2-[(cyclopropylamino)carbonyl]phenoxy}-2 hydroxypropyl)-N-ethyl-3,7-diazabicyclo[3.3.1] nonane-3-carboxamide A mixture of 5-cyano-N-cyclopropyl-2-[(2S)-oxiranylmethoxy]benzamide 25 (0.97 g, 3.8 mmol, from step (b) above) and N-ethyl-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide (0.89 g, 4.5 mmol, see Example 6(b) above) in iso-propanol:water (22 mL of 10:1) was refluxed overnight. The solvent was removed in vacuo and the resulting residue purified by WO 00/77000 62 PCT/SE00/01254 column chromatography on silica gel, eluting with DCM:MeOH (9:1), to yield 1.37 g (79%) of the title compound. 1 3 C NMR (CDCl 3 ): 8 6.62, 6.78, 15.81, 23.55, 29.61, 29.90, 32.48, 5 36.20, 48.32, 49.84, 53.68, 57.48, 60.92, 62.06, 65.61, 71.72, 105.42, 113.69, 118.64, 123.78, 136.26, 136.77, 159.70, 159.97, 164.75 Example 8 N-Ethyl-7-(4-nitrophenethyl)-3,7-diazabicyclo[3.3.1]nonane-3 10 carboxamide A mixture of 1-(2-bromoethyl)-4-nitrobenzene (1.6 g, 7.0 mmol), N-ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide (1.0 g, 5.1 mmol, see Example 6(b) above) and KCO 3 (1.38 g, 10 mmol) was stirred at rt overnight. The mixture was then filtered and concentrated in vacuo and 15 the resulting residue purified by column chromatography, eluting with a gradient of DCM:MeOH (100:0 to 90:10), to yield 1.5 g (85%) of the title compound. 13C NMR (CDCl 3 ): 6 15.71, 28.83, 30.11, 33.03, 35.67, 47.97, 59.22, 20 59.49, 123.34, 129.65, 146.26, 149.15, 157.95 Example 9 N-(Cyanomethyl)-7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diaza bicyclo[3.3.1]nonane-3-carboxamide 25 (a) Cyanomethyl isocyanate The title compound was prepared according to the procedure described in Example 2(a) above, using 2-aminoacetonitrile in place of cyclopropylmethylamine.

WO 00/77000 63 PCT/SE00/01254 (b) N-(Cyanomethyl)-7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7 diazabicyclo[3.3.1] nonane-3-carboxamide The title compound was prepared in 26% yield (counting steps (a) and (b) 5 together) according to procedure described in Example 2(b) above, using cyanomethyl isocyanate (from step (a) above) in place of cyclopropylmethyl isocyanate. 13C NMR (CDCl 3 ): 8 28.99. 29.27, 29.47, 31.77, 48.32, 49.33, 56.88, o10 60.33, 61.61, 65.32, 70.63, 103.96, 115.31, 117.63, 119.21, 133.93, 157.74, 162.08 Example 10 N-Ethyl-7- {4-[(methanesulfonyl)amino]phenethyl }-3,7-diazabicyclo 15 [3.3.1]nonane-3-carboxamide (a) 4-[(Methanesulfonyl)amino]phenethyl methanesulfonate Methanesulfonyl chloride (45 g, 0.39 mol) was added, dropwise over 30 minutes, to a cooled (-5 0 C) solution of 4-aminophenethyl alcohol (25.2 g, 20 0.18 mol) in pyridine (200 mL). The mixture was stirred at O'C for 1 h and then at rt overnight. The resulting red suspension was poured in to a mixture of ice (300 mL) and conc. HC1 (60 mL). The pink precipitate that formed was filtered off, redissolved in DCM, dried and treated with activated carbon. The resulting solution was concentrated in vacuo to give 25 a residue, which, on recrystallisation from ethyl acetate, gave 34.5 g (64%) of the sub-title compound. mp 133-134 0

C

WO 00/77000 64 PCT/SE00/01254 (b) N-Ethyl-7- {4- [(methanesulfonyl)amino]phenethyl} -3,7-diazabicyclo [3.3. 1]nonane-3-carboxamide A mixture of N-ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide (1 g, 5 mmol, see Example 6(b) above), 4-[(methanesulfonyl)amino]phenethyl 5 methanesulfonate (1.5 g, 5 mmol, from step (a) above) and NaHCO 3 (3 g, 35.7 mmol) in MeCN (50 mL) was refluxed for 3 h under nitrogen. The reaction mixture was filtered and concentrated in vacuo to give 2.2 g of crude product, which was filtered through a silica plug, with MeOH/2 N HC1. The pH of the fractions was raised to pH 6 and extracted with o10 DCM, yielding 0.2 g of the title compound. 1 3 C NMR (CDCl 3 ): 6 15.75, 28.87, 30.23, 32.58, 35.64, 35.76, 39.14, 48.18, 59.17, 60.26, 121.41, 129.85, 134.72 15 Example 11 7-[3-(4-Cyanophenoxy)-2-fluoropropyl]-N-ethyl-3,7-diazabicyclo [3.3. 1]nonane-3-carboxamide (a) 7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N-ethyl-3,7-diazabicyclo 20 [3.3.1]nonane-3-carboxamide The title compound was prepared according to the procedure described in Example 1 above, using 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2 hydroxypropoxy]benzonitrile (see Example G above) in place of 4-{[(2S) 3-(3,7-diazabicyclo[3.3. 1]non-3-yl)-2-hydroxypropyl]loxy}benzonitrile. 25 (b) 7-[3-(4-Cyanophenoxy)-2-fluoropropyl]-N-ethyl-3,7-diazabicyclo [3.3.1 ]nonane-3-carboxamide A solution of 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-ethyl-3,7-diaza bicyclo[3.3.1]nonane-3-carboxamide (1.0 g, 2.7 mmol, from step (a) WO 00/77000 65 PCT/SE00/01254 above) in DCM (2.5 mL) was cooled to -78 0 C. A solution of (diethylamino)sulfurtrifluoride in DCM (2.5 mL) was added slowly under stirring. Stirring was continued for 35 minutes, during which time the reaction was allowed to warm to room temperature. Dichloromethane was 5 added and the reaction mixture was then washed with NaHCO 3 , dried and concentrated in vacuo. The resulting residue was purified by column chromatography, eluting with DCM:MeOH (98:2), to yield 0.68 g (67%) of the title compound. 10 1 3 C NMR (CDCl 3 ): 8 15.63, 29.00, 30.33, 35.70, 47.78, 47.93, 58.36, 58.67, 59.82, 60.39, 68.60, 68.89, 89.56, 91.86, 104.15, 115.56, 119.25, 133.97, 157.61, 161.92 Example 12 15 7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N-[2-oxo-2-(propylamino) ethyl]-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide (a) Ethyl 2-[({7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo [3.3.1 ] non-3-yl}carbonyl)amino]acetate 20 A cooled (00C) solution of 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2 hydroxypropoxy]benzonitrile (23.1 g, 77 mmol, see Example G above) in DCM (700 mL) was treated with ethyl 2-isocyanatoacetate (9.92 g, 77 mmol), and then stirred at rt for 7 h. The reaction mixture was concentrated in vacuo to yield 33.6 g (100%) of the sub-title compound. 25 (b) 7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N-[2-oxo-2-(propylamino) ethyl] -3,7-diazabicyclo [3.3. 1]nonane-3-carboxamide A mixture of ethyl 2-[({7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7 diazabicyclo[3.3.1]non-3-yl}carbonyl)amino]acetate (0.76 g 1.8 mmol, WO 00/77000 66 PCT/SE00/01254 from step (a) above), propylamine (5 mL, 3.6 g, 69.1 mmol) and NaCN (0.01 g, 0.2 mmol) in methanol (10 mL) was warmed to 75 0 C in a sealed tube overnight. The solvent was then removed in vacuo and the residue diluted with Na 2

CO

3 solution. The aqueous mixture was extracted with 5 DCM, and the resulting organic layer separated, dried and concentrated in vacuo. The resulting residue was purified by column chromatography, eluting with a gradient of dichloromethane:methanol (100:0 to 90:10), to give the title compound in 70 % yield. 10 13C NMR (CDCl 3 ): 6 11.36, 22.65, 29.12, 29.42, 31.78, 41.15, 44.75, 48.15, 49.10, 56.99, 60.40, 61.35, 65.33, 70.74, 103.99, 115.27, 119.12, 133.91, 158.71, 162.10, 170.62 Example 13 15 7- {3-(4-Cyanophenoxy)-2-[(4-morpholinylcarbonyl)amino]propyl}-N ethyl-3,7-diazabicyclo[3.3.1] nonane-3-carboxamide (a) tert-Butyl 3-(4-cyanophenoxy)-2-hydroxypropylcarbamate A cooled (0 0 C) solution of 4-(3-amino-2-hydroxypropoxy)benzonitrile 20 (44.6 g, 0.23 mol, see Example 4(a) above) in THF:H 2 0 (1.5 L of 1:1) was treated with di-tert-butyl dicarbonate (53 g, 0.24 mol). The mixture was stirred at rt overnight, after which NaCl was added and the resulting organic layer separated. The water layer was extracted with ether and the combined organics were dried and concentrated in vacuo. The resulting 25 oil (70 g) was filtered through a plug of silica, and then crystallised from diethyl ether:di-iso-propyl ether to yield 50 g of the sub-title compound.

WO 00/77000 67 PCT/SE00/01254 (b) 2-[(tert-Butoxycarbonyl)amino]- 1-[(4-cyanophenoxy)methyl] ethyl methanesulfonate Methanesulfonyl chloride (22.3 g 0.195 mol) was added over the course of 1.5 hours to a cooled (0'C) solution of tert-butyl 3-(4-cyanophenoxy)-2 5 hydroxypropylcarbamate (51.2 g, 0.177 mol, from step (a) above) and 4 (dimethylamino)pyridine (1.3 g, 10.6 mmol) in pyridine (250 mL), kept under an inert atmosphere. The reaction mixture was stirred for 2 h at rt before water and DCM were added. The organic layer was separated, washed with water, dried (MgSO 4 ) and concentrated in vacuo to yield 10 68.1 g (100%) of the sub-title compound. (c) tert-Butyl 2-[(4-cyanophenoxy)methyl]-1l-aziridinecarboxylate A cooled (0 0 C) solution of 2-[(tert-butoxycarbonyl)amino]-1-[(4-cyano phenoxy)methyl]ethyl methanesulfonate (30.6 g, 82.6 mmol, from step (b) 15 above) and tetrabutylammonium hydrogensulfate (3 g, 8.8 mmol) in DCM (100 mL) was treated with 50 wt.% aqueous NaOH (60 mL) under an inert atmosphere. The resulting mixture was stirred, and the temperature was slowly allowed to rise to rt over for 4 h, and then extracted with ether. The organic layer was washed with water and concentrated in 20 vacuo to give a residue that was purified by column chromatography (dichloromethane eluant). Crystallisation from diethyl ether:di-iso-propyl ether gave the sub-title compound in quantitative yield. (d) tert-Butyl 2-(4-cyanophenoxy)-1-({7-[(ethylamino)carbonyl]-3,7-diaza 25 bicyclo[3.3.1]non-3-yl}methyl)ethylcarbamate A mixture of N-ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide (2.88 g, 14.6 mmol, see Example 6(b) above) and tert-butyl 2-[(4 cyanophenoxy)methyl]-1-aziridinecarboxylate (4.0 g, 14.6 mmol, from step (c) above) in iso-propanol (20 mL) was refluxed overnight. The WO00/77000 68 PCT/SE00/01254 reaction mixture was concentrated in vacuo to give 7.4 g of a yellow oil, which was purified by column chromatography, eluting with a gradient of DCM:MeOH (100:0 to 90:10), to yield 3.33 g of the sub-title compound. 5 (e) 7-[2-Amino-3-(4-cyanophenoxy)propyl]-N-ethyl-3,7-diazabicyclo [3.3. 1]nonane-3-carboxamide A solution of tert-butyl 2-(4-cyanophenoxy)- 1-({7-[(ethylamino)carbonyl] 3,7-diazabicyclo[3.3.1]non-3-yl}methyl)ethylcarbamate (2.4 g, 5.1 mmol, from step (d) above) in HCl-saturated ethyl acetate was stirred for 1 h at o10 rt. The reaction mixture was then concentrated in vacuo and resulting residue re-dissolved in water. The aqueous solution was treated with aqueous NaHCO 3 and extracted with DCM, which organic layer was then dried and concentrated in vacuo to give 2 g of the sub-title compound. 15 (f) 7- {3-(4-Cyanophenoxy)-2-[(4-morpholinylcarbonyl)amino]propyl}-N ethyl-3,7-diazabicyclo[3.3.1] nonane-3-carboxamide A cooled (5 0 C) solution of 7-[2-amino-3-(4-cyanophenoxy)propyl]-N ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide (0.33 g, 0.7 mmol, from step (e) above) and triethylamine (0.4 mL, 3.0 mmol) in DCM 20 (5 mL) was treated with 4-morpholinecarbonyl chloride (0.11 g, 0.7 mmol), and then stirred at 5 0 C for 3 h. After further stirring at room temperature overnight, tlc analysis indicated incomplete reaction, and so a further portion of 4-morpholinecarbonyl chloride (40 mg, 0.27 mmol) was added. Stirring was continued at rt overnight again before NaHCO 3 25 solution was added. The organic layer was separated, dried and concentrated in vacuo to give 400 mg of crude product, which was purified by column chromatography on silica gel, eluting with dichloromethane:methanolic ammonia (95:5) to give 250 mg of the title compound.

WO 00/77000 69 PCT/SE00/01254 13 C NMR (CDC1 3 ): 8 161.94, 158.26, 157.81, 133.94, 119.15, 115.37, 103.90, 67.26, 66.66, 60.66, 60.51, 57.99, 48.93, 48.37, 47.39, 44.06, 35.93, 30.71, 29.34, 29.02, 15.51 5 Example 14 N-(4-Cyanophenethyl)-7-(4-oxoheptyl)-3,7-diazabicyclo[3.3.1] nonane-3 carboxamide o10 (a) 3-Benzyl-7-[3-(2-propyl-1,3-dioxolan-2-yl)propyl]-3,7-diazabicyclo [3.3. 1]lnonane A mixture of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (10.5 g, 48.5 mmol, see Example E above), 2-(3-bromopropyl)-2-propyl-1,3-dioxolane (11.5 g, 48.5 mmol, Bajrowicsz et al., Tetrahedron, 41 (1985) 1833) and K 2

CO

3 15 (13.8 g, 0.1 mol) in MeCN (50 mL) was refluxed overnight. The reaction mixture was filtered and concentrated in vacuo to yield 18.8 g (100%) of the sub-title compound. (b) 3-[3-(2-Propyl-1,3-dioxolan-2-yl)propyl]-3,7-diazabicyclo[3.3.1] 20 nonane A solution of 3-benzyl-7-[3-(2-propyl-1,3-dioxolan-2-yl)propyl]-3,7 diazabicyclo[3.3.1]nonane (18.8 g, 4.85 mmol, from step (a) above) in ethanol (100 mL) was hydrogenated over 5% Pd/C at ambient pressure. The catalyst was removed by filtration through a pad of Celite®, and the 25 filtrate concentrated in vacuo to yield 13.7 g (100%) of the sub-title compound.

WO 00/77000 70 PCT/SE00/01254 (c) N-(4-Cyanophenethyl)-7-(4-oxoheptyl)-3,7-diazabicyclo[3.3.1]nonane 3-carboxamide A solution of 4-(2-aminoethyl)benzonitrile (1.0 g, 6.9 mmol, Wiley et al., Bioorg. Med. Chem. Lett., 6 (1996) 2387) in dry THF (10 mL) was 5 treated with 1,1 '-carbonyldiimidazole (1.17 g, 7.2 mmol), and the mixture was stirred for 30 min. A solution of 3-[3-(2-propyl-1,3-dioxolan-2 yl)propyl]-3,7-diazabicyclo[3.3.1]nonane (1.3 g, 4.6 mmol, from step (b) above) in THF (5 mL) was added to the reaction mixture, and stirring was continued overnight at rt. The solution was then concentrated in vacuo and o10 the resulting residue diluted with MeOH and 2 M HC1, which solution was stirred for 2 h at rt. The mixture was made alkaline and extracted with DCM. The organic layer was separated, dried and concentrated in vacuo to give a residue which was purified by flash chromatography, eluting with DCM:MeOH (92:8), to yield 0.57 g (30%) of the title compound. 15 13C NMR (CDCl 3 ): 8 13.73, 17.21, 20.85, 28.79, 30.38, 36.91, 39.84, 41.83, 44.73, 47.94, 57.65, 59.05, 110.06, 118.93, 129.67, 132.20, 145.52, 157.47, 211.67 20 Example 15 N'-(4-Cyanobenzoyl)-7-(4-oxoheptyl)-3,7-diazabicyclo[3.3.1 ]nonane-3 carbohydrazide A mixture of 4-cyanobenzohydrazide (0.82 g, 5.0 mmol) and 1,1' carbonyldiimidazole (0.82 g, 5 mmol) in THF (15 mL) was stirred for 10 25 min at rt before 3-[3-(2-propyl-1,3-dioxolan-2-yl)propyl]-3,7-diazabicyclo [3.3.1]nonane (1.44 g, 5.0 mmol, see Example 14(b) above) was added. The reaction mixture was stirred overnight at rt, before being concentrated in vacuo. The resulting residue was dissolved in DCM, and washed with water. The organic layer was separated and concentrated in vacuo to give WO00/77000 71 PCT/SE00/01254 a residue which was dissolved in methanol/2M HC1. Evaporation of the MeOH in vacuo and extraction of the remaining aqueous solution with DCM, gave, after purification by flash chromatography on silica gel (dichloromethane:methanolic ammonia eluant), 0.5 g (25%) of the title 5 compound. 1 3 C NMR (CDCl 3 ): 6 213.21, 164.24, 157.01, 136.31, 132.19, 128.24, 118.11, 115.11, 58.65, 57.89, 48.38, 44.31, 40.55, 31.52, 29.12, 21.60, 17.08, 13.69 10 Example 16 4-{2-Amino-3-[7-(1-piperidinylcarbonyl)-3,7-diazabicyclo[3.3.1]non-3 yl]propoxy}benzonitrile 15 (a) 7-Benzyl-3,7-diazabicyclo[3.3.1]non-3-yl(1-piperidinyl)methanone The sub-title compound was prepared by way of a reaction between 3 benzyl-3,7-diazabicyclo[3.3.1]nonane (see Example E above) and 1 piperidinecarbonyl chloride (Boon, J. Chem. Soc., (1947) 307, 313). 20 (b) 3,7-Diazabicyclo[3.3.1]non-3-yl(1-piperidinyl)methanone The sub-title compound was obtained in quantitative yield according to the procedure described in Example 14(b) above, using 7-benzyl-3,7 diazabicyclo[3.3.1 ]non-3-yl( 1 -piperidinyl)methanone (from step (a) above) in place of 3-benzyl-7-[3-(2-propyl-1,3-dioxolan-2-yl)propyl]-3,7 25 diazabicyclo[3.3.1]nonane.

WO 00/77000 72 PCT/SE00/01254 (c) tert-Butyl 2-(4-cyanophenoxy)- 1- { [7-(1-piperidinylcarbonyl)-3,7-diaza bicyclo [3.3.1 ]non-3-yl]methyl} ethylcarbamate A mixture of tert-butyl 2-[(4-cyanophenoxy)methyl]-1l-aziridinecarboxylate (1.92 g, 7 mmol, see Example 13(c) above) and 3,7-diaza 5 bicyclo[3.3.1]non-3-yl(1-piperidinyl)methanone (1.85 g, 7 mmol, from step (a) above) in iso-propanol (15 mL) was refluxed for 30 h. The solution was concentrated in vacuo to yield 3.7 g of crude product, which was purified by chromatography using 2.5% MeOH in DCM to give 2.0 g (56%) of sub-title compound. 10 (d) 4-{2-Amino-3-[7-(1-piperidinylcarbonyl)-3,7-diazabicyclo[3.3.1]non-3 yl]propoxy}benzonitrile A cooled (0 0 C) solution of tert-butyl 2-(4-cyanophenoxy)-1-{[7-(1 piperidinylcarbonyl)-3,7-diazabicyclo[3.3.1 ]non-3-yl] methyl} ethyl 15 carbamate (1.9 g, 3.7 mmol, from step (c) above) in ethyl acetate was treated with HCl-saturated ethyl acetate. The mixture was stirred for 4 h before being concentrated in vacuo. The resulting residue was dissolved in water, made basic with NaHCO 3 and extracted with DCM. The organic layer was separated, dried and concentrated in vacuo to yield 1.5 20 g (100%) of the title compound. 13C NMR (CDC1 3 ): 8 24.73, 25.72, 29.62, 29.95, 32.11, 47.44, 48.14, 49.53, 50.98, 57.87, 60.57, 62.59, 72.03, 103.90, 115.30, 119.22, 133.91, 162.23, 164.35 25 WO 00/77000 73 PCT/SE00/01254 Example 17 N-Ethyl-7-{2-hydroxy-3-[4-(1H-imidazol-1-yl)phenoxy]propyl}-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide 5 (a) 1-[4-(2-Oxiranylmethoxy)phenyl]-1H-imidazole A mixture of 4-(1H-imidazol-1-yl)phenol (10 g, 60 mmol), K 2

CO

3 (8.63 g, 60 mmol ) and 2-oxiranylmethyl 3-nitrobenzenesulfonate (15.5 g, 60 mmol, see Example B above) in DMF (140 mL) was stirred at 40 0 C overnight. The mixture was then concentrated in vacuo and the resulting o10 residue diluted with DCM, washed with water, dried and then concentrated in vacuo. The crude product was then purified by flash chromatography, eluting with a gradient of dichloromethane:methanol (100:0 to 70:30) to yield 3.4 g, (72.6%) of the title compound. 15 (b) N-Ethyl-7- {2-hydroxy-3-[4-(1H-imidazol-1-yl)phenoxy]propyl}-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide A mixture of 1-[4-(2-oxiranylmethoxy)phenyl]-1H-imidazole (3.16 g, 14.6 mmol, from step (a) above) and N-ethyl-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide (2.88 g 14.6 mmol, see Example 6(b) 20 above) in iso-propanol:HO 2 0 (18 mL of 9:1) was refluxed for 3 hours, concentrated in vacuo and purified by acid/base extraction to yield 4.4 g (72.6%) of the title compound.

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3 C NMR (CDCl 3 ): 5 15.52, 29.13, 29.44, 31.84, 35.70, 47.92, 49.07, 25 57.21, 60.44, 61.94, 65.45, 70.76, 115.49, 118.58, 122.90, 129.86, 130.56, 135.66, 158.16, 158.78 WO 00/77000 74 PCT/SE00/01254 Example 18 N-[3-(4-Cyanophenoxy)propyl]-7-(2-hydroxyethyl)-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide 5 (a) 4-(3-Bromopropoxy)benzonitrile 1,3-Dibromopropane (1.02 L; 10 mol) was added to a stirred suspension of p-cyanophenol (238 g; 2 mol), K 2

CO

3 (276.4 g; 2 mol) in MeCN (2.7 L). The reaction mixture was refluxed for 4 h, filtered and concentrated. The residue was recrystallized from iso-propyl ether to give the sub-title o10 compound in a 69% yield. (b) 4-[3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]benzonitrile A mixture of 4-(3-bromopropoxy)benzonitrile (20 g, 84 mmol, see step (a) above) and potassium phthalimide (15.5 g, 84 mmol) in DMF (120 mL) 15 was stirred at 950C for 4 h. The solution was then concentrated in vacuo and the resulting residue dissolved in DCM and washed with water. The organic layer was separated, dried (Na2SO 4 ) and concentrated in vacuo to yield 25.5 g (99%) of the sub-title compound. 20 (c) 4-(3-Aminopropoxy)benzonitrile A mixture of 4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy] benzonitrile (25.5 g, 83 mmol, from step (b) above) and hydrazine hydrate (4.15 g, 83 mmol) in methanol (100 mL) was refluxed for 1 h before water (120 mL) was added. The methanol was evaporated under reduced 25 pressure and concentrated hydrochloric acid (120 mL) was added. The resulting mixture was heated on a steam bath for 1.5 h and then cooled in the refrigerator overnight. The resulting precipitate was filtered off and the filtrate was concentrated in vacuo. Water was added to the resulting residue and the solution made basic. The aqueous solution was extracted WO 00/77000 75 PCT/SE00/01254 with DCM, which organic layer was then separated, dried and concentrated in vacuo to yield 6 g (41%) of the sub-title compound. (d) 7-Benzyl-3,7-diazabicyclo[3.3.1]nonane-3-ethanol 5 The compound was prepared in 72% yield by reacting 3-benzyl-3,7 diazabicyclo[3.3.1]nonane (see Example E above) with 2-bromoethanol. (e) 3,7-Diazabicyclo[3.3.1] nonane-3-ethanol The sub-title compound was prepared according to the procedure io described in Example 14(b) above, using 7-benzyl-3,7 diazabicyclo[3.3.1]nonane-3-ethanol (from step (d) above) in place of 3 benzyl-7-[3-(2-propyl-1,3-dioxolan-2-yl)propyl]-3,7-diazabicyclo[3.3.1] nonane. 15 (f) N-[3-(4-Cyanophenoxy)propyl]-7-(2-hydroxyethyl)-3,7-diazabicyclo [3.3. 1]nonane-3-carboxamide The title compound was prepared in 11% yield according to the procedure described in Example 14(c) above, using 3,7-diazabicyclo[3.3.1]nonane-3 ethanol (from step (e) above) and 4-(3-aminopropoxy)benzonitrile (from 20 step (c) above) in place of 3-[3-(2-propyl-1,3-dioxolan-2-yl)propyl]-3,7 diazabicyclo[3.3.1]nonane and 4-(2-aminoethyl)benzonitrile, respectively. 13C NMR (CDCl 3 ): 6 162.04, 158.99, 133.66, 118.99, 115.03, 103.35, 66.55, 60.24, 57.87, 57.18, 50.02, 48.63, 37.93, 31.81, 29.26, 28.96 25 WO 00/77000 76 PCT/SEOO/01254 Example 19 N- { [7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1] non 3-yl]carbonyl}-4-methylbenzenesulfonamide A solution of 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy] 5 benzonitrile (200 mg, 0.66 mmol, see Example G above) in chloroform (20 mL) was treated with a solution of p-toluenesulfonyl isocyanate (110 pL of 96% purity, 0.136 g, 0.69 mmol in chloroform (4 mL), added dropwise. A white precipitate immediately formed and the mixture was then concentrated in vacuo. The crude product so obtained was subjected o10 to chromatography on silica gel, eluting with hexane:ethyl acetate:methanolic ammonia (75:75:50) to give the title compound in 53% yield. 13 C NMR (CDCl 3 ): 8 15.77, 29.18, 32.37, 36.13, 48.72, 52.27, 56.32, 15 109.83, 113.13, 118.27, 118.93, 120.10, 127.80, 131.39, 132.46, 132.73, 134.62, 138.75, 159.14, 167.09 Example 20 N-Allyl-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1] 20 nonane-3-carboxamide A mixture of allylamine (125 pL, 1.66 mmol) and 1,1'-carbonyl diimidazole (269 mg, 1.66 mmol) in THF (10 mL) was stirred at rt for 40 min. The mixture was then treated with a solution of 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]benzonitrile (see 25 Example G above) in THF (5 mL), and stirring continued overnight. The mixture was concentrated in vacuo and the resulting residue purified by chromatography on silica gel, eluting with hexane:methanolic ammonia (1:1) to give the title compound in 57% yield.

WO 00/77000 77 PCT/SE00/01254 13C NMR (MeOD): 8 29.37, 30.79, 41.95, 42.91, 58.91, 59.55, 61.12, 66.52, 70.75, 103.31, 113.81, 115.39, 118.72, 133.73, 135.57, 136.06, 158.93, 162.67 5 Example 21 7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N-[2-(2-thienyl)ethyl]-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide The title compound was prepared in 83 % yield according to the procedure described in Example 19 above, using 2-(2-isocyanatoethyl)thiophene in io place of p-toluenesulfonyl isocyanate.

"

3 C NMR (CDC13): 8 29.19, 29.50, 30.59, 32.11, 42.26, 47.94, 49.37, 56.23, 60.47, 61.95, 65.32, 70.74, 103.88, 115.36, 119.52, 123.69, 125.25, 127.04, 133.90, 142.19, 158.74, 162.22 15 Example 22 7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N-[3-(ethylamino)-3 oxopropyl]-3,7-diazabicyclo[3.3.1 ]nonane-3-carboxamide 20 (a) Ethyl 3-[({7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo [3.3.1]non-3-yl}carbonyl)amino]propanoate The sub-title compound was prepared in 90% yield according to the procedure described in Example 12(a) above, using ethyl 3 isocyanatopropanoate in place of ethyl 2-isocyanatoacetate. 25 (b) 7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N-[3-(ethylamino)-3-oxo propyl] -3,7-diazabicyclo[3.3.1 ]nonane-3-carboxamide The title compound was prepared in 22 % yield according to the procedure described in Example 12(b) above, using ethyl 3-[({7-[3-(4- WO 00/77000 78 PCT/SE00/01254 cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]non-3-yl} carbonyl)amino]propanoate (from step (a) above) and ethylamine in place of ethyl 2-[({7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo [3.3.1 ]non-3-yl} carbonyl)amino] acetate and propylamine, respectively. 5

"

3 C NMR (CDCl 3 ): 8 172.46, 162.17, 158.89, 133.96, 119.14, 115.37, 104.16, 65.27, 61.73, 60.58, 56.97, 49.23, 47.89, 37.51, 36.60, 34.26, 32.00, 29.54, 29.16, 14.87 o10 Example 23 N-(1-Cyanoethyl)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diaza bicyclo[3.3. 1]nonane-3-carboxamide (a) 2-Aminopropanenitrile 15 Lactonitrile (28 g, 375 mmol) was added to liquid ammonia at -78 0 C in a reaction tube. The tube was sealed and the mixture was stirred overnight at rt. The ammonia was removed by evaporation and the crude material was used directly in the next step without any further purification. 20 (b) N-(1-Cyanoethyl)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diaza bicyclo[3.3. 1]nonane-3-carboxamide A mixture of 2-aminopropanenitrile (250 mg, 3.58 mmol, from step (a) above) and N-ethyl di-iso-propylamine (0.67 mL, 0.50 g, 3.84 mmol) in DCM (9 mL) was added (by syringe pump), over the course of 1 hour, to 25 a solution of triphosgene (352 mg, 1.19 mmol) in DCM (7 mL). The resulting mixture was stirred for 1 h at rt before a mixture of 4-[3-(3,7 diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]benzonitrile (1.08 g, 3.58 mmol, see Example G above) and N-ethyl di-iso-propylamine (0.67 mL, 0.50 g, 3.84 mmol) in DCM (14 mL) was added. Stirring was continued WO 00/77000 79 PCT/SE00/01254 for a further 20 min, before the solution was concentrated in vacuo and the resulting residue purified by flash chromatography, eluting with dichloromethane:methanol (95:5), to give the title compound in 65% yield. 5

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3 C NMR (CDCl 3 ): 8 20.02, 20.16, 29.11, 29.32, 29.46, 31.91, 37.83, 37.89, 48.23, 48.47, 49.36, 49.61, 56.95, 60.26, 60.51, 61.58, 62.077, 65.43, 70.69, 104.06, 115.40, 119.27, 120.77, 133.96, 157.08, 162.21 io Example 24 7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N-(2,2,2-trifluoroethyl)-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide The title compound was prepared in 46% yield according to the procedure described in Example 23(b) above, using 2,2,2-trifluoroethylamine in 15 place of 2-aminopropanenitrile. 13C NMR (CDCl 3 ): 5 29.11, 29.42, 31.79, 42.17, 42.51, 48.36, 49.58, 57.09, 60.45, 61.77, 65.39, 70.76, 104.08, 115.39, 119.23, 123.28, 126.05, 133.93, 157.76, 162.21 20 Example 25 7-[3-(4-Cyanophenoxy)-2-hydroxypropyl]-N-[2-oxo-2-(1-piperidinyl) ethyl] -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide The title compound was prepared in 49% yield according to the procedure 25 described in Example 12(b) above, using piperidine in place of propylamine. 13C NMR (CDCl 3 ): 6 24.33, 25.41, 26.06, 28.74, 29.29, 29.44, 32.13, 42.67, 43.10, 45.30, 47.99, 48.09, 49.14, 49.28, 57.18, 60.42, 61.90, WO 00/77000 80 PCT/SE00/01254 65.55, 70.77, 94.22, 103.89, 115.24, 115.43, 119.24, 133.74, 134.02, 158.49, 162.20, 167.42 Example 26 5 N-(1,3-Benzodioxol-5-yl)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7 diazabicyclo[3.3.1] nonane-3-carboxamide The title compound was prepared in 33 % yield according to the procedure described in Example 23(b) above, using 1,3-benzodioxol-5-amine in place of 2-aminopropanenitrile. 10 13C NMR (CDCl 3 ): 6 162.22, 156.51, 147.47, 143.20, 133.98, 133.83, 119.41, 115.40, 113.68, 107.68, 103.83, 103.59, 100.96, 70.70, 65.98, 61.34, 60.34, 57.87, 49.17, 48.13, 31.52, 29.41, 29.11 15 Example 27 7-[3-(4-Cyanoanilino)propyl] -N-[2-oxo-2-(propylamino)ethyl]-3,7 diazabicyclo[3.3.1 ]nonane-3-carboxamide (a) 4-[(3-Hydroxypropyl)amino]benzonitrile 20 A mixture of 4-fluorobenzonitrile (12.0 g, 99.1 mmol) and 3-amino-1 propanol (59.6 g, 793 mmol) was stirred at 80 0 C under an inert atmosphere for 3 hours before water (150 mL) was added. The mixture was allowed to cool to rt, and was then extracted with diethyl ether. The organic layer was separated, dried (Na 2

SO

4 ), filtered and concentrated in 25 vacuo to yield 17 g (97%) of the title compound as a oil that crystallised upon standing.

WO 00/77000 81 PCT/SE00/01254 (b) 3-(4-Cyanoanilino)propyl 4-methylbenzenesulfonate A cooled (0 0 C) solution of 4-[(3-hydroxypropyl)amino]benzonitrile (17 g, 96.5 mmol, from step (a) above) in dry MeCN (195 mL) was treated with triethylamine (9.8 g, 96.5 mmol) and then p-toluenesulfonyl chloride 5 (20.2 g, 106 mmol). The mixture was stirred at 0 0 C for 90 minutes before being concentrated in vacuo. Water (200 mL) was added to the residue, and the aqueous solution was extracted with DCM. The organic phase was dried (Na 1

SO

4 ), filtered and concentrated in vacuo. The resulting residue was purified by crystallisation from iso-propanol to yield o10 24.6 g (77%) of the sub-title compound. (c) Ethyl 2- { [(7-benzyl-3,7-diazabicyclo[3.3.1] non-3-yl)carbonyl] amino } acetate The sub-title compound was prepared in 99% yield according to the 15 procedure described in Example 5(a) above, using 4-[3-(3,7-diazabicyclo[3.3.1]non-3-yl)-2-hydroxypropoxy]benzonitrile (see Example G above) and ethyl 2-isocyanatoacetate in place of 3-benzyl-3,7 diazabicyclo[3.3.1]nonane and iso-propyl isocyanate, respectively. 20 (d) 7-Benzyl-N-[2-oxo-2-(propylamino)ethyl]-3,7-diazabicyclo[3.3.1] nonane-3-carboxamide The sub-title compound was prepared in 88% yield according to the procedure described in Example 12(b) above, using ethyl 2-{[(7-benzyl 3,7-diazabicyclo[3.3.1]non-3-yl)carbonyl]amino}acetate (from step (c) 25 above) in place of ethyl 2-[({7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7 diazabicyclo[3.3.1] non-3-yl} carbonyl)amino] acetate.

WO 00/77000 82 PCT/SE00/01254 (e) N-[2-Oxo-2-(propylamino)ethyl]-3,7-diazabicyclo[3.3.1] nonane-3 carboxamide The title compound was prepared according to the procedure described in Example 5(b) above, using 7-benzyl-N-[2-oxo-2-(propylamino)ethyl]-3,7 5 diazabicyclo[3.3.1]nonane-3-carboxamide (from step (d) above) in place of 7-benzyl-N-iso-propyl-3,7-diazabicyclo[3.3.1] nonane-3-carboxamide. (f) 7-[3-(4-Cyanoanilino)propyl]-N-[2-oxo-2-(propylamino)ethyl]-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide o10 A mixture of N-[2-oxo-2-(propylamino)ethyl]-3,7-diazabicyclo[3.3.1] nonane-3-carboxamide (3.35 g, 12.5 mmol, from step (e) above),

K

2

CO

3 (6.9 g, 50 mmol) and sodium iodide (0.19 g, 1.25 mmol) in acetonitrile (600 mL) was treated with 3-(4-cyanoanilino)propyl 4-methyl benzenesulfonate (4.2 g, 12.7 mmol, from step (b) above) and stirred 15 under reflux for 5 h, followed by a further 21 h at rt. The mixture was filtered, concentrated in vacuo and the crude product so obtained was diluted with water. The aqueous solution was extracted with DCM, which organic layer was separated, dried and concentrated in vacuo. The crude product so obtained was purified by chromatography on silica gel, eluting 20 with DCM:MeOH (95:5) to yield 3.08 g (58%) of the title compound. 1 3 C NMR (CDCl 3 ): 6 11.49, 22.85, 25.11, 29.09, 31.03, 40.78, 41.40, 44.80, 48.41, 56.22, 59.32, 97.43, 111.99, 120.97, 133.74, 151.98, 157.92, 170.37 25 WO 00/77000 PCT/SE00/01254 83 dichloromethane:methanol (9:1) to yield 0.8 g (30%) of the title compound. 1 3 C NMR (CDCl 3 ): 6 162.18, 133.92, 119.24, 115.34, 103.92, 69.07, 5 67.86, 59.52, 58.42, 48.18, 35.68, 30.25, 28.81, 15.69 Example 29 7-[4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-N-ethyl-3,7-diaza bicyclo[3.3.1]nonane-3-carboxamide 10 (a) 4-[1-(3,4-Dimethoxyphenoxy)-3-butenyl]benzonitrile A cooled (0 0 C) mixture of 4-(1-hydroxy-3-butenyl)benzonitrile (14.6 g, 84.3 mmol) and 3,4-dimethoxyphenol (19.5 g, 125.4 mmol) in toluene (500 mL) was treated with tributylphosphine (32.14 mL of 97% purity, 15 25.6 g, 126.4 mmol), followed by 1,1'-(azodicarbonyl)dipiperidine (31.8 g, 126.4 mmol). After addition was complete, the reaction mixture thickened and the temperature rose to 15 0 C. Additional toluene was added (500 mL), and the mixture stirred at rt overnight. The precipitate of tributylphosphine oxide was then removed by filtration and the filtrate 20 concentrated in vacuo to give 65.8 g of crude product. This was purified by chromatography on silica gel, eluting with toluene:methanol (98:2) to yield 17.9 g of the sub-title compound. (b) 4-[1-(3,4-Dimethoxyphenoxy)-4-hydroxybutyl]benzonitrile 25 Borane-methyl sulfide complex (2 M in ether, 11 mL, 22 mmol) was added dropwise to a cooled (-5 0 C) solution of 4-[1-(3,4-dimethoxy phenoxy)-3-butenyl]benzonitrile (17.6 g, 56.8 mmol, from step (a) above) in dry THF (15 mL) over a period of 15 minutes (during which time the reaction temperature rose to 0 0 C). The resulting mixture was stirred at WO 00/77000 84 PCT/SE00/01254 dichloromethane:methanol (9:1) to yield 0.8 g (30%) of the title compound. 1 3 C NMR (CDCl 3 ): 8 162.18, 133.92, 119.24, 115.34, 103.92, 69.07, 5 67.86, 59.52, 58.42, 48.18, 35.68, 30.25, 28.81, 15.69 Example 29 7-[4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-N-ethyl-3,7-diaza bicyclo[3.3. 1]nonane-3-carboxamide 10 (a) 4-[1-(3,4-Dimethoxyphenoxy)-3-butenyl]benzonitrile A cooled (0 0 C) mixture of 4-(1-hydroxy-3-butenyl)benzonitrile (14.6 g, 84.3 mmol) and 3,4-dimethoxyphenol (19.5 g, 125.4 mmol) in toluene (500 mL) was treated with tributylphosphine (32.14 mL of 97% purity, 15 25.6 g, 126.4 mmol), followed by 1,1'-(azodicarbonyl)dipiperidine (31.8 g, 126.4 mmol). After addition was complete, the reaction mixture thickened and the temperature rose to 15 0 C. Additional toluene was added (500 mL), and the mixture stirred at rt overnight. The precipitate of tributylphosphine oxide was then removed by filtration and the filtrate 20 concentrated in vacuo to give 65.8 g of crude product. This was purified by chromatography on silica gel, eluting with toluene:methanol (98:2) to yield 17.9 g of the sub-title compound. (b) 4-[1-(3,4-Dimethoxyphenoxy)-4-hydroxybutyl]benzonitrile 25 Borane-methyl sulfide complex (2 M in ether, 11 mL, 22 mmol) was added dropwise to a cooled (-5 0 C) solution of 4-[1-(3,4-dimethoxy phenoxy)-3-butenyl]benzonitrile (17.6 g, 56.8 mmol, from step (a) above) in dry THF (15 mL) over a period of 15 minutes (during which time the reaction temperature rose to 0 0 C). The resulting mixture was stirred at WO 00/77000 85 PCT/SE00/01254 between 0 and 10 0 C for 1.5 h, before being allowed to warm to rt. Stirring was continued for a further 3.5 h at this temperature before water (22 mL) and sodium perborate tetrahydrate (11 g, 66 mmol) were added. The biphasic mixture was stirred for 2 h at rt before the water layer was 5 separated and extracted with ether. The combined organic layers were washed with brine, dried and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel, eluting with iso propanol:ethyl acetate:heptane (5:25:70) to yield 14.5 g (77%) of the sub title compound. 10 (c) 4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl methanesulfonate A solution of methanesulfonyl chloride (3.4 mL, 5.0 g, 44 mmol) in DCM (15 mL) was added slowly to a cooled (-5 0 C) mixture of 4-[1-(3,4 dimethoxyphenoxy)-4-hydroxybutyl]benzonitrile (11 g, 34 mmol, from 15 step (b) above) and triethylamine (7 mL, 5.2 g, 50.6 mmol) in DCM (50 mL), during which addition the temperature did not rise above 2 0 C. Stirring was continued at between 0 and 5 0 C for a further 2 h before water was added. The resulting organic layer was separated, and washed with water, separated again and then dried to give the sub-title compound 20 in 100% yield. (d) tert-Butyl 7-[4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-3,7 diazabicyclo[3.3. 1]nonane-3-carboxylate A mixture of 4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl methane 25 sulfonate (522 mg, 1.29 mmol, from step (c) above), tert-butyl 3,7 diazabicyclo[3.3.1]nonane-3-carboxylate (307 mg, 1.356 mmol, see Example F above) and K 2

CO

3 (216 mg, 1.56 mmol) in chloroform:acetonitrile (10 mL of 1:1) was stirred at 70'C for 23 h. The reaction mixture was filtered and the filtrate concentrated in vacuo to give WO 00/77000 86 PCT/SE00/01254 708 mg of crude product. This was purified by flash chromatography, eluting with a gradient of toluene:methanol (97:3 to 10:1), to yield 607 mg (88%) of the sub-title compound. 5 (e) 4-[4-(3,7-Diazabicyclo[3.3.1] non-3-yl)- 1-(3,4-dimethoxyphenoxy) butyl]benzonitrile A cooled (0OC) solution of tert-butyl 7-[4-(4-cyanophenyl)-4-(3,4 dimethoxyphenoxy)butyl]-3,7-diazabicyclo[3.3. 1]nonane-3-carboxylate (1.92 g, 3.6 mmol, from step (d) above) in ethyl acetate (20 mL) was 10 treated with HCl-saturated ethyl acetate (30 mL). The resulting mixture was stirred for 2 h at between 0 and 5 0 C before being concentrated in vacuo. The resulting residue was dissolved in acetonitrile (50 mL) and treated with K 2

CO

3 (3.5 g, 25.2 mmol) and water (2.25 mL). This mixture was stirred for 3h at rt and the solids removed by filtration, 15 before the solvent was removed in vacuo (with toluene added to effect azeotropic removal of water) to give 1.5 g of the sub-title compound. (f) 7-[4-(4-Cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl]-N-ethyl-3,7 diazabicyclo [3.3.1] nonane-3-carboxamide 20 A solution of 4-[4-(3,7-diazabicyclo[3.3.1]non-3-yl)-1-(3,4-dimethoxy phenoxy)butyl]benzonitrile (109 mg, 0.25 mmol, from step (e) above), in CHC1 3 (1.43 mL) was treated with a solution of ethyl isocyanate (18.6 PL, 16.8 mg, 0.237 mmol) in MeCN (0.5 mL). The resulting mixture was stirred for 30 h. at rt. The solution was then loaded onto an ion-exchange 25 solid phase extraction plug (SiO 2 , 0.5 g from ISOLUTE). The plug was washed with CHC1 3 (2.5 mL) and the product then eluted with MeCN (3 x 2.5 mL). This gave the title compound (93 mg, 73%) in a purity better than 90% (as determined by HPLC: UV at 254 nm and ELS detection).

WO 00/77000 87 PCT/SE00/01254 MS (ES) m/z = 507 (M + 1)

+

, 505 (M - 1) Example 30 5 7-(3- {4-Cyano-2-[(cyclopropylamino)carbonyl]phenoxy}-2-hydroxy propyl)-N-phenyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide (a) 5-Cyano-N-cyclopropyl-2-[2-oxiranylmethoxy]benzamide The sub-title compound was prepared according to the method described o10 in Example 7(b) above using 2-oxiranylmethyl 3-nitrobenzenesulfonate (prepared analogously to the method described in Example B above). (b) 7-Benzyl-N-phenyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide A cooled (0 0 C) solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (10 g, 15 46 mmol, see Example E above) in DCM (100 mL) was treated with phenyl isocyanate (4.9 mL, 45 mmol). The mixture was stirred at rt for 30 min. The product formed as white crystals, which were removed by filtration to give 10 g (66%) of the sub-title compound. 20 (c) N-Phenyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide A solution of 7-benzyl-N-phenyl-3,7-diazabicyclo[3.3.1]nonane-3 carboxamide (10 g, 29.8 mmol, from step (b) above) in ethanol (100 mL) was subjected to hydrogenation, over 10% Pd/C and at ambient pressure, overnight. The catalyst was removed through a pad of Celite® and the 25 residue was concentrated in vacuo to give the sub-title compound in quantitative yield.

WO 00/77000 88 PCT/SE00/01254 (d) 7-(3-{4-Cyano-2-[(cyclopropylamino)carbonyl]phenoxy}-2-hydroxy propyl)-N-phenyl-3,7-diazabicyclo[3.3.1 ]nonane-3-carboxamide A mixture of 5-cyano-N-cyclopropyl-2-[2-oxiranylmethoxy]benzamide (0.8 g, 3.1 mmol, from step (a) above) and N-phenyl-3,7-diaza 5 bicyclo[3.3.1]nonane-3-carboxamide (0.9 g, 3.6 mmol, from step (c) above) in iso-propanol:H, 2 0 (10 mL of 9:1) was refluxed for 180 min. before dichloromethane was added and the solvent removed in vacuo. Purification of the resulting residue by flash chromatography, eluting with DCM:MeOH (9:1), gave 1 g (64%) of the title compound. 10

"

3 C NMR (CDCl 3 ): 8 6.33, 6.56, 23.23, 29.18, 29.51, 31.66, 48.27, 49.60, 53.44, 57.94, 60.51, 65.74, 71.28, 104.93, 113.46, 118.45, 119.54, 119.65, 122.88, 123.27, 128.84, 136.07, 156.44, 159.69, 164.53 15 Example 31 N-(4-Cyanophenyl)-7-[3-(ethanesulfonyl)propyl]-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide (a) 3-(Ethanesulfonyl)propyl 4-methylbenzenesulfonate 20 Triethylamine (13.36 g, 132 mmol) was added dropwise to a mixture of 3-(ethanesulfonyl)-1-propanol (13.4 g, 88 mmol, Martin-Smith et al., J. Pharm. Pharmacol., 19, (1967) 649) and p-toluenesulfonyl chloride (16.78 g, 88 mmol) in DCM (150 mL), resulting in a mildly exothermic reaction. After addition was complete, the reaction mixture was washed 25 twice with aqueous ammonium chloride solution, the organic layer was then separated, dried, and concentrated in vacuo. The resulting residue was recrystallised from diethyl ether/DCM to give 17.9 g (65%) of the sub-title compound.

WO00/77000 89 PCT/SE00/01254 (b) tert-Butyl 7-[(4-cyanoanilino)carbonyl]-3,7-diazabicyclo[3.3.1]nonane 3-carboxylate A suspension of tert-butyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (2.0 g, 8.8 mmol, see Example F above) in chloroform (15 mL) was 5 treated with 4-isocyanatobenzonitrile (1.53 g, 10.6 mmol). The mixture was stirred at rt for 1.5 h, at which time some solid particles were observed in the mixture. An additional 10 mL of chloroform was added in order to dissolve the particles. Mass spectroscopic analysis of the mixture indicated that the starting materials had been consumed, and so o10 the solvent was removed in vacuo. The resulting residue was purified by flash chromatography, eluting with a gradient of DCM:MeCN (5:1 to 2:1) to yield 2.31 g (71%) of the sub-title compound. (c) N-(4-Cyanophenyl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide 15 A cooled (0 0 C) solution of tert-butyl 7-[(4-cyanoanilino)carbonyl]-3,7 diazabicyclo[3.3.1]nonane-3-carboxylate (2.2 g 5.94 mmol, from step (b) above) in ethyl acetate (40 mL) was treated with HCl-saturated ethyl acetate (65 mL) over the course of 30 minutes. The resulting mixture was stirred at rt for a further 4 h before being concentrated in vacuo to give 20 1.8 g (99%) of the hydrochloride salt of the sub-title compound. (d) N-(4-Cyanophenyl)-7-[3-(ethanesulfonyl)propyl]-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide A mixture of N-(4-cyanophenyl)-3,7-diazabicyclo[3.3.1]nonane-3 25 carboxamide (67.6 mg, 0.25 mmol, from step (c) above) and K 2

CO

3 (80 mg, 0.57 mmol) in DMF (0.5 mL) was treated with a solution of 3-(ethanesulfonyl)propyl 4-methylbenzenesulfonate (153 mg, 0.50 mmol, from step (a) above), in MeCN (1.0 mL). The resulting suspension was stirred for 5 days at 50 0 C before being cooled and filtered. The filtrate WO 00/77000 90 PCT/SE00/01254 was then added to a ion-exchange solid phase extraction plug (CBA, 2 g from ISOLUTE). After 1 h the plug was washed with CHC1 3 (3 x 2.5 mE) and the product eluted with CHCl 3 :MeOH:Et 3 N (8:1:1) to give the title compound (63.6 mg, 63%) in a purity better than 90% (as determined by 5 HPLC: UV at 254 nm and ELS detection). MS (ES): m/z = 405 (M + 1)', m/z = 403 (M - 1) Example 32 10 7-{3-[(2-Cyano-1H-indol-4-yl)oxy]-2-hydroxypropyl}-N-phenyl-3,7 diazabicyclo[3.3. 1]nonane-3-carboxamide A mixture of 4 -(2-oxiranylmethoxy)-1H-indole-2-carbonitrile (1.0 g, 4.7 mmol, Pitha et al., J. Med. Chem., 30 (1987) 612) and N-phenyl-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide (1.4 g, 5.5 mmol, see Example 15 30(d) above) in iso-propanol:H 2 0 (10 mL of 9:1) was stirred under reflux for 3 h before being concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel, eluting with a gradient of DCM:MeOH (99:1 to 97:3), to yield 0.8 g (37%) of the title compound. 20 13C NMR (CDCl 3 ): 8 29.03, 29.39, 31.27, 48.37, 49.31, 57.89, 60.42, 61.41, 66.07, 70.04, 100.72, 104.39, 105.13, 111.31, 114.95, 117.66, 120.18, 120.30, 123.00, 126.54, 128.84, 138.39, 139.16, 152.55, 156.29 25 WO 00/77000 91 PCT/SE00/01254 Example 33 7-[(7-Cyano-2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-N-ethyl-3,7 diazabicyclo[3.3. 1]nonane-3-carboxamide 5 (a) 5-Bromo-2-(3-chloro-2-hydroxypropoxy)benzaldehyde A mixture of 5-bromo-2-hydroxy benzaldehyde (20.1 g, 0.1 mol), epichlorohydrin (25 mL, 0.32 mol) and 6 drops of piperidine was stirred under reflux for 6 h before being concentrated in vacuo. The resulting residue was dissolved in chloroform (25 mL) and treated with io concentrated HC1 (10 mL). The resulting mixture was stirred for 3 h at rt before the organic layer was washed with water, separated, dried and concentrated in vacuo to yield 28.2 g (96%) the sub-title compound. This was used directly in the next step without any further purification. 15 (b) 5-Bromo-2-(3-chloro-2-hydroxypropoxy)phenyl formate A solution of 5-bromo-2-(3-chloro-2-hydroxypropoxy)benzaldehyde (28.2 g, 96 mmol, from step (a) above) in DCM (200 niL) was treated with 3-chloroperoxybenzoic acid (25 g of 70-75% purity, approximately 100 mmol). The resulting exothermic reaction caused the mixture to 20 reflux for 20 min. Stirring was continued for a further 3 days before the mixture was filtered (to remove precipitated 3-chlorobenzoic acid). The filtrate was washed with K 2

CO

3 -solution and water, dried and concentrated in vacuo to yield 26.1 g of sub-title compound. This was used directly in the next step without any further purification. 25 (c) (7-Bromo-2,3-dihydro-1,4-benzodioxin-2-yl)methanol A solution of 5-bromo-2-(3-chloro-2-hydroxypropoxy)phenyl formate (26.1 g, 84 mmol, from step (b) above) in ethanol (100 mL) was treated with a solution of potassium hydroxide (6.1 g of 85% purity, WO 00/77000 92 PCT/SE00/01254 approximately 92 mmol) in water (10 mL). The resulting mixture was refluxed for 1.5 h before being filtered and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and washed with brine. The organic layer was separated, dried and concentrated in vacuo to give 5 28.8 g of crude product. This was purified by column chromatography on silica gel, eluting with diethyl ether:hexane (70:30), to yield 10.0 g (49.1%) of the sub-title compound. (d) 3-(Hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-carbonitrile o10 A mixture of (7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl)methanol (10.0 g, 41.2 mrmol, from step (c) above) and CuCN (4. 0 g, 45.3 mmol) in DMF (10 mL, dried over molecular sieves) was stirred at 170 0 C for 4.5 h. The reaction mixture was poured into a warm aqueous solution of sodium cyanide (8.10 g, 165 mmol of NaCN in 25 mL HO 2 0). The 15 resulting mixture was extracted with toluene and DCM. The combined organic layers were washed with water and then brine, dried and concentrated in vacuo. The residue so obtained was crystallised from toluene and DCM to yield 2.8 g (35%) of the sub-title compound. 20 (e) (7-Cyano-2,3-dihydro-1,4-benzodioxin-2-yl)methyl methanesulfonate A solution of methanesulfonyl chloride (1.81 g, 15.8 mmol) in dichloromethane (5 mL) was added dropwise to a cooled (0 0 C) mixture of 3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-carbonitrile (2.75 g, 14.4 mmol, from step (d) above) and pyridine (1.26 g, 16 mmol) in DCM 25 (25 mL). After addition was complete, the mixture was stirred at 0 0 C for 1 h, and then at rt overnight. TLC analysis indicated incomplete reaction after this time, and so further portions of methanesulfonyl chloride (0.4 g, 3.5 mmol) and pyridine (0.5 mL, 0.49 g, 6.2 mmol) were added. The mixture was refluxed for 3.5 h before being washed twice with saturated WO 00/77000 93 PCT/SE00/01254 Na 2

CO

3 solution, dried and concentrated in vacuo. The crude product (4.5 g) so obtained was purified by flash chromatography, eluting with DCM, to give 3.5 g of the sub-title compound, which crystallised on standing. 5 (f) 7-[(7-Cyano-2,3-dihydro-1,4-benzodioxan-2-yl)methyl]-N-ethyl-3,7 diazabicyclo [3.3.1 ]nonane-3-carboxamide A mixture of (7-cyano-2,3-dihydro-1,4-benzodioxin-2-yl)methyl methane sulfonate (150 mg, 0.9 mmol, from step (e) above), N-ethyl-3,7-diaza o10 bicyclo[3.3.1]nonane-3-carboxamide (186 mg, 0.94 mmol, see Example 6(b) above), K 2

CO

3 (265 mg, 2.0 mmol) and Nal (14 mg, 0.09 mmol) in

CH

3 CN was refluxed for 20 h. The solvent was removed in vacuo and the resulting residue treated with DCM and water. The organic layer was separated, dried (Na 2

SO

4 ) and concentrated in vacuo. The resulting 15 residue was purified by flash chromatography, eluting with DCM:MeOH (95:5) to yield 113.2 mg (34%) of the title compound. 1 3 C NMR (CDC13): 6 15.61, 29.19, 30.72, 35.72, 47.78, 58.34, 59.02, 60.64, 67.01, 71.38, 71.49, 71.60, 104.10, 120.76, 120.89, 125.39, 20 125.79, 143.50, 147.80, 157.46 Example 34 7-{f [(2S)-6-Cyano-4-(methanesulfonyl)-3,4-dihydro-2H-1,4-benzoxazin-2 yl]methyl } -N-ethyl-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide 25 (a) (2R)-2-(Hydroxymethyl)-3,4-dihydro-2H-1,4-benzoxazine-6 carbonitrile A mixture of 3-amino-4-hydroxybenzonitrile (25 g, 0.186 mol) and S epichlorohydrin (10.7 g, 0.22 mol) in aqueous ethanol (500 mL of 99%) WO 00/77000 94 PCT/SE00/01254 was stirred at 60'C for 24 h. The mixture was concentrated in vacuo before ethanol (500 mL) was added, followed by K 2

CO

3 (27 g, 0.195 mol). The resulting mixture was refluxed for 1 h before being filtered. The filtrate was concentrated in vacuo to give 61 g of a black oil. This 5 was diluted with water (500 mL), and then extracted twice with DCM and ethyl acetate. The combined organic extracts were dried and concentrated in vacuo to yield 20 g (57%) of the sub-title compound as yellow crystals. (b) (2R)-6-Cyano-4-(methanesulfonyl)-3,4-dihydro-2H-1,4-benzoxazin-2 10 yl]methyl methanesulfonate Methanesulfonyl chloride (45 g, 0.395 mol) was added dropwise to a cooled (0OC) mixture of (2R)-2-(hydroxymethyl)-3,4-dihydro-2H-1,4 benzoxazine-6-carbonitrile (30 g, 0.158 mol, from step (a) above) and pyridine (200 mL, excess). The mixture was stirred at rt overnight before 15 being concentrated in vacuo. The resulting residue was treated with water and crystals of the product were isolated by filtration. These were recrystallised from MeCN to give 29 g of pure material. The mother liquor was concentrated in vacuo to give a residue which was crystallised from chloroform to give a further crop (7.5 g) of product. The total yield 20 of the sub-title compound was 36.5 g (67%). (c) 7-{ [(2S)-6-Cyano-4-(methanesulfonyl)-3,4-dihydro-2H-1,4-benzoxazin 2-yl]methyl}-N-ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide A solution of (2R)-6-cyano-4-(methanesulfonyl)-3,4-dihydro-2H-1,4 25 benzoxazin-2-yl]methyl methanesulfonate (1 g, 2.89 mmol, from step (b) above) in MeCN (5 mL) was treated with triethylamine (8 mL, 5.8 g, 57.4 mmol), followed by N-ethyl-3,7-diazabicyclo[3.3. 1]nonane-3 carboxamide (0.85 g, 4.33 mmol, see Example 6(b) above). The resulting mixture was stirred at 70 0 C for 5h, and then at rt overnight. The mixture WO 00/77000 95 PCT/SE00/01254 was concentrated in vacuo and purified by acid/base extraction, followed by flash chromatography, eluting with DCM:MeOH, to yield 100 mg (14%) of the title compound. 5 " 3 C NMR (CDCl 3 ): 5 15.63, 28.87, 29.09, 30.48, 35.73, 39.50, 45.96, 47.65, 48.11, 59.03, 59.19, 60.59, 73.40, 104.15, 118.72, 119.90, 124.92, 126.51, 128.92, 150.04, 157.74 Example 35 10 7-[2-({2-[4,5-Bis(4-cyanophenyl)- 1H-pyrazol-1-yl]acetyl} amino)ethyl]-N ethyl-3,7-diazabicvclo[3.3. 1]nonane-3-carboxamide (a) 4-[(E)- 1-(4-Cyanobenzoyl)-2-(dimethylamino)ethenyl]benzonitrile N,N-Dimethylformamide dimethylacetal (135.2 g, 0.29 mol) was added 15 dropwise, under an inert atmosphere, to a heated (60 0 C) solution of 4-[2-(4-cyanophenyl)acetyl]benzonitrile (60.2 g, 0.24 mol, Ashley et al., J. Chem. Soc. (1942) 103, 110) in 1,2-dimethoxyethane. The resulting mixture was then filtered and concentrated in vacuo to give a residue that was crystallised from MeOH. This gave 27.9 g (38%) of the sub-title 20 compound. (b) Ethyl 2- [4,5-bis(4-cyanophenyl)- 1H-pyrazol- 1 -yl] acetate A solution of 4-[(E)-1-(4-cyanobenzoyl)-2-(dimethylamino)ethenyl] benzonitrile (6.2 g, 20 mmol from step (a) above) in aqueous ethanol (100 25 mL of 99%) was treated with ethyl 2-hydrazinoacetate hydrochloride (3.5 g, 22.6 mmol). The mixture was stirred at rt overnight before being concentrated in vacuo. The resulting residue was diluted with water, which aqueous mixture was extracted with DCM. The organic layer was then separated, dried and concentrated in vacuo to give a residue which WO 00/77000 96 PCT/SE00/01254 was recrystallised from diethyl ether to yield 1.7 g (23.5 %) of the sub-title compound. (c) 2-[4,5-Bis(4-cyanophenyl)- 1H-pyrazol-1-yl]-N-(2-hydroxyethyl) 5 acetamide A mixture of ethyl 2-[4,5-bis(4-cyanophenyl)- 1H-pyrazol- 1 -yl]acetate (3.9 g, 10.9 mmol, from step (b) above), 2-amino-1-ethanol (1.3 g, 21.8 mmol) and triethylamine (0.8 g, 76 mmol) was stirred at 100 0 C overnight. Water and DCM were added, the product crystallised and was lo isolated by filtration to yield 3.53 g of sub-title compound. (d) 2-[4,5-Bis(4-cyanophenyl)- 1H-pyrazol-1-yl]-N-(2-bromoethyl) acetamide A mixture of 2-[4,5-bis(4-cyanophenyl)-1H-pyrazol-1l-yl]-N-(2-hydroxy 15 ethyl)acetamide (0.7 g, 1.88 mmol, from step (c) above), N-bromo succinimide (0.75 g, 5.64 mmol) and triphenylphosphine (2.22 g, 8.4 mmol) in DCM (100 mL) was stirred under reflux for 3 h. The reaction mixture was allowed to cool before being washed with water. The organic layer was separated, dried and concentrated in vacuo to give a 20 residue that was purified by flash chromatography, eluting with diethyl ether:methanol (95:5), to yield 0.7 g sub-title compound contaminated with triphenylphosphine oxide. This product was used directly in the next step without any further purification. 25 (e) 7-[2-({2-[4,5-Bis(4-cyanophenyl)- 1H-pyrazol-1-yl] acetyl}amino)ethyl] N-ethyl-3,7-diazabicyclo[3.3. 1]nonane-3-carboxamide A mixture of 2-[4,5-bis(4-cyanophenyl)-1H-pyrazol-1-yl]-N-(2-bromo ethyl)acetamide (0.7 g, 1.6 mmol, from step (d) above), N-ethyl-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide (0.32 g, 1.6 mmol, see WO 00/77000 97 PCT/SE00/01254 Example 6(b) above) and K 2

CO

3 (0.55 g, 4 mmol) in acetonitrile (15 mL) was stirred under reflux overnight. Extraction with diethyl ether and water gave an organic layer that was separated, dried and concentrated in vacuo. The resulting residue was purified by chromatography on silica 5 gel, eluting with diethyl ether : MeOH (95:5), to yield 0.27 g of the title compound. 13C NMR (CDCl 3 ): 8 15.77, 29.18, 32.37, 36.13, 48.72, 52.27, 56.32, 109.83, 113.13, 118.27, 118.93, 120.10, 127.80, 131.39, 132.46, o10 132.73, 134.62, 138.75, 159.14, 167.09 Example 36 The following compounds (all of which are title compounds of this Example 36) were also prepared, using analogous methods to those 15is described herein: 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-ethyl-3,7-diazabicyclo[3.3.1] nonane-3-carboxamide; 7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-ethyl-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide; 20 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-propyl-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide; 7-[2-(4-cyanophenoxy)ethyl]-N-ethyl-3,7-diazabicyclo[3.3.1]nonane-3 carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-tetrahydro-2H-pyran-2-yl-3,7 25 diazabicyclo[3.3.1]nonane-3-carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1] nonane 3-carboxamide; 7-(4-cyanophenethyl)-N-ethyl-3,7-diazabicyclo[3.3.1]nonane-3 carboxamide; WO 00/77000 98 PCT/SE00/01254 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N,N-dimethyl-3,7 diazabicyclo[3.3. 1]nonane-3-carboxamide; tert-butyl 2-(4-cyanophenoxy)-1-({7-[(ethylamino)carbonyl]-3,7-diazabi cyclo[3.3. 1]non-3-yl } methyl)ethylcarbamate; 5 7-(3-(4-cyanophenoxy)-2-{ [(ethylamino)carbonyl]amino}propyl)-N-ethyl 3,7-diazabicyclo[3.3. 1]nonane-3-carboxamide; 7-(3-(4-cyanophenoxy)-2- { [(ethylamino)carbonyl] amino}propyl)-N-ethyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxamide; 7-(3-(4-cyanophenoxy)-2- { [(dimethylamino)carbonyl] amino}propyl)-N 10 ethyl-3,7-diazabicyclo[3.3.1 ]nonane-3-carboxamide; methyl 2-(4-cyanophenoxy)-1-({7-[(ethylamino)carbonyl]-3,7-diazabi cyclo[3.3. 1]non-3-yl}methyl)ethylcarbamate; 7-[2-(acetylamino)-3-(4-cyanophenoxy)propyl]-N-ethyl-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide; 15 7-[3-(2,4-dicyanophenoxy)-2-hydroxypropyl]-N-ethyl-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide; tert-butyl (1S)-2-(4-cyanophenoxy)- 1-({7-[(ethylamino)carbonyl]-3,7 diazabicyclo[3.3.1]non-3-yl}methyl)ethylcarbamate; 7-[(2S)-2-[(aminocarbonyl)amino]-3-(4-cyanophenoxy)propyl]-N-ethyl-3,7 20 diazabicyclo[3.3.1]nonane-3-carboxamide; tert-butyl (1R)-2-(4-cyanophenoxy)- 1-({7-[(ethylamino)carbonyl]-3,7 diazabicyclo[3.3.1]non-3-yl}methyl)ethylcarbamate; N-acetyl-7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide; 25 N-acetyl-7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide; 7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-methyl-3,7-diazabi cyclo[3.3. 1]nonane-3-carboxamide; 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-methyl-3,7-diazabicyclo- WO 00/77000 99 PCT/SE00/01254 [3.3. lnonane-3-carboxamide; 7-[(2S)-3-(4-cyano-2- { [(2-cyanoethyl)amino]carbonyl}phenoxy)-2 hydroxypropyl] -N-ethyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxamide; methyl (1R)-2-(4-cyanophenoxy)- 1-({7-[(ethylamino)carbonyl]-3,7-diaza 5 bicyclo[3.3.1]non-3-yl}methyl)ethylcarbamate; 7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-propyl-3,7-diazabicyclo [3.3. 1]nonane-3-carboxamide; 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-propyl-3,7-di azabicyclo[3.3. 1]nonane-3-carboxamide; o10 7-((2S)-3- {4-cyano-2-[(methylamino)carbonyl]phenoxy}-2-hydroxypropyl) N-ethyl-3,7-diazabicyclo[3.3. 1]nonane-3-carboxamide; 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-propionyl-3,7-diaza bicyclo[3.3.1]nonane-3-carboxamide; 7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-propionyl-3,7-diazabi 15 cyclo[3.3.1]nonane-3-carboxamide; 7-[2-(4-cyanophenyl)-2-hydroxyethyl]-N-ethyl-3,7-diazabicyclo[3.3.1] nonane-3-carboxamide; 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(2-propynyl)-3,7-diazabi cyclo[3.3. 1]nonane-3-carboxamide; 20 7-(4-cyanophenethyl)-N-iso-propyl-3,7-diazabicyclo[3.3.1]nonane-3 carboxamide; N-ethyl-7-[(2S)-2-hydroxy-3-(4-nitrophenoxy)propyl]-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide; methyl (1S)-2-(4-cyanophenoxy)- 1-({7-[(ethylamino)carbonyl]-3,7-diazabi 25 cyclo[3.3. 1]non-3-yl}methyl)ethylcarbamate; 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(cyclopropylmethyl)-3,7 diazabicyclo[3.3. 1]nonane-3-carboxamide; N-(4-nitrophenyl)-7-(4-oxoheptyl)-3,7-diazabicyclo[3.3.1]nonane-3 carboxamide; WO 00/77000 100 PCT/SE00/01254 7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(2-propynyl)-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide; 7-(3- {4-cyano-2-[(cyclopropylamino)carbonyl]phenoxy}-2-hydroxy propyl)-N-propionyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide; 5 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-phenyl-3,7-diaza bicyclo[3.3.1]nonane-3-carboxamide; 7-[(2R)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(cyclopropylmethyl)-3,7 diazabicyclo[3.3. 1]nonane-3-carboxamide; tert-butyl (1R)-2-(4-cyanophenoxy)- 1-({7-[(propionylamino)carbonyl]-3,7 10 diazabicyclo[3.3.1]non-3-yl}methyl)ethylcarbamate; 7-(3-{4-cyano-2-[(iso-propylamino)carbonyl]phenoxy}-2-hydroxypropyl) N-ethyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide; tert-butyl 2-(4-cyanophenoxy)- 1-({7- [(propionylamino)carbonyl]-3,7-di azabicyclo[3.3.1] non-3-yl} methyl)ethylcarbamate; 15 tert-butyl 2-(4-cyanophenoxy)-1-({7-[(iso-propylamino)carbonyl]-3,7 diazabicyclo[3.3.1]non-3-yl}methyl)ethyl(methyl)carbamate; 7-[3-(4-cyanophenoxy)-2-(methylamino)propyl]-N-iso-propyl-3,7 diazabicyclo[3.3. 1]nonane-3-carboxamide; 7-{ 3-(4-cyanophenoxy)-2- [methyl(methylsulfonyl)amino]propyl}-N-iso 20 propyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide; N-(tert-butyl)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo [3.3. 1]nonane-3-carboxamide; 7-[2-amino-3-(4-cyanophenoxy)propyl]-3,7-diazabicyclo[3.3.1]nonane-3 carboxamide; 25 tert-butyl 2-[7-(aminocarbonyl)-3,7-diazabicyclo[3.3.1]non-3-yl]-1-[(4 cyanophenoxy)methyl]ethylcarbamate; tert-butyl 2-(4-cyanophenoxy)- 1-({7-[(tetrahydro-2H-pyran-2-ylamino) carbonyl]-3,7-diazabicyclo[3.3.1]non-3-yl}methyl)ethylcarbamate; N-(4-cyanophenyl)-7-(4-oxoheptyl)-3,7-diazabicyclo[3.3.1] nonane-3- WO 00/77000 101 PCT/SE00/01254 carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(2,2-dimethylpropanoyl)-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide; N-(tert-butoxy)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7 5 diazabicyclo[3.3.1]nonane-3-carboxamide; 2-[7-(aminocarbonyl)-3,7-diazabicyclo[3.3.1 ]non-3-yl]-1-[(4-cyano-2 methylphenoxy)methyl]ethyl tert-butylcarbamate; 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-iso-propyl-N-methyl-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide; o10 N-(4-cyanophenethyl)-7-iso-propyl-3,7-diazabicyclo[3.3.1]nonane-3 carboxamide; N-(tert-butoxy)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-methyl-3,7 diazabicyclo[3.3.1] nonane-3-carboxamide; N-(4-cyanophenethyl)-7-(3,4-dimethoxyphenethyl)-3,7-diazabicyclo 15 [3.3.1]nonane-3-carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-cyclopropyl-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide; 7-[2-amino-3-(4-cyanophenoxy)propyl]-N-(tert-butyl)-3,7-diazabicyclo [3.3. 1]nonane-3-carboxamide; 20 N-[3-(4-cyanophenoxy)propyl]-7-[5-(ethylamino)-5-oxopentyl]-3,7-diaza bicyclo[3.3.1]nonane-3-carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(3,5-dimethyl-4-isoxazolyl) 3,7-diazabicyclo[3.3.1] nonane-3-carboxamide; 7-[3-(4-cyanoanilino)propyl]-N-iso-propyl-3,7-diazabicyclo[3.3.1]nonane 25 3-carboxamide; 7-[4-(4-cyanophenyl)-4-hydroxybutyl]-N-ethyl-3,7-diazabicyclo[3.3.1] nonane-3-carboxamide; ethyl {7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1] non-3-yl} carbonylcarbamate; WO 00/77000 102 PCT/SE00/01254 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(2,6-dimethoxyphenyl)-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(4-cyanophenyl)-3,7-diazabi cyclo[3.3.1]nonane-3-carboxamide; 5 N-benzyl-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo [3.3. 1]nonane-3-carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-hexyl-3,7-diazabicyclo[3.3.1] nonane-3-carboxamide; ethyl 3-[({7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo 10 [3.3.1]non-3-yl}carbonyl)amino]propanoate; N-(4-butoxyphenyl)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabi cyclo[3.3. 1]nonane-3-carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(3-cyanophenyl)-3,7-diazabi cyclo[3.3.1] nonane-3-carboxamide; 15 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(3,4-dimethoxyphenyl)-3,7 diazabicyclo[3.3.1] nonane-3-carboxamide; butyl 2-[({7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo [3.3.1 ]non-3-yl} carbonyl)amino] acetate; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(4-methoxyphenyl)-3,7-diaza 20 bicyclo[3.3.1]nonane-3-carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(3,4-dimethoxyphenethyl) 3,7-diazabicyclo[3.3.1]nonane-3-carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(3,4-dimethoxybenzyl)-3,7 diazabicyclo[3.3. 1]nonane-3-carboxamide; 25 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(3,4,5-trimethoxyphenyl)-3,7 diazabicyclo[3.3. 1]nonane-3-carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(3,4-dihydro-2H-1,5-benzo dioxepin-7-yl)-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(2,6-dimethylphenyl)-3,7- WO 00/77000 103 PCT/SE00/01254 diazabicyclo[3.3.1]nonane-3-carboxamide; iso-propyl {7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo [3.3. 1]non-3-yl}carbonylcarbamate; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-(2-fluoroethyl)-3,7-diazabi 5 cyclo[3.3.1]nonane-3-carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N- {2-[(cyclopropylmethyl) amino]-2-oxoethyl} -3,7-diazabicyclo[3.3.1]nonane-3-carboxamide; N-(tert-butyl)-7-{2-hydroxy-3- [(2-methyl-1-oxo-1,2-dihydro-4 isoquinolinyl)oxy]propyl} -3,7-diazabicyclo[3.3.1]nonane-3-carboxamide; 10 N-(1-cyano- 1-methylethyl)-7- [3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7 diazabicyclo[3.3.1]nonane-3-carboxamide; 7-[2-amino-3-(4-cyanophenoxy)propyl]-N-(1,3-benzodioxol-5-ylmethyl) 3,7-diazabicyclo[3.3.1]nonane-3-carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-iso-propyl-3,7-diazabicyclo 15 [3.3. 1]nonane-3-carboxamide; 4-(3-{7-[(2,6-dimethyl-4-morpholinyl)carbonyl]-3,7-diazabicyclo[3.3.1] non-3-yl} -2-hydroxypropoxy)benzonitrile; N-[cyano(4-fluorophenyl)methyl]-7-[3-(4-cyanophenoxy)-2-hydroxy propyl] -3,7-diazabicyclo[3.3.1 ]nonane-3-carboxamide; 20 N-(cyanomethyl)-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-methyl-3,7 diazabicyclo [3.3.1] nonane-3-carboxamide; 7-[4-(4-cyanophenoxy)-2-hydroxybutyl] -N-ethyl-3,7-diazabicyclo[3.3.1] nonane-3-carboxamide; 7-[4-(4-cyanophenyl)butyl]-N-[2-oxo-2-(propylamino)ethyl]-3,7-diazabi 25 cyclo[3.3.1]nonane-3-carboxamide; 7-[4-(4-cyanophenyl)butyl] -N-propyl-3,7-diazabicyclo [3.3.1] nonane-3 carboxamide; 7-[2-amino-4-(4-cyanophenoxy)butyl]-N-propyl-3,7-diazabicyclo[3.3.1] nonane-3-carboxamide; WO 00/77000 104 PCT/SE00/01254 7-[4-(4-cyanophenyl)butyl]-N-ethyl-3,7-diazabicyclo[3.3.1]nonane-3 carboxamide; 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-N-[2-(2-methoxyethoxy)ethyl] 3,7-diazabicyclo[3.3. 1]nonane-3-carboxamide; 5 N-(4-cyanophenyl)-7-(3,3-dimethyl-2-oxobutyl)-3,7-diazabicyclo[3.3.1] nonane-3-carboxamide; N-(4-cyanophenyl)-7-(3,4-dimethoxyphenethyl)-3,7-diazabicyclo[3.3.1] nonane-3-carboxamide; N-(4-cyanophenyl)-7-(cyclopropylmethyl)-3,7-diazabicyclo[3.3.1] nonane 10 3-carboxamide; N-(4-cyanophenyl)-7- [2-(2-methoxyethoxy)ethyl] -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide; N-(4-cyanophenyl)-7-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxoethyl] 3,7-diazabicyclo[3.3.1] nonane-3-carboxamide; 15 7-[3-(4-acetyl- 1-piperazinyl)propyl]-N-(4-cyanophenyl)-3,7-diazabicyclo [3.3.1]nonane-3-carboxamide; and 7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-N-[2-oxo-2-(propylamino) ethyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxamide. 20 Example 37 Title compounds of the above Examples were tested in Test A above and were found to exhibit DI 0 values of more than 6.0. Abbreviations 25 AcOH = acetic acid ADDP = 1, l'-(azodicarbonyl)dipiperidine aq. = aqueous atm. = atmospheres WO 00/77000 105 PCT/SE00/01254 CBz = benzyloxycarbonyl CDI = carbonyl diimidazole Bu = butyl DCM = dichloromethane 5 DMF = dimethylformamide DMSO = dimethylsulfoxide Et = ethyl EtOAc = ethyl acetate EtOH = ethanol o10 ESI = electron spray interface eq. = equivalents FAB = fast atom bombardment h = hours IPA = iso-propanol 15 i-PrOH = iso-propanol LC = liquid chromatography HPLC = high performance liquid chromatography mCPBA = meta-chloroperbenzoic acid Me = methyl 20 MeCN = acetonitrile MeOH = methanol mesyl = methanesulfonate mm. = minutes Ms = mesylate 25 MS = mass spectroscopy NADPH = nicotinamide adenine dinucleotide phosphate, reduced form NMR = nuclear magnetic resonance OSu = O-succinyl WO 00/77000 106 PCT/SE00/01254 Pd/C = palladium on carbon pTSA = para-toluenesulfonic acid rt. = room temperature satd. = saturated 5 TEA = triethylamine THF = tetrahydrofuran tic = thin layer chromatography TMS = tetramethylsilane 10 Prefixes n-, s-, i-, iso-, t- and tert- have their usual meanings: normal, iso, secondary and tertiary.

Claims (37)

1. A compound of formula I, R2 45 R43 R41 AI p j N R 4 3 R R5 R44 0 R7 B N R46 RR4 R 6 5 R 3 wherein o10 R' and R 2 independently represent H, C 14 alkyl, OR 2 b or N(R 2 c)R 2 d, or together form -O-(CH 2 ) 2 -O-, -(CH 2 ) 3 -, -(CH 2 ) 4 - or -(CH 2 ) 5 -; R 2 b, R 2 c and R 2 d independently represent H or C 1 6 alkyl; R 3 represents H, C- 6 alkyl or, together with R 4 , represents C 3 - 6 alkylene 15 (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C_ 3 alkyl groups); R 4 represents H, Cl12 alkyl, C- 6 alkoxy (which latter two groups are both optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, C 14 alkyl and/or C 1 - 4 alkoxy), 20 -(CH)q-aryl, -(CH2)q-oxyaryl, -(CH 2 )q-Het' (which latter three groups are optionally substituted (at the -(CH 2 )q- part and/or the aryl/Het' part) by one or more substituents selected from -OH, halo, cyano, nitro, -C(O)R 1 0 , -C(O)OR I , -N(H)S(O) 2 R i ta, C 1 - 6 alkyl and/or CI-6 alkoxy), WO 00/77000 108 PCT/SE00/01254 -(CH 2 )qN(H)C(O)R 8 , -(CH 2 )qS(O) 2 R', -(CH 2 )qC(O)R s , -(CH 2 )qC(O)OR 8 , -(CH 2 )qC(O)N(R 9 )R 8 or, together with R 3 , represents C 3 - 6 alkylene (which alkylene group is optionally interrupted by an O atom and/or is optionally substituted by one or more C- 3 alkyl groups); 5 q represents 0, 1, 2, 3, 4, 5 or 6; R 8 represents H, C 16 alkyl, aryl (which latter group is optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, -C(O)R 1 o, -C(O)OR", -N(H)S(O) 2 Rlla, C 1 - 6 alkyl and/or C 1 6 alkoxy) or, together with R 9 , represents C 3 - 7 alkylene; 10 R 9 represents H, C 1 -4 alkyl or, together with R 8 , represents C 3 - 7 alkylene; Het 1 represents a five to twelve-membered heterocyclic ring containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, and which also optionally includes one or more = O substituents; 15 R 41 , R 4 2 , R 43 , R 44 , R 45 or R 46 independently represent H or C 1 - 3 alkyl; R 5 represents H, halo, C 1 3 alkyl, -OR 12 , -N(R 3 )R 1 2 or, together with R 6 , represents = O; R 6 represents H, C 1 - 4 alkyl or, together with R 5 , represents =O; 20 R 2 represents H, C, 6 alkyl, -S(O) 2 -C 14 -alkyl, -C(O)R 4 , -C(O)OR 14 -C(O)N(R 5 )R s a or aryl (which latter group is optionally substituted and/or terminated by one or more substituents selected from -OH, halo, cyano, nitro, -C(O)R 1 o, -C(O)OR" 1 , -N(H)S(O) 2 RIa, C 1 6 alkyl and/or C 1 -6 alkoxy); 25 R 13 represents H or C 1 - 4 alkyl; R 14 represents H or C 1 - 6 alkyl; R1 5 and R1 5 a independently represent H or C 1 - 4 alkyl, or together represent C 3 -6 alkylene, optionally interrupted by an O atom; WO 00/77000 109 PCT/SE00/01254 A represents a single bond, CI_ 6 alkylene, -N(R16)(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); B represents a single bond, C1-4 alkylene, -(CH 2 )nN(R17)-, -(CH 2 )nS(O)p-, 5 -(CH 2 )nO- (in which three latter groups, the -(CH2)n- group is attached to the carbon atom bearing R 5 and R 6 ), -C(O)N(R17)- (in which latter group, the -C(O)- group is attached to the carbon atom bearing R 5 and R 6 ), -N(R 1 7 )C(O)O(CH 2 )n - , -N(R 17 )(CH 2 )n- (in which two latter groups, the N(R 17 ) group is attached to the carbon atom bearing R 5 and R 6 ) or o10 -(CH 2 )mC(H)(OH)(CH 2 )n- (in which latter group, the -(CH 2 ) m- group is attached to the carbon atom bearing R 5 and R 6 ); m represents 1, 2 or 3; n and r independently represent 0, 1, 2, 3 or 4; p represents 0, 1 or 2; 15 R 16 and R 17 independently represent H or CI_4 alkyl; R 7 represents C 16 alkyl, aryl or Het 2 , all of which groups are optionally substituted and/or terminated (as appropriate) by one or more substituents selected from -OH, cyano, halo, amino, nitro, Het 3 , -C(O)R 1 0 , 20 -C(O)OR 1 , C 1 - 6 alkyl, C 1 . 6 alkoxy, -N(H)S(O) 2 R' 8 , -S(O) 2 R 19 , -OS(O) 2 R 20 -N(H)C(O)N(H)R 21 , -C(O)N(H)R 2 2 and/or aryl (which latter group is optionally substituted by one or more cyano groups); Het 2 and Het 3 independently represent a five to twelve-membered heterocyclic group containing one or more heteroatoms selected from 25 oxygen, nitrogen and/or sulfur, and which also optionally includes one or more = O substituents; R 18 , R" 9 and R 20 independently represent C 1 - 6 alkyl; R 2 1 and R 22 independently represent H or C_ 6 alkyl (optionally terminated by cyano); and WO 00/77000 110 PCT/SE00/01254 R' I o and R" independently represent, at each individual occurrence, H or C, 6 alkyl; R 1 1 a represents, at each individual occurrence, C1- 6 alkyl; 5 or a pharmaceutically acceptable derivative thereof; provided that: (a) when A and B are both single bonds and R 7 is optionally substituted o10 aryl, then R 5 and R 6 do not both represent H; (b) when A represents a single bond, then R 5 and R 6 do not together represent = O; and (c) when R 5 represents -OR 12 or -N(R1 3 )R 2 , then: (i) A does not represent -N(R1 6 )(CH 2 )r, - or -O(CH 2 )r-; and/or 15 (ii) n does not represent 0 when B represents -(CH)nN(R 17 )-, -(CH,)nS(O)p- or -(CH 2 )nO-.

2. A compound as claimed in Claim 1, wherein R' represents H. 20

3. A compound as claimed in Claim 1 or Claim 2, wherein R 2 represents H.

4. A compound as claimed in any one of the preceding claims, wherein R 3 represents H; C,_ 2 alkyl; or, together with R 4 represents C4-5 alkylene, optionally interrupted by an O atom and/or optionally substituted by one or 25 more methyl groups.

5. A compound as claimed in Claim 4, wherein R 3 represents H. WO 00/77000 111 PCT/SE00/01254

6. A compound as claimed in any one of the preceding claims, wherein R 4 represents H; linear or branched and/or saturated or unsaturated and/or cyclic, acyclic and/or part cyclic/acyclic C 1 -8 alkyl (which alkyl group is optionally substituted by one or more cyano or halo groups and/or 5 interrupted by an O atom); C 1 . 6 alkoxy; -(CH 2 )qS(O) 2 R 8 , -(CH 2 )qC(O)OR', -(CH,)qN(H)C(O)R 8 , -(CH 2 )qC(O)R 8 , (in which latter four groups, q represents 0, 1 or 2 and R 8 represents linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic C 1 , 4 alkyl, or phenyl (which phenyl group is optionally substituted by one or more cyano and/or C- 3 alkyl groups)); 10 -(CH 2 )qC(O)N(R 9 )R 8 (in which latter group, q represents 0, 1 or 2 and R 8 and R 9 independently represent H, linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic C1-4 alkyl, or together represent C 4 -6 alkylene); -(CHz)q-phenyl, -(CH 2 )q-oxyphenyl or -(CHE)q-Het 1 (in which latter three groups, q represents 0, 1, 2 or 3, the -(CH)q - part is optionally substituted 15 by a cyano group, and the phenyl, or Het 1 , part is optionally substituted with one or more substituents selected from cyano, nitro, linear or branched C 1 . 4 alkyl, linear or branched C1-4 alkoxy and N(H)S(O) 2 Rta); or, together with R 3 , represents C4- 5 alkylene, optionally interrupted by an O atom and/or optionally substituted by one or more methyl groups. 20

7. A compound as claimed in any one of the preceding claims, wherein R 5 represents H; fluoro; OR 1 2 (in which R1 2 represents H, phenyl (optionally substituted by one or more methoxy groups) or C(O)N(H)R Sa (in which R S a represents linear or branched C1-4 alkyl)); -N(R13)(R 1 2 ) (in which R12 25 represents H, C 1 2 alkyl, -S(O) 2 -CI 1 2 alkyl, -C(0)R 14 (in which R 1 4 represents C 1 - 2 alkyl), -C(0)OR 14 (in which R 14 represents linear or branched C 1 . 5 alkyl) or -C(0)N(R 15)(Rs 15 a) (in which R 15 and R 15a independently represent H or linear or branched Cl- 3 alkyl or together represent C 4 - 5 alkylene, which WO 00/77000 112 PCT/SE00/01254 alkylene group is optionally interrupted by an O atom) and R 13 represents H or C 1 - 2 alkyl); or, together with R 6 , represents =O.

8. A compound as claimed in Claim 7, wherein R 5 represents H, OH or 5 -N(H)C(O)N(R' 5 )(Rsa).

9. A compound as claimed in any one of the preceding claims, wherein R 6 represents H or C 1 2 alkyl or together with R 5 represents =O.

10 10. A compound as claimed in Claim 9, wherein R 6 represents H.

11. A compound as claimed in any one of the preceding claims, wherein A represents a single bond, linear or branched C 1 , 4 alkylene (which group is also optionally interrupted by O), -N(H)(CH 2 )r- or -O(CH 2 )r - (in which 15 latter two cases r is 1 or 2).

12. A compound as claimed in Claim 11, wherein A represents -CH 2 - or -(CH,)2-. 20

13. A compound as claimed in any one of the preceding claims, wherein B represents a single bond, C 1 4 alkylene, -(CH 2 )nO-, -(CH,)nS(0) 2 -, -(CH2)nN(H)- or -N(H)(CH 2 )n- (in which latter four cases n is 0, 1, 2 or 3).

14. A compound as claimed in Claim 13, wherein B represents a single 25 bond, -CH 2 N(H)- or -CH 2 0-.

15. A compound as claimed in any one of the preceding claims, wherein R 7 represents linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic C 1 6 alkyl (optionally substituted and/or terminated by OH); WO 00/77000 113 PCT/SE00/01254 Het 2 (optionally substituted by one or more substituents selected from cyano, C 1 3 alkyl, phenyl (which latter group is optionally substituted with one or more cyano groups), =0O, C(0)Ro (in which R 1 o is linear or branched C 1 - 3 alkyl) or S(0) 2 R 19 (in which R 19 is C 1 2 alkyl)); or phenyl 5 (optionally substituted by one or more substituents selected from cyano, nitro, linear or branched Cl- 3 alkyl, linear or branched C_ 3 alkoxy, fluoro, chloro, C(0)N(H)R 22 (in which R 2 2 represents linear or branched and/or acyclic, cyclic and/or part cyclic/acyclic C1, alkyl, which alkyl group is optionally terminated by cyano), N(H)S(0) 2 R" (in which R" represents C-2 o10 alkyl) or Het 3 ).

16. A compound as claimed in Claim 15, wherein R 7 represents phenyl (substituted by a cyano group (preferably in the 4-position relative to B) and by one or more optional C(0)N(H)R 2 2 substituent). 15

17. A compound as claimed in any one of the preceding claims, wherein R 4 1 , R 42 , R 43 , R 44 , R 45 and R 46 all represent H.

18. A pharmaceutical formulation including a compound as defined in any 20 one of Claims 1 to 17 in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

19. A pharmaceutical formulation for use in the prophylaxis or the treatment of an arrhythmia, comprising a compound as defined in any one 25 of Claims 1 to 17.

20. A compound as defined in any one of Claims 1 to 17 for use as a pharmaceutical. WO 00/77000 114 PCT/SE00/01254

21. A compound as defined in any one of Claims 1 to 17 for use in the prophylaxis or the treatment of an arrhythmia.

22. The use of a compound as defined in any of one Claims 1 to 17 as 5 active ingredient in the manufacture of a medicament for use in the prophylaxis or the treatment of an arrhythmia.

23. The use as claimed in Claim 22, wherein the arrhythmia is an atrial or a ventricular arrhythmia. 10

24. 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 17 to a person suffering from, or susceptible to, such a condition. 15

25. A process for the preparation of a compound of formula I as defined in Claim 1 which comprises: (a) for compounds of formula I in which R 3 is H, reaction of a compound of formula II, 20 1 R2 45 R43 R41 R s R44 N R46 R 4 2 N H NH R6 WO 00/77000 115 PCT/SE00/01254 wherein R', R 2 , R 5 , R 6 , R 7 , R 4 1 , R 42 , R 43 , R 44 , R 45 , R', A and B are as defined in Claim 1 with a compound of formula III, R 4 -N=C=O III wherein R 4 is as defined in Claim 1; 5 (b) reaction of a compound of formula II, as defined above, with a carbonic acid derivative of formula IV, (R 3 )(R 4 )NC(O)-L' IV wherein L' represents a leaving group and R 3 and R 4 are as defined in Claim 1; 10 (c) reaction of a compound of formula V, 'R2 45 R43 R2 R41 V R5 R44 R7- B AN R46 R4 N o R 6 wherein and L' is as defined above and R' , R, R 5 , R 6 , R 7 , R 41 , R 42 , R 43 , 15 R 4 , R 45 , R 4 6 , A and B are as defined in Claim 1, with a compound of formula VA, (R 3 )(R 4 )NH VA wherein R 3 and R 4 are as defined in Claim 1; (d) for compounds of formula I in which A represents CH 2 and R 5 20 represents -OH or -N(H)R12, reaction of a compound of formula VI, WO 00/77000 116 PCT/SE00/01254 1 R2 45 R43 R41 R 44 O R46 R42 N /N H N- R4 R3 wherein R', R 2 , R 3 , R 4 , R 4 1 , R 42 , R 4 3 , R 4 , R 45 and R 46 are as defined in Claim 1, with a compound of formula VII, 5 R6 R 7 - B 6 VII wherein X represents O or N(R 1 2 ) and R 6 , R 7 , R 1 2 and B are as defined in Claim 1; 10 (e) reaction of a compound of formula VI, as defined above, with a compound of formula VIII, R 7 B A-L 2 R 6 VIIIl 15 wherein L 2 represents a leaving group and R 5 , R 6 , R 7 , A and B are as defined in Claim 1; (f) for compounds of formula I in which R 5 represents H or OH and R 6 represents H, reduction of a compound of formula IX, WO 00/77000 117 PCT/SE00/01254 1 R2 45 R 43 R41 Ix O R44 O R B AR 4 6 R42 N - R4 R 3 wherein R', R 2 , R 3 , R 4 , R 7 , R 41 , R 42 , R 4 3 , R" 44 , R 4 5 , R, 4 6 A and B are as 5 defined in Claim 1; (g) for compounds of formula I in which one of R' and R 2 represents H or OH and the other represents H, reduction of a corresponding compound of formula X, O 0x 45 R43 R41 , R 4 3 R / ,, X R 5 R 44 O R7B A / N R46 R42 N R 6 R4 R 3 10 wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 4 1 , R 42 , R 43 , R 4 , R 4 5 , R , A and B are as defined in Claim 1; (h) for compounds of formula I in which R' and R 2 together represent 15 -O(CH,)20-, reaction of a corresponding compound of formula X as defined above with ethane- 1,2-diol; WO 00/77000 118 PCT/SE00/01254 (i) for compounds of formula I in which B represents -(CH 2 )nO-, reaction of a compound of formula XI, R2 R5 R44 O i wh h i aR 46 R42 i C m HO-(CH2 fo A R Rn-r R6N R4 R 3 5 wherein R , R 2, R 3, R 4, R , R 6 , R 4 , R 42 , R 3, R , R 4 5, R , A and n are as defined in Claim 1, with a compound of formula XIA, R'OH XIA in which R' is as defined in Claim 1; (j) for compounds of formula I which are bispidine-nitrogen N-oxide io derivatives, oxidation of the corresponding bispidine nitrogen of a corresponding compound of formula I; (k) for compounds of formula I which are C,-4 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 15 of formula I with a compound of formula XII, RbL 3 XII wherein Rb represents C 1 . 4 alkyl and L 3 is a leaving group; (1) for compounds of formula I in which R 5 and R 6 represent H, A represents C 1 - 6 alkylene and B represents -N(R17)(CH 2 )n-, reaction of a 20 compound of formula XIII, WO 00/77000 119 PCT/SE00/01254 1 R2 45 R43 R41 Xll kR44 O 11 R17 N R 46 R42 N- CH2-Aa H N R4 R 3 wherein A a represents C 1 - 6 alkylene and R', R 2 , R 3 , R 4 , R 41 , R 42 , R 43 , R 44 ", 5 R 45 , R 46 and R 17 are as defined in Claim 1 with a compound of formula XIV, R7-(CH2)n-L 2 XIV wherein L 2 is as defined above and R 7 and n are as defined in Claim 1; (m) for compounds of formula I in which R 5 represents -NH 2 , reduction of a o10 corresponding compound of formula XV, R2 45 R43 R2 R41 xv N 3 R 44 RN R 4 6 R42N R7.B+ A N R6 N -R4 R 3 wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 4 1 , R 42 , R 43 , R" 44 , R 45 , R 46 , A and B are as defined in Claim 1; WO 00/77000 120 PCT/SE00/01254 (n) for compounds of formula I in which R 5 represents -N(R" 3 )C(O)NH(R" 5 ), reaction of a corresponding compound of formula I in which R 5 represents -N(R" 3 )H with a compound of formula XVI, R1 5 N=C=O XVI 5 wherein R 15 is as defined in Claim 1; (o) for compounds of formula I in which R 5 represents -N(R" 3 )C(O)R" 4 , reaction of a corresponding compound of formula I in which R 5 represents -N(R13)H with a compound of formula XVII, R14C(O)Rx XVII o10 wherein Rx represents a suitable leaving group and R 14 is as defined in Claim 1; (p) for compounds of formula I in which R 5 represents -N(H)R 1 2 , wherein R1 2 is as defined in Claim 1 provided that it does not represent H, reaction of a corresponding compound of formula I, in which R 5 represents -NH 2 15 with a compound of formula XVIII, R1 2 aL' XVIII wherein RI 2 a represents R1 2 as defined in Claim 1 provided that it does not represent H and L' is as defined above; (q) for compounds of formula I in which R 5 represents -OR 12 in which R 12 20 represents C1- 6 alkyl or optionally substituted aryl, reaction of a corresponding compound of formula I in which R 5 represents -OH with a compound of formula XIX, R1 2 aOH XIX wherein R 1 2a represents C. 6 alkyl or optionally substituted aryl; 25 (r) for compounds of formula I in which R 5 represents -OR 12 , in which R1 2 represents C1- 6 alkyl or optionally substituted aryl, reaction of a compound of formula XX, WO 00/77000 121 PCT/SE00/01254 xx L2 k 0 R 7 1 1 , A N R 4 6- -- - _ R 4 R6R R 3 wherein L 2 is as defined above and R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 4 1 , R 42 , R 4 3 , 5 R 4 , R 45 , R 46 , A and B are as defined in Claim 1 with a compound of formula XIX as defined above; (s) for compounds of formula I in which R 5 represents OR 1 2 and R 12 represents C(O)R 14 , reaction of a corresponding compound of formula I in which R 5 represents OH with a compound of formula XXI, 10 R1 4 CO 2 H XXI wherein R 14 is as defined in Claim 1; (t) for compounds of formula I in which R 5 represents halo, substitution of a corresponding compound of formula I in which R 5 represents -OH, using an appropriate halogenating agent; 15 (u) for compounds of formula I in which R 3 and/or R 4 as appropriate represent alkyl groups, alkylation of a corresponding compound of formula I, in which R 3 and/or R 4 (as appropriate) represent H; (v) conversion of one R 4 group to another; (w) for compounds of formula I in which one of R 2 and R 3 represents 20 -NH 2 and the other represents H, reduction of a compound of formula XXIA, WO 00/77000 122 PCT/SE00/01254 NOH 45 R43 R41 XXIA R 5 R44 O R 7 1BA N R 4 6 R 4 2N BT A R6 N- R4 R 3 wherein R 3 , R 4 , R', R 6 , R 7 , R 4 1 , R 42 , R 43 , R, R 45 , R 46 , A and B are as 5 defined in Claim 1; (x) for compounds of formula I in which one or both of R' and R 2 represent -N(R 2 c)R 2 d in which one or both of R 2 c and R 2 d represents C1-6 alkyl, alkylation of a corresponding compound of formula I in which R' and/or R 2 represent -N(R 2 c)R 2 d (as appropriate) in which R 2 c and/or R 2 d 10 (as appropriate) represent H, using a compound of formula XXIB, R 2 eLI XXIB wherein R 2 ' represents C 1 - 6 alkyl and L' is as defined above; (y) conversion of one substituent on R 7 to another; or (z) deprotection of a protected derivative of a compound of formula I as 15 defined in Claim 1.

26. A compound of formula II, as defined in Claim 25, or a protected derivative thereof, provided that R 7 does not represent optionally substituted phenyl. 20 WO 00/77000 123 PCT/SE00/01254

27. A compound of formula V, as defined in Claim 25, or a protected derivative thereof, provided that R 7 does not represent optionally substituted phenyl. 5

28. A compound of formula X as defined in Claim 25, or a protected derivative thereof.

29. A compound of formula XI as defined in Claim 25, or a protected derivative thereof. 10

30. A compound of formula XIII, as defined in Claim 25, or a protected derivative thereof.

31. A compound of formula XV, as defined in Claim 25, or a protected 15 derivative thereof.

32. A compound of formula XX, as defined in Claim 25, or a protected derivative thereof. 20

33. A compound of formula XXIII, O 45 R43 R41 XXIII R5 R44 RT B A N R R42 H R 6 WO 00/77000 124 PCT/SE00/01254 wherein R 5 , R 6 , R 7 , R 41 , R 4 2 , R 43 , R 44 , R 45 , R , A and B are as defined in Claim 1, or a protected derivative thereof.

34. A compound of formula XXV, O 45 R43 R41 R44 O N R 4 6 R42 N - 0 H N - R4 5 R 3 wherein R 3 , R 4 , R 4 ', R 42 , R 43 , R", R 45 and R 46 are as defined in Claim 1, or a protected derivative thereof. 10

35. A process for the preparation of a compound of formula X, of formula XXIII, or of formula XXV (in which, in all cases, R 45 and R 46 both represent H), which comprises (as appropriate) reaction of either: (i) a compound of formula XXXV, 0 R 43 R44 XXXV R 4 1 N R42 o ORz 15 wherein Rz represents C 1 - 1 0 alkyl or C 1 - 3 alkylaryl and R 41 , R 42 , R 43 and R 4 4 are as defined in Claim 1, or WO00/77000 125 PCT/SE00/01254 (ii) 4-piperidone (or a protected derivative thereof), with (as appropriate) either: (1) a compound of formula XXXVI, R 7 -B-C(R 5 )(R 6 )-A-NH 2 XXXVI 5 wherein R 5 , R 6 , R 7 , A and B are as defined in Claim 1, or (2) NH 3 (or a protected derivative thereof), in all cases in the presence of a formaldehyde and, in the case of compounds of formulae X and XXV, followed by conversion of the C(O)ORz group in the resultant intermediate to a C(O)N(R 3 )(R 4 ) group. 10

36. A process as claimed in Claim 35, in which the reaction is carried out in the presence of an organic acid.

37. A process as claimed in Claim 36, in which the organic acid is acetic 15 acid.