RU2250903C2 - New bispidine compounds useful in treatment of cardiac arrhythmias - Google Patents

Abstract

FIELD: organic chemistry, medicine.

SUBSTANCE: compounds of formula I

are disclosed, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, A, and B are as described in description.

EFFECT: new compounds with increased electrophysiological activity useful in treatment of cardiac arrhythmias.

132 cl, 1 tbl, 37 ex

Description

Field of Invention

This invention relates to new pharmaceutically useful compounds, in particular to compounds that are useful in the treatment of cardiac arrhythmias.

BACKGROUND AND BACKGROUND

Cardiac arrhythmias can be defined as abnormalities in the speed, regularity or place of occurrence of a cardiac impulse or as abnormalities in conduction that cause an abnormal excitation sequence. From a clinical point of view, arrhythmias can be classified by their presumptive site of origin (i.e., as supraventricular, including atrial and atrial ventricular arrhythmias, and ventricular arrhythmias) and / or by the frequency of contractions (i.e. bradyarrhythmias (delayed) and tachyarrhythmias (accelerated)).

The negative result of some clinical trials (see, for example, the result of the Cardiac Arrhythmia Suppression Trial (CAST) test described in New England Journal of Medicine, 321, 406 (1989)) in treating cardiac arrhythmias with “traditional” antiarrhythmic drugs acting mainly by reducing the rate of conduction (class I antiarrhythmic drugs), prompted the development of drugs for compounds that selectively slow down cardiac repolarization, thereby lengthening the QT interval. Class III antiarrhythmic drugs can be defined as drugs that lengthen the duration of the trans-membrane action potential (which can be caused by blocking outward directed K ⁺ currents or an increase in inward ion currents) and the refractory period without affecting cardiac conduction.

It is known that one of the key shortcomings of drugs known so far that act by slowing repolarization (class III or others) is that they all exhibit a unique form of proarrhythmia, known as torsades de pointes (polymorphic ventricular tachyarrhythmia), which can sometimes end fatal. From a safety point of view, minimizing this phenomenon (for which it has also been shown to occur as a result of the administration of non-cardiac drugs such as phenothiazines, tricyclic antidepressants, antihistamines and antibiotics) is a key problem to be addressed in providing precautions when taking effective antiarrhythmic medicines.

Anti-arrhythmic drugs based on bispidines (3,7-diazabicyclo [3.3.1] nonanes) are known, inter alia, from international patent application WO 91/07405, European patent applications 306871, 308843 and 655228 and US patents 3962449, 4556662, 4550112, 4459301 and 5,468,858, as well as journal articles, including but not limited to J. Med. Chem. 39, 2559 (1996), Pharmacol. Res., 24, 149 (1991), Circulation, 90, 2032 (1994) and Anal. Sci. 9, 429 (1993). Known bispidin-based antiarrhythmic compounds include bisaramil (3-methyl-7-ethyl-9α, 4 ′ - (Cl-benzoyloxy) -3,7-diazabicyclo [3.3.1] nonane, tedisamil (tedisamil) ( 3 ', 7'-bis (cyclopropylmethyl) spiro (cyclopentane-1.9') - 3,7-diazabicyclo [3.3.1] nonane), SAZ-VII-22 (3- (4-chlorobenzoyl) -7-isopropyl -3,7-diazabicyclo [3.3.1] nonane), SAZ-VII-23 (3-benzoyl-7-isopropyl-3,7-diazabicyclo [3.3.1] nonane), GLG-V-13 (3- [ 4- (1H-imidazol-1-yl) benzoyl] -7-isopropyl-3,7-diazabicyclo [3.3.1] nonane), KMS-IV-84 (7- [4 '- (1H-imidazolo-1- il) benzenesulfonyl] -3-isopropyl-3,7-diazabicyclo [3.3.1] nonane dihydroperchlorate) and ambasilide (3- (4-ami nobenzoyl) -7-benzyl-3,7-diazabicyclo [3.3.1] nonane).

The inventors have unexpectedly found that a new group of bispidine-based compounds exhibits electrophysiological activity, preferably class III electrophysiological activity, and therefore are expected to be useful in the treatment of cardiac arrhythmias.

Description of the invention

The present invention provides compounds of formula I

where R ¹ and R ² independently represent H, C _1-4 alkyl, OR ^2b or N (R ^2c ) R ^2d , or together form —O— (CH ₂ ) ₂ —O—, - (CH ₂ ) ₃ - , - (CH ₂ ) ₄ - or - (CH ₂ ) ₅ -;

R ^2b , R ^2c and R ^2d independently represent H or C _1-6 alkyl;

R ³ represents H, C _1-6 alkyl, or together with R ⁴ represents C _3-6 alkylene (wherein the alkylene group is optionally interrupted by an O atom and / or is optionally substituted with one or more C _1-3 alkyl groups);

R ⁴ represents H, C _1-12 alkyl, C _1-6 alkoxy (wherein the last two groups are both optionally substituted and / or end with one or more substituents selected from —OH, halo, cyano, nitro, C _{1- 4} alkyl and / or C _1-4 alkoxy), - (CH ₂ ) _q aryl, - (CH ₂ ) _q- hydroxyapyl, - (CH ₂ ) _q -Het ¹ (the last three groups being possibly substituted (by (CH ₂ ) the _{q part} and / or aryl / He ^{1 part} ) with one or more substituents selected from —OH, halogen, cyano, nitro, —C (O) R ¹⁰ , —C (O) OR ¹¹ , - N (H) S (O) ₂ R ^11a , C _1-6 alkyl and / or C _1-6 alkoxy), - (CH ₂ ) _q N (H) C (O) R ⁸ , - (CH ₂ ) _q S (O) ₂ R ⁸ , - (CH ₂ ) _q C (O) R ⁸ , - (CH ₂ ) _q C (O) OR ⁸ , - (CH ₂ ) _q C (O) N (R ⁹ ) R ⁸ if together with R ³ represents C _3-6 alkylene (which alkylene group is optionally interrupted by O atom and / or optionally substituted by one or more than one C _1-3 alkyl group);

q represents 0, 1, 2, 3, 4, 5, or 6;

R ⁸ represents H, C _1-6 alkyl, aryl (wherein the last group is optionally substituted and / or ends with one or more substituents selected from —OH, halo, cyano, nitro, —C (O) R ¹⁰ , - C (O) OR ¹¹ , —N (H) S (O) ₂ R ^11a , C _1-6 alkyl and / or C _1-6 alkoxy) or together with R ⁹ is C _3-7 alkylene;

R ⁹ represents H, C _1-4 alkyl, or together with R ⁸ represents C _3-7 alkylene;

Het ¹ is 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 substituents = O;

R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ or R ⁴⁶ independently represent H or C _1-3 alkyl;

R ⁵ represents H, halogen, C _1-3 alkyl, —OR ¹² , —N (R ¹³ ) R ^12, or together with R ⁶ represents = O;

R ⁶ represents H, C _1-4 alkyl, or together with R ⁵ represents = O;

R ¹² represents H, C _1-6 alkyl, —S (O) ₂ —C _1-4 alkyl, —C (O) R ¹⁴ , —C (O) OR ¹⁴ , —C (O) N (R ¹⁵ ) R ^15a or aryl (wherein the last group is optionally substituted and / or terminated by one or more substituents selected from —OH, halo, cyano, nitro, —C (O) R ¹⁰ , —C (O) OR ¹¹ , -N (H) S (O) ₂ R ^11a , C _1-6 alkyl and / or C _1-6 alkoxy);

R ¹³ represents H or C _1-4 alkyl;

R ¹⁴ represents H or C _1-6 alkyl;

R ¹⁵ and R ^15a independently represent H or C _1-4 alkyl, or together represent C _3-6 alkylene, optionally interrupted by an O atom;

A is a single bond, C _1-6 alkylene, —N (R ¹⁶ ) (CH ₂ ) _r - or —O (CH ₂ ) _r - (wherein the group - (CH ₂ ) _r - in the last two groups is attached to the atom bispidine nitrogen);

B is a single bond, C _1-4 alkylene, - (CH ₂ ) _n N (R ¹⁷ ) -, - (CH ₂ ) _n S (O) _p -, - (CH ₂ ) _n O- (and the group - (CH ₂ ) _n - in the last three groups attached to a carbon atom bearing R ⁵ and R ⁶ ), -C (O) N (R ¹⁷ ) - (and the group -C (O) - in the last group attached to a carbon atom bearing R ⁵ and R ⁶ ), -N (R ¹⁷ ) C (O) O (CH ₂ ) _n -, -N (R ¹⁷ ) (CH ₂ ) _n - (and the group N (R ¹⁷ ) in the last two groups attached to a carbon atom bearing R ⁵ and R ⁶ ) or - (CH ₂ ) _m C (H) (OH) (CH ₂ ) _n - (and the group - (CH ₂ ) _m - in the last 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;

R ¹⁶ and R ¹⁷ independently represent H or C _1-4 alkyl;

R ⁷ represents C _1-6 alkyl, aryl or Net ² , each group of which is optionally substituted and / or terminated (as appropriate) with one or more substituents selected from —OH, cyano, halo, amino, nitro, Het ³ , -C (O) R ¹⁰ , -C (O) OR ¹¹ , C _1-6 alkyl, C _1-6 alkoxy, -N (H) S (O) ₂ R ¹⁸ , -S (O) ₂ R ¹⁹ , -OS (O) ₂ R ²⁰ , -N (H) C (O) N (H) R ²¹ , -C (O) N (H) R ²² and / or aryl (the latter group being possibly substituted with one or more than one cyano group);

Het ² and Het ³ independently represent a five to twelve membered heterocyclic group containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur, and which also possibly includes one or more than one substituent = O;

R ¹⁸ , R ¹⁹ and R ²⁰ independently represent C _1-6 alkyl;

R ²¹ and R ²² independently represent H or C _1-6 alkyl (possibly ending in cyano); and

R ¹⁰ and R ¹¹ independently represent, in each individual case, H or C _1-6 alkyl;

R ^11a represents, in each individual case, C _1-6 alkyl;

or a pharmaceutically acceptable derivative thereof;

provided that:

(a) when A and B both represent simple bonds and R ⁷ represents a possibly substituted aryl, then R ⁵ and R ⁶ both do not represent H;

(b) when A is a single bond, then R ⁵ and R ⁶ together do not represent = O; and

(c) when R ⁵ is —OR ¹² or —N (R ¹³ ) R ¹² , then:

1) A is not —N (R ¹⁶ ) (CH ₂ ) _r - or —O (CH ₂ ) _r ; and / or

2) n is not 0 when B is - (CH ₂ ) _n N (R ¹⁷ ) -, - (CH ₂ ) _n S (O) _p - or - (CH ₂ ) _n O-, such compounds are called hereinafter referred to as “the compounds of the invention”.

Aryl groups that may be mentioned include C _6-10 aryl groups such as phenyl, naphthyl and the like. Oxyaryl groups that may be mentioned include C _6-10 hydroxyaryl groups such as oxyphenyl (phenoxy), oxynaphthyl (naphthoxy) and the like. When they are substituted, the aryl and aryloxy groups are preferably substituted with one to three substituents.

The groups Het ¹ , Het ² and Met ³ that may be mentioned include groups containing from 1 to 4 heteroatoms (selected from the group of oxygen, nitrogen and / or sulfur), and in which the total number of atoms in the ring system is from five to twelve. Het groups (Het ¹ , Het ² and Het ³ ) may be fully / partially aromatic and may be bicyclic.

Heterocyclic groups that may be mentioned include morpholinyl, thiazolyl, oxazolyl, isoxazolyl, cinnolinyl, quinazolinyl, phthalazinyl, purinyl, benzimidazolyl, pyrimidinyl, piperazinyl, pyrazinyl, piperidinyl, pyridinyl, triazolyl, imidazolyl, quinolinyl, isoquinolinyl, dioxanyl, benzdioksanil , benzodioxolyl, benzodioxepanyl, benzmorpholinyl, indolyl, pyrazolyl, pyrrolyl, benzthiophenyl, thiophenyl, chromanyl, thiochromeanil, benzofuranyl, pyranyl, tetrahydropyranyl, tetrahydrofuranyl, furanyl and the like. Het ¹ values that may be mentioned include tetrahydropyranyl, isoxazolyl, benzodioxolyl, benzodioxepanyl, and thiophenyl. Het ² values that may be mentioned include quinolinyl, isoquinolinyl, benzmorpholinyl, benzodioxanyl, piperazinyl, indolyl and pyrazolyl. Het ³ values that may be mentioned include imidazolyl. The substituents on the Het groups (Het ¹ , Het ² and Het ³ ) can, where appropriate, be localized on any atom in the ring system, including the heteroatom. The attachment point of Het groups (Het ¹ , Het ² and Het ³ ) can be any atom in the ring system, including (where appropriate) a heteroatom. Het groups (Het ¹ , Het ² and Het ³ ) may also be in the N- or S-oxidized form.

Pharmaceutically acceptable derivatives include salts and solvates. Salts that may be mentioned include acid addition salts. Pharmaceutically acceptable derivatives also include, on bispidine nitrogen, C _1-4 alkyl quaternary ammonium salts and M-oxides, provided that when an N-oxide is present, then:

(a) no Het group (Het ¹ , Het ² , Het ³ ) contains an unoxidized S atom; and / or

(b) p is not 0 when B is - (CH ₂ ) _n S (O) _p -.

The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of this invention.

The compounds of the invention may also contain one or more asymmetric carbon atoms and therefore may exhibit optical and / or diastereoisomerism. Diastereoisomers can be resolved using conventional techniques, for example, chromatography or fractional crystallization. Various stereoisomers can be isolated by resolution of a racemic or other mixture of compounds using conventional techniques, for example fractional crystallization or HPLC. Alternatively, the desired optical isomers can be obtained by reacting the corresponding optically active starting materials under conditions that will not cause racemization or epimerization, or by derivatization, for example with homochiral acid, followed by separation of the diastereomeric esters using conventional methods (e.g., HPLC, chromatography on silica). All stereoisomers are included within the scope of this invention.

Alkyl groups with which R ¹ , R ² , R ^2b , R ^2c , R ^2d , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R can be represented ^11a , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ^15a , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ and R ⁴⁶ , which may include R ¹² and which may be substituted with R ³ , R ⁴ , R ⁷ , R ⁸ and R ¹² ; and alkoxy groups with which R ⁴ may be represented and with which R ⁴ , R ⁷ , R ⁸ and R ¹² may be substituted, may be linear or, when there are a sufficient number (i.e. three) carbon atoms, may be branched and / or cyclic . In addition, when there is a sufficient number (i.e. four) of carbon atoms, such alkyl and alkoxy groups may also be partially cyclic / acyclic. In addition, such alkyl and alkoxy groups may be saturated or, when there is a sufficient number (i.e. two) carbon atoms, may be unsaturated and / or interrupted by oxygen.

Alkylene groups with which R ³ and R ⁴ , R ⁸ and R ⁹ , R ¹⁵ and R ^15a , A and B may be represented; and - (CH ₂ ) _m -, - (CH ₂ ) _n -, - (CH ₂ ) _q - and - (CH ₂ ) _r chains, which may include A, B and R ⁴ (as appropriate), can be linear or, when there is a sufficient number (i.e. two) of carbon atoms, they can be branched. In addition, such alkylene groups and - (CH ₂ ) -containing chains may be saturated or, when there are a sufficient number (i.e. two) carbon atoms, may be unsaturated and / or interrupted by oxygen.

Halo groups with which R ⁵ may be represented and with which R ⁴ , R ⁷ , R ⁸ and R ¹² may be substituted include fluoro, chloro, bromo and iodo.

For the avoidance of doubt, each group R ¹⁰ , R ¹¹ and R ^11a identified here is independent of the other groups R ¹⁰ , R ¹¹ and R ^11a , respectively. For example, when R ⁴ and R ^{7 are} both aryl substituted with —C (O) R ¹⁰ , these two individual substituents —C (O) R ¹⁰ are independent of each other and are not necessarily identical (although this possibility is not excluded) .

The abbreviations are listed in the end of this description.

According to another aspect of the present invention, there are provided compounds of formula I as defined hereinbefore, but under additional conditions that:

(a) when A is —N (R ¹⁶ ) (CH ₂ ) _r - or —O (CH ₂ ) _r , then g is not 0 or 1; and

(b) when R ⁵ is —OH or —N (R ¹³ ) R ¹² , then B is not —N (R ¹⁷ ) C (O) O (CH ₂ ) _n - or —N (R ¹⁷ ) ( CH ₂ ) _m -.

Preferred compounds of the invention include those wherein:

R ¹ represents H;

R ² represents H;

R ³ represents

- H;

- C _1-2 alkyl; or

- together with R ⁴ represents C _4-5 alkylene, possibly interrupted by an O atom and / or possibly substituted by one or more than one methyl group;

R ⁴ represents

- H;

- linear or branched, and / or saturated or unsaturated, and / or cyclic, acyclic and / or partially cyclic / acyclic C _1-8 alkyl (where the alkyl group is optionally substituted by one or more cyano or halogeno groups and / or interrupted by an atom ABOUT);

- C _1-6 alkoxy;

- - (CH ₂ ) _q S (O) ₂ R ⁸ , - (CH ₂ ) _q C (O) OR ⁸ , - (CH ₂ ) _q N (H) C (O) R ⁸ , - (CH ₂ ) _q C (O) R ⁸ (where q in the last four groups is 0, 1 or 2, and R ⁸ is a linear or branched and / or acyclic, cyclic and / or partially cyclic / acyclic C _1-4 alkyl or phenyl (wherein the phenyl group is optionally substituted with one or more cyano and / or C _1-3 alkyl groups);

- - (CH ₂ ) _q C (O) N (R ⁹ ) R ⁸ (where q in the last group represents 0, 1 or 2, and R ⁸ and R ⁹ independently represent H, linear or branched and / or acyclic cyclic and / or partially cyclic / acyclic C _1-4 alkyl, or together represent C _4-6 alkylene);

- - (CH ₂ ) _q- phenyl, - (CH ₂ ) _q- hydroxyphenyl or - (CH ₂ ) _q -Het ¹ (where q in the last three groups is 0, 1, 2 or 3, - (CH ₂ ) _{the q} part is optionally substituted by a cyano group, and the phenyl or Net ¹ part is optionally substituted by one or more substituents selected from cyano, nitro, linear or branched C _1-4 alkyl, linear or branched C _1-4 alkoxy and -N ( H) S (O) ₂ (R ^11a ); or

- together with R ³ represents C _4-5 alkylene, possibly interrupted by an O atom and / or possibly substituted by one or more than one methyl group;

R ⁵ represents H;

- fluoro;

- —OR ¹² (where R ¹² is H, phenyl (optionally substituted with one or more methoxy groups) or C (O) N (H) R ^15a (where R ^15a is straight or branched C _1-4 alkyl)) ;

- -N (R ¹³ ) R ¹² (where R ¹² represents H, C _1-2 alkyl, -S (O) ₂ -C _1-2 alkyl, -C (O) R ¹⁴ (where R ¹⁴ represents C _1-2 alkyl), —C (O) OR ¹⁴ (where R ¹⁴ is a linear or branched C _1-5 alkyl) or —C (O) N (R ¹⁵ ) (R ^15a ) (where R ¹⁵ and R ^15a independently represent H, either linear or branched C _1-3 alkyl, or together represent C _4-5 alkylene, wherein the alkylene group is optionally interrupted by O) and R ¹³ represents H or C _1-2 alkyl); or

- together with R ⁶ represents = O (especially in the case when R ⁷ represents alkyl or Het ² );

R ⁶ represents H or C _1-2 alkyl, or together with R ⁵ represents = O (especially in the case where R ⁷ represents alkyl or Het ² );

A is a single bond, a linear or branched C _1-4 alkylene (and this group is also optionally interrupted by an O atom), -N (H) (CH ₂ ) _r - or -O (CH ₂ ) _r - (where r is in the latter two groups is equal to 1 or 2);

B is a single bond, C _1-4 alkylene, - (CH ₂ ) _n O-, - (CH ₂ ) _n S (O) ₂ -, - (CH ₂ ) _n N (H) - or —N (H ) (CH ₂ ) _n - (where n in the last four cases is 0, 1, 2 or 3);

R ⁷ represents

- linear or branched and / or acyclic, cyclic and / or partially cyclic / acyclic C _1-6 alkyl (possibly substituted and / or terminated by OH);

- Net ² (possibly substituted by one or more substituents selected from cyano, C _1-3 alkyl, phenyl (the latter group being possibly substituted by one or more cyano), = O, -C (O) R ¹⁰ (where R ¹⁰ represents a linear or branched C _1-3 alkyl) or —S (O) ₂ R ¹⁹ (where R ¹⁹ represents C _1-2 alkyl)); or

phenyl (possibly substituted by one or more substituents selected from cyano, nitro, linear or branched C _1-3 alkyl, linear or branched C _1-3 alkoxy, fluoro, chloro, C (O) N (H) R ²² (where R ²² is a linear or branched and / or acyclic, cyclic and / or partially cyclic / acyclic C _1-4 alkyl, and this alkyl group may end with cyano), N (H) S (O) ₂ R ¹⁸ (where R ¹⁸ represents C _1-2 alkyl) or Het ³ );

R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ and R ⁴⁶ all represent N.

More preferred compounds of the invention include those wherein:

R ³ represents H;

R ⁵ represents H, OH or —N (H) C (O) (R ¹⁵ ) (R ^15a );

R ⁶ represents H;

A represents —CH ₂ - or - (CH ₂ ) ₂ -;

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

R ⁷ represents phenyl (substituted by cyano (preferably at position 4 with respect to B) and one or more possible substituents C (O) N (H) R ²² ).

Preferred compounds of the invention include those of the Examples described hereinafter.

Getting

The invention also provides a process for the preparation of compounds of formula I, wherein:

(a) for compounds of formula I, where R ³ is H, the compounds of formula II are reacted,

where R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , A and B are as defined hereinbefore, with a compound of formula III,

R ⁴ -N = C = O III

where R ⁴ is as previously defined herein, for example, at a temperature between 0 ° C. and reflux temperature in the presence of an appropriate organic solvent (eg dichloromethane) or by solid phase synthesis under conditions known to those skilled in the art;

(b) reacting a compound of formula II as defined hereinbefore with a carboxylic acid derivative of formula IV,

(R ³ ) (R ⁴ ) NC (O) -L ¹ IV

where L ¹ represents a leaving group, such as halogen, imidazole or R ²³ O- (where R ²³ represents, for example, C _1-10 alkyl, aryl or C _1-3 alkylaryl, and these groups are optionally substituted with one or more a single halo or nitro group), and R ³ and R ⁴ are as previously defined here, for example, at a temperature between room temperature and reflux temperature in the presence of a suitable base (e.g. triethylamine or potassium carbonate) and an appropriate organic solvent (e.g. dichloromethane, tetrahydrofuran (THF), acetonitri and toluene or mixtures thereof);

(C) carry out the interaction of the compounds of formula V,

where R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , A, B and L ¹ are as defined hereinbefore, with a compound of the formula VA

(R ³ ) (R ⁴ ) NH VA

where R ³ and R ⁴ are as previously defined here, for example, at a temperature between room temperature 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 their mixtures) or by solid phase synthesis under conditions known to those skilled in the art;

(d) for compounds of formula I, where A is CH ₂ and R ⁵ is —OH or —N (H) R ¹² , where R ¹² as defined hereinbefore, the compounds of formula VI are reacted,

where R ¹ , R ² , R ³ , R ⁴ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ R ⁴⁶ are as defined hereinbefore, with a compound of formula VII,

where X represents O or N (R ¹² ), a R ⁶ , R ⁷ , R ¹² and B are as previously defined here, for example, at elevated temperature (for example, from 60 ° C to reflux temperature) in the presence of a suitable solvent (e.g. lower alkyl alcohol (e.g., IPA), acetonitrile, or a mixture of lower alkyl alcohol and water);

(e) reacting a compound of formula VI as defined hereinbefore with a compound of formula VIII,

where L ² represents a leaving group (for example, mesylate, tosylate or halogen), a R ⁵ , R ⁶ , R ⁷ , A and B are as previously defined here, for example, at elevated temperatures (for example, between 35 ° 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 dimethyl sulfoxide (DMSO));

(e) for compounds of formula I, where R ⁵ is H or OH and R ⁶ is H, a compound of formula IX is reduced,

where R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , A and B are as previously defined herein, in the presence of a suitable reducing agent and under appropriate reaction conditions; for example, to form compounds of formula I, where R ⁵ is OH, reduction can be carried out under mild reaction conditions in the presence of, for example, sodium borohydride and an appropriate organic solvent (eg, THF); and to form compounds of formula I where R ⁵ is H, reduction can be carried out by activating the relevant C = O group using an appropriate agent (such as tosyl hydrazine) in the presence of a suitable reducing agent (e.g. sodium borohydride or sodium cyanoborohydride) and the corresponding an organic solvent (e.g., lower (e.g., C _1-6 ) alkyl alcohol);

(g) for compounds of formula I, where R ¹ and R ^{2 are} both H, the corresponding compound of formula X is reduced,

where R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , A and B are as defined hereinbefore, and where the protruding bridge group C = O can be activated using an appropriate agent, such as tosyl hydrazine, in the presence of a suitable reducing agent (e.g. sodium borohydride, sodium cyanoborohydride) and an appropriate organic solvent (e.g. lower alkyl alcohol) or under standard Wolf-Kischner conditions (Wolff-Kischner ) known to those skilled in the art; when the C = O group is activated, the activation step can be carried out at a temperature between room temperature and reflux temperature in the presence of an appropriate organic solvent (for example, lower alkyl alcohol such as methanol, ethanol or IPA), after which a reducing agent can be added to the reaction mixture and the recovery is carried out at a temperature between 60 ° C and a reflux temperature, mainly in the presence of a suitable organic acid (e.g., acetic acid);

(h) for compounds of formula I, where R ¹ and R ² together represent —O (CH ₂ ) ₂ O—, the corresponding compound of formula X, as defined hereinbefore, is reacted with ethane-1,2-diol in the corresponding reaction conditions, for example, by refluxing in the presence of p-TSA and an appropriate organic solvent (eg, toluene);

(i) for compounds of formula I, where B is - (CH ₂ ) _n O-, the compounds of formula XI are reacted,

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , A and n are as defined hereinbefore, with a compound of the formula XIA

R ⁷ OH XIA

where R ⁷ is as defined hereinbefore, for example, under conditions such as Mitsunobu conditions, for example, at a temperature between ambient temperature (e.g. 25 ° C.) and reflux temperature in the presence of tertiary phosphine (e.g. tributylphosphine or triphenylphosphine), an azodicarboxylate derivative (e.g., diethyl azodicarboxylate or 1,1 '- (azodicarbonyl) dipiperidine) and an appropriate organic solvent (e.g., dichloromethane or toluene);

(k) for compounds of formula I, which are N-oxide derivatives with respect to bispidine nitrogen, oxidize the corresponding bispidine nitrogen of the corresponding compound of formula I in the presence of a suitable oxidizing agent (e.g. m-CPBA), for example, at 0 ° C in the presence of a suitable organic solvent (e.g. dichloromethane (DCM));

(k) for compounds of formula I, which are derivatives of C _1-4 alkyl quaternary ammonium salts, where the alkyl group is attached to bispidine nitrogen, the bispidine nitrogen is reacted with the corresponding compound of formula I with a compound of formula XII,

R ^b L ³ XII

where R ^b represents C _1-4 alkyl, and L ³ is a leaving group, such as halogen, alkanesulfonate or arylsulfonate, for example, at room temperature in the presence of an appropriate organic solvent (e.g. DMF), followed by purification (using, for example, HPLC) in the presence of a suitable counterion donor (e.g., NH ₄ OAc);

(m) for compounds of formula I, where R ⁵ and R ⁶ are H, A is C _1-6 alkylene, and B is —N (R ¹⁷ ) (CH ₂ ) _n -, the compounds of formula XIII are reacted,

where ^{a a} represents C _1-6 alkylene, a R ¹ , R ² , R ³ , R ⁴ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ and R ¹⁷ as defined hereinbefore with a compound of formula XIV,

R ⁷ - (CH ₂ ) _n -L ² XIV

where R ⁷ , n and L ² are as previously defined herein, for example, at 40 ° C. in the presence of a suitable organic solvent (eg, acetonitrile);

(n) for compounds of formula I, where R ⁵ is —NH ₂ , the corresponding compound of formula XV is reduced,

where R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , A and B are as defined hereinbefore, for example, by hydrogenation at an appropriate pressure in the presence of a suitable catalyst (e.g. palladium-carbon) and a suitable solvent (e.g. water-ethanol mixture);

(o) for compounds of formula I, where R ⁵ is —N (R ¹³ ) C (O) NH (R ¹⁵ ), the corresponding compound of formula I, where R ⁵ is —N (R ¹³ ) H, is reacted with a compound of formula XVI,

R ¹⁵ N = C = O XVI

where R ¹⁵ is as previously defined herein, for example, at ambient temperature (e.g. 25 ° C.) in the presence of a suitable solvent (e.g. benzene);

(p) for compounds of formula I, where R ⁵ is —N (R ¹³ ) C (O) R ¹⁴ , the corresponding compound of formula I, where R ⁵ is —N (R ¹³ ) H, is reacted with a compound of formula XVII ,

R ¹⁴ C (O) R ^X XVII,

where R ^X represents a suitable leaving group, such as C _1-4 alkoxy, halogen (eg Cl, Br) or para-nitrophenyl, and R ¹⁴ as defined hereinbefore, for example, at a temperature between ambient temperature and temperature refluxing in the presence of a suitable solvent (e.g. dichloromethane or acetonitrile) and possibly in the presence of a suitable base (e.g. triethylamine or potassium carbonate);

(p) for compounds of formula I, where R ⁵ is —N (H) R ¹² , where R ¹² is as previously defined, provided that it is not H, the corresponding compound of formula I is reacted where R ⁵ represents —NH ₂ , with a compound of formula XVIII,

R ^12a L ¹ XVIII

where R ¹² a represents R ¹² as defined hereinbefore, provided that it does not represent H, a L ¹ is as defined hereinbefore, for example, under conditions known to those skilled in the art;

(c) for compounds of formula I, where R ⁵ is —OR ¹² , where R ¹² is C _1-6 alkyl or optionally substituted aryl, the corresponding compound of formula I, where R ⁵ is —OH, is reacted with a compound of the formula XIX,

R ^12a OH XIX

where R ^12a is C _1-6 alkyl or optionally substituted aryl, for example, at a temperature between ambient temperature (e.g. 25 ° C) and reflux temperature under conditions such as Mitsunobu conditions (i.e. in the presence of, for example, triphenylphosphine, an azodicarboxylate derivative (e.g. 1,1 '- (azodicarbonyl) dipiperidine) and a suitable organic solvent (e.g. dichloromethane));

(t) for compounds of formula I, where R ⁵ is —OR ¹² , where R ¹² is C _1-6 alkyl or optionally substituted aryl, a compound of formula XX is reacted,

where L ² , R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , A and B are as defined hereinbefore, with a compound of formula XIX, as previously defined here, for example, at a temperature between ambient temperature (e.g. 25 ° C.) and reflux temperature under conditions such as Williamson conditions (i.e. in the presence of a suitable base (e.g. KOH or NaH ) and a suitable organic solvent (e.g. dimethyl sulfoxide or DMF));

(y) for compounds of formula I, where R ⁵ is OR ¹² and R ¹² is C (O) R ¹⁴ , and R ¹⁴ as defined hereinbefore, the corresponding compound of formula I is reacted as defined herein previously, where R ⁵ represents OH, with a compound of formula XXI,

R ¹⁴ CO ₂ H XXI

where R ¹⁴ is as defined hereinbefore, for example, at ambient temperature (e.g. 25 ° C.) in the presence of a suitable coupling agent (e.g. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide), an appropriate catalyst (e.g. 4-dimethylaminopyridine) and a reaction-inert organic solvent (e.g. THF);

(f) for compounds of formula I where R ⁵ is halogen, the corresponding compound of formula I where R ⁵ is —OH is replaced with a suitable halogenating agent (for example, for compounds where R ⁵ is fluoro, reaction with diethylaminosulfotrifluoride);

(x) for compounds of formula I, where R ³ and / or R ⁴ are suitable as alkyl groups (e.g., C _1-6 or C _1-12 alkyl, as appropriate), the corresponding compound of formula I is alkylated, where R ³ and / or R ⁴ (as appropriate) are H, under conditions well known to those skilled in the art;

(c) converting one R ⁴ group to another (for example, converting - (CH ₂ ) _q C (O) OR ⁸ to - (CH ₂ ) _q C (O) N (R ⁹ ) R ⁸ , where R ⁸ , R ⁹ and q are as defined hereinbefore) using techniques well known to those skilled in the art; or

(h) for compounds of formula I, where one of R ¹ and R ² is H and the other is —OH, the corresponding compound of formula X, as defined hereinbefore, is reduced in the presence of a mild reducing agent, for example sodium borohydride, and an appropriate organic solvent (e.g., lower alcohol, such as methanol or ethanol);

(iii) for compounds of formula I, where one of R ² and R ³ is —NH ₂ and the other is H, a compound of formula XXIA is reduced,

where R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , A and B are as previously defined herein, in the presence of a suitable reducing agent ( for example, LiAIH ₄ ), for example, under conditions well known to those skilled in the art;

(u) for compounds of formula I, where one or both of R ¹ and R ² are —N (R ^2c ) R ^2d , where one or both of R ^2c and R ^2d are C _1-6 alkyl, alkylate the corresponding compound formula I, where R ¹ and / or R ² are —N (R ^2c ) R ^2d (as appropriate), where R ^2c and / or R ^2d (as appropriate) are H, using a compound of formula XXIB.

R ^2e L ¹ XXIB

where R ^2e represents C _1-6 alkyl, and L ¹ as defined hereinbefore, for example, under conditions well known to those skilled in the art; or

(e) converting one substituent on R ⁷ to another using techniques well known to those skilled in the art.

Compounds of formula II can be prepared by reacting a compound of formula XXII,

where R ¹ , R ² , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ and R ⁴⁶ are as defined hereinbefore, with a compound of formula VIII as defined hereinbefore, for example, as described hereinbefore for the synthesis of compounds of formula I (step (e) of the preparation method) or, in the case of compounds of formula II, wherein A is CH ₂ and R ⁵ is OH or N (H) R ¹² , with a compound of formula VII as defined hereinbefore, for example as described hereinbefore for the synthesis of compounds of formula 1 (step (g) of the preparation method).

Compounds of formula II, wherein R ¹ and R ^{2 are} both H, can be prepared by reducing a compound of formula XXIII,

where R ⁵ , R ⁶ , R ⁷ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , A and B are as defined hereinbefore, and where the group C = O can be activated using the appropriate an agent such as tosyl hydrazine, for example, as described hereinbefore for the synthesis of compounds of formula I (step (g) of the preparation method).

Compounds of formula IV can be prepared by reacting a compound of formula VA, as hereinbefore defined, with a compound of formula XXIV,

L ¹ -C (O) -L ¹ XXIV

where L ¹ is as previously defined here, and where the two L ¹ groups may be the same or different, for example, at a temperature between 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).

Compounds of formula V can be prepared by reacting a compound of formula II, as defined hereinbefore, with a compound of formula XXIV, as defined hereinbefore, for example, as described hereinbefore for the synthesis of compounds of formula IV.

Compounds of formula VI can be prepared by reacting a compound of formula XXII, as defined hereinbefore, with a compound of formula III, as defined hereinbefore, for example, as described hereinbefore for the synthesis of compounds of formula I (step (a) of the preparation method), or a compound of formula IV, as defined hereinbefore, for example, as described hereinbefore for the synthesis of compounds of formula I (step (b) of the preparation method).

Compounds of formula VI can alternatively be prepared by reacting a compound of formula XXII, as defined hereinbefore, with a compound of formula XXIV, as defined hereinbefore, for example, as described hereinbefore for the synthesis of compounds of formula IV, followed by reaction of the resulting intermediate with a compound of formula VA, as defined hereinbefore, for example, as described hereinbefore for the synthesis of compounds of formula I (step (c) of the preparation method).

The compounds of formula VI, where R ¹ and R ² represent H, can alternatively be obtained by recovery of the corresponding compounds of formula XXV,

where R ³ , R ⁴ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ and R ⁴⁶ are as defined hereinbefore, and where the C = O group can be activated using an appropriate agent such as tosyl hydrazine, for example as described hereinbefore for compounds of formula I (step (g) of the preparation method).

Compounds of formula VI, where one or more than one of R ⁴¹ , R ⁴² , R ⁴⁵ and / or R ⁴⁶ is C _1-3 alkyl, can be prepared by reacting a compound of formula VI, where R ⁴¹ , R ⁴² , R ⁴⁵ and / or R ⁴⁶ (as appropriate) are H, with an appropriate alkylating agent (e.g. dimethyl sulfate), for example, in the presence of a suitable strong base (e.g. sec-BuLi), N, N, N ', N'-tetramethylethylenediamine and a reaction inert solvent (e.g. THF).

The compounds of formula VII can be obtained in accordance with methods that are well known to specialists in this field of technology. For example, compounds of formula VII, where:

(1) B is —CH ₂ O—, and X is O, can be prepared by reacting a compound of formula XIA, as hereinbefore defined, with a compound of formula XXVI,

where R ⁶ and L ² are as previously defined here, for example, at elevated temperature (for example, between 60 ° C and reflux temperature) in the presence of a suitable base (for example, K ₂ CO ₃ or NaOH) and an appropriate organic solvent (for example, acetonitrile or toluene / water mixtures), or otherwise described in the prior art;

(2) R ⁶ represents H, and X represents O, can be obtained by reducing the compounds of formula XXVII,

where R ⁷ and B are as defined hereinbefore, for example, at a temperature between −15 ° C. and room temperature in the presence of a suitable reducing agent (eg, NaBH ₄ ) and an appropriate organic solvent (eg, THF), followed by an internal substitution reaction in the resulting intermediate, for example, at room temperature in the presence of a suitable base (eg, K ₂ CO ₃ ) and an appropriate organic solvent (eg, acetonitrile);

(3) B represents C _1-4 alkylene, - (CH ₂ ) _n N (R ¹⁷ ) -, - (CH ₂ ) _n S (O) 2 - or - (CH ₂ ) _n O- (where n the last three groups represents 1, 2, 3 or 4) either - (CH ₂ ) _m C (H) (OH) (CH ₂ ) _n -, and X represents O, can be obtained by oxidation of the compounds of formula XXVIII,

where In ^a represents a single bond, C _1-3 alkylene, - (CH ₂ ) _n-1 N (R ¹⁷ ) -, - (CH ₂ ) _n-1 S (O) ₂ - or - (CH ₂ ) _{n -1} O- (where n in the last three groups is 1, 2, 3 or 4) or - (CH ₂ ) _m-1 C (H) (OH) (CH ₂ ) _n - (where n in the last group is as defined hereinbefore) and in all cases R ¹⁷ and m are as defined hereinbefore in the presence of a suitable oxidizing agent (e.g. m-CPBA), for example, by refluxing in the presence of a suitable organic solvent (e.g. DXM); or

(4) B represents - (CH ₂ ) _n O—, and X represents N (R ¹² ), and R ¹² represents —S (O) ₂ —C _1-4 alkyl or —C (O) OR ¹⁴ can be obtained by cyclization of the compounds of formula XXVIIIA,

where R ^12a represents —S (O) ₂ —C _1-4 alkyl or —C (O) OR ¹⁴ , an, R ⁶ , R ⁷ , R ¹⁴ and L ² as defined hereinbefore, for example, at a temperature between 0 ° C and the reflux temperature in the presence of a suitable base (e.g. sodium hydroxide), an appropriate solvent (e.g. dichloromethane, water or a mixture thereof) and, if necessary, a phase transfer catalyst (such as tetrabutylammonium hydrogen sulfate).

Compounds of formula VIII can be prepared using standard procedures. For example, compounds of formula VIII, where:

(1) B represents - (CH ₂ ) _n O—, can be obtained by combining a compound of formula XIA, as defined hereinbefore, with a compound of formula XXIX,

L ⁴ - (CH ₂ ) _n -C (R ⁵ ) (R ⁶ ) -AL ² XXIX

where L ⁴ represents a suitable leaving group (for example, halogen), an, R ⁵ , R ⁶ , A and L ² are as defined hereinbefore; or

(2) B represents —C (O) N (R ¹⁷ ) -, can be prepared by combining a compound of formula XXX,

R ⁷ N (H) R ¹⁷ XXX

where R ⁷ and R ¹⁷ are as defined hereinbefore, with a compound of formula XXXI,

L ⁴ -C (O) -C (R ⁵ ) (R ⁶ ) -AL ² XXXI

where L ⁴ , R ⁵ , R ⁶ , A and L ² are as previously defined herein;

in both cases, under conditions that are well known to those skilled in the art.

Compounds of formula VIII where A is C ₂ alkylene and R ⁵ is OR ¹² where R ¹² is C _1-6 alkyl or optionally substituted aryl can alternatively be prepared by reacting a compound of formula XIX as defined herein previously, with a compound of formula XXXIA,

where R ^y represents C _1-4 alkyl or aryl (wherein these two groups are optionally substituted with one or more substituents selected from C _1-4 alkyl or halogen), a R ⁶ , R ⁷ and B are as defined herein previously, for example, between ambient temperature (e.g. 25 ° 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 functional group to the L ² group ( where L ² is as defined here earlier) in the condition they are well known to those skilled in the art.

The compounds of formulas VII and VIII, where B represents - (CH ₂ ) _n S (O) - or - (CH ₂ ) _n S (O) ₂ - can be obtained by oxidation of the corresponding compounds of formulas VII and VIII, where B represents itself - (CH ₂ ) _n S-, where n is as previously defined herein, in the presence of an appropriate amount of a suitable oxidizing agent (e.g. m-CPBA) and an appropriate organic solvent.

Compounds of formulas IX and XI can be prepared by a method analogous to compounds of formula I (see, for example, steps (a), (b), (c) or (d) of the preparation process).

Alternatively, compounds of formula IX, wherein A is C ₂ alkylene, can be prepared by reacting a compound of formula VI as defined hereinabove with a compound of formula XXXII,

R ⁷ -BC (O) -CH = CH ₂ XXXII

where B and R ⁷ are as previously defined herein, for example, at room temperature in the presence of a suitable organic solvent (eg, ethanol).

Compounds of formula XIII can be prepared by removing a possibly substituted benzyloxycarbonyl unit (i.e., deprotection) from the corresponding compound of formula I, wherein R ⁷ is optionally substituted phenyl, R ⁵ and R ^{6 are} both H, B is —N (R ¹⁷ ) C (O) O (CH ₂ ) -, A represents A ^a , and A ^a as defined hereinbefore, under conditions that are well known to those skilled in the art.

Compounds of formula XV can be prepared by reacting a corresponding compound of formula I as defined hereinbefore, wherein R ⁵ is —OH, with a compound of formula XXXIII,

R ^y S (O) ₂ Cl XXXIII

where R ^y is as defined hereinbefore, for example, at a temperature between -10 ° C and 25 ° C in the presence of a suitable solvent (e.g. dichloromethane), followed by reaction with a suitable source of azide ion (e.g. sodium azide), e.g. the temperature between ambient temperature and reflux temperature in the presence of an appropriate solvent (e.g. DMF) and a suitable base (e.g. NaHCO ₃ ).

Compounds of formula XV may alternatively be prepared by reacting the corresponding compound of formula VI, as hereinbefore defined, with a compound of formula XXXIIIA,

R ⁷ -BC (R ⁶ ) (N ₃ ) -AL ² XXXIIIA

where L ² , R ⁶ , R ⁷ , A and B are as defined hereinbefore, for example, under conditions similar to those described hereinbefore for the preparation of compounds of formula I (preparation method step (e)).

Compounds of formula XX can be prepared by substituting an OH group for a compound of formula I, wherein R ⁵ is an OH, L ² group under conditions that are well known to those skilled in the art.

Compounds of formula XXIA can be prepared by reacting the corresponding compound of formula X with hydroxylamine, for example, at elevated temperature (for example, reflux temperature) in the presence of a suitable organic solvent (for example methanol).

Compounds of formula XXII are well known in the literature or are readily available through the use of known techniques. For example, compounds of formula XXII, where R ¹ and R ² together are —O— (CH ₂ ) ₂ —O—, - (CH ₂ ) ₃ -, - (CH ₂ ) ₄ -, or - (CH ₂ ) ₅ - , a R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ and R ^{46 are} all H, can be prepared by reducing a compound of formula XXXIV,

where R ^1a and R ^2a together are —O— (CH ₂ ) ₂ —O—, - (CH ₂ ) ₃ -, - (CH ₂ ) ₄ - or - (CH ₂ ) ₅ -, in the presence of a suitable reducing agent (e.g., LiAIH ₄ ) under conditions that are well known to those skilled in the art.

Compounds of formula XXXIIIA can be prepared in a manner analogous to compounds of formula XV (i.e., from the corresponding alcohol).

Compounds of formulas X, XXIII and XXV (where in all cases R ⁴⁵ and R ^{46 are} both H) can be obtained predominantly by reacting either (as appropriate) (1) a compound of formula XXXV,

where R ^z represents C _1-10 alkyl or C _1-3 alkylaryl (e.g. alkylphenyl such as benzyl), a R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁴ are as defined hereinbefore, or (2) 4 β-piperidone (or a protected derivative thereof), or (as appropriate) (1) with a compound of the formula XXXVI,

R ⁷ -BC (R ⁵ ) (R ⁶ ) -A-NH ₂ XXXVI

where R ⁵ , R ⁶ , R ⁷ , A and B are as previously defined here, or (2) with NH ₃ (or its protected (e.g. benzyl) derivative), in all cases in the presence of formaldehyde (i.e., the corresponding source formaldehyde such as paraformaldehyde or formalin solution), and, in the case of compounds of formulas X and XXV, by converting the C (O) OR ^z group in the resulting intermediate to the C (O) N (R ³ ) (R ⁴ ) group using methods, such as the methods described here (for example, step (c) of the preparation method described above).

The formation of compounds of formulas X, XXIII and XXV in this way can be carried out, for example, at a temperature between room temperature and reflux temperature (depending on the concentration of the reacting substances) in the presence of an appropriate solvent (for example ethanol or methanol) and, preferably, in the presence of an organic acids (e.g. C _1-6 carboxylic acid, especially acetic acid).

It will also be clear to those skilled in the art that compounds of formula XXII, where R ¹ and R ^{2 are} both H, can also be prepared by this method (i.e., by reacting a 4-piperidone compound (or its protected derivative) with NH ₃ (or its protected derivative) in the presence of formaldehyde) provided that the intermediate thus formed is then reduced under the appropriate reaction conditions.

It will also be clear to those skilled in the art that this method can also be used to prepare compounds of formula I, wherein R ⁴¹ and R ⁴² are H and R ⁴⁵ and / or R ⁴⁶ are other than H, for example, by:

1) the interaction of the compounds of formula XXXV, where R ⁴¹ and / or R ⁴² , different / different from H, for example, with benzylamine or its derivative;

2) removal of the —C (O) OR ^{z z} unit;

3) the interaction on the free nitrogen of bispidine of the obtained compound with the compound of formula VIII, as defined here previously;

4) removal of the benzyl protective group; and

5) the interaction on the free nitrogen of bispidine obtained compounds, for example, with a compound of formula III or IV, as defined here previously,

under conditions well known to those skilled in the art, including the conditions described hereinbefore. This interaction will be accompanied at some stages by the conversion of the protruding bridging carbonyl functional group to the desired R ¹ / R ² groups.

Compounds of formula XXXIV may be prepared according to methods that are well known to those skilled in the art. For example, compounds of formula XXXIV, where R ^1a and R ^2a together are - (CH ₂ ) ₃ -, - (CH ₂ ) ₄ - or - (CH ₂ ) ₅ -, can be prepared by reacting a compound of formula XXXVII,

where R ^{1a '} and R ^2a' together represent - (CH ₂ ) ₃ -, - (CH ₂ ) ₄ - or - (CH ₂ ) ₅ -, with a mixture of phosphoric acid and sulfuric acid, for example, at 120 ° C.

Compounds of formula XXXVI are well known in the literature or are readily available through the use of known techniques. For example, compounds of formula XXXVI where R ⁵ is OH, R ⁶ is H and A is CH ₂ can be prepared by reacting a compound of formula VII where R ⁶ is H and X is O, s ammonium hydroxide under conditions that are well known to specialists in this field of technology.

The compounds of formulas 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 their derivatives are either commercially available, known from the literature, or can be obtained either analogously to the methods described here or using conventional synthesis methods in accordance with standard procedures from readily available starting materials using appropriate reagents and reaction conditions.

Substituents on the aryl (e.g., phenyl) and (if appropriate) heterocyclic group (s) in the compounds defined herein can be converted to other substituents using techniques well known to those skilled in the art. For example, nitrobenzene can be reduced to aminobenzene, hydroxy can be converted to alkoxy, alkoxy can be hydrolyzed to hydroxy and so on.

The compounds of this invention can be isolated from their reaction mixtures using conventional techniques.

It will be clear to those skilled in the art that in the methods described above, the functional groups of the intermediates may be protected or may need to be protected with protecting groups.

Functional groups that it is desirable to protect include a hydroxy, amino and carboxyl group. Suitable hydroxy protecting groups include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, mpem-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and alkylcarbonyloxy groups (e.g. methyl and ethylcarbonyloxy). Suitable protecting groups for amino include benzyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acids include C _1-6 alkyl or benzyl esters.

Protection and deprotection of functional groups may take place before or after any reaction steps described hereinabove.

Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and in a manner as described hereinafter.

The use of protecting groups is fully described in “Protective Groups in Organic Chemistry”, edited by JWFMcOmie, Plenum Press (1973) and “Protective Groups in Organic Synthesis”, 2 ^nd edition, T W Greene & PGM Wutz, Wiley-lnterscience (1991).

It will be clear to those skilled in the art that in order to obtain the compounds of this invention in an alternative and in some cases more convenient way, the individual steps of the process mentioned here can be performed in a different order and / or the individual reactions can be performed at a different stage of the general paths (i.e., substituents can be added to other intermediates and / or chemical transformations performed on other intermediates compared to those that were previously here with yazany 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 adopted strategy (if one exists) of the protective groups. Obviously, the type of chemistry involved will affect the choice of reagent that is used in the indicated stages of synthesis, the necessity and type of protective groups used, and the sequence of synthesis.

It will also be clear to those skilled in the art that although certain protected derivatives of the compounds of formula I, which can be prepared prior to the final deprotection step, may not have pharmacological activity per se, they can be administered parenterally or orally and thereafter undergo metabolism in the body to form compounds of this invention that are pharmacologically active. Therefore, such derivatives can be described as “prodrugs”. Moreover, the inventors have found that certain compounds of formula I can act as prodrugs of other compounds of formula I.

All prodrugs of compounds of formula I are included within the scope of the present invention.

Some intermediate compounds mentioned here are new. Thus, according to another aspect of the present invention, it is proposed: (a) a compound of formula II, as defined hereinbefore, or a protected derivative thereof, provided that R ^{7 is} not a possibly substituted phenyl; (b) a compound of formula V, as defined hereinbefore, or a protected derivative thereof, provided that R ^{7 is} not a possibly substituted phenyl; (c) a compound of formula X, as defined hereinbefore, or a protected derivative thereof; (d) a compound of formula XI, as defined hereinbefore, or a protected derivative thereof; (e) a compound of formula XIII, as defined hereinbefore, or a protected derivative thereof; (e) a compound of formula XV, as defined hereinbefore, or a protected derivative thereof; (g) a compound of formula XX, as defined hereinbefore, or a protected derivative thereof; (h) a compound of formula XXIII, as defined hereinbefore, or a protected derivative thereof, provided that R ^{7 is} not a possibly substituted phenyl; and (i) a compound of formula XXV, as defined hereinbefore, or a protected derivative thereof.

Medical and pharmaceutical applications

The compounds of this invention are useful since they have pharmaceutical activity. Therefore, they are indicated as pharmaceuticals.

Thus, according to another aspect of the present invention, there are provided compounds of the invention for use as pharmaceuticals.

In particular, the compounds of the invention exhibit myocardial electrophysiological activity, for example, as demonstrated in the test described below.

Thus, it is expected that the compounds of the invention will be useful both in the prophylaxis and in the treatment of arrhythmias, and in particular atrial and ventricular arrhythmias.

Thus, the compounds of the invention are indicated for the treatment or prophylaxis of heart diseases or for indications related to heart diseases in which arrhythmias are believed to play a major role, including coronary heart disease, sudden heart attack, myocardial infarction, heart failure, surgery for heart and cases of thromboembolism.

In the treatment of arrhythmias, it was found that the compounds of the invention selectively slow down cardiac repolarization, thereby increasing the QT interval, and, in particular, exhibit class III activity. Despite the fact that it was shown that the compounds of the invention exhibit class III activity, in particular in the treatment of arrhythmias, the type (s) of their activity is not necessarily limited (s) to this class.

According to yet another aspect of the present invention, there is provided a method of treating arrhythmia, wherein a subject suffering from or suffering from such a condition is administered a therapeutically effective amount of a compound of the invention.

Pharmaceuticals

The compounds of this invention will typically be administered orally, subcutaneously, intravenously, intraarterially, transdermally, intranasally, by inhalation, or by any other parenteral route of administration, in the form of pharmaceutical preparations containing the active ingredient either as a free base, a pharmaceutically acceptable ion exchanger, or a non-toxic salt joining an organic or inorganic acid in a pharmaceutically acceptable dosage form. Depending on the disease and the patient being treated, as well as on the route of administration, the compositions may be administered in various doses.

The compounds of the invention can also be combined with any other drugs useful in the treatment of arrhythmias and / or other cardiovascular diseases.

Thus, according to another aspect of the present invention, there is provided a pharmaceutical preparation comprising a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Suitable daily doses of the compounds of the invention for the therapeutic treatment of humans are from about 0.05 to 5.0 mg / kg body weight when administered parenterally.

The compounds of the invention have the advantage of being effective against cardiac arrhythmias.

The compounds of the invention also have the advantage that they can be more effective, less toxic, have a wider range of action (including the manifestation of any combination of class I, class II, class III and / or class IV activity (especially class I, class II and / or class IV in addition to class III activity)), be more potent, have longer activity, cause fewer side effects (including a lower percentage of proarrhythmias such as torsades de pointes), are easier to absorb than compounds, known in the art, or in that they may have other useful pharmacological properties besides those of compounds known in the art.

Biological tests

Test a

Primary electrophysiological effects on anesthetized guinea pigs

Guinea pigs weighing between 660 and 1100 g were used. The animals were kept for at least one week before the experiment with free access to food and tap water during this period.

Anesthesia was performed by intraperitoneal injection of pentobarbital (40 to 50 mg / kg), and catheters were inserted into one carotid artery (for recording blood pressure and blood sampling) and in one cervical vein (for drug infusion). Needle electrodes were placed on the limbs for ECG recording (lead II). A thermistor was placed in the rectum, and the animal was placed on an heating pad, setting the rectal temperature between 37.5 and 38.5 ° C.

A tracheotomy was performed and the animal was artificially ventilated using room air using a small fan for animals set up to maintain normal blood gases for these species. In order to reduce the effects on the autonomic nervous system, both vagus nerves in the neck were cut 15 minutes before the start of the experiment and 0.5 mg / kg of propranolol was injected intravenously.

The left ventricular epicardium was exposed through left-side thoracotomy, and a custom-made suction electrode was applied to the free wall of the left ventricle to record a single-phase action potential (OPD). The electrode was kept in this position until an acceptable signal was registered, otherwise it was moved to a new position. A bipolar electrode for pacing was attached to the left atrium. Pacemaker (2 ms duration, twice diastolic threshold) was performed using a custom-made direct current stimulator. The heart was stimulated at a frequency slightly higher than the normal sinus rhythm for 1 minute every five minutes throughout the study.

Blood pressure, an SPD signal, and ECG II abduction were recorded on a Mingograph inkjet recorder (Siemens-Elema, Sweden). All signals were collected (collection frequency 1000 Hz) on a PC during the last 10 seconds of each stimulation sequence and the last 10 seconds of the next minute of the sinus rhythm. The signals were processed using a custom program designed to collect and analyze physiological signals measured in experimental animals (see Axenborg and Hirsch, Comput. Methods Programs Biomed. 41, 55 (1993)).

The testing procedure consisted in the removal of two basic control records with an interval of 5 minutes in the continuation of both pacemaker and sinus rhythm. After the second control record, the first dose of the test substance was infused for 30 seconds in a volume of 0.2 ml into a catheter in the cervical vein. 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 administered. During each experiment, six to ten consecutive doses were given.

Data analysis

Of the many variables measured in this type of analysis, three were chosen as the most important for comparison and selection of active compounds. These three selected variables were: the duration of heart failure at 75 percent repolarization during pacing, the time of atrioventricular (AV) conduction (defined as the interval between the atrial stimulus and the onset of ventricular heart failure) during heart pacing, and the heart rate (defined as the RR interval in continuation of the sinus rhythm). Systolic and diastolic blood pressure was measured in order to assess the hemodynamic status of the anesthetized animal. The ECG was then checked for arrhythmias and / or morphological changes.

The average value for the two control records was taken as zero, and the effects recorded after successive doses of the test substance were expressed as deviations from this value, in percent. The construction of dose-response curves was carried out by plotting these values as a percentage against the total dose administered before each recording. Thus, each experiment gave three dose-response curves, one for the duration of the CPD, one for the AV conduction time, and one for the sinus rhythm frequency (RR interval). The average curve was calculated for all experiments conducted with the test substance, and efficiency values were obtained from the average curve. All dose-response curves in these experiments were constructed by linearly connecting the obtained experimental points. The cumulative dose, increasing the duration of OPD by 10% compared with the baseline, was used as an index to assess the electrophysiological effectiveness of class III of the studied agent (D ₁₀ ).

Test b

Metabolic Stability of Test Compounds

In vitro screening was performed to determine the metabolic stability of the compounds of the invention.

The hepatic fraction S-9 of the dog, human, rabbit and rat was used together with NADPH as a cofactor. The assay conditions were as follows: S-9 (3 mg / ml), NADPH (0.83 mM), Tris-Hcl buffer (50 mM) at pH 7.4 and 10 μM of test compound.

The reaction was started by adding the test compound and ended after 0, 1, 5, 15, and 30 minutes by increasing the pH in the sample above 10 (NaOH; 1 mM). After solvent extraction, the concentration of the test compound was measured against the internal standard using LC (fluorescence detection / UV).

The percentage of test compound remaining after 30 minutes (and therefore t _1/2 ) was calculated and used as a unit of metabolic stability.

The invention is illustrated by the following examples.

Examples

General experimental techniques

Mass spectra were recorded on a Finnigan MAT TSQ 700 triple quadrupole mass spectrometer equipped with an electrospray interface (FAB-MS) and a VG Platform II mass spectrometer equipped with an electrospray interface (LC-MS), a Hewlett Packard Model 6890 gas chromatograph, connected to a Model 5973A Hewlett-Packard mass spectrometer via a Hewlett Packard HP-5-MS GC column, or a Shimadsu QP-5000 GC / MS spectrometer (CI, methane). ¹ H NMR and ¹³ C NMR measurements were performed on BRUKER ACP 300 and Varian UNITY plus 400 and 500 spectrometers operating at ¹ H-frequencies 300, 400 and 500 MHz, respectively, and at ¹³ C-frequencies 75.5, 100.6 and 125.7 MHz, respectively. Alternatively, ¹³ C NMR measurements were performed on a BRUKER ACE 200 spectrometer at a frequency of 50.3 MHz.

Rotamers may or may not vary in spectrum, depending on the ease of interpretation of the spectrum. Unless otherwise noted, chemical shifts are given in parts per million with a solvent as an internal standard.

Synthesis of Intermediates

Example A

4- (2-hydroxyranylmethoxy) benzonitrile

Epichlorohydrin (800 ml) and K ₂ CO ₃ (414 g) were added to a stirred solution of para-cyanophenol (238 g) in 2.0 L MeCN and the reaction mixture was refluxed under an inert gas atmosphere for 2 hours. The hot solution was filtered and the filtrate was concentrated to give a clear oil, which was crystallized from di-iso-propyl ether to give the title product in 75% yield.

¹³ C NMR (CDCl ₃ ): δ 44.4, 49.7, 69.0, 104.5, 115.3, 118.9, 134.0, 161.6.

Example B

2 (S) -Oxiranyl-3-nitrobenzenesulfonate

meta-Nitrobenzenesulfonyl chloride (12.6 g; 57 mmol) was added to a cooled (-20 ° C) solution of (R) - (+) - glycidic alcohol (5.5 g; 74 mmol) and TEA (10.3 ml; 74 mmol). The reaction mixture was stirred at −20 ° C. for 96 hours. The solution was filtered and the filtrate was washed with tartaric acid (10% w / w), brine, H ₂ O and concentrated to give the title compound in 97% yield.

¹ H NMR (CDCl ₃ ): δ 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).

Example B

4 - [(2S) -Oxiranylmethoxy] benzonitrile

The title compound was obtained in 90% yield according to the procedure described above in Example A, starting with (R) - (-) - epichlorohydrin.

Example D

4 - [(2R) -Oxiranylmethoxy] benzonitrile

The title compound was prepared according to the procedure described above in Example A, starting with (S) - (-) - epichlorohydrin.

[α] $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{D}}$ = 14.1 ° (c = 1.0; acetone)

¹ H NMR (CDCl ₃ ): δ 2.79 (1H, m), 2.98 (1H, m), 3.39 (1H, m), 3.98 (1H, m), 4.37 (1H, m), 6.99 (2H, d) 7.60 (2H, d).

Example D

3-benzyl-3,7-diazabicyclo [3.3.1] nonane

(a) 3,7-Dibenzyl-3,7-diazabicyclo [3.3.1] nonane

The subtitle compound was prepared according to the procedure described in J. Chem., 41, 1593, (1976), except that instead of N-benzyl-N-methylbispidone, 3,7-dibenzyl-3,7-diazabicyclo [3.3.1] nonan-9-one (also obtained in in accordance with the method described in J. Org. Chem., 41, 1593, (1976)).

(b) 3-Benzyl-3,7-diazabicyclo [3.3.1] nonane

3,7-Dibenzyl-3,7-diazabicyclo [3.3.1] nonane (1.97 g; 6.4 mmol; from step (a) described above) was dissolved in EtOH (95%) and hydrogenated over 5% - Pd / C at a pressure of 98 kPa (1 atm) until, according to TLC, the reaction was complete. The catalyst was removed by filtration through a pad of Celite® and the residue was concentrated under reduced pressure to obtain the title compound in quantitative yield.

¹³ C NMR (CDCl ₃ ): δ 30.1, 33.4, 36.0, 52.5, 59.6, 64.3, 126.9, 128.3, 128.7, 138.8.

Example E

tert-Butyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxylate

(a) tert-Butyl-7-benzyl-9-hydroxy-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 ° C and a solution of acetic acid (15.2 g; 252 mmol) in ethanol (160 ml) was added over 2 hours. After further stirring for 1 hour, the 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 para-formaldehyde (4.80 g; 152 mmol) in ethanol (270 ml), which was heated to 60 ° C. After refluxing overnight, the solution was cooled to room temperature. Ethanol was removed by evaporation. Extractive processing was carried out in a mixture of toluene: water and the material was filtered through silica in the toluene: ethyl acetate system. Evaporation of the eluent gave a solid material (37.4 g). The degree of purity was 90% by area (HPLC), and the yield was 60%. As a result of crystallization in IPA, a compound with a purity of 98% by 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%).

¹³ C NMR (CDCl ₃ ): δ 28.72, 47.71, 49.91, 50.60, 58.83, 59.16. 61.96, 80.18, 127.37, 128.45, 128.89, 137.57, 154.89, 213.66 (using TMS as a control).

(b) tert-Butyl-7-benzyl-9-hydroxy-3,7-diazabicyclo [3.3.1] nonane-3-carboxylate (alternative method of 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) was added to ethanol (300 ml). The solution was heated to 65 ° C and stirred at this temperature for 2 hours. The same processing procedure was carried out as in step (a) described above, obtaining 15.78 g of material with a purity of 92% by area (HPLC) and a yield of 70%. Recrystallization from isopropanol afforded a compound with a purity of 94% by area (HPLC) and a yield of 54%.

(c) tert-Butyl-7-benzyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxylate

A mixture of 4-toluenesulfonhydrazide (12.4 mmol; 2.30 g) and tert-butyl-7-benzyl-9-hydroxy-3,7-diazabicyclo [3.3.1] nonane-3-carboxylate (10.1 mmol; 4 , 00 g; 83.3%; from step (a) above) was dissolved in iso-propanol (30 ml) and refluxed 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 refluxed for 2 hours. The suspension was cooled to ambient temperature and filtered. The filtrate was concentrated and extractive processing was performed in a mixture of toluene: water. The toluene solution was concentrated to give 0.95 g of the subtitled compound with a purity of 90% by area (GC) and 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%).

¹³ C NMR (CDCl ₃ ): δ 28.67, 28.95, 31.11, 47.55, 48.38, 58.70, 58.96, 63.46, 78.71, 126.57, 128.00, 128.53, 138.94, 155.20 (using TMS as a control).

(g) tert-Butyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxylate

tert-Butyl-7-benzyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxylate (from step (c) described above) was debenzylated in accordance with the method described in Example D (b) above, to obtain the above in the title compound with quantitative yield.

¹³ C NMR (CDCl ₃ ): δ 28.05, 28.29, 31.33, 48.35, 49.11, 51.53, 79.34, 155.16.

Example G

4- [3- (3,7-Diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropoxy] benzonitrile

HCI 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-carboxylate (62 g ; see Example 2 of International Patent Application No. PCT / SE98 / 02276) in EtOAc (600 ml) and the mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, the residue was dissolved in MeCN (1.3 L) and added K ₂ CO ₃ (100 g). The suspension was stirred for 12 hours and filtered. Concentration of the filtrate afforded the title compound in 90% yield.

¹³ C NMR (CDCl ₃ ): δ 28.9, 29.2, 32.3, 50.9, 57.7, 60.8, 62.1, 66.0, 71.2, 104.0, 115.3, 119.1, 133.9, 162.1.

(The title compound can also be easily converted to the hydrochloride salt using standard techniques).

Obtaining compounds of formula I

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 (5.0 g; 20 mmol; see Example G described above) in 30 ml of dichloromethane. The mixture was stirred for 4 hours at room temperature and then concentrated in vacuo and purified by silica column chromatography, eluting with dichloromethane: methanol (95: 5), to give 3.2 g (51%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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.

Example 2

7- [3- (4-Cyanophenoxy) -2-hydroxypropyl] -N- (cyclopropylmethyl) -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

(a) Cyclopropylmethylisocyanate

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 distilled to obtain 0.4 g (21%) of the subtitled compound.

b) 7- [3- (4-Cyanophenoxy) -2-hydroxypropyl] -N- (cyclopropylmethyl) -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

Cyclopropylmethylisocyanate (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-hydroxypropyl] benzonitrile (1.2 g; 4 mmol; see example W described above) in DXM. The solution was stirred overnight, concentrated in vacuo. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane: methanol (93: 7), to give 0.85 g (50%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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.

Example 3

4 - ({((2S) -2-Hydroxy-3- [7- (4-morpholinylcarbonyl) -3,7-diazabicyclo [3.3.1] non-3-yl] propyl} hydroxy) benzonitrile

Solution 4 - {[(2S) -3- (3,7-diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropyl] -oxy} benzonitrile (2.0 g; 6.6 mmol; prepared analogously the method described above in Example G) in DCM (10 ml) was treated with aqueous NaOH (0.8 ml 10 M), then 4-morpholinecarbonyl chloride (1.2 g; 8 mmol). The resulting mixture was stirred for 30 minutes at room temperature before adding water. The organic layer was separated, washed with 2 M NaOH, then with brine before separation, dried (MgSO ₄ ) and concentrated in vacuo. The residue was recrystallized twice, first from isopropanol and then from ethanol, to give 0.73 g (26.5%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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

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 described above) was added to a mixture of concentrated aqueous ammonium hydroxide (500 ml) and isopropanol (300 ml). The resulting suspension was stirred at room temperature for 3 days. The reaction mixture was filtered to remove an insoluble by-product, and the filtrate was concentrated in vacuo to give a crude product that was crystallized from acetonitrile to give 50 g (46%) of the subtitled compound.

(b) 2- (4-Cyanophenoxy) -1 - {[(methanesulfonyl) amino] methyl} ethyl 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 at room temperature for 1.5 hours, concentrated in vacuo and then redissolved in DCM. This solution was washed twice with 2M HCI and once with a solution of NaHCO ₃ before separating the organic phase, dried (MgSO ₄ ) and concentrated in vacuo to give 23.5 g (100%) of the subtitled compound.

(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), with the formation of a dense precipitate. After 1 hour, another portion of K ₂ CO ₃ (30 g; 210 mmol) was added. Stirring was continued for 2 hours at room temperature before the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The resulting oil (13 g) was crystallized from toluene to give 8 g (47%) of the subtitle compound. Mp 79-81 ° C.

(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 D described above) and 4 - {[1- (methanesulfonyl) aziridin-2-yl] methoxy} benzonitrile ( 2.5 g; 10 mmol; from step (c) described above) in iso-propanol was refluxed overnight. The mixture was then concentrated in vacuo to give a residue, which was then dissolved in water (pH 3) and extracted with ether. The aqueous layer was made basic with 2M NaOH and extracted with DCM. The dichloromethane layer was separated, dried and concentrated in vacuo to give a residue which was purified by column chromatography, eluting with a gradient of DCM: methanol: methanol ammonia (98: 2: 0 to 97: 0: 3), to give 2.5 g (53%) ) specified in the subtitle of the connection.

(e) N- [2- (4- (Cyanophenoxy) -1- (3,7-diazabicyclo [3.3.1] non-3-ylmethyl) ethyl] methanesulfonamide

Solution 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 (g) described above) in aqueous ethanol (95%; 55 ml) was hydrogenated over 5% Pd / C at atmospheric 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 product was recrystallized from methanol to give 0.3 g (16%) of the subtitled compound.

(f) 7- {3- (4-Cyanophenoxy) -2 - [(methanesulfonyl) amino] propyl} -N-ethyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

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 (d) (described above) in DCM (10 ml) was treated with ethyl isocyanate (66 μl; 0.84 mmol) to obtain a clear solution.The mixture was stirred for 1 h at room temperature, concentrated in vacuo and then purified by column chromatography, eluting with 5% - MeOH in DCM to afford the title compound in 73% yield.

¹³ C NMR (CDCl ₃ ): δ 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

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-propylisocyanate (1.7 g; 20 mmol) was slowly added to a solution of 3-benzyl-3,7-diazabicyclo [3.3.1] nonane (3.1 g; 14.3 mmol; see Example D described above) in DXM (10 ml). The mixture was stirred at room temperature overnight and then concentrated in vacuo to give 4.2 g (97%) of the subtitled compound.

(b) N-iso-propyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

Solution

7-benzyl-N-iso-propyl-3,7-diazabicyclo [3.3.1] nonan-3-carboxamide (4.2 g; 14 mmol; from step (a) above) in a methanol / water mixture (17 ml of the mixture in a ratio of 15: 2) was hydrogenated over 5% Pd / C at atmospheric pressure. The catalyst was removed by filtration through a pad of Celite® and the filtrate was concentrated in vacuo to give 2.6 g (87%) of the subtitle compound.

(c) 7 - [(2S) -3- (4-Cyanophenoxy) -2-hydroxypropyl] -N-iso-propyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

A mixture of 7 - [(2S) -oxyranylmethoxy] benzonitrile (0.55 g; 3.14 mmol; see Example B described above) and N-iso-propyl-3,7-diazabicyclo [3.3.1] nonan-3- carboxamide (0.85 g; 4 mmol; from step (b) described above) in an iso-propanol / water mixture (6.5 ml of the mixture in a 12: 1 ratio) was stirred overnight at 60 ° C. The mixture was then concentrated in vacuo and the residue was redissolved in DCM again. The organic solution was washed with water, then with brine, dried (MgSO ₄ ) and concentrated in vacuo to give the title compound in 91% yield.

¹³ C NMR (CDCl ₃ ): δ 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.

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

(a) 7-Benzyl-N-ethyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

A cooled (0 ° C) solution of 3-benzyl-3,7-diazabicyclo [3.3.1] nonane (32.45 g; 0.15 mol; see Example D described above) in DCM (300 ml) was treated with ethyl isocyanate (11 , 4 g; 0.16 mol), adding it dropwise. The solution was stirred for 2 hours at room temperature before being concentrated in vacuo. The resulting residue was purified by silica gel chromatography, eluting with a gradient of DCM: MeOH (100: 0 to 90:10), to obtain 36.4 g (84%) of the subtitle compound.

(b) N-Ethyl-3,7-diazabicyclo [3.3.1] nonan-3-carboxamide

Solution

7-benzyl-N-ethyl-3,7-diazabicyclo [3.3.1] nonan-3-carboxamide (4.4 g; 15.3 mmol; from step (a) described above) in aqueous ethanol (25 ml 95 %) was hydrogenated over 5% Pd / C at atmospheric pressure. The catalyst was removed by filtration through a pad of Celite® and the residue was concentrated in vacuo to give 2.88 g (95%) of the subtitle compound.

(c) Methyl 5-bromo-2-hydroxybenzoate

Br ₂ (52 g) was slowly added to a stirred solution of methyl salicylate (50 g; 330 mmol) in 300 ml of acetic acid. The reaction mixture was stirred at room temperature for 10 hours, poured into ice-cooled water, and the precipitate was recrystallized from MeOH to give the subtitled compound in 83% yield.

(g) Methyl 5-cyano-2-hydroxybenzoate

Methyl 5-bromo-2-hydroxybenzoate (190.8 g; from step (c) described above) and CuCN (73.9 g) were refluxed in DMF (500 ml) for 7 hours. The temperature was allowed to lower. to 80 ° C and HCI (500 ml) and FeCl ₃ (160.5 g) were added. The reaction mixture was stirred for 30 minutes, concentrated and partitioned between H ₂ O and DCM. The organic layer was dried, concentrated, the residue was recrystallized from methyl ethyl ketone to give the subtitled compound in 61% yield.

(e) 5-cyano-N- (2-cyanoethyl) -2-hydroxybenzamide

A mixture of methyl 5-cyano-2-hydroxybenzoate (20 g; 0.113 mol; from step (g) described above), 3-aminopropanenitrile (15.4 g; 0.22 mol) and sodium cyanide (1 g; 20 mmol ) in methanol (200 ml) was refluxed overnight. TLC analysis showed incomplete reaction; therefore, DMSO (50 ml) was added, and refluxing was continued for the next 5 hours. The solution was concentrated in vacuo, water was added, then conc. Hcl until a precipitate has formed. The product was filtered off, washed with water and dried, yielding 19.4 g (80%) of the subtitle compound.

(e) 5-Cyano-N- (2-cyanoethyl) -2 - [(2R) -oxyranylmethoxy] 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 a mixture of iso-propanol: water (55 ml of the mixture in a ratio of 10: 1) was refluxed overnight. The mixture was concentrated in vacuo and the residue was purified by column chromatography eluting with ethyl acetate to give 0.63 g (24%) of the subtitled 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

A mixture of 5-cyano-N- (2-cyanoethyl) -2 - [(2R) -oxyranylmethoxy] benzamide (0.63 g; 2.3 mmol; from step (e) above) and N-ethyl-3, 7-diazabicyclo [3.3.1] nonane-3-carboxamide (0.59 g; 3 mmol; from step (b) described above) in a mixture of isopropanol: water (33 ml of the mixture in a 10: 1 ratio) was stirred at reflux temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography eluting with a DCM / MeOH mixture (9: 1) to obtain 0.78 g (73%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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, 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-MC (M + 1) ⁺ 469.0 (m / z).

Example 7

7 - ((2S) -3- {4-Cyano-2 - [(cyclopropylamino) carbonyl] phenoxy} -2-hydroxypropyl] -N-ethyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

a) N ¹ -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 (g) described above) in DMSO (40 ml). The reaction mixture was heated overnight at 80 ° C in a sealed steel vessel, diluted with H ₂ O, acidified and extracted with EtOAc to give the subtitled compound (11.0 g) after concentrating the organic layer.

(b) 5-Cyano-N-cyclopropyl-2 - [(2S) -oxyranylmethoxy] benzamide

A mixture of N ¹ -cyclopropyl-5-cyano-2-hydroxybenzamide (1.56 g; 7.7 mmol; from step (a) described above), (2S) -oxyranylmethyl-3-nitrobenzenesulfonate (2 g; 7.7 mmol; see Example B described above) and K ₂ CO ₃ (1.16 g; 8.4 mmol) in 2-butanone (15 ml) was stirred at 60 ° C for 18 hours. The mixture was concentrated in vacuo and the residue was crystallized. from a mixture of di-iso-propyl ether: MeCN (9: 1) to obtain 0.97 g (97%) of the subtitle compound.

(c) 7 - ((2S) -3- {4-Cyano-2 - [(cyclopropylamino) carbonyl] phenoxy} -2-hydroxypropyl) -N-ethyl-3,7-diazabicyclo [3.3.1] nonan-3 carboxamide

A mixture of 5-cyano-N-cyclopropyl-2 - [(2S) -oxyranylmethoxy] benzamide (0.97 g; 3.8 mmol; from step (b) described above) and N-ethyl-3,7-diazabicyclo [ 3.3.1] nonane-3-carboxamide (0.89 g; 4.5 mmol, see Example 6 (b) described above) in a mixture of isopropanol: water (22 ml of the mixture in a 10: 1 ratio) was refluxed fridge overnight. The solvent was removed in vacuo and the resulting residue was purified by silica gel column chromatography eluting with a DCM: MeOH mixture (9: 1) to obtain 1.37 g (79%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 6.62, 6.78, 15.81, 23.55, 29.61, 29.90, 32.48, 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-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) described above) and K ₂ CO ₃ (1.38 g; 10 mmol) was stirred at room temperature overnight. The mixture was then filtered, concentrated in vacuo, and the obtained residue was purified by column chromatography, eluting with a gradient of DCM: MeOH (100: 0 to 90:10), to give 1.5 g (85%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 15.71, 28.83, 30.11, 33.03, 35.67, 47.97, 59.22, 59.49, 123.34, 129.65, 146.26, 149.15, 157.95.

Example 9

N- (Cyanomethyl) -7 - [(2 (S) -3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

(a) Cyanomethyl isocyanate

The title compound was prepared according to the procedure described for Example 2 (a) above using 2-aminoacetonitrile instead of cyclopropylmethylamine.

(b) N- (Cyanomethyl) -7 - [(2 (5) -3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

The title compound was obtained in 26% yield (taking into account steps (a) and (b) together) in accordance with the procedure described above in Example 2 (b) using cyanomethyl isocyanate (from step (a) described above) instead of cyclopropylmethylisocyanate.

¹³ C NMR (CDCl ₃ ): δ 28.99, 29.27, 29.47, 31.77, 48.32, 49.33, 56.88, 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 [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 chilled (-5 ° C) solution of 4-aminophenethyl alcohol (25.2 g; 0.18 mol) in pyridine (200 ml). The mixture was stirred at 0 ° C. for 1 h and then at room temperature overnight. The resulting red suspension was poured into a mixture of ice (300 ml) and conc. HCl (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 a residue which, after recrystallization from ethyl acetate, gave 34.5 g (64%) of the subtitle compound. Mp = 133-134 ° C.

(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] nonan-3-carboxamide (1 g; 5 mmol; see Example 6 (b); described above), 4 - [(methanesulfonyl) amino] phenethyl methanesulfonate ( 1.5 g; 5 mmol; from step (a) above) and NaHCO ₃ (3 g; 35.7 mmol) in MeCN (50 ml) were refluxed under nitrogen for 3 hours. The reaction mixture was filtered and concentrated in vacuo to give 2.2 g of a crude product, which was filtered through a pad of silica with MeOH / 2 N HCl. The pH in the fractions was increased to 6.0 and extracted with DCM to give 0.2 g of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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.

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 [3.3.1] nonane-3-carboxamide

The title compound was prepared according to the procedure described for Example 1 above using 4- [3- (3,7-diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropoxy] benzonitrile (see Example G, described above), instead of 4 - {[(2S) -3- (3,7-diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropyl] oxy} benzonitrile.

(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-diazabicyclo [3.3.1] nonane-3-carboxamide (1.0 g; 2.7 mmol; from step ( a) described above) in DCM (2.5 ml) was cooled to -78 ° C. Slowly, with stirring, a solution of (diethylamino) sulfur trifluoride in DCM (2.5 ml) was added. Stirring was continued for 35 minutes, during which time the reaction mixture was allowed to warm to room temperature. Dichloromethane was added and then the reaction mixture was washed with NaHCO ₃ , dried and concentrated in vacuo. The resulting residue was purified by column chromatography, eluting with a DCM: MeOH mixture (98: 2), to give 0.68 g (67%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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

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.

Chilled (0 ° C) solution of 4- [3- (3,7-diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropoxy] benzonitrile (23.1 g; 77 mmol; see Example G described above ) in DCM (700 ml) was treated with ethyl 2-isocyanate acetate (9.92 g; 77 mmol) and then stirred at room temperature for 7 hours. The reaction mixture was concentrated in vacuo to give 33.6 g (100%) of the subtitled compound.

(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; from step (a) described above), propylamine (5 ml; 3.6 g; 69.1 mmol) and NaCN (0.01 g; 0.2 mmol) in methanol (10 ml) heated to 75 ° C in a sealed tube overnight. The solvent was then removed in vacuo and the residue was diluted with a solution of Na ₂ CO ₃ . The aqueous mixture was extracted with DCM and the resulting organic layer was separated, dried and concentrated in vacuo. The resulting residue was purified by column chromatography, eluting with a gradient of a dichloromethane: methanol mixture (100: 0 to 90:10), to give the title compound in 70% yield.

¹³ C NMR (CDCl ₃ ): δ 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

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

Chilled (0 ° C) solution of 4- (3-amino-2-hydroxypropoxy) benzonitrile (44.6 g; 0.23 mol; see Example 4 (a) described above) in a mixture of THF: H ₂ O (1, 5 l of the mixture in a 1: 1 ratio) was treated with di-tert-butyl dicarbonate (53 g; 0.24 mmol). The mixture was stirred at room temperature overnight, after which NaCl was added and the resulting organic layer was separated. The aqueous layer was extracted with ether and the combined organic extracts were dried and concentrated in vacuo. The resulting oil (70 g) was filtered through a pad of silica and then crystallized from diethyl ether: di-iso-propyl ether to give 50 g of the subtitle compound.

(b) 2 - [(tert-butoxycarbonyl) amino] -1 - [(4-cyanophenoxy) methyl] ethyl methanesulfonate

Methanesulfonyl chloride (22.3 g; 0.195 mol) was added over 1.5 hours to a cooled (0 ° C) solution of tert-butyl 3- (4-cyanophenoxy) -2-hydroxypropylcarbamate (51.2 g; 0.177 mol; co stage (a) described above) and 4- (dimethylamino) pyridine (1.3 g; 10.6 mmol) in pyridine (250 ml) in an inert gas atmosphere. The reaction mixture was stirred for 2 hours at room temperature before adding water and DCM. The organic layer was separated, washed with water, dried (MgSO ₄ ) and concentrated in vacuo to give 68.1 g (100%) of the subtitled compound.

(c) tert-Butyl-2 - [(4-cyanophenoxy) methyl] -1-aziridinecarboxylate

Chilled (0 ° C) solution of 2 - [(tert-butoxycarbonyl) amino] -1 - [(4-cyanophenoxy) methyl] ethyl methanesulfonate (30.6 g; 82.6 mmol; from step (b) described above ) and tetrabutylammonium hydrosulfate (3 g; 8.8 mmol) in DCM (100 ml) were treated with 50 wt.% aqueous NaOH (60 ml) in an inert gas atmosphere. The resulting mixture was stirred, and the temperature was allowed to slowly rise to room temperature over 4 hours, and then was extracted with ether. The organic layer was washed with water and concentrated in vacuo to give a residue, which was purified by column chromatography (dichloromethane as eluent). Crystallization from diethyl ether: di-iso-propyl ether gave the subtitle compound in quantitative yield.

(d) tert-Butyl-2- (4-cyanophenoxy) -1 - ({7 - [(ethylamino) carbonyl] -3,7-diazabicyclo [3.3.1] non-3-yl) methyl) ethylcarbamate

A mixture of N-ethyl-3,7-diazabicyclo [3.3.1] nonan-3-carboxamide (2.88 g; 14.6 mmol, see Example 6 (b) described above) and tert-butyl-2 - [( 4-cyanophenoxy) methyl] -1-aziridine carboxylate (4.0 g; 14.6 mmol; from step (c) described above) in iso-propanol (20 ml) was refluxed overnight. The 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 a DCM: MeOH mixture (100: 0 to 90:10), to give 3.33 g of the subtitle compound.

(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) ethyl carbamate (2.4 g ; 5.1 mmol, from step (g) described above) in saturated HCl ethyl acetate was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was redissolved in water. The aqueous solution was treated with aqueous NaHCO ₃ and extracted with DCM, the organic layer of which was then dried and concentrated in vacuo to give 2 g of the subtitle compound.

(f) 7- {3- (4-Cyanophenoxy) -2 - [(4-morpholinylcarbonyl) amino] propyl} -N-ethyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

Chilled (5 ° 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) described above) and triethylamine (0.4 ml; 3.0 mmol) in DCM (5 ml) was treated with 4-morpholinecarbonyl chloride (0.11 g; 0.7 mmol) and then stirred at 5 ° C for 3 hours. After further stirring at room temperature overnight, TLC analysis showed that the reaction did not complete completely, so an additional portion of 4-morpholinecarbonyl chloride (40 mg; 0.27 mmol) was then added. Stirring was continued at room temperature overnight before adding a NaHCO ₃ solution. The organic layer was separated, dried and concentrated in vacuo to give 400 mg of a crude product, which was purified by silica gel column chromatography, eluting with dichloromethane: methanol ammonia (95: 5), to give 250 mg of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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 .

Example 14

N- (4-Cyanophenethyl) -7- (4-oxoheptyl) -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

(a) 3-Benzyl-7- [3- (2-propyl-1,3-dioxolan-2-yl) propyl] -3,7-diazabicyclo [3.3.1] nonane

A mixture of 3-benzyl-3,7-diazabicyclo [3.3.1] nonane (10.5 g; 48.5 mmol; see Example D described 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 (13.8 g; 0.1 mol) in MeCN (50 ml) were boiled with reflux overnight. The reaction mixture was filtered and concentrated in vacuo to give 18.8 g (100%) of the subtitle compound.

(b) 3- [3- (2-Propyl-1,3-dioxolan-2-yl) propyl] -3,7-diazabicyclo- [3.3.1] 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) described above) in ethanol (100 ml) was hydrogenated over 5% Pd / C at atmospheric pressure. The catalyst was removed by filtration through a pad of Celite® and the filtrate was concentrated in vacuo to give 13.7 g (100%) of the subtitle compound.

(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 at., Bioorg. Med. Chem. Lett., 6 (1996) 2387) in anhydrous THF (10 ml) was treated with 1, 1'-carbonyldiimidazole (1.17 g; 7.2 mmol) and the mixture was stirred for 30 minutes. To the reaction mixture was added 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) described above) in THF (5 ml) and stirring was continued at room temperature overnight. The solution was then concentrated in vacuo and the resulting residue was diluted with MeOH and 2 M HCl, while this solution was stirred for 2 hours at room temperature. The mixture was made basic 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 a DCM: MeOH mixture (92: 8), to give 0.57 g (30%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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.

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 min at room temperature before adding 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 ) described above). The reaction mixture was stirred overnight at room temperature 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 a residue, which was dissolved in methanol / 2 M HCl. Evaporation of MeOH in vacuo and extraction of the remaining aqueous solution with dichloromethane afforded, after purification by flash chromatography on silica gel (dichloromethane: methanol ammonia as eluent) 0.5 g (25%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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.

Example 16

4- {2-amino-3- [7- (1-piperidinylcarbonyl) -3,7-diazabicyclo [3.3.1] non-3-yl] propoxy} benzonitrile

(a) 7-Benzyl-3,7-diazabicyclo [3.3.1] non-3-yl (1-piperidinyl) methanone

The subtitle compound was prepared by reacting 3-benzyl-3,7-diazabicyclo [3.3.1] nonane (see Example D described above) and 1-piperidinecarbonyl chloride (Boon, J. Chem. Soc. (1947) 307 , 313).

(b) 3,7-Diazabicyclo [3.3.1] non-3-yl (1-piperidinyl) methanone The subtitle compound was obtained in quantitative yield in accordance with 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) described above) instead of 3-benzyl-7- [3- (2-propyl- 1,3-dioxolan-2-yl) propyl] -3,7-diazabicyclo [3.3.1] nonane.

(c) tert-Butyl-2- (4-cyanophenoxy) -1 - {[7- (1-piperidinylcarbonyl) -3,7-diazabicyclo [3.3.1] non-3-yl] methyl} ethyl carbamate

A mixture of tert-butyl-2 - [(4-cyanophenoxy) methyl] -1-aziridinecarboxylate (1.92 g; 7 mmol; see Example 13 (c) described above) and 3,7-diazabicyclo [3.3.1] non -3-yl (1-piperidinyl) methanone (1.85 g; 7 mmol; from step (a) described above) in isopropanol (15 ml) was refluxed for 30 hours. The solution was concentrated in vacuo, yielding 3.7 g of a crude product which was purified by chromatography using 2.5% MeOH in DCM to give 2.0 g (56%) of the subtitled compound.

(d) 4- {2-amino-3- [7- (1-piperidinylcarbonyl) -3,7-diazabicyclo [3.3.1] non-3-yl1propoxy} benzonitrile

Chilled (0 ° C) solution of tert-butyl-2- (4-cyanophenoxy) -1 - {[7- (1-piperidinylcarbonyl) -3,7-diazabicyclo [3.3.1] non-3-yl] methyl} ethyl carbamate (1.9 g; 3.7 mmol; from step (c) described above) in ethyl acetate was treated with ethyl acetate saturated with HCl. The mixture was stirred for 4 hours 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 give 1.5 g (100%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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.

Example 17

N-Ethyl-7- {2-hydroxy-3- [4- (1H-imidazol-1-yl) phenoxy] propyl} -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

(a) 1- [4- (2-Oxiranylmethoxy) phenyl] -1H-imidazole

A mixture of 4- (1-H-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 described above) in DMF (140 ml) was stirred at 40 ° C. overnight. The mixture was then concentrated in vacuo and the resulting residue was diluted with DCM, washed with water, dried and then concentrated in vacuo. The crude residue was then purified by flash chromatography, eluting with a gradient of dichloromethane: methanol (100: 0 to 70:30) to give 3.4 g (72.6%) of the title compound.

(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) described above) and N-ethyl-3,7-diazabicyclo [3.3. 1] nonane-3-carboxamide (2.88 g; 14.6 mmol; see Example 6 (b) described above) in a mixture of isopropanol: H ₂ O (18 ml of the mixture in a 9: 1 ratio) was refluxed refrigerator for 3 hours, concentrated in vacuo and purified by acid-base extraction to give 4.4 g (72.6%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 15.52, 29.13, 29.44, 31.84, 35.70, 47.92, 49.07, 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.

Example 18

N- [3- (4-Cyanophenoxy) propyl] -7- (2-hydroxyethyl) -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

(a) 4- (3-Bromopropoxy) benzonitrile

1,3-Dibromopropane (1.02 L; 10 mol) was added to a stirred suspension of para-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 hours, filtered and concentrated. The residue was recrystallized from isopropyl ether to give the subtitled compound in 69% yield.

(b) 4- [3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) propoxy] benzonitrile

Mixture

4- (3-bromopropoxy) benzonitrile (20 g; 84 mmol; see step (a) described above) and potassium phthalimide (15.5 g; 84 mmol) in DMF (120 ml) were stirred at 95 ° C for 4 h. The solution was then concentrated in vacuo and the resulting residue was dissolved in DCM and washed with water. The organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 25.5 g (99%) of the subtitle compound.

(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 adding water (120 ml). Methanol was evaporated under reduced pressure and concentrated hydrochloric acid (120 ml) was added. The resulting mixture was heated in a steam bath for 1.5 hours 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 obtained residue, and the solution was made basic. The aqueous solution was extracted with DCM, and the organic layer was then separated, dried and concentrated in vacuo to give 6 g (41%) of the subtitle compound.

(d) 7-Benzyl-3,7-diazabicyclo [3.3.1] nonan-3-ethanol

The compound was obtained in 72% yield by reacting 3-benzyl-3,7-diazabicyclo [3.3.1] nonane (see Example D described above) with 2-bromoethanol.

(e) 3,7-Diazabicyclo [3.3.1] nonan-3-ethanol

The subtitle compound was prepared according to the procedure described in Example 14 (b) above using 7-benzyl-3,7-diazabicyclo [3.3.1] nonan-3-ethanol (from step (g) described above) ) instead of 3-benzyl-7- [3- (2-propyl-1,3-dioxolan-2-yl) propyl] -3,7-diazabicyclo [3.3.1] nonane.

(e) N- [3- (4-Cyanophenoxy) propyl] -7- (2-hydroxyethyl) -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

The title compound was obtained in 11% yield according to the procedure described above in Example 14 (c) using 3,7-diazabicyclo [3.3.1] nonan-3-ethanol (from step (e), described above) and 4- (3-aminopropoxy) benzonitrile (from step (c) described above) instead of 3- [3- (2-propyl-1,3-dioxolan-2-yl) propyl] -3,7- diazabicyclo [3.3.1] nonane and 4- (2-aminoethyl) benzonitrile, respectively.

¹³ C NMR (CDCl ₃ ): δ 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.

Example 19

N - {[7- [3- (4-Cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] non-3-yl] carbonyl} -4-methylbenzenesulfonamide

Solution of 4- [3- (3,7-diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropoxy] benzonitrile (200 mg; 0.66 mmol; see Example G described above) in chloroform (20 ml) was treated with a solution of para-toluenesulfonyl isocyanate (110 μl of 96% purity; 0.136 g; 0.69 mmol) in chloroform (4 ml), adding it dropwise. A white precipitate formed immediately and the mixture was then concentrated in vacuo. The crude product thus obtained was subjected to silica gel chromatography, eluting with hexane: ethyl acetate: methanol ammonia (75:75:50), to obtain the title compound in a 53% yield.

¹³ C NMR (CDCl ₃ ): δ 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, 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] nonane-3-carboxamide

A mixture of allylamine (125 μl; 1.66 mmol) and 1,1'-carbonyldiimidazole (269 mg; 1.66 mmol) in THF (10 ml) was stirred at room temperature for 40 minutes. The mixture was then treated with a solution of 4- [3- (3,7-diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropoxy] benzonitrile (see Example G described above) in THF (5 ml) and stirring was continued in overnight. The mixture was concentrated in vacuo and the obtained residue was purified by silica gel chromatography eluting with hexane: methanol ammonia (1: 1) to obtain the title compound in a 57% yield.

¹³ C NMR (MeOD): δ 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.

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 obtained in 83% yield according to the procedure described in Example 19 above, using 2- (2-isocyanatoethyl) thiophene instead of para-toluenesulfonylisocyanate.

¹³ C NMR (CDCl ₃ ): δ 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.

Example 22

7- [3- (4-Cyanophenoxy) -2-hydroxypropyl] -N- [3- (ethylamino) -3-oxopropyl] -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

(a) Ethyl 3 - [({7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] non-3-yl} carbonyl) amino] propanoate

The subtitled compound was obtained in 90% yield according to the procedure described above in Example 12 (a) using ethyl 3-isocyanatopropanoate instead of ethyl 2-isocyanatoacetate.

(b) 7- [3- (4-Cyanophenoxy) -2-hydroxypropyl] -N- [3- (ethylamino) -3-oxopropyl] -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

The title compound was obtained in 22% yield according to the procedure described above in Example 12 (b) using 3 - [({7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3 , 7-diazabicyclo [3.3.1] non-3-yl} carbonyl) amino] propanoate (from step (a) described above) and ethylamine instead of 2 - [({7- [3- (4-cyanophenoxy) -2 -hydroxypropyl] -3,7-diazabicyclo- [3.3.1] non-3-yl} carbonyl) amino] acetate and propylamine, respectively.

¹³ C NMR (CDCl ₃ ): δ 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 .

Example 23

N- (1-Cyanoethyl) -7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

(a) 2-Aminopropanenitrile

Lactonitrile (28 g; 375 mmol) was added to liquid ammonia at -78 ° C in a reaction tube. The tube was sealed and the mixture was stirred overnight at room temperature. Ammonia was removed by evaporation and the crude material was used directly in the next step without further purification.

(b) N- (1-Cyanoethyl) -7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3.7-diazabicyclo [3.3.1] nonane-3-carboxamide

A mixture of 2-aminopropanenitrile (250 mg; 3.58 mmol; from step (a) described above) and N-ethyl-di-iso-propylamine (0.67 ml; 0.50 g; 3.84 mmol) in DCM (9 ml) was added (using a syringe pump) to a solution of triphosgene (352 mg; 1.19 mmol) in DCM (7 ml) over 1 hour. The resulting mixture was stirred for 1 h at room temperature before adding 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 described above) and N-ethyl-di-iso-propylamine (0.67 ml; 0.50 g; 3.84 mmol) in DCM (14 ml). Stirring was continued for the next 20 minutes before the solution was concentrated in vacuo and the resulting residue was purified by flash chromatography, eluting with dichloromethane: methanol (95: 5), to give the title compound in 65% yield.

¹³ C NMR (CDCl ₃ ): δ 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.

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 obtained in 46% yield according to the procedure described above in Example 23 (b) using 2,2,2-trifluoroethylamine instead of 2-aminopropanenitrile.

¹³ C NMR (CDCl ₃ ): δ 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.

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 obtained in 49% yield according to the procedure described above in Example 12 (b), using piperidine instead of propylamine.

¹³ C NMR (CDCl ₃ ): δ 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, 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

N- (1,3-Benzodioxol-5-yl) -7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] nonan-3-carboxamide

The title compound was obtained in 33% yield according to the procedure described above in Example 23 (b) using 1,3-benzodioxol-5-amine instead of 2-aminopropanenitrile.

¹³ C NMR (CDCl ₃ ): δ 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.

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

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 ° C. under an inert gas atmosphere for 3 hours before being added water (150 ml). The mixture was allowed to warm to room temperature and then was extracted with diethyl ether. The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 17 g (97%) of the title compound as an oil, which crystallized upon standing.

(b) 3- (4-cyanoanilino) propyl] -4-methylbenzenesulfonate

A cooled (0 ° C) solution of 4 - [(3-hydroxypropyl) amino] benzonitrile (17 g; 96.5 mmol; from step (a) described above) in anhydrous MeCN (195 ml) was treated with triethylamine (9.8 g ; 96.5 mmol) and then para-toluenesulfonyl chloride (20.2 g; 106 mmol). The mixture was stirred at 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 ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was purified by crystallization from isopropanol to obtain 24.6 g (77%) of the subtitled compound.

(c) Ethyl 2 - {[(7-benzyl-3,7-diazabicyclo [3.3.1] non-3-yl) carbonyl] amino} acetate

The subtitle compound was obtained in 99% yield according to the procedure described above in Example 5 (a) using 4- [3- (3,7-diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropoxy] benzonitrile (see Example G described above) and ethyl 2-isocyanatoacetate instead of 3-benzyl-3,7-diazabicyclo [3.3.1] nonane and iso-propylisocyanate, respectively.

(d) 7-Benzyl-N- [2-oxo-2- (propylamino) ethyl] -3,7-diazabicyclo- [3.3.1] nonane-3-carboxamide

The subtitle compound was obtained in 88% yield according to the procedure described above in Example 12 (b) using ethyl 2 - {[(7-benzyl-3,7-diazabicyclo [3.3.1] non -3-yl) -carbonyl] amino} acetate (from step (c) described above) instead of ethyl 2 - [({7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] non-3-yl} carbonyl) amino] acetate.

(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-diazabicyclo [3.3.1 ] nonan-3-carboxamide (from step (g) described above) instead of 7-benzyl-N-iso-propyl-3,7-diazabicyclo [3.3.1] nonan-3-carboxamide.

(e) 7- [3- (4-Cyanoanilino) propyl] -N- [2-oxo-2- (propylamino) ethyl] -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

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) were treated with 3- (4-cyanoanilino) propyl-4-methylbenzenesulfonate (4 , 2 g; 12.7 mmol; from step (b) described above) and stirred at reflux for 5 hours, followed by stirring for 21 hours at room temperature. The mixture was filtered, concentrated in vacuo and the crude product thus obtained was diluted with water. The aqueous solution was extracted with DCM, while the organic layer was separated, dried and concentrated in vacuo. The crude product thus obtained was purified by silica gel chromatography, eluting with a DCM: MeOH mixture (95: 5), to give 3.08 g (58%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 11.49, 22.85, 25.11, 09.09, 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.

Example 28

7- {2- [2- (4-Cyanophenoxy) ethoxy] ethyl} -N-ethyl-3,7-diazabicyclo- [3.3.1] nonane-3-carboxamide

(a) 4- [2- (2-Hydroxyethoxy) ethoxy] benzonitrile

A mixture of para-cyanophenol (11.9 g; 100 mmol), K ₂ CO ₃ (15 g; 110 mmol) and chloroethoxyethanol (12.4 g; 100 mmol) in CH ₃ CN was refluxed for 24 hours, then stirred at room temperature for the next two days. The reaction mixture was filtered and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (eluent hexane: ethyl acetate (1: 1)). This resulted in 10 g (50%) of the subtitled compound.

(b) 2- [2- (4-Cyanophenoxy) ethoxy] ethyl methanesulfonate

Methanesulfonyl chloride (3.0 g; 26 mmol) was added dropwise to a cooled (-5 ° C) mixture of 4- [2- (2-hydroxyethoxy) ethoxy] benzonitrile (5.0 g; 24 mmol, from step (a), described above) and triethylamine (4 ml; 2.9 g; 29 mmol) in DCM (50 ml). Upon completion of the addition, the reaction mixture was allowed to warm to room temperature over a period of 2 hours. Then the reaction mixture was washed twice with water, the organic layer was separated, dried (Na ₂ CO ₃ ) and concentrated in vacuo to give 7 g (100%) of the subtitle compound.

(c) 7- {2- [2- (4-Cyanophenoxy) ethoxy] ethyl} -N-ethyl-3,7-diazabicyclo- [3.3.1] nonane-3-carboxamide

A mixture of 2- [2- (4-cyanophenoxy) ethoxy] ethyl methanesulfonate (2 g; 7.0 mmol, from step (b) described above), N-ethyl-3,7-diazabicyclo [3.3.1] nonane -3-carboxamide (1.4 g; 7.0 mmol, see Example 6 (b) described above) and K ₂ CO ₃ (1.5 g; 10.5 mmol) in MeCN (50 ml) was stirred at a temperature reflux overnight. The reaction mixture was then concentrated in vacuo and the resulting residue was purified by flash chromatography on silica gel, eluting with a dichloromethane: methanol mixture (9: 1) to obtain 0.8 g (30%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 162.18, 133.92, 119.24, 115.34, 103.92, 69.07, 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-diazabicyclo [3.3.1] nonane-3-carboxamide

(a) 4- [1- (3,4-Dimethoxyphenoxy) -3-butenyl] benzonitrile Chilled (0 ° С) 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) were treated with tributylphosphine (32.14 ml of 97% purity; 25.6 g; 126.4 mmol) and then 1,1 '- (azodicarbonyl) dipiperidine (31.8 g; 126.4 mmol). Upon completion of the addition, the reaction mixture was thickened, and the temperature rose to 15 ° C. Additional toluene (500 ml) was added and the mixture was stirred at room temperature overnight. Then the precipitate of tributylphosphine oxide was removed by filtration and the filtrate was concentrated in vacuo to give 65.8 g of a crude product. This product was purified by silica gel chromatography, eluting with toluene: methanol (98: 2), to obtain 17.9 g of the subtitle compound.

(b) 4- [1- (3,4-Dimethoxyphenoxy) -4-hydroxybutyl] benzonitrile The borane methyl sulfide complex (2 M in ether; 11 ml; 22 mmol) was added dropwise over 15 minutes to the cooled (- 5 ° C) a solution of 4- [1- (3,4-dimethoxyphenoxy) -3-butenyl] benzonitrile (17.6 g; 56.8 mmol; from step (a) described above) in anhydrous THF (15 ml) (during this period of time, the temperature of the reaction mixture increased to 0 ° C). The resulting mixture was stirred at a temperature between 0 and 10 ° C. for 1.5 hours before being allowed to warm to room temperature. Stirring at this temperature was continued for the next 3.5 hours before adding water (22 ml) and sodium perborate tetrahydrate (11 g; 66 mmol). The biphasic mixture was stirred at room temperature for 2 hours before the aqueous layer was separated and extracted with ether. The combined organic layers were washed with brine, dried and concentrated in vacuo. The resulting residue was purified by silica gel chromatography, eluting with iso-propanol: ethyl acetate: heptane (5:25:70), to give 14.5 g (77%) of the subtitled compound.

(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 slowly added to a cooled (-5 ° C) mixture of 4- [1- (3,4-dimethoxyphenoxy) -4-hydroxybutyl] benzonitrile (11 g; 34 mmol; from step (b) described above) and triethylamine (7 ml; 5.2 g; 50.6 mmol) in DCM (50 ml), and during the addition, the temperature did not rise above 2 ° FROM. Stirring was continued at a temperature between 0 and 5 ° C for the next 2 hours before adding water. The resulting organic layer was separated and washed with water, separated again and then dried, obtaining the subtitled compound in 100% yield.

(g) 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 methanesulfonate (522 mg; 1.29 mmol; from step (c) described above), tert-butyl-3,7-diazabicyclo [3.3. 1] nonane-3-carboxylate (307 mg; 1.356 mmol; see Example E described above) and K ₂ CO ₃ (216 mg; 1.56 mmol) in a mixture of chloroform: acetonitrile (10 ml of the mixture in a 1: 1 ratio) stirred at 70 ° C. for 23 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 708 mg of a crude product. This product was purified by flash chromatography, eluting with a gradient of a toluene: methanol mixture (97: 3 to 10: 1), to give 607 mg (88%) of the subtitled compound.

(e) 4- [4- (3,7-Diazabicyclo [3.3.1] non-3-yl) -1- (3,4-dimethoxyphenoxy) butyl] benzonitrile

Chilled (0 ° C) 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 (g) described above) in ethyl acetate (20 ml) was treated with ethyl acetate saturated with HCl (30 ml). The resulting mixture was stirred for 2 hours at a temperature between 0 and 5 ° 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 3 hours at room temperature and the solids were removed by filtration before the solvent was removed in vacuo (with the addition of toluene to effect azeotropic removal of water) to obtain 1.5 g of the subtitle compound.

(e) 7- [4- (4-Cyanophenyl) -4- (3,4-dimethoxyphenoxy) butyl] -N-ethyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

Solution 4- [4- (3,7-diazabicyclo [3.3.1] non-3-yl) -1- (3,4-dimethoxyphenoxy) butyl] benzonitrile (109 mg; 0.25 mmol; from step (d) (described above) in CHCl ₃ (1.43 ml) was treated with a solution of ethyl isocyanate (18.6 μl; 16.8 mg; 0.237 mmol) in MeCN (0.5 ml). The resulting mixture was stirred for 30 hours at room temperature. The solution was then applied to an ion-exchange solid-phase extraction pad (SiO ₂ ; 0.5 g from ISOLUTE). The packing was washed with CHCl ₃ (2.5 ml) and then the product was eluted with MeCN (3 × 2.5 ml). As a result, the title compound (93 mg; 73%) was obtained with a purity of more than 90% (as determined by HPLC: UV at 254 nm and by ELS detection).

MS (ES) m / z = 507 (M + 1) ⁺ , 505 (M-1) ^- .

Example 30

7- (3- {4-Cyano-2 - [(cyclopropylamino) carbonyl] phenoxy} -2-hydroxypropyl) -N-phenyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

(a) 5-Cyano-N-cyclopropyl-2- [2-oxiranylmethoxy] benzamide

The subtitle compound was prepared according to the method described in Example 7 (b) above using 2-oxiranylmethyl-3-nitrobenzenesulfonate (obtained analogously to the method described above in Example B).

(b) 7-Benzyl-N-phenyl-3,7-diazabicyclo [3.3.1] nonan-3-carboxamide

A cooled (0 ° C) solution of 3-benzyl-3,7-diazabicyclo [3.3.1] nonane (10 g; 46 mmol; see Example D described above) in DCM (100 ml) was treated with phenylisocyanate (4.9 ml; 45 mmol). The mixture was stirred at room temperature for 30 minutes. The product formed as white crystals which were collected by filtration to obtain 10 g (66%) of the subtitle compound.

(c) N-Phenyl-3,7-diazabicyclo [3.3.1] nonan-3-carboxamide

A solution of 7-benzyl-N-phenyl-3,7-diazabicyclo [3.3.1] nonan-3-carboxamide (10 g; 29.8 mmol; from step (b) described above) in ethanol (100 ml) was hydrogenated over 10% Pd / C and at atmospheric pressure overnight. The catalyst was removed by padding with Celite® and the residue was concentrated in vacuo to give the subtitle compound in quantitative yield.

(d) 7- (3- {4-Cyano-2 - [(cyclopropylamino) carbonyl] phenoxy} -2-hydroxypropyl) -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) described above) and N-phenyl-3,7-diazabicyclo [3.3. 1] nonane-3-carboxamide (0.9 g; 3.6 mmol; from step (c) described above) in a mixture of iso-propanol: H ₂ O (10 ml of the mixture in a 9: 1 ratio) was refluxed for 180 minutes before adding dichloromethane and removing the solvent in vacuo. Purification of the resulting residue by flash chromatography, eluting with a DCM: MeOH (9: 1) mixture, afforded 1 g (64%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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.

Example 31

N- (4-Cyanophenyl) -7- [3- (ethanesulfonyl) propyl] -3,7-diazabicyclo [3.3.1] nonan-3-carboxamide

(a) 3- (Ethanesulfonyl) propyl-4-methylbenzenesulfonate

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 para-toluenesulfonyl chloride (16.78 g; 88 mmol) in DCM (150 ml), which led to a moderately exothermic reaction. Upon completion of the addition, the reaction mixture was washed twice with an aqueous solution of ammonium chloride, the organic layer was then separated, dried and concentrated in vacuo. The resulting residue was recrystallized from diethyl ether: DCM, to give 17.9 g (65%) of the subtitle compound.

(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] nonan-3-carboxylate (2.0 g; 8.8 mmol; see Example E above) in chloroform (15 ml) was treated with 4-isocyanatobenzonitrile (1 , 53 g; 10.6 mmol) The mixture was stirred at room temperature for 1.5 hours, during which time a certain amount of solid particles was observed in the mixture. An additional 10 ml of chloroform was added to dissolve these particles. Mass spectroscopic analysis of the mixture showed that the starting materials were consumed, and because of this, the solvent was removed under vacuum. The resulting residue was purified by flash chromatography, eluting with a gradient of a DCM: MeCN mixture (5: 1 to 2: 1), to give 2.31 g (71%) of the subtitled compound.

(c) N- (4-Cyanophenyl) -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide

Chilled (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) described above) in ethyl acetate (40 ml) was treated for 30 min with ethyl acetate saturated with HCl (65 ml). The resulting mixture was stirred at room temperature for the next 4 hours before being concentrated in vacuo to give 1.8 g (99%) of the hydrochloride salt of the subtitle 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] nonan-3-carboxamide (67.6 mg; 0.25 mmol; from step (c) described 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) described above) in MeCN (1 , 0 ml). The resulting suspension was stirred for 5 days at 50 ° C. before being cooled and filtered. The filtrate was then added to the ion exchange solid phase extraction packing (CBA; 2 g; from ISOLUTE). After 1 h, the packing was washed with CHCl ₃ (3 × 2.5 ml) and the product was eluted with CHCl ₃ : MeOH: Et ₃ N (8: 1: 1) to give the title compound (63.6 mg; 63%) with degree of purity more than 90% (as determined by HPLC: UV at 254 nm and using ELS detection).

MS (ES): m / z = 405 (M + 1) ⁺ , m / z = 403 (M-1) ^- .

Example 32

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 30 (g) described above) in a mixture of isopropanol: H ₂ O (10 ml of a mixture in a ratio of 9: 1) was stirred at reflux for 3 hours before being concentrated in vacuo. The resulting residue was purified by silica gel column chromatography, eluting with a gradient of DCM: MeOH mixture (99: 1 to 97: 3), to give 0.8 g (37%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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.

Example 33

7 - [(7-cyano-2,3-dihydro-1,4-benzodioxin-2-yl) methyl] -N-ethyl-3,7-diazabicyclo [3.3.1] nonan-3-carboxamide

(a) 5-Bromo-2- (3-chloro-2-hydroxypropoxy) benzaldehyde

A mixture of 5-bromo-2-hydroxybenzaldehyde (20.1 g; 0.1 mol), epichlorohydrin (25 ml; 0.32 mol) and 6 drops of piperidine was stirred at reflux for 6 hours before being concentrated in vacuo. The resulting residue was dissolved in chloroform (25 ml) and treated with concentrated HCl (10 ml). The resulting mixture was stirred for 3 hours at room temperature before the organic layer was washed with water, separated, dried and concentrated in vacuo to give 28.2 g (96%) of the subtitle compound. This compound was directly used in the next step without further purification.

(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 ml) was treated with 3-chloroperoxybenzoic acid (25 g; 70-75% purity; approximately 100 mmol). As a result of the exothermic reaction, the mixture was heated to reflux for 20 minutes. Stirring was continued for the next 3 days before the mixture was filtered (to remove the precipitated 3-chlorobenzoic acid). The filtrate was washed with a solution of K ₂ CO ₃ and water, dried and concentrated in vacuo to give 26.1 g of the subtitle compound. This compound was directly used in the next step without any further purification.

(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) described above) in ethanol (100 ml) was treated with a solution of potassium hydroxide (6.1 g ; 85% purity; approximately 92 mmol) in water (10 ml). The resulting mixture was refluxed for 1.5 hours 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 28.8 g of a crude product. This product was purified by silica gel column chromatography, eluting with diethyl ether: hexane (70:30), to give 10.0 g (49.1%) of the subtitled compound.

(g) 3- (Hydroxymethyl) -2,3-dihydro-1,4-benzodioxin-6-carbonitrile

A mixture of (7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl) methanol (10.0 g; 41.2 mmol; from step (c) described above) and CuCN (4.0 g ; 45.3 mmol) in DMF (10 ml; dried over molecular sieves) was stirred at 170 ° C for 4.5 hours. The reaction mixture was poured into a warm aqueous solution of sodium cyanide (8.10 g; 165 mmol NaCN in 25 ml H ₂ O). The resulting mixture was extracted with toluene and DCM. The combined organic layers were washed with water and then with brine, dried and concentrated in vacuo. The resulting residue was crystallized from toluene and DCM to give 2.8 g (35%) of the subtitled compound.

(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 ° C) mixture of 3- (hydroxymethyl) -2,3-dihydro-1,4-benzodioxin-6- carbonitrile (2.75 g; 14.4 mmol; from step (g) described above) and pyridine (1.26 g; 16 mmol) in DCM (25 ml). Upon completion of the addition, the mixture was stirred at 0 ° C for 1 h and then at room temperature overnight. TLC analysis showed incomplete reaction after this period of time, therefore, additional 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 hours, washed twice with saturated Na ₂ CO ₃ solution, dried and concentrated in vacuo. The resulting crude product (4.5 g) was purified by flash chromatography eluting with DCM to give 3.5 g of the subtitled compound that crystallized upon standing.

(f) 7 - [(7-Cyano-2,3-dihydro-1,4-benzodioxan-2-yl) methyl] -N-ethyl-3,7-diazabicyclo [3.3.1] nonan-3-carboxamide

A mixture of (7-cyano-2,3-dihydro-1,4-benzodioxin-2-yl) methyl methanesulfonate (150 mg; 0.9 mmol; from step (e) above), N-ethyl-3,7- diazabicyclo [3.3.1] nonane-3-carboxamide (186 mg; 0.94 mmol; see Example 6 (b) described 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 hours. The solvent was removed in vacuo and the resulting residue was treated with DCM and water. The organic layer was separated, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The resulting residue was purified by flash chromatography, eluting with a DCM: MeOH mixture (95: 5), to give 113.2 mg (34%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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, 125.79, 143.50, 147.80, 157.46.

Example 34

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) (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; 99%) was stirred at 60 ° C for 24 h. The mixture was concentrated in vacuo before adding ethanol (500 ml) and then 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 oil 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 afford 20 g (57%) of the subtitle compound as yellow crystals.

(b) (2R) -6-Cyano-4- (methanesulfonyl) -3,4-dihydro-2H-1,4-benzoxazin-2-yl] methyl methanesulfonate

Methanesulfonyl chloride (45 g; 0.395 mol) was added dropwise to a cooled (0 ° C) mixture of (2R) -2- (hydroxymethyl) -3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (30 g; 0.158 mol; from step (a) described above) and pyridine (200 ml; excess). The mixture was stirred at room temperature overnight before being concentrated in vacuo. The resulting residue was treated with water and product crystals were separated by filtration. These crystals were recrystallized from MeCN to give 29 g of pure material. The mother liquor was concentrated in vacuo to give a residue that was crystallized from chloroform to give an additional portion (7.5 g) of product. The total yield of the subtitle 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-benzoxazin-2-yl] methyl methanesulfonate (1 g; 2.89 mmol; from step (b) described above) in MeCN (5 ml) was treated with triethylamine (8 ml; 5.8 g; 57.4 mmol), then N-ethyl-3,7-diazabicyclo [3.3.1] nonan-3-carboxamide (0.85 g ; 4.33 mmol; see Example 6 (b) described above). The resulting mixture was stirred at 70 ° C. for 5 hours and then at room temperature overnight. The mixture was concentrated in vacuo and purified by acid / base extraction followed by flash chromatography, eluting with a DCM: MeOH mixture, to give 100 mg (14%) of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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

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) 4 - [(E) -1- (4-Cyanobenzoyl) -2- (dimethylamino) ethenyl] benzonitrile

N, N-Dimethylformamide-dimethylacetal (135.2 g; 0.29 mol) was added dropwise under an inert gas atmosphere to a heated (60 ° 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, which was crystallized from MeOH. This procedure yielded 27.9 g (38%) of the subtitled 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) described above) in aqueous ethanol (100 ml; 99%) was treated with ethyl 2-hydrazinoacetate hydrochloride (3.5 g; 22.6 mmol). The mixture was stirred at room temperature overnight before being concentrated in vacuo. The resulting residue was diluted with water, while the aqueous mixture was extracted with DCM. The organic layer was then separated, dried and concentrated in vacuo to give a residue which was recrystallized from diethyl ether to give 1.7 g (23.5%) of the subtitle compound.

(c) 2- [4,5-Bis (4-cyanophenyl) -1H-pyrazol-1-yl] -N- (2-hydroxyethyl) -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) were stirred at 100 ° C. overnight. Water and DCM were added, the product was crystallized and isolated by filtration to obtain 3.53 g of the subtitle compound.

(g) 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-1-yl] -N- (2-hydroxyethyl) -acetamide (0.7 g; 1.88 mmol; from step (c), described above), N-bromosuccinimide (0.75 g; 5.64 mmol) and triphenylphosphine (2.22 g; 8.4 mmol) in DCM (100 ml) was stirred at reflux for 3 hours. The reaction mixture was allowed to cool before rinsing with water. The organic layer was separated, dried and concentrated in vacuo to give a residue which was purified by flash chromatography, eluting with diethyl ether: methanol (95: 5), to give 0.7 g of the subtitle compound contaminated with triphenylphosphine oxide. This product was directly used in the next step without any further purification.

(e) 7- [2 - ({2- [4,5-Bis (4-cyanophenyl) -1H-pyrazol-1-yl] acetyl} amino) ethyl] -N-ethyl-3,7-diazabicyclo [ 3.3.1] nonan-3-carboxamide

A mixture of 2- [4,5-bis (4-cyanophenyl) -1H-pyrazol-1-yl] -N- (2-bromoethyl) -acetamide (0.7 g; 1.6 mmol; from step (g), described above), N-ethyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxamide (0.32 g; 1.6 mmol; see Example 6 (b) described above), K ₂ CO _s ( 0.55 g; 4 mmol) in acetonitrile (15 ml) was stirred at reflux overnight. Extraction with diethyl ether and water gave an organic layer, which was separated, dried and concentrated in vacuo. The resulting residue was purified by silica gel chromatography, eluting with diethyl ether: MeOH (95: 5), to give 0.27 g of the title compound.

¹³ C NMR (CDCl ₃ ): δ 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, 132.73, 134.62, 138.75, 159.14, 167.09.

Example 36

Using methods similar to those described herein, the following compounds were obtained (each of which is a compound indicated in the title of this Example 36):

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] nonan-3-carboxamide;

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-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] nonan-3-carboxamide;

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-diazabicyclo [3.3.1] non-3-yl} methyl) ethylcarbamate;

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-ethyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxamide;

methyl 2- (4-cyanophenoxy) -1 - ({7 - [(ethylamino) carbonyl] -3,7-diazabicyclo- [3.3.1] non-3-yl} methyl) ethyl carbamate;

7- [2- (acetylamino) -3- (4-cyanophenoxy) propyl] -N-ethyl-3,7-diazabicyclo- [3.3.1] nonan-3-carboxamide;

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-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;

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-diazabicyclo [3.3.1] nonane-3-carboxamide;

7 - [(2S) -3- (4-cyanophenoxy) -2-hydroxypropyl] -N-methyl-3,7-diazabicyclo- [3.3.1] nonane-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-diazabicyclo [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-diazabicyclo [3.3.1] nonane-3-carboxamide;

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-diazabicyclo [3.3.1] nonane-3-carboxamide;

7 - [(2R) -3- (4-cyanophenoxy) -2-hydroxypropyl] -N-propionyl-3,7-diazabicyclo [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-diazabicyclo [3.3.1] nonane-3-carboxamide;

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-diazabicyclo [3.3.1] non-3-yl} methyl) ethyl carbamate;

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;

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-hydroxypropyl) -N-propionyl-3,7-diazabicyclo [3.3.1] nonane-3-carboxamide;

7 - [(2S) -3- (4-cyanophenoxy) -2-hydroxypropyl] -N-phenyl-3,7-diazabicyclo [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-diazabicyclo [3.3.1] non-3-yl} methyl) ethyl carbamate;

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-diazabicyclo [3.3.1] non-3-yl} methyl) ethyl carbamate;

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] nonan-3-carboxamide;

7- {3- (4-cyanophenoxy) -2- [methyl (methylsulfonyl) amino] propyl} -N-iso-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;

tert-butyl-2- [7- (aminocarbonyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -1 - [(4-cyanophenoxy) methyl] ethyl carbamate;

tert-butyl-2- (4-cyanophenoxy) -1 - ({7 - [(tetrahydro-2H-pyran-2-ylamino) -carbonyl] -3,7-diazabicyclo [3.3.1] non-3-yl} methyl) ethyl carbamate;

N- (4-cyanophenyl) -7- (4-oxoheptyl) -3,7-diazabicyclo [3.3.1] nonane-3-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-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;

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 [3.3.1] nonan-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;

N- [3- (4-cyanophenoxy) propyl] -7- [5- (ethylamino) -5-oxopentyl] -3,7-diazabicyclo [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-ouzo-propyl-3,7-diazabicyclo- [3.3.1] nonane-3-carboxamide;

7- [4- (4-cyanophenyl) -4-hydroxybutyl] -N-ethyl-3,7-diazabicyclo- [3.3.1] nonan-3-carboxamide;

ethyl {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo- [3.3.1] non-3-yl} carbonyl carbamate;

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-diazabicyclo [3.3.1] nonane-3-carboxamide;

N-benzyl-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo- [3.3.1] nonan-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- [3.3.1] non-3-yl} carbonyl) amino] propanoate;

N- (4-butoxyphenyl) -7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide;

7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N- (3-cyanophenyl) -3,7-diaza-bicyclo [3.3.1] nonan-3-carboxamide;

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-bicyclo [3.3.1] nonan-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;

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-benzodioxepin-7-yl) -3,7-diazabicyclo [3.3.1] nonane- 3-carboxamide;

7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N- (2,6-dimethylphenyl) -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide;

iso-propyl- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo- [3.3.1] non-3-yl} carbonyl carbamate;

7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N- (2-fluoroethyl) -3,7-diazabicyclo [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;

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] nonan-3-carboxamide;

7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N-iso-propyl-3,7-diazabicyclo [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-hydroxypropyl] -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide;

N- (cyanomethyl) -7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N-methyl-3,7-diazabicyclo [3.3.1] nonan-3-carboxamide;

7- [4- (4-cyanophenoxy) -2-hydroxybutyl] -N-ethyl-3,7-diazabicyclo [3.3.1] nonan-3-carboxamide;

7- [4- (4-cyanophenyl) butyl] -N- [2-oxo-2- (propylamino) ethyl] -3,7-diazabicyclo [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] nonan-3-carboxamide;

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;

N- (4-cyanophenyl) -7- (3,3-dimethyl-2-oxobutyl) -3,7-diazabicyclo [3.3.1] nonan-3-carboxamide;

N- (4-cyanophenyl) -7- (3,4-dimethoxyphenyl) -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide;

N- (4-cyanophenyl) -7- (cyclopropylmethyl) -3,7-diazabicyclo [3.3.1] nonane-3-carboxamide;

N- (4-cyanophenyl) -7- [2- (2-methoxyethoxy) ethyl] -3,7-diazabicyclo [3.3.1] nonan-3-carboxamide;

N- (4-cyanophenyl) -7- [2- (2,3-dihydro-1,4-benzodioxin-6-yl) -2-oxoethyl] -3,7-diazabicyclo [3.3.1] nonan-3- carboxamide;

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] nonan-3- carboxamide.

Example 37

The compounds of the above Examples were tested in Test A described above, and for all of them it was found that they show D ₁₀ values of more than 6.0.

The data obtained in Test A are shown in the following table.

Example D ₁₀ Example D ₁₀ Example D ₁₀ 1 7.2 thirteen 7.1 25 6.6 2 8 14 7.0 26 7.3 3 6.7 fifteen 7.0 27 7.2 4 6.1 16 7.1 28 6.8 5 6.9 17 - 29th - 6 6.2 eighteen 6.3 thirty 6.8 7 7.1 19 - 31 - 8 7.8 twenty 7.4 32 6.1 nine 7.2 21 7.2 33 6.0 10 6.4 22 6.9 34 6.6 eleven 6.2 23 6.9 35 6.0 12 6.6 24 6.5

Abbreviations

AcOH = acetic acid

ADDP = 1,1 '- (azodicarbonyl) dipiperidine

aq. = water

atm. = atmosphere

CBz = benzyloxycarbonyl

CDI = carbonyldiimidazole

Bu = butyl

DXM = dichloromethane

DMF = dimethylformamide

DMSO = dimethyl sulfoxide

Et = ethyl

EtOAc = ethyl acetate

EtOH = ethanol

ESI = electrospray interface

equiv = equivalent

FAB = Fast Atom Bombing

h = hour

IPA = iso-propanol

i-PrON = iso-propanol

LC = liquid chromatography

HPLC = high performance liquid chromatography

m-CPBA = meta-chloroperbenzoic acid

Me = methyl

MeCN = acetonitrile

MeOH = methanol

mesyl = methanesulfonate

min = minute

Ms = Mesylate

MS = mass spectroscopy

NADPH = nicotinamide adenine dinucleotide phosphate, reduced

the form

NMR = nuclear magnetic resonance

OSu = 0-succinyl

Pd / C = palladium on carbon

p-TSA = para-toluenesulfonic acid

ct = room temperature

sat. = saturated

TEA = triethylamine

THF = tetrahydrofuran

TLC = thin layer chromatography

TMS = tetramethylsilane

The prefixes n-, sec-, and-, iso, m- and tert- have the usual meanings:

normal, iso, secondary and tertiary.

Claims (32)

1. The compound of formula I

Where R ¹ and R ² independently represent H, C _1-4 alkyl, OR ^2b or N (R ^2c ) R ^2d, or together form —O— (CH ₂ ) ₂ —O—, - (CH ₂ ) ₃ -, - (CH ₂ ) ₄ - or - (CH ₂ ) ₅ -; R ^2b , R ^2c and R ^2d independently represent H or C _1-6 alkyl; R ³ represents H, C _1-6 alkyl, or together with R ⁴ represents C _3-6 alkylene (wherein the alkylene group is optionally interrupted by an O atom and / or optionally substituted by one or more C _1-3 alkyl groups); R ⁴ represents H, C _1-12 alkyl, C _1-6 alkoxy (wherein the last two groups are both optionally substituted and / or end with one or more substituents selected from —OH, halo, cyano, nitro, C _{1- 4} alkyl and / or C _1-4 alkoxy), - (CH ₂ ) _q - (C ₆ -C ₁₀ ) aryl, - (CH ₂ ) _q -oxy (C ₆ -C ₁₀ ) aryl, - (CH ₂ ) _q -Het ¹ (wherein the last three groups are optionally substituted (in the - (CH ₂ ) _q -particle and / or (C ₆ -C ₁₀ ) aryl / Het ¹ -particle) with one or more substituents selected from -OH, halogen, cyano, nitro, —C (O) R ¹⁰ , —C (O) OR ¹¹ , —N (H) S (O) ₂ R ^11a , C _1-6 alkyl and / or C _1-6 alkoxy), - (CH ₂ ) _q N (H) C (O) R ⁸ , - (CH ₂ ) _q S (O) ₂ R ⁸ , - (CH ₂ ) _q C (O) R ⁸ , - (CH ₂ ) _q C (O) OR ⁸ , - (CH ₂ ) _q C (O) N (R ⁹ ) R ⁸ or together with R ³ represents C _3-6 alkylene (moreover, the alkylene group is possibly interrupted by the O atom and / or optionally substituted with one or more C _1-3 alkyl groups); q represents 0, 1, 2, 3, 4, 5, or 6; R ⁸ represents H, C _1-6 alkyl, C ₆ -C ₁₀ aryl (the last group being optionally substituted and / or terminated by one or more substituents selected from —OH, halo, cyano, nitro, —C (O ) R ¹⁰ , —C (O) OR ¹¹ , —N (H) S (O) ₂ R ^11a , C _1-6 alkyl and / or C _1-6 alkoxy) or together with R ⁹ is C _3-7 alkylene; R ⁹ represents H, C _1-4 alkyl, or together with R ⁸ represents C _3-7 alkylene; Het ¹ is 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 substituents = O; R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ or R ⁴⁶ independently represent H or C _1-3 alkyl; R ⁵ represents H, halogen, C _1-3 alkyl, —OR ¹² , —N (R ¹³ ) R ^12, or together with R ⁶ represents = O; R ⁶ represents H, C _1-4 alkyl, or together with R ⁵ represents = O; R ¹² represents H, C _1-6 alkyl, —S (O) ₂ —C _1-4 alkyl, —C (O) R ¹⁴ , —C (O) OR ¹⁴ , —C (O) N (R ¹⁵ ) R ^15a or C ₆ -C ₁₀ aryl (the last group being optionally substituted and / or terminated by one or more substituents selected from —OH, halo, cyano, nitro, —C (O) R ¹⁰ , —C (O ) OR ¹¹ , —N (H) S (O) ₂ R ^11a , C _1-6 alkyl and / or C _1-6 alkoxy); R ¹³ represents H or C _1-4 alkyl; R ¹⁴ represents H or C _1-6 alkyl; R ¹⁵ and R ^15a independently represent H or C _1-4 alkyl or together represent C _3-6 alkylene, optionally interrupted by an O atom; A is a single bond, C _1-6 alkylene, —N (R ¹⁶ ) (CH ₂ ) _r - or —O (CH ₂ ) _r - (wherein the group - (CH ₂ ) _r - in the last two groups is attached to the atom bispidine nitrogen); B is a single bond, C _1-4 alkylene, - (CH ₂ ) _n N (R ¹⁷ ) -, - (CH ₂ ) _n S (O) _p -, - (CH ₂ ) _n O- (and the group - (CH ₂ ) _n - in the last three groups attached to a carbon atom bearing R ⁵ and R ⁶ ), -C (O) N (R ¹⁷ ) - (and the group -C (O) - in the last group attached to a carbon atom bearing R ⁵ and R ⁶ ), -N (R ¹⁷ ) C (O) O (CH ₂ ) _n -, -N (R ¹⁷ ) (CH ₂ ) _n - (and the group N (R ¹⁷ ) in the last two groups attached to a carbon atom bearing R ⁵ and R ⁶ ) or - (CH ₂ ) _m С (H) (OH) (CH ₂ ) _n - (and the group - (CH ₂ ) _m - in the last 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; R ¹⁶ and R ¹⁷ independently represent H or C _1-4 alkyl; R ⁷ represents a linear or branched and / or acyclic, cyclic and / or partially cyclic / acyclic C _1-6 alkyl (possibly substituted and / or terminated by OH); Het ² (possibly substituted by one or more substituents selected from cyano, C _1-3 alkyl, phenyl (the latter group being possibly substituted by one or more cyano), = O, C (O) R ¹⁰ (where R ¹⁰ represents a linear or branched C _1-3 alkyl) or S (O) ₂ R ¹⁹ (where R ¹⁹ represents C _1-2 alkyl)); or phenyl (substituted with one or more substituents selected from cyano, nitro, C (O) N (H) R ²² (wherein R ²² is a linear or branched and / or acyclic, cyclic and / or partially cyclic / acyclic C _1-4 alkyl, the alkyl group possibly ending in cyano), N (H) S (O) ₂ R ¹⁸ (where R ¹⁸ is C _1-2 alkyl) or Het ³ ); Het ² and Het ³ independently represent a five to twelve membered heterocyclic group containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur, and which also optionally includes one or more substituents = O; R ¹⁰ and R ¹¹ independently represent, in each individual case, H or C _1-6 alkyl; and R ^11a represents, in each individual case, C _1-6 alkyl; or a pharmaceutically acceptable derivative thereof; provided that: (a) when A and B are both simple bonds and R ⁷ is a possibly substituted (C ₆ -C ₁₀ ) aryl, then R ⁵ and R ⁶ are not both H; (b) when A is a single bond, then R ⁵ and R ⁶ together do not represent = O; and (c) when R ⁵ is —OR ¹² or —N (R ¹³ ) R ¹² , then: 1) A is not —N (R ¹⁶ ) (CH ₂ ) _r - or —O (CH ₂ ) _r -; and / or 2) n is not 0 when B is - (CH ₂ ) _n N (R ¹⁷ ) -, - (CH ₂ ) _n S (O) _p - or - (CH ₂ ) _n O -. 2. The compound according to claim 1, where R ¹ represents N. 3. The compound according to claim 1 or 2, where R ² represents N. 4. The compound according to any one of claims 1 to 3, where R ³ represents H; C _1-2 alkyl; or together with R ⁴ represents C _4-5 alkylene, optionally interrupted by an O atom and / or optionally substituted with one or more methyl groups. 5. The compound according to claim 4, where R ³ represents N. 6. The compound according to any one of claims 1 to 5, where R ⁴ represents H; linear or branched, and / or saturated or unsaturated, and / or cyclic, acyclic and / or partially cyclic / acyclic C _1-8 alkyl (wherein the alkyl group is optionally substituted with one or more cyano or halogeno groups and / or interrupted by O ); C _1-6 alkoxy; - (CH ₂ ) _q S (O) ₂ R ⁸ , - (CH ₂ ) _q C (O) OR ⁸ , - (CH ₂ ) _q N (H) C (O) R ⁸ , - (CH ₂ ) _q C (O) R ⁸ (where q in the last four groups is 0, 1 or 2, and R ⁸ is a linear or branched and / or acyclic, cyclic and / or partially cyclic / acyclic C _1-4 alkyl or phenyl ( moreover, the phenyl group is possibly substituted by one or more than one cyano and / or C _1-3 alkyl group)); - (CH ₂ ) _q C (O) N (R ⁹ ) R ⁸ (where q in the last group represents 0, 1 or 2, and R ⁸ and R ⁹ independently represent H, linear or branched and / or acyclic, cyclic and / or partially cyclic / acyclic C _1-4 alkyl, or together represent C _4-6 alkylene); - (CH ₂ ) _q- phenyl, - (CH ₂ ) _q- hydroxyphenyl or - (CH ₂ ) _q -Het ¹ (where q in the last three groups is 0, 1, 2 or 3, - (CH ₂ ) _q - the part is optionally substituted by a cyano group, and the phenyl or Het ¹ part is optionally substituted by one or more substituents selected from cyano, nitro, linear or branched C _1-4 alkyl, linear or branched C _1-4 alkoxy and N (H) S (O) ₂ R ^11a ); or together with R ³ represents C _4-5 alkylene, optionally interrupted by an O atom and / or optionally substituted with one or more methyl groups. 7. The compound according to any one of claims 1 to 6, where R ⁵ represents H; fluoro; OR ¹² (where R ¹² represents H, phenyl (optionally substituted with one or more methoxy groups) or C (O) N (H) R ^15a (where R ^15a represents a linear or branched C _1-4 alkyl)); —N (R ¹³ ) (R ¹² ) (where R ¹² represents H, C _1-2 alkyl, —S (O) ₂ —C _1-2 alkyl, —C (O) R ¹⁴ (where R ¹⁴ represents C _1-2 alkyl), -C (O) OR ¹⁴ (where R ¹⁴ is a linear or branched C _1-5 alkyl) or -C (O) N (R ¹⁵ ) (R ^15a ) (where R ¹⁵ and R ^15a independently represent H, either linear or branched C _1-3 alkyl, or together represent C _4-5 alkylene, wherein the alkylene group is optionally interrupted by O) and R ¹³ represents H or C _1-2 alkyl); or together with R ⁶ represents = O. 8. The compound of claim 7, wherein R ⁵ is H, OH, or —N (H) C (O) N (R ¹⁵ ) (R ^15a ). 9. The compound according to any one of claims 1 to 8, where R ⁶ represents H or C _1-2 alkyl or together with R ⁵ represents = O. 10. The compound according to claim 9, where R ⁶ represents N. 11. The compound according to any one of claims 1 to 10, where A is a single bond, a linear or branched C _1-4 alkylene (moreover, this group is also possibly interrupted by an O atom), -N (H) (CH ₂ ) _r -O (CH ₂ ) _r - (where r in the last two cases is 1 or 2). 12. The compound of claim 11, wherein A is —CH ₂ - or - (CH ₂ ) ₂ -. 13. The compound according to any one of claims 1 to 12, where B is a single bond, C _1-4 alkylene, - (CH ₂ ) _n O-, - (CH ₂ ) _n S (O) ₂ -, - (CH ₂ ) _n N (H) - or -N (H) (CH ₂ ) _n - (where n in the last four cases is 0, 1, 2 or 3). 14. The compound of claim 13, wherein B is a single bond, —CH ₂ N (H) - or —CH ₂ O—. 15. The compound according to claim 1, where R ⁷ represents phenyl (substituted by a cyano group (preferably at position 4 relative to B) and one or more possible substituents C (O) N (H) R ²² ). 16. The compound according to any one of claims 1 to 15, where R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ and R ⁴⁶ all represent N. 17. A pharmaceutical preparation having a class III myocardial electrophysiological activity, comprising a compound according to any one of claims 1-16, mixed with a pharmaceutically acceptable adjuvant, diluent or carrier. 18. A pharmaceutical preparation for use in the prevention or treatment of arrhythmia, containing the compound according to any one of claims 1 to 16. 19. The compound according to any one of claims 1 to 16 for use as a pharmaceutical preparation. 20. The compound according to any one of claims 1 to 16 for use in the prevention or treatment of arrhythmia. 21. The compound according to any one of claims 1 to 16 as an active ingredient in the manufacture of a medicament for use in the prevention or treatment of arrhythmia. 22. The compound according to item 21, where the arrhythmia is an atrial or ventricular arrhythmia. 23. A method for the prevention or treatment of arrhythmia, in which a therapeutically effective amount of a compound according to any one of claims 1 to 16 is administered to a subject suffering from or subject to such a condition. 24. The method of obtaining the compounds of formula I according to claim 1, where R ³ represents H, which carry out the interaction of compounds of formula II

where R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , A and B are as defined in claim 1, with a compound of formula III , R ⁴ -N = C = O III where R ⁴ is as defined in claim 1. 25. A method of obtaining a compound of formula I according to claim 1, wherein the compound of formula II, as defined in paragraph 24, is reacted with a carboxylic acid derivative of formula IV, (R ³ ) (R ⁴ ) NC (O) -L ¹ IV where L ¹ represents a leaving group, and R ³ and R ⁴ are as defined in claim 1. 26. The method of obtaining the compounds of formula I according to claim 1, in which carry out the interaction of the compounds of formula V

where L ¹ is as defined in claim 25, and R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , A and B are as defined in claim 1, with a compound of formula VA (R ³ ) (R ⁴ ) NH VA where R ³ and R ⁴ are as defined in claim 1. 27. The method of obtaining the compounds of formula I according to claim 1, where A represents CH ₂ and R ⁵ represents —OH or —N (H) R ¹² , wherein the compounds of formula VI are reacted

where R ¹ , R ² , R ³ , R ⁴ , R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ , R ⁴⁵ and R ⁴⁶ are as defined in claim 1, with a compound of formula VII

where X represents O or N (R ¹² ), and R ⁶ , R ⁷ , R ¹² and B are as defined in claim 1. 28. A method of obtaining a compound of formula I according to claim 1, wherein the compound of formula VI, as defined in paragraph 27, is reacted with a compound of formula VIII

where L ² represents a leaving group, and R ⁵ , R ⁶ , R ⁷ , A and B are as defined in claim 1. 29. The method of obtaining the compounds of formula I according to claim 1, where R ⁵ represents —N (H) R ¹² , where R ¹² is as defined in claim 1, provided that it does not represent H, in which the interaction of the corresponding compounds of formula I, where R ⁵ represents-NH ₂ , with the compound of formula XVIII R ^12a L ¹ XVIII where R ^12a represents R ¹² as defined in claim 1, provided that it does not represent H, but L ¹ is as defined in paragraph 25. 30. The method of obtaining the compounds of formula I according to claim 1, where R ⁵ represents a halogen, which carry out the substitution of the corresponding compounds of formula I, where R ⁵ represents —OH, using a suitable halogenating agent. 31. The compound of formula II, as defined in paragraph 24,

or a protected derivative thereof, provided that R ^{7 is} not optionally substituted phenyl or C _1-6 alkyl. 32. The compound of formula V, as defined in paragraph 26,

or a protected derivative thereof, provided that R ^{7 is} not optionally substituted phenyl.