SK42003A3 - New bispidine compounds and their use in the treatment of cardiac arrhythmias - Google Patents

Abstract

There is provided compounds of formula (I), wherein R<1>, R<2>, R<3a>, R<3b> and R<41> to R<46> have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.

Description

Bispidine compounds, process for their preparation and their use in the treatment of cardiac arrhythmias

Technical field

The present invention relates to novel pharmaceutically active compounds, in particular compounds which are useful in the treatment of cardiac arrhythmias.

BACKGROUND OF THE INVENTION

Cardiac arrhythmias may be defined as anomalies in the heart rate, regularity and location of cardiac pulses, or as transmission disorders of these pulses that cause an incorrect activation order. Arrhythmias may be clinically classified according to the predicted site of origin (i.e., supraventricular arrhythmias, including atrial and atrioventricular arrhythmias and ventricular arrhythmias) and / or heart rate (i.e., bradyarrhythmia (low frequency) and tachyarrhythmia).

Negative results of clinical trials for the treatment of cardiac arrhythmias (see, for example, the results of the cardiac arrhythmia suppression test, Cardiac Arrythmia Suppression Trial (CAST), described in the New England Journal of Medicne, 321, .406, (1989) with traditional antiarrhythmic drugs by slowing the transfer rate (class I of antarrhythmic drugs), they accelerate drug development to those compounds that selectively retard cardiac repolarization and thus prolong the QT interval Class III antiarrhythmic drugs may be defined as drugs that prolong the transmembrane potential interval (which may be caused by blockage) external K ⁺ currents or increase in internal ion currents) and resistance, without affecting cardiac transmission.

One of the main drawbacks of the hitherto known repolarization retardant drugs (class III or further) is that all exhibit a special form of proarrhythmia known as "torsades de pointes", which may possibly be fatal. For safety reasons, minimizing this phenomenon (also found with other non-cardiac drugs such as phenothiazines, tricyclic antidepressants, antihistamines and antibiotics) is a key issue to be addressed to provide effective antiarrhythmic drugs.

Bispidine-based antiarrhythmic drugs (3,7-diazabicyclo [3.3.1] nonanes) are known, inter alia, from International Patent Applications WO 91/07405 and WO 99/31100, European Patent Applications EP 000 074, EP 301 245, EP 306 871, EP 308 843, EP 461 574 and EP 665 228, German patent applications DE 2 428 792,

DE 2 658 558 and DE 2 744 248 and U.S. Patents 3,962,449,

U.S. Pat. No. 4,556,662, U.S. Pat. No. 4,550,112, U.S. Pat. No. 4,559,301, U.S. Pat. No. 5,468,858 and U.S. Pat

786 481 as well as from articles in magazines such as J.

Med. Chem. 39, 2559 (1996); Pharmacol. Res. 24: 149 (1991); Circulation, 90, 2032 (1994); Anal. Sci. 9, 429 (1993) and J. Med. Chem. 20, 1668 (1997). Known anti-arrhythmic bispidine compounds include bisaramil (syn-9- (4-chlorobenzyloxy) -3-methyl-7-ethyl-3,7-diazabicyclo [3.3.1] nonane), tedisamil (3,7-di- ( cyclopropylmethyl) -9,9-tetramethylene-3,7-diazabicyclo [3.3.1] nonane), SAZ-VII-22 [3- (4-chlorobenzoyl) -7-isopropyl-3,7-diazabicyclo [3.3. ljnonane], SAZ-VII-23 (3-benzoyl-7-isopropyl-3,7-diazabicyclo [3.3.1] nonane), GLG-V-13 (3- [4- (1H-imidazole-1- yl) benzcyl] -7-isopropyl-3,7-diazabicyclo [3.3.1] nonane), KMC-IV-84 (7- [4 '- (1H-imidazol-1-yl) benzenesulfonyl] -3-benzenesulfonyl] -3- isopropyl-3,7-diazabicyclo [3.3.1] nonane) and ambasilide [3- (4-aminobenzoyl) -7-benzyl-3,7-diazabicyclo [3.3.1] nonane).

Other bispidine compounds are known, inter alia, from Eur. J. Med. Chem. 25, 1 (1990); Bull. Polish Acad. Sci. Chem. 34 (5-6), 205 (1986); J. Org. Chem. 60, 8148 (1995); Eur. J. Med.

Chem. Chimica Therapeutica 12 (4): 301 (1977); Phosphorus, Sulfur and Silicon 123: 385 (1997); J. Org. Chem. 42 (6), 937 (1977); and J. Molecular Structure 127: 185 (1985).

We have now found that a novel class of compounds based on 3,7-diazabicyclo [3.3. Ionane is characterized by electrophysiological activity, preferably class III, and therefore it is expected that these compounds will be effective in the treatment of cardiac arrhythmias.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I

where

R ¹ represents a structural fraction of formula Ia,

Δ R-R 6 (Ia) \ X

R ^{4 R5} where

R ⁴ is hydrogen, halogen, C 1 -C 4 alkyl, -D-OR ⁷ , -DN (R ⁸ ) R ⁹ , or R ⁴ together with R ⁵ represent oxo;

R ⁵ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or R ⁵ together with R ⁴ represents an oxo group;

D represents a direct bond or an alkylene group having 1 to 4 carbon atoms;

R ⁷ is hydrogen, C 1-6 alkyl, -E-aryl, -E-Het ¹ , -C (O) R ^10a , -C (O) OR ^10b, or -C (O) N (R ^11a ) R ^11b ;

q

R is H, alkyiovú 1 -C 6 alkyl, -E-aryl, -E-Het ^1, -C (O) R ^10, -C (O) OR ^10b, -S (O) 2 R ^10c - [C (O)] n N (R ^11a ) R ^11b or -C (NH) NH ₂ ;

R ⁹ is hydrogen, C 1 -C 6 alkyl, -E-aryl or -C (O) R ^10d ;

E represents, at each occurrence, when used herein, a direct bond or an alkylene group having 1 to 4 carbon atoms;

R ^10a to R ^10d independently at each occurrence, when used herein, are C 1 -C 6 alkyl (optionally substituted and / or terminated with one or more substituents selected from halogen, aryl, and Het ² ), aryl Het ³ , or R ^10a and R ^10d independently represents a hydrogen atom;

R ^11a and R ^11b, independently at each occurrence, when used herein, represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (optionally substituted and / or terminated with one or more substituents selected from halogen, aryl, and Het) ⁴ ), aryl, Het ⁵ , or R ^11a and R ^11b together represent an alkylene group having 3 to 7 carbon atoms, wherein the alkylene group is optionally interrupted by an oxygen atom;

n is 1 or 2;

A is -G-, -JN (R ¹² ) -, or -J-O- (wherein in the last two groups J is attached to the nitrogen atom of bispidine);

B is -L-, -LN (R ¹³ ) -, -N (R ¹³ ) -L-, -LS (O) _P or -L-O- (where in the last two groups L is bound to a carbon atom, which carries the groups R ⁴ and R ⁵ );

G represents a direct bond or an alkylene group having 1 to 6 carbon atoms;

J represents an alkylene group having 2 to 6 carbon atoms;

L represents a direct bond or an alkylene group having 1 to 4 carbon atoms;

p is 0, 1 or 2;

and R ¹³ independently represent hydrogen or C 1 -C 4 alkyl;

represents aryl, Het ⁶ (both optionally substituted and / or terminated (as appropriate) with one or more substituents selected from the group consisting of hydroxy, cyano, halogen, nitro, alkyl of 1 to 6 atoms carbon (optionally terminated with -N (H) C (O) OR ^14a ), (C 1 -C 6) alkoxy, aryl,

Het ⁷ ,

-N ( ^R15a ) ^R15b ,

-C (O) ^R15c ,

-C (O) ^OR15d ,

-C (O) N (R ^15e ) R ^15f , -N (R ^15m ) S (O) ₂ R ^14b ,

N (R ¹⁵⁹⁾ C (0) R ^15h, -N (R ¹⁵ⁱ⁾ C (0) N (R ^15j) R ^15k, - S (O) q R ^14c, -OS (O) 2 R ^14d and -S ( O) 2N (R ¹⁵ⁿ ) R ^15p ), or when R ⁴ and R ⁵ together form an oxo group, R ⁶ may represent an alkyl group having 1 to 6 carbon atoms;

represents 0, 1 or 2;

R ² is cyano, Het ⁸ , -C (O) R ¹⁶ , -C (S) OR ¹⁷ ,

-C (S) N (R ¹⁸ ) R ¹⁹ , -S (O) ₂ N (R ²³ ) R ²⁴ ,

20a \ _n 20b - [C (O)] ₂ N (R 2 ^Ua ) R -C (= N-CN) N (R ²⁵ ) R ²⁶ ,

- [C (O)] ₂ OR

-s (O) ₂ y

-C (= N-CN) OR ²⁷ or an alkyl group having 1 to 12 carbon atoms (wherein the alkyl group is optionally substituted with and / or terminated by one or two more substituents selected from -C (O) R,

-C (O) N (R ^29a) R ^29b, -N (R ³⁰⁾ R ^31, -OR ^32, -S (O) _r R ^33, halo, cyano, nitro, aryl and Het ^9);

R ¹⁵ represents a hydrogen atom, an aryl group, a Het ¹⁰ group or an alkyl group having from 1 to 6 carbon atoms (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from halogen, hydroxy, cyano, -N (R ³⁴⁾ R ³⁵ , aryl and Het ¹¹ );

R ³⁴ is hydrogen, C 1 -C 6 alkyl, aryl, Het ¹² , -C (O) R 3 ^Sa or -C (O) OR ^36b ;

io i g

R is hydrogen, aryl, Het, -C (O) R ^36a or -C (O) OR ^36b or C ¹ radical having 1 to 6 carbon atoms (wherein the alkyl group is optionally substituted and / or terminated by one or more substituents selected from halogen, hydroxy, cyano, -C (O) R ^36a or -C (O) OR ^36b ;

R ²² represents Het ¹⁴ , aryl, C 1 -C 6 alkyl (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from halogen, hydroxy,

cyano, Het ¹⁵ and aryl); represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms; 6 atoms carbon, aryl, or -C (O) SR ^36b ; Het ^1c , -C (O) R ^36a , -C (O) OR ^36b represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms; 6 atoms

carbon (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from a halogen atom, a hydroxy group, a cyano group, an alkyl group having 1 to 6 carbon atoms (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected C1-C4alkyl, hydroxy, C1-C6alkoxy and aryl);

R ²⁷ represents an alkyl group having 1 to 6 carbon atoms or an aryl group;

R ²⁸ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group or a group Het ¹⁷ ;

R ^29a and R ^29b independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group or a group Het ¹⁸ ;

R ³⁰ is hydrogen, carbon, aryl, or -C (O) N (R ^37c ) R ^37d ;

C 1-6 alkyl, Het ¹⁹ , -C (Ô) R ^37a , -C (O) OR ^37b is hydrogen, C 1-6 alkyl

O, aryl or Het;

R ³² is hydrogen, C 1 -C 6 alkyl, aryl, Het ²¹ , -C (O) R ^37a , -C (O) OR ^37b or -C (O) N (R ^37c ) R ^37d ;

R ³³ is C 1 -C 6 alkyl, aryl or Het ²² ;

r is 0, 1 or 2;

R ^36a and R ^36b independently represent, when present herein, an alkyl group of 1 to 6 carbon atoms, or R ^36a represents a hydrogen atom;

R ^37a to R ^37d independently represent, when present herein, an alkyl group of 1 to 6 carbon atoms, an aryl group or Het ²³ , or R ^37a , R ^37c and R ^37d independently represent a hydrogen atom;

Het ¹ to Het ²³ independently represent, when present herein, five to twelve membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen, and / or sulfur;

R ^3a and R ^{3b are} independently hydrogen, C 1 -C 4 alkyl, -OR ^38a , -SR ^38b , -N (R ³⁹ ) R ^38c , or

R ^3a and R ^3b together form an alkylene group having 3 to 5 carbon atoms, -OZO-, -OZS- or -SZS-;

R ³⁹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a structural moiety 1a as defined above;

Z represents an alkylene group having 2 to 3 carbon atoms optionally substituted by one or more alkyl groups having 1 to 4 carbon atoms;

R ⁴¹ to R ^{46 are} independently hydrogen or C 1 -C 3 alkyl;

R ^14a to R ^14d , R ¹⁷ and R ²¹ independently represent C 1 -C 6 alkyl;

R ^15a to R ^15p , R ¹⁹ , R ^20a , R ^20b , R ²⁴ , R ²⁶ , R ³⁵ and R ^38a to R ^38c independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;

wherein each aryl group and Het (Het ¹ to Het ²³ ), unless otherwise specified, is optionally substituted;

or a pharmaceutically acceptable salt thereof;

with the proviso that (a) when R ¹ represents a structural fraction of formula Ia in which:

R ⁴ and R ³ together form an oxo group;

A represents a direct bond;

then B is not a direct bond, -N (R ¹³ ) -L- (wherein -N (R ¹³ ) - is attached to a carbon atom bearing R ⁴ and R ⁵ ), -N (R ¹³ ) - , -S (O) _p - or -O-;

(b) when R ⁵ represents a hydrogen atom or a C 1 -C 4 alkyl group; and

A is -jN (R ¹²⁾ - or-J-0-;

then B is not -N (R ¹³ ) -L-, -N (R ¹³ ) -, -S (O) _P - or

-0-;

(c) when R ⁴ represents a group -D-OR ⁷ , -DN (R ⁸ ) R ⁹ , wherein D represents a direct bond, then:

(i) A is not -JN (R ¹² ) - or -J-O-; and (ii) B is not -N (R ¹³ ) -L-, -N (R ¹¹ ) -, -S (O) _p or -O-;

(d) when R ^3a and R ^{3b are} both hydrogen; and

R ¹ represents unsubstituted benzyl;

then R ² does not represent an unsubstituted benzyl or optionally substituted benzoyl; and (e) the compound is not:

(i) N'-phenyl-3- (7-benzyl-3,7-diazabicyclo [3.3.1] non-3-yl) propanamide;

(ii) 3-Benzyl-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -6,8-dimethyl-3,7-diazabicyclo [3.3. Ijnonán;

(iii) 3-Benzyl-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -6-methyl-3,7-diazabicyclo [3.3. Ijnonán;

(iv) N- {2- (7-benzyl-3,7-diazabicyclo [3.3.1] non-3-yl) -1 - [(4-cyanophenoxy) methyl] ethyl} methanesulfonamide;

(v) 3-Benzyl-7- [3- (2-propyl-1,3-dioxolan-2-yl) propyl] -3,7-diazabicyclo [3.3. ] nonane; or (vi) 7-benzyl-3,7-diazabicyclo [3.3. ] nonane-3-ethanol;

these compounds are hereinafter referred to as "the compounds of the invention".

Unless otherwise indicated, alkyl and alkoxy groups as defined herein may be straight chain or, if they have a sufficient number (i.e. at least three) carbon atoms, may be branched chain and / or cyclic. Further, if they have a sufficient number of carbon atoms (i.e. at least four), such alkyl groups and alkoxy groups may be partially cyclic / acyclic. Such alkyl and alkoxy groups may also be saturated or, if they have a sufficient number of carbon atoms (i.e., at least two), be unsaturated and / or interrupted by one or more oxygen and / or sulfur atoms. Unless otherwise stated, alkyl and alkoxy groups may be substituted by one or more halogen atoms, especially fluorine atoms.

Unless otherwise indicated, alkylene groups as defined herein may be straight chain or, if they have a sufficient number (i.e., at least two) carbon atoms, may be branched chain. Such alkylene chains may also be saturated or, if they have a sufficient number of carbon atoms (i.e. at least two), may be unsaturated and / or interrupted by one or more oxygen atoms and / or sulfur atoms. Unless otherwise indicated, alkylene groups may be substituted with one or more halogen atoms.

The term "aryl" as used herein includes aryl groups of 6 to 10 carbon atoms such as phenyl, naphthyl and the like. Unless otherwise indicated, aryl groups may be substituted by one or more substituents including hydroxy, cyano, halogen, nitro, (C 1 -C 6) alkyl (optionally terminated with -N (H) C (O) OR ^14a ), (C 1 -C 6) alkoxy, Het ¹ , aryl (wherein the aryl group may not be substituted by any other aryl groups), -N (R ^15a ) R ^15b , -C (O) R ^15c , -C (O) OR ^15d , -C (O) N (R ^15e ) R ^15f , -N (R ^15g ) C (O) R ^15h ,

-N (R ¹⁵ⁱ ) C (O) N (R ^15j ) R ^15k , -N (R ^15m ) S (O) 2 R ^14b , -S (O) q R ^14c , -OS (O) ₂ R ^14d, and

-S (O) ₂ N (R ¹⁵ⁿ ) R ^15p (wherein Het ¹ , R ^14a to R ^14d , R ^15a to R ^{15p and} q are as previously defined). When aryl groups are substituted, they are preferably substituted with one to three substituents.

The term "halogen" as used herein means fluoro, chloro, bromo and iodo.

The Het groups (Het ¹ to Het ²³ ) referred to herein include groups containing 1 to 4 heteroatoms (selected from the group consisting of oxygen atoms, nitrogen atoms, and / or sulfur atoms) and wherein the total number of atoms in the ring system is between five and twelve. The Het groups (Het ¹ to Het ²³ ) may be fully saturated, partially unsaturated, fully aromatic, partially aromatic and / or bicyclic. Exemplary heterocyclic groups include benzodioxanyl, benzodioxepanyl, benzodioxolyl, benzofuranyl, benzofurazanyl, benzimidazolyl, benzomorpholinyl, benzothienyl, chromanyl, cinolinyl, dioxanyl, furyl, hydantoinyl, imidazolyl, imidazo [1,2-aol] pyridyl, 1,2-ayl] pyridyl , maleimido, morpholinyl, 2-oxazolidonyl, oxazolyl, phthalazinyl, piperazinyl, piperidyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrolinyl, pyrrolyl, quinazolinyl, quinolyl, sulfolanyl, tetrahydrofuran, 3-sulfolenyl, tetrahydrofuran, 3-sulfolenyl, , tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiochromanyl, triazolyl and the like. The values of Het ¹ which may be mentioned include pyridyl. The values of Het ⁶ which may be mentioned include benzodioxanyl, benzomorpholinyl, furyl, isoquinolyl, isoxazolyl, 2-oxazolidonyl, piperazinyl, pyrazolyl, pyrrolidinonyl and 1,2,3-thiadiazolyl. The values of the group Het ⁸ which may be mentioned include pyrimidinyl, quinazolinyl, tetrazolyl, thiazolyl and 1,2,4-triazolyl. The values of Het ⁹ which may be mentioned include benzomorpholinyl, 2-oxazolidonyl and piperazinyl. The values of Het ¹⁰ which may be mentioned include furyl, isoxazolyl, pyrazolyl, pyrrolidinonyl and 1,2,3-thiadiazolyl. The meanings of the group Het ¹⁴ which may be mentioned include imidazolyl, sulfolanyl, thienyl and quinolyl. The meanings of Het ¹⁵ which may be mentioned include pyrrolinyl. The meanings of the group Het ¹⁷ which may be mentioned include benzomorpholinyl. The meanings of the Het ²¹ group which may be mentioned include isoquinolyl.

Unless otherwise indicated, Het groups (Het ¹ to Het ²³ ) may be substituted with one or more substituents selected from oxo, hydroxy, cyano, halogen, nitro, (C 1 -C 6) alkyl (optionally terminated with -N (H) (C (O) OR ^14a ), (C 1 -C 6) alkoxy, Het ¹ , aryl, -N (R ^15a ) R ^15b , -C (O) R ^15c , -C (O) OR ^15d , -C (O) N (R ^15e ) R ^15f , -N (R ^15a ) C (O) R ^15h ,

-N (R ¹⁵¹ ) C (O) N (R ¹⁵³ ) R ^15k , -N (R ^15m ) S (O) 2 R ^14b , -S (O) q R ^14c , -OS (O) ₂ R ^14d, and

-S (O) ₂ N (R ¹⁵ⁿ ) R ^15p , wherein Het ¹ , an aryl group, R ^14a to R ^14a , R ^15a to R ^{15p and} q are as previously defined). When the Het (Het ¹ to Het) groups are substituted with one or more Het * groups and / or aryl groups, these Het * and / or aryl substituents may not themselves be further substituted with aryl groups or Het ¹ groups. The substituents on the Het groups (Het to Het) may, where appropriate, be located on any atom in the ring system, including a heteroatom. The point of attachment of the Het groups (Het ¹ to Het ²³ ) may be any atom in the ring system, including (where appropriate) a heteroatom. The Het groups (Het ¹ to Het ²³ may be in N- or S-oxidized form).

Pharmaceutically acceptable derivatives include salts and solvates. Salts mentioned herein include acid addition salts. Pharmaceutically acceptable derivatives also include alkyl quaternary ammonium salts of 1 to 4 carbon atoms and N-oxides on the nitrogen atom of 3,7-diazabicyclo [3.3. ljonán, provided it is present

N-oxide:

(a) no Het group (Het ¹ to Het ²³ ) contains an unoxidized sulfur atom;

(b) p is not 0 when B is -LS (O) _P -;

I (c) q does not represent 0 when -S (O) _q R ^14c is present as a substituent on an aryl group, a Het (Het ¹ to Het ²³ ) group or R ⁶ ; and / or (d) r is not 0 when -S (O) _r R ³³ is present as a substituent on the alkyl group R ² represents.

The compounds of the present invention may be characterized by tautomerism. All tautomeric forms and mixtures thereof are included within the scope of this invention.

The compounds of the present invention may also contain one or more asymmetric carbon atoms and therefore may exhibit optical isomerism and / or diastereoisomerism. Diastereoisomers can be separated using conventional techniques, such as chromatography or fractional crystallization. The various stereoisomers may be isolated by separation of a racemic or other mixture of these compounds using conventional techniques such as fractional crystallization or HPLC. Alternatively, the desired optical isomers may be prepared by reacting suitable optically active starting materials using conditions not causing racemization and epimerization, or may be prepared by derivatization with, for example, a homochiral acid followed by separation of diastereomeric esters using conventional laboratory techniques such as HPLC and silica chromatography. All stereoisomers are included within the scope of the present invention.

Abbreviations are given at the end of this description.

Compounds of the invention which may be mentioned include the compounds of formula I as defined hereinbefore with the proviso that:

(i) when R represents an alkyl group having 1 to 6 carbon atoms (optionally substituted with one or more aryl groups), then:

(I) when R ⁴ represents a hydrogen atom, a C 1 -C 4 alkyl group, -OR ⁷ , or R ⁴ together with R ⁵ represents an oxo group;

y

R is H, alkyl of 1 to 6 carbon atoms or a -C (O) R ^10; and

R ⁶ represents an aryl group;

then B is not -L-; and / or (II) when A represents a single bond; and

R ⁴ and R ⁵ together represent oxo;

then R ^3a and R ^{3b are} not both C 1 -C 4 alkyl or together are not C 3 -C 5 alkylene;

(ii) when R ² is -C (O) R ¹⁶ and -AC (R ⁴ ) (R ⁵ ) -B represents an alkylene group having 1 to 6 carbon atoms, then:

(I) R ^{6 is} not an aryl group; and / or (II) R ^3a and R ^3b both do not represent C 1 -C 4 alkyl or together do not represent C 3 -C 5 alkylene; and (iii) when R ² is -S (OHR ^22;

R ^3a and R ^3b independently represent a hydrogen atom or a C 1 -C 4 alkyl group; and

R ⁶ represents an aryl group;

then A and B do not simultaneously represent direct bonds wherein said aryl groups are, unless otherwise indicated, optionally substituted as previously described.

Compounds of the invention which may be mentioned include the compounds of formula I as defined hereinbefore with the proviso that:

when R ^3a and R ^{3b are} independently hydrogen, C 1 -C 4 alkyl, hydroxy or N (R ³⁹ ) R ^38c ; and

R ³⁹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, then:

(a) when R ² is cyano or alkyl optionally substituted with hydroxy, N (R ³⁰ ) R ³¹ or Het ⁹ ;

R ³⁰ and R ³¹ independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms;

Het ⁹ represents an unsubstituted, saturated 3- to 8-membered heterocycle containing one nitrogen atom (through which the heterocyclic group is attached to the rest of the molecule);

I '

R ⁴ and R ⁵ in each case represent a hydrogen atom; and

R ⁶ represents a phenyl group substituted in the meta- or para-position (relative to group B) by carboxy or amino, then:

(i) when A represents a direct bond, a C 1 -C 6 -alkylene group or a -J-O- group; and

J is n-alkylene of 2 to 3 carbon atoms;

then B is not -LN (R ¹³ ) - or -L-O- (wherein in the two groups L represents a direct bond or a C 1 -C 4 -alkylene group and binds to the carbon atom bearing the R ⁴ groups and R ⁵ ); and (ii) when A is -J-O-; and

J is n-alkylene of 2 to 3 carbon atoms;

then B is not a direct bond; and (b) when R ⁶ is Het ⁶ ;

Het ⁶ represents an unsubstituted saturated, 3- to 8-membered heterocycle containing one nitrogen atom (through which the heterocyclic group binds to the rest of the molecule); and the group -AC (R ⁴ ) (R ⁵ ) -B- represents a n-alkylene group having 1 to 6 carbon atoms;

then R ² does not represent:

(i) n-alkyl group having 1 to 6 carbon atoms, which alkyl group is optionally interrupted by oxygen and is terminated by N (R ³⁰⁾ R ³¹ or OR ^32; wherein one of R ³⁰ and R ³¹ represents a hydrogen atom or a phenyl group substituted in the meta- or para-position (with respect to the point of attachment) by a carboxy or amino group and the other represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and

R ³² represents a hydrogen atom or a phenyl group substituted in the meta- or para-position (with respect to the point of attachment) by carboxy or amino;

(ii) -C (O) R ¹⁶ where R ¹⁶ represents a hydrogen atom or a phenyl group substituted in the meta- or para-position (with respect to the point of attachment) by a carboxy or amino group;

(iii) -S (O) -R ²² , wherein R ²² represents a phenyl group of sub17 substituted at the meta- or para-position (with respect to the point of attachment) by carboxy or amino;

(iv) -S (O) ₂ N (R ²³ ) R ²⁴ , wherein R ²³ represents a phenyl group substituted in the meta- or para-position (with respect to the point of attachment) by a carboxy or amino group; and

R ²⁴ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and (v) an n-alkyl group wherein the alkyl group is terminated with a phenyl group, wherein the phenyl group is substituted in the meta or para-position (relative to the point of attachment) by carboxy or amino, and wherein the alkyl group is interrupted in the β-position point of attachment of the phenyl group) by an oxygen atom _Ί

Other compounds of the invention which may be mentioned herein include those compounds of formula I as defined herein, with the further proviso that:

R ⁶ does not represent:

(i) an unsubstituted saturated three- to eight-membered heterocycle containing one nitrogen atom (through which the heterocyclic group binds to the rest of the molecule); or (ii) a phenyl group substituted at the meta- or para-position (relative to group B) by carboxy or amino.

Other compounds that may be mentioned include those wherein R ⁶ is an aryl group which is optionally substituted and / or terminated (if appropriate) with one or more substituents selected from hydroxy, cyano, halogen, nitro, alkyl (C 1 -C 6) (optionally terminated with -N (H) C (O) OR ^14a ), (C 1 -C 6) alkoxy, aryl, Het ⁷ , -C (O) R ^15c , -C ( 0) N ( ^R15e ) ^R15f , -N ( ^R15g ) C (0) ^R15h ,

-N (R ¹⁵¹ ) C (O) N (R ^15j ) R ^15k , -N (R ^15m ) S (O) 2 R ^14b , -S (O) q R ^14c , -OS (O) ₂ R ^14d, and

-S (O) ₂ N (R ¹⁵ⁿ ) R ^15p , or when R ⁴ and R ⁵ together form an oxo group, R ⁶ can be an alkyl group having 1 to 6 carbon atoms.

Preferred compounds of the present invention also include those wherein:

R ⁴ represents a hydrogen atom, a C 1 -C 2 alkyl group, -OR ⁷ or -N (H) R ⁸ , or R ⁴ together with R ⁵ represents an oxo group;

R ⁵ represents a hydrogen atom, or R ⁵ together with R ⁴ represents an oxo group;

R ⁷ is hydrogen, C 1 -C 4 alkyl, optionally substituted phenyl, -C (O) R ^10a or -C (O) N (R ^11a ) R ^11b ;

R ⁸ is hydrogen, C 1 -C 4 alkyl, -C (O) R ^10a , -C (O) OR ^10b, or -C (O) N (R ^11a ) R ^11b ;

R ^10a and R ^10b independently represent, at each occurrence, when used herein, an alkyl group having 1 to 5 carbon atoms (optionally substituted and / or terminated with one or more substituents selected from a halogen atom and a phenyl group), an optionally substituted phenyl group or R ^10a represents a hydrogen atom;

R ^11a and R ^11b independently represent, at each occurrence, when used herein, a hydrogen atom or a C 1 -C 5 alkyl group (optionally substituted and / or terminated with one or more substituents selected from a halogen atom and a phenyl group);

A is -G- or -JN (R ¹² ) -;

B represents a direct bond, a (C 1 -C 4) alkylene group, -LN (H) -, -LS (O) ₂ - or -L-O- (wherein in the three groups, L is attached to a carbon atom bearing

R ⁴ and R ⁵ );

G represents a direct bond or an alkylene group having 1 to 4 carbon atoms;

J represents an alkylene group having 2 to 4 carbon atoms;

L represents an alkylene group having 1 to 4 carbon atoms;

R c is phenyl, Het ⁶ (both optionally substituted with one or more substituents selected from the group consisting of cyano, halogen, nitro, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, optionally substituted phenyl, -N (H) R ^15b , -C (O) R ^15c ,

-C (O) N (H) ^R15f , -N (H) C (O) ^R15h , -N (H) C (O) N (H) ^R15k , -N (H) S (O) 2R ^14b , -S (O) 2R ^14c , and -S (O) ₂ N (R ¹⁵ⁿ ) R ^15p ), or when R ⁴ and R ⁵ together form an oxo group, R ⁶ can be an alkyl group of 1 to 5 carbon atoms;

R ² is cyano, Het ⁸ , -C (O) R ¹⁶ , -C (S) OR ¹⁷ , -C (S) N (H) R ¹⁸ , - [C (O)] 2 N (H) R ^20b , - [C (0)] 2 OR ²¹ , -S (O) ₂ R ²² ,

-S (O) ₂ N (R ²³ ) R ²⁴ , -C (= N-CN) N (R ²⁵ ) R ²⁶ , -C (= N-CN) OR ^27, or (C 1 -C 6) alkyl ( wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from -C (O) R 1, -C (O) N (H) R ^29b , -N (R ³⁰ ) R ³¹ , -OR ³² , -S (O) ₂ R ³³ , halogen, cyano, nitro, optionally substituted phenyl, and Het ⁹ );

R ¹⁶ represents an optionally substituted phenyl, Het ¹⁰ or C 1 -C 6 alkyl group (wherein the alkyl group is optionally substituted or terminated with one or more substituents selected from halogen, cyano, -N (H) R ^34, and optionally substituted phenyl);

R ³⁴ is hydrogen, C 1 -C 4 alkyl, -C (O) R ^36a or -C (O) OR ^36b ;

R ¹⁸ represents a hydrogen atom, a -C (O) OR ^36b group or an alkyl group having 1 to 6 carbon atoms (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from a halogen atom and a -C (O) OR group ^36b );

R ²² is Het ¹⁴ , optionally substituted phenyl or C 1 -C 4 alkyl (wherein the alkyl is optionally substituted and / or terminated with one or more substituents selected from halogen, Het ^15, and optionally substituted phenyl);

R ²³ is hydrogen, C 1 -C 4 alkyl, -C (O) OR ^36b, or -C (O) SR ^36b ;

R ²⁵ represents a hydrogen atom or a C 1 -C 6 alkyl group (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from a halogen atom, a hydroxy group, an alkyl group having 1 to 6 carbon atoms (wherein the alkyl group is optionally substituted and / or terminated by one or more substituents selected from C 1-4 alkyl and hydroxy), C 1-4 alkoxy, naphthyl, and optionally substituted phenyl);

R ²⁷ represents an optionally substituted phenyl group;

R ²⁸ is C 1 -C 5 alkyl, optionally substituted phenyl or Het ¹⁷ ;

R represents a hydrogen atom, a C 1 -C 4 alkyl group or an optionally substituted phenyl group;

R ³⁰ represents a hydrogen atom, an optionally substituted phenyl group, -C (O) R ^37a or -C (O) OR ^37b ;

R ³¹ represents a hydrogen atom or a C 1 -C 2 alkyl group or an optionally substituted phenyl group;

R ³² represents a hydrogen atom, a C 1 -C 4 alkyl group (wherein the alkyl group is optionally interrupted by an oxygen atom), an optionally substituted phenyl group or a Het ²¹ group;

R ³³ represents an alkyl group having 1 to 6 carbon atoms or an optionally substituted phenyl group;

R ^37a and R ^37b independently represent, at each occurrence, when used herein, an alkyl group having 1 to 5 carbon atoms, optionally substituted phenyl, or R ^37a represents a hydrogen atom;

R ^3a and R ^3b independently represent hydrogen, C 1 -C 2 alkyl, -SR ^38b , -N (R ³⁹ ) R ^38c , or R ^3a, and

R ^3b together represent an alkylene group having 3 to 4 carbon atoms or -OZO-;

R ³⁹ represents a hydrogen atom, an alkyl group having 1 to 2 carbon atoms or a structural moiety of formula (Ia);

Z represents an alkylene group having 2 to 3 carbon atoms;

R ⁴¹ to R ^{46 are} independently hydrogen or C 1 -C 2 alkyl;

R ^14b , R ^14c , R ¹⁷ and R ²¹ independently represent C 1 -C 4 alkyl;

R ¹⁵⁰ to R ^15p , R ^20b , R ²⁴ , R ²⁶ , R ^38b and R ^38c independently represent hydrogen or C 1 -C 5 alkyl; and wherein the optional substituents on the phenyl groups are one or more substituents selected from the group consisting of cyano22, halogen, nitro, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, Het ¹ , amino, -C (O) ^R15c , -C (O) N (H) ^R15f , -N (H) C (O) ^R15h , -N (H) C (O) N (H) ^R15k , -N (H) S (O) 2 R ^14b and -S (O) 2 N (R ¹⁵ⁿ ) R ^15b .

When R ^3a and / or R ^3b represent a group -, N (R ³⁹ ) R ^38c in which

R ³⁹ represents a structural fraction of formula Ia, preferred compounds of formula I are those in which in group R ³⁹ :

R ⁴ represents a hydrogen atom, -OR ⁷ or N (H) R ⁸ , or R ⁴ together with R ⁵ represent an oxo group;

R ⁵ represents a hydrogen atom, or R ⁵ together with R ⁴ represents an oxo group;

R ⁷ represents a hydrogen atom, a phenyl group (wherein this group is optionally substituted with one to three methoxy groups), a -C (O) CH ₃ or -C (O) N (H) -alkyl group wherein the alkyl group contains 1 to 4 atoms alkyl;

R ⁸ represents a hydrogen atom, a -C (O) O-alkyl group wherein the alkyl group contains 1 to 4 carbon atoms, or -C (O) N (H) CH ₃ ;

A represents an alkylene group having 1 to 3 carbon atoms or an -alkylene-N (H) - group wherein the alkylene group contains 2 to 3 carbon atoms;

B represents a direct bond, -CH ₂ -, -CH ₂ -N (H) -,

-CH ₂ -S (O) ₂ -, -CH ₂ -O- (wherein in the three groups the CH ₂ group is attached to the carbon atom bearing the groups R ⁴ and R ⁵ ) or -O-;

R 0 represents a phenyl group optionally substituted with up to three substituents (in the para and / or ortho position) selected from cyano, -N (H) C (O) N (H) CH ₃ , -N (H) S (O) ₁₂ CH ₃ and -S (O) N (CH ₃ ) ₂ .

More preferred compounds of the present invention are those wherein:

R ⁴ represents a hydrogen atom, -OR ⁷ or N (H) R ⁸ , or R ⁴ together with R ⁵ represent an oxo group;

R ⁵ represents a hydrogen atom, or R ⁵ together with R ⁴ represents an oxo group;

R ⁷ represents a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an optionally substituted phenyl group, a -C (O) R ^10a or -C (O) N (R ^11a ) R ^8b ;

R ⁸ is H, alkyl having 1 or 2 carbon atoms, -C (O) OR ^10b or -C (0) N (R ^IIa) R ^IIb;

R ^10a and R ^10b independently at each occurrence, when used herein, are C 1 -C 5 alkyl (optionally substituted and / or phenyl-terminated), optionally substituted phenyl, or R ^10a is hydrogen;

R ^11a and R ^11b independently represent, at each occurrence, when used herein, a hydrogen atom or a C 1 -C 5 alkyl group (optionally substituted or terminated with a phenyl group);

A is -G- or -JN (R ¹² ) -;

B represents a bond, a (C 1 -C 4) alkylene group, -LN (H) -, -LS (O) 2 ^- or -L-O- (wherein in the three groups L is attached to the carbon atom carrying groups R ⁴ and R ⁵ );

G represents a direct bond or an alkylene group having 1 to 4 carbon atoms;

J represents an alkylene group having 2 to 4 carbon atoms;

L represents an alkylene group having 1 to 4 carbon atoms;

R ⁶ is phenyl, Het ⁶ (both optionally substituted by one or more substituents selected from the group consisting of cyano, halogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, -C (O) ^R15c , -N (H) C (O) ^R15h , -N (H) C (O) N (H) ^R15k , -N (H) S (O) ^2R14b , - S (O) 2 R ¹⁴ a

-S (O) ₂ N (R ¹⁵ⁿ ) R ^15p ).

When R ² represents the group -S (O) ₂ R ²² , more preferred compounds of the invention are those wherein:

R ⁴ together with R ⁵ represent oxo;

A is C 1 -C 4 alkylene;

B represents a direct bond or an alkylene group having 1 to 4 carbon atoms;

R ⁶ represents an alkyl group having 1 to 5 carbon atoms.

Other preferred compounds of the present invention are those wherein:

A is -G-, -JN (R ¹² ) -, or -J-O- (wherein in the last two groups J binds to the nitrogen atom of bispidine);

G represents an alkylene group having 1 to 6 carbon atoms;

R ⁴ is -D-OR ⁷ , -DN (R ⁸ ) R ⁹ , or R ⁴ together with

R ⁵ is oxo;

R ² is cyano, Het ⁸ , -C (O) R ¹⁶ , -C (S) OR ¹⁷ , -C (S) N (R ¹⁸ ) R ¹⁹ , - [C (O)] 2N (R ^20a ) R ^20b , - [C (0)] 2 OR ²¹ , -S (O) ₂ R ²² ,

-S (O) ₂ N (R ²³ ) R ²⁴ , -C (= N-CN) N (R ²⁵ ) R ²⁶ , -C (= N-CN) OR ^27, or C 1 -C 12 alkyl ( wherein the alkyl group is optionally substituted and / or terminated by one or 28 more substituents selected from -C (O) R,

-C (O) N (R ²⁹⁾ R ^29b, -N (R ³⁰⁾ R ^31, -OR ^32, -S (O) _r R ^33, halo, cyano, nitro and Het ^9);

R ¹⁵ is hydrogen, Het ^10, or C 1 -C 6 alkyl (wherein the alkyl is optionally substituted or terminated with one or more substituents selected from halogen, hydroxy, cyano, -N (R ³⁴ ) R ³⁵ , aryl and Het ¹¹ ;

R ⁶ is aryl, Het ⁵ (both optionally substituted by one or more substituents selected from the group consisting of hydroxy, cyano, halogen, nitro, alkyl of 1 to 6 carbon atoms (optionally terminated with -N ( H) C (O) OR ^14a ), (C 1 -C 6) alkoxy, aryl, Het ⁷ , -N (R ^15a ) R ^15b , -C (O) R ^15c , -C (O) OR ^15d , -C (O) N ( ^R15e ) ^R15f , -N ( ^R15g ) C (O) ^R15h , -N ( ^R15i ) C (O) N (R15 ⁾ ) ^R15k ,

-N (R ^15m ) S (O) 2 R ^14b , -S (O) q R ^14c , -OS (O) 2 R ^14d and -S (O) 2 N (R ¹⁵ⁿ ) R ^15p ), or when R ⁴ and R ⁵ together form an oxo group, R ⁵ can be an alkyl group having 1 to 6 carbon atoms.

Preferred compounds of the present invention are those exemplified in the Examples described below.

Preparation procedures

The present invention also provides a process for the preparation of compounds of formula I which comprises:

(a) reacting a compound of formula II

II)

R ²

N - H where R ² , R ^3a , R ^3b and R ⁴¹ to R ⁴⁶ are as defined above, with a compound of formula III

A \ A ~ ^{R 6 L} 'and _R 4 R 5 (III) wherein L ¹ represents a leaving group (e.g. mesylate, tosylate or halo) and R ^4, R ^5, R ^6, A and B are as hereinbefore defined, for example at a temperature between -10 ° C and boiling point, in the presence of a suitable base (e.g. triethylamine or potassium carbonate) and a suitable solvent (e.g. dichloromethane, acetonitrile or dimethylsulfoxide);

(b) for compounds of formula I, wherein R ¹ represents a structural fraction of formula Ia, wherein A represents a C 2 alkylene group and R ⁴ and R ⁵ together form an oxo group, the reaction of the corresponding compound of formula II as defined above, with a compound of formula IV (IV)

R®

wherein R ⁶ and B are as defined above, for example at room temperature, in the presence of a suitable organic solvent (e.g. ethanol);

(c) for compounds of formula I wherein R ^3a or R ^3b is -N (R ³⁹ ) R ^38c and R ³⁹ is a structural fraction of formula Ia, a reaction of a corresponding compound of formula I wherein R ^3a or R ^3b ( as appropriate) represents the group -N (H) R ^38c , where R ^38c has already been defined, with a compound of formula III as defined above, for example under the conditions described above (see step (a));

(d) for a compound of formula I wherein R ¹ is a structural fraction of formula Ia, wherein A is CH ₂ and R ⁴ is hydroxy or -N (H) R ⁸ , the reaction of the corresponding compound of formula II, such as has already been defined, with a compound of formula V

wherein X is O or N (R ⁸⁾ - and R ^5, R ^6, R ⁸ and B are as hereinbefore defined, for example at elevated temperature (e.g. 60 ° C to reflux temperature) in the presence of a suitable solvent (e.g. a lower alcohol such as isopropanol, acetonitrile or a mixture of a lower alcohol and water);

(e) for compounds of formula I wherein R ^3a and R ^3b are -N (R ³⁹ ) R ^38c and R ³⁹ is a structural fraction of formula Ia wherein A is CH ₂ and R ⁴ is hydroxy or -N (H) R ⁸ , the reaction of the corresponding compound of formula I wherein R ^3a or R ^3b (as appropriate) represents an -N (H) R ^{3Sc group} , where R ^38c has already been defined, with a compound of formula V as has already been defined, for example using the conditions described above (see preparation step (d));

(f) for compounds of formula I wherein A is C 1 -C 6 alkylene, B is C 1 -C 4 alkylene, and both R ⁴ and R ⁵ are hydrogen, reduction of the corresponding compound of formula I, wherein R ⁴ and R ⁵ together represent an oxo group, in the presence of a suitable reducing agent and under suitable reaction conditions, for example by activating the relevant C = O group with a suitable reagent (such as tosylhydrazine) in the presence of a suitable reducing agent (e.g. sodium borohydride or sodium cyanoborohydride); an organic solvent (e.g., a C 1 -C 6 lower alkyl alcohol);

(g) for compounds of formula I wherein R ⁴ and R ⁵ are both hydrogen, and (1) A is a single bond or -JN (R ¹² ) and B is C 1 -C 4 alkylene, or ( 2) A is a C 1 -C 6 alkylene group and B is -N (R ¹³ ) - or -N (R ¹³ ) -L-, a reduction of the corresponding compound of formula I wherein R ⁴ and R ⁵ together represent oxo , in the presence of a suitable reducing agent (e.g. lithium aluminum hydride) and a suitable solvent (e.g. tetrahydrofuran);

(h) for compounds of formula I; wherein A represents a C 1 -C 6 alkylene group, B represents a direct bond, a C 1 -C 4 alkylene group, -LN (R ¹³ ) -, -LS (O) _P - or -L-O- (wherein in the three groups, L is (C 1 -C 4) alkylene, R ⁴ is hydroxy and R ⁵ is hydrogen, a reduction of the corresponding compound of formula I wherein R ⁴ and R ⁵ together are oxo, in the presence of a suitable reducing agent ( sodium borohydride) and a suitable organic solvent (e.g. tetrahydrofuran);

(i) for compounds of formula I wherein R ^3a and R ^{3b are} both hydrogen, reduction of the corresponding compound of formula VI

wherein R ¹ , R ² and R ⁴¹ to R ⁴⁶ are as defined above, and wherein the terminal bridging group C = O can be activated using a suitable reagent such as tosylhydrazine in the presence of a suitable reducing agent (e.g. sodium borohydride or sodium cyanoborohydride) and a suitable an organic solvent (e.g., a lower alcohol) using standard Wolf-Kischner reaction conditions 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 boiling point in the presence of a suitable solvent (e.g. a lower alcohol such as methanol or ethanol or isopropanol), then a reducing agent and a reduction can be added to the reaction mixture. is carried out at a temperature between 60 DEG C. and the boiling point of ^1, preferably in the presence of a suitable organic acid (e.g. acetic acid);

(j) for compounds of formula I wherein one of R ³ and R ^3b represents a hydrogen atom and the other a hydroxy group, reduction of the corresponding compound of formula VI as defined above in the presence of a mild reducing agent such as sodium borohydride in a suitable organic a solvent (e.g., a lower alcohol such as methanol or ethanol);

(k) for compounds of formula I wherein R ^3a and R ^{3b are} both -OR ^38a or -SR ^38b , or wherein R ^3a and R ^3b together represent -OZO-, -OZS- or -SZS-, a reaction corresponding to a compound of formula VI as defined above with a compound of formula HOR ^38a , HSR ^38b , -HO-Z-OH, HO-Z-SH or HS-Z-SH (as appropriate), wherein R ^38a , R ^38b and Z have already been defined using suitable conditions, for example by heating to boiling in the presence of a suitable protic or Lewis acid catalyst (e.g. p-toluenesulfonic acid, trimethylsilyl chloride or boron trifluoride) and a suitable organic solvent (e.g. toluene or diethyl ether);

(1) for compounds of formula I wherein one of R ^3a and R ^3b is amino and the other is hydrogen, reducing the compound of formula VII

wherein R ¹ , R ² and R ⁴¹ to R ⁴⁶ have already been defined, in the presence of a suitable reducing agent (for example lithium aluminum hydride), using conditions known to those skilled in the art;

(m) for compounds of formula I wherein one or both of R ^3a and R ^3b is -N (R ³⁹ ) R ^38c , wherein one or both of R ³⁹ and R ^38c are C 1-6 alkyl, alkylation of the corresponding the compounds of formula I wherein R ^3a and / or R ^3b are -N (R ³⁹ ) R ^38c (as appropriate), wherein R ³⁹ and / or R ^38c (as appropriate) are hydrogen, wherein: using a compound of formula VIII

R ^a -L ^x (VIII) wherein R ^a represents an alkyl group having 1 to 6 carbon atoms and L ¹ has already been defined, for example using conditions well known to the person skilled in the art;

(n) for compounds of formula I, wherein R ¹ represents a structural fraction of formula Ia, wherein B is -LO, the reaction of a compound of formula IX

where R ⁶ has already been defined, for example using Mitsunobu reaction conditions, for example at a temperature between ambient temperature (e.g. 25 ° C) and boiling point, in the presence of a tertiary phosphine (e.g. tributylphosphine or triphenylphosphine), azodicarboxylate derivative (e.g. - (azodicarbonyl) dipiperidine) and a suitable organic solvent (e.g. dichloromethane or toluene);

(o) for compounds of formula I, wherein R ¹ is a structural fraction of formula Ia, wherein A is C 1 -C 6 alkylene and B is -N (R ¹³ ) -L- (wherein the -N (R 1) ¹³ ) - binds to a carbon atom carrying R ⁴ and R ⁵ ) by reacting a compound of formula XI

wherein A ^a represents an alkylene group having 1 to 6 carbon atoms and R ² , R ^3a , R ^3b , R ⁴ , R ⁵ , R ¹³ and R ⁴¹ to R ⁴⁶ are as defined above, with a compound of formula XII

R ⁶ -LL ² (XII) wherein L ² represents a leaving group such as a halogen atom, an alkanesulfonate, a perfluoroalkanesulfonate or an arenesulfonate, and R ⁶ and L have already been defined, for example at 40 ° C ·, in the presence of a suitable organic solvent ( such as acetonitrile);

(p) for compounds of formula I, wherein R ¹ is a structural fraction of formula Ia, wherein R ⁴ is -D-NH 2, a reduction of the corresponding compound of formula XIII

(xiii) wherein R ^2, R ^3a, R ^3b, R ^5,

R ⁶ , R ⁴¹ to R ⁴⁶ , A, B and D have already been defined, for example, by hydrogenation at a suitable pressure in the presence of a suitable catalyst (for example palladium on carbon) and a suitable solvent (for example a mixture of water and ethanol);

(q) for compounds of formula I wherein R ⁴ is -DN (R ⁹ ) C (O) NH (R ^11b ), the reaction corresponds to the corresponding compounds of formula I wherein R ⁴ 'is' -DN (R ⁹ ) H, with a compound of formula XIV

^Ub R N = C = O (XIV) wherein R ^IIb hereinbefore defined, for example at ambient temperature (e.g. 25 DEG C.), in a suitable solvent (e.g., benzene);

(r) for compounds of formula I wherein R ⁴ is -DN (H) [C (O)] 2 NH 2, reacting a corresponding compound of formula I wherein R ⁴ is -D-NH ₂ with oxalic diamide, for example at a temperature between -10 and 25 ° C, in the presence of a suitable coupling agent (e.g. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide), a suitable activating agent (e.g. 1-hydroxybenzotriazole), a suitable base (e.g. triethylamine) and an organic solvent reaction-inert (e.g., dimethylformamide);

(s) for compounds of formula I wherein R ⁴ is -DN (R ⁸ ) R ⁹ , wherein R ⁸ and R ⁹ are as defined above, provided that R ^{8 is} not hydrogen, the reaction of the corresponding compound of formula I, wherein R ⁴ is -DN (H) R ', with a compound of formula XV

R ^8a -L ³ (XV) wherein R ^8a represents R ⁸ as defined above, except that it is not a hydrogen atom, and L ³ represents a leaving group such as a halogen atom (for example a chlorine atom or a bromine atom), p- nitrophenolate, C 1 -C 4 alkoxide, C 1 -C 4 alkylthiolate, -OC (O) R ^10a , -OC (O) OR * ^0b, or

-OS (O) ₂ R ^10c , wherein R ^10a to R ^10c have already been defined, for example using conditions known to those skilled in the art;

(t) for compounds of formula I wherein R ⁴ is -D-OR ⁷ , wherein R ⁷ is C 1 -C 6 alkyl, -E-aryl, or -E-Het ¹ , the reaction of the corresponding compound of general formula of formula I wherein R ⁴ is -D-OH with a compound of formula XVI

R ^7a OH (XVI) wherein R ^7a represents a C 1 -C 6 alkyl group, -E-aryl group, or -E-Het ¹ group, wherein Het ¹ group has already been defined, for example between ambient temperature (e.g. -25 ° C) ) and boiling point using Mitsunobu reaction conditions (ie in the presence of, for example, triphenylphosphine, an azodicarboxylate derivative (for example 1,1 (azodicarbonyl) dipiperidine) and a suitable organic solvent (for example dichloromethane));

(u) for compounds of formula I wherein R ¹ is a structural fraction of formula Ia wherein R ⁴ is -D-OR ⁷ (wherein R ⁷ is C 1 -C 6 alkyl, -E-aryl or -E-Het ¹ ), reacting the corresponding compound of formula XVII

with a compound of formula XVI as defined above, for example at a temperature between ambient temperature (e.g. 25 ° C) and boiling point, using Williamson reaction conditions (in the presence of a suitable base (e.g. potassium hydroxide or sodium hydride) and a suitable organic solvent ( for example dimethylsulfoxide or dimethylformamide));

(v) for compounds of formula I wherein R ⁴ is -D-OR ⁷ where R ⁷ is as defined above, provided that it is not hydrogen, the reaction of the corresponding compound of formula I wherein R ⁴ is -D- OH, with a compound of formula XVIII

R ^7b -L ⁴ (XVIII) wherein R ^7b represents R ⁷ as defined above, except that it is not a hydrogen atom, and L ⁴ represents a leaving group such as hydroxy, halogen, alkanesulfonate, arenesulfonate or -OC (O) R ¹⁰ , where R ¹⁰ is as defined above, for example at a temperature between room temperature and boiling point, optionally in the presence of an organic solvent inert to the reaction (e.g. tetrahydrofuran or dichloromethane) of a suitable base (e.g. triethylamine or potassium carbonate) and / or a suitable coupling agent (e.g., 1,3-dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, optionally in conjunction with a suitable catalyst such as 4-dimethylaminopyridine) (e.g., when R ^7b represents -C ( O) R ^10a and L ⁴ are hydroxy, this reaction can be carried out at ambient temperature (e.g. 25 ° C) in the presence of a condensing agent such as 1- (3-dimethylaminop ropyl) -3-ethylcarbodiimide, and a suitable catalyst such as 4- (dimethylamino) pyridine, and a solvent such as tetrahydrofuran);

(w) for compounds of formula I wherein R ⁴ is a halogen atom, the substitution of the corresponding compound of formula I wherein R ⁴ is hydroxy using a suitable halogenating agent (for example a compound wherein R ⁴ is fluorine, reaction with diethylaminosulfurtrifluoride) ;

(x) reacting the corresponding compound of formula XIX

wherein R ¹ , R ^3a , R ^3b and R ⁴¹ to R ⁴⁶ are as defined above, with a compound of formula XX

R ² -L ⁵ (XX) wherein L ⁵ is a leaving group such as halogen, hydroxy, alkanesulfonate, arenesulfonate, C 1 -C 4 alkoxy, phenoxy, -OC (O) R ¹⁶ , -OC (O OR ²¹ or -OS (O) 2 R ²² , and R ² , R ¹⁶ , R ²¹ and R ²² have already been defined, for example at a temperature between -10 ° C and boiling point, optionally in the presence of a suitable solvent (e.g. acetonitrile, isopropanol, diethyl ether or mixtures thereof) and / or a suitable base (such as potassium carbonate, pyridine or triethylamine);

(y) for compounds of formula I wherein R ² is C 1 -C 12 alkyl wherein the alkyl group is substituted in the 2-position (relative to the bispidine nitrogen atom) by hydroxy or N (H) R ³⁰ , and is otherwise optionally substituted with one or more additional substituents, as specified for R ² , by reacting a compound of Formula XIX as defined above with a compound of Formula XXA

2a (XXA) wherein X ⁴ represents an oxygen atom or -N (R ³⁰ ) - and R ^2a represents an alkyl group having 1 to 10 carbon atoms, optionally substituted with one or more substituents, as already specified for R ² , for example as already described for the preparation of compounds of formula I (preparation step (d));

(z) for compounds of formula I wherein R ² is thrazol-5-yl, reacting the corresponding compound of formula I wherein R ² is cyano with a suitable azide ion source (e.g. sodium azide), e.g. at elevated temperature (e.g. 100 ° C) in the presence of a suitable solvent (e.g. dimethylformamide) and optionally in the presence of a suitable proton source (e.g. ammonium chloride);

(aa) for compounds of formula I that are N-oxide derivatives of bispidine nitrogen atom, oxidizing the corresponding bispidine nitrogen atom of the corresponding compound of formula I in the presence of a suitable oxidizing agent (e.g. m-CPBA), e.g. at 0 ° C in the presence a suitable organic solvent (e.g. dichloromethane);

(ab) for compounds of formula I which are derivatives of an alkyl quaternary ammonium salt of 1 to 4 carbon atoms in the alkyl moiety where the alkyl group is attached to the bispidine nitrogen atom, reacting the bispidine nitrogen atom of the corresponding compound of formula I with a compound of formula XXI

R ^b -L ² (XXI) wherein R ^b is C 1 -C 4 alkyl and L ² is already defined, for example at room temperature, in the presence of a suitable organic solvent (for example dimethylformamide) and subsequent purification (using HPLC) in the presence a suitable counterion (e.g., ammonium acetate) provider;

(ac) converting one substituent in the R ⁶ group to another using techniques well known to those skilled in the art; or (ad) converting one R ² group to another using techniques known to those skilled in the art.

Compounds of formula II may be prepared by reacting the corresponding compound of formula XXII

wherein R ^3a , R ^3b and R ⁴¹ to R ⁴⁶ are as defined above, with a compound of formula XX as defined above, for example as previously described for the synthesis of compounds of formula I (preparation step (x));

Compounds of formula II wherein R ^3a and R ^3b both represent hydrogen may be prepared by reduction of the corresponding compound of formula XXIII

wherein R ² and R ⁴¹ to R ⁴⁶ are as defined above, and wherein the C = O group can be activated using a suitable reagent such as tosylhydrazine, for example as described above for the preparation of compounds of Formula I (preparation step (i));

Compounds of formula II wherein one of R ^3a and R ^3b is hydroxy and the other is C 1 -C 4 alkyl may be prepared by reacting a compound of formula XXIII or a protected derivative thereof with a compound of formula XXIV

R ^alk -Mg-Hal '(XXIV), wherein R ^alk represents a C 1 -C 4 alkyl group and Hal represents a chlorine, bromine or iodine atom, for example at a temperature between -25 ° C and ambient temperature, in the presence of a suitable solvent ( such as diethyl ether).

Compounds of formula III may be prepared by standard techniques. For example, compounds of formula III wherein:

(1) B represents a group -L-Ο-, may be prepared by condensing a compound of formula X as defined above with a compound of formula XXV

L ⁶ -LC (R ⁴ ) (R ⁵ ) -AL ¹ (XXV), wherein L 0 represents a suitable leaving group (for example, a halogen atom), and R ⁴ , R ⁵ , A, L and L ¹ are already defined; or (2) B is -N (R ¹³ ) -L- and R ⁴ and R ⁵ together form an oxo group, may be prepared by condensation of a compound of formula XXVI

R ⁶ -LN (R ¹³ ) H (XXVI), wherein R ⁵ , R ¹³ and L are as defined above, with a compound of formula XXVII

L ⁶ -C (O) -AL ¹ (XXVII), wherein L ⁶ , A and L ¹ are already defined;

in both cases, using conditions known to those skilled in the art.

Compounds of formula (III) wherein A is C 2 alkylene and R ⁴ is -OR ⁷ wherein R ⁷ is C 1-6 alkyl, -E-aryl or -E-Het ¹ may be: alternatively prepared by reacting a compound of formula XVI as defined above with a compound of formula XXVIII

(XXVIII)

R ⁶ wherein R ^y is C 1 -C 4 alkyl or aryl (the two groups being optionally substituted with one or more substituents selected from C 1 -C 4 alkyl or halogen), and R ⁵ , R 7 ⁶ and B have already been defined, for example at a temperature between ambient temperature (e.g. 25 ° C) and boiling in the presence of a suitable base (e.g. potassium carbonate) and a suitable organic solvent (e.g. acetonitrile), and then the ester functional group is converted to L ¹ (where L ¹ has already been defined), using conditions known to those skilled in the art.

Compounds of formula III wherein A is C 2 -C 6 alkylene can be prepared by reduction of the corresponding compound of formula XXIX

(XXIX) wherein A ^b represents a direct bond or an alkylene group having 1 to 4 carbon atoms, and R ⁴ , R ⁵ , R ⁶ and B have already been defined, with a suitable borane or borane-Lewis base complex (e.g. borane-dimethylsulfide) in a suitable solvent (e.g. diethyl ether, tetrahydrofuran or a mixture thereof), followed by oxidation of the resulting borane adduct with a suitable oxidising agent (e.g. sodium perborate) and converting the resulting hydroxy group to the group L ^{1 1} under conditions that are known to the expert.

Compounds of formula III wherein A is C 2 -C 6 alkylene and B is -LN (R ¹³ ) - (wherein L is C 1 -C 4 alkylene) can be prepared by condensation of a compound of formula XXX

R ⁶ -L ⁶ (XXX) wherein R ⁶ and L ⁶ are as defined above, with a compound of formula XXXI

HN (R ¹³ ) -L ^and -C (R ⁴ ) (R ⁵ ) -A ^c -OH (XXXI) wherein L ^a represents an alkylene group having 1 to 4 carbon atoms> A ^c represents an alkylene group having 2 to 6 carbon atoms R ⁴ , R ⁵ and R ¹³ have already been defined, for example at a temperature between room temperature and boiling point, optionally in the presence of a solvent and / or a suitable base, followed by conversion of the hydroxy group to L ¹ using conditions known to those skilled in the art.

Compounds of formula III wherein B is -LS (O) - or -LS (O) ₂ - may be prepared by oxidation of the corresponding compounds of formula III, wherein B is -LS-, where L has already been defined, in the presence of a suitable amount of an oxidizing agent (e.g., m-CPBA) and a suitable organic solvent.

Compounds of formula (V) may be prepared by methods known to those skilled in the art. For example, a compound of formula V wherein:

(1) B is -CH ₂ O- and X is O, may be prepared by reacting a compound of formula X as defined above with a compound of formula XXXII

L * Λ— (xxxii) where R ⁵ and L ² have already been defined, for example at elevated temperature (e.g. between 60 ° C and boiling point) in the presence of a suitable base (e.g. potassium carbonate or sodium hydroxide) and a suitable organic solvent (e.g. acetonitrile) or a mixture of toluene and water), or as otherwise described in the art;

(2) R ⁵ represents a hydrogen atom and X represents an oxygen atom, may be prepared by reduction of a compound of formula XXXIII

(XXXIII) wherein R ⁶ and B have already been defined, for example at a temperature between -15 ° C and room temperature, in the presence of a suitable reducing agent (e.g. sodium borohydride) and a suitable organic solvent (e.g. tetrahydrofuran) and subsequent internal displacement of the reaction to the resulting intermediate , for example at room temperature, in the presence of a suitable base (for example potassium carbonate) and a suitable organic solvent (for example acetonitrile); ³ (3) B represents -L-, -LN (R ¹³ ) -, -LS (O) ₂ - or -LO (in all four groups, L represents an alkylene group having 1 to 4 carbon atoms) and X represents an oxygen atom , can be prepared by oxidizing a compound of formula XXXIV (XXXIV)

where B ^a represents a group -L-, -LN (R ¹³ ) -, -LS (O) 2 ^- or -L-O (in all four groups L represents an alkylene group having 1 to 3 carbon atoms) and R ⁵ , R ⁶ and R ¹³ have already been defined, in the presence of a suitable oxidizing agent (e.g. m-CPBA), for example by heating to boiling in the presence of a suitable organic solvent (e.g. dichloromethane); or (4) B is -L-O- (wherein L is C 1 -C 4 alkylene) and X is -N (R ⁸ ) (wherein R ⁸ is -C (O) OR ^10b or - S (O) 2 R ^10c ) can be prepared by crystallizing a compound of formula XXXV

(XXXV) wherein R ^8b is -C (O) OR ^10b or -S (O) ₂ R ^10c 3 R ³ , R ⁶ ,

R ^10b , R ^10c , L ^a and L ² have already been defined, for example at a temperature between 0 ° C and boiling point, in the presence of a suitable base (e.g. sodium hydroxide), a suitable solvent (e.g. dichloromethane, water or a mixture thereof), if necessary, a phase transfer catalyst (such as tetrabutylammonium hydrogen sulfate).

Compounds of formula VII may be prepared by reacting the corresponding compound of formula VI with hydroxylamine, for example at elevated temperature (e.g., boiling temperature), in the presence of a suitable organic solvent (e.g., methanol).

Compounds of formula (IX), (XI), (XIII) and (XVII) may be prepared similarly to compounds of formula (I) (see Example 44 of Preparation Steps (a), (b) and (x)).

Compounds of formula XIII may alternatively be prepared by reacting the corresponding compound of formula I wherein R ⁴ is -D-OH with a compound of formula XXXVI

R ^y S (O) ₂ Cl (XXXVI) wherein R ^y is as defined above, for example at a temperature between -10 and 25 ° C, in the presence of a suitable solvent (eg dichloromethane) and subsequent reaction with a suitable azide ion source (eg sodium azide) for example at a temperature between ambient and boiling, in the presence of a suitable solvent (e.g. dimethylformamide) and a suitable base (e.g. sodium bicarbonate).

Alternatively, compounds of formula XVII may be prepared by displacement of a hydroxy group in a compound of formula I wherein R ⁴ is -D-OH, L ² using conditions known to those skilled in the art.

Compounds of formula (XIX) may be prepared by reacting a corresponding compound of formula (XXII) as defined above with a compound of formula (III) as defined above.

Compounds of formula XIX wherein X is C 2 alkylene and R ⁴ and R ⁵ together form an oxo group can be prepared by reacting the corresponding compound of formula XXII as defined above with a compound of formula IV as defined above, for example as previously described for the preparation of compounds of formula I (preparation step (b)).

Compounds of formula XIX wherein A is CH ₂ and R ⁴ is hydroxy or -N (H) R ² may be prepared by reacting the corresponding compound of formula XXII as defined above with a compound of formula

V as defined above, for example as previously described for the preparation of compounds of formula I (preparation step (d)).

Compounds of formula (XIX) wherein R ^3a and R ^{3b are} both hydrogen may alternatively be prepared by reduction of the corresponding compound of formula (XXXVII).

wherein R ¹ and R ⁴¹ to R ⁴⁶ are as defined above, and wherein the group C = O can be activated using a suitable reagent such as tosylhydrazine, for example as described above for the preparation of compounds of formula I (preparation step (i)).

Compounds of formula II and XIX, wherein one of R *, R ⁴² , R ⁴⁵ and / or R ⁴⁶ is C 1 -C 3 alkyl, may alternatively be prepared by reacting a compound of formula II or XIX (as appropriate) wherein R ⁴¹ , R ⁴² , R ⁴⁵ and / or R ⁴⁶ (as appropriate) represent a hydrogen atom with a suitable alkylating agent (e.g. dimethylsulfate), for example in the presence of a suitable strong base (e.g. sec-butyllithium), N, N , N ', N'-tetramethylenediamine and a reaction-inert solvent (e.g. tetrahydrofuran).

Compounds of formula XX wherein R ² is -C (= N-CN) N (R ²⁵ ) R ²⁶ and L ⁵ is phenoxy may be prepared by reaction of the corresponding compound of formula XXXVIII

HN (R ²⁵ ) R ²⁶ (XXXVIII) wherein R and R are as previously defined, with diphenylcyanocarbonimidoate, for example at a temperature between -10 ° C and room temperature, in the presence of a suitable solvent (for example isopropanol).

Compounds of formula XXII are known from the literature or are readily prepared using known procedures. For example, compounds of formula XXII wherein R ^3a and R ^3b 'together represent an alkylene group having 3 to 5 carbon atoms, -O-Z-O-, -OZS- or -SZS-, and all R ⁴¹ to R ⁴⁶ are an atom hydrogen, may be prepared by reduction of a compound of formula XXXIX

(XXXIX) from wherein R and R together are C 3 -C 5 alkylene, -OZO-, -OZS- or -SZS-, where Z has already been defined, in the presence of a suitable reducing agent (e.g. lithium aluminum hydride), using the conditions which are well known to those skilled in the art.

Compounds of formula XXIX wherein B is C 1 -C 4 alkylene may be prepared by condensation of a compound of formula XL

R ⁵ R ⁴

Hal-M

B ^b -

(XL) wherein B ^b represents a C 1 -C 4 alkylene group and Hal, A ^b , R ⁴ and R ⁵ have already been defined, with a compound of formula XXX as defined above, for example at a temperature between

-25 ° C and room temperature, in the presence of a suitable zinc salt (e.g. anhydrous zinc bromide), a suitable catalyst (e.g. Pd (PPh ₃ ) ₄ ) and a solvent inert to the reaction (e.g. tetrahydrofuran, toluene or diethyl ether).

Compounds of formula VI, XXIII and XXXVII (wherein in all cases R ⁴¹ and R ⁴² both represent hydrogen) may be conveniently prepared by reaction (as appropriate) of either (i) compounds of formula XLI

(XLI) wherein R ² represents a C 1 -C 10 alkyl group or a C 1 -C 3 alkylaryl group (for example an alkylphenyl group such as a benzyl group) and R ⁴³ -R ⁴⁶ have already been defined, or (ii ) 4-piperidone (or a protected derivative thereof), either (as appropriate) (1) with a compound of formula XLII

R ⁶ -BC (R ⁴ ) (R ⁵ ) -ANH ₂ (XLII) wherein R ⁴ R ⁵ , R ⁶ , A and B have already been defined, or (2) With ammonia or a protected (e.g. benzyl) derivative thereof, in all cases in the presence of formaldehyde (ie a suitable formaldehyde source, such as paraformaldehyde or formalin solution), and in the case of compounds of formulas VI and XXIII, by converting the -C (O) OR ^{Z group} in the resulting intermediate to R ^{(i) 2} ; employ techniques such as those described herein (for example, by removing the -C (O) OR ^{Z group} and subsequent coupling, for example, according to the preparation step (x)).

The formation of compounds of formulas VI, XXIII and XXXVII can be carried out in this process, for example at a temperature between room temperature and boiling point (depending on the concentration of the reactants) in the presence of a suitable solvent (e.g. ethanol or methanol) and preferably in the presence of an organic acid (e.g. carboxylic acid having 1 to 6 carbon atoms, in particular acetic acid).

It will be appreciated by those skilled in the art that compounds of formula XXII wherein R ^3a and R ^{3b are} both hydrogen may also be prepared by this method (ie, by reacting 4-piperidone (or a protected derivative thereof) with ammonia (or a protected derivative thereof) in the presence formaldehyde), provided that the thus formed intermediate is subsequently reduced under suitable reaction conditions.

It will also be appreciated by those skilled in the art that this process may also be used to prepare compounds of formula I wherein R ⁴³ and R ⁴⁶ are hydrogen and R ⁴¹ and / or R ⁴² are other than hydrogen, for example:

(i) reacting a compound of formula XLI wherein R ⁴⁵ and / or R ⁴⁶ is / are other than hydrogen, for example, with benzylamine or a derivative thereof;

(ii) removing the -C (O) OR ^{Z group} ;

(iii) reacting the free bispidine nitrogen atom of the resulting compound with a compound of formula III, IV or V (as appropriate) as defined above;

(iv) removing the benzyl protecting group; and (v) reacting the free bispidine nitrogen atom of the resulting compound with a compound of formula XX as described above using conditions well known to those skilled in the art, including those already described. This reaction will be accompanied at the same site by the conversion of the terminal bridged carbonyl functionality to the desired R ^3a / R ^3b groups.

Compounds of formula XXXIX may be prepared according to procedures well known to those skilled in the art. For example, compounds of formula XXXIX, wherein R ^c and R ^d together form an alkylene group of 3 to 5 carbon atoms, can be prepared by reacting a compound of formula XLIII

wherein R ® and R ^f together represent an alkylene group having 3 to 5 carbon atoms, with a mixture of phosphoric acid and sulfuric acid, for example at 120 ° C.

Compounds of formula XLII are well known in the literature or are readily obtained using known methods. For example, compounds of formula XLII wherein R ⁴ is hydroxy, R ⁵ is hydrogen and A is CH ₂ may be prepared by reacting the corresponding compound of formula V, where R ⁵ is hydrogen and X is oxygen, with ammonium hydroxide, using conditions well known to those skilled in the art.

Compounds of formulas IV, VIII, X, XII, XIV, XV, XVI, XVIII, XX (wherein R ² is other than -C (= N-CN) N (R ²⁵ ) R ²⁶ and / or L ⁵ is other group other than phenoxy), XXA, XXI, XXIV, XXV, XXVI, XXVII, XXVIII, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVIII, XL, XLI, XLIII. and their derivatives are either commercially available, known from the literature, or can be prepared either analogously to the procedures described herein, or by conventional synthesis procedures according to standard techniques from readily available starting materials using appropriate reagents and reaction conditions.

The substituents on the aryl group (e.g., the phenyl group) and (if appropriate) the heterocyclic group in the compounds defined herein can be converted to other claimed substituents using techniques known to those skilled in the art. For example, a hydroxy group can be converted to an alkoxy group, a phenyl group can be halogenated to form a halophenyl group, a nitro group can be reduced to form an amino group, an amino group can be acylated to form an acetylamino group, and the like.

It will be appreciated by those skilled in the art that the interconversions of various standard substituents or functional groups in certain compounds of Formula I will provide additional compounds of Formula I. For example, a carbonyl group may be reduced to a hydroxy or alkylene group, the hydroxy group may be acylated to give an alkylcarbonyloxy group. the nitro group may be reduced to an amino group, the amide group may be reduced to an amino group, the amino group may be sulfonated or acylated to give a sulfonylamino or acylamino group, and certain acyclic groups may be converted to certain heterocyclic groups using conditions known to those skilled in the art as described in Comprehensive Heterocyclic Chemistry II, AR Katritzky, CW Rees and EEV Scriven eds., l ^st Ed., Elsevier Science Ltd., Vol. 1-11 (1996).

The compounds of the invention can be isolated from their reaction mixtures using conventional procedures.

It will be apparent to those skilled in the art that in the methods described, functional groups may or must be protected by protecting groups.

Functional groups that are desirable to protect include hydroxy, amino and carboxy. Suitable hydroxy protecting groups include trialkylsilyl and diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl groups, and alkylcarbonyl groups (e.g. methyl and ethylcarbonyl groups). Suitable amino protecting groups include benzyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for amidino and guanidino include benzyloxycarbonyl. Suitable protecting groups for carboxy include C 1 -C 6 alkyl or benzyl.

The introduction or removal of the protecting groups may take place before or after any of the steps described herein.

Protecting groups can be removed by procedures known to those skilled in the art and described in the next section of the present invention.

The use of protecting groups is described in detail in "Protective Groups in Organic Chemistry, JWF Mc Omie Ed., Plenum Press (1973) and in" Protective Groups in Organic Synthesis ", 3 ^rd Ed., TW Greene and PGM Wuts Eds., Wiley-Interscience. (1999).

It will be appreciated by those skilled in the art that, in order to obtain the compounds of the present invention in an alternative or in some cases more advantageous manner, the individual steps of the method described in the present invention may be performed in a different order and / or individual reactions may be performed at different stages of the overall synthesis (ie substituents). may be added and / or chemical transformations may be performed on different intermediates than those reported in the reaction).

This will depend, inter alia, on factors such as the nature of the other functional groups present in a particular substrate, the availability of major intermediates, and the strategy of using protecting groups. The nature of the chemistry will influence the choice of reagents used in each synthetic step, the need and type of protecting groups used, as well as the order of steps to achieve the synthesis.

It will also be appreciated by those skilled in the art that although certain protected derivatives of the compounds of Formula I do not possess pharmacological activity prior to the final deprotection, they may be metabolized in the body after parenteral or oral administration to produce compounds of the present invention that are pharmacologically active. Such derivatives may be referred to as "prodrugs." In addition, it has been found that certain compounds of formula I may act as precursors to other compounds of formula I.

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

Some of the intermediates mentioned herein are new. Thus, in a further aspect, the invention provides:

(a) a compound of formula (II) as defined above, or a protected derivative thereof;

b) a compound of formula VI as defined above, or a protected derivative thereof;

c) a compound of formula VII as defined above, or a protected derivative thereof;

d) a compound of formula IX as defined above or a protected derivative thereof;

e) a compound of formula XI as defined above, or a protected derivative thereof;

f) a compound of formula (XIII) as defined above, or a protected derivative thereof;

g) a compound of formula (XVII) as defined above, or a protected derivative thereof;

(h) a compound of formula (XIX) as defined above, provided that at least one of R ^3a and R ^3b is -N (R ³⁹ ) R ^38c wherein R ³⁹ is a structural fraction of formula Ia as defined above) or a protected derivative thereof;

(i) a compound of formula XXII as defined above, provided that at least one of R ^3a and R ^3b is -N (R ³⁹ ) R ^38c , where R ³⁹ is a structural fraction of formula Ia as defined above) or a protected derivative thereof;

j) a compound of formula XXIII as defined above, or a protected derivative thereof.

Compounds of formula (II) which may be mentioned herein include those where:

when R ^3a and R ^{3b are} independently hydrogen, C 1 -C 4 alkyl, hydroxy or -N (R ³⁹ ) R ^38c ; and

R ³⁹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;

then R ² does not represent:

(i) cyano;

(ii) C 1 -C 6 alkyl optionally substituted by hydroxy, -N (R ³⁰ ) R ³¹ or Het ⁹ ; wherein R ³⁰ and R ³¹ independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms; and

Het ⁹ represents an unsubstituted saturated three- to eight-membered heteroaryl containing one nitrogen atom (through which the heterocyclic group atom binds to the rest of the molecule);

(iii) a n-alkyl group having 1 to 6 carbon atoms, wherein the alkyl group is optionally interrupted by an oxygen atom and is terminated by a group -N (R ³⁰ ) R ³¹ or -OR ³² ; wherein one of R ³⁰ and R ³¹ represents a hydrogen atom or a phenyl group substituted in the meta- or para-position (with respect to the point of attachment) by a carboxy or amino group, and the other represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; Yes

R represents a hydrogen atom or a phenyl group substituted in the meta-position (with respect to the point of attachment) by a carboxy or amino group;

(iv) -C (O) R ¹⁶ , wherein R ¹⁶ represents a hydrogen atom or a phenyl group substituted at the meta- or para-position (with respect to the point of attachment) by a carboxy or amino group;

(v) -S (O) ₂ R ²² , wherein R ²² represents a phenyl group substituted at the meta- or para-position (with respect to the point of attachment) by a carboxy or amino group;

(vi) -S (O) ₂ N (R ²³ ) R ²⁴ , wherein R ²³ represents a phenyl group substituted at the meta- or para-position (with respect to the point of attachment) by a carboxy or amino group; and

R ²⁴ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and (vii) a C 3 -C 4 n-alkyl group wherein the alkyl group is terminated by a phenyl group, wherein the phenyl group is substituted at the meta- or para-position (relative to the point of attachment) with a carboxy or amino group and wherein the alkyl group is interrupted. in the β-position (relative to the phenyl group's attachment point) by an oxygen atom.

Compounds of formulas II, IX and XI which may be mentioned herein include those where:

when R ^3a and R ^3b independently represent hydrogen, C 1 -C 4 alkyl, hydroxy or -N (R ³⁹ ) R ³⁸ 5;

R ³⁹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and

R ⁴ and R ^{5 are} both hydrogen;

then ^R2 does not represent a cyano group, -C (O) ^R16, -S (O) ₂ R ^22,

-S (O) ₂ N (R ²³ ) R ²⁴ or an alkyl group optionally substituted as defined above with respect to R ² .

Other compounds of formulas II, IX and XI that may be mentioned include those where:

R ² represents Het ^8, -C (O) ^R16, -C (S) OR ^17, -C (S) N (R ¹⁸⁾ R ^19, - [C (0)] 2 N (R ^20a) R ^20b, - [C (O)] 2 OR ²¹ , -S (O) 2 R ²² , -S (O) 2 N (R ²³ ) R ²⁴ ,

-C (= N-CN) N (R ²⁵ ) R ²⁶ , -C (= N-CN) OR ²⁷ or an alkyl group having 1 to 12 carbon atoms (wherein the alkyl group is optionally substituted and / or terminated by one or more substituents selected from -C (O) R ²⁸ , -C (O) N (R ^29a ) R ^29b , -N (R ³⁰ ) R ³¹ , -OR ³² ,

S (O) _r R ^33, halogen, cyano and nitro);

R ¹⁶ is Het ¹⁰ or C 1 -C 6 alkyl (wherein the alkyl is optionally substituted and / or terminated with one or more substituents selected from halogen, hydroxy, cyano, -N (R ³⁴ ) R ³⁵ , aryl and Het groups ¹¹ );

R ²² is Het ¹⁴ or C 1 -C 6 alkyl (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from halogen, hydroxy, cyano, Het ¹⁵ and aryl);

R ²³ is hydrogen, C 1 -C 6 alkyl, Het ¹⁶ , -C (O) R ^36a , -C (O) OR ^36b, or -C (O) SR ^36b ;

R ³⁰ is Het ¹⁹ , -C (O) R ^37a , -C (O) OR ^37b, or -C (O) N (R ^37c ) R ^37d ;

R ³² represents an alkyl group having 1 to 6 carbon atoms, Het ²¹ , -C (O) R ^37a , -C (O) OR ^37b or -C (O) N (R ^37c ) R ^37d .

Medical and pharmaceutical use

The compounds of the present invention are useful because they have pharmacological activity. They are therefore referred to as pharmaceuticals.

Thus, in a further aspect, compounds of the invention are provided for use as medicaments.

In particular, the compounds of the present invention have myocardial electrophysiological activity, as shown, for example, in the assay described in the next section of the present invention.

The compounds of the present invention are expected to be useful in both the prevention and treatment of arrhythmias, particularly atrial and ventricular arrhythmias.

The compounds of the present invention are used in the treatment or prevention of heart disease, or in indications related to heart disease where arrhythmias are believed to play an important role, such as ischemic heart disease, sudden cardiac attack, myocardial infarction, heart failure, in cardiac disease. surgery and thromboembolic events.

It has been found that the compounds of the present invention selectively retard cardiac repolarization in the treatment of arrhythmias and thus prolong the QT interval, and are particularly characterized by class III activity. Although it has been found that the compounds of the invention are particularly characterized by class III activity in the treatment of arrhythmias, their modes of action are not necessarily limited to this class.

The invention further provides a method of treating an arrhythmia, the method comprising administering a therapeutically effective amount of a compound of the present invention to a person suffering from or susceptible to such medical conditions.

Pharmaceutical preparations i

The compounds of the present invention will normally be administered orally, subcutaneously, intravenously, intraarterially, transdermally, intranasally, by inhalation or by any other parenteral route in the form of pharmaceutical preparations containing the active ingredient either as a free phase, a pharmaceutically acceptable ion exchanger or a non-toxic organic or inorganic acid in a pharmaceutically acceptable dosage form. The compositions may be administered at various dosages, depending on the type of disease, the subject, and the route of administration.

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

In another aspect, the present invention provides pharmaceutical formulations comprising a compound of the present invention in admixture with a pharmaceutically acceptable vehicle, diluent or carrier. Suitable daily dosages of the compounds of the present invention are from about 0.005 to 10.0 mg / kg body weight on oral administration and from about 0.005 mg / kg body weight on parenteral administration:

The compounds of the present invention are effective in the treatment of cardiac arrhythmias.

The compounds of the present invention may also have the advantage over the compounds already known that they may be more effective, less toxic, have a broader range of activity (including characterized by a combination of class I, class II, class III and / or class IV activities I and / or Class IV in addition to Class III activity) may be stronger, may exhibit longer exposure times, cause fewer side effects (including lower proarrhythmia effects such as torsades de pointes), may be more easily absorbed, or may have other useful pharmacological properties.

Biological tests

Test A

Primary electrophysiological effects on guinea pigs under anesthesia

The experiments were carried out on guinea pigs weighing 660 to 1100 g. These animals were acclimatized for at least one week prior to the start of the experiment, with free access to food and running water.

Anesthesia was induced by intraperitoneal injection of pentobarbital (40-50 mg / kg body weight) and catheters were inserted into one carotid artery (for blood pressure measurement and blood sampling) and one jugular vein (for drug infusion). Needle electrodes were placed on the limbs to record electrocardiograms (set II). A thermistor was inserted into the rectum and the animal was placed on a heated pad, which was set to a rectal temperature between 37.5 and 38.5 ° C.

A tracheotomy was performed and the animal was artificially ventilated by ambient air through a small animal fan that was adjusted to maintain blood gas levels within the normal range that corresponds to the animal species. Fifteen minutes before the start of the experiment, both cranial nerves were cut through the neck to reduce autonomous effects and 0.5 mg / kg of propranolol was administered intravenously to the animal.

The left ventricular epicardium was exposed to left-sided thoracotomy and the prepared aspiration electrode for recording the monophasic action potential (MAP) was applied to the left ventricular free wall. The electrode was held in a certain position until it could sense an acceptable signal, otherwise it moved to a new position. The bipolar pacing electrode was attached to the left atrium. Stimulation (duration of 2 ms, twice the diastolic threshold) was performed with a prepared constant current stimulator. The heart was stimulated to a frequency slightly above the normal sinus frequency for 1 minute during every five minutes during the experiment.

Blood pressure, MAP signal and ECG file II were recorded on a Mingograph ink recorder (Siemens-Eiema, Sweden). All signals were collected (1000 Hz sampling frequency) into the PC during the last 10 seconds of each stimulation sequence and the last 10 seconds after a minute of sinus rhythm. The signals were processed using a program developed to obtain and analyze physiological signals measured for experimental animals (see Axenborg and Hirsch, Comput. Methods Programs Biomed. 41, 55 (1993)).

The test procedure consisted of measurements of two baseline control records after 5 minutes and measurements of both stimulation and sinus rhythm. After the second control record, a first dose of 0.2 ml of test substance was administered to the jugular vein over a 30-second period. After three minutes pacing was started and a new record was measured. Five minutes after the last dose, was the next dose of test substance administered? During each experiment, 6 to 10 consecutive doses were administered to the animal.

Data analysis

Of the many variables found in these assays, three were selected as the most important for comparison and selection of active compounds. The three selected variables were the duration of MAP at 75% repolarization during pacing, atrioventricular (AV) conduction time (defined as the interval between atrial pacing pulse and the onset of ventricular MAP during pacing), and heart rate (defined as RR interval during sinus rhythm). Systolic and diastolic blood pressure were measured to assess hemodynamic conditions of the animals after anesthesia. Further, the ECG was checked for arrhythmic and / or morphological changes.

The mean of the two control measurements was chosen to be zero, and the effect recorded after sequential dosing of the test compound was expressed as a percentage of change relative to this value. By plotting these percentages against the cumulative dose administered before each record, dose response curves could be generated. In this way, three dose-response curves were generated for each experiment. One for MAP duration, one for AV-conduction time and one for sinusoidal frequency (RR interval). The mean curve for all experiments performed with the test substance was recalculated and the efficacy values were derived from this mean curve. All dose response curves in these experiments were constructed as a linear connection of the data points obtained. A cumulative dose extending the duration of MAP by 10% from baseline was used as an index to achieve the electrophysiological efficacy of Class III of the agent of interest (Di ₀ ).

Test B

Glucocorticoid-treated mouse fibroblasts as a model for the determination of delayed current K blockers

The IC ₅₀ value for channel K blocking was determined using a microtiter plate monitoring method based on changes in the membrane potential of glucocorticoid-treated mouse fibroblasts. The membrane potential of glucocorticoid-treated mouse fibroblasts was measured using the fluorescence of the bisoxonol dye DiBac4 (3j, which can be reliably detected using a laser imaging plate fluorescence reader (FLIPR). Blocking these channels depolarized fibroblasts, resulting in increased diBac ₄ fluorescence ₍₃₎ .

Mouse LTK fibroblasts (L-cells) were purchased from American Type Culture C.ollection (ATCC, Manassa, VA) and cultured in Dulbecco's medium supplemented with fetal calf serum (5% v / v), penicillin (500 units / ml), streptomycin (500 µg / ml and L-alanine-L-glutamine (0.862 mg / ml)) The cells were passaged every 3-4 days using trypsin (0.5 mg / ml in calcium-free phosphate buffered saline, Gibco BRL). Three days before the experiment, the cell suspension was pipetted onto a 96-well black bottom plastic plate (Costar) at a concentration of 25,000 cells / well.

A fluorescent probe DiBac _{4 (} 3) (molecular probe DiBac) was used to measure the membrane potential. DiBac _{4 (3)} maximally absorbs at 488 nm and emits at 513 nm. DiBac _{4 (3)} is bisoxonol and negatively charged at pH 7. Due to this negative charge, the distribution of DiBac _{4 (3)} across the membrane depends on the transmembrane potential: if the cell depolarizes (ie the inner part of the cell becomes less negative towards the outer part) , the concentration of DiBac _{4 (3)} within the cell increases due to electrostatic forces. Once in the cell, DiBac ₄ (3) molecules can bind to lipids and proteins, resulting in increased fluorescence emission. Thus, depolarization is imaged by increasing the fluorescence of DiBac _{4 (3)} . The change in fluorescence of DiBac _{4 (} 3) was detected by FLIPR.

Prior to each experiment, cells were washed four times in phosphate buffered saline (PBS) to remove the culture medium. Cells were then treated at room temperature with 5 μΜ DiBac _{4 (3} ) (in 180 μΐ PBS). Once stable fluorescence was reached (usually after 10 minutes), 20 μΐ of test substance was added using a 96-well pipetting system built into the FLIPR.

Fluorescence measurements were taken every 20 seconds for an additional 10 minutes. All experiments were performed at 35 ° C due to the high sensitivity of the delayed rectification of the conductivity of the potassium channel and the fluorescence of DiBac _{4 (} 3). The substances were prepared in a second 96-well plate in PBS containing 5 μΜ DiBAc4 (3 ₎ . _{and the} concentration of substance prepared was ten times higher than the desired concentration in the experiment as it occurs during the addition of further substances dilution 1: 10, as a positive _control; dofetilide (10 μΜ) was used to determine the maximum increase in fluorescence.

Plots of curves used to determine IC 50 values were performed using Graphpad Prism (Graphpad Software, Inc., San Diego, CA).

Test C

Metabolic stability of test compounds

The metabolic stability of the compounds of the invention was determined by in vitro assays.

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

The reaction was initiated by the addition of the test compound and terminated after 0, 1, 5, 15 and 30 minutes by increasing the pH of the sample to 10 (NaOH; 1 mM). After solvent extraction, the concentration of test compounds was measured against an internal LC standard (fluorescence / UV detection).

Percentages of test compound remaining after 30 minutes (thus, t 1/2 was calculated and used to determine metabolic activity).

The present invention is illustrated by the following examples. These examples are illustrative only and in no way limit the scope of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 tert-Butyl 2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] trans-3-yl} ethylcarbamate (i) tert-Butyl-2 -brómetylkarbamát

A mixture of 2-bromoethylamine hydrobromide (10.0 g, 0.049 mol), NaOH (1.84 g, 0.046 mol), water (50 mL) and THF (200 mL) was cooled to 0 ° C. Di-tert-butyl dicarbonate (10.1 g, 0.046 mol) was added slowly and the mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo and the residue was dissolved in DCM. This organic solution was washed with water and purified by chromatography on silica eluting with DCM to give 5.6 g (50%) of the title compound.

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

EtOAc saturated with HCl (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 PCT / SE 98/02276) in EtOAc (600 mL) and the mixture was stirred at room temperature for 4 hours. Remove the solvent under reduced pressure, dissolve the residue in MeCN (1.3 L) and add K ₂ CO ₃ (100 g). The suspension was stirred for 12 hours and filtered. Concentration of the filtrate affords the title compound in 96% 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.

(iii) tert-Butyl 2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] non-3-yl} ethylcarbamate t

4- [3- (3,7-Diazabicyclo [3.3.1] trans-3-yl) -2-hydroxypropoxy] -benzonitrile (see step (ii); 7.7 g, 25.6 mmol) and tert-butyl The 2-bromomethylcarbamate (see step (i); 5.7 g, 2.56 mmol) and K 2 CO 3 (3.5 g, 2.56 mmol) were combined in CH 3 CN (50 mL) and stirred at 60 ° C for 60 hours. The reaction mixture was filtered and evaporated. The residue was purified using column chromatography (DCM: 10 to 20% MeOH saturated with NH ₃ (g)) to give 8 g (71%) of the title compound.

¹³ C-NMR (CDCl 3): δ 28.4, 29.6, 30.3, 32.0, 36.9, 54.8, 58.4,

58.6, 59.5, 64.8, 71.1, 78.8, 104.1, 115.3, 119, 2, 133.9,

156.4, 162.2;

FAB-MS (M + 1) &lt; ^{+ &gt}; = 445 (m / z).

Example 2

4- {3- [7- (3,3-dimethyl-2-oxobutyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -2-hydroxypropoxy} benzonitrile

4- [3- (3,7-Diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropoxy] -benzonitrile (see Example 1 (ii); 0.6 g, 2.0 mmol), 1- chlorpinacolone (0.27 g, 2.0 mmol) and K 2 CO 3 (0.27 g, 20 mmol) were combined in CH ₃ CN and the mixture was stirred at 60 ° C for 1 hour and then at room temperature overnight. The reaction mixture was filtered and evaporated to give 0.7 g (90%) of the title compound.

¹³ C-NMR (CDCl 3): δ 26.2, 30.0, 30.6, 31.9, 43.5, 55.1, 57.3,

57.6, 59.2, 59.8, 61.7, 64.8, 71.1, 103.9, 115, 3, 119.2,

133.9, 162.3, 212.2;

FAB-MS (M + 1) &lt; ^{+ &gt}; = 400 (m / z).

Example 3

4- {3- [7- (2-Ety1-2H-1,2,3,4-tetrazol-5-yl) -3,7-diazabicyclo [3.3.1] non-3-y1] -2- hydroxypropoxy] benzonitrile (i) 3,7-Dibenzyl-3,7-diazabicyclo [3.3.1] nonan-9-one

The sub-title compound was prepared according to the procedure described in J. Org. Chem., 41 (9), 1593-1597 (1976).

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

The sub-title compound was prepared according to the procedure described in J. Org. Chem., 41 (9), 1593-1597 (1976) using 3,7-dibenzyl-3,7-diazabicyclo [3.3.1] nonan-9-one (see step (i)) instead of N-benzyl N 'methylbispidone.

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

A solution of 3,7-dibenzyl-3,7-diazabicyclo [3.3.1] nonane (see step (ii); 97 g, 6.4 mmol) in aqueous ethanol (95%) is hydrogenated to 5% Pd / C at 0.101 MPa until TLC indicated complete reaction. The catalyst was removed by filtration through a pad of Celite® and the filtrate was concentrated under reduced pressure to give the sub-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.

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

3-Benzyl-3,7-diazabicyclo [3.3.1] nonane (see step (iii); 20 g, 92 mmol) was dissolved in ether (120 mL). Cyanogen bromide (9.8 g, 92 mmol) dissolved in ether (80 mL) was then added dropwise at room temperature. The mixture was stirred at 0 ° C for 15 minutes and then overnight at room temperature to give a white precipitate. The ether was evaporated. Add water and saturated aqueous Na 2 CO 3. The mixture was extracted with ether. The ether layer was separated and dried (MgSO 4) to give 20.3 g (91%) of the sub-title compound.

(v) 3-Benzyl-7- (2H-1,2,3,4-tetrazol-5-yl) -3,7-diazabicyclo [3.3.1] nonane, ammonium salt

A mixture of 3-benzyl-7-cyano-3,7-diazabicyclo [3.3.1] nonane (see step (iv); 10.2 g, 42 mmol), NaN ₃ (2.92 g, 45 mmol), NH ₄ Cl (2.41 g, 45 mmol) and DMF (50 mL) were stirred at 100 ° C for 22 h. The DMF was evaporated, toluene was added and evaporated to give 12 g of an orange-colored powder. The product was purified by reverse phase preparative HPLC to give 5.8 g (46%) of the sub-title compound.

(vi) 3-Benzyl-7- (2-ethyl-2H-1,2,3,4-tetrazol-5-yl) -3,7-diazabicyclo [3.3.1] nonane

3-Benzyl-7- (2H-1,2,3,4-tetrazol-5-yl) -3,7-diazabicyclo [3.3.1] nonane ammonium salt (see also step (v); 4 g) , mmol), ethyl iodide (2.20 mL, 26 mmol) and NaOH (0.62 g, 15.6 mmol) were heated at reflux for 2 hours. The solvent was evaporated and the residue was purified by flash chromatography (hexane / ethyl acetate 1: 1, MeOH (NH ₃ ) 0 to 32%) to give 1.5 g (37%) of the sub-title compound.

(vii) 3- (2-Ethyl-2H-1,2,3,4-tetrazol-5-yl) -3,7-diazabicyclo [3.3.1] nonane

3-Benzyl-7- (2-ethyl-2H-1,2,3,4-tetrazol-5-yl) -3,7-diazabicyclo [3. 3 .1] nonane (see step (vi); 0.5 g, 1.6 mmol) dissolved in ethanol (5 mL, 95%) was hydrogenated overnight at 5% Pd / C at 100 psi. The catalyst was filtered off through Celite® and the residue was evaporated to give 0.2 g (56%) of the sub-title compound.

(viii) 4- {3- [7- (2-Ethyl-2H-1,2,3,4-tetrazol-5-yl) -3,7-diazabicyclo [3.3.1] non-3-yl] - 2-hydroxy-propoxy} benzonitrile

I

4- (2-oxiranylmethoxy) benzonitrile (see International Patent Application WO 99/31100; 0.18 g, 1 mmol ·) and 3- (2-ethyl-2H-1,2,3,4-tetrazol-5-yl) ) -3,7-diazabicyclo [3.3.1] nonane (see step (vii); 0.9 g, 0.9 mmol) is mixed in a mixture of isopropanol and water (1.1 mL, 10: 1) and the mixture Stir at 60 ° C overnight. The solvent was evaporated and the residue was purified by chromatography (hexane / ethyl acetate (1: 1), MeOH (NH ₃ ) 0 to 32%) to give 0.28 g (77%) of the title compound.

¹³ C-NMR (CD ₃ CN): δ 14.4, 29.7, 30.0, 31.2, 48.6, 51.2, 51.3,

58.6, 60.8, 61.0, 66.3, 71.9, 104.3, 116.2, 118.2, 119.9,

134.9, 163.3, 170.1.

Example 4

4- {2-Hydroxy-3- [7- (1,3-thiazol-2-yl) -3,7-diazabicyclo [3.3.1] -ηοη-3-yl] propoxy} benzonitrile

4- [3- (3,7-Diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropoxy] -benzonitrile (see Example 1 (ii); 1 g, 3.3 mmol), 2-bromothiazole ( 0.54 g, 3.3 mmol) and K ₂ SO ₃ (0.91 g, 6.5 mmol) were combined in DMF (15 mL). The mixture was stirred overnight at 60 ° C.

The solvent was evaporated, toluene was added and evaporated again. The residue was dissolved in ethyl acetate and washed with NaOH solution (2 M). The organic layer was separated and dried (Na ₂ SO ₄ ). The residue was purified by chromatography (hexane / ethyl acetate (1: 1)). Yield: 0.57 g (45%).

¹³ C-NMR (CDCl ₃ ): δ 29.1, 29.4, 30.5, 52.8, 53.0, 57.9, 60.7,

65.3, 70.4, 104.1, 105.6, 115.3, 119.2, 133.9, 139.7, 162.0,

171.2.

Example 5

N'-Cyano-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N- (3,4,5-trimethoxybenzyl) -3,7-diazabicyclo [3.3.1] nonane-3-carboximidamide (i) ) Phenyl-N'-cyano-N- (3,4,5-trimethoxybenzyl) carbamimidoate

3,4,5-Trimethoxybenzylamine (1.08 mL, 6.3 mmol) was dissolved in isopropanol (10 mL). The mixture was cooled to 0 ° C and diphenylcyanocarbonimidoate (1.5 g, 6.3 mmol) was added portionwise. The reaction mixture was allowed to warm to room temperature and then stirred at room temperature overnight. The precipitate thus formed is filtered off and then purified by chromatography (DCM / MeOH, gradient 100: 0 to 99: 1). Yield: 1.37 g (63.5%).

(ii) N'-Cyano-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N- (3,4,5-trimethoxybenzyl) -3,7-diazabicyclo [3.3.1] nonane-3- carboximidamide

4- [3- (3,7-Diazabicyclo [3.3.1] trans-3-yl) -2-hydroxypropoxy] benzonitrile (see Example 1 (ii); 1 g, 3.3 mmol) and phenyl-N'- cyano-N- (3,4,5-trimethoxybenzyl) carbamimidoate (see step (i); 1.13 g, 3.3 mmol) was treated with isopropanol (15 mL) and then stirred at reflux for 3 hours. The mixture was cooled to room temperature and the resulting product was filtered off. The product was purified by chromatography (DCM / MeOH, 0 to 1% gradient) to give 1.67 g (92%) of the title compound.

¹³ c-nmr (CDC1 ₃ ): δ 29.0, 29.3, 31.2, 47, 9, 50.9, 51.3, 56.1. 57.1, 60.0. 60.7 , 61.3, 65.6, 70.6, 103.9, 105.1, 115.2. 118.3. 119.1, 133 2, 133.9, 137.4, 153.3, 160.2, 161.9, 176.3. 176.4.

Example 6

4- {3-Amino-4- [7- (butylsulfonyl) -3,7-diazabicyclo [3.3.1] non-3-yl] butoxy} benzonitrile (i) 4- (3-Butenyloxy) benzonitrile

4-cyanophenyl (30 g, 250 mmol) mixes with K ₂ CO ₃ (72.5 g, 525 mmol) and mixture is stirred for 60 minutes minutes. Then was added After drops 4-bromo-l · butane (50 g, 370 mmol) a reaction mixture the Stir at temperature 60 ° C through night. Solid is filtered off and

the solvent was evaporated. The residue was dissolved in DCM and washed with 1 N NaOH. The organic layer was separated, dried (Na ₂ SO ₄ ) and evaporated to give 37 g (58%) of the sub-title compound.

(ii) 4- [2- (2-Oxiranyl) ethoxy] benzonitrile

4- (3-Butenyloxy) benzonitrile (see step (i); 37 g,

0.21 mol) was treated with m-CPBA (61.6 g, 0.25 mol) and DCM (700 ml) and stirred at room temperature for 4 hours. The reaction mixture was filtered and 2 mL of DMSO was added to quench excess m-CPBA. The mixture was washed with NaHCO ₃ , then separated, dried and evaporated to give 38.7 g (97%) of the sub-title compound.

(iii) 4- (4-Amino-3-hydroxybutoxy) benzonitrile

4- [2- (2-Oxiranyl) ethoxy] benzonitrile (see step (ii); 38.5 g, 204 mmol) was treated with aqueous NH ₃ (1200 mL, conc.) And isopropanol (450 mL). The mixture was stirred at room temperature for 24 hours. The solid (by-product) was filtered off and the solvent was evaporated, yielding 39.1 g (93%) of the sub-title compound.

(iv) tert-Butyl 4- (4-cyanophenoxy) -2-hydroxybutylcarbamate

4- (4-Amino-3-hydroxybutoxy) benzonitrile (see step (iii); 34.3 g, 166 mmol) was dissolved in THF / H ₂ O (600 mL,

ΊΟ

8: 2). Di-tert-butyl dicarbonate (36.3 g, 166 mmol) was added at 0 ° C. The mixture was then stirred at room temperature overnight and then evaporated to give 50 g (100%) of the sub-title compound (which was used in the next step without further purification).

(v) 1 - {[(tert-Butoxycarbonyl) amino] methyl} -3- (4-cyanophenoxy) propyl methanesulfonate tert-Butyl 4- (4-cyanophenoxy) -2-hydroxybutylcarbamate (see step (iv); 38.1 g, 120 mmol) and 4- (dimethylamino) pyridine (10 mol%) were dissolved in pyridine (200 mL). The mixture was cooled to 0 ° C. Methanesulfonyl chloride (10.7 mL, 0.136 mol) was then added dropwise at 0 ° C. The mixture was then warmed to room temperature and the pyridine was evaporated. DCM was added and the solution was washed with 2M HCl and water and dried and evaporated. The compound was purified by silica chromatography eluting with DCM (5% ethyl acetate) to give 27 g of the sub-title compound.

(vi) tert-Butyl 2- [2- (4-cyanophenoxy) ethyl] -1-aziridinecarboxylate

1 - {[(tert-Butoxycarbonyl) amino] methyl} -3- (4-cyanophenoxy) propyl methanesulfonate (see step (v); 25.3 g, 0.066 mol) are mixed with tetrabutylammonium hydrogen sulfate (2.7 g, 7, 8 mmol) and DCM (170 mL) The mixture was cooled to 0 ° C and NaOH (50% aqueous solution) was added slowly, then warmed to room temperature and DCM was added The organic layer was separated, washed with water The residue was dried and evaporated to give the subtitle compound Yield: 19 g (99%) The product was used in the next step without further purification.

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

Butanesulfonyl chloride was added dropwise at 0 ° C to a mixture of 3-benzyl-3,7-diazabicyclo [3.3.1] nonane (see Example 3 (iii); 13 g, 60 mmol), K 2 CO 3 (8.3 g, 60 mmol) and MeCN (100 mL). The mixture was warmed to room temperature and then stirred overnight at room temperature. The reaction mixture was filtered through a pad of silica and then eluted with ethyl acetate to give 15 g (75%) of the sub-title compound.

(viii) 3- (Butylsulfonyl) -3,7-diazabicyclo [3.3.1] nonane

3-Benzyl-7- (butylsulfonyl) -3,7-diazabicyclo [3.3.1] nonane (see step (vii); 12.7 g, 38 mmol) was dissolved in ethanol (150 mL, 95%) and hydrogenated at 5% Pd / C at 0.101 MPa overnight. TLC analysis indicated that the reaction was not complete. The catalyst was filtered off and a new catalyst (5% Pd / C) was added along with water (10 mL) and acetic acid (2 mL). The mixture was then hydrogenated at 100 psi overnight. The catalyst was filtered off, 2 N NaOH was added and the mixture was extracted with toluene. Evaporation of toluene gave 8 g (85%) of the sub-title compound.

(ix) tert-Butyl 1 - {[7- (butylsulfonyl) -3,7-diazabicyclo [3.3.1] -η-3-yl] methyl} -3- (4-cyanophenoxy) propylcarbamate tert-Butyl-2 - [2- (4-cyanophenoxy) ethyl] -1-aziridinecarboxylate (see step (vi); 1 g, 3.5 mmol) is mixed with 3- (butylsulfonyl) -3,7-diazabicyclo [3.3.1.0 &lt; 2,7 &gt; 3. 1] nonane (see step (viii); 0.85 g, 3.5 mmol) in isopropanol (25 mL). The mixture was stirred at 60 ° C overnight. Evaporation and purification of the residue on silica (DCM, 2% MeOH) gave 1.5 g (81%) of the sub-title compound.

H-NMR (CDC1 ₃₎ δ 1.44 (3H, t), 1.91 (9H, s), 2.08 (2H, m), 2.1 (2H, m) 2.2 (2H, m), 2.4 (2H, br s), 2.6 (2H, m), 2.8 (2H, d), 2.9 (2H, dd), 3.3-3.6 (6H, m), 4.3 (3H, m), 4.6 (2H, m), 5.7 (1 H, br s) 7.4 (2H, dd), 8.0 (2H, dd).

(x) 4- {3-Amino-4- [7- (butylsulfonyl) -3,7-diazabicyclo [3.3.1] non-3-yl] butoxy] benzonitrile tert-Butyl-1 - {[7- (butylsulfonyl)] -3,7-diazabicyclo [3.3.1] 72

3-yl-methyl} -3- (4-cyanophenoxy) propylcarbamate (see step (ix); 0.9 g, 1.7 mmol) was dissolved in ethyl acetate (20 mL). Ethyl acetate saturated with HCl gas (50 mL) was then added at 0 ° C. The resulting mixture was allowed to reach room temperature over 2 hours. The solvent was evaporated, the residue was dissolved in water and the solution was freeze-dried. There was thus obtained the dihydrochloride salt of the title compound.

ES-MS (M + H) &lt; ^{+ &gt}; = 435 (m / z).

Example 7

The compounds listed in the next section of the present invention are prepared according to the procedures described herein or prepared as follows: An appropriate 3- or 7-unsubstituted bispidine (dissolved in CHCl 3) is reacted with 2 equivalents of a suitable electrophile (dissolved in CH ₃ CN) in presence of base (2.5 equivalents of K 2 CO 3). The reaction mixture is heated to 50-100 ° C. After completion of the reaction (as determined by mass spectral analysis), the inorganic salts are filtered off and the reaction mixture is added to an ion exchange extraction plug (CBA). The plug was washed with CHCl ₃ and the product was finally eluted with CHCl 3 / MeOH / Et ₃ N (8: 1: 1). The products were analyzed by HPLC and MS. Compounds of less than 90% purity are purified by preparative HPLC.

The mass spectra of the compounds are given in brackets:

4- (3- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] non-3-y1} -2-hydroxypropoxy) benzonitrile;

4- (3- (7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -9- (l, 2-ethylenedioxy) -3,7-diazabicyclo [3.3.1] ηοη-3-yl} -2 hydroxypropoxy) benzonitrile;

4- {3- [7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -9,9-bis (propyl 73 sulfanyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -2 hydroxypropoxy} benzonitrile;

3,7-bis (4-nitrophenethyl) -3,7-diazabicyclo [3.3.1] nonane;

4- (3- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -9,9-tetramethylene-3,7-diazabicyclo [3.3.1] trans-3-yl} -2-hydroxypropoxy) benzonitrile ;

4- {2- [7- (4-cyanophenethyl) -3,7-diazabicyclo [3.3.1] ηοη-3-yl] ethyl} benzonitrile;

N- {4 - [(7- {4 - [(methylsulfonyl) amino] benzyl} -3,7-diazabicyclo [3.3.1] non-3-yl) methyl] phenyl] methanesulfonamide;

4-cyano-N- [2- (7- {2 - [(4-cyanobenzoyl) amino] ethyl} -3,7-diazabicyclo [3.3.1] non-3-yl) ethyl] benzamide;

4- (2- {7- [2- (4-cyanophenyl) -2-hydroxyethyl] -3,7-diazabicyclo [3.3.1] non-3-y1} -1-hydroxyethyl) benzonitrile;

4- {3 - [(3,7-dibenzyl-3,7-diazabicyclo [3.3.1] non-9-yl) methylamino] -2-hydroxypropoxy} benzonitrile;

2 - [(7 - ([6-cyano-4- (methylsulfonyl) -3,4-dihydro-2H-1,4-benzoxazin-2-yl] methyl} -3,7-diazabicyclo [3.3.1] non) -3-ylmethyl] -4- (methylsulfonyl) -3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;

4- [2-hydroxy-3- (7-methyl-3,7-diazabicyclo [3.3.1] non-3-y1) propoxy] benzonitrile;

2 - [(7-methyl-3,7-diazabicyclo [3.3.1] non-3-yl) methyl] -4- (methylsulfonyl) -3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile ;

4- [3- (7-benzyl-3,7-diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropoxy] benzonitrile;

4- {2-Hydroxy-3- [7- (4-oxoheptyl) -3,7-diazabicyclo [3.3.1] -ηοη-3-yl] propoxy} benzonitrile;

- [((2R) -3- {7 - [(2R) -3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] non-3-yl} -2-hydroxypropyl ) oxy] benzonitrile;

- [((2S) -3- {7 - [(2S) -3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] non-3-yl} -2- hydroxypropyl) oxy] benzonitrile;

'I

[3- (7-Butyryl-3,7-diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropoxy] benzonitrile;

4- {3- [7- (ethylsulfonyl) -3,7-diazabicyclo [3.3.1] trans-3-yl] -2-hydroxypropoxy} benzonitrile;

4 - [((2S) -3- {7 - [(2R) -3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] inden-3-yl} -2- hydroxypropyl) oxy] benzonitrile;

4 - {[(2S) -2-hydroxy-3- (7-propionyl-3,7-diazabicyclo [3.3.1] non-3-yl) propyl] oxy] benzonitrile;

4 - {[(2R) -2-hydroxy-3- (7-propionyl-3,7-diazabicyclo [3.3.1] -non-3-yl) propyl] oxy} benzonitrile;

2- {7 - [(2S) -3- (4-Cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] inden-3-yl} -N-ethyl-2-oxoacetamide;

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

tert-butyl (1S) -2- (7-benzyl-3,7-diazabicyclo [3.3.1] non-3-yl) -1 - [(4-cyanophenoxy) methyl] ethylcarbamate;

tert-butyl (1S) -2- (4-cyanophenoxy) -1 - ({7 - [(ethylamino) carbothioyl] -3,7-diazabicyclo [3.3.1] non-3-yl} methyl) ethylcarbamate;

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

tert-butyl - (1S) -1 - ([7 - [(2S) -3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] non-3-yl} carbonyl) -2-methylpropyl carbamate;

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

4 - [((2S) -3- {7 - [(2S) -2-amino-3-methylbutanoyl] -3,7-diazabicyclo [3.3.1] trans-3-yl} -2-hydroxypropyl) oxy] benzonitrile;

4 - {[(2S) -2-hydroxy-3- (7 - {[(2S) -5-oxopyrrolidinyl] carbonyl} -3,7-diazabicyclo [3.3.1] non-3-yl) propyl] oxy } benzonitrile;

N- (5-cyano-2- {3- [7- (ethylsulfonyl) -3,7-diazabicyclo [3.3.1] -ηοη-3-yl] -2-hydroxypropoxy} phenyl) -N'-ethyl-urea;

N- (2- {2-Amino-3- [7- (ethylsulfonyl) -3,7-diazabicyclo [3.3.1] ηοη-3-yl] propoxy] -5-cyano-phenyl) -N-ethyl-urea;

4- {3- [7- (3,3-dimethylbutanoyl) -3,7-diazabicyclo [3.3.1] -η-3-yl] -2-hydroxypropoxy} benzonitrile;

N- (2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] ηοη-3-yl] -2-oxo-ethyl) -acetamide;

tert-butyl- (1S) -2- {7 - [(2S) -3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] non-3-yl} -1- (4-methoxybenzyl) -2-oxoethylcarbamate;

- [((2S) -3- {7 - [(2S) -2-amino-3- (4-methoxyphenyl) propanoyl] -3,7-diazabicyclo [3.3.1] non-3-yl} -2 hydroxypropyl) oxy] benzonitrile;

2- [7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] inden-3-yl} -N- (2,6-dimethylphenyl) acetamide (m / m) z = 463);

tert-butyl-2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1.0 &lt; 2,7 &gt; 3. 1] trans-3-yl} -2-oxoethylcarbamate (m / z = 344);

4- {3- [7- (2-aminoethyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -2-hydroxypropoxy [benzonitrile (m / z = 345);

N- (2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] inden-3-yl} ethyl) -4-nitrobenzamide (m / z = 494);

4-amino-N- (2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] inden-3-yl} ethyl) benzamide (m / m) z = 464);

N- (2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1.1] non-3-yl} ethyl) -4 - [(methylsulfonyl) amino] benzamide (m / z = 542);

4- (acetylamino) -N- (2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] trans-3-yl} ethyl) benzamide (m / m) z = 506);

- [7- (2 - {[4- (acetylamino) benzoyl] amino} ethyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -1 - [(4-cyanophenoxy) methyl] ethyl acetate ( m / z = 548);

4- (3- {7 - [(3,5-dimethyl-4-isoxazolyl) carbonyl] -3,7-diazabicyclo [3.3.1] inden-3-yl} -2-hydroxypropoxy) benzonitrile (m / z) = 425);

4- {2-hydroxy-3- [7- (2-isopropyl-2H-1,2,3,4-tetrazol-5-yl) -3,7-diazabicyclo [3.3.1] trans-3-yl] propoxy} benzonitrile (m / z = 412);

4- (2-hydroxy-3- {7 - [(5-methyl-3-isoxazolyl) carbonyl] -3,7-diazabicyclo [3.3.1] trans-3-yl} propoxy) benzonitrile (m / z = 411) );

4- [3- (7 - {[3- (tert-butyl) -1-methyl-1H-pyrazol-5-yl] carbonyl} -3,7-diazabicyclo [3.3.1] non-3-yl) - 2-hydroxypropoxy] benzonitrile (m / z = 466);

4- (2-hydroxy-3- {7 - [(4-methyl-l, 2,3-thiadiazol-5-yl) carbonyl] -3,7-diazabicyclo [3.3.1] non-3-y1} propoxy benzonitrile (m / z = 428);

[3- (7-cyano-3,7-diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropoxy] benzonitrile (m / z = 327);

2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] inden-3-yl} -2-oxoacetamide (m / z = 373);

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

[3.3.1] non-3-yl} propyl) -N- (3,4-dimethoxyphenyl) -4-nitrobenzamide (m / z = 644);

4 - {[7- (4-oxoheptyl) -3,7-diazabicyclo [3.3.1] non-3-yl] sulfonyl} -benzonitrile (m / z = 404);

4- {2-hydroxy-3- [7- (1-phenyl-1H-1,2,3,4-tetrazazol-5-yl) -3,7-diazabicyclo [3.3.1] indo-3-yl] propoxybenzonitrile (m / z = 446);

4- {2-hydroxy-3- [7- (1-methyl-1H-1,2,3,4-tetrazol-5-yl) -3,7-diazabicyclo [3.3.1] trans-3-yl] propoxy} benzonitrile (m / z = 384);

4- {2-hydroxy-3- [7- (2-methyl-2H-1,2,3,4-tetrazol-5-yl) -3,7-diazabicyclo [3.3.1] trans-3-yl] propoxy} benzonitrile (m / z = 384);

N ' -cyano-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N-cyclopropyl-3,7-diazabicyclo [3.3. ] nonane-3-carboximidamide;

5-propyl {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] inden-3-yl} sulfonylcarbamothioate (m / z = 483);

- ((H) -3- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] trans-3-yl} -3-oxo-1-propenyl ) benzonitrile (m / z = 457);

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

4- (2-hydroxy-3- {7 - [(2-oxo-1,3-oxazolidin-4-yl) methyl] -3,7-diazabicyclo [3.3.1] non-3-yl} propoxy) benzonitrile ;

tert-butyl-2- {7- [2-amino-3- (4-cyanophenoxy) propyl] -3,7-diazabicyclo [3.3.1.0 &lt; 2,7 &gt; 3. 1] trans-3-yl} ethylcarbamate (m / z = 444);

tert-butyl 3 - [({7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] non-3-y1} carbothioyl) amino] propanoate;

tert-butyl 2- {7- [3- (4-cyanoanilino) propyl] -3,7-diazabicyclo [3.3.1] trans-3-yl} ethylcarbamate (m / z = 428);

4- (3- {7 - [(£) -3- (3,4-dimethoxyphenyl) -2-propenoyl] -3,7-diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropoxy) benzonitrile ;

4- (3- (7 - [(E) -3- (4-fluorophenyl) -2-propenoyl) -3,7-diazabicyclo [3.3.1] trans-3-yl} -2-hydroxypropoxy) benzonitrile ( m / z = 450);

2- (7- (3- (4-cyanophenoxy) -2-hydroxypropyl) -3,7-diazabicyclo [3.3.1] trans-3-yl) -N-isopropylacetamide (m / z = 401);

4 - (((2S) -3- [7- (cyclopropylmethyl) -9,9-tetramethylene-3,7-diazabicyclo [3.3.1] non-3-yl] -2-hydroxypropyl} oxy) benzonitrile (m / m) z = 410);

phenyl-N-cyano-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diaza-bicyclo [3.3.1] nonane-3-carboximidoate (m / z = 446);

4 - ([7- (3,4-dimethoxyphenethyl) -3,7-diazabicyclo [3.3.1] trans-3-yl] carbonyl (benzonitrile (m / z = 420));

4- {3- [7- (3-amino-1H-1,2,4-triazol-5-yl) -3,7-diazabicyclo [3.3.1] inden-3-yl] -2-hydroxypropoxy] benzonitrile ( m / z = 384);

N'-cyano-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N- (2-hydroxyethyl) -3,7-diazabicyclo [3.3.1] nonane-3-carboximidamide (m / z = 413) );

tert-butyl 3- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diaza-bicyclo [3.3.1] non-3-yl} -1-methyl-3-oxopropylcarbamate;

N'-cyano-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N - [(5-hydroxy-1,3,3-trimethylcyclohexyl) methyl] -3,7-diazabicyclo [3.3.1] -nonane-3-carboximidamide (m / z = 523);

4- [2-hydroxy-3- (7- {2-hydroxy-3 - [(2-methyl-1-oxo-1,2-dihydro-4-isoquinolyl) oxy] propyl} -3,7-diazabicyclo [ 3.3.1] non-3-y1) propoxy] benzonitrile;

- {7 - [(3,4-Dimethoxyphenyl) sulfonyl] -3,7-diazabicyclo [3.3.1] 79

-ηo-3-yl} -2-hydroxypropoxy) benzonitrile (m / z = 502);

4- {3- [7- (benzylsulfonyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -2-hydroxypropoxy) benzonitrile (m / z = 456);

4- {3- [7- (butylsulfonyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -2-hydroxypropoxy [benzonitrile (m / z = 4.22);

7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N, N-dimety1-3,7-diazabicyclo [3.3.1] nonane-3-sulfonamide;

4- {3- [7- (3-aminobutanoyl) -3,7-diazabicyclo [3.3.1] non-3-y1] -2-hydroxypropoxy [benzonitrile;

4- {3- [7- (1,3-dimethyl-2,6-dioxo-l, 2,3,6-tetrahydro-4-pyrimidinyl) -3,7-diazabicyclo [3.3.1] non-3 y1] -2-hydroxypropoxy [benzonitrile (m / z = 440);

N'-cyano-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N- (2-methoxyethyl) -3,7-diazabicyclo [3.3.1] nonane-3-carboximidamide (m / z = 427) ); 4- {2-hydroxy-3- [7- (2,2,2-trifluoroacetyl) -3,7-diazabicyclo [3.3.1] inden-3-yl] propoxy} benzonitrile (m / z = 398);

4- {2-hydroxy-3- [7- (3,3,3-trifluoropropanoyl) -3,7-diazabicyclo [3.3.1] inden-3-yl] propoxy} benzonitrile;

N'-cyano-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N - [(1 S) -1- (1-naphthyl) ethyl] -3,7-diazabicyclo [3.3.1] nonane 3-carboximidamide (m / z = 523);

N'-cyano-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N-isopropyl-N-methyl-3,7-diazabicyclo [3.3.1] nonane-3-carboximidamide (m / z = 425) );

N'-cyano-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N- (3,4-dimethoxyphenethyl) -3,7-diazabicyclo [3.3.1] nonane-3-carboximidamide;

N'-cyano-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -N- (3,4-dimethoxyphenethyl) -N-methyl-3,7-diazabicyclo [3.3.1] nonane-3-carboximidamide (m / z = 547);

4- (2-hydroxy-3- {7 - [(3-methyl-8-quinolyl) sulfonyl] -3,7-diazabicyclo [3.3.1] trans-3-yl} propoxy) benzonitrile (m / z = 507) );

4- (2-hydroxy-3- {7 - [(1-methyl-1 H -imidazol-4-yl) sulfonyl] -3,7-diazabicyclo [3.3.1] hη-3-yl} propoxy) benzonitrile ( m / z = 446);

4- (2-hydroxy-3- {7 - [(trifluoromethyl) sulfonyl] -3,7-diazabicyclo [3.3.1] inden-3-yl} propoxy) benzonitrile (m / z - 434);

4- {2-hydroxy-3- [7- (2-oxobutyl) -3,7-diazabicyclo [3.3.1] hη-3-yl] propoxy} benzonitrile (m / z = 372);

4- {3- [7- (2-furoyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -2-hydroxypropoxy} benzonitrile (m / z = 396);

4- [2-hydroxy-3- (7 - {[5- (2-pyridyl) -2-thienyl] sulfonyl} -3,7-diazabicyclo [3.3.1] trans-3-yl) propoxy] benzonitrile (m m / z = 525);

N- [4- (2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] trans-3-yl} acetyl) phenyl] methanesulfonamide (m / z) = 513)

4- [2-hydroxy-3- (7 - {[2- (4-morpholinyl) ethyl] sulfonyl] -3,7-diazabicyclo [3.3.1] non-3-yl) propoxy] benzonitrile;

4- {3- [7- (4-amino-6,7-dimethoxy-2-quinazolinyl) -3,7-diazabicyclo [3.3.1] non-3-y1] -2-hydroxypropoxy} benzonitrile;

3,7-bis [3- (4-cyanophenoxy) -2-hydroxypropyl] -7-aza-3-azoniabicyclo [3.3.1] nonane-3-olate (m / z = 493);

4- (3- {7 - [(3-fluorophenyl) sulfonyl] -3,7-diazabicyclo [3.3.1] -η-3-yl} -2-hydroxypropoxy) benzonitrile (m / z = 460);

- {3- [7- (3,4-dimethoxyphenethyl) -3,7-diazabicyclo [3.3.1] indol-3-yl] -2-hydroxypropoxy] benzonitrile (m / z = 466);

4- [4- (7-butyryl-3,7-diazabicyclo [3.3.1] non-3-yl) -1- (3,4-dimethoxyphenoxy) butyl] benzonitrile (m / z = 506);

4- [4- [7- (butylsulfonyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -1- (3,4-dimethoxyphenoxy) butyl] benzonitrile (m / z = 556);

4- {1- (3,4-dimethoxyphenoxy) -4- [7- (3,3-dimethyl-2-oxobutyl) -3,7-diazabicyclo [3.3.1] inden-3-yl] butyl] benzonitrile (m / m) z = 534);

4- [4- [7- (3,4-dimethoxyphenethyl) -3,7-diazabicyclo [3.3.1] indol-3-yl] -1- (3,4-dimethoxyphenoxy) butyl] benzonitrile (m / z) = 600);

4- [4- (7-Butyryl-3,7-diazabicyclo [3.3.1] non-3-yl) butyl] -benzonitrile (m / z = 354);

4- {2- [7- (butylsulfonyl) -3,7-diazabicyclo [3.3.1] non-3-yl] ethoxy} benzonitrile (m / z = 404);

4- {4- [7- (3,3-Dimethyl-2-oxobutyl) -3,7-diazabicyclo [3.3.1] indol-3-yl] butyl} benzonitrile (m / z = 382);

- {4- [7- (3,4-dimethoxyphenethyl) -3,7-diazabicyclo [3.3.1] -η-3-yl] butyl} benzonitrile (m / z = 448);

4- [2- (7-butyryl-3,7-diazabicyclo [3.3.1] non-3-yl) ethoxy] benzonitrile (m / z 342);

4- {2- [7- (3,3-Dimethyl-2-oxobutyl) -3,7-diazabicyclo [3.3.1] indol-3-yl] ethoxy} benzonitrile (m / z = 370);

4- {2- [7- (3,4-dimethoxyphenethyl) -3,7-diazabicyclo [3.3.1] non-3-yl] ethoxy} benzonitrile (m / z = 436);

O-ethyl-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] nonane-3-carbothioate;

4- [2-hydroxy-3- [7 - [(tetrahydro-3-thienyl) sulfonyl] -3,7-diazabicyclo [3.3.1.0 &lt; 2,7 &gt; 3 .1] trans-3-yl] propoxy] benzonitrile, S, S-dioxide;

4 - ({(2S) -2-amino-3- [7- (3,3-dimethyl-2-oxobutyl) -3,7-diazabicyclo [3.1.1] non-3-yl] propyl} oxy) benzonitrile ;

4- {2- [7- (1,3-thiazol-2-yl) -3,7-diazabicyclo [3.3.1] non-3-yl] ethoxy] benzonitrile (m / z = 355);

4- (1- (3,4-dimethoxyphenoxy) -4- [7- (1,3-thiazol-2-yl) -3,7-diazabicyclo [3.3.1] trans-3-yl] butyl [benzonitrile ( m / z = 519);

4 - ({3- [7- (1,3-thiazol-2-yl) -3,7-diazabicyclo [3.3.1] trans-3-yl] propyl} sulfonyl) benzonitrile (m / z = 417) ;

4-Cyano-N- {3- [7- (1,3-thiazol-2-yl) -3,7-diazabicyclo [3.3.1] non-3-yl] propyl] benzamide (m / z = 396) );

4- {3- [7- (cyclopropylmethyl) -3,7-diazabicyclo [3.3.1] trans-3-yl] -2-hydroxypropoxy [benzonitrile (m / z = 356);

4- {2- [7- (cyclopropylmethyl) -3,7-diazabicyclo [3.3.1] trans-3-yl] ethoxy [benzonitrile (m / z = 326);

4- [4- [7- (cyclopropylmethyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -1- (3,4-dimethoxyphenoxy) butyl] benzonitrile (m / z = 490);

4 - ({3- [7- (cyclopropylmethyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -propyl} amino) benzonitrile (m / z = 339);

4- (3- (7- (cyclopropylmethyl) -3,7-diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropoxy} -N, N-dimethylbenzenesulfonamide (m / z = 438);

- ({3- [7- (3,3-dimethyl-2-oxobutyl) -3,7-diazabicyclo [3.3.1] -η-3-yl] propyl} amino) benzonitrile (m / z = 383);

4- (4- (4-cyanophenyl) -1- (2- (7- (3,3-dimethyl-2-oxobutyl) -3,7-diazabicyclo [3.3.1] non-3-yl) -2 -oxoethyl} -1H-pyrazol-5-yl) benzonitrile (m / z = 535);

4- (3- (7- (3,3-dimethyl-2-oxobutyl) -3,7-diazabicyclo [3.3.1] -en-3-yl) -2-hydroxypropoxy} -N, N-dimethylbenzenesulfonamide (m / z = 482);

4- {7- [2- (2-methoxyethoxy) ethyl] -3,7-diazabicyclo [3.3.1] -η-3-yl} ethoxy) benzonitrile (m / z = 374);

N- [2- (4-cyanophenoxy) -1 - ({7- [2- (2-methoxyethoxy) ethyl] -3,7-diazabicyclo [3.3.1] non-3-yl} methyl) ethyl] -N methyl urea (m / z = 460);

4 - [(3- {7- [2- (2-methoxyethoxy) ethyl] -3,7-diazabicyclo [3.3.1] indol-3-yl] propyl) amino] benzonitrile (m / z = 387);

4- [4- (4-cyanophenyl) -1- (2- {7- [2- (2-methoxyethoxy) ethyl] -3,7-diazabicyclo [3.3.1] inden-3-yl} -2 (oxoethyl) -1 H -pyrazol-5-yl] benzonitrile (m / z = 539);

4- {3- [7- (4-fluorobenzyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -2-hydroxypropoxy} benzonitrile (m / z = 410);

4- {2- [7- (4-fluorobenzyl) -3,7-diazabicyclo [3.3.1] non-3-yl] ethoxy} benzonitrile (m / z = 380);

4- (1- (3,4-dimethoxyphenoxy) -4- [7- (4-fluorobenzyl) -3,7-diazabicyclo [3.3.1] inden-3-yl] butyl} benzonitrile (m / z = 544);

4 - ({3- [7- (4-fluorobenzyl) -3,7-diazabicyclo [3.3.1] non-3-yl] propyl} amino) benzonitrile (m / z = 393);

4 - ({3- [7- (4-fluorobenzyl) -3,7-diazabicyclo [3.3.1] non-3-yl] propyl} sulfonyl) benzonitrile (m / z = 442);

4-cyano-N-3- [7- (4-fluorobenzyl) -3,7-diazabicyclo [3.3.1] indol-3-yl] propyl] benzamide (m / z = 421);

4- {3- [7- (4-fluorobenzyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -2-hydroxypropoxy} -N, N-dimethylbenzenesulfonamide (m / z = 492);

4- {2-hydroxy-3- [7- (isopropylsulfonyl) -3,7-diazabicyclo [3.3.1] non-3-yl] propoxy} benzonitrile;

4- (3- [7- (1-cyanoethyl) -3,7-diazabicyclo [3.3.1] non-3-y1] -2-hydroxypropoxy} benzonitrile;

4- {2- [7- (1-cyanoethyl) -3,7-diazabicyclo [3.3.1] non-3-y1] -etoxybenzonitril;

4- [4- [7- (1-cyanoethyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -1- (3,4-dimethoxyphenoxy) butyl] benzonitrile (m / z = 489) ;

4- {3- [7- (2-cyanopropyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -2-hydroxypropoxy} -N, N-dimethylbenzenesulfonamide (m / z = 451);

4 - ({3- [7- (3,4-dimethoxyphenethyl) -3,7-diazabicyclo [3.3.1] trans-3-yl] propyl} amino) benzonitrile (m / z = 44.9);

4 - ((3- [7- (3,4-dimethoxyphenethyl) -3,7-diazabicyclo [3.3.1] indol-3-yl] propyl} sulfonyl) benzonitrile (m / z = 498);

4- (4- (4-cyanophenyl) -1- {2- [7- (3,4-dimethoxyphenethyl) -3,7-diazabicyclo [3.3.1] non-3-yl] -2-oxoethyl} - N-pyrazol-5-yl) benzonitrile (m / z = 601);

4-cyano-N- {3- [7- (3,4-dimethoxyphenethyl) -3,7-diazabicyclo [3.3.1] -en-3-yl] propyl} benzamide (m / z = 477);

4- (1- (3,4-dimethoxyphenoxy) -4- [7- (4-oxoheptyl) -3,7-diazabicyclo [3.3.1] trans-3-yl] butyl} benzonitrile (m / z = 548) );

4- (4- (4-cyanophenyl) -1- {2-oxo-2- [7- (4-oxoheptyl) -3,7-diazabicyclo [3.3.1] inden-3-yl] ethyl} - 1 H -pyrazol-5-yl) benzonitrile (m / z = 549);

4-cyano-N- {3- [7- (4-oxoheptyl) -3,7-diazabicyclo [3.3.1] non-3-yl] propyl} benzamide (m / z = 425);

4- (3- (7- [2- (2,3-dihydro-l, 4-benzodioxin-6-yl) -2-oxo-ethyl] -3,7-diazabicyclo [3.3.1] non-3-y1} -2-hydroxypropoxy) benzonitrile (m / z = 478);

4 - ((3- {7- [2- (2,3-dihydro-l, 4-benzodioxin-6-yl) -2-oxo-ethyl] -3,7-diazabicyclo [3.3.1] non-3-y1Jpropyl amino] benzonitrile (m / z - 461);

4- (3- (7- [3- (ethylsulfonyl) propyl) -3,7-diazabicyclo [3.3.1] -η-3-yl} -2-hydroxypropoxy) benzonitrile (m / z = 436);

4- (1- (3,4-dimethoxyphenoxy) -4- (7- (3- (ethylsulfonyl) propyl) -3,7-diazabicyclo [3.3.1] trans-3-yl} butyl) benzonitrile (m / m) z = 570) '

N- (2- (7- [3- (4-acetyl-l-piperazinyl) propyl] -3,7-diazabicyclo [3.3.1] ηοη-3-yl} -1 - [(4-cyanophenoxy) methyl ethyl} -N-methylurea (m / z = 526);

4- [1- (2- {7- [3- (4-acetyl-1-piperazinyl) propyl] -3,7-diazabicyclo [3.3.1] inden-3-yl} -2-oxoethyl) -4- (4-cyanophenyl) -1H-pyrazol-5-yl] benzonitrile (m / z = 605);

- ({3- [7- (1,3-thiazol-2-yl) -3,7-diazabicyclo [3.3.1] non-3-yl] propyl} amino) benzonitrile (m / z = 368);

4- (2-hydroxy-3- [7- (1,3-thiazol-2-yl) -3,7-diazabicyclo [3.3.1] hη-3-yl] propoxy} -N, N-dimethylbenzenesulfonamide ( m / z = 467);

N- (2- (4-cyanophenoxy) -1 - {[7- (cyclopropylmethyl) -3,7-diazabicyclo [3.3.1] trans-3-yl] methyl} ethyl) -N'-methylurea (m / z) = 412);

4 - ((3- (7- (cyclopropylmethyl) -3,7-diazabicyclo [3.3.1] trans-3-yl) propyl} sulfonyl) benzonitrile (m / z = 388);

4- (2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -3,7-diazabicyclo [3.3.1] inden-3-yl} acetyl) benzonitrile;

N- (2- (4-cyanophenoxy) -1 - {[7- (3,3-dimethyl-2-oxobutyl) -3,7-diaza-bicyclo [3.3.1] non-3-yl] methyl} ethyl) -N'-methylurea (m / z = 456);

4 - ((3- (7- (3,3-dimethyl-2-oxobutyl) -3,7-diazabicyclo [3.3.1] 86

(E-3-yl) propyl} sulfonyl) benzonitrile (m / z = 432);

4-Cyano-N- {3- [7- (3,3-dimethyl-2-oxobutyl) -3,7-diazabicyclo [3.3.1] inden-3-yl] propyl} benzamide (m / z = 411) );

4- (2-hydroxy-3- {7- [2- (2-methoxyethoxy) ethyl] -3,7-diazabicyclo [3.3.1] trans-3-yl} propoxy) benzonitrile (m / z = 404);

4- (1- (3,4-dimethoxyphenoxy) -4- {7- [2- (2-methoxyethoxy) ethyl] -3,7-diazabicyclo [3.3.1] non-3-yl} butyl) benzonitrile (m m / z = 538);

- [(3- (7- [2- (2-methoxyethoxy) ethyl) -3,7-diazabicyclo [3.3.1] hη-3-yl} propyl) sulfonyl] benzonitrile (m / z = 436);

4-Cyano-N- (3- {7- [2- (2-methoxyethoxy) ethyl] -3,7-diazabicyclo [3.3.1] trans-3-yl} propyl) benzamide (m / z = 415) ;

4- (2-hydroxy-3- {7- [2- (2-methoxyethoxy) ethyl] -3,7-diazabicyclo [3.3.1] trans-3-yl} propoxy) -N, N-dimethylbenzenesulfonamide (m m / z = 486);

N- {2- [7- (1-cyanoethyl) -3,7-diazabicyclo [3.3.1] non-3-y1] -1 - [(4-cyanophenoxy) methyl] ethyl) -N-methyl urea;

4-cyano-N- (3- [7- (2-cyanopropyl) -3,7-diazabicyclo [3.3.1] indol-3-yl] propyl} benzamide (m / z = 380);

N- (2- (4-cyanophenoxy) -l - {[7- (3,4-dimethoxyphenethyl) -3,7-diazabicyclo [3.3.1] ηοη-3-yl] methyl} ethyl) -N'-methylurea (m / z - 522);

- {3- [7- (3,4-dimethoxyphenethyl) -3,7-diazabicyclo [3.3.1] -η-3-yl] -2-hydroxypropoxy) -N, N-dimethylbenzenesulfonamide (m / z = 548) ;

4- {2- [7- (4-oxoheptyl) -3,7-diazabicyclo [3.3.1] non-3-yl] ethoxy] benzonitrile (m / z = 384);

4- {2-hydroxy-3- [7- (4-oxoheptyl) -3,7-diazabicyclo [3.3.1] -en-3-yl] propoxy} -N, N-dimethylbenzenesulfonamide (m / z = 496) ;

N- [2- (4-cyanophenoxy) -1 - ({7- [2- (2,3-dihydro-l, 4-benzodioxin-6-yl) -2-oxo-ethyl] -3,7-diazabicyclo [3.3 .1] non-3-yl} methyl) ethyl] -N-methyl urea (m / z = 496);

- [(3- (7- (2- (2,3-dihydro-1,4-benzodioxin-6-yl) -2-oxoethyl) -3,7-diazabicyclo [3.3.1] non-3-yl)} - propyl) sulfonyl] benzonitrile (m / z = 510);

4- [4- (4-cyanophenyl) -1- (2- (7- (2- (2,3-dihydro-1,4-benzodioxin-6-yl) -2-oxoethyl) -3,7-diazabicyclo) [3.3.1] non-3-yl} -2-oxoethyl) -1H-pyrazol-5-yl] benzonitrile (m / z = 510);

4-Cyano-N- (3- (7- [2- (2,3-dihydro-1,4-benzodioxin-6-yl) -2-oxoethyl) -3,7-diazabicyclo [3.3.1] non- 3-yl} propyl) benzamide (m / z = 489);

4- (3- (7- [2- (2,3-dihydro-1,4-benzodioxin-6-yl) -2-oxoethyl) -3,7-diazabicyclo [3.3.1] non-3-yl) -2-hydroxypropoxy) -N, N-dimethylbenzenesulfonamide (m / z = 560);

- (2- [7- [3- (ethylsulfonyl) propyl] -3,7-diazabicyclo [3.3.1] -zη-3-yl} ethoxy) benzonitrile (m / z = 406);

N- [2- (4-cyanophenoxy) -1 - ({7- [3- (ethylsulfonyl) propyl] -3,7-diaza-bicyclo [3.3.1] trans-3-yl} methyl) ethyl] -N ' methyl urea (m / z = 492);

- [(3- (7- (3- (ethylsulfonyl) propyl) -3,7-diazabicyclo [3.3.1] hη-3-yl} propyl) amino] benzonitrile (m / z = 419);

- [(3- (7- (3- (ethylsulfonyl) propyl) -3,7-diazabicyclo [3.3.1] -η-3-yl} propyl) sulfonyl] benzonitrile (m / z = 468);

- [4- (4-cyanophenyl) -1- (2- (7- (3- (ethylsulfonyl) propyl) -3,7-diazabicyclo [3.3.1] non-3-yl} -2-oxoethyl) 1 H-pyrazol-5-yl] benzoic nitrile (m / z = 571);

4-cyano-N- (3- {7- [3- (ethylsulfonyl) propyl] -3,7-diazabicyclo [3.3.1] inden-3-yl} propyl) benzamide (m / z = 447);

- (3- {7- [3r (Ethylsulfonyl) propyl] -3,7-diazabicyclo [3.3.1] -en-3-yl} -2-hydroxypropoxy) -N, N-dimethylbenzenesulfonamide (m / z = 518) );

4- (2- {7- [3- (4-acetyl-1-piperazinyl) propyl] -3,7-diazabicyclo [3.3.1] trans-3-yl} ethoxy) benzonitrile (m / z = 440) ;

4- [4- {7- [3- (4-acetyl-1-piperazinyl) propyl] -3,7-diazabicyclo [3.3.1] non-3-yl} -1- (3,4-dimethoxyphenoxy) butyl ] benzonitrile (m / z = 604);

4 - [(3- {7- [3- (4-acetyl-1-piperazinyl) propyl] -3,7-diazabicyclo [3.3.1] inden-3-yl} propyl) amino] benzonitrile (m / z) = 453);

4 - [(3- {7- [3- (4-acetyl-1-piperazinyl) propyl] -3,7-diazabicyclo [3.3.1] trans-3-yl} propyl) sulfonyl] benzonitrile (m / z) = 502);

4- (3- {7- [3- (4-acetyl-1-piperazinyl) propyl] -3,7-diazabicyclo [3.3.1] non-3-yl} -2-hydroxypropoxy) -N, N- dimethylbenzenesulfonamide (m / z - 552);

4- (3- {7- [3- (4-acetyl-1-piperazinyl) propyl] -3,7-diazabicyclo [3.3.1] non-3-yl} -2-hydroxypropoxy) benzonitrile;

N-2- (4-cyanophenoxy) -1 - {[7- (1,3-thiazol-2-yl) -3,7-diazabicyclo [3.3.1] trans-3-yl] methyl} ethyl) - N'-methylurea (m / z = 441);

4- (1- (3,4-dimethoxyphenoxy) -4- [7- (2-ethyl-2H-1,2,3,4-tetrazol-5-yl) -3,7-diazabicyclo [3.3.1] non-3-yl] butyl} benzonitrile;

4 - ({3- [7- (2-ethyl-2H-1,2,3,4-tetrazol-5-yl) -3,7-diazabicyclo [3.3.1] non-3-yl] propyl} amino) benzonitrile.

Example 8

Compounds te A and found

Example 9

Compounds te B and found

abbreviations

Ac

API aq.

br

Bt t-BuOH

CI m-CPBA d

DBU

DCM dd

DMAP

DMF

DMSO

EDO

et

EtOAc eq.

ES

FAB h

according to the present invention were tested in a test having a D 10 value of at least 6.0.

according to the present invention were tested in a test having a pIC 50 value of at least 5.5.

atmospheric pressure acetyl ionization (relative to

MS) aqueous wide benzotriazole tert-butanol chemical ionization (relative to MS) m-chloroperoxybenzoic acid doublet (relative to NMR) diazabicyclo [5.4.0] undec-7-ene dichloromethane doublet of doublets (relative to NMR)

4-dimethylaminopyridine

N, N-dimethylformamide dimethyl sulfoxide 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide ethyl ethyl acetate equivalents electron spraying (relative to MS) fast atom bombardment hours

HC1

HEPES

HPLC

IPA m

Me

MeCN

MeOH min.

MS

NADPH

OAC

Pd / C q

s t

TEA

THF

TLC hydrochloric acid 4- (2-hydroxyethyl) -1-piperazinethanesulfonic acid high-performance liquid chromatography isopropyl alcohol multiplet methyl acetonitrile methanol minutes mass spectroscopy nicotinamide adenine dinucleotide phosphate, reduced form acetate

palladium on the coal quartet (in the relationship to NMR) s (in the relationship to NMR) triplet (in the relationship to NMR)

triethylamine tetrahydrofuran thin layer chromatography

Claims (51)

PATENT CLAIMS A compound of formula I (I) wherein R ¹ represents a structural fraction A. .B-R6 _R 4 R5 R ⁴ represents a hydrogen atom, an atom of the formula Ia, (Ia) halogen, an alkyl group s C 1 -C 4, -D-OR ⁷ , -DN (R ⁸ ) R ⁹ , or R ⁴ together with R ⁵ represent oxo; R ⁵ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or R ⁵ together with R ⁴ represents an oxo group; D represents a direct bond or an alkylene group having 1 to 4 carbon atoms; R ⁷ is hydrogen, C 1 -C 6 alkyl, -E-aryl, -E-Het ¹ , -C (O) R ^10a , -C (O) OR ^10b, or -C (O) N (R ^11a ) R ^Ub ; R ⁸ is hydrogen, C 1 -C 6 alkyl, -E-aryl, -E-Het ¹ , -C (O) R ^10a , -C (O) ^OR10b , -S (O) ^2R10c , - [C (O)] n N (R ^11a ) R ^11b, or -C (NH) NH ₂ ; R ⁹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an -E-aryl group or a -C (O) R ^{10d group} ; E represents at each occurrence, if. use herein a direct bond or an alkylene group having 1 to 4 carbon atoms; R ^10a to R ^10d independently at each occurrence, when used herein, are C 1 -C 6 alkyl (optionally substituted and / or terminated with one or more substituents selected from halogen, aryl, and Het ² ), aryl, Het ³ , or R ^10a and R ^10d independently represent a hydrogen atom; R ^11a and R ^11b independently represent, at each occurrence, when used herein, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (optionally substituted and / or terminated with one or more substituents selected from halogen, aryl, and Het) ⁴ ), aryl, Het ⁵ , or R ^11a and R ^11b together represent an alkylene group of 3 to 7 carbon atoms, wherein the alkylene group is optionally interrupted by an oxygen atom; n is 1 or 2; A is -G-, -JN (R ¹² ) -, or -J-O- (wherein in the latter two groups, J is attached to the nitrogen atom of bispidine); B is -L-, -LN (R ¹³ ) -, -N (R ¹³ ) -L-, -LS (O) _P or -LO- (wherein in the latter two groups, L is attached to a carbon atom which carries groups R ⁴ and R ⁵ ); G represents a direct bond or an alkylene group having 1 to 6 carbon atoms; J represents an alkylene group having 2 to 6 carbon atoms; L represents a direct bond or an alkylene group having 1 to 4 carbon atoms; I p is 0, 1 or 2; R ¹² and R ¹³ independently represent hydrogen or C 1 -C 4 alkyl; R ⁶ is aryl, Het ⁶ (both of which groups are optionally substituted and / or terminated (as appropriate) by one or more substituents selected from the group consisting of hydroxy, cyano, halo, nitro, alkyl of 1 to 6 carbon atoms (optionally terminated with -N (H) C (O) OR ^14a ), (1-6C) alkoxy, aryl, Het ⁷ , -N (R ^15a ) R ^15b , -C (O) R ^15c , -C (O) ^OR15d , -C (O) N (R ^L5e) R ^15f, -N (R ^{15 grams)} C (O) R ^15h, -N (R ¹⁵ⁱ⁾ C (O) N (R ^15j) R ^15k, -N (R ^{15 m)} S (O) 2 R ^14b , -S (O) q R ^14c , -OS (O) 2 R ^14d and -S (O) 2 N (R ¹⁵ⁿ ) R ^15p ) or when R ⁴ and R ⁵ together form an oxo group, R ⁶ may represent an alkyl group having 1 to 6 carbon atoms; q is 0, 1 or 2; R ² is cyano, Het ⁸ , -C (O) R ¹⁶ , -C (S) OR ¹⁷ , -C (S) N (R ¹⁸ ) R ¹⁹ , - [C (O)] 2 N (R ^20a ) R ^20b , - [C (0)] 2 OR ²¹ , -S (O) ₂ R ²² , -S (O) ₂ N (R ²³ ) R ²⁴ , -C (= N-CN) N (R ²⁵ ) R ²⁶ , -C (= N-CN) OR ^27, or (C 1 -C 12) alkyl group (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from -C (O) R ²⁸ , -C (O) N (R ^29a ) R ^29b , -N ( R ³⁰⁾ R ^31, -OR ^32, -S (O) _r R ^33, halo, cyano, nitro, aryl and Het ^9); R ¹⁶ represents a hydrogen atom, an aryl group, a Het ¹⁰ group or an alkyl group having 1 to 6 carbon atoms (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from halogen, hydroxy, cyano, -N (R 1) ³⁴ ) R ³⁵ , aryl and Het ¹¹ ); R ³⁴ is hydrogen, C 1 -C 6 alkyl, aryl, Het ¹² , -C (O) R ^36a or -C (O) OR ^36b ; R ¹⁸ represents a hydrogen atom, an aryl group, a Het ¹³ group, -C (O) R ^36a or -C (O) OR ^36b or an alkyl group having 1 to 6 carbon atoms (wherein the alkyl group is optionally substituted and / or terminated with one or a plurality of substituents selected from halogen, hydroxy, cyano, -C (O) R ^36a or -C (O) OR ^36b ; R ²² is Het ¹⁴ , aryl, C 1 -C 6 alkyl (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from halogen, hydroxy, cyano, Het ^15, and aryl); R ²³ is hydrogen, C 1 -C 6 alkyl, aryl, Het ¹⁶ , -C (O) R ^36a , -C (O) OR ^36b, or -C (O) SR ^36b ; R ²⁵ represents hydrogen, C 1 -C 6 alkyl (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from halogen, hydroxy, cyano, C 1 -C 6 alkyl (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from C 1 -C 4 alkyl and hydroxy), C 1 -C 6 alkoxy (and aryl); R ²⁷ represents an alkyl group having 1 to 6 carbon atoms or an aryl group; R ²⁸ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group or a group Het ¹⁷ ; R ^29a and R ^29d independently represent hydrogen, C 1 -C 6 alkyl, aryl or Het ¹⁸ ; R ³⁰ is hydrogen, C 1 -C 6 alkyl, aryl, Het ¹⁹ , -C (O) R ^37a , -C (O) OR ^37b, or -C (O) N (R ^37c ) R ^37d ; R ³¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group or a group Het ²⁰ ; R ³² is hydrogen, C 1 -C 6 alkyl, aryl, Het ²¹ , -C (O) R ^37a , -C (O) OR ^37b or -C (O) N (R ^37c ) R ^37d ; R ³³ is C 1 -C 6 alkyl, aryl or Het ²² ; r is 0, 1 or 2; R ^36a and R ^36b independently represent, when present herein, an alkyl group of 1 to 6 carbon atoms, or R ^36a represents a hydrogen atom; R ^37a to R ^37d independently represent, when present herein, an alkyl group having 1 to 6 carbon atoms, an aryl group or Het ²³ , or R ^37a , R ^37c and R ^37d independently represent a hydrogen atom; Het ¹ to Het ²³ independently represent, when present herein, five to twelve membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and / or sulfur; R ^3a and R ^3b independently represent hydrogen, C 1 -C 4 alkyl, -OR ^38a , -SR ^38b , -N (R ³⁹ ) R ^38c , or R ^3a and R ^3b together form an alkylene group with 3 up to 5 carbon atoms, -O-Z-O-, -OZS- or -SZS-; R ³⁹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a structural fraction of formula Ia as defined above; Z represents an alkylene group having 2 to 3 carbon atoms optionally substituted by one or more alkyl groups having 1 to 4 carbon atoms; R ⁴¹ to R ^{46 are} independently hydrogen or C 1 -C 3 alkyl; R ^14a to R ^14d , R ¹⁷ and R ²¹ independently represent C 1 -C 6 alkyl; R ^15a to R ^15p , R ¹⁹ , R ^20a , R ^20b , R ²⁴ , R ²⁶ , R ³⁵ and R ^38a to R ^38c independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; wherein each aryl group and Het (Het ¹ to Het ²³ ), unless otherwise specified, is optionally substituted; or a pharmaceutically acceptable salt thereof; with the proviso that (a) when R ¹ represents a structural fraction of formula Ia in which: R ⁴ and R ⁵ together form an oxo group; A represents a direct bond; then B is not a direct bond, -N (R ¹³ ) -L- (wherein -N (R ¹³ ) - is attached to the carbon atom bearing R ⁴ and R ⁵ ), -N (R ¹³ ) - , -S (O) _p - or -O-; (b) when R ⁵ represents a hydrogen atom or a C 1 -C 4 alkyl group; at A is -jN (R ¹²⁾ - or-J-0-; then B is not -N (R ¹³ ) -L-, -N (R ¹³ ) -, -S (O) _p or -O-; (c) when R ⁴ represents a group -D-OR ⁷ , -DN (R ⁸ ) R ⁹ , wherein D represents a direct bond, then: (i) A is not -JN (R ¹² ) - or -J-O-; and (ii) B is not -N (R ¹³ ) -L-, -N (R ¹³ ) -, -S (O) _p - or -O-; (d) when R ^3a and R ^{3b are} both hydrogen; and R ¹ represents unsubstituted benzyl; then R ² does not represent an unsubstituted benzyl or optionally substituted benzoyl; and (e) the compound is not: (i) N '-phenyls 1-3- (7-benzyl-3,7-diazabicyclo [3.3.1] non-3-yl) propanamide; (ii) 3-Benzyl-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -6,8-dimethyl-3,7-diazabicyclo [3.3. ] nonane; (iii) 3-Benzyl-7- [3- (4-cyanophenoxy) -2-hydroxypropyl] -6-methyl-3,7-diazabicyclo [3.3. ljnonán; (iv) N- {2- (7-benzyl-3,7-diazabicyclo [3.3.1] non-3-yl) -198 - [(4-cyanophenoxy) methyl] ethyl] methanesulfonamide; (v) 3-Benzyl-7- [3- (2-propyl-1,3-dioxolan-2-yl) propyl] -3,7-diazabicyclo [3.3. ljnonán; or (vi) 7-benzyl-3,7-diazabicyclo [3.3. ljnonán-3-ethanol; (f) when R ² represents an alkyl group having 1 to 6 carbon atoms (optionally substituted with one or more aryl groups), then: (I) when R ⁴ represents a hydrogen atom, a C 1 -C 4 alkyl group, -OR ⁷ , or R ⁴ together with R ⁵ represent an oxo group; R ⁷ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a -C (O) R ^{10a group} ; and R ⁶ represents an aryl group; then B is not -L-; and / or (II) when A represents a single bond; and R ⁴ and R ⁵ together represent oxo; then R ^3a and R ^{3b are} not both C 1 -C 4 alkyl or together are not C 3 -C 5 alkylene; (g) when R ² is -C (O) R ¹⁶ and -AC (R ⁴ ) (R ⁵ ) -B- is C 1 -C 6 alkylene, then: (I) R ^{6 is} not an aryl group; and / or (II) R ^3a and R ^3b both do not represent C 1 -C 4 alkyl or together do not represent C 3 -C 5 alkylene; and (h) when R ² is -S (O) ₂ R ^22; R ^3a and R ^3b independently represent a hydrogen atom or a C 1 -C 4 alkyl group; and R ⁶ represents an aryl group; Even then, A and B do not simultaneously represent direct bonds wherein said aryl groups are optionally substituted, unless otherwise indicated. A compound according to claim 1, wherein R ⁴ is hydrogen, C 1 -C 2 alkyl, -OR ⁷ or -N (H) R ⁸ , or R ⁴ together with R ⁵ represent oxo. A compound according to claim 1 or claim 2, wherein R ⁵ represents a hydrogen atom, or R ⁵ together with R ⁴ represents an oxo group. A compound according to any one of claims 1 to 3, wherein R ⁷ represents a hydrogen atom, a C 1 -C 4 alkyl group, an optionally substituted phenyl group, a -C (O) R ^10a or -C (O) N (R ^{11a) group.} ) R ^11b . A compound according to any one of claims 1 to 3, wherein R ⁸ is hydrogen, C 1 -C 4 alkyl, -C (O) R ^10a , -C (O) OR ^10b, or -C (O) N (R ^11a ) R ^11b . A compound according to any one of claims 1 to 5, wherein R ^xOa and R ^10b independently at each occurrence, when used herein, are C 1 -C 5 alkyl (optionally substituted and / or terminated with one or more substituents selected from). from a halogen atom and a phenyl group), an optionally substituted phenyl group, or R ^10a 100 represents a hydrogen atom. A compound according to claim 4 or claim 5, wherein R ^11a and R ^11b independently represent, at each occurrence, when used herein, a hydrogen atom or a C 1 -C 5 alkyl group (optionally substituted and / or terminated by one or more) substituents selected from a halogen atom and a phenyl group). A compound according to any one of claims 1 to 7, wherein A is -G- or -JN (R ¹² ) -. A compound according to claim 8, wherein G represents a direct bond or an alkylene group having 1 to 4 carbon atoms. A compound according to claims 1 to 8, wherein J represents an alkylene group having 2 to 4 carbon atoms. A compound according to claims 1 to 10, wherein B represents a direct bond, a C 1 -C 4 alkylene group, -LN (H) -, -LS (O) 2 - or -L-O- (wherein in the last three in the above groups, L is attached to the carbon atom bearing the groups R ⁴ and R ⁵ ). A compound according to any one of claims 1 to 11, wherein L represents an alkylene group having 1 to 4 carbon atoms. A compound according to any one of claims 1 to 12 wherein R ⁶ is phenyl, Het ⁶ (both optionally substituted by one or more substituents selected from cyano, halogen, nitro, C 1 -C 4 alkyl, (C 1 -C 4) alkoxy, optionally substituted phenyl, 101 of the group -N (H) R ^15b , -C (O) R ^15c , -C (O) N (H) R ^15f , -N (H) C (O) R ^15h , -N (H) C (O N (H) R ^15k , -N (H) S (O) 2 R ^14b , -S (O) 2 R ^14c , and -S (O) ₂ N (R ¹⁵ⁿ ) R ^15p ), or when R ⁴ and R ^{When taken} together they form an oxo group, R ⁶ can be an alkyl group having 1 to 5 carbon atoms. A compound according to any one of claims 1 to 13, wherein R ² is cyano, Het ⁸ , -C (O) R ¹⁶ , -C (S) OR ¹⁷ , -C (S) N (H) R ¹⁸ , - [C (O)] 2 N (H) R ^20b , - [C (O)] 2 OR ²¹ , -S (O) ₂ R ²² , -S (O) ₂ N (R ²³ ) R ²⁴ , -C (= N-CN) N (R ²⁵ ) R ²⁶ , -C (= N-CN) OR ^27, or (C 1 -C 6) alkyl ( wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from -C (O) R ²⁸ , -C (O) N (H) R ^29b , -N (R ³⁰ ) R ³¹ , -OR ³² , -S (O) ₂ R ³³ , halogen, cyano, optionally substituted phenyl, and Het ⁹ ). 15. The compound of claim 14, wherein R ^lD is optionally substituted phenyl, Het ^10, or alkyl of 1 to 6 carbon atoms (wherein the alkyl group is optionally unsaturated and / or optionally substituted and / or terminated by one or more substituents selected from atom halogen, cyano, groups of the phenyl group). -N (H ) R ³⁴ , and possibly substr- A compound according to claim 15, where R ³⁴ predstavuj e átom vo- alkyl, having 1 to -C (O) R ^36a or -C (O) OR ^36b . 4 carbon alkyl, group A compound according to claim 14, where R ¹⁸ predstavuj e atom vo- Length, -C (O) OR ^36b or C 1 -C 6 alkyl (which alkyl group is optionally substituted and / or terminated by one or more substituents selected from halo and -C (O) OR ^{36 b).} 102 A compound according to claim 14, wherein R ²² is Het ¹⁴ , optionally substituted phenyl or C 1 -C 4 alkyl (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from halogen, Het ¹⁵ and optionally substituted phenyl). A compound according to claim 14, wherein R ^{23 *} is hydrogen, C 1 -C 4 alkyl, -C (O) OR ^36b, or -C (O) SR ^36b . A compound according to claim 14, wherein R ²⁵ represents a hydrogen atom or a C 1-6 alkyl group (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from a halogen atom, a hydroxy group, a C 1-6 alkyl group carbon atoms (wherein the alkyl group is optionally substituted and / or terminated with one or more substituents selected from C 1 -C 4 alkyl and hydroxy), C 1 -C 4 alkoxy, naphthyl, and optionally substituted phenyl). The compound of claim 14, wherein R ²⁷ is an optionally substituted phenyl group. The compound of claim 14, wherein R ²⁸ is C 1 -C 5 alkyl, optionally substituted phenyl, or Het ¹⁷ . A compound of any one of claims 1 to 14 or 22 wherein R ^29b represents a hydrogen atom, a C 1 -C 4 alkyl group or an optionally substituted phenyl group. 103 A compound according to any one of claims 14, 22 and 23, wherein R ³⁰ represents a hydrogen atom, an optionally substituted phenyl group, a -C (O) R ^37a or -C (O) OR ^{37b group} . A compound according to any one of claims 14 or 22 to 24, wherein R ^{31 *} represents a hydrogen atom or a C 1 -C 2 alkyl group or an optionally substituted phenyl group. A compound according to any one of claims 14 or 22 to 25, wherein R represents a hydrogen atom, a C 1 -C 4 alkyl group (wherein the alkyl group is optionally interrupted by an oxygen atom), an optionally substituted phenyl group or a Het ²¹ group. A compound according to any one of claims 14 or 22 to 26, wherein R ³³ represents an alkyl group having 1 to 6 carbon atoms or an optionally substituted phenyl group. A compound according to any one of claims 1 to 14 or 22 to 27, wherein R ^37a and R ^37b independently represent, at each occurrence, when used herein, a C 1 -C 5 alkyl group, an optionally substituted phenyl group, or R 3 ^37a represents a hydrogen atom. A compound according to any one of claims 1 to 28, wherein R ^3a and R ^{3b are} independently hydrogen, C 1 -C 2 alkyl, -SR ^38b , -N (R ³⁹ ) R ^38c , or R ^3a and R ³ . ^3b together represent an alkylene group having 3 to 4 carbon atoms or -O-Z-O-. A compound according to claim 29, wherein R ³⁹ represents a hydrogen atom, an alkyl group having 1 to 2 carbon atoms, or a structural fraction of formula Ia. 104 A compound according to any one of claims 1 to 30, wherein Z represents an alkylene group having 2 to 3 carbon atoms. A compound according to any one of claims 1 to 31, wherein R ⁴¹ to R ⁴⁶ independently represent a hydrogen atom or an alkyl group having 1 to 2 carbon atoms. A compound according to claim 13 or 14, wherein R ^14b , R ^14c , R ¹⁷ and R ²¹ independently represent an alkyl group having 1 to 4 carbon atoms. A compound according to any one of claims 13, 14 and 29, wherein R ^15b to R ^15p , R ^20b , R ²⁴ , R ²⁶ , R ^38b and R ^38c independently represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. A compound according to any one of claims 1 to 34, wherein the optional substituents on the phenyl groups are one or more substituents selected from cyano, halogen, nitro, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, Het ¹ , amino, -C (O) ^R15c , -C (O) N (H) ^R15f , -N (H) C (O) ^R15h , -N (H) C (O) N (H) R ^15k , -N (H) S (O) 2 R ^14b, and -S (O) 2 N (R ¹⁵ⁿ ) R ^15b . 36. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 35 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. A pharmaceutical composition for use in the prophylaxis or treatment of an arrhythmia comprising a compound as defined in any one of claims 1 to 35. ³⁸ A compound as defined in any one of claims 1 to 15 105 35, but without condition (s) for use as a medicament. A compound as defined in any one of claims 1 to 35, but without condition (s), for use in the prophylaxis or treatment of an arrhythmia. I I Use of a compound as defined in any one of claims 1 to 35, but without condition (s), as an active ingredient for the preparation of a medicament for use in the prophylaxis or treatment of an arrhythmia. The use of claim 40, wherein the arrhythmia is atrial or ventricular arrhythmia. A method of prophylaxis or treatment of an arrhythmia comprising administering to a subject suffering from or susceptible to such a condition a therapeutically effective amount of a compound as defined in any one of claims 1 to 35, but without condition (s). A process for the preparation of compounds of formula I as defined in claim 1, characterized in that it comprises: (a) reacting the corresponding compound of formula II 106 wherein R ^2, R ^3a, R ^3b, and R ⁴¹ to R ⁴⁶ are as defined above, with a compound of formula III, R ^.B-6 R ⁵ (III) wherein L ¹ represents a leaving group and R ⁴ , R ⁵ , R ⁶ , A and B are as defined in claim 1; (b) for compounds of formula I, wherein R ¹ represents a structural fraction of formula Ia, wherein A represents a C 2 alkylene group and R ⁴ and R ⁵ together form an oxo group, the reaction of the corresponding compound of formula II as defined above, with a compound of formula IV (IV) Wherein R and B are as defined in claim 1; (c) for compounds of formula I wherein R ^3a or R ^3b are -N (R ³⁹ ) R ^38c and R ³⁹ is a structural fraction of formula Ia, a reaction of a corresponding compound of formula I wherein R ^3a or R ^3b ( as appropriate) represents the group -N (H) R ^38c , where R ^38c has already been defined in the claim I, with a compound of formula III as defined above; (d) for compounds of formula I wherein R ¹ is a structural fraction of formula Ia, wherein A is CH ₂ and R ⁴ is hydroxy or -N (H) R ⁸ , the reaction of the corresponding compound of formula II as defined above with a compound of formula V 107 R 5 (V) wherein X represents an oxygen atom or -N (R ⁸ ) - and R ⁵ , R ⁶ , R ⁸ and B are as defined in claim 1; (e) for compounds of formula I wherein R ^3a and R ^3b are -N (R ³⁹ ) R ^38c and R ³⁹ is a structural fraction of formula Ia wherein A is CH ₂ and R ⁴ is hydroxy or - N (H) R ⁸ , the reaction of a corresponding compound of formula I wherein R ^3a or R ^3b (as appropriate) represents an -N (H) R ^{38c group} , wherein R ^38c is as defined in claim 1, with a compound of formula V, as already defined; (f) for compounds of formula I wherein A is C 1 -C 6 alkylene, B is C 1 -C 4 alkylene, and R ⁴ and R ^{5 are} both hydrogen, reducing the corresponding compound of formula I, wherein R ⁴ and R ⁵ together represent oxo; (g) for compounds of formula I wherein R ⁴ and R ^{5 are} both hydrogen, and (1) A is a single bond or -JN (R ¹² ) and B is C 1 -C 4 alkylene, or ( 2) A is a C 1 -C 6 alkylene group and B is -N (R ¹³ ) - or -N (R ¹³ ) -L-, a reduction of the corresponding compound of formula I wherein R ⁴ and R ⁵ together represent oxo ; (h) for compounds of formula I wherein A is C 1 -C 6 alkylene, B is direct bond, C 1 -C 4 alkylene, 108 -LN (R ¹³ ) -, -LS (O) _P - or -LO- (wherein in the three groups L is C 1 -C 4 alkylene), R ⁴ is hydroxy and R ⁵ is hydrogen, reduction of the corresponding Compounds of formula I wherein R ⁴ and R ⁵ together represent oxo; (i) for compounds of formula I wherein R ^3a and R ^{3b are} both hydrogen, a reduction of the corresponding compound of formula VI (VI) wherein R ¹ , R ² and R ⁴¹ to R ⁴⁶ are as defined above, and wherein the terminal the bridging group C = O can be activated; (j) for compounds of formula I wherein one of R ^3a and R ^3b is hydrogen and the other hydroxy is reducing a corresponding compound of formula VI as defined above; (k) for compounds of formula I wherein R ^3a and R ^{3b are} both -OR ^38a or -SR ^38b , or wherein R ^3a and R ^3b together represent -OZO-, -OZS- or -SZS-, a reaction corresponding to a compound of formula VI as defined above with a compound of formula HOR ^38a , HSR ^38b , -HO-Z-OH, HO-Z-SH or HS-Z-SH (as appropriate), wherein R ^38a , R ^38b and Z are as defined in claim 1; (1) for compounds of formula I wherein one of R ^3a and R ^3b is amino and the other is hydrogen, re 109 production of a compound of formula VII wherein R ¹ , R ² and R ⁴¹ to R ⁴⁶ are as defined in claim 1; (m) for compounds of formula I wherein one or both of R ^3a and R ^3b is -N (R ³⁹ ) R ^38c , where one or both of R ³⁹ and R ^38c are C 1 -C 6 alkyl, the alkylation of the corresponding compounds of formula I wherein R ^3a and / or R ^3b are -N (R ³⁹ ) R ^38c (as appropriate), wherein R ³⁹ and / or R ^38c (as appropriate) are hydrogen, wherein: using a compound of formula VIII R ^and -I? (VIII) wherein R ^a represents an alkyl group having 1 to 6 carbon atoms and L ¹ is as previously defined; (n) for compounds of formula I wherein R ¹ is a structural fraction of formula Ia, wherein B is -L-O, the reaction of a compound of formula IX 110.3b (IX) R ² wherein R ^z, R ^3, R ^JD, R ^q, R ^3, R and R ^{zi QB,} A and L are as defined in Claim 1 with a compound of formula X R ⁶ OH (X) wherein R ⁵ is as defined in claim 1; (o) for compounds of formula I, wherein R ¹ is a structural fraction of formula Ia, wherein A is C 1 -C 6 alkylene and B is -N (R ¹³ ) -L- (wherein the -N (R 1) ¹³ ) - is attached to a carbon atom which carries the groups R ⁴ and R ⁵ 'by the reaction of a compound of the general formula XI R ² (xi: wherein A ^a represents an alkylene group having 1 to 6 carbon atoms and, 3b> 13 R ^z, R ^3, R ^jd, R ', R ^3, R and R ^{iJ qi QB} and R are as defined in Claim 1, 111 with a compound of formula XII R ⁶ -LL ² (XII) wherein L ² represents a leaving group and R ⁶ and L are as defined in claim 1; (p) for compounds of formula I, wherein R ¹ is a structural fraction of formula Ia, wherein R ⁴ is -D-NH ₂ , a reduction of the corresponding compound of formula XIII wherein R ² , R ^3a , R ^3b , R ⁵ , v Claim 1; R ⁶ , R ⁴¹ az R ⁴⁶ , And, B and D have already been defined (q) for compounds of formula I wherein R ⁴ is -DN (R ⁹ ) C (O) NH (R ^11b ), the reaction of the corresponding compound of formula I wherein R ⁴ is -DN (R ⁹ ) H,. with a compound of formula XIV ^IIb R N = C = O (XIV) wherein R ^nb is as defined in Claim 1; (r) for compounds of formula I wherein R ⁴ is -DN (H) [C (O)] 2 NH 2, reacting a corresponding compound of formula I wherein R ⁴ is -D-NH 2 with diamyl oxalic acid; (s) for compounds of formula I wherein R ⁴ is -DN (R ⁸ ) ⁹ wherein R ⁸ and R ⁹ are as defined in claim 1, provided that R ^{8 is} not hydrogen, the reaction of the corresponding compound of formula I, wherein R ⁴ is i -DN (H) R ⁹ , with a compound of formula XV R ^8a -L ³ (XV) wherein R ^a represents R as defined in claim 1, except that it is not a hydrogen atom, and L ³ represents a leaving group; (t) for compounds of formula I wherein R ⁴ is -D-OR ⁷ , wherein R ⁷ is C 1 -C 6 alkyl, -E-aryl, or -E-Het ¹ , the reaction of the corresponding compound of general formula of formula I wherein R ⁴ is -D-OH with a compound of formula XVI R ^7a OH (XVI) wherein R ^7a represents a C 1-6 alkyl, -E-aryl, or -E-Het ^{1 group} , wherein Het ¹ is as previously defined in claim 1; (u) for compounds of formula I wherein R ¹ is a structural fraction of formula Ia wherein R ⁴ is -D-OR ⁷ (wherein R ⁷ is C 1 -C 6 alkyl, -E-aryl or -E-Het ¹ ), reacting the corresponding compound of formula XVII 113 wherein L ² , R ² , R ^3a , R ^3b , R ⁵ , R ⁶ , R ⁴¹ to R ⁴⁶ , A, B and D are already defined in claim 1 and L ² is already defined, with a compound of formula XVI, as defined above; (v) for compounds of formula I wherein R ⁴ is -D-OR ⁷ where R ⁷ is as defined in claim 1, provided that it is not hydrogen, the reaction of the corresponding compound of formula I wherein R ⁴ is a group -D-OH, with a compound of formula XVIII R ^7b -L ⁴ (XVIII) wherein R ^7b represents R ⁷ as defined in claim 1, except that it is not hydrogen, and, L ⁴ represents a leaving group; (w) for compounds of formula I wherein R ⁴ is halogen, substitution of the corresponding compounds of formula I wherein R ⁴ is hydroxy, using a suitable halogenating agent; 114 (x) reacting a corresponding compound of formula XIX wherein R ¹ , R ^3a , R ^3b and R ⁴¹ to R ⁴⁶ are as defined in claim 1 with a compound of formula XX R ² -L ⁵ (XX) wherein L ⁵ represents a leaving group and R ² is already defined; (y) for compounds of formula I wherein R ² is C 1 -C 12 alkyl wherein the alkyl group is substituted in the 2-position (relative to the bispidine nitrogen atom) by hydroxy or -N (H) R ³⁰ , and otherwise is optionally substituted with one or more additional substituents as specified in claim 1 for R ² , reacting a compound of formula XIX as defined above with a compound of formula XXA (XXA) wherein X ⁴ represents an oxygen atom or -N ( R ³⁰ ) - and R ^2a represents an alkyl group having 1 to 10 carbon atoms optionally substituted by one or more substituents as specified in claim 1 for R; (z) for compounds of formula I wherein R ² is tetrazol-5-yl, reacting the corresponding compound of formula 115 of formula I, wherein R ² is CN, with a suitable source of the azide ion; (aa) for compounds of formula I which are N-oxide derivatives of bispidine nitrogen atom, oxidizing the corresponding bispidine nitrogen atom of the corresponding compound of general formula I, in the presence of a suitable oxidizing agent; (ab) for compounds of formula I which are derivatives of an alkyl quaternary ammonium salt of 1 to 4 carbon atoms in the alkyl moiety where the alkyl group is attached to the bispidine nitrogen atom, reacting the bispidine nitrogen atom of the corresponding compound of formula I with a compound of formula XXI R ^b -L ² (XXI) wherein R ^b is C 1 -C 4 alkyl; (ac) converting one substituent to R ⁶ to another; (ad) converting one R ² group to another; or (ae) removing the protected derivative of a compound of formula I as defined in claim 1. A compound of formula II as defined in claim 43, or a protected derivative thereof. A compound of formula VI as defined in claim 43, or a protected derivative thereof. A compound of formula VII as defined in claim 43, or a protected derivative thereof. A compound of formula IX as defined in claim 116 43, or a protected derivative thereof. A compound of formula XI as defined in claim 43, or a protected derivative thereof. A compound of formula XIII as defined in claim 43, or a protected derivative thereof. A compound of formula (XVII) as defined in claim 43, or a protected derivative thereof. A compound of formula XIX as defined in claim 43 (provided that at least one of R ^3a and R ^3b is -N (R ³⁹ ) R ^38c , wherein R ³⁹ is a structural fraction of formula Ia as already described as defined in claim 1), or a protected derivative thereof. 52. A compound of formula XXII R 3b R 3a (XXII) wherein R ^3a , R ^3b and R ⁴¹ to R ⁴⁶ are as previously defined in claim 1 (provided that at least one of R ^3a and R ^3b is -N (R ³⁹ ) R ^38c wherein R ³⁹ represents a structural fragment of formula Ia as defined in claim 1), or a protected derivative thereof. 117 53. A compound of formula XXIII is a derivative.