CN1440407A - Bispidine compounds and their use in 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

Novel bispidine compounds and their use in the treatment of cardiac arrhythmias

Technical Field

The present invention relates to novel pharmaceutical compounds, in particular compounds useful for the treatment of cardiac arrhythmias.

Background of the invention and Prior Art

Arrhythmia may be defined as an abnormality in the rate, regularity, or onset of cardiac activity, or a disturbance in conduction that causes an abnormal activation sequence. Clinically, arrhythmias can be classified by assumed origin (i.e., as supraventricular arrhythmias, including atrial and atrioventricular arrhythmias, and ventricular arrhythmias) and/or by heart rate (i.e., bradycardia (slow) and tachycardia (fast)).

In the treatment of cardiac arrhythmias, the negative results in clinical trials (see for example the results of the arrhythmia inhibition test (CAST), reported in New England Journal of medicine, 321, 406 (1989)) mainly by "traditional" antiarrhythmic drugs (class I antiarrhythmic drugs) which slow down the conduction velocity have prompted drug development towards compounds which selectively delay cardiac repolarization, thereby prolonging the QT interval. Class III antiarrhythmic drugs may be defined as drugs that prolong transmembrane action potential duration (which may be caused by blocking outward K + flow or increasing inward ion flow) and refractory period, while not affecting cardiac conduction.

The major drawback of the known drugs (class III drugs or other drugs) to date by delaying repolarization is that they are known to exhibit a unique form of pro-arrhythmia known as the torsade de point, which can sometimes be fatal. From a safety point of view, minimizing this phenomenon (which is also shown to be the result of administration of non-cardiac drugs such as phenothiazines, tricyclic anti-suppressive drugs, antihistamines and antibiotics) is a first problem to be solved in providing effective antiarrhythmic drugs.

Anti-arrhythmic drugs based on bispidines (3, 7-diazabicyclo [3.3.1] nonane) can be found in particular in international patent applications WO91/07405 and WO99/31100, european patent applications 000074, 301245, 306871, 308843, 461574 and 665228, european patent applications DE2428792, DE2658558 and DE2744248, and US patents 3,962,449, 4,556,662, 4,550,112, 4,459,301, 5,468,858 and 5,786,481, as well as in journal articles, including in particular: 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 (1977). Known bispidine-based antiarrhythmic compounds include bisaramil (cis-9- (4-chlorobenzoyloxy) -3-methyl-7-ethyl-3, 7-diazabicyclo [3.3.1] nonane), tedisamil (3, 7-bis- (cyclopropylmethyl) -9, 9-tetramethylene-3, 7-diazabicyclo [3.3.1] nonane), SAZ-VII-22(3- (4-chlorobenzoyl) -7-isopropyl-3, 7-diazabicyclo [3.3.1] nonane), SAZ-VII-23 (3-benzoyl-7-isopropyl-3, 7-diazabicyclo [3.3.1] nonane), GLG-V-13(3- [4- (1H-imidazol-1-yl) benzoyl ] -7-isopropyl-nonane Propyl-3, 7-diazabicyclo [3.3.1] nonane), KMC-IV-84(7- [ 4' - (1H-imidazol-1-yl) -benzenesulfonyl ] -3-isopropyl-3, 7-diazabicyclo [3.3.1] nonane diperchlorate (dihydroperchlorate) and ambaride (3- (4-aminobenzoyl) -7-benzyl-3, 7-diazabicyclo [3.3.1] nonane). Other bispidine compounds can be found, inter alia: eur.j.med.chem.25, 1 (1990); ball. Polish Acad. Sci. chem.34(5-6), 205 (1986); j. org chem.60, 8148 (1995); eur.j.med.chem. -Chimica therapeutics 12(4), 301 (1977); phosphorus, Sulfur and Silicon 123, 385 (1997); chem.42(6), 937 (1977); molecular Structure 127, 185 (1985).

We have surprisingly found that a novel group of 3, 7-diazabicyclo [3.3.1] nonane-based compounds exhibit electrophysiological activity, preferably class III electrophysiological activity, and are therefore expected to be useful in the treatment of cardiac arrhythmias.

Disclosure of the invention

The invention provides a compound of formula ICompound or pharmaceutically acceptable derivative thereof

Wherein

R¹Represents a structural fragment of formula Ia

R⁴Represents H, halogen, C_1-4Alkyl, -D-OR⁷、-D-N(R⁸)R⁹Or R is⁴And R⁵Together represent ═ O;

R⁵representative H, C_1-4Alkyl, or R⁵And R⁴Together represent ═ O;

d represents a bond or C_1-4An alkylene group;

R⁷representative H, C_1-6Alkyl, -E-aryl, -E-Het¹、-C(O)R^10a、-C(O)OR^10bor-C (O) N (R)^11a)R^11b；

R⁸Representative H, C_1-6Alkyl, -E-aryl, -E-Het¹、-C(O)R^10a、-C(O)OR^10b、-S(O)₂R^10c、-[C(O)]_nN(R^11a)R^11bor-C (NH) NH₂；

R⁹Representative H, C_1-6Alkyl, -E-aryl, or-C (O) R^10d；

In each use, E represents a bond or C_1-4An alkylene group;

at each time of use, R^10aAnd R^10dEach independently represents C_1-6Alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het)²) Aryl, Het³Or R is^10aAnd R^10dIndependently represents H;

at each time of use, R^11aAnd R^11bEach independently represent H, C_1-6Alkyl (optionally substituted and/or terminated by one or more substituents selected from halo, aryl and Het)⁴) Aryl, Het⁵Or R is^11aAnd R^11bTogether represent C_3-7Alkylene, wherein the alkylene may optionally be interrupted by oxygen atoms;

n represents 1 or 2;

a represents-G-, -J-N (R)¹²) -or-J-O- (wherein in the latter two groups, J is attached to the bispidine nitrogen atom);

b represents-L-, -L-N (R)¹³)-、-N(R¹³)-L-、-L-S(O)_p-or-L-O- (wherein in the latter two groups L is linked carrying R⁴And R⁵On the carbon atom of (c);

g represents a bond or C_1-6An alkylene group;

j represents C_2-6An alkylene group;

l represents a bond or C_1-4An alkylene group;

p represents 0,1 or 2;

R¹²and R¹³Independently represent H or C_1-4An alkyl group;

R⁶represents aryl, Het⁶(both of these groups are optionally substituted and/or terminated, if appropriate, by one or more substituents selected from-OH, cyano, halogen, nitro, C_1-6Alkyl (optionally with-N (H) C (O) OR)^14aAs terminal), C_1-6Alkoxy, aryl, Het⁷、-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(R¹⁵ⁱ)C(O)N(R^15j)R^15k、-N(R^15m)S(O)₂R^14b、-S(O)_qR^14c、-OS(O)₂R^14dand-S (O)₂N(R¹⁵ⁿ)R^15p) Or when R is⁴And R⁵When together represent ═ O, R⁶Can represent C_1-6An alkyl group;

q represents 0,1 or 2;

R²represents-CN, Het⁸、-C(O)R¹⁶、-C(S)OR¹⁷、-C(S)N(R¹⁸)R¹⁹、-[C(O)]₂N(R^20a)R^20b、-[C(O)]₂OR²¹、-S(O)₂R²²、-S(O)₂N(R²³)R²⁴、-C(＝N-CN)N(R²⁵)R²⁶、-C(＝N-CN)OR²⁷Or C_1-12Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from-C (O) R²⁸、-C(O)N(R^29a)R^29b、-N(R³⁰)R³¹、-OR³²、-S(O)_rR³³Halogen, -CN, nitro, aryl and Het⁹)；

R¹⁶Represents H, aryl, Het¹⁰Or C_1-6Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from the group consisting of halogen, -OH, -CN, -N (R)³⁴)R³⁵Aryl and Het¹¹)；

R³⁴Representative H, C_1-6Alkyl, aryl, Het¹²、-C(O)R^36aOR-C (O) OR^36b；

R¹⁸Represents H, aryl, Het¹³、-C(O)R^36a、-C(O)OR^36bOr C_1-6Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from the group consisting of halogen, -OH, -CN, -C (O) R^36aand-C (O) OR^36b)；

R²²Represents Het¹⁴Aryl, or C_1-6Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from the group consisting of halogen, -OH, -CN, Het¹⁵And aryl groups);

R²³representative H, C_1-6Alkyl, aryl, Het¹⁶、-C(O)R^36a、-C(O)OR^36bor-C (O) SR^36b；

R²⁵Represents H or C_1-6Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from the group consisting of halogen, -OH, -CN, C_1-6Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from C_1-4Alkyl and-OH), C_1-6Alkoxy and aryl);

R²⁷represents C_1-6An alkyl or aryl group;

R²⁸representative H, C_1-6Alkyl, aryl or Het¹⁷；

R^29aAnd R^29bIndependently represent H, C_1-6Alkyl, aryl or Het¹⁸；

R³⁰Representative H, C_1-6Alkyl, aryl, Het¹⁹、-C(O)R^37a、-C(O)OR^37bor-C (O) N (R)^37c)R^37d；

R³¹Representative H, C_1-6Alkyl, aryl or Het²⁰；

R³²Representative H, C_1-6Alkyl, aryl, Het²¹、-C(O)R^37a、-C(O)OR^37bor-C (O) N (R)^37c)R^37d；

R³³Represents C_1-6Alkyl, aryl or Het²²；

r represents 0,1 or 2;

at each time of use, R^36aAnd R^36bEach independently represents C_1-6Alkyl, or R^36aRepresents H;

at each timeWhen in use, R^37a-R^37dEach independently represents C_1-6Alkyl, aryl or Het²³Or R is^37a、R^37cAnd R^37dIndependently represents H;

at each use, Het¹-Het²³Independently represent a 5-12 membered heterocyclyl group containing one or more heteroatoms selected from oxygen, nitrogen and/or sulphur;

R^3aand R^3bIndependently represent H, C_1-4Alkyl, -OR^38a、-SR^38b、-N(R³⁹)R^38cOr R is^3aAnd R^3bTogether represent C_3-5Alkylene, -O-Z-O-, -O-Z-S-, or-S-Z-S-;

R³⁹representative H, C_1-6Alkyl or a structural fragment of formula Ia as defined above;

z represents optionally substituted one or more C_1-4Alkyl substituted C_2-3An alkylene group;

R⁴¹-R⁴⁶independently represent H or C_1-3An alkyl group;

R^14a-R^14d、R¹⁷and R²¹Independently represent C_1-6An alkyl group;

R^15a-R^15p、R¹⁹、R^20a、R^20b、R²⁶、R³⁵、R^38aand R^38cIndependently represent H or C_1-6An alkyl group;

wherein each aryl and Het (Het) is, unless otherwise specified¹-Het²³) May be optionally substituted;

with the following conditions:

(a) when R is¹Represents a structural fragment of formula Ia, and wherein

R⁴And R⁵Together represent ═ O;

when A represents a bond, the compound is,

then B does not represent a bond, -N (R)¹³) -L- (wherein the radical-N (R)¹³) Is connected to

Carry R⁴And R⁵On carbon atom of (B), -N (R)¹³)-、-S(O)_p-or-O-;

(b) when R is⁵Represents H or C_1-4An alkyl group; and is

A represents-J-N (R)¹²) when-or-J-O-is present,

then B does not represent-N (R)¹³)-L-、-N(R¹³)-、-S(O)_p-or-O-;

(c) when R is⁴represents-D-OR⁷、-D-N(R⁸)R⁹And wherein D represents a bond,

then:

(i) a does not represent-J-N (R)¹²) -or-J-O-; and is

(ii) B does not represent-N (R)¹³)-L-、-N(R¹³)-、-S(O)_p-or-O-;

(d) when R is^3aAnd R^3bAll represent H;

and R is¹When represents an unsubstituted benzyl group, the compound (A) is,

then R is²Does not represent unsubstituted benzyl or optionally substituted benzoyl; and

(e) the compound is not:

(i)N¹-phenyl-3- (7-benzyl-3, 7-diazabicyclo [3.3.1]Nonane-3-

Mesityl) propionamide;

(ii) 3-benzyl-7- [3- (4-cyanophenoxy) -2-hydroxypropyl ] -6, 8-bis

Methyl-3, 7-diazabicyclo [3.3.1] nonane;

(iii) 3-benzyl-7- [3- (4-cyanophenoxy) -2-hydroxypropyl ] -6-methyl

-3, 7-diazabicyclo [3.3.1] nonane;

(iv) n- {2- (7-benzyl-3, 7-diazabicyclo [3.3.1] non-3-yl) -1-

[ (4-cyano-phenoxy) methyl ] ethyl } methanesulfonamide;

(v) 3-benzyl-7- [3- (2-propyl-1, 3-dioxolan-2-yl) propane

-3, 7-diazabicyclo [3.3.1] nonane; or

(vi) 7-benzyl-3, 7-diazabicyclo [3.3.1] nonane-3-ethanol;

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

Unless otherwise specified, alkyl and alkoxy groups as defined herein may be straight chain or, when they have a sufficient number (i.e. a minimum of 3) of carbon atoms, they may be branched and/or cyclic groups. Furthermore, such alkyl and alkoxy groups may also be partially cyclic/acyclic groups when having a sufficient number of carbon atoms (i.e. a minimum of 4). Such alkyl and alkoxy groups may be saturated or, when having a sufficient number of carbon atoms (i.e. a minimum of 2), may be unsaturated and/or interrupted by one or more oxygen and/or sulfur atoms. Unless otherwise indicated, alkyl and alkoxy groups may be substituted by one or more halogen, in particular fluorine, atoms.

Unless otherwise specified, an alkylene group as defined herein may be straight-chain or, when having a sufficient number of carbon atoms (i.e. a minimum of 2), branched-chain. Such alkylene chains may also be saturated or, when having a sufficient number of carbon atoms (i.e. a minimum of 2), may be unsaturated and/or interrupted by one or more oxygen and/or sulphur atoms. Unless otherwise specified, an alkylene group may be substituted with one or more halogen atoms.

As used herein, the term "aryl" includes C_6-10Aryl groups such as phenyl, naphthyl, and the like. Unless otherwise specified, an aryl group may be substituted with one or more substituents including-OH, cyano, halogen, nitro, C_1-6Alkyl (optionally with-N (H) C (O) OR)^14aAs terminal), C_1-6Alkoxy, Het¹Aryl (which may be unsubstituted by any further aryl), -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(R¹⁵ⁱ)C(O)N(R^15j)R^15k、-N(R^15m)S(O)₂R^14b、-S(O)_qR^14c、-OS(O)₂R^14dand-S (O)₂N(R¹⁵ⁿ)R^15p) (wherein Het¹、R^14a-R^14d、R^15a-R^15pAnd q is as defined above). When substituted, aryl groups are preferably substituted with 1-3 substituents.

As used herein, the term "halogen" includes fluorine, chlorine, bromine and iodine.

Het (Het) which may be mentioned¹-Het²³) Groups include those containing 1 to 4 heteroatoms (selected from oxygen, nitrogen and/or sulfur) and having a total number of atoms in the ring system of from 5 to 12. Het (Het)¹-Het²³) The groups may be fully saturated, partially unsaturated, fully aromatic, partially aromatic and/or bicyclic groups. Heterocyclic groups which may be mentioned include benzodioxanyl, benzodioxepinyl, benzodioxolyl, benzofuranyl, benzofurazanyl, benzimidazolyl, benzomorpholinyl, benzothienyl, chromanyl, cinnolinyl, dioxanyl, furanyl, hydantoinyl, imidazolyl, imidazo [1, 2a ] group]Pyridyl, indolyl, isoquinolyl, isoxazolyl, maleimido, morpholinyl, 2-oxazolidonoyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidineKeto, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolyl, tetrahydrothiophenyl, 3-thiophenyl (sulfolenyl), tetrahydropyranyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiochromanyl, triazolyl, and the like. Mention may be made of Het¹Including pyridyl. Mention may be made of Het⁶Including benzodioxinyl, benzomorpholinyl, furanyl, isoquinolyl, isoxazolyl, 2-oxazolidonyl, piperazinyl, pyrazolyl, pyrrolidinonyl and 1, 2, 3-thiadiazolyl. Mention may be made of Het⁸Including pyrimidinyl, quinazolinyl, tetrazolyl, thiazolyl, and 1, 2, 4-triazolyl. Mention may be made of Het⁹Including benzomorpholyl, 2-oxazolidonoyl and piperazinyl. Mention may be made of Het¹⁰Including furyl, isoxazolyl, pyrazolyl, pyrrolidinonyl and 1, 2, 3-thiadiazolyl. Mention may be made of Het¹⁴Including imidazolyl, tetrahydrothiophenesulfonyl, thienyl and quinolinyl. Mention may be made of Het¹⁵Including morpholinyl. Mention may be made of Het¹⁷Including benzomorpholinyl. Mention may be made of Het²¹Including isoquinolinyl.

Het (Het) unless otherwise stated¹-Het²³) A group may be substituted with one or more substituents including ═ O, -OH, cyano, halogen, nitro, C_1-6Alkyl (optionally with-N (H) C (O) OR)^14aAs terminal), C_1-6Alkoxy, Het¹Aryl, -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(R¹⁵ⁱ)C(O)N(R^15j)R^15k、-N(R^15m)S(O)₂R^14b、-S(O)_qR^14c、-OS(O)₂R^14dand-S (O)₂N(R¹⁵ⁿ)R^15p) (wherein Het¹Aryl, R^14a-R^14d、R^15a-R^15pAnd q is as defined above). When Het (Het)¹-Het²³) The radicals being substituted by one or more Het¹And/or aryl substituted, said Het¹And/orThe aryl substituents may themselves be free of any aryl and/or Het¹And (4) substitution. Het (Het) if appropriate¹-Het²³) The substituents on the group may be located at any atom in the ring system that includes the heteroatom. Het (Het)¹-Het²³) The attachment site of (a) may be via any atom of the ring system that includes, if appropriate, a heteroatom. Het (Het)¹-Het²³) It may also be in the N-or S-oxidized form.

Pharmaceutically acceptable derivatives include salts and solvates. Salts that may be mentioned include acid addition salts. Pharmaceutically acceptable derivatives are also included in 3, 7-diazabicyclo [3.3.1]C on nonane nitrogen_1-4Alkyl quaternary ammonium salts and N-oxides, with the proviso that when N-oxide is present:

(a) no Het (Het)¹-Het²³) Containing unoxidized S-atoms;

(b) when B represents-L-S (O)_p-when p does not represent 0;

(c) when-S (O)_qR^14cAs aryl, Het (Het)¹-Het²³) Or R⁶Substituent(s) on

Q, when present, does not represent 0; and/or

(d) when-S (O)_rR³³As R²R does not represent

0。

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

The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereomers may be separated using conventional techniques such as chromatography or fractional crystallization. The different stereoisomers may be separated by separation of the racemates or other mixtures of the compounds using conventional techniques, such as fractional crystallisation or HPLC techniques. Alternatively, the desired optical isomer may be obtained by: suitable optically active starting materials are reacted under conditions which do not lead to racemization or epimerization or are derivatized, for example with a homochiral acid, and the diastereomeric esters are then separated off by customary methods (e.g. HPLC, silica chromatography). All stereoisomers are included within the scope of the present invention.

Abbreviations are listed at the end of this specification.

Compounds of the invention which may be mentioned include compounds of formula I as defined above, but with the following additional conditions:

(i) when R is²Represents C_1-6Alkyl (optionally substituted with one or two aryl groups) then:

(I) when R is⁴Representative H, C_1-4Alkyl, -OR⁷Or R is⁴And R⁵Together represent ═ O;

R⁷representative H, C_1-6Alkyl or-C (O) R^10a(ii) a And is

R⁶When represents aryl, then

B does not represent-L-; and/or

(II) when A represents a single bond; and is

R⁴And R⁵When taken together represent ═ O,

then R is^3aAnd R^3bDo not simultaneously represent C_1-4Alkyl, or they do not together represent

C_3-5An alkylene group;

(ii) when R is²represents-C (O) R¹⁶And the group-A-C (R)⁴)(R⁵) -B-represents C_1-6Alkylene radical

Then:

(I)R¹⁶does not represent an aryl group; and/or

(II)R^3aAnd R^3bDo not simultaneously represent C_1-4Alkyl, or they do not together represent C_3-5

An alkylene group; and

(iii) when R is²represents-S (O)₂R²²；

R^3aAnd R^3bIndependently represent H or C_1-4An alkyl group; and is

R⁶When the compound represents an aromatic group, the compound is,

then a and B do not represent a bond at the same time,

wherein in the above conditions, unless otherwise specified, aryl groups may be optionally substituted as described above.

Compounds of the invention which may also be mentioned include compounds of formula I as defined above, but with the following additional conditions: when R is^3aAnd R^3bIndependently represent H, C_1-4Alkyl, OH or N (R)³⁹)R^38c(ii) a And R is³⁹Represents H or C_1-6When alkyl, then:

(a) when R is²Represents CN or is optionally substituted by OH, N (R)³⁰)R³¹Or Het⁹Substituted C_1-6An alkyl group;

R³⁰and R³¹Independently represent H, C_1-6Alkyl or C_3-8A cycloalkyl group;

Het⁹represents an unsubstituted saturated 3-to 8-membered heterocyclic ring containing one nitrogen atom (heterocyclic ring)

The radical is attached to the rest of the molecule via this nitrogen atom);

R⁴and R⁵All represent H; and is

R⁶Represents a compound which is substituted by CO in the meta-or para-position (relative to the radical B)₂H or NH₂Substituted benzenes

When the base is used, the following steps are carried out:

(i) when A represents a bond, C_1-6n-alkylene or-J-O-; and is

J represents C_2-3In the case of an n-alkylene group,

then B does not represent-L-N (R)¹³) -or-L-O- (in the latter two radicals, L

Represents a bond or C_1-4n-alkylene, linked to a radical carrying R⁴And R⁵Carbon of (2)

On an atom); and

(ii) when A represents-J-O-; and is

J represents C_2-3In the case of an n-alkylene group,

b does not represent a bond; and (b) when R is⁶Represents Het⁶；

Het⁶Represents an unsubstituted saturated 3-to 8-membered heterocyclic ring containing one nitrogen atom (heterocyclic ring)

The radical is attached to the rest of the molecule via this nitrogen atom); and is

The radical-A-C (R)⁴)(R⁵) -B-represents C_1-6In the case of an n-alkylene group,

then R is²Not to represent:

(i)C_1-6n-alkyl, wherein the alkyl is optionally interrupted by O and is N (R)³⁰)R³¹

OR OR³²Is a terminal end; wherein

R³⁰And R³¹Wherein one represents H or is in the meta or para position (relative to the link)

Attachment site) by CO₂H or NH₂Substituted phenyl, the other represents H or

C_1-6An alkyl group; and is

R³²Represents H or is substituted by CO in the meta or para position (relative to the attachment site)₂H or

NH₂Substituted phenyl;

(ii)-C(O)R¹⁶wherein R is¹⁶Represents H or in the meta or para position (relative to the linkage)

Site) by CO₂H or NH₂Substituted phenyl;

(iii)-S(O)₂R²²wherein R is²²Represents in meta or para position (relative to the linking position)

Point) is covered with CO₂H or NH₂Substituted phenyl;

(iv)-S(O)₂N(R²³)R²⁴(ii) a Wherein

R²³Representing a CO bond in the meta or para position (relative to the attachment site)₂H or NH₂

Substituted phenyl; and is

R²⁴Represents H or C_1-6An alkyl group; and

(v)C_3-4n-alkyl, wherein the alkyl is terminated with phenyl, said phenyl

By CO in the meta-or para-position (relative to the attachment site)₂H or NH₂The substitution is carried out by the following steps,

and the alkyl group is interrupted at the beta-site (relative to the attachment site of the phenyl group) by O

And (4) separating.

Other compounds of the invention which may be mentioned include compounds of formula I as defined above, but with the following additional conditions: r⁶Not to represent:

(i) an unsubstituted saturated 3-8 membered heterocyclic ring containing one nitrogen atom (the heterocyclic group being attached to the remainder of the molecule via this nitrogen atom); or

(ii) By CO in meta-or para-position (relative to the radical B)₂H or NH₂A substituted phenyl group.

Other compounds of the invention which may also be mentioned include those defined below: wherein R is⁶Represents aryl, optionally substituted and/or terminated (if appropriate) by one or more substituents selected from: -OH, cyano, halogen, nitro, C_1-6Alkyl (optionally with-N (H) C (O) OR)^14aAs terminal), C_1-6Alkoxy, aryl, Het⁷、-C(O)R^15c、-C(O)N(R^15e)R^15f、-N(R^15g)C(O)R^15h、-N(R¹⁵ⁱ)C(O)N(R^15j)R^15k、-N(R^15m)S(O)₂R^14b、-S(O)_qR^14c、-OS(O)₂R^14dand-S (O)₂N(R¹⁵ⁿ)R^15pOr when R is⁴And R⁵When together represent ═ O, R⁶Can represent C_1-6An alkyl group.

Preferred compounds of the invention also include those defined as follows:

R⁴representative H, C_1-2Alkyl, -OR⁷Or N (H) R⁸Or R is⁴And R⁵Together represent ═ O;

R⁵represents H, or R⁵And R⁴Together represent ═ O;

R⁷representative H, C_1-4Alkyl, optionally substituted phenyl, -C (O) R^10aor-C (O) N (R)^11a)R^11b；

R⁸Representative H, C_1-4Alkyl, -C (O) R^10a、-C(O)OR^10bor-C (O) N (R)^11a)R^11b；

At each time of use, R^10aAnd R^10bEach independently represents C_1-5Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from halogen and phenyl), optionally substituted phenyl, or R^10aRepresents H;

at each time of use, R^11aAnd R^11bEach independently represents H or C_1-5Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from the group consisting of halogen and phenyl);

a represents-G-or-J-N (R)¹²)-；

B represents a bond, C_1-4Alkylene, -L-N (H) -, -L-S (O)₂-or-L-O- (in the last three groups, L is linked to carry R⁴And R⁵On the carbon atom of (c);

g represents a bond or C_1-4An alkylene group;

j represents C_2-4An alkylene group;

l represents C_1-4An alkylene group;

R⁶represents phenyl, Het⁶(both of which are optionally substituted with one or more substituents selected from cyano, halogen, nitro, C_1-4Alkyl radical, C_1-4Alkoxy, optionally substituted phenyl, -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)₂R^14b、-S(O)₂R^14cand-S (O)₂N(R¹⁵ⁿ)R^15p) Or when R is⁴And R⁵When together represent ═ O, R⁶Can represent C_1-5An alkyl group;

R²represents-CN, Het⁸、-C(O)R¹⁶、-C(S)OR¹⁷、-C(S)N(H)R¹⁸、-[C(O)]₂N(H)R^20b、-[C(O)]₂OR²¹、-S(O)₂R²²、-S(O)₂N(R²³)R²⁴、-C(＝N-CN)N(R²⁵)R²⁶、-C(＝N-CN)OR²⁷Or C_1-6Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from-C (O) R²⁸、-C(O)N(H)R^29b、-N(R³⁰)R³¹、-OR³²、-S(O)₂R³³Halogen, -CN, optionally substituted phenyl and Het⁹)；

R¹⁶Represents optionally substituted phenyl, Het¹⁰Or C_1-6Alkyl (said alkyl being optionally unsaturated and/or optionally substituted and/or terminated by one or more substituents selected from the group consisting of halogen, -CN, -N (H) R³⁴And optionally substituted phenyl);

R³⁴representative H, C_1-4Alkyl, -C (O) R^36aOR-C (O) OR^36b；

R¹⁸Represents H, -C (O) OR^36bOr C_1-6Alkyl (said alkyl being optionally substituted and/OR terminated by one OR more substituents selected from halogen and-C (O) OR^36b)；

R²²Represents Het¹⁴Optionally substituted phenyl or C_1-4Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from the group consisting of halogen, Het¹⁵And optionally substituted phenyl);

R²³representative H, C_1-4Alkyl, -C (O) OR^36bor-C (O) SR^36b；

R²⁵Represents H or C_1-6Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from halogen, -OH, C_1-6Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from C_1-4Alkyl and-OH), C_1-4Alkoxy, naphthyl, and optionally substituted phenyl);

R²⁷represents optionally substituted phenyl;

R²⁸represents C_1-5Alkyl, optionally substituted phenyl or Het¹⁷；

R^29bRepresentative H, C_1-4Alkyl or optionally substituted phenyl;

R³⁰represents H, optionally substituted phenyl, -C (O) R^37aOR-C (O) OR^37b；

R³¹Representative H, C_1-2Alkyl or optionally substituted phenyl;

R³²representative H, C_1-4Alkyl (said alkyl being optionally interrupted by oxygen), optionally substituted phenyl or Het²¹；

R³³Represents C_1-6Alkyl or optionally substituted phenyl;

at each time of use, R^37aAnd R^37bEach independently represents C_1-5Alkyl, optionally substituted phenyl, or R^37aRepresents H;

R^3aand R^3bStanding representative H, C_1-2Alkyl, -SR^38b、-N(R³⁹)R^38cOr R is^3aAnd R^3bTogether represent C_3-4Alkylene or-O-Z-O-;

R³⁹representative H, C_1-2Alkyl or a structural fragment of formula Ia;

z represents C_2-3An alkylene group;

R⁴¹-R⁴⁶independently represent H or C_1-2An alkyl group;

R^14b、R^14c、R¹⁷and R²¹Independently represent C_1-4An alkyl group;

R^15b-R^15p、R^20b、R²⁴、R^38band R^38cIndependently represent H or C_1-5An alkyl group;

optional substituents on the phenyl group are one or more substituents selected from the group consisting of: cyano, halogen, nitro, C_1-2Alkyl radical, C_1-2Alkoxy, Het¹、-NH₂、-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)₂R^14band-S (O)₂N(R¹⁵ⁿ)R^15p。

When R is^3aAnd/or R^3brepresents-N (R)³⁹)R^38cWherein R is³⁹When representing a structural fragment of formula Ia, preferred compounds of formula I include those defined as follows: wherein at R³⁹In the group:

R⁴represents H, -OR⁷Or N (H) R⁸Or R is⁴And R⁵Together represent ═ O;

R⁵represents H, or R⁵And R⁴Together represent ═ O;

R⁷represents H, phenyl (said phenyl being optionally substituted by 1-3 methoxy groups), -C (O) CH₃or-C (O) N (H) -C_1-4An alkyl group;

R⁸represents H, -C (O) O-C_1-4Alkyl or-C (O) N (H) CH₃；

A represents C_1-3Alkylene or-C_2-3alkylene-N (H) -;

b represents a bond, -CH₂-、-CH₂-N(H)-、-CH₂-S(O)₂-、-CH₂-O- (wherein in the last three groups, CH₂Is connected to the carrier R⁴And R⁵On the carbon atom of) or-O-;

R⁶represents phenyl optionally substituted (in para and/or ortho position) by up to 3 substituents selected from: cyano, -N (H) C (O) N (H) CH₃、-N(H)S(O)₂CH₃and-S (O)₂N(CH₃)₂。

More preferred compounds of the invention include those defined below:

R⁴represents H, -OR⁷Or N (H) R⁸Or R is⁴And R⁵Together represent ═ O;

R⁵represents H, or R⁵And R⁴Together represent ═ O;

R⁷representative H, C_1-2Alkyl, optionally substituted phenyl, -C (O) R^10aor-C (O) N (R)^11a)R^11b；

R⁸Representative H, C_1-2Alkyl, -C (O) OR^10bor-C (O) N (R)^11a)R^11b；

At each time of use, R^10aAnd R^10bEach independently represents C_1-5Alkyl (optionally substituted or terminated by phenyl), optionally substituted phenyl, or R^10aRepresents H;

at each time of use, R^11aAnd R^11bEach independently represents H or C_1-5Alkyl (optionally substituted with or terminated by phenyl);

a represents-G-or-J-N (R)¹²)-；

B represents a bond, C_1-4Alkylene, -L-N (H) -, -L-S (O)₂-or-L-O- (wherein in the last three groups L is linked carrying R⁴And R⁵On the carbon atom of (c);

g represents a bond or C_1-4An alkylene group;

j represents C_2-4An alkylene group;

l represents C_1-4An alkylene group;

R⁶represents phenyl or Het⁶(both of which are optionally substituted by one or more substituents selected from cyano, halogen, C_1-2Alkyl radical, C_1-2Alkoxy, -C (O) R^15c、-N(H)C(O)R^15h、-N(H)C(O)N(H)R^15k、-N(H)S(O)₂R^14b、-S(O)₂R^14cand-S (O)₂N(R¹⁵ⁿ)R^15p)。

When R is²represents-S (O)₂R²²More preferred compounds of the invention also include those defined below:

R⁴and R⁵Together represent ═ O;

a represents C_1-4An alkylene group;

b represents a bond or C_1-4An alkylene group;

R⁶represents C_1-5An alkyl group.

Other preferred compounds of the invention include those defined below:

a represents-G-, -J-N (R)¹²) -or-J-O- (wherein in the latter two groups, J is attached to the bispidine nitrogen atom);

g represents C_1-6An alkylene group;

R⁴represents-D-OR⁷、-D-N(R⁸)R⁹Or R is⁴And R⁵Together represent ═ O;

R²represents-CN, Het⁸、-C(O)R¹⁶、-C(S)OR¹⁷、-C(S)N(R¹⁸)R¹⁹、-[C(O)]₂N(R²⁰)R^20b、-[C(O)]₂OR²¹、-S(O)₂R²²、-S(O)₂N(R²³)R²⁴、-C(＝N-CN)N(R²⁵)R²⁶、-C(＝N-CN)OR²⁷Or C_1-12Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from-C (O) R²⁸、-C(O)N(R^29a)R^29b、-N(R³⁰)R³¹、-OR³²、-S(O)_rR³³Halogen, -CN, nitro and Het⁹)；

R¹⁶Representative H, Het¹⁰Or C_1-6Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from the group consisting of halogen, -OH, -CN, -N (R)³⁴)R³⁵Aryl and Het¹¹)；

R⁶Represents aryl, Het⁶(both of these groups are optionally substituted and/or terminated, if appropriate, by one or more substituents selected from-OH, cyano, halogen, nitro, C_1-6Alkyl (optionally with-N (H) C (O) OR)^14aAs terminal), C_1-5Alkoxy, aryl, Het⁷、-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(R¹⁵ⁱ)C(O)N(R^15j)R^15k、-N(R^15m)S(O)₂R^14b、-S(O)_qR^14c、-OS(O)₂R^14dand-S (O)₂N(R¹⁵ⁿ)R^15p) Or when R is⁴And R⁵When together represent ═ O, R⁶Can represent C_1-6An alkyl group.

Preferred compounds of the present invention include the compounds of the examples disclosed hereinafter. Preparation of

The present invention also provides a process for preparing a compound of formula I, said process comprising:

(a) reacting a corresponding compound of formula IIWherein R is²、R^3a、R^3bAnd R⁴¹-R⁴⁶As defined above, with a compound of the formula III

Wherein L is¹Represents a leaving group (e.g. mesylate, tosylate or halogen), and R⁴、R⁵、R⁶A and B are as defined above, e.g. in a suitable base (e.g. triethylamine or K)₂CO₃) And in the presence of a suitable organic solvent (e.g., dichloromethane, acetonitrile or DMSO) at-10 ℃ to reflux temperature;

(b) for R in the formula¹Represents a structural fragment of formula Ia, A represents C₂Alkylene, and R⁴And R⁵(II) compounds of formula I together representing ═ O, reaction of the corresponding compounds of formula II as defined above with compounds of formula IVWherein R is⁶And B is as defined above, e.g. in the presence of a suitable organic solvent (e.g. ethanol) at room temperature;

(c) for R in the formula^3aOr R^3brepresents-N (R)³⁹)^38c-, and R³⁹A compound of formula I representing a structural fragment of formula Ia, wherein R^3aOr R^3bIf appropriate represents-N (H) R^38c、R^38cReacting a corresponding compound of formula I as defined above with a compound of formula III as defined above, for example under the conditions described above (see step (a));

(d) for R in the formula¹Represents a fragment of formula Ia, A represents CH₂And R is⁴represents-OH or-N (H) R⁸By reacting a corresponding compound of formula II as defined above with a compound of formula VWherein X represents O or N (R)⁸) And R is⁵、R⁶、R⁸And B is as defined above, e.g., in the presence of a suitable solvent (e.g., a lower alkyl alcohol (e.g., IPA), acetonitrile, or a mixture of a lower alkyl alcohol and water) at an elevated temperature (e.g., 60 ℃ to reflux temperature);

(e) for R in the formula^3aOr R^3brepresents-N (R)³⁹)R^38c，R³⁹Representative formulaIa, A represents CH₂And R is⁴represents-OH or-N (H) R⁸A compound of formula I, wherein R^3aOr R^3bIf appropriate represents-N (H) R^38c、R^38cReacting a corresponding compound of formula I as defined above with a compound of formula V as defined above, for example under the conditions described above (see step (d));

(f) for a compound in which A represents C_1-6Alkylene, B represents C_1-4Alkylene, and R⁴And R⁵A compound of formula I, wherein R represents H, reacting under suitable reducing agents and suitable reaction conditions⁴And R⁵Reduction of the corresponding compound of formula I together representing ═ O, for example in a suitable reducing agent (e.g. sodium borohydride or sodium cyanoborohydride) and a suitable organic solvent (e.g. lower (e.g. C)_1-6) Alkyl alcohol) by activating the C ═ O concerned with a suitable reagent (e.g. tosylhydrazine);

(g) for R in the formula⁴And R⁵All represent H, and (1) A represents a single bond or-J-N (R)¹²) B represents C_1-4Alkylene, or (2) A represents C_1-6Alkylene, and B represents N (R)¹³) or-N (R)¹³) L-in a suitable reducing agent (e.g. LiAlH)₄) And a suitable solvent (e.g., THF), in the presence of a solvent⁴And R⁵Reduction of the corresponding compounds of formula I together representing ═ O;

(h) for a compound in which A represents C_1-6Alkylene, B represents a bond, C_1-4Alkylene, -L-N (R)¹³)-、-L-S(O)_p-or-L-O- (wherein in the last three groups, L represents C_1-4Alkylene) group, R⁴Represents OH, and R⁵A compound of formula I, representing H, in a suitable reducing agent (e.g. NaBH)₄) And a suitable solvent (e.g., THF), in the presence of a solvent⁴And R⁵Reduction of the corresponding compounds of formula I together representing ═ O;

(i) for R in the formula^3aAnd R^3bCompounds of formula I, all representing H, correspondingThe reduction of the compound of formula VI,

wherein R is¹、R²And R⁴¹-R⁴⁶As defined above, and wherein the bridgehead C ═ O group can be activated with a suitable reagent such as tosylhydrazine, in the presence of a suitable reducing agent (e.g. sodium borohydride, sodium cyanoborohydride) and a suitable organic solvent (e.g. a lower alkyl alcohol), or under standard Wolff-Kischner conditions known to those skilled in the art; when C ═ O is activated, the activation step may be carried out in the presence of a suitable organic solvent (e.g. a lower alkyl alcohol such as methanol, ethanol or IPA) at room temperature-reflux temperature, after which a reducing agent may be added to the reaction mixture and the reduction carried out at 60 ℃ to reflux temperature, advantageously in the presence of a suitable organic acid (e.g. acetic acid);

(j) for R in the formula^3aAnd R^3bCompounds of formula I, wherein one represents H and the other represents-OH, are reduced in the presence of a weak reducing agent such as sodium borohydride and a suitable organic solvent (e.g. a lower alcohol such as methanol or ethanol) to the corresponding compound of formula VI as defined above;

(k) for R in the formula^3aAnd R^3bAll represent-OR^38aor-SR^38bOr R is^3aAnd R^3bTogether represent-O-Z-O-, -O-Z-S-or-S-Z-S-, with a corresponding compound of formula VI as defined above and wherein R^38a、R^38bAnd Z is of the formula HOR as defined above^38a、HSR^38bHO-Z-OH, HO-Z-SH or HS-Z-SH compounds, if appropriate, under suitable reaction conditions, for example by refluxing in the presence of a suitable protonic or Lewis acid catalyst (e.g. pTSA, trimethylsilyl chloride or boron trifluoride) and a suitable organic solvent (e.g. toluene or diethyl ether);

(1) for R in the formula^3aAnd R^3bWherein one represents-NH₂And the other compound of formula I represents H, reducing the compound of formula VII,

wherein R is¹、R²And R⁴¹-R⁴⁶As defined above, the reduction is carried out in a suitable reducing agent (e.g. LiAlH)₄) In the presence of, for example, conditions well known to those skilled in the art;

(m) for one or both of R^3aAnd R^3brepresents-N (R)³⁹)R^38cOne or two R³⁹And R^38cRepresents C_1-6Alkyl compounds of the formula I, in which R is^3aAnd/or R^3brepresents-N (R)³⁹)R^38cIf appropriate, and R³⁹And/or R^38c(if appropriate) alkylation of the corresponding compound of the formula I which represents H with a compound of the formula VIII

R^a-L¹VIII wherein R^aRepresents C_1-6Alkyl, and L¹As defined above, for example, alkylation is carried out under conditions well known to those skilled in the art;

(n) for R¹A compound of formula I representing a structural fragment of formula Ia and B represents-L-O-, a compound of formula IX

Wherein R is²、R^3a、R^3b、R⁴、R⁵、R⁴¹-R⁴⁶A and L are as defined above, with a compound of formula X,

R⁶OH X wherein R⁶As defined above, for example under Mitsunobu-type conditions, for example at room temperature (e.g. 25 ℃) to reflux temperature, in the presence of a tertiary phosphine (e.g. tributylphosphine or triphenylphosphine), an azodicarboxylate derivative (e.g. diethyl azodicarboxylate or 1, 1' - (azodicarbonyl) dipiperidine) and a suitable organic solvent (e.g. dichloromethane or toluene);

(o) for R¹Represents a structural fragment of formula Ia, A representsC_1-6Alkylene, and B represents-N (R)¹³) -L- (wherein the radical-N (R)¹³) -is attached to the carrier R⁴And R⁵On the carbon atom of) a compound of the formula I, a compound of the formula XI

Wherein A is^aRepresents C_1-6Alkylene, and R²、R^3a、R^3b、R⁴、R⁵、R¹³And R⁴¹-R⁴⁶As defined above, with a compound of the formula XII

R⁶-L-L²XII wherein L²Represents a leaving group such as halogen, alkanesulfonate, perfluoroalkanesulfonate or arenesulfonate, and R⁶And L is as defined above, for example in the presence of a suitable organic solvent (e.g. acetonitrile) at 40 ℃;

(p) for R¹Represents a structural fragment of formula Ia, and R⁴represents-D-NH₂The corresponding compound of formula XIII is reduced,

wherein R is²、R^3a、R^3b、R⁵、R⁶、R⁴¹-R⁴⁶A, B and D are as defined above, for example by hydrogenation in the presence of a suitable catalyst (e.g. palladium on charcoal) and a suitable solvent (e.g. a water-ethanol mixture) under suitable pressure;

(q) for R in⁴represents-D-N (R)⁹)C(O)NH(R^11b) A compound of formula I, wherein R⁴represents-D-N (R)⁹) H with a compound of the formula XIV,

R^11bwherein R is^11bAs defined above, for example in the presence of a suitable solvent (e.g. benzene) at room temperature (e.g. 25 ℃);

(R) for R⁴represents-D-N (H) [ C (O)]₂NH₂A compound of formula I, wherein R⁴represents-D-NH₂With oxalic acid diamide, for example 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 a reaction-inert organic solvent (e.g. DMF) at-10-25 ℃;

(s) for R⁴represents-D-N (R)⁸)R⁹，R⁸And R⁹As defined above, provided that R⁸A compound of formula I, not representing H, wherein R⁴represents-D-N (H) R⁹By reaction of the corresponding compound of formula I with a compound of formula XV

R^8a-L³XV wherein R^8aRepresents R as defined above⁸Except that it does not represent H, and L³Represents a leaving group such as halogen (e.g. ammonia or bromine), p-nitrophenolate, C_1-4Alcoholate, C_1-4Alkylthio (thio) compounds, -OC (O) R^10a、-OC(O)OR^10bor-OS (O)₂R^10cWherein R is^10aAnd R^10cAs defined above, for example, the reaction is carried out under conditions well known to those skilled in the art;

(t) for R⁴represents-D-OR⁷，R⁷Represents C_1-6Alkyl, -E-aryl or-E-Het¹A compound of formula I, wherein R⁴The corresponding compound of formula I, representing-D-OH, is reacted with a compound of formula XVI,

R^7aOH XVI wherein R^7aRepresents C_1-6Alkyl, -E-aryl or-E-Het¹Wherein Het is¹As defined above, for example under Mitsunobu-type conditions, i.e. in the presence of triphenylphosphine, an azodicarboxylate derivative (e.g. 1, 1' - (azodicarbonyl) dipiperidine) and a suitable organic solvent (e.g. dichloromethane), at room temperature (e.g. 25 ℃) to reflux temperatureCarrying out reaction;

(u) for R¹Represents a structural fragment of formula Ia, R⁴represents-D-OR⁷(wherein R is⁷Represents C_1-6Alkyl, -E-aryl or-E-Het¹) Of the formula (I), to the corresponding compounds of the formula (XVII)Wherein L is²、R²、R^3a、R^3b、R⁵、R⁶、R⁴¹-R⁴⁶A, B and D are as defined above, with a compound of formula XVI as defined above, for example under Williamson-type conditions (i.e. with a suitable base (e.g. KOH or NaH) and a suitable organic solvent (e.g. dimethyl sulfoxide or DMF)) at room temperature (e.g. 25 ℃) to reflux temperature;

(v) for R in the formula⁴represents-D-OR⁷，R⁷As defined above, with the proviso that it does not represent a compound of formula I of H, wherein R⁴The corresponding compound of formula I, representing-D-OH, is reacted with a compound of formula XVIII,

R^7b-L⁴XVIII wherein R^7bRepresents R as defined above⁷Except that it does not represent H, and L⁴Represents a leaving group such as OH, halogen, alkanesulfonate, arenesulfonate or-OC (O) R^10aWherein R is^10aAs defined above, the above-mentioned,

for example at room temperature-reflux temperature, optionally in a reaction-inert organic solvent (e.g. THF or CH)₂Cl₂) A suitable base (e.g. triethylamine or K)₂CO₃) And/or a suitable coupling agent (e.g., 1, 3-dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, optionally in the presence of a suitable catalyst such as 4-dimethylaminopyridine) (e.g., when R is^7brepresents-C (O) R^10aAnd L is⁴When OH is represented, the reaction may be carried out in a suitable coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, a suitable catalyst such as 4- (dimethylamino)Yl) pyridine and a solvent such as THF at room temperature (e.g., 25 ℃));

(w) for R⁴Compounds of formula I, wherein R represents halogen, by reaction with a suitable halogenating agent⁴Corresponding compounds of formula I which represent-OH (for example for R therein)⁴A compound representing fluorine, with diethylaminosulfur trifluoride);

(x) Reacting the corresponding compound of formula XIX

Wherein R is¹、R^3a、R^3bAnd R⁴¹-R⁴⁶As defined above, with a compound of formula XX,

R²-L⁵XX wherein L⁵Represents a leaving group such as halogen, OH, alkanesulfonate, arenesulfonate, C_1-4Alkoxy, phenoxy, -OC (O) R¹⁶、-OC(O)OR²¹or-OS (O)₂R²²And R is²、R¹⁶、R²¹And R²²As defined above, e.g. at-10 ℃ to reflux temperature, optionally in a suitable solvent (e.g. CHCl)₃、CH₃CN, 2-propanol, diethyl ether, or mixtures thereof) and/or a suitable base (e.g., K)₂CO₃Pyridine or triethylamine);

(y) for R²Represents C_1-12Alkyl substituted at the C-2 carbon (relative to the bispidine nitrogen) by OH or N (H) R³⁰Substituted or optionally substituted by one or more of R as hereinbefore defined²Said substituent substituted compound of formula I, reacting a compound of formula XIX as defined above with a compound of formula XXA

Wherein X_aRepresents O or N (R)³⁰) And R is^2aRepresents C_1-10Alkyl optionally substituted by one or more as hereinbefore defined for R²Said substituents being substituted, e.g. by performing the reaction as described above for the preparation of compounds of formula I (process step (d)) (step (d))The preparation method comprises the following steps of;

(z) for R²A compound of formula I representing a tetrazol-5-yl group, wherein R²The corresponding compound of formula I representing-CN is reacted with a suitable source of azide ion (e.g. sodium azide), for example at elevated temperature (e.g. 100 ℃), optionally in the presence of a suitable proton source (e.g. NH) in a suitable solvent (e.g. DMF)₄Cl) is carried out;

(aa) for compounds of formula I which are bispidine-nitrogen N-oxide derivatives, the corresponding bispidine of the corresponding compound of formula I is nitroxidated in the presence of a suitable oxidizing agent (e.g. mCPBA), for example in the presence of a suitable organic solvent (e.g. DCM) at 0 ℃;

(ab) is for C_1-4Alkyl quaternary ammonium salt derivatives, and the alkyl is attached to the bispidine nitrogen, reacting the corresponding compound of formula I with a compound of formula XXI at the bispidine nitrogen,

R^b-L²XXI wherein R^bRepresents C_1-4Alkyl, and L²As defined above, for example, the reaction is carried out at room temperature in the presence of a suitable organic solvent (e.g. DMF) and then in the presence of a suitable counterion provider (e.g. NH)₄OAc) in the presence of (using, e.g., HPLC);

(ac) R is reacted using techniques well known to those skilled in the art⁶One substituent on is converted to another substituent; or

(ad) converting an R using techniques well known to those skilled in the art²Conversion of a radical into another R²A group.

Compounds of the formula II can be prepared by reacting the corresponding compounds of the formula XXII

Wherein R is^3a、R^3bAnd R⁴¹-R⁴⁶As defined above, with a compound of formula XX as defined above, e.g. as described above for the synthesis of compounds of formula IProcess step (x)) is carried out.

Wherein R is^3aAnd R^3bCompounds of the formula II which both represent H can be prepared by reduction of the corresponding compounds of the formula XXIII,wherein R is²And R⁴¹-R⁴⁶As defined above, wherein the C ═ O group can be activated with a suitable reagent, e.g. tosylhydrazine, for example, reduction as described above for the synthesis of compounds of formula I (process step (I)).

Wherein R is^3aAnd R^3bOne of them represents-OH and the other represents C_1-4Alkyl compounds of formula II can be prepared by reacting a compound of formula XXIII or a protected derivative thereof with a compound of formula XXIV,

R^a1k-Mg-Hal XXIV wherein R^alkRepresents C_1-4Alkyl and Hal represents chlorine, bromine or iodine, for example in the presence of a suitable solvent (e.g. diethyl ether) at-25 ℃ to room temperature.

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

(1) a compound of formula III wherein B represents-L-O-can be prepared by: coupling a compound of formula X as defined above with a compound of formula XXV,

L⁶-L-C(R⁴)(R⁵)-A-L¹XXV wherein L⁶Represents a suitable leaving group (e.g. halogen), and R⁴、R⁵A, L and L¹As defined above; or

(2) Wherein B represents-N (R)¹³) -L-, and R⁴And R⁵Compounds of formula III, which together represent ═ O, can be prepared by: reacting a compound of formula XXVI

R⁶-L-N(R¹³) H XXVI wherein R⁶、R¹³And L is as defined above, with a compound of the formula XXVII

L⁶-C(O)-A-L¹XXVII wherein L⁶A and L¹As defined above; both couplings are carried out under conditions well known to those skilled in the art.

Or, wherein A represents C₂Alkylene radical, R⁴represents-OR⁷And R is⁷Represents C_1-6Alkyl, -E-aryl or-E-Het¹The compounds of formula (III) can be prepared by: a compound of formula XVI as defined above is reacted with a compound of formula XXVIII,wherein R is^yRepresents C_1-4Alkyl or aryl (these two groups are optionally substituted by one or more groups selected from C_1-4Alkyl or halogen), and R⁵、R⁶And B is as defined above, e.g. at room temperature (e.g. 25 ℃) to reflux temperature, in a suitable base (e.g. K)₂CO₃) And a suitable organic solvent (e.g. acetonitrile), and then converting the ester functionality to L under conditions well known to those skilled in the art¹Group (wherein L¹As defined above).

Wherein A represents C_2-6Alkylene compounds of formula III can be prepared by: the corresponding compound of formula XXIX is reduced,

wherein A is^bRepresents a bond or C_1-4Alkylene, and R⁴、R⁵、R⁶And B is as defined above, said reduction being carried out with a suitable borane or borane-Lewis base complex (e.g. borane-dimethylsulfide) in the presence of a suitable solvent (e.g. diethyl ether, THF, or mixtures thereof), followed by oxidation of the resulting borane adduct with a suitable oxidizing agent (e.g. sodium perborate) and subsequent conversion of the resulting OH group to L under conditions known to those skilled in the art¹And (4) a base.

Wherein A isWatch C_2-6Alkylene and B represents-L-N (R)¹³) - (wherein L represents C)_1-4Alkylene) compounds of the formula III can be prepared by: reacting a compound of formula XXX

R⁶-L⁶XXX wherein R⁶And L⁶As defined above, to compounds of formula XXXI,

HN(R¹³)-L^a-C(R⁴)(R⁵)-A^c-OH XXXI wherein L^aRepresents C_1-4Alkylene radical, A^cRepresents C_2-6Alkylene, and R⁴、R⁵And R¹³As defined above, the coupling is carried out, for example, at room temperature to reflux temperature, optionally in the presence of a suitable solvent and/or a suitable base, and the resulting OH groups are then converted to L under conditions known to those skilled in the art¹And (4) a base.

Wherein B represents-L-S (O) -or-L-S (O)₂The compounds of formula III (III) can be prepared by oxidation of the corresponding compounds of formula III (III) wherein B represents-L-S-, and L is as defined above, in the presence of a suitable amount of a suitable oxidizing agent (e.g. mCPBA) and a suitable organic solvent.

The compounds of formula V may be prepared according to techniques known to those skilled in the art. For example, a compound of formula V, wherein:

(1) b represents-CH₂Compounds of formula V in which O-and X represents O can be prepared by reacting a compound of formula X as defined above with a compound of formula XXXII,wherein R is⁵And L²As defined above, e.g. in a suitable base (e.g. K)₂CO₃Or NaOH) and a suitable organic solvent (e.g., acetonitrile or toluene/water) at elevated temperatures (e.g., 60 ℃ to reflux temperature), or as prepared in the prior art;

(2) wherein R is⁵Compounds of formula V, which represent H and X represents O, can be prepared by: will be of the formula XXXIReduction of II compoundsWherein R is⁶And B is as defined above, e.g. in a suitable reducing agent (e.g. NaBH)₄) And a suitable organic solvent (e.g., THF) at-15 deg.C to room temperature, followed by a metathesis reaction in the resulting intermediate, e.g., in the presence of a suitable base (e.g., K)₂CO₃) And a suitable organic solvent (e.g., acetonitrile) at room temperature;

(3) wherein B represents-L-, -L-N (R)¹³)-、-L-S(O)₂-or-L-O- (in all 4 of these groups, L represents C_1-4Alkylene) and X represents O, can be prepared by: oxidizing a compound of formula XXXIV in the presence of a suitable oxidizing agent (e.g., mCPBA),wherein B is^arepresents-L-, -L-N (R)¹³)-、-L-S(O)₂-or-L-O- (in all 4 groups, L represents a single bond or C_1-3Alkylene) and R⁵、R⁶And R¹³As defined above, the oxidation is carried out, for example, by refluxing in the presence of a suitable organic solvent (e.g., DCM); or

(4) Wherein B represents-L-O- (wherein the group L represents C)_1-4Alkylene), X represents N (R)⁸) (wherein R is⁸represents-C (O) OR^10bor-S (O)₂R^10c) The compounds of formula V (I) can be prepared by: (ii) ring closure of a compound of formula XXXV,

wherein R is^8brepresents-C (O) OR^10bor-S (O)₂R^10cAnd R is⁵、R⁶、R^10b、R^10c、L^aAnd L²As defined above, the ring closure is carried out, for example, in the presence of a suitable base (e.g., sodium hydroxide), a suitable solvent (e.g., dichloromethane, water, or a mixture thereof), and, if desired, a phase transfer catalyst (e.g., tetrabutylammonium hydrogen sulfate) at a temperature of from 0 ℃ to reflux temperature.

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

The compounds of the formulae IX, XI, XIII and XVII can be prepared analogously to the process for preparing the compounds of the formula I (see, for example, process steps (a), (b) and (x)).

Alternatively, the compound of formula XIII may be prepared by: in which R is⁴Reaction of a corresponding compound of formula I, representing-D-OH, with a compound of formula XXXVI

R^yS(O)₂Cl XXXVI wherein R^yAs defined above, for example in the presence of a suitable solvent (e.g. dichloromethane) at-10 to 25 ℃, followed by reaction with a suitable source of azide ion (e.g. sodium azide), for example in a suitable solvent (e.g. DMF) and a suitable base (e.g. NaHCO)₃) The reaction was carried out in the presence of room temperature-reflux temperature.

Alternatively, the compound of formula XVII may be prepared by: using L under conditions well known to those skilled in the art²Group replacement of R therein⁴OH groups of compounds of formula I representing-D-OH.

The compounds of formula XIX can be prepared by reacting the corresponding compounds of formula XXII as defined above with the compounds of formula III as defined above.

Wherein A represents C₂Alkylene, and R⁴And R⁵Compounds of formula XIX, which together represent ═ O, can be prepared by: a compound of formula XXII as defined above is reacted with a compound of formula IV as defined above, for example as described above for the synthesis of a compound of formula I (method step (b)).

Wherein A represents CH₂And R is⁴represents-OH or-N (H) R⁸The compounds of formula XIX can be prepared by: the corresponding compound of formula XXII as defined above is reacted with a compound of formula V as defined above, for example as described above for the synthesis of a compound of formula I (method step (d)).

Or, wherein R^3aAnd R^3bCompounds of formula XIX, both of which represent H, may be prepared by: the corresponding compound of formula XXXVII is reduced,

wherein R is¹And R⁴¹-R⁴⁶As defined above, wherein the C ═ O group can be activated with a suitable reagent, e.g. tosylhydrazine, for example, reduction is carried out as described above for the synthesis of compounds of formula I (process step (I)).

Or, wherein one or more R⁴¹、R⁴²、R⁴⁵And/or R⁴⁶Represents C_1-3Alkyl compounds of formula II and XIX can be prepared by: in which R is⁴¹、R⁴²、R⁴⁵And/or R⁴⁶If appropriate, the compounds of the formula II or XIX which represent H, if appropriate, are reacted with suitable alkylating agents, for example dimethyl sulfate, for example in the presence of suitable strong bases, for example s-BuLi, N, N, N ', N' -tetramethylethylenediamine and reaction-inert solvents, for example THF.

Wherein R is²represents-C (═ N-CN) N (R)²⁵)R²⁶And L is⁵Compounds of formula XX which represent phenoxy may be prepared by: reacting the corresponding compound of formula XXXVIII

H-N(R²⁵)R²⁶XXXVIII wherein R²⁵And R²⁶As defined above, with diphenylcyanoimidocarbonate (diphenylcyanocarbonimidate), for example in the presence of a suitable solvent, such as isopropanol, at a temperature of-10 c to room temperature.

The compounds of formula XXII are known in the literature or can be readily obtained using known techniques. For example, wherein R^3aAnd R^3bTogether represent C_3-5Alkylene, -O-Z-O-, -O-Z-S-or-S-Z-S-, and R⁴¹-R⁴⁶Compounds of formula XXII, both of which represent H, can be prepared by: the compound of formula XXXIX is reduced,

wherein R is^cAnd R^dTogether represent C_3-5Alkylene, -O-Z-O-, -O-Z-S-or-S-Z-S-, wherein Z is as defined above, in a suitable reducing agent (e.g. LiAlH)₄) In the presence of oxygen under conditions well known to those skilled in the art.

Wherein B represents C_1-4Alkylene compounds of formula XXIX can be prepared by: a compound of formula XL

Wherein B is^bRepresents C_1-4Alkylene and Hal, A^b、R⁴And R⁵As defined above, with a compound of formula XXX as defined above, e.g. in the presence of a suitable zinc (II) salt (e.g. anhydrous ZnBr)²) Suitable catalysts (e.g. Pd (PPh)₃)₄) And a reaction-inert organic solvent (e.g., THF, toluene or diethyl ether) at-25 deg.C to room temperature.

Compounds of formulae VI, XXIII and XXXVII (R in all compounds)⁴¹And R⁴²Both represent H) can be advantageously prepared by: if appropriate, (i) compounds of the formula XLI

Wherein R is^zRepresents C_1-10Alkyl or C_1-3Alkylaryl (e.g., alkylphenyl such as benzyl), and R⁴³-R⁴⁶As defined above, or (ii) 4-piperidone (or a protected derivative thereof) with (if appropriate) (1) a compound of the formula XLII

R⁶-B-C(R⁴)(R⁵)-A-NH₂XLII wherein R⁴、R⁵、R⁶A and B are as defined above, or (2) NH₃(OR protected (e.g. benzyl) derivatives thereof), all in the presence of formaldehyde (i.e. a suitable source of formaldehyde such as paraformaldehyde OR formalin solution), and for compounds of formulae VI and XXIII, using techniques such as those described herein (e.g. removal of c (o) OR^zThen coupled, coupled according to step (x) of the process described above) of the intermediate obtainedC(O)OR^zConversion of radicals to R²And (4) a base.

The formation of compounds of formulae VI, XXIII and XXXVII can be carried out by: for example at room temperature-reflux temperature (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. C)_1-6Carboxylic acids, especially acetic acid).

It will also be understood by those skilled in the art that where R is^3aAnd R^3bCompounds of the formula XXII, which both represent H, can also be prepared in this way (i.e. by reacting 4-piperidone (or a protected derivative thereof) with NH in the presence of formaldehyde₃(or a protected derivative thereof) under conditions such that the intermediate formed is then reduced under suitable reaction conditions.

It will also be appreciated by those skilled in the art that the process may also be used to prepare compounds wherein R is⁴⁵And R⁴⁶Are all H, and R⁴¹And/or R⁴²A compound of formula I other than H, for example by:

(i) in which R is⁴⁵And/or R⁴⁶Reacting a compound of formula XLI other than H with, for example, benzylamine or a derivative thereof;

(ii) removal of-C (O) OR^zA unit;

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

(iv) removing the benzyl protecting group; and

(v) the free bispidine nitrogen of the resulting compound is reacted with a compound of formula XX as defined above under conditions well known to those skilled in the art, including those described above. This reaction converts the carbonyl function with a bridgehead at a certain point into the desired R^3a/R^3bAnd (4) a base.

Compounds of formula XXXIX may be prepared according to techniques well known to those skilled in the art. For example, wherein R^cAnd R^dTogether represent C_3-5Alkylene compounds of formula XXXIX can be prepared by: reacting a compound of formula XLIIIWherein R is^eAnd R^fTogether represent C_3-5Alkylene, with a mixture of phosphoric acid and sulfuric acid, for example at 120 ℃.

Compounds of formula XLII are well known in the literature or can be readily prepared by known techniques, e.g., wherein R is⁴Represents OH, R⁵Represents H and A represents CH₂By reacting a compound of formula (I) wherein R is⁵The corresponding compounds of formula V, which represent H and X represents O, are prepared by reaction with ammonium hydroxide under conditions well known to those skilled in the art.

Formula IV, VIII, X, XII, XIV, XV, XVI, XVIII, XX (wherein R is²Is not-C (═ N-CN) N (R)²⁵)R²⁶And/or L⁵Other than phenoxy), XXA, XXI, XXIV, XXV, XXVI, XXVII, XXVIII, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVIII, XL, XLI, XLIII compounds and derivatives thereof are commercially available, are known in the literature, or can be prepared from readily available starting materials by methods similar to those described herein, or by conventional synthetic methods, according to standard techniques, using appropriate reagents and reaction conditions.

Substituents on aryl (e.g., phenyl), and, where appropriate, heterocyclyl groups in the compounds of the invention can be converted to other claimed substituents using techniques well known to those skilled in the art. For example, a hydroxyl group can be converted to an alkoxy group, a phenyl group can be halogenated to produce a halophenyl group, a nitro group can be reduced to produce an amino group, an amino group can be acetylated to produce an acetylamino group, and the like.

It will be appreciated by those skilled in the art that various standard substituents or functional groups within some compounds of formula I can be interconverted and transformed to provide other compounds of formula I. For example, a carbonyl group may be reduced to a hydroxyl or alkylene group, a hydroxyl group may be acylated to produce an alkylcarbonyloxy group, a nitro group may be reduced to an amino group, an amido group may be reduced to an amino group, an amino group may be sulfonated or acylated to produce a sulfonylamino or acylamino group (respectively), some acyclic groups may be converted to some Heterocyclic groups under conditions known to those skilled in the art, for example as described in Comprehensive Heterocyclic Chemistry II, AR Katritsky, CW Rees and EFV Scripten, first edition, Elsevier Science Ltd, Volumes 1-11 (1996).

The compounds of the present invention can be isolated from their reaction mixtures by conventional techniques.

It will be appreciated by those skilled in the art that in the above processes, it may be possible or necessary to protect functional groups of the intermediate compound with protecting groups.

Functional groups to be protected include hydroxyl, amino and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl and diarylalkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and alkylcarbonyl groups (e.g.methylcarbonyl and ethylcarbonyl). Suitable amino protecting groups include benzyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable amidino and guanidino protecting groups include benzyloxycarbonyl. Suitable carboxylic acid protecting groups include C_1-6Alkyl or benzyl esters.

The protection and deprotection of the functional groups may be performed before or after any of the above reaction steps.

The protecting groups may be removed according to techniques well known to those skilled in the art and as described below.

The use of protecting groups is well described in "protecting groups in organic chemistry", written by J.W.F.McOmie, Plenum Press (1973), and "protecting groups in organic Synthesis", 3 rd edition, T.W.Greene & P.G.M.Wutz, Wiley-Interscience (1999).

It will be appreciated by those of skill in the art that the individual process steps set forth herein may be performed in a different order and/or that separate reactions may be performed at different steps throughout the pathway (i.e., substituents may be added and/or chemical transformations may be performed for the different intermediates described above in connection with a particular reaction) in order to obtain the compounds of the invention in an additional, and in some cases more convenient, manner.

This depends inter alia on factors such as: the nature of the other functional groups present in a particular reaction substrate, the availability of key intermediates, and the protecting group strategy to be employed, if any. It will be apparent that the type of chemistry involved will influence the choice of reagents used in the synthetic steps, the need for and type of protecting groups used, and the order in which the synthesis is carried out.

It will be appreciated by those skilled in the art that although some of the protected derivatives of the compounds of formula I which may be prepared prior to the final deprotection stage may not possess pharmacological activity per se, they may be administered parenterally or orally and thereafter metabolised in vivo to form the compounds of the invention which are pharmacologically active. Thus, such derivatives may be described as "prodrugs". In addition, some compounds of formula I may act as prodrugs of other compounds of formula I.

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

Some of the intermediates described above are novel. According to another aspect, the present 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 R is^3aAnd R^3bAt least one of them represents-N (R)³⁹)R^38cWherein R is³⁹Represents a structural fragment of formula Ia as defined above) or a protected derivative thereof; (i) a compound of formula XXII (provided that R is^3aAnd R^3bAt least one of them represents-N (R)³⁹)R^38cWherein R is³⁹Represents a structural fragment of formula Ia as defined above) or a protected derivative thereof; and (j) a compound of formula XXIII as defined above or a protected derivative thereof.

Compounds of formula II that may be mentioned include those defined below:

when R is^3aAnd R^3bIndependently represent H, C_1-4Alkyl, OH or N (R)³⁹)R^38c(ii) a And R is³⁹Represents H or C_1-6When the alkyl group is used, the alkyl group,

then R is²Not to represent:

(i)CN；

(ii) optionally substituted by OH, N (R)³⁰)R³¹Or Het⁹Substituted C_1-6An alkyl group; wherein R is³⁰And

R³¹independently represent H, C_1-6Alkyl or C_3-8Cycloalkyl groups); and is

Het⁹Represents an unsubstituted saturated 3-to 8-membered heterocyclic ring containing one nitrogen atom

The cyclic group being attached to the remainder of the molecule via the nitrogen atom);

(iii)C_1-6n-alkyl optionally interrupted by O or substituted by N (R)³⁰)R³¹OR OR³²

As a terminus; wherein R is³⁰And R³¹Wherein one represents H or is in meta or para position

Position (relative to the attachment site) by CO₂H or NH₂Substituted phenyl, another generation

Tables H or C_1-6An alkyl group; and is

R³²Represents H or is substituted by CO in the meta or para position (relative to the attachment site)₂H or NH₂

Substituted phenyl;

(iv)-C(O)R¹⁶wherein R is¹⁶Represents H or in the meta or para position (relative to the attachment site)

Quilt CO₂H or NH₂Substituted phenyl;

(v)-S(O)₂R²²wherein R is²²Represents in the meta or para position (relative to the attachment site)

Quilt CO₂H or NH₂Substituted phenyl;

(vi)-S(O)₂N(R²³)R²⁴(ii) a Wherein

R²³Representing a CO bond in the meta or para position (relative to the attachment site)₂H or NH₂Substitution

Phenyl of (a); and is

R²⁴Represents H or C_1-6An alkyl group; and

(vii)C_3-4n-alkyl, wherein the alkyl is terminated with a phenyl group, which phenyl group is meta-positioned

Para or para (relative to the attachment site) by CO₂H or NH₂Substituted, and alkyl

Spaced at the beta-site (relative to the attachment site for the phenyl group) by O.

Compounds of formulae II, IX and XI which may be mentioned include those defined below, wherein:

when R is^3aAnd R^3bIndependently represent H, C_1-4Alkyl, OH or N (R)³⁹)R^38c；

R³⁹Represents H or C_1-6An alkyl group; and is

R⁴And R⁵When the two compounds are all represented by H,

then R is²Not representing CN, -C (O) R¹⁶、-S(O)₂R²²、-S(O)₂N(R²³)R²⁴Or optionally as hereinbefore described for R²Said substituted C_1-6An alkyl group.

Compounds of formulae II, IX and XI which may be mentioned include those defined below, wherein:

R²represents Het⁸、-C(O)R¹⁶、-C(S)OR¹⁷、-C(S)N(R¹⁸)R¹⁹、-[C(O)]₂N(R^20a)R^20b、-[C(O)]₂OR²¹、-S(O)₂R¹²、-S(O)₂N(R²³)R²⁴、-C(＝N-CN)N(R²⁵)R²⁶、-C(＝N-CN)OR²⁷Or C_1-12Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from-C (O) R²⁸、-C(O)N(R^29a)R^29b、-N(R³⁰)R³¹、-OR³²、-S(O)_rR³³Halogen, -CN and nitro);

R¹⁶represents Het¹⁰Or C_1-6Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from the group consisting of halogen, -OH, -CN, -N (R)³⁴)R³⁵Aryl and Het¹¹)；

R²²Represents Het¹⁴Or C_1-6Alkyl (said alkyl being optionally substituted and/or terminated by one or more substituents selected from the group consisting of halogen, -OH, -CN, Het¹⁵And aryl groups);

R²³representative H, C_1-6Alkyl, Het¹⁶、-C(O)R^36a、-C(O)OR^36bor-C (O) SR^36b；

R³⁰Represents Het¹⁹、-C(O)R^37a、-C(O)OR^37bor-C (O) N (R)^37c)R^37d；

R³²Represents C_1-6Alkyl, Het²¹、-C(O)R^37a、-C(O)OR^37bor-C (O) N (R)^37c)R^37d. Medical application

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

Thus, in another aspect, the present invention provides a compound of the invention for use as a medicament.

The compounds of the invention exhibit inter alia myocardial electrophysiological activity, for example as demonstrated in the following tests.

The compounds of the invention are therefore expected to be useful in the prophylaxis and treatment of cardiac arrhythmias, in particular atrial and ventricular arrhythmias.

The compounds of the invention are useful in the treatment or prevention of heart disease in which arrhythmias are believed to play a major role, or indications relating to heart disease, including ischemic heart disease, sudden heart attack, myocardial infarction, heart failure, cardiac surgery and thromboembolic disorders.

In the treatment of cardiac arrhythmias, it has been found that the compounds of the present invention selectively delay cardiac repolarization, thereby prolonging the QT interval and, in particular, exhibiting class III activity. Although the compounds of the invention have been found to exhibit class III activity, particularly in the treatment of cardiac arrhythmias, their mode of action is not limited to this class of activity.

According to another aspect, the invention provides a method of treating cardiac arrhythmias which comprises administering a therapeutically effective amount of a compound of the invention to a person suffering from, or susceptible to, such a condition. Pharmaceutical preparation

The compounds of the present invention are generally administered orally, subcutaneously, intravenously, intraarterially, transdermally, intranasally, by inhalation, or by any other parenteral route in the form of pharmaceutical preparations comprising the active ingredient in a pharmaceutically acceptable dosage form either as a free base, a pharmaceutically acceptable ion exchanger, or a non-toxic organic or inorganic acid addition salt. The compositions may be administered in different doses depending on the condition and patient being treated and the route of administration.

The compounds of the present invention may also be used in combination with any other drug used in the treatment of cardiac arrhythmias and/or other cardiovascular disorders.

According to another aspect, the present invention provides a pharmaceutical formulation including a compound of the present invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. When treating humans, suitable daily dosages of the compounds of the present invention are: about 0.005-10.0mg/kg body weight for oral administration and about 0.005-5.0mg/kg body weight for parenteral administration.

The compounds of the present invention have the advantage that they are effective against arrhythmias.

The compounds of the invention also have the following advantages: they may have higher potency, less toxicity, a broader spectrum of activity (including exhibiting any combination of class I, class II, class III and/or class IV activity (especially class I and/or class IV activity in addition to class III activity)), be more efficacious, be longer lasting, produce fewer side effects (including lower incidence of proarrhythmia such as torsades de points), be more readily absorbed, or have more useful pharmacological properties than compounds known in the art. Biological assayTest A Major electrophysiological effects in anesthetized guinea pigs

Guinea pigs weighing 660-1100g were used. Animals were kept for at least one week prior to the experiment, during which time they were allowed free access to food and tap water.

Anesthesia was induced by intraperitoneal injection of pentobarbital (40-50mg/kg) and catheters were inserted into one carotid artery (for blood pressure recording and blood sample collection) and one jugular vein (for drug infusion). Needle electrodes for recording ecgs (lead ii) were placed on the limbs. A thermistor was placed in the rectum and the animal was placed on a heating pad, setting the rectal temperature to 37.5-38.5 ℃.

A tracheotomy was performed, and the animals were manually ventilated (air) using a small animal ventilator, setting the blood gases to within the normal range of the animal. To reduce autonomic effects, both vagus nerves in the neck were severed and 0.5mg/kg propranolol was administered intravenously and the experiment was started 15 minutes later.

The left ventricular epicardium was exposed by left thoracotomy and a self-designed inhalation electrode recording Monophasic Action Potential (MAP) was applied to the left ventricular wall. The electrodes are placed in a position where an acceptable signal can be recorded, otherwise they are moved to a new position. Bipolar electrodes are applied to the left atrium. Pacing was performed with a custom-made galvanostatic stimulator (2ms duration, twice the diastolic threshold). Every 5 minutes of the experiment, the rhythm of the heart was paced 1 minute above the normal sinus rate.

Blood pressure, MAP signal and lead II ECG were recorded on a Mingograph ink jet recorder (Siemens-Elema, Sweden). All signals were collected on the PC during the last 10 seconds of each pacing frequency and the last 10 seconds of the sinus rhythm minutes thereafter (sampling frequency 1000 Hz). Signals were processed using a custom program developed to obtain and analyze physiological signals determined in experimental animals (see Axenborg and Hirsch, comput. methods programbiomed.41, 55 (1993)).

The test procedure included two baseline control recordings separated by 5 minutes during the pacing and sinus melodies. After the second control recording, the first dose of test substance was infused into the jugular vein catheter in a volume of 0.2mL for 30 seconds. After 3 minutes, pacing was started and a new recording was made. 5 minutes after the previous dose, the next dose of test substance is administered. The administration was continued 6-10 times during each experiment.Data analysis

Of the multiple variables measured in this assay, 3 were selected as the most important variables for comparison and selection of active compounds. The 3 variables selected were MAP duration at 75% repolarization during pacing, atrial-ventricular (AV) conduction time during pacing (defined as the time interval between atrial beats and ventricular MAP onset), and heart rate (defined as the RR interval during sinus rhythm). Systolic and diastolic blood pressure were measured to determine the hemodynamic status of the anesthetized animals. In addition, ECG changes are examined to assess arrhythmias and/or morphology changes.

The average of the two control recordings was set to 0 and the effect recorded after successive administrations of the test substance was expressed as a percentage change relative to this value. By plotting these percentage values against the cumulative dose administered prior to each record, a dose-response curve can be constructed. In this way, each experiment produced 3 dose response curves, one for MAP duration, one for AV conduction time, and one for sinus frequency (RR time interval). The average curve of all experiments with one test article was calculated and potency values were derived from the average curve. All dose-response curves in these experiments were constructed by linearly connecting the data points obtained. Cumulative dose extending MAP duration by 10% compared to baseline was used as an index to evaluate the class III electrophysiological efficacy of test substances (D)₁₀)。Test B Glucocorticoid-treated mouse adults as models to detect blockers of delayed rectifier K-flow Fiber cell

Determination of IC of K channel blockade Using microtiter plate-based screening methods based on Membrane potential Change in glucocorticoid-treated mouse fibroblasts₅₀. DiBac using bisoxonol dye₄₍₃₎The membrane potential of glucocorticoid-treated mouse fibroblasts was determined, which fluorescence could be reliably determined with a Fluorescent Laser Imaging Plate Reader (FLIPR). Expression of delayed rectifier potassium channels in mouse fibroblasts was induced by exposure to the glucocorticoid dexamethasone (5 μm) for 24 hours. Blocking these potassium channels depolarizes the fibroblast, resulting in DiBac₄₍₃₎The fluorescence increases.

Mouse 1tk fibroblasts (L-cells) were purchased from American Type CultureCo (ATCC, Manassa, Va.) and cultured in Dulbeccos modified eagle medium supplemented with the following components: fetal bovine serum (5% vol/vol), penicillin (500 units/mL), streptomycin (500. mu.g/mL), and L-alanine-L-glutamine (0.862 mg/mL). Cells were passaged every 3-4 days using trypsin (0.5mg/mL in calcium-free phosphate buffered saline, Gibco BRL). 3 days before the assay, the cell suspension was pipetted into a bottom clear black plastic 96-well plate (Costar) at 25000 cells/well.

Using fluorescent Probe DiBac₄₍₃₎(DiBac Molecular probes) to determine the membrane potential. DiBac₄₍₃₎Mainly absorbs at 488nM and emits at 513 nM. DiBac₄₍₃₎Is bisoxonol and is therefore negatively charged at pH7. Due to its negative charge, DiBac₄₍₃₎The distribution across the membrane depends on the transmembrane potential: intracellular DiBac if a cell depolarizes (i.e., becomes less negatively charged intracellularly relative to the outside of the cell), then intracellular DiBac₄₍₃₎The concentration will increase due to electrostatic forces. Once intracellular, DiBac₄₍₃₎The molecule can bind to lipids and proteins, causing an increase in fluorescence emission. Thus, DiBac₄₍₃₎The fluorescence enhancement will reflect depolarization. DiBac₄₍₃₎The change in fluorescence can be detected by FLIPR.

Prior to each experiment, cells were washed 4 times with Phosphate Buffered Saline (PBS) to remove all media. Then 5 μm DiBac at 35 deg.C₄₍₃₎Cells were treated (in 180. mu.L PBS). Once stable fluorescence is achieved (typically after 10 minutes), 20. mu.L of test substance is added using a 96-well pipetting system in FLIPR's. Fluorescence was measured every 20 seconds for 10 minutes. All experiments were performed at 35 ℃ due to delayed rectifier potassium channel conductivity and DiBac₄₍₃₎Fluorescence has high temperature sensitivity. In a second 96-well plate, in a medium containing 5. mu.M DiBac₄₍₃₎The test substance was prepared in PBS. The test substance was formulated at a concentration 10 times the concentration required for the experiment and diluted 1: 10 during the experiment when the test substance was added. The maximum increase in fluorescence was determined using Dofetilide (10 μ M) as a positive control.

For determination of IC Using the Graphpad Prism program (Graphpad software Enc., San Diego, Calif.)₅₀Curve fitting of the values.Test C Metabolic stability of test CompoundsCharacterization of nature

In vitro screens were performed to determine the metabolic stability of the compounds of the invention.

Liver S-9 fractions from dogs, humans, rabbits and rats with NADPH as cofactor were used. The measurement conditions were as follows: s-9(3mg/mL), NADPH (0.83mM), Tris-HCl buffer (50mM) pH7.4, and 10 μm test compound.

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

After 30 minutes of calculation (and thus t)_1/2) The percentage of test compound remaining and used as a measure of metabolic stability.

The invention is illustrated by the following examples.

ExamplesGeneral experimental procedures

Mass spectra were recorded on one of the following instruments: finnigan MAT TSQ 700 triple quadrupole mass spectrometer (FAB-MS) equipped with an electrospray interface; Perkin-Elmer SciXAPI150ex Spectrometer (spectrometer); VG Quattro II triple quadrupole mass spectrometer; VG Platform II single quadrupole mass spectrometer; or a Micromass Platform LCZ single quadrupole mass spectrometer (the latter three instruments are equipped with a pneumatically-assisted electrospray interface (LC-MS)).¹H NMR and¹³the C NMR measurements were performed on BRUKER ACP300 and Varian 300, 400 and 500 spectrometers (specrometers) at 300, 400 and 500MHz respectively¹H frequency and 75.5, 100.6 and 125.7MHz¹³C frequency operation. Or,¹³the C NMR measurements were carried out on a BRUKER ACE200 spectrometer at a frequency of 50.3 MHz.

Depending on whether the spectral interpretation is convenient, rotamers may or may not be indicated in the spectrum. Unless otherwise stated, chemical shifts are in the orderppm are given, using the solvent as an internal standard.Example 1 2- {7- [3- (4-Cyanophenoxy) -2-hydroxypropyl]-3, 7-diazabicyclo [3.3.1]Nonane- 3-yl } ethylcarbamic acid tert-butyl ester(i) 2-Bromoethylcarbamic acid tert-butyl ester

A mixture of 2-bromoethylamine hydrobromide (10.0g, 0.049mol), NaOH (1.84g, 0.046mol), water (50mL) and THF (200mL) was cooled to 0 ℃. To the mixture was slowly added di-tert-butyl dicarbonate (10.1g, 0.046mol), followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and the residue was dissolved in DCM. The organic solution was washed with water and purified by silica chromatography eluting with DCM to give 5.6g (50%) of the title compound. (ii)4- [3- (3, 7-Dichloroheterobicyclo [3.3.1]]Nonan-3-yl) -2-hydroxypropoxy]Benzonitrile

HCl-saturated EtOAc (600mL) was added to 7- [3- (4-cyanophenoxy) -2-hydroxypropyl]3, 7-diazabicyclo [3.3.1]A solution of tert-butyl nonane-3-carboxylate (62 g; see example 2 of International patent application PCT/SE 98/02276) in EtOAc (600mL) and the mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure, the residue was dissolved in MeCN (1.3L) and K was added₂CO₃(100g) In that respect The suspension was stirred for 12 hours and filtered. The filtrate was concentrated to obtain the title compound in 90% yield.¹³C NMR(CDCl₃)：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) 2- {7- [3- (4-Cyanophenoxy) -2-hydroxypropyl]-3, 7-diazabicyclo ring [3.3.1]Non-3-yl ethyl carbamic acid tert-butyl ester

4- [3- (3, 7-diazabicyclo [3.3.1]]Nonan-3-yl) -2-hydroxypropoxy]Benzonitrile (see step (ii) above; 7.7g, 25.6mmol) and tert-butyl 2-bromoethylcarbamate (see step (i) above; 5.7g, 2.56mmol) and K₂CO₃(3.5g, 2.56mmol) in CH₃CN (50mL) and stirred at 60 ℃ for 60 hours. The reaction mixture was filtered and evaporated. Purification of the residue using column chromatographySubstance (DCM: with NH)₃(g) Saturated 10-20% MeOH) to yield 8g (71%) of the title compound.¹³C NMR(CDCl₃)：δ28.4，29.6，30.3，32.0，36.9，54.8，58.4，58.6，59.5，64.8，71.1，78.8，104.1，115.3，119.2，133.9，156.4，162.2.FAB-MS(M+1)⁺＝445(m/z)Example 2 4- {3- [7- (3, 3-dimethyl-2-oxobutyl) -3, 7-diazabicyclo [3.3.1]Nonane-3- Base of]-2-hydroxypropoxy } benzonitrile

4- [3- (3, 7-diazabicyclo [3.3.1]]Nonan-3-yl) -2-hydroxypropoxy]Benzonitrile (see example 1 (ii); 0.6g, 2.0mmol) and 1-chloroppinacolone (0.27g, 2.0mmol) and K₂CO₃(0.27g, 20mmol) in CH₃CN, and stirred at 60 ℃ for 1 hour, then at room temperature overnight. The reaction mixture was filtered and evaporated to yield 0.7g (90%) of the title compound.¹³C NMR(CDCl₃)：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)⁺＝400(m/z)Example 3 4- {3- [7- (2-Ethyl-2H-1, 2, 3, 4-tetrazol-5-yl) -3, 7-diazabicyclo [3.3.1] Non-3-yl]-2-hydroxypropoxy } benzonitrile(i) 3, 7-dibenzyl-3, 7-diazabicyclo [3.3.1]Nonane-9-ones

The subtitle compound is prepared according to the method described in J.org.chem., 41(9), 1976, pp.1593-1597. (ii)3, 7-dibenzyl-3, 7-diazabicyclo [3.3.1]Nonane

The subtitle compound is prepared according to the method described in J.org.chem., 41(9), 1976, pp.1593-1597, using 3, 7-dibenzyl-3, 7-diazabicyclo [3.3.1]Nonan-9-one (see step (i) above) instead of N-benzyl-N' -methyl bispidone. (iii)3-benzyl-3, 7-diazabicyclo [3.3.1]Nonane

Reacting 3, 7-dibenzyl-3, 7-diazabicyclo [3.3.1]]Dissolution of nonane (see step (ii) above; 97g, 6.4mmol) in absolute ethanol (95%)The solution was hydrogenated in the presence of 5% Pd/C at 1atm until tlc indicated that the reaction was complete. The catalyst was removed by filtration through a pad of Celite  and the filtrate was concentrated under reduced pressure to give the subtitle compound in quantitative yield.¹³C NMR(CDCl₃)：δ30.1，33.4，36.0，52.5，59.6，64.3，126.9，128.3，128.7，138.8(iv) 3-benzyl-7-cyano-3, 7-dichloroheterobicyclo [3.3.1]Nonane

Reacting 3-benzyl-3, 7-diazabicyclo [3.3.1]]Nonane (see step (iii) above; 20g, 92mmol) was dissolved in diethyl ether (120 mL). Cyanogen bromide (9.8g, 92mmol) dissolved in ether (80mL) was added dropwise at 0 deg.C. The mixture was stirred at 0 ℃ for 15 minutes and then at room temperature overnight, after which a white precipitate formed. The ether was evaporated. Adding water and saturated Na₂CO₃(aqueous) solution. The mixture was extracted with diethyl ether. The ether layer was separated and dried (MgSO)₄) 20.3g (91%) of the sub-title compound are obtained. (v)3-benzyl-7- (2H-1, 2, 3, 4-tetrazol-5-yl) -3, 7-diazabicyclo [3.3.1]None Alkyl, ammonium salts

Reacting 3-benzyl-7-cyano-3, 7-diazabicyclo [3.3.1]Nonane (see step (iv) above; 10.2g, 42mmol), NaN₃(2.92g，45mmol)、NH₄A mixture of Cl (2.41g, 45mmol) and DMF (50mL) was stirred at 100 ℃ for 22 h. DMF was evaporated and toluene was added and evaporated to yield 12g of an orange powder. The product was purified by preparative reverse phase HPLC to yield 5.8g (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

Reacting 3-benzyl-7- (2H-1, 2, 3, 4-tetrazol-5-yl) -3, 7-diazabicyclo [3.3.1]A mixture of nonane, ammonium salt (see step (v) above; 4g, 13mmol), ethyl iodide (2.20mL, 26mmol) and NaOH (0.62g, 15.6mmol) was refluxed for 2 hours. The solvent was evaporated and the residue was purified by flash chromatography (hexane: ethyl acetate (1: 1), MeOH (NH)₃) 0-32%) to yield 1.5g (37%) of the sub-title compound. (vii)3- (2-ethyl-2H-1, 2, 3, 4-tetrazole-5)-yl) -3, 7-diazabicyclo [3.3.1] Nonane

Reacting 3-benzyl-7- (2-ethyl-2H-1, 2, 3, 4-tetrazol-5-yl) -3, 7-diazabicyclo [3.3.1]Nonane (see step (vi) above; 0.5g, 1.6mmol) was dissolved in ethanol (5mL, 95%) and hydrogenated in the presence of 5% Pd/C at 1atm overnight. The catalyst was filtered off through a pad of Celite  and the residue was evaporated to yield 0.2g (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-hydroxypropoxy } benzonitrile

4- (2-Oxiranylmethoxy) benzonitrile (cf. International patent application WO 99/31100; 0.18g, 1mmol) and 3- (2-ethyl-2H-1, 2, 3, 4-tetrazol-5-yl) -3, 7-diazabicyclo [3.3.1]Nonane (see step (vii) above; 0.2g, 0.9mmol) in isopropanol: h₂O (1.1mL, 10: 1) and the mixture was stirred at 60 ℃ overnight. The solvent was evaporated and the residue was purified by chromatography (hexane: ethyl acetate (1: 1), MeOH (NH)₃) 0-32%) to yield 0.28g (77%) of the title compound.¹³CNMR(CD₃CN)：δ14.4，29.7，30.0，31.2，48.6，51.2，51.3，58.6，60.8，61.0，66.3，71.9，104.3，116.2，118.2，119.9，134.9，163.3，170.1.Example 4 4- { 2-hydroxy-3- [7- (1, 3-thiazol-2-yl) -3, 7-diazabicyclo [3.3.1]Non-3-yl] Propoxy benzonitrile

4- [3- (3, 7-diazabicyclo [3.3.1]]Nonan-3-yl) -2-hydroxypropoxy]Benzonitrile (see example 1(ii) above; 1g, 3.3mmol), 2-bromothiazole (0.54g, 3.3mmol) and K₂CO₃(0.91g, 6.5mmol) was mixed in DMF (15 mL). The mixture was stirred at 60 ℃ overnight. The solvent was evaporated, toluene was added, and then evaporated. The residue was dissolved in ethyl acetate and washed with NaOH solution (2M). The organic layer was separated and dried (Na)₂SO₄). The residue was purified by chromatography (hexane: ethyl acetate (1: 1)). Yield: 0.57g (45%).¹³C NMR(CDCl₃)：δ29.1，29.4，30.5，52.8，53.0，57.9，60.7，65.3，70.4，104.1，105.6，115.3，119.2，133.9，139.7，162.0，171.2.Example 5 N' -cyano-7- [3- (4-cyanophenoxy) -2-hydroxypropyl]-N- (3, 4, 5-trimethoxybenzyl) 3, 7-diazabicyclo [3.3.1] radicals]Nonane-3-azomethine amides (carboximidamide)(i) N' -cyano-N- (3, 4, 5-trimethoxybenzyl) iminocarbamic acid (carbamimidoate) phenyl ester

3, 4, 5-trimethoxybenzylamine (1.08mL, 6.3mmol) was dissolved in isopropanol (10 mL). The mixture was cooled to 0 ℃ and then cyanoiminocarbonate diphenyl ester (1.5g, 6.3mmol) was added in portions. The reaction mixture was allowed to reach room temperature and then stirred at room temperature overnight. The precipitate formed was filtered off and then purified by chromatography, eluting with DCM: MeOH (gradient 100: 0-99: 1). Yield: 1.37g (63.5%) (ii)N' -cyano-7- [3- (4-cyanophenoxy) -2-hydroxypropyl]-N- (3, 4, 5-trimethyl) Oxybenzyl) -3, 7-diazabicyclo [3.3.1]Nonane-3-azomethine amides

4- [3- (3, 7-diazabicyclo [3.3.1]]Nonan-3-yl) -2-hydroxypropoxy]Benzonitrile (see example 1(ii) above; 1g, 3.3mmol) and phenyl N' -cyano-N- (3, 4, 5-trimethoxybenzyl) iminocarbamate (see step (i) above; 1.13g, 3.3mmol) were mixed with isopropanol (15mL) and then stirred under reflux for 3 hours. The mixture was cooled to room temperature and the product formed was filtered off. The product was purified by chromatography (DCM: MeOH (gradient 0-1%) to yield 1.67g (92%) of the title compound.¹³C NMR(CDCl₃)：δ29.0，29.3，31.2，47.9，50.9，51.3，56.1，57.1，60.0，60.7，61.3，65.6，70.6，103.9，105.1，115.2，118.3，119.1，133.2，133.9，137.4，153.3，160.2，161.9，176.3，176.4.Example 6 4- { 3-amino-4- [7- (butylsulfonyl) -3, 7-diazabicyclo [3.3.1]Non-3-yl]T-shirt Oxy } -benzonitrile(i) 4- (3-butenyloxy) benzonitrile

4-Cyanophenol (30g, 250mmol) was reacted with K₂CO₃(72.5g，525mmol) and stirred for 60 minutes. 4-bromo-1-butene (50g, 370mmol) was added dropwise and the reaction mixture was stirred at 60 ℃ overnight. The solid was filtered off and the solvent was evaporated. The residue was dissolved in DCM and washed with 1n naoh. The organic layer was separated and dried (Na)₂SO₄) And evaporated to yield 37g (58%) of the sub-title compound. (ii)4- [2- (2-Oxiranyl) ethoxy]Benzonitrile

4- (3-butenyloxy) benzonitrile (see step (i) above; 37g, 0.21mol) was mixed with mCPBA (61.6g, 0.25mol) and DCM (700mL) and stirred at room temperature for 4 hours. The reaction mixture was filtered and 2mL DMSO was added to destroy excess mCPBA. The mixture is taken up in NaHCO₃Washed, then separated, dried and evaporated to yield 38.7g (97%) of the sub-title compound. (iii)4- (4-amino-3-hydroxybutoxy) benzonitrile

Reacting 4- [2- (2-oxiranyl) ethoxy]Benzonitrile (see step (ii) above; 38.5g, 204mmol) was mixed with ammonia (1200mL, conc. ammonia) 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 to yield 39.1g (93%) of the sub-title compound. (iv)4- (4-Cyanophenoxy) -2-hydroxybutylcarbamate tert-butyl ester

4- (4-amino-3-hydroxybutoxy) benzonitrile (see step (iii) above; 34.3g, 166mmol) was dissolved in THF: H₂O (600mL, 8: 2). Di-tert-butyl dicarbonate (36.3g, 166mmol) is added at 0 ℃. The mixture was stirred at rt overnight and then evaporated to yield 50g (100%) of the sub-title compound (used in the next step without further purification). (v)Methanesulfonic acid 1- { [ (tert-butoxycarbonyl) amino]Methyl } -3- (4-cyanophenoxy) propyl Esters

Tert-butyl 4- (4-cyanophenoxy) -2-hydroxybutylcarbamate (see step (iv) above; 38.1g, 120mmol) and 4- (dimethylamino) pyridine (10 mol%) were dissolved in pyridine (200 mL). The mixture was cooled to 0 ℃. Methanesulfonyl chloride (10.7mL, 0.1) was then added dropwise at 0 deg.C36 mol). The mixture was allowed to reach room temperature, and then the pyridine was evaporated. DCM was added and the solution washed with 2MHCl and water, then dried and evaporated. The compound was purified by silica chromatography eluting with DCM (5% ethyl acetate) to yield 27g of the sub-title compound. (vi)2- [2- (4-Cyanophenoxy) ethyl]-1-aziridinecarboxylic acid tert-butyl ester

Coupling methanesulfonic acid 1- { [ (tert-butoxycarbonyl) amino group]Methyl } -3- (4-cyanophenoxy) propyl ester (see step (v) above; 25.3g, 0.066mol) was combined with tetrabutylammonium hydrogen sulfate (2.7 g; 7.8mmol) and DCM (170 mL). The mixture was cooled to 0 ℃ and NaOH (50% (aq)) was added slowly. The mixture was then allowed to reach room temperature before water and DCM were added. The organic layer was separated, washed with water, dried and evaporated to give the sub-title compound. Yield: 19g (99%). The product was used directly in the next step without further purification. (vii)3-benzyl-7- (butylsulfonyl) -3, 7-diazabicyclo [3.3.1]Nonane

Butanesulfonylchloride is added dropwise to 3-benzyl-3, 7-diazabicyclo [3.3.1] at 0 DEG]Nonane (see example 3(iii) above; 13g, 60mmol), K₂CO₃(60mmol) and MeCN (100 mL). The mixture was allowed to reach room temperature and then stirred at room temperature overnight. The reaction mixture was filtered through a plug of silica, then eluted with ethyl acetate to yield 15g (75%) of the sub-title compound. (viii)3- (Butylsulfonyl) -3, 7-diazabicyclo [3.3.1]Nonane

Reacting 3-benzyl-7- (butylsulfonyl) -3, 7-diazabicyclo [3.3.1]Nonane (see step (vii) above; 12.7g, 38mmol) was dissolved in ethanol (150mL, 95%) and hydrogenated in the presence of 5% Pd/C at 1atm overnight. TLC analysis showed no reaction. The catalyst was filtered off and fresh catalyst (5% Pd/C) and H were added₂O (10mL) and acetic acid (2 mL). The mixture was hydrogenated at 1atm overnight. The catalyst was filtered off, 2n naoh was added and the mixture was extracted with toluene. The toluene solution was evaporated to obtain 8g (85%) of the sub-title compound. (ix)1-{[7- (butylsulfonyl) -3, 7-diazabicyclo [3.3.1]Non-3-yl]Methyl- 3- (4-Cyanophenoxy) propylcarbamic acid tert-butyl ester

2- [2- (4-cyanophenoxy) ethyl]-tert-butyl 1-aziridinecarboxylate (see step (vi) above; 1g, 3.5mmol) with 3- (butylsulfonyl) -3, 7-diazabicyclo [ 3.3.1%]Nonane (see step (viii) above; 0.85g, 3.5mmol) was mixed in isopropanol (25 mL). The mixture was stirred at 60 ℃ overnight. The residue was evaporated and purified on silica (DCM, 2% MeOH) to give 1.5g (81%) of the sub-title compound.¹H NMR(CDCl₃): δ 1.44(3H, t), 1.91(9H, s), 2.08(2H, m), 2.1(2H, m), 2.2(2H, m), 2.4(2H, s (width)), 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(1H, s (width)), 7.4(2H, dd), 8.0(2H, dd) (x)4- { 3-amino-4- [7- (butylsulfonyl) -3, 7-diazabicyclo [3.3.1]Nonane-3- Base of]Butoxy benzonitrile

1- { [7- (butylsulfonyl) -3, 7-diazabicyclo [3.3.1]Non-3-yl]Methyl } -3- (4-cyanophenoxy) propylcarbamic acid tert-butyl ester (see step (ix) above; 0.9g, 1.7mmol) was dissolved in ethyl acetate (20 mL). Ethyl acetate (50mL) saturated with HCl (g) was added at 0 ℃. The resulting mixture was allowed to reach room temperature for 2 hours. The solvent was evaporated and the resulting residue was dissolved in water to obtain a solution, which was freeze-dried. The dihydrochloride salt of the title compound was obtained. ES-MS (M + H)⁺＝435(m/z)Example 7

The compounds listed below are prepared according to or analogously to the methods described herein, otherwise prepared according to the following methods: the appropriate 3-or 7-unsubstituted bispidine (dissolved in CHCl)₃Middle) with 2 equivalents of the appropriate electrophile (dissolved in CH)₃CN) in base (2.5 equivalents K)₂CO₃) In the presence of a catalyst. The reaction mixture was warmed to 50-100 ℃. When the reaction is complete (as determined by mass spectrometry), the inorganic salt is filtered off and the reaction mixture is added to an ion-exchange solid phase extraction plug(CBA). With CHCl₃The stopper was washed and finally CHCl₃∶MeOH∶Et₃The product was eluted with N (8: 1). The product was analyzed by HPLC and MS. Compounds with less than 90% purity were purified by preparative HPLC.

When recorded, mass spectra of compounds are in parentheses:

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

4- (3- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl ] -9- (1, 2-ethylenedioxy) -3, 7 diazabicyclo [3.3.1] non-3-yl } -2-hydroxypropoxy) benzonitrile;

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

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

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

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

4- {3- [ (3, 7-dibenzyl-3, 7-diazabicyclo [3.3.1] non-9-yl) (methyl) amino ] -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-yl) methyl ] -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-yl) 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] non-3-yl ] propoxy } benzonitrile;

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

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

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

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

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

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

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

(1S) -tert-butyl 2- (4-cyanophenoxy) -1- ({7- [ (ethylamino) thiocarbonyl ] -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-carbothioic acid amide;

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

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-methylbutyryl ] -3, 7-diazabicyclo [3.3.1] non-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] non-3-yl ] -2-hydroxypropoxy } phenyl) -N' -ethylurea;

n- (2- { 2-amino-3- [7- (ethylsulfonyl) -3, 7-diazabicyclo [3.3.1] non-3-yl ] propoxy } -5-cyanophenyl) -N' -ethylurea;

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

n- (2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } -2-oxoethyl) acetamide;

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

4- [ ((2S) -3- {7- [ (2S) -2-amino-3- (4-methoxyphenyl) propionyl ] -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] non-3-yl } -N- (2, 6-dimethylphenyl) acetamide (m/z ═ 463);

2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } -2-oxoethylcarbamic acid tert-butyl ester (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] non-3-yl } ethyl) -4-nitrobenzamide (m/z ═ 494);

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

n- (2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl ] -3, 7-diazabicyclo [3.3.1] 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] non-3-yl } ethyl) benzamide (m/z ═ 506);

2- [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] non-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] non-3-yl ] propoxy } benzonitrile (m/z ═ 412);

4- (2-hydroxy-3- {7- [ (5-methyl-3-isoxazolyl) carbonyl ] -3, 7-diazabicyclo [3.3.1] non-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-1, 2, 3-thiadiazol-5-yl) carbonyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } propoxy) benzonitrile (m/z ═ 428);

4- [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] non-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-tetrazol-5-yl) -3, 7-diazabicyclo [3.3.1] non-3-yl ] propoxy } benzonitrile (m/z ═ 446);

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

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

{7- [3- (4-cyanophenoxy) -2-hydroxypropyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } sulfonyl thiocarbamic acid (carba othioate) (S-propyl) ester (m/z-483);

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

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

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] non-3-yl } ethylcarbamate (m/z ═ 444);

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

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

4- (3- {7- [ (E) -3- (3, 4-dimethoxyphenyl) -2-acryloyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } -2-hydroxypropoxy) benzonitrile;

4- (3- {7- [ (E) -3- (4-fluorophenyl) -2-acryloyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } -2-hydroxypropoxy) benzonitrile (m/z ═ 450);

2- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl ] -3, 7-diazabicyclo [3.3.1] non-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/z ═ 410);

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

4- { [7- (3, 4-dimethoxyphenethyl) -3, 7-diazabicyclo [3.3.1] non-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] non-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);

3- {7- [3- (4-cyanophenoxy) -2-hydroxypropyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } -1-methyl-3-oxopropylcarbamic acid tert-butyl ester;

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-isoquinolinyl) oxy ] propyl } -3, 7-diazabicyclo [3.3.1] non-3-yl) propoxy ] benzonitrile;

4- (3- {7- [ (3, 4-dimethoxyphenyl) sulfonyl ] -3, 7-diazabicyclo [3.3.1] non-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 ═ 422);

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

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

4- {3- [7- (1, 3-dimethyl-2, 6-dioxo-1, 2, 3, 6-tetrahydro-4-pyrimidinyl) -3, 7-diazabicyclo [3.3.1] non-3-yl ] -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] non-3-yl ] propoxy } benzonitrile (m/z ═ 398);

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

n' -cyano-7- [3- (4-cyanophenoxy) -2-hydroxypropyl-N- [ (1S) -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-azoimidamide (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-quinolinyl) sulfonyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } propoxy) benzonitrile (m/z ═ 507);

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

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

4- { 2-hydroxy-3- [7- (2-oxobutyl) -3, 7-diazabicyclo [3.3.1] non-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. gtoreq. 396);

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

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

3, 7-bis [3- (4-cyanophenoxy) -2-hydroxypropyl ] -7-aza-3-azoniabicyclo [3.3.1] nonan-3-oic acid salt (m/z ═ 493);

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

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

4- [4- (7-butanoyl-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] non-3-yl ] butyl } benzonitrile (m/z ═ 534);

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

4- [4- (7-butanoyl-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] non-3-yl ] butyl } benzonitrile (m/z ═ 382);

4- {4- [7- (3, 4-bis-methoxyphenethyl) -3, 7-diazabicyclo [3.3.1] non-3-yl ] butyl } benzonitrile (m/z ═ 448);

4- [2- (7-butanoyl-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] non-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);

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

benzonitrile, 4- [ 2-hydroxy-3- [7- [ (tetrahydro-3-thienyl) sulfonyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl ] propoxy ] -, S-dioxide;

4- ({ (2S) -2-amino-3- [7- (3, 3-dimethyl-2-oxobutyl) -3, 7-diazabicyclo [3.3.1] 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] non-3-yl ] butyl } benzonitrile (m/z ═ 519);

4- ({3- [7- (1, 3-thiazol-2-yl) -3, 7-diazabicyclo [3.3.1] non-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] non-3-yl ] -2-hydroxypropoxy } benzonitrile (m/z ═ 356);

4- {2- [7- (cyclopropylmethyl) -3, 7-diazabicyclo [3.3.1] non-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);

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

4- (2- {7- [2- (2-methoxyethoxy) ethyl ] -3, 7-diazabicyclo [3.3.1] non-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' -methylurea (m/z ═ 460);

4- [ (3- {7- [2- (2-methoxyethoxy) ethyl ] -3, 7-diazabicyclo [3.3.1] non-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] non-3-yl } -2-oxoethyl) -1H-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] non-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] non-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-yl ] -2-hydroxypropoxy } benzonitrile;

4- {2- [7- (1-cyanoethyl) -3, 7-diazabicyclo [3.3.1] non-3-yl ] ethoxy } benzonitrile;

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] non-3-yl ] propyl } amino) benzonitrile (m/z ═ 449);

4- ({3- [7- (3, 4-dimethoxyphenethyl) -3, 7-diazabicyclo [3.3.1] non-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 } -1H-pyrazol-5-yl) benzonitrile (m/z ═ 601);

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

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

4- (4- (4-cyanophenyl) -1- { 2-oxo-2- [7- (4-oxoheptyl) -3, 7-diazabicyclo [3.3.1] non-3-yl ] ethyl } -1H-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-1, 4-benzodioxin) -6-yl) -2-oxoethyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } -2-hydroxypropoxy) benzonitrile (m/z ═ 478);

4- [ (3- {7- [2- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -2-oxoethyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } propyl) amino ] benzonitrile (m/z ═ 461);

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

4- (1- (3, 4-dimethoxyphenoxy) -4- {7- [3- (ethylsulfonyl) propyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } butyl) benzonitrile (m/z ═ 570);

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

4- ({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] non-3-yl ] propoxy } -N, N-dimethylbenzenesulfonamide (m/z ═ 467);

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

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

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

n- (2- (4-cyanophenoxy) -1- { [7- (3, 3-dimethyl-2-oxobutyl) -3, 7-diazabicyclo [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] non-3-yl ] propyl } sulfonyl) benzonitrile (m/z ═ 432);

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

4- (2-hydroxy-3- {7- [2- (2-methoxyethoxy) ethyl ] -3, 7-diazabicyclo [3.3.1] non-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/z ═ 538);

4- [ (3- {7- [2- (2-methoxyethoxy) ethyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } propyl) sulfonyl ] benzonitrile (m/z ═ 436);

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

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

n- {2- [7- (1-cyanoethyl) -3, 7-diazabicyclo [3.3.1] non-3-yl ] -1- [ (4-cyanophenoxy) methyl ] ethyl } -N' -methylurea;

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

n- (2- (4-cyanophenoxy) -1- { [7- (3, 4-dimethoxyphenethyl) -3, 7-diazabicyclo [3.3.1] non-3-yl ] methyl } ethyl) -N' -methylurea (m/z ═ 522);

4- {3- [7- (3, 4-dimethoxyphenethyl) -3, 7-diazabicyclo [3.3.1] non-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] non-3-yl ] propoxy } -N, N-dimethylbenzenesulfonamide (m/z ═ 496);

n- [2- (4-cyanophenoxy) -1- ({7- [2- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -2-oxoethyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } methyl) ethyl ] -N' -methylurea (m/z ═ 496);

4- [ (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);

4- (2- {7- [3- (ethylsulfonyl) propyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } ethoxy) benzonitrile (m/z ═ 406);

n- [2- (4-cyanophenoxy) -1- ({7- [3- (ethylsulfonyl) propyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } methyl) ethyl ] -N' -methylurea (m/z. RTM. 492);

4- [ (3- {7- [3- (ethylsulfonyl) propyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } propyl) amino ] benzonitrile (m/z ═ 419);

4- [ (3- {7- [3- (ethylsulfonyl) propyl ] -3, 7-diazabicyclo [3.3.1] non-3-yl } propyl) sulfonyl ] benzonitrile (m/z ═ 468);

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

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

4- (3- {7- [3- (ethylsulfonyl) propyl ] -3, 7-diazabicyclo [3.3.1] non-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] non-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] non-3-yl } propyl) amino ] benzonitrile (m/z ═ 453);

4- [ (3- {7- [3- (4-acetyl-1-piperazinyl) propyl ] -3, 7-diazabicyclo [3.3.1] non-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] non-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; and

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

The title compounds of the above examples were tested in test A above and found to exhibit a D of at least 6.0₁₀The value is obtained.Example 9

The title compounds of the above examples were assayed in test B above and were found to exhibit a pIC of at least 5.5₅₀The value is obtained. Abbreviations

Ac ═ acetyl group

API atmospheric pressure ionization (for MS)

aq. being aqueous

br as broad peak (for NMR)

Bt ═ benzotriazole

t-BuOH ═ tert-butanol

CI-chemical ionization (for MS)

mCPBA ═ m-chloroperbenzoic acid

d ═ bimodal (for NMR)

DBU ═ diazabicyclo [5.4.0] undec-7-ene

DCM ═ dichloromethane

dd doublet (for NMR)

DMAP ═ 4-dimethylaminopyridine

DMF ═ N, N-dimethylformamide

DMSO ═ dimethyl sulfoxide

EDC ═ 1- [3- (dimethylamino) propyl ] -3-ethylcarbodiimide

Et is ethyl

EtOAc ═ ethyl acetate

eq. -. equivalent

ES ═ electronic spray (for MS)

FAB ═ fast atom bombardment (for MS)

h is hour

HCl ═ hydrochloric acid

HEPES-4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid

HPLC ═ high performance liquid chromatography

IPA ═ isopropanol (propan-2-ol)

multiple peaks (for NMR)

Me is methyl

MeCN ═ acetonitrile

MeOH ═ methanol

min. (min.)

m.p. ═ melting point

MS mass spectrum

NADPH-nicotinamide adenine dinucleotide phosphate, reduced

Acetic acid salt OAc ═

Pd/C-palladium on carbon

q is quartet (for NMR)

rt-room temperature

Unimodal (for NMR)

triplet peak (for NMR)

TEA ═ triethylamine

THF ═ tetrahydrofuran

tlc (thin layer chromatography)

The prefixes n-, s-, i-, t-and tert-have their usual meanings: normal, secondary, iso and tertiary.

Claims (53)

1. Formula I compound or its pharmaceutically acceptable derivative in ^R represents the structural fragment shown in formula Ia R ⁴ represents H, halogen, C _1-4 alkyl, -D-OR ⁷ , -DN(R ⁸ )R ⁹ , or R ⁴ and R ⁵ together represent =O; R ⁵ represents H, C _1-4 alkyl, or R ⁵ and R ⁴ together represent =O; D represents a bond or C _1-4 alkylene; R ⁷ represents H, C _1-6 alkyl, -E-aryl, -E-Het ¹ , -C(O)R ^10a , -C(O)OR ^10b or -C(O)N(R ^11a ) ^R11b ; R ⁸ represents H, C _1-6 alkyl, -E-aryl, -E-Het ¹ , -C(O)R ^10a , -C(O)OR ¹⁰ , -S(O) ₂ R ^10c , - [C(O)] _n N(R ^11a )R ^11b or -C(NH)NH ₂ ; R ⁹ represents H, C _1-6 alkyl, -E-aryl, or -C(O)R ^10d ; In each use, E represents a bond or C _1-4 alkylene; In each use, R ^10a to R ^10d independently represent C _1-6 alkyl (optionally substituted by and/or terminated by one or more substituents selected from the group consisting of halogen, aryl and Het ² ), aryl, Het ³ , or R ^10a and R ^10d independently represent H; In each use, R ^11a and R ^11b independently represent H, C _1-6 alkyl (optionally substituted by and/or terminated by one or more substituents selected from the group consisting of: halogen, aryl group and Het ⁴ ), aryl group, Het ⁵ , or R ^11a and R ^11b together represent a C _3-7 alkylene group, wherein the alkylene group may optionally be interrupted by an oxygen atom; n stands for 1 or 2; A represents -G-, -JN(R ¹² )- or -JO- (wherein in the latter two groups, J is connected to the bispidine nitrogen atom); B stands for -L-, -LN(R ¹³ )-, -N(R ¹³ )-L-, -LS(O) _p - or -LO- (wherein in the last two groups, L is connected to carry R ⁴ and R ⁵ carbon atoms); G represents a bond or C _1-6 alkylene; J represents C _2-6 alkylene; L represents a bond or C _1-4 alkylene; p stands for 0, 1 or 2; R ¹² and R ¹³ independently represent H or C _1-4 alkyl; R ⁶ represents aryl, Het ⁶ (both of which are optionally substituted and/or terminated (if appropriate) by one or more substituents selected from: -OH, cyano, halogen, Nitro, C _1-6 alkyl (optionally terminated with -N(H)C(O)OR ^14a ), C _1-6 alkoxy, aryl, Het ⁷ , -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 ), or when R ⁴ and R ⁵ together represent =O, R ⁶ may represent C _1-6 alkyl; q stands for 0, 1 or 2; R ² represents -CN, Het ⁸ , -C(O)R ¹⁶ , -C(S)OR ¹⁷ , -C(S)N(R ¹⁸ )R ¹⁹ , -[C(O)] ₂ N(R ^20a )R ^2b , -[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 _1-12 alkyl (the alkyl is optionally substituted by 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, -CN, nitro, aryl Base and Het ⁹ ); R ¹⁶ represents H, aryl, Het ¹⁰ or C _1-6 alkyl (the alkyl is optionally substituted by one or more substituents selected from the following and/or terminated by them: halogen, -OH, - CN, -N(R ³⁴ )R ³⁵ , aryl and Het ¹¹ ); R ³⁴ represents H, C _1-6 alkyl, aryl, Het ¹² , -C(O)R ^36a or -C(O)OR ^36b ; R ¹⁸ represents H, aryl, Het ¹³ , -C(O)R ^36a , -C(O)OR ^36b or C _1-6 alkyl (the alkyl group is optionally substituted by one or more selected from the following Substituted by and/or terminated by: halogen, -OH, -CN, -C(O)R ^36a and -C(O)OR ^36b ); R ²² represents Het ¹⁴ , aryl, or C _1-6 alkyl (the alkyl is optionally substituted by one or more substituents selected from the following and/or terminated by them: halogen, -OH, -CN , Het ¹⁵ and aryl); R ²³ represents H, C _1-6 alkyl, aryl, Het ¹⁶ , -C(O)R ^36a , -C(O)OR ^36b or -C(O)SR ^36b ; R ²⁵ represents H or C _1-6 alkyl (the alkyl is optionally substituted by one or more substituents selected from the following and/or terminated by them: halogen, -OH, -CN, C _1-6 Alkyl (the alkyl is optionally substituted and/or terminated by one or more substituents selected from the group consisting of C _1-4 alkyl and -OH), C _1-6 alkoxy and aryl ); R ²⁷ represents C _1-6 alkyl or aryl; R ²⁸ represents H, C _1-6 alkyl, aryl or Het ¹⁷ ; R ^29a and R ^29b independently represent H, C _1-6 alkyl, aryl or Het ¹⁸ ; R ³⁰ represents H, C _1-6 alkyl, aryl, Het ¹⁹ , -C(O)R ^37a , -C(O)OR ^37b or -C(O)N(R ^37c )R ^37d ; R ³¹ represents H, C _1-6 alkyl, aryl or Het ²⁰ ; R ³² represents H, C _1-6 alkyl, aryl, Het ²¹ , -C(O)R ^37a , -C(O)OR ^37b or -C(O)N(R ^37c )R ^37b ; R ³³ represents C _1-6 alkyl, aryl or Het ²² ; r stands for 0, 1 or 2; When used each time, R ^36a and R ^36b independently represent C _1-6 alkyl, or R ^36a represents H; When used each time, R ^37a to R ^37d independently represent C _1-6 alkyl, aryl or Het ²³ , or R ^37a , R ^37c and R ^37b independently represent H; When used each time, Het ¹ -Het ²³ independently represent a 5-12 membered heterocyclic group comprising one or more heteroatoms selected from oxygen, nitrogen and/or sulfur; R ^3a and R ^3b independently represent H, C _1-4 alkyl, -OR ^38a , -SR ^39b , -N(R ³⁹ )R ^38c , or R ^3a and R ^3b together represent C _3-5 alkylene, -OZO-, -OZS- or -SZS-; R ³⁹ represents H, C _1-6 alkyl or the structural fragment shown in formula Ia as defined above; Z represents a C _2-3 alkylene group optionally substituted by one or more C _1-4 alkyl groups; R ⁴¹ -R ⁴⁶ independently represent H or C _1-3 alkyl; R ^14a -R ^14d , R ¹⁷ and R ²¹ independently represent C _1-6 alkyl; R ^15a -R ^15p , R ¹⁹ , R ^20b , R ²⁴ , R ²⁶ , R ³⁵ , R ^38a and R ^38a -R ^38c independently represent H or C _1-6 alkyl; wherein unless otherwise stated, each aryl and Het (Het ¹ -Het ²³ ) group can be optionally substituted; requirement is: (a) when R ¹ represents a structural fragment shown in formula Ia, and wherein R ⁴ and R ⁵ together represent =O; When A represents a key, Then B does not represent a bond, -N(R ¹³ )-L- (wherein the group -N(R ¹³ )- is attached to Carrying R ⁴ and R ⁵ carbon atoms), -N(R ¹³ )-, -S(O) _p -or -O-; (b) when ^R represents H or C _1-4 alkyl; and When A stands for -JN(R ¹² )- or -JO-, Then B does not represent -N(R ¹³ )-L-, -N(R ¹³ )-, -S(O) _p -or -O-; (c) When R ⁴ represents -D-OR ⁷ , -DN(R ⁸ )R ⁹ , and wherein D represents a bond, but: (i) A does not represent -JN(R ¹² )- or -JO-; and (ii) B does not represent -N(R ¹³ )-L-, -N(R ¹³ )-, -S(O) _p - or -O-; (d) when both R ^3a and R ^3b represent H; and R ¹ represents unsubstituted benzyl, R ^then does not represent unsubstituted benzyl or optionally substituted benzoyl; and (e) the compound is not: (i) N ¹ -phenyl-3-(7-benzyl-3,7-diazabicyclo[3.3.1]nonan-3- Base) propionamide; (ii) 3-benzyl-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-6,8-di  Methyl-3,7-diazabicyclo[3.3.1]nonane; (iii) 3-benzyl-7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-6-methyl   -3,7-diazabicyclo[3.3.1]nonane; (iv) N-{2-(7-benzyl-3,7-diazabicyclo[3.3.1]non-3-yl)-1- [(4-cyano-phenoxy)methyl]ethyl}methanesulfonamide; (v) 3-benzyl-7-[3-(2-propyl-1,3-dioxolan-2-yl)propane yl]-3,7-diazabicyclo[3.3.1]nonane; or (vi) 7-Benzyl-3,7-diazabicyclo[3.3.1]nonane-3-ethanol. 2. The compound of claim 1, wherein R ⁴ represents H, C _1-2 alkyl, -OR ⁷ or N(H)R ⁸ , or R ⁴ and R ⁵ together represent =O. 3. A compound according to claim 1 or 2, wherein ^R5 represents H, or ^R5 and ^R4 together represent =O. 4. The compound of any one of claims 1-3, wherein R ⁷ represents H, C _1-4 alkyl, optionally substituted phenyl, -C(O)R ^10a , or -C(O)N(R ^11a ) R ^11b . 5. The compound of any one of claims 1-3, wherein R ⁸ represents H, C _1-4 alkyl, -C(O)R ^10a , -C(O)OR ^10b or -C(O)N(R ^11a ) R ^11b . 6. The compound of any one of claims 1-5, wherein each use, R ^10a and R ^10b independently represent C _1-5 alkyl (the alkyl is optionally selected from one or more of the following Substituents substituted and/or terminated by: halogen and phenyl), optionally substituted phenyl, or R ^10a represents H. 7. The compound of claim 4 or 5, wherein in each use, R ^11a and R ^11b independently represent H or C _1-5 alkyl (the alkyl is optionally replaced by one or more selected from the following Substituents substituted and/or terminated by: halogen and phenyl). 8. The compound according to any one of claims 1-7, wherein A represents -G- or -JN( ^R12 )-. 9. The compound of claim 8, wherein G represents a bond or C _1-4 alkylene. 10. The compound of any one of claims 1-8, wherein J represents _C2-4alkylene . 11. The compound of any one of claims 1-10, wherein B represents a bond, C _1-4 alkylene, -LN(H)-, -LS(O) ₂ - or -LO- (the latter three In the group, L is attached to the carbon atom carrying ^R4 and ^R5 ). 12. The compound according to any one of claims 1-11, wherein L represents C _1-4 alkylene. 13. The compound of any one of claims 1-12, wherein R represents phenyl, ^Het (these two groups ^are all optionally substituted by one or more substituents selected from the group consisting of cyano, halogen, nitro base, C _1-4 alkyl, C _1-4 alkoxy, optionally substituted phenyl, -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 ^24c and -S(O) ₂ N(R ¹⁵ⁿ )R ^15p ), or when R ⁴ and R ⁵ together represent =O, R ⁶ may represent C _1-5 alkyl. 14. The compound of any one of claims 1-13, wherein R ² represents -CN, 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 _1-6 alkyl (the alkyl group is optionally substituted by one or more selected from Substituted and/or terminated with: -C(O)R ²⁸ , -C(O)N(H)R ^29b , -N(R ³⁰ )R ³¹ , -OR ³² , -S(O) ₂ R ³³ , halogen, -CN, optionally substituted phenyl, and Het ⁹ ). 15. The compound of claim 14, wherein R ¹⁶ represents optionally substituted phenyl, Het ¹⁰ or C _1-6 alkyl (the alkyl is optionally unsaturated and/or optionally selected from one or more Substituted and/or terminated by substituents selected from: halogen, -CN, -N(H)R ³⁴ and optionally substituted phenyl). 16. The compound of claim 15, wherein R ³⁴ represents H, C _1-4 alkyl, -C(O)R ^36a or -C(O)OR ^36b . 17. The compound of claim 14, wherein R ¹⁸ represents H, -C(O)OR ^36b or C _1-6 alkyl (the alkyl is optionally substituted by one or more substituents selected from the following and/or With these as ends: halogen and -C(O)OR ^36b ). 18. The compound of claim 14, wherein R ²² represents Het ¹⁴ , optionally substituted phenyl or C _1-4 alkyl (the alkyl is optionally substituted by one or more substituents selected from the following and/or with these as terminal: halogen, Het ¹⁵ and optionally substituted phenyl). 19. The compound of claim 14, wherein R ²³ represents H, C _1-4 alkyl, -C(O)OR ^36b or -C(O)SR ^36b . 20. The compound of claim 14, wherein R ²⁵ represents H or C _1-6 alkyl (the alkyl is optionally substituted by one or more substituents selected from the following group and/or is terminal with them: halogen, - OH, C _1-6 alkyl (the alkyl is optionally substituted by and/or terminated by one or more substituents selected from the group consisting of: C _1-4 alkyl and -OH), C _1-4 alkoxy, naphthyl and optionally substituted phenyl). 21. The compound of claim 14, wherein R ²⁷ represents optionally substituted phenyl. 22. The compound of claim 14, wherein R ²⁸ represents C _1-5 alkyl, optionally substituted phenyl or Het ¹⁷ . 23. The compound of any one of claims 1-14 or 22, wherein R ^29b represents H, C _1-4 alkyl or optionally substituted phenyl. 24. The compound of any one of claims 14, 22 and 23, wherein R ³⁰ represents H, optionally substituted phenyl, -C(O)R ^37a or -C(O)OR ^37b . 25. The compound of any one of claims 14 or 22-24, ^wherein R represents H, C _1-2 alkyl or optionally substituted phenyl. 26. The compound according to any one of claims 14 or 22-25, wherein ^R32 represents H, _C1-4alkyl (the alkyl group is optionally interrupted by oxygen), optionally substituted phenyl or ^Het21 . 27. The compound of any one of claims 14 or 22-26, wherein R ³³ represents C _1-6 alkyl or optionally substituted phenyl. 28. The compound of any one of claims 1-14 or 22-27, wherein each use, R ^37a and R ^37b independently represent C ^1-5 alkyl, optionally substituted phenyl, or R ^37a stands for H. 29. The compound of any one of claims 1-28, wherein R ^3a and R ^3b independently represent H, C _1-2 alkyl, -SR ^38b , -N(R ³⁹ ) ^38c , or R ^3a and R ^3b together Represents C _3-4 alkylene or -OZO-. 30. The compound of claim 29, wherein R ³⁹ represents H, C _1-2 alkyl or a structural fragment shown in formula Ia. 31. The compound of any one of claims 1-30, wherein Z represents _C2-3 alkylene. 32. The compound of any one of claims 1-31, wherein R ⁴¹ -R ⁴⁶ independently represent H or C _1-2 alkyl. 33. The compound of claim 13 or 14, wherein R ^14b , R ^14c , R ¹⁷ and R ²¹ independently represent C _1-4 alkyl. 34. The compound according to any one of claims 13, 14 and 29, wherein R ^15b -R ^15p , R ^20b , R ²⁴ , R ²⁶ , R ^38b and R ^38c independently represent H or C _1-5 alkyl. 35. The compound of any one of claims 1-34, wherein the optional substituent on the phenyl is one or more substituents selected from the group consisting of cyano, halogen, nitro, C _1-2 alkyl, C _1-2 alkoxy, Het ¹ , -NH ₂ , -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 and -S(O) ₂ N(R ¹⁵ⁿ )R ^15p . 36. A pharmaceutical formulation comprising a compound according to any one of claims 1-35 together with a pharmaceutically acceptable adjuvant, diluent or carrier. 37. Pharmaceutical preparations for the prophylaxis or treatment of cardiac arrhythmias, which comprise compounds according to any one of claims 1-35. 38. A compound according to any one of claims 1-35, but without condition (e), for use as a medicament. 39. A compound according to any one of claims 1-35, without condition (e), for use in the prevention or treatment of cardiac arrhythmias. 40. Use of a compound according to any one of claims 1-35 as an active ingredient for the manufacture of a medicament for the prevention or treatment of cardiac arrhythmias, but without condition (e). 41. The use of claim 40, wherein the arrhythmia is an atrial or ventricular arrhythmia. 42. A method of preventing or treating cardiac arrhythmias comprising administering to a human suffering from or prone to suffering from such a disorder a therapeutically effective amount of a compound according to any one of claims 1-35, but without condition (e). 43. The method for preparing the compound of formula I of claim 1, said method comprising: (a) the corresponding formula II compound

wherein R ² , R ^3a , R ^3b and R ⁴¹ -R ⁴⁶ are as defined in claim 1, reacting with the compound of formula 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 wherein R ¹ represents a structural fragment shown in formula Ia, A represents C ₂ alkylene, and R ⁴ and R ⁵ together represent a compound of formula I =O, the corresponding compound of formula II as defined above is combined with formula IV compound reaction

Wherein R ⁶ and B are as defined in claim 1; (c) For a compound of formula I wherein R ^3a or R ^3b represents -N(R ³⁹ )R ^38c , and R ³⁹ represents a structural fragment shown in formula Ia, where R ^3a or R ^3b (if appropriate) represents -N (H) R ^38c , R ^38c are as defined in claim 1 and the corresponding compound of formula I is reacted with the compound of formula III as defined above; (d) For the compound of formula I wherein R ¹ represents the structure shown in formula Ia, A represents CH ₂ , and R ⁴ represents -OH or -N(H)R ⁸ , the corresponding compound of formula II as defined above is combined with formula V compound reaction

wherein X represents O or N (R ⁸ ), and R ⁵ , R ⁶ , R ⁸ and B are as defined in claim 1; (e) For wherein R ^3a or R ^3b represents -N(R ³⁹ )R ^38c , R ³⁹ represents a structural fragment shown in formula Ia, A represents CH ₂ , and R ⁴ represents -OH or -N(H)R ⁸ A compound of formula I, wherein R ^3a or R ^3b (if appropriate) represents -N(H)R ^38c , R ^38c as defined in claim 1 corresponding to a compound of formula I reacted with a compound of formula V as defined above; (f) For compounds of formula I wherein A represents C _1-6 alkylene, B represents C _1-4 alkylene, and R ⁴ and R ⁵ both represent H, wherein R ⁴ and R ⁵ together represent =O Reduction of the corresponding compound of formula I; (g) For wherein both R ⁴ and R ⁵ represent H, and (1) A represents a single bond or -JN(R ¹² ), B represents C _1-4 alkylene, or (2) A represents C _{1- 6} alkylene, and B represents N(R ¹³ ) or -N(R ¹³ )-L- compound of formula I, wherein R ⁴ and R ⁵ together represent ═O corresponding reduction of the compound of formula I; (h) For wherein A represents C _1-6 alkylene, B represents a bond, C _1-4 alkylene, -LN(R ¹³ )-, -LS(O)p- or -LO- (wherein In the latter three groups, L represents C _1-4 alkylene), R ⁴ represents OH, and R ⁵ represents a compound of formula I representing H, wherein R ⁴ and R ⁵ together represent =O The corresponding compound of formula I is reduced ; (i) for a compound of formula I wherein R and ^{R both represent} H, reducing the corresponding compound of formula VI,

wherein R ¹ , R ² and R ⁴¹ -R ⁴⁶ are as defined in claim 1, and wherein the bridgehead C=O group can be activated; (j) for a compound of formula I wherein one of R ^3a and R ^3b represents H and the other represents -OH, reducing the corresponding compound of formula VI as defined above; (k) For compounds of formula I wherein R ^3a and R ^3b both represent -OR ^38a or -SR ^38b , or R ^3a and R ^3b together represent -OZO-, -OZS- or -SZS-, the corresponding Reaction of a compound of formula VI with a compound of formula HOR ^38a , HSR ^38b , HO-Z-OH, HO-Z-SH or HS-Z-SH (if appropriate) wherein R ^38a , R ^38b and Z are as defined in claim 1 ; (1) For a compound of formula I wherein one of R ^3a and R ^3b represents -NH ₂ , and the other represents H, the compound of formula VII is reduced,

wherein R ¹ , R ² and R ⁴¹ -R ⁴⁶ are as defined in claim 1; (m) For a compound of formula I wherein one or both R ^3a and R ^3b represent -N(R ³⁹ )R ^38c , and one or both R ³⁹ and R ^38c represent C _1-6 alkyl, wherein R ^3a and Alkylation of the corresponding compound of formula I where R ^3b represents -N(R ³⁹ )R ^38c (if appropriate) and R ³⁹ and/or R ^38c (if appropriate) represents H with a compound of formula VIII R ^a -L ¹ VIII wherein R ^a represents C _1-6 alkyl, and L ¹ is as defined above; (n) for wherein R ¹ represents the structural fragment shown in formula Ia, and B represents the compound of formula I of -LO-, the compound of formula IX

wherein R ² , R ^3a , R ^3b , R ⁴ , R ⁵ , R ⁴¹ -R ⁴⁶ , A and L are as defined in claim 1, reacted with a compound of formula X, R ⁶ OH X wherein R ⁶ is as defined in claim 1; (o) For wherein R ¹ represents the structural fragment shown in formula Ia, A represents C _1-6 alkylene, and B represents -N(R ¹³ )-L- (wherein the group -N(R ¹³ )- is connected to Carry on the carbon atom of R ⁴ and R ⁵ ) the compound of formula I, the compound of formula XI wherein A ^a represents a C _1-6 alkylene group, and R ² , R ^3a , R ^3b , R ⁴ , R ⁵ , R ¹³ and R ⁴¹ -R ⁴⁶ are as defined in claim 1, and react with the 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 wherein R ¹ represents a structural fragment shown in Formula Ia, and R ⁴ represents a compound of formula I of -D-NH ₂ , reducing the corresponding compound of formula XIII, wherein R ² , R ^3a , R ^3b , R ⁵ , R ⁶ , R ⁴¹ -R ⁴⁶ , A, B and D are as defined in claim 1; (q) For a compound of formula I wherein R ⁴ represents -DN(R ⁹ )C(O)NH(R ^11b ), the corresponding compound of formula I wherein R ⁴ represents -DN(R ⁹ )H is reacted with a compound of formula XIV , R ^11b N=C=O XIV wherein R ^11b is as defined in claim 1; (r) for a compound of formula I wherein R ⁴ represents -DN(H)[C(O)] ₂ NH ₂ , the corresponding compound of formula I wherein R ⁴ represents -D-NH ₂ is reacted with oxalic acid diamide; (s) For compounds of formula I wherein R ⁴ represents -DN(R ⁸ )R ⁹ , R ⁸ and R ⁹ are as defined in claim 1, with the proviso that R ⁸ does not represent H, wherein R ⁴ represents -DN(H ) ^R The corresponding formula I compound reacts with the formula XV compound R ^8a -L ³ XV wherein R ^8a represents R ⁸ as defined in claim 1, except that it does not represent H, and L ³ represents a leaving group; (t) For compounds of formula I wherein R ⁴ represents -D-OR ⁷ , and R ⁷ represents C _1-6 alkyl, -E-aryl or -E-Het ¹ , wherein R ⁴ represents -D-OH The corresponding compound of formula I reacts with the compound of formula XVI, R ^7a OH XVI wherein R ^7a represents C _1-6 alkyl, -E-aryl or -E-Het ¹ , wherein Het ¹ is as defined in claim 1; (u) For the formula I in which R ¹ represents the structural fragment shown in Formula Ia, R ⁴ represents -D-OR ⁷ (wherein R ⁷ represents C _1-6 alkyl, -E-aryl or -E-Het ¹ ) Compound, the corresponding formula XVII compound wherein R ² , R ^3a , R ^3b , R ⁵ , R ⁶ , R ⁴¹ -R ⁴⁶ , A, B and D are as defined in claim 1, and L ² is as defined above, reacted with a compound of formula XVI as defined above ; (v) For a compound of formula I wherein R ⁴ represents -D-OR ⁷ , R ⁷ being as defined in claim 1 , with the proviso that it does not represent H, the corresponding compound of formula I wherein R ⁴ represents -D-OH is combined with the formula Compound XVIII reacts, R ^7b -L ⁴ XVIII wherein R ^7b represents R ⁷ as defined in claim 1, except that it does not represent H, and L ⁴ represents a leaving group; (w) for a compound of formula ^I wherein R represents halogen, the corresponding compound of formula I wherein R represents ^-OH is substituted with a suitable halogenating agent; (x) the corresponding compound of formula XIX wherein R ¹ , R ^3a , R ^3b and R ⁴¹ -R ⁴⁶ are as defined in claim 1, reacted with a compound of formula XX, R ² -L ⁵ XX wherein L ⁵ represents a leaving group, and R ² is as defined in claim 1; (y) for wherein R ² represents a C _1-12 alkyl group substituted at the C-2 carbon (relative to the bispidine nitrogen) by OH or N(H)R ³⁰ and optionally by one or more Compounds of formula I substituted with further substituents as described in claim ¹ for R , reacting compounds of formula XIX as defined above with compounds of formula XXA

wherein X _a represents O or N(R ³⁰ ), and R ^2a represents a C _1-10 alkyl group, which is optionally substituted by one or more substituents as described in claim 1 for R ² ; (z) for a compound of formula I wherein ^R represents tetrazol-5-yl, reacting the corresponding compound of formula I wherein ^R represents -CN with an azide ion source; (aa) for a compound of formula I which is a bispine-nitrogen N-oxide derivative, oxidizing the corresponding bispidine nitrogen of the corresponding compound of formula I in the presence of a suitable oxidizing agent; (ab) For the compound of formula I that is C _1-4 alkyl quaternary ammonium salt derivative and said alkyl is connected on the bispidine nitrogen, the corresponding formula I compound is reacted with the formula XXI compound on the bispidine nitrogen, R ^b -L ² XXI wherein R ^b represents C _1-4 alkyl, and L ² is as defined above; (ac) converting one substituent on ^R to another substituent; (ad) converting one ^R2 group into another ^R2 group; or (ae) Deprotecting the protected derivative of the compound of formula I as defined in claim 1 . 44. A compound of formula II as defined in claim 43 or a protected derivative thereof. 45. A compound of formula VI as defined in claim 43 or a protected derivative thereof. 46. A compound of formula VII or a protected derivative thereof as defined in claim 43. 47. A compound of formula IX as defined in claim 43 or a protected derivative thereof. 48. A compound of formula XI or a protected derivative thereof as defined in claim 43. 49. A compound of formula XIII or a protected derivative thereof as defined in claim 43. 50. A compound of formula XVII or a protected derivative thereof as defined in claim 43. 51. A compound of formula XIX as defined in claim 43 (with the proviso that at least one of R ^3a and R ^3b represents -N(R ³⁹ )R ^38c , wherein R ³⁹ represents formula Ia as defined in claim 1 Structural fragments) or their protected derivatives. 52. A compound of formula XXII or a protected derivative thereof

wherein R ^3a , R ^3b and R ⁴¹ -R ⁴⁶ are as defined in claim 1 (provided that at least one of R ³⁴ and R ^3b represents -N(R ³⁹ )R ^38c , wherein R ³⁹ represents Structural fragment shown in the formula Ia). 53. A compound of formula XXIII or a protected derivative thereof wherein R ² and R ⁴¹ -R ⁴⁶ are as defined in claim 1.