WO2006021399A2 - Azabicyclononene derivatives as renin inhibitors - Google Patents

Abstract

The invention relates to novel bicyclononene derivatives and the use thereof as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as inhibitors of renin.

Description

Bicyclononene Derivatives

The invention relates to novel compounds of the formula (I). The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I) and especially their use as renin inhibitors in cardiovascular events and renal insufficiency.

In the renin-angiotensin system (RAS) the biologically active angiotensin II (Ang II) is generated by a two-step mechanism. The highly specific enzyme renin cleaves angiotensinogen to angiotensin I (Ang I), which is then further processed to Ang II by the less specific angiotensin-converting enzyme (ACE). Ang II is known to work on at least two receptor subtypes called ATI and AT2. Whereas

ATI seems to transmit most of the known functions of Ang II, the role of AT2 is still unknown.

Modulation of the RAS represents a major advance in the treatment of cardiovascular diseases. ACE inhibitors and ATI blockers have been accepted to treat hypertension (Waeber B. et al., "The renin-angiotensin system: role in experimental and human hypertension", in Birkenhager W. H., Reid J. L. (eds): Hypertension, Amsterdam, Elsevier Science Publishing Co, 1986, 489-519; Weber M. A., Am. J. Hypertens., 1992, 5, 247S). In addition, ACE inhibitors are used for renal protection (Rosenberg M. E. et al., Kidney International, 1994, 45, 403; Breyer J. A. et al., Kidney International, 1994, 45, S156), in the prevention of congestive heart failure (Vaughan D. E. et al., Cardiovasc. Res., 1994, 28, 159; Fouad-Tarazi F. et al., Am. J. Med., 1988, 84 (Suppl. 3A), 83) and myocardial infarction (Pfeffer M. A. et al., N. Engl. J. Med., 1992, 327, 669). The rationale to develop renin inhibitors is the specificity of renin (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The only substrate known for renin is angiotensinogen, which can only be processed (under physiological conditions) by renin. In contrast, ACE can also cleave bradykinin besides Ang I and can be by- passed by chymase, a serine protease (Husain A., J. Hypertens., 1993, 11, 1155). In patients inhibition of ACE thus leads to bradykinin accumulation causing cough (5-20%) and potentially life-threatening angioneurotic edema (0.1-0.2%) (Israili Z. H. et al., Annals of Internal Medicine, 1992, 117, 234). Chymase is not inhibited by ACE inhibitors. Therefore, the formation of Ang II is still possible in patients treated with ACE inhibitors. Blockade of the ATI receptor (e.g. by losartan) on the other hand overexposes other AT-receptor subtypes (e.g. AT2) to Ang II, whose concentration is significantly increased by the blockade of ATI receptors. In summary, renin inhibitors are expected to demonstrate a different pharmaceutical profile than ACE inhibitors and ATI blockers with regard to efficacy in blocking the RAS and in safety aspects.

Only limited clinical experience (Azizi M. et al., J. Hypertens., 1994, 12, 419; Neutel J. M. et al., Am. Heart, 1991, 122, 1094) has been created with renin inhibitors because of their insufficient oral activity due to their peptidomimetic character (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The clinical development of several compounds has been stopped because of this problem together with the high cost of goods. Only one compound containing four chiral centers has entered clinical trials (Rahuel J. et al., Chem. Biol., 2000, 7, 493; Mealy N. E., Drugs of the Future, 2001, 26, 1139). Thus, renin inhibitors with good oral bioavailability and long duration of action are required. Recently, the first non-peptide renin inhibitors were described which show high in vitro activity (Oefner C. et al., Chem. Biol., 1999, 6, 127; Patent Application WO97/09311; Marki H. P. et al., Il Farmaco, 2001, 56, 21). However, the development status of these compounds is not known.

The present invention relates to renin inhibitors of a non-peptidic nature and of low molecular weight. Described are orally active renin inhibitors of long duration of action which are active in indications beyond blood pressure regulation where the tissular renin-chymase system may be activated leading to pathophysiological^ altered local functions such as renal, cardiac and vascular remodeling, atherosclerosis, and possibly restenosis. So, the present invention describes these non-peptidic renin inhibitors of formula (I).

In particular, the present invention relates to novel compounds of the formula (I),

(I)

wherein

X represents -NH-, -N(L)-, -CH₂-, -CH(L)-, -O-, or -S-;

W represents a phenyl substituted by V in/rørø-position;

V represents -CH₂-NC-R)-CH₂-, -CH₂-N(-R)-CH₂-CH₂-, -CH₂-CH₂-NC-R)-, -N(- R)-CH₂-CH₂-, -O-CH₂-CH₂-N(-R)-, -CH₂-CH₂-N(-R)-CH₂-, -CH₂~CH₂-N(-R)- CH₂-CH₂-, -CH₂-NC-R)-CH₂-CH₂-O-, -CH₂-CH₂-CH₂-N(-R)-, -N(-R)-CH₂-CH₂- CH₂-, or -CH₂-CH₂-N(-R)-CO-;

U represents phenyl; mono-, di-, tri-, or tetra-substituted phenyl, wherein the substituents are independently selected from the group consisting of alkyl, alkoxy, hydroxy-alkyl, halogen, -CF₃, -OCF₂O-, and cyano; a five-membered heteroaryl ring, wherein said heteroaryl ring is optionally mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of alkyl, hydroxy-alkyl, halogen and trifluoromethyl; or a quinolinyl;

T represents -COTSlR¹-;

Q represents methylene;

M represents phenyl; mono- or di-substituted phenyl, wherein the substituents are independently selected from the group consisting of alkyl, alkoxy, alkoxy-alkyl, -OCF₃, -CF₃, and halogen; or mono- or di-substituted pyridinyl, wherein the substituents are independently selected from the group consisting of halogen, alkyl, -OCF₃, -CF₃ and alkoxy; with the proviso, that the halogen substituents are not in 2- or 6-position of the pyridinyl ring;

L represents -R³, -COR³, -COOR³, -CONR²R³, -SO₂R³, or -SO₂NR²R³;

R represents hydrogen, alkyl, cycloalkyl, or -CH₂CFa;

R¹ and R¹ independently represent alkyl or cycloalkyl;

R² and R² independently represent hydrogen, alkyl, alkenyl, cycloalkyl, or cycloalkyl-alkyl; and

R³ represents alkyl, cycloalkyl, or cycloalkyl-alkyl, wherein these groups may be unsubstituted or mono-, di- or tri-substituted, wherein the substituents are independently selected from hydroxy, -NH₂, -OCOR², -COOR², -SO₃H, -SO₂CH₃, alkoxy, cyano, -CONR²R^2', -NH(NH)NH₂, -NR¹R^1', tetrazolyl, and alkyl, with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp³ -hybridized;

and optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, and meso-forms, as well as salts and solvent complexes of such compounds, and morphological forms. The general terms used hereinbefore and hereinafter preferably have, within this disclosure, the following meanings, unless otherwise indicated:

Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.

Any reference to a compound of formula (I) is to be understood as referring also to optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, and meso-forms, as well as salts (especially pharmaceutically acceptable salts) and solvent complexes (including hydrates) of such compounds, and morphological forms, as appropriate and expedient.

In the definitions of formula (I) - if not otherwise stated - the term alkyl, alone or in combination with other groups, means saturated, straight or branched chain groups with one to seven carbon atoms, preferably one to four carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, pentyl, hexyl and heptyl. The methyl, ethyl and isopropyl groups are preferred.

The term hydroxy-alkyl refers to an HO-R group, wherein R is an alkyl group. Examples of hydroxy-alkyl groups are HO-CH₂-, HO-CH₂CH₂-, HO- CH₂CH₂CH₂- and CH₃-CH(OH)-.

The term alkoxy refers to an R-O group, wherein R is an alkyl. Examples of alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, iso-butoxy, sec-butoxy and tert-butoxy.

The term alkenyl means straight or branched chain groups comprising an olefmic bond and consisting of two to seven carbon atoms, preferably two to four carbon atoms. Examples of alkenyl are vinyl, propenyl and butenyl. The term halogen means fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine.

The term cycloalkyl alone or in combination, means a saturated cyclic hydrocarbon ring system with 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term five-membered heteroaryl ring means a five-membered aromatic ring containing two heteroatoms, especially independently selected from nitrogen, oxygen and sulfur, preferably a nitrogen and a sulfur atom, and especially represents an isothiazole ring.

Within the context of the present invention the beginning part of an asymmetric group V is linked to the group W of a compound of formula (I) (that means that for example the -0-CH₂ part Of -O-CH₂-CH₂-N(R)- is linked to the group W of a compound of formula (I).

The term T within the present invention represents -CONR¹- which may be connected in both possible ways to the bicyclononene core structure of formula

(I). In a preferred embodiment of the invention the beginning part of the group T is linked to the bicyclononene core structure of formula (I) (that means that the

-C(=O) part of -CONR¹- is linked to the bicyclononene core structure of formula

(I)). Preferably, the term T within the present invention represents -CONR¹-, wherein R¹ represents cycloalkyl, especially cyclopropyl.

The expression pharmaceutically acceptable salts encompasses either salts with inorganic acids or organic acids like hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, phosphorous acid, nitrous acid, citric acid, formic acid, acetic acid, oxalic acid, maleic acid, lactic acid, tartaric acid, fumaric acid, benzoic acid, mandelic acid, cinnamic acid, palmoic acid, stearic acid, glutamic acid, aspartic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, /7-toluenesulfonic acid, salicylic acid, succinic acid, trifluoroacetic acid, and the like that are non toxic to living organisms or in case the compound of formula (I) is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and the like. For other examples of pharmaceutically acceptable salts, reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.

The compounds of the formula (I) contain two or more asymmetric carbon atoms and may be prepared in form of optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, or meso-forms.

The present invention encompasses all these forms. Mixtures may be separated in a manner known per se, e.g. by column chromatography, thin layer chromatography, HPLC or crystallization.

Compounds of the invention also include nitrosated compounds of formula (I) that have been nitrosated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfydryl condensation) and/or nitrogen.

The nitrosated compounds of the present invention can be prepared using conventional methods known to one skilled in the art. For example, known methods for nitrosating compounds are described in U.S. Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; WO 98/21193; WO 99/00361 and Oae et al., Org. Prep. Proc. Int., 15(3): 165-198 (1983).

A preferred embodiment of the present invention relates to a compound of formula (I), wherein

X represents -NH-;

V represents -CH₂-NC-R)-CH₂-, -CH₂-NC-R)-CH₂-CH₂-, -CH₂-CH₂-N(-R)-, -O- CH₂-CH₂-NC-R)-, -CHa-CH₂-NC-R)-CHa-, -CH₂-CH₂-N(-R)-CH₂-CH₂-, -CH₂- CH₂-CH₂-NC-R)-, or -CH₂-CH₂-N(-R)-CO-; U represents phenyl; mono-, di-, or tri-substituted phenyl, wherein the substituents are independently selected from the group consisting of alkyl, alkoxy, and halogen; or a five-membered heteroaryl ring, wherein said heteroaryl ring is optionally mono- or di-substituted, wherein the substituents are independently selected from the group consisting of alkyl, hydroxy-alkyl, halogen and trifiuoromethyl;

M represents phenyl; mono- or di-substituted phenyl, wherein the substituents are independently selected from the group consisting of alkyl, alkoxy, -OCF₃, -CF3, and halogen; or mono- or di-substituted pyridinyl, wherein the substituents are independently selected from the group consisting of halogen, alkyl, -OCF3, -CF3 and alkoxy; with the proviso, that the halogen substituents are not in 2- or 6- position of the pyridinyl ring; and

R represents hydrogen, alkyl, or cycloalkyl; and wherein the remaining substituents and symbols are as defined for formula (I) above.

Preferred compounds of formula (I) are also those wherein X, W, V, U, Q and M are as defined in formula (I) and T represents -CONR¹-, wherein R¹ represents a cyclopropyl group.

More preferred compounds of formula (I) are those wherein X, W, U, T, Q and M are as defined in formula (I) and V represents -CH₂-N(-CH₃)-CH₂-, -CH₂-N(-CH₂- CHs)-CH₂-, -CH₂-CH₂-N(-CH₃)-CH₂-, -CH₂-N(-CH₃)-CH₂-CH₂-, -CH₂-N(-CH₃)- CH₂-CH₂-O-, or -CH₂-CH₂-N(-CH₃)-CO-.

Further preferred compounds of formula (I) are those wherein X, W, U, T, Q and M are as defined in formula (I) and V represents -CH₂-N(-CH₃)-CH₂-, -CH₂-CH₂- N(-CH₃)-CH₂-, or -CH₂-CH₂-N(-CH₃)-CO-.

Also more preferred compounds of formula (I) are those wherein X, W, U, T, Q and M are as defined in formula (I) and V represents -CH₂-N(-CH3)-CH₂- or -CH₂-CH₂-N(-CH₃)-CH₂-. Preferred compounds of formula (I) are those wherein X, W, V, U, T and Q are as defined in formula (I) and M represents di-substituted phenyl.

Very preferred compounds of formula (I) are also those wherein X, U, T, Q, W and V are as defined in formula (I) and M represents phenyl di-substituted by methoxy and methyl .

Very preferred compounds of formula (I) are also those wherein X, U, T, Q, W and V are as defined in formula (I) and M represents 2,3-dichlorophenyl.

Very preferred compounds of formula (I) are also those wherein X, W, V, T, Q and M are as defined in formula (I) and U represents an isothiazole ring di- substituted by halogen.

Very preferred compounds of formula (I) are also those wherein X, W, V, Q, T and M are as defined in formula (I) and U represents a mono-, di- or tri-substituted phenyl, wherein the substituents are selected from halogen, methyl and methoxy, especially from halogen and methyl.

Very preferred compounds of formula (I) are also those wherein U, W, V, Q, T and M are as defined in formula (I) and X represents -NH-, -N(-COCH3)-, or -N(-CONHCH₂C(CH₃)₂CONH₂)-, especially -NH-.

The present invention also relates to compounds of formula (I) wherein the meanings of one or more of the substituents and symbols as defined for formula (I), or a preferred embodiment of formula (I), are replaced by their preferred meanings such as those defined for the above-given preferred compounds.

In an especially preferred embodiment, the present invention relates to a compound of formula (I), wherein

X represents -NH-; W represents a phenyl substituted by V in pαra-position; V represents -CH₂-N(-R)-CH₂-, -CH₂-NC-R)-CH₂-CH₂-, -O-CH₂-CH₂-N(-R)-, -CH₂-CH₂-NC-R)-CH₂-, -CH₂-NC-R)-CH₂-CH₂-O-, -CH₂-CH₂-CH₂-N(-R)-, or -CH₂-CH₂-NC-R)-CO-;

U represents phenyl; mono-, di-, or tri-substituted phenyl, wherein the substituents are independently selected from the group consisting of alkyl, alkoxy, halogen, -CF₃, -OCF₂O-, and cyano; or a quinolinyl;

T represents -CONR¹-; Q represents methylene;

M represents di-substituted phenyl, wherein the substituents are independently selected from the group consisting of alkyl, alkoxy, and halogen;

R represents alkyl, cycloalkyl, or -CH₂CF₃; and R¹ represents cycloalkyl.

Especially preferred derivatives of formula (I) are those selected from the group consisting of:

(rac.)-(lR*, 55'*)-7-(4-{3-[(2,4-difluoroρhenyl)methylamino]propyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 5£*)-7-{4-[3~(methylphenylamino)propyl]phenyl}-3,9-diaza-bi- cyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2-methyl- benzyl)amide;

(rac.)-(lR*, 55'*)-7-{4-[3-(methyl-m-tolylamino)propyl]phenyl}-3,9-diazabi- cyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2-methyl- benzyl)amide;

(mc.)-(lR*, 5S*)-7-{4-[3-(methyl-o-tolylamino)propyl]phenyl}-3,9-diazabi- cyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-C3-methoxy-2-methyl- benzyl)amide; (rac.)-(lR*, 55*)-7-(4-{3-[(2-chlorophenyl)methylamino]propyl}phenyl)-3,9-di- azabicyclo [3.3.1 ]non-6-ene-6-carboxylic acid cyclopropyl-(3 -methoxy-2-methyl- benzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{3-[(3-chlorophenyl)methylamino]propyl}phenyl)-3,9-di- azabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2-methyl- benzyl)amide;

(rac.)-(lR*, 5S*)-7-{4-[2-(methylphenylamino)ethoxy]phenyl}-3,9-diaza-bi- cyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2-methyl- benzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{2-[(3-chloro-2,6-difluorobenzoyl)methylamino]ethyl}- phenyl)-3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide; \

(rac.)-(lR*, J6'*)-7-(4-{2-[(4,5-dichloroisothiazole-3-carbonyl)methylamino]- ethyl}phenyl)-3,9-diazabicyclo[3.3.l]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac. )-(lR *, 5S*)-7-(4- { [(2,4-dichlorobenzyl)methylamino]methyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{[(2-chloro-6-fluoro-3-methylbenzyl)methylamino]- methyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (3-methoxy-2-methylbenzyl)amide;

(me. )-(lR * 5S*)-7-(4- { [(2-chloro-3,6-difluorobenzyl)methylamino]methyl} - phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)-(lR*_> 55^r*)-7-(4-{[(2-chloro-4-fluorobenzyl)methylamino]methyl}phenyl)- 3,9-diazabicyclo[3.3. ^non-ό-ene-β-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide; (rac.)-(lR * 5S*)-7-(4- { [(2-chloro-6-fluorobenzyl)methylamino]methyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 5₍S^r*)-7-(4-{[(2,3-dichlorobenzyl)methylamino]raethyl}ρhenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 5₁S*)-7-(4-{[(2-chlorobenzyl)methylamino]methyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{[(2,6-dichlorobenzyl)methylamino]methyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 55^r*)-7-(4-{2-[(2-chloro-6-fluoro-3-methylbenzyl)methylamino]- ethyl} phenyl)-3 ,9-diazabicyclo[3.3.1 ]non-6-ene-6-carboxylic acid cyclopropyl-(3 - methoxy-2-methylbenzyl)amide;

(me. )-(lR * 5S*)-7-(4- {2-[(2-chloro-3,6-difluorobenzyl)methylamino]ethyl} - phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)-(lR*, 55^r*)-7-(4-{2-[(2-chloro-6-fluorobenzyl)methylamino]ethyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide ;

(rac.)-(lR*, 55'*)-7-(4-{2-[(2,3-dichlorobenzyl)methylamino]ethyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{2-[(2-chlorobenzyl)methyIamino]ethyl}phenyl)-3,9- diazabicyclo[3.3.1 ]non-6-ene-6-carboxylic acid cyclopropyl-(3 -methoxy-2- methylbenzyl)amide; (rac.)-(lR*, 5-S*)-7-(4-{2-[(2,6-dichlorobenzyl)methylamino]ethyl}phenyl)-3,9- diazabicyclo [3.3.1 ]non-6-ene-6-carboxylic acid cyclopropyl-(3 -methoxy-2- methylbenzyl)amide;

(mc.)-(lR*, 55*)-7-[4-({[2-(2,4-dimethylphenoxy)ethyl]methylamino}methyl)- phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)-(lR*, 5₁S*)-7-(4-{[(2,6-dichloro-4-methylbenzyl)methylamino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-rnethylbenzyl)amide;

(rac.)-{lR *, 5S*)-7-(4- { ^-chlorobenzyOcyclopropylaminoJmethyllphenyO-S^- diazabicyclo[3.3. ^non-β-ene-β-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(mc.y(lR*, 55'*)-7-[4-({methyl-[2-(2₅3,6-trichlorophenyl)ethyl]ainino}methyl)- phenyl] -3 ,9-diazabicyclo[3.3.1 ]non-6-ene-6-carboxylic acid cyclopropyl-(3 - methoxy-2-methylbenzyl)amide;

(rac.)-(lR*, 56'*)-7-(4-{2-[(3-chlorobenzyl)methylamino]ethyl}phenyl)-3,9-diaza- bicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2-methyl- benzyl)amide;

(rac. )-(lR *, 5S*)-7-(4- {2-[(2,6-dimethylbenzyl)methylamino]ethyl} phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide ;

(rac.)-(lR*, 55^f*)-7-(4-{2-[methyl-(2,3,6-trichlorobenzyl)amino]ethyl}phenyl)- 3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide ;

(rac.)-(ii?*, JS*)-7-(4- { [methyl-(2,3 ,6-trichlorobenzyl)amino]methyl} phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide; (Wc)-(IR*, 55*)-7-(4-{[(3-chloro-2,6-difluorobenzyl)ethylamino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(rac.)-(lR*, 55*)-7-(4-{[(3-chlorobenzyl)ethylamino]methyl}phenyl)-3,9-diaza- bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichlorobenzyl)- amide;

(mc.)-(lR*, 5,S*)-7-(4-{[ethyl-(2,3,5-trifluorobenzyl)aniino]methyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac.)-(lR*, 5₁S'*)-7-(4-{[ethyl-(2,3,6-trifluorobenzyl)amino]methyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac.)-(lR*, J5'*)-7-(4-{[(2-chloro-3,6-difluorobenzyl)ethylamino]methyl}- phenyl)-3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{[(2,2-difluorobenzo[l,3]dioxol-4-ylmethyl)ethylamino]- methyl}phenyl)-3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxyIic acid cyclopropyl- (2,3-dichloroben2yl)amide;

(rac.)-(lR*, 55*)-7-(4-{[ethyl-(2,3,6-trichlorobenzyl)amino]methyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac.)-(ii?*, 55^r*)-7-(4-{[(2-cyanobenzyl)ethylamino]methyl}phenyl)-3,9-diaza- bicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichlorobenzyl)- amide;

(rac.)-(lR*, 55'*)-7-(4-{[(2₅6-difluorobenzyl)ethylamino]methyl}phenyl)-3,9- diazabicyclo[3.3. llnon-ό-ene-θ-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide; (rac.)-(lR*, 55*)-7-(4-{[ethyl-(2,4,6-trifluorobenzyl)amino]methyl}ρhenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{[(2-chloro-6-fluoro-3-methylben2yl)ethylamino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(rac. )-(lR * 5S*)-7-(4- { [(2,4-dichlorobenzyl)ethylamino]methyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac.)-(lR*, J5^r*)-7-(4-{[(2-chloro-6-fluorobenzyl)ethylamino]methyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac.)-{lR*, 5_lS^r*)-7-(4-{[ethyl-(2-fluoro-5-methoxybenzyl)amino]methyl}- phenyl)-3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(rac. )-{lR * 5S*)-l-(4- { [ethyl-(2-fluoro-6-trifluoromethylbenzyl)amino]niethyl} - phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(rac.)-(lR ^♦ 5S*)-7-(4- { [(2,5-dichlorobenzyl)ethylamino]methyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cycloproρyl-(2,3-dichloro- benzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{[(2,6-dimethylbenzyl)methylamino]methyl}phenyl)-3,9- diazabicyclo[3.3. ljnon-β-ene-ό-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.y(lR*, J,S'*)-7-(4-{[(6-chloro-2-fluoro-3-methylbenzyl)niethylamino]- methyl}phenyl)-3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl- (3-methoxy-2-methylbenzyl)amide; (rac.)-(lR*, 5^*)-7-(4-{[(2,3-difluorobenzyl)methylamino]methyl}ρhenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{2-[(3-chloro-2,6-difluorobenzyl)cyclopropylamino]- ethyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichlorobenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{[(3-chloro-2-fluorobenzyl)isopropylamino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(VUC)-(IR*, J_lS'*)-7-(4-{[(3-chloro-2,6-difluorobenzyl)cyclopropylamino]- methyl}phenyl)-3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl- (2,3 -dichlorobenzyl)amide;

(rac. )-(lR*, 5S*)-7-(4-{ [cyclopropyl-(2, 6-dichlorobenzyl)amino]methyl} - phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(mc.)-(lR*, 55^r*)-7-(4-{[cyclopropyl-(2,3-dichlorobenzyl)amino]methyl}- phenyl)-3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(rac. )-(lR *, 5S*)-7-(4- { [cyclopropyl-(2,3,6-trichlorobenzyl)amino]methyl} - phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{[cyclopropyl-(2,6-dimethylbenzyl)amino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(rac. )-(lR *, 5S*)-7-(4- { [(2-cyanobenzyl)cyclopropylamino]methyl}phenyl)-3,9- diazabicyclo[3.3. ^non-ό-ene-ό-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide; 45

17

(rac.)-(lR*, 55'*)-7-{4-[(cyclopropyl-quinolin-4-ylmethylamino)methyl]-phenyl}- 3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac.)-(lR*, 5_JS*)-7-(4-{[(6-chloro-2-fluoro-3-methylbenzyl)cyclopropylamino]- methyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6~carboxylic acid cyclopropyl- (2,3-dichloroben2yl)amide;

(røc.)-(ii?*, 55*)-7-(4-{[cyclopropyl-(2-fluoro-6-trifluoromethylbenzyl)amino]- methyl}phenyl)-3 ,9-diazabicyclo[3.3. ljnon-θ-ene-ό-carboxylic acid cyclopropyl- (2,3-dichlorobenzyl)amide;

(mc.)-(lR*, 55'*)-7-(4-{3-[(2-fluoro-5-methylphenyl)inethylammo]propyl}- phenyl)-3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)-(ii?*, 55'*)-7-(4-{3-[(2,3-diclilorophenyl)methylamino]propyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 55^r*)-7-(4-{3-[(2,6-difluorophenyl)methylamino]propyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cycloproρyl-(3-methoxy-2- methylbenzyl)amide;

(rctc.)-(lR*, 55'*)-7-(4-{3-[(2,6-dichlorophenyl)methylamino]propyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{3-[(2,5-difluorophenyl)methylamino]propyl}phenyl)-3,9- diazabicyclo [3.3.1 ]non-6-ene-6-carboxylic acid cyclopropyl-(3 -methoxy-2- methylbenzyl)amide;

(røc.)-(ii?*, 5,S*)-7-(4-{3-[(5-chloro-2-methylphenyl)methylamino]propyl}- phenyl)-3₅9-diazabicyclo[3.3.1 ]non-6-ene-6-carboxylic acid cyclopropyl-(3 - methoxy-2-methylbenzyl)amide; 45

18

(rac.)-(lR*, 55'*)-7-(4-{3-[(2,5-dichloroρhenyl)methylamino]proρyl}ρhenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 5₁S'^!ic)-7-(4-{3-[(3-fluoro-2-methylphenyl)methylamino]propyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)-(li?*, 5S'^!f!)-7-(4-{3-[(5-fluoro-2-methylphenyl)methylamino]propyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-rnethylbenzyl)amide;

{rac.)-(lR*, 55*)-7-(4-{3-[(2-chloro-5-methylphenyl)methylamino]ρropyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(røc.)-(ii?*, 5,S*)-7-(4-{[(3-chloro-2,6-difluorobenzyl)-(2,2,2-trifluoroethyl)- amino]methyl}phenyl)-3,9-diazabicyclo[3.3.l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichlorobenzyl)amide; and

(rac. )-(lR *, 5S*)-7-(4- { [(3-chloro-2-fluoro-6-trifluoromethylbenzyl)-(2,2,2- trifluoroethy^aminolmethylJphenyO-S^-diazabicyclofS.S.llnon-δ-ene-δ- carboxylic acid cyclopropyl-(2,3-dichlorobenzyl)amide.

The compounds of formula (I) are useful for the treatment and/or prophylaxis of diseases such as or related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, atherosclerosis, restenosis post angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications of treatments with immunosuppressive agents, and other diseases known to be related to the renin-angiotensin system.

The compounds of formula (I) are especially useful for the treatment and/or prophylaxis of hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy.

In one embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases, which are associated with a dysregulation of the renin- angiotensin system, in particular to a method for the treatment or prophylaxis of the above-mentioned diseases, said methods comprising administering to a patient a pharmaceutically active amount of a compound of formula (I).

A further aspect of the present invention relates to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier material. These pharmaceutical compositions may be used for the treatment or prophylaxis of the above-mentioned diseases. The pharmaceutical compositions can be used for enteral, parenteral, or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.

The invention also relates to the use of a compound of formula (I) for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of the above-mentioned diseases.

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Mark P2005/009045

20

Gibson, Editor, Pharmaceutical Preformulation and Formulation, IHS Health Group, Englewood, CO, USA, 2001; Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science) by bringing the described compounds of formula (I) and their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

The pharmaceutical preparations conveniently contain about 1 - 500 mg, preferably 5 - 200 mg of a compound of formula (I).

Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injections are, for example, water, alcohols, polyols, glycerols and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents, consistency- improving agents, flavor-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants. The dosage of compounds of formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 mg to about 1000 mg, especially about 50 mg to about 500 mg, comes into consideration.

In a preferred embodiment, this amount is comprised between 2 mg and 1000 mg per day. In a particular preferred embodiment, this amount is comprised between 1 mg and 500 mg per day. In a more particularly preferred embodiment, this amount is comprised between 5 mg and 200 mg per day.

Another aspect of the invention is related to a process for the preparation of a pharmaceutical composition comprising a compound of the formula (I). According to said process, one or more active ingredients of the formula (I) are mixing with inert excipients in a manner known per se.

Compounds of formula (I) or the above-mentioned pharmaceutical compositions are also of use in combination with other pharmacologically active compounds such as ACE-inhibitors, neutral endopeptidase inhibitors, aldosterone antagonists, angiotensin II receptor antagonists, endothelin receptors antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholytics, beta- adrenergic antagonists, alpha-adrenergic antagonists and/or other drugs beneficial for the prevention or the treatment of the above-mentioned diseases.

The present invention also relates to pro-drugs of a compound of formula (I) that convert in vivo to the compound of formula (I) as such. Any reference to a compound of formula (I) is therefore to be understood as referring also to the corresponding pro-drugs of the compound of formula (I), as appropriate and expedient.

The compounds of formula (I) can be manufactured by the methods outlined below, by the methods described in the examples or by analogous methods. The chemistry is described hereby for the more complex diazabicyclononene moiety. The same chemistry can be used for the oxaazabicyclononene and thiaazabicyclononene moieties as included in formula (I), using also the preparations described in WO 2004/096366. For the azabicyclononene moiety, the chemistry described in WO 2004/096803 can be used.

Compounds of type A in Scheme 1 may be prepared as described in the patent application WO 03/093267, or using very similar chemistry (see experimental part for details). R^a represents a linker, which, together with its terminal substituent, will be completed and converted later into a U-V-substituent, as defined in formula (I). PG stands for a suitable protecting group. Compounds of type A can be oxidized to compounds of type B, following standard procedures (for instance: Swern oxidation, Dess-Martin oxidation, Ley oxidation). A reductive animation with the desired amine or aniline derivative leads to a compound of type C that is deprotected into a final compound of formula (I). Also, a compound of type A can be converted into a compound of type C directly, by nucleophilic substitution (see experimental part for details). Finally, deprotection step(s) will yield the desired final compound of formula (I).

Scheme 1 If a secondary amine or aniline derivative is necessary but is not commercially available, the corresponding primary amine or aniline derivative is prepared according to the literature, and is then N-alkylated by reductive amination.

A compound of type B is transformed into a compound of type D as well by reductive amination, as indicated in Scheme 2. An amide bond formation with a carboxylic acid or acyl chloride leads to a compound of type E. Finally, deprotection step(s) will yield the desired final compound of formula (I). Also a compound of type A is activated in a compound of type F, wherein X stands for a good leaving group, like a mesylate, a tosylate, or a triflate group, or an iodine or a bromine atom. A compound of type F is then transformed into a compound of type G, whereas PG" stands for a suitable protecting group. A compound of type G is then deprotected to a compound of type D.

Scheme 2

Selective removal of the Boc protecting group on a compound of type C or E, then alkylation or acylation, allows the introduction of the L-substituent as defined in formula (I). Also, a compound of formula (I) with X = NH can be acylated selectively at its 3-position.

The bicyclic core of oxaazabicyclononene derivatives (X = O in formula (I)), or thiaazabicyclononene derivatives (X = S in formula (I)) can be prepared as described in WO 2004/096366, using the chemistry described herein. The azabicyclononene core (X = -CH₂- or -CH(L)- in formula (I)) can be prepared as described in WO 2004/096803, using the chemistry described herein.

It will be obvious to the person skilled in the art that many steps presented herein can be exchanged with each other under certain circumstances. Also some steps can be omitted.

The following examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.

Chemistry

Abbreviations fas used herein^")

AcOH Acetic acid

Ang Angiotensin aq. aqueous

Boc tert-Butyloxycarbonyl

BSA Bovine serum albumine

BuLi «-Butyllithium

DIPEA Diisopropylethylamine

DMAP 4-N,N-Dimethylaminopyridine

DMF N,N-Dimethylformamide

DMSO Dimethylsulfoxide

EDC-HCl Ethyl-N,N-dimethylaminopropylcarbodiimide hydrochloride

EDTA Ethylene diamine tetra acetate

EIA Enzyme immunoassay

ELSD Evaporating Light Scattering detection eq. Equivalent(s)

ES Electrospray (in MS)

Et Ethyl

EtOAc Ethyl acetate

EtOH Ethanol

FC Flash Chromatography h hour(s)

HOBt Hydroxybenzotriazol

HPLC High Performance Liquid Chromatography

LC-MS Liquid Chromatography - Mass Spectroscopy

Me Methyl

MeOH Methanol min minute(s)

MS Mass Spectroscopy

NMO N-Methylmorpholine JV-oxide

OD Optical density org. organic

P para

PG protecting group

Ph phenyl

It room temperature sat. saturated sol. Solution

TBAF Tetra-n-butylammonium fluoride

TBDMS tert-Butyldimethylsilyl

TBME te?t-Butylmethylether

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin Layer Chromatography t_R retention time (in HPLC or LC-MS)

UV Ultra violet Vis visible

HPLC- or LC-MS-conditions (if not indicated otherwise):

Analytic: Zorbax 59 SB Aqua column, 4.6 x 50 mm from Agilent Technologies. Eluents: A: acetonitrile; B: H₂O + 0.5% TFA. Gradient: 90% B → 5% B over 2 min. Flow: 1 mL/min. Detection: UV/Vis + MS.

Preparative: Zorbax SB Aqua column, 20 x 500 mm from Agilent Technologies.

Eluent: A: Acetonitrile; B: H₂O + 0.05% ammonium hydroxide (25% aq.).

Gradient: 80% B -> 10% B over 6 min. Flow: 40 mL/min. Detection: UV + MS, or UV + ELSD.

Chiral analytic :Regis Whelk column, 4.6 x 250 mm, 10 μm. Eluent A: EtOH +

0.05% Et₃N. Eluent B: hexane. Isocratic conditions, 60% B, over 40 min, 1 mL/min. The isocratic mixture may vary, depending on the compounds.

Chiral, preparative: As analytical conditions, but on a Regis Whelk 01 column, 50x250 mm and a flow of 100 mL/min.

All t_R are given in min.

General procedures

General procedure A (reductive amination): An aldehyde (0.08 mmol) was dissolved in CH₂Cl₂ (0.5 mL). The aniline (0.16 mmol) or amine (0.16 mmol), NaBH(OAc)₃ (35 mg, 0.167 mmol) and AcOH (20 μL, 0.33 mmol) were added. The mixture was stirred overnight and aq. IM NaOH (0.200 mL) was added. The mixture was filtered through Isolute® (1 g) pre- washed with aq. IM NaOH (0.7 mL). After 5 min. Isolute was rinsed with CH₂Cl₂ (3 x 1 mL). The combined org. filtrates were evaporated under reduced pressure, and the crude was directly used in the next step.

General procedure B (final compounds):

To a sol. of crude compound of type C or E in CH₂Cl₂ (1 mL) at 0 ⁰C was added 4M HCl / dioxane (1 mL). The mixture was stirred at 0 ⁰C until no more starting material was visible by TLC or LC-MS. The solvents were rapidly removed under reduced pressure, and the residue was dried under high vacuum. Purification of the crude by HPLC yielded the final compounds.

General procedure C (amide formation):

A compound of type D (0.05mmol), Amberlyst A21 (100 mg), and the acid chloride (0.075 mmol) were stirred at rt in EtOAc overnight. Some water was added and the mixture was stirred for 1 h. The Amberlyst was filtered, and the mixture was evaporated under reduced pressure. The crude was used without further purification.

General procedure D (reductive amination)

A compound of type D (0.05 mmol) was dissolved in CH₂Cl₂ (1 mL).

NaBH(OAc)₃ (21 mg, 0.1 mmol) and the desired aldehyde (0.1 mmol) were added. The mixture was stirred for 2 h. If the reaction was not complete, more aldehyde was added. Aq. IM NaOH (0.200 mL) was added. The mixture was filtered through Isolute^® (1 g) treated with aq. IM NaOH (0.7 mL). After 5 min the Isolute^® was rinsed with CH₂Cl₂ (3 x 1 mL). The combined org. filtrates were evaporated under reduced pressure, and the crude was directly used in the next step.

General procedure E (N-methylation of anilines)

The aniline (1.00 g) was dissolved in dimethylcarbonate (8.00 mL). Na-Y-zeolite (1.00 g) was added. The mixture was stirred at 90 ⁰C for several weeks, while the reaction was followed by LC-MS. When the conversion was complete, the mixture was filtered through Celite, the precipitate was washed with EtOAc, and the filtrate was evaporated under reduced pressure. Purification of the crude by FC (EtO Ac/heptane 1 :40) yielded the title compound. [2-(4-Bromophenyl)ethoxy]-tøtf-butyldimethylsilane

TBDMS-Cl (10.50 g, 69.6 mmol) and imidazole (5.10 g, 76.6 mmol) were added to a sol. of 2-(4-bromophenyl)ethanol (7.00 g, 34.8 mmol) in DMF (0.12 L), and the mixture was stirred at rt overnight. The reaction mixture was partitioned between EtOAc and aq. IM HCl, the phases were separated, and the organic layer washed again with aq. IM HCl₅ dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification of the residue by FC (EtO Ac/heptane 1:1) yielded the title compound as a transparent oil (10.93 g, 99%). LC-MS: t_R= 1.18 min.

Benzylcyclopropylamine

Cyclopropylamine (6.61 mL, 94.23 mmol, 2.00 eq.) was added to a sol. of benzaldehyde (5.00 g, 47.11 mmol, 1.00 eq.) in MeOH (0.11 L), and the mixture was stirred at rt overnight. The reaction mixture was cooled to 0 ⁰C, and portionwise was added NaBH₄ (2.32 g, 61.25 mmol). The reaction mixture was stirred at rt over 6 h. The reaction mixture was quenched with ice, the solvents were removed under pressure, and the residue was extracted with EtOAc. The org. layer was washed with aq. IM NaOH. The aq. layer was extracted again with EtOAc, the combined org. extracts were washed with brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to yield the title compound (6.27 g, 90%), which was not further purified. LC-MS: t_R = 0.49 min, ES+: 148.20.

(4-Bromobenzyloxy)-te/^#/-butyldimethyIsilane

TBDMS-Cl (16.00 g, 0.11 mol) and imidazole (7.90 g, 0.12 mol) were added to a stirred sol. of 4-bromobenzylalcohol (10.00 g, 53.46 mmol) in DMF (0.20 L), and the mixture was stirred at rt over 72 h. The reaction mixture was partitioned between EtOAc and aq. IM HCl, the phases were separated, and the org. layer was washed again with aq. IM HCl, dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification of the residue by FC (50% EtOAc in heptane) yielded the title compound (13.52 g, 84 %). LC-MS: t_R = 1.18 min. 2-(2,4-Dimethylphenoxy)-JV-methyIacetamide

Carbonyldiimidazole (162 nig, 1.00 mmol) was added to a mixture of (2,4- dimethylphenoxy)acetic acid (180 mg, 1.00 mmol) in CH₂Cl₂ (4 mL). The mixture was stirred for 1 h at rt, and was cooled to 0 ⁰C. MeNH₂ (41% in H₂O, 0.506 mL, 6.00 mmol) was added, and the mixture was stirred for 2 h at 0 ⁰C. The mixture was washed with water. The org. layer was dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the title compound (170 mg, 88%) that was used without further purification. LC-MS: t_R = 0.94 min, ES+: 235.13 (Eluent A: water + 0.04% TFA; eluent B: acetonitrile; gradient: 5% → 95% B over 1.00 min, then 95% B over 0.55 min).

[2-(2,4-Dimethy!phenoxy)ethyl]methylamine

LiAlH₄ (IM in THF, 3.00 mL, 3.00 mmol) was added to a sol. of 2-(2,4- dimethylphenoxy)-7V-methylacetamide (170 mg, 0.88 mmol) in THF (3 mL). The mixture was stirred for 30 min at rt, then for 4 h at 60 ⁰C. The mixture was cooled to 0 ⁰C, and water (0.114 mL) was added carefully. Aq. 15% NaOH (0.114 mL), then water (0.342 mL) were added, and the mixture was stirred overnight. The mixture was filtered, and the precipitate was washed with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was loaded on a FC-column filled with SCX-silica gel (Varian, Cat. No. 12213039). The FC was eluted with

MeOH, then 7M NHs/MeOH. After evaporation, the title compound was obtained

(44 mg, 24%). LC-MS: t_R = 0.76 min, ES+: 180.18 (Eluent A: water + 0.04%

TFA; eluent B: acetonitrile; gradient: 5% -» 95% B over 1.00 min, then 95% B over 0.55 min).

2,6-DichIoro-4-methylbeαzaldehyde

MnO₂ (4.56 g, 52 mmol) was added to a sol. of (2,6-dichloro-4-methylphenyl)- methanol (Wigal, C. T.; McKinley, J. D.; Coyle, J.; Porter, D. J.; Lehman, D. E., J. Org. Chem., 1995, 60, 8421; 3.00 g, 15.7 mmol) in CH₂Cl₂ (100 mL). The mixture was stirred for 1 h, and MnO₂ (9.12 g, 104 mmol) was added again. The mixture was stirred for 30 h at rt. The mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure. Purification by FC (EtOAc/heptane 1:19 → 1:9) yielded the title compound (1.22 g, 42%). LC-MS: t_R = 0.99 min, ES+: 241.01.

iV-Methy--2-(2,3,6-trichlorophenyl)acetamide

Carbonyldiimidazole (200 mg, 1.23 mmol) was added to a sol. of (2,3,6-trichloro- phenyl)acetic acid (294 mg, 1.23 mmol) in CH₂Cl₂ (5,00 mL). The mixture was stirred for 2 h at rt, and cooled to 0 ⁰C. MeNH₂ (41% in water, 0.560 mL, 7.38 mmol) was added, and the mixture was stirred for 2 h at rt. The mixture was washed with water. The org. layer was dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the title compound (266 mg, 85%) as a solid that was not purified further. LC-MS: t_R - 0.93 min, ES+: 294.93 (Eluent A: water + 0.04% TFA; eluent B: acetonitrile; gradient: 5% -» 95% B over 1.00 min, then 95% B over 0.55 min).

Methyl-[2-(2,3,6-tπchlorophenyl)ethyl]amine

BH₃ (IM in THF, 7.37 mL, 7.37 mmol) was added to a sol. of N-methyl-2-(2,3,6- trichlorophenyl)acetamide (266 mg, 1.05 mmol) in THF (5.00 mL). The mixture was heated to reflux for 24 h. The mixture was allowed to cool to rt, and aq. 6M

HCl (10 mL) was added. The mixture was heated to reflux for 1 h. The mixture was allowed to cool to rt, and diluted with EtOAc. The mixture was washed with aq. 10% NaOH (3x). The org. layer was dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by

HPLC yielded the title compound (140 mg, 56%).

(2-Fluoro-5-methylphenyl)methylamine

Prepared according to general procedure E, from 2-fluoro-5-methylaniline. 32 mg were obtained. LC-MS: t_R = 0.65 min, ES+: 140.13. (2,3-Dichlorophenyl)methyIamine

Prepared according to general procedure E, from 2,3-dichloroaniline. 137 mg were obtained. LC-MS: t_R = 0.97 min, ES+: 176.12.

(2,6-Difluorophenyl)methylamine

Prepared according to general procedure E, from 2,6-difluoroaniline.

38 mg were obtained. LC-MS: t_R = 0.72 min.

(2,6-Dichlorophenyl)methylamine Prepared according to general procedure E, from 2,6-dichloroaniline. 107 mg were obtained. LC-MS: t_R = 0.89 min, ES+: 176.08.

(2,5-Difluorophenyl)methyIamine

Prepared according to general procedure E, from 2,5-difluoroaniline. 10 mg were obtained. LC-MS: t_R = 0.88 min.

(5-Chloro-2-methylphenyl)methyIamine

Prepared according to general procedure E, from 5-chloro-2-methylaniline. 10 mg were obtained. LC-MS: t_R = 0.86 min, ES+: 156.70.

(2,5-Dichlorophenyl)methylamine

Prepared according to general procedure E, from 2,5-dichloroaniline. 86 mg were obtained. LC-MS: t_R = 0.98 min, ES+: 176.02.

(3-FIuoro-2-methylphenyI)methylamine

Prepared according to general procedure E, from 3-fluoro-2-methylaniline.

39 mg were obtained. LC-MS: t_R = 0.62 min, ES+: 140.15.

(5-Fluoro-2-methylphenyl)methylamine Prepared according to general procedure E, from 5-fluoro-2-methylaniline. 691 mg were obtained. LC-MS: t_R = 0.74 min, ES+: 140.14. (2-Chloro-5-methyIphenyI)methyIamine

Prepared according to general procedure E, from 2-chloro-5-methylaniline. 87 mg were obtained. LC-MS: t_R = 0.92 min, ES+: 156.14.

(rac.)-(lR*, 5₎S^l*)-6-[Cyclopropyl-(3-raethoxy-2-methylbeiizyl)carbamoyl]-7- [4^2-hydroxypropyl)phenyl]-3,9-diazabicycIo[33.1]noiι-6-ene-3,9-di- carboxylic acid di-fert-butyl ester (Al)

To a suspension of NaHCO₃ (15.5 g, 184 mmol) and 7-{4-[2-(tert-butyl- dimethylsilanyloxy)propyl]phenyl}-9-methyl-3,9-diazabicyclo[3.3.1]non-6-ene- 3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (WO 03/093267, 10.3 g, 18.4 mmol) in CH₂ClCH₂Cl (190 πiL) was added 1-chloroethyl chloroformate (20.0 mL, 55.1 mmol). The mixture was heated and stirred at 80 ⁰C for 3 h. The reaction mixture was allowed to cool to rt, filtered, and the solvents were thoroughly removed in vacuo. The residue was dried under high vacuum for 15 min. MeOH (130 mL) was added and the mixture was stirred at 50 ⁰C for 20 min. The sol. was allowed to cool to rt, and the solvents were removed in vacuo. The residue was dried under high vacuum. The residue was dissolved in CH₂Cl₂ (190 mL), DIPEA (15.7 mL, 91.8 mmol) and BoC₂O (12.0 g, 55.1 mmol) were added, and the mixture was stirred at rt for 30 min. The mixture was washed with aq. IM HCl (Ix), and aq. sat. NaHCO₃ (Ix). The org. phase was dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification by FC (50% EtOAc in heptane) yielded 7-[4-(2-hydroxypropyl)phenyl]-3,9-diazabicyclo[3.3.1]non-6- ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-ethyl ester (8.86 g, 91%). LC-MS: t_R = 1.04 min, ES+: 531.22.

1 M NaOH (198 mL) was added to a sol. of the former compound (15.0 g, 28.3 mmol) in EtOH (396 mL). The resulting mixture was stirred at 80 ⁰C for 3 h, cooled to rt and the solvents were partially removed in vacuo. The crude mixture was partitioned between EtOAc and aq. IM HCl. The aq. layer was extracted once more with EtOAc. The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to yield 7-[4-(2- hydroxypropyl)phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester (13.3 g, 94%).

TBDMS-Cl (7.38 g, 48.7 mmol) and imidazole (5.32 g, 77.9 mmol) were added to a stirred sol. of the former compound (9.79 g, 19.5 mmol) in DMF (100 mL). The reaction mixture was stirred at rt over 15 h. The solvents were removed in vacuo, the crude mixture partitioned between Et₂O and aq. sat. NH₄Cl. The org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. To a sol. of the reaction mixture in THF (190 mL) were added MeOH (63 mL), water (33 mL) and K₂CO₃ (1.46 g), and the mixture stirred at rt for 30 min. The mixture was then partitioned between Et₂O and aq. sat. NH₄Cl and the aq. layer extracted once more with Et₂O. The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed in vacuo to yield 7-{4-[2- (tert-butyldimethylsilanyloxy)propyl]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene- 3,6,9-tricarboxylic acid 3,9-di-ferf-butyl ester (12.2 g, quantitative yield) as a yellow foam. LC-MS: t_R = 1.19 min, ES+: 617.48.

To a stirred sol. of the former compound (12.0 g, 19.4 mmol) in CH₂Cl₂ (158 mL) were added EDCΗC1 (9.34 g, 48.7 mmol), HOBt (3.18 g, 23.4 mmol), DMAP (0.596 g, 4.87 mmol), cyclopropyl-(3-methoxy-2-methylbenzyl)amine (prepared by reductive amination from 3-methoxy-2-methylbenzaldehyde, Comins, D. L.; Brown, J. D., J. Org. Chem., 1989, 54, 3730 and cycloproρylamine,_l 1.2 g, 58.4 mmol) and DIPEA (13.4 mL, 77.9 mmol). The mixture was stirred at rt for 5 days. The reaction mixture was partitioned between aq. IM HCl and CH₂Cl₂, and the org. phase was washed with aq. sat. NaHCθ₃. The org. extracts were dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification by FC (heptane/EtOAc 8/2) yielded 7-{4-[2-(tert-butyldimethylsilanyloxy)propyl]- phenyl}-6-[cycloproρyl-(3-methoxy-2-methylbenzyl)carbamoyl]-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester (8.20 g, 52%). LC-MS: t_R = 1.32 min, ES+: 790.53. To a sol. of the former compound (10.0 g, 12.7 mmol) in THF (225 mL) was added TBAF (IM in THF, 25.3 mL, 25.3 mmol) and the mixture was stirred at 0 ⁰C for 4 h. The reaction mixture was partitioned between aq. sat. NH₄Cl and EtOAc, the org. phase washed with brine, dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification by FC (0-10% MeOH in CH₂Cl₂) yielded the title compound (7.00 g, 82 %) as a yellow foam. LC-MS: t_R = 1.11 min, ES+: 676.54.

(rac.)-(lR*, 55*)-6-[Cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-7-

[4-(2-hydroxyethyl)phenyI]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester (A2)

BuLi (1.60 M in hexane, 41.00 mL, 65.44 mmol) was added dropwise to a cooled (-78 ⁰C) sol. of [2-(4-bromophenyl)ethoxy]-tert-butyldimethylsilane (16.00 g, 49.1 mmol) in THF (0.45 L). The reaction mixture was stirred at -78 ⁰C for 1 h, and ZnCl₂ (IM in THF, 79.00 mL, 79.00 mmol) was added dropwise at -78 ⁰C. The cooling bath was removed, and the reaction mixture was stirred for 1 h at rt. A sol. of (rac.)-(ii-*, 5»S'*)-9-methyl-7-trifluoromethanesulfonyloxy-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid 3-terf-butyl ester 6-ethyl ester (WO 03/093267, 15.00 g, 32.72 mmol) in THF (50.00 mL) was added dropwise, followed by Pd(PPh₃)₄ (0.94 g, 0.82 mmol). The reaction mixture was stirred at rt for 30 min, partitioned between EtOAc and aq. IM NaOH, the layers were separated and the aq. layer was extracted with EtOAc. The combined org. phases were washed with brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc) yielded (rac.)-(lR*, 55"*)-7-{4-[2-(tert-butyldimethylsilanyloxy)ethyI]phenyl}-9- methyl-3,9-diazabicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid 3-ter£-butyl ester 6-ethyl ester (17.00 g, 95%) as an orange oil. LC-MS: t_R = 0.97 min, ES+: 545.44.

1-Chloroethyl chloroformate (29.00 mL, 0.26 mol) was added dropwise to a suspension of NaHCO₃ (22.00 g, 0.26 mol) and (mc.)-(lR*, 55*)-7-{4-[2-(teιt- butyldimethylsilanyloxy)ethyl]phenyl}-9-methyl-3,9-diazabicyclo[3.3.1]non-6- ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (14.30 g, 26.25 mmol) in 1,2-dichloroethane (0.17 L), and the mixture was heated to reflux for 2 h. The reaction mixture was allowed to cool to rt, filtered, and the solvents were thoroughly removed in vacuo. MeOH (0.17 L) was added, and the mixture was stirred at 50 ⁰C for 60 min. The solution was allowed to cool to rt and the solvents were removed in vacuo. The residue was dissolved in CH₂Cl₂ (190 mL), DIPEA (22 mL, 0.13 mol) was added, followed by BoC₂O (17.00 g, 78.75 mmol), and the mixture was stirred at rt for 60 min. The mixture was washed with aq. IM HCl, and aq. sat. NaHCO₃. The org. phase was dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification of the residue by FC (EtOAc/heptane 1:1) yielded (røc.)-(Ji?*, 5S*)-7-[4-(2-hydroxyethyl)phenyl]-3,9- diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6- ethyl ester (9.00 g, 66%). LC-MS: t_R = 1.02 min, ES+: 517.37.

A sol. of (rac.)-(lR*, 5S*)-7-[4-(2-hydroxyethyl)phenyl]-3,9-diazabicyclo[3.3.1]- non-6-ene-3,6,9-tricarboxylic acid 3,9-di-terΛ-butyl ester 6-ethyl ester (9.23 g, 17.86 mmol) in EtOH (0.18 L) was treated with aq. IM NaOH (180 mL). The resulting mixture was stirred at 70 ⁰C for 5 h, cooled to rt, and the solvents were removed in vacuo. The crude mixture was partitioned between TBME and aq. sat. NH₄Cl. The aq. layer was extracted once more with TBME, then acidified (pH ~ 4) with aq. 2M HCl. and extracted again with TBME. The combined org. layers were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to yield (mc.)-(lR*, 5S*)-7-[4-(2-hydroxyethyl)phenyl]-3,9- diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-ter/-butyl ester, as a pale brown foam, which was not further purified (6.61 g, 76%). LC-MS: t_R = 0.90 min, ES+: 489.41.

TBDMS-Cl (6.61 g, 33.82 mmol) and imidazole (4.00 g, 54.12 mmol) were added to a stirred sol. of (rac.)-(lR*, 55^r*)-7-[4-(2-hydroxyethyl)phenyl]-3,9- diazabicyclo[3.3,l]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester (6.61 g, 13.53 mmol) in DMF (50.00 mL). The reaction mixture was stirred at rt over 15 h. The solvents were removed in vacuo, and the crude mixture was partitioned between Et₂O and water. The org. layer was washed with aq. sat. NaHCO3, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. To a sol. of the crude residue in THF (120.00 mL) were added MeOH (23.00 mL), water (23.00 mL) and K₂CO₃ (1.00 g, 7.23 mmol), and the mixture was stirred at 5 009045

36 rt for 1 h. The mixture was then partitioned between Et₂O and aq. sat. NH₄Cl, the layers were separated, and the aq. layer was extracted once more with Et₂O. The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed in vacuo to yield (rac.)-(lR*, 5S*)-7-{4-[2-(tert- butyldimethylsilanyloxy)ethyl]ρhenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9- tricarboxylic acid 3,9-di-tert-butyl ester (7.65 g, 94% yield), which was not further purified, as a yellow foam. LC-MS: t_R = 1.16 min, ES+: 603.48. To a stirred sol. of the (rac.)-(lR*, 5S*)-7-{4-[2-(tert- butyldimethylsilanyloxy)ethyl]ρhenyl} -3,9-diazabicyclo[3.3. l]non-6-ene-3,6,9- tricarboxylic acid 3,9-di-tert-butyl ester (7.65 g, 12.7 mmol) in CH₂Cl₂ (77.0 mL) were added EDC-HCl (6.10 g, 31.7 mmol), HOBt (2.30 g, 15.2 mmol), DMAP (0.39 g, 3.17 mmol), cyclopropyl-(3-methoxy-2-methylbenzyl)amine (prepared by reductive amination from 3-methoxy-2-methylbenzaldehyde, Comins, D. L.; Brown, J. D., J. Org. Chem., 1989, 54, 3730 and cyclopropylamine, 3.60 g, 19.03 mmol), and DIPEA (10.00 mL, 57.10 mmol). The mixture was stirred at rt for 6 days. Twice were added EDCΗC1 (2.44 g, 12.7 mmol), HOBt (1.92 g, 12.7 mmol), DMAP (0.39 g, 3.17 mmol), cyclopropyl-(3-methoxy-2- methylbenzyl)amine (2.40 g, 12.7 mmol), and DIPEA (2.22 mL, 12.7 mmol). The reaction mixture was partitioned between aq. IM HCl and CH₂Cl₂, and the phases were separated. The org. phase was washed with aq. sat. NaHCO₃, dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification of the residue by FC (heptane/EtOAc = 8/2) yielded (rac.)-(lR*, 5S*)-7-{4-[2-(tert- butyldimethylsilanyloxy)ethyl]phenyl}-6-[cyclopropyl-(3-methoxy-2- methylbenzyl)-carbamoyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester (5.70 g, 58%). LC-MS: t_R = 1.31 min, ES+: 776.51.

TBAF (5.00 g, 15.74 mmol, 2.00 eq.) was added to a sol. of (rac.)-(lR*, 55^r*)-7- {4-[2-(?ert-butyldimethylsilanyloxy)ethyl]phenyl}-6-[cyclopropyl-(3-methoxy-2- methylbenzyl)carbamoyl]-3 ,9-diazabicyclo [3.3.1 ]non-6-ene-3 ,9-dicarboxylic acid di-tert-butyl ester (6.11 g, 7.87 mmol) in THF (60.00 mL), and the mixture was stirred at rt for 60 min. The reaction mixture was partitioned between water and EtOAc, the phases were separated and the aq. phase extracted once more with EtOAc. The combined org. phases were washed with brine, dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification of the residue by FC (0-10% MeOH in CH₂Cl₂) resulted in the title compound as a yellow foam (4.45 g, 85%). LC-MS: t_R = 1.09 min, ES+: 662.48.

(rαc)-(XR*, 55^r*)-6-[Cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyI]-7-

[4-(2-hydroxyethoxy)phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxy-

Hc acid di-tert-butyl ester (A3)

To a suspension Of NaHCO₃ (29.2 g, 0.347 mol) and (rac.)-(IR* 5S*)-7-{4-[2- (tert-butyldimethylsilanyloxy)ethoxy]phenyl}-9-methyl-3,9-diazabicyclo-

[3.3.1]non-6-ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (prepared as described in WO 03/093267, 19.4 g, 34.7 mmol) in 1,2-dichloroethane (400 niL) was added dropwise 1-chloroethyl chloroformate (37.8 mL, 0.347 mol). The mixture was heated to 80 ⁰C. After 2 h, the reaction mixture was allowed to cool to rt, filtered, and the solvents were thoroughly removed in vacuo. MeOH (400 mL) was added and the mixture was stirred at 50 ⁰C for 15 min. The sol. was allowed to cool to rt, and the solvents were removed in vacuo. The residue was dried under high vacuum. The residue was dissolved in CH₂Cl₂ (400 mL), and cooled to 0 °C. DIPEA (30.0 mL, 0.174 mol) and BoC₂O (11.4 g, 52 mmol) were added. The mixture was stirred at 0 ⁰C for 1 h, then at rt for 3 h. The mixture was washed with aq. IM HCl (Ix), and aq. sat. NaHCO₃ (Ix). The org. extracts were dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification by FC (EtOAc/heptane 1:5 → 1:1 -> MeOH/AcOEt 1:9) yielded 7-[4-(2- hydroxyethoxy)phenyl]-3,9-diazabicyclo[3.3.1]-non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-ethyl ester (14.1 g, 76%). LC-MS: t_R = 1.02 min, ES+: 533.38.

Aq. 1 M NaOH (550 mL) was added to a sol. of the former compound (17.8 g, 33.4 mmol) in EtOH (1000 mL). The resulting mixture was stirred at 80 ⁰C overnight, cooled to rt and the solvents were partially removed in vacuo. The crude mixture was partitioned between EtOAc and aq. IM HCl. The aq. phase was extracted again with EtOAc. The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to yield 7-[4-(2-hydroxyethoxy)phenyl]-3,9-diazabicyclo[3.3. l]non-6-ene-3,6,9- tricarboxylic acid 3,9-di-tørt-butyl ester (6.61 g, 76%). LC-MS: t_R = 0.89 min, ES+: 505.32. TBDMS-Cl (15.5 g, 92 mmol) and imidazole (9.28 g, 166 mmol) were added to a stirred sol. of the former compound (6.61 g, 32.8 mmol) in DMF (115 mL). The reaction mixture was stirred at rt overnight. The solvents were removed in vacuo, and the crude mixture partitioned between heptane and aq. sat. NH₄Cl. The aq. phase was extracted with heptane. The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. To a sol. of the residue in THF (100 mL) were added MeOH (40 mL), water (40 mL) and K₂CO₃ (1.30 g), and the mixture stirred at rt for 2 h. It was then partitioned between Et₂O and aq. sat. NH₄Cl and the aq. layer extracted once more with Et₂O. The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed in vacuo to yield 7-{4-[2-(tert- butyldimethylsilanyloxy)ethoxy]phenyl} -3 ,9-diazabicyclo[3.3. l]non-6-ene-3,6,9- tricarboxylic acid 3,9-di-tert-butyl ester (23.05 g, quantitative yield). LC-MS: t_R = 1.15 min, ES+: 619.41. To a stirred sol. of the former compound (8.66g, 12.7 mmol) in CH₂Cl₂ (210 mL) were added EDCΗC1 (9.33 g, 49.0 mmol), HOBt (2.08 g, 15.4 mmol), DMAP (0.428 g, 3.5 mmol), cycloproρyl-(3-methoxy-2-methylbenzyl)amine (prepared by reductive animation from 3-methoxy-2-methylbenzaldehyde, Comins, D. L.; Brown, J. D., J. Org. Chem., 1989, 54, 3730 and cyclopropylamine,_8.03 g, 42 mmol) and DIPEA (9.54 mL, 56 mmol). The mixture was stirred at rt for 3 days. The reaction mixture was partitioned between aq. IM HCl and CH₂Cl₂, and the org. phase was washed with aq. sat. NaHCO₃. The org. extracts were dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification by FC (EtOAc/heptane 1:9 → 2:8 -> 3:7 → 4:6 → 1:1) yielded 7-{4-[2-(tert- butyldimethylsilanyloxy)ethoxy]phenyl}-6-[cyclopropyl-(3-methoxy-2- methylbenzyl)carbamoyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester (6.42 g, 57%). LC-MS: t_R = 1.31 min, ES+: 776.51. To a sol. of the former compound (6.42 g, 8.10 mmol) in THF (90 mL) at 0 ⁰C was added TBAF (IM in THF, 12.2 mL, 12.2 mmol) and the mixture was stirred at 0 ⁰C over 60 min. The reaction mixture was partitioned between water and EtOAc, the org. phase was washed with brine, dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification by FC (EtO Ac/heptane 1:3 → 1:1 → EtOAc) yielded the title compound (4.75 g, 93 %). LC-MS: t_R = 1.09 min, ES+: 678.33.

(rαc)-(XR*, 5S*)-6-lCyclopropyl-(2,3-dichlorobenzyl)carbamoyl]-7-[4-(2- hydroxyethyl)phenyl]-3,9-diazabicycIo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester (A4)

To a stirred sol. of the (rac.)-(lR*_t 55'*)-7-{4-[2-(tert- butyldimethylsilanyloxy)ethyl]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9- tricarboxylic acid 3,9-di-tert-butyl ester (24.71 g, 41 mmol) in CH₂Cl₂ (0.34 L) were added EDCΗC1 (19.65 g, 0.10 mol), HOBt (9.41 g, 61.5 mmol), DMAP (1.25 g, 10.25 mmol), cyclopropyl-(2,3-dichlorobenzyl)amine (prepared by reductive animation from 2,3-dichlorobenzaldehyde and cyclopropylamine, 17.72 g, 82.00 mmol), and DIPEA (32.14 mL, 0.18 mol). The mixture was stirred at rt for 5 days. On day 4 were added EDCΗC1 (4.00 g, 20.86 mmol), HOBt (3.00 g, 19.60 mmol), cyclopropyl-(2,3-dichlorobenzyl)amine (5.00 g, 23.163 mmol), and DIPEA (6.00 mL, 34.44 mol). The reaction mixture was partitioned between aq. sat. NaHCθ₃ and EtOAc, and the phases were separated. The org. phase was washed with aq. IM HCl, dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification of the residue by FC (heptane/EtOAc = 8/2) yielded (rac.)-(ii?*, 55'*)-7-{4-[2-(tert-butyldimethylsilanyloxy)ethyl]phenyl}-6- [cyclopropyl-(2,3-dichlorobenzyl)carbamoyl]-3,9-diazabicyclo[3.3.1]non-6-ene- 3,9-dicarboxylic acid di-fer/-butyl ester (25.79 g, 78%). LC-MS: t_R = 1.33 min, ES+: 800.53. p-Toluene sulfonic acid (11.09 g, 64.40 mmol) was added to a stirred sol. of (rac.)-(lR*, 55'*)-7-{4-[2-(te^-butyldimethylsilanyloxy)ethyl]phenyl}-6-

[cyclopropyl-(2,3-dichlorobenzyl)carbamoyl]-3,9-diazabicyclo[3.3.1]non-6-ene- 3,9-dicarboxylic acid di-tert-butyl ester (25.79 g, 32.20 mmol) in MeOH (320 mL), and the mixture was stirred at rt for 30 min. The reaction mixture was quenched with aq. 10% Na₂Cθ₃ and the solvents were removed under pressure. To the resulting suspension was added EtOAc (200 mL), the precipitate was filtered, and the phases were separated. The org. layer was washed with Na₂CO₃, brine, dried over Na₂SO₄, filtered, and the solvents were removed in vacuo. Purification of the residue by FC (20-100% EtOAc/Heptane) resulted in the title compound as a yellow foam (13.36 g, 60%). LC-MS: t_R = 1.13 min, ES+: 648.49.

(rac.)-(lR *, 55^r*)-6-[Cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-7- (4-hydroxymethylphenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester (A5)

BuLi (1.60 M in hexane, 34.00 mL, 53.87 mmol) was added dropwise to a cooled (-78 ⁰C) sol. of (4-bromobenzyloxy)-te^butyldimethylsilane (15.30 g, 51.05 mmol) in THF (0.47 L). The reaction mixture was stirred at -78 ⁰C for 1 h, and ZnCl₂ (IM in THF, 68.0 mL, 68.0 mmol) was added dropwise at -78 ⁰C. The cooling bath was removed, and the reaction stirred for 1 h at rt. A sol. of (rac.)- (IR*, J5'*)-9-methyl-7-trifluoromethanesulfonyloxy-3,9-diazabicyclo[3.3.1]non- 6-ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (WO 03/093267, 13.00 g, 28.36 mmol) in THF (50.0 mL) was added dropwise, followed by Pd(PPh₃)₄ (0.95 g, 0.82 mmol). The reaction mixture was stirred at rt for 1 h, partitioned between EtOAc and aq. IM NaOH, and the layers were separated. The aq. layer was extracted with EtOAc. The combined org. extracts were washed with brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc) yielded (røc.)-(ii?*, J₁S¹*)^- [4-(terr-butyldimethylsilanyloxymethyl)phenyl]-9-methyl-3,9-diazabicyclo[3.3.1]- non-6-ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (17.85 g, >99%) as an orange oil. LC-MS: t_R = 0.95 min, ES+: 531.34. 1-Chloroethyl chloroformate (37.00 mL, 0.33 mol) was added dropwise to a suspension of (rac.)-(ii?*, 5ιS*)-7-[4-(ter^bu1yldimethylsilanyloxymethyl)- phenyl]-9-methyl-3,9-diazabicyclo[3.3. l]non-6-ene-3,6-dicarboxylic acid 3-tert- butyl ester 6-ethyl ester (17.85 g, 33.63 mmol) and NaHCO₃ (28.00 g, 0.33 mol) in 1,2-dichloroethane (0.23 L). The mixture was heated to reflux for 3 h, then allowed to cool to rt, filtered, and the solvents were thoroughly removed in vacuo. MeOH (0.23 L) was added and the mixture was stirred at 50 ⁰C for 60 min. The sol. was allowed to cool to rt, and the solvents were removed in vacuo. The residue was dissolved in CH₂Cl₂ (0.23 L), DIPEA (29.00 mL, 0.17 mol, 5.00 eq.) was added, followed by BoC₂O (22.00 g, 0.10 mol), and the mixture was stirred at rt for 45 min. The mixture was washed with aq. IM HCl, and aq. sat. NaHCO₃. The organic phase was dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification of the crude by FC (50% EtOAc in heptane) yielded (røc.)- (IR*, 55*)-7-(4-hydroxymethylphenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9- tricarboxylic acid 3,9-di-fert-butyl ester 6-ethyl ester (11.62 g, 69%). LC-MS: t_R = 1.01 min, ES+: 503.24. Aq. IM NaOH (162.00 mL) was added to a sol. of the (røc.)-(ii?*, 5S*)-7-(4- hydroxymethylphenyl)-3,9-diazabicyclo[3.3. l]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-ethyl ester (8.20 g, 16.31 mmol) in EtOH (0.32 L). The resulting mixture was stirred at 70 ⁰C for 3 h, cooled to rt, and the solvents were removed in vacuo. The crude mixture was partitioned between TBME and aq. sat. IM HCl. The aq. layer was extracted twice more with TBME, the combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to yield (rac.)-(lR*, 55^r*)-7-(4-hydroxymethylphenyl)-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester (5.80 g, 75%), which was not further purified. LC-MS: t_R = 0.88 min, ES+: 475.05. TBDMS-Cl (4.51 g, 29.92 mmol) and imidazole (3.26 g, 47.87 mmol) were added to a stirred sol. of the (rac.)-(lR*, 55'*)-7-(4-hydroxymethylphenyl)-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester (5.68 g, 11.96 mmol) in DMF (50 mL). The reaction mixture was stirred at rt over 15 h. The solvents were removed in vacuo, the crude mixture partitioned between Et₂O and water. The aq. phase was extracted again with Et₂O. The combined org. extracts were washed with aq. sat. NaHCO₃, brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. The residue was dissolved in THF (100.00 mL), MeOH (21.00 mL), and water (21.00 mL), and K₂CO₃ (0.83 g, 6.00 mmol) was added. The mixture was stirred at it for 1 h. The mixture was partitioned between Et₂O and aq. sat. NH₄Cl, the phases were separated, and the aq. layer was extracted once more with Et₂O. The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed in vacuo to yield (rac.)-(lR*, 5£*)-7-[4-(ter/-butyldimethylsilanyloxymethyl)- phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert- butyl ester (7.53 g, >99% yield) as a yellow foam. No further purification. LC- MS: t_R= 1.14 min, ES+: 589.53. To a stirred sol. of the (rac.)-(lR*, 5S*)-7-[4-(tert- butyldimethylsilanyloxymethyl)phenyl]-3,9-diazabicyclo[3.3.1 ]non-6-ene-3,6,9- tricarboxylic acid 3,9-di-tert-butyl ester (7.53 g, 11.96 mmol) in CH₂Cl₂ (0.10 L) were added EDC»HC1 (5.73 g, 29.90 mmol), HOBt (2.19 g, 14.35 mmol), DMAP (0.36 g, 2.99 mmol), cyclopropyl-(3-methoxy-2-methylbenzyl)amine (prepared by reductive amination from 3-methoxy-2-methylbenzaldehyde, Comins, D. L.; Brown, J. D., J. Org. Ghent., 1989, 54, 3730 and cyclopropylamine, 3.43 g, 17.94 mmol) and DIPEA (9.37 mL, 53.82 mmol). The mixture was stirred at rt for 5 days. The reaction mixture was partitioned between aq. sat. NaHCO₃ and EtOAc, the phases were separated, and the aq. layer was extracted once more with EtOAc. The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification of the crude by FC (10-30% EtOAc in heptane) yielded (rac.)-(lR*, 55'*)-7-[4-(tert-butyldimethylsilanyloxymethyl)- phenyl]-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester (7.74 g, 85%). LC-MS: t_R = 1.29 min, ES+: 762.61.

TBAF (6.42 g, 20.34 mmol) was added to a sol. of (rac.)-{lR*, 5.S'*)-7-[4-(^rt- butyldimethylsilanyloxymethyl)-phenyl]-6-[cyclopropyl-(3-methoxy-2-methyl- benzyl)carbamoyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di- ført-butyl ester (7.74 g, 10.16 mmol) in THF (70.0 mL) and stirred at rt for 2 h. The reaction mixture was partitioned between water and EtOAc, the phases were separated, and the aq. layer was extracted again with EtOAc. The combined org. extracts were washed with brine, dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification of the crude by FC (0-100% EtOAc in heptane followed by 10% MeOH in CH₂Cl₂) yielded the title compound (6.53 g, 99 %). LC-MS: t_R = 1.09 min, ES+: 648.58.

(rac.)-(lR*, 5S*)-6-[Cyclopropyl-(2,3-dichlorobenzyl)carbamoyl]-7-(4- hydroxymethylphenyl)-3,9-diazabicycIo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-buty\ ester (A6)

To a stirred sol. of (rac.)-(lR*, 5S*)-7-[4-(fer^butyldimethyl- silanyloxymethyl)phenyl]-3,9-diazabicyclo[3.3. l]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester (32.3 g, 54.8 mmol), EDCΗCl (26.28 g, 0.14 mol), HOBt (10.07 g, 65.86 mmol), DMAP (1.67 g, 13.71 mmol), and DIPEA (42.30 niL, 0.246 mol) in CH₂Cl₂ (0.46 L) was added after 15 min cyclopropyl-(2,3- dichlorobenzyl)amine (17.78 g, 82.27 mmol). The mixture was stirred at rt for 7 days. After 36 h HOBt (7.00 g, 45.74 mmol), cyclopropyl-(2,3- dichlorobenzyl)amine (prepared by reductive amination from 2,3- dichlorobenzaldehyde and cyclopropylamine, 10.00 g, 46.27 mmol), and DMAP (1.67 g, 13.71 mmol) were added. On the third day only cyclopropyl-(2,3- dichlorobenzyl)amine was added (5.00 g, 23.13 mmol). On the fourth day, EDC.HC1 (5.00 g, 26.08 mmol), HOBt (4.00 g, 26.14 mmol), DIPEA (5.00 mL, 28.70 mmol,) and cyclopropyl-(2,3-dichlorobenzyl)amine (5.00 g, 23.13 mmol, 0.42 eq.) were added. The reaction mixture was partitioned between EtOAc and aq. IM HCl. The layers were separated, and the aq. phase was extracted again with EtOAc (2x 10OmL). The combined org. extracts were washed with aq. sat. NaHCO₃, brine, dried over MgSO₄, filtered, and the solvents were removed in vacuo to yield an orange oil. Purification of the crude by FC (30% EtOAc in heptane) yielded (rac.)-(lR*, 55'*)-7-[4-(tert- butyldimethylsilanyloxymethyl)phenyl]-6-[cyclopropyl-(2,3-dichlorobenzyl)- carbamoyl]-3,9-diazabicyclo[3.3. l]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester (25.04 g, 58%) as a yellow oil. LC-MS: t_R = 1.32 min, ES+: 786.48. p-Tohiene sulfonic acid (12.28 g, 64.60 nitnol) was added to a sol. of (rac.)-(lR*, 55'*)-7-[4-(tert-butyldimethylsilanyloxymethyl)phenyl]-6-[cyclopropyl-(2,3- dichlorobenzyl)carbamoyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester (25.40 g, 32.30 mmol) in MeOH (330 mL). The mixture was stirred at rt over 30 min. The reaction mixture was treated with aq. 10% Na₂CO₃ (50 mL), and the solvents were removed under pressure. The resulting suspension was treated with EtOAc (0.20 L), filtered, and washed with aq. 10% Na₂CO₃ (0.10 L) and brine (0.10 L), dried over Na₂SO₄, filtered, and the solvents were removed in vacuo. Purification of the residue by FC (20 - 40% EtOAc in heptane followed by EtOAc then 10% MeOH in CH₂Cl₂) yielded the title compound (8.18 g, 38%) as a white foam. LC-MS: t_R = 1.12 min, ES+: 672.40.

(rac.)-(lR*, 55'*)-6-[Cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-7- [4-(3-oxopropyI)phenyl]-3,9-diazabicyclo-[3.3.1]non-6-ene-3,9-dicarboxyIic acid di-fert-butyl ester (Bl)

Compound Al (101 mg, 0.15 mmol) was dissolved in CH₂Cl₂ (1 mL). 4 A Molecular sieve (75 mg), NMO (26.4 mg, 0.225 mmol), and tetrapropylammonium perruthenate (2.64 mg, 0.0075 mmol) were added. The mixture was stirred overnight. The mixture was filtered through Isolute^® (1 g) pre- washed with aq. water (1.8 mL). After 5 min the Isolute^® was rinsed with CH₂Cl₂ (2 x 1 mL). The combined org. filtrates were evaporated under reduced pressure, and the crude was directly used in the next step. LC-MS: t_R = 1.11 min, ES+: 674.49.

(rac.)-(lR *, 55^l*)-6-[Cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyI]-7- (4-formyIphenyl)-3 ,9-diazabicyclo [3.3.1] non-6-ene-3,9-dicarboxylic acid di- tert-hutyl ester (B2)

Anhydrous DMSO (0.44 mL, 6.17 mmol) in CH₂Cl₂ (4.00 mL) was added dropwise over 10 min to a cooled (-63 ⁰C) sol. of oxalyl chloride (0.392 mL, 3 mmol) in CH₂Cl₂ (8.00 mL). After additional 30 min at -63 ⁰C, the reaction mixture was treated dropwise over 20 min with compound A5 (1.00 g, 1.54 mmol) in CH₂Cl₂ (8.00 mL), and the mixture was stirred for 30 min at -63 ⁰C, followed by warming to -30 ⁰C for 1 h, and finally cooled back to -63 ⁰C. Et₃N (1.29 mL, 9.26 mmol, 6.00 eq.) was added dropwise over 20 min, and the mixture was stirred for additional 30 min at -63 ⁰C. The reaction mixture was allowed to warm up to rt, and poured onto aq. 10% citric acid (10 mL). The org. layer was separated, and the aq. layer was extracted with EtOAc (3 x 20 mL). The combined org. extracts were washed with aq. sat. NaHCO₃ (10 mL), brine (10 mL), dried over MgSO₄, and filtered. The solvents were removed under reduced pressure to yield the title compound as a white crystalline foam, which was not further purified (0.99 g, 99%). LC-MS: t_R = 1.16 min, ES+: 646.43.

(rac.)-(lR*, 5i_»*)-6-[Cyclopropyl-(2,3-dichlorobenzyI)carbamoyI]-7-(4-formyI- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxyIic acid di-tert-bntyl ester (B3) Anhydrous DMSO (0.85 mL, 11.89 mmol, 4.00 eq.) in CH₂Cl₂ (8.00 mL) was added dropwise over 10 min to a cooled (-63 ⁰C) sol. of oxalyl chloride (0.75 mL, 8.92 mmol, 3.00 eq.) in CH₂Cl₂ (8.00 mL). After additional 30 min at -63 ⁰C, the reaction mixture was treated dropwise over 20 min with compound A6 (2.00 g, 2.974 mmol) in CH₂Cl₂ (8.00 mL), and the mixture was stirred for 30 min at -63 ⁰C, warmed to -30 ⁰C for 1 h, and finally cooled back to -63 ⁰C. Et₃N (2.48 mL, 17.84 mmol, 6.00 eq.) was added dropwise over 20 min, and the mixture was stirred for 30 min at -63 ⁰C. The reaction mixture was allowed to warm up to rt, quenched with aq. 10% citric acid, and the org. layer was separated. The aq. layer was extracted with EtOAc (3 x 50.00 mL). The combined org. extracts were washed with aq. sat. NaHCO₃ (50.00 mL), brine (50.00 mL), dried over MgSO₄ and filtered. The solvents were removed under reduced pressure to yield the title compound as a white foam, which was not further purified (2.00 g, 99%). LC- MS: t_R = 1.18 min, ES+: 670.43. T/EP2005/009045

46

(rac.)-(lR% JiS^-ό-tCyclopropyl-β-methoxy^-methylbenzytycarbamoyl]^- [4-(2-methyIaminoethyl)phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9- dicarboxylic acid di-tert-buty\ ester (Dl)

A sol. of glacial AcOH (0.50 niL) and compound Gl (1.69 g, 2.21 mmol) in EtOAc (20.00 mL) was treated with 10% Pd/C (50% H₂O₅ 0.17 g) and submitted to a hydrogen atmosphere for two days. 10% Pd/C (50% H₂O, 0.05 g) was added, and the reaction mixture set again under a hydrogen atmosphere overnight. The mixture was filtered through Celite, washed thoroughly with EtOAc, and the solvents were removed in vacuo to yield the title compound as a transparent foam (1.35 g, 91%), which was not further purified. LC-MS: t_R = 0.92 min, ES+:

675.62.

(rac.)-(lR*, 55^f*)-6-[Cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-7- [4-(2-ethylaminoethyl)phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9- dicarboxylic acid di-tert-buty\ ester (D2)

A sol. of glacial AcOH (0.35 mL) and compound G2 (1.10 g, 1.41 mmol) in EtOAc (14.00 mL) was treated with 10% Pd/C (0.11 g) and submitted to a hydrogen atmosphere for three days. 10% Pd/C (0.05 g) was added together with glacial AcOH (4 mL), and the reaction mixture was set under a 3 bar hydrogen atmosphere over 2 h. The mixture was then filtered through Celite, washed thoroughly with EtOAc, and the solvents were removed in vacuo to yield the title compound as a yellow foam (0.973 g, 97%), which was not further purified. LC- MS: tR = 0.94 min, ES+: 689.53.

(rac.)-(lR *, 5S*)-6-[CyclopropyI-(3-methoxy-2-methylbenzyl)carbamoyl]-7- [4-(2-isopropylaminoethyl)phenyl]-3,9-diazabicycIo[3.3.1]non-6-ene-3,9- dicarboxylic acid di-tert-butyl ester (D3)

A sol. of glacial AcOH (0.16 mL) and compound G3 (0.50 g, 0.63 mmol) in EtOAc (6.00 mL) was treated with 10% Pd/C (0.05 g). The reaction mixture was submitted to a 3 bar hydrogen atmosphere overnight. 10% Pd/C (0.05 g) was added, and the reaction mixture submitted to a 3 bar hydrogen atmosphere again overnight. The mixture was then filtered through Celite, washed thoroughly with EtOAc, and the solvents were removed in vacuo to yield the title compound as a yellow foam (0.44 g, >99%), which was not further purified. LC-MS: t_R = 0.95 min, ES+: 703.52.

(rac.)-(lR*, J-y^-T-^-Cl-CyclopropylammoethyOphenyll-o-JcyclopropyHljS- dichlorobenzyl)carbamoyl]-3,9-diazabicyclo[3.3.1]non-6-eiie-3,9-dicarboxyIic acid di-fert-butyl ester (D4)

A sol. of glacial AcOH (0.54 mL), 1,2-dichlorobenzene (2.50 mL) and compound G4 (2.00 g, 2.45 mmol) in EtOAc (25.0 mL) was treated with 10% Pd/C (0.20 g), and submitted to a hydrogen atmosphere for 8 h. The mixture was filtered trough

Celite, washed thoroughly with EtOAc, and the solvents were removed in vacuo.

Purification of the residue by FC (10% MeOH in CH₂Cl₂) yielded the title compound (1.40 g, 79%), as a transparent foam. LC-MS: t_R == 0.96 min, ES+: 725.47.

(rac.)-(lR*, 55'*)-6-[Cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-7- (4-methylaminomethylphenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-3,9- dicarboxylic acid di-tert-buty\ ester (D5) Compound B2 (5.00 g, 7.74 mmol) and N-methyl-amine (20 mL, 41% aq. sol.) were mixed in MeOH (20 mL), and the mixture was heated to reflux under N₂ for 4 h. The mixture was cooled to rt, and carefully treated with solid NaBH₄ (1.10 g, 28.40 mmol). The reaction was stirred for 30 min and partitioned between EtOAc and H₂O. The phases were separated, and the aq. phase was extracted with EtOAc. The combined org. extracts were washed with aq. sat. NaHCO₃, brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to yield the crude title compound (4.33 g, 85%) as a white foam. No further purification was necessary. LC-MS: tR = 0.91 min, ES+: 661.66. (jrac.)-{lR*, iiS^-ό-JCycIopropyl-CS-methoxy^-methylbenzylJcarbamoyl]-?- ^-(isopropylaminomethyOphenylJ-S^-diazabicycloβJ.llnoii-ό-ene-SjP- dicarboxylic acid di-tert-butyl ester (D6)

Compound B2 (2.00 g, 3.10 mmol) and isopropyl amine (0.53 mL, 6.20 mL) were mixed in MeOH (40 mL) and heated to reflux overnight. The mixture was cooled to 0⁰C, and carefully treated with solid NaBH₄ (0.23 g, 6.20 mmol, 2.00 eq.). The reaction mixture was stirred for 60 min, and partitioned between EtOAc and aq.

IM NaOH. The phases were separated, and the aq. phase was extracted with

EtOAc. The combined org. extracts were washed with brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to yield the crude title product (2.02 g, 95%) as a white foam. No further purification was undertaken. LC-MS: t_R = 0.95 min, ES+: 689.56.

(rac.)-(lR*, 5£*)-7-(4-Ammomethylphenyl)-6-[cyclopropyl-(3-methoxy-2- methylbenzyl)carbamoyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-fert-butyl ester (DT)

Compound A5 (0.674 g, 1.041 mmol) was dissolved in toluene (20 mL) and THF (20 mL). N-phthalimide (0.23 g, 1.56 mmol), polymer bound-PPh₃ (0.654 g), and di-tert-butyl azodicarboxylate (0.36g, 1.56 mmol) were added, and the reaction mixture was heated to 50 ⁰C overnight. The mixture was filtered through Celite, washed with THF, and the filtrate was reduced in vacuo to yield a cream colored foam. Purification of the residue by FC (30-50% EtOAc in heptane) yielded (rac.)-(lR*, 55^r*)-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-7-[4- (l_jS-dioxo-l_jS-dihydroisoindol^-ylmethyOphenylj-S^-diazabicyclotS.S.ljnon-δ- ene-3,9-dicarboxylic acid di-fert-butyl ester as a white powder (0.57 g, 71%). LC- MS: I_R = 1.18 min, ES+: 777.41.

Methylamine (41% in H₂O, 9.27 mL) was added to a sol. of (røc.)-(ii?*, 5S*)-6- [cyclopropyl-(3 -methoxy-2-methylbenzyl)carbamoyl]-7-[4-( 1 , 3 -dioxo- 1,3- dihydroisoindol-2-ylmethyl)phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9- dicarboxylic acid di-tert-butyl ester (0.57 g) in EtOH (10.0 mL), and the mixture was stirred at rt over 4 h. The reaction mixture was partitioned between EtOAc (50.0 mL) and aq. sat. NaHCO₃ (30 niL), and the aq. layer was extracted again with EtOAc (2x 20 mL). The combined org. extracts were washed with brine, dried over MgSO₄, filtered, and the solvents were removed in vacuo to yield a yellow oil. Purification over HPLC yielded the title compounds as a white foam (0.195, 41%). LC-MS: t_R = 0.90 min, ES+: 648.60.

(rac.y{lR*, 55^r*)-6-[CyclopropyI-(2,3-dichlorobenzyI)carbamoyI]-7-(4- ethylaminomethylphenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester (D8) Compound B3 (5.00 g, 7.74 mmol) and N-ethyl-amine (2.70 mL, 70% aq. sol.) were mixed in MeOH (18.0 mL) and the mixture was heated to reflux overnight. The mixture was cooled to rt, and carefully treated with solid NaBH₄ (0.20 g, 5.37 mmol). The reaction was stirred for 30 min and partitioned between EtOAc and NaHCO₃. The phases were separated, and the aq. phase was extracted with EtOAc (3x 30 mL). The combined org. extracts were washed with brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to yield the title compound (1.90 g, quantitative yield) as a white foam. No further purification was undertaken. LC-MS: t_R = 0.95 min, ES+: 699.49.

(rac.)-(lR *, 5iS'*)-7-(4-CyclopropyIaminomethylphenyl)-6-[cyclopropyl-(2,3- dichIorobenzyI)carbamoyI]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester (D9)

Compound B3 (1.60 g, 2.39 mmol) and N-cyclopropyl-amine (0.50 mL, 7.16 mmol) were mixed in MeOH (25.0 mL), and the mixture was heated to reflux for 4 h in an autoclave. The mixture was cooled to rt and carefully treated with solid NaBH₄ (0.22 g, 5.96 mmol). The reaction was stirred overnight, then partitioned between EtOAc and NaHCO₃. The phases were separated and the aq. phase was extracted with EtOAc (3x 30 mL). The combined org. extracts were washed with brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to yield the title compound (1.61 g, 95%) as a white foam. No further purification was undertaken. LC-MS: t_R = 0.96 min, ES+: 711.40. (rac.)-(lR*, 55'*)-6-[Cyclopropyl-(2,3-dichlorobenzyl)carbamoyl]-7-{4-[(2,2,2- trifluoroethylamino)methyl] phenyl}-3,9-diazabicyclo [3.3.1] noii-6-ene-3 ,9- dicarboxylic acid di-tert-buty\ ester (DlO) Compound B3 (2.00 g, 2.98 mmol) and N-(2,2,2-trifluoroethyl)amine (0.469 niL, 5.96 mmol) were mixed in MeOH (30.0 mL), and the mixture was heated to reflux in an autoclave overnight. The mixture was cooled to rt and carefully treated with solid NaBH₄ (0.225 g, 5.96 mmol). The mixture was stirred for 60 min and partitioned between EtOAc and H₂O. The phases were separated, and the aq. phase was extracted with EtOAc. The combined org. extracts were washed with aq. sat. NaHCO₃, brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to yield crude product (1.57 g) as a mixture of aldehyde and amine. The reaction was restarted in the autoclave, with the addition of an excess of N-(2,2,2-trifluoroethyl)amine (2.34 mL, 29.82 mmol), and the mixture was heated to reflux in MeOH (20.0 mL) overnight. The mixture was allowed to cool to rt and treated with NaBH₄ (0.28 g, 7.54 mmol). The mixture was stirred for 60 min and partitioned between EtOAc and H₂O. The phases were separated, and the aq. phase was extracted with EtOAc. The combined org. extracts were washed with aq. sat. NaHCO₃, brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to yield the title compound (1.57 g, 70%, 82% pure) as a white foam, which was not further purified. LC- MS: t_R = 1.06 min, ES+: 753.33.

{rac.)'(lR*, 55^r*)-6-[Cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-7- [4-(3-methylaminopropyl)phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9- dicarboxylic acid di-tert-butyl ester (DIl)

Compound Bl (3.40 g, 5.04 mmol) and N-methylamine (35.0 mL, 41% aq. sol.) were mixed in MeOH (70.0 mL), and the mixture was heated to reflux under N₂ for 4 h. The mixture was cooled to rt and carefully treated with solid NaBH₄ (0.57 g, 15.14 mmol). The reaction was stirred for 60 min and partitioned between EtOAc and H₂O. The phases were separated, and the aq. phase was extracted with EtOAc. The combined org. extracts were washed with aq. sat. NaHCO₃, brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to yield the title compound (3.60 g, 87%) as a white foam. No further purification was undertaken. LC-MS: t_R = 0.92 min, ES+: 689.55.

(rac.)-(lR*, 55'*)-6-[Cyclopropyl-(3-methoxy-2-methylbenzyl)carbainoyl]-7- [4-(2-methanesuIfonyloxyethyI)phenyI]-3,9-dia2abicyclo[3.3.1]non-6-ene-3,9- dicarboxylic acid di-fert-butyl ester (Fl)

Et₃N (2.53 mL, 18.1 mmol, 3.00 eq.) and methane sulfonyl chloride (0.71 mL, 9.07 mmol, 1.50 eq.) were added to a cooled (0 ⁰C) sol. of compound A2 (4.00 g,

5.83 mmol) in CH₂Cl₂ (36.00 mL). The reaction mixture was stirred at 0 ⁰C for 15 min, quenched with ice water, and the aq. layer was extracted with CH₂Cl₂ (2 x

40.00 mL). The combined org. layers were washed with aq. IM HCl, (2x), aq. sat. NaHCO₃ (50.00 mL), and brine (50.00 mL). The org. layer was dried over Na₂SO₄, filtered, and the solvents were removed in vacuo to yield 4.40 g (99%) of the title compound, which was not further purified. LC-MS: t_R = 1.13 min, ES+:

740.50.

(rac.)-{lR*, 5£*)-6-[CycIopropyl-(2,3-dichlorobenzyl)carbamoyl]-7-[4-(2- methanesuIfonyloxyethyl)phenyI]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9- dicarboxylic acid di-fe/tf-butyl ester (F2)

Et₃N (2.43 mL, 17.48 mmol) and methane sulfonyl chloride (0.68 mL, 8.74 mmol) were added to a cooled (0⁰C) sol. of compound A4 (4.00 g, 5.82 mmol) in CH₂CI₂ (30.0 mL). The reaction mixture was stirred at 0 ⁰C for 15 min, quenched with ice water, and the aq. layer was extracted with CH₂Cl₂ (2 x 40 mL). The combined org. extracts were washed with aq. IM HCl, (2x 40 mL), aq. sat. NaHCO₃ (50.00 mL), brine (50.00 mL), dried over MgSO₄, filtered, and the solvents were removed in vacuo to yield of the title compound (4.40 g, 99%) as a white foam, which was not further purified. LC-MS: t_R = 1.16 min, ES+: 764.29. 005/009045

52

(rac)-(lR*, 55*)-7-{4-[2-(Benzylmethylamino)ethyl]phenyI}-6-[cyclopropyI-

(S-methoxy-l-methylbenzy^carbamoyy-S^-diazabicyclop.S.lJnon-θ-ene-S^- dicarboxylic acid di-tert-butyl ester (Gl)

Compound Fl (0.55 g, 0.74 mmol) and N-benzyl-methylamine (0.38 mL, 2.97 mmol, 4.00 eq.) were mixed in EtOH (4.00 mL), and the mixture was heated to reflux for 3 h. The mixture was diluted with CH₂Cl₂, washed with brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (5-10% MeOH in CH₂Cl₂) resulted in the title compound as a white foam (0.29 g, 51%). LC-MS: t_R = 0.96 min, ES+: 765.71.

(rac.)-(lR*, 5S*)-7-{4-[2-(BenzyIethylamino)ethyl]phenyI}-6-[cyclopropyl-(3- methoxy^-methylbenzy^carbamoyll-S^-diazabicyclopj.lJnon-θ-ene-S^- dicarboxylic acid di-tert-butyl ester (G2)

Compound Fl (2.20 g, 2.97 mmol) and N-benzyl-ethyl-amine (2.65 mL, 17.84 mmol, 6.00 eq.) were stirred in EtOH (18.00 mL) and heated to reflux overnight. EtOH was removed in vacuo, the residue was dissolved in CH₂Cl₂, and washed with brine. The aq. layer was extracted with CH₂Cl₂, the combined org. extracts dried over Na₂SO₄, and the solvents were removed under reduced pressure to yield an oil (4.82 g). Purification of the residue by FC (1-20% 7M NH₃ZMeOH in CH₂Cl₂) yielded the title compound as a white foam (1.10 g, 47%). LC-MS: t_R = 1.00 min, ES+: 779.51.

(rac.)-(lR*, 55*)-7-{4-[2-(Benzylisopropylamino)ethyl]phenyl}-6-

[cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-3,9-diazabicycIo[3.3.1]- non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester (G3)

Compound Fl (2.20 g, 2.97 mmol) and N-benzyl-isoproylamine (2.704 mL, 17.84 mmol) were stirred in EtOH (18.00 mL) and heated to reflux overnight. N- benzyl-isoproylamine (0.9 mL, 5.94 mmol, 2.00 eq.) was added, and the reaction mixture was stirred for additional 4 h at reflux. EtOH was removed in vacuo, the residue was dissolved in CH₂Cl₂, and the mixture was washed with brine. The aq. layer was extracted with CH₂Cl₂, and the combined org. extracts were dried over Na₂SO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1-20% 7M NH₃ZMeOH in CH₂Cl₂) yielded the title compound a white foam (0.5 g, 21%). LC-MS: t_R = 1.01 min, ES+: 793.52.

(rac.)-(lR *, 55^r*)-7-{4-[2-(Benzylcyclopropylamino)ethyl]phenyI}-6-

[cyclopropyl-(2,3-dichlorobenzyl)carbamoyl]-3,9-diazabicyclo[3.3.1]non-6- ene-3,9-dicarboxyIic acid di-tert-bxήy\ ester (G4)

Compound F2 (2.20 g, 2.88 mmol) and benzylcyclopropylamine (1.67 mL, 11.50 mmol) were stirred in EtOH (18.00 mL) and heated to reflux overnight. The reaction mixture was diluted with CH₂Cl₂, washed with brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (20-30% EtOAc in heptane) yielded the title compound as a white foam (2.00 g, 85%). LC-MS: t_R = 1.02 min, ES+: 815.41.

Examples

Example 1

(rac.)-(lR*, 5iS^r*)-7-(4-{3-[(2,4-Difluorophenyl)methylamino]propyl}phenyl)-

3,9-diazabicycIo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide From compound Bl and (2,4-difluorophenyl)methylamine, according to the general procedures A and B. LC-MS: t_R = 0.80 min; ES+: 601.30.

Example 2

(rac.)-(lR*, 55'*)-7-{4-[3-(Methylphenylamino)propyl]phenyl}-3,9-diaza- bicycIo[3.3.1]non-6-ene-6-carboxylic acid cyeIopropyl-(3-methoxy-2-methyl- benzyl)amide

From compound Bl and N-methylaniline, according to the general procedures A and B. LC-MS: t_R = 0.70 min; ES+: 579.34.

Example 3 (rac.)-(lR*, 55'*)-7-{4-[3-(Methyl-/M-tolylamino)propyl]phenyI}-3,9-diaza- bicycIo[3.3.1]non-6-ene-6-carboxyIic acid cycIopropyl-(3-methoxy-2-methyI- benzyl)amide

From compound Bl and (3-methylphenyl)methylamine, according to the general procedures A and B. LC-MS: t_R = 0.67 min; ES+: 579.38.

Example 4

(rac.y(lR*, 5S*)-7-{4-[3-(Methyl-o-tolylamino)propyl]phenyl}-3,9-diaza- bicycIo[3.3.1]non-6-ene-6-carboxyIic acid cyclopropyl-(3-methoxy-2-methyl- benzyl)amide

From compound Bl and (2-methylphenyl)methylamine, according to the general procedures A and B. LC-MS: t_R = 0.67 min; ES+: 579.36.

Example 5 (rac.)~(lR*, 5S*)-7-(4-{3-[(2-Chlorophenyl)methylamino]propyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-eae-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide

From compound Bl and (2-chlorophenyl)methylamine, according to the general procedures A and B. LC-MS: t_R = 0.79 min; ES+: 599.30.

Example 6

(rac.)-(lR*, 55*)-7-(4-{3-[(3-Chlorophenyl)methylamino]propyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide From compound Bl and (3-chlorophenyl)methylamine., according to the general procedures A and B. LC-MS: t_R = 0.85 min; ES+: 599.30.

Example 7

(rαα)-(XR*, 55*)-7-{4-[2-(Methylphenylamino)ethoxy]phenyI}-3,9-diaza- bicyclo[3.3.1]non-6-ene-6-carboxyIic acid cyclopropyl-(3-methoxy-2-methyl- benzyl)amide A mixture of compound A3 (68 mg), DIPEA (0.027 mL) and N-methylaniline (0.020 mL) was stirred in propionitrile (1 mL). Cyanomethyltrimethyl- phosphonium iodide (F. Zaragoza, H. Stephensen , J. Org. Chem., 2001, 66, 2518, 36 mg) was added, and the mixture was stirred at 90 ⁰C overnight. The mixture was filtered through Isolute^® (1 g) pre-washed with aq. IM NaOH (0.7 mL). After 5 min the Isolute^® was rinsed with CH₂Cl₂ (3 x 1 mL). The combined org. filtrates were evaporated under reduced pressure. The crude was directly used in general procedure B. LC-MS: t_R = 0.74 min; ES+: 581.30.

Example 8

(rac.)-(lR*, 5_lS^f*)-7-(4-{2-[(3-ChIoro-2,6-difluorobenzoyl)methylaraino]ethyl}- phenyI)-3,9-diazabicycIo[3.3.1]uon-6-ene-6-carboxylic acid cyclopropyI-(3- methoxy-2-methylbenzyl)amide

From compound Dl and 3-chloro-2,6-difluorobenzoyl chloride, according to the general procedures C and B. LC-MS: t_R = 0.80 min; ES+: 649.38.

Example 9

(rac)-(lR*, 55*)-7-(4-{2-[(4,5-Dichloroisothiazole-3-carbonyl)methylamino]- ethyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (3-methoxy-2-methylbenzyl)amide

From compound Dl and 4,5-dichloroisothiazole-3-carbonyl chloride, according to the general procedures C and B. LC-MS: t_R = 0.78 min; ES+: 654.37.

Example 10 (rac.)-(lR *, 5£*)-7-(4-{[(2,4-Dichlorobenzyl)methylamino]methyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- metliylbeiizyl)aniide

From compound D5 and 2,4-dichlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.70 min; ES+: 619.43.

Example 11 (rac.)-(lR\ 55'*)-7-(4-{[(2-Chloro-6-fluoro-3-methylbenzyl)methylamino]- methyl}phenyI)-3,9-diazabicycIo[3.3.1]non-6-ene-6-carboxylic acid cyclo- propyl-(3-methoxy-2-methylbenzyl)amide

From compound D5 and 2-chloro-6-fluoro-3-methylbenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.69 min; ES+: 617.45.

Example 12

(rac.)-(lR*, 55*)-7-(4-{[(2-Chloro-3,6-difluorobenzyl)methyl-amino]methyl}- phenyI)-3,9-diazabicycIo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methyIbenzyl)amide

From compound D5 and 2-chloro-3,6-difluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.68 min; ES+: 621.41.

Example 13 (rac.)-(lR*, 5₁S*)-7-(4-{l(2-Chloro-4-fluorobenzyl)methylamino]methyl}- phenyl)-3,9-diazabicyc-o[3.3.1Jnon-6-ene-6-carboxyIic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide

From compound D5 and 2-chloro-4-fluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.68 min; ES+: 603.44.

Example 14

(rac.)'(lR*, 5-S'*)-7-(4-{[(2-Chloro-6-fluorobenzyl)methylamino]methyl}- phenyl)-3,9-diazabicyclo [3.3.1] non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide From compound D5 and 2-chloro-6-fluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.67 min; ES+: 603.48.

Example 15

(rac.)-(lR*, 5₁S'*)-7-(4-{[(2,3-Dichlorobenzyl)methylamino]methyI}phenyI)- 3,9-diazabicycIo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide From compound D5 and 2,3-dichlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.69 min; ES+: 619.38.

Example 16 (rac.)-(lR*, 55^r*)-7-(4-{[(2-Chlorobenzyl)methylamino]methyl}phenyI)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide

From compound D5 and 2-chlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.68 min; ES+: 585.46.

Example 17

(rac.)-(lR*, 55*)-7-(4-{[(2,6-Dichlorobenzyl)methylamino]methyI}phenyI)-

3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide From compound D5 and 2,6-dichlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.68 min; ES+: 619.47.

Example 18

(rac.)-(lR*, 55*)-7-(4-{2-[(2-Chloro-6-fluoro-3-methyIbenzyI)methylamino]- ethyl}phenyl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyI-(3-methoxy-2-methylbenzyl)amide

From compound Dl and 2-chloro-6-fluoro-3-methylbenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.71 min; ES+: 631.49.

Example 19

(rac.)-(lR*, 55^r*)-7-(4-{2-[(2-ChIoro-3,6-difluorobenzyI)methyIamino]ethyl}- phenyl)-3,9-diazabicyclo[3.3.1] non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide

From compound Dl and 2-chloro-3,6-difluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.69 min; ES+: 635.49. Example 20

(rac.)-(lR*, 5^*)-7-(4-{2-[(2-ChIoro-6-fluorobenzyI)methyIamino]ethyl}- phenyl)-3,9-diazabicyclo[3.3.1] non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide From compound Dl and 2-chloro-6-fluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.68 min; ES+: 617.51.

Example 21

(rac.)-(lR*, 5^*)-7-(4-{2-[(2,3-Dichlorobeπzyl)methylamino]ethyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide

From compound Dl and 2,3-dichlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.71 min; ES+: 633.42.

Example 22

(rac.)-(lR*, 5_t9*)-7-(4-{2-[(2-Chlorobenzyl)methylamino]ethyl}phenyl)-3,9- diazabicyclo[3.3.11non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide

From compound Dl and 2-chlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.69 min; ES+: 599.42.

Example 23

(mc.)-(lR*, 5,S'*)-7-(4-{2-[(2,6-Dichlorobenzyl)methylamino]ethyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxyIic acid cycIopropyl-(3-methoxy-2- methylbenzy])amide

From compound Dl and 2,6-dichlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.70 min; ES+: 633.39.

Example 24 (rac.)-{lR *, 5S*)-7-[4-({[2-(2,4-Dimethylphenoxy)ethyl] methylamino}- methyI)phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxyIic acid cycIopropyl-(3-methoxy-2-methylbenzyl)amide

From compound B2 and [2-(2,4-dimethylphenoxy)ethyl]methylamine, according to the general procedures A and B. LC-MS: t_R = 0.73 min; ES+: 609.46.

Example 25

{rac.)-(lR*, 55'*)-7-(4-{[(2,6-Dichloro-4-methylbenzyl)methylamino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide

From compound D5 and 2,6-dichloro-4-methylbenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.74 min; ES+: 633.37

Example 26 (rac.)-(lR*, 5-S^r*)-7-(4-{[(2-Chlorobenzyl)cyclopropylammo]methyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyI-(3-methoxy-2- methylbenzyl)amide

From compound B2 and N-(2-chlorobenzyl)(cyclopropyl)amine (WO 2003/093267), according to the general procedures A and B. LC-MS: t_R = 0.70 min; ES+: 611.35.

Example 27

(mc.)-(lR*, 55'*)-7-[4-({Methyl-[2-(2,3,6-trichlorophenyl)ethyl]amino}- methyl)phenyl]-3,9-diazabicycIo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2-methyIbenzyl)amide

From compound B2 and methyl-[2-(2,3,6-trichlorophenyl)ethyl]amine, according to the general procedures A and B. LC-MS: t_R = 0.73 min; ES+: 667.30.

Example 28 (TaC)-(IR*, 55^r*)-7-(4-{2-[(3-Ch]orobenzyI)methylamino]ethyl}phenyI)-3,9- diazabicycIo[3.3.1]non-6-ene-6-carboxyIic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide

From compound Dl and 3-chlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.69 min; ES+: 599.34.

Example 29

(rac.y{lR*, 55'*)-7-(4-{2-[(2_J6-Dimethylbenzyl)methylamiiio]etUyl}phenyl)- 3,9-diazabicyclo[3.3.1]noπ-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide

From compound Dl and 2,6-dimethylbenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.71 min; ES+: 593.42.

Example 30 (rac.)-(lR*, 5S*)-7-(4-{2-[Methyl-(2,3,6-trichlorobenzyl)amino]ethyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyI-(3-methoxy-2- methylbenzyl)amide

From compound Dl and 2,3,6-trichlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.71 min; ES+: 667.27.

Example 31

(rac.)-(lR*, 55'*)-7-(4-{[Methyl-(2,3,6-trichlorobenzyl)amino]methyl}phenyl)-

3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide From compound D5 and 2,3,6-trichlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.703 min; ES+: 655.24.

Example 32

(rac.)-(lR*, 55'*)-7-(4-{[(3-Chloro-2,6-difluorobenzyI)ethyIamino]methyI}- pheuyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxyϊic acid cyclopropyl-(2,3- dichlorobenzyl)amide From compound D8 and 3-chloro-2,6-difluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.72 min; ES+: 659.36.

Example 33 (rac.)-(lR*, 5£>7-(4-{[(3-Chlorobenzyl)ethylamino]methyI}phenyI)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)-amide

From compound D8 and 3-chlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.71 min; ES+: 625.29.

Example 34

(rac.)-(lR*, 55^r*)-7-(4-{[Ethyl-(2,3,5-trifluorobenzyI)amino]methyl}phenyl)-

3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide From compound D8 and 2,3,5-trifluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.71 min; ES+: 643.31.

Example 35

(rac.)-(lR*, 55^r*)-7-(4-{[EthyI-(2,3,6-trifluorobenzyl)amino]methyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide

From compound D8 and 2,3,6-trifluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.70 min; ES+: 643.29.

Example 36

(rac.)-(lR *, 5-S'*)-7-(4-{[(2-ChIoro-3,6-difluorobenzyl)ethylamino] methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide

From compound D8 and 2-chloro-3,6-difluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.71 min; ES+: 659.38. Example 37

(rac.)-(lR*, 5_l?*)-7-(4-{[(2,2-Difluorobenzo[l,3]dioxol-4-ylmethyl)ethyl- amino]methyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichIorobenzyl)amide From compound D8 and 2,2-difluorobenzo[l,3]dioxole-4-carbaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.75 min; ES+: 669.41.

Example 38

(rac.)-(IR*, 5^*)-7-(4-{[Ethyl-(2,3,6-trichlorobenzyl)amino]methyl}phenyl)- 3,9-diazabicycIo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- beiizyl)aniide

From compound D8 and 2,3,6-trichlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.74 min; ES+: 693.27.

Example 39

(rac.)-(lR *, 5£*)-7-(4-{[(2-Cyanobenzyl)ethylamino] methyl}phenyl)-3,9- diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyI-(2,3- dichlorobenzyl)-amide

From compound D8 and 2-cyanobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.69 min; ES+: 614.42.

Example 40

(rac.)-(lR*, 5.y*)-7-(4-{[(2,6-Difluorobenzyl)ethylamino]niethyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyI-(2,3-dich!oro- benzyl)amide

From compound D8 and 2,6-difluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.70 min; ES+: 625.34.

Example 41 (rac.)-(lR*, 55^r*)-7-(4-{[Ethyl-(2,4,6-trifluorobenzyl)amino]methyI}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxyIic acid cyc!opropyI-(2,3-dichloro- benzyl)amide

From compound D8 and 2,4,6-trifluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.70 min; ES+: 643.32.

Example 42

(rac.)-(lR*, 55*)-7-(4-{[(2-Chloro-6-fluoro-3-methylbenzyl)ethylamino]- methyI}phenyl)-3,9-diazabicycIo[3.3.1]non-6-ene-6-carboxyIic acid cyclopropyI-(2,3-dichlorobenzyl)amide

From compound D8 and 2-chloro-6-fluoro-3-methylbenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.72 min; ES+: 657.35.

Example 43 (rac.)-(lR*, 5S'*)-7-(4-{[(2,4-Dichlorobenzyl)ethylamino]methyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyI-(2,3-dichloro- benzyl)amide

From compound D8 and 2,4-dichlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.74 min; ES+: 659.32.

Example 44

(rac.)-(lR*, 5S*)-7-(4-{[(2-Chloro-6-fluorobenzyl)ethylamino]methyl}phenyl)-

3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide From compound D8 and 2-chloro-6-fluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.71 min; ES+: 643.25.

Example 45

(rac.)-(lR*, 55^r*)-7-(4-{[Ethyl-(2-fluoro-5-methoxybenzyl)amino]methyI}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide From compound D8 and 2-fluoro-5-methoxybenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.71 min; ES+: 637.33.

Example 46 (rac.)-(lR *, 5£*)-7-(4-{[Ethyl-(2-fluoro-6-trifluoromethylbenzyl)amino]- methyl}-phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichlorobenzyl)amide

From compound D8 and 2-fluoro-6-txifluoromethylbenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.73 min; ES+: 675.36.

Example 47

(rac.)-(lR*, 55^r*)-7-(4-{[(2,5-DichIorobenzyl)ethyIamino]methyl}phenyI)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide From compound D8 and 2,5-dichlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.73 min; ES+: 659.31.

Example 48

(rac.)-(lR*, 5S*)-7-(4-{[(2,6-DimethyIbenzyI)methylamino]methyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cycIopropyl-(3-methoxy-2- methylbenzyl)amide

From compound D5 and 2,6-dimethylbenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.69 min; ES+: 579.31.

Example 49

(rac.)-(lR*, 55^f*)-7-(4-{[(6-ChIoro-2-fluoro-3-methylbenzyl)methyIamino]- methyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2-methylbenzyl)amide

From compound D5 and 2-chloro-6-fluoro-3-methylbenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.69 min; ES+: 617.29. Example 50

(rac.)-(lR*, 5₁S'*)-7-(4-{[(2,3-difluorobenzyl)methylamino]methyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyI-(3-methoxy-2- methylbenzyl)amide From compound D5 and 2,3-difluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.67 min; ES+: 587.33.

Example 51

(rac.)-(lR*, 5S^r*)-7-(4-{2-[(3-Chloro-2,6-difluorobenzyl)cyclopropylamino]- ethyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichlorobenzyl)amide

From compound D4 and 3-chloro-2,6-difluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.75 min; ES+: 685.33.

Example 52

(rac)-(ZjR*, 5£*)-7-(4-{[(3-Chloro-2-fluorobenzyl)isopropylamino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxyIic acid cyclopropyI-(3- methoxy-2-methylbenzyl)amide

From compound D6 and 3-chloro-2-fluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.71 min; ES+: 649.43.

Example 53

(rac.)-(lR*, 5-y*)-7-(4-{[(3-Chloro-2,6-difluorobenzyl)cyclopropylamino]- methyl}phenyl)-3,9-diazabkyclo[3.3.1]nou-6-ene-6-carboxyIic acid cyclopropyl-(2,3-dichlorobenzyl)amide

From compound D9 and 3-chloro-2,6-difluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.79 min; ES+: 671.33.

Example 54 005/009045

66

(rαc)-(lR*, 55*)-7-(4-{[Cyclopropyl-(2,6-dichlorobenzyI)amino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxy!ic acid cyclopropyl-(2,3- dichlorobenzyl)amide

From compound D9 and 2,6-dichlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.77 min; ES+: 671.31.

Example 55

(rac.)-(lR*, 5-S'*)-7-(4-{[Cyclopropyl-(2,3-dichlorobenzyl)amino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide

From compound D9 and 2,3-dichlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.77 min; ES+: 671.37.

Example 56 {rac.)-(lR *, 5-S*)-7-(4-{[Cyclopropyl-(2,3,6-trichlorobenzyl)amino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide

From compound D9 and 2,3,6-trichlorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.84 min; ES+: 705.29.

Example 57

(rac.)-(lR*, 55*)-7-(4-{[CyclopropyI-(2,6-dimethylbenzyl)amino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-

(lichlorobenzyl)amide From compound D9 and 2,6-dimethylbenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.75 min; ES+: 629.45.

Example 58

(rac.)-(lR *, „ 55'*)-7-(4-{[(2-Cyanobenzyl)cyclopropylamino]methyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide From compound D9 and 2-cyanobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.76 min; ES+: 626.39.

Example 59 (rac.)-(lR *, 5£*)-7-{4-[(Cyclopropylquinolin-4-ylmethyIamino)methyl]- phenyl}-3,9-diazabicycIo[3.3.1]non-6-ene-6-carboxyIic acid cyclopropyl-(2,3- dichloro-benzyl)amide

From compound D9 and quinoline-4-carbaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.74 min; ES+: 652.45.

Example 60

(rac.)-(lR*, 5S*)-7-(4-{[(6-Chloro-2-fluoro-3-methylbenzyl)cyclopropyl- amino]methyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichIorobenzyl)amide From compound D9 and β-chloro-l-fluoro-S-methylbenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.76 min; ES+: 667.37.

Example 61

(rac.)-(lR*, 55*)-7-(4-{[CyclopropyI-(2-fluoro-6-trifluoromethyIbenzyl)- amino]methyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cycIopropyI-(2,3-dichlorobenzyl)amide

From compound D9 and 2-fluoro-6-trifluoromethylbenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.81 min; ES+: 687.41.

Example 62

(rac.)-(lR*, 55^f*)-7-(4-{3-[(2-Fluoro-5-methyIphenyl)methylamino]propyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide

From compound Bl and (2-fluoro-5-methylphenyl)methylamine, according to the general procedures A and B. LC-MS: t_R = 0.77 min; ES+: 597.51. Example 63

(rac.)-(lR*, 5S*)-7-(4-{3-[(2,3-DichIorophenyI)methylamino]propyl}phenyl)-

3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide From compound Bl and (2,3-dichlorophenyl)methylamine, according to the general procedures A and B. LC-MS: t_R = 0.87 min; ES+: 633.42.

Example 64

(rac.)-(IR*, 55'*)-7-(4-{3-[(2,6-Difluorophenyl)methylaiπino]propyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide

From compound Bl and (2,6-difluorophenyl)methylamine, according to the general procedures A and B. LC-MS: t_R = 0.84 min; ES+: 601.47.

Example 65

(rac.)-(lR*, 55^r*)-7-(4-{3-[(2,6-Dichlorophenyl)methylamino]propyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide

From compound Bl and (2,6-dichIorophenyl)methylamine, according to the general procedures A and B. LC-MS: t_R = 0.89 min; ES+: 633.46.

Example 66

(rac.)-(lR*, 55^l*)-7-(4-{3-[(2,5-Difluorophenyl)methylamino]propyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylk acid cyclopropyI-(3-methoxy-2- methylbenzyl)amide

From compound Bl and (2,5-difluorophenyl)methylamine, according to the general procedures A and B. LC-MS: t_R = 0.86 min; ES+: 601.50.

Example 67 09045

69

(rac.)-(lR% 55^r*)-7-(4-{3-[(5-Chloro-2-methylphenyl)methyIamino]propyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyI-(3- methoxy-2-methyIbenzyl)amide

From compound Bl and (5-chloro-2-methylphenyl)methylamine, according to the general procedures A and B. LC-MS: t_R = 0.79 min; ES+: 613.49.

Example 68

{rac.)-(lR*, 55*)-7-(4-{3-[(2,5-Dichlorophenyl)methylamino]propyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide

From compound Bl and (2,5-dichlorophenyl)methylamine, according to the general procedures A and B. LC-MS: t_R = 0.88 min; ES+: 633.44.

Example 69 (rac.)-(lR*, 5S*)-7-(4-{3-[(3-Fluoro-2-methylphenyl)methylamino]propyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide

From compound Bl and (3-fluoro-2-methylphenyl)methylamine, according to the general procedures A and B. LC-MS: t_R = 0.76 min; ES+: 597.53.

Example 70

(rac.)-(lR*, 5i-»*)-7-(4-{3-[(5-Fluoro-2-methylphenyl)methylamino]propyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide From compound Bl and (5-fluoro-2-methylphenyl)methylamine, according to the general procedures A and B. LC-MS: t_R = 0.76 min; ES+: 597.52.

Example 71

(rac.)-(lR*, 55^r*)-7-(4-{3-[(2-Chloro-5-methylphenyl)methylamino]propyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide From compound Bl and (2-chloro-5-methylphenyl)methylamine, according to the general procedures A and B. LC-MS: t_R = 0.80 min; ES+: 613.51.

Example 72 (rac.)-(lR *, 55'*)-7-(4-{[(3-ChIoro-2,6-difluorobenzyl)-(2,2,2-trifluoroethyI)- amino] methyl}phenyl)-3,9-diazabicyclo[3.3.1] non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichIorobenzyI)amide

From compound DlO and 3-chloro-2,6-difluorobenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.91 min; ES+: 715.34.

Example 73

(rac.)-(lR% 55*)-7-(4-{[(3-Chloro-2-fluoro-6-trifluoromethylbenzyI)-(2,2,2- trifluoroethytyaminoJmethyllphenyrj-SjP-diazabicycloβ.S.llnon-ό-ene-ό- carboxylic acid cyclopropyl-(2,3-dichlorobenzyl)amide From compound DlO and 3-chloro-2-fluoro-3-6-trifluoromethylbenzaldehyde, according to the general procedures D and B. LC-MS: t_R = 0.93 min; ES+: 763.40.

Biological Assays

1. Enzyme immuno assay (EIA) to estimate Angl accumulation and renin inhibition

1.1 Preparation of Angl-BSA conjugate 1.3 mg (1 μmol) of Angl [1-10 (Bachem, H-1680)] and 17 mg (0.26 μmol) of BSA (Fluka, 05475) were dissolved in 4 mL of 0.1M phosphate buffer, pH 7.4, after which 2 mL of a 1:100 dilution of glutaraldehyde in H₂O (Sigma G-5882) was added dropwise. The mixture was incubated overnight at 4 ⁰C, then dialyzed against 2 liters of 0.9% NaCl, twice for 4 h at rt, followed by dialysis against 2 liters of PBS IX overnight at rt. The solution was then filtered with a Syringe filter, 0.45 μm (Nalgene, Cat. No. 194-2545). The conjugate can be stored in polypropylene tubes in 0.05% sodium azide at 4 ⁰C for at least 12 months. 1.2 Preparation of BSA-Angl coated MTP

Microtiter plates (MPT384, MaxiSorpTM₅ Nunc) were incubated overnight at 4

°C with 80 μl of Angl (MO)ZBSA conjugate, diluted l:100'000 in PBS IX in a teflon beaker (exact dilution dependent on batch of conjugate), emptied, filled with 90 μl of blocking solution [0.5% BSA (Sigma A-2153) in PBS IX, 0.02%

NaN₃], and incubated for at least 2 h at rt, or overnight at 4 ⁰C. 96 well MTP

(MaxiSorp™, Nunc) were coated with 200 μl conjugate and blocked with 250 μl blocking solution as above, except that the blocking solution contained 3% BSA. The plates can be stored in blocking solution at 4 ⁰C for 1 month.

1.3 Angl-EIA in 384 well MTP

The Angl (l-10)/BSA coated MTP were washed 3 times with wash buffer (PBS IX, 0.01% Tween 20) and filled with 75 μl of primary antibody solution (anti- Angl antiserum, pre-diluted 1:10 in horse serum), diluted to a final concentration of l:100'000 in assay buffer (PBS IX, ImM EDTA, 0.1% BSA, pH 7.4). 5 μl of the renin reaction (or standards in assay buffer) (see below) were added to the primary antibody solution and the plates were incubated overnight at 4 ⁰C. After the incubation the plates were washed 3 times with wash buffer and incubated with secondary antibody [anti-rabbit IgG, linked to horseradish peroxidase (Amersham Bioscience, NA 934V), diluted l:2'000 in wash buffer] for 2 h at rt. The plates were washed 3 times with wash buffer and then incubated for 1 h at rt with substrate solution [1.89mM ABTS (2.2'-azino-di-(3-ethyl- benzthiazolinsulfonate)] (Roche Diagnostics, 102 946) and 2.36mM H₂O₂ [30%, (Fluka, 95300] in substrate buffer (0.1M sodium acetate, 0.05M sodium dihydrogen phosphate, pH 4.2). The OD of the plate was read at 405 nm in a microplate reader (FLUOStar Optima from BMG). The production of Angl during the renin reaction was quantified by comparing the OD of the sample with the OD of a standard curve of Angl(l-lO), measured in parallel.

2. Primary renin inhibition assay: IC₅0 in buffer, 384 well MTP P2005/009045

72

The renin assay was adapted from an assay described before (Fischli W. et ah, Hypertension, 1991, 18:22-31) and consists of two steps: in the first step, recombinant human renin is incubated with its substrate (commercial human tetradecapeptide renin substrate) to create the product Angiotensin I (Angl). In the second step, the accumulated Angl is measured by an immunological assay (enzyme immuno assay, EIA). The detailed description of this assay is found below. The EIA is very sensitive and well suited for renin activity measurements in buffer or in plasma. Due to the low concentration of renin used in this assay (2 finol per assay tube or 10 pM) it is possible to measure inhibitor affinities in this primary assay down to low pM concentration.

2.1 Methodology

Recombinant human renin (3 pg/μl) in assay buffer (PBS IX, ImM EDTA, 0.1% BSA, pH 7.4), human tetradecapeptide (1-14) substrate (Bachem, M-1120) [5 μM in 10 mM HCl], hydroxyquinoline sulfate (Fluka, 55100) [30 mM in H₂O] and assay buffer were premixed at 4⁰C at a ratio of 100:30:10:145. 47.5 μl per well of this premix was transferred into polypropylene plates (MTP384, Nunc). Test compounds were dissolved and diluted in 100% DMSO and 2.5 μl added to the premix, then incubated at 37 ⁰C for 3 h. At the end of the incubation period, 5 μl of the renin reaction (or standards in assay buffer) were transferred into EIA assays (as described above) and Angl produced by renin was quantified. The percentage of renin inhibition (Angl decrease) was calculated for each concentration of compound and the concentration of renin inhibition was determined that inhibited the enzyme activity by 50% (IC₅₀). The IC₅₀-values of all compounds tested are below 300 nM. However, selected compounds exhibit a very good bioavailability and are metabolically more stable than prior art compounds. Examples of inhibition:

Claims

Claims

1. A compound selected from the group consisting of bicyclononene compounds of the general formula (I)

CD

wherein

X represents -NH-, -N(L)-, -CH₂-, -CH(L)-, -O-, or -S-;

W represents a phenyl substituted by V in/?αrα~position;

V represents -CH₂-NC-R)-CH₂-, -CH₂-N(-R)-CH₂-CH₂-, -CH₂-CH₂-NC-R)-, -NC- R)-CH₂-CH₂-, -O-CH₂-CH₂-N(-R)-₅ -CH₂-CH₂-N(-R)-CH₂-, -CH₂-CH₂-NC-R)- CH₂-CH₂-, -CH₂-N(-R)-CH₂-CH₂-O-, -CH₂-CH₂-CH₂-N(-R)-₅ -NC-R)-CH₂-CH₂- CH₂-, or -CH₂-CH₂-NC-R)-CO-;

U represents phenyl; mono-, di-, tri-, or tetra-substituted phenyl, wherein the substituents are independently selected from the group consisting of alkyl, alkoxy, hydroxy-alkyl, halogen, -CF₃, -OCF₂O-, and cyano; a five-membered heteroaryl ring, wherein said heteroaryl ring is optionally mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of alkyl, hydroxy-alkyl, halogen and trifluoromethyl; or a quinolinyl; T represents -CONR¹-;

Q represents methylene;

M represents phenyl; mono- or di-substituted phenyl, wherein the substituents are independently selected from the group consisting of alkyl, alkoxy, alkoxy-alkyl, -OCF₃, -CF₃, and halogen; or mono- or di-substituted pyridinyl, wherein the substituents are independently selected from the group consisting of halogen, alkyl, -OCF₃, -CF₃ and alkoxy; with the proviso, that the halogen substituents are not in 2- or 6-position of the pyridinyl ring;

L represents -R³, -COR³, -COOR³, -CONR²R³, -SO₂R³, or -SO₂NR²R³;

R represents hydrogen, alkyl, cycloalkyl, or -CH₂CF₃;

R¹ and R¹ independently represent alkyl or cycloalkyl;

R² and R² independently represent hydrogen, alkyl, alkenyl, cycloalkyl, or cycloalkyl-alkyl; and

R³ represents alkyl, cycloalkyl, or cycloalkyl-alkyl, wherein these groups may be unsubstituted or mono-, di- or tri-substituted, wherein the substituents are independently selected from hydroxy, -NH₂, -OCOR², -COOR², -SO₃H, -SO₂CH₃, alkoxy, cyano, -CONR²R^2', -NH(NH)NH₂, -NR¹R^1', tetrazolyl, and alkyl, with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp³ -hybridized;

and optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, and meso-forms, as well as salts and solvent complexes of such compounds, and morphological forms.

2. A compound according to claim 1, wherein X represents -NH-; V represents -CH₂-NC-R)-CH₂-, -CH₂-N(-R)-CH₂-CH₂-, -CH₂-CH₂-NC-R)-, -O- CH₂-CH₂-N(-R)-, -CH₂-CH₂-NC-R)-CH₂-, -CH₂-CH₂-NC-R)-CH₂-CH₂-, -CH₂- CH₂-CH₂-NC-R)-, or -CH₂-CH₂-N(-R)-CO-;

U represents phenyl; mono-, di-, or tri-substituted phenyl, wherein the substituents are independently selected from the group consisting of alkyl, alkoxy, and halogen; or a five-membered heteroaryl ring, wherein said heteroaryl ring is optionally mono- or di-substituted, wherein the substituents are independently selected from the group consisting of alkyl, hydroxy-alkyl, halogen and trifluoromethyl; M represents phenyl; mono- or di-substituted phenyl, wherein the substituents are independently selected from the group consisting of alkyl, alkoxy, -OCF₃, -CF₃, and halogen; or mono- or di-substituted pyridinyl, wherein the substituents are independently selected from the group consisting of halogen, alkyl, -OCF₃, -CF₃ and alkoxy; with the proviso, that the halogen substituents are not in 2- or 6- position of the pyridinyl ring; and

R represents hydrogen, alkyl, or cycloalkyl.

3. A compound according to claim 1 or 2, wherein R¹ represents a cyclopropyl group.

4. A compound according to any one of claims 1 to 3, wherein V represents -CH₂-NC-CHa)-CH₂-, -CH₂-CH₂-N(-CH₃)-CH₂-, or -CH₂-CH₂-NC-CH₃)-CO-.

5. A compound according to any one of claims 1 to 4, wherein M represents di- substituted phenyl.

6. A compound according to claim 5, wherein M represents phenyl di-substituted by methoxy and methyl.

7. A compound according to claim 5, wherein M represents 2,3-dichlorophenyl.

8. A compound according to any one of claims 1 to 7, wherein U represents a mono-, di- or tri-substituted phenyl, wherein the substituents are independently selected from halogen and methyl.

9. A compound according to any one of claims 1 to 7, wherein U represents an isothiazole ring di-substituted by halogen.

10. A compound according to claim 1, wherein X represents -NH-;

V represents -CH₂-N(-R)-CH₂-, -CH₂-N(-R)-CH₂-CH₂-, -0-CH₂-CH₂-NC-R)-,

-CH₂-CH₂-NC-R)-CH₂-, -CH₂-NC-R)-CH₂-CH₂-O-, -CH₂-CH₂-CH₂-NC-R)-, or

-CH₂-CH₂-NC-R)-CO-;

U represents phenyl; mono-, di-, or tri-substituted phenyl, wherein the substituents are independently selected from the group consisting of alkyl, alkoxy, halogen,

-CF₃, -OCF₂O-, and cyano; or a quinolinyl;

M represents di-substituted phenyl, wherein the substituents are independently selected from the group consisting of alkyl, alkoxy, and halogen;

R represents alkyl, cycloalkyl, or -CH₂CF₃; and R¹ represents cycloalkyl.

11. A compound according to claim 1 selected from the group consisting of:

(mc.)-(lR*, 55'*)-7-(4-{3-[(2,4-difluorophenyl)methylamino]propyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-C3-methoxy-2- methylbenzyl)amide;

(mc.)-(lR*, 5S*)-7-{4-[3-(methylphenylamino)propyl]phenyl}-3,9-diazabi- cyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2-methyl- benzyl)amide; (rac.)-(lR*, 5^*)-7-{4-[3-(methyl-w-tolylamino)propyl]phenyl}-3,9-diazabi- cyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2-methyl- benzyl)amide;

(rac.)-(lR*, 5S*)-7-{4-[3-(methyl-o-tolylamino)propyl]phenyl}-3,9-diazabi- cyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2-methyl- benzyl)amide;

(rac.)-(lR*, 55^r*)-7-(4-{3-[(2-chlorophenyl)methylammo]propyl}phenyl)-3,9-di- azabicyclo[3.3.llnon-δ-ene-ό-carboxylic acid cyclopropyl-(3-tnethoxy-2-methyl- benzyl)amide;

(rac.)-(lR*, 56'*)-7-(4-{3-[(3-chlorophenyl)methylamino]propyl}phenyl)-3,9-di- azabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2-methyl- benzyl)amide;

(rac.)-{lR*, 55⁽*)-7-{4-[2-(methylphenylamino)ethoxy]phenyl}-3,9-diazabi- cyclo [3.3.1 ]non-6-ene-6-carboxylic acid cyclopropyl-(3 -methoxy-2-methyl- benzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{2-[(3-chloro-2,6-difluorobenzoyl)methylamino]ethyl}- phenyl)-3,9-diazabicyclo[3.3.1 ]non-6-ene-6-carboxylic acid cyclopropyl-(3 - methoxy-2-methylbenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{2-[(4,5-dichloroisothiazole-3-carbonyl)methylaniino]- ethyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)-(lR*, 5^*)-7-(4-{[(2,4-dichlorobenzyl)methylamino]methyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

{rac.)-(lR*, J5'*)-7-(4-{[(2-chloro-6-fluoro-3-methylbenzyl)methylamino]- methyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (3-methoxy-2-methylbenzyl)amide; {rac. )~(1R * 5S*)-7-(4- { [(2-chloro-3,6-difluorobenzyl)methylamino]methyl} - phenyl)-3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)-(lR*, 55^r*)-7-(4-{[(2-chloro-4-fluorobenzyl)methylamino]methyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 55*)-7-(4-{[(2-chloro-6-fluorobenzyl)methylamino]methyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 5₁S'*)-7-(4-{[(2,3-dichlorobenzyl)methylamino]methyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3 -methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 55^I*)-7-(4-{[(2-chlorobenzyl)methylamino]methyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{[(2,6-dichlorobenzyl)inethylamino]niethyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 5»S^f*)-7-(4-{2-[(2-chloro-6-fluoro-3-methylbenzyl)methylamino]- ethyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)-(lR*, J.S'*)-7-(4-{2-[(2-chloro-3,6-difluorobenzyl)methylamino]ethyl}- phenyl)-3,9-diazabicyclo[3.3. ^non-ό-ene-ό-carboxylic acid cyclopropyl-(3- methoxy-2-methyIbenzyl)amide;

(rac.)-(lR*, 55*)-7-(4-{2-[(2-chloro-6-fluorobenzyl)methylamino]ethyl}phenyi)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide; (rac.)-(lR\ 55*)-7-(4-{2-[(2,3-dichlorobenzyl)methylamino]ethyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rare. HH-* 5»S'*)-7-(4-{2-[(2-chlorobenzyl)methylamino]ethyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide; and

(rac.)-(lR*, 55'*)-7-(4-{2-[(2,6-dichlorobenzyl)methylamino]ethyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide.

12. A compound according to claim 1 selected from the group consisting of:

(røe.)-(H?*, 5₁S'*)-7-[4-({[2-(2,4-dimethylphenoxy)ethyl]methylamino}methyl)- phenyl]-3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)~(lR*, 55'*)-7-(4-{[(2,6-dichloro-4-methylbenzyl)methylamino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1 ]non-6-ene-6-carboxylic acid cyclopropyl-(3 - methoxy-2-methylbenzyl)amide;

(rac.)-(]R*, 55'*)-7-(4-{[(2-chlorobenzyl)cyclopropylamino]methyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(H?*, 55'*)-7-[4-({niethyl-[2-(2_>3,6-trichloroρhenyl)ethyl]amino}methyl)- phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)-(ii?*, 55^r*)-7-(4-{2-[(3-chlorobenzyl)methylamino]ethyl}phenyl)-3,9-diaza- bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyI-(3-methoxy-2-methyl- benzyl)amide; (rac.)-(ii?* 55*)-7-(4-{2-[(2,6-dimethylbenzyl)methylamino]ethyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{2-[methyl-(2,3,6-trichlorobenzyl)amino]ethyl}ρhenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(røc.)-(7i?* 55^r*)-7-(4-{[methyl-(2,3,6-trichlorobenzyl)amino]methyl}phenyl)- 3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, J^^-y^-ltCS-chloro^^-difluorobenzyOethylammoJmethyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(rac.)-(lR*, J5"*)-7-(4-{[(3-chlorobenzyl)ethylamino]methyl}phenyl)-3,9-diaza- bicyclo[3.3.1 ]non-6-ene-6-carboxylic acid cyclopropyl-(2,3 -dichlorobenzyl)- amide;

(rac.)-(lR*, 55'*)-7-(4-{[ethyl-(2,3,5-trifluorobenzyl)amino]methyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{[ethyl-(2,3,6-trifluorobenzyl)amino]methyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyI-(2,3-dichloro- benzyl)amide;

(rac.)-(lR*, 5,S*)-7-(4-{[(2-chloro-3,6-difluorobenzyl)ethylamino]methyl}- phenyl)-3,9-diazabicyclo[3.3. ljnon-ό-ene-ό-carboxylic acid cyclopropyl-(2,3 - dichlorobenzyl)amide;

(rac.)-(lR *, 5S*)-7-(4- { [(2,2-difluorobenzo[ 1 ,3]dioxol-4-ylmethyl)ethylamino]- methyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichlorobenzyl)amide; (rac.)-(lR*, 55'*)-7-(4-{[ethyl-(2,3,6-trichlorobenzyl)amino]methyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

{me. )-{lR * 5S*)-l-(4- { [(2-cyanobenzyl)ethylamino]methyl}phenyl)-3,9-diaza- bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichlorobenzyl)- amide;

(rac. )-(JR * J6^l*)-7-(4- { [(2,6-difluorobenzyl)ethylamino]methyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxyIic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac.)-(lR*, 5,S^<*)-7-(4-{[ethyl-(2,4,6-trifluorobenzyl)aniino]methyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{[(2-chloro-6-fluoro-3-methylbenzyl)ethylamino]-methyl}- phenyl)-3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{[(2,4-dichlorobenzyl)ethylamino]methyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac.)-(lR*, 55^r*)-7-(4-{[(2-chloro-6-fluorobenzyl)ethylamino]methyl}phenyl)- 3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac.)-(lR*, 55^rH!)-7-(4-{[ethyl-(2-fluoro-5-methoxybenzyl)amino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(rac.)-(ii?*, 55'*)-7-(4-{[ethyl-(2-fluoro-6-trifluoromethylbenzyl)amino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide; (rac.)-(lR*, 56"^i!)-7-(4-{[(2,5-dichlorobenzyl)ethylainino]methyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac.)~(lR*, 5^*)-7-(4-{[(2,6-dimethylbenzyl)methylamino]methyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{[(6-chloro-2-fluoro-3-methylbenzyl)methylammo]- methyl}phenyl)-3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl- (3-methoxy-2-methylbenzyl)amide;

(rac.)-(lR*, J5'*)-7-(4-{[(2,3-difluorobenzyl)methylamino]methyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(mc.)-(lR*, J,S'*)-7-(4-{2-[(3-chloro-2,6-difluorobenzyl)cyclopropylamino]- ethyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichlorobenzyl)amide;

(rac. )-(lR *, 5S*)-7-(4- { [(3 -chloro-2-fluorobenzyl)isopropylamino]methyl} - phenyl)-3 ,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3 - dichlorobenzyl)amide;

(rac.)-(lR*, 5₁S'*)-7-(4-{[(3-chloro-2,6-difluorobenzyl)cyclopropylamino]- methyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxyIic acid cyclopropyl- (2, 3 -dichlorobenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{[cyclopropyl-(2,6-dichlorobenzyl)amino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(rac.)-(ii?*, 55*)-7-(4-{[cyclopropyl-(2,3-dichlorobenzyl)amino]methyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide; (rac.)-(^]R*, 55^l*)-7-(4-{[cyclopropyl-(2,3,6-trichlorobenzyl)amino]methyl}- phenyl)-3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(rac. )-(lR *, 55*)-7-(4- { [cyclopropyl-(2,6-dimethylbenzyl)amino]methyl} - phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichlorobenzyl)amide;

(rac.)-(lR*, 56'*)-7-(4-{[(2-cyanobenzyl)cyclopropylamino]methyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac.)-(lR*, 5»S'*)-7-{4-[(cyclopropyl-quinolin-4-ylmethylamino)methyl]phenyl}- 3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro- benzyl)amide;

(rac. )-(JR *, 5S*)-7-(4- { [(6-chloro-2-fluoro-3 -methylbenzy^cyclopropylamino] - methyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichlorobenzyl)amide;

(rac. )-(JR *, 5S*)-7-(4- { [cyclopropyl-(2-fluoro-6-trifluoromethylbenzyl)amino] - methyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichlorobenzyl)amide;

(rac. )-(//?* 5,S'*)-7-(4-{3-[(2-fluoro-5-methylphenyl)methylamino]propyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)-(lR*, J5^f*)-7-(4-{3-[(2,3-dichlorophenyl)methylamino]propyl}phenyl)-3,9- diazabicyclo[3.3. ljnon-β-ene-ό-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{3-[(2,6-difluorophenyl)methylamino]propyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide; (rac.)-(lR*, 55*)-7-(4-{3-[(2,6-dichlorophenyl)methylamino]propyl}phenyl)-3₅9- diazabicyclo[3.3. ljnon-ό-ene-ό-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(lR\ 55*)-7-(4-{3-[(2,5-difluoroρhenyl)methylamino]propyl}phenyl)-3,9- diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(mc.)-(lR*, 55^r*)-7-(4-{3-[(5-chloro-2-methylphenyl)methylamino]ρropyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)-(lR*, J,S'*)-7-(4-{3-[(2,5-dichlorophenyl)methylamino]propyl}phenyl)-3,9- diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methylbenzyl)amide;

(rac.)-(JR*, i.S'^^^-IS-tCS-fluoro^-methylphenyOmethylaminojpropyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)-(lR*, 55^l*)-7-(4-{3-[(5-fluoro-2-methylphenyl)methylamino]propyl}- phenyl)-3,9-diazabicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)-(lR*, 55'*)-7-(4-{3-[(2-chloro-5-methylphenyl)methylamino]propyl}- phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methylbenzyl)amide;

(rac.)-(lR*, 5^*)-7-(4-{[(3-chloro-2,6-difluorobenzyl)-(2,2,2-trifluoroethyl)- amino]methyl}phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichlorobenzyl)amide; and

(rac.)-(lR*, 55^r*)-7-(4-{[(3-chloro-2-fluoro-6-trifluoromethylbenzyl)-(2,2,2- trifluoroethyl)amino]methyl}phenyl)-3 ,9-diazabicyclo[3.3.1 ]non-6-ene-6- carboxylic acid cyclopropyl-(2,3-dichlorobenzyl)amide.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier material.

14. A compound according to any one of claims 1 to 12, or composition according to claim 13, for use as a medicament.

15. Use of a compound according to any one of claims 1 to 12 for the preparation of a pharmaceutical composition for the treatment or prophylaxis of diseases selected from hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, atherosclerosis, restenosis post angioplasty, ςomplications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications of treatments with immunosuppressive agents, and other diseases known to be related to the renin-angiotensin system.