WO2006131884A2 - Thiazole substituted diazabicyclononane or-nonene derivatives as renin inhibitors - Google Patents

Abstract

The invention relates to novel thiazole derivatives and their use 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 comprising one or more of those compounds and especially their use as inhibitors of renin.

Description

Novel Thiazole 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 comprising 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 bypassed 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). ACE inhibitors do not inhibit Chymase. 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 WO 97/09311; 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 formula (I) which have a long duration of action and which are active in indications beyond blood pressure regulation where the tissular renin-chymase system may be activated leading to pathophysiologically 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),

wherein

L represents H, -R², -COR², -COOR², or -CONHR²;

V represents -CH₂-CH₂-CH₂-; -0-CH₂-CH₂-; -CH₂-CH₂-O-; -CH₂-O-CH₂-; -CH₂- CH₂-CH₂-CH₂-; -0-CH₂-CH₂-O-; -0-CH₂-CH₂-CH₂-; -CH₂-CH₂-CH₂-O-; -CH₂- 0-CH₂-CH₂-; -CH₂-CH₂-O-CH₂-; -NH-R³-, -N(CH₃)-R³-, -NH-R³-0-, -N(CH₃)- R³-0-, -NH-CH₂-Q-, -N(CH₃)-CH₂-Q-, -NH-CH₂-Q-X-, or -N(CH₃)-CH₂-Q-X-, wherein the groups which have an underlined nitrogen atom are bound to the -(CH₂)_m- group of formula (I) via this underlined nitrogen atom; or

V represents a heterocyclic group selected from

wherein said heterocyclic groups are bound to the -(CH₂)_m- group of formula (I) via their nitrogen ring atom;

U represents aryl that can be mono-, di-, tri-, or tetra- substituted, wherein the substituents are independently selected from halogen, alkyl, -CF₃, -OCF₃, and hydroxy- alkyl; or five-membered heteroaryl containing two heteroatoms independently selected from nitrogen and oxygen (preferably pyrazole or isoxazole), wherein said heteroaryl can be mono-, di-, or tri- substituted, wherein the substituents are independently selected from halogen, alkyl, -CF₃, -OCF₃, and hydroxy- alkyl;

M represents an aryl, quinolinyl, isoquinolinyl, dihydroquinolinyl or tetrahydroquinolinyl group, wherein said groups can be mono-, di-, or tri- substituted, wherein the substituents are independently selected from halogen, alkyl, -CF₃, -OCF₃, alkoxy, alkyl-O-(CH₂)₀-₄-CH₂-, alkyl-O-(CH₂)₂_₄-O-, and R⁵ ₂N-(CH₂)o-₄-CH₂-; preferred substituents are chlorine, -CF₃, methyl, methoxy, alkyl-0-(CH₂)o-₄-CH₂-, alkyl-O-(CH₂)₂_₄-O-, and R⁵ ₂N-(CH₂)₀-₄-CH₂-;

Q represents a five-membered heteroaryl group containing at least one oxygen atom and 1 or 2 nitrogen atoms (preferably isoxazole or oxadiazole);

X represents -CH₂-, -0-, -NH-, or -N(CH₃)-;

R¹ represents alkyl, cycloalkyl, or cycloalkyl-alkyl, preferably cyclopropyl; R² represents alkyl that can be substituted by -CO₂H, -CO₂R⁴, -CONH₂, -SO₂CH₃, -SO₃H, -SO₂R⁴, tetrazolyl, -OH, -NH₂, or -NHCOR⁴;

R³ represents alkylene, preferably methylene;

R⁴ represents alkyl;

R⁵ represents hydrogen, alkyl, cyclopropyl, or -C(=0)-R' wherein R' is C₁-C₄- alkyl, -CF₃, -CH₂-CF₃, or cyclopropyl;

n represents the integer O or 1 ; and m represents the integer O, 1 or 2;

and wherein when n = O, a double bond is present in the 3,9-diaza- bicyclo[3.3.1]nonane ring of formula (I) at the 6,7-position; and when n = 1, the double bond is present at the 7,8-position;

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 solvates 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 solvates (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, i.e. C₁-C₄-alkyl. Examples of alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, sec -butyl, tert-butyl, 2,2-dimethylpropyl, pentyl, hexyl and heptyl. The methyl, ethyl and isopropyl groups are preferred.

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

The term hydroxy-alkyl, alone or in combination with other groups, 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 CH₃CH(OH)-.

The term halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

The term cycloalkyl, alone or in combination with other groups, means a saturated cyclic hydrocarbon ring system with 3 to 7 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The cyclopropyl group is a preferred group.

The term alkylene, alone or in combination with other groups, means straight and branched divalent chain groups with one to seven carbon atoms, preferably one to four carbon atoms. Examples of alkylene are methylene, ethylene, propylene and butylene. The term aryl, alone or in combination with other groups, relates to a phenyl, naphthyl or indanyl group, preferably a phenyl group.

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, p-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 can be separated in a manner known per se, e.g. by column chromatography, thin layer chromatography (TLC), high performance liquid 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, 5,703,073, 5,994,294, 6,242,432 and 6,218,417; WO 98/19672; and Oae et al., Org. Prep. Proc. Int., 15(3): 165-198 (1983).

A group of preferred compounds of formula (I) is that wherein V represents -NH- R³-, -N(CH₃)-R³-, -NH-R³-O-, -N(CH₃)-R³-O-, -NH-CH₂-Q-, -N(CH₃)-CH₂-Q-, -NH-CH₂-Q-X-, or -N(CH₃)-CH₂-Q-X-, wherein these groups are bound to the -(CH₂)_m- group of formula (I) via the underlined nitrogen atom; or V represents a heterocyclic group selected from

wherein said heterocyclic groups are bound to the -(CH₂)_m- group of formula (I) via their nitrogen ring atom, and wherein R³, Q and X are as defined for formula (I).

A further group of preferred compounds of formula (I) is that wherein L is H, -COCH₃, or -CONHCH₂C(CH₃)₂CONH₂.

Another group of even more preferred compounds of formula (I) is that wherein m represents the integer 0 and V represents the following heterocyclic group:

wherein the nitrogen ring atom is bound to the thiazole group of formula (I).

Another group of even more preferred compounds of formula (I) is that wherein m represents the integer 1 and V represents -N(CH₃)-CH₂-, wherein the nitrogen atom is bound to the -(CH₂)_m- group of formula (I). Another group of even more preferred compounds of formula (I) is that wherein m represents the integer 0; and

V represents -NH-CH₂-Q-, wherein Q is an isoxazole or oxadiazole group and wherein the underlined nitrogen atom is bound to the thiazole group of formula (I).

Another group of even more preferred compounds of formula (I) is that wherein m represents the integer 0; and V represents -NH-CH₂-Q-, wherein Q is an isoxazole group and wherein the underlined nitrogen atom is bound to the thiazole group of formula (I).

Another group of also more preferred compounds of formula (I) is that wherein U is mono-, di-, tri-, or tetra- substituted aryl, preferably mono-, di-, tri-, or tetra- substituted phenyl, wherein the substituents are independently selected from halogen, alkyl, -CF₃, -OCF₃, and hydroxy-alkyl; preferably the substituents are independently selected from chlorine, methyl, fluorine, and hydroxy-alkyl.

Another group of also more preferred compounds of formula (I) is that wherein M is mono-, di-, or tri- substituted aryl, preferably mono-, di-, or tri- substituted phenyl, wherein the substituents are independently selected from halogen, alkyl,

-CF₃, -OCF₃, alkoxy, alkyl-O-(CH₂)₀-₄-CH₂-, alkyl-O-(CH₂)₂_₄-O-, and R⁵ ₂N-

(CH₂)o-₄-CH₂-, wherein R⁵ is as defined above for formula (I); most preferably M is 2,3-dichlorophenyl, 2,3-dimethylphenyl, 2-methyl-3-methoxyphenyl, 2-chloro- 3-trifluoromethylphenyl, or 2-chloro-3-methylphenyl.

Another group of also more preferred compounds of formula (I) is that wherein R¹ is cyclopropyl.

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 as defined herein, such as those defined for the above-given preferred groups of compounds.

The present invention therefore especially relates to compounds of formula (I) wherein one or all of the substituents and symbols as defined for formula (I) are replaced by their preferred meanings as defined above.

A preferred embodiment of the present invention relates to compounds of formula (I), wherein L is H;

V represents -0-CH₂-CH₂-O-, -N(CH₃)-R³-, -NH-CH₂-Q-, or -N(CH₃)-CH₂-Q-, wherein the groups which have an underlined nitrogen atom are bound to the -(CH₂)_m- group of formula (I) via this underlined nitrogen atom; or

V represents a heterocyclic group selected from

wherein these heterocyclic groups are bound to the -(CH₂)_m- group of formula (I) via their nitrogen ring atom; U represents di-, tri-, or tetra- substituted phenyl, wherein the substituents are independently selected from halogen, alkyl and hydroxy- alkyl;

M represents mono- or di-substituted phenyl, wherein the substituents are independently selected from halogen, alkyl and alkoxy;

Q represents an isoxazole group; R¹ represents cycloalkyl, such as especially cyclopropyl;

R³ represents alkylene, such as especially methylene; n represents the integer 0 or 1 ; and m represents the integer 0 or 1 ; and wherein when n = 0, a double bond is present in the 3,9-diaza- bicyclo[3.3.1]nonane ring of formula (I) at the 6,7-position; and when n = 1, the double bond is present at the 7,8-position.

An especially preferred embodiment of the present invention relates to compounds of formula (I), wherein L is H;

V represents -N(CH₃)-R³-, -NH-CH₂-Q-, or -N(CH₃)-CH₂-Q-, wherein these groups are bound to the -(CH₂)_m- group of formula (I) via the underlined nitrogen atom; or

V represents a heterocyclic group selected from

wherein these heterocyclic groups are bound to the -(CH₂)_m- group of formula (I) via their nitrogen ring atom;

U represents di-, tri-, or tetra- substituted phenyl, wherein the substituents are independently selected from halogen, alkyl and hydroxy- alkyl;

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

Q represents an isoxazole group;

R¹ represents cycloalkyl, such as especially cyclopropyl;

R³ represents alkylene, such as especially methylene; n represents the integer 0; and m represents the integer 0 or 1 ; and wherein a double bond is present in the 3,9-diaza-bicyclo[3.3.1]nonane ring of formula (I) at the 6,7-position. Very especially preferred compounds of formula (I) are those selected from the group consisting of:

(IR*, 5_lS'*)-7-(2-{ [(2-chloro-6-fluoro-benzyl)-methyl-amino]-methyl}-thiazol-5- yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide;

(IR*, 5_lS'*)-7-(2-{ [(2-chloro-3,6-difluoro-benzyl)-methyl-amino]-methyl}-thiazol- 5-yl)-3,9-diaza-bicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide;

(IR, 55)-7-{2-[(Ji?)-3-(2,6-dichloro-3,4-dimethyl-phenoxy)-pyrrolidin-l-yl]- thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methyl-benzyl)-amide;

(IS, 5i?)-7-{2-[(Ji?)-3-(2,6-dichloro-3,4-dimethyl-phenoxy)-pyrrolidin-l-yl]- thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methyl-benzyl)-amide;

(IR, 55)-7-{2-[(Ji?)-3-(2,6-dichloro-phenoxy)-pyrrolidin-l-yl]-thiazol-5-yl}-3,9- diaza-bicyclo[3.3. ^non-ό-ene-ό-carboxylic acid cyclopropyl-(3-methoxy-2- methyl-benzyl) - amide ;

(IS, 5i?)-7-{2-[(Ji?)-3-(2,6-dichloro-phenoxy)-pyrrolidin-l-yl]-thiazol-5-yl}-3,9- diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methyl-benzyl) - amide ;

(IR, 55')-7-{2-[(Ji?)-3-(2,6-dichloro-4-methyl-phenoxy)-pyrrolidin-l-yl]-thiazol- 5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methyl-benzyl)-amide; (IS, 5i?)-7-{2-[(Ji?)-3-(2,6-dichloro-4-methyl-phenoxy)-pyrrolidin-l-yl]-thiazol- 5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methyl-benzyl)-amide;

(IR*, 5S*)-7-(2-{ [3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethyl]-amino}- thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl)-amide;

(IR*, 55'*)-7-(2-{ [3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethyl]-methyl- amino}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3- dichloro-benzyl) - amide ;

(IR*, 55'*)-7-{2-[3-(2,6-dichloro-4-methyl-phenoxymethyl)-azetidin-l-yl]- thiazol-5-yl } -3 ,9-diaza-bicyclo [3.3.1] non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl)-amide;

(IR*, 55'*)-7-{2-[3-(2,6-dichloro-phenoxymethyl)-azetidin-l-yl]-thiazol-5-yl}- 3 ,9-diaza-bicyclo [3.3.1] non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichloro- benzyl)-amide;

(IR*, 55'*)-7-{2-[3-(2-chloro-6-fluoro-3-methyl-phenoxymethyl)-azetidin-l-yl]- thiazol-5-yl } -3 ,9-diaza-bicyclo [3.3.1] non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl)-amide;

(IR*, 55'*)-7-(2-{3-[2,6-dichloro-4-(2-hydroxy-ethyl)-phenoxymethyl]-azetidin-l- yl}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3- dichloro-benzyl) - amide ;

(IR, 55)-7-(2-{3-[2,6-dichloro-4-((i5)-l-hydroxy-ethyl)-phenoxymethyl]- azetidin-l-yl}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3- dichloro-benzyl) - amide ; (IS, 5i?)-7-(2-{3-[2,6-dichloro-4-((ii?)-l-hydroxy-ethyl)-phenoxymethyl]- azetidin-l-yl}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3- dichloro-benzyl) - amide ;

(IR, 55>7-(2-{3-[2,6-dichloro-4-((iR)-l-hydroxy-ethyl)-phenoxymethyl]- azetidin-l-yl}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3- dichloro-benzyl) - amide ;

(IS, 5R)-7-(2-{3-[2,6-dichloro-4-((iS)-l-hydroxy-ethyl)-phenoxymethyl]- azetidin-l-yl}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3- dichloro-benzyl) - amide ;

(IR*, 55'*)-7-{2-[3-(2,6-dichloro-4-fluoro-phenoxymethyl)-azetidin-l-yl]-thiazol- 5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide;

(IR*, 55'*)-7-{2-[3-(2-chloro-3,6-difluoro-phenoxymethyl)-azetidin-l-yl]-thiazol- 5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide; and

(IR*, 55'*)-7-{2-[3-(3-chloro-2,6-difluoro-phenoxymethyl)-azetidin-l-yl]-thiazol- 5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide.

Further very especially preferred compounds of formula (I) are those selected from the group consisting of:

(IR, 55^l)-7-{2-[(J5^<)-3-(2-chloro-3,6-difluoro-phenoxy)-pyrrolidin-l-yl]-thiazol-5- yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide; (IS, 5i?)-7-{2-[(J5')-3-(2-chloro-3,6-difluoro-phenoxy)-pyrrolidin-l-yl]-thiazol-5- yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide;

N-cyclopropyl-2-((ii?*, 55'*)-7-{2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]- thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-7-en-6-yl)-N-(2,3-dimethyl-benzyl)- acetamide;

N-(2-chloro-benzyl)-N-cyclopropyl-2-((iR* 5S*)-7-{2-[2-(2,6-dichloro-4- methyl-phenoxy)-ethoxy]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-7-en-6-yl)- acetamide;

N-cyclopropyl-2-((ii?*, 55'*)-7-{2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]- thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-7-en-6-yl)-N-(3-methoxy-2-methyl- benzyl) -acetamide; and

N-(2-Chloro-3-methyl-benzyl)-N-cyclopropyl-2-((ii?*, 55*)-7-{2-[2-(2,6- dichloro-4-methyl-phenoxy)-ethoxy]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-7- en-6-yl)-acetamide.

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 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, 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 and/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

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) or 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.

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, sympatholitics, beta- adrenergic antagonists, alpha- adrenergic antagonists and/or other drugs beneficial for the prevention or the treatment of the above-mentioned diseases such as 1 lbeta-hydroxysteroid dehydrogenase type 1 inhibitors and soluble guanylate cyclase activators.

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 preparation of compounds of formula (I) begins with 9-methyl-7-oxo-3,9- diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-hwtyl ester (WO 2003/093267).

An N-demethylation and formation of a suitable carbamate as protecting group PG leads to a compound of type A, as described in Scheme 1. An acylation or an alkylation leads then to a compound of type B, wherein R^a stands for a suitable ester substituent. A compound of type C is prepared from the same starting material, via an enolate for instance, and a suitable R^a-ester of a bromoacetate.

Again, demethylation and formation of a suitable carbamate leads to a compound of type B. Finally triflate formation leads to a compound of type D, whereas the double bond can be in position 6,7 (n = 0), or 7,8 (n = 1), as defined for formula (I).

Scheme 1

A compound of type D can be transformed into a compound of type E, as described in Scheme 2, via a Negishi coupling for instance, or any type of coupling, usually catalyzed by a transition metal, between two sp²-hybridized carbon centers. Under such circumstances m = 0, according to formula (I). R^b and R^c represent two independent groups that can be a precursor of a group as defined for V in formula (I), or a protecting group. R^b and R^c can also form together a pyrrolidinyl or an azetidinyl derivative, as defined for formula (I). In many instances the 2-aminothiazolyl moiety substituted with R^b and R^c must be prepared separately (see examples for details). R^b and R^c can be modified along the synthesis, if necessary. A saponification leads to the carboxylic acid derivative of type F, then an amide coupling to a derivative of type G. Final construction of the U-V chain leads to a compound of type L. Scheme 2

A Negishi (or an other type of) coupling from a compound of type D can lead to a compound of type H as well (m = 1), as described in Scheme 3. R^d stands for a substituent, generally equipped with a protecting group and/or a functional group, that shall finally lead to the V-group as defined for formula (I). R^d can be modified along the synthesis if necessary. A saponification leads to a compound of type J, then an amide coupling to a compound of type K. Finally the U-V fragment is fully constructed to give a compound of type L. Scheme 3

Alternatively, a compound of type D can be transformed directly into a compound of type O, as described in Scheme 4. A saponification or hydrolysis leads to a compound of type P, then an amide coupling to a compound of type L.

Scheme 4

A compound of type L can be deprotected to a compound of type M as described in Scheme 5. Acylation or alkylation leads to a compound of type N. Final removal of the protecting group PG leads to a compound of formula (I). If L represents hydrogen in formula (I), the final compound can be obtained from a compound of type L as well.

Scheme 5

The skilled person in the art will notice as well that many steps can be inverted to lead finally to a compound of formula (I).

Also, the skilled person in the art will notice that any of these compounds that is prepared as a racemate can be resolved in its enantiomers using a chromatographic separation with a column equipped with a chiral solid support.

Examples

Abbreviations (as used herein):

AcOH Acetic acid

Ang Angiotensin aq. aqueous

Boc teTt-Butyloxycarbonyl

BSA Bovine serum albumine

Bu Butyl

BuLi n-Butyllithium DDQ 3,6-Dioxo-cyclohexa- 1 ,4-diene- 1 ,2,4,5-tetracarbonitrile

DIPEA Diisopropylethylamine

DMAP 4-N,N-Dimethylaminopyridine

DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide

EDCΗC1 Ethyl-NN-dimethylaminopropylcarbodiimide hydrochloride

EIA Enzyme immunoassay

ELSD Evaporative Light Scattering Detection eq. Equivalent(s) ES Electrospray (as method of ionization)

Et Ethyl

EtOAc Ethyl acetate

EtOH Ethanol

FC Flash Chromatography h hour(s)

HOBt Hydroxybenzotriazol

HPLC High Performance Liquid Chromoatography

LC-MS Liquid Chromatography - Mass Spectroscopy

Me Methyl MeOH Methanol min minute(s)

MS Mass Spectroscopy

OAc Acetate

OD Optical density org. organic

PBS Phosphate Buffered Saline

PG Protecting Group

Ph Phenyl

R_f Retention value (on TLC) rt room temperature sat. saturated sol. Solution TBAF Tetrafluoroammonium fluoride trihydrate

TBDMS terr-Butyldimethylsilyl

Tf Trifluoromethylsulfonyl

TFA Trifluoroacetic acid THF Tetrahydrofuran

TLC Thin Layer Chromatography t_R Retention time (in chromatography) given in minutes

UV ultra violet

Vis visible

HPLC 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, usually 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.

General procedure A (Mitsunobu reaction)

A compound of type G or K (0.10 mmol) was dissolved in toluene (2 mL). The desired phenol (0.20 mmol), azodicarboxylic dipiperidide (0.20 mmol), and PBu₃ (0.30 mmol) were added, and the mixture was stirred at rt for 2 h, then at 80 °C for 3 - 6 h. The reaction mixture was checked by LC-MS, and PBu₃ (0.40 mmol) was added again if the reaction was not complete. When the conversion was complete, the mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. Purification of the crude by HPLC yielded the title compound.

General procedure B for deprotection A compound of type L (with L = H; 0.01 - 0.20 mmol) was dissolved in CH₂Cl₂ (1.5 mL), and the sol. was cooled to 0 °C. HCl (4M in dioxane, 0.5 mL) was added. The mixture was stirred for 30 min at 0 °C, then for 1.5 h at rt. Aq. NaOH (IM, 4 mL) was added, and the mixture was eluted through syringes filled with Isolute^®, and CH₂Cl₂. The solvents were removed under reduced pressure, and the residue was purified by HPLC to yield the title compound.

General procedure C for amide coupling

A mixture of the carboxylic derivative (0.1 mmol), of the mentioned amine (0.3 mmol), DIPEA (0.4 mmol), DMAP (0.025 mmol), HOBt (0.1 mmol) and EDCΗC1 (0.15 mmol) in CH₂Cl₂ (2 mL) was stirred for 3 days at rt. The reaction mixture was checked by LC-MS, and stirred further in case the reaction was not complete. A 2 mL-syringe was filled with Isolute^®, and aq. IM HCl (0.80 mL) was added. After 5 min the reaction mixture was eluted with CH₂Cl₂. The solvents were removed under reduced pressure. Unless otherwise stated the crude product was purified by HPLC.

Thiazole-2-carb aldehyde

To a sol. of BuLi (73.2 mmol, 45.7 mL of a 1.6M sol. in hexane) at -78 ⁰C was added slowly a solution of 2-bromothiazole (10.0 g, 61.0 mmol) in Et₂O (30 mL). The temperature was maintained bellow -65 ⁰C during the addition (45 min). The mixture was then stirred 2 h at -78 ⁰C. A sol. of DMF (7.13 g, 97.5 mmol) in Et₂O (42 mL) was finally added dropwise over 30 min, maintaining the reaction temperature bellow -65 ⁰C. The reaction mixture was allowed to warm up to -40 ⁰C over 1 h and was stirred for 1 h at -40 ⁰C. Cold aq. 4M HCl was added carefully to the reaction. The org. layer was separated, and washed with aq. 4M HCl. The aq. layer was neutralized carefully with solid K₂CO₃, and extracted with Et₂O, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to yield the title compound (6.94 g) as an orange-brown oil that was used for the next step without further purification.

Thiazol-2-yl-methanol To a solution of thiazole-2-carbaldehyde (6.82 g, 60.28 mmol) in MeOH (60 mL) at -60 ⁰C was added NaBH₄ (2.28 g, 60.28 mmol). The reaction mixture was stirred at -60 ⁰C for 1.5 h. The reaction mixture was then carefully treated with acetone (5.1 mL), and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 80:20) yielded the title compound (2.05 g, 30%).

2-(teτt-Butyl-dimethyl-silanyloxymethyl)-thiazole

A solution of thiazol-2-yl-methanol (2.05 g, 17.8 mmol) in DMF (17.8 mL) was treated at rt with imidazole (3.03 g, 44.5 mmol), followed by TBDMS-Cl (4.02 g, 26.7 mmol), and the resulting solution was stirred for 2 h at rt. The mixture was diluted with EtOAc, washed with aq. sat. NH₄Cl, brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 15:85) yielded the title compound (3.76 g, 92%). LC-MS: t_R = 1.06 min; ES+: 230.16.

(5')-l-(5-Bromo-thiazol-2-yl)-pyrrolidin-3-ol

A mixture of 2,5-dibromothiazole (15 g, 59.9 mmol), (S^-hydroxypyrrolidine (6.0 mL, 71.9 mmol) and DIPEA (13.3 mL, 77.9 mmol) in dioxane (875 mL) was stirred at 80 ⁰C for 17 h. The solvents were removed under reduced pressure. Aq. sat. NaHCO₃ (50 mL) was added, and the mixture was extracted with CH₂Cl₂ (2x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. The crude title compound (12.2 g) was used in the next reaction without purification.

(i?)-l-(5-Bromo-thiazol-2-yl)-pyrrolidin-3-ol

A mixture of 2,5-dibromothiazole (10 g, 41.2 mmol), (i?)-hydroxypyrrolidine (4.0 mL, 49.4 mmol) and DIPEA (9.2 mL, 53.5 mmol) in dioxane (700 mL) was stirred at 85 ⁰C for 15 h. The solvents were removed under reduced pressure. Aq. sat. NaHCO₃ (50 mL) was added, and the mixture was extracted with CH₂Cl₂ (2x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. The crude title product (9.3 g) was used in the next reaction without purification. LC-MS: tR = 0.53 min; ES+: 249.08.

(,S')-5-Bromo-2-[3-(rerr-butyl-dimethyl-silanyloxy)-pyrrolidin-l-yl]-thiazole A mixture of (S)-l-(5-bromo-thiazol-2-yl)-pyrrolidin-3-ol (12.2 g, 48.9 mmol), TBDMS-Cl (8.84 g, 58.7 mmol) and imidazole (8.3 g, 122.2 mmol) in DMF (150 mL) was stirred at rt for 30 min. Water (150 mL) was added, and the mixture was extracted with heptane (3x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/EtOAc 14:1 → 13: l→ 12: l→ 10:1) yielded the title compound (11.3 g, 52% over 2 steps). LC-MS: t_R = 1.10 min; ES+: 363.14.

(i?)-5-Bromo-2-[3-(?err-butyl-dimethyl-silanyloxy)-pyrrolidin-l-yl]-thiazole A mixture of (i?)-l-(5-bromo-thiazol-2-yl)-pyrrolidin-3-ol (9.3 g, 31.7 mmol), TBDMS-Cl (5.7 g, 38.0 mmol) and imidazole (5.4 g, 79.2 mmol) in DMF (100 mL) was stirred at rt for 30 min. Aq. sat. NH₄Cl (150 mL) was added and the mixture was extracted with heptane (3x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/EtOAc 9:1 → 1:1) yielded the title compound (7.6 g, 51% over 2 steps). LC-MS: t_R = 1.11 min; ES+: 363.10.

[l-(5-Bromo-thiazol-2-yl)-azetidin-3-yl]-methanol

A mixture of 2,5-dibromothiazole (7.2 g, 30 mmol), azetidin-3-yl-methanol (3.1 g, 36 mmol) and DIPEA (7 mL, 39 mmol) in dioxane (50 mL) was stirred at 8O⁰C for 15 h. The solvents were removed under reduced pressure. Aq. sat. NaHCO₃ (50 mL) was added, and the mixture was extracted with CH₂Cl₂ (2x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by crystallisation from CH₂Cl₂/heptane yielded the title compound (2.7 g, 37%). LC-MS: t_R = 0.59 min; ES+: 249.08.

5-Bromo-2-[3-(?ert-butyl-dimethyl-silanyloxymethyl)-azetidin-l-yl]-thiazole A mixture of [l-(5-bromo-thiazol-2-yl)-azetidin-3-yl] -methanol (2.7 g, 10.9 mmol), TBDMS-Cl (2.0 g, 13.1 mmol) and imidazole (1.8 g, 27.2 mmol) in DMF (30 mL) was stirred at rt overnight. Aq. sat. NH₄Cl was added (30 mL), and the mixture was extracted with heptane (3x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/EtOAc 4:1) yielded the title compound (2.3 g, 58%). LC-MS: t_R = 1.10 min; ES+: 363.13.

2,6-Dichlor o-4-hydr oxymethylphen ol

BH₃ (IM in THF, 250 mL, 250 mmol) was added dropwise to a cooled sol. of 3,5- dichloro-4-hydroxybenzoic acid (20 g, 96.6 mmol) in THF (200 mL) at 0 °C. The resulting mixture was stirred at 0 ⁰C for 15 min, and then at rt for 13 h. The milky mixture was cooled to 0 ⁰C, and MeOH (150 mL), then water (100 mL), were added dropwise. The mixture was further stirred at 0 ⁰C for 15 min, and then at rt for 5 h. The mixture was then partially concentrated under reduced pressure. EtOAc (200 mL) and water (50 mL) were added to the residue, and the phases were shaken and separated. The aq. phase was further extracted with EtOAc. The combined org. extracts were washed with brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. Purification by FC (CH₂C1₂/CH₃OH, 100:1) yielded the title compound as a slightly beige solid (17.86 g, 96%). LC-MS: t_R = 0.69 min.

3,5-Dichlor o-4-hydr oxybenzaldehyde

2,6-Dichloro-4-hydroxymethylphenol (3.56 g, 18.4 mmol) was dissolved in dioxane, and DDQ (4.19 g, 18.4 mmol) was added. The reaction mixture was stirred at rt overnight. The solvents were removed under reduced pressure. The residue was diluted with CH₂Cl₂, and the mixture was filtered. The filtrate was dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Crystallization from EtOAc yielded the title compound (0.77g, 22%). LC-MS: t_R = 0.82 min.

(rac.)-2,6-Dichloro-4-(l-hydroxyethyl)phenol A sol. of 3,5-dichloro-4-hydroxybenzaldehyde (1.635 g, 8.56 mmol) in Et₂O (30 mL) was cooled to -78 ⁰C. MeMgBr (3M in Et₂O, 7.15 mL, 21.5 mmol) was added dropwise to the cooled reaction mixture over 18 min. Et₂O (20 mL) was added again during the addition of MeMgBr. Stirring was continued at -78 ⁰C for 1 h, and then the reaction mixture was allowed to warm up to rt over 1 h. The mixture was cooled to 0 ⁰C, and aq. sat. NH₄Cl (10 mL) was added dropwise. The mixture was allowed to warm up to rt, and additional aq. sat. NH₄Cl (35 mL) and water (35 mL) were added. The phases were then separated and the aq. phase was extracted with Et₂O. The combined org. extracts were then washed with brine (50 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. Purification by FC (EtOAc/heptane, 1:1) yielded the title compound (1.683 g, 95%). LC-MS: t_R = 0.74 min.

(røc.)-2-(rm-Butyldimethylsilanyloxy)-5-[l-(rm-butyldimethylsilanyloxy)- ethyl]-l,3-dichlorobenzene To a sol. of (rac.)-2,6-dichloro-4-(l-hydroxyethyl)phenol (100 mg, 0.483 mmol) in DMF (5.5 mL) were added TBDMS-Cl (175 mg, 1.16 mmol), and imidazole (145 mg, 2.42 mmol). The sol. was stirred at rt overnight. The sol. was cooled to 0 ⁰C, and aq. sat. NH₄Cl was added. The mixture was extracted with a heptane/Et₂O (1/1, 4x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification by FC (CH₂Cl₂) yielded the title compound (188 mg, 90%).

(rac.)-4-[l-(?ert-Butyldimethylsilanyloxy)ethyl]-2,6-dichlorophenol A sol. of (røc.)-2-(rm-butyldimethylsilanyloxy)-5-[l-(rm-butyldimethyl- silanyloxy)ethyl]-l,3-dichlorobenzene (188 mg, 0.432 mmol) and Cs₂CO₃ (76.2 mg, 0.126 mmol) in DMF (0.50 mL) and water (50 μL) was stirred at rt overnight. Et₂O (75 mL) was added. The sol. was washed with brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification by FC (CH₂Cl₂) yielded the title compound (122 mg, 88%). LC-MS: t_R = 1.15 min.

(3,5-Dichloro-4-hydroxyphenyl)acetic acid A mixture of 4-hydroxyphenylacetic acid (5.00 g, 32.9 mmol) in SO₂Cl₂ (11.1 mL, 82.2 mmol) was heated at 50 ⁰C for 1 h. The mixture turned solid, and more SO₂Cl₂ (2.00 mL) was added. The mixture was stirred at 50 ⁰C for 1 h again. The reaction mixture was poured onto ice water, and the title compound was filtered off as pure compound (3.14 g, 43%).

2,6-Dichloro-4-(2-hydroxyethyl)phenol

To an ice-cooled sol. of (3,5-dichloro-4-hydroxyphenyl)acetic acid (3.14 g, 14.2 mmol) in THF (140 mL) was added dropwise BH₃ (IM in THF, 43.0 mL, 43.0 mmol). The sol. was stirred overnight while warming up to rt. The reaction mixture was cooled to 0 ⁰C, and MeOH (10 mL) was carefully added, followed by water (100 mL). The solvents were partially removed under reduced pressure, and the residue was extracted with EtOAc (3x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH₂Cl₂MeOH 50/1) yielded the title compound (2.94 g, quantitative yield).

2-(?ert-Butyldimethylsilanyloxy)-5-[2-(tert-butyldimethylsilanyloxy)ethyl]-l,3- dichlorobenzene

To a sol. of 2,6-dichloro-4-(2-hydroxyethyl)phenol (2.40 g, 14.2 mmol) in DMF (134 mL) were added imidazole (4.27 g, 71.0 mmol) and TBDMS-Cl (5.14 g, 34.1 mmol). The sol. was stirred at rt overnight. The sol. was cooled to 0 ⁰C, and aq. sat. NH₄Cl was added. The mixture was extracted with Et₂O (3x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification by FC (CH₂Cl₂) yielded the title compound (4.94 g, 80%).

4-[2-(?ert-Butyldimethylsilanyloxy)ethyl]-2,6-dichlorophenol A sol. of 2-(rm-butyldimethylsilanyloxy)-5-[2-(teτt-butyldimethylsilanyloxy)- ethyl]-l,3-dichlorobenzene (4.94 g, 11.3 mmol) and Cs₂CO₃ (2.00 g, 5.67 mmol) in DMF (15 mL) and water (1.5 mL) was stirred at rt for 2 h. Et₂O was added, and the mixture was washed with brine (3x), dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH₂Cl₂) yielded the title compound (3.5 g, 96%).

2,6-Dichloro-3, 4-dimethylphenol

To a sol. of 3,4-dimethylphenol (3.00 g, 24.6 mmol) in CH₂Cl₂ (5 mL) was added SO₂Cl₂ (4.98 mL, 61.3 mmol). The resulting sol. was heated to 50 ⁰C for 4 h. The mixture was poured onto ice water. CH₂Cl₂ (200 mL) was added, the layers were separated, and the org. layer was washed with water, then with aq. sat. NaHCO₃. The org. layer was dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification by FC (EtO Ac/heptane 1:4) yielded the title compound (1.174 g, 25%).

2-Chloro-3,6-difluorobenzaldehyde oxime

A mixture of 2-chloro-3,6-difluorobenzaldehyde (1.13 mmol, 200 mg) and

NaHCO₃ (3.4 mmol, 286 mg) in water (1.9 mL) was treated at rt with H₂NOH-HCl (2.3 mmol, 160 mg) and Bu₄NCl (0.06 mmol, 16 mg). Acetonitrile (1.2 mL) was then added and the mixture was stirred at rt for 90 min. AcOH (0.2 mL) was then added and the mixture was stirred for 30 min at rt. The mixture was extracted with EtOAc, washed with brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 3:7) yielded the title compound (170 mg, 78%). LC-MS: t_R = 0.84 min; ES+: 233.81.

5-(?ert-Butyldimethylsilanyloxymethyl)-3-(2-chloro-3,6-difluorophenyl)- isoxazole A sol. of 2-chloro-3,6-difluoro-benzaldehyde oxime (0.834 mmol, 170 mg) in DMF (0.53 mL) was added dropwise at rt to a sol. of N-chlorosuccinimide (0.83 mmol, 111 mg) and pyridine (2 drops) in DMF (1.8 mL). After 1 h, tert-butyl- dimethyl-prop-2-ynyl-oxysilane (0.33 mmol, 0.07 mL) was added and the mixture was heated to 85 ⁰C. Et₃N (0.83 mmol, 0.12 mL, 2.5 eq.) in DMF (0.7 mL) was then added over 35 min. At the end of the addition, the mixture was stirred for 1 h at 85 ⁰C. Water was added at rt and the mixture was extracted with EtOAc. The org. extracts were washed with aq. 10% KHSO₄, water, and brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtO Ac/heptane 5:95) yielded the title compound (94 mg, 79%). LC-MS: t_R = 1.16 min; ES+: 360.05.

[3-(2-Chloro-3, 6-difluorophenyl)isoxazol-5-yl]methanol

A sol. of 5-(rm-butyldimethylsilanyloxymethyl)-3-(2-chloro-3,6-difluorophenyl)- isoxazole (0.25 mmol, 94 mg) in THF (6.8 mL) at 0 ⁰C was treated with TBAF (0.50 mmol, 0.50 mL of a 1 M solution in THF). After 1 h at rt, aq. sat. NH₄Cl was added. The mixture was extracted with EtOAc, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 3:7) yielded the title compound (60 mg, 98%). LC-MS: t_R = 0.84 min; ES+: 287.14.

Methanesulfonic acid 3-(2-chloro-3, 6-difluoro-phenyl)-isoxazol-5-ylmethyl ester

To a sol. of [3-(2-chloro-3,6-difluorophenyl)isoxazol-5-yl]methanol (550 mg, 2.24 mmol) in CH₂Cl₂ (1.50 mL) at 0 °C was added DIPEA (0.575 mL, 3.36 mmol) and then dropwise methanesulfonyl chloride (0.261 mL, 3.36 mmol). This mixture was stirred at 0 ⁰C for 30 min and at rt for 2 h. The mixture was poured into ice and water. The mixture was stirred for 10 min, and was acidified with aq. IM HCl. The mixture was extracted with CH₂Cl₂, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. This crude product (720 mg) was used directly without further purification.

9-Methyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (rac.)-(lR*, JS^^-Methyl^-oxo-S^-diaza-bicycloPJ.^nonane^ό- dicarboxylic acid 3-tert-buty\ ester 6-ethyl ester (WO 03/093267, 105 g, 289 mmol) was dissolved in aq. 6M HCl (513 mL) to obtain a brown sol. This reaction mixture was stirred under reflux for 5 days. The reaction mixture was then cooled to -18 ⁰C, and was basified with NaOH until pH = 10. EtOH (172 mL) and BoC₂O (63.1 g, 289 mmol) were then added, and the reaction mixture was stirred for 12 h. The pH was controlled (pH = 8), and the reaction was basified again with NaOH to pH = 11-12. BoC₂O (31.6 g, 145 mmol) was added, and the reaction mixture was stirred for 24 h. The mixture was concentrated and dried under high vacuum overnight. The residue was triturated with EtOH, and stirred for 5 min. The suspension was filtrated, and the filtrate was concentrated under reduced pressure. Purification by FC (CH₂Cl₂ → CH₂Cl₂MeOH 95:5 → 90:10) yielded the title compound (50.1 g, 68%).

3-Thiazol-2-yl-prop-2-yn-l-ol

Propargylic alcohol (0.72 mL, 12.1 mmol) and 2-bromothiazole (2.00 g, 12.2 mmol) were added to a suspension of cupric acetate monohydrate (122 mg, 0.61 mmol), PPh₃ (0.32 g, 1.219 mmol) and bis(benzonitrile) dichloropalladium (58 mg, 0.512 mmol) in diisopropylamine (6 mL). The reaction mixture was heated to 45°C overnight, then partitioned between aq. sat. NH₄Cl and Et₂O. The aq. layer was extracted again with Et₂O, the combined org. extracts were dried over MgSO₄, filtered, and solvents were removed in vacuo. Purification of the crude by FC (EtOAc) yielded the title compound as an orange oil (1.06, 62%). LC-MS: t_R = 0.55 min, ES+: 140.15.

3-Thiazol-2-yl-pr op an- 1 -ol

Pd on charcoal (0.5 g) was added to a sol. of 3-thiazol-2-yl-prop-2-yn-l-ol (2.31 g, 16.6 mmol) in EtOH (85 mL), and the mixture was subjected to an atmosphere of H₂ overnight. The reaction mixture was filtered through Celite, thoroughly washed with EtOH, and the solvents were removed in vacuo to yield the title compound (2.16 g, 91%), which was not further purified. LC-MS: tR = 0.30 min, ES+: 144.14. 2-[3-(teτt-Butyldimethylsilanyloxy)propyl]thiazole

TBDMS-Cl (10.74 g, 71.2 mmol) and imidazole (5.38 g, 76.8 mmol) were added to a solution of 3-thiazol-2-yl-propan-l-ol (10.0 g 69.8 mmol) in THF (350 mL). Stirring was continued at rt overnight. The reaction mixture was partitioned between aq. sat. NH₄Cl and Et₂O. The aq. layer was extracted again with Et₂O, the combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed in vacuo. Purification of the crude by FC (CH₂Cl₂/Me0H 95:5) yielded the title compound as an orange oil (13.00 g, 72%). LC-MS: tR = 1.05 min, ES+: 258.24.

2-(Thiazol-2-yloxy)ethanol

/?αra-Toluenesulfonic acid (11.2 g, 58.0 mmol) was added to a sol. of 2-[2-(tert- butyldimethylsilanyloxy)ethoxy]thiazole (15.0 g, 58.0 mmol) in MeOH (300 mL) at 0 °C. The mixture was stirred for 2 h at 0 °C. Aq. sat. NaHCO₃ was added until a pH of 6-7 was reached. The solvents were partially removed under reduced pressure, and the residue was diluted with EtOAc. The mixture was washed with aq. sat. NaHCO₃ (Ix), and the aq. phase was extracted back with EtOAc (Ix). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:1) yielded the title compound (5.43 g, 65%). LC-MS: t_R = 0.48 min, ES+: 146.09.

2-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]thiazole A mixture of 2-(thiazol-2-yloxy)ethanol (6.39 g, 44.0 mmol), 2,6-dichloro-/?- cresol (15.6 g, 88.0 mmol), azodicarboxylic-dipiperidide (22.2 g, 88.0 mmol) and PBu₃ (85%, 38.3 mL, 132 mmol) in toluene (325 mL) was heated to reflux for 30 min. The mixture was allowed to cool to rt, filtered, and the precipitate was washed thoroughly with toluene. The filtrate was evaporated under reduced pressure. The residue was diluted with EtOAc, and washed with aq. IM NaOH (4x). The org. phase was dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:19 → 1:9 → 1:4) yielded the title compound as a colourless solid (9.24 g, 69%). LC-MS: t_R = 1.06 min, ES+: 304.05.

7-Oxo-3, 9-diazabicyclo[3.3. l]nonane-3,9-dicarboxylic acid άi-tert-buty\ ester (A)

A mixture of 9-methyl-7-oxo-3,9-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (50.1 g, 197 mmol), 1-chloroethyl chloroformate (215 mL, 1.97 mol), and NaHCO₃ (165.5 g, 1.97 mol) in CH₂ClCH₂Cl (1.90 L) was heated to reflux for 16 h. The mixture was allowed to cool to it, and was filtered. The filtrate was evaporated under reduced pressure, and the residue was dried under high vacuum. The resulting foam was dissolved in MeOH (1.47 L), and the sol. was heated to reflux for 1 h. The sol. was allowed to cool to rt, and the solvents were removed under reduced pressure. The residue was dried under high vacuum. The residue was dissolved in CH₂Cl₂ (985 mL), and cooled to 0 °C. BoC₂O (129 g, 591 mmol) and DIPEA (168 mL, 985 mmol) were added, and the mixture was stirred overnight while warming up to rt. The mixture was diluted with more CH₂Cl₂, and was washed with aq. IM HCl, and brine. The org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtO Ac/heptane 3:7) yielded the title compound (18.4 g, 27%).

(rac.)-(lR*, JS^^-Oxo-S^-diazabicycloPJ.lJnonane^ό^-tricarboxylic acid

3,9-di-teτt-butyl ester 6-methyl ester (B)

Compound A (15.91 g, 46.7 mmol) was dissolved in THF (100 mL). NaH (55% in oil, 4.71 g, 98 mmol) was added portionwise, followed by dimethylcarbonate

(8.86 mL, 105 mmol). The reaction mixture was heated to reflux for 1 h. The mixture was cooled to 0 °C with an ice bath, and treated cautiously with ice-water

(50 mL). The org. layer was diluted with EtOAc (200 mL), and acidified with aq.

IM HCl (100 mL). The org. layer was separated, and washed with brine. The org. layer was dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtO Ac/heptane 1:3 → 1:2 → 1:1 — > 2:1) yielded the title compound (R_f=0.7, EtO Ac/heptane 1:1) as a yellow oil (11.0 g, 58%).

(rac.)-(lR*, JS^^-Trifluoromethanesulfonyloxy-S^-diazabicycloPJ.^non- 6-ene-3,6,9-tricarboxylic acid 3,9-di-teτt-butyl ester 6-methyl ester (D)

To a sol. of compound B (10.92 g, 27.4 mmol) in dry THF (150 mL) was added portionwise NaH (55% in oil, 1.49 g, 34 mmol) at 0 ⁰C. The mixture was stirred at 0 ⁰C for 75 min, and Tf₂NPh (11.55 g, 32.3 mmol) was added. The reaction mixture was stirred at rt for 3 days. The mixture was poured onto a mixture of ice and water, and was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3x). The combined org. extracts were washed with water (Ix) and with brine (Ix). The org. layer was dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtO Ac/heptane 6:1 → 5:1 → 4:1 → 3:1) yielded the title compound (10.82 g, 74.5%).

(rac.)-(lR*, 55'*)-{7-[2-(^rr-Butyl-dimethyl-silanyloxymethyl)-thiazol-5-yl] }- 3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-methyl ester (Hl) BuLi (11.31 mmol, 7.06 mL of a 1.6M sol. in hexane) was added dropwise to a solution of 2-(rm-butyl-dimethyl-silanyloxymethyl)-thiazole (2.33 g, 10.18 mmol) in THF (56 mL) at -78 ⁰C. After 1 h, ZnCl₂ (12.4 mmol, 12.4 mL of a 1.0 M sol. in THF) was added dropwise at -78 ⁰C. The cooling bath was removed, and the mixture was stirred for 1.5 h. Compound D (3.0 g, 5.66 mmol), followed by Pd(PPh₃ )₄ (197 mg, 0.17 mmol), were added, and the reaction was directly heated to 50 ⁰C. After 1.5 h it was allowed to cool down to rt, and diluted with EtOAc (60 mL). The mixture was poured in sat. aq. NH₄Cl. The aq. layer was extracted twice with EtOAc, and the combined org. phases were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/Heptane 40:60) yielded the title compound (2.33 g, 67%). LC-MS: t_R = 1.19 min; ES+: 610.36. 1: 1 Mixture of (IR, 5S)-7-{2-[(3S)-3-(tert-butyl-dimethyl-silanyloxy)- pyrrolidin-l-yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9- tricarboxylic acid 3,9-di-teτt-butyl ester 6-methyl ester and (IS, 5R)-7-{2- [(J_lS')-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-l-yl]-thiazol-5-yl}-3,9- diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-buty\ ester 6- methyl ester (E2)

BuLi (1.6 M in hexane, 6.2 mL, 9.9 mmol) was added to a sol. of (5')-5-bromo-2- [3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-l-yl]-thiazole (3.39 g, 9.3 mmol) in THF (80 mL) at -78 °C. The sol. was stirred for 30 min at -78 °C, and ZnCl₂ (1.0 M in THF, 12.4 mL, 12.4 mmol) was added. The mixture was allowed to warm to rt, and compound D (3.30 g, 6.2 mmol) in THF (20 mL), and Pd(PPh₃)₄ (0.185 g, 0.16 mmol) were added. The mixture was stirred at rt for 45 min, and aq. sat. NH₄Cl was added. The mixture was extracted with Et₂O (2x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/EtOAc 2:1 → 1:1→ 1:2) yielded the title compounds mixture (3.4 g, 83%). LC-MS: t_R = 1.06 min; ES+: 665.51.

(rac.)-(lR*, 5,S'*)-7-{2-[3-(rerr-Butyl-dimethyl-silanyloxymethyl)-azetidin-l- yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9- άi-tert-buty\ ester 6-methyl ester (E3)

BuLi (1.6 M in hexane, 4.3 mL, 6.9 mmol) was added to a sol. of 5-bromo-2-[3-

(?err-butyl-dimethyl-silanyloxymethyl)-azetidin-l-yl]-thiazole (2.3 g, 6.3 mmol) in THF (80 mL) at -78 °C. The sol. was stirred for 30 min at -78 °C, and ZnCl₂ (1.0 M in THF, 8.7 mL, 8.7 mmol) was added. The mixture was allowed to warm to rt, and compound D (2.3 g, 4.3 mmol) in THF (20 mL) and Pd(PPh₃)₄ (0.12 g,

0.11 mmol) were added. The mixture was stirred at rt for 20 min, and aq. sat.

NH₄Cl was added. The mixture was extracted with Et₂O (2x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/EtOAc 2:1) yielded the title compound (2.5 g, 87%). LC-MS: t_R = 1.07 min; ES+: 665.19. (rac.)-(lR*, JS^^-^-Amino-thiazol-S-yrj-S^-diaza-bicycloPJ.^non-ό-ene- 3,6,9-tricarboxylic acid 3,9-di-teτt-butyl ester 6-methyl ester (E4) To a sol. of 2-aminothiazole (480 mg, 4.79 mmol) in THF (35 mL) at -78 °C was added BuLi (1.6M in hexane, 6.00 mL, 9.58 mmol). The slightly cloudy, light brown sol. was stirred for 1 h at -78 ⁰C, followed by the addition of (CH₃)₃SiCl (1.21 mL, 9.58 mmol). The reaction mixture was allowed to warm up to -20 ⁰C, and was cooled again to -78 ⁰C. BuLi (1.6M in hexane, 3 mL, 4.79 mmol) was added to the reaction mixture at -78 ⁰C, and the mixture was stirred for 15 min at -78⁰C. ZnCl₂ (IM in THF, 7.2 mL, 7.2 mmol) was added at -78 ⁰C, and the mixture was allowed to warm up to rt. Compound D (1.27 g, 2.39 mmol) and Pd(PPh₃ )₄ (70 mg, 0.060 mmol) were added, and the mixture was heated to reflux for 30 min. The mixture was allowed to cool to rt, and poured onto aq. sat. NH₄Cl. The mixture was extracted with EtOAc (50 mL), and the org. phase was washed with aq. IM NaOH (50 mL). The org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH₂Cl₂MeOH 49:1 → 45:5) yielded the title compound (1.40 g, quantitative yield) mixed with some 2-aminothiazole. LC-MS: tR = 0.82 min; ES+: 481.28.

(rac.)-(lR*, 55'*)-7-(2-Benzyloxycarbonylamino-thiazol-5-yl)-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid-3,9-di-teτt-butyl ester 6- methyl ester (E5)

A sol. of compound E4 (1.41 g, 2.93 mmol) in CH₂Cl₂ (20 mL) was cooled to 0 ⁰C. At 0 °C were successively added DMAP (72 mg, 0.59 mmol), benzyl chloroformate (0.48 mL, 3.23 mmol) and DIPEA (0.5 mL, 2.93 mmol). This mixture was stirred for 10 min at 0 ⁰C, then at rt for 4 h. More CH₂Cl₂ was added to the mixture, and the mixture was washed with an aq. sat. NaHCO₃ (50 mL). The org. phase was dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH₂Cl₂/Me0H 100:1 → 99:1 → 98:2 → 96:4 → 94:6) yielded the title compound (1.20 g, 66%) as a light brown foam. LC-MS: t_R = 1.08 min; ES+: 615.45. (rac.)-(lR*, JS^^-^-IBenzyloxycarbonyl-P-^-chloro^ό-difluoro-phenyl)- isoxazol-S-ylmethy^-aminoj-thiazol-S-yl^^-diaza-bicycloPJ.^non-ό-ene- 3,6,9-tricarboxylic acid 3,9-di-teτt-butyl ester 6-methyl ester (E6) To a sol. of compound E5 (250 mg, 0.407 mmol) in toluene (10 mL) were added [3-(2-chloro-3,6-difluorophenyl)isoxazol-5-yl]methanol (99.9 mg, 0.407 mmol), azodicarboxylic dipepiridide (205 mg, 0.814 mmol) and PBu₃ (85%, 0.317 mL, 1.22 mmol). The mixture was heated to reflux for 1 h, and was allowed to cool to rt. The mixture was diluted with EtOAc (50 mL), and was washed with aq. IM NaOH (2 x 20 mL). The org. layer was dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:19 → 1:1) yielded the title compound (273 mg, 79%) as a white foam. LC-MS: t_R = 1.19 min; ES+: 842.45.

(rac.)-(lR*, 55'*)-7-[2-(Benzyloxycarbonyl-methyl-amino)-thiazol-5-yl]-3,9- diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-teτt-butyl ester 6- methyl ester (E7)

To a sol. of compound E5 (1.20 g, 1.95 mmol) in DMF (18 mL) at 0 ⁰C were successively added MeI (0.244 mL, 3.91 mmol) and K₂CO₃ (527 mg, 3.81 mmol).

This mixture was stirred for 10 min at 0 ⁰C, then at rt for 5 h. EtOAc was added, and the mixture was washed with water. The org. layer was separated and the aq. layer was extracted with EtOAc. The combined org. extracts were dried over

MgSO₄, filtered, and the solvents were removed under reduced pressure.

Purification of the crude by FC (EtOAc/heptane 1:5 → 1:4 → 1:3 → 1:2 → 1:1) yielded the title compound (813 mg, 66%) as a light yellow foam. LC-MS: t_R = 1.12 min; ES+: 629.33.

1: 1 Mixture of (IR, 55>7-{2-[(3i?)-3-(tert-butyl-dimethyl-silanyloxy)- pyrrolidin-l-yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9- tricarboxylic acid 3,9-di-tert-butyl ester 6-methyl ester and (IS, 5R)-I -{2- [(Ji?)-3-(?err-butyl-dimethyl-silanyloxy)-pyrrolidin-l-yl]-thiazol-5-yl}-3,9- diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6- methyl ester (E8) BuLi (1.6 M in hexane, 15.4 mL, 24.4 mmol) was added to a sol. of (i?)-5-bromo- 2-[3-(tm-butyl-dimethyl-silanyloxy)-pyrrolidin-l-yl]-thiazole (7.6 g, 21.0 mmol) in THF (200 mL) at -78 °C. The sol. was stirred for 30 min at -78 °C, and ZnCl₂ (1.0 M in THF, 30.9 mL, 30.5 mmol) was added. The mixture was allowed to warm to rt, and compound D (8.1 g, 15.3 mmol) in THF (50 mL) and Pd(PPh₃)₄ (0.443 g, 0.37 mmol) were added. The mixture was stirred at rt for 60 min, and aq. sat. NH₄Cl was added. The mixture was extracted with CH₂Cl₂ (2x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/EtOAc 4:1) yielded the title compound (4.O g, 40%). LC-MS: t_R = 1.05 min; ES+: 665.41.

(rac.)-(lR*, 55'*)-{7-[2-(^rr-Butyl-dimethyl-silanyloxymethyl)-thiazol-5-yl] }- 3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester (Fl)

A solution of compound Hl (2.33 g, 3.82 mmol) in Et₂O (38 mL) was treated with Me₃SiOK (1.23 g, 9.55 mmol) in four portions every 15 min. After 1 h at rt, NaHCO₃ was added, and the reaction mixture was stirred for 5 min, diluted with Et₂O, and poured in sat. aq. NH₄Cl. The aq. phase was extracted with EtOAc (2x). The combined org. phases were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to afford the title compound, which was used for the next step without further purification. LC-MS: t_R = 1.10 min; ES+: 596.35.

1: 1 Mixture of (IR, 5S)-7-{2-[(3S)-3-(tert-butyl-dimethyl-silanyloxy)- pyrrolidin-l-yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9- tricarboxylic acid 3,9-di-tert-butyl ester and (IS, 5R)-7-{2-[(3S)-3-(tert-butyl- dimethyl-silanyloxy)-pyrrolidin-l-yl]-thiazol-5-yl}-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester (F2) A mixture of compounds E2 (1.0 g, 1.5 mmol) and Me₃SiOK (0.67 g, 5.2 mmol) in Et₂O (30 mL) was stirred at rt for 6 h. NaHCO₃ (approx. 0.2 g) was added and the mixture was stirred for 5 min. Aq. sat. NH₄Cl (sat., 50 mL) was added and the mixture was extracted with Et₂O (2x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. The crude title compounds mixture (3.2 g) was used in the next reaction without purification.

(rac.)-(lR*, JS'^-T-il-P-Ctert-Butyl-dimethyl-silanyloxymethy^-azetidin-l- yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9- άi-tert-buty\ ester (F3) A mixture of compound E3 (1.5 g, 2.26 mmol) and Me₃SiOK (1.2 g, 9.3 mmol) in Et₂O (40 mL) was stirred at rt for 6 h. NaHCO₃ (approx. 0.2 g) was added, and the mixture was stirred for 5 min. Aq. sat. NH₄Cl (50 mL) was added, and the mixture was extracted with CH₂Cl₂ (2x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. The crude title compound (1.58 g) was used in the next reaction without purification.

(rac.)-(lR*, 5S*)-7-(2-{[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5- ylmethyl]-amino}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9- tricarboxylic acid 3,9-di-teτt-butyl ester (F4) To a sol. of compound E6 (470 mg, 0.558 mmol) in EtOH (10 mL) was added aq. IM NaOH (5 mL). The mixture was heated to 65 ⁰C for 6 h, and was allowed to cool to rt. The solvents were partially removed under reduced pressure. The residue was acidified with aq. 3M HCl, and was extracted with EtOAc (100 mL). The org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. The crude title product (243 mg, 62%) was used further without purification. LC-MS: t_R = 0.90 min; ES+: 694.42.

(rac.)-(lR*, 55'*)-7-(2-Methylamino-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non- 6-ene-3,6,9-tricarboxylic acid 3,9-di-teτt-butyl ester (F5) To a sol. of compound E7 (813 mg, 1.29 mmol) in EtOH (10 mL) was added aq. IM NaOH (5 mL). The mixture was heated to 65 ⁰C, and stirred at this temperature for 3 h. The mixture was partially concentrated under reduced pressure, and the aq. phase was acidified with aq. 3M HCl. The mixture was extracted with EtOAc (50 mL). The org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH₂Cl₂MeOH 19:1 → 15:1 → 9:1) yielded the title compound (350 mg, 56%) as a light yellow foam. LC-MS: t_R = 0.74 min; ES+: 481.29.

1: 1 Mixture of (IR, 55>7-{2-[(3R)-3-(rerr-butyl-dimethyl-silanyloxy)- pyrrolidin-l-yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9- tricarboxylic acid 3,9-di-tert-butyl ester and (IS, 5R)-7-{2-[(3R)-3-(tert-butyl- dimethyl-silanyloxy)-pyrrolidin-l-yl]-thiazol-5-yl}-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-teτt-butyl ester (F6) A mixture of compound E8 (4.0 g, 6.0 mmol) and Me₃SiOK (3.86 g, 30.1 mmol; added portionwise during 2 h) in Et₂O (100 mL) was stirred at rt for 6 h. NaHCO₃ (about 0.2 g) was added, and the mixture was stirred for 5 min. Aq. NH₄Cl (sat., 50 mL) was added and the mixture was extracted with Et₂O (2x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. The crude title compound (4.15 g) was used in the next reaction without purification. LC-MS: t_R = 0.97 min; ES+: 651.36.

(rac.)-(lR*, 55*)-{7-[2-(rerr-Butyl-dimethyl-silanyloxymethyl)-thiazol-5-yl]-6- [cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl] }-3,9-diaza-bicyclo[3.3.1]non- 6-ene-3,9-dicarboxylic acid άi-tert-bλxty\ ester (Kl) A sol. of compound J l (2.03 g, 3.41 mmol) in CH₂Cl₂ (34.0 mL) was treated at rt with DMAP (104 mg, 0.85 mmol), HOBt (552 mg, 4.09 mmol), EDC-HCl (1.63 g, 8.52 mmol) and DIPEA (2.33 mL, 13.63 mmol), and the mixture was stirred for

30 min at rt. Cyclopropyl-(2,3-dichloro-benzyl)-amine (prepared from 2,3- dichlorobenzaldehyde and cyclopropylamine by reductive amination, 2.21 g,

10.22 mmol) was then added and the reaction was stirred for 5 days. The reaction was diluted with CH₂Cl₂ (70 mL), washed twice with aq. IM HCl, brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure.

Purification of the residue by FC (EtOAc/heptane 30:70) yielded the title compound (1.20 g, 44% over two steps). LC-MS: t_R = 1.29 min; ES+: 793.53. (rac.)-(lR*, 5S*)-{6-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-7-(2- hydroxymethyl-thiazol-5-yl)}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9- dicarboxylic acid di-tert-buty\ ester (K2) A sol. of compound Kl (1.2O g, 1.51 mmol) in dry THF (30 mL) at 0 ⁰C was treated dropwise with TBAF (3.02 mmol, 3.02 mL of a 1.0 M sol. in THF). The reaction was then allowed to warm up to rt, and was further stirred for 1.5 h. The reaction mixture was poured in EtOAc (100 mL), and washed with sat. aq. NH₄Cl. The aq. layer was extracted twice with EtOAc. The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to afford the title compound which was used for the next step without further purification. LC-MS: t_R = 1.08 min; ES+: 679.41.

(rac.)-(lR*, 55'*)-{6-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-7-(2- formyl-thiazol-5-yl)}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-bvLtyl ester (K3)

A sol. of compound K2 (1.04 g, 1.53 mmol) in CH₂Cl₂ (15.3 mL) at rt was treated with Dess-Martin periodinate (836 mg, 1.91 mmol). After 2 h the reaction mixture was diluted with EtOAc (50 mL), washed twice with Na₂S₂O₃, brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 30:70) yielded the title compound (806 mg, 78% over two steps). LC-MS: tR = 1.16 min; ES+: 677.20.

(rac.)-(lR*, 55'*)-{6-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-7-(2- methylaminomethyl-thiazol-5-yl)}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9- dicarboxylic acid άi-tert-buty\ ester (K4)

A sol. of compound K3 (806 mg, 1.19 mmol) in MeOH (4 mL) was treated with N-methylamine (39.3 mmol, 3.3 mL of a 41% solution in water) and the mixture was heated to reflux for 4 h. The reaction was then cooled to rt, and NaBH₄ (328 mg, 8.7 mmol) was added. After 30 min, the reaction mixture was diluted with EtOAc (50 mL), washed with sat. aq. NaHCO₃, brine, dried over MgSO₄, filtered, and the solvents were removed under reduced pressure to afford the title compound which was used for the next step without further purification. LC-MS: t_R = 0.93 min; ES+: 692.20.

1: 1 Mixture of (IR, 55^lj-7-{2-[(J5^<)-3-(^rr-butyl-dimethyl-silanyloxy)- pyrrolidin-l-yl]-thiazol-5-yl}-6-[cyclopropyl-(3-methoxy-2-methyl-benzyl)- carbamoyl]-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert- butyl ester and (IS, 5/?j-7-{2-[(35')-3-(tert-butyl-dimethyl-silanyloxy)- pyrrolidin-l-yl]-thiazol-5-yl}-6-[cyclopropyl-(3-methoxy-2-methyl-benzyl)- carbamoyl]-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert- butyl ester (Gl)

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, 2.85 g, 14.9 mmol), DIPEA (3.4 mL, 19.8 mmol), DMAP (152 mg, 1.2 mmol), HOBt (0.80 g, 6.0 mmol), and EDC-HCl (2.38 g, 12.4 mmol) were added to a sol. of mixture of compounds F2 (3.2 g, 5.0 mmol) in CH₂Cl₂ (80 mL). The mixture was stirred at rt for 4 days. The sol. was diluted with CH₂Cl₂ (50 mL), the mixture was washed with aq. IM HCl (2x), and aq. sat. NaHCO₃ (Ix). The org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/EtOAc 2:1 — » 1:1— > 1:2) yielded the title mixture of compounds (3.88 g, 95%, contains some impurities). LC-MS: t_R = 1.13 min; ES+: 824.43.

1: 1 Mixture of (IR, 5,S'j-6-[cyclopropyl-(3-methoxy-2-methyl-benzyl)- car b amoyl] -7- [2-((3S)-3-hyάr oxy-pyr r olidin- 1 -yl)-thiazol-5-yl] -3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert-buty\ ester and (IS, 5R)-

6-[cyclopropyl-(3-methoxy-2-methyl-benzyl)-carbamoyl]-7-[2-((J5')-3- hydroxy-pyrrolidin-l-y^-thiazol-S-yri-S^-diaza-bicycloP.S.^non-ό-ene-S^- dicarboxylic acid di-tert-buty\ ester (G2) The mixture of compounds Gl (3.0 g, 3.6 mmol) and TBAF (IM in THF, 2.1 mL,

7.3 mmol) in THF (55 mL) was stirred at 0 ⁰C for 1 h. Aq. sat. NH₄Cl was added.

The mixture was extracted with Et₂O (2x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH₂Cl₂MeOH 20:1) yielded the title compounds mixture (1.4 g, 54%). LC-MS: t_R = 0.93 min; ES+: 710.32.

(rac.)-(lR*, 55'*)-7-{2-[3-(^rr-Butyl-dimethyl-silanyloxymethyl)-azetidin-l- yl]-thiazol-5-yl}-6-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert-buty\ ester (G3) Cyclopropyl-(2,3-dichlorobenzyl)amine (prepared from 2,3-dichlorobenzaldehyde and cyclopropylamine by reductive amination, 2.6 g, 11.9 mmol), DIPEA (4.0 mL, 15.8 mmol), DMAP (121 mg, 1.0 mmol), HOBt (0.64 g, 4.8 mmol), and

EDC-HCl (1.9 g, 9.9 mmol) were added to a sol. of compound F3 (2.6 g, 4.0 mmol) in CH₂Cl₂ (50 mL). The mixture was stirred at rt for 4 days. The sol. was diluted with CH₂Cl₂ (50 mL), the mixture was washed with aq. IM HCl (2x), and aq. sat. NaHCO₃ (Ix). The org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/EtOAc 2:1) yielded the title compound (1.1 g, 32%). LC-MS: t_R = 1.17 min; ES+: 848.28.

(rac.)-(lR*, 55'*)-6-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-7-[2-(3- hydroxymethyl-azetidin-l-y^-thiazol-S-yy-S^-diaza-bicycloPJ.^non-ό-ene-

3,9-dicarboxylic acid di-tert-buty\ ester (G4)

A mixture of compound G3 (1.01 g, 1.2 mmol) and TBAF (IM in THF, 1.2 mL,

2.4 mmol) in THF (20 mL) was stirred at 0 ⁰C for 1 h. Aq. sat. NH₄Cl was added.

The mixture was extracted with Et₂O (2x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure.

Purification of the residue by FC (CH₂Cl₂MeOH 20:1) yielded the title compound

(0.77 g, 88%). LC-MS: t_R = 0.97 min; ES+: 734.24.

(rac.)-(lR*, 55'*)-6-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-7-(2- methylamino-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert-buty\ ester (G5) To a sol. of compound F5 (285 mg, 0.594 mmol) in CH₂Cl₂ (7 mL) were succesively added DIPEA (0.406 mL, 2.373 mmol), DMAP (18.1 mg, 0.149 mmol), HOBt (120 mg, 0.89 mmol) and EDC-HCl (170 mg, 0.89 mmol). The mixture was stirred at rt for 45 min, and cyclopropyl-(2,3-dichlorobenzyl)amine (prepared from 2,3-dichlorobenzaldehyde and cyclopropylamine by reductive amination, 385 mg, 1.78 mmol) was added. The mixture was stirred at rt overnight. Cyclopropyl-(2,3-dichlorobenzyl)amine (128 mg, 0.59 mmol), HOBt

(40 mg, 0.29 mmol) and EDC-HCl (57 mg, 0.289 mmol) were added and the mixture was stirred for 3 days. More CH₂Cl₂ was added, and the mixture was washed with aq. IM HCl (3x) and with aq. sat. NaHCO₃ (Ix). The org. layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. Purification of the crude by FC (CH₂Cl₂ZMeOH; 49:1 → 48:2 → 47:3 → 46:4) yielded the title compound (200 mg, 49%) as a yellow solid. LC-MS: t_R = 0.97 min; ES+: 678.31.

Mixture of (IR, 55>7-{2-[(R)-3-(rm-butyl-dimethyl-silanyloxy)-pyrrolidin-l- yl]-thiazol-5-yl}-6-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-buty\ ester and (IS, 5R)- 7-{2-[(i?)-3-(?er?-butyl-dimethyl-silanyloxy)-pyrrolidin-l-yl]-thiazol-5-yl}-6- [cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3,9-diaza-bicyclo[3.3.1]non-6- ene-3,9-dicarboxylic acid di-tert-buty\ ester (G6)

Cyclopropyl-(2,3-dichlorobenzyl)amine (prepared by reductive amination of 2,3- dichlorobenzaldehyde and cyclopropylamine, 3.9 g, 17.9 mmol), DIPEA (5.2 mL,

24.2 mmol), DMAP (193 mg, 1.6 mmol), HOBt (1.0 g, 7.6 mmol), and EDC-HCl (3.0 g, 15.7 mmol) were added to a sol. of compound F6 (4.1 g, 6.3 mmol) in CH₂Cl₂ (120 mL). The mixture was stirred at rt for 4 days. The solution was diluted with CH₂Cl₂ (50 mL), the mixture was washed with aq. IM HCl (2x), and aq. sat. NaHCO₃ (Ix). The org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH₂Cl₂MeOH 30:1) yielded the title compound (3.2 g, 59%). LC-MS: t_R = 1.16 min; ES+: 848.39. Mixture of (IR, 55>6-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-7-[2- ((i?)-3-hydroxy-pyrrolidin-l-yl)-thiazol-5-yl]-3,9-diaza-bicyclo[3.3.1]non-6- ene-3,9-dicarboxylic acid di-tert-buty\ ester and (IS, 5i?)-6-[cyclopropyl-(2,3- dichlor o-benzyl)-car b amoyl]-7- [2-((R )-3-hydr oxy-pyr r olidin- 1 -yl)-thiazol-5- yl]-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-buty\ ester (G7)

A mixture of compound G6 (3.2 g, 3.7 mmol) and TBAF (IM in THF, 7.5 mL, 7.5 mmol) in THF (20 mL) was stirred at O⁰C for Ih. Aq. sat. NH₄Cl was added. The mixture was extracted with Et₂O (2x). The combined org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH₂Cl₂MeOH 30:1) yielded the title compound (1.2 g, 44%). LC-MS: t_R = 0.94 min; ES+: 734.27.

(rac.)-(lR*, 55'*)-{7-(2-{[(2-Chloro-6-fluoro-benzyl)-methyl-amino]-methyl}- thiazol-5-yl)-6-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl] }-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert-butyl ester (Ll) A sol. of compound K4 (70 mg, 0.10 mmol) in CH₃CN (1 mL) was treated with 2- chloro-6-fluoro-benzaldehyde (24 mg, 0.15 mmol) followed by NaBH(OAc)₃ (43 mg, 0.20 mmol) and the reaction was stirred overnight at rt. Formic acid (100 μL) was added, the residual solid was filtered, and the sol. was purified by HPLC to yield the title compound (26 mg, 31% over two steps). LC-MS: tR = 1.05 min; ES+: 836.51.

(rac.)-(lR*, 55'*)-{7-(2-{[(2-Chloro-3,6-difluoro-benzyl)-methyl-amino]- methyl }thiazol-5-yl)-6-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl] }-3, 9- diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid ai-tert-butyl ester (L2) A sol. of compound K4 (70 mg, 0.10 mmol) in CH₃CN (1 mL) was treated with 2- chloro-3,6-difluoro-benzaldehyde (26 mg, 0.15 mmol) followed by NaBH(OAc)₃ (43 mg, 0.20 mmol), and the reaction was stirred overnight at rt. Formic acid (100 μL) was added, the residual solid was filtered, and the sol. was purified by HPLC to yield the title compound (26 mg, 33% over two steps). LC-MS: tR = 1.09 min; ES+: 854.50. 1: 1 Mixture of (IR, 5,S')-6-[cyclopropyl-(3-methoxy-2-methyl-benzyl)- carbamoyl]-7-{2-[(Ji?)-3-(2,6-dichloro-3,4-dimethyl-phenoxy)-pyrrolidin-l- yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di- tert-butyl ester and (IS, 5i?)-6-[cyclopropyl-(3-methoxy-2-methyl-benzyl)- carbamoyl]-7-{2-[(Ji?)-3-(2,6-dichloro-3,4-dimethyl-phenoxy)-pyrrolidin-l- yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di- tert-butyl ester (L3)

Prepared according to general procedure A, from compound G2 and 2,6-dichloro- 3,4-dimethylphenol. LC-MS: t_R = 1.14 min; ES+: 882.50.

1: 1 Mixture of (IR, 5_lS')-6-[cyclopropyl-(3-methoxy-2-methyl-benzyl)- carbamoyl]-7-{2-[(Ji?)-3-(2,6-dichloro-phenoxy)-pyrrolidin-l-yl]-thiazol-5- yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-buty\ ester and (IS, 5i?)-6-[cyclopropyl-(3-methoxy-2-methyl-benzyl)-carbamoyl]-7-{2- [(Ji?)-3-(2,6-dichloro-phenoxy)-pyrrolidin-l-yl]-thiazol-5-yl}-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert-buty\ ester (L4) Prepared according to general procedure A, from compound G2 and 2,6-dichloro- phenol. LC-MS: t_R = 1.11 min; ES+: 882.54.

1: 1 Mixture of (IR, 5_lS')-6-[cyclopropyl-(3-methoxy-2-methyl-benzyl)- carbamoyl]-7-{2-[(Ji?)-3-(2,6-dichloro-4-methyl-phenoxy)-pyrrolidin-l-yl]- thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert- butyl ester and (IR, 5,S')-6-[cyclopropyl-(3-methoxy-2-methyl-benzyl)- carbamoyl]-7-{2-[(Ji?)-3-(2,6-dichloro-4-methyl-phenoxy)-pyrrolidin-l-yl]- thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert- butyl ester (L5)

Prepared according to general procedure A, from compound G2 and 2,6-dichloro- /?-cresol. LC-MS: t_R = 1.13 min; ES+: 868.56.

(rac.)-(lR*, 55'*)-7-(2-{[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5- ylmethyl]-amino}-thiazol-5-yl)-6-[cyclopropyl-(2,3-dichloro-benzyl)- carbamoyl]-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert- butyl ester (L6)

To a sol. of compound F4 (243 mg, 0.351 mmol) in dry CH₂Cl₂ (7 mL) were succesively added DIPEA (0.24 mL, 1.40 mmol), DMAP (10.7 mg, 0.088 mmol), HOBt (59.1 mg, 0.438 mmol) and EDC-HCl (101 mg, 0.526 mmol). The mixture was stirred at rt for 45 min, and cyclopropyl-(2,3-dichlorobenzyl)amine (prepared from 2,3-dichlorobenzaldehyde and cyclopropylamine by reductive amination, 227 mg, 1.05 mmol) was added. The mixture was stirred at rt for 3 days. Cyclopropyl-(2,3-dichlorobenzyl)amine (76 mg, 0.35 mmol), HOBt (24 mg, 0.178 mmol) and EDCΗC1 (34 mg, 0.172 mmol) were added, and the mixture was stirred for 48 h. More CH₂Cl₂ was added, and the org. layer was washed with aq. IM HCl (3x), with aq. sat. NaHCO₃ (Ix), dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:5 → 1:1) yielded the title compound (123 mg, 39%). LC-MS: t_R = 1.16 min; ES+: 893.13.

(rac.)-(lR*, 55'*)-7-(2-{[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5- ylmethyl]-methyl-amino}-thiazol-5-yl)-6-[cyclopropyl-(2,3-dichloro-benzyl)- carbamoyl]-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert- butyl ester (L7)

To a sol. of compound G5 (200 mg, 0.303 mmol) in dry THF (8 mL) was added portionwise at 0 ⁰C NaH (65% suspension in oil, 20 mg, about 0.5 mmol). The resulting mixture was stirred for 30 min at 0 ⁰C. To this mixture was added at 0 ⁰C methanesulfonic acid 3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethyl ester (195 mg, 0.605 mmol). The mixture was stirred at 0 ⁰C for 10 min, and was allowed to warm up to rt. The mixture was stirred at rt for 3 h, and was stirred at 40 ⁰C overnight. The mixture was allowed to cool to rt, and was diluted with EtOAc (25 mL). The mixture was washed with aq. IM HCl (10 mL) and with aq. sat. NaHCO₃ (10 mL). The org. extracts were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:5 → 1:4 → 1:3 → 1:2 → 1:1 → 2:1) yielded the title compound (55 mg, 20%) as a yellow oil. LC-MS: t_R = 1.21 min; ES+: 907.14. (rac.)-(lR*, 55*)-6-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-7-{2-[3- (2,6-dichloro-4-methyl-phenoxymethyl)-azetidin-l-yl]-thiazol-5-yl}-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-buty\ ester (L8) Prepared according to general procedure A, from compound G4 and 2,6-dichloro- /?-cresol. LC-MS: t_R = 1.18 min; ES+: 894.49.

(rac.)-(lR*, 55'*)-6-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-7-{2-[3- (2,6-dichloro-phenoxymethyl)-azetidin-l-yl]-thiazol-5-yl}-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-buty\ ester (L9)

Prepared according to general procedure A, from compound G4 and 2,6- dichlorophenol. LC-MS: t_R = 1.15 min; ES+: 880.46.

(rac.)-(lR*, 55'*)-7-{2-[3-(2-Chloro-6-fluoro-3-methyl-phenoxymethyl)- azetidin-l-yl]-thiazol-5-yl}-6-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-

3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-buty\ ester

(LlO)

Prepared according to general procedure A, from compound G4 and 2-chloro-6- fluoro-3-methylphenol. LC-MS: t_R = 1.16 min; ES+: 878.51.

(rac.)-(lR*, 55'*)-7-[2-(3-{4-[2-(^rr-Butyl-dimethyl-silanyloxy)-ethyl]-2,6- dichloro-phenoxymethyl}-azetidin-l-yl)-thiazol-5-yl]-6-[cyclopropyl-(2,3- dichloro-benzyl)-carbamoyl]-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9- dicarboxylic acid άi-tert-buty\ ester (LIl) Prepared according to general procedure A, from compound G4 and A-\2-{tert- butyldimethylsilanyloxy)ethyl]-2,6-dichlorophenol. LC-MS: t_R = 1.27 min; ES+:

>1000.

Mixture of (IR, 55')-7-[2-(3-{4-[(ii?)-l-(^rr-butyl-dimethyl-silanyloxy)-ethyl]- 2,6-dichloro-phenoxymethyl}-azetidin-l-yl)-thiazol-5-yl]-6-[cyclopropyl-(2,3- dichloro-benzyl)-carbamoyl]-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9- dicarboxylic acid di-tert-butyl ester, (IS, 5R)-7-[2-(3-{4-[(lR)-l-(tert-butyl- dimethyl-silanyloxy)-ethyl]-2,6-dichloro-phenoxymethyl}-azetidin-l-yl)- thiazol-5-yl]-6-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-buty\ ester, (IR, 5 S)-I -[2- (3-{4-[(i5')-l-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2,6-dichloro- phenoxymethyl}-azetidin-l-yl)-thiazol-5-yl]-6-[cyclopropyl-(2,3-dichloro- benzyl)-carbamoyl]-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert-buty\ ester, and (IS, 5R)-7-[2-(3-{4-[(i5)-l-(rerr-butyl-dimethyl- silanyloxy)-ethyl]-2,6-dichloro-phenoxymethyl}-azetidin-l-yl)-thiazol-5-yl]-6- [cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3,9-diaza-bicyclo[3.3.1]non-6- ene-3,9-dicarboxylic acid άi-tert-buty\ ester (L12)

Prepared according to general procedure A, from compound G4 and (røc.)-4-[l- (rerr-butyldimethylsilanyloxy)ethyl]-2,6-dichlorophenol. LC-MS: t_R = 1.27 min; ES+: >1000.

(rac.)-(lR*, 55'*)-6-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-7-{2-[3- (2,6-dichloro-4-fluoro-phenoxymethyl)-azetidin-l-yl]-thiazol-5-yl}-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert-butyl ester (L 13) Prepared according to general procedure A, from compound G4 and 2,6-dichloro- 4-fluorophenol. LC-MS: t_R = 1.16 min; ES+: 898.36.

(rac.)-(lR*, 55'*)-7-{2-[3-(2-Chloro-3,6-difluoro-phenoxymethyl)-azetidin-l- yl]-thiazol-5-yl}-6-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert-bλxty\ ester (L 14) Prepared according to general procedure A, from compound G4 and 2-chloro-3,6- difluorophenol. LC-MS: t_R = 1.14 min; ES+: 882.21.

(rac.)-(lR *, 5S *)-!- {2- [3-(3-Chlor o-2,6-difluor o-phenoxymethyl)-azetidin- 1 - yl]-thiazol-5-yl}-6-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert-bλxty\ ester (L 15) Prepared according to general procedure A, from compound G4 and 3-chloro-2,6- difluorophenol. Mixture of (IR, 55>7-{2-[(3R)-3-(2-chloro-3,6-difluoro-phenoxy)-pyrrolidin- l-yl]-thiazol-5-yl}-6-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-buty\ ester and (IS, 5R)- 7-{2-[(Ji?)-3-(2-chloro-3,6-difluoro-phenoxy)-pyrrolidin-l-yl]-thiazol-5-yl}-6- [cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-3,9-diaza-bicyclo[3.3.1]non-6- ene-3,9-dicarboxylic acid di-tert-buty\ ester (L16)

Prepared according to general procedure A, from compound G7 and 3-chloro-2,6- difluorophenol. LC-MS: t_R = 1.17 min.

(rac.)-(lR*, 5S*)-%-{[Cyc\oyx opyl-(2,3-dimethyl-benzyl)-carbamoyl]-methyl }- 7-{2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-thiazol-5-yl}-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert-bλxty\ ester (L17) Prepared according to general procedure C, from compound P and cyclopropyl- 2,3-dimethyl-benzyl-amine. LC-MS: t_R = 1.27 min; ES+: 841.52.

(rac.)-(lR*, 5,S'*)-8-{[(2-Chloro-benzyl)-cyclopropyl-carbamoyl]-methyl}-7-{2- [2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-thiazol-5-yl}-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert-butyl ester (L18) Prepared according to general procedure C, from compound P and 2-chloro- benzyl-cyclopropyl-amine. LC-MS: t_R = 1.27 min; ES+: 847.41.

(rac.)-(lR*, 5_lS'*)-8-{[Cyclopropyl-(3-methoxy-2-methyl-benzyl)-carbamoyl]- methyl}-7-{2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-thiazol-5-yl}-3,9- diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid

ester (L19) Prepared according to general procedure C, from compound P and cyclopropyl-3- methoxy-2-methyl-benzyl-amine. LC-MS: t_R = 1.26 min; ES+: 863.47.

(rac.)-(lR*, 5_lS'*)-8-{[(2-Chloro-3-methyl-benzyl)-cyclopropyl-carbamoyl]- methyl}-7-{2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-thiazol-5-yl}-3,9- diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert-bλxty\ ester (L20) Prepared according to general procedure C, from compound P and 2-chloro-3- methyl-benzyl-cyclopropyl-amine. LC-MS: t_R = 1.28 min; ES+: 865.41. 7-{2-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-thiazol-5-yl}-8- methoxycarbonylmethyl-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-buty\ ester (O) A solution of 2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-thiazole (2.46 g; 8.08 mmol) in THF (18.0 mL) at -78 ⁰C was treated dropwise over 5 min with BuLi (1.6M in hexane, 5.55 mL; 8.89 mmol). After completion of the addition, the resulting solution was stirred at -78 ⁰C for 1 h. ZnCl₂ (10.1 mL of a 1.0 M THF sol.; 10.10 mmol) was added dropwise over 5 min, and the reaction mixture was allowed to warm up to rt, and stirred for 1.5 h. A sol. of 8- methoxycarbonylmethyl-7-trifluoromethanesulfonyloxy-3,9-diaza- bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert-buty\ ester (prepared from compound A with lithium diisopropylamide and methyl bromoacetate, then like the preparation of compound D) (2.20 g; 4.04 mmol) in THF (3.0 mL) was added followed by Pd(PPh₃)₄ (140 mg; 0.12 mmol). The resulting sol. was stirred at 50 ⁰C for 1 h. The reaction mixture was cooled to rt, and EtOAc (75 mL) was added. The mixture was then poured in sat. aq. NH₄Cl (50 mL). The phases were shaken, separated and the aq. phase was extracted with EtOAc (2 x 25 mL). The combined org. phases were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 50/50) yielded the title compound (2.08 g, 74%). LC-MS: t_R = 1.19 min; ES+: 698.27.

8-Carboxymethyl-7-{2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-thiazol-5- yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid άi-tert-buty\ ester

(P)

A sol. of compound O (2.49 g, 3.56 mmol) in MeOH (72.0 mL) and IM NaOH (36.0 mL) was heated at 80 ⁰C for 1 h. The reaction mixture was then allowed to cool to rt, and the MeOH was removed under reduced pressure. Water and Et₂O were added, and the aq. phase was washed twice with ether. The pH of the aq. phase was adjusted to 2 with aq. 2M HCl, and the mixture was extracted twice with Et₂O. The combined org. phases were dried over MgSO₄, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH₂Cl₂MeOH 95/5) yielded the title compound (1.90 g, 78%). LC-MS: t_R = 1.13 min; ES+: 684.38.

Examples

Example 1

(rac.)-(lR*, 55'*)-7-(2-{[(2-Chloro-6-fluoro-benzyl)-methyl-amino]-methyl}- thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl)-amide

A sol. of compound Ll (26 mg, 0.03 mmol) in CH₂Cl₂ (0.5 mL) was cooled to 0 ⁰C and treated with 4M HCl in dioxane (0.5 mL). After 1 h at rt, the solvents were removed under reduced pressure to afford the title compound (25 mg, 95%). LC- MS: t_R = 0.73 min; ES+: 634.19

Example 2

(rac.)-(lR*, 55'*)-7-(2-{[(2-Chloro-3,6-difluoro-benzyl)-methyl-amino]- methyl}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)-amide A solution of compound L2 (26 mg, 0.03 mmol) in CH₂Cl₂ (0.5 mL) was cooled to 0 ⁰C and treated with 4M HCl in dioxane (0.5 mL). After 1 h at rt the solvents were removed under reduced pressure to afford the title compound (27 mg, 98%). LC-MS: t_R = 0.77 min; ES+: 654.21.

Example 3

1: 1 Mixture of (IR, 5S)-7-{2-[(3i?)-3-(2,6-dichloro-3,4-dimethyl-phenoxy)- pyrrolidin-l-yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2-methyl-benzyl)-amide and of (IS, 5R)-7-{2- [(Ji?)-3-(2,6-dichloro-3,4-dimethyl-phenoxy)-pyrrolidin-l-yl]-thiazol-5-yl}- 3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy- 2-methyl-benzyl)-amide Prepared according to general procedure B, from compound L3. LC-MS: tR = 0.84 min; ES+: 682.23.

Example 4 1: 1 Mixture of (IR, 55>7-{2-[(3R)-3-(2,6-dichloro-phenoxy)-pyrrolidin-l-yl]- thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (3-methoxy-2-methyl-benzyl)-amide and of (IS, 5R)-7-{2-[(3R)-3-(2,6- dichloro-phenoxy)-pyrrolidin-l-yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non- 6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2-methyl-benzyl)-amide Prepared according to general procedure B, from compound L4. LC-MS: tR = 0.80 min; ES+: 654.20.

Example 5

1: 1 Mixture of (IR, 5S)-7-{2-[(3R)-3-(2,6-dichloro-4-methyl-phenoxy)- pyrrolidin-l-yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2-methyl-benzyl)-amide and of (IS, 5R)-7-{2-

[(Ji?)-3-(2,6-dichloro-4-methyl-phenoxy)-pyrrolidin-l-yl]-thiazol-5-yl}-3,9- diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methyl-benzyl)-amide Prepared according to general procedure B, from compound L5. LC-MS: tR =

0.82 min; ES+: 668.21.

Example 6

(rac.)-(lR*, 5S*)-7-(2-{[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5- ylmethyl]-amino}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)-amide

Prepared according to general procedure B, from compound L6 (123 mg, 0.138 mmol). LC-MS: t_R = 0.81 min; ES+: 691.19.

Example 7 (rac.)-(lR*, 55*)-7-(2-{[3-(2-Chloro-3,6-difluoro-phenyl)-isoxazol-5- ylmethy^-methyl-aminoJ-thiazol-S-y^-S^-diaza-bicycloCS.S.^non-ό-ene-ό- carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)-amide Prepared according to general procedure B, from compound L 7 (55 mg, 0.06 mmol). The crude was not purified by HPLC. LC-MS: t_R = 0.85 min; ES+: 707.4.

Example 8

(rac.)-(lR *, 5S *)-!- {2- [3-(2,6-Dichlor o-4-methyl-phenoxymethyl)-azetidin- 1 - yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)-amide

Prepared according to general procedure B, from compound L 8. LC-MS: t_R = 0.88 min; ES+: 694.34.

Example 9

(rac.)-(lR *, 5S *)-!- {2- [3-(2,6-Dichlor o-phenoxymethyl)-azetidin- 1 -yl] -thiazol-

5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide

Prepared according to general procedure B, from compound L9. LC-MS: t_R = 0.85 min; ES+: 680.29.

Example 10

(rac.)-(lR*, 55'*)-7-{2-[3-(2-Chloro-6-fluoro-3-methyl-phenoxymethyl)- azetidin-l-yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)-amide

Prepared according to general procedure B, from compound LlO. LC-MS: t_R = 0.86 min; ES+: 676.37.

Example 11 (rac.)-(lR *, 5S *)-7-(2- {3- [2,6-Dichlor o-4-(2-hydr oxy-ethyl)-phenoxymethyl]- azetidin-l-yl}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)-amide Prepared according to general procedure B, from compound LIl. LC-MS: tR = 0.81 min; ES+: 724.26.

Example 12 Mixture of (IR, 5S)-7-(2-{3-[(2,6-dichloro-4-((iS)-l-hydroxy-ethyl)- phenoxymethy^-azetidin-l-ylJ-thiazol-S-y^-S^-diaza-bicycloP.S.^non-ό- ene-6-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)-amide, (IS, 5R)-7-(2- {3-[(2,6-dichloro-4-((ii?)-l-hydroxy-ethyl)-phenoxymethyl]-azetidin-l-yl}- thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl)-amide, (IR, 5S)-7-(2-{3-[(2,6-dichloro-4-((ii?)-l- hydroxy-ethyl)-phenoxymethyl]-azetidin-l-yl}-thiazol-5-yl)-3,9-diaza- bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)- amide, and (IS, 5tf)-7-(2-{3-[(2,6-dichloro-4-((iS)-l-hydroxy-ethyl)- phenoxymethy^-azetidin-l-ylJ-thiazol-S-yl^^-diaza-bicycloP.S.^non-ό- ene-6-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)-amide

Prepared according to general procedure B, from compound L 12. LC-MS: t_R = 0.81 min; ES+: 724.38.

Example 13 (rac.)-(lR*, 55'*)-7-{2-[3-(2,6-Dichloro-4-fluoro-phenoxymethyl)-azetidin-l- yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)-amide

Prepared according to general procedure B, from compound L 13. LC-MS: tR =

0.86 min; ES+: 698.34.

Example 14

(rac.)-(lR*, 55'*)-7-{2-[3-(2-Chloro-3,6-difluoro-phenoxymethyl)-azetidin-l- yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)-amide Prepared according to general procedure B, from compound L 14. LC-MS: tR =

0.84 min; ES+: 680.36. Example 15

(rac.)-(lR *, 5S *)-!- {2- [3-(3-Chlor o-2,6-difluor o-phenoxymethyl)-azetidin- 1 - yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)-amide Prepared according to general procedure B, from compound L 14. LC-MS: t_R = 0.85 min; ES+: 680.33.

Example 16

Mixture of (IR, 55>7-{2-[(3S>3-(2-chloro-3,6-difluoro-phenoxy)-pyrrolidin- l-yl]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)-amide and (IS, 5i?)-7-{2-[(J5')-3-(2-chloro-

3,6-difluoro-phenoxy)-pyrrolidin-l-yl]-thiazol-5-yl}-3,9-diaza- bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)- amide Prepared according to general procedure B, from compound L 16. LC-MS: t_R =

0.83 min; ES+: 680.36.

Example 17

(rac.)-N-Cyclopropyl-2-((2R*, 5S*)-7-{2-[2-(2,6-dichloro-4-methyl-phenoxy)- ethoxy]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-7-en-6-yl)-N-(2,3-dimethyl- benzyl)-acetamide

Prepared according to general procedure B, from compound L 17. LC-MS: t_R = 0.85 min; ES+: 641.35.

Example 18

(røc.)-N-(2-chloro-benzyl)-N-cyclopropyl-2-((H? *, 5S*)-7-{2-[2-(2,6-dichloro-

4-methyl-phenoxy)-ethoxy]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-7-en-6- yl)-acetamide

Prepared according to general procedure B, from compound L 18. LC-MS: t_R = 0.84 min; ES+: 647.38.

Example 19 (rac.)-N-cyclopropyl-2-((iR *, 55*)-7-{2-[2-(2,6-dichloro-4-methyl-phenoxy)- ethoxy]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-7-en-6-yl)-N-(3-methoxy-2- methyl-benzyl)-acetamide

Prepared according to general procedure B, from compound L 19. LC-MS: t_R = 0.83 min; ES+: 657.39.

Example 20

(rac.)-N-(2-Chloro-3-methyl-benzyl)-N-cyclopropyl-2-((ii?*, 55*)-7-{2-[2-(2,6- dichloro-4-methyl-phenoxy)-ethoxy]-thiazol-5-yl}-3,9-diaza- bicyclo[3.3. l]non-7-en-6-yl)-acetamide

Prepared according to general procedure B, from compound L20. LC-MS: tR = 0.85 min; ES+: 663.46.

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 Micro titer plates (MPT384, MaxiSorpTM_; N_unc) were incubated overnight at 4 ⁰C with 80 μl of Angl (1-1O)ZBSA conjugate, diluted lilOO'OOO 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 (1-1O)ZBSA 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 lrlOO'OOO 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 1:2' 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 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 fmol 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) [5μM in 1OmM HCl], hydroxyquinoline sulfate (Fluka, 55100) [3OmM in H₂O] and assay buffer were premixed at 4 ⁰C 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 compounds of formula (I) exhibit IC50 values between 0.1 nM to 300 nM, especially between 1 nM to 30 nM.

Examples of inhibition:

Claims

Claims

1. A compound selected from the group consisting of thiazole compounds of the formula (I),

wherein

L represents H, -R², -COR², -COOR², or -CONHR²;

V represents -CH₂-CH₂-CH₂-; -0-CH₂-CH₂-; -CH₂-CH₂-O-; -CH₂-O-CH₂-; -CH₂- CH₂-CH₂-CH₂-; -0-CH₂-CH₂-O-; -0-CH₂-CH₂-CH₂-; -CH₂-CH₂-CH₂-O-; -CH₂- 0-CH₂-CH₂-; -CH₂-CH₂-O-CH₂-; -NH-R³-, -N(CH₃)-R³-, -NH-R³-0-, -N(CH₃)- R³-0-, -NH-CH₂-Q-, -N(CH₃)-CH₂-Q-, -NH-CH₂-Q-X-, or -N(CH₃)-CH₂-Q-X-, wherein the groups which have an underlined nitrogen atom are bound to the -(CH₂)_m- group of formula (I) via this underlined nitrogen atom; or

V represents a heterocyclic group selected from

wherein said heterocyclic groups are bound to the -(CH₂)_m- group of formula (I) via their nitrogen ring atom;

U represents aryl that can be mono-, di-, tri-, or tetra- substituted, wherein the substituents are independently selected from halogen, alkyl, -CF₃, -OCF₃, and hydroxy- alkyl; or five-membered heteroaryl containing two heteroatoms independently selected from nitrogen and oxygen, wherein said heteroaryl can be mono-, di-, or tri-substituted, wherein the substituents are independently selected from halogen, alkyl, -CF₃, -OCF₃, and hydroxy-alkyl;

M represents an aryl, quinolinyl, isoquinolinyl, dihydroquinolinyl or tetrahydroquinolinyl group, wherein said groups can be mono-, di-, or tri- substituted, wherein the substituents are independently selected from halogen, alkyl, -CF₃, -OCF₃, alkoxy, alkyl-O-(CH₂)₀-₄-CH₂-, alkyl-O-(CH₂)₂_₄-O-, and R⁵ ₂N-(CH₂)o-₄-CH₂-;

Q represents a five-membered heteroaryl group containing at least one oxygen atom and 1 or 2 nitrogen atoms;

X represents -CH₂-, -0-, -NH-, or -N(CH₃)-;

R¹ represents alkyl, cycloalkyl, or cycloalkyl-alkyl;

R² represents alkyl that can be substituted by -CO₂H, -CO₂R⁴, -CONH₂, -SO₂CH₃, -SO₃H, -SO₂R⁴, tetrazolyl, -OH, -NH₂, or -NHCOR⁴; R represents alkylene;

R⁴ represents alkyl;

R⁵ represents hydrogen, alkyl, cyclopropyl, or -C(=O)-R' wherein R' is C₁-C₄- alkyl, -CF₃, -CH₂-CF₃, or cyclopropyl;

n represents the integer 0 or 1 ; and m represents the integer 0, 1 or 2;

and wherein when n = 0, a double bond is present in the 3,9-diaza- bicyclo[3.3.1]nonane ring of formula (I) at the 6,7-position; and when n = 1, the double bond is present at the 7,8-position;

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 solvates of such compounds, and morphological forms.

2. A compound according to claim 1 wherein V represents -NH-R -, -N(CH₃)- R³-, -NH-R³-O-, -N(CH₃)-R³-O-, -NH-CH₂-Q-, -N(CH₃)-CH₂-Q-, -NH-CH₂-Q- X-, or -N(CH₃)-CH₂-Q-X-; or

V represents a heterocyclic group selected from

3. A compound according to claim 1 or 2 wherein L is H, -COCH₃, or -CONHCH₂C(CH₃)₂CONH₂.

4. A compound according to any one of claims 1 to 3 wherein m represents the integer 0 and V represents the following heterocyclic group:

5. A compound according to any one of claims 1 to 3 wherein m represents the integer 1 and V represents -N(CH₃)-CH₂-.

6. A compound according to any one of claims 1 to 3 wherein m represents the integer 0; and V represents -NH-CH₂-Q-, wherein Q is an isoxazole or oxadiazole group.

7. A compound according to claim 6 wherein Q is an isoxazole group.

8. A compound according to any one of claims 1 to 7 wherein U is mono-, di-, tri-, or tetra- substituted aryl, wherein the substituents are independently selected from halogen, alkyl, -CF₃, -OCF₃, and hydroxy-alkyl.

9. A compound according to any one of claims 1 to 8 wherein M is mono-, di-, or tri- substituted aryl, wherein the substituents are independently selected from halogen, alkyl, -CF₃, -OCF₃, alkoxy, alkyl-O-(CH₂)₀-₄-CH₂-, alkyl-O-(CH₂)₂_₄-O-, and R⁵ ₂N-(CH₂)o-₄-CH₂-, wherein R⁵ is as defined in claim 1.

10. A compound according to any one of claims 1 to 9 wherein R¹ is cyclopropyl.

11. A compound according to claim 1 wherein L is H;

V represents -0-CH₂-CH₂-O-, -N(CH₃)-R³-, -NH-CH₂-Q-, or -N(CH₃)-CH₂-Q-; or

V represents a heterocyclic group selected from

U represents di-, tri-, or terra- substituted phenyl, wherein the substituents are independently selected from halogen, alkyl and hydroxy- alkyl; M represents mono- or di-substituted phenyl, wherein the substituents are independently selected from halogen, alkyl and alkoxy;

Q represents an isoxazole group;

R¹ represents cycloalkyl;

R³ represents alkylene; n represents the integer O or 1; and m represents the integer O or 1 ; and wherein when n = 0, a double bond is present in the 3,9-diaza- bicyclo[3.3.1]nonane ring of formula (I) at the 6,7-position; and when n = 1, the double bond is present at the 7,8-position.

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

(IR*, 5_lS'*)-7-(2-{ [(2-chloro-6-fluoro-benzyl)-methyl-amino]-methyl}-thiazol-5- yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide;

(IR*, 5_lS'*)-7-(2-{ [(2-chloro-3,6-difluoro-benzyl)-methyl-amino]-methyl}-thiazol- 5-yl)-3,9-diaza-bicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide;

(IR, 55)-7-{2-[(Ji?)-3-(2,6-dichloro-3,4-dimethyl-phenoxy)-pyrrolidin-l-yl]- thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methyl-benzyl)-amide; (IS, 5i?)-7-{2-[(Ji?)-3-(2,6-dichloro-3,4-dimethyl-phenoxy)-pyrrolidin-l-yl]- thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methyl-benzyl)-amide;

(IR, 55)-7-{2-[(Ji?)-3-(2,6-dichloro-phenoxy)-pyrrolidin-l-yl]-thiazol-5-yl}-3,9- diaza-bicyclo[3.3. ljnon-ό-ene-ό-carboxylic acid cyclopropyl-(3-methoxy-2- methyl-benzyl) - amide ;

(IS, 5i?)-7-{2-[(Ji?)-3-(2,6-dichloro-phenoxy)-pyrrolidin-l-yl]-thiazol-5-yl}-3,9- diaza-bicyclo[3.3. l]non-6-ene-6-carboxylic acid cyclopropyl-(3-methoxy-2- methyl-benzyl) - amide ;

(IR, 55')-7-{2-[(Ji?)-3-(2,6-dichloro-4-methyl-phenoxy)-pyrrolidin-l-yl]-thiazol- 5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methyl-benzyl)-amide;

(IS, 5i?)-7-{2-[(Ji?)-3-(2,6-dichloro-4-methyl-phenoxy)-pyrrolidin-l-yl]-thiazol- 5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(3- methoxy-2-methyl-benzyl)-amide;

(IR*, 55'*)-7-(2-{ [3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethyl]-amino}- thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl)-amide;

(IR*, 55'*)-7-(2-{ [3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-ylmethyl]-methyl- amino } -thiazol-5-yl)-3 ,9-diaza-bicyclo [3.3.1] non-6-ene-6-carboxylic acid cyclopropyl- (2,3- dichloro-benzyl) - amide ;

(IR*, 55'*)-7-{2-[3-(2,6-dichloro-4-methyl-phenoxymethyl)-azetidin-l-yl]- thiazol-5-yl } -3 ,9-diaza-bicyclo [3.3.1] non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl)-amide; (IR*, JS^H-^-P-^ό-dichloro-phenoxymethyl^azetidin-l-yri-thiazol-S-yl}- 3 ,9-diaza-bicyclo [3.3.1] non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichloro- benzyl)-amide;

(IR*, 55'*)-7-{2-[3-(2-chloro-6-fluoro-3-methyl-phenoxymethyl)-azetidin-l-yl]- thiazol-5-yl } -3 ,9-diaza-bicyclo [3.3.1] non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl)-amide;

(IR*, 55'*)-7-(2-{3-[2,6-dichloro-4-(2-hydroxy-ethyl)-phenoxymethyl]-azetidin-l- yl}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3- dichloro-benzyl) - amide ;

(IR, 55>7-(2-{3-[2,6-dichloro-4-((iS)-l-hydroxy-ethyl)-phenoxymethyl]- azetidin-l-yl}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3- dichloro-benzyl) - amide ;

(IS, 5i?)-7-(2-{3-[2,6-dichloro-4-((ii?)-l-hydroxy-ethyl)-phenoxymethyl]- azetidin-l-yl}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3- dichloro-benzyl) - amide ;

(IR, 55>7-(2-{3-[2,6-dichloro-4-((iR)-l-hydroxy-ethyl)-phenoxymethyl]- azetidin-l-yl}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3- dichloro-benzyl) - amide ;

(IS, 5i?)-7-(2-{3-[2,6-dichloro-4-((i5)-l-hydroxy-ethyl)-phenoxymethyl]- azetidin-l-yl}-thiazol-5-yl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl- (2,3- dichloro-benzyl) - amide ;

(IR*, 55'*)-7-{2-[3-(2,6-dichloro-4-fluoro-phenoxymethyl)-azetidin-l-yl]-thiazol- 5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide; (IR*, JS^-T-il-tS-Cl-chloro-S.ό-difluoro-phenoxymethy^-azetidin-l-yy-thiazol- 5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide; and

(IR*, 55'*)-7-{2-[3-(3-chloro-2,6-difluoro-phenoxymethyl)-azetidin-l-yl]-thiazol- 5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide.

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

(IR, 55^l)-7-{2-[(J5^<)-3-(2-chloro-3,6-difluoro-phenoxy)-pyrrolidin-l-yl]-triiazol-5- yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide;

(IS, 5i?)-7-{2-[(J5')-3-(2-chloro-3,6-difluoro-phenoxy)-pyrrolidin-l-yl]-triiazol-5- yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3- dichloro-benzyl)-amide;

N-cyclopropyl-2-((ii?*, 55'*)-7-{2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]- thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-7-en-6-yl)-N-(2,3-dimethyl-benzyl)- acetamide;

N-(2-chloro-benzyl)-N-cyclopropyl-2-((iR*, 55*)-7-{2-[2-(2,6-dichloro-4- methyl-phenoxy)-ethoxy]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-7-en-6-yl)- acetamide;

N-cyclopropyl-2-((ii?*, 55'*)-7-{2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]- thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-7-en-6-yl)-N-(3-methoxy-2-methyl- benzyl) -acetamide; and N-(2-Chloro-3-methyl-benzyl)-N-cyclopropyl-2-((ii?*, 55*)-7-{2-[2-(2,6- dichloro-4-methyl-phenoxy)-ethoxy]-thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-7- en-6-yl)-acetamide.

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

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

16. Use of a compound according to any one of claims 1 to 13 for the preparation of a pharmaceutical composition for the treatment 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.